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Cannabis and mental health: for young people

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Cannabis and mental health: for young people

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Royal college of Psychiatrists

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Cannabis (also known as marijuana, weed, pot,, grass, herb, and many others) is a preparation of the cannabis plant that produces psychoactive effects when consumed (via smoking, vaporizing, or ingestion). The principal psychoactive constituent of cannabis is tetrahydrocannabinol (THC), which makes up one of 483 known compounds in the plant, including at least 84 other cannabinoids such as cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV), and cannabigerol (CBG).

The genus cannabis is indigenous to central Asia and the Indian subcontinent. The earliest recorded uses of cannabis date from the 3rd millennium BC. At least three species are recognized: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. In modern times, cannabis is used for recreational or medicinal and religious or spiritual purposes.[citation needed ]

Since the early 20th century, cannabis has been subject to legal restrictions with the possession, use, and sale of cannabis preparations containing psychoactive cannabinoids currently illegal in most countries. However, there is a recent growing trend towards decriminalization and legalization and the plant is legal in some states and countries such as Amsterdam. According to a United Nations report, cannabis is the most used illicit drug in the world. In 2004, the U.N. estimated that global consumption patterns of cannabis indicated that approximately 4% of the adult world population (162 million people) used cannabis annually and that approximately 0.6% (22.5 million) of people used cannabis daily.

History and culture

This History and culture section is a stub. As a result, it may contain incomplete or wrong information. You can help by expanding it.

Tombs in China reveal humans were smoking cannabis 2500 years ago.

The potency of illicit cannabis plant material has consistently increased over time since 1995 from ~4% in 1995 to ~12% in 2014. The cannabidiol content has decreased on average from ~.28% in 2001 to <.15% in 2014, resulting in a change in the ratio of Δ9-tetrahydrocannabinol to cannabidiol from 14 times in 1995 to ~80 times in 2014.

Cannabis plants contain a number of different specific compounds at various ratios. Cannabis contains more than 460 compounds; at least 80 of these are cannabinoids, chemical compounds that interact with cannabinoid receptors in the brain. The most common cannabinoids are listed below:

Pharmacology

The most psychoactive cannabinoid found in the cannabis plant is tetrahydrocannabinol (or delta-9-tetrahydrocannabinol), commonly known as THC. Other cannabinoids include delta-8-tetrahydrocannabinol, cannabidiol (CBD), cannabinol (CBN), cannabicyclol (CBL), cannabichromene (CBC) and cannabigerol (CBG); they have less psychotropic effects than THC, but may play a role in the overall effect of cannabis. The most studied are THC, CBD and CBN. The entourage effect is a proposed mechanism by which compounds present in cannabis which are largely non-psychoactive by themselves modulate the overall psychoactive effects of the plant (these resulting principally from the action of the main psychoactive component of cannabis, tetrahydrocannabinol (THC)).

THC appears to alter mood and cognition through its agonist actions on the CB1 receptors, which inhibit a secondary messenger system (adenylate cyclase) in a dose dependent manner. Via CB1 activation, THC indirectly increases dopamine release and produces psychotropic effects. Cannabidiol acts as an allosteric modulator of the mu and delta opioid receptors. THC also potentiates the effects of the glycine receptors. However, the role of these interactions and how they result in the cannabis high remains subject to on-going scientific investigation.

Drugs that activate the CB1 and CB2 receptors are known to upregulate and enhance 5-HT 2A receptor activity. The ERK1/ERK2 signaling pathway has been shown to mediate this effect, but the exact biochemical mechanism is unknown. This upregulation and enhancement of the 5-HT 2A receptor is why cannabis potentiates the effects of psychedelic drugs.

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. These effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances of inducing a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious injury or death.

Combination effects

Psychedelics - Cannabis strongly intensifies the sensory and cognitive effects of all psychedelics. Extreme caution is advised when combining these substances as this can significantly increase the chances of a negative psychological reaction like anxiety, confusion and psychosis. Users are advised to start off with only a fraction of their usual cannabis dose and take long breaks between hits. Many users report that cannabis is effective at briefly recreating the peak of the experience if consumed during the come down phase.

Dissociatives - Cannabis enhances the cognitive, visual and general hallucinatory effects of dissociatives. Dissociative-induced holes, spaces, and voids and internal hallucinations become more vivid and intense on cannabis. These effects correspond with an increased risk of confusion, delusions, and psychosis.

Depressants - Depressants such as benzodiazepines or opioids reduce the hallucinogenic aspects of the cannabis high. Instead, the focus shifts to bodily sensations, such as muscle relaxation, sedation, information processing suppression, and anxiety suppression.

Alcohol - When used with alcohol, cannabis often creates feelings of extreme nausea, double vision, dizziness and changes in gravity. It is generally recommended that people take the cannabis before drinking and not the other way around as this is reported to induce these effects less readily.

Stimulants - Cannabis tends to increase the thought accelerating, immersion enhancing and euphoric effects of stimulants, particularly as it relates to one's appreciation of music and sexual pleasure. This combination should be used with caution, however, as it can easily induce states of anxiety, paranoia, confusion, delusions, and psychosis.

Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

Additional experience reports can be found here:

Strains and forms

Sativa and indica are the two major types of cannabis plants which can mix together to create hybrid strains. Each strain has its own range of effects on the body and mind, resulting in a wide range of medicinal benefits.

Indica plants typically grow short and wide compared to sativa plants which grow tall and thin. Indica plants are better suited for indoor growing because of their short growth and sativa plants are better suited for outdoor growing because some strains can reach over 25 ft. in height.

The high produced from smoking indica bud is a strong physical "body high" that will make one sleepy or sedated and provides a deep relaxation feeling compared to a sativa high, which is known to be more energetic and uplifting.

Marijuana strains range from pure sativas to pure indicas with hybrid strains consisting of both indica and sativa (for example, 30% indica - 70% sativa, 50% - 50% combinations, or 80% indica - 20% sativa). Because sativa and indica buds have very different medicinal benefits and effects, certain strains can be targeted to better treat specific illnesses.

Kief is a powder which can be sifted from the leaves and flowers of cannabis plants and either consumed in powder form or compressed to produce cakes of hashish.

Hashish (also spelled hasheesh, hashisha, or simply hash) is a concentrated resin cake or ball produced from pressed kief.

Hash oil is obtained from the cannabis plant by solvent extraction, and contains the cannabinoids present in the highly concentrated natural oils of cannabis flowers and leaves.

Common usage

Consumption methods

Cannabis is consumed in many different ways:

Smoking typically involves inhaling vaporized cannabinoids ("smoke") from small pipes, bongs (portable versions of hookahs with water chamber), paper-wrapped joints, tobacco-leaf-wrapped blunts, and other items.

Vaporizers heat herbal cannabis to 165-190 °C (329-374 °F), causing the active ingredients to evaporate into a vapor without burning the plant material (the boiling point of THC is 157 °C (315 °F) at 760 mmHg pressure).

Cannabis tea contains relatively small concentrations of THC because THC is an oil (lipophilic) and is only slightly water-soluble (with a solubility of 2.8 mg per liter). Cannabis tea is made by first adding a saturated fat to hot water (e.g., cream or any milk except skim) with a small amount of cannabis.

Edibles are cannabis added as an ingredient to one of a variety of foods.

Sublingual/buccal consumption typically involves the absorption of cannabinoids through the membranes inside the mouth (usually through a candy or tincture).

Tincture

Topical consumption typically involves the use of either a cream or lip balm containing cannabinoids absorbed through the skin.

Preparation methods

Preparation methods for this compound within our tutorial index include:

Medical use

Cannabis is an emerging treatment option for those suffering from many serious diseases, including cancer. Due to its pain relieving, nausea suppressing effects, cannabis can be useful for those undergoing radiation therapy and chemotherapy.[citation needed ] Oral doses of cannabis are more effective in reducing nausea and vomiting.

In addition to the anti-nausea effects, the appetite enhancement effects of cannabis can combine with the antiemetic effects and make it more likely that the patient will gain or maintain weight through cancer treatment.

Toxicity and harm potential

Cannabis is not known to cause brain damage, and has an extremely low toxicity relative to dose. There are relatively few physical side effects associated with acute cannabis exposure. Various studies have shown that in reasonable doses in a responsible context, cannabis produces little to no negative cognitive, psychiatric or physical consequences.[citation needed ]

It is advised that those with severe pre-existing mental conditions should not ingest cannabis due to the way it strongly amplifies the user's current state of mind and emotions. The prolonged usage of THC and other cannabinoids may also increase one's disposition to mental illness and psychosis, particularly in vulnerable individuals with risk factors for psychotic illnesses (like a past or family history of schizophrenia).

It is strongly recommended that one use harm reduction practices when using this substance.

Lethal dosage

No fatal overdoses associated with cannabis use have been reported as of 2010. A review published in the British Journal of Psychiatry in February 2001 said that "no deaths directly due to acute cannabis use have ever been reported."

THC, the principal psychoactive constituent of the cannabis plant, has an extremely low toxicity and the amount that can enter the body through the consumption of cannabis plants poses no threat of death. In lab animal tests, scientists have had much difficulty administering a dose of THC that is high enough to be lethal. The dose of THC needed to kill 50% of tested rodents is very high, 2.594 mol/kg, about 815.7 grams of THC per kilogram of body weight, and human deaths from overdose are unheard of.

At present, it is estimated that the of cannabis is around 1:20,000 or 1:40,000. This means that, in order to induce death, a cannabis smoker would have to consume 20,000 to 40,000 times as much cannabis as is contained in one cannabis cigarette. A user would theoretically have to smoke nearly 1,500 pounds of cannabis within about 15 minutes to induce a lethal response.

Dependence and abuse potential

Cannabis is moderately habit-forming. Research has shown the overall dependence potential for cannabis to be less than that for caffeine, tobacco, alcohol, cocaine or heroin, but higher than that for psilocybin, mescaline, or LSD.

Dependence on cannabis is more common amongst heavy users. Cannabis use can lead to increased tolerance and withdrawal symptoms upon stopping usage. Prolonged cannabis usage requires the user to consume higher doses of the substance to achieve a common desirable effect, and reinforce the body's metabolic systems for synthesizing and eliminating it more efficiently.

Tolerance to many of the effects of cannabis develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 1 - 2 weeks for the tolerance to be reduced to half and 2 - 3 weeks to be back at baseline (in the absence of further consumption). THC has been detected in heavy cannabis users after 77 days of drug abstinence (Ellis et al., 1985).

Cannabis produces cross-tolerance with all cannabinoids, meaning that after the consumption of cannabis all cannabinoids will have a reduced effect. The mechanisms that create this tolerance to THC are thought to involve changes in cannabinoid receptor function.

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become dangerous or even life-threatening when taken with other substances. The following lists some known dangerous combinations, but cannot be guaranteed to include all of them. Independent research should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from Tripsit.

Legal status

External links

Further reading

References

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Cannabis (also known as marijuana,[1] weed,[2] pot,[3], grass,[4] herb,[5] and many others) is a preparation of the cannabis plant that produces psychoactive effects when consumed (via smoking, vaporizing, or ingestion). The principal psychoactive constituent of cannabis is tetrahydrocannabinol (THC), which makes up one of 483 known compounds in the plant,[6] including at least 84 other cannabinoids such as cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabivarin (THCV),[7][8] and cannabigerol (CBG).

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Cannabis is a drug that comes from a plant, or a plant which is used as a drug. Cannabis use has been falling; most people in the UK ( more than two out of three) have never tried cannabis, but it's still the most popular illegal drug.

Cannabis comes in many different forms. Its users are varied too, taking the drug in different ways, for different reasons. Some people use it looking for fun and laughter, some hope for medical benefits, some want help to relax. Some people use cannabis out of habit or because they find it difficult to resist. Cannabis can deliver the positive effects its users hope for, but it doesn't always do so, and it can cause harm too.

This page will let you know some of the risks of cannabis use that users can easily avoid, and also help you to recognise those risks you can never totally get away from if you use it. With this information, it's easier to make informed personal decisions about whether it's worth the risk to use cannabis at all, and if you do use it, to keep those risks as low as you can make them.

It's hard to say how harmful the use of a drug like cannabis is 'overall', because it depends so much on the user, how they use it, and even the type of cannabis. Most people who try cannabis are not harmed by it at all. However, cannabis can play a very destructive role in some people's lives, particularly if they become addicted to it. Regular users sometimes notice that cannabis is damaging their physical or mental wellbeing, others feel it holds them back from fulfilling their potential. As with any drug, the only relationship with cannabis that is 100% safe is avoiding it entirely. However, if somebody wants to enjoy cannabis and accepts the possibility of harm, there are many important choices that can reduce the risks. There are powerful choices to be made about what cannabis to use, when and how to use it.

An analysis by DrugScience which added up and compared the harm caused by 20 different drugs in the UK placed cannabis roughly in the middle; it causes more harm to society than several other illegal drugs (mostly because there are many more users) but less harm to its users than the legal drugs tobacco and alcohol, both of which have a higher potential to cause serious illness and death. This study estimated the total harm done by cannabis in 2010 in the UK, it can't tell us how high or how low the risks of cannabis could be made under different laws, or when used by different individuals. Someone can make cannabis into a dangerous drug for themselves through their choices, and maybe better political choices could make cannabis safer overall.

Similarly to alcohol, cannabis can help people relax and feel pleasantly sleepy and 'stoned', or in another setting, people use it to socialize, feel 'high' and laugh. It can make people clumsy with their bodies and words. Less like alcohol, cannabis also can alter the senses in unusual ways, so music, food, films, computer games might seem different, more fascinating, and easier to feel immersed in.

Cannabis has some side effects such as drying out the mouth and eyes (which can look red and feel itchy), and generating a strong appetite; 'the munchies'.

Especially for someone who has never taken cannabis before, the effects can be hard to predict, and can be unpleasant for some people. It's common for people to try cannabis and not want to use it again.

Taking cannabis has the effects it has because it contains some unique drug chemicals called 'cannabinoids'. The cannabinoid which is most important in making someone 'stoned' or 'high' is called THC. Some cannabis varieties (such as skunk) can contain much more THC than other types, and so give stronger effects or can be used in smaller amounts. However scientists and cannabis users are also discovering that it's not just the amount of THC that is important, but also the balance of THC with other cannabinoids, especially one called CBD. Cannabis varieties with lots of CBD (like most 'hash') might feel different (more relaxing, less confusing) and have a lower chance of causing harm, than cannabis varieties with little or no CBD (such as skunk).

Our minds respond to cannabinoids from cannabis because we have an endocannabinoid system in our brains that has a role in controlling memory, mood, appetite, sleep and other functions. The endocannabinoid system is not there to be triggered by cannabinoids from cannabis; the fact that it can be manipulated by this plant is just a lucky or unlucky accident. The endocannabinoid system evolved along with its own endocannabinoids; cannabinoid chemicals made in our own brains.

The effect of cannabinoids from cannabis on the endocannabinoid system doesn't entirely explain how cannabis users feel and act when they are stoned. Without realizing it, people learn to fit in with acting a certain way when they are stoned and around other stoned people. This helps explain why one substance, in different cultural contexts, can have such different effects.

The two main ways that people get the cannabis chemicals into their body are through the lungs, by smoking or vaporizing it, or through the gut (orally), by eating or drinking it.

The effects of cannabis when smoked or vaporized appear almost immediately, reach their strongest in the first 15 minutes or so, start to fade before an hour has passed, and are nearly gone after about 3 hours, although the exact timings vary from person to person.

When used orally, the effects of cannabis take much longer to appear and rise to their peak, you might feel nothing for an hour. Then the effects can last 5 hours or even more. This time can be very different from person to person.

The commonest way of using cannabis in the UK is also the worst for your health. That is adding it to tobacco in a cigarette paper, rolling it with no filter and smoking this 'joint'. Tobacco smoke can give you lung cancer, COPD, and other potentially deadly diseases. Tobacco is also addictive, much more so than cannabis, so smoking cannabis joints can be a 'gateway'' to a harmful and expensive tobacco addiction. Or it might lead you to craving more joints, and so smoking more cannabis than you might otherwise. Smoking cannabis as well as tobacco might lead to more harm than smoking tobacco only.

Smoking cannabis on its own (in a pipe or bong for example, or rolled in a tobacco-free cigarette) is much less harmful. The risk of lung cancer is far lower, maybe as low as someone who doesn't smoke at all. Also, using tobacco makes it harder to breathe deeply and freely, cannabis alone seems not to. However, burning any plant, cannabis or tobacco, makes hundreds of toxic chemicals, and a cannabis smoker is still breathing in this cloud full of little irritating particles. This can cause inflammation, coughing and wheezing ( bronchitis, which goes away when a user quits). How badly cannabis affects the lungs depends, of course, on how much someone uses it. People who smoke occasionally might not notice any problem, but constant cannabis smoking might do damage.

People who want the rapid effects of inhaling cannabis without the smoke can use a vaporiser instead. Vaporisers heat up the cannabis hot enough that the cannabinoids and some other substances evaporate and can be inhaled, but not so hot that the plant material is burnt. The vapour can still make you cough, and there has not been enough research done to show for sure that is causes far less harm. Even so, avoiding the chemicals that result from burning is likely to be a good move.

Cannabis can also be cooked into food (such as brownies). This avoids any risks to the lungs, but a possible downside is that the effects can take ages to come on, and can take longer for some people than others, making it much harder to judge how much to take. This can lead to taking way too much and having a horrible few hours.

The immediate effects of cannabis can be nasty but are rarely catastrophic. Let's start with common unwanted effects, things which might sound familiar to many people who have tried the drug.

Taking too much too fast (which is easy when the cannabis is very strong) can be horrible. Someone may suddenly look and feel pale, shaky and ill, (sometimes called greening out, or pulling a whitey) they may even vomit or collapse. This effect can be a result of a rapid drop in blood pressure. It's a good reason to smoke at a slow pace, to get a feel for the strength of the cannabis. If someone does feel ill, it usually doesn't last long and the person may recover faster if they lie down with their feet up. Whatever the drug is, never leave someone alone who is vomiting and intoxicated, as there is a risk of choking. Combining cannabis with alcohol or other drugs creates a higher risk of feeling awful and regretting it.

Even people who have enjoyed using cannabis before can unexpectedly find that it gives them bad rather than good feelings. Sometimes people just feel overwhelmed and might need to lie down for a bit, especially if they get more stoned than they intended to. Even when taking a typical amount, the same as you might have enjoyed before or the amount that your friends are enjoying, users might find that they feel worried, suspicious, sad, confused or even feel trapped going round in circles of weird thoughts.

Usually, if someone becomes panicked, confused, or behaves oddly when intoxicated on cannabis, they will be alright given time, especially if they are reassured and guided to breathe slowly and relax. Sometimes, they will feel fine after a few minutes, sometimes they will not feel good, but will be able to hold out with some friendly support until they sober up a bit. Very very occasionally, if someone remains very frightened or paranoid, and does not seem to respond to reassurance, or their behavior is very alarming, it may be sensible to get help, for example by calling an ambulance. This can be a difficult judgement to make, remember that the good or bad effects of cannabis usually start to decline on their own after about an hour after inhalation, or a couple of hours after eating it.

It is very common for people who are intoxicated on cannabis (especially strong stuff like 'skunk') to say things or feel things which are just like symptoms of psychosis, for example to think other people are taking about them. Experiencing some psychotic symptoms whilst stoned isn't the same as actually being psychotic. However, if you or someone else should have sobered up, but are still feeling paranoia or delusional ideas, it is important to get medical help. Extremely rarely, getting intoxicated on cannabis can trigger a mental health crisis such as a 'psychotic episode', which carries on even after the person should have sobered up. This can be a serious situation, and they need to have medical assistance to give them the best chance of getting better fast without any lasting effects. This usually only happens to people who already have a vulnerability to mental health problems. Most people who have a psychotic episode triggered by cannabis (or anything else) recover well over the next few days with treatment. However, having this type of reaction to cannabis even once is a strong indication that continuing to use cannabis could be very harmful. There's more information on this in the section Will cannabis make me lose control of my mind?

Cannabis is one of the least toxic drugs. Unlike drugs such as alcohol, paracetamol, heroin or ecstasy, users do not die after accidentally taking too much. But like all drugs that distort the way you think and behave, cannabis use creates a risk of hurting yourself doing something stupid, ranging from trying to cook to trying to cross a motorway. People who drive stoned double or triple their risk of crashing, injuring and killing others as well as themselves.

Occasionally after using cannabis, people feel their heart flutter, skip beats, race or pound in their chest. These unpleasant but usually harmless feelings (called palpitations and tachycardia) can be scary, especially as cannabis can make sensations feel more intense than usual, and make anxiety worse. Of course, when someone gets scared by this effect, it can make the heart beat even harder and lead to a panic attack.

Cannabis use does put some extra stresses on the body, and there is some evidence suggesting that heart attacks and strokes are slightly more likely to happen soon after using cannabis, just as they can be triggered by exercise or sex. This is a tiny risk that is not relevant to most users, but people with health problems (like an irregular heartbeat) should always be aware that drugs might have greater risks to them.

Cannabis smokers sometimes do some unnecessary things involving breath-holding, either as part of smoking games or in the mistaken belief that holding in the smoke will get them higher, faster. Struggling to hold your breath when you want to cough or breathe out can create sudden pressure changes in the lungs, as can sucking very forcefully from a bong. These habits have led to surprising lung injuries , where air has forced its way through tiny tears in the lung and ended up in places where it shouldn't be, but these injuries are rare.

Using cannabis when pregnant could have effects on the foetus. The baby might weigh less when it is born, and the child might have a bigger chance of having behaviour problems and doing worse at school as it grows up. More research is needed to be sure about this.

Most of the serious harm caused by cannabis use is suffered by the minority of users who use it regularly, who take it daily or nearly daily, not to the majority of users who like to have some now and then. Like alcohol or fast food, the most important thing is staying in control, not letting cannabis become an essential part of your lifestyle. Using less is the simplest and most effective way to avoid harm. Don't be discouraged from cutting down by the thought "I smoke loads of cannabis; if I smoked half as much I'd still be smoking loads". In fact, halving the amount you consume will probably take away more than half of the risk.

It used to be thought that cannabis isn't addictive. Now it is clear that this is not true at all, about 9% of users will become addicted. Some people choose to use cannabis frequently but fit it around their life and can take a break from it easily, but others can't go without it and find that it has become a real problem in their life. People who live alone, have gone through recent difficulties like money troubles, and who use cannabis to cope with their problems are most likely to get addicted, but it could happen to any heavy user.

Addictions to different drugs have very different consequences. People who are addicted to alcohol can become very ill and even die if they are unable to drink it. People who are addicted to cannabis don't get seriously ill without it, but might find it just as hard to quit the drug or regain control over their use. A person addicted to cannabis can become irritable and anxious if they try to go without it, lose their appetite, and feel unable to relax and sleep. These effects get considerably better after the first three days. Going to your doctor can help you access support towards finding a way to overcome cannabis addiction. People trying to quit cannabis also support each other online.

A small number of people who smoke lots of cannabis get a illness where they feel sick, have stomach aches and vomit. Mysteriously, these people usually find that very hot baths and showers help a bit, although stopping cannabis use is the only known solution. This illness is called Cannabis Hyperemesis, and in one case, the vomiting was violent enough to tear a hole in the oesophagus (food pipe).

In the UK, the thing about cannabis use that is most talked about by politicians and written about in newspapers is the fear that it can make young people become mentally ill, and maybe never recover. There is some truth and often plenty of exaggeration to these concerns. To put it in proportion, for most young people experimenting with cannabis, the risk of going on to become addicted is much higher than the risk of going on to develop serious mental illness such as psychosis. Psychosis is most clearly linked to very heavy use of cannabis like 'skunk', which has lots of THC in it (making it strong), but almost no CBD (a protective chemical). Using cannabis with lots of CBD in it, like most types of hash, might not be linked to psychosis at all. In fact, CBD on its own is being tried out as a treatment for psychosis, and early results are promising.

For some people, this issue should matter more because the risk of cannabis provoking psychosis will be higher for them. For example, if you have a close relative who has had episodes of psychosis, or has schizophrenia, cannabis might be enough to give you a push towards developing such conditions yourself.

To understand the risk, you have to understand a little about what psychosis is and what causes it to develop (often in early adulthood). Someone with psychosis may experience paranoia (e.g. thinking people are plotting against you) delusions (e.g. thinking that you have a mission, and are being sent guidance through the radio) and hallucinations (e.g. hearing voices). Most of us are very unlikely to ever get psychosis, but this depends on a combination of our genes and the life we live. In a world in which no-one used cannabis, people would still develop psychosis, sometimes this is a one-off episode of a few days or weeks, sometimes someone dips in and out of periods of psychosis over their lifetime, sometimes it is more or less constant, and occurs with other problems (schizophrenia). All of us have an inbuilt genetic risk for psychosis that ranges from virtually zero up to a maximum of more than 50% (the risk if your identical twin has schizophrenia). Then, on top of that inbuilt risk, things in our lives act as nudges towards or away from psychosis developing.

Someone with a high genetic risk might only need a little nudge, someone with a lower risk may need many nudges all added together for psychosis to emerge. These nudges towards psychosis can include challenging, isolated lives, losing a parent, facing hostility (e.g. the stresses of being a gang-member or a struggling immigrant) stressful events (like having a baby), or even just living in a city. It has become clear that THC in cannabis should be added to this list. Heavy use of high-THC cannabis like skunk seems to nudge people towards developing psychosis, makes it appear earlier in people who might have got it anyway, makes psychosis worse in people living with it already, and makes it harder to recover.

Overstating the role of cannabis in psychosis could be as harmful as ignoring it. For young people who are developing psychosis, a supportive, open, understanding family environment works against psychosis and for recovery, whilst a hostile, blaming response worsens the outcome. People in the process of developing schizophrenia often turn to cannabis, (rather than the cannabis causing the illness) possibly because it feels like it helps them in dealing with some of the symptoms. Understanding their perspective, recognizing that cannabis alone is unlikely to have caused the problem and supporting them to live without cannabis (or first to swap skunk for hash) is a more helpful response than angrily blaming them, and considering their life ruined.

Being a cannabis user or being addicted to cannabis seems to go along with problems like depression and anxiety a bit more often than would happen just by chance. It is hard to work out though whether the cannabis causes these problems or if the cannabis use is a result of them, or if both the drug use and the problems are caused by something else entirely. Looking at the best evidence on this question, it seems that heavy cannabis use, especially from a young age probably does increase an individual's chance of becoming depressed or suffering from an anxiety disorder, although the increase is not huge.

We have written blog post on this topic. Once again, it depends. Scientists have shown that if someone young is addicted to cannabis for a long time, maybe smoking it at least several times a week while whilst they are still at school, they might end up doing quite a bit worse on intelligence tests. On average, cannabis users do less well at school and leave education earlier too.

Chemicals in cannabis might directly interfere with the long slow development of an adult brain, which doesn't finish until people are in their mid-twenties. Cannabis interferes with memory, so someone might not do well if they try to learn whilst stoned, or even the day after being stoned.

However, cannabis might not be the direct cause of lower achievement, or not the only cause. Researchers looked at twins who differed in their cannabis use but had the same family background, it was the disadvantaged background not the cannabis use that made the difference to their success. Another reason might be that the unfair 'stoner' stereotype of lazy, muddle-headed cannabis users (especially young males) subconsciously affects how they start to think about themselves or lowers the expectations other people like teachers have of their abilities, actually leading to lower achievement.

At any age, becoming addicted to a drug makes it harder to succeed in many parts of life. Regularly using drugs such as cannabis can hold someone back simply by using up their time, and re-ordering their priorities, even if the drug itself doesn't damage the brain.

Some types of cannabis might be more likely to hold young people back. Cannabis with lots of THC and no CBD seems to be more addictive and have worse effects on memory.

To summarise, using lots of cannabis while still young (especially being addicted) could prevent someone reaching their full potential. However, there are many successful and intelligent cannabis users. The same research that found that long-term heavy cannabis use when young might make people less intelligent seemed to show that once people are grown up, starting to smoke cannabis probably doesn't affect their intelligence. Stereotyping cannabis users as slow thinkers and underachievers can make things worse, because people have an unconscious tendency to be limited by negative stereotypes.

Yes. Cannabis has been used as a medicine for thousands of years, and is helping increasing numbers of people now. But some people misunderstand what this means. Sometimes people argue with one side saying "cannabis is a harmful drug" and the other side saying "no it isn't, cannabis is a wonderful medicine". Both sides are right and wrong. Cannabis itself isn't either good or bad; it depends on the type, how it is used, in what situation, and who uses it. It is just like a knife; a surgeon can use one kind of knife to make a sick person better, or a healthy person can accidentally harm themselves with a knife.

For a drug to be recognized as a proper medicine, scientists have to have done a trial in which they take a group of people who all have a particular problem or illness, give only half of them the drug, and find out if the people who were given the drug do better overall than the people who were not given it. Some forms of cannabis or chemicals from cannabis have passed this test, showing for example that it can help reduce painful symptoms for some people with MS. Other medical uses of cannabis, like preventing seizures, seem very promising but need more research. But not everyone can benefit from the medical properties of cannabis, and trying to use it as a medicine without a doctor's guidance might do more harm than good.

There are many scientists who are trying hard to help patients by investigating and testing all the interesting chemicals in the cannabis plant that could maybe work as medicines, so that as many people as possible can benefit in future. This work takes a long time, especially as research and medical use of the drug is restricted by the law. This leads to a very sad situation where people who might possibly benefit from using a carefully produced cannabis medicine like Sativex cannot get it from their doctor, or can only buy unpredictable illegal cannabis. The distress this causes is made worse when people put their hope in stories, which often spread online, that cannabis is a miracle cure for cancer and almost everything else. These stories are often passed to ill people with good intentions, but they can be a dangerously persuasive mix of misinterpreted facts and total nonsense. They can mislead people into thinking that radiotherapy and chemotherapy are evil treatments that don't work, their doctors are their enemies, and that all a person with cancer needs is natural cannabis. In the future, cannabis may be proven to have an important place in the toolkit doctors have to fight cancer, in short, it may become a useful chemotherapy, but it is not a replacement for current chemotherapy. At the moment, the evidence for cannabis as a chemotherapy is incomplete and uncertain, it might help, it might not. But it is certain that despite the damage they can do, the chemotherapies and radiotherapy in use now have helped millions of people beat cancer or extend their lives.

Cannabis is a Class B drug in the UK. That means that in theory, getting caught by the police with any amount of cannabis can lead to up to 5 years in prison, an unlimited fine or both. However, this political classification of cannabis is not a good guide to its harmfulness compared to other drugs or to the likely legal consequences of getting caught with it.

The first time that the police find cannabis in someone's possession, they are likely to give a 'cannabis warning', and each time afterwards they will take tougher action, such as fining you, or arresting you. It is very unusual in the UK for someone to go to prison just for possessing cannabis for personal use.

Growing cannabis or selling it to others can result in more serious consequences. Remember that the law doesn't distinguish between dealing cannabis and sharing or giving it to your friends, it all can be counted as supplying the drug.

Getting a criminal record for a cannabis offence can have many bad consequences. It can make it harder to get your dream job, or can mean you can be blocked from travelling to some countries such as America. It might make it harder for you to become Prime Minister and produce great laws to minimise the harms of cannabis to society.

Any time you have an opportunity to use cannabis, make sure you are making a thoughtful, deliberate yes or no choice that you can justify to yourself. If deciding not to use the drug doesn't seem like a realistic option freely available to you, because you are under pressure from other people or if you are perhaps becoming addicted, recognize that your power to limit the risks you face is being threatened and see what you can do to escape that situation.

Remember that your choices go well beyond yes or no. If you are young and think you might like to try cannabis, you don't necessarily need to say yes at the first opportunity; waiting until you are older reduces the risks, and waiting for a perfect relaxed opportunity rather than the first available chance makes it more likely you'll enjoy it anyway. If you have chosen 'yes' to cannabis use, that firmly closes the door on avoiding risk entirely, but opens up a range of new choices you can make to push those risks down; the hows, whats, whens and whys.

Perhaps consider some or all of these questions:

1. How am I consuming my cannabis?

2. Could I switch from smoking to a less harmful method?

3. Can I avoid mixing it with tobacco?

4. Would I be satisfied using less, or saving some for another time?

5. When am I using cannabis?

6. Is this a risky time and place to get stoned?

7. Will I need to drive or be responsible for others in the next few hours?

8. Am I using it more than I used to?

9. Can I set myself a limit?

10. Am I taking long regular breaks to confirm I can do without it?

11. Could I be pregnant?

12. What cannabis am I using?

13. Would I prefer something a bit less strong?

14. Could I find and switch to a lower-risk type of cannabis such as hash?

15. Why am I using it?

16. Do I really want this one?

17. Am I just rolling a joint out of habit?

18. Could I be becoming addicted?

19. Could I be equally happy doing something else?

20. Am I feeling under pressure to fit in?

21. Am I getting stoned to avoid dealing with something?

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Cannabis is a drug that comes from a plant, or a plant which is used as a drug. Cannabis use has been falling; most people in the UK ( more than two out of three) have never tried cannabis, but it's still the most popular illegal drug.

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(PDF Version - 2,236 K) Dried or fresh plant and oil for administration by ingestion or other means
Psychoactive agent
This document has been prepared by the Cannabis Legalization and Regulation Branch at Health Canada to provide information on the use of cannabis (marihuana) and cannabinoids for medical purposes. This document is a summary of peer-reviewed literature and international reviews concerning potential therapeutic uses and harmful effects of cannabis and cannabinoids. It is not meant to be comprehensive and should be used as a complement to other reliable sources of information. This document is not a systematic review or meta-analysis of the literature and has not rigorously evaluated the quality and weight of the available evidence nor has it graded the level of evidence. Despite the similarity of format, it is not a Drug Product Monograph, which is a document which would be required if the product were to receive a Notice of Compliance authorizing its sale in Canada.

This document should not be construed as expressing conclusions or opinions from Health Canada about the appropriate use of cannabis (marihuana) or cannabinoids for medical purposes.

Cannabis is not an approved therapeutic product, unless a specific cannabis product has been issued a drug identification number (DIN) and a notice of compliance (NOC). The provision of this information should not be interpreted as an endorsement of the use of this product, or cannabis and cannabinoids generally, by Health Canada.

Prepared by Health Canada

Date of latest version: Spring 2018

Reporting Adverse Reactions to Cannabis (marihuana, marijuana) Products

Reporting adverse reactions associated with the use of cannabis and cannabis products is important in gathering much needed information about the potential harms of cannabis and cannabis products for medical purposes. When reporting adverse reactions, please provide as much complete information as possible including the name of the licensed producer, the product brand name, the strain name, and the lot number of the product used in addition to all other information available for input in the adverse reaction reporting form. Providing Health Canada with as much complete information as possible about the adverse reaction will help Health Canada with any follow-ups or actions that may be required.

Any suspected adverse reactions associated with the use of cannabis and cannabis products (dried, oils, fresh) for medical purposes should be reported to the Canada Vigilance Program by one of the following three ways:

1. Report online

2. Call toll-free at 1-866-234-2345

3. Complete a Canada Vigilance Reporting Form and:

Fax toll-free to 1-866-678-6789, or

Mail to:
Canada Vigilance Program
Health Canada
Postal Locator 0701D
Ottawa, Ontario K1A 0K9

Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site.

Table of contents

List of figures and tables

Figures

Tables

List of abbreviations

2-AG:

2-arachidonoylglycerol

5-ASA:

5-aminosalicylic acid

5-HT:

5-hydroxytryptamine

2-OG:

2-oleoylglycerol

AA:

arachidonic acid

AB:

Alberta

ACCESS:

AIDS Care Cohort to evaluate Exposure to Survival Services

ACE:

angiotensin-converting enzyme

ACMPR:

Access to Cannabis for Medical Purposes Regulations

ACTH:

adrenocorticotropic hormone

AD:

Alzheimer's disease

AED:

anandamide

AIDS:

acquired immune deficiency syndrome

AKT1:

AKT Serine/Threonine Kinase 1

ALS:

amyotrophic lateral sclerosis

ALSPAC:

Avon Longitudinal Study of Parents and Children

ALT:

alanine transaminase

AMP:

adenosine monophosphate

AOR:

adjusted odds ratio

ApoE:

apolipoprotein E

APP:

amyloid precursor protein

APRI:

AST-to-platelet ratio index

ART:

anti-retroviral therapy

AST:

aspartate transaminase

AUC:

area-under-the-curve

12-hour AUC

Aβ:

amyloid-beta

b.i.d.:

bis in die (i.e. twice per day)

BAC:

blood alcohol concentration

BC:

British Columbia

BCOS:

Bipolar Comprehensive Outcomes Study

BDNF:

brain-derived neurotrophic factor

BDS:

botanical drug substance

BHO:

butane hash oil

BMI:

body mass index

BPI:

Brief Pain Inventory

calcium

CADUMS:

Canadian Alcohol and Drug Use Monitoring Survey

CAMPS:

Cannabis Access for Medical Purposes Survey

CAMS:

Cannabis in Multiple Sclerosis

CAPS:

Clinician-Administered PTSD Scale

CARDIA:

Coronary Artery Risk Development In young Adults

CB:

cannabinoid

CBC:

cannabichromene

CBD:

cannabidiol

CBDA:

cannabidiolic acid

CBDV:

cannabidivarin

CBG:

cannabigerol

CBN:

cannabinol

CCL:

chemokine (C-C motif) ligand

CDAI:

Crohn's disease activity index

CDKL5:

cyclin-dependent kinase-like 5 gene

CHS:

cannabis hyperemesis syndrome

CI:

confidence interval

CINV:

chemotherapy-induced nausea and vomiting

CGI-I:

clinical global impression improvement

CGI-S:

clinical global impression scale

cMAS:

combined modified Ashworth score

Cmax:

Maximal concentration of a drug in the blood

CNR1:

cannabinoid receptor 1

CNR2:

cannabinoid receptor 2

CNS:

central nervous system

COMT:

catechol-O-methyltransferase

COX:

cyclo-oxygenase

CRP:

C-reactive protein

CRPS:

complex regional pain syndrome

CSF:

cerebrospinal fluid

CUD:

cannabis use disorder

CUPID:

Cannabinoid Use in Progressive Inflammatory Brain Disease

CYP:

cytochrome P450

D:

duration of action

DAG:

diacylglycerol

DAGL:

diacylglycerol lipase

DAT1:

dopamine active transporter 1

DIO:

diet-induced obesity

DNA:

deoxyribonucleic acid

DNBS:

dinitrobenzene sulfonic acid

DSM-5:

diagnostic and statistical manual of mental disorders (fifth edition)

DSM-IV:

diagnostic and statistical manual of mental disorders (fourth edition)

DUIA:

driving under the influence of alcohol

DUIC:

driving under the influence of cannabis

ECS:

endocannabinoid system

median effective dose

EDSP:

Early Developmental Stages of Psychopathology

EDSS:

expanded disability status scale

EEG:

electroencephalogram

e.g.:

for example

EMBLEM:

European Mania in Bipolar Longitudinal Evaluation of Medication

EORTC QLQ-C30:

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Module

EQ-5D:

EuroQoL five dimensions questionnaire

ESM:

experience sampling methodology

ETA:

ethanolamine

FAACT:

Functional Assessment of Anorexia-Cachexia Therapy

FAAH:

fatty acid amide hydrolase

forced expiratory volume in one second

fMRI:

functional magnetic resonance imaging

FSH:

follicle stimulating hormone

FVC:

forced vital capacity

g:

gram

GABA:

gamma-aminobutyric acid

GAD:

generalized anxiety disorder

GI:

gastrointestinal

GnRH:

gonadotropin-releasing hormone

GPR55:

G protein-coupled receptor 55

GRADE:

Grading of Recommendations, Assessment, Development and Evaluation

GVHD:

graft-versus-host disease

h:

hour

proton magnetic resonance spectroscopy

HD:

Huntington's disease

HDL:

high density lipoprotein

HIV:

human immunodeficiency virus

HMG-CoA:

3-hydroxy-3-methyl-glutaryl-coenzyme A

HMO:

health maintenance organization

HOMA-IR:

homeostatic model assessment of insulin resistance

HPA:

hypothalamic-pituitary-adrenal

HPO:

hypothalamic-pituitary-ovarian

HRQoL:

health-related quality of life

I.M.:

intramuscular

I.P.:

intraperitoneal

I.V.:

intravenous

IBD:

inflammatory bowel disease

IBS:

irritable bowel syndrome

IBS-A:

alternating pattern (alternation constipation/diarrhea) IBS

IBS-C:

constipation-predominant IBS

IBS-D:

diarrhea-predominant IBS

median inhibitory concentration

ICAM-1:

intercellular adhesion molecule-1

ICD:

International Classification of Diseases

ICM:

inner cell mass

IFN:

interferon

IL:

interleukin

IND:

investigational new drug

iNOS:

inducible nitric oxide synthase

IOP:

intraocular pressure

IQ:

intelligence quotient

IQR:

interquartile range

IRR:

incident rate ratio

potassium

kg:

kilogram

L:

liter

LCT:

lipid long-chain triglyceride

median lethal dose

LDL:

low density lipoprotein

LH:

luteinizing hormone

LOX:

lipo-oxygenase

MAGL:

monoacylglycerol lipase

MB:

Manitoba

Met:

methionine

mg:

milligram

min:

minute

miRNA:

micro ribonucleic acid

mL:

milliliter

MMP:

matrix metalloproteinase

MOVE 2:

Mobility Improvement in MS-Induced Spasticity Study

mRNA:

messenger ribonucleic acid

MS:

multiple sclerosis

MSIS-29:

MS Impact Scale 29

MUSEC:

Multiple Sclerosis and Extract of Cannabis trial

N/A:

not applicable

sodium

NAFLD:

non-alcoholic fatty liver disease

NAPE:

N-arachidonoylphosphatidylethanolamine

NASEM:

National Academy of Sciences, Engineering and Medicine

NB:

New Brunswick

NCS:

National Comorbidity Survey

NCS-R:

National Comorbidity Survey-Replication

NEMESIS:

Netherlands Mental Health Survey and Incidence Study

NESARC:

National Epidemiological Survey on Alcohol and Related Conditions

ng:

nanogram

NHANES:

National Health and Nutrition Examination Survey

NK:

natural killer

NK-1:

neurokinin 1

NL:

Newfoundland and Labrador

nM:

nanomolar

NMDA:

N-methyl-D-aspartic acid

nmol:

nanomole

NNT:

number needed to treat

NRG1:

neuregulin 1

NRS:

numerical rating scale

NRS-PI:

numerical rating scale for pain intensity

NS:

Nova Scotia

NSAIDs:

nonsteroidal anti-inflammatory drugs

NSDUH:

National Survey on Drug Use and Health

NT:

Northwest Territories

NU:

Nunavut

O:

onset of effects

OA:

osteoarthritis

OEA:

oleoylethanolamide

ON:

Ontario

OR:

odds ratio

P:

peak effects

PE:

Prince Edward Island

P.O.:

oral administration

PD:

Parkinson's disease

PDQ-39:

39-Item Parkinson Disease Questionnaire

PEA:

palmitoylethanolamide

PLD:

phospholipase-D

pNRS:

pain numerical rating score

PPAR:

peroxisome proliferator-activated receptor

PRISMA:

Preferred Reporting Items for Sytematic Reviews and Meta-Analyses

PTSD:

post-traumatic stress disorder

PWID:

people who inject drugs

QC:

Quebec

q.i.d.:

quater in die (i.e. four times per day)

QoL:

quality of life

RA:

rheumatoid arthritis

RCT:

randomized controlled trial

REM:

rapid eye movement

RNA:

ribonucleic acid

Rx:

prescription

s:

second

SAFTEE:

Systematic Assessment of Treatment Emergent Events

s.c.:

subcutaneous

SCI:

spinal cord injury

SD:

standard deviation

SDLP:

standard deviation of lateral position

SF-36:

36-Item Short Form Health Survey

SIBDQ:

short IBD questionnaire

SIV:

simian immunodeficiency virus

SK:

Saskatchewan

SNP:

single nucleotide polymorphism

sNRS:

subjective numerical rating spasticity scale

S-TOPS:

Short-Form Treatment Outcomes in Pain Survey

SYS:

Saguenay Youth Study

t.i.d.:

ter in die (i.e. three times per day)

TGCT:

testicular germ cell tumours

THC:

delta-9-tetrahydrocannabinol

THCA:

tetrahydrocannabinolic acid

THCV:

tetrahydrocannabivarin

TIA:

transient ischemic attack

Tmax:

Time to maximal blood concentration of a drug

TNBS:

trinitrobenzene sulfonic acid

TNF:

tumor necrosis factor

TRH:

thyrotropin-releasing hormone

TRP:

transient receptor potential

TRPV1:

transient receptor potential vanilloid channel 1

TS:

Tourette's syndrome

TWSTRS:

Toronto Western Spasmodic Torticollis Rating Scale

U.K.:

United Kingdom

UPDRS:

Unified Parkinson's Disease Rating Scale

Val:

valine

VAS:

visual analogue scale

VCAM-1:

vascular cellular adhesion molecule-1

w/w:

weight/weight

WHO:

World Health Organization

YT:

Yukon

delta-9-tetrahydrocannabinol

µg:

microgram

μM:

micromolar

Authorship and acknowledgements

Author: Hanan Abramovici Ph.D.
Co-authors: Sophie-Anne Lamour, Ph.D.: and George Mammen, Ph.D.

Affiliations:
Cannabis Legalization and Regulation Branch, Health Canada, Ottawa, ON, Canada K1A 0K9
Email: hanan.abramovici@canada.ca

Acknowledgements:
Health Canada would like to acknowledge and thank the following individuals for their comments and suggestions with regard to the content in this information document:

Pierre Beaulieu, M.D., Ph.D., F.R.C.A.
Full professor
Department of Pharmacology and Anesthesiology
Faculty of Medicine
University of Montreal
Office R-408, Roger-Gaudry Wing
P.O. Box 6128 - Downtown Branch
Montréal, Québec
H3C 3J7
Canada

Paul J. Daeninck, M.D., M.Sc., F.R.C.P.C.
Chair, Symptom Management and Palliative Care Disease Site Group
CancerCare Manitoba
Assistant Professor,
College of Medicine, University of Manitoba
St. Boniface Hospital
409 Taché Ave
Winnipeg, MB
R2H 2A6
Canada

Mary Lynch, M.D., F.R.C.P.C.
Professor of Anaesthesia, Psychiatry and Pharmacology
Dalhousie University
Director, Pain Management Unit-Capital Health
Queen Elizabeth II Health Sciences Centre
4 th Floor Dickson Building
5820 University Avenue
Halifax, NS
B3H 1V7
Canada

Mark Ware, M.D., M.R.C.P., M.Sc.
Associate professor
Departments of Anesthesia and Family Medicine
McGill University
Director of Clinical Research
Alan Edwards Pain Management Unit
A5.140 Montreal General Hospital
1650 Cedar Avenue
Montréal, Québec
H3G 1A4
Canada

Overview of Summary Statements

The following bullet-point statements are meant to summarize the content found within sections 4.0 (Potential Therapeutic Uses) and 7.0 (Adverse Effects) and their respective subsections. The bullet-point statements can also be found in their respective sections and sub-sections in the body of the document itself. Note: most, but not all, clinical studies of cannabis (experimental or therapeutic) have been conducted with dried cannabis containing more THC than CBD and typically, but not always, with lower-potency THC (< 9% THC). Furthermore, the majority of the clinical studies of cannabis (experimental or therapeutic) have administered dried cannabis by smoking. Lastly, the findings from clinical studies of cannabis for therapeutic purposes may not be applicable to other chemotypes of cannabis or other cannabis products with different THC and CBD amounts and ratios.
4.0 Potential Therapeutic Uses 4.1 Palliative care 4.2 Quality of life

The available clinical studies report mixed effects of cannabis and prescription cannabinoids on measures of quality of life (QoL) for a variety of different disorders.
4.3 Chemotherapy-induced nausea and vomiting

Pre-clinical studies show that certain cannabinoids (THC, CBD, THCV, CBDV) and cannabinoid acids (THCA and CBDA) suppress acute nausea and vomiting as well as anticipatory nausea.

Clinical studies suggest that certain cannabinoids and cannabis (limited evidence) use may provide relief from chemotherapy-induced nausea and vomiting (CINV).

4.4 Wasting syndrome (cachexia, e.g., from tissue injury by infection or tumour) and loss of appetite (anorexia) in AIDS and cancer patients, and anorexia nervosa

The available evidence from human clinical studies suggests that cannabis (limited evidence) and dronabinol may increase appetite and caloric intake, and promote weight gain in patients with HIV/AIDS.

However the evidence for dronabinol is mixed and effects modest for patients with cancer and weak for patients with anorexia nervosa.

4.5 Multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury and disease 4.6 Epilepsy

Anecdotal evidence suggests an anti-epileptic effect of cannabis (THC- and CBD-predominant strains).

The available evidence from pre-clinical studies suggests certain cannabinoids (CBD) may have anti-epileptiform and anti-convulsive properties, whereas CB₁R agonists (THC) may have either pro- or anti-epileptic properties.

However, the clinical evidence for an anti-epileptic effect of cannabis is weaker, but emerging, and requires further study.

Evidence from clinical studies with Epidiolex® (oral CBD) suggest efficacy and tolerability of Epidiolex® for drug-resistant seizures in treatment-resistant Dravet syndrome or Lennox-Gastaut syndrome.

Evidence from observational studies suggest an association between CBD (in herbal and oil preparations) and a reduction in seizure frequency as well as an increase in quality of life among adolescents with rare and serious forms of drug-resistant epilepsy.

Epidiolex® has received FDA approval (in June 2018) for use in patients 2 years of age and older to treat treatment-resistant seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

4.7 Pain 4.7.1 Acute pain 4.7.2 Chronic pain 4.7.2.1 Experimentally-induced inflammatory and chronic neuropathic pain

Endocannabinoids, THC, CBD, nabilone and certain synthetic cannabinoids have all been identified as having an anti-nociceptive effect in animal models of chronic pain (inflammatory and neuropathic).
4.7.2.2. Neuropathic pain and chronic non-cancer pain in humans

A few studies that have used experimental methods having predictive validity for pharmacotherapies used to alleviate chronic pain, have reported an analgesic effect of smoked cannabis.

Furthermore, there is more consistent evidence of the efficacy of cannabinoids (smoked/vapourized cannabis, nabiximols, dronabinol) in treating chronic pain of various etiologies, especially in cases where conventional treatments have been tried and have failed.

4.7.2.3 Cancer pain

The limited available clinical evidence with certain cannabinoids (dronabinol, nabiximols) suggests a modest analgesic effect of dronabinol and a modest and mixed analgesic effect of nabiximols on cancer pain.
4.7.2.4 "Opioid-sparing" effects and cannabinoid-opioid synergy

While pre-clinical and case studies suggest an "opioid-sparing" effect of certain cannabinoids, epidemiological and clinical studies with oral THC and nabiximols are mixed.

Observational studies suggest an association between U.S. states with laws permitting access to cannabis (for medical and non-medical purposes) and lowered rates of prescribed opioids and opioid-associated mortality.

4.7.2.5 Headache and migraine

The evidence supporting using cannabis/certain cannabinoids to treat headache and migraine is very limited and mixed.
4.8. Arthritides and musculoskeletal disorders

The evidence from pre-clinical studies suggests stimulation of CB₁ and CB₂ receptors alleviates symptoms of osteoarthritis (OA), and THC and CBD alleviate symptoms of rheumatoid arthritis (RA).

The evidence from clinical studies is very limited, with a modest effect of nabiximols for RA.

There are no clinical studies of cannabis for fibromyalgia, and the limited clinical evidence with dronabinol and nabilone suggest a modest effect on decreasing pain and anxiety, and improving sleep.

The role of cannabinoids in osteoporosis has only been investigated pre-clinically and is complex and conflicting.

4.9 Other diseases and symptoms 4.9.1 Movement disorders 4.9.1.1 Dystonia

Evidence from limited pre-clinical studies suggests that a synthetic CB1 and CB₂ receptor agonist may alleviate dystonia-like symptoms, and CBD delays dystonia progression.

Evidence from a limited number of case studies and small placebo-controlled or open-label clinical trials suggests improvement in symptoms of dystonia with inhaled cannabis, mixed effects of oral THC, improvement in symptoms of dystonia with oral CBD, and lack of effect of nabilone on symptoms of dystonia.

4.9.1.2 Huntington's disease

Evidence from pre-clinical studies reports mixed results with THC on Huntington's disease (HD)-like symptoms.

Limited evidence from case studies and small clinical trials is mixed and suggests a lack of effect with CBD, nabilone and nabiximols, and a limited improvement in HD symptoms with smoked cannabis.

4.9.1.3 Parkinson's disease 4.9.1.4 Tourette's syndrome

The limited evidence from small clinical studies suggests that oral THC improves certain symptoms of Tourette's syndrome (TS) (tics).
4.9.2 Glaucoma

The limited evidence from small clinical studies suggests oral administration of THC reduces intra-ocular pressure (IOP) while oral administration of CBD may, in contrast, cause an increase in IOP.
4.9.3 Asthma

The limited evidence from pre-clinical and clinical studies on the effect of aerosolized THC on asthmatic symptoms is mixed.

Inhalation of lung irritants generated from smoking/vapourizing cannabis may worsen asthmatic symptoms.

4.9.5 Stress and psychiatric disorders 4.9.5.1 Anxiety and depression 4.9.5.2 Sleep disorders

Human experimental data suggests cannabis and THC have a dose-dependent effect on sleep-low doses appear to decrease sleep onset latency and increase slow-wave sleep and total sleep time, while high doses appear to cause sleep disturbances.

Limited evidence from clinical studies also suggest that certain cannabinoids (cannabis, nabilone, dronabinol, nabiximols) may improve sleep in patients with disturbances in sleep associated with certain chronic disease states.

4.9.5.3 Post-traumatic stress disorder 4.9.5.4 Alcohol and opioid withdrawal symptoms (drug withdrawal symptoms/drug substitution)

Pre-clinical studies suggest CB₁ receptor agonism (e.g. THC) may help increase the reinforcing properties of alcohol, increase alcohol consumption, and increase risk of relapse of alcohol use, as well as exacerbate alcohol withdrawal symptom severity.

Pre-clinical studies suggest certain cannabinoids (e.g. THC) may alleviate opioid withdrawal symptoms.

Evidence from observational studies suggests that cannabis use could help alleviate opioid withdrawal symptoms, but there is insufficient clinical evidence from which to draw any reliable conclusions.

4.9.5.5 Schizophrenia and psychosis

Significant evidence from pre-clinical, clinical and epidemiological studies supports an association between cannabis (especially THC-predominant cannabis) and THC, and an increased risk of psychosis and schizophrenia.

Emerging evidence from pre-clinical, clinical and epidemiological studies suggests CBD may attenuate THC-induced psychosis.

4.9.6 Alzheimer's disease and dementia

Pre-clinical studies suggest that THC and CBD may protect against excitotoxicity, oxidative stress and inflammation in animal models of Alzheimer's disease (AD).

Limited case, clinical and observational studies suggest that oral THC and nabilone are associated with improvement in a number of symptoms associated with AD (e.g. nocturnal motor activity, disturbed behaviour, sleep, agitation, resistiveness).

4.9.7 Inflammation 4.9.7.1 Inflammatory skin diseases (dermatitis, psoriasis, pruritus)

The results from pre-clinical, clinical and case studies on the role of certain cannabinoids in the modulation of inflammatory skin diseases are mixed.

Some clinical and prospective case series studies suggest a protective role for certain cannabinoids (THC, CBD, HU-210), while others suggest a harmful role (cannabis, THC, CBN).

4.9.8 Gastrointestinal system disorders (irritable bowel syndrome, inflammatory bowel disease, hepatitis, pancreatitis, metabolic syndrome/obesity) 4.9.8.1 Irritable bowel syndrome 4.9.8.2 Inflammatory bowel diseases (Crohn's disease, ulcerative colitis)

Pre-clinical studies in animal models of inflammatory bowel disease (IBD) suggest that certain cannabinoids (synthetic CB₁ and CB₂ receptor agonists, THC, CBD, CBG, CBC, whole plant cannabis extract) may limit intestinal inflammation and disease severity to varying degrees.

Evidence from observational studies suggests that patients use cannabis to alleviate symptoms of IBD.

A very limited number of small clinical studies with patients having IBD and having failed conventional treatments reported improvement in a number of IBD-associated symptoms with smoked cannabis.

4.9.8.3 Diseases of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury, hepatic encephalopathy)

Pre-clinical studies suggest CB₁ receptor activation is detrimental in liver diseases (e.g. promotes steatosis, fibrosis); while CB₂ receptor activation appears to have some beneficial effects.

Furthermore, pre-clinical studies also suggest that CBD, THCV and ultra-low doses of THC may have some protective effects in hepatic ischemia-reperfusion injury and hepatic encephalopathy.

4.9.8.4 Metabolic syndrome, obesity, diabetes

Pre-clinical studies suggest acute CB₁ receptor activation results in increased fat synthesis and storage while chronic CB₁ receptor activation (or CB₁ receptor antagonism) results in weight loss and improvement in a variety of metabolic indicators.

Observational studies suggest an association between chronic cannabis use and an improved metabolic profile, while pre-clinical and very limited clinical evidence suggests a potential beneficial effect of THCV on glycemic control (in patients with type II diabetes).

4.9.8.5 Diseases of the pancreas (diabetes, pancreatitis) 4.9.9 Anti-neoplastic properties

Pre-clinical studies suggest that certain cannabinoids (THC, CBD, CBG, CBC, CBDA) often, but not always block growth of cancer cells in vitro and display a variety of anti-neoplastic effects in vivo, though typically at very high doses that would not be seen clinically.

While limited evidence from one observational study suggests cancer patients use cannabis to alleviate symptoms associated with cancer (e.g. chemosensory alterations, weight loss, depression, pain), there has only been one limited clinical study in patients with glioblastoma multiforme, which reported that intra-tumoural injection of high doses of THC did not improve patient survival beyond that seen with conventional chemotherapeutic agents.

7.0 Adverse effects 7.1 Carcinogenesis and mutagenesis

Evidence from pre-clinical studies suggests cannabis smoke contains many of the same carcinogens and mutagens as tobacco smoke and that cannabis smoke is as mutagenic and cytotoxic, if not more so, than tobacco smoke.

However, limited and conflicting evidence from epidemiological studies has thus far been unable to find a robust and consistent association between cannabis use and various types of cancer, with the possible exception of a link between cannabis use and testicular cancer (i.e. testicular germ cell tumours).

7.2 Respiratory tract 7.3 Immune system 7.4 Reproductive and endocrine systems 7.5 Cardiovascular system 7.6 Gastrointestinal system and liver

Evidence from case reports suggests chronic, heavy (THC-predominant) cannabis use is associated with an increased risk of cannabis hyperemesis syndrome (CHS).

Limited evidence from observational studies suggests mixed findings between (THC-predominant) cannabis use and risk of liver fibrosis progression associated with hepatitis C infection.

7.7 Central nervous system 7.7.1 Cognition

Evidence from clinical studies suggests acute (THC-predominant) cannabis use is associated with a number of acute cognitive effects.

Evidence from observational studies suggests chronic cannabis use is associated with some cognitive and behavioural effects that may persist for varying lengths of time beyond the period of acute intoxication depending on a number of factors.

Limited evidence from human clinical imaging studies suggests THC and CBD may exert opposing effects on neuropsychological/neurophysiological functioning.

Evidence from mainly cross-sectional human clinical imaging studies suggests heavy, chronic cannabis use is associated with a number of structural changes in grey and white matter in different brain regions.

Furthermore, early-onset use and use of high-potency, THC-predominant cannabis, has been associated with an increased risk of some brain structural changes and cognitive impairment.

7.7.2 Psychomotor performance and driving 7.7.3 Psychiatric effects 7.7.3.1 Anxiety, PTSD, depression and bipolar disorder 7.7.3.2 Schizophrenia and psychosis 7.7.3.3 Suicidal ideation, attempts and mortality

Evidence from epidemiological studies also suggests a dose-dependent association between cannabis use and suicidality, especially in men.
7.7.3.4 Amotivational syndrome

The available limited evidence for an association between cannabis use and an "amotivational syndrome" is mixed.

Important Note: For the sake of completeness and for contextual purposes, the content in the following document includes information on dried cannabis and other cannabis-based products as well as selected cannabinoids. However, cannabis products and cannabinoids should not be considered equivalent even though the information on such products is presented together within the text. Cannabis and cannabis products are highly complex materials with hundreds of chemical constituents whereas cannabinoids are typically single molecules. Drawing direct comparisons between cannabis products and cannabinoids must necessarily take into account differences in the route of administration, dosage, individual pharmacological components and their potential interactions, and the different pharmacokinetic and pharmacodynamic properties of these different substances.

1.0 The Endocannabinoid System

The endocannabinoid system (ECS) is an ancient, evolutionarily conserved, and ubiquitous lipid signaling system found in all vertebrates, and which appears to have important regulatory functions throughout the human body. The ECS has been implicated in a very broad number of physiological as well as pathophysiological processes including nervous system development, immune function, inflammation, appetite, metabolism and energy, homeostasis, cardiovascular function, digestion, bone development and bone density, synaptic plasticity and learning, pain, reproduction, psychiatric disease, psychomotor behaviour, memory, wake/sleep cycles, and the regulation of stress and emotional state/mood. Furthermore, there is strong evidence that dysregulation of the ECS contributes to many human diseases including pain, inflammation, psychiatric disorders and neurodegenerative diseases.

Components of the endocannabinoid system

The ECS consists mainly of: the cannabinoid 1 and 2 (CB ₁ and CB ₂) receptors; the cannabinoid receptor ligands N-arachidonoylethanolamine ("anandamide") and 2-arachidonoylglycerol (2-AG); the endocannabinoid-synthesizing enzymes N-acyltransferase, phospholipase D, phospholipase C-β and diacylglycerol-lipase (DAGL); and the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) . Anandamide and 2-AG are considered the primary endogenous activators of cannabinoid signaling, but other endogenous molecules, which exert "cannabinoid-like" effects, have also been described. These other molecules include 2-arachidonoylglycerol ether (noladin ether), N -arachidonoyl-dopamine, virodhamine, N -homo-γ-linolenoylethanolamine and N-docosatetraenoylethanolamine. Other molecules such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) do not appear to bind to cannabinoid receptors but rather to a specific isozyme belonging to a class of nuclear receptors/transcription factors known as peroxisome proliferator-activated receptors (PPARs). These fatty acyl ethanolamides may, however, potentiate the effect of anandamide by competitive inhibition of FAAH, and/or through direct allosteric effects on other receptors such as the transient receptor potential vanilloid (TRPV1) channel. This type of effect has been generally referred to as the so-called "entourage effect". The term "entourage effect" is also used in the context of the interactions between phytocannabinoids and terpenes in a physiological system (see Section 1.1.2).

Endocannabinoid synthesis

Endocannabinoids are arachidonic acid derivatives which are synthesized "on demand" (e.g. in response to an action potential in neurons or in response to another type of biological stimulus) from membrane phospholipid precursors in response to cellular requirements. Synthesis of endocannabinoids "on demand" ensures that endocannabinoid signaling is tightly controlled both spatially and temporally. Anandamide is principally, but not exclusively, produced by the transfer of arachidonic acid from phosphatidylcholine to phosphatidylethanolamine by N-acyltransferase to yield N-arachidonoylphosphatidylethanolamine (NAPE). NAPE is then hydrolyzed to form anandamide by a NAPE-specific phospholipase D. Other synthetic routes include acyl-chain removal from NAPE by α/β-hydrolase 4 to yield glycerophospho-N-arachidonoylethanolamine followed by phosphodiester bond hydrolysis of glycerophospho-N-arachidonoylethanolamine by phosphodiesterase 1 to yield anandamide. In contrast, 2-AG is principally synthesized through phospholipase C-β-mediated hydrolysis of phosphatidylinositol-4,5-bisphosphate, with arachidonic acid on the sn-2 position, to yield diacylglycerol (DAG). DAG is then hydrolyzed to 2-AG by a DAGL. While anandamide and 2-AG are both derivatives of arachidonic acid, they are synthesized by pathways distinct from those used to synthesize eicosanoids. Nevertheless, it appears that there may be a certain amount of cross talk between the eicosanoid and endocannabinoid pathways.

Genetics and signaling through the cannabinoid receptors

Endocannabinoids such as anandamide and 2-AG, as well as the phytocannabinoids Δ ⁹-tetrahydrocannabinol (Δ ⁹-THC), Δ ⁸-THC, cannabinol (CBN) and others, bind to and activate (with differing affinities and efficacies) the CB ₁ and CB ₂ receptors which are G-protein coupled receptors that activate G i/G o-dependent signaling cascades. The receptors are encoded by separate genes located on separate chromosomes; in humans, the CB ₁ receptor gene (CNR1) locus is found on chromosome 5q15 whereas the CB ₂ receptor gene (CNR2) locus is located on chromosome 1p36. The CNR1 coding sequence consists of one exon encoding a protein of 472 amino acids. The CB ₁ receptor protein shares 97 - 99% amino acid sequence identity across species (human, rat, mouse). As with the CNR1 coding sequence, the CNR2 coding sequence consists of only one exon, but it encodes a shorter protein 360 amino acids in length. The human CB ₂ receptor shares 48% amino acid identity with the human CB ₁ receptor; the mouse CB ₂ receptor shares 82% amino acid sequence identity with the human CB ₂ receptor.

Activation of the CB ₁ or CB ₂ G i/o-protein coupled receptors results in inhibition of adenylyl cyclase activity, decreased formation of cyclic AMP with a corresponding decrease in protein kinase A activity, and inhibition of Ca ²⁺ influx through various Ca ²⁺ channels; it also results in stimulation of inwardly rectifying potassium (K⁺) channels and the mitogen-activated protein kinase signaling cascades. Anandamide is a partial agonist at cannabinoid receptors, and binds with slightly higher affinity at CB ₁ compared to CB ₂ receptors. 2-AG appears to bind equally well to both cannabinoid receptors (with slightly higher affinity to CB ₁), but has greater potency and efficacy than anandamide at cannabinoid receptors.

In the central nervous system (CNS), the overall effect of CB ₁ receptor activation is suppression of neurotransmitter release (5-hydroxytryptamine (5-HT), glutamate, acetylcholine, GABA, noradrenaline, dopamine, D-aspartate, cholecystokinin) at both excitatory and inhibitory synapses with both short and long-term effects. Inhibition of neurotransmitter release occurs through a retrograde signaling mechanism whereby endocannabinoids synthesized and released from the cell membrane of post-synaptic neurons diffuse backwards across the synaptic cleft and bind to CB ₁ receptors located on the pre-synaptic terminals . This retrograde signaling mechanism permits the regulation of neurotransmission in a precise spatio-temporal manner. In immune cells, activation of CB ₂ receptors inhibits cytokine/chemokine release and neutrophil and macrophage migration, giving rise to complex modulatory effects on immune system function.

Cannabinoid receptor expression and receptor distribution

Most tissues contain a functional ECS with the CB ₁ and CB ₂ receptors having distinct patterns of tissue expression. The CB ₁ receptor is one of the most abundant G-protein coupled receptors in the central and peripheral nervous systems. It has been detected in the cerebral cortex, hippocampus, amygdala, basal ganglia, substantia nigra pars reticulata, internal and external segments of the globus pallidus and cerebellum (molecular layer), and at central and peripheral levels of the pain pathways including the periaqueductal gray matter, the rostral ventrolateral medulla, the dorsal primary afferent spinal cord regions including peripheral nociceptors, and spinal interneurons. CB ₁ receptor density is highest in the cingulate gyrus, the frontal cortex, the hippocampus, the cerebellum, and the basal ganglia. Moderate levels of CB ₁ receptor expression are found in the basal forebrain, amygdala, nucleus accumbens, periaqueductal grey, and hypothalamus and much lower expression levels of the receptor are found in the midbrain, the pons, and the medulla/brainstem. Relatively little CB ₁ receptor expression is found in the thalamus and the primary motor cortex. The CB ₁ receptor is also expressed in many other organs and tissues including adipocytes, leukocytes, spleen, heart, lung, the gastrointestinal (GI) tract (liver, pancreas, stomach, and the small and large intestine), kidney, bladder, reproductive organs, skeletal muscle, bone, joints, and skin. CB ₂ receptors are most highly concentrated in the tissues and cells of the immune system such as the leukocytes and the spleen, but can also be found in bone and to a lesser degree in liver and in nerve cells including astrocytes, oligodendrocytes and microglia, and even some neuronal sub-populations.

Other molecular targets for cannabinoids

Besides the well-known CB ₁ and CB ₂ receptors, a number of different cannabinoids are believed to bind to a number of other molecular targets. Such targets include the third putative cannabinoid receptor GPR55 (G protein-coupled receptor 55), the transient receptor potential (TRP) cation channel family, and a class of nuclear receptors/transcription factors known as the PPARs, as well as 5-HT 1A receptors, the α ₂ adrenoceptors, adenosine and glycine receptors. For additional details on this subject please see and consult the following resources. Modulation of these other cannabinoid targets adds additional layers of complexity to the known myriad effects of cannabinoids.

Signal termination

Dysregulation of the endocannabinoid system and general therapeutic challenges of using cannabinoids

Role of the endocannabinoid system in nervous system development

The CB ₁ receptor is highly expressed in the developing brain. For example, CB ₁ receptors are highly expressed from early fetal stages, beginning as early as E12.5 (in mice) and into late fetal stages (E21) with high expression in white matter within a number of different structures including the hippocampus, cerebellum, caudate-putamen and cerebral cortex that continues to increase after birth and into adulthood; in contrast, after birth there is tapering of CB ₁ receptor expression in other structures such as the corpus callosum, fornix, stria terminalis and the fasciculus retroflexus. Furthermore, in the adult brain, the CB ₁ receptor appears to be localized on the axonal plasma membrane and in somatodendritic endosomes, whereas in fetal brain the CB ₁ receptor is mostly localized to endosomes both in axons and in the somatodendritic region. The available evidence suggests a neurodevelopmental role for the ECS including in functions such as survival, proliferation, migration and differentiation of neuronal progenitors. CB ₁ receptor activation, in response to stimulation by endocannabinoids, such as 2-AG and anandamide, promotes these functions but delays the transition from multipotent, proliferating, and migration-competent progenitor phenotype towards a more settled, well-differentiated, post-mitotic neuronal phenotype. In vitro studies examining the effects of CB ₁ receptor activation in primary neuronal cultures suggest that the CB ₁ receptor is mainly a negative regulator of neurite growth since activation of the receptor results in growth cone arrest, repulsion or collapse and thereby influences the ability of axons to reach their targets. However, these CB ₁ receptor-mediated responses may be surmountable by the effects of local growth-promoting effectors at the growth cone and the balance between the effects of endocannabinoids and growth factors would determine the overall outcome of neuronal development. The CB ₁ receptor appears also to act as a negative regulator of synaptogenesis and in doing so can also affect the fate of neuronal communication. Exposure to cannabinoids that activate the CB ₁ receptor (such as THC) during developmental periods of nervous system development such as during embryonic development in pregnancy could alter the course of normal neuronal development in offspring and negatively affect normal brain function potentially causing long-lasting impairment of a number of cognitive functions and behaviours (and also see for additional information). For example, a study conducted in pregnant mice using a low dose of THC has been shown to alter the expression level of 35 proteins in the fetal cerebrum. Furthermore this study concretely identified a specific molecular target for THC in the developing CNS whose modifications can directly and permanently impair the wiring of neuronal networks during corticogenesis by enabling formation of ectopic neuronal filopodia and altering axonal morphology. Another in vitro study with retinal ganglion cell explants showed that CBD decreased neuronal growth cone size and filopodia number as well as total projection length and induced growth cone collapse and neurite retraction (i.e. chemo-repulsion) through the GPR55 receptor.

Figure 1. The Endocannabinoid System in the Nervous System

(1) Endocannabinoids are manufactured "on-demand" (e.g. in response to an action potential in neurons) in the post-synaptic terminals: anandamide (AEA) is generated from phospholipase-D (PLD)-mediated hydrolysis of the membrane lipid N-arachidonoylphosphatidylethanolamine (NAPE); 2-AG from the diacylglycerol lipase (DAGL)-mediated hydrolysis of the membrane lipid diacylglycerol (DAG); (2) These endocannabinoids (anandamide (AEA) and 2-AG) diffuse retrogradely towards the pre-synaptic terminals and like exogenous cannabinoids such as THC (from cannabis), dronabinol, and nabilone, they bind to and activate the pre-synaptic G-protein-coupled CB ₁ receptors; (3) Binding of phytocannabinoid and endocannabinoid agonists to the CB ₁ receptors triggers G i/G o protein signalling that, for example, inhibits adenylyl cyclase, thus decreasing the formation of cyclic AMP and the activity of protein kinase A; (4) Activation of the CB ₁ receptor also results in G i/G o protein-dependent opening of inwardly-rectifying K⁺ channels (depicted with a "+") causing a hyperpolarization of the pre-synaptic terminals, and the closing of Ca ²⁺ channels (depicted with a "-"), arresting the release of stored excitatory and inhibitory neurotransmitters (e.g. glutamate, GABA, 5-HT, acetylcholine, noradrenaline, dopamine, D-aspartate and cholecystokinin) which (5) once released, diffuse and bind to post-synaptic receptors; (6) Anandamide and 2-AG re-enter the post- or pre-synaptic nerve terminals (possibly through the actions of a specialized transporter depicted by a "dashed" line) where they are respectively catabolized by fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) to yield either arachidonic acid (AA) and ethanolamine (ETA), or arachidonic acid (AA) and glycerol. See text for additional details. Figure adapted fromReference 64-Reference 66.

1.1 Cannabis

1.1.1 Chemistry and composition

Cannabis sativa (i.e. cannabis, marihuana, marijuana) is a hemp plant that grows throughout temperate and tropical climates. The leaves and flowering tops of Cannabis contain over 500 distinct compounds distributed among 18 different chemical classes, and harbor over 100 different phytocannabinoids The principal phytocannabinoids appear to be delta-9-tetrahydrocannabinol (i.e. Δ ⁹-THC, THC), CBN, and cannabidiol (CBD), although the relative abundance of these and other phytocannabinoids can vary depending on a number of factors such as the Cannabis strain, the soil and climate conditions, and the cultivation techniques. Other phytocannabinoids found in cannabis include cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV) and many others. In the living plant, these phytocannabinoids exist as both inactive monocarboxylic acids (e.g. tetrahydrocannabinolic acid, THCA) and as active decarboxylated forms (e.g. THC); however, heating (at temperatures above 120 °C) promotes decarboxylation (e.g. THCA to THC). Furthermore, pyrolysis (such as by smoking) transforms each of the hundreds of compounds in cannabis into a number of other compounds, many of which remain to be characterized both chemically and pharmacologically. Therefore, cannabis can be considered a very crude drug containing a very large number of chemical and pharmacological constituents, the properties of which are only slowly being understood.

Among all the chemical constituents of cannabis, and particularly among the cannabinoids, Δ ⁹-THC is by far the best studied and is responsible for many, if not most, of the physical and psychotropic effects of
cannabis. Other phytocannabinoids (e.g. CBD, CBC, CBG) are present in lesser amounts in the plant and have little, if any, psychotropic properties. However, Canadian licensed producers of cannabis for medical purposes have now made available a large variety of cannabis strains containing varying levels of THC and CBD, including THC-predominant, CBD-predominant or balanced strains for patients who have received authorization from their healthcare practitioner to access cannabis for medical purposes. For more information, please consult the Health Canada authorized licensed producers of cannabis for medical purposes website.

1.1.2 Other constituents

The large number of compounds found in cannabis spans many chemical classes including phytocannabinoids, nitrogenous compounds, amino acids, proteins, enzymes, glycoproteins, hydrocarbons, simple alcohols, aldehydes, ketones and acids, fatty acids, simple esters and lactones, steroids, terpenes, non-cannabinoid phenols, flavonoids, vitamins, and pigments. Furthermore, differences in the presence and the relative abundance of some of these various components have been investigated, and differences in various components have been noted between cannabis extract, vapour, and smoke, and also between cannabis varieties. Of note, cannabis smoke contains many compounds not observed in either extracts or vapour, including a number which are known or suspected carcinogens or mutagens. Moreover, comparisons between cannabis smoke and tobacco smoke have shown that the former contains many of the same carcinogenic chemicals found in the latter (see for more information).

1.1.3 Stability and storage

Most of the information on the stability of cannabis does not distinguish between Δ ⁹-THC and its carboxylic acid (Δ ⁹-THCA). The latter is transformed to Δ ⁹-THC by heating during vapourization or cooking, or by pyrolysis during smoking or in the inlet of gas chromatographs used in forensic analysis. Complete decarboxylation of Δ ⁹-THCA to Δ ⁹-THC has been shown to occur starting at 98 °C and up to a temperature of 200 °C. As the temperature increases, the rate of decarboxylation increases: it takes 4 hours for complete decarboxylation at 98 °C, but only seconds at 200 °C. Heat, light, humidity, acidity and oxidation all affect the stability of cannabis and phytocannabinoids. The National Institute on Drug Abuse reports that retention samples of their carefully prepared and standardized cigarettes are stable for months, particularly when stored below 0 oC (-18 °C) in the dark, in tightly-closed containers. Even when stored at +18 °C, only a third of the Δ ⁹-THC content is lost over a five-year period with some increase in the concentration of CBN. Cannabis cigarettes with lower Δ ⁹-THC content (1.15% THC) appear to lose more Δ ⁹-THC compared to cigarettes with higher Δ ⁹-THC content (2.87% THC). Turner et al. found that the THC content of cannabis decayed at a rate of 3.83, 5.38, and 6.92% per year for cannabis stored at -18 °C, 4 °C and 22 °C respectively. Sevigny has provided the following formula for calculating decay of THC: THC ₀ = THC a / e-(k)(t) where THC ₀ is the unknown initial concentration of THC, THC a is the assayed concentration of THC, k is the decay rate constant which can vary according to two conditions: k = 0.0263 (the lower-bound average decay rate for samples stored in darkness at 3 ºC) and k = 0.0342 (the upper-bound average decay rate for samples stored in natural light of a laboratory at 22 °C), and t is the seizure-to-assay analysis lag (in months). For specific stability and storage conditions for cannabis provided by licensed commercial producers in Canada, please consult information provided by the licensed commercial producers.

2.0 Clinical Pharmacology

2.1 Pharmacodynamics

Much of the pharmacodynamic information on cannabis refers to the effects of the major constituent, Δ ⁹-THC, which acts as a partial agonist at both CB receptors, has activity at non-CB receptors and other targets, and is responsible for the psychoactive and potential therapeutic effects of cannabis through its actions at the CB ₁ receptor. Δ ⁸ -THC (an isomer of Δ ⁹-THC) is found in smaller amounts in the plant, but like Δ ⁹-THC, it is a partial agonist at both CB receptors and shares relatively similar efficacy and potency with Δ ⁹-THC in in vitro assays. An in vivo animal study and one clinical study suggest Δ ⁸ -THC to be a more potent anti-emetic than Δ ⁹-THC.

CBN is a product of Δ ⁹-THC oxidation and has 10% of the activity of Δ ⁹-THC at the CB ₁ receptor. Its effects are not well studied but it appears to have some possible immunosuppressive properties in a small number of in vitro studies.

CBG is a partial CB 1/2 receptor agonist and a small number of in vitro studies suggest it may have some anti-inflammatory and analgesic properties. For example, in vitro assays have shown that CBG, at a concentration of 100 µg/ml (approximately equivalent to a concentration of 300 µM and above the typical physiological range, and therefore not truly representative of human in vivo conditions), is associated with a greater than 30% inhibition of cyclooxygenase (COX) 1 and 2 enzymes, but only produced weak inhibition (<10%) of prostaglandin production in vivo at concentrations that did not cause cytotoxicity. Cannabigerolic acid has a similar profile. CBG has also been shown to block 5-HT 1A receptors and act as an α ₂-adrenoceptor agonist. There is some emerging evidence that suggests CBG can produce signs of analgesia by activation of α ₂-adrenoceptors.

CBD lacks detectable psychoactivity and does not appear to bind to either CB ₁ or CB ₂ receptors at physiologically meaningful concentrations, but there is some emerging evidence suggesting it may act as a non-competitive, negative, allosteric modulator of CB ₁ receptors. There is also a considerable body of evidence suggesting CBD also affects the activity of a significant number of other targets including ion channels, receptors, and enzymes. For example, CBD has been shown to block the activity of FAAH resulting in an increase in anandamide levels, act as an agonist of the TRPV1 channel, inhibit adenosine uptake by acting as an indirect agonist at adenosine receptors, act as an agonist of 5-HT 1A receptors, act as a positive allosteric modulator of glycine receptors, and act as an anti-oxidant and reactive oxygen species scavenger as well as regulating calcium homeostasis via the mitochondrial sodium/calcium (Na⁺/Ca ²⁺)-exchanger. The effects of CBD at these and other molecular targets are associated with anti-inflammatory, analgesic, anti-nausea, anti-emetic, anti-psychotic, anti-ischemic, anxiolytic, and anti-epileptiform effects.

THCV acts as a CB ₁ receptor antagonist and CB ₂ receptor partial agonist in vitro and in vivo, as well as a 5-HT 1A receptor agonist and pre-clinical studies suggest it may have anti-epileptiform/anti-convulsant, anti-nociceptive and potential anti-psychotic properties.

Phytocannabinoid-phytocannabinoid interactions and phytocannabinoid differences among cannabis strains

Despite anecdotal claims, there is limited reliable information regarding actual or potential interactions, of biological or physiological significance, among phytocannabinoids, especially Δ ⁹-THC and CBD. The limited information that exists is complex and requires further clarification through additional investigation. The following paragraphs summarize the available information on this subject.

Factors affecting the nature of the potential phytocannabinoid-phytocannabinoid interactions

Various studies have reported either potentiating, opposing, or neutral interactions between Δ ⁹-THC and CBD. The discrepancies in the nature of the interactions between Δ ⁹-THC and CBD reported in the literature may be explained by differences in the doses and ratios of THC and CBD used in the different studies, differences in the routes of administration, dose ordering effects (CBD pre-treatment vs. simultaneous co-administration with Δ ⁹-THC), differences in the duration or chronicity of treatment (acute vs. chronic), differences in the animal species used, as well as the particular biological or physiological end-points being measured.

Pharmacokinetic vs. pharmacodynamic interactions

In general, there appear to be two types of mechanisms which could govern possible interactions between CBD and Δ ⁹-THC: those of apharmacokinetic origin, and those of a pharmacodynamic origin. Despite the limited and complex nature of the available information, it generally appears that pre-administration of CBD may potentiate some of the effects of THC (through a pharmacokinetic mechanism). Potentiation of THC effects by CBD may be caused by inhibition of THC metabolism in the liver, resulting in higher plasma levels of THC.Simultaneous co-administration of CBD and THC may result in the attenuation of some of the effects of THC (through a pharmacodynamic mechanism). Furthermore, the ratio between the two phytocannabinoids also appears to play a role in determining whether the overall effect will be of a potentiating or antagonistic nature. CBD-mediated attenuation of THC-induced effects may be observed when the ratio of CBD to THC is at least 8: 1, whereas CBD appears to potentiate some of the effects associated with THC when the CBD to THC ratio is around 2: 1. Some emerging pre-clinical evidence suggests combined anti-emetic sub-threshold doses of THC and CBD or cannabidiolic acid (CBDA) may be effective in animal models of acute nausea and/or anticipatory nausea (see for additional details).

Psychological and physiological effects associated with varying phytocannabinoid concentrations

A number of studies have examined the neurophysiological, cognitive, subjective, or behavioural effects of varying the concentrations of Δ ⁹-THC, CBD, or other cannabinoids such as CBC in smoked cannabis. In one study, 24 healthy men and women who had reported using cannabis at least 10 times in their lifetime were subjected to a double-blind, placebo-controlled, mixed between- and within-subject clinical trial that showed that deliberate systematic variations in the levels of either CBD or CBC in smoked cannabis were not associated with any significant differences in any of the measured subjective, physiological, or performance tests. In another study, the subjective effects associated with the smoked or oral administration of cannabis plant material were directly compared to those associated with smoked or oral administration of Δ ⁹-THC (using matched doses of Δ ⁹-THC) to normal, healthy subjects. This double-blind, placebo-controlled, within-subject, crossover clinical study reported few reliable differences between the THC-only and whole-plant cannabis conditions. The authors further concluded that other cannabinoids present in the cannabis plant material did not alter the subjective effects of cannabis, but they speculated that cannabis samples with higher levels of cannabinoids or different ratios of the individual cannabinoids could conceivably produce different results, although no evidence to support this claim was provided in the study. They also hypothesized that whole-plant cannabis and THC alone could differ on other outcome measures more relevant to clinical entities (e.g. spasticity or neuropathic pain). With the possible exception of one study, (see Section 4.7.2.3. Cancer Pain), which suggested differences between a whole-plant cannabis extract (i.e. nabiximols, marketed as Sativex ®) and THC alone on cancer pain analgesia, no other clinical studies have examined this possibility. One study compared the subjective and physiological effects of oral THC to those of nabiximols in normal, healthy subjects. The authors reported the absence of any modulatory effect of CBD (or other components of cannabis) at low therapeutic cannabinoid doses, with the potential exception of the subjective "high".

In summary, although it appears that CBD may modulate some of the behavioural effects of THC, further careful study is required to elucidate the influence of CBD, and other phytocannabinoids or terpenoids, on the physiological or psychological effects associated with the use of Δ ⁹-THC, as well as on any medical disorders.

Overview of pharmacological actions of cannabis

Most of the available information regarding the acute and long-term effects of cannabis use comes from studies conducted on non-medical users, with much less information available from clinical studies of patients using cannabis for medical purposes.

The acute effects of smoking or eating cannabis include euphoria (the marijuana "high") as well as cardiovascular, bronchopulmonary, ocular, psychological and psychomotor effects. Euphoria typically occurs shortly after smoking and generally takes longer with oral administration. However, some people can experience dysphoria and anxiety. Tachycardia is the most consistent of the acute physiological effects associated with the consumption of cannabis.

Table 1 (below), adapted from a review, notes some of the pharmacological effects of cannabis in the therapeutic dosage range. Many of the effects are biphasic, with increased activity with acute or smaller doses, and decreased activity with larger doses or chronic use. Effects differ greatly among individuals and may be greater in those who are young, severely ill, elderly, or in those taking other drugs.

Body System/Effect

Detail of Effects

Central Nervous System (CNS)

Euphoria ("high"), dysphoria, anxiety, depersonalization, precipitation or aggravation of psychosis, schizophrenia or bipolar disorder (esp. in vulnerable individuals) and suicidal ideation/attempts (esp. among men), limited and mixed evidence in PTSD, mixed evidence for amotivational syndrome.

Heightened sensory perception, distortion of space and time sense, hallucinations, misperceptions.

Fragmentation of thoughts, mental clouding (attention and concentration), memory impairment/amnesia, global impairment of performance especially in complex and demanding tasks and additive effect with other CNS depressants (e.g. alcohol).

Anti-epileptiform and anti-convulsive properties with CBD (and possibly also with CBDV and THCV). Mixed pro- and anti-epileptiform and pro- and anti-convulsive effects with THC.

Observed with acute doses. Tolerance may occur with chronic use. Conversely, nausea and/or vomiting may also be observed with use for medical purposes. Hyperemesis has also been observed with larger doses or chronic use in non-medical contexts.

To most behavioural and somatic effects, including the "high" (with chronic use).

Cardiovascular and Cerebrovascular System

Tachycardia with acute dosing; tolerance developing with chronic exposure. Premature ventricular contractions, palpitations, atrial fibrillation, ventricular arrhythmia also seen with acute doses.

Increased risk of experiencing stroke after an acute episode of smoking cannabis.

Carcinogenesis/mutagenesis

(Section 7.1)

Cannabis smoke contains many of the same chemicals as tobacco smoke, and cannabis smoke condensates are more cytotoxic and mutagenic than condensates from tobacco smoke. Conflicting evidence linking cannabis smoking and cancer. Possible link between cannabis smoking and testicular cancer.

Respiratory System

Acute THC exposure causes dilatation; possibly reversed with chronic exposure (by smoking). Smoked/vapourized cannabis may worsen asthmatic symptoms.

Acute, low-level exposure possibly stimulatory; long-term, heavy smoking possibly associated with decreased lung function.

Gastrointestinal System

Increased risk of hepatic steatosis/fibrosis, especially in patients with Hepatitis C. Increased Hepatitis C treatment adherence resulting in a potential sustained absence of detectable levels of Hepatitis C virus.

Risk of acute pancreatitis with chronic, daily, heavy use.

Musculoskeletal system

(Section 4.9.2)

Limited evidence for decreased intraocular pressure.

Immune System

Reproductive System

2.2 Pharmacokinetics

This section covers human pharmacokinetics of smoked and vapourized cannabis, oral preparations including prescription cannabinoid medicines such as dronabinol (Marinol ®) and nabiximols (Sativex ®), and other routes of administration (e.g. rectal, topical). See (below) for a graphical representation of the pharmacokinetics of THC.

Figure 2. Pharmacokinetics of THC (and other cannabinoids). Figure adapted fromReference 400.

THC (and other cannabinoids) can be administered by inhalation (e.g. smoking/vapourizing), orally (e.g. edibles, capsules, sprays), rectally (e.g. suppositories) or dermally (e.g. topicals) resulting in absorption through the lung, intestine, colon or skin. The concentration of THC (and other cannabinoids) in the extracellular water varies depending on serum protein binding (lipoproteins, albumin), tissue storage (fat, protein), metabolism (hepatic microsomal, non-microsomal, extrahepatic), biliary excretion (enterohepatic recirculation) and renal excretion (glomerular filtration, tubular secretion, passive reabsorption). The metabolism of THC (and other cannabinoids) produces metabolites which can also be found in the extracellular water. The concentration of THC in the extracellular water affects the THC (and other cannabinoids) concentration at the site of action. The effects of THC (and other cannabinoids) are observed when THC (and other cannabinoids) interacts with cannabinoid receptors or other targets of action. THC (and other cannabinoids) can also be detected in hair, saliva and sweat.

2.2.1 Absorption

2.2.1.1 Smoked cannabis

Smoking cannabis results in more rapid onset of action (within minutes), higher blood levels of cannabinoids, and a shorter duration of acute pharmacodynamic effects compared to oral administration. The amount of Δ ⁹-THC (and other cannabinoids) delivered from cannabis cigarettes is not uniform and is a major variable in the assessment of absorption. Uncontrolled factors include the source of the plant material and the composition of the cigarette/joint, together with the efficiency and method of smoking used by the subject. While it has been reported that smokers can titrate their Δ ⁹-THC intake, to a certain extent, by adapting their smoking behaviour to obtain desired levels of Δ ⁹-THC, other reasons may also explain the observed variation in smoking topography. As mentioned, Δ ⁹-THC absorption by inhalation is extremely rapid but quite variable, with a bioavailability of 2 to 56% through the smoking route depending on depth of inhalation, puff duration, and breathhold. In practice, a maximum of 25 to 27% of the THC content in a cannabis cigarette is absorbed or delivered to the systemic circulation from the total available amount. It has been estimated that between 2 and 44 µg of THC penetrates the brain following smoking of a cannabis cigarette containing 2 to 22 mg of THC (e.g. 1 g joint containing 0.2 - 2.2% THC, delivering between 0.2 and 5.5 mg of THC based on a smoked bioavailability of 10 to 25%).

The relationships between cannabis Δ ⁹-THC content, dose administered, and resultant plasma levels have been investigated. Mean plasma Δ ⁹-THC concentrations were 7.0 ng/mL and 18.1 ng/mL upon a single inhalation of either a 1.75% "low-dose" Δ ⁹-THC cannabis cigarette (total available dose ~16 mg Δ ⁹-THC), or a 3.55% Δ ⁹-THC "high-dose" cannabis cigarette (total available dose ~34 mg Δ ⁹-THC). Smoking cannabis containing 1.64% Δ ⁹-THC (mean available dose 13.0 mg Δ ⁹-THC) resulted in mean peak THC plasma levels of 77 ng/mL. Similarly, smoking cannabis joints containing 1.8% Δ ⁹-THC (total available dose ~14 mg Δ ⁹-THC) resulted in mean peak plasma THC levels of approximately 75 ng/mL, whereas with 3.6% Δ ⁹-THC (total available dose ~28.8 mg Δ ⁹-THC), mean peak plasma Δ ⁹-THC levels of 100 ng/mL were attained. Smoking a 25 mg dose of cannabis in a pipe containing 2.5, 6, or 9.4% Δ ⁹-THC (total available doses of ~0.6, 1.5, or 2.4 mg Δ ⁹-THC) was associated with mean peak plasma Δ ⁹-THC concentrations of 10, 25, or 45 ng/mL Δ ⁹-THC, respectively. Smoking one cannabis cigarette (800 mg) containing 6.8% THC, (w/w) yielding a total THC content of 54 mg per cigarette was associated with a median whole blood peak THC concentration of approximately 60 ng/mL Δ ⁹-THC (occurring 15 min after starting smoking). Compared to the data available for absorption with smoked THC, there is far less such information available for smoked CBD. In one early clinical study, smoking one cannabis cigarette containing 19 mg CBD (~2.4% CBD) was associated with a mean peak blood plasma level of CBD of 110 ng/mL (range: 42 - 191 ng/mL) at 3 min post-dose. The estimated systemic bioavailability of CBD by smoking was 31 % (range: 11 - 45%), generally similar to that seen with Δ ⁹-THC.

2.2.1.2 Vapourized cannabis

Vapourization of cannabis has been explored as an alternative to smoking. The potential advantages of vapourization include the formation of a smaller quantity of toxic by-products such as carbon monoxide, polycyclic aromatic hydrocarbons, and tar, as well as a more efficient extraction of Δ ⁹-THC (and CBD) from the cannabis material. The subjective effects and plasma concentrations of Δ ⁹-THC obtained by vapourization of cannabis are comparable to those obtained by smoking cannabis. In addition, the study reported that vapourization was well tolerated with no reported adverse effects, and was preferred over smoking by the test subjects. While vapourization has been reported to be amenable to self-titration (as has been claimed for smoking), the proper use of the vapourizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detail. The amount and type of cannabis placed in the vapourizer, the vapourizing temperature and duration of vapourization, and, in the case of balloon-type vapourizers, the balloon volume are some of the parameters that can affect the delivery of Δ ⁹-THC and other phytocannabinoids. Bioequivalence of vapourization compared to smoking has not been thoroughly established. Inhalation of vapourized cannabis (900 mg of 3.56% Δ ⁹-THC; total available dose of 32 mg of Δ ⁹-THC) in a group of patients taking stable doses of sustained-release morphine or oxycodone resulted in mean plasma Δ ⁹-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ ⁹-THC at 10 min, and reaching 6.4 ng/mL Δ ⁹-THC at 60 min. Peak Δ ⁹-THC concentration (C max) was achieved at 3 min in all study participants. No statistically significant changes were reported for the AUC ₁₂ (12-hour area-under-the-curve) for either morphine or oxycodone, but there appeared to be a statistically significant decrease in the C max of morphine sulfate, and a delay in the time needed to reach C max for morphine during cannabis exposure. One clinical study reported that vapourizing 500 mg cannabis containing low-dose (2.9%) THC (~14.5 mg THC), or high-dose (6.7%) THC (~33.5 mg THC) was associated with median whole-blood C max values of 32.7 (low-dose) and 42.2 ng/mL (high-dose) THC, and median plasma C max values of 46.5 (low-dose) and 62.1 ng/mL (high-dose) THC at 10 min post-inhalation respectively. Median whole-blood C max values for 11-hydroxy-THC were 2.8 (low-dose) and 5.0 ng/mL (high-dose) and median plasma C max values were 4.1 (low-dose) and 7 ng/mL (high-dose) at 10 - 11 min post-inhalation respectively. Another clinical study reported that vapourizing cannabis with 11 - 12% THC content (administered dose of 300 µg/kg) was associated with mean plasma concentrations of 73.8 ng/mL THC and 6.9 ng/mL 11-hydroxy-THC 5 min post-vapourization. A different clinical study showed that inhalation of 8 to 12 puffs of vapourized cannabis containing either 2.9% or 6.7% THC (400 mg each) was associated with a blood plasma C max of 68.5 ng/mL and 177.3 ng/mL respectively and median blood plasma concentration of 23 and 47 ng/mL respectively. Plasma C max of 11-hydroxy-THC was 5.6 and 12.8 ng/mL for the 2.9 and 6.7% doses, respectively.

2.2.1.3 Oral

For orally administered prescription cannabinoid medicines such as synthetic Δ ⁹-THC (dronabinol, formerly marketed as Marinol ®), only 10 to 20% of the administered dose enters the systemic circulation indicating extensive hepatic first-pass metabolism. Administration of a single 2.5 mg dose of dronabinol in healthy volunteers was associated with a mean plasma Δ ⁹-THC C max of 0.7 ng/mL (range: 0.3 - 1 ng/mL), and a mean time to peak plasma Δ ⁹-THC concentration of 2 h (range: 30 min - 4 h). A single 5 mg dose of dronabinol gave a reported mean plasma Δ ⁹-THC C max of 1.8 ng/mL (range: 0.4 - 3.3 ng/mL), whereas a single 10 mg dose yielded a mean plasma Δ ⁹-THC C max of 6.2 ng/mL (range: 3.5 - 9 ng/mL). Again, the mean time to peak plasma Δ ⁹-THC concentration ranged from 30 min to 3 h. Twice daily dosing of dronabinol (individual doses of 2.5 mg, 5 mg, 10 mg, b.i.d.) in healthy volunteers yielded plasma Δ ⁹-THC C max values of 1.3 ng/mL (range: 0.7 - 1.9 ng/mL), 2.9 ng/mL (range: 1.2 - 4.7 ng/mL), and 7.9 ng/mL (range: 3.3 - 12.4 ng/mL), respectively, with a time to peak plasma Δ ⁹-THC concentration ranging between 30 min and 4 h after oral administration. Continuous dosing for seven days with 20 mg doses of dronabinol (total daily doses of 40 - 120 mg dronabinol) gave mean plasma Δ ⁹-THC concentrations of ~20 ng/mL.

A phase I study evaluating the pharmacokinetics of three oral doses of THC (3 mg, 5 mg and 6.5 mg) in 12 healthy older subjects (mean age 72, range: 65 - 80 years) showed wide inter-individual variation in plasma concentrations of THC and 11-hydroxy-THC. For those subjects who reached C max within 2 hours, the mean THC concentration was 1.42 ng/mL (range: 0.53 - 3.48 ng/mL) for the 3 mg dose, 3.15 ng/mL (range: 1.54 - 6.95 ng/mL) for the 5 mg dose, and 4.57 ng/mL (range: 2.11 - 8.65 ng/mL) for the 6.5 mg dose.

A randomized, double-blind, placebo-controlled, cross-over trial that evaluated the pharmacokinetics of oral THC in 10 older patients with dementia (mean age 77 years) over a 12-week period reported that median time to reach C max (T max) was between one and two hours with THC pharmacokinetics increasing linearly with increasing dose, but again with wide inter-individual variation. Patients received 0.75 mg THC orally twice daily over the first six weeks and 1.5 mg THC twice daily over the second six-week period. The mean C max after the first 0.75 mg THC dose was 0.41 ng/mL and after the first 1.5 mg THC dose was 1.01 ng/mL. After the second dose of 0.75 mg THC or 1.5 mg THC, the C max was 0.50 and 0.98 ng/mL respectively.

Δ ⁹-THC can also be absorbed orally by ingestion of foods containing cannabis (e.g. butters, oils, brownies, cookies), and teas prepared from leaves and flowering tops. Absorption from an oral dose of 20 mg Δ ⁹-THC in a chocolate cookie was described as slow and unreliable, with a systemic availability of only 4 to 12%. While most subjects displayed peak plasma Δ ⁹-THC concentrations (6 ng/mL) between one and two hours after ingestion, some of the 11 subjects in the study only peaked at 6 h, and many had more than one peak. Consumption of cannabis-laced brownies containing 2.8% Δ ⁹-THC (44.8 mg total Δ ⁹-THC) was associated with changes in behaviour, although the effects were slow to appear and variable. Peak effects occurred 2.5 to 3.5 h after dosing. Modest changes in pulse and blood pressure were also noted. Plasma concentrations of Δ ⁹-THC were not measured in this study. In another study, ingestion of brownies containing a low dose of Δ ⁹-THC (9 mg THC/brownie) was associated with mean peak plasma Δ ⁹-THC levels of 5 ng/mL. Ingestion of brownies containing a higher dose of Δ ⁹-THC (~13 mg Δ ⁹-THC/brownie) was associated with mean peak plasma Δ ⁹-THC levels of 6 or 9 ng/mL depending on whether the THC in the brownie came from plant material or was added as pure THC. Using equivalent amounts of Δ ⁹-THC, inhalation by smoking cannabis yielded peak plasma levels of Δ ⁹-THC several-fold (five to six times or more) higher than when Δ ⁹-THC was absorbed through the oral route. Tea made from dried cannabis flowering tops (19.1% Δ ⁹-THCA, 0.6% Δ ⁹-THC) has been documented, but the bioavailability of Δ ⁹-THC from such teas is likely to be smaller than that achieved by smoking because of the poor water solubility of Δ ⁹-THC and the extensive hepatic first-pass effect.

While cannabinoids are lipophilic and anecdotal evidence suggests that cannabinoids dissolve better in fats and oils, the influence of various fats on cannabinoid absorption in vivo has been poorly studied. A pre-clinical study examined the effect of dietary fats on THC and CBD absorption in in rats. A dose of 12 mg/kg of THC or CBD in either lipid-free formulation or lipid long-chain triglycerides (LCT)-based formulation (sesame oil) was administered to rats by oral gavage. The absolute bioavailability of THC was 2.5 times higher in the lipid-based (C max = 172 ng/mL; AUC = 1050 h.ng/mL) versus lipid-free formulation (C max = 65 ng/mL; AUC = 414 h.ng/mL). The absolute bioavailability of CBD was three times higher in the lipid-based (C max = 308 ng/mL; AUC = 932 h.ng/mL) versus lipid-free formulation (C max = 87 ng/mL; AUC = 327 h.ng/mL). Furthermore, an in vitro lipolysis model was used to assess the mechanism by which lipids could enhance the bioavailability of THC and CBD. Results showed that 30% of THC and CBD was solubilized in the micellar layer and therefore was readily available. Incubation studies suggested that cannabinoids have a 70 to 80% association range with natural chylomicrons from rat and human. Chylomicrons act as carriers in the intestine and potentially transfer THC and CBD to the systemic circulation via the intestinal lymphatic system and therefore avoid hepatic first-pass metabolism, which would explain the increased bioavailability with the lipid-based formulation. The authors concluded that administration of cannabinoids with a fatty meal or in the form of a lipid-rich cannabis-containing cookie may increase systemic exposure and therefore change the efficacy of the drug by turning a barely effective dose into a highly effective one, or even, a therapeutic dose into a toxic one.
Comparing smoked, vapourized and oral administration
A randomized, double-blind, placebo-controlled, double-dummy, cross-over clinical study examined the pharmacokinetics of THC and its phase I and II metabolites between frequent and occasional cannabis smokers after smoked, vapourized and oral cannabis administration. Cannabis plant material (800 mg) containing 6.9% THC and 0.20% CBD was used, delivering a maximal THC dose of 51 mg and a maximal CBD dose of 1.5 mg. Vapourization was carried out using the Volcano ® vapourizer (210 °C). Cannabis was administered orally by ingestion of cannabis-containing brownies. In frequent cannabis smokers (≥ five times per week over previous three months), the mean baseline-adjusted THC C maxafter smoking was 151 ng/mL, after vapourization it was 85 ng/mL, and after oral consumption it was 15 ng/mL. Mean T max was 7 min (smoking), 5 min (vapourization), and 2.5 h (oral). The mean AUC 0-72 h (ug ∙ h/L) was 200 (smoking), 174 (vapourization), and 167 (oral). In occasional cannabis smokers (> two times per month but ≤ three times per week), the mean baseline-adjusted THC C max after smoking was 52 ng/mL, after vapourization it was 48 ng/mL, and after oral consumption it was 10 ng/mL. Mean T max was 7 min (smoking), 7 min (vapourization), and 2.3 h (oral). The mean AUC 0-72 h (ug ∙ h/L) was 20 (smoking), 12 (vapourization), and 43 (oral). In frequent cannabis smokers, the mean baseline-adjusted 11-hydroxy-THC C max after smoking was 9 ng/mL, after vapourization it was 5 ng/mL, and after oral consumption it was 7 ng/mL. Mean T max was 13 min (smoking), 11 min (vapourization), and 2.3 h (oral). The mean AUC 0-72 h (ug ∙ h/L) was 31 (smoking), 27 (vapourization), and 52 (oral). In occasional cannabis smokers, mean baseline-adjusted C max after smoking was 3 ng/mL, after vapourization it was 2 ng/mL, and after oral consumption, it was 5 ng/mL. Mean T maxwas 13 min (smoking), 6 min (vapourization), and 2.4 h (oral). The mean AUC 0-72 h (ug ∙ h/L) was 3 (smoking), 2 (vapourization), and 33 (oral). These findings suggest, among other things, that peak blood THC concentration (THC C max) was significantly lower after oral consumption compared to either route of inhalation and time to peak blood THC concentration (T max) occurred significantly later for oral consumption compared to inhalation for both frequent and occasional cannabis smokers. In addition, C max was significantly higher for the smoking route compared to vapourization, but only among frequent cannabis smokers. In addition, THC C max values were significantly greater among frequent smokers compared to occasional smokers after smoking and vapourization only, and 11-hydroxy-THC C max values were significantly greater among frequent smokers regardless of route of administration.

2.2.1.4 Oro-mucosal and intranasal

Following a single oro-mucosal administration of nabiximols (Sativex ®) (four sprays totalling 10.8 mg Δ ⁹-THC and 10 mg CBD), mean peak plasma concentrations of both THC (~5.5 ng/mL) and CBD (~3 ng/mL) typically occur within 2 to 4 h, although there is wide inter-individual variation in the peak cannabinoid plasma concentrations and in the time to onset and peak of effects. When administered oro-mucosally, blood levels of Δ ⁹-THC and other cannabinoids are lower than those achieved by inhalation of the same dose of smoked cannabis, but Δ ⁹-THC blood levels are comparable to those seen with oral administration of dronabinol. Oro-mucosal administration of nabiximols is also amenable to self-titration.

A small number of pre-clinical studies have explored intranasal administration of both THC and CBD. In one study in rabbits, intranasal administration of a 1 mg/kg dose of THC in a liquid solution or in a chitosan-based gel formulation produced a C max of 20 ng/mL and 31 ng/mL, with T max of 20 and 45 min respectively, compared to intravenous administration where the C max and T max were 1475 ng/mL and 0 min respectively. In rats, intranasal administration of 200 µg/kg CBD in various formulations yielded C max values ranging from 20 - 35 ng/mL with T max values ranging between 20 and 30 min; by comparison, intravenous administration yielded a C max of 3 596 ng/mL.

2.2.1.5 Rectal

While Δ ⁹-THC itself is not absorbed through the rectal route, the pro-drug Δ ⁹-THC-hemisuccinate is absorbed; this fact, combined with decreased first-pass metabolism through the rectal route, results in a higher bioavailability of Δ ⁹-THC by the rectal route (52 - 61%) than by the oral route. Plasma concentrations of Δ ⁹-THC are dose and vehicle-dependent, and also vary according to the chemical structure of the THC ester. In humans, rectal doses of 2.5 to 5.0 mg of the hemisuccinate ester of Δ ⁹-THC were associated with peak plasma levels of Δ ⁹-THC ranging between 1.1 and 4.1 ng/mL within 2 to 8 h, and peak plasma levels of carboxy-Δ ⁹-THC ranging between 6.1 and 42.0 ng/mL within 1 to 8 h after administration.

2.2.1.6 Topical

Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion process. No clinical studies have been published regarding the percutaneous absorption of cannabis-containing ointments, creams, or lotions. However, some pre-clinical research has been carried out on transdermal delivery of synthetic and natural cannabinoids using a dermal patch. A patch containing 8 mg of Δ ⁸-THC yielded a mean steady-state plasma concentration of 4.4 ng/mL Δ ⁸ -THC within 1.4 h in a guinea pig model, and this concentration was maintained for at least 48 h. Permeation of CBD and CBN was found to be 10-fold higher than for Δ ⁸-THC. Transdermal application of a gel containing CBD with or without permeation enhancers in hairless guinea pigs showed that C max without the enhancer was 9 ng/mL, and 36 ng/mL with the enhancer, and that maximal concentrations (T max) were reached by 38 and 31 h post-application, respectively. Furthermore, steady-state concentrations were 6 and 24 ng/mL without and with the permeation enhancer, respectively. Another pre-clinical study of a transdermal CBD gel formulation (1% or 10%) applied with increasing daily dose of 0.6, 3.1, 6.2 and 62 mg/day yielded plasma concentrations of 4 ng/mL, 18 ng/mL, 33 ng/mL, and 1 630 ng/mL respectively. Lastly, a pre-clinical study conducted with a 1% CBD cream reported a C max of 8 ng/mL, a T max of 38 h, and a steady-state plasma concentration of 6 ng/mL.

2.2.2 Distribution

Distribution of Δ ⁹-THC is time-dependent and begins immediately after absorption. Due to its lipophilicity, it is taken up primarily by fatty tissues and highly perfused organs such as the brain, heart, lung, and liver. Δ ⁹-THC has a large apparent volume of distribution, approximately 10 L/kg, because of its high lipid solubility. The apparent average volume of distribution of CBD is 32.7 L/kg (higher than THC) owing also to its very high lipid solubility. CBN has an even higher volume of distribution, 50 L/kg. The plasma protein binding of Δ ⁹-THC and its metabolites is approximately 97%. Δ ⁹-THC is mainly bound to low-density lipoproteins (LDL), with up to 10% present in red blood cells, while the metabolite, 11-hydroxy-THC is strongly bound to albumin with only 1% found in the free-fraction.

The highest concentrations of Δ ⁹-THC are found in the heart and in adipose tissue, with levels reaching 10 and 1 000 times that of plasma, respectively. Despite the high perfusion level of the brain, the blood-brain barrier appears to limit the access and accumulation of Δ ⁹-THC in this organ, and the delay in correlating peak plasma concentration to psychoactive effects may be attributed, in part, to the time required for Δ ⁹-THC to traverse this barrier. Pre-clinical studies in mice suggest a more rapid penetration of 11-hydroxy-THC into the brain compared to the parent compound, on the order of 6: 1 for 11-hydroxy-THC to THC.

As mentioned, Δ ⁹-THC accumulates and is retained in fatty tissue, and its release from this storage site into the blood is slow. It is also not entirely certain if Δ ⁹-THC persists in the brain (a highly fatty tissue) in the long-term; however, the presence of residual cognitive deficits in abstinent heavy cannabis users suggests this may be the case, at least in the short-term. A study that characterized cannabinoid elimination in blood from 30 male daily cannabis smokers during monitored sustained abstinence for up to 33 days on a closed residential unit found that both THC and its inactive metabolite 11-nor-9-carboxy Δ ⁹-THC were detected in blood up to one month after last smoking, which was reported by the authors as being four times longer than previously described. This finding lends further support to the evidence on the distribution, accumulation, and storage of THC (and metabolites) in the adipose tissue and the slow release of THC (and metabolites) from adipose tissue stores back into the bloodstream. Residual THC in plasma (likely coming from bodily adipose stores) detected weeks after last smoking episode may be associated with persisting psychomotor impairment in frequent chronic cannabis smokers according to the study authors. Lastly, one animal study suggested food deprivation or adrenocorticotropic hormone (ACTH) administration in rats accelerates lipolysis and the release of Δ ⁹-THC from fat stores, however further research is needed to determine if these effects are associated with subsequent intoxication or behavioural/cognitive changes.

2.2.3 Metabolism

Most cannabinoid metabolism occurs in the liver, and different metabolites predominate depending on the route of administration. The complex metabolism of Δ ⁹-THC involves allylic oxidation, epoxidation, decarboxylation, and conjugation. Δ ⁹-THC is oxidized by the xenobiotic-metabolizing cytochrome P450 (CYP) mixed-function oxidases 2C9, 2C19, and 3A4. The major initial metabolites of Δ ⁹-THC are the active 11-hydroxy Δ ⁹-THC, and the non-active 11-nor-9-carboxy Δ ⁹-THC. The psychoactive 11-hydroxy Δ ⁹-THC is rapidly formed by the action of the above-mentioned hepatic microsomal oxidases, and plasma levels of this metabolite parallel the duration of observable drug action.

Xenobiotics are not only metabolized by CYPs but they also modulate the expression level and activity of these enzymes; CYPs are therefore a focal point in drug-drug interactions and adverse drug reactions. Polyaromatic hydrocarbons found in tobacco and cannabis smoke induce the expression of CYP1A2, while Δ ⁹-THC, CBD, and CBN inhibit the activity of the CYP1A1, 1A2, 1B1 and 2A6 enzymes. CBD has also been shown to inhibit the formation of Δ ⁹-THC metabolites catalyzed by CYP3A4, with less effect on CYP2C9, albeit sufficiently to decrease the formation of 11-hydroxy-THC. Please see for more detailed information.

Results from in vitro experiments also suggest that Δ ⁹-THC inhibits CYP3A4, CYP3A5, CYP2C9, and CYP2C19, while CBD inhibits CYP2C19, CYP3A4, and CYP3A5; however, higher concentrations than those seen clinically appear to be required for inhibition. While few clinical studies have specifically sought to evaluate cannabis-drug interactions per se, many, if not most, studies investigating the therapeutic effects of cannabis (e.g. smoked, vapourized, or orally ingested) and cannabinoid-based medicines (e.g. dronabinol, nabilone, nabiximols) have used patients that were concomitantly taking other medications (e.g. nonsteroidal anti-inflammatory agents (NSAIDs), opioids, anti-depressants, anti-convulsants, protease inhibitors) and, in general, did not report significantly increased incidences of severe adverse effects associated with the combination of cannabis or cannabinoids and these other medications. Nevertheless, careful monitoring of patients who are concomitantly consuming cannabis/cannabinoids and other medications that are metabolized by the above-mentioned enzymes may be warranted. Please see for more detailed information.

The Sativex ® product monograph cautions against combining Sativex ® with amitriptyline or fentanyl (or related opioids) which are metabolized by CYP3A4 and 2C19. One clinical study that investigated the effects of rifampicin, ketoconazole, and omeprazole on the pharmacokinetics of THC and CBD delivered from Sativex ® reported that co-administration of rifampicin with Sativex ® is associated with slight decreases in the plasma levels of THC, CBD and 11-hydroxy-THC, while co-administration of ketoconazole with Sativex ® is associated with slight increases in plasma levels of THC, CBD, and 11-hydroxy-THC. No significant effects on plasma levels of THC, CBD or 11-hydroxy-THC were noted with omeprazole.

In addition, and as seen with tobacco smoke, cannabis smoke has the potential to induce CYP1A2 thereby increasing the metabolism of xenobiotics biotransformed by this isozyme such as theophylline or the anti-psychotic medications clozapine or olanzapine. Further detailed information on drug-drug interactions can be found in .

2.2.3.1 Inhalation

Plasma values of 11-hydroxy-THC appear rapidly and peak shortly after Δ ⁹-THC, at about 15 min after the start of smoking. Peak plasma concentrations of 11-hydroxy-THC are approximately 5% to 10% of parent THC, and the AUC profile of this metabolite averages 10 to 20% of the parent THC. Similar results were obtained with intravenous THC administration. Following oxidation, the phase II metabolites of the free drug or hydroxylated-THC appear to be glucuronide conjugates.

2.2.3.2 Oral

In contrast to the limited metabolism of Δ ⁹-THC to the 11-hydroxy metabolite through pulmonary administration, oral administration of Δ ⁹-THC results in a significantly greater metabolism of Δ ⁹-THC to the 11-hydroxy metabolite resulting in similar plasma concentrations of Δ ⁹-THC and 11-hydroxy Δ ⁹-THC through the oral route. The plasma levels of active 11-hydroxy metabolite, achieved through oral administration, are about three times higher than those seen with smoking. Furthermore, 11-hydroxy- Δ ⁹-THC has been reported to be as psychoactive or even more psychoactive than the parent THC. Concentrations of both parent drug and metabolite peak between approximately 2 to 4 h after oral dosing, and decline over several days.

Information from the dronabinol (Marinol ®) product monograph suggests that single doses of 2.5 mg, 5 mg, and 10 mg of Δ ⁹-THC in healthy volunteers result in mean plasma C max values of 11-hydroxy Δ ⁹-THC of 1.19 ng/mL (range: 0.4 - 1.9 ng/mL), 2.23 ng/mL (range: 0.7 - 3.7 ng/mL), and 7.51 ng/mL (range: 2.25 - 12.8 ng/mL), respectively. Twice daily dosing of dronabinol (individual doses of 2.5 mg, 5 mg, 10 mg, b.i.d.) in healthy volunteers resulted in mean plasma C max values of 1.65 ng/mL (range: 0.9 - 2.4 ng/mL), 3.84 ng/mL (range: 1.5 - 6.1 ng/mL), and 7.95 ng/mL (range: 4.8 - 11.1 ng/mL) of 11-hydroxy Δ ⁹-THC, respectively. Time to reach C max for 11-hydroxy Δ ⁹-THC ranged from 30 min to 4 h, with a mean of approximately 2.5 h. As stated above, 11-hydroxy Δ ⁹-THC has psychotomimetic properties equal to or greater than those of Δ ⁹-THC.

2.2.4 Excretion

Δ ⁹-THC and CBD levels in plasma decrease rapidly after cessation of smoking. Mean THC plasma concentrations are approximately 60% and 20% of peak plasma THC concentrations 15 and 30 min post-smoking, respectively, and are below 5 ng/mL THC 2 h after smoking, although mean serum THC concentrations may be slightly higher when smoking higher THC potency cigarettes. One study showed that CBD levels fall to below 5 ng/mL in the plasma about 2.5 h after smoking a 19 mg CBD cigarette.

Following smoking, elimination of THC and its metabolites occurs via the feces (65%) and the urine (20%). Whole-body clearance of Δ ⁹-THC and its hydroxy metabolite averages about 0.2 L/kg-h, but is highly variable due to the complexity of cannabinoid distribution. The psycho-inactive 11-nor-9-carboxy Δ9-THC is the primary acid metabolite of Δ9-THC excreted in urine and it is the cannabinoid often screened for in forensic analysis of body fluids. A study that characterized cannabinoid elimination in blood from 30 male daily cannabis smokers during monitored sustained abstinence for up to 33 days on a closed residential unit found that low levels (approx. < 1 ng/mL) of both THC and its inactive metabolite 11-nor-9-carboxy THC were detected in blood up to one month after last smoking, which was reported by the authors as being four times longer than previously described.

The decline of Δ ⁹-THC levels in plasma is multi-phasic, and the estimates of the terminal half-life of Δ ⁹-THC in humans have progressively increased as analytical methods have become more sensitive. While figures for the terminal elimination half-life of Δ ⁹-THC appear to vary, it is probably safe to say that it averages at least four days and could be considerably longer. The variability in terminal half-life measurements are related to the dependence of this measure on assay sensitivity, as well as on the duration and timing of blood measurements. Low levels of THC metabolites have been detected for more than five weeks in the urine and feces of cannabis users. The degree of Δ ⁹-THC consumption does not appear to influence the plasma half-life of Δ ⁹-THC.

2.3 Pharmacokinetic-pharmacodynamic relationships

Much of the information on cannabinoid pharmacokinetic-pharmacodynamic relationships (mostly on Δ ⁹-THC) is derived from studies of non-medical cannabis use rather than from studies looking at therapeutic use, but in either case, this relationship depends to some extent on the point in time at which observations are made following the administration of the cannabinoid. Furthermore, the temporal relationship between plasma concentrations of Δ ⁹-THC and the associated clinical/therapeutic, psychotropic, cognitive and motor effects is not well established. But it is known that these effects often lag behind the plasma concentrations of Δ ⁹-THC, and tolerance is known to develop to some of the effects but not to others (See Tolerance and Dependence).

As mentioned above, the relationship between dose (and plasma concentration) versus response for possible therapeutic applications is ill-defined, except for some information obtained for oral dosing with dronabinol (synthetic Δ ⁹-THC, marketed as Marinol ® but no longer available in Canada), nabiximols (a botanical cannabis extract containing approximately equal concentrations of Δ ⁹-THC and CBD as well as other cannabinoids, terpenoids and flavonoids, marketed as Sativex ®), or nabilone (synthetic Δ ⁹-THC analog marketed as Cesamet ®) for their limited indications. More limited information is available for inhaled cannabis. Interpretations of the pharmacokinetics of Δ ⁹-THC are also complicated by the presence of active metabolites, particularly the potent psychoactive 11-hydroxy THC metabolite, which is found in higher concentration after oral administration than after inhalation.

Target Δ ⁹-THC plasma concentrations have been derived based on the subjective "high" response that may or may not be related to the potential therapeutic applications. Various pharmacodynamic models provide blood plasma concentration estimates in the range of 7 to 29 ng/mL Δ ⁹-THC necessary for the production of a 50% maximal subjective "high" effect. Other studies suggest that Δ ⁹-THC plasma concentrations associated with 50% of the maximum "high" effect range between 2 and 250 ng/mL Δ ⁹-THC (median of 19 ng/mL; mean of 43 ng/mL Δ ⁹-THC) for the smoked or intravenous routes, while for the oral route the values range between 1 and 8 ng/mL Δ ⁹-THC (median and mean of 5 ng/mL Δ ⁹-THC). Notably, impairment of driving performance is seen with plasma concentrations between 7 and 10 ng/mL (whole blood, approximately 3 - 5 ng/mL) and this blood THC concentration has been compared to a blood-alcohol concentration (BAC) of 0.05% which itself is associated with driver impairment.

Smoked cannabis

Simulation of multiple dosing with a 1% THC cigarette containing 9 mg Δ ⁹-THC yielded a maximal "high" lasting approximately 45 min after initial dosing, declining to 50% of peak at about 100 min following smoking. A dosing interval of 1 h with this dose would give a "continuous high", and the recovery time after the last dose would be 150 min (i.e. 2.5 h). The peak Δ ⁹-THC plasma concentration during this dosage is estimated at about 70 ng/mL.

One clinical study reported a peak increase in heart rate and perceived "good drug effect" within 7 min after test subjects smoked a 1 g cannabis cigarette containing either 1.8% or 3.9% THC (mean doses of Δ ⁹-THC being 18 mg or 39 mg in the cigarette, respectively). Compared to the placebo, both doses yielded statistically significant differences in subjective and physiological measures; the higher dose was also significantly different from the lower dose for subjective effects, but not physiological effects such as an effect on heart rate. Pharmacokinetic-pharmacodynamic modelling of the concentration-effect relationship of Δ ⁹-THC on CNS parameters and heart rate suggests that THC-evoked effects typically lag behind THC plasma concentration, with the effects lasting significantly longer than Δ ⁹-THC plasma concentrations. The equilibration half-life estimate for heart rate was approximately 7 min, but varied between 39 and 85 min for various CNS parameters. According to this model, the effects on the CNS developed more slowly and lasted longer than the effect on heart rate.

Vapourized cannabis

Inhalation of vapourized cannabis (900 mg of 3.56% Δ ⁹-THC; total available dose of 32 mg of Δ ⁹-THC) resulted in mean plasma Δ ⁹-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ ⁹-THC at 10 min, and reaching 6.4 ng/mL Δ ⁹-THC at 60 min. Peak Δ ⁹-THC concentration (C max) was achieved at 3 min in all study participants. Maximal subjective "high" ratings occurred at 60 min following beginning of inhalation.

One clinical study reported that ad libitum vapourization of 500 mg cannabis containing a low-dose (2.9%) of THC (~14.5 mg THC), or high-dose (6.7%) of THC (~33.5 mg THC) was associated with median whole-blood C max values of 32.7 (low-dose) and 42.2 ng/mL (high-dose) THC, and median plasma C max values of 46.5 (low-dose) and 62.1 ng/mL (high-dose) THC at 10 min post-inhalation. Median whole-blood C max values for 11-hydroxy-THC were 2.8 (low-dose) and 5.0 ng/mL (high-dose) and median plasma C max values were 4.1 (low-dose) and 7 ng/mL (high-dose) at 10 - 11 min post-inhalation. Subjective effects were then measured at several time points and effects were correlated with concentrations of cannabinoids in oral fluid and blood. Blood THC was positively associated with "high", "good drug effect", "stimulated", "stoned", "anxious", and "restless" and with feelings of altered time, "slowed/slurred speech", "dizziness", and "dry mouth/throat". There were no significant differences between the effects seen with the low (2.9%) and the high (6.7%) dose of cannabis. Vapourized cannabis significantly increased measures of "stoned" and "sedated" immediately post-dose and lasted 3.3 h (or 4.3 h with the addition of alcohol). Feelings of "anxious" showed significant cannabis-dose effects through 1.4 h. Undesirable effects, including "feeling thirsty" and "dry mouth/throat", increased for the first 3.3 h post-dose. "Difficulty concentrating" and "altered sense of time" produced mixed effects over 2.3 h. Effects and time course of effects were similar between vapourized and smoked cannabis.

Another study measured 17 different psychoactive effects as a function of THC dose and time in vapourized cannabis. In this randomized, double-blind, placebo-controlled clinical study, patients inhaled a total of 8 to 12 puffs of vapourized cannabis containing either 0%, 2.9% or 6.7% THC (400 mg each). The 2.9% dose was associated with a C max of 68.5 ng/mL and the 6.7% dose was associated with a C max of 177.3 ng/mL. Plasma 11-hydroxy-THC C max for the 2.9% dose was 5.6 ng/mL and for the 6.7% dose was 12.8 ng/mL. The lower dose produced effects lower than that for the high dose and placebo effects were lower than both active doses for "any drug effect", "good drug effect", "high", "impaired", "stoned", "sedated" and "changes perceiving space". For "bad drug effect", "like the drug", "nauseous", "changes perceiving time", ratings with placebo were significantly lower than both active doses. The higher dose (6.7%) was associated with significantly higher ratings of "desires more", "hungry", "difficulty remembering things", "drunk", "confused", and "difficulty paying attention" compared with placebo, with only "drunk", "confused" and "difficulty paying attention" significantly different between the high and low dose. There was a clear dose-response effect for the majority of psychoactive effects.

Oral and oro-mucosal cannabinoids

The subjective and physiological effects after controlled administration of oro-mucosal nabiximols (Sativex ®) or oral Δ ⁹-THC have also been compared. Increases in systolic blood pressure occurred with low (5 mg) and high (15 mg) oral doses of THC, as well as low (5.4 mg Δ ⁹-THC and 5 mg CBD) and high (16.2 mg Δ ⁹-THC and 15 mg CBD) oro-mucosal doses of nabiximols, with the effect peaking at around 3 h after administration. In contrast, diastolic blood pressure decreased between 4 and 8 h after dosing. Heart rate increased after all active treatments. A statistically significant increase in heart rate relative to placebo was observed after high-dose oral THC (15 mg Δ ⁹-THC) and high-dose oro-mucosal nabiximols (16.2 mg Δ ⁹-THC and 15 mg CBD), but the authors indicated that the increases appeared to be less clinically significant than those typically seen with smoked cannabis. High-dose oral THC (15 mg Δ ⁹-THC) and high-dose oro-mucosal nabiximols (16.2 mg Δ ⁹-THC and 15 mg CBD) were associated with significantly greater "good drug effects" compared to placebo, whereas low-dose oro-mucosal nabiximols (5.4 mg Δ ⁹-THC and 5 mg CBD) was associated with significantly higher "good drug effects" compared to 5 mg THC. A subjective feeling of a "high" was reported to be significantly greater after 15 mg oral THC compared to placebo and to 5 mg oral THC. In contrast, neither the high nor the low doses of oro-mucosal nabiximols were reported to produce a statistically significant subjective "high" feeling. Study subjects reported being most "anxious" approximately 4 h after administration of 5 mg oral THC, 3 h after 15 mg oral THC, 5.5 h after low-dose nabiximols, and 4.5 h after high-dose oro-mucosal nabiximols. All active drug treatments induced significantly more anxiety compared to placebo. After 15 mg oral THC, the concentration of THC in plasma was observed to have a weak, but statistically significant, positive correlation with systolic and diastolic blood pressure, "good drug effect", and "high". After high-dose oro-mucosal nabiximols, positive correlations were also observed between plasma THC concentrations and "anxious", "good drug effect", "high", "stimulated", and M-scale (marijuana-scale) scores. Consistent with other studies, the authors of this study reported that linear correlations between plasma THC concentrations and physiological or subjective effects were weak. Lastly, although CBD did not appear to significantly modulate the effects of THC, the authors suggested it might have attenuated the degree of the subjective "high".

2.4 Tolerance, dependence, and withdrawal symptoms

Tolerance

Tolerance to the effects of cannabis or cannabinoids appears to result mostly from pharmacodynamic rather than pharmacokinetic mechanisms. Pre-clinical studies indicate that pharmacodynamic tolerance is mainly linked to changes in the availability of the cannabinoid receptors, principally the CB ₁ receptor, to signal. There are two independent but interrelated molecular mechanisms producing these changes: receptor desensitization (or uncoupling of the receptor from intracellular downstream signal transduction events), and receptor downregulation (resulting from the internalization and/or degradation of the receptor). Furthermore, within the brain, these adaptations appear to vary across different regions suggesting cellular- and tissue-specific mechanisms regulating desensitization/downregulation. Studies have reported that CB ₁ receptors in the caudate-putamen and its projection areas (e.g. globus pallidus and substantia nigra) show the least magnitude of CB ₁ receptor desensitization and downregulation, whereas CB ₁ receptors in the hippocampus exhibit the greatest magnitude of desensitization and downregulation in response to chronic THC exposure. CB 1 receptors located in the striatum are also less susceptible to desensitization and downregulation relative to the hippocampus.

One clinical study showed that chronic cannabis use was associated with a global decrease in CB ₁ receptor availability in the brain with significant decreases in CB ₁ receptor availability in the temporal lobe, anterior and posterior cingulate cortices, and the nucleus accumbens. Study subjects were mostly male, had a mean age at onset of cannabis use of 16 years of age, a mean duration of cannabis use of 10 years, a mean amount of cannabis use of three joints per day, and 60% of the study subjects were considered heavy users (several times per day), 30% were moderate users (once per day to 3 - 4 times per week), and 10% used infrequently (two to three times per month or less). Furthermore, a couple of clinical studies have examined the time course of changes in the availability of CB ₁ receptors following chronic THC administration and abstinence. In the first study, heavy chronic daily cannabis smoking (average 10 joints/day for average of 12 years) was associated with reversible and regionally selective downregulation (20% decrease) of brain cortical (but not subcortical) cannabinoid CB ₁ receptors. In the second study, cannabis dependence (with chronic, moderate daily cannabis smoking) was associated with CB ₁ receptor downregulation (i.e. ~15% decrease at baseline, not under intoxication or withdrawal) compared to healthy controls. CB ₁ receptor downregulation began to reverse rapidly upon termination of cannabis use (within two days), and after 28 days of continuous monitored abstinence CB ₁ receptor availability was not statistically significantly different from that of healthy controls (although CB ₁ receptor availability never reached the levels seen with healthy controls). CB ₁ receptor availability was also negatively correlated with cannabis dependence and withdrawal symptoms.

Dependence and withdrawal

Psychological dependence

The National Epidemiological Survey on Alcohol and R elated Conditions ( NESARC), a large U.S. national prospective study conducted among 34 653 respondents examining the association between cannabis use and risk of mental health and substance use disorders in the U.S. general adult population, reported that cannabis use (at Wave 1, 2001 - 2002) was associated with later development (at Wave 2, 2004 - 2005) of substance use disorders (i.e. any substance use disorder: OR = 6.2, 95% CI = 4.1 - 9.4; any alcohol use disorder: OR = 2.7, 95% CI = 1.9 - 3.8; any CUD: OR = 9.5, 95% CI = 6.4 - 14.1; any other drug use disorder: OR = 2.6, 95% CI = 1.6 - 4.4; and nicotine dependence: OR = 1.7; 95% CI = 1.2 - 2.4), but not any mood disorder or anxiety disorder. Higher frequency of cannabis use was associated with greater risk of disorder incidence and prevalence, supporting a dose-response association between cannabis use and risk of substance use disorders.

Another study using the U.S. NESARC data (2012 - 2013) found that the odds of 12-month and lifetime CUD were higher for men, Native Americans, unmarried individuals, those with low incomes, and young adults (e.g. among those 18 - 24 years of age compared to those over 45, OR = 7.2, 95% CI = 5.5 - 9.5). Furthermore, 12-month CUD was associated with other substance use disorders (OR = 6.0 - 9.3), affective/mood disorders (OR = 2.7 - 5.0), anxiety disorders (OR = 1.7 - 3.7), and personality disorders (OR = 3.8 - 5.0). Survey respondents with 12-month CUD differed significantly from others on all disability components of the survey, with disability increasing significantly, as cannabis disorder severity increased. Among participants with 12-month DSM-5 CUD, 61% had craving for cannabis, 32% had cannabis withdrawal symptoms, and 23% had both.

Comparing data between the NESARC 2001 - 2002 (Wave 1) and 2012 - 2013 (Wave 2), one study reported that the prevalence of cannabis use more than doubled between the two waves of the survey. Furthermore, there was a large increase in CUD during this intervening time, with nearly 3 out of 10 cannabis users reporting a CUD in 2012 - 2013. Young adults were at highest risk of CUD in both survey waves (OR = 7.2 for ages 18 - 29; OR = 3.6 for ages 30 - 44) however, the relative increases in prevalence of CUD among adults aged 45 to 64 years and 65 years and older were much greater than the increases in young adults.

Physical dependence

Physical dependence is most often manifested in the appearance of withdrawal symptoms when use is abruptly halted or discontinued. Withdrawal symptoms associated with cessation of cannabis use (oral or smoked) appear within the first one to two days following discontinuation; peak effects typically occur between days 2 and 6 and most symptoms resolve within one to two weeks. The most common symptoms include craving, anger or aggression, irritability, anxiety, nightmares/strange dreams, insomnia/sleep difficulties, headache, restlessness, and decreased appetite or weight loss. Other symptoms appear to include depressed mood, chills, stomach pain, shakiness and sweating. Withdrawal symptoms are reported by up to one-third of regular users in the general population and by 50 - 95% in heavy users in treatment or in research studies. Cannabis withdrawal symptoms appear to be moderately inheritable with both genetic and environmental factors at play. There are also emerging reports of increased physical dependence with highly potent cannabis extracts (e.g. concentrates such as butane hash oil and dabs) (OR = 1.2, p = 0.014).

Cannabidiol for cannabis and other drug dependence

2.5 Special populations

Pediatric/Adolescent

The ECS is present in early development, is critical for neurodevelopment and maintains expression in the brain throughout life. Furthermore, the ECS undergoes dynamic changes during adolescence with significant fluctuations in both the levels and locations of the CB ₁ receptor in the brain as well as changes in the levels of the endocannabinoids 2-AG and anandamide. The dynamic changes occurring in the ECS during adolescence also overlap with a significant period of neuronal plasticity that includes neuronal proliferation, rewiring and synaptogenesis, and dendritic pruning and myelination that occurs at the same time. This period of significant neuroplasticity does not appear to be complete until at least the age of 25. Thus, this neurodevelopmental time window is critical for ensuring proper neurobehavioural and cognitive development and is also influenced by external stimuli, both positive and negative (e.g. neurotoxic insults, trauma, chronic stress, drug abuse). Based on the available scientific evidence, youths are more susceptible to the adverse effects associated with cannabis use, especially chronic use. Studies examining non-medical use of cannabis strongly suggest early onset (i.e. in adolescence and especially before age 15), regular and persistent cannabis use (of THC-predominant cannabis) is associated with a number of adverse effects on brain and behavioural development including CUD and addiction, other illicit drug use, compromised cognitive functioning and decreased IQ, deficits in attention, poorer educational attainment, suicidal ideation, suicide attempt, and increased risk of schizophrenia as well as an earlier onset of the latter disease. Based on the current available evidence, it is unclear for how long some or all of the neurocognitive effects persist following cessation of use. Some investigators have found certain cognitive deficits to persist for up to one year or longer after cannabis cessation, while others have demonstrated a far shorter period of recovery (i.e. 28 days) for at least some of the evidenced deficits. A recent literature review of observational and pre-clinical studies revealed consistent evidence of an association between adolescent cannabis use (frequent/heavy use) and persistent adverse neuropsychiatric outcomes in adulthood. Though the data from human studies do not establish causality solely from cannabis use, the pre-clinical studies in animals do indicate that adolescent exposure to cannabinoids can catalyze molecular processes leading to functional deficits in adulthood - deficits that are not found following adult exposure to cannabis. The authors note that definitive conclusions cannot be made yet as to whether cannabis use - on its own - negatively impacts the adolescent brain, and future research can help elucidate this relationship by integrating assessments of molecular, structural, and behavioral outcomes. Factors that may influence persistence of cognitive deficits can include age at onset of use, frequency and duration of use, co-morbidities, and use of other drugs (tobacco, alcohol, and other psychoactive drugs).

While adverse effects associated with THC-predominant cannabis use in youth have been well documented, far less is known about the adverse effects associated with CBD-predominant cannabis use. Nevertheless, as mentioned above, the ECS plays important roles in nervous system development in utero as well as during youth (see ) and exposure to exogenous cannabinoids, especially at higher doses, on a daily basis and over a protracted period of time may alter the course of neurodevelopment (see for additional information on the role of the ECS in the development of the nervous system).

Geriatric

There is evidence to suggest that like the changes seen with the ECS during development and adolescence, there are changes in the ECS associated with ageing. In rodents, there is a marked decline in the levels of CB ₁ mRNA and/or specific binding of CB ₁ agonists in the cerebellum, cortex, hippocampus and hypothalamus of older animals. In addition, the coupling of CB ₁ receptors to G proteins is also reduced in specific brain areas in older animals. Age-related changes in the expression of components of the ECS appear similar in rodents and humans. Disruption of CB receptors appears to enhance age-related decline of a number of tissues suggesting an important role for the ECS in the control of the ageing process.

Clinical Studies

A randomized, double-blind, placebo-controlled, cross-over clinical trial that evaluated the pharmacokinetics of THC in 10 older patients with dementia (mean age 77 years) over a 12-week period reported that the median time to reach maximal concentration in the blood (T max) was between 1 and 2 h with THC pharmacokinetics increasing linearly with increasing dose but with wide inter-individual variation. Patients received 0.75 mg THC twice daily over the first six weeks and 1.5 mg THC twice daily over the second six-week period. The mean C max after the first 0.75 mg THC dose was 0.41 ng/mL and after the first 1.5 mg THC dose was 1.01 ng/mL. After the second dose of 0.75 mg THC or 1.5 mg THC, the C max was 0.50 and 0.98 ng/mL respectively.

Only one clinical study has thus far been carried out looking specifically at the safety of THC in an elderly population. This phase I, randomized, double-blind, double-dummy, placebo-controlled, cross-over trial of three single oral doses of Namisol ®, a novel tablet form of THC (i.e. 3 mg, 5 mg, 6.5 mg THC) reported that, overall, the pharmacodynamic effects of THC in healthy older individuals were smaller than effects previously reported in young adults and that THC, at the doses tested, appeared to be well-tolerated by healthy older individuals. In this study, 12 adults aged 65 and older who were deemed to be healthy were included, and exclusion criteria included high falls risk, regular cannabis use, history of sensitivity to cannabis, drug and alcohol abuse, compromised cardiopulmonary function, and psychiatric comorbidities. The most commonly reported health problems were hypertension and hypercholesterolemia and subjects reported using an average of 2 medications (e.g. lipid-lowering drugs, aspirin, and beta-blockers). The most frequently reported adverse effects associated with THC were drowsiness (27%), dry mouth (11%), coordination disturbance (9%), headache (9%), difficulties concentrating (7%), blurred vision (5%), relaxation, euphoria and dizziness (5% each); nausea, dry eyes, malaise and visual hallucinations were all reported at a frequency of 2% in this trial. Adverse events first occurred within 20 min of dosing, with all adverse events occurring between 55 and 120 min after dosing and resolving completely within 3.5 h after dosing. There appeared to be a dose-dependent increase in the number of individuals reporting an increased number of adverse events with increasing doses of Namisol ®. No moderate or serious adverse events were reported in this trial. While this clinical study adds important information regarding the safety and tolerability of THC in a healthy elderly population, additional studies are needed to evaluate the safety and tolerability of cannabis and cannabinoids in elderly populations having various co-morbidities.

Sex-dependent effects

In humans, sex-dependent differences have been often observed in the biological and behavioural effects of substances of abuse, including cannabis. In male animals, higher densities of CB ₁ receptors have been observed in almost all cerebral regions analyzed whereas in females a more efficient coupling of the CB ₁ receptor to downstream G-protein signaling has been observed. In humans, sex differences in CB ₁ receptor density have also been reported, with men having higher receptor density compared to women. Sex-dependent differences have also been noted with respect to cannabinoid metabolism. Pre-clinical studies in females report increased metabolism of THC to 11-hydroxy-THC compared to males where THC was also biotransformed to at least three different, less active metabolites. There is also evidence to suggest that effects of cannabinoids vary as a function of fluctuations in reproductive hormones. Together, these findings suggest that the neurobiological mechanism underlying the sex-dependent effects of cannabinoids may arise from sexual dimorphism in the ECS and THC metabolism, but also from the effects of fluctuations in hormone levels on the ECS.

3.0 Dosing

The College of Family Physicians of Canada, along with other provincial medical regulatory colleges, has issued a guidance document (in 2018) for authorizing the use of cannabis for medical purposes. Please consult these and any other official guidance documents, as applicable, for additional information regarding dosing and other matters associated with authorizing cannabis for medical purposes.

While precise dosages have not been established, some "rough" dosing guidelines for smoked or vapourized cannabis have been published (see below). Besides smoking and vapourization, cannabis is known to be consumed in baked goods such as cookies or brownies, or drunk as teas or infusions. However, absorption of these products by the oral route is slow and erratic, varies with the ingested matrix (e.g. fat content), and the onset of effects is delayed with the effects lasting much longer compared to smoking (see ); furthermore, dosages for orally administered products are even less well established than for smoking/vapourization, however, some preliminary data has emerged for dosing with cannabis oils. Other forms of preparation reported in the lay literature include cannabis-based butters, candies, edibles, oils, compresses, creams, ointments, and tinctures but again, limited dosing information exists here with much of the information being anecdotal in nature.

Dosing remains highly individualized and relies largely on titration. Patients with no prior experience with cannabis and initiating cannabis therapy for the first time are cautioned to begin at the very lowest dose and to stop therapy if unacceptable or undesirable side effects occur. Consumption of smoked/inhaled or oral cannabis should proceed slowly, waiting a minimum of 10 - 20 minutes between puffs or inhalations and waiting a very minimum of 30 minutes, but preferably 3 h, between bites of cannabis-based oral products (e.g. cookies, baked goods) to gauge for strength of effects or for possible overdosing. Subsequent dose escalation should be done slowly, once experience with the subjective effects is fully appreciated, to effect or tolerability. If intolerable adverse effects appear without significant benefit, dosing should be tapered and stopped. Tapering guidelines have not been published, but the existence of a withdrawal syndrome (see Section 2.4) suggests that tapering should be done slowly (i.e. over several days or weeks).

Minimal therapeutic dose and dosing ranges

Clinical studies of cannabis and cannabis-based products for therapeutic purposes are limited to studies carried out with dried cannabis that was smoked or vapourized and with synthetic or natural cannabis-based products that have received market authorization (i.e. dronabinol, nabilone, and nabiximols). With the possible exception of trials conducted with Epidiolex ® (CBD-enriched oil) for epilepsy and one open-label pilot clinical trial of oral THC oil for symptoms associated with post-traumatic stress disorder (PTSD) there are no other clinical studies of fresh cannabis or cannabis oils for therapeutic purposes. As such, providing precise dosing guidelines for such products is not possible although existing sources of information can be used as a reference point (see below).

Prescription cannabinoids

Information obtained from the monograph for Marinol ® (dronabinol; no longer available in Canada) indicates that a daily oral dose as low as 2.5 mg Δ ⁹-THC is associated with a therapeutic effect (e.g. treatment of AIDS-related anorexia/cachexia). Naturally, dosing will vary according to the underlying disorder and the many other variables mentioned above. Dosing ranges for Marinol ® (dronabinol) vary from 2.5 mg to 40 mg Δ ⁹-THC/day (maximal tolerated daily human dose = 210 mg Δ ⁹-THC/day). Average daily dose of dronabinol is 20 mg and maximal recommended daily dose is 40 mg. Doses less than 1 mg of THC per dosing session may further avoid incidence and risks of adverse effects. Dosing ranges for Cesamet ® (nabilone) vary from 0.2 mg to 6 mg/day. Dosing ranges for Sativex ® (nabiximols) vary from one spray (2.7 mg Δ ⁹-THC and 2.5 mg CBD) to 16 sprays (43.2 mg Δ ⁹-THC and 40 mg CBD) per day. Information from clinical studies with Epidiolex ®, an oil-based extract of cannabis containing 98% CBD, suggests a daily dosing range between 5 and 20 mg/kg/day. For additional information on dosing, please see the Access to Cannabis for Medical Purposes Regulations - Daily Amount Fact Sheet (Dosage).

Survey and clinical data

Data from randomized, double-blind, placebo-controlled clinical studies of smoked or vapourized cannabis used a daily dose of up to 3.2 grams of dried cannabis of varying potencies (range: 1 - 23 % THC; see Table 5).

Data from a pilot clinical trial with the Syqe Inhaler™ has shown that an inhaled (vapourized) dose of 3 mg THC (delivered from an amount as low as 15 mg of dried cannabis plant material at a potency of 20% THC; actual dose absorbed 1.5 mg THC) was associated with analgesic efficacy with minimal adverse effects. In contrast to the gram amounts of cannabis used with smoked, vapourized, and oral routes of administration, the mean daily amounts for prescription cannabinoids such as dronabinol were 30 mg, for nabilone 4.4 mg, and for nabiximols 46 mg THC and 43 mg CBD (i.e. 17 sprays).

Taken together, data from patient surveys and clinical studies suggests that most patients use up to 3 g of dried cannabis per day for medical purposes, although much less (< 1 g/day) can be used with apparent efficacy and decreased incidence of side-effects.

Dosing and threshold of psychotropic effects

With respect to the relationship between dosing and psychotropic effects, it has been estimated that an inhaled dose of 0.045 - 0.1 mg/kg of THC (i.e. an individual inhaled dose of 3 - 6 mg THC) would be sufficient to reach the threshold for psychotropic effects, with an inhaled dose of 0.15 - 0.3 mg/kg THC (i.e. an individual inhaled dose of 10 - 20 mg THC) being sufficient to produce marked intoxication. Furthermore, it has been estimated that between one and three puffs of higher potency cannabis would be sufficient to produce significant psychoactive effects. One study has shown that while cannabis smokers titrate their dose of THC by inhaling lower volumes of smoke when smoking "strong" joints (i.e. "skunk", > 15% THC), this did not fully compensate for the higher THC doses per joint when using "strong" cannabis and therefore users of more potent cannabis are exposed to greater quantities of THC. For oral administration, a dose of 0.15 - 0.3 mg/kg of THC (i.e. an individual oral dose of 10 - 20 mg THC) would be sufficient to reach the threshold for psychotropic effects and a dose of 0.45 - 0.6 mg/kg of THC (i.e. an individual oral dose of 30 - 40 mg of THC) would be sufficient to produce marked intoxication.

Monitoring and clinical practice guidelines
Table 2. Recommendations for the Evaluation and Management of Patients

1. Take a medical history and perform a physical examination

2. Assess symptoms to be treated, identify any active diagnoses, and ensure patients are under optimal management

3. Assess psychological contributors and risk of addiction or substance abuse

4. Document any history or current use of illicit or non-prescribed drugs, including cannabis and synthetic cannabinoids

5. Determine the effect of previous use of cannabinoids for medical purposes

6. Consider a urinary drug screening to assess current use of prescribed and non-prescribed medications

7. Set goals for treatment with cannabis - e.g., pain reduction, increased functional abilities, improved sleep quality, increased quality of life, reduced use of other medications

8. Develop a treatment plan incorporating these goals

9. Discuss likely and possible side effects that might be experienced with cannabis/cannabinoid use

10. Discuss the risks of addiction

11. Develop a follow-up schedule to monitor the patient

12. Determine whether the goals of treatment are being achieved and the appropriateness of the response

13. Monitor for potential misuse or abuse (being aware of clinical features of cannabis dependence)

14. Develop a treatment strategy, particularly for patients at risk

15. Maintain an ongoing relationship with the patient

3.1 Smoking

According to the World Health Organization (WHO), a typical joint contains between 500 mg and 1.0 g of cannabis plant matter (average weight = 750 mg) which may vary in Δ ⁹-THC content between 7.5 and 225 mg (i.e. typically between 1 and 30%; see ), and in CBD content between 0 and 180 mg (i.e. between 0 and 24%). The majority of clinical trials with smoked cannabis for medical purposes have used joints of dried cannabis weighing between 800 and 900 mg. Estimates that are more recent suggest the mean weight of cannabis in a joint is 320 mg. The gram amount of cannabis plant material combusted in a "typical" puff has been estimated to range between 25 and 50 mg/puff, although amounts as high as 160 mg/puff have been noted.

The actual amount of Δ ⁹-THC delivered in the smoke varies widely and has been estimated at 20 to 70%, the remainder being lost through combustion or side-stream smoke. Furthermore, the bioavailability of Δ ⁹-THC (the fraction of Δ ⁹-THC in the cigarette which reaches the bloodstream) from the smoking route is highly variable (2 - 56%) and influenced by the smoking topography (i.e. the number, duration, and spacing of puffs, hold time and inhalation volume). In addition, expectation of drug reward can also influence smoking dynamics. Thus, the actual dose of Δ ⁹-THC absorbed systemically when smoked is not easily quantified, but has been approximated to be around 25% of the total available amount of Δ ⁹-THC in a cigarette.

Relationship between a smoked/vapourized dose and an oral dose

Little reliable information exists regarding conversion of a "smoked dose" of THC to an equivalent oral dose. However, based solely on measures of bioavailability, multiplication of a "smoked dose" of Δ ⁹-THC by a conversion factor of 2.5 (to correct for differences between the bioavailability of Δ ⁹-THC through the smoked route (~25%) vs. the oral route (~10%), ~ three-fold difference between inhaled and oral routes) can yield an approximately equivalent oral dose of Δ ⁹-THC. However, it is important to point out that these studies did not accurately measure the exact smoked dose of Δ ⁹-THC that was delivered, and as such remains a very rough approximation. It is also important to emphasize that this "conversion factor" appears to relate mostly to psychoactive effects (e.g. euphoria, feeling mellow, feeling a good drug effect, feeling sedated, feeling stimulated, Addiction Research Center Inventory marijuana scale), psychomotor performance, and food intake and is based on a very small number of comparative pharmacology studies. Further rigorous comparative pharmacology studies are required. In addition, no comparative studies have been done with vaping. In addition, this theoretical conversion factor may or may not apply for therapeutic effects. Indeed, it is important to highlight that two studies reported that individuals using cannabis for therapeutic purposes indicated they used approximately similar gram amounts of cannabis regardless of route of administration.

Plasma concentrations of Δ⁹-THC following smoking/vapourization and therapeutic efficacy

There are a small number of efficacy studies on the amounts of smoked/vapourized cannabis and plasma concentrations of Δ ⁹-THC required for therapeutic effects (see for a quick overview, and information throughout this document for more detailed information).

A Canadian dose-ranging study showed that a single inhalation of a 25 mg dose of smoked cannabis (Δ ⁹-THC content 9.4%; total available dose of Δ ⁹-THC = 2.35 mg) yielded a mean plasma Δ ⁹-THC concentration of 45 ng/mL within 2 min after initiating smoking. The study reported improvements in sleep and pain relief in patients suffering from chronic neuropathic pain with minimal/mild psychoactive effects.

These above-mentioned studies suggest that, at least in the case of chronic neuropathic pain, psychoactive effects can be separated from therapeutic effects and that very low doses of THC may actually be sufficient to produce analgesia while keeping psychoactive effects to a minimum.

Cannabinoid
(Generic name)

Brand/Registered name

Principal constituents/Source

Official status in Canada

Approved indications

Onset of effects (O) / Peak effects (P)/ Duration of action (D)

Route of administration

Availability on provincial/ territorial formulary

Standard marketing authorization: Adjunctive treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy.

Marketing authorization with conditions: Adjunctive treatment for symptomatic relief of neuropathic pain in adult patients with multiple sclerosis; and adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.

AB: Alberta; BC: British Columbia; MB: Manitoba; N/A: not applicable; NB: New Brunswick; NL: Newfoundland and Labrador; NS: Nova Scotia; NU: Nunavut; NT: Northwest Territories; ON: Ontario; PE: Prince Edward Island; QC: Quebec; Rx: prescription; SK: Saskatchewan; YT: Yukon

3.2 Oral

The pharmacokinetic information described in Section 2.2.1.3 reports the erratic and slow absorption of Δ ⁹-THC from the oral route, and oral doses of THC are estimated from the information in the monograph for Marinol ® (dronabinol, no longer available in Canada). A 10 mg b.i.d. dose of Marinol ® (20 mg total Δ ⁹-THC per day) yielded a mean peak plasma Δ ⁹-THC concentration of 7.88 ng/mL (range: 3.33 - 12.42 ng/mL), with a bioavailability ranging between 10 and 20%. By comparison, consumption of a chocolate cookie containing 20 mg Δ ⁹-THC resulted in a mean peak plasma Δ ⁹-THC concentration of 7.5 ng/mL (range: 4.4 - 11 ng/mL), with a bioavailability of 6%. An 8 mg orally-administered THC tablet (Namisol ®) yielded a mean plasma THC C max of 4 ng/mL and a similar mean plasma 11-hydroxy-THC C max . Tea prepared from Cannabis flowering tops and leaves has been documented, but no data are available regarding efficacy.

Marinol

Although Marinol ® (dronabinol) is no longer available for sale in Canada, the Marinol ® product monograph suggests a mean of 5 mg Δ ⁹-THC/day (range: 2.5 - 20 mg Δ ⁹-THC/day) for AIDS-related anorexia associated with weight loss. A 2.5 mg dose may be administered before lunch, followed by a second 2.5 mg dose before supper. On the other hand, to reduce or prevent CINV, a dosage of 5 mg t.i.d. or q.i.d. is suggested. In either case, the dose should be carefully titrated to avoid the manifestation of adverse effects. Please consult the Marinol® drug product monograph for more detailed instructions.

Cesamet

The Cesamet ® (nabilone) product monograph suggests administration of 1 to 2 mg of the drug, twice a day, with the first dose given the night before administration of the chemotherapeutic medication. A 2 mg dose of nabilone gave a mean plasma concentration of 10 ng/mL nabilone, 1 to 2 h after administration. The second dose is usually administered 1 to 3 h before chemotherapy. If required, the administration of nabilone can be continued up to 24 h after the chemotherapeutic agent is given. The maximum recommended daily dose is 6 mg in divided doses. Dose adjustment (titration) may be required in order to attain the desired response, or to improve tolerability. More recent clinical trials report starting doses of nabilone of 0.5 mg at night for pain or insomnia in fibromyalgia, and for insomnia in PTSD. Please consult the Cesamet® drug product monograph for more detailed instructions.

Epidiolex

Data from an open-label clinical study of Epidiolex ® for treatment-resistant childhood-onset epilepsy suggest that dosing with Epidiolex ® (98 - 99% pure CBD oil) begin at a starting dose of 2 to 5 mg/kg per day divided in twice-daily dosing in addition to baseline antiepileptic drug regimen, then up-titrated by 2 to 5 mg/kg once a week until intolerance or a maximum dose of 25 mg/kg per day is reached. In some specific situations, the study authors mention that an increase to a maximum dose of 50 mg/kg per day could be considered. In patients with drug- resistant seizures in the Dravet syndrome or treatment-resistant Lennox-Gastaut syndrome, a dose of 20 mg/kg per day is efficacious and generally well tolerated.

Cannabis oil

3.3 Oro-mucosal

Dosing with nabiximols (Sativex ®) is described in the product monograph along with a titration method for proper treatment initiation. Briefly, dosing indications in the drug product monograph suggest that on the first day of treatment patients take one spray during the morning (anytime between waking and noon), and another in the afternoon/evening (anytime between 4 p.m. and bedtime). On subsequent days, the number of sprays can be increased by one spray per day, as needed and tolerated. A fifteen-minute time gap should be allowed between sprays. During the initial titration, sprays should be evenly spread out over the day. If at any time unacceptable adverse reactions such as dizziness or other CNS-type reactions develop, dosing should be suspended or reduced or the dosing schedule changed to increase the time intervals between doses. According to the drug product monograph, the average dose of nabiximols is five sprays per day (i.e. 13 mg Δ ⁹-THC and 12.5 mg CBD) for patients with MS, whereas those patients with cancer pain tend to use an average of eight sprays per day (i.e. 21.6 mg Δ ⁹-THC and 20 mg CBD). The majority of patients appear to require 12 sprays or less; dosage should be adjusted as needed and tolerated. Administration of four sprays to healthy volunteers (total 10.8 mg Δ ⁹-THC and 10 mg CBD) was associated with a mean maximum plasma concentration varying between 4.90 and 6.14 ng/mL Δ ⁹-THC and 2.50 to 3.02 ng/mL CBD depending whether the drug was administered under the tongue or inside the cheek. Please consult the Savitex® drug product monograph for more detailed information.

3.4 Vapourization

Studies using the Volcano ® vapourizer have reported using up to 1 g of dried cannabis in the chamber, but 50 to 500 mg of plant material is typically used; Δ ⁹-THC concentrations up to 6.8% have been tested with the Volcano ® vapourizer. Subjects appeared to self-titrate their intake in accordance with the Δ ⁹-THC content of the cannabis. Peak plasma Δ ⁹-THC levels varied between 70 and 190 ng/mL depending on the strength of Δ ⁹-THC. The levels of cannabinoids released into the vapour phase increased with the temperature of vapourization. Vapourization temperature has typically been reported to be between 180 - 195 °C; higher temperatures (e.g. 230 °C) greatly increase the amounts of cannabinoids released, but also increase the amounts of by-products.

Data from a pilot clinical trial with the Syqe Inhaler™ has shown that an inhaled dose of as little as 3 mg THC (~1.5 mg THC absorbed, delivered from an amount as low as 15 mg of dried cannabis plant material at a potency of 20% THC) was associated with analgesic efficacy with minimal adverse effects. THC was detected in the plasma within 1 min following inhalation and reached a maximum within 3 min at a mean THC concentration of 38 ng/ml.

4.0 Potential Therapeutic Uses

While there are countless anecdotal reports concerning the therapeutic uses of cannabis, clinical studies supporting the safety and efficacy of cannabis for therapeutic purposes in a variety of disorders are limited, but slowly increasing in number. Furthermore, the current level of evidence for the safety and efficacy of cannabis for medical purposes does not meet the requirements of the Food and Drugs Act and its Regulations except for those products that have received a notice of compliance and market authorization from Health Canada. With the exception of one small open-label, pilot clinical study of orally-administered THC in an olive oil solution for symptoms associated with PTSD and clinical trials of orally-administered CBD in an oil solution (Epidiolex ®) for symptoms associated with childhood epilepsy (see section 4.6 Epilepsy), there are no well-controlled clinical studies on the use of other orally-administered cannabis products such as cannabis edibles (e.g. cookies, baked goods) or topicals for therapeutic purposes.

The National Academy of Sciences, Engineering and Medicine (NASEM) has published a report on the health effects of cannabis and cannabinoids. This comprehensive report includes information on the therapeutic effects of cannabis and the cannabinoids but also other health effects such as cancer, cardiometabolic risks, respiratory disease, immunity, injury and death, prenatal, perinatal and neonatal effects, psychosocial and mental health effects. It also discusses challenges and barriers in conducting cannabis research as well as recommendations to support and improve cannabis research. Much of the evidence included in the report came from systematic reviews and meta-analyses and selected high quality primary research. Evidence gathered from in vitro or in vivo animal studies was not included.

Dronabinol is the generic name for the oral form of synthetic Δ ⁹-THC and is marketed in the U.S. as Marinol ®. It was available for sale in Canada in capsules containing 2.5, 5, or 10 mg of the drug dissolved in sesame oil. It is indicated for the treatment of severe CINV in cancer patients, and for AIDS-related anorexia associated with weight loss. The drug is no longer sold in Canada (post-market discontinuation of the drug product as of February 2012; not for safety reasons). Please consult the Marinol® drug product monograph for more detailed information.

Nabilone is the generic name for an orally administered synthetic structural analogue of Δ ⁹-THC, which is marketed in Canada as Cesamet ® but also now available in generic forms (e.g. RAN-nabilone, PMS-nabilone, TEVA-nabilone, CO-nabilone, ACT-nabilone). It is available as capsules (0.25, 0.5, 1 mg) and is indicated for severe CINV in cancer patients. Please consult the Cesamet® drug product monograph for more detailed instructions.

Nabiximols is the generic name for a whole-plant extract of two different, but standardized, strains of Cannabis sativa giving an oro-mucosal spray product containing approximately equivalent amounts of Δ ⁹-THC (27 mg/mL) and CBD (25 mg/mL), and other cannabinoids, terpenoids, and flavonoids per 100 μl of dispensed spray. Nabiximols is marketed as Sativex ® in Canada and has received a notice of compliance for use as an adjunctive treatment for the symptomatic relief of spasticity in adult patients with MS who have not responded adequately to other therapy, and who demonstrate meaningful improvement during an initial trial of therapy. It is also marketed (with conditions) as an adjunctive treatment for the symptomatic relief of neuropathic pain in adults with MS and (with conditions) as an adjunctive analgesic in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain. Please consult the Sativex® drug product monograph for more detailed instructions.

Epidiolex® is the brand name for a whole-plant cannabis extract of a high CBD strain of Cannabis sativa and is an oral oil-based solution product containing > 98% CBD at a concentration of 100 mg/ml. Epidiolex ® has received Orphan Drug Designation in the U.S. for the treatment of Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex. At the time of writing this document Epidiolex ® has not received a Notice of Compliance from Health Canada and is not marketed in Canada.

The existing scientific and clinical evidence for cannabis and certain cannabinoids in treating various symptoms associated with various medical conditions is summarized in the following sections beginning on the next page.

Primary medical conditions and associated secondary end-points (if any) for which benefits were observed

Percent and dose of Δ⁹-THC (if known)

Trial duration; and number of patients/participants

Reference

HIV/AIDS-associated weight loss

One cannabis cigarette (~800 mg) containing 1.8% or 3.9% THC by weight, smoked once daily (i.e. one dose per day)
(~14 - 31 mg Δ ⁹-THC /day)

8 sessions total
(3 sessions per week);
30 participants

Central and peripheral chronic neuropathic pain (various etiologies)

One cannabis cigarette (~800 mg) containing either 3.5% or 7% THC by weight, smoked in bouts over a 3 h period (i.e. one dose per day) (daily dose of THC unavailable)

1 day total;
38 patients

HIV-associated chronic neuropathic pain refractory to other medications

One cannabis cigarette (~800 mg) containing between 1 and 8% THC by weight, smoked four times daily (i.e. four doses per day) (daily dose of THC unavailable)

5 days total;
28 patients

Chronic post-traumatic or post-surgical neuropathic pain refractory to other medications and associated insomnia

One 25 mg dose of cannabis containing 9.4% THC by weight, smoked three times daily (i.e. three doses per day) (~7 mg Δ ⁹-THC /day)

5 days total; 21 patients

Neuropathic pain of various etiologies (spinal cord injury, complex regional pain syndrome (CRPS) type I, causalgia-CRPS type II, diabetic neuropathy, multiple sclerosis, post-herpetic neuralgia, idiopathic peripheral neuropathy, brachial plexopathy, lumbosacral radiculopathy, and post-stroke neuropathy)

Inhalation of vapourized cannabis (800 mg) containing either a low (1.29% or 10.3 mg Δ ⁹-THC) or a medium-dose of Δ ⁹-THC (3.53% Δ ⁹-THC or 28.2 mg Δ ⁹-THC)

3 sessions total;
39 patients

Neuropathic pain of various etiologies

Inhalation of a single vapourized dose of 15 mg dried containing 20% Δ ⁹-THC by weight (~3 mg Δ ⁹-THC)

One session only;
10 patients

Diabetic peripheral neuropathy (i.e. diabetes mellitus type I and II)

Inhalation of single vapourized doses of dried cannabis (400 mg/dose) containing either low (1% Δ ⁹-THC or 4 mg Δ ⁹-THC), medium (4% Δ ⁹-THC or 16 mg Δ ⁹-THC) or high (7% Δ ⁹-THC or 28 mg Δ ⁹-THC) doses of Δ ⁹-THC (four single dosing sessions; each separated by two weeks)

4 sessions total;
16 patients

Neuropathic pain from spinal cord injury or disease

Inhalation of between 8 and 12 puffs from 400 mg of dried cannabis (2.9% and 6.7% THC)

3 sessions total;
42 patients

4.1 Palliative care

The evidence thus far from some observational studies and clinical studies suggests that cannabis (limited evidence) and prescription cannabinoids (e.g. dronabinol, nabilone, or nabiximols) may be useful in alleviating a wide variety of single or co-occurring symptoms often encountered in the palliative care setting.

These symptoms may include, but are not limited to, intractable nausea and vomiting associated with chemotherapy or radiotherapy, anorexia/cachexia, severe intractable pain, severe depressed mood and anxiety, and insomnia.

A limited number of observational studies suggest that the use of cannabinoids for palliative care may also potentially be associated with a decrease in the number of some medications used by this patient population.

Data from observational studies

For information on the use of cannabis/cannabinoids for the control of nausea and vomiting please consult of this document. For additional information on the use of cannabis/cannabinoids for anorexia/cachexia associated with HIV/AIDS infection or cancer, please consult , respectively. For further information on the use of cannabis/cannabinoids for chronic pain syndromes (including cancer pain), please consult . For further information on the use of cannabis/cannabinoids in the treatment of sleep disorders associated with chronic diseases please see Section 4.9.5.2, and please consult Section 4.9.9 for information on the use of cannabis/cannabinoids in oncology.

4.2 Quality of life

The available clinical studies report mixed effects of cannabis and prescription cannabinoids on measures of quality of life (QoL) for a variety of different disorders.

A handful of clinical studies have used standardized QoL instruments to measure whether the use of cannabis or prescription cannabinoids (e.g. nabilone, dronabinol, or nabiximols) is associated with improvements in QoL. The evidence from these studies is summarized below.

Clinical studies with dronabinol

Clinical studies with cannabis extract

Clinical studies with nabilone

Clinical studies with nabiximols

Clinical and observational studies with smoked cannabis

4.3 Chemotherapy-induced nausea and vomiting

Whereas chemotherapy-induced vomiting generally appears to be well-controlled with current first-line therapies/triple-combination therapies (e.g. 5-HT ₃ antagonists, neurokinin-1 antagonists, and corticosteroids), the associated acute, delayed, and especially anticipatory nausea remain more poorly controlled and the use of cannabis/cannabinoids may provide some measure of benefit in such cases. A significant proportion (25 - 59%) of patients undergoing chemotherapy experience anticipatory nausea during treatment and once it develops, it is refractory to standard treatment with 5-HT ₃ antagonists. Non-specific anti-anxiety treatments (e.g. benzodiazepines) are used to treat anticipatory nausea but drawbacks include significant sedation.

It is important to note that excessive use of cannabis has been reported to paradoxically trigger a chronic cyclic vomiting syndrome (i.e. hyperemesis) (see Section 7.6.1 for further details on this syndrome).

Pre-clinical studies

Patient claims that smoked cannabis relieves CINV are widely recognized, and increasing evidence suggests a role for the ECS in the regulation of nausea and vomiting. CB ₁ and CB ₂ receptors have been found in areas of the brainstem associated with emetogenic control, and results from animal studies suggest the anti-nausea and anti-emetic properties of certain cannabinoids (e.g. Δ ⁹-THC, dronabinol, nabilone) are most likely related to their agonistic actions at centrally-located CB ₁ receptors. Levels of 2-AG are increased in the visceral insular cortex during an acute episode of nausea in rats and localized blockade of 2-AG through targeted MAGL inhibition in the insular cortex reduces acute nausea. Similarly, infusion of 2-AG into the insular cortex dose-dependently blocks anticipatory nausea, while infusion of anandamide was without effect. These findings suggest that 2-AG, but not anandamide, drives acute and anticipatory nausea. Elsewhere, elevation of endocannabinoids such as anandamide and 2-AG by inhibition of the endocannabinoid degradative enzymes FAAH and MAGL, has been shown to suppress acute and anticipatory nausea in animal models and localized infusion of a peripherally-restricted CB ₁ receptor agonist into the visceral insular cortex suppressed nausea-like behaviour in rats, whereas systemic administration had no effect.

An in vivo animal study and one small clinical study have also suggested Δ ⁸-THC to be a more potent anti-emetic than Δ ⁹-THC. In addition to its actions at CB ₁ receptors, an in vitro study has also shown that Δ ⁹-THC antagonizes the 5-HT ₃ receptor, a target of current standard anti-emetic drugs, raising the possibility that cannabinoids may exert their anti-emetic action through more than one mechanism. Other studies carried out in animal models of nausea and vomiting have shown that CBD (5 mg/kg, subcutaneous (s.c.)) suppressed chemical-induced vomiting (and nausea) through potential activation of somatodendritic 5-HT 1A autoreceptors located in the dorsal raphe nucleus, while another study showed that the anti-nausea/vomiting effects of CBD could be reversed by pre-treatment with CBG (5 mg/kg, i.p.).

Cannabinoid acids and other cannabinoids

THCA has been shown to lack CB ₁ receptor activity and administration of THCA was not associated with some of the classical animal behavioural signs of CB ₁ receptor agonists (i.e. hypothermia, catalepsy), supporting previous findings of lack of THCA-associated psychoactivity in animals. THCA was also found to be at least 10 times more potent than THC in reducing acute and anticipatory nausea models.

Other work has shown that THC, CBDA, and the benzodiazepine chlordiazepoxide reduced behaviour modelling anticipatory nausea. In this study, CBDA (0.001, 0.01, and 0.1 mg/kg i.p.) was shown to be between 5 and 500 times more potent than THC (0.5 mg/kg) in reducing anticipatory nausea and 20 times more potent than chlordiazepoxide (10 mg/kg). Treatment with CBDA was not associated with any effects on locomotor activity at any tested dose whereas chlordiazepoxide significantly reduced locomotor activity. Co-administration of subthreshold doses of CBDA (0.1 µg/kg i.p.) and THCA (5 µg/kg i.p.) reduced behaviour modelling anticipatory nausea, and pharmacological studies suggest the involvement of CB ₁ (for THCA) and 5-HT 1A (for CBDA) receptors in the mechanism of suppression of anticipatory nausea. Further research is needed to resolve the conflicting evidence around the mechanism of action, if any, of THCA at the CB ₁ receptor. As for CBDA, a dose as low as 1 µg/kg (i.p.) potently suppressed anticipatory nausea in an animal model and compared to the doses of CBD needed for the same degree of effect (1 - 5 mg/kg i.p.), CBDA could be said to be between 1 000 and 5 000 times more potent than CBD in suppressing anticipatory nausea.

In addition to THC, CBD, THCA and CBDA, two other phytocannabinoids THCV and cannabidivarin (CBDV) have been studied, though to a far lesser extent, for their potential to alleviate nausea in animal models. THCV at a dose of 10 mg/kg (i.p.) and CBDV at a dose of 200 mg/kg (i.p.) have been shown to reduce acute nausea in rats, potentially through a CB ₁ receptor-independent mechanism, but nothing is known about their ability to suppress anticipatory nausea.

Taken together, the findings from the above pre-clinical studies suggest that Δ ⁹-THC, CBD, CBDA, and THCA can all suppress acute nausea and vomiting as well as anticipatory nausea to varying degrees, and with varying potencies and efficacies, whereas THCV and CBDV suppress acute nausea. Furthermore, certain subthreshold combinations of some of these cannabinoids can produce synergistic anti-nausea and vomiting effects compared to when used alone.

Clinical studies

The evidence for smoked cannabis and prescription cannabinoids such as nabilone (Cesamet ®), dronabinol (Marinol ®), (and levonantradol) in treating CINV has been reviewed. One systematic review and meta-analysis of 28 randomized controlled trials (RCTs) (N = 2 454 participants) of cannabinoids using the GRADE approach reported a greater benefit of cannabinoids compared with both active comparators and placebo, but statistical significance was not reached in all of the studies. The average number of patients showing a complete anti-nausea and vomiting response was greater with prescription cannabinoids (dronabinol or nabiximols) than placebo (OR = 3.82 [95% CI 1.55 - 9.42]).

While no peer-reviewed clinical trials of smoked cannabis for the treatment of CINV exist, Musty and Rossi have published a review of U.S. state clinical trials on the subject. Patients who smoked cannabis showed a 70 to 100% relief from nausea and vomiting, while those who used a Δ ⁹-THC capsule experienced 76 to 88% relief. Plasma levels of > 10 ng/mL Δ ⁹-THC were associated with the greatest suppression of nausea and vomiting, although levels ranging between 5 and 10 ng/mL were also effective. In all cases, patients were admitted only after they failed treatment with standard phenothiazine anti-emetics.

In one small open label trial with eight children with various blood cancers were administered Δ ⁸-THC (18 mg/m ²) two hours before the initiation of chemotherapy as well as every six hours for the next 24 hours showed that Δ ⁸-THC successfully prevented vomiting and no delayed nausea or vomiting episodes were observed in the next two days following antineoplastic treatment. Δ ⁸-THC could also be administered at doses considerably higher than the doses of Δ ⁹-THC generally administered to adult patients, with a lack of major side effects.

Few, if any, clinical trials directly comparing cannabinoids to newer anti-emetics such as 5-HT ₃ (Ondansetron, Granisetron) or NK-1 receptor antagonists have been reported to date. A small clinical trial comparing smoked cannabis (2.11% Δ ⁹-THC, in doses of 8.4 mg or 16.9 mg Δ ⁹-THC; 0.30% CBN; 0.05% CBD) to ondansetron (8 mg) in ipecac-induced nausea and vomiting in healthy volunteers showed that both doses of Δ ⁹-THC reduced subjective ratings of queasiness and objective measures of vomiting; however, the effects were very modest compared to ondansetron. Furthermore, only cannabis produced changes in mood and subjective state. In another clinical study with a small sample size, ondansetron and dronabinol (2.5 mg Δ ⁹-THC first day, 10 mg second day, 10 - 20 mg thereafter) provided equal relief of delayed CINV, and the combination of dronabinol and ondansetron did not provide added benefit beyond that observed with either agent alone. However, two animal studies showed that low doses of Δ ⁹-THC, when combined with low doses of the 5-HT ₃ receptor antagonists ondansetron or tropisetron, were more efficacious in reducing nausea and emesis frequency than when administered individually. More research is required to determine if combination therapy provides added benefits above those observed with newer standard treatments.

A retrospective chart review of dronabinol use for CINV in an adolescent oncology population (i.e. leukemia, lymphoma, sarcoma, brain tumour) in a tertiary pediatric hospital reported that the majority of patients who received moderate or highly emetogenic chemotherapy and standard anti-emetogenic therapy (i.e. 5-HT ₃ receptor antagonist and corticosteroids) also received dronabinol. The most commonly prescribed dose of dronabinol in this study was 2.5 mg/m ² oral solution every 6 h (as needed), and the median number of dronabinol doses received per hospitalization was 3.5. Sixty percent of the pediatric patients in this study were reported to have had a "good" response to dronabinol. Limitations of this study include retrospective design, lack of a comparison group, lack of chemotherapy standardization, and lack of standardized anti-emetic regimens.

The use of cannabinoids (whether administered orally or by smoking cannabis) is currently considered a fourth-line adjunctive therapy in CINV when conventional anti-emetic therapies have failed. Nabilone (Cesamet ®) and dronabinol (Marinol ®) are indicated for the management of severe nausea and vomiting associated with cancer chemotherapy, however dronabinol is no longer available for sale on the Canadian market. Nabilone may be administered orally every 12 h at dosages ranging from 1 - 2 mg, whereas dronabinol may be administered every 6 - 8 h orally, rectally, or sub-lingually at doses ranging from 5 - 10 mg.

4.4 Wasting syndrome (cachexia, e.g., from tissue injury by infection or tumour) and loss of appetite (anorexia) in AIDS and cancer patients, and anorexia nervosa

The ability of acute cannabis exposure to increase appetite has been recognized anecdotally for many years. In addition, results from epidemiological studies suggest that people actively using cannabis have higher intakes of energy and nutrients than non-users. Controlled laboratory studies with healthy subjects suggest acute exposure to cannabis, whether by inhalation or oral ingestion of Δ ⁹-THC-containing capsules, correlates positively with an increase in food consumption, caloric intake, and body weight. Studies showing a high concentration of CB ₁ receptors in brain areas associated with control of food intake and satiety lend further support to the link between cannabis consumption and appetite regulation. Furthermore, increasing evidence suggests a role for the ECS not only in modulating appetite, food palatability, and intake, but also in energy metabolism and the modulation of both lipid and glucose metabolism (reviewed in).

4.4.1 To stimulate appetite and produce weight gain in AIDS patients

The ability of cannabis to stimulate appetite and food intake has been applied to clinical situations where weight gain is deemed beneficial such as in HIV-associated muscle wasting and weight loss.

Despite the findings of the above-noted study, AIDS-related anorexia associated with weight loss was an approved indication in Canada for dronabinol (Marinol ®) (no longer available in Canada). The Marinol ® product monograph summarizes a six-week, randomized, double-blind, placebo controlled-trial in 139 patients, with the 72 patients in the treatment group initially receiving 2.5 mg dronabinol twice a day, then reducing the dose to 2.5 mg at bedtime due to side effects (feeling high, dizziness, confusion and somnolence). Over the treatment period, dronabinol significantly increased appetite, with a trend towards improved body-weight and mood and a decrease in nausea. At the end of the six-week period, patients were allowed to continue receiving dronabinol, during which appetite continued to improve. This secondary, open-label, 12 month follow-up study suggested that dronabinol was safe and effective for long-term use for the treatment of anorexia associated with weight loss in patients with AIDS. The use of higher doses of dronabinol (20 mg - 40 mg per day) has been reported both in the Marinol ® product monograph as well as in the literature. However, caution should be exercised in escalating dosage because of the increased frequency of dose-related adverse effects.

A clinical study that used higher doses of dronabinol or smoked cannabis showed that acute administration of high doses of dronabinol (four to eight times the standard 2.5 mg Δ ⁹-THC b.i.d. dose, or 10 - 20 mg Δ ⁹-THC daily, three times per week for a total of eight sessions) and smoked cannabis (three puffs at 40 sec intervals; ~800 mg cigarettes containing 1.8 - 3.9% THC giving an estimated total daily amount of 14.4 mg - 31.2 mg THC in the cigarette, three times per week, over a total of eight study sessions) increased caloric intake in experienced HIV-positive cannabis smokers with clinically significant muscle mass loss. Another subsequent inpatient study employed even higher doses of dronabinol (20 - 40 mg total Δ ⁹-THC daily, for four days) and smoked cannabis (~800 mg cannabis cigarettes containing 2.0 and 3.0% THC, administered four times per day, with an estimated 64 - 125 mg total Δ ⁹-THC daily in the cigarette, over a total study period of four days). Both drugs produced substantial and comparable increases in food intake and body weight, as well as improvements in mood and sleep. Others have shown that the cannabis-associated increase in body weight in this patient population appears to result from an increase in body fat rather than lean muscle mass.

4.4.2 To stimulate appetite and produce weight gain in cancer patients

Anorexia is ranked as one of the more troublesome symptoms associated with cancer, with more than half of patients with advanced cancer experiencing a lack of appetite and/or weight loss. While it is anecdotally known that smoking cannabis can stimulate appetite, the effects of smoking cannabis on appetite and weight gain in patients with cancer cachexia have not been studied. The results from clinical trials with oral Δ ⁹-THC (dronabinol) or oral cannabis extract are mixed and the effects, if any, appear to be modest (reviewed in.

In two early studies, oral THC (dronabinol) improved appetite and food intake in some patients undergoing cancer chemotherapy. An open-label study of dronabinol (2.5 mg Δ ⁹-THC, two to three times daily, four to six weeks) in patients with unresectable or advanced cancer reported increases in appetite and food intake, but weight gain was only achieved in a few patients. Modest weight gain was obtained with a larger dosing regimen of dronabinol (5 mg t.i.d.), but the CNS side effects including dizziness and somnolence were limiting factors. In contrast, a randomized, double-blind, placebo-controlled study involving cancer patients with related anorexia-cachexia syndrome failed to demonstrate any differences in patients' appetite across treatment categories (oral cannabis extract, Δ ⁹-THC, or placebo). Furthermore, when compared to megestrol acetate, an orexigenic medication, dronabinol was significantly less efficacious in reported appetite improvement and weight gain.

A two-centre, phase II, randomized, double-blind, placebo-controlled, 22-day pilot study carried out in adult patients suffering from advanced cancer reported improved and enhanced chemosensory perception among patients treated with dronabinol (2.5 mg Δ ⁹-THC b.i.d.) compared to those receiving placebo. The majority (73%) of dronabinol-treated patients self-reported an increased overall appreciation of food compared to those receiving placebo (30%). Similarly, the majority of dronabinol-treated patients (64%) reported increased appetite, whereas the majority of patients receiving placebo reported either decreased appetite (50%) or no change (20%). Total caloric intake per kilogram body weight did not differ significantly between treatment groups but did increase in both groups compared to baseline. Furthermore, compared to placebo, dronabinol-treated patients reported an increase in their protein intake as a proportion of total energy. According to the study authors, negative psychoactive effects were minimized by starting patients at a low dose (2.5 mg Δ ⁹-THC once a day, for three days) followed by gradual dose escalation (up to a maximum of 7.5 mg dronabinol per day).

4.4.3 Anorexia nervosa

The ECS has been implicated in appetite regulation and is suspected to play a role in eating disorders such as anorexia nervosa. Increased peripheral ECS activity (i.e. increased plasma anandamide and increased CB ₁ mRNA expression in blood) has been found in patients with eating disorders. In spite of epidemiological and familial studies, which suggest a genetic basis for anorexia nervosa, genetic studies have thus far failed to agree on an association between genes coding for ECS proteins and the manifestation of anorexia nervosa.

No studies have examined the effects of smoking cannabis on anorexia nervosa and limited information exists on the use of cannabinoids to treat anorexia nervosa. Furthermore, inter- and intra-species differences in animals with respect to anorexia nervosa-like behaviour have to some extent hampered pre-clinical research on the effects of Δ ⁹-THC in this disorder.

One study in a mouse model of anorexia nervosa reported conflicting results, while another study in a rat model reported a significant attenuation in weight loss only at high doses of Δ ⁹-THC (2.0 mg/kg/day Δ ⁹-THC i.p.).

A small, randomized, crossover trial of oral Δ ⁹-THC in female anorexic patients suggested that THC produced a weight gain equivalent to the active placebo (diazepam). Δ ⁹-THC was administered in daily doses increasing from 7.5 mg (2.5 mg, t.i.d.) to a maximum of 30 mg (10 mg, t.i.d.), 90 min before meals, for a period of two weeks. Three of the eleven patients administered Δ ⁹-THC also reported severe dysphoric reactions, withdrawing from the study.

4.5 Multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injury and disease

Evidence from pre-clinical studies suggests THC, CBD and nabiximols improve multiple sclerosis (MS) associated symptoms of tremor, spasticity and inflammation.

The available evidence from clinical studies suggests cannabis (limited evidence) and certain cannabinoids (dronabinol, nabiximols, THC/CBD) are associated with some measure of improvement in symptoms encountered in MS and spinal cord injury (SCI) including spasticity, spasms, pain, sleep and symptoms of bladder dysfunction.

Very limited evidence from pre-clinical studies suggests that certain cannabinoids modestly delay disease progression and prolong survival in animal models of amyotrophic lateral sclerosis (ALS), while the results from a very limited number of clinical studies are mixed.

Differences between the findings from these two systematic reviews of cannabinoids for selected neurological disorders include differences in methodology, approach, and inclusion/exclusion criteria. Nevertheless, both systematic reviews suggest that cannabis/cannabinoids are associated with some measure of improvement in spasticity, spasms and pain in selected neurological disorders (e.g. MS, SCI/disease).

Below is a summary of the peer-reviewed evidence on the use of cannabis and cannabinoids in MS, ALS and SCI and disease.

4.5.1 Multiple sclerosis

A number of studies, both in patients suffering from MS and in animal models of the disease, suggest the disorder is associated with changes in endocannabinoid levels, although the findings are conflicting.

Pre-clinical studies

Pre-clinical studies across different animal species suggest cannabinoids improve the signs of motor dysfunction in experimental models of MS (reviewed in). Lyman was one of the first to report the effects of Δ ⁹-THC in one such model. In that study, affected animals treated with Δ ⁹-THC either had no clinical signs of the disorder or showed mild clinical signs with delayed onset. The treated animals also typically had a marked reduction in CNS tissue inflammation compared to untreated animals. Subsequent studies in murine models of MS have supported and extended these findings demonstrating that Δ ⁹-THC, but not CBD, ameliorated both tremor and spasticity and reduced the overall clinical severity of the disease. Further work highlighted the importance of the CB ₁ receptor in controlling tremor, spasticity, and the neuro-inflammatory response. In contrast to findings with the CB ₁ receptor, the exact function of the CB ₂ receptor in MS remains somewhat unclear, although it is believed to play a role in regulating the neuro-inflammatory response.

Historical and survey data

Clinical studies with orally administered cannabinoid medications (cannabis extract, oral THC, nabiximols)

The results of randomized, placebo-controlled trials with orally administered cannabinoids for the treatment of muscle spasticity in MS are encouraging, but modest.

The large, multi-centre, randomized, placebo-controlled CAnnabis in Multiple Sclerosis ( CAMS) study researching the effect of cannabinoids for the treatment of spasticity and other symptoms related to MS enrolled over 600 patients. The primary outcome was change in overall spasticity scores measured using the Ashworth scale. The study did not show any statistically significant improvement in the (objective) Ashworth score in patients taking either an oral cannabis extract ((Cannador ®) containing 2.5 mg Δ ⁹-THC, 1.25 mg CBD, and < 5% other cannabinoids), or oral Δ ⁹-THC, for 15 weeks. However, there was evidence of a significant treatment effect on subjective, patient-reported spasticity and pain, with improvement in spasticity using either orally administered cannabis extract (61%) (dosing: 5 - 25 mg Δ ⁹-THC; 5 - 15 mg CBD/day; and < 5% other cannabinoids, adjusted to body weight and titrated according to side effects) or oral Δ ⁹-THC (60%) (dosing: 10 - 25 mg Δ ⁹-THC/day, adjusted to body weight and titrated according to side effects) compared to placebo (46%). Patients were concomitantly taking other medications to manage MS-associated symptoms. In contrast, a long-term (12 months), double-blind, follow-up to the CAMS study showed evidence of a small treatment effect of oral Δ ⁹-THC (dosing: 5 - 25 mg Δ ⁹-THC/day, adjusted to body weight and titrated according to side effects) on muscle spasticity measured by objective methods, whereas a subjective treatment effect on muscle spasticity was observed for both oral Δ ⁹-THC and oral cannabis extract (Cannador ®). Cannador ® is not available in Canada at this time.

Other randomized clinical trials using standardized cannabis extract capsules (containing 2.5 mg Δ ⁹-THC and 0.9 mg CBD per capsule) or nabiximols (Sativex ®) reported similar results, in that improvements were only seen in patient self-reports of symptoms but not with objective measures (e.g. Ashworth scale). The reasons behind the apparent discrepancies between subjective and objective measures are not clear; however, a number of possible explanations may be found to account for the differences. For example, it is known that spasticity is a complex phenomenon and is affected by patient symptoms, physical functioning, and psychological disposition. Spasticity is also inherently difficult to measure, and has no single defining feature. In addition, the reliability and sensitivity of the Ashworth scale (for objectively measuring spasticity) has been called into question.

Nabiximols

An observational, prospective, multicenter, non-interventional, clinical practice study examined the safety and effectiveness of nabiximols in the treatment of symptoms associated with MS (i.e. the MObility impro VEment in MS-induced spasticity study, MOVE 2). MS patients were followed over a three- to four-month period on outcomes, tolerability, QoL and treatment satisfaction. Prior to initiation on nabiximols, other anti-spastic medications were tried in 90% of study patients and the majority of the patients in the study (73%) were put on nabiximols. The mean number of nabiximols sprays/day was 6.9 (range: 1 - 12) reported at follow-up period 1, and 6.7 (range: 1 - 16) reported at follow-up period 2. Physician-based assessment of patients suggested a one-month course of treatment with nabiximols provided relief of resistant MS spasticity in the majority of patients who were administered the drug. After a one-month period, there was an initial response for spasticity detected in 42% of patients and a clinically relevant response for spasticity detected in 25% of these patients. At three-months' time, an initial response for spasticity was detected in 59% of patients and a clinically relevant response for spasticity detected in 40% of these patients. Scores in mean sleep disturbance decreased by 33% over a one-month treatment period in patients with an initial response, and by 40% in patients with a clinically relevant response. Scores on the combined modified Ashworth score (cMAS) decreased by 12% after one-month treatment in patients with an initial response and by 15% in patients with a clinically relevant response. Scores on the MSQoL-54 physical health composite scale and the mental health composite score showed statistically significant improvements over the three-month period in patients with an initial response and a clinically relevant response. After three-months' treatment with nabiximols, the mean EQ-5D-3L index value remained stable and a statistically significant reduction was observed in the percentages of patients considering muscle stiffness, restricted mobility, pain, and bladder disorders as most disturbing symptoms. Overall, at three-months' treatment time, almost 80% of the entire study population of patients on nabiximols was either "completely satisfied" or "satisfied" with the effectiveness of nabiximols. Most commonly observed adverse events with nabiximols were dizziness (4%), fatigue (2.5%), drowsiness (1.9%), nausea (1.9%), and dry mouth (1.2%).

A 12-month prolongation study of the MOVE 2 clinical trial to determine long-term effectiveness and safety of nabiximols in clinical practice reported that from among 52 patients enrolled in the study that were included in the effectiveness analysis, the mean spasticity numerical rating scale score decreased significantly from 6.0 points at baseline to 4.8 points after one month and remained at this level after the 12-month period, including in patients who were classified as "initial responders". At baseline, the mean sleep disturbance numerical rating scale (NRS) score was 5.1 points in the subsample of participants and after 12 months it decreased to 3.2 points; in patients with an initial response, scores dropped from 5.4 to 2.4, and in patients with a clinically relevant response mean sleep disturbance NRS scores decreased from 5.3 to 1.9 points. Furthermore, the mean values of the MSQoL-54 physical health composite score and the mean mental health composite score both showed improvements, but were not statistically significant. The EQ-5D-3L index value showed improvement over the 12-month period for those patients who showed an initial and clinically relevant response. Furthermore, at study end, fewer patients who showed an initial and clinically-relevant response considered the MS spasticity-related symptoms of muscle stiffness, pain, restricted mobility, fatigue, and bladder disorders as the most disturbing symptoms compared to baseline. From the patient's perspective, impairment of daily activities was significantly improved after 12-month treatment with nabiximols compared to baseline and fewer patients complained about daily impairment of activities and notably, the improvement was more prominent in responders than in the entire study group. The majority of patients did not report adverse events. Most commonly reported adverse events included GI disorders, psychiatric disorders, and nervous system disorders. Mean daily number of nabiximols sprays was 6.2 (range: 2 - 12) and at least one other anti-spastic drug was still prescribed in 28 patients (e.g. baclofen, tizanidine, tolperisone, or gabapentin).

CUPID and MUSEC clinical studies

The Cannabinoid Use in Progressive Inflammatory Brain Disease ( CUPID) study was a randomized, double-blind, clinical investigation designed to measure whether orally administered Δ ⁹-THC was able to slow the progression of MS. This three-year publicly-funded trial took place at the Peninsula Medical School in the U.K. and followed the earlier, one-year long, CAMS study. A total of 493 subjects with primary or secondary progressive, but not relapse-remitting, MS had been recruited from across the U.K. in 2006. The CUPID trial found no evidence to support an effect of Δ ⁹-THC on MS progression, as measured by using either the EDSS or the MS Impact Scale 29 (MSIS-29). However, the authors concluded that there was some evidence to suggest a beneficial effect in participants who were at the lower end of the disability scale at the time of patient enrolment. Since the observed benefit only occurred in a small sub-group of patients, further studies would be required to more closely examine the reasons for this selective effect.

A double-blind, placebo-controlled, phase III clinical study (the MUltiple Sclerosis and Extract of Cannabis trial, MUSEC) published by the same group of researchers that conducted the CUPID trial, reported that a twelve-week treatment with an oral cannabis extract (Cannador ®) (2.5 mg Δ ⁹-THC and 0.9 mg CBD/capsule) was associated with a statistically significant relief in patient-reported muscle stiffness, muscle spasms, and body pain as well as a statistically significant improvement in sleep compared to placebo, in patients with stable MS. There were no statistically significant differences between cannabis extract and placebo on functional measures such as those examining the effect of spasticity on activities of daily living, ability to walk, or on social functioning. The majority of the patients using cannabis extract used total daily doses of 10, 15, or 25 mg of Δ ⁹-THC with corresponding doses of 3.6, 5.4, and 9 mg of CBD. The majority of the study subjects were concomitantly using analgesics and anti-spasticity medications, but were excluded if they were using immunomodulatory medications (e.g. interferons). Active treatment with the extract was associated with an increase in the number of adverse events, but the majority of these were considered mild to moderate and did not persist beyond the study period. The highest number of adverse events were observed during the initial two-week titration period and appeared to decrease progressively over the course of the remaining treatment sessions. The most commonly observed adverse events were those associated with disturbances in CNS function (e.g. dizziness, disturbance in attention, balance disorder, somnolence, feeling abnormal, disorientation, confusion, and falls). Disturbances in GI function were the second most commonly occurring adverse events (e.g. nausea, dry mouth).

Clinical studies with smoked cannabis

There has only been one clinical study so far using smoked cannabis for symptoms associated with MS. The study, a double-blind, placebo-controlled, crossover clinical trial reported a statistically significant reduction in patient scores on the modified Ashworth scale for measuring spasticity after patients smoked cannabis once daily for three days (each cigarette contained 800 mg of 4% Δ ⁹-THC; total available Δ ⁹-THC dose of 32 mg per cigarette). Smoking cannabis was also associated with a statistically significant reduction in patient scores on the VAS for pain, although patients reportedly had low levels of pain to begin with. No differences between placebo and cannabis were observed in the timed-walk task, a measure of physical performance. Cognitive function, as assessed by the Paced Auditory Serial Addition Test, appeared to be significantly decreased immediately following administration of cannabis; however, the long-term clinical significance of this finding was not examined in this study. The majority of patients (70%) were on disease-modifying therapy (e.g. interferon β-1a, interferon β-1b, or glatiramer), and 60% were taking anti-spasticity agents (e.g. baclofen or tizanidine). Cannabis treatment was associated with a number of different, but commonly observed adverse effects including dizziness, headache, fatigue, nausea, feeling "too high", and throat irritation. Study limitations included the fact that the majority of patients had prior experience with cannabis, and that the study was unblinded since most of the patients were able to tell apart the placebo from the active treatment with cannabis.

Cannabis/cannabinoid tolerability in multiple sclerosis

Generally speaking, cannabis and orally administered prescription cannabinoids (e.g. dronabinol, nabilone, nabiximols, Cannador ®) are reported to be well tolerated in patients with MS. Clinical trials to date do not indicate serious adverse effects associated with the use of these prescription cannabinoid medications (or cannabis). However, there appears to be an increase in the number of non-serious adverse effects associated with the short-term use of cannabinoids. The most commonly reported short-term physical adverse effects are dizziness, drowsiness, and dry mouth.

Bladder dysfunction associated with multiple sclerosis or spinal cord injury

An early survey of MS patients regularly using cannabis for symptomatic relief of urinary problems reported that over half of these patients claimed improvement in urinary urgency. A sixteen-week, open-label, pilot study of cannabis-based extracts (a course of nabiximols treatment followed by maintenance with 2.5 mg Δ ⁹-THC only) for bladder dysfunction, in 15 patients with advanced MS, reported significant decreases in urinary urgency, number and volume of incontinence episodes, frequency, and nocturia. Improvements were also noted in patient self-assessments of pain and quality of sleep. A subsequent RCT of 250 MS patients suggested a clinical effect of orally administered cannabinoids (2.5 mg Δ ⁹-THC or 1.25 mg CBD with < 5% other cannabinoids per capsule, up to a maximum 25 mg/day) on incontinence episodes.

4.5.2 Amyotrophic lateral sclerosis

4.5.3 Spinal cord injury (or spinal cord disease)

Pre-clinical animal studies have shown the existence of an ECS in the spinal cord and a basal endocannabinoid tone in non-injured spinal cords. While the role of the ECS in the intact spinal cord is only partially known, endocannabinoids modulate spinal cord analgesia as well as excitability, participating in the physiological control of reflexes. Pre-clinical animal studies suggest that SCI triggers changes in the activity of the ECS, with an acute spike in production of anandamide and 2-AG in the epicenter of the damaged area. The spike in endocannabinoid levels, reflecting an active protective process induced by injury, returns to basal levels within a few days' post-injury; however 2-AG levels go through a subsequent secondary and more protracted rise in levels over a subsequent 28-day period. Blocking both CB ₁ and CB ₂ receptors worsens SCI-associated damage, whereas stimulation of these two cannabinoid receptors appears to be protective and may also alleviate neuropathic pain associated with SCI. One pre-clinical study also reported a beneficial effect of CBD in restoring motor function and reducing extent of injury following SCI in a mouse model. Subjective improvements have been anecdotally reported by SCI patients smoking cannabis

However, despite the evidence from animal studies and anecdotal claims, limited clinical information exists regarding the use of cannabis and cannabinoids to treat symptoms associated with SCI such as pain, spasticity, muscle spasms, urinary incontinence, and difficulties sleeping. Double-blind, crossover, placebo-controlled studies of oral Δ ⁹-THC and/or nabiximols suggested modest improvements in pain, spasticity, muscle spasms, and sleep quality in patients with SCI. More recently, a randomized, double-blind, placebo-controlled parallel study using a minimum of 15 to 20 mg Δ ⁹-THC/day (mean daily doses of 31 mg Δ ⁹-THC orally, or 43 mg Δ ⁹-THC-hemisuccinate rectally) showed a statistically significant improvement in spasticity scores in patients with SCI and a double-blind, placebo-controlled, crossover study using nabilone (0.5 mg b.i.d.) also showed an improvement in spasticity compared to placebo in patients with SCI.

4.6 Epilepsy

Anecdotal evidence suggests an anti-epileptic effect of cannabis (THC- and CBD-predominant strains).

The available evidence from pre-clinical and limited clinical studies suggests certain cannabinoids (CBD) may have anti-epileptiform and anti-convulsive properties, whereas CB₁R agonists (THC) may have either pro- or anti-epileptic properties.

However, the clinical evidence for an anti-epileptic effect of cannabis is weaker, but emerging, and requires further study.

Evidence from clinical studies with Epidiolex® (oral CBD) suggests efficacy and tolerability of Epidiolex® for drug-resistant seizures in treatment-resistant Dravet syndrome or Lennox-Gastaut syndrome.

Evidence from observational studies suggests an association between CBD (in herbal and oil preparations) and a reduction in seizure frequency as well as an increase in quality of life among adolescents with rare and serious forms of drug-resistant epilepsy.

Epidiolex® has received FDA approval (June 2018) for use in patients 2 years of age and older to treat treatment-resistant seizures associated with Dravet syndrome and Lennox-Gastaut syndrome.

The endocannabinoid system and epilepsy

Temporal lobe epilepsy, one of the most common kinds of epilepsy seen in adults, is associated with changes in the hippocampus where CB ₁ receptor expression is downregulated during the acute phase, shortly after the precipitating insult, but then upregulated in the chronic phase of the disorder. Furthermore, it appears that the expression of the CB ₁ receptor on excitatory glutamatergic axon terminals, as well as the expression of DAGL, which is responsible for yielding the endocannabinoid 2-AG, are both downregulated. In contrast, CB ₁ receptor expression on inhibitory GABAergic axon terminals appears to be upregulated. In addition, reduced levels of the endocannabinoid anandamide have been detected in the cerebrospinal fluid (CSF) of patients with untreated, newly diagnosed, temporal lobe epilepsy, whereas normally, anandamide is found in high concentrations in the hippocampus, a brain region known to be involved in epileptogenesis and seizure disorders. Taken together, these and other studies demonstrating changes in CB ₁ receptor and DAGL expression in the hippocampus and changes in anandamide levels suggest important and widespread changes in the functioning of the ECS in epilepsy. Since the ECS is generally thought to act as a neurotransmitter braking system, the reported dysregulation of the ECS in epilepsy may play a role in the generation and maintenance of epileptic seizures. There is also some evidence to suggest that endocannabinoids promote the maintenance, but not the initiation, of epileptiform activity by activating CB ₁ receptors located on astrocytes.

Pre-clinical studies

CB ₁ receptors are located mainly pre-synaptically where they typically inhibit the release of classical neurotransmitters.The purported anti-epileptic effect of certain cannabinoids (e.g. THC) is thought to be mediated by CB ₁-receptor dependent pre-synaptic inhibition of glutamate release; on the other hand, epileptogenic effects may be triggered by pre-synaptic inhibition of GABA release. CB ₁ receptor agonists (e.g. THC) therefore have the potential to trigger or suppress epileptiform activity depending upon which cannabinoid-sensitive pre-synaptic terminals are preferentially affected (i.e. glutamatergic or GABAergic). Because of the ability of CB ₁ receptor agonists such as THC to yield either pro- or anti-convulsant activities and because of the reported development of tolerance to their anti-convulsant effects, CB ₁ receptor agonists are thought to be unlikely to yield therapeutic benefit for patients with epilepsy.

In contrast to the ambiguous situation with CB ₁ receptor agonists such as THC, phytocannabinoids such as CBD, CBDV, THCV, and CBN appear to mainly have anti-convulsant roles and may have more potential therapeutic value for the treatment of epilepsy. A number of in vivo studies have demonstrated the anti-epileptic effects of CBD across different animal models of epilepsy (reviewed in). Early studies using various rat and mouse models of epilepsy reported that CBD was an effective anti-convulsant and its potency was significantly increased when combined with anti-epileptic drugs such as phenytoin and phenobarbital used to treat major seizures. In contrast, CBD reduced the anti-convulsant potencies of chlordiazepoxide, clonazepam, trimethadione, and ethosuximide used for minor seizures. ED ₅₀ doses for CBD in rats ranged from as low as 12 mg/kg (p.o.) to as high as 380 mg/kg (i.p.) in mice. Another study reported that CBD attenuated epileptiform activity in vitro in hippocampal slices and displayed anti-convulsant activity in vivo (100 mg/kg) in one rat model of epilepsy, attenuating seizure severity, tonic-clonic seizures and mortality. A follow-up study by this same group examined the anti-convulsive effects of CBD in two other rat models of temporal lobe and partial epilepsy. CBD at doses of 1, 10, and 100 mg/kg significantly attenuated the percentage of animals displaying seizure events (temporal lobe epilepsy); however, there was no significant effect upon the mean number of seizure occurrences per animal or on seizure severity. In the model of partial seizure, CBD (1, 10, 100 mg/kg) decreased the percentage of animals that developed tonic-clonic seizures and was associated with decreased mortality rate (at 10 and 100 mg/kg), but had no effect on overall seizure severity. CBD was also reported to have some minor negative effects on motor function at a dose of 100 mg/kg, which was paradoxically attenuated when the dose was doubled (200 mg/kg).

In contrast with CBD and CBDV, the anti-convulsant effects of CBN have not been as well studied. In one study, CBN produced anti-convulsant effects with an ED ₅₀ of 18 mg/kg.

Although in vitro studies show that THCV binds with relatively high affinity at CB ₁ receptors, THCV does not appear to be a potent CB ₁ receptor agonist. Instead, experimental studies suggest THCV acts more like a CB ₁ receptor antagonist and a potent CB ₂ receptor partial agonist. At higher doses however, THCV appears to have some agonist activity at the CB ₁ receptor. Furthermore, in vitro studies suggest THCV has some anti-epileptiform effects at micromolar concentrations and in vivo studies suggest THCV (0.25 mg/kg) has some limited anti-convulsant effects in one mouse model of epilepsy.

Data from observational studies and patient surveys

Treatment-resistant, childhood-onset epilepsy

Clinical studies

Note: Epidiolex ® is the brand name for a whole-plant cannabis extract of a high CBD strain of Cannabis sativa and is an oral oil solution product containing > 98% CBD at a concentration of 100 mg/ml. Epidiolex ® has received FDA approval (June 2018) for use in patients 2 and older to treat Dravet syndrome and Lennox-Gastaut syndrome. It has also received Orphan Drug Designation in the U.S. for the treatment of Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex. At the time of writing of this publication, Epidiolex ® has not received a Notice of Compliance from Health Canada, and is not marketed in Canada.

A Cochrane review of the clinical evidence for cannabinoid treatment for epilepsy reviewed the four clinical studies discussed above and concluded that, based on their evaluation criteria, all of these reports were of low quality and no reliable conclusions could be drawn based on these studies regarding the efficacy of cannabinoids (CBD) as a treatment for epilepsy. However, a dose of 200 to 300 mg of CBD daily could be safely administered to small numbers of patients for short periods of time but the safety of long-term CBD treatment could not be reliably assessed in these studies.

Treatment-resistant, childhood-onset epilepsy

A clinical study investigating differences in ECS components and in molecular targets associated with CBD action found an increase in expression levels of the voltage-dependent calcium channel α-1h subunit, in CB ₂ receptor gene expression, and a decrease in the expression of the serotonin transporter gene in lymphocytes isolated from Dravet Syndrome patients.

A report from an expanded access investigational new drug (IND) trial of Epidiolex ®, an oil-based cannabis extract containing 98% v/v CBD, examined the interaction between clobazam and Epidiolex ® (CBD) during the treatment of refractory pediatric epilepsy. Thirteen subjects with refractory epilepsy were included in the study. Diagnoses included Dravet syndrome, Doose syndrome, cortical dysgenesis, isodicentric duplication chromosome 15q13, CDKL5 (Cyclin-Dependent Kinase-Like 5) mutation, Tuberous sclerosis complex, and lissencephaly. Seventy percent of the included patients had a > 50% decrease in seizures. Daily doses of Epidiolex ® ranged from 5 mg/kg/day to a maximum of 25 mg/kg/day. The average daily dose of clobazam was 1 mg/kg/day with a range of 0.18 to 2.24 mg/kg/day. Co-administration of CBD and clobazam was associated with higher plasma levels of clobazam and its active metabolite n-desmethylclobazam and close monitoring of plasma levels of clobazam and n-desmethylclobazam is recommended as is dose adjustment of clobazam, as needed, to prevent overdose. Side effects were reported in 77% of the 13 study subjects and included drowsiness, ataxia, irritability, restless sleep, urinary retention, tremor and loss of appetite.

A randomized, double-blind, placebo-controlled clinical trial was conducted to investigate the efficacy of Epidiolex ® as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. After a 4-week baseline period, 171 eligible patients (aged 2-55 years) were randomized (1:1) to either receive 20 mg/kg CBD daily (n = 86) or placebo (n = 85) as 2 equivalent doses (morning and evening) for 14 weeks (2 weeks of dose escalation and 12 weeks of dose maintenance). The median percentage reduction in monthly drop seizure frequency from baseline (primary endpoint) was 43.9% [interquartile range (IQR) -69.6 to -1.9] in the CBD group and 21.8% (IQR -45.7 to 1.7) in the placebo group. The estimated median difference between the treatment groups was -17.21 (95% CI -30.32 to -4.09; p = 0.0135) during the 14-week treatment period. The treatment effect of CBD on the primary endpoint was established during the first 4 weeks of the maintenance period and was maintained during the full treatment period. In the CBD group, 38 patients (44%) had a reduction in drop seizure frequency of ≥50% from baseline during the treatment period compared with 20 patients (24%) in the placebo group (OR 2.57, 95% CI 1.33-4.97; p = 0.0043). There were 3 patients in the CBD group who were free of drop seizures throughout the 12-week maintenance period; their monthly frequency of drop seizures at baseline was in the lower range of 15.6 to 99.2. During the treatment period, CBD also significantly decreased the estimated median difference in the monthly frequency of total seizures [-21.1 (95% CI -33.3 to -9.4; p = 0.0005)] and non-drop seizures [-26.1 (95% CI -46.1 to -8.3; p = 0.0044)] compared to placebo. This suggested that add-on CBD may have broad spectrum effects on seizure reduction. Common adverse events (occurring in ≥10% of patients) in the CBD group were diarrhea (19%), somnolence (15%), pyrexia (13%), decreased appetite (13%) and vomiting (10%). Most of the adverse events were mild or moderate in severity (78% in the CBD group) and resolved by the end of the trial (61%). Adverse events led to study withdrawal in 12 patients (14%) in the CBD group and 1 (1%) patient in the placebo group. Of the 20 patients in the CBD group who had elevations in ALT or AST (>3 times upper limit of normal), irrespective of whether they were reported as adverse events, 16 were also taking valproate. The most common serious treatment-related adverse events (occurring in >3% of patients) were collectively reported in 4 patients in the CBD group and comprised increased ALT (n = 4), AST (n = 4) and γ-glutamyltransferase (n = 3) concentrations. No patients met standard criteria for drug-induced severe liver injury (Hy's law). Overall, this trial demonstrated that add-on CBD was efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and was generally well tolerated. However, only a single dose of CBD was tested in this trial; dose-response effects will be assessed further in another study (GWPCARE3; ClinicalTrials.gov, number NCT02224560). Further assessment of the long-term efficacy and safety of CBD is being carried out in the ongoing open-label extension of this trial and will also be done using real-world data, once available.

4.7 Pain

It is now well established that the ECS plays an important role in the modulation of nociceptive and pain states. Key in these roles is the specific positioning of the endocannabinoid signaling machinery at neuronal synapses in pain processing pathways at supraspinal, spinal, and peripheral levels.

Role of CB₁ and CB₂ receptors

The CB ₁ and CB ₂ receptors play important roles in nociception and pain. Structures involved in transmission and processing of nociceptive signals such as the nociceptors, the dorsal horn of the spinal cord, the thalamus, the periaqueductal grey matter, the amygdala and the rostroventromedial medulla show a moderate to high level of CB ₁ receptor expression. In various animal models of chronic pain, both CB ₁ and CB ₂ receptor mRNA and protein levels in the CNS are upregulated. Selective deletion of the CB ₁ receptor in mice appears to greatly attenuate the anti-nociceptive efficacy of cannabinoids in animal models of acute and chronic pain, suggesting an essential role for this receptor in modulating nociception and pain. At peripheral and central terminals of nociceptive sensory nerves, CB ₁ receptors gate the transduction of peripheral noxious stimuli into central neuronal pain signals, while in the spinal cord, CB ₁ receptors act to reduce or enhance propagation of pain signals to the brain. At the neuronal circuit level, the end result of CB ₁ receptor activity can be either excitatory or inhibitory depending on the identity of the presynaptic cell and its location within the neural network. In higher brain regions tasked with processing of nociceptive input such as the periaqueductal grey matter and the rostroventromedial medulla, the CB ₁ receptors can initiate descending inhibition or block descending facilitation to the spinal cord nociceptive circuitry. Most importantly to the subject of pain, CB ₁ receptors are highly expressed in frontal-limbic pathways in the brain, which play a key role in the affective/emotional aspects of pain in humans. CB ₂ receptors appear to also play an important role in pain signaling, especially in the development of chronic pain states, by inhibiting the release of pro-inflammatory and pro-nociceptive mediators thereby attenuating the inflammatory and hyperalgesic responses. In this respect, the strategic localization of CB ₂ receptors on a variety of immune cells (macrophages, lymphocytes, and mast cells in the periphery), astrocytes and microglia in the CNS (i.e. the spinal cord) is essential to the roles of the CB ₂ receptors in modulating pain states.

Role of endocannabinoids, anandamide and 2-AG

Considerations and caveats

Animal vs. human studies

Pre-clinical studies in animals predict that cannabinoids should relieve both acute and chronic pain in humans. However, results from both experimental models of pain in human volunteers and from clinical trials of patients suffering from pain instead suggest cannabinoids may be more effective for chronic rather than acute pain in humans. A number of possible explanations can exist to account for discrepancies in findings between animal studies and human clinical trials. Such explanations include interspecies differences, differences in experimental stimuli and protocols used in the studies, and differences in the outcomes measured in the studies. Data from animal pain models are mostly based on observations of behavioural changes, and cannabinoid doses sufficient to produce relevant anti-nociception in rodents are similar to those which cause other behavioural effects such as hypomotility and catatonia. This pharmacological overlap can make it difficult to distinguish between cannabinoid-associated anti-nociceptive effects and behavioural effects.

Experimental models of acute pain vs. chronic pain

Placebo effect

Patient/study subject population

Many, if not most, of the clinical trials of cannabinoids for the treatment of pain (and even other disorders such as MS) have recruited patients or volunteers who have had prior exposure or experience with cannabis or cannabinoids. This has raised the issue of "unblinding" because any study subjects having prior experience with cannabis or cannabinoids would be more likely to be able to distinguish active treatment with these drugs from the placebo control. Furthermore, a number of clinical trials of cannabis/cannabinoids for the treatment of pain (or other disorders) have also used an "open-phase" period which enriched for patients that responded favourably to the treatment and conversely, eliminated subjects who would have either responded poorly to cannabinoids or who would have had greater chances of experiencing adverse effects. Therefore, the use of individuals with prior experience with cannabis or cannabinoids or the use of an "open-phase" period would increase the proportion of patients yielding results tending to overestimate some of the potential therapeutic benefits of cannabis/cannabinoids, while also tending to underestimate the extent or degree of adverse effects among the general patient population. There is also some evidence from pre-clinical and clinical studies that suggests sex-dependent effects on cannabinoid and cannabis-induced analgesia (see ,Sex-dependent effects, for more information).

Other considerations

With the above considerations and caveats in mind, the sections below summarize the results of studies examining the analgesic potential of cannabis or cannabinoids in pre-clinical and clinical models of experimentally-induced acute pain, as well as in clinical studies of chronic pain.

4.7.1 Acute pain

Pre-clinical studies suggest that certain cannabinoids can block the response to experimentally-induced acute pain in animal models.

The results from clinical studies with smoked cannabis, oral THC, cannabis extract, and nabilone in experimentally-induced acute pain in healthy human volunteers are limited and mixed and suggest a dose-dependent effect in some cases, with lower doses of THC having an analgesic effect and higher doses having a hyperalgesic effect.

Clinical studies of certain cannabinoids (nabilone, oral THC, levonontradol, AZD1940, GW842166) for post-operative pain suggest a lack of efficacy.

4.7.1.1 Experimentally-induced acute pain
Pre-clinical studies
Cannabinergic modulation of neuronal circuits in the brain and spinal cord can inhibit nociceptive processing and a number of pre-clinical studies suggest that anandamide, THC, and certain synthetic cannabinoids block pain responses in different animal models of acute pain (reviewed in).
Clinical studies with smoked cannabis
An early study by Hill of 26 healthy male cannabis smokers failed to demonstrate an analgesic effect of smoked cannabis (1.4% Δ ⁹-THC, 12 mg Δ ⁹-THC available in the cigarette) in response to transcutaneous electrical stimulation. The study did, however, report an increase in sensory and pain sensitivity to the applied stimulus. In contrast, Milstein showed that smoked cannabis (1.3% Δ ⁹-THC, 7.5 mg Δ ⁹-THC available in the cigarette) increased pain tolerance to a pressure stimulus in both healthy cannabis-naïve and cannabis-experienced subjects compared to placebo. Another study employing healthy cannabis smokers reported that smoking cannabis cigarettes (containing 3.55% Δ ⁹-THC, or approximately 62 mg Δ ⁹-THC available in the cigarette) was associated with a mild, dose-dependent, anti-nociceptive effect to a thermal heat stimulus. A more recent randomized, double-blind, placebo-controlled, crossover trial examined the effects of three different doses of smoked cannabis on intra-dermal capsaicin-induced pain and hyperalgesia in 15 healthy volunteers. Capsaicin was administered either 5 min or 45 min after smoking cannabis. Effects appeared to be dose- and time-dependent. No effect was observed 5 min after smoking, but analgesia was observed 45 min after smoking, and only with the medium dose of smoked cannabis (4% Δ ⁹-THC); the low dose (2% Δ ⁹-THC) had no effect whereas a high dose (8% Δ ⁹-THC) was associated with significant hyperalgesia. This study identified a so-called "narrow therapeutic window"; a medium dose provided analgesic benefit, a high dose worsened the pain and was associated with additional adverse effects, and a low dose had no effect.
Clinical studies with oral THC and cannabis extract Clinical studies with nabilone
4.7.1.2 Post-operative pain

Despite the introduction of new standards, guidelines, and educational efforts, data indicate that post-operative pain continues to be under or poorly managed and many of the drugs commonly used in this setting either lack sufficient efficacy or cause unacceptable side effects. To date, there are eight published reports and a systematic review on the use of cannabinoids in post-operative pain. The conclusions from the systematic review was that the studied cannabinoids (THC, nabilone, or an oral cannabis extract containing a 2: 1 ratio of THC to CBD, levonontradol, AZD1940, GW842166) were not ideally suited for the management of acute post-operative pain because they were either only moderately effective, less effective than placebo, not different from placebo, or even anti-analgesic at high doses.

4.7.2 Chronic pain

4.7.2.1 Experimentally-induced inflammatory and chronic neuropathic pain

Endocannabinoids, THC, CBD, nabilone and certain synthetic cannabinoids have all been identified as having an anti-nociceptive effect in animal models of chronic pain (inflammatory and neuropathic).

4.7.2.2 Neuropathic pain and chronic non-cancer pain in humans
Clinical studies with cannabinoids
The following summarizes the existing clinical information on the use of smoked/vapourized cannabis and cannabinoids (THC, nabilone, dronabinol and nabiximols) to treat neuropathic and chronic non-cancer pain.
Clinical studies with smoked or vapourized cannabis
In a randomized, placebo-controlled study, a greater than 30% decrease in HIV-associated sensory neuropathic pain was reported in 52% of cannabis-experienced patients smoking cannabis cigarettes containing 3.56% Δ ⁹-THC (32 mg total available Δ ⁹-THC per cigarette), three times per day (96 mg total daily amount of Δ ⁹-THC) for five days, compared to a 24% decrease in pain in the placebo group. The NNT to observe a 30% reduction in pain compared to controls was 3.6 and was comparable to that reported for other analgesics in the treatment of chronic neuropathic pain. In the "experimentally-induced pain" portion of the study, smoked cannabis was not associated with a statistically significant difference in acute heat pain threshold compared to placebo. However, it did appear to reduce the area of heat and capsaicin-induced acute secondary hyperalgesia. Patients were taking other pain control medications during the trial such as opioids, gabapentin or other drugs. Adverse effects of smoked cannabis in this study included sedation, dizziness, confusion, anxiety, and disorientation.

In another randomized, double-blind, placebo-controlled, cross-over study of cannabis-experienced patients suffering from chronic neuropathic pain of various etiologies (complex regional pain syndrome (CRPS), central neuropathic pain from SCI or MS, or peripheral neuropathic pain from diabetes or nerve injury) reported that administration of either a low dose or a high dose of smoked cannabis (3.5% Δ ⁹-THC, 19 mg total available Δ ⁹-THC; or 7% Δ ⁹-THC, 34 mg total available Δ ⁹-THC) was associated with significant equianalgesic decreases in central and peripheral neuropathic pain. No analgesic effect was observed in tests of experimentally-induced pain (tactile or heat stimuli) in these participants. Patients were taking other pain control medications during the trial such as opioids, anti-depressants, NSAIDs, or anti-convulsants. Adverse effects associated with the use of cannabis appeared to be dose-dependent and included feeling "high", sedation, confusion, and neurocognitive impairment. Cognitive changes appeared to be more pronounced with higher doses of Δ ⁹-THC.

A randomized, double-blind, placebo-controlled, four-period, crossover clinical study of smoked cannabis for chronic neuropathic pain caused by trauma or surgery and refractory to conventional therapies reported that compared to placebo, a single smoked inhalation of 25 mg of cannabis containing 9.4% Δ ⁹-THC (2.35 mg total available Δ ⁹-THC per cigarette), three times per day (7.05 mg total Δ ⁹-THC per day) for five days, was associated with a modest but statistically significant decrease in average daily pain intensity. In addition, there were statistically significant improvements in measures of sleep quality and anxiety with cannabis. The majority of subjects had previous experience with cannabis and most were concomitantly taking other analgesics such as opioids, anti-depressants, anti-convulsants, or NSAIDs. Adverse effects associated with the use of cannabis included headache, dry eyes, burning sensation in the upper airways (throat), dizziness, numbness, and cough.

A clinical study examined the effects of vapourized cannabis on the pharmacokinetics, subjective effects, pain ratings and safety of orally-administered opioids in patients suffering from chronic pain (musculoskeletal, post-traumatic, arthritic, peripheral neuropathy, cancer, fibromyalgia, MS, sickle cell disease, and thoracic outlet syndrome). The study reported that inhalation of vapourized cannabis (900 mg, 3.56% Δ ⁹-THC), three times per day for five days, was associated with a statistically significant decrease in pain (-27%, CI = 9 - 46). Subjects were on stable doses of sustained-release morphine sulfate or oxycodone, and had prior experience with smoking cannabis. There was a statistically significant decrease in the C max of morphine sulfate, but not oxycodone, during cannabis exposure. No clinically significant adverse effects were noted, but all subjects reported experiencing a "high". The study design carried a number of limitations including small sample size, short duration, a non-randomized subject population, and the lack of a placebo.

A double-blind, placebo-controlled, crossover study of patients suffering from neuropathic pain of various etiologies (SCI, CRPS type I, causalgia-CRPS type II, diabetic neuropathy, MS, post-herpetic neuralgia, idiopathic peripheral neuropathy, brachial plexopathy, lumbosacral radiculopathy, and post-stroke neuropathy) reported that inhalation of vapourized cannabis (800 mg containing either a low dose of Δ ⁹-THC (1.29% Δ ⁹-THC; total available amount of Δ ⁹-THC 10.3 mg) or a medium dose of Δ ⁹-THC (3.53% Δ ⁹-THC; total available amount of Δ ⁹-THC 28.2 mg)) during three separate 6 h sessions was associated with a statistically significant reduction in pain intensity. Inhalation proceeded using a standardized protocol (i.e. the "Foltin procedure"): participants were verbally signaled to hold the vapourizer bag with one hand, put the vapourizer mouthpiece in their mouth, get ready, inhale (5 s), hold vapour in their lungs (10s), and finally exhale and wait before repeating the inhalation cycle (40s). Non-significant differences were observed between placebo and active treatments with respect to pain ratings at the 60 min time point following study session initiation. Following four cued inhalations of either dose of THC at the 60 min time point, a significant treatment effect was recorded 60 min later (i.e. at the 120 min time point following trial initiation). A second cued inhalation of vapourized cannabis, at the 180 min time point following trial initiation (four to eight puffs, flexible dosing, 2 h after first inhalation), was associated with continued analgesia lasting another 2 h. Both the 1.29% and 3.53% Δ ⁹-THC doses were equianalgesic and significantly better in achieving analgesia than placebo. The NNT to achieve a 30% pain reduction was 3.2 for the low-dose vs. placebo, 2.9 for the medium-dose vs. placebo, and 25 for the medium- vs. the low-dose. The authors suggested that the NNT for active vs. placebo conditions is in the range of two commonly used anti-convulsants used to treat neuropathic pain (pregabalin, 3.9; gabapentin, 3.8). Using a Global Impression of Change rating scale, pain relief appeared to be maximal after the second dosing at 180 min, and dropped off between 1 and 2 h later. Both active doses had equal effects on ratings of pain "sharpness", while the low-dose was more effective than either the placebo or medium-dose for pain described as "burning" or "aching". All patients had prior experience with cannabis and were concomitantly taking other medications (opioids, anti-convulsants, anti-depressants, and NSAIDs). Cannabis treatment was associated with a small impairment of certain cognitive functions, with the greatest effects seen in domains of learning and memory. The study suffered from a number of drawbacks including a relatively small number of patients, a short study period, and the possibility of treatment unblinding.

A review of the use of smoked cannabis for the treatment of neuropathic pain suggested that the efficacy of smoked cannabis (NNT = 3.6, for a 30% reduction in pain) was comparable to that of traditional therapeutic agents (e.g. gabapentin, NNT = 3.8), slightly less than that observed with tricyclic antidepressants (NNT = 2.2), but better than lamotrigine (NNT = 5.4) and selective serotonin reuptake inhibitors (NNT = 6.7). The author reports that the concentrations of THC in the smoked cannabis ranged between 2 and 9% with an average concentration of 4% yielding good efficacy. Furthermore, the author suggests that cannabis may present a reasonable alternative or adjunctive treatment for patients with severe, refractory peripheral neuropathy who have tried other therapeutic avenues without satisfactory results. This review, along with another more recent review provide a useful clinical algorithm for determining if a patient would be a candidate for treatment with cannabis for peripheral neuropathic pain (see ).

Figure 3. A Possible Clinical Algorithm for Physicians Considering Supporting Therapeutic Use of Cannabis for a Patient with Chronic, Intractable Neuropathic Pain. Figure adapted fromReference 275 Reference 832

Figure 3 - Text description

Determine if the patient has persisting neuropathic pain. Screening criteria for persisting neuropathic pain include daily or almost daily pain with typical neuropathic characteristics; a duration of at least three months; and an impact on the patient's quality of life. If the patient does not meet the screening criteria for persisting neuropathic pain, conduct another evaluation and make a referral to another healthcare professional. If the patient does meet the screening criteria for persisting neuropathic pain, determine if the patient has tried standard medications. If no, try standard medications. (Note a: Standard medications include antidepressants, anticonvulsants, opioids, nonsteroidal anti-inflammatory drugs). If yes, determine if they have/had a good response to standard medications. (Note b: At least 30% reduction in pain intensity). If yes, continue standard medications. If no, determine if the patient is willing to consider cannabinoids or cannabis. (Note c: Consider past experience with cannabis or cannabinoids, potential for side effects or history of side effects, willingness to smoke/vaporize/ingest orally). If no, consider continuing standard medications. If yes, determine if there is a risk of substance abuse and psychiatric or mood disorders. (Note d: Determine substance abuse history; history of psychiatric or mood disorders. If yes or at high risk for substance abuse, proceed with caution and close observation (see Sections 2.4, 5.0, and 6.0); coordinate with substance abuse treatment programs. If there is a history or risk of psychiatric disease (schizophrenia) or bipolar disorder see Section 7.7.3 and consult with a psychiatric specialist before proceeding). If yes, coordinate with the proper substance abuse or psychiatric resource to determine if the risk/benefit is favourable with coordinated care. If it is not favourable, the patient is not a candidate for cannabinoids or cannabis. If it is favourable or if there is no risk of substance abuse and psychiatric or mood disorders, determine if the patient is cannabis or cannabinoid naïve. If no, obtain a full history of previous cannabinoid use. (Note e: Specific cannabinoid, dose, route of administration; symptoms treated and outcome; adverse effects). If the patient is cannabis or cannabinoid naïve or once the full history of previous cannabinoid use from a non-naïve patient has been obtained, try an oral cannabinoid by prescription, such as nabilone or nabiximols buccal spray. If the trial with the prescription oral cannabinoid fails or if it is not financially feasible, consider cannabis. (Note f: Discuss the fact that there are not yet clear guidelines regarding efficacy, doses and toxicity; raise awareness of oral and vaporized routes of cannabis administration; refer patient to Health Canada website and documents regarding access to cannabis product(s); follow the usual clinical guideline to start low and titrate dose slowly). Cannabis can be administered orally, by smoking or by vaporization. It is important to educate the patient regarding the risks, benefits, side effects and non-diversion of cannabis. Finally, monitor the patient to determine efficacy, side effects and diversion of cannabis and adjust treatment accordingly. (Note g: Efficacy should aim for at least 30% decrease in pain intensity).

Legend:
a Standard medications include antidepressants, anticonvulsants, opioids, nonsteroidal anti-inflammatory drugs.

b At least 30% reduction in pain intensity.

c Consider past experience with cannabis or cannabinoids, potential for side effects or history of side effects, willingness to smoke/vapourize/ingest orally.

d Determine substance abuse history; history of psychiatric or mood disorders. If yes or at high risk for substance abuse, proceed with caution and close observation (see Sections 2.4, 5.0, and 6.0); coordinate with substance abuse treatment programs. If there is a history or risk of psychiatric disease (schizophrenia) or bipolar disorder see Section 7.7.3 and consult with a psychiatric specialist before proceeding.

e Specific cannabinoid, dose, route of administration; symptoms treated and outcome; adverse effects.

f Discuss the fact that there are not yet clear guidelines regarding efficacy, doses and toxicity; raise awareness of oral and vapourized routes of cannabis administration; refer patient to Health Canada website and documents regarding access to cannabis product(s); follow the usual clinical guideline to start low and titrate dose slowly.

g Efficacy should aim for at least 30% decrease in pain intensity.

A Canadian multi-centre, prospective, cohort safety study of patients using cannabis as part of their pain management regimen for chronic non-cancer pain reported that cannabis use was not associated with an increase in the frequency of serious adverse events vs. controls, but was associated with an increase in the frequency of non-serious adverse events. In this study, 216 patients with chronic non-cancer pain (nociceptive, neuropathic, or both) using cannabis and 215 control patients with chronic pain with no cannabis use were followed for a period of one year and evaluated for frequency and type of adverse effects associated with the use of a standardized herbal cannabis product (CanniMed 12.5% THC, <0.5% CBD). A significant proportion of study subjects were taking opioids, anti-depressants or anti-convulsants. Almost one third of study subjects who reported smoking cannabis at least once reported consuming it exclusively by smoking, 44% reported smoking and oral ingestion, 14% reported vapourizing, smoking or ingesting cannabis orally, and slightly less than 4% reported only smoking or vapourizing. Secondary objectives were to examine the effects of cannabis use on pulmonary and neurocognitive function and to explore the effectiveness of cannabis for chronic non-cancer pain, including pain intensity and QoL. For the primary outcome, the total number of serious adverse events was similar between the cannabis group and the control group and none of the serious adverse events were considered to be either "certainly" or "very likely" related to the cannabis provided by the investigators. One serious adverse event (convulsion) was considered to be "probably/likely" related to the study cannabis. Patients in the cannabis-treatment group experienced a median of three events per subject (vs. a median of two events per subject among controls). The incidence rate of adverse events in the cannabis treatment group was 4.61 events/person-year and was significantly higher than in the control group where the incidence rate was 2.85 events/person-year. The most common adverse event categories in the cannabis-treatment group were nervous system (20%), GI (13.4%), and respiratory disorders (12.6%) and the rate of nervous system disorders, respiratory disorders, infections, and psychiatric disorders was significantly higher in the cannabis group than in the control group. Furthermore, mild (51%) and moderate (48%) events were more common than severe ones (10%) in the cannabis-treatment group. Somnolence (0.6%), amnesia (0.5%), cough (0.5%), nausea (0.5%), dizziness (0.4%), euphoric mood (0.4%), hyperhidrosis (0.2%), and paranoia (0.2%) were assessed as being "certainly/very likely" related to treatment with cannabis. Increasing the daily dose of cannabis was not associated with a higher risk of serious or non-serious adverse events, although the recommended maximum daily amount of cannabis was set at 5 g per day (the median daily cannabis dose was 2.5 grams per day). With respect to secondary outcomes, no difference in neurocognitive function was found between cannabis users and controls, after one year of treatment and after controlling for multiple potential confounders. No significant changes were noted in certain pulmonary function tests (Slow Vital Capacity, Functional Residual Capacity, Total Lung Capacity) over the course of the study period, although reductions were noted in residual volume, forced expiratory volume in one second (FEV ₁) and in the FEV ₁/forced vital capacity (FVC) ratio (0.78% decrease). No changes were observed in liver, renal or endocrine functions. In terms of efficacy for pain, compared to baseline, there was a significant reduction in average pain intensity in the cannabis-treatment group but not in the control (difference = 1.10). Notably, patients using cannabis had higher baseline pain and disability than controls. While there was a significant improvement from baseline pain intensity in both the control and cannabis-treatment groups, greater improvement of physical function was observed in the cannabis group vs. control. Lastly, the sensory component of pain and total symptom distress score (Edmonton Symptom Assessment System) as well as the total mood disturbance scale of the Profile of Mood States all showed improvement in the cannabis group vs. control. Limitations of the study included relatively small sample size and short follow-up time which prevented the identification of rare serious adverse events, a significant drop-out rate attributable to adverse events (especially among cannabis naïve and former users), perceived lack of efficacy, and/or dislike of the study product. The majority (66%) of individuals in the cannabis group was composed of experienced cannabis users and the authors of the study suggest that a higher rate of adverse events for cannabis may have been observed if only new cannabis users had been included. Therefore, the study findings regarding safety of cannabis use for chronic non-cancer pain cannot be generalized to patients who are cannabis naïve. Lastly, the study was not a RCT and allocation was not blinded, therefore improvements in secondary efficacy measures should be interpreted with caution.
Clinical studies with orally administered prescription cannabinoids Nabilone Dronabinol Nabiximols
A number of randomized, placebo-controlled, double-blind crossover and parallel studies have shown a significant reduction in central or peripheral neuropathic pain of various etiologies (e.g. brachial plexus avulsion, MS-related) following treatment with nabiximols (Sativex ®). In all three studies, patients were concomitantly using other drugs to manage their pain (anti-epileptics, tricyclic anti-depressants, opioids, NSAIDs, selective serotonin reuptake inhibitors, benzodiazepines, skeletal muscle relaxants). The NNT for 30% pain reduction (deemed clinically significant) varied between 8 and 9, whereas the NNT for 50% pain reduction for central neuropathic pain was 3.7, and 8.5 for peripheral pain. In two of the three studies, the majority of subjects had prior experience with cannabis for therapeutic or non-medical purposes. Furthermore, the majority of subjects allocated to the active treatment experienced minor to moderate adverse effects compared to the placebo group. These included nausea, vomiting, constipation, dizziness, intoxication, fatigue, and dry mouth among other effects.

According to the updated consensus statement and clinical guidelines on the pharmacological management of chronic neuropathic pain published by the Canadian Pain Society in 2014, cannabinoid-based therapies (e.g. dronabinol, nabiximols, smoked cannabis) are now considered to be third-line treatments (in 2007 they were considered fourth-line treatments) for neuropathic pain; mostly as adjuvant analgesics for pain conditions refractory to standard drugs (but also see Section 4.8.3 and for updated clinical guidelines on the use of cannabinoids for the treatment of symptoms associated with fibromyalgia).

4.7.2.3 Cancer pain

The limited available clinical evidence with certain cannabinoids (dronabinol, nabiximols) suggests a modest analgesic effect of dronabinol and a modest and mixed analgesic effect of nabiximols on cancer pain.
Clinical studies with dronabinol
Two randomized, double-blind, placebo-controlled clinical studies suggested oral Δ ⁹-THC (dronabinol) provided an analgesic benefit in patients suffering from moderate to severe continuous pain due to advanced cancer. The first study was a small dose-ranging study of 5, 10, 15, and 20 mg Δ ⁹-THC, given in successive days, to 10 cancer patients. Significant pain relief was found at the 15 and 20 mg dose levels, but at these higher doses patients were heavily sedated and mental clouding was common. A second, placebo-controlled study compared 10 and 20 mg oral Δ ⁹-THC with 60 and 120 mg codeine in 36 patients with cancer pain. While the lower and higher doses of THC were equianalgesic to the lower and higher doses of codeine, respectively, statistically significant differences in analgesia were only obtained between placebo and 20 mg Δ ⁹-THC, and between placebo and 120 mg codeine. The 10 mg Δ ⁹-THC dose was well tolerated, and despite its sedative effect appeared to have mild analgesic potential. The 20 mg Δ ⁹-THC dose induced somnolence, dizziness, ataxia, and blurred vision. Extreme anxiety was also observed at the 20 mg dose in a number of patients.
Clinical studies with nabiximols
In Canada, nabiximols (Sativex ®) is approved (with conditions) as an adjunctive analgesic in adults with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain. Current dosing recommendations for nabiximols suggest a maximum daily dose of 12 sprays (32.4 mg THC and 30 mg CBD) over a 24 h period, although higher numbers of sprays/day have been used or documented in clinical studies. It should be noted that increases in the number of sprays/day were accompanied by increases in the incidence of adverse effects.

4.7.2.4 "Opioid-sparing" effects and cannabinoid-opioid synergy

The "opioid-sparing" effect refers to the ability of a non-opioid medication (e.g. cannabis, THC) to confer adjunctive opioid analgesia with the use of a lower dose of the opioid, thereby decreasing opioid-associated side effects. While there are some pre-clinical data and data from case studies supporting such an effect for cannabinoids, this is less well-established in published clinical studies. Furthermore, there is some evidence from epidemiological/observational studies to suggest that individuals using opioids for chronic non-cancer pain may also use cannabis to manage distress from unmanaged pain, and that a certain portion of individuals using higher doses of opioids for chronic non-cancer pain may also have greater problems across a number of domains, including greater risk of a CUD.

The following information summarizes the results from pre-clinical, epidemiological and clinical studies investigating cannabinoid-opioid interactions and the potential "opioid-sparing effect" of cannabinoids.
Pre-clinical data
There is a fair amount of evidence to suggest a functional interaction between the cannabinoid and the opioid systems, although additional research is needed to understand precisely how the two systems communicate with one another. The evidence supporting a putative interaction between the cannabinoid and opioid systems comes from a number of observations. First, it is known that cannabinoids and opioids produce similar biological effects such as hypothermia, sedation, hypotension, inhibition of GI motility, inhibition of locomotor activity, and anti-nociception. Furthermore, neuroanatomical studies in animals have demonstrated overlapping tissue distribution of the cannabinoid and opioid receptors, with both receptor types found in nervous system tissues associated with the processing of painful stimuli, namely the periaqueductal gray, raphe nuclei, and central-medial thalamic nuclei. There is also some evidence that the CB ₁ and mu-opioid receptors can co-localize in some of the same neuronal sub-populations such as those located in the superficial dorsal horn of the spinal cord. This co-localization may play an important role in spinal-level modulation of peripheral nociceptive inputs. Both receptors also share similar signal transduction molecules and pathways, the activation of which generally results in the inhibition of neurotransmitter release. The role of these receptors in inhibiting neurotransmitter release is further supported by their strategic localization on pre-synaptic membranes. Evidence from some pre-clinical studies also suggests that acute administration of cannabinoid receptor agonists can lead to endogenous opioid peptide release, and that chronic THC administration increases endogenous opioid precursor gene expression (e.g. preproenkephalin, prodynorphin, and proopiomelanocortin) in different spinal and supraspinal structures involved in the perception of pain. A few studies have even demonstrated the existence of cannabinoid-opioid receptor heteromers, although the exact biological significance of such receptor heteromerization remains to be fully elucidated. Taken together, these findings suggest the existence of cross-talk between the cannabinoid and opioid systems. Furthermore, pre-clinical studies using a combination of different opioids (morphine, codeine) and cannabinoids (THC), at acute or sub-effective doses, have reported additive and even synergistic analgesic effects. A recent systematic review and meta-analysis of pre-clinical studies examining the strength of the existing evidence for the "opioid-sparing" effect of cannabinoids in the context of analgesia concluded that there was a significant opioid-sparing effect between morphine and THC when co-administered, although there was significant heterogeneity in the data. Nevertheless, when compared to morphine administration alone, the median ED ₅₀ of morphine was 3.6 times lower when given in combination with THC. A significant "opioid-sparing" effect was also reported for THC when co-administered with codeine (ED ₅₀ 9.5 times lower when THC combined with codeine vs. codeine alone).
Clinical case series and epidemiological data Data from clinical trials
4.7.2.5 Headache and migraine

The evidence supporting using cannabis/certain cannabinoids to treat headache and migraine is very limited and mixed.

4.8 Arthritides and musculoskeletal disorders

The evidence from pre-clinical studies suggests stimulation of CB₁ and CB₂ receptors alleviates symptoms of osteoarthritis (OA), and THC and CBD alleviate symptoms of rheumatoid arthritis (RA).

The evidence from clinical studies is very limited, with a modest effect of nabiximols for RA.

There are no clinical studies of cannabis for fibromyalgia, and the limited clinical evidence with dronabinol and nabilone suggests a modest effect on decreasing pain and anxiety, and improving sleep.

The role of cannabinoids in osteoporosis has only been investigated pre-clinically and is complex and conflicting.

The arthritides include a broad spectrum of different disorders (e.g. osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis, gout, and many others) all of which have in common the fact that they target or involve the joints. Scientific studies have demonstrated that joints, bone, and muscle all contain a working ECS, that some arthritides such as OA and RA are associated with changes in the functioning of the ECS, and that modulation of the ECS may help alleviate some of the symptoms associated with certain arthritides. The section below summarizes the evidence for cannabis/cannabinoids in OA and RA. Also covered are musculoskeletal disorders such as fibromyalgia and osteoporosis.

Information from surveys

The 2011 Canadian Alcohol and Drug Use Monitoring Survey ( CADUMS) indicated that a significant proportion of Canadians aged 15 and over who reported using cannabis for medical purposes reported using it for chronic pain associated with, for example, arthritis.

4.8.1 Osteoarthritis

Pre-clinical studies

Both CB ₁ and CB ₂ receptors have been localized in knee joints confirming that local control of joint pain is achievable without the need to involve central cannabinoid receptors. Downregulation of CB ₁ and CB ₂ receptor gene expression was reported in the lumbar spinal cord of osteoarthritic mice, likely in response to an elevated endocannabinoid tone coming from the affected osteoarthritic joints.

A study in rats reported that intra-articular injection of the CB ₁ receptor agonist arachidonyl-2-chloroethylamide in control animals was associated with a reduction in firing rate and suppression of nociceptive activity from pain fibers innervating the joints when the joints were subjected to either normal or noxious joint rotation. Furthermore, animals with osteoarthritic joints produced an augmented response to articular CB ₁ receptor activation. The anti-nociceptive effect was blocked by co-administration of a CB ₁ receptor antagonist in osteoarthritic joints, but not in control joints.

Systemic administration of a CB ₂ receptor agonist in a rat model of OA was associated with a dose-dependent reversal of decreased grip force in the affected limb, a proxy measure for pain. The maximal analgesic efficacy was comparable to that seen with celecoxib in this animal model of OA.

One animal study conducted in a rat model of OA reported that CB ₂ receptor mRNA levels were significantly increased in spinal cord of osteoarthritic rats. Furthermore, selective stimulation of the CB ₂ receptor by systemic dosing with a synthetic cannabinoid receptor agonist was associated with significant attenuation of the development and maintenance of pain behaviour and spinal neuronal responses. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor (TNF) α, and IL-10 were also significantly attenuated following treatment with the CB ₂ receptor agonist. Rats also did not appear to develop tolerance to the anti-nociceptive effects of the CB ₂ receptor agonist after multiple administrations of the drug. The study also showed a negative association between CB ₂ mRNA levels and chondropathy in post-mortem samples of human spinal cord.

An animal study of OA in mice reported that the condition was associated with significant increases in 2-AG levels in the prefrontal cortex, the area of the brain implicated in pain, cognitive and emotional processing, as well as in the plasma. OA in this mouse model was also associated with increases in stress and anxiety-like behaviour in affected wild-type mice and in mice lacking CB ₁ receptor expression, but not in mice lacking CB ₂ receptor expression suggesting distinct roles for these two receptors in the pathophysiology of OA. Selective stimulation of CB ₁ and CB ₂ receptors was associated with improvements in mechanical allodynia. Lastly, patients with OA were shown to have significant increases in their plasma levels of 2-AG, but not anandamide, compared to healthy controls consistent with the findings obtained in the mouse model. Furthermore, expression of CB ₁ and CB ₂ receptors was upregulated in blood lymphocytes of these patients and significant positive correlations were noted between plasma levels of 2-AG, knee pain, and depression scores as well as significant negative correlations with SF-36 (QoL) and memory performance scores.

Further support for a role for the CB ₂ receptor in the pathophysiology of OA comes from a pre-clinical study in mice lacking CB ₂ receptor expression. These mice developed significantly more severe OA compared with wild-type controls. Furthermore, treatment of wild-type mice with a CB ₂ receptor agonist was associated with partial protection from OA. In contrast, another study found that local delivery of a CB ₂ receptor agonist actually increased joint nociceptor activity and the resulting heightened pain response was thought to involve TRPV1 ion channels.

Clinical studies

4.8.2 Rheumatoid arthritis

Pre-clinical studies

The results from a study examining the anti-nociceptive effects of THC in a rat model of RA suggested that intraperitoneal administration of 4 mg/kg THC was associated with a significant decrease in the levels of spinal dynorphin, an increase in kappa-opioid receptor-mediated analgesia, and a decrease in NMDA-receptor-mediated hyperalgesia. Another study by the same group and using the same animal model demonstrated that THC was equipotent and equiefficacious to morphine with regard to anti-nociception in the paw-pressure test, and that there was a synergistic anti-nociceptive interaction between THC and morphine in both arthritic and non-arthritic rats in the same paw-pressure test. A follow-up study again using the same animal model suggested an important role for the CB ₂ receptor in modulating the anti-nociceptive effects of THC.

Indeed, a number of additional studies have continued to support an important role for the CB ₂ receptor in RA. Tissue samples taken from human rheumatoid joints showed increased CB ₂ receptor expression compared to osteoarthritic joints, with expression of the CB ₂ receptor localized to the lining layer and interstitial sub-lining layer as well as follicle-like aggregates. Furthermore, CB ₂ receptor activation on fibroblast-like synoviocytes derived from rheumatoid joints was associated with inhibition of the production of a variety of inflammatory mediators seen in RA including IL-6, matrix metalloproteinase (MMP)-3, MMP-13, and chemokine (C-C motif) ligand (CCL) 2. CB ₂ receptor activation was also associated with dose-dependent amelioration of arthritis severity in a mouse model of RA. Selective stimulation of the CB ₂ receptor significantly decreased joint swelling, synovial inflammation, and joint destruction, as well as serum levels of anti-collagen II antibodies in a mouse model of RA. However, others have reported that stimulation of joint CB ₂ receptors causes synovial hyperaemia through a mechanism involving TRPV1 ion channels. The vasodilator effect of these CB ₂ receptor agonists is attenuated in models of acute and chronic arthritis suggesting that CB ₂ receptors are downregulated in inflamed joints.

Clinical studies

There are no published clinical studies of cannabis for RA.

4.8.3 Fibromyalgia

Fibromyalgia is a disorder characterized by widespread pain (allodynia and hyperalgesia) and a constellation of other symptoms including sleep disorders, fatigue, and emotional or cognitive disturbances. While the underlying pathophysiology of fibromyalgia remains unclear, disturbances in the recruitment or functioning of peripheral and central pain processing pathways and in the levels of several important neurotransmitters (serotonin, noradrenaline, dopamine, opioids, glutamate and substance P) have been noted in fibromyalgia patients. Co-morbid depressive symptoms have also been associated with a more pronounced deficit in pain inhibition, as well as increased pain in fibromyalgia patients.

Clinical studies with smoked or orally ingested cannabis

Clinical studies with prescription cannabinoid medications

There are relatively few properly controlled clinical studies examining the role of cannabinoids in the treatment of fibromyalgia. The available evidence is summarized below.

Dronabinol

A non-placebo controlled pilot study examining the effect of dronabinol monotherapy (2.5 - 15 mg Δ ⁹-THC/day; with weekly increases of 2.5 mg Δ ⁹-THC, up to a maximum of 15 mg THC/day) on experimentally-induced pain, axon reflex flare, and pain relief in patients suffering from fibromyalgia reported that a sub-population of such patients experienced significant pain relief (reduced pain perception) with 10 and 15 mg/day Δ ⁹-THC, but no changes were observed in axon reflex flare. Touch-evoked allodynia and pinprick-induced hyperalgesia were also not significantly affected by Δ ⁹-THC. Subjects who completed a three-month course of therapy (15 mg/day Δ ⁹-THC) reported a > 50% decrease in pain. The study however suffered from low power due to the high rate of patient drop-out caused by intolerable side effects of the treatment.

Nabilone

4.8.4 Muscular pain

Muscular pain affects a large share of the population and is a major clinical problem. Findings from pre-clinical studies using two animal models of acute muscle pain suggest that both systemic (0.3 - 5 mg/kg i.p.) and local administration (0.0125 - 0.1 mg/kg i.m.) of THC is associated with a dose-dependent reduction in frequency of paw shaking and a reduction in time spent in nocifensive behaviour following a noxious muscular stimulus. Differences in the types of cannabinoid receptors engaged were observed according to the route of administration: systemic administration of THC was associated with engagement of CB ₁ and/or CB ₂ receptors, while local administration of THC in the paw was predominantly associated with engagement of CB ₂ receptors. No human experimental or clinical studies exist with cannabinoids for muscular pain.

4.8.5 Osteoporosis

Pre-clinical studies

CB ₁ and CB ₂ receptors have been detected in mouse osteoblasts and osteoclasts, although CB ₁ is expressed at very low levels compared to CB ₂. In fact, it appears that CB ₁ receptors are expressed more abundantly in skeletal sympathetic nerve terminals in close proximity to osteoblasts. Besides the receptors, the endocannabinoids 2-AG and anandamide have been detected in mouse trabecular bone and in cultures of mouse osteoblasts and human osteoclasts. Taken together, these findings suggest the existence of a functional ECS in bone.

The role of the ECS in bone physiology has been investigated using mice carrying genetic deletions of either the CNR1 or CNR2 genes. The skeletal phenotypes of CB ₁ receptor knockout mice appear to vary depending on the gene targeting strategy used, the mouse strain, gender, time points at which the phenotypes were assessed, and the different experimental methodologies used to measure bone density. In one CB ₁-deficient mouse strain, young female mice had normal trabecular bone with slight cortical expansion whereas young male mice had high bone mass. Loss of CB ₁ receptor function was associated with protection from ovariectomy-induced bone loss. In addition, antagonism of CB ₁ and CB ₂ receptors prevented ovariectomy-induced bone loss in vivo.

A subsequent study by the same group reported that CB ₁ knockout mice had increased peak bone mass but eventually developed age-related osteoporosis. The increased peak bone mass was attributed to a reduction in osteoclast formation and activity, with preservation of normal osteoblast activity. In contrast, age-related bone loss in the knockout mice appeared to be caused by preferential formation and accumulation of adipocytes at the expense of osteoblasts within the bone-marrow space, as well as decreased bone formation. In contrast to these studies, another study using a different gene targeting strategy and mouse strain reported that both male and female CB ₁ knockout mice exhibited low bone mass, increased numbers of osteoclasts, and a decrease in the rate of bone formation. The effects of ovariectomy in this mouse line were not examined, most likely because the baseline bone mass was too small to properly measure differences between mice subjected to ovariectomy and controls.

In mice, activation of CB ₁ receptors by THC has been shown to significantly slow bone elongation and possibly overall body size, at least in female adolescent mice. The concentration of systemic THC administered in the mice (5 mg/kg/day) was reported to be similar to that described for human daily cannabis smokers.

The skeletal phenotypes of CB ₂ receptor knockout mice have also been investigated. Ofek reported that CB ₂-deficient mice display a low bone mass phenotype as well as age-related trabecular bone loss. These deficits were associated with increased numbers of osteoclasts and decreased numbers of osteoblast precursors. Furthermore, a selective CB ₂ receptor agonist was reported to increase osteoblast proliferation and activity and to decrease the formation of osteoclast-like cells in vitro, and administration of this agonist attenuated ovariectomy-induced bone loss in vivo. While a more recent study supported the finding of age-related bone loss, it failed to find any significant differences in peak bone mass between wild-type and knockout mice. Furthermore, in contrast to the study by Ofek, selective stimulation of the CB ₂ receptor was associated with an increase in osteoblast differentiation and function rather than proliferation. Another study reported no differences in peak bone mass between CB ₂ receptor knockout mice and wild-type mice under normal conditions. Age-related bone loss was not measured in this study. Genetic ablation of the CB ₂ receptor appeared to protect against ovariectomy-induced bone loss, an effect mimicked by administration of a CB ₂-selective antagonist. Conversely, results from in vitro studies suggested that CB ₂-selective agonists significantly increased osteoclast formation and osteoclast size. It may be relevant to note here that single nucleotide polymorphisms (SNPs) and SNP haplotypes located in the coding region of the CB ₂ receptor gene have also been associated with osteoporosis in humans.

4.9 Other diseases and symptoms

4.9.1 Movement disorders

The individual components of the ECS are particularly abundant in areas of the brain that control movement, such as the basal ganglia. Motor effects generally arise as a consequence of changes in ECS activity, with activation of the CB ₁ receptor typically resulting in inhibition of movement. A number of studies have reported changes in CB ₁ receptor levels and CB ₁ receptor activity in motor diseases such as Parkinson's disease (PD) and Huntington's disease (HD), and the findings from such studies suggest a complex link between the ECS and the pathophysiology of these and other neurological diseases.

4.9.1.1 Dystonia

Evidence from limited pre-clinical studies suggests that a synthetic CB₁ and CB₂ receptor agonist may alleviate dystonia-like symptoms, and CBD delays dystonia progression.

Evidence from a limited number of case studies and small placebo-controlled or open-label clinical trials suggests improvement in symptoms of dystonia with inhaled cannabis, mixed effects of oral THC, improvement in symptoms of dystonia with oral CBD, and lack of effect of nabilone on symptoms of dystonia.

Pre-clinical data
A pre-clinical study in a hamster model of primary generalized dystonia reported a dose-dependent decrease in disease severity with administration of the synthetic CB ₁ and CB ₂ receptor agonist WIN 55,212-2. However, anti-dystonic doses of the agonist were associated with severe side effects including depression of spontaneous locomotor activity and catalepsy. In addition, this CB receptor agonist increased the anti-dystonic effect of diazepam. A follow-up study by the same group confirmed the anti-dystonic efficacy of WIN 55,212-2 and also showed that CBD delayed the progression of dystonia, but only at a very high dose. A pre-clinical study of anti-psychotic-induced acute dystonia and tardive dyskinesia in monkeys showed that oral dyskinesia, but not dystonia, was dose-dependently reduced by the synthetic CB ₁ receptor agonist CP 55,940.
Clinical data
4.9.1.2 Huntington's disease
Pre-clinical and human experimental data
Results from studies carried out in animal models of HD as well as post-mortem studies carried out in deceased HD patients suggest that brain CB ₁ receptors, especially those found in the basal ganglia, are downregulated and/or desensitized as a result of the expression of the mutant Huntingtin protein, and that this occurs early in the course of the disease and prior to the appearance of overt clinical symptoms. In vivo positron emission topography (PET) study of HD patients supports these findings, demonstrating profound decreases in CB ₁ receptor availability throughout the gray matter of the cerebrum, cerebellum, and brainstem of HD patients even in early stages of the disease. Additional pre-clinical and post-mortem studies in deceased HD patients indicate that the decrease in CB ₁ receptor levels appears to be accompanied by an increase in CB ₂ receptor levels in glial elements, astrocytes, and in reactive microglial cells. Thus, a significant amount of pre-clinical evidence and some limited clinical evidence suggests that changes in the ECS are tightly linked to the pathophysiology of HD.

One pre-clinical study in a mouse model of HD reported no beneficial effects of Δ ⁹-THC (10 mg/kg/day), while another study reported that Δ ⁹-THC (2 mg/kg/day) was associated with decreased pathology and delayed onset of HD-like symptoms compared to untreated HD mice. Another pre-clinical animal study in a rat model of HD showed that CB 2 receptor activation was associated with reduction in inflammatory markers associated with an HD-like phenotype and protection of striatal projection neurons. A pre-clinical study has also reported that a restricted population of CB ₁ receptors selectively located on glutamatergic terminals in corticostriatal projections may play a potentially protective role in attenuating excitotoxic damage associated with excessive glutamate release in HD, raising the possibility that selective targeting of this receptor population may help attenuate neurodegeneration in patients with HD.
Clinical data
4.9.1.3 Parkinson's disease

The evidence from a limited number of pre-clinical, case, clinical and observational studies of certain cannabinoids for symptoms of Parkinson's disease (PD) is mixed.

One case study of smoked cannabis suggests no effect while an observational study of smoked cannabis suggests improvement in symptoms.

One small clinical study of nabilone suggests improvement in symptoms, while another clinical study of an oral cannabis extract (THC/CBD) and a clinical study with CBD suggest no improvement in symptoms.

Pre-clinical and human experimental data
Endocannabinoid ligands, their synthesizing and degrading enzymes, and cannabinoid-activated receptors are highly abundant in the basal ganglia, the brain structures primarily affected in PD. Newly diagnosed PD patients and those undergoing PD medication washout were reported to have more than double the level of anandamide in their CSF compared to controls, and these results parallel those seen in animal models of PD where dopamine cell loss is accompanied by elevations in anandamide levels. In animal models of PD, the levels of CB ₁ receptors appear to be downregulated during the early, pre-symptomatic stages of the disease, but during the intermediate and advanced phases of the disease there is an increase in CB ₁ receptor density and function and an increase in endocannabinoid levels. Together, these studies suggest a complex link between the pathophysiology of PD and changes in the ECS.

Results from some animal studies suggest cannabinoid receptor agonists induce hypokinesia and thus are reported to be unlikely as suitable first-line treatments for PD. On the other hand, cannabinoid-induced hypokinesia could be useful in attenuating the dyskinesia observed in PD patients on long-term levodopa treatment. Other animal studies suggest CB ₁ receptor antagonism (via treatment with rimonabant) partially attenuates hypokinesia associated with nigral cell death and promotes dopaminergic neuron survival in the substantia nigra pars compacta through an increase in astrocyte cell density. However, this beneficial effect of CB ₁ receptor antagonism could not be replicated in a small clinical study. Given the current level of evidence for cannabinoids in the treatment of PD, it would appear that cannabinoid-based neuroprotective therapy for PD would need to be based on an adequate combination of selected compounds that confer antioxidant effects (e.g. through CB-receptor independent mechanisms) such as through activation of the nuclear PPAR receptor family, CB ₂ receptor activation and control of inflammation, and CB ₁ receptor antagonism to improve akinesia and reduce motor inhibition. Combining a cannabinoid with anti-inflammatory and anti-oxidant properties (CBD) with a cannabinoid having mixed CB ₁ antagonist/CB ₂ agonist properties as well as anti-oxidant effects (THCV) may possibly hold some therapeutic potential, but much further research is required.
Clinical data
The results of clinical trials examining the role of cannabinoids (smoked cannabis, nabilone, CBD, rimonabant and a standardized oral cannabis extract) in the treatment of PD are mixed.

Lastly, an exploratory double-blind clinical trial of 21 patients with PD (without dementia or comorbid psychiatric conditions) assessed the motor and general symptoms score (UPDRS), functioning/well-being and QoL (39-item Parkinson Disease Questionnaire, PDQ-39) and possible neuroprotective effects (plasma brain-derived neurotrophic factor (BDNF) and proton magnetic resonance spectroscopy, H ¹-MRS) following treatment with placebo or CBD (75 mg or 300 mg/day) for six weeks. No statistically significant differences were observed between placebo and all CBD doses for UPDRS scores, plasma BDNF levels or H ¹-MRS measures. However, the 300 mg CBD dose was associated with a statistically significant difference in mean total scores from placebo in the PDQ-39 suggesting that the 300 mg daily CBD dose is associated with an improvement in QoL measures in PD patients with no psychiatric comorbidities.

4.9.1.4 Tourette's syndrome

The limited evidence from small clinical studies suggests that oral THC improves certain symptoms of Tourette's syndrome (TS) (tics).

Anecdotal and case-reports have suggested amelioration of symptoms associated with TS when smoking cannabis. In addition, a two-day, randomized, double-blind, placebo-controlled, crossover trial of single oral doses of Δ ⁹-THC (5, 7.5, or 10 mg) in 12 adult patients with TS showed plasma concentration-related improvements in control of motor and vocal tics and obsessive-compulsive behaviour, with no serious side effects; although transient, mild side effects (e.g. headache, nausea, ataxia, fatigue, anxiety) were noted in five patients. In contrast to healthy cannabis users, neither a 5 mg nor a 10 mg dose of Δ ⁹-THC caused cognitive impairment in patients with TS. This study was followed up by a six-week, randomized, double-blind, placebo-controlled trial by the same research group. The authors reported a significant difference in tic reduction compared to placebo in some patients, and no detrimental effects on neuropsychological performance during or after treatment with 10 mg doses of Δ ⁹-THC. The major limitations of all three clinical studies were their small sample size and their relatively short duration.

4.9.1.5 Spinocerebellar ataxias

There is emerging evidence of a role for the ECS in the pathophysiology of spinocerebellar ataxias. Post-mortem studies of cerebellar samples collected from deceased patients with hereditary autosomal dominant ataxias revealed significant increases in the protein expression levels of FAAH and MAGL in the Purkinje cells in the cerebellar granular layer, in neurons of the dentate nucleus, and in cerebellar white matter compared to controls. In another study, the protein expression levels of the CB ₁ and CB ₂ receptors in these same areas of the cerebellum were also found to be significantly increased compared to controls. These studies suggest an increase in the expression levels of a number of components of the ECS in cerebellar areas associated with hereditary autosomal dominant ataxias.

4.9.2 Glaucoma

The limited evidence from small clinical studies suggests oral administration of THC reduces intra-ocular pressure (IOP) while oral administration of CBD may, in contrast, cause an increase in IOP.

Glaucoma is a multi-factorial disease characterized by the progressive degeneration of the optic nerve and the death of retinal ganglion cells ultimately leading to irreversible blindness. Increased IOP has been implicated in the pathophysiology of glaucoma; however, inadequate blood supply to the optic nerve, oxidative damage, and apoptosis of retinal ganglion cells are also contributing factors. An ECS exists in a number of ocular tissues, and post-mortem studies have detected decreased levels of endocannabinoids in such tissues taken from deceased glaucoma patients.

Ocular (as well as systemic) administration of cannabinoids typically lowers IOP by up to 30% (see for a full reference list). How cannabinoids reduce IOP is unclear, but several possible mechanisms have been proposed including reduction of capillary pressure, decreased aqueous humour production, and improved aqueous humour uveoscleral outflow and outflow facility.

A well-controlled pilot clinical study of six patients with ocular hypertension or early primary open-angle glaucoma reported that single sub-lingual doses of 5 mg Δ ⁹-THC (applied by means of an oro-mucosal spray) significantly but temporarily reduced IOP 2 h after administration. A single sub-lingual dose of 20 mg CBD (co-administered with approx. 1 mg Δ ⁹-THC) had no effect, while a single sub-lingual dose of 40 mg of CBD (co-administered with ~ 2 mg Δ ⁹-THC) caused a significant transient increase in IOP 4 h after administration. A non-randomized, unmasked, uncontrolled clinical study reported some improvement in IOP after oral ingestion of Δ ⁹-THC (2.5 or 5 mg q.i.d., up to a maximum of 20 mg/day; treatment duration range: 3 - 36 weeks) in patients with end-stage, open-angle glaucoma not responsive to standard medications or surgery. Some patients appeared to develop tolerance to the IOP-lowering effects of Δ ⁹-THC, and almost half discontinued treatment due to Δ ⁹-THC-associated side effects (e.g. dizziness, dry mouth, sleepiness, depression, confusion). Aside from lowering IOP, cannabinoids such as Δ ⁹-THC (and CBD) may also have neuroprotective effects which could also be useful in the management of glaucoma.

In conclusion, while smoking or eating cannabis (or oral Δ ⁹-THC) has been reported to reduce IOP, cannabinoid-based therapy appears to be limited by the short duration of cannabinoid action (3 - 4 h) and unwanted physical and psychotropic effects.

4.9.3 Asthma

There is some historical and anecdotal evidence for cannabis as a treatment for asthma. In terms of pre-clinical data, there is some evidence suggesting a role for the ECS in regulating bronchial smooth muscle tone and studies with animals using classical and synthetic cannabinoids suggest a possible role for cannabinoid-based compounds in the treatment of asthma.

Early clinical studies demonstrated significant decreases in airway resistance and increases in specific airway conductance in healthy, habitual cannabis smokers shortly after smoking cannabis. This effect has been largely attributed to the bronchodilatory properties of Δ ⁹-THC. However, for asthmatics, the benefits of smoking cannabis are likely to be minimal. While smoking cannabis appears to decrease bronchospasm, increase bronchodilatation, and modestly improve respiratory function in some asthmatics in the short-term, cannabis smoke contains noxious gases and particulates that irritate and damage the respiratory system; hence, it is likely not a viable long-term therapy for asthma. A number of studies have also reported hypersensitivity reactions, including asthmatic attacks in response to inhalation of cannabis smoke.

Importantly, therefore, alternate methods of Δ ⁹-THC delivery by aerosol or oral administration have been studied. Doses of 100 and 200 µg of aerosolized Δ ⁹-THC significantly improved ventilatory function in asthmatics and were generally well tolerated. In another study, 5 to 20 mg of aerosolized Δ ⁹-THC rapidly and effectively increased airway conductance in healthy subjects, but caused either bronchodilatation or bronchoconstriction in asthmatics. Oral administration of 10 mg Δ ⁹-THC or 2 mg nabilone did not produce clinically significant bronchodilatation in patients with reversible airways obstruction.

4.9.4 Hypertension

CB ₁ receptors are expressed on various peripheral tissues including the heart and vasculature, and CB receptor agonists and endocannabinoids decrease arterial blood pressure and cardiac contractility (reviewed in).

There are no reports on the use of low-dose cannabinoids as supplementary therapy in hypertension.

4.9.5 Stress and psychiatric disorders

There are anecdotal and, in some cases, historical claims regarding the beneficial effects of cannabis and cannabinoids in the treatment of a variety of psychiatric disorders including anxiety, depression, sleep disorders, PTSD, and withdrawal symptoms associated with drug abuse/addiction. The following sections provide information gathered from the scientific and medical literature regarding the use of cannabis and cannabinoids in the treatment of such disorders.

The endocannabinoid system, stress and psychiatric disorders

4.9.5.1 Anxiety and depression

Evidence from pre-clinical and clinical studies suggests that THC exhibits biphasic effects on mood, with low doses of THC having anxiolytic and mood-elevating effects and high doses of THC having anxiogenic and mood-lowering effects.

Limited evidence from a small number of clinical studies of THC-containing cannabis/certain prescription cannabinoids suggests that these drugs could improve symptoms of anxiety and depression in patients suffering from anxiety and/or depression secondary to certain chronic diseases (e.g. patients with HIV/AIDS, MS, and chronic neuropathic pain).

Evidence from pre-clinical studies suggests that CBD exhibits anxiolytic effects in various animal models of anxiety, while limited evidence from clinical studies suggest CBD may have anxiolytic effects in an experimental model of social anxiety.

Limited evidence from some observational studies also suggests that cannabis containing equal proportions of CBD and THC is associated with an attenuation of some perturbations in mood (anxiety/dejection) seen with THC-predominant cannabis in patients using cannabis for medical purposes.

Pre-clinical studies
Pre-clinical (and clinical) evidence indicates important roles for the ECS in both anxiety and mood disorders. Results from animal studies suggest low doses of CB ₁ receptor agonists reduce anxiety-like behaviour and increase anti-depressant-like responses. CB ₁ receptor agonists appear to enhance central serotonergic and noradrenergic neurotransmission similar to the actions of anti-depressant medications. On the other hand, high-level stimulation of the CB ₁ receptor, or administration of CB ₁ receptor antagonists, reverse this response and can also trigger depressive-like symptoms or depression. Suppression of endocannabinoid signalling is sufficient to induce a depressive-like state both in animals and in humans (reviewed in). Furthermore, basal serum concentrations of both anandamide and 2-AG have been found to be significantly reduced in women with major depression. These findings suggest proper endocannabinoid tone plays an important role in regulating mood.
Clinical and observational data for cannabis and THC
While the routine use of THC-predominant cannabis or prescription cannabinoid medications containing primarily THC (dronabinol) to treat primary anxiety or depression should be viewed with caution, and especially discouraged in patients with a history of psychotic disorders (see Section 7.7.3.2), limited clinical evidence indicates that these drugs may present alternative therapeutic avenues in patients suffering from anxiety or depression secondary to certain chronic diseases. For example, in a study of HIV+ patients who reported using cannabis to manage their symptoms, 93% cited an improvement in anxiety and 86% cited an improvement in depression. It is important to note that 47% of those surveyed reported deterioration in memory. In another within-subject, double-blind, placebo-controlled, clinical study of HIV+ cannabis smokers, high-dose dronabinol (5 mg q.i.d., for a total daily dose of 20 mg, for two days, followed by 10 mg q.i.d., for a total daily dose of 40 mg, for 14 days) was associated with an increase in self-reported "positive affect" (feeling "content"), but no change was observed in measures of anxiety or "negative affect". The dosage employed in this study was eight times the recommended starting dose for appetite stimulation (i.e. 2.5 mg b.i.d), and double the maximal daily recommended dose. Improved mood was also reported as a beneficial effect of cannabis consumption in patients suffering from MS. Improvements in anxiety or depression were equally noted in a clinical study of patients suffering from chronic neuropathic pain who smoked cannabis. It may be interesting to note here that rimonabant, a CB ₁ receptor antagonist initially marketed as an anti-obesity medication, was withdrawn from the market because its use was associated with a significant incidence of anxiety, depression, and suicide, underscoring the role of the CB ₁ receptor in regulating mood. For additional information on the association between cannabis and anxiety and depression please see Section 7.7.3.1 and between cannabis and suicide, please see Section 7.7.3.3.
Cannabidiol Pre-clinical data
More than 30 pre-clinical studies have been carried out examining the anxiolytic effects of CBD in a variety of animal models of various types of anxiety disorders including generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder and PTSD. In general, the findings from these pre-clinical studies support the anxiolytic effects of CBD. In addition, CBD also appears to have panicolytic and anti-compulsive effects and decreases autonomic arousal and conditioned fear expression. CBD also appears to enhance fear extinction, promote reconsolidation blockade, and prevent long-term anxiogenic effects of stress. While the exact anxiolytic mechanism of action of CBD is unclear, one proposed molecular target of CBD is the 5-HT 1A receptor.
Clinical data
Findings from functional neuroimaging studies suggest differential cerebral blood flow effects associated with administration of CBD compared with those seen with placebo or THC. Single-photon emission computed tomography (SPECT) brain imaging studies showed that in contrast to placebo, CBD decreased regional cerebral blood flow in the limbic and paralimbic cortical areas, regions implicated in the pathophysiology of anxiety. Furthermore, a randomized, double-blind, placebo-controlled study showed that 600 mg of CBD attenuated brain activity (blood oxygenation level-dependent response) in these cortical regions in response to anxiogenic stimuli. In contrast, 10 mg of Δ ⁹-THC increased anxiety at baseline or in response to anxiogenic stimuli, and the brain regions affected by Δ ⁹-THC differed from those affected by CBD. Although the precise mechanism by which CBD exerts its anxiolytic effects is not well established, it may act either by decreasing blood flow to brain regions associated with the processing of anxiety or fear-based stimuli (as mentioned above), or possibly through the modulation of serotonergic neurotransmission

4.9.5.2 Sleep disorders
Human experimental data
There is some evidence from experimental studies to suggest a role for the ECS in the regulation of sleep. Subjects deprived of sleep for a 24 h period had increased levels of OEA, a natural analogue of anandamide, in their CSF but not in serum, whereas levels of anandamide were unchanged. Recent studies have shown daily variation in 2-AG concentrations that are amplified under sleep restriction. 2-AG levels appear lowest around midsleep and increase continually across the morning, peaking in the early to mid-afternoon with concentrations of 2-oleoylglycerol (2-OG), a structural analogue of 2-AG, following a similar pattern. In rats, both acute and sub-chronic administration of anandamide induces sleep. Cannabis containing mainly THC, as well as Δ ⁹-THC itself are known to have a number of effects on sleep in humans, which may be dose-dependent (i.e. low doses appearing beneficial on some measures of sleep, high doses causing sleep disturbances). In general, it appears that at low doses these substances (THC-predominant cannabis, THC) decrease sleep onset latency and are associated with greater ease in getting to sleep whereas the opposite is true at high doses; there is a consistent reduction in total rapid eye movement (REM) sleep and REM density (reviewed in). Low doses of THC also increase beneficial slow-wave sleep (critical for learning, memory consolidation, and memory retrieval) and total sleep time, while high doses decrease slow-wave sleep. Furthermore, due to the long half-life of THC, sedative effects may typically persist into the day following administration.
Data from withdrawal studies Clinical data
Indeed, a number of clinical studies point to a potential beneficial role for smoked cannabis or prescription cannabinoids (dronabinol, nabilone, nabiximols) in the treatment of sleep difficulties or disturbances associated with chronic pain (cancer pain, chronic non-cancer pain, diabetic peripheral neuropathy), HIV-associated anorexia-cachexia, MS, ALS, SCI, RA, fibromyalgia, inflammatory bowel disease (IBD), MS-associated bladder dysfunction, PTSD, chemosensory alterations and anorexia-cachexia associated with advanced cancer. In most of these studies, the effect on sleep was measured as a secondary outcome.

Although presented elsewhere throughout the text in the relevant sections, brief summaries of a number of these studies are presented below.
Dronabinol
A four-week, randomized, double-blind, crossover pilot clinical study of 19 patients suffering from ALS taking 2.5 - 10 mg per day of dronabinol reported improvements in sleep. Two clinical studies reported that dronabinol (20 - 40 mg total Δ ⁹-THC/day) and smoked cannabis (~800 mg cigarettes containing 2 or 3.9% THC, administered four times per day for four days, corresponding to an estimated daily amount of 64 - 125 mg of Δ ⁹-THC consumed) produced improvements in mood and sleep in patients with HIV/AIDS-associated anorexia-cachexia. A clinical study of HIV+ cannabis smokers treated with dronabinol for 14 days (10 mg q.i.d., 40 mg daily) reported improvements in both objective and subjective measures of sleep, but only during the first eight days of the treatment regimen. A two-centre, phase II, randomized, double-blind, placebo-controlled, 22-day pilot clinical study carried out in adult patients suffering from chemosensory alterations and poor-appetite associated with advanced cancer of various etiologies reported statistically significant improvements in measures of quality of sleep and relaxation with dronabinol treatment (2.5 mg b.i.d.) compared to placebo. An open-label pilot study of add-on oral THC (25 mg/mL THC in olive oil; 2.5 mg THC b.i.d., maximal daily dose 10 mg THC) in patients with chronic PTSD reported improvement in sleep quality and frequency of nightmares.
Nabilone Smoked cannabis Orally administered pres

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For health care professionals: Cannabis and cannabinoids - Canada.ca

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(PDF Version - 2,236 K) Dried or fresh plant and oil for administration by ingestion or other means Psychoactive agent This document has been prepared by the Cannabis Legalization and Regulation Branch at Health Canada to provide information on the use of cannabis (marihuana) and cannabinoids for medical purposes.

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Around the world, on the 20 April - or "420" - cannabis users will be lighting up to celebrate "weed culture" and protest about its prohibition in many countries.

But even though recreational cannabis has been illegal in the UK since 1928, the evidence shows that punishments for its possession have plummeted in recent years in England and Wales.

Comparative figures for policing in Scotland and Northern Ireland are not available.

Today cannabis is classified as a Class B - or middle-risk - substance.

Despite this, prosecutions are lower than when it was considered a low-risk, Class C drug in 2008.

In theory, possession of cannabis can still land you with five years in prison.

However, if you only have a small amount on you, then you are more likely to get a cannabis warning, often used for first offenders. These warnings do not show up on criminal records checks, but are recorded on the police database.

Repeat offenders could face a penalty notice (fine), a caution or prosecution.

A Home Office spokesperson said that enforcement of cannabis laws is "an operational decision for chief constables, but we are clear that we expect them to enforce the law".

Some police forces have openly changed tack towards small-scale users, with Somerset and Avon Police, for example, offering drug awareness courses for those caught with small amounts, while maintaining a tough approach to dealers and growers.

The drugs lead for the National Police Chiefs' Council, Assistant Chief Constable Jason Harwin, says it is up to chief constables to determine "operational priorities".

"However, there is strong evidence to suggest that recommending minor offenders for early intervention treatment instead of pursuing convictions can prevent reoffending and result in the best outcome for both the user and the criminal justice system," he says.

Despite this, the vast majority of police seizures are of fewer than five grams (0.18oz) - or about £25 street value in the UK.

Last year, almost 36,000kg (79,000lb) of cannabis was seized by the police and Border Force, with the largest seizure weighing more than 100kg.

Racial disparities

A lot of the time, small-scale seizures of cannabis come from stop and searches, the police power which allows officers to search someone under the "reasonable" suspicion that they are engaged in an illegal activity.

Stop and searches disproportionately affect black people, who are nine times more likely to be searched for drugs than white individuals.

Research carried out by by the London School of Economics suggests this is why black people are so heavily represented in cannabis prosecutions, with more than 20% of those convicted being black people. who only make up 5% of the population.

In 2016, the College of Policing issued guidance saying that the smell of cannabis was no longer a good enough reason for a stop and search.

Currently, almost half of all stop and searches are linked to suspicion of drug possession.

Most popular illegal drug

Cannabis remains the country's most popular illegal drug.

In England and Wales, 30% - that's around 10 million - adults aged 16 to 64 have tried the drug at least once, according to the annual crime survey.

Regular use is far less common, with only 3.3% of adults saying they had used it in the past week.

Among young adults cannabis is used more widely, but weekly use has more than halved since 2002, down to 7.3%.

Issues around health

The NHS warns that regular use of cannabis can lead to dependency, similar to alcohol, and severe mental health issues, such as psychosis.

In 2017-18, almost 55,000 people were receiving support for cannabis use in England, making it the fourth most-represented substance after opiates, crack cocaine and alcohol (although in many cases it is abused alongside other drugs).

The number of people under 18 who are receiving support stands at 12,066; a small decrease from a decade ago.

Because of its illegal nature, it is impossible to fully assess the potency - and therefore the health risks - of cannabis being sold on the street, but research in 2016 highlighted that people are being sold higher-strength strains of the drug.

The research comes as A&E admissions because of mental and behavioural problems linked to cannabis in England have increased by 50% in five years.

But when the chemicals in the plant are controlled, some evidence suggests medicinal cannabis can help patients suffering from illnesses such as epilepsy, multiple sclerosis or sickness linked to chemotherapy.

Towards the end of 2018, cannabis was reclassified to allow some cannabis-derived medicines to be prescribed by specialist doctors in limited situations, but so far very few prescriptions have been issued.

England's Chief Medical Officer, Prof Dame Sally Davies, has called for more research into the plant's benefits, so that any future guidance on prescribing cannabis-based medicines has a more solid scientific basis.

The UK is in a good position to lead this research.

According to the UN, the UK produced 44% of global cannabis plants intended for medicine and scientific research in 2016, even though the end product is still tightly restricted.

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How cannabis use has changed, in seven charts

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Around the world, on the 20 April - or "420" - cannabis users will be lighting up to celebrate "weed culture" and protest about its prohibition in many countries. But even though recreational cannabis has been illegal in the UK since 1928, the evidence shows that punishments for its possession have plummeted in recent years in England and Wales.

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Significant changes have taken place in the policy landscape surrounding cannabis legalization, production, and use. During the past 20 years, 25 states and the District of Columbia have legalized cannabis and/or cannabidiol (a component of cannabis) for medical conditions or retail sales at the state level and 4 states have legalized both the medical and recreational use of cannabis. These landmark changes in policy have impacted cannabis use patterns and perceived levels of risk.

However, despite this changing landscape, evidence regarding the short- and long-term health effects of cannabis use remains elusive. While a myriad of studies have examined cannabis use in all its various forms, often these research conclusions are not appropriately synthesized, translated for, or communicated to policy makers, health care providers, state health officials, or other stakeholders who have been charged with influencing and enacting policies, procedures, and laws related to cannabis use. Unlike other controlled substances such as alcohol or tobacco, no accepted standards for safe use or appropriate dose are available to help guide individuals as they make choices regarding the issues of if, when, where, and how to use cannabis safely and, in regard to therapeutic uses, effectively.

Shifting public sentiment, conflicting and impeded scientific research, and legislative battles have fueled the debate about what, if any, harms or benefits can be attributed to the use of cannabis or its derivatives, and this lack of aggregated knowledge has broad public health implications. The Health Effects of Cannabis and Cannabinoids provides a comprehensive review of scientific evidence related to the health effects and potential therapeutic benefits of cannabis. This report provides a research agenda-outlining gaps in current knowledge and opportunities for providing additional insight into these issues-that summarizes and prioritizes pressing research needs.

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Read "The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research" at NAP.edu

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Significant changes have taken place in the policy landscape surrounding cannabis legalization, production, and use. During the past 20 years, 25 states and the District of Columbia have legalized cannabis and/or cannabidiol (a component of cannabis) for medical conditions or retail sales at the state level and 4 states have legalized both the medical and recreational use of cannabis.

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This website can help you assess your cannabis use, its impact on your life and how to make changes if you want to. Smoking or vaping cannabis can cause you problems in different areas of your life; it is illegal and potentially harmful. Some regular cannabis smokers choose to cut down and stop, many find it easy, others find it hard.

Are you in control of your cannabis use? Read on and then decide for yourself.

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This website can help you assess your cannabis use, its impact on your life and how to make changes if you want to. Smoking or vaping cannabis can cause you problems in different areas of your life; it is illegal and potentially harmful.

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Explore cannabis 101 information including ways to consume, cultivation guides, and resources for beginners to advanced connoisseurs.

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Practice Clinical Update BMJ 2019; 365 doi: Cite this as: BMJ 2019;365:l1141 https://doi.org/10.1136/bmj.l1141

1. Tom P Freeman , senior lecturer 1 2 3 4,

2. Chandni Hindocha , research fellow 3 4 5,

3. Sebastian F Green , academic foundation doctor 4,

4. Michael A P Bloomfield , UCL excellence fellow and consultant psychiatrist 3 4 5 6 7

Correspondence to T Freeman t.p.freeman{at}bath.ac.uk

What you need to know

Cannabis based products for medicinal use contain cannabinoids derived from the cannabis plant, including ∆ ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC and CBD. Synthetic cannabinoids for medicinal use typically mimic the effects of specific cannabinoids such as THC

THC is the constituent of cannabis that causes the "high," whereas CBD is not intoxicating at typical doses. THC and CBD have contrasting mechanisms of action and therapeutic indications; THC carries a higher risk of adverse events compared with CBD

Rescheduling on 1 November 2018 permits some unlicensed cannabis based products to be prescribed for the first time in the UK, but only by doctors on the relevant Specialist Register of the General Medical Council

Indications for treatment, supported by evidence of low to moderate certainty, include chronic pain, some treatment resistant epilepsies, and nausea and vomiting caused by chemotherapy ( table 2)

Non-medicinal CBD products are legal and widely available on the internet and from health food retailers, but they lack quality standards and should not be used for medicinal purposes

Until recently, cannabis and its derivatives were widely restricted under legislation which stated they had no medical value and carried a substantial risk of misuse. Policy is rapidly changing, and cannabis can now be prescribed for medicinal use in many countries, including the UK. This provides important new opportunities for treating patients although these need to be weighed up against potential risks. Several different medicinal products exist, with contrasting mechanisms of action, efficacy, and safety. Use of these products may increase as new evidence arises and policy changes occur. Here we review this emerging field.

What are the latest developments in regulation, in the UK and internationally?

In the UK, drugs perceived by policy makers to have no medical value and a high risk of misuse, such as MDMA (3,4-methylenedioxy-methamphetamine, common street name "ecstasy") are placed in Schedule 1 of the Misuse of Drugs Regulations 2001. These drugs cannot be prescribed, and research can only be conducted under a Home Office licence.

On 1 November 2018, unlicensed cannabis based products were moved from Schedule 1 to Schedule 2 in the UK, enabling them to be prescribed for the first time. 1 This amendment of UK legislation affected some but not all products, as some were already listed in Schedule 2 or 4 ( table 1). Non-medicinal synthetic cannabinoids (which are found in products such as "Spice") were not rescheduled and remain in Schedule 1. Cannabidiol (CBD) has minimal risk of misuse 5 and was never scheduled in the UK.

At the time of writing, in the US cannabis is available for medicinal use in 33 US states and for non-medicinal use in 10 US states, although both remain illegal under federal law. Other recent developments include the legalisation of cannabis for non-medicinal use in Canada on 17 October 2018. The World Health Organization has proposed that cannabis should be rescheduled within international law because of growing evidence of its medicinal applications. 6

What types of product are available and where?

The cannabis plant can produce at least 144 naturally occurring compounds known as cannabinoids. 7 The most widely researched cannabinoids are ∆ ⁹-tetrahydrocannabinol (THC) and CBD. THC is the primary constituent of cannabis that causes the "high" whereas CBD is not intoxicating at typical doses. Several different products exist for medicinal use and these differ in THC/CBD profile, formulation, licensed indications, and conditions for prescribing ( table 1). See the glossary of terms ( box 1) for accepted definitions.

Box 1

Key terms

Cannabinoid- a drug that acts on the endocannabinoid system. The cannabis plant synthesises many cannabinoids such as THC and CBD

THC-∆ ⁹-tetrahydrocannabinol, a cannabinoid used for medicinal purposes and non-medicinally for its intoxicating effects

CBD- cannabidiol, a cannabinoid with contrasting mechanisms of action and therapeutic indications to THC. Not intoxicating at typical doses

Cannabis based products for medicinal use- medicinal products containing cannabis or cannabinoids derived from the cannabis plant (eg, THC and/or CBD)

Synthetic cannabinoids for medicinal use- medicinal products containing synthetically produced cannabinoids which typically mimic the effects of THC

Non-medicinal CBD products- products containing CBD that are widely sold as herbal remedies but are not regulated as medicinal products

Non-medicinal cannabis- material from the cannabis plant that is not regulated as a medicinal product, widely used for its intoxicating effects

Non-medicinal synthetic cannabinoids- synthetic cannabinoids that are not structurally related to naturally occurring cannabinoids and are not currently recognised for medicinal use (eg, synthetic cannabinoid receptor agonists, which are found in products such as "Spice")

RETURN TO TEXT

Cannabis based products for medicinal use

Cannabis based products that were previously listed in Schedule 1 can now be prescribed by doctors on the General Medical Council Specialist Register in the UK, on a named patient basis. Currently, general practitioners in the UK cannot prescribe them.

These products are not licensed for specific medical indications but are used off licence for medicinal purposes in many countries, and are certified for quality according to good manufacturing practice. Examples include herbal cannabis (floral material from the cannabis plant). The recommended route of administration is through a medical vapouriser device 9 and smoking is currently prohibited under NHS guidance. 10 Extracts from the cannabis plant (such as cannabis oils containing THC) are also available for oral administration.

Some cannabis based products were already available for medicinal use before rescheduling in 2018. Sativex, an oral spray derived from the cannabis plant containing THC and CBD in a 1:1 ratio, is licensed for the treatment of spasticity in multiple sclerosis in 29 countries, including the UK, Israel, Canada, Brazil, and Australia. However, meta-analysis suggests its effectiveness may be limited 11 and it is not recommended by the UK's National Institute for Health and Care Excellence (NICE) because of poor cost effectiveness. 12 Epidiolex, an oral CBD solution derived from the cannabis plant, was licensed by the US Food and Drug Administration in June 2018 for the treatment of seizures in two rare and severe forms of childhood epilepsy-Lennox-Gastaut syndrome and Dravet syndrome. At the time of writing, an application for the same indication is under review by the European Medicines Agency, and it can currently be prescribed on a named patient basis in the UK.

Synthetic cannabinoids for medicinal use

Dronabinol and nabilone are synthetically produced medicinal products that mimic the effects of THC. Dronabinol has an identical structure to THC, while nabilone has a related structure and is more potent than dronabinol, requiring lower doses to achieve clinical efficacy. Countries including the US, the Netherlands, Germany, Austria, and Croatia have licensed the use of both products. They are licensed for the treatment of weight loss in patients with AIDS and of nausea and vomiting in people receiving chemotherapy who have failed to respond adequately to conventional anti-emetics. Nabilone is licensed in the UK while dronabinol is not licensed but can be prescribed on a named patient basis.

Non-medicinal products

CBD products are also widely available in health food shops and on the internet in the UK and elsewhere ( fig 1) and are not scheduled or regulated as medicines. Their THC or psychoactive content is legally controlled not to exceed 0.2% in the EU. 8 As with other herbal remedies, the declared contents of non-medicinal CBD preparations is variable, and often inaccurate, 2 13 and these products sometimes exceed the legal limit of THC. 13 Moreover, the amount of CBD in these products is typically far lower 14 15 than in clinical trials 16 (eg, 25 mg in a non-medicinal product versus 150-1500 mg/day in clinical trials). Advise patients that these widely available CBD products lack quality assurance and should not be treated as medicines.

Other products include non-medicinal cannabis and non-medicinal synthetic cannabinoids, which are both currently illegal in the UK.

Why and how are cannabis based products and cannabinoids therapeutic (or harmful)?

THC and CBD have contrasting mechanisms of action on the endocannabinoid system, 17 18 which is widely expressed in the mammalian central and peripheral nervous systems. These actions may account for their therapeutic effects. For example, CBD increased plasma endocannabinoid levels in a clinical trial in schizophrenia, which correlated with the degree of symptom improvement. 19 When taken together with THC, CBD may offset some of the adverse effects of THC, such as memory impairment and paranoia. 20 21 Therefore, the balance of THC and CBD may contribute to safety as well as therapeutic effects. CBD has an excellent safety profile and is well tolerated, even at high doses. 22 THC carries an increased risk of adverse events (including serious adverse events). In a systematic review and meta-analysis, cannabinoids (primarily THC) were associated with a fivefold increase in rates of disorientation and dizziness, compared with placebo or active comparators. 11

What is the evidence underpinning medicinal use of cannabis based products and cannabinoids?

Table 2 summarises evidence from systematic reviews of cannabis based products and cannabinoids for the treatment of chronic pain, multiple sclerosis, treatment resistant epilepsy, and nausea and vomiting associated with chemotherapy. 11 23 24 There is less available evidence to estimate the effectiveness of these products for other indications, such as appetite and weight loss associated with HIV/AIDS, Tourette syndrome, anxiety, post-traumatic stress disorder, and schizophrenia. 11 26 27

The limited number of randomised trials for unlicensed cannabis based products is partly attributable to the regulatory challenges of conducting research on drugs in Schedule 1. 28 Removing these barriers is an important benefit of rescheduling, which should lead to a stronger evidence base to guide clinical decision making. At the time of writing, the UK National Institute for Health Research (NIHR) has pledged dedicated funding and has called for grant proposals to investigate cannabis based products for medicinal use.

Limitations of current evidence include the inappropriate handling of withdrawals from treatment, selective reporting of outcomes, and inadequate descriptions of randomisation, allocation concealment, and blinding. 11 Heterogeneity in the types of product tested, including differences in pharmacokinetics and the balance of THC and CBD content, makes it difficult to establish optimal therapeutic formulations and dosing regimens. More larger and rigorous clinical trials are needed, including further exploration of dose-response and interactions with other medicines. 27 For example, both nabilone (THC) and epidiolex (CBD) may increase the effects of central nervous system depressants such as alcohol. 29 30 Epidiolex is metabolised by cytochrome P450 enzymes and may increase the risk of adverse effects from other medicines metabolised by this pathway, such as clobazam and valproate. 29

How should doctors manage requests for cannabis based products and cannabinoids? (box 2)

Box 2

Managing requests for cannabis based products and cannabinoids

Consider

Is this indication supported by evidence from randomised clinical trials? ( table 2)

What is the cannabinoid profile of the medicinal product being requested (THC, CBD, THC+CBD?)

Is this medicinal product available, and who can prescribe it? ( table 1)

Might this medicinal product interact with other prescribed drugs?

Are specific considerations necessary for young people, children and babies, older people, people with mental health problems, people with a learning disability, pregnant women, and women who are breastfeeding?

If a prescription is not offered, might this patient seek or use a non-medicinal product lacking safety and quality assurance?

RETURN TO TEXT

Guidelines are currently being prepared by NICE, which will initially focus on the indications listed in table 2. Interim guidance from England's Chief Medical Officer states that unlicensed cannabis based products can only be prescribed by doctors on the General Medical Council Specialist Register. 10 The same guidance also stipulates that doctors should prescribe products only for disorders within their specialty; when there is clear published evidence or UK guidelines to support treatment; when clinical need cannot be met by a licensed medicine; and when established treatment options have been exhausted. Additional guidance has been provided by the Royal College of General Practitioners 31 and NHS England. 32

Within this framework, specialists in the UK will need authorisation from their medical director and agreement from the multidisciplinary team, using existing protocols on controlled drugs. Therefore, use of unlicensed cannabis based products in the UK may be limited initially, even in specialist settings. Active, compassionate, and fully informed engagement with patients requesting treatment remains important, and questions to consider are given in box 2. As this is a rapidly evolving field, seek confirmation from the relevant statutory authorities before changing practice.

Education into practice

To what extent might it be stigmatising for a patient to request and use a cannabis based product, and how can this be managed?

Are patients fully aware of the difference between medicinal and non-medicinal products, their legal status, and the risk of harm or prosecution associated with them?

How can I record and share information from my practice on requests for, uses of, and responses to cannabis based products to ensure that future regulations and guidance better meet the needs of patients?

How this article was created

We used the most up to date and relevant information available to us from systematic reviews, meta-analyses, and key clinical trials. Summary statistics and grading of evidence were obtained from systematic reviews for indications included in forthcoming NICE guidelines. We referred to NICE, the Department for Health & Social Care, NHS England, the UK Home Office, and the Advisory Council for the Misuse of Drugs (ACMD). We discussed our article with clinicians, researchers, and patients.

How patients were involved in the creation of this article

We discussed our article with patients who had health conditions for which there is evidence that cannabis based products or cannabinoids may be effective. We conducted interviews with them asking what they thought would be helpful for patients and clinicians to learn from this article. We showed them drafts of this article and invited them to provide feedback which was incorporated into subsequent versions of the article. On the basis of this feedback, we adapted the structure of the article such that recent policy developments were presented first. We expanded our discussion of the differences between medicinal products and health food supplements, and added a new table to provide an accessible overview of these different products. We highlighted that some patients may seek unlicensed or illegal products if they are unavailable on prescription, and that requesting cannabis based products from a doctor and using them could be stigmatising.

Footnotes

Provenance: commissioned, peer reviewed.

Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests:

TPF was funded by a senior academic fellowship from the Society for the Study of Addiction (SSA). MAPB is funded by a UCL Excellence Fellowship. MAPB, SFG, and CH are supported by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. The views expressed here are those of the authors, and do not reflect those of the SSA, the University of Bath, UCL, or NIHR. The funders had no role on the planning, researching, or writing of this report or in the decision to submit it for publication.

Further details of The BMJ policy on financial interests is here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

Contributorship statement and guarantor TPF had the idea for this article and wrote the first draft. All authors provided substantial contributions to the design of the work. CH, SFG, and MAPB wrote additional sections. Two anonymous patients suggested additional changes. All authors revised the article and approved the final version. As the guarantor, TPF affirms that the manuscript provides an honest, accurate, and transparent account of the issues covered, that there are no important omissions, and that there are no discrepancies between what was planned and the final version. All authors accept full responsibility for the work and the decision to publish.

Acknowledgments We thank two patients for their feedback on previous versions of this article. Both preferred to stay anonymous.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

View Abstract

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Medicinal use of cannabis based products and cannabinoids

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What you need to know Until recently, cannabis and its derivatives were widely restricted under legislation which stated they had no medical value and carried a substantial risk of misuse. Policy is rapidly changing, and cannabis can now be prescribed for medicinal use in many countries, including the UK.

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"Teen cannabis use is to blame for 60,000 people suffering depression in the UK," reports The Sun.

A review has found that teenagers aged under 18 who used cannabis were 37% more likely to get depression in early adulthood than teenagers who didn't.

Cannabis use among teenagers has been linked to poor mental health previously, with research finding a strong link between cannabis use and schizophrenia. About 4% of adolescents aged 11 to 15 in England are thought to use cannabis each month. That means a lot of people may be at increased risk of mental health problems.

This study cannot prove that cannabis use in teenagers caused depression in young adults. Depression is a complex disorder with many potential risk factors, including hereditary influence and life circumstances. Other, unmeasured factors may have contributed to the study results. For example, difficult childhood circumstances could increase both the chances of getting depression as a young adult, and of using cannabis as a teenager.

However, the study joins other research to suggest that cannabis use may be putting teenagers at risk of poor mental health.

Researchers make the point that as teenagers' brains are still developing up until adulthood, exposure to cannabis could impact on this development in a number of potentially harmful ways.

Read more facts about cannabis.

Where did the story come from?

The researchers who carried out the analysis were from McGill University in Canada, Rutgers University in the US and the University of Oxford in the UK. It was funded by the Canadian Institutes of Health Research, the Quebec Network on Suicide, Mood Disorders and Related Disorder, and the UK's National Institute for Health Research. The study was published in the peer-reviewed journal JAMA Psychiatry.

The research was widely reported in the UK media. The headline claims in the Mail Online and elsewhere that "half a million" cases of adult depression "could be prevented" if teenagers avoided cannabis are an oversimplification. They are based on the researcher's estimate that 7% of the cases of depression recorded in the study among adults aged 18 to 32 might be attributable to cannabis use. It is unclear whether this statistic would translate to all adult cases of depression in the UK.

The reporting in The Guardian and BBC News did explain that the results could not prove a direct cause and effect link.

Other UK sources did not make this point clear.

What kind of research was this?

This was a systematic review and meta-analysis of cohort studies. Systematic reviews and meta-analyses are good ways of summarising the state of research into a topic. Cohort studies are good for spotting patterns and links between risk factors. However, they cannot prove cannabis use causes depression. Other, unmeasured confounding factors might affect the results.

What did the research involve?

The researchers looked for cohort studies that had recorded cannabis use of people aged under 18, and then followed them up to see if they developed anxiety, depression, suicidal thoughts or attempted suicide, up to the age of 32. The studies had records of whether people already had anxiety, depression or suicidal thoughts at the start of the study and adjusted their figures to take account of this.

Researchers looked to see whether under-18s who had used cannabis were more likely to develop these mental health conditions between the ages of 18 and 32, compared to non-users, and pooled the data from the studies. The reports of cannabis use were based on self-reported questionnaires filled in by the adolescents. Depression, anxiety and suicidal thoughts were assessed by a variety of questionnaires, interviews and symptom scores.

The researchers checked the studies for potential sources of bias and conducted an analysis to see whether 2 studies that might have had overlapping populations had a strong influence on the results (they concluded this made little difference to the overall result).

What were the basic results?

The researchers found 11 studies of interest, with 7 studies looking at depression, 3 at anxiety and 3 at suicidal thoughts or attempts (some studies looked at more than 1 outcome). The total number of people studied was 23,317, although it's not reported how many people were involved in the analysis of each outcome.

The risk of depression in early adulthood among adolescents who used cannabis was 37% higher than those who did not use cannabis ( odds ratio (OR) 1.37, 95% confidence interval (CI) 1.16 to 1.62).

The chance of having suicidal thoughts was 50% higher (OR 1.50, 95% CI 1.11 to 2.03) and the chance of making a suicide attempt was almost 4 times higher (OR 3.46, 95% CI 1.53 to 7.84).

There was no increased risk of anxiety in early adulthood linked to cannabis use in adolescence.

How did the researchers interpret the results?

The researchers said: "This meta-analysis suggests that cannabis exposure could be one factor contributing to depression in young adulthood." They described the risk of depression as "moderately increased" but acknowledge that a "strong causal association cannot be made".

However, they say that the research suggests "cannabis is a serious public health concern and there is an urgent need to implement better drug use prevention programs targeting the use of cannabis among adolescents".

Conclusion

This study raises the possibility that cannabis, the most commonly used illegal drug in the UK, could increase the risk of depression and suicidal thoughts or suicide attempts. We already know its use seems to be linked to the less common condition of schizophrenia.

That's not to say that it definitely causes depression or other mental health problems. There are a number of limitations to the research.

This type of study cannot prove that one factor directly causes another, as there are many factors that can influence both the likelihood of getting depression and likelihood of using cannabis.

The study doesn't include some important information, such as the amount or potency of cannabis used, whether people used other drugs, their alcohol and tobacco use, or whether people were in school and what their home environment was like. We don't know whether people in the studies continued to use cannabis after the age of 18, so continuing drug use could also have affected the results.

The studies included in the review assessed depression and suicidal thoughts through a variety of methods, so we don't know if the results would have been the same if all studies had used the same method.

While the study does provide the increase of risk in depression in people who smoked cannabis compared to those who didn't ( the relative risk), it doesn't provide a figure of how many people were in this group. And this group could consist of just a small amount of people. So the overall increase in risk in terms of population levels ( absolute risk) could still remain low.

Having said that, this is one of those cases where it would seem sensible to avoid the risk of cannabis if possible, especially if you are a young person who's brain is still developing.

Find out more about cannabis and mental health.

Analysis by Bazian
Edited by NHS Website

Links to the headlines
Smoking cannabis as a teen 'increases risk of depression and TRIPLES suicide risk'
The Sun, 13 February 2019
Smoking cannabis in your teens IS linked to depression in later life: Major study reveals drug 'damages children's brains' and half a MILLION adults could avoid mental-health disorder if they had turned down marijuana
Mail Online, 13 February 2019
Smoking cannabis as a teenager can cause depression in later life
Metro, 14 February 2019
Cannabis smoking in teenage years linked to adulthood depression
The Guardian, 13 February 2019
Cannabis use in teens linked to depression
BBC News, 13 February 2019
Teenage cannabis users 'face bigger depression and suicide risk'
The Times (subscription required), 14 February 2019

Links to the science

Gobbi G, Atkin T, Zytynski T, et al.
Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood - A Systematic Review and Meta-analysis
JAMA Psychiatry. Published online February 13 2019

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Teenage cannabis use linked to depression in later life

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"Teen cannabis use is to blame for 60,000 people suffering depression in the UK," reports The Sun. A review has found that teenagers aged under 18 who used cannabis were 37% more likely to get depression in early adulthood than teenagers who didn't.

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Whether it's knocking on a door down the road, making a quick call, or agreeing a deal on the way to school, there's no ID necessary and no questions asked: teenagers in London never have to venture too far to find 'Skunk'.
In fact, they find the highly potent form of the Class B drug cannabis much easier to buy than both alcohol and cigarettes, where regulation steps in and requires them to prove that they are old enough.

No such barriers seem to exist when it comes to buying cannabis.

The country's most popular illicit drug, the average age people start smoking it is 14.

But, for most young people today, it is the stronger, more harmful and seemingly ubiquitous variety of cannabis - high in the cannabinoid THC and low in CBD - and known universally as skunk, that is finding its way into their hands.

To investigate how easy it is for young people to buy cannabis and the risks that come with this, Volteface carried out a nationwide survey and spoke to a group of users and non-users, aged 15-17, from London.

Without chemical analysis, we can't know for certain what type of cannabis young people are consuming, but we could find out what they thought it was.

The results showed that the overwhelming majority of people said they used skunk, with many reporting that was the only form of cannabis they could get.

And Volteface's research suggests that skunk is very easy for young people, particularly in urban areas, to get hold of it.

Indeed, when asked how easy it is to buy cannabis, how often they smoked it or whether any of them had ever had any trouble getting the drug because of their age, the teenagers Volteface interviewed collapsed into laughter at how "ridiculous" these questions were.

In their world, these aren't things they need to think much about, they are a given.
The cannabis most commonly smoked in the UK, in and before the 1990s, was the low-potency hash. This changed as the decade progressed and the development of high potency strains such as skunk came to dominate the market in the Netherlands - a trend which found its way here.
With this in mind, Volteface's research raises important questions about how much autonomy young people living in areas like London really have when it comes to the cannabis they are smoking.

Unlike previous generations, skunk - and closely related strains, high in THC and low in CBD - is perhaps all they will have known, with these varieties accounting for 80-95% of the cannabis sold illegally on Britain's streets, according to most recent analyses.

How clued-up are today's young cannabis users as to where and how to find regular weed, safer strains and the benefits of why they might want to do this?

Under the Misuse of Drugs Act 1971, anyone caught in possession of cannabis could (in theory, but rarely in practice) face five years in prison or an unlimited fine.

Deterrence and censure - the law's intentions are clear, and young people are well aware of the prohibition. Nevertheless, this doesn't stop them from wanting to buy cannabis.

76% of those who completed Volteface's survey, and several of the teenagers interviewed, said they were worried about getting into trouble with the police.

But, one 16-year-old Volteface spoke to was still smoking it, despite one occasion on which "I went straight to the cells for having 0.6 grams of weed on me" and his mother being called to collect him.

It appears that the only real barrier when it comes to young people getting cannabis is money: the supply comes to them.

"If you've got the money, you can get cannabis, no problem," said a 17-year-old user from London.

A 16-year-old added: "When we're walking to school people come up and ask if we want to buy weed."

"If they think you're the kind of person who smokes weed, they might just come up to you and ask you to take their number and then you just call them," said another.

One teenager said that if a group are seen smoking cigarettes, they could be approached by cannabis dealers.

Although those interviewed in London for the research said cigarettes were seen as the most "socially acceptable" substance, most said it was still much easier to buy cannabis than tobacco.

As regulated products with a minimum age requirement, young people wanting to buy alcohol and cigarettes from any retail outlet must be able to show they are at least 18.

With cannabis, no such difficulty gets in the way.

96% of those who completed Volteface's nationwide survey and said it was "extremely easy" for them to find cannabis were from cities.

"Getting tobacco is harder than getting cannabis, 100%," said one of the group interviewed.

"It's too easy."

"Knock on a door," said one 16-year-old.

"It's legit if you have the money. There's times when you got the money for tobacco, but you're not going to get served inside the shop as you're too young."

"Weed is the easiest thing out of cannabis, cigarettes and alcohol to get because you don't have to have ID."

Some of the teenagers said they sometimes tried their luck by asking an older young person standing outside a shop to go in and buy some drinks for them, but that this was rare.

In any case, as some of them pointed out, shops shut.

Dealers don't close for business at 11pm on a Friday night.
Cannabis, more than cigarettes and alcohol, is seen as a greater part of the 'every day' lives of the young people smoking it, Volteface's research showed.
"You don't need a motive to smoke it" is how one 16-year-old from London summed up its popularity.

"When I wake up, at lunch... any time I can," said another teenager about when they smoked it.

"If I'm not doing anything and I've got money, I'll buy some and smoke it".

"It just chills you out," another added.

Whereas other drugs such as LSD, ecstasy and magic mushrooms, as well as alcohol, are used by young people "every few weeks" at parties or on nights out, the young people we interviewed said they often smoked a joint while listening to music, gaming, relaxing by themselves or with friends.

Most of the teenagers we spoke to in London said they smoked cannabis more commonly on weekends and week nights, but some said they smoked it during school hours, with one 16-year-old stating: "I smoke when I wake up".

On average, the group spent £30 every three days on the drug.

In fact, this seemed to be the group's biggest problem with cannabis, with one commenting: "If I think about all the money I could have saved by now..."

Another added: "We get deals init, so our dealers bus us a gram for £10, a z [ounce] for £200, should be £240."

The most striking finding confirmed by Volteface's research was the extent to which young people, to their knowledge at least, are smoking skunk, rather than any other form of weed.

The majority of the teenagers interviewed in London said they smoked skunk, which has come to dominate the market as the cheapest way to get really high.

Cannabis contains two important ingredients: THC (tetrahydrocannabinol) and CBD (cannabidiol).

THC gets smokers 'high'. It has also been correlated, particularly when consumed in high concentrations, with greater incidences of psychosis and development of dependence.

CBD while not psychoactive itself, modifies the effects of THC, including reducing its anxiety and paranoia-inducing effects. It also, crucially, significantly lessens both the incidence of psychosis when people consume it alongside THC, and seems to make cannabis less dependence forming.

Whereas other forms of weed often contain the two substances in more equal ratios, skunk tends to contain solely high amounts of THC and hardly any CBD.

The teenagers Volteface interviewed were aware of the distinction between weed and skunk and the difference in their potential harmfulness, but the sheer ease of availability of the latter meant they were continuing to smoke it. Convenience trumps effort.

"We don't smoke weed, we smoke skunk. But skunk is more available," one 16-year-old said.

"Skunk is bare chemicals and THC to make it stronger. It's much more available," another added.

One 17-year-old said: "I don't even think it's that great, but it's all you can get, there's just bare THC in it."

"My mum thinks I should smoke Thai because skunk will make you crazy," said another 17-year-old.

A 16-year-old agreed: "My mum says I should smoke high grade rather than skunk because it's gonna turn me mental."

"When you first start buying weed, you don't actually know what you're buying. Now you can ask them what it is and they'll tell you," another teenager added.

In a 2015 study published in The Lancet Psychiatry, scientists from Kings College London found that 24% of all new cases of psychosis are associated with the use of skunk and the risk of psychosis was three times higher for skunk users and five times higher for those who use it every day. No increased risk of psychosis was found for those regularly smoking other forms of cannabis.

The causality between cannabis use and psychosis has been questioned though, with the possibility that those more likely to take the drug are also more prone to psychosis in the first place.

When asked whether they worried about the effects of skunk on their mental health, one teenager said: "Yeah - it's when I'm older isn't it? Long-term effects."

But another added: "I can't see myself getting something like depression."

Some said they could feel cannabis having a negative effect on their physical health, with their ability to run and play sports affected.
After getting stopped by the police, parents were the second biggest concern for young cannabis users who participated in Volteface's research, but this was mainly the case in non-urban areas and those outside of London.
For most of the young cannabis users interviewed in London, their parents were not concerned enough to stop them smoking it, although they did try to advise their children against consuming stronger strains.

"I think part of the reason my mum is okay with me smoking is because I do well in school," one 17-year-old told us.

Another said: "They lecture me about it but they don't try and stop me taking it. If my mum found weed in my room she probably wouldn't take it."

Skunk is in the lives of young people because it's in the dealers' interest to keep it there.

The environment in which they are operating, particularly in urban areas such as London, mean teenagers are regularly smoking a highly potent strain of a drug, which can result in severe mental health problems in later life, even though much less harmful strains are available.

As Volteface's research suggests, young people today don't have much control over the quality or type of cannabis they are smoking. They only know the dealers they know, many of whom will have targeted them specifically.

When something is so easy, the incentive to look elsewhere and acquire knowledge about other options diminishes. We are also creatures of habit - the behaviours we become accustomed are difficult to shift. Particularly if any adverse effects of these behaviours fail to manifest themselves in the here and now. Make hay while the sun shines.

In young people, dealers seem to have found an ideal target market to push skunk and make a tidy profit, all within a context which runs counterintuitive to what many of us may believe: that making something illegal is keeping us safer.

Teenagers may be laughing at our ignorance on this issue now, but it's skunk's dexterous dealers who may well be having the last laugh in the end.
Hardeep Matharu is a writer and researcher at Volteface. Tweets @Hardeep_Matharu

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How Easy is it for Young People to Access 'Skunk' in the UK? - Volteface

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Whether it's knocking on a door down the road, making a quick call, or agreeing a deal on the way to school, there's no ID necessary and no questions asked: teenagers in London never have to venture too far to find 'Skunk'. In fact, they find the highly potent form of the Class B drug ...

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The children's inquiry: how effectively are the UK's cannabis policies safeguarding young people? Volteface, September 2018
Volteface, a think tank which looks at alternatives to current drug policies in the UK, have published a report on how effectively the UK's cannabis policies are safeguarding young people from harm including from a criminal justice perspective.
Details
Overall, the number of people (children and adults) criminalised for the possession and cultivation of cannabis is decreasing. However, young people are increasingly being criminalised for possession with intent to supply cannabis, while the number of adults criminalised for supply offences is decreasing.

The data analysed revealed that the increasing number of young people are not only arrested but also increasingly prosecuted and convicted for supply offences. In the context of recent cuts to policing, a deprioritisation of supply by police on the ground, a decline in the use of Stop and Search and an increased use of youth diversion, the criminalisation of young people should be decreasing.

The research indicates that young people are increasingly being groomed by adults to sell cannabis on their behalf, although the nature of the grooming does not fall within the framework of county lines. Young people are also selling it or giving it to their peers 'socially'. This could explain why they are increasingly being criminalised for supply offences.

Cuts to youth services, a lack of opportunities, the glamorisation of drugs and money as well as social media are proposed as reasons for making young people vulnerable to becoming cannabis dealers.
Commentary
Youth justice practitioners should have this research in mind when representing children for offences relating to the supply of cannabis. Whether the young clients are the victims of child criminal exploitation clients should be explored. The fact that young people are disproportionaly prosecuted for these offences should be brought to the court's attention so that they are not also also disproportionately punished.

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Report on how the UK's cannabis policies are affecting young people - Youth Justice Law in England and Wales

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The children's inquiry: how effectively are the UK's cannabis policies safeguarding young people? Volteface, September 2018 Volteface, a think tank which looks at alternatives to current drug policies in the UK, have published a report on how effectively the UK's cannabis policies are safeguarding young people from harm including from a criminal justice perspective.

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Research on Cannabinoids Over the Decades and What’s to Come - Raphael Mechoulam

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In 1987, a major Swedish study based at the Karolinska Institute suggested that those who took cannabis were six times as likely to be hospitalized for schizophrenia as those who never took it. Although the study involved over 50,000 men, it only illustrated a correlation rather than cause and effect. Many 'confounding factors' were ignored, and the possibility was raised that another factor predisposed the men to both schizophrenia and taking cannabis.

The self-medicating theory was also raised - that the men were taking the drug to alleviate their symptoms. This theory became more popular as further research found that schizophrenic patients often report that cannabis makes them feel better. One of the chemical ingredients of cannabis, cannabidiol, has even been investigated as a treatment for schizophrenia.

Nevertheless, research on cannabis as a risk factor continued. Psychiatrists from the University of Amsterdam published data suggesting that schizophrenia patients who used cannabis showed worse outcomes than those who didn't, and further studies confirmed this observation. Recent work following large groups over time also added to the risk theory - and these were careful to include all relevant factors.

Mary Cannon, of Ireland's Royal College of Surgeons, took part in a New Zealand-based study which found that smoking cannabis before the age of 15 increased the risk of schizophrenia from 3% to 10% by age 26.

"Cannabis is part of the cause of schizophrenia," she believes. Her team concluded that there is a minority of teenagers who are particularly vulnerable, and this is backed up by evidence from Greece, in which children with disturbed thought processes at age 11 were at a 25% risk of psychosis if they didn't go on to take cannabis, and a 50% risk if they did.

In fact, many of these research studies indicate that the risk is higher for teenagers and young adults, probably because the brain is still developing and more susceptible to damage. What's more, cannabis use among teenagers is rising, and the strength of cannabis is increasing. On the other hand, the rate of schizophrenia has not risen during the last 30 years, in which cannabis use has increased.

Overall, cannabis is estimated to be responsible for 10% of all schizophrenia cases (approximately 400,000 people in the US). The UK government is currently under pressure to reverse their reclassification of the drug - in 2004 it was downgraded from a class B to a class C drug, meaning people caught with small quantities are not usually arrested.

Robin Murray of the Institute of Psychiatry is now convinced there is a small but significant minority who are predisposed to psychotic illness and should steer clear of cannabis at all costs.

So who is at risk? It seems that for those with a genetic predisposition for schizophrenia, cannabis can spell trouble, but few people have had their genes analysed. The sensible course of action is to look at your family history and avoid cannabis if a close relative has a mental illness including schizophrenia, manic depression, and to a lesser extent, depression or dementia. You are also at higher risk after an injury to the head, a brain tumor, or even a traumatic event.

Avoid cannabis if you personally have a history of mental illness, have had an episode of paranoid thinking or hearing voices, or had a bad response when first using cannabis or when using a small amount. For people with schizophrenia, cannabis may make a relapse more likely and make the symptoms worse. Using cannabis also makes it more likely that an individual will not stick to their treatment plan.

The New Zealand-based researchers conclude that "cannabis use among psychologically vulnerable adolescents should be strongly discouraged by parents, teachers, and health practitioners."

Cannabis is linked to schizophrenia in predisposed individuals

Related Articles

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Cannabis is linked to schizophrenia in predisposed individuals

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In 1987, a major Swedish study based at the Karolinska Institute suggested that those who took cannabis were six times as likely to be hospitalized for schizophrenia as those who never took it. Although the study involved over 50,000 men, it only illustrated a correlation rather than cause and effect.

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Attitudes toward cannabis in the United States have undergone a substantive shift, with, for the first time in history, a majority of Americans favoring cannabis legalization. Nationwide, marked public opinion and policy changes are occurring in what is largely a scientific vacuum, with well-controlled, scientific evidence contributing little to the debate on legalization of cannabis for medical or recreational use. Even among scientists, debates on cannabis can be polarized and high in emotional content, making it difficult to distinguish evidence from hyperbole.

In adolescents, increased social acceptance and decreases in the perception of cannabis' risks are associated with increased use ( Hall and Weier, 2015; Scheurmeyer et al, 2014). Already 2.6 million more people in the United States report near-daily cannabis use in 2013 compared with 2008 ( Substance Abuse and Mental Health Services Administration (SAMHSA), 2014). And cannabis legalization creates a powerful profit motive to create and maintain cannabis users, with the burgeoning marijuana industry following a similar business strategy as the tobacco industry ( Richter and Levy, 2014), which will likely further increase cannabis use.

In light of these major policy changes, defining what is known about the potential consequences of cannabis use has considerable public health significance and is the purpose of this circumspectives piece. We will discuss the influence of cannabis use on post-traumatic stress disorder (PTSD) and psychotic disorders. Each author will present data supporting one perspective regarding the link between cannabis use and the course of these disorders, and they will then present their shared perspectives on critical studies needed to move the field forward. An important caveat: clearly, cannabis is a pharmacologically complex plant with constituents that have the potential for producing both positive and negative effects. We will take opposing positions to accommodate the circumspectives framework, but emphasize that there is considerable overlap and nuance in our viewpoints.

PTSD

Meg Haney

Many with PTSD report using cannabis to cope with anxiety, stress, and insomnia ( Cougle et al, 2011; Boden et al, 2013). Consistent with a potential therapeutic effect, oral cannabinoids such as dronabinol (synthetic Δ ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis) and nabilone (a synthetic analog of THC), have been shown to reduce the acute response to fear stimuli as well as trauma-related symptomatology in those with PTSD. Nabilone reduced nightmares and improved sleep in both an open label and placebo-controlled trial, while also increasing clinician ratings of improvement and self-reported measures of well being ( Fraser, 2009; Jetly et al, 2015). A retrospective study of nabilone for PTSD-related nightmares also showed promising results ( Cameron et al, 2014).

But cannabinoids may do more than simply provide acute symptom relief. Unlike drugs such as alcohol, which may temporarily alleviate certain symptoms of PTSD while not affecting (or exacerbating) the underlying clinical condition, cannabinoid agonists specifically target the root cause of many PTSD symptoms: dysregulated threat responding and impaired extinction of fear-based memories ( Passie et al, 2012; Marsicano et al, 2002; Ganon-Elazar and Akirav, 2009, 2012). There is a dense expression of cannabinoid (CB1) receptors in amygdala-hippocampal-cortico-striatal circuits that have a role in anxiety, emotional learning and the consolidation of fear-related memories, as well as coordinating fear-related behavior ( Lutz, 2007; Neumeister et al, 2013; Chhatwal et al, 2005). There is also a high density of CB1 receptors in the hippocampus, which mediates the retrieval of fear-related memories ( Atsak et al, 2012), demonstrating a potential biological substrate for a therapeutic effect of cannabinoids in this population.

In patients with PTSD, the amygdala is hyperresponsive to threat-related or emotional stimuli, whereas the ventral/medial prefrontal cortex and hippocampus are hypoactive, resulting in inadequate top-down control of amygdalar activation relative to healthy controls ( Rauch et al, 2006; Etkin and Wager, 2007; Killgore et al, 2014). In fact, hypoactivity in the medial PFC was associated with greater symptom severity, and is suggested to reflect anxiety generalization and a deficit in emotional regulation ( Etkin and Wager, 2007).

Endogenous cannabinoids also influence fear responding. Healthy individuals with higher basal levels of the endogenous cannabinoid anandamide, due to a common variant in the fatty-acid amide hydrolase (FAAH) gene, have enhanced fronto-amygdala connectivity and fear extinction learning, as well as reduced anxiety-like behaviors ( Dincheva et al, 2015) and threat-related amygdala reactivity ( Hariri et al, 2009). Patients with PTSD have altered levels of both CB1 receptors and plasma levels of endogenous cannabinoids ( Hill et al, 2013; Neumeister et al, 2013), which may contribute to heightened alarm and other PTSD symptoms. It is telling that patients maintained on CB1 antagonists for the treatment of obesity were over three times more likely to discontinue treatment because of mood-related side effects (primarily anxiety) relative to placebo ( Christensen et al, 2007; Moreira et al, 2009), illustrating the role of endocannabinoids in mood regulation.

In terms of fear extinction, the importance of the CB1 receptor has been best demonstrated in a series of preclinical studies, showing that CB1 knockout mice learned and could recall the association between a tone and an electric shock but were unable to extinguish this pairing despite elevated levels of endocannabinoids in the basolateral amygdala ( Marsicano et al, 2002; Chhatwal et al, 2005). Cannabinoid agonists, conversely, facilitated extinction in preclinical models of PTSD ( de Bitencourt et al, 2013): agonist administration within 24 h of exposure to stressful stimuli prevented the development of enhanced acoustic startle response, impaired extinction, and an altered neuroendocrine stress response, as compared with placebo administration ( Korem and Akirav, 2014).

In human laboratory studies, dronabinol facilitated fear extinction. In a placebo-controlled, double-blind study, healthy non-cannabis using volunteers learned to associate two visual stimuli with an aversive white noise burst. The next day, participants were treated with placebo or dronabinol 2 h prior to an extinction session. Those treated with dronabinol had less reinstatement of fear responding 24 h later relative to the placebo group ( Rabinek et al, 2013). Given that exposure therapy to treat PTSD is often associated with poor extinction retention (eg, Milad et al, 2009), these data suggest that cannabinoid administration during extinction training might reduce the reinstatement of fear responding. CBD may also enhance consolidation of extinction learning ( Das et al, 2013), perhaps by inhibiting FAAH and thereby boosting endocannabinoid levels ( Leweke et al, 2012; de Bitencourt et al, 2008).

In sum, a therapeutic goal for the treatment of PTSD is to reduce threat responding and to re-learn emotional memories to reduce their aversive intensity. Existing data suggest that endogenous and exogenous cannabinoid agonists both acutely improve stress reactivity and reduce responding to perceived threats and facilitate extinction of fear responding, supporting further research of cannabinoid agonists for clinical treatment of PTSD.

Eden Evins: PTSD

As of January 2015, 23 states have passed legislation allowing possession of smoked cannabis for medical purposes. There is evidence from human studies of a correlation between regular cannabis use and a range of potentially adverse outcomes, including adverse effects on learning and cognition ( Solowij and Battisti, 2008; Solowij et al, 2011), effects on brain structure and function ( Lorenzetti et al, 2014, 2015; but see Weiland et al, 2015), negative psychiatric impact ( Hall and Degenhardt, 2009), and addiction ( Anthony, 2006; Lopez-Quintero et al, 2011), particularly among daily users, where it is estimated that 25-50% will become dependent ( Hall and Degenhardt, 2009; Hall, 2009). Nearly all of these studies, however, assess recreational, and not medical, cannabis use. Virtually nothing is known about potential effects of medical cannabis that is used instead of, or complementary to, traditional medicine for disorders such as pain, insomnia, anxiety, depression, and PTSD. Data are also lacking on whether those who use cannabis daily for chronic conditions also develop similar rates of addiction to those who use cannabis daily for recreational purposes.

Although legislation in many states provides very broad conditions for which 'medical' cannabis may be made available, PTSD, specifically, is being or has been added to the list of conditions in Arizona, Connecticut, Delaware, Michigan, and Nevada. Although preclinical data on effects of cannabinoids on consolidation of fear-related memory and particularly on extinction are intriguing and should be pursued in well-controlled trials in people with PTSD, the current evidence base for safety and efficacy for use of cannabis for psychiatric disorders, in general, and PTSD, in particular, is exceedingly thin. The American Psychiatric Association has taken the position that 'There is no current scientific evidence that marijuana is in any way beneficial for the treatment of any psychiatric disorder. In contrast, current evidence supports, at minimum, a strong association of cannabis use with the onset of psychiatric disorders. Adolescents are particularly vulnerable to harm, given the effects of cannabis on neurological development.'

PTSD is a serious, often debilitating illness for which currently available treatments are effective but often leave people with residual symptoms, for which some may turn to cannabis. For example, cognitive behavioral therapy (CBT) and prolonged exposure (PE) therapy are proven effective behavioral treatments for PTSD, but symptom reduction with inpatient PTSD treatment, particularly for symptoms of numbing, is inversely correlated with cannabis use following inpatient treatment ( Bonn-Miller and Vujanovic, 2011). This provides evidence that improved treatments for PTSD is needed, not that cannabis is effective. In fact, a longitudinal cohort study in 2276 veterans reported outcomes in four groups, classified on their cannabis use as (i) those not using before treatment or 4 months after discharge, 'never used', (ii) those using at admission but not after discharge 'stoppers', (iii) those using after discharge but not at admission, 'starters', and (iv) those using at both time points before and after treatment, 'continuing users'. Adjusting for relevant covariates, cannabis use was associated with greater PTSD symptom severity, more violent behavior, and more alcohol and drug use in the group as a whole. Stoppers and never users had the lowest PTSD symptoms, whereas starters had the highest levels of violent behavior ( Wilkinson et al, 2014). Thus, initiating cannabis use after initiating treatment was associated with worse PTSD symptoms, more violent behavior, and alcohol use. The authors concluded that cannabis may actually worsen PTSD symptoms or nullify the benefits of specialized intensive treatment, and that cessation or prevention of use may be an important goal of treatment, but this was a naturalistic study and controlled trials are needed, particularly in relatively cannabis-naive patients.

A retrospective study of PTSD symptoms in the first 80 people to obtain medical cannabis for PTSD in New Mexico suggested that self-reported symptoms were lower when smoking cannabis ( Greer et al, 2014). However, inclusion criteria for this study included self-report of 'significant relief of several major PTSD symptoms when using cannabis.' Participants were asked to report PTSD symptom severity retrospectively when not using cannabis, and this served as the control condition. It is not surprising and not particularly meaningful that retrospective ratings of PTSD symptoms pre-cannabis use were higher than during cannabis use in a sample that had to report relief of PTSD symptoms with cannabis to be included. Controlled trials with methodological rigor are sorely needed in this field, particularly considering the potential for cannabis-related adverse effects on cognition and addiction in these patients ( Silins et al, 2013). Those with PTSD who use cannabis experience greater problems associated with cannabis use than those without PTSD ( Boden et al, 2013). Given the significant potential adverse effects of use of cannabis for PTSD, including worsening of potentially life-threatening symptoms of the illness itself, prospective trials are urgently needed to assess safety and efficacy of cannabinoids for this use. The efficacy of cannabinoids, available as FDA-approved medications, dronabinol, and nabilone, should be studied for primary and residual symptoms of PTSD, alone and in combination with CBT or PE.

Haney and Evins: Moving the Field Forward

The two authors agree that given the central role of endocannabinoids in the neurocircuitry mediating the response to emotionally salient stimuli and emotional learning, there is a potential clinical utility of cannabinoid agonists in PTSD treatment: CB1 agonists may reduce anxiety, improve sleep, and enhance extinction of trauma-related memories.

In terms of advancing the field, placebo-controlled studies testing a range of oral cannabinoid doses during extinction training are needed, as are studies demonstrating the optimal time window for this intervention ( Ganon-Elazar and Akirav, 2009, 2012). In theory, cannabinoid agonists administered in temporal proximity to the stressor would prevent the over-consolidation of fear memory, but this needs further testing ( Trezza and Campolongo, 2013). The finding that dronabinol attenuated amygdala reactivity to fear stimuli in healthy controls should be repeated in those with PTSD. In addition to analogs of THC, studies testing CBD for discrete PTSD symptoms are needed, as is further research of FAAH inhibition ( Kathuria et al, 2003), given the 'on demand' nature of endocannabinoid release ( Gunduz-Cinar et al, 2013). Both CBD and FAAH inhibitors might maximize the therapeutic potential of cannabinoids for PTSD without risking the abuse-related or cognitive side effects of THC.

Overall, there are several advantages to slow-onset, long-duration, FDA-approved oral cannabinoids, rarely discussed in the debates about medical cannabis. First, oral cannabinoids have low abuse liability relative to smoked cannabis. A considerable subset of daily cannabis smokers develop a cannabis-use disorder (CUD), characterized by withdrawal symptoms, functional impairment, and difficulty maintaining abstinence, and using cannabis to cope with anxiety, in particular, is associated with an increased risk for developing CUD ( Johnson et al, 2010). Inhaled cannabis also produces more deleterious effects on cognitive performance than oral administration ( Ranganathan and D'Souza, 2006), which would be counter-therapeutic for PTSD. Also, cannabis withdrawal symptoms (disrupted sleep, anxiety, irritability; Haney et al, 1999; Budney et al, 2004) may be especially troublesome for PTSD patients, perhaps explaining why those with PTSD are more likely to relapse to cannabis use relative to controls ( Bonn-Miller and Vujanovic, 2011). A second benefit of oral cannabinoids is that although cannabis marketers target particularly strains of cannabis toward patients for a range of medical conditions, the products sold rarely contain the cannabinoid concentrations advertised ( Vandrey et al, 2015). Thus, in the absence of well-controlled data and product regulation, advertising is all that consumers and physicians currently have to make medical decisions regarding the clinical use of cannabis.

Controlled trials testing the effects of smoked cannabis on PTSD outcomes have not been conducted, to our knowledge. A concern with state-by-state allowances for medical cannabis use for the treatment of PTSD is that patients would begin using the drug in the absence of controlled evidence of efficacy or recommended timing of administration, particularly in terms of facilitating extinction. Given the potential for adverse effects of smoked cannabis, we call for a slowing in the pace of legalization of cannabis for therapeutic use until safety and efficacy data exist to enable evaluation of risks and benefits of cannabinoids for specific features of PTSD.

A final point is that both oral and smoked cannabinoids can be anxiogenic, particularly for those who do not use cannabis regularly (eg, Haney, 2007). Although regular cannabis smokers often report smoking for relaxation and tension relief, anxiety, and panic following cannabis use are not uncommon and in fact drive the high rates of emergency room visits attributed to cannabis use ( Moreira et al, 2009; Crippa et al, 2009; Hall and Solowij, 1998). This raises the possibility that oral or smoked cannabinoids would worsen anxiety in some PTSD patients. Clearly, FDA-approved treatments for PTSD (antidepressants, anticonvulsants, atypical antipsychotics, benzodiazepines) have the potential to worsen mood as well. If cannabinoid agonists are proven beneficial, the risk/benefit of each approach would have to be weighed with the understanding that increased anxiety is a possible outcome from cannabinoid use.

Psychotic disorders

Eden Evins

It is clear that THC can cause acute psychotic symptoms, such as paranoia, in a dose-dependent manner ( D'Souza et al, 2004; Murray et al, 2013), and those with a psychotic illness who do not stop using cannabis have a poorer prognosis on average than those who do ( Tarricone et al, 2014; Alvarez-Jimenez et al, 2012), controlling for other substance use ( Foti et al, 2010). What is somewhat controversial is whether to draw causal inference from the now well-replicated finding from large, prospective, longitudinal, epidemiologic studies that cannabis use, particularly heavy adolescent use of high potency cannabis, is associated with increased odds of developing schizophrenia ( Andreasson et al, 1987; Arseneault et al, 2002; Di Forti et al, 2009; Fergusson et al, 2003; Giordano et al, 2014; Large et al, 2011; van Os et al, 2002; Zammit et al, 2002; Stefanis et al, 2014). There is a well-replicated dose effect, such that daily use and use of high THC potency cannabis further increase odds of developing a psychotic illness and of earlier onset of psychosis ( Di Forti et al, 2009, 2013, 2015). Galvez-Buccollini and colleagues (2012) found a direct association between age of onset of cannabis use and age of onset of psychosis.

While presence of schizophrenia prodrome confounds establishment of precise onset of schizophrenia illness, and those in the prodrome may be more likely to use intoxicants ( Giordano et al, 2014; DeLisi et al, 1991), strong evidence that cannabis exposure preceded onset of psychosis by up to 7 years has been reported in several large studies, controlling for or removing those with other drug use ( Andreasson et al, 1987; Di Forti et al, 2009; Fergusson et al, 2003). Control for familial risk of schizophrenia attenuates but does not eliminate the association between cannabis use and schizophrenia, further supporting the hypothesis that cannabis exposure, particularly early, frequent exposure to high THC potency cannabis is a causal factor in the development of schizophrenia ( Giordano et al, 2014).

Interactive effects between genotype, cannabis use, and psychosis suggest that cannabis use confers far greater risk of psychosis for some, in some cases a five- to sevenfold greater risk among daily users. Among cannabis users and daily cannabis users, respectively, carriers of the DRD2, rs1076560, T allele had three- and fivefold increased odds of developing a psychotic disorder compared with cannabis users who were GG carriers ( Colizzi et al, 2015). Carriers of the COMT valine158 (Val) allele were more likely to develop schizophreniform disorder if they used cannabis in adolescence, although cannabis use had no influence on individuals homozygous for the methionine (Met) allele ( Caspi et al, 2005). In a randomized clinical trial, COMT Val allele carriers experienced greater cognitive impairment with THC (300 μg/kg), and more psychotic symptoms in those prone to psychosis compared with placebo than M et allele carriers ( Henquet et al, 2006). An AKT1 genotype by cannabis use interaction has also been reported, with those with C/C rs2494732 genotypes who used cannabis having twofold odds of having a psychotic disorder ( van Winkel and Genetic R, Outcome of Psychosis I, 2011). In another study, those with AKT1 C/C genotype with prior cannabis use and daily use, respectively, showed two- and sevenfold increased likelihood of a psychotic disorder compared with users and daily users who were T/T carriers ( Di Forti et al, 2012).

There is evidence that individuals with or vulnerable to psychosis have a neurobiological response to THC that renders them more vulnerable to psychotogenic effects of cannabis. Those with psychotic disorder and their siblings are more sensitive than matched controls to the psychotogenic effects of acute THC administration ( D'Souza et al, 2005; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). This may explain why even among those taking medications for psychotic disorders, cannabis use is associated with an increased risk of relapse into psychotic symptoms ( Alvarez-Jimenez et al, 2012). Inhalation of vaporized THC (8 mg) by cannabis users with a psychotic disorder (not on medication) and those with first-degree relatives with a psychotic disorder showed significantly greater striatal DA release following THC administration than control cannabis users without psychiatric illness, despite having a similar subjective response to THC ( Kuepper et al, 2013). Therefore, although a common argument against causality is that cannabis use has risen considerably in the past 40 years, whereas rates of schizophrenia have not (eg, Frisher et al, 2009; Degenhardt et al, 2003; but see Hickman et al, 2007), its impact in the general population would be expected to be modest if cannabis precipitates psychosis preferentially in those with specific genetic vulnerability ( Hall, 2014).

Thus, although schizophrenia etiology is multifactorial, and the majority of people who use cannabis do not develop schizophrenia, these findings, taken together, support the hypothesis that cannabis use, particularly frequent use of high THC content cannabis, increases the risk for development of psychosis, particularly in those with genetic susceptibility that influences vulnerability to environmental exposures. This warrants serious consideration from the point of view of public health policy ( Radhakrishnan et al, 2014).

Meg Haney

Although heavy cannabis use by individuals with a psychotic disorder or vulnerable to one is largely associated with a poorer prognosis, there are sufficient reasons to question the causality of this relationship. To start, it is important to emphasize that although meta-analyses show a consistent association between cannabis use and psychotic disorders, the odds ratio is small. For those ever using cannabis, the association with psychotic disorders is 1.41 (95% CI 1.20-1.65), whereas the odds ratio is 2.09 (95% CI 1.54-2.84) for those using cannabis frequently ( Moore et al, 2007). As noted by Moore et al (2007), larger effect sizes have been reported in other analyses, but these were based on cross-sectional data or were not adjusted for factors such as cumulative cannabis use, presence of psychiatric illness at baseline, other concurrent drug use, or cannabis use at least once vs dependence ( Arseneault et al, 2002; Henquet et al, 2005, Semple et al, 2005). Thus, an association between cannabis and psychosis exists, but, at best, it is only one small factor in a much larger constellation of factors associated with this disorder.

So why might a diagnosis of schizophrenia be associated with higher rates of cannabis use relative to the general population ( Foti et al, 2010)? As noted above, the apparent dose-response relationship between amount of cannabis smoked and the likelihood of a disorder is one piece of evidence consistent with causality. The more cannabis used at baseline in large prospective studies, the greater the risk of developing schizophrenia or psychotic symptoms ( Zammit et al, 2002; van Os et al, 2002; Fergusson et al, 2003) and the greater likelihood that psychotic symptoms at baseline persist ( Henquet et al, 2005).

Yet, psychotic disorders rarely emerge without warning. Even when cannabis use unequivocally predates a diagnosis, schizophrenia is a neurodevelopmental disorder with origins in early development. Those destined to develop schizophrenia exhibit unusual thoughts and behaviors years before they develop delusions and hallucinations ( Schiffman et al, 2005). This presents the possibility that, prior to a diagnosis of psychotic disorder and perhaps even prior to the prodrome phase of schizophrenia, those who have unusual thoughts or behaviors smoke more cannabis than those without these features; if this is the case, then a dose-response relationship, ie, heavier cannabis use prior to a diagnosis, does not support a causality association but could reflect heavier use by those neurodevelopmentally vulnerable to developing a psychotic disorder.

In terms of the interaction between genetic vulnerability and cannabis use, the link between COMT alleles and vulnerability to psychosis ( Caspi et al, 2005; Henquet et al, 2006) has been deemed 'very weak' upon subsequent analysis ( Moore et al, 2007). A comparison of relatives of individuals with schizophrenia who smoked cannabis versus those relatives who did not did smoke cannabis showed that both groups were more likely to develop the illness compared with relatives of healthy controls regardless of cannabis use ( Proal et al, 2014), which does not support the hypothesis that cannabis worsens outcome in individuals genetically vulnerable to psychosis.

At last, in assessing the interaction between cannabis and psychotic disorder, it is useful to consider tobacco cigarette smoking in this population, as tobacco is more strongly linked to schizophrenia than cannabis. In a meta-analysis assessing tobacco use among patients with first-episode psychosis, there was a strong association (OR=6.04; 95% CI, 3.03-12.02) compared with healthy controls ( Myles et al, 2012). Similar to the data with cannabis, patients with first-episode psychosis usually smoked tobacco cigarettes for some years prior to the onset of psychosis, have high prevalence of tobacco use when presenting for treatment, and are more likely to smoke than aged-matched controls ( Myles et al, 2012). Also similar to cannabis, some suggest this association reflects the underlying neurobiology of psychotic disorders, which may enhance nicotine reinforcement; or those with schizophrenia use cigarettes to moderate the effects of the illness and the antipsychotic medications (eg, Dalack et al, 1998). Conversely, Kendler and colleagues (2015) recently presented evidence supporting the idea that tobacco use prospectively increases the risk of schizophrenia. These authors thoughtfully considered the same factors argued to support a cannabis-schizophrenia link, but acknowledge that the data support but do not prove causality. They also demonstrate that familial/genetic factors contribute to the association between tobacco use and schizophrenia.

To conclude, public perception and popular media often interpret associations shown in longitudinal studies as demonstrating causation, so the scientific community has to consistently emphasize the distinction between association and causation. Given the low odds ratio and evidence that schizophrenia is a neurodevelopmental disorder, the most scientifically conservative stance is that the association between cannabis and psychotic disorders is not causal. As described by Dumas et al (2002), there are three possible models explaining the cannabis-schizotypal link: (1) cannabis use increases risk for schizotypal traits; (2) schizotypal traits increase risk for cannabis use; (3) a third causal variable underlies both cannabis use and schizotypal traits. The data do not demonstrate causality but may reflect self-medication or a shared risk factor.

Haney and Evins: Moving the Field Forward

Despite differing on their interpretation of the evidence-supporting causality, the authors agree on the biological plausibility of a causal relationship between adolescent cannabis use and negative psychiatric outcome. CB1 cannabinoid receptors are the most common G-coupled protein receptors in the brain, at concentrations 10-fold higher than opioid receptors, for example, and endocannabinoids are an abundant CNS neuromodulatory system ( Passie et al, 2012). Further, adolescence is a critical time of synaptic and circuit development, and CB1 receptors are ubiquitous in the prefrontal cortex, a brain site heavily impacted by schizophrenia ( Malone et al, 2010; Hill, 2014). Exogenous cannabinoid use could disrupt endocannabinoid-directed brain organization during this period of rapid development, impacting neurobiological and therefore psychiatric outcome. The authors therefore agree with those (eg, Moore et al, 2007) who argue that even without data to demonstrate causation, the potential for long-term brain changes by regular cannabis exposure during adolescence is sufficient to warn the public against the risk of adverse psychiatric outcomes with adolescent cannabis use.

The authors also share concern about the impact of extraordinarily high THC concentrations in new routes of THC administration, such as marijuana e-cigarettes and dabbing (>60%THC), which may heighten the likelihood of adverse psychiatric consequences, particularly if regular use begins in adolescence. Cannabis smokers typically adjust their inhalation patterns and smoking topography as a function of cannabis strength (eg, inhaling more forcefully on low potency than high potency cannabis cigarettes; Heishman et al, 1989; Cooper and Haney, 2009), but this titration would be difficult with new routes of very potent THC administration.

In terms of moving the field forward: further study of the gene-environment interaction could improve our understanding of the association between cannabis use and schizophrenia. Polygenic effects ( Pan et al, 2015) from large genome-wide association studies ( Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) could be calculated for those who do or do not use cannabis to potentially clarify some of the shared genetic risks that may underlie the association. Prospective, longitudinal studies, with assessments commencing in youth prior to initiation of drug use that include family history, prospective and ongoing psychiatric evaluation, genetics and neuroimaging such as the upcoming ABCD study would contribute understanding of how cannabis use influences the onset of schizophrenia (albeit not definitively demonstrating causality). Given that intellectual and neuromotor abnormalities in childhood are evident long before a diagnosis of schizophrenia ( Larson et al, 2010), it would be useful to capture these symptoms early in development to observe whether those who later smoke cannabis have a worse prognosis than a group with comparable childhood symptoms who do not smoke cannabis.

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Does Cannabis Cause, Exacerbate or Ameliorate Psychiatric Disorders? An Oversimplified Debate Discussed

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There have been extensive policy shifts in the legality of recreational and therapeutic use of cannabis in the United States, as well as a steady increase in the number of people using the drug on a regular basis. Given these rapid societal changes, defining ...

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How Cannabis Affects The Human Body

How Did We Make Cannabis Medicine?

The legal cannabis movement started in San Francisco in the early 1990's when it was discovered that cannabis treated many symptoms that AIDS patients suffered from, including pain. It was medical marijuana laws that changed the legal status of cannabis nationwide, opening the doors for an adult-use market and creating a path towards full legalization. Cannabis patients across the country have used the plant to treat a growing number of medical conditions. In Colorado alone, there are nine different qualifying conditions for a medical card: cancer, glaucoma, HIV or AIDS, cachexia (wasting syndrome), persistent muscle spasms, seizures, severe nausea, severe pain, and Post Traumatic Stress Disorder (PTSD).
What's The Real Story
How does cannabis address so many different conditions? How does the body interact with the plant to produce these medicinal effects? What research has been to done to demonstrate the efficacy of medicinal cannabis? To dive into these questions, it's crucial to have a basic understanding of the endogenous cannabinoid system, otherwise known as the endocannabinoid system (ECS). The endocannabinoid system is essential to human health because it maintains homeostasis in the body. Research into the endocannabinoid system has increased in recent years as scientists begin to reveal how complex and important this system is to our bodies. By understanding the endocannabinoid system and how it interacts with cannabis, patients and consumers can become more informed about their health and can ask their caregivers, doctors, or budtenders better questions.

Further Reading: What is CBD?

What is the endocannabinoid system?

Put simply, the endocannabinoid system is responsible for maintaining homeostasis in the body. The Encyclopedia Britannica definition of homeostasis is, "any self-regulating process by which biological systems tend to maintain stability while adjusting to conditions that are optimal for survival. If homeostasis is successful, life continues; if unsuccessful, disaster or death ensues."The endocannabinoid system is made up of three parts: cannabinoid receptors, endocannabinoids, and metabolic enzymes.
It's There, Silently Working:
Endocannabinoid receptors are found throughout the body on the surface of cells in the brain, organs, tissues, and glands. These receptors are embedded in cell membranes and produce varying reactions when stimulated by cannabinoids. Cannabinoids come from two distinct places - the body, which produces naturally occurring endocannabinoids, and the cannabis plant, which produces phytocannabinoids. The third part of the ECS is metabolic enzymes. Metabolic enzymes act like a natural referee in that they destroy endocannabinoids once they are used and no longer useful to the body. The two main metabolic enzymes are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). This self-regulating system ensures the interaction only happens when needed and therefore keeps the workings of the endocannabinoid system relatively quiet to the conscious brain, unlike, the hormonal system, which can keep the chemicals around longer than the interaction. Because homeostasis is so important to health, all vertebrates and invertebrates are known to have an ECS.

What Is The Endocannabinoid System? Whiteboard Explainer Video from Canna Insider.
Pain, Emotion, and More:
Dr. Ethan Russo, a neurologist and psychopharmacology researcher, breaks down the ECS this way, "the endocannabinoid system affects the levels of all the neurotransmitters, and so it is important in pain, in emotion, whether you're going to vomit or not, whether you're going to have a seizure or not, almost any function you can name, and it's not just the brain."

Research and discovery

Despite its critical importance, the endocannabinoid system was only discovered in the early 1990s when Lisa Matsuda, a researcher at the National Institute of Mental Health, and her colleagues discovered a DNA sequence that defines a THC-sensitive receptor in a rat's brain. This discovery was quickly followed up with further evidence by Dr. Raphael Mechoulam, the famous chemist who discovered THC. With less than 30 years of research, the endocannabinoid system is one of the less studied systems in the body. Currently, restrictions on cannabis research limit what scientists can examine in terms of furthering our understanding of how cannabis interacts with the endocannabinoid system.
Dr. Ethan Russo states, "if we look at any aspect of how our bodies work, our physiology, you've got some element of the endocannabinoid system that affects that. So it is a key modulator of what we call homeostasis, that's a natural balance in the body. When someone uses cannabis medicinally they are keying into these natural mechanisms which sometimes are deficient and need supplementation."

Cannabinoid receptors

So what do we know about how cannabis interacts with our bodies and the endocannabinoid system? Two cannabinoid receptors have been discovered by researchers: CB1 and CB2. CB1 is found in the central and peripheral nervous system. It's also found in the brain and is the receptor that THC interacts with, giving the user a high. CB2 receptors are predominantly found in the immune system and the gastrointestinal system where they regulate inflammatory responses in the bowels. CB2 receptors are also found in the brain, although not as densely as CB1 receptors. These receptors, a large part of the endocannabinoid system, play roles in regulating cardiovascular activity, appetite, mood, memory, and pain in the body.

CBD and the endocannabinoid system

CBD does not fit exactly into either CB1 or CB2 receptors. CBD stimulates both receptors and causes a reaction without binding directly, creating changes in cells that contain them. CBD also binds to a protein-receptor couple, TRPV-1, responsible for regulating body temperature, pain, and inflammation. CBD is also known for counteracting the effects of THC, activating serotonin receptors, and inhibiting a gene attributed to several cancers. CBD has grown in popularity recently as research and anecdotal evidence increasingly demonstrates the impact it can have on the body. Julianna Carella, the Founder & CEO of two edible companies, Auntie Dolores and Treatibles, states, "if you haven't acknowledged that the endocannabinoid system exists, then it's very easy to dispute the purported results that people and animals get from CBD because how can this possibly work so profoundly. Well, it works very profoundly because apparently, we're set up to need this in our systems."

Further Reading: The New Thing, Smoking CBD-Rich Hemp Flower

Where do cannabinoids come from?

Cannabinoids generally come from two places - the human body or the cannabis plant. However, there is a third place that is important to consider, a lab. Cannabinoids can be produced synthetically and distributed on the market. Marinol (dronabinol) and Cesamet (nabilone) are synthetic versions of THC that have FDA approval to be marketed and sold as a prescription drug. Synthetic cannabinoids do bind the endocannabinoid system to produce effects, but they often fail to incorporate one of the most important ideas in the medical cannabis community, the entourage effect. The entourage effect states that the sum of the different cannabinoids works better as a whole unit than any cannabinoid individually. With an understanding of the endocannabinoid system and its role in ensuring homeostasis in the body, it may be easier to see how this could be true.

The endocannabinoid system and health

The endocannabinoid system is a huge part of the human body that we are just beginning to understand. Carella states, "it's largely overlooked in the medical community. It's not taught in medical schools. It's definitely not taught in veterinary schools. So doctors and veterinarians are essentially misguided around a huge, huge piece of science that has been sort of strategically removed from the consciousness and unfortunately it means that we're quite behind with our research, but there's enough research out there for us to know that indeed all animals have an endocannabinoid system and that this endocannabinoid system is actually incredibly important in our physiology." The American Medical Association and the American College of Physicians are calling for more research into medical cannabis and its impact on humans. Until then, it's important, especially for patients and consumers, to stay informed about the endocannabinoid system and the evolving science of medical cannabis. Learn more about the endocannabinoid system at Wikipedia and The Top 10 Cannabinoids and How They Help You.

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The Endocannabinoid System - How Cannabis & CBD Affect Our Bodies

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How Cannabis Affects The Human Body How Did We Make Cannabis Medicine? The legal cannabis movement started in San Francisco in the early 1990's when it was discovered that cannabis treated many symptoms that AIDS patients suffered from, including pain.

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Demystifying the endocannabinoid system. | Ruth Ross | TEDxMississauga

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The main active chemical in Cannabis (Weed) is THC which can have various effects on the brain. Find out the effects, the risks and the law from FRANK. | FRANK

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Many people will try self-help-strategies as the first option in managing concerns about their cannabis use. Evidence suggests that cognitive behavioural therapy (CBT) can help people to reduce or stop cannabis use. Some self-help strategies can also be very useful, and the self-help information on this site offers practical tips for self-management.

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Whatever you do or think when it comes to weed, this site may challenge your beliefs. Designed to help you make informed choices and promote your well-being, this site covers current evidence, helps examine your relationship with weed, provides tips and tools to reduce harms, and more.

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Effects of cannabis on the teenage brain NCPIC + Turning Point

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Cannabis in Israel is illegal but decriminalized partially, although home use and possession of up to 15 grams and below is not enforced by the authorities but there are reports of enforcing occurring in low visibility, private places such as one's garden or private home. It is allowed for some specified medical usages. Citizens caught using cannabis in public for the first and second times cannot be arrested if no previous record of Cannabis use, but may face fines ($275 for first timers and $550 for second timers), with the money collected from these fines going to education and rehabilitation programs.

On July 19, 2018, The Israeli Knesset approved the bill for decriminalization, although the Israeli Cannabis community insists that this isn't a real decriminalization. The law will go into place on April 1, 2019.

A survey in 2017 found that 8.88% of Israelis use cannabis, 16th place among the world's nations surveyed (the highest rates of annual cannabis usage in the world being found in Iceland and the US at 18% and 16% respectively).

THC, the psychoactive chemical component in marijuana that causes a high, was first isolated by Israeli scientists Raphael Mechoulam of the Hebrew University in Jerusalem's Center for Research on Pain and Yechiel Gaoni of the Weizmann Institute in 1964.

Marijuana for medical use has been permitted in Israel since the early 1990s for cancer patients and those with pain-related illnesses such as Parkinson's, multiple sclerosis, Crohn's disease, other chronic pain and post-traumatic stress disorder. Patients can smoke cannabis, ingest it in liquid and caplet form, or apply it to the skin as a balm.

In 2004, the Israeli military began using Tetrahydrocannabinol (THC), one of the active ingredients in cannabis, for experimental treatment of post traumatic stress disorder (PTSD) of soldiers.

In 2012, the number of registered patients using medical cannabis was about 10,000. There are eight government-sanctioned cannabis growing operations in Israel, which distribute it for medical purposes to patients who have a license from the Ministry of Health and a prescription from an authorized doctor, via either a company's store, or in a medical center.

The Tikkun Olam Company has developed a variety of cannabis strains and marijuana-derived products that are reported to provide medical benefits. These products contain different levels of CBD and THC for optimum efficacy, depending on the medical condition they are taken for. CBD is the Cannabis substance that is believed to be an anti-inflammatory ingredient, which helps alleviate pain. THC in low levels does not cause a "high". Tikun Olam has now developed a range of 230 different varieties and is considered one of the leading medical cannabis suppliers in the world, while the Israeli-American company Cannabics Pharmaceuticals is aiming to put the medicinal compounds of cannabis into a sustained-release capsule in standardized doses.

In 2017, it was reported that the Israeli medical cannabis industry could soon be worth "hundreds of millions of dollars", with research innovation in the area being backed by Israel's Ministry of Health. Currently there are about 26,000 registered medical cannabis users, with the number expected to double by 2018.

In April 2017, with global demand growing, Israel gave medical cannabis companies the green light to start exporting their products, with analyses estimating that the measure could generate Israel some $267 million per year. It was reported that formal legislation was coming but could take months to complete.

An inter-ministerial report said in August 2017 that exports could add 4 billion shekels to the Israeli economy.

Israel is considered to have a climate that is especially good for producing cannabis, with the "perfect level of humidity", according to Tamir Gedo, the head of BOL Pharma, one of the companies authorized to grow and distribute medical cannabis.

Research and Innovation

Israel is considered a global leader in medical cannabis research and innovation. Research and innovation in the area is supported by the Ministry of Health and currently being dedicated 8 million shekels a year, making Israel one of three countries in the world where cannabis research is sponsored by the government. Cannabis researchers have relocated to Israel to pursue their studies, including entire firms which do their cannabis research in Israel to evade onerous regulations on cannabis research in the US, where it is "easier to research heroin than cannabis". At least 15 US companies have moved their entire R&D operations onto Israeli soil.

Israel's government-sponsored Breath of Life company plans to apply for FDA status for its new cannabinoid pills designed for treatment of autism.

According to iCan, an Israeli company which invests in the local cannabis market, more than 50 U.S. companies are doing cannabis research in Israel, and in 2016 they invested more than $125 million in Israeli cannabis operations.

Before 6 March, 2017, cannabis for recreational purposes was illegal. Before March 2017, those charged with public cannabis usage could have faced heavy fines or incarceration, although it was reported that in 2015 the number of arrests that had been made for that law were under 200; The New York Times noted of the previous situation that cannabis usage had long been overlooked by enforcement in Israel, but there was notable enforcement against growers and dealers.

As of 2015, most Israeli political parties favor legalizing marijuana for medicinal purposes. Parties represented in the Knesset that supported the legalization of medical marijuana in 2015 include the Zionist Union, the Joint List, Meretz, and Kulanu. The latter two supported decriminalization of the drug altogether. The Green Leaf Party, which had made cannabis legalization its raison d'être, has thus far never won a Knesset seat.

However, in 2017, it was the right-wing government of Benjamin Netanyahu, led by Likud and consisting of various right-wing, religious and Sefardi-interest parties that planned to decriminalize cannabis usage. Despite acute tension at the time between left- and the right-wing parties, the initiative was supported in the Knesset by parties across the political spectrum; right-wing Justice Minister Ayelet Shaked remarked that "whether one supports the use of cannabis or is opposed, it is wrong to judge cannabis users per criminal law and its derivatives", while left-wing Meretz member Tamar Zandberg also applauded the decision, calling it a "message that millions of Israelis who consume cannabis are not criminals" and "an important step but not the end of the road", while Public Security Minister Gilad Erdan said it marked a change in policy toward a rehabilitation oriented approach.

Cannabis usage remains illegal and those found using it in public could face fines or, after the fourth offense, incarceration; offenses before the fourth result in fines which go towards education and rehabilitation efforts and do not result in criminal records; the third offense results in mandatory participation in rehabilitation programs. Enforcement appears to be lax unless cannabis consumption occurs in public, high-visibility places. Israel's liberal stance on cannabis stands in contrast to the rest of the Middle East region where in some countries "drug trafficking" is punishable with death.

In April 2017, it was reported that Israel's government was considering further liberalization of laws concerning recreational usage. In November 2017, it was reported that Israeli Ministry of Health considering to withdraw its objection to making CBD component of cannabis legal.

On April 20, 2018, Israeli pharmacies began selling cannabis oil legally under a pilot program.

In 2013, Hagai Bar Giora, an Israeli rabbi and member of the Kashrut Department, stated in an interview with Israel's magazine that "if you smoke it, there is no problem whatsoever." Bar Giora noted that cannabis seeds, being legumes, are not kosher for Passover for Ashkenazi Jews, but are for Sefardic Jews who permit eating legumes on Passover.

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Cannabis in Israel is illegal but decriminalized partially, although home use and possession of up to 15 grams and below is not enforced by the authorities but there are reports of enforcing occurring in low visibility, private places such as one's garden or private home. It is allowed for some specified medical usages.

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One of the major advantages to vaping weed is having control over the temperature. When you smoke, there is nothing stopping that bud from reaching temperatures as high as 4000° F! You also lose most of the flavor and the subtleties of each strain. The only problem is, what's the best temperature for weed? In this guide, we detail three main temperature ranges, highlighting their differences and advantages. Each range provides a different experience, so it also depends on what you want to get out of it.

Keep in mind that everyone's experience can vary based on a few key factors. For example, two weed vaporizers set to the same temperature can sometimes produce a different type of vapor. Additionally, each strain contains different levels of terpenes and cannabinoids, which contribute to their smell, taste and effects. These organic compounds volatilize at various temperatures and will alter the experience.

Don't worry, you won't need to graduate weed college for this. Just use this guide and play around with different settings. See how they make you feel. Eventually, you will find the best temperature for you.

THC, the main psychoactive ingredient in cannabis has a boiling point of 315° F. You don't want to go much lower than 325° F, especially if you want to really feel something. Low temps might appeal to you if you want the best flavor from your bud. It produces a fresh taste, with citrusy and/or piney undertones.

The vapor will also be much cooler, and less harsh on the throat, so you probably won't cough as much. The possible side effects like paranoia, red eyes and cotton mouth will be less severe. If you're a wake and baker, low temp vaping can give you the feeling you want, without burning you out for the day. This is also the ideal setting for newcomers and lightweights who don't want to get too intoxicated.

Light euphoria, calming, invigorating

Intense terpene flavor, fresh, citrusy, piney

Cooler vapor, less coughing

Decreased side effects (lethargy, anxiety, red eyes, dry mouth etc.)

Best suited for newcomers, lightweights or flavor chasers

Better suited for getting chores done

Terpenes: A-pinene, β-caryophyllene, β-myrcene, citronellol, limonene
Cannabinoids: THC, CBD, CBG, CBC, THCa, CBDa

This is a safe place to start while you're still experimenting. In this range, you still get plenty of terpenes, but now with more access to cannabinoids. The vapor is thicker and warmer. You'll also taste more of the cannabinoids, which can give it a richer flavor. The warm vapor is satisfying for transitioning smokers.

The psychoactive effects will be noticeably stronger at these temperatures mostly because more THC is being volatilized. It can be relaxing, euphoric and put you in a meditative state without feeling drowsy. This temp range is an excellent middle ground for the best of both worlds between effects and flavor.

Relaxing, euphoric, meditative but not sleepy

Flavorful and rich, terpenes plus cannabinoids

Warmer vapor, can be satisfying for smokers

More THC gets volatilized

Can experience minor side effects

Increased cannabinoid availability

Terpenes: limonene, terpinolene, linalool, humulene
Cannabinoids: THC, CBD, CBN, CBG, CBC, THCa, CBDa

For maximum cannabinoid extraction, this is the range to be in. The vapor will be hotter and less flavorful, but you will feel the strongest psychotropic effects. This range is best suited for night time sessions because of its ability to induce lethargy, also called the dreaded "couch-lock". The activation of compounds THCv and humulene can actually suppress appetite and prolong the inevitable munchies.

At these temperatures, many terpenes will be depleted fast. If you're a real terp connoisseur, then you might want to reserve this range for the end of your sessions, for when you really want to blast off. This is the closest you can get to combustion without actually smoking, though it can still induce coughing.

Intense effects, strong euphoria, lethargy, "couch-lock"

Maximum THC volatilization

Hotter vapor, may cause coughing

Less terpenes, higher cannabinoid extraction

Activates THCv and humulene, appetite suppressants that can prolong "the munchies"

Closest experience to smoke/combustion

Terpenes: humulene, phytol, caryophyllene oxide
Cannabinoids: THC, CBD, CBN, CBG, CBC, THCa, CBDa, THCv

Here are the average boiling points for THC, CBD and the most common terpenes and cannabinoids found in cannabis. Each organic compound has its own unique function, so you can check the profile of your strain and decide the perfect temperature is for exactly what you're trying to achieve with it.
Cannabinoids: Terpenes:

A-Pinene: 311°F

β-Caryophyllene: 320°F

β-Myrcene: 334°F

Citronellol: 437°F

Limonene: 349°F

Terpinolene: 365°F

Linalool: 388°F

Humulene: 388°F

Phytol: 399°F

Caryophyllene oxide: 495°F

(Source: Medium/MarijuanaBreak/Leafly)
Still not sure what temperature to set your vaporizer at? It can be difficult to find the setting that works best for you. The best way to experiment is to start in the 350-400°F range and then work your way up or down by 5-10° at a time. Play around a bit and eventually you will find the temp that is just right for you.

If your herb is too moist, most of the heat will be wasted on drying out your buds. Vaporizers tend to work much better and produce more vapor with dryer herb. You can always let your weed air out for a few hours or even overnight, grinding it first will speed up that process.

Modern vaporizers are now capable of vaporizing concentrates these days. The best temps for dabs and THC oil will typically be higher than for dry herb. The same general principle applies: less heat = better taste. However, if it's too hot, you'll be losing valuable terpenes and flavor.

Lower temps are better suited for morning and daytime use, higher temps are more appropriate for evening and late-night sessions.

Generally speaking, lower temps are more conducive to flavor whereas higher temps will give you the strongest psychoactive effects. The boiling point of THC is around 315°F, so anything lower will produce minimal psychoactive effects.

CBD tends to boil at a slightly higher temperature than THC, so keep that in mind if you are using cannabis for medicinal purposes with hemp or cannabidiol-rich strains.

You'll typically want to vape 10°F hotter than the average boiling point of the desired terpenes and/or cannabinoids, but be aware that it can slightly vary with different devices or strains.

If you're vaping in the lower temperature range, don't throw out your already vaped bud. If it's greenish, or even light brown, it probably still contains valuable cannabinoids. It's also now decarboxylated, which simply means that it's now primed and ready for making edibles or tea.

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Guide to the Best Temperature for Vaping Weed

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One of the major advantages to vaping weed is having control over the temperature. When you smoke, there is nothing stopping that bud from reaching temperatures as high as 4000° F! You also lose most of the flavor and the subtleties of each strain. The only problem is, what's the best temperature for weed?

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UK58_Practice standards for young people with substance misuse problems (2012)

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Youth worker demonstrating motivational enhancement for cannabis change

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A Los Angeles doctor's license is reportedly at risk after he told a father give his four-year-old a cannabis-infused cookie to control his temper tantrums. The incident, which emerged last month, captures the concerns of legalization opponents who fear easier access will lead to increased use among children, in this case facilitated by what the California medical board called "grossly negligent" doctoring.

Just about everyone agrees minors shouldn't use cannabis. But what does changing policy mean for children's use of the drug?

Legalization opponents don't want to normalize the drug in children's eyes, while supporters say the best way to keep weed away from kids is to sell it in stores where only adults can shop. After all, illegal dealers don't ask for ID.

The argument was central to the Canadian prime minister Justin Trudeau's successful push to legalize the drug last year. (Most of the US data I've seen shows that legalization has led to increased use by adults, but not by minors.)

When new markets write their laws, children remain a central concern. Proposals about how far dispensaries need to be from schools and whether companies can make edibles in animal shapes are nightly news staples. Cannabis companies have generally been accommodating, eager to avoid any perception that they are targeting underage customers.

With cannabis, the instinct to protect young people is amplified by the scientific literature. The data shows marijuana poses the greatest danger to people under 25, whose brains are still developing. In the significant US markets, the current buying age is 21, compared with 18 or 19 in Canadian provinces.

From a public health perspective, then, it might be smart to experiment with a buying age of 25, though this would cut into the industry's core demographic. If, say, New York state, which is expected to debate legalization this year, proposed a buying age of 25, the industry would almost certainly counter that raising the legal age would prop up the illegal market, which sells to everyone.

While keeping pot away from kids is a widely shared priority, stories in which children benefit from medical marijuana have helped the legalization movement spread its message.

The 2013 CNN documentary Weed featured the story of Charlotte Figi, a little girl who suffered from a debilitating childhood seizure disorder. After Charlotte's parents exhausted their other options, they connected with the Stanley brothers, a Colorado family of marijuana growers.

Charlotte began taking oil from a strain of cannabis low in intoxicating THC but high in CBD, and her condition dramatically improved. The strain she took became known as Charlotte's Web.

The documentary inspired a number of similarly afflicted families to uproot their lives and move to Colorado where they could access the medicine. For the families who didn't move, smuggling networks arose to disperse the oil.

Last year, a pharmaceutical form of CBD called Epidiolex, produced by the UK company GW Pharmaceuticals, won approval from the US Food and Drug Administration as a treatment for patients like Charlotte, making it easier and safer to access the medicine.

Perhaps more than any other patient's, Charlotte's story helped shift US public opinion in favor of medical marijuana. This year the cannabis company Acreage Holdings tried to air a commercial featuring a similar story during the Super Bowl. Though it was rejected, it still went viral.

Now parents of kids with some other complex disorders, such as severe autism, have called for their children to have access to cannabis oil. Dr Peter Grinspoon, an instructor at Harvard Medical School and board member of Doctors for Cannabis Regulation, said decisions about recommending cannabis for children were "taboo and emotionally charged". But in cases of severe autism, he said, there was promising research that cannabis may help control behavior.

"You always have to ask what else you would be using," he said. In cases of low-functioning autism, the argument for using cannabis may be stronger because the patients instead receive "heavy anti-psychotics that turn people into zombies".

Stories like Charlotte's are undeniably affecting. They demonstrate the need for more research to be done. "There are a lot of indications where it's too early to tell," if cannabis has any benefit, Grinspoon said. "We don't know what the consequences are, but we're desperate for the benefits."
Topics

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Cannabis for kids: a medicinal miracle or 'gross negligence'?

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A Los Angeles doctor's license is reportedly at risk after he told a father give his four-year-old a cannabis-infused cookie to control his temper tantrums. The incident, which emerged last month, captures the concerns of legalization opponents who fear easier access will lead to increased use among children, in this case facilitated by what the California medical board called "grossly negligent" doctoring.

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Investigating the proposition that cannabis is worth bothering with, this hot topic looks at reports that stronger cannabis on the market is increasing harms to users, prospects of recovery from disorders and dependence, and the emerging response to synthetic forms of cannabis like 'spice'.

Cannabis in the law

A controlled 'Class B' substance, cannabis carries legal penalties for possession, supply, and production. Between 2004-2009 cannabis was reclassified as a 'Class C' substance, meaning for a brief period of time it carried lesser penalties for possession.

In 2009, the Association of Chief Police Officers issued new guidance, advising officers to take an escalating approach to the policing of cannabis possession for personal use:
* A warning
* A penalty notice for disorder (PND)
* Arrest

This three-tiered approach was designed to be "ethical and non-discriminatory", but also reinforce the "national message that cannabis is harmful and remains illegal ".

For more on the classification of drugs, including the difference between Class A, Class B, and Class C drugs, visit this UK government page.

In 1990s Britain a common reaction to allocating resources to treating cannabis users was, 'Why bother? We have more than enough patients with problems with serious drugs like heroin.' The typically calming use of the drug by adults was seen as preferable to the main alternative - alcohol and its associated violence and disorder. Calls for a treatment response were seen as pathologising what in many societies is both normal and in some ways desirable youth development: trying new experiences, challenging conventions, and exposing the hypocrisy of alcohol-drinking adults.

In 1997 the Independent on Sunday launched a campaign to decriminalise cannabis, culminating in a mass 'roll-up', and 16,000-strong pro-cannabis march from Hyde Park to Trafalgar Square. Its Editor Rosie Boycott wrote in the paper about her own coming-of-age experience smoking cannabis, telling readers:

"I Rolled my first joint on a hot June day in Hyde Park. Summer of '68. Just 17. Desperate to be grown-up. ... My first smoke, a mildly giggly intoxication, was wholly anti-climatic. The soggy joint fell apart. I didn't feel changed. But that act turned me - literally - into an outlaw. I was on the other side of the fence from the police - or the fuzz, as we used to call them. So were a great many of my generation."

The campaign was explosive, but short-lived, apparently subsiding when Boycott left to take up her role as Editor of the Daily Express. A decade later, the Independent issued an apology for the campaign. 'If only they had known then, what they knew now', was the message of the article, referring to the reportedly damaging impact of the more potent strains of cannabis and its links to "mental health problems and psychosis for thousands of teenagers".

Are stronger strains creating more problems?

There has been a long-standing, but controversial, association between cannabis strength and harm. Reading newspaper articles on the subject, it wouldn't be unusual to see a headline drawing a straight line between 'super-strength skunk' and addiction, violence, deaths, or psychosis. In 2008, then Prime Minister Gordon Brown spoke in a similar vein, telling a breakfast-television viewing audience:

I have always been worried about cannabis, with this new skunk, this more lethal part of cannabis.

I don't think that the previous studies took into account that so much of the cannabis on the streets is now of a lethal quality and we really have got to send out a message to young people - this is not acceptable.

Brown was warning of a dangerous new strain of cannabis on the market, that caused very severe harms to users - contrasting starkly with the common perception of cannabis as a 'low harm' or 'no harm' drug.

The strength or potency of cannabis is determined by the amount of ' THC' it contains. THC produces the 'high' associated with cannabis, and another major component ' CBD' produces the sedative and anti-anxiety effects. As well as potency, the relative amounts of THC and CBD are important for understanding the effects of cannabis - something explored in a University College London study during the programme Drugs Live: Cannabis on Trial. The research team compared two different types of cannabis: the first had high levels of THC (approx. 13%) but virtually no CBD; and the second had a lower level of THC (approx. 6.5%) and substantial amounts of CBD (approx. 8%). They found that CBD had a moderating or protective effect on some of the negative effects of THC, and that "many of the effects that people enjoy are still present in low-potency varieties without some of the harms associated with the high-potency varieties".

At least in the US over the last two decades (between 1995-2014), potency has increased from around 4% to 12%, and the protective CBD content of cannabis has decreased, from around 28% to less than 15%, significantly affecting the ratio of THC to CBD, and with it, the nature and strength of the psychoactive effect of cannabis.

Until the 1990s, herbal cannabis sold in the UK was predominantly imported from the Caribbean, West Africa, and Asia. After this time, it was increasingly produced in the UK, being grown indoors using intensive means (artificial lighting, heating, and control of day-length). A study funded by the Home Office analysed samples of cannabis confiscated by 23 police forces in England and Wales in 2008, and found that over 97% of herbal cannabis had been grown by intensive methods; its average potency of 16% compared with just 8% for traditional imported herbal cannabis. This matched other reports of home-grown cannabis being consistently (around 2-3 times) stronger than imported herbal cannabis and cannabis resin.

In 2015, observing a decrease in the use of cannabis in England and Wales, but parallel increase in demand for treatment, a UK study examined whether the trend could be explained by an increase in the availability of higher-potency cannabis. Over 2500 adults were surveyed about their use of different types of cannabis, severity of dependence, and cannabis-related concerns. The researchers found that higher potency cannabis was associated with a greater severity of dependence, especially in young people, and was rated by participants as causing more memory impairment and paranoia than lower potency types. However at the same time, it was reported to produce the best 'high', and to be the preferred type.

By definition cannabis is a psychoactive substance, which means it can change people's perceptions, mood, and behaviour. Higher potency cannabis contains more of the psychoactive component, so it makes sense that higher potency cannabis could increase the risk of temporary or longer-term (adverse) problems with perceptions, mood, and behaviour. However, there is a particular concern that cannabis use could be linked to 'psychosis', a term describing a mental illness where a person perceives or interprets reality in a very different way to those around them, which can include hallucinations or delusions.

Whether cannabis causes psychosis, precipitates an existing predisposition, aggravates an existing condition, or has no impact at all on psychotic symptoms, has for decades been hotly contested. With our focus on evaluations of interventions, Drug and Alcohol Findings is in no position to pronounce on this issue, nor on the possibility that the drug might sometimes improve mental health, but some examples of research informing this debate are included below.

A recently published paper from the University of York has demonstrated the complications of attributing any association between cannabis use and psychosis to a causal effect of cannabis use rather than other factors or a reverse causal effect. A calculation based on data from England and Wales helped to put this into perspective, indicating that even if cannabis did cause psychosis more than 20,000 people would need to be stopped using cannabis to prevent just one case of psychosis.

Cannabis accounts for half of all new drug treatment patients

The most widely used illegal drug in Europe, many seemingly enjoy cannabis without it leading to any significant negative social or health effects. However, numbers entering treatment for cannabis use problems have been on the rise (both in the UK, and the rest of Europe), while heroin treatment numbers have fallen chart. According to Public Health England, this is not because more people are using cannabis, but perhaps because services relieved of some of the recent pressure of opiate user numbers are giving more priority to cannabis, because they are making themselves more amenable to cannabis users, and because of emerging issues with stronger strains of the drug.

Whatever the causes, across the UK figures submitted to the European drug misuse monitoring centre show that the proportion of patients starting treatment for drug problems who did so primarily due to their cannabis use rose steadily from 11% in 2003/04 to 22% in 2011/12. With the caveat that data from 2013 onwards is not directly comparable due to changes in methodology, in 2014 and 2015 the proportion of patients who entered treatment primarily because of a cannabis issue hovered above previous years at 26% (25,278 and 26,295 respectively). Among first ever treatment presentations, the increase from 2003/04 was more pronounced, from 19% to 37%. By 2013, cannabis use had become the main prompt for half the patients who sought treatment for the first time (at 49%), and stayed relatively constant at 47% in 2014, and 48% in 2015.

The treatment figures largely reflect trends in England, where in 2013/14 the number of patients starting treatment with cannabis use problems had risen to 30,422, 21% of all treatment starters, up from 23,018 and 19% in 2005/06. Subsequently the number dropped to 27,965 in 2015/16, still around a fifth of all treatment starters. Among the total treatment population - starting or continuing in treatment - cannabis numbers rose from 40,240 in 2005/06 to peak at 64,407 in 2013/14 before falling back to 59,918 in 2015/16; corresponding proportions again hovered around a fifth.

As a primary problem substance among under-18s cannabis dominated, accounting for three-quarters of all patients in treatment in 2015/16 and in numbers, 12,863. The dominance of cannabis increased from 2008/09 as numbers primarily in treatment for drinking problems fell.

'All treatments appear to work'

According to the two main diagnostic manuals used in Europe and the USA, problem cannabis use can develop into a cannabis use disorder or cannabis dependence, identifiable by a cluster of symptoms including: loss of control; inability to cut down or stop; preoccupation with use; neglecting activities unrelated to use; continued use despite experiencing problems; and the development of tolerance and withdrawal.

This level of clinical appreciation for cannabis use problems didn't exist when researcher and writer William L. White entered the addictions field half a century ago:

"When I first entered the rising addiction treatment system in the United States nearly half a century ago, there existed no clinical concept of cannabis dependence and thus no concept of recovery from this condition. In early treatment settings, cannabis was not consider[ed] a "real" drug, the idea of cannabis addiction was scoffed at as remnants of "Reefer Madness," and casual cannabis use was not uncommon among early staff working in addiction treatment programs of the 1960s.

Many in the field remain sceptical of the idea of cannabis dependence, specifically whether problem users at the severe end experience physiological withdrawal. However, reviewing what they believe is mounting evidence, these authors suggest there can be confidence in the existence of a "true withdrawal syndrome" - albeit one that differs qualitatively from the "significant medical or psychiatric problems as observed in some cases of opioid, alcohol, or benzodiazepine withdrawals". In the case of cannabis, the main symptoms are primarily emotional and behavioural, although appetite change, weight loss, and some physical discomfort are reported. A brief review aimed at practitioners in UK primary care provides guidance on how to manage symptoms of withdrawal among patients trying to stop or reduce their cannabis use.

Research has come a long way, says William L. White, with now "clear data supporting the dependency producing properties of cannabis, a clear conceptualization of cannabis use disorders (CUD) and cannabis dependence (CD)", but until recently, very little evidence about the prospects of long-term recovery. Yet, key papers - found here and here - indicate that:
* Full remission from cannabis use disorders is not only possible, but probable.
* Stable remission takes time - an average of 33 months.
* Abstinence may not be initially realistic for heavy cannabis users - but those in remission are usually able to reduce the intensity of their use and its consequences.

At least in the United States, it seems dependence is more quickly overcome from cannabis than the main legal drugs. A survey of the US general adult population found that within a year of first becoming dependent, 3% each of smokers and drinkers were in remission and remained so until they were surveyed. For cannabis the figure was nearly 5% and for cocaine, nearly 9%. After ten years the proportions in remission had risen to 18% for nicotine, 37% for alcohol, 66% for cannabis and 76% for cocaine. About 26 years after first becoming dependent, half the people at some time dependent on nicotine were in remission, a milestone reached for alcohol after 14 years, for cannabis six years, and for cocaine, five.

Generally for people with cannabis use problems, the European Monitoring Centre for Drugs and Drug Addiction concluded in 2015, and before that in 2008, that "all treatments appear to work". For adults, effective treatments include motivational interviewing, motivational enhancement therapy and cognitive-behavioural therapy, and for younger people, family-based therapies seem most beneficial. Less important than the type of treatment is the treatment context and the individual's determination to overcome their problems through treatment. And there is "no firm basis for a conclusion" that cannabis-specific interventions (designed around the risks and harms associated with cannabis) are more effective than general substance use treatment tailored to the individual needs of the cannabis user seeking treatment chart.

In some studies brief interventions have been found to work just as well as more intensive treatment, but when the patients are heavily dependent, and the most difficult cases are not filtered out by the research, longer and more individualised therapies can have the advantage.

When the World Health Organization trialled its ASSIST substance use screening and brief advice programme in Australia, India, the United States, and Brazil, just over half the identified patients (all had to be at moderate risk of harm but probably not dependent) were primarily problem cannabis users. Among these, risk reduction in relation to this drug was significantly greater among patients allocated to a brief advice session than among those placed on a three-month waiting list for advice. In each country too, risk reduction was greater among intervention patients, except for the USA, where the order was reversed. Suggesting that severity of use was not a barrier to reacting well to brief intervention, only patients at the higher end of the moderate risk spectrum further reduced their cannabis use/risk scores following intervention. The ASSIST study was confined to adults, but young people in secondary schools in the USA whose problem substance use focused mainly on cannabis also reacted well to brief advice.

The relative persistence of opiate use problems versus the transitory nature of those primarily related to cannabis seemed reflected in an analysis of treatment entrants in England from 1 April 2005 to the end of 2013/14, the last time this particular analysis was published. At the end of this period just 7% of primary cannabis users were still in or back in treatment compared to the 30% overall figure and 36% for primary opiate users. The figure peaked at 43% for users of opiates and crack. Over half - 53% - of primary cannabis users had left treatment as planned, apparently having overcome their cannabis problems, compared to 27% of primary opiate users and just 20% with dual opiates and crack use problems. Another 40% of cannabis users had left treatment in an unplanned manner, a slightly higher proportion than among opiate users. The figures tell a tale of relatively high level of success which enables cannabis users to leave treatment, though even in the absence of recorded success, few stay long-term.

However, the forms patients in England complete with their keyworkers while in treatment seem to tell a different story. Compared to how they started treatment, around six months later 45% of primary cannabis users were assessed as using just as often (including a few using more), compared to 30% of opiate users and 42% whose main problem drugs were both opiates and crack, suggesting more rapid and/or more complete remission for opiate users than for cannabis users. One interpretation is that the widespread use of substitute drugs like methadone more reliably reduced the illegal opiate use of opiate users and also helped retain them in treatment, while cannabis users tended quickly to leave treatment, having done well or not. However, these figures relate only to patients who completed the forms at their six-month review, which in practice could have happened anywhere from about one to six months after their assessment for treatment. What proportion of primary cannabis users were still in treatment at that point and available to complete the forms is not clear, but they may have been the patients whose problems were deep seated enough to require extended treatment.

Enjoyable and trouble-free for many, but not without harms

Many formal cannabis harm reduction programmes borrow from the fields of alcohol and tobacco. Advice includes:
* safer modes of administration (eg, on the use of vaporisers, on rolling safer joints, on less risky modes of inhaling)
Many people experience cannabis as enjoyable and trouble free ... some people require help to reduce or stop * skills to prevent confrontation with those who disapprove of use
* encouraging users to moderate their use
* discouraging mixing cannabis with other drugs
* drug driving prevention and controls
* reducing third-party exposure to second-hand smoke
* education about spotting signs of problematic use
* self-screening for problematic use

In some parts of the UK, National Health Service tobacco smoking cessation services incorporated cannabis into their interventions with adults; and Health Scotland, also addressing the risks of tobacco and cannabis smoking, published a booklet for young people titled Fags 'n' Hash: the essential guide to cutting down the risks of using tobacco and cannabis.

Vaporising or swallowing cannabis offers a way to avoid respiratory risks, but only a minority of cannabis do this, most choosing to smoke cannabis joints (or cannabis and tobacco joints). While not all will know about the different health risks, cannabis users may choose against safer consumption methods anyway for a range of reasons (including their own thoughts about safe use):
* Users may find it easier to control the effects (eg, severity, length of effect) of cannabis when inhaling in the form of a joint or spliff
* Preparing and sharing joints can be an enjoyable part of the routine, or part of a person's social activities
* Alternative methods of smoking (eg, bongs and vaporisers) may be inconvenient to use, or expensive to buy

Most harm reduction advice is delivered informally long before users come into contact with drugs professionals - for example through cannabis magazines, websites, and headshops - highlighting the importance of official sources engaging with non-official sources to promote the delivery of accurate, evidence-based harm reduction messages.

A new high

Prior to this, in 2014, there had been 163 reported deaths from new psychoactive substances in the UK, and 204 the year after. The average age was around 28, younger than the average age for other drug misuse deaths of around 38. The fact that these psychoactive substances - which produced similar effects to illicit drugs like cannabis, cocaine, and ecstasy - could be bought so easily online or on the high street, appeared inconsistent; and each fatality prompted "an outcry for something to be done to prevent further tragedies". This was the context (and arguably the political trigger) for the introduction of the Psychoactive Substances Act. While possession of a psychoactive substance as such wasn't criminalised;, production, supply, offer to supply, possession with intent to supply, import or export were - with a maximum penalty of seven years' imprisonment.

The paper "From niche to stigma" examined the changing face of the new psychoactive substance user between 2009 and 2016, focusing on people using the synthetic cannabis known as 'spice'. It looked at the transition of (then) 'legal highs' from an "experimental and recreational" scene associated with a "niche middle class demographic", to "those with degrees of stigma", especially homeless, prison, and socially vulnerable youth populations (including looked after children, those involved in or at risk of offending, and those excluded or at risk of exclusion from mainstream education). In 2014, the DrugScope Street Drug Survey also observed a problem among these particular groups, recording a "rapid rise in the use of synthetic cannabinoids such as Black Mamba and Exodus Damnation by opiate users, the street homeless, socially excluded teenagers and by people in prison".

'Spice' and other synthetics

Cannabis contains two key components:
* 'THC' (tetrahydrocannabinol), which produces the 'high'
* 'CBD' (cannabidiol), which produces the sedative and anti-anxiety effects

Synthetic forms of cannabis contain chemicals that aim to copy the effects of 'THC' in cannabis. But the effects of synthetic cannabis can be quite different (and often stronger): firstly, because synthetic production makes it easier to manipulate the amount of the THC-like chemical; and secondly, because of the absence of the moderating equivalent of 'CBD'.

Some synthetics are purposely designed to resemble herbal cannabis, and can be consumed in the same ways (eg, smoked or inhaled). The names also often have deliberate cannabis connotations. The risk of this is that people wishing to take cannabis may be initially unaware that they have been sold the synthetic form, or may believe from the look of it that it will produce similar sought-after effects. The greater intensity of synthetic cannabis at lower dose levels ( box) ensures that it has an appeal in terms of potency and affordability, but may put those with fewer resources at greater harm.

In 2014, the prison inspectorate for England and Wales raised concerns about the rise in the use of psychoactive substances in prisons, in particular synthetic cannabis. A study set in an English adult male prison found that the nature of the market was posing significant challenges to the management of offenders. There, the primary motivation for consumption was being able to take a substance without it being detected. Given this motivation, and the greater likelihood of harms from synthetic versus natural cannabis, the researchers concluded that it was imperative for mandatory drug-testing policies to be revised, and instead rooted in harm reduction - something which would also apply to people on probation subject to mandatory drug-testing.

Cannabis throws up a range of issues rather different from those associated with the drugs treatment in the UK has normally focused on. If current trends continue, understanding the findings will become yet more important to British treatment services.

Last revised 10 July 2017. First uploaded 01 March 2011

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Investigating the proposition that cannabis is worth bothering with, this hot topic looks at reports that stronger cannabis on the market is increasing harms to users, prospects of recovery from disorders and dependence, and the emerging response to synthetic forms of cannabis like 'spice'.

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As restrictions around cannabis research ease, scientists are exploring how the plant could be medically useful. Here are four of the hardest questions they face.
1. How many types of cannabis are there?
What we know Cannabis seems to come in many forms, partly because of millennia of breeding by humans. Producers have allocated a 'folk taxonomy' to strains with various medicinal and chemical properties, but the evolutionary relationship between species is unclear (see page S4).

Why it matters Researchers need to characterize plants for drug development, including by species or subspecies. Without an accurate taxonomy, there is no comparative base to work from and some varieties might become extinct.

Major hurdles Because cannabis is wind pollinated with separate male and female plants, controlling breeding can be difficult. There is no organized seed bank and legal restrictions impede the collection of samples. Little government funding means there are few research labs.
2. What are the medically useful compounds in cannabis and what diseases can they treat?
What we know Of the 100 or so cannabinoids, tetrahydrocannabinol (THC) and cannabidiol have been the focus of most research. Compounds such as the volatile terpenes also seem to have intriguing properties. All constituents might act alone or in combination.

Why it matters Those who use medical marijuana claim that the herb can treat a range of ailments, but evidence is thin. To test these claims and create a pharmaceutical product, the active compounds need to be isolated and investigated.

Major hurdles Research has been undermined by a lingering assumption that all cannabinoids share the properties of THC - and regulators apply the same restrictions to all of them (see page S6).
3. Can the endocannabinoid system be targeted by compounds other than those found in cannabis?
What we know So far, drugs that target the endocannabinoid system have failed. Cannabidiol has an anti-schizophrenia effect by increasing levels of the endocannabinoid anandamide, a type of neurotransmitter, suggesting that anandamide is the active molecule.

Why it matters Therapies based on endogenous molecules are a mainstay of medicine. The hormone insulin was successfully given to patients with diabetes shortly after its discovery. And cortisone-based medicines can be used to relieve pain and reduce swelling.

Major hurdles Endocannabinoids have localized actions and short half-lives, so their use as systemic therapies is challenging. Endocannabinoid receptors are found throughout the body, making it difficult to target specific physiological processes without side effects.
4. What are the best ways to deliver cannabis-based medicines?
What we know Delivery through the lung by smoking or vaporizing facilitates fast absorption. Administration that involves compounds passing through the liver is tricky because this organ destroys cannabinoids. Only an oral, under-tongue spray has so far been approved.

Why it matters Route of delivery determines how much of a compound is absorbed by different parts of the body, and how quickly. The faster that THC-containing medicines are delivered to the brain, the more potential there is for psychoactive side effects, as well as for abuse.

Major hurdles Regulators require that cannabis-based drugs have no psychoactive effects, so delivery of THC to the brain needs to be controlled. Little is known about the metabolism of other cannabinoids and hence appropriate delivery routes.

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As restrictions around cannabis research ease, scientists are exploring how the plant could be medically useful. Here are four of the hardest questions they face. 1. How many types of cannabis are there? What we know Cannabis seems to come in many forms, partly because of millennia of breeding by humans.

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No Smoking in The Booth: A Film About Skunk, Grime and Mental Health

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Abstract

This article examines harm reduction from a novel perspective. Its central thesis is that harm reduction is not only a social concept, but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote survival of the fittest. Evidence will be provided from peer-reviewed scientific literature that supports the hypothesis that humans, and all animals, make and use internally produced cannabis-like products (endocannabinoids) as part of the evolutionary harm reduction program. More specifically, endocannabinoids homeostatically regulate all body systems (cardiovascular, digestive, endocrine, excretory, immune, nervous, musculo-skeletal, reproductive). Therefore, the health of each individual is dependant on this system working appropriately.

Introduction

The concept of harm reduction is at the heart of conflicting international drug policies. The Dutch pioneered this approach. Today most European countries and Canada have embraced the idea that society benefits most when drug policy is designed to help people with drug problems to live better lives rather than to punish them. In contrast, the United States federal policy demands rigid zero tolerance with overwhelming emphasis on incarceration of offenders (the Drug War). Although, seemingly reasonable arguments can be made to support both sides of the dispute, the recent global trend towards harm reduction has resulted from the acknowledgement that drug use has been a part of all societies throughout history and the realization that repressive policies are expensive, ineffective, and often harmful.

A dramatic example of the benefits that can result from a harm reduction approach to drugs is seen with needle exchange programs. While prohibitionists argue that providing clean injection equipment promotes drug use, the facts do not support this contention. For example, the Australian needle exchange program is credited with keeping the HIV/AIDS infection rate very much lower than what is typically found globally http://www.chr.asn.au/about/harmreduction. Commonly cited examples of the failed repressive policies championed by the United States are the now repealed alcohol prohibition and the current drug war. Crime, financial support for terrorism, disrespect for the law, and destruction of families, communities, and ecosystems can all be attributed to drug prohibition. Yet, the staggering cost of the drug war, driven by United States policy and taxpayers' money, amounts to many billions of dollars a year.

A little explored question is what does harm reduction specifically mean with respect to cannabis consumption? This article will address cannabis harm reduction from a biological perspective. Two directions will be examined: what are the biological effects of cannabis use and what are the social effects that emerge from the biological foundation.

Like many substances that are put into the human body, there can be positive or negative consequences that result from cannabis consumption, depending on amount, frequency, quality, and probably most importantly, the idiosyncratic biochemistry of the user. Prohibitionists concentrate their efforts on the negative effects of cannabis use, while anti-prohibitionists tend to focus on the positive effects. If we assume that both sides have valid arguments, the issue to be resolved is one of balance between the negative and positive effects. Would a policy of tolerance, or prohibition, be more likely to reduce harm overall? Which policy would better serve society as a whole, as well as problematic drug users?

Biological science can be more objectively evaluated than social science. The central theme that will be presented in this article is that appropriate cannabis use reduces biological harm caused by biochemical imbalances, particularly those that increase in frequency with age. Proper cannabis use, as distinguished from misuse, may have significant positive health effects associated with the way cannabis mimics natural cannabinoids. In essence, it is proposed that the endocannabinoid system, selected by 600 million years of evolution, is a central mediator of biological harm reduction through its homeostatic activities. The social implications of cannabis use will be viewed as emerging from the biological platform. Herein lies the paradox of cannabis and harm reduction. Is appropriate use of cannabis better than no use?

The Endocannabinoid System

Cannabis preparations have been used medically for thousands of years for illnesses such as epilepsy, migraine headaches, childbirth, and menstrual symptoms. However, it is only relatively recently that the active components have been identified and their mechanisms of action have begun to be understood. While delta-9-tetrahydrocannabinol (THC) was first synthesized by Mechoulam in 1967 [ 5], it was not until 1990 that the cannabinoid receptor was localized in the brain [ 6] and cloned [ 7]. Since then, discoveries in the field have proceeded at an ever-increasing pace. The discovery of cannabinoid receptors on cells naturally prompted the search for internal compounds (endogenous ligands) that would activate the receptors since it seemed unlikely that cannabis receptors had evolved so people could partake of cannabis. In 1992, anandamide was discovered [ 8]. This lipid metabolite was the first ligand of an ever-expanding class of molecules known as endocannabinoids (internal marijuana-like compounds) to be discovered. Endocannabinoid synthesis, degradation, transport, and receptors together form the endocannabinoid system.

The broad therapeutic potential that can result from correctly manipulating the endocannabinoid system is just beginning to be realized[ 9, 10]. In fact, major pharmaceutical companies, and university researchers all around the world are now engaged in the cannabinoid-related research [ 11]. Their efforts focus on learning how the endocannabinoid system functions, and on how to manipulate it in order to increase or decrease its activity, depending on the illness or condition under consideration. GW Pharmaceuticals in Britain has been developing and testing a plant extract-based product line that is in clinical trials in Britain and Canada [ 12]. The results thus far have been positive to the extent that Bayer AG has entered into a 25-million-dollar distribution agreement for GW's product, Sativex which has recently been approved in Canada. In contrast, Sanofi Research has developed an antagonist that will inhibit the ability of endocannabinoids to stimulate hunger and thus potentially be useful for weight control.

Cannabinoids: Homeostatic Regulators

Physical Characteristics of Living Systems

To illustrate the multidimensional biochemical balancing act performed by cannabinoids, a variety of endo- and exocannabinoid activities will be reviewed below. In order to appreciate these activities a brief introduction to cell biology may provide the context for this review. All life is dependant upon the maintenance of its dynamic organization through sufficient input of nutrients and removal of wastes. The more complicated an organism is, the more complex the coordination required to accomplish the essential tasks necessary to maintain this vital flow of inputs and outputs. Coordination requires communication. Cells communicate by thousands of different, but specific, receptors on cell surfaces that respond to thousands of different, but also specific, molecules (ligands) that bind to the receptors. A receptor that is bound to its activating ligand causes biochemical changes to occur in the cell. In response to such regulatory signals on the membrane, biochemical regulation within the cell occurs at the level of gene expression as well as at the level of enzyme action and other processes outside the nucleus. Ultimately these changes, through complex biochemical pathways, allow cells to divide, carry out specialized tasks, lie dormant, or die. Any of these cellular activities, when not properly coordinated, can result in illness. Two major categories of disease states are those that result from acute illness commonly caused by infections and those that are age-related. Historically, in the United States, the cause of death has transitioned from being pathogen-induced to age-related. Current scientific literature regarding cannabis indicates that its use is often bad for the former but good for the latter (see Immunology section below).

Cannabinoids and the Healthy Brain

In a healthy individual, cannabinoids play a direct role in neurotransmission of many nerve cell types. They exhibit the unusual property of retrograde transmission, in which the cannabinoid neurotransmitter diffuses backwards across the neural cleft to inhibit the presynaptic action potential [ 42]. This function essentially regulates the sensitivity of a nerve cell by acting as a feedback mechanism that prevents excessive activity. Some nerve cells die when they are excessively stimulated by excitatory neurotransmitters (excitotoxins) such as glutamate. Cannabinoids can reduce the level of stimulation and protect against this form of cell death [ 43, 44]. In addition to their down-regulatory effect on neurotransmission, cannabinoids play other roles in reducing this type of cell death (biological harm reduction) by regulating the role of interleukin-1 (IL-1, an inflammatory cytokine) and the IL-1 receptor antagonist (IL-1ra) [ 45]. For example, cannabinoids were shown to modulate the release of IL-1ra thereby protecting against IL-1 assisted cell death [ 46].

Multiple Sclerosis

Both animal and human studies provide strong evidence of the therapeutic potential of cannabinoids to provide relief from a number of neurological disease states [ 49]. The use of cannabinoids to treat people suffering from multiple sclerosis (MS) is an excellent example of the importance of "medical marijuana" as an agent of harm reduction[ 50] MS is a neurodegenerative disease in which the immune system attacks components of the nervous system. The axons of many central nervous system (CNS) neurons are surrounded by a myelin sheath that acts much like an insulator around a wire. MS is associated with the degradation of the myelin sheath that leads to loss of axon function and cell death, thus producing the disease symptoms.

Cannabis-based therapies for the treatment of MS can provide symptomatic and true therapeutic relief. On the one hand, cannabinoids help to reduce spasticity in an animal model of MS (chronic relapsing experimental autoimmune encephalomyelitis (CREAE) [ 51]. However, the involvement of the cannabinoid system in the etiology of MS goes much deeper. MS is in reality an autoimmune disease. In order to appreciate why cannabinoids can have in important role, beyond what has already been mentioned, in treating MS on a mechanistic level [ 52], a brief introduction to immunology is required.

Cannabinoids and the Immune System

The role of the immune system is simplistically thought of as protecting us from foreign attack. More inclusively, however, the immune system has the biological function of modulating the life, death, and differentiation of cells in order to protect us. The immune system accomplishes these tasks, in part, by balancing two mutually opposed pathways known, respectively, as the "Th1" and "Th2" response. The Th1 immune response is critical for fighting infections caused by specific infectious agents [ 53]. This function is inhibited by cannabinoids. Thus cannabinoids are important homeostatic modulators of the immune system. While often classified as immune inhibitors, cannabinoids actually promote the Th2 response while they inhibit the Th1 response. Therefore cannabinoids are immune system modulators. A specific cannabinoid receptor (Cb2) [ 54] is found on most cells of the immune system.

Cannabinoids and Th1 Mediated Auto-Immune Diseases

In contrast to the Th1 immune response, the Th2 immune response promotes the humoral arm of the immune system. It turns down the Th1 response, is characterized by antibody production, and is typically anti-inflammatory. Ideally, the Th1 and Th2 pathways are functionally balanced to optimally meet the survival needs of an organism in its environment. In reality however, many autoimmune diseases, and other age related diseases, are characterized by an excessive Th1-driven immune response at the site of the of the tissue damage involved. Multiple sclerosis, arthritis, Crohn's disease, and diabetes are all diseases that fall into this category.

Cannabinoid Actions-Biphasic Responses

The brief interludes into cell biology, neurology, and immunology provide a biological platform for considering how cannabinoids might impact a variety of other disease states. It is important to keep in mind that in its role as a general homeostatic modulator, too much or too little cannabinoid activity can be harmful. Cannabinoid levels or concentration ranges vary as a function of an organism's genetics, the cell types under consideration, and their health and environment. Care must be taken when evaluating the scientific literature on cannabinoids and their effects. Cannabinoids often exhibit biphasic responses [ 59]. Low doses of cannabinoids may stimulate the Th2 immunological response, whereas high doses may inhibit the Th2 response and shift the balance in favor of a Th1 response. From a harm reduction perspective, these observations demonstrate the critical importance of dose-dependent, disease-dependent, state-dependent, and individually tailored approaches to cannabis therapeutics [ 60].

The use of cannabinoids in the treatment of Parkinson's disease is an example of a condition where excessive or deficient cannabinoid activity may prove problematic. Parkinson's disease results from the loss of levo-dopamine (L-dopa) producing neurons. In an animal model of Parkinson's disease, L-dopa producing cells are killed with 6-hydroxydopamine. Rats so treated exhibit spontaneous glutamatergic activity that can be suppressed by exo- as well as endocannabinoids [ 61]. The standard treatment for Parkinson's disease involves L-dopa replacement therapy. Unfortunately, this treatment often results in dyskinesia (abnormal voluntary movements). Recent clinical trials have shown that cannabinoid treatment reduces the reuptake of gamma-aminobutyric acid (GABA) and relieves the L-dopa-induced dyskinesia [ 33], as well as L-dopa induced rotations in 6-hydroxydopamine-lesioned rats [ 62]. In contrast to the potential benefits of cannabinoid agonists just cited, using a different animal model, the cannabis antagonist SR141716A reduced reserpine-induced suppression of locomotion [ 63]. Thus, in this model locomotion was restored by inhibiting the endocannabinoid pathway.

Cannabinoids and Cancer

Possibly the greatest harm-reducing potential afforded by cannabinoids comes from their use by cancer patients. Cannabinoids possess numerous pharmacological properties that are often beneficial to cancer patients. Many people are aware of the anti-emetic and appetite stimulating effects of cannabinoids [ 64]. A systemic study designed to quantify the efficacy of cannabinoids as an anti-emetic agent examined data from 30 randomized controlled studies that were published between 1975 and 1997 and included 1366 patients who were administered non-smoked cannabis [ 65]. For patients requiring a medium level of control, cannabinoids were the preferred treatment (between 38% and 90%). This preference was lost for patients requiring a low or a high level of control. Sedation and euphoria were noted as beneficial side effects, whereas dizziness, dysphoria, hallucinations, and arterial hypotension were identified as harmful side effects.

The cancer cell killing [ 66] and pain relieving properties of cannabinoids are less well known to the general public. Cannabinoids may prove to be useful chemotherapeutic agents [ 67]. Numerous cancer types are killed in cell cultures and in animals by cannabinoids. For example, cannabinoids kill the cancer cells of various lymphoblastic malignancies such as leukemia and lymphoma [ 68], skin cancer [ 69], glioma [ 70], breast and prostate cancer [ 71], pheochromocytoma [ 72], thyroid cancer [ 73], and colorectal cancer[ 74]. Since 2002 THC has been used in a clinical trial in Spain for the treatment of glioma [ 75]. However, not all cancers are the same, and cannabinoid-induced biochemical modifications, while effective in killing the cells of some cancers, as indicated above, can have the opposite effect on the cells of other types of cancer. For example, recent work has shown that the synthetic cannabinoid, methanandamide, can promote the growth of lung cancer cells by a receptor independent pathway that involves the up-regulation of COX2 [ 76]. Although much has been learned about the therapeutic value of cannabinoid agonists and antagonists in different situations, scientific understanding of how to appropriately modulate the endocannabinoid pathways remains preliminary, with much remaining to be learned.

Cannabinoids Affect Drug Metabolism

Another important cannabis and harm reduction topic that must be considered is that of how the use of cannabis impacts on the pharmacokinetics of other drugs [ 99]. A number of drugs are metabolized by the P450 family of isoenzymes, including numerous cannabinoids [ 100]. Even though cannabinoids stimulate the transcription of P450 (2A and 3C), they also directly inhibit the activity of this enzyme [ 101]. There are likely to be pros and cons associated with P450 inhibition. P450 activity activates procarcinogens in tobacco smoke to create active cancer-causing mutations [ 102]. Thus, the inhibition of these enzymes by cannabinoids may minimize some of the negative consequences of smoke inhalation. On the other hand, many pharmaceutical drugs are metabolized by these enzymes. The reduction of the rate of drug metabolism by cannabinoids with pharmokinetic consequences has been shown for cocaine [ 103], barbiturates [ 104], opiates [ 105], alcohol, the antipsychotic haloperidol [ 106], and others [ 107].

Thus far, both endo- and exocannabinoids are seen to reduce harm in numerous circumstances. Cannabinoid-based therapies have been especially helpful for the treatment of a variety of neurological and immunological disorders. Yet, we have only scratched the surface of the scientific literature on cannabinoids and their biological effects. Nevertheless, it should be apparent that cannabinoids have enormous medical potential as we learn to manipulate the natural cannabinoid harm reduction system that has evolved in the animal kingdom.

A fundamental question that remains unanswered is how basic, complex biochemical phenomena, as touched on briefly in this article, collectively emerge as substantial contributors to health and behavior. In far-from-equilibrium thermodynamic systems, such as living organisms, there are discontinuities between underlying molecular dynamics and associated emergent macroscopic phenomena [ 108]. In such systems, small changes (called "perturbations") can amplify with consequences for the organization of the whole system. The cannabinoids help to regulate an amazingly broad range of biochemical events. All of these effects have genetic foundations. As such, natural genetic/biochemical variation in a population can be expected to have significant effects on health and behavior. It should be expected that in a population distribution of cannabinoid levels and sensitivities, as a function of an individual's health/disease status, some individuals would naturally need to increase their cannabinoid activity while others would need theirs lowered. Although the focus of this paper has been to suggest the many circumstances in which higher cannabinoid activity would be beneficial, these circumstances will necessarily differ among individuals with different congenital cannabinoid levels and sensitivities. Therefore, reduced cannabinoid activity would be beneficial under some conditions. A prime example of potential harmful effects of excess cannabinoids is their effects on pregnancy where low levels are needed but high levels are harmful [ 109].

Behavioral Effects: Self-administration and Reward

The broad homeostatic activities of cannabinoids that have been developed in this article have been rooted in hard science. The extension of these ideas to the psychological and behavioral levels is intrinsically more speculative, but remains consistent with the literature. For years, researchers have looked into the possible addictive qualities of cannabis. The lack of significant reward behavior was indicated by the lack of self-administration in primates. Experiments examining preference in rats demonstrated that low doses of THC could induce place preference but that higher doses produced drug aversion [ 110], again demonstrating the homeostatic nature of cannabinoids. Self-administration is typical of most psychoactive drugs of abuse. Hence, one could conclude that marijuana has a low potential for abuse.

Additional cannabinoid involvement in reward behavior is suggested by the increased activity of dopaminergic neurons stimulated with psychoactive cannabinoids [ 114]. This pathway is shared by other major drugs of abuse including, morphine, ethanol, and nicotine [ 115]. However, the production of glucocorticoid hormones that are normally produced in response to stress [ 116], are suppressed by cannabinoids [ 117]. Are cannabinoids addictive, is pleasure addictive, or is a low stress state addictive?

Cannabinoids and Stress

Stress and reward are complicated components of addictive behavior. How does repeated use of THC influence these states? A recent study examines this question by measuring glucose utilization in different areas of the rat brain following repeated treatment with THC [ 118]. After 7 and 21 days of THC treatment, THC no longer resulted in reduced glucose utilization in many areas of the brain typically affected by a single THC dose (most cortical, thalamic, and basal ganglia regions). In contrast, glucose utilization in other areas of the brain remained unaltered (nucleus accumbens, mediodorsal thalamus, basolateral amygdala, portions of the hippocampus and median raphe). Thus while the effects of THC on body temperature and locomotor activity become resistant to repeated THC administration, those areas involved in many higher brain functions remain responsive to THC. This differential adaptation to THC administration is consistent with a low addictive potential. The best evidence that demonstrates the absence of an addictive response to cannabis use is the fact that most people who use it do not continue to use it, and stop using it without any effort.

The stress-relieving properties of cannabinoids are an important aspect of their pharmacological activity. An interesting mechanism by which cannabinoids may promote stress relief is through their effects on memory. Cannabinoids control the extinction of painful memories [ 119]. What a blessing for those suffering from debilitating or life threatening illnesses: cannabinoids may help them to forget their misfortune.

Independent of the direct addictive or non-addictive properties of cannabis, the cannabis-opioid connection will be examined in more detail. Both drug families function (not necessarily exclusively) through biochemical pathways that are regulated by specific receptor-ligand interactions. However, there appears to be, as yet not fully defined, crosstalk between these pathways [ 120]. For example, CB1 receptor knockout mice are non-responsive to CB1 cannabinoid activities and show reduced addictive effects of opiates [ 121]. Similarly, Lewis rats showed enhanced sensitivity to morphine self-administration after treatment with the synthetic cannabinoid CP55040 [ 122]. Examining the cannabis-opioid connection from the other direction, chronic morphine administration results in some down-regulation of cannabinoid receptors along with a significant reduction in 2AG [ 123]. These results show both positive and negative feedback relationships between the endocannabinoid and opiate systems. They also suggest that cannabinoids might serve to reduce the symptoms of opiate withdrawal [ 124].

The possibility that cannabinoids could serve as an addiction interrupter was demonstrated in rats where the synthetic cannabinoid agonist Win 55-212,2 reduced intravenous self-administration of cocaine [ 125]. Similarly, recent studies indicate that THC may facilitate nicotine withdrawal in mice [ 126] and inhibit alcohol preference in a model of alcoholism [ 127]. The opposite indications, that blocking cannabinoids receptors could serve as an addition interrupter has also been made [ 128].

Behavioral Complexity

Behavioral processes and their complexities set humans apart from other animals. Can we simply extrapolate from animal to human behavior? It is one thing to comparatively examine the molecular and cell biology of animals and extrapolate to humans. However, the behavioral repertoire of humans appears to be dramatically enhanced over other animals and is therefore more difficult to connect between the species. Evolutionary relationships show that the cannabinoid receptors are located in the more advanced areas of our brains. Again, any population is always a spread around the average value of any parameter. A subset of the human population will inevitably retain a more primitive behavioral repertoire. Is this subset more susceptible to addictive behavior or psychological problems that could result from cannabis consumption? Has the cannabinoid system been optimized for the regulation of more primitive behavior or, alternatively, is it better optimized for the behavioral flexibility required of modern humans? Indeed, is there any evidence that the cannabinoid system, like our cortical capacity, may enable even greater behavioral flexibility in the more complex societies and altered environments of the future?

Answers to these questions are suggested by the data of human cannabis consumption. Most people who use cannabis in their youth stop using it as their lives progress. Most do so as a natural part of their development. They do so without outside intervention or help. They do so without ever having become heroin users, schizophrenic, or motivationally compromised. These facts indicate that for the majority of people who try marijuana, it is not addictive, does not lead to heroin use, nor is it a trigger for the onset of psychological problems. However, due to the complexity of cannabinoid activities, it is likely that in a small percentage of the population, cannabis use may foster problems. The biology presented in this paper suggests that such individual differences should be expected. We must learn to identify individuals who would be negatively affected by cannabis use; they are the people that an intelligent drug policy would help to identify and assist. In contrast, our policy criminalizes the majority of users and further harms them, perhaps psychologically as well as medically, through its repercussions.

In an important recent study, De Marchi et al [ 132], examined the endocannabinoid levels in healthy volunteers and compared them to that of schizophrenic patients, both before and after successful antipsychotic treatment. Patients suffering with acute disease had significantly higher anandamide levels in their blood than did the normal individuals or patients in clinical remission. Might these elevated cannabinoid levels be contributing to the disease symptoms, and what might be causing them? Cannabinoids act homeostatically across biological subsystems. A possible immune involvement in schizophrenia has long been suspected, and immunological parameters have been implicated in the disease. For example, there is an inverse correlation between schizophrenia and rheumatoid arthritis; an individual generally does not get both illnesses [ 133]. Interestingly, schizophrenia has been correlated with HLA type, Toxoplasma gonodii infection, and exposure to cats [ 133]. Toxoplasma gonodii infects brain neurons, and is best controlled with a strong pro-inflammatory immune response. Endocannabinoids modulate the pro-inflammatory TH1 response by up-regulating the anti-inflammatory Th2 response. Hence, it is likely that some individuals idiosyncratically respond to Toxoplasma gonodii infections by producing excess endocannabinoids and suffering the associated abnormal mental state. Antipsychotic drugs have actually improved the outcome of infection with this parasite[ 134].

Conclusion

Evolution has selected the endocannabinoids to homeostatically regulate numerous biological phenomena that can be found in every organized system in the body, and to counteract biochemical imbalances that are characteristic of numerous damaged or diseased states, in particular those associated with aging. Starting from birth, cannabinoids are present in mother's milk [ 135], where they initiate the eating process. If the activity of endocannabinoids in the mouse milk is inhibited with a cannabinoid antagonist, the newborn mice die of starvation. As life proceeds, endocannabinoids continuously regulate appetite, body temperature, reproductive activity, and learning capacity. When a body is physically damaged, the endocannabinoids are called on to reduce inflammation, protect neurons [ 136], regulate cardiac rhythms [ 137] and protect the heart form oxygen deprivation [ 20]. In humans suffering from colorectal cancer, endocannabinoid levels are elevated in an effort to control the cancer [ 74]. They help relieve emotional suffering by reducing pain and facilitating movement beyond the fears of unpleasant memories [ 119].

While this review is far from complete, it attempts to provide a conceptual overview that supports the endocannabinoid system as being nature's method of harm reduction. There is a pattern to all the cannabinoid-mediated activities described. Many of the biochemical imbalances that cannabinoids protect against are associated with aging. Aging itself is a system-wide movement towards chemical equilibrium (away from the highly regulated far-from-equilibrium state) and as such is an imbalance from which all living organisms suffer. In contrast, the harmful consequences of cannabis use, however exaggerated they often appear to be, are likely to represent significant potential risk for a minority of the population for whom reduced cannabinoid levels might promote mental stability, fertility or more regulated food consumption.

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Affiliations

1. Biology Department, 1420 Austin Bluffs Parkway, University of Colorado, Colorado Springs, 80918, USA

2. Bioenergetics Institute, 1420 Austin Bluffs Parkway, University of Colorado, Colorado Springs, 80918, USA

Corresponding author

Correspondence to Robert Melamede.

Electronic supplementary material

# data[].attributes.attachment_link.description
This article examines harm reduction from a novel perspective. Its central thesis is that harm reduction is not only a social concept, but also a biological one. More specifically, evolution does not make moral distinctions in the selection process, but utilizes a cannabis-based approach to harm reduction in order to promote survival of the fittest.

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Abstract

Keywords: marijuana, tobacco, alcohol, smoking cessation treatment

1. Introduction

Current cigarette smokers are nearly four times more likely to use marijuana than non-smokers ( Bell et al., 1997), and current marijuana users are five to seven times more likely than non-users to smoke tobacco ( Mohler-Kuo et al., 2003; Richter et al., 2004). In addition, heavy drinking is prevalent among both cigarette ( Chiolero et al., 2006; Dawson, 2000; Weitzman and Chen, 2005) and marijuana smokers ( Bonn-Miller and Zvolensky, 2009; Dennis et al., 1999), and comorbid heavy drinking and marijuana use are particularly prevalent among heavy cigarette smokers ( Bell, et al., 1997; Everett et al,. 1998; Richter, et al., 2004; Wu et al., 1988). The concurrent use of marijuana, tobacco, and heavy alcohol use are linked to a number of health risks ( Engs and Aldo-Benson, 1995; Giancola, 2002; Hall et al., 1994; Kalant, 2004; Presley et al., 1996; Tashkin et al., 1990; Wu, et al., 1988), behavioral problems ( Abbey, 1991; Abbey et al., 1998; Giancola, 2002; Hingson et al., 2002; Hingson et al., 2005; Jones et al., 2003; Kalant, 2004; Katz et al., 2000; Marcus and Reio, 2002; Montgomery and Haemmerlie, 1993; Newcomb and Bentler, 1999; Wood et al., 2000), and psychiatric comorbidity ( Stinson et al., 2006). Recently, increased attention has been called to the importance of examining interactions among different substances and the impact of cessation of one substance on use of the other substance ( Bonn-Miller and Zvolensky, 2009; The Substance Abuse and Mental Health Service Administration, 2009).

In contrast to growing research examining the relationship between alcohol and tobacco use in smoking cessation ( Abrams et al., 1992; Monti et al., 1995; Prochaska et al., 2008) and alcohol treatment outcomes ( Fu et al., 2008; Gulliver et al., 2000; Joseph et al., 2004), much less is known about the relationship of marijuana to cigarette use and heavy drinking in smoking cessation outcomes. Marijuana use has been examined as a predictor of tobacco smoking cessation with mostly equivocal findings ( Ford et al., 2002; Gourlay et al., 1994; Humfleet et al., 1999). One prospective study found that cigarette smokers who reported using marijuana at baseline were two to three times more likely than nonusers to still use tobacco at a 13-year follow-up ( Ford et al., 2002). Similarly, others have found a reduced likelihood for marijuana users to stop smoking tobacco, as compared to non-users ( Gourlay et al., 1994). However, one randomized clinical trial found no differences in post-treatment tobacco smoking cessation outcomes for individuals who used marijuana during smoking cessation treatment as compared to those who did not ( Humfleet et al., 1999). In laboratory studies, marijuana administration did not alter typical tobacco smoking topography in one study ( Nemeth-Coslett et al., 1986), but led to a significant decrease in cigarette smoking in another study ( Kelly et al., 1990). Furthermore, unlike alcohol ( Kahler et al., 2010), the role of marijuana use as a proximal predictor of smoking relapse has not been previously examined.

Similarly, very little is known about the impact of marijuana use on drinking during a smoking cessation trial. Although heavy drinking impedes smoking cessation ( Hymowitz et al., 1997; Kahler et al., 2009; Osler et al., 1999), many tobacco smokers are able to successfully reduce hazardous drinking in the context of smoking cessation ( Kahler et al., 2008; O'Malley et al., 2009). Also, marijuana users in a heavy drinking sample were able to decrease drinking after a brief alcohol motivational intervention ( Magill et al., 2009). Findings from these few studies would suggest that heavy drinking marijuana users should have similar positive drinking outcomes as the rest of the sample in a smoking cessation trial.

It is also largely unknown whether marijuana users make any changes to their marijuana use as part of their smoking cessation effort. Among young adults who smoke tobacco and marijuana, quitting cigarette smoking is considered a desirable goal, but few intend to stop using cannabis as part of their smoking cessation efforts ( Amos et al., 2004). It is plausible that marijuana use may either remain stable if the person has other available alternatives or even increase following smoking cessation. Restriction of one reinforcer tends to increase the use of other available reinforcers ( Vuchinich and Tucker, 1988). It is thus conceivable that abstinent tobacco smokers might continue to use marijuana or perhaps increase their levels of marijuana use to counteract or reduce aversive effects of nicotine withdrawal. Preclinical evidence confirms that acute THC administration indeed helps alleviate symptoms of nicotine withdrawal in animals ( Balerio et al., 2004). Despite nicotine replacement treatment, the expectation that quitting smoking may be associated with increased irritability and negative mood ( Baker et al., 2004) may be sufficient to motivate other drug use to help cope with these symptoms following cessation of smoking.

Aside from some notable exceptions ( McCambridge et al., 2008; McCambridge and Strang, 2004), the problem of trying to change several health-risk behaviors simultaneously has not been studied extensively. Many clinicians also express concern over difficulty in concomitant targeting of multiple substances ( Bobo et al., 1995; Monti, et al., 1995) with mixed empirical support for the feasibility of doing so ( Kodl et al., 2006). For example, some substance abuse treatment programs suggest delaying smoking cessation efforts for patients in treatment for alcohol dependence and other drugs and some believe that their clients may rely on tobacco smoking for mood management or as a substitute for illicit drug abuse ( Richter, 2006).

Despite these concerns, a meta-analysis examining smoking cessation interventions with individuals in substance abuse treatments revealed positive outcomes of concomitant interventions for multiple substances ( Prochaska et al., 2004). Exposure to a smoking cessation intervention was associated with a 25% increased likelihood of long-term abstinence from alcohol and illicit drugs. Similarly, a study of pregnant women attempting to quit tobacco, alcohol, and/or caffeine found a clustering of quitting behavior. Although women using multiple substances were less likely to quit than those using only one substance, women who stopped using at least one substance were more likely to stop using a second one ( Pirie et al., 2000). Furthermore, smokers in substance abuse treatment do not find the concurrent treatment of drug problems with smoking cessation programs incompatible ( Stein and Anderson, 2003). Overall, these studies suggest that smoking cessation efforts with concomitant reductions in drinking and use of other drugs, such as marijuana, are quite feasible and can be successful.

The primary aim of the present investigation was to test the association between marijuana use, alcohol use, and smoking cessation outcomes in a randomized clinical trial that tested the utility of incorporating a brief alcohol intervention into smoking cessation treatment for heavy social drinkers ( Kahler et al., 2008). We first examined whether marijuana smokers differed from the rest of the sample in their tobacco smoking and alcohol use outcomes. We then investigated whether marijuana users changed their marijuana use during smoking cessation treatment. Finally, we also examined whether the odds of lapses to smoking were significantly lower on days when marijuana was used compared to non-marijuana days.

2. Methods

2.1. Participants

Participants were 236 heavy drinking smokers recruited from the local community in Southeastern New England who took part in a randomized smoking cessation clinical trial comparing standard smoking cessation treatment (ST) to standard treatment incorporating a brief alcohol intervention (ST-BI) while on nicotine patch (see Kahler et al., 2008 for full details of the clinical trial). Participants were included if they: (a) were at least 18 years old; (b) had regularly smoked cigarettes for at least one year; (c) were currently smoking at least 10 cigarettes per day; (d) were not using any other tobacco products or nicotine replacement; and (e) drank heavily according to NIAAA guidelines but were not dependent on alcohol (National Institute on Alcohol Abuse and Alcoholism, 1995): for men, >14 drinks per week or ≥5 drinks per occasion at least once per month over the past 12 months; for women, >7 drinks per week or ≥4 drinks per occasion at least once per month). Participants were excluded if they: (a) met full DSM-IV criteria for alcohol dependence in the past 12 months; (b) met criteria for other current psychoactive substance abuse or dependence (excluding nicotine dependence and alcohol abuse) in the past 12 months; (c) had a current affective disorder; (d) were psychotic or suicidal; (e) had an unstable medical condition that would suggest caution in the use of the nicotine patch (e.g., unstable angina, arrhythmia, recent congestive heart failure); (f) were currently pregnant or lactating or intended to become pregnant.

The sample used in these analyses was 45% female, 90.7% non-Hispanic White, and 33% married. The mean age of the sample was 41.5 ( SD = 12.0) years, and the mean education was 14.0 ( SD = 2.6) years. At baseline, participants smoked an average of 21.3 ( SD = 9.4) cigarettes per day and had been smoking for an average of 22.7 years ( SD = 11.5). The sample mean on the FTND ( Heatherton et al., 1991) was 5.0 ( SD = 2.2). Participants reported that during the eight weeks prior to treatment, they drank on 54.7% ( SD = 27.3) of possible days and consumed an average of 16.5 ( SD = 11.9) drinks per week.

Of the 236 participants, 57 were identified as past month marijuana users with 22.5% meeting DSM-IV criteria for Lifetime Cannabis Abuse and 7.7% meeting criteria for Lifetime Cannabis Dependence. The sample was divided into three groups based on baseline TLFB reports: non-users (no use in past 8 weeks, n = 179); infrequent-users (smoked < 8 times in 8 weeks, n = 28); and weekly-users (≥8 times in 8 weeks, n = 29).

2.2. Procedures

Treatment consisted of four weekly individual counseling sessions with the quit date occurring at session 2 (70 min for Session 1, 40 min for Session 2, and 20 min for Sessions 3 and 4). ST-BI incorporated focused discussion of participant's alcohol use, including feedback on the risk of smoking relapse associated with drinking and goal setting regarding changing drinking during smoking cessation. All participants received transdermal nicotine patch (21 mg for the first four weeks, 14 mg for the next two weeks, and 7 mg during the last two weeks). Follow-ups were conducted at 8, 16, and 26 weeks after quit date.

2.3. Measures

Prior to treatment, participants provided demographic and other clinically relevant information. Alcohol and substance use disorder diagnoses and lifetime history of major depressive disorder were assessed using the Structured Clinical Interview for DSM-IV ( Spitzer et al., 1990). Severity of nicotine dependence was assessed using the Fagerstrom Test for Nicotine Dependence (FTND; Heatherton et al., 1991), a well-validated 6-item measure (α = .62). The Timeline Followback Interview (TLFB) ( Sobell and Sobell, 1992) was used at baseline (for the prior 8 weeks) and during follow-up to assess cigarettes/day, number of drinks/week, percent of marijuana use days, and number of other drug use days.

Seven-day point prevalence abstinence was assessed at 2, 8, 16, and 26 weeks after quit date. Self-reported abstinence was verified by alveolar carbon monoxide (CO) at all time points and by cotinine analysis of saliva samples collected at 16- and 26-week follow-ups. Abstinence was verified by a combination of CO ≤ 10 ppm and cotinine ≤ 15 ng/ml ( Society for Research on Nicotine and Tobacco Subcommittee on Biochemical Verification, 2002).

A total of 216 (91.5%) participants provided at least some daily TLFB data on alcohol, tobacco, and marijuana use after quit date with 207 (87.7%) providing complete data through 8 weeks after treatment, and 200 (84.7%) providing complete data through 26 weeks. Analyses were conducted using all available data ( N = 216).

2.4. Data Analysis

As a first step, we conducted preliminary analyses to examine potential differences in variables between the three groups; non-marijuana users, infrequent marijuana users, and weekly marijuana users. One way ANOVAs were used on all continuous variables and chi-square tests were used with dichotomous variables.

3. Results

presents descriptive statistics for the sample. The three marijuana use groups did not differ significantly on demographic characteristics such as gender, ethnicity, marital status, or education, or DSM-IV diagnoses of major depressive disorder and alcohol use disorders, all p's > .11. However, significant group differences were detected for age F (2, 235) = 6.32, p < .01, with weekly users being significantly younger than non-users. Consistent with this effect, groups also differed significantly on the total number of years smoked tobacco, F (2, 235) = 4.45, p < .05. Weekly marijuana users reported smoking tobacco cigarettes for less number of years as compared to non-marijuana users; however, there were no group difference on age of initiation of tobacco smoking (both first cigarette smoked and daily smoking), FTND scores or number of tobacco cigarettes smoked per day. Groups differed on number of days they used other illicit drugs at baseline, F (2, 235) = 4.74, p < .05, with non-marijuana users reporting less involvement with other drugs as compared to marijuana user groups.

Table 1

3.1. Smoking Outcomes

Seven day point prevalence abstinence rates for non-users, infrequent, and weekly marijuana users, respectively, were 34.1%, 39.3%, and 37.9% at 8 weeks (χ ² (2, n = 236) = .40, p = .82); 20.1%, 17.9%, and 3.4% at 16 weeks (χ ² (2, n = 236) = 4.74, p = .09); and 19.7%, 14.3%, and 14.3% at 26 weeks (χ ² (2, n = 236) = .82, p = .66). GEE analyses controlling for gender, age, FTND, and treatment condition indicated that infrequent users and weekly users did not differ from non-users in the odds of smoking abstinence across follow-up: AOR = 0.96, 95% CI = 0.48-1.90, p = .91 and AOR = 1.13, 95% CI = 0.63-2.04, p = .69, respectively.

We next conducted discrete-time survival analysis using Cox proportional hazards regression models to test the hypothesis that the risk of an initial smoking lapse was significantly lower on days when marijuana was used compared to non-marijuana use days. Fifty-one marijuana users were included who provided data on daily alcohol, tobacco, and marijuana use after quit date. Analyses, covaried gender, FTND, treatment condition, and both drinking status and marijuana use status (use on the day when the lapse occurred) as two dichotomous time-varying covariates. Consistent with a past analysis of these data ( Kahler et al., 2010), drinking status was associated with significantly increased risk of smoking lapse, hazards ratio ( HR) = 3.35, p <.0001. However, marijuana use status was not significant, HR = 0.97, p = .94, indicating that alcohol but not marijuana use was a predictor of smoking lapse.

3.2. Drinking Outcomes

shows the number of drinks consumed per week for each of the three marijuana use groups from baseline through the 26-week follow-up. In all groups there was a large reduction in weekly alcohol consumption, as previously reported ( Kahler et al., 2008), with a particularly notable reduction among the weekly marijuana users by 47% during follow-up. GEE analyses of average drinks per week (square-root transformed) with the chosen covariates indicated that there were no significant differences between non-users and infrequent users ( B = 0.01, 95% CI = −0.53-0.54, p = .98) or between non-users and weekly users ( B = 0.26, 95% CI = −0.14-0.67, p = .20) at the 8-week follow-up. However, one of the two marijuana groups by time interactions was significant, B = −0.22, 95% CI = −0.41 to −0.03, p = .02, suggesting that weekly marijuana users, as compared with non-users, reduced their drinking at a faster rate after the 8-week follow-up (see ).

An additional set of analyses indicated that treatment condition did not moderate marijuana use group effects on smoking ( p > .20) and drinking outcomes ( p > .30).

3.3. Marijuana Use Outcomes

shows percent of marijuana use days for each of the three marijuana use groups from baseline through the 26-week follow-up. GEE analyses controlling for gender, age, and treatment condition indicated no significant reduction in marijuana use from baseline through the 26-week follow-up for infrequent users. However, for weekly users, there was a significant linear effect of time, indicating that percent marijuana use days decreased about 4.1 percentage points at each follow-up, B = −4.10, 95% CI = −7.74, −0.46, p < .03. Overall, weekly users reduced marijuana smoking by more than 24% during follow-up.

4. Discussion

The current study aimed to extend the literature on marijuana use in smoking cessation by examining the role of marijuana use in a sample of heavy social drinkers enrolled in smoking cessation clinical trial. The study's aims were to examine: (1) the relation of marijuana use to smoking cessation outcomes; (2) the association between marijuana use and changes in alcohol use; and (3) changes in marijuana use during tobacco cessation process.

Results showed that marijuana use status (non users vs. infrequent users vs. weekly users) during the 8 weeks prior to enrolling in the study did not significantly predict smoking cessation outcome. These findings are consistent with a prior study, which demonstrated that individuals who reported marijuana use at any point during tobacco cessation treatment did not significantly differ from non-users in post-treatment tobacco outcomes ( Humfleet et al., 1999). In contrast, Gourlay et al. (1994) found that past month marijuana use at baseline predicted poorer 26-week post quit tobacco cessation outcomes. Although the Gourlay et al. (1994) study involved a larger sample of marijuana users, they did not screen specifically for heavy drinking and did not examine potential differences between the various marijuana use groups, as was done in the present study. Another potential difference to explain the discordant outcomes is that the Gourlay et al. (1994) provided brief 5-10 minute monthly counseling sessions focused on managing weight gain and smoking urges, whereas the current and the Humfleet et al. (1999) studies provided participants with counseling of longer duration focusing on a wider variety of behavioral skills designed to enhance cessation success. It is therefore possible that providing more intensive counseling may perhaps mitigate the influence of marijuana use status on tobacco cessation outcomes. Humfleet et al. (1999) also suggested that differences in cultural norms about marijuana use may account for the divergent findings (the Gourlay et al. study was conducted in Australia).

The current study was the first to examine marijuana use as a proximal predictor of same day tobacco use during treatment. Results showed that, among marijuana users, risk of tobacco smoking lapse was not significantly different on days when marijuana was used compared to non-marijuana use days throughout the tobacco cessation attempt. This finding, in context with the null association between pre-treatment marijuana use and tobacco outcomes, illustrates that marijuana use had little proximal or distal relation to tobacco use outcomes in our sample. It is possible that the consistent relation between current marijuana and tobacco use that has been demonstrated at the population level ( Bell et al., 1997; Mohler-Kuo et al., 2003; Richter et al., 2004) may not be explained by a heightened vulnerability to relapse after making a tobacco cessation attempt among marijuana users. An alternate explanation is that marijuana users are more persistent tobacco smokers because they are less interested in quitting rather than more likely to fail following a quit attempt. Indeed, a previous naturalistic study found that marijuana users were less likely to make a tobacco cessation attempt over a subsequent 13 year follow-up period ( Ford et al., 2002).

Regarding drinking outcomes, weekly marijuana users, as compared with non-users, reduced their drinking at a significantly faster rate after the 8-week follow-up. Infrequent marijuana users were not significantly different from weekly users and non-users in drinking outcomes. Past research examining individuals undergoing alcohol treatment have generally demonstrated that comorbid drug use predicts poorer drinking outcomes following alcohol treatment (e.g., Kranzler et al., 1996). However, marijuana users may be quite different from other illicit drug users as our findings are consistent with other reports (e.g., Magill et al., 2009) showing that marijuana use does not hamper the effectiveness of an intervention at least among non-dependent heavy drinkers.

We also examined changes in marijuana use during the study. Infrequent marijuana users evidenced no significant change in marijuana use from baseline through the 26-week follow-up for infrequent users. Infrequent users were using at very low rates at the study's outset, which could have resulted in a floor effect, whereby our ability to detect reductions in marijuana use in this group was limited. Nonetheless, we can conclude that marijuana use did not increase during the trial among infrequent users. Among weekly marijuana users, however, there was a significant linear reduction in proportion of marijuana use days following quit day, with more than a 24% reduction during follow-up. These findings are consistent with reduced marijuana outcomes reported by Magill and colleagues (2009) and add to a growing literature that challenges assumptions that illicit drug use increases following tobacco use cessation ( Sussman and Black, 2008) and suggests that drug use typically reduces during smoking cessation treatment ( Prochaska et al., 2004).

Mechanisms that might explain such reduction in marijuana use following a smoking cessation treatment have not been studied. All participants in this study were provided transdermal nicotine patch for eight weeks. Nicotine patch has been shown to enhance the cardiovascular effects of smoked marijuana and to increase subjective ratings of stimulation ( Penetar et al., 2005). Such findings from human and similar preclinical experimental studies ( Valjent et al., 2002) might explain why these two drugs are often used together but would not suggest that nicotine replacement would reduce marijuana smoking. That marijuana use continued to decline beyond the eight weeks of nicotine replacement therapy also suggests that other factors may play a larger role. One possibility is that the behavioral treatment offered in this study influenced marijuana outcomes. However, marijuana use was not explicitly discussed in either of the two behavioral treatment conditions. Because motivation or readiness to change marijuana use was not assessed, we do not know the extent to which reductions in use were a conscious decision. Finally, it is possible that reduction resulted from assessment reactivity effects ( Clifford et al., 2007; Maisto et al., 2007; Walters et al., 2009); that is, mere exposure to a structured assessment of marijuana use may have contributed to the subsequent changes in marijuana use.

The current findings should be considered within the context of the study's limitations. First, past year marijuana abuse or dependence was an exclusion criterion for study entry. Thus, it remains unclear whether the current findings will generalize to individuals with more severe patterns of marijuana use. Second, marijuana use was measured via self-report days of marijuana use using the time-line-follow-back calendar method. It would have been preferable to also track marijuana use outcomes via biochemical indicators and alternate self-report measures of marijuana use to examine if findings were consistent across multiple measures. Third, the sample of marijuana users was relatively small, which may have limited statistical power to detect some relationships including smoking outcomes. However, it should be noted that significant effects were detected on several outcomes (i.e., marijuana use change, drinking outcomes), suggesting that statistical power was not a limiting factor for all analyses. As expected from studies with regular marijuana users (e.g., Stinson et al., 2006), frequent (weekly) marijuana users were somewhat younger and therefore had less years of smoking than other groups. However, age was covaried and did not account for any of the findings. Because the sample of frequent marijuana users was particularly small, current findings need to be replicated with a larger sample of heavy marijuana users. Further replication with larger samples of marijuana users would support the inclusion of frequent marijuana users in smoking cessation trials.

The present study was the first trial to examine marijuana use as a proximal predictor of same-day smoking lapse, assess the influence of marijuana use on drinking during smoking cessation, and investigate changes in marijuana use during the smoking cessation process. The findings are encouraging and suggest that marijuana use: (a) is not necessarily detrimental to tobacco use cessation; (b) does not predict increases in alcohol use during smoking cessation (and may actually predict greater drinking reductions); and (c) can decrease during smoking cessation. Accordingly, individuals who concurrently use marijuana, alcohol, and tobacco may profit from combined interventions that target reductions in all three forms of substance use (e.g., McCambridge and Strang, 2004)). The current findings also suggest that such individuals may perhaps derive collateral benefit from tobacco use cessation treatment resulting in corresponding reductions in marijuana and alcohol use.

Acknowledgments

The authors gratefully acknowledge Andrea Resendes, Jennifer Larence, Dan Belenky, Catherine Costantino, Cheryl Eaton, Timothy Souza, Kara Szczesny, and Heather LaChance for their assistance on this project, as well as treatment providers John McGeary, Jane Metrik, Patricia Relli-Moniz, Gail Schilke, and James MacKillop.

Role of Funding Source: This study was supported by grant R01 DA15534 from the National Institute on Drug Abuse to Christopher Kahler. NIDA had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of Interest: No conflict of interest declared.

References

Giancola PR. Alcohol-related aggression during the college years: theories, risk factors and policy implications. J. Stud. Alcohol Suppl. 2002;(14):129-139. [[PubMed] Google Scholar]

Hall W, Solowij N, Lemon J. Canberra, Australia: Australian Government Publishing Service; 1994. The health and psychological consequences of cannabis use. National Drug Strategy Monograph Series No. 25. [Google Scholar]

Jones RK, Shinar D, Walsh JM. State of Knowledge of Drug-Impaired Driving. 2003 Retrieved from http://www.nhtsa.dot.gov.

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Marijuana Use and Tobacco Smoking Cessation Among Heavy Alcohol Drinkers

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Keywords: marijuana, tobacco, alcohol, smoking cessation treatment Current cigarette smokers are nearly four times more likely to use marijuana than non-smokers ( Bell et al., 1997), and current marijuana users are five to seven times more likely than non-users to smoke tobacco ( Mohler-Kuo et al., 2003; Richter et al., 2004).

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I gave up smoking cannabis eight years ago. I'd been promoted - from Telemarketing Supervisor to the noble heights of Telemarketing Manager - and I couldn't turn up with a head wrapped in cotton wool any more. My abiding memory of the ensuing week was a nightly stream of terrifying dreams. It was like I was dreaming in stereo, as my brain experienced the novelty of truly deep sleep for the first time in years.

And then the dreams pretty much stopped. Within a week, once the night terrors and the cold sweats had desisted, my short-term memory started to improve. I had more energy. I was more sociable in and outside work. I left the job within a few months and started doing something I loved. Everything about my life improved. But giving up weed isn't so easy for everyone, and for some it's fraught with acute problems - physical, mental and emotional.

"Stopping my consumption of cannabis used to mean a lot of pain, vomiting, diarrhoea and not being able to sleep or eat," says Alex Fraser, 26. Alex has Crohn's disease, which was diagnosed when he was 19. He just had an an ileostomy, in which a diseased part of his bowel was removed. This has drastically improved his quality of life, but he's still hugely reliant on cannabis to keep his motor running.

"Despite the surgery, I still have issues with eating, nausea and sleep," he says. "If I don't have cannabis, I end up using Pharma meds: zopiclone for sleep and oxycodone for pain. But nothing particularly helps my nausea or appetite, except cannabis."
WATCH: The Safest Possible Way to Use Weed
Alex, who generally vapes but occasionally smokes and eats marijuana, also relies on it to keep his mental health in check. "It's extremely helpful with the mental health issues I've had since surgery. Anxiety attacks, self-esteem issues and energy levels are all improved or eliminated with cannabis," he explains.

Jon Liebling is a Director of the United Patient's Alliance, which is currently lobbying hard for the legalisation of medical weed in the UK. Jon has a long history of profound mental health issues and has recently been diagnosed with complex PTSD.

"I've been managing my anxiety, depression and suicidal thoughts most of my life, but have kept myself relatively happy with the use of cannabis," says Jon. "About two years ago, I had a number of traumatic events take place in a rather short space of time. I realised I needed a bit more help, so I asked my doctor to refer me for talking therapy. When I informed him I used cannabis he refused to refer me unless I stopped using. He prescribed me prozac and diazepam. I've always had suicidal thoughts, but what's kept me alive is my dissatisfaction with them. Prozac made my thoughts happier, but also made me happier with those suicidal tendencies. So I acted on them for the first time in 20 years."

Jon went back to the doctors and found that a locum was working that day. She immediately removed him from his prozac prescription and referred him to talking therapy. She also told him to return to managing his condition with cannabis, and he's thankfully still here to tell the tale.

Unfortunately, beyond anecdotal evidence it's quite hard to back up Alex and Jon's comments with science as, at the time of writing, there just isn't much out there. Plus, their personal health conditions - despite being undoubtedly severe - are not indicative of the population as a whole. A 2010 paper called "Assessment and management of cannabis use disorders in primary care" suggests that, to differentiate between a psychiatric disorder and chronic cannabis intoxication, a patient should cease cannabis use for two to four weeks. In a small 20-person impatient study of withdrawal it found that "mean baseline depression symptom scores reduced to normal levels after four weeks of abstinence".

One of the study's creators was Professor Adam Winstock, founder of the Global Drug Survey - a study of how the world consumes drugs - and a Consultant Psychiatrist and Addiction Medicine Specialist. Between these two roles he's analysed the drug-taking habits of approximately 500,000 people, and 300,000 cannabis users. He's extremely well-placed to advise on dealing with the more established effects of cannabis withdrawal. For most people, as it was with me during my Big Promotion back in the mid-2000s, that means: a) insomnia and vivid dreams; and b) nicotine withdrawal. A huge part of the first problem comes from an unlikely source.

"Lots of people who smoke lots of weed drink too much caffeine. Tea, coffee, fizzy drinks, Red Bull. This is often to offset the sedating effects of their weed. If you keep drinking 15 cups of tea when you've given up weed, this is going to worsen your insomnia, which will make you agitated," says Winstock.

To Take Part in This Year's Global Drug Survey, Click Here

If you've grown up smoking spliffs with tobacco in them, there's a good chance you will also experience cravings from the nicotine withdrawal. For those looking to give up weed, Adam advocates giving up cannabis and nicotine at the same time - but adds that, crucially, you should gradually reduce your tobacco intake in the run-up to quitting. This will have an unexpected second benefit in the fight against withdrawal sleeplessness.

"Tobacco metabolises caffeine. It breaks it down," he explains. "So when you stop smoking tobacco, your caffeine levels go through the roof. You're left with this double whammy: not only taking a stimulant drug [caffeine] that you likely drink too much of anyway, but you're taking a stimulant drug whose levels are going to go through the roof because tobacco is no longer breaking it down."

Adam also says that the intensity of your withdrawal will likely be affected by the type of weed you smoke. "If you smoke a high THC cannabis, like skunk, then I think the insomnia would be worse - your weird dreams would be worse, your craving would be worse, your low mood would be worse."

Withdrawal symptoms with weed peak around day two or three and are generally over after seven. Sleeplessness and vivid dreams may last for two weeks, but Adam's absolute gold standard advice for giving up is to "get into good sleep hygiene". Admittedly easier said than done, but there are some common sense habits that will help.

"Exercise is probably the best thing you can do," he says. "Obviously don't over-exert yourself, but if you're tired out when you go to bed, you're much more likely to sleep well. Turn off screens a couple of hours before bed, avoid caffeine. And don't give up and call your dealer if you get a bad night's sleep! It will get easier soon."
To take part in this year's Global Drug Survey, an anonymous study on how the world uses drugs, click here.

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I gave up smoking cannabis eight years ago. I'd been promoted - from Telemarketing Supervisor to the noble heights of Telemarketing Manager - and I couldn't turn up with a head wrapped in cotton wool any more.

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Dr Adam Winstock - Cannabis: The waft of change

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The Cannabis (marijuana) Use Disorder Identification Test-Revised (CUDIT-R) is a brief cannabis misuse-screening tool, which is widely used to identify cannabis use problems. Your responses will remain confidential.

All responses to screening tools on this site are completely anonymous. Results from the screening tools are intended to identify risk and not to diagnose or treat. The information provided here cannot substitute for a full evaluation by your medical or mental health professional. Discuss the results of your screening with your medical or mental health provider.

# data[].attributes.attachment_link.description
The Cannabis (marijuana) Use Disorder Identification Test-Revised (CUDIT-R) is a brief cannabis misuse-screening tool, which is widely used to identify cannabis use problems. Your responses will remain confidential. All responses to screening tools on this site are completely anonymous. Results from the screening tools are intended to identify risk and not to diagnose or treat.

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Hundreds of thousands of people who smoke cannabis describe themselves as non-smokers, a study has revealed. Experts fear the findings mean cannabis users may not appreciate that smoking the drug carries many of the same health risks as smoking tobacco.

The study, published in the journal Addiction, and based on a survey of almost 13,000 British adults, estimates that 380,000 people who describe themselves as non-smokers are smoking cannabis with or without tobacco at least weekly.

A further 830,000 tobacco smokers also smoke cannabis at least weekly, suggesting that there may be around 1.2 million weekly cannabis smokers in Britain, a figure borne out by previous studies.

"It is extremely concerning," said Hannah Walsh of King's College London, one of the study's authors. "It is possible that they do not realise they are putting their health at risk. It's also a concern that people may be unwittingly establishing a tobacco addiction, with cannabis acting as their route into a lifetime of smoking tobacco."

The study discusses recent research suggesting that UK-based recreational cannabis users who mix the drug with tobacco will use about 0.35g of tobacco per joint, equivalent to one third of the content of a cigarette.

"This exposes participants to cotinine (the main metabolite of nicotine found in the bloodstream) levels suggestive of moderate tobacco exposure, equivalent to that found in light/moderate cigarette smokers," the study notes. It also points to research that finds mixing cannabis and tobacco produces more negative acute cardiovascular effects and is associated with chronic bronchitis.

"Government generally sees cannabis and tobacco as separate issues but plainly their use is deeply interwoven," said Hazel Cheeseman, director of policy at Action on Smoking and Health. "There is an opportunity to address this in the government's planned Addiction Strategy. This strategy must include measures to tackle the overlapping use of cannabis and tobacco and the resulting harm to health."

The study found that cannabis was disproportionately used by younger people. Seven out of 10 of people who had taken the drug in the past year were under 39 years old. It also identified that people who said that they used cannabis and tobacco together were more likely to report mental health problems than those who used either product on their own.

Surveys suggest more than 75% of cannabis users in the UK mix the drug with tobacco - significantly lower than in other European countries.
Topics

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Cannabis users 'fail to grasp health risks of smoking,' study says

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Hundreds of thousands of people who smoke cannabis describe themselves as non-smokers, a study has revealed. Experts fear the findings mean cannabis users may not appreciate that smoking the drug carries many of the same health risks as smoking tobacco.

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Multiple Bad Cannabis Trips - Help, FAQ - Cannabinoid Hyperemesis Syndrome - CHS

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Given that many states have or are now moving forward with the legalization of medical and recreational marijuana, it should be no surprise that we are seeing an increasing number of women in our clinic who are using marijuana on a regular basis. According to a nationwide survey, 7.3% of Americans 12 or older regularly used marijuana in 2012 , up from 5.8% of Americans in 2007. Among younger and socioeconomically disadvantaged women, prevalence of marijuana use is even higher, in the range of 15 to 28 percent.

The majority of marijuana users are young and of reproductive age. It is estimated that roughly half of female marijuana users continue to use during pregnancy . These changes in the prevalence of marijuana use raise important questions about the effects of marijuana use during pregnancy on embryo development. At th is point in time, the data, though limited, suggests that marijuana use during pregnancy is associated with elevated risk for miscarriages, birth defects, developmental delays, and learning disabilities. Animal data supports these findings and suggests even further potential for developmental issues. Researchers at Georgetown University Medical Center summarized the adverse outcomes associated with marijuana use during pregnancy and linked those outcomes to specific molecular signaling pathways (1). It is one of the most comprehensive review papers on marijuana effects during pregnancy to date and provides clinicians with information which can be used to discuss the risks of using of marijuana during pregnancy.

Metabolism of THC as it Relates to Pregnancy:

THC, the main psychoactive component of marijuana, has a half life of 8 days in fat and is detectable for up to 30 days in the bloodstream. Once circulating in the bloodstream, THC is readily able to cross the blood brain barrier and the placenta due to its lipophilic nature. In a primate study, THC was detectable in fetal blood just 15 minutes after intravenous infusion in the mother. Three hours following infusion, fetal blood levels of THC equilibrated to maternal blood levels (2). A separate study in canines found that THC was deposited in fetal fat at concentrations that are approximately 30% of maternal plasma levels (3). Given the pharmacokinetic properties of THC, maternal tissues act as a reservoir for THC and other cannabinoids which results in prolonged fetal exposure. Taken one step further, when marijuana is used occasionally during pregnancy, say once per month, fetal exposure to marijuana persists throughout the fetus' entire development in the womb.

Marijuana Administration and THC Dosage:

Typically, marijuana is inhaled (through smoking or vaping) or consumed in edible form. Inhalation results in rapid drug delivery and onset of physiological effects, whereas oral consumption is associated with a slower and lower peak THC concentration. Dosages of THC are difficult to assess through clinical interview when a patient reports smoking because drug exposure varies according to smoking topography (the number, length, depth, and volume of inhalations). Dosages of THC in commercially available edibles are much more straightforward.

It is also important to note that older research on the effects of marijuana on embryo development is not reflective of today's typical dosages. The National Institute on Drug Abuse maintains a program to track THC potency and has found that THC levels in marijuana have increased nearly 25-fold since the 1970s (4).

How Cannabinoids Act Upon the Brain:

Cannabinoids mainly act upon two prominent G protein-coupled receptors: CB1 and CB2 . CB1 receptors are present in high levels in the brain and gonads (testes and ovaries) whereas CB2 receptors are more sparse and are found in immune cells and some neuronal cells (5). Endogenous cannabinoids produced by the human body interact with these receptors and current data indicate that the endocannabinoid system plays a role in the regulation of sleep, feeding, pain, learning, and memory.

It is thought that the psychoactive effects of THC are a result of binding (partial agonist) to CB1 receptors in the brain. Under homeostatic conditions, cannabinoid signaling is involved in a number of important, tightly regulated processes that are necessary for healthy embryo development. Disruption of these tightly regulated signaling pathways by exogenous cannabinoids may have a number of downstream adverse effects on: (1) Obstetrical Outcomes (ie., preimplantation and implantation), and (2) Embryo Development (ie., direct effects on the fetus).

How Cannabinoids Affect Obstetrical Outcomes:

Implantation, the attachment of the fertilized egg to the uterine wall, is dependent upon a number of tightly regulated processes. Evidence suggests that there are five ways in which cannabinoids can affect implantation:

1. Impairment of Fallopian Motility: Cannabinoid signaling controls muscle contraction and relaxation in the fallopian tube responsible for the movement of a fertilized egg through the fallopian tube and into the uterus.

2. Ectopic Pregnancy: Previous studies have shown that the blood collected from women who have had ectopic pregnancies contains significantly higher levels of the naturally occurring cannabinoid, anandamide, compared to normal pregnant controls. Consistency between human and animal data adds confidence that the observed findings in animal models of altered cannabinoid signaling may play a role in ectopic pregnancy.

3. Non-Hatched or Non-Viable Embryo: In mice models known to have altered cannabinoid signaling, an increased mortality of offspring was observed in association with implantation of slowly developing embryos (6).

4. Decreased Uterine Receptivity: It is theorized that the binding of exogenous cannabinoids to CB1 receptors in the uterus has embryotoxic effects on the uterine environment. Modeling of this scenario has halted the development of blastocysts and (7)

5. Miscarriage (Spontaneous Abortion): Folic acid (Vitamin B9) is essential for embryo development and cannot be synthesized by the body which is why women are encouraged to take folic acid supplements during pregnancy. THC significantly decreases fetal folic acid uptake. Low levels of folic acid during pregnancy are associated with higher rates of miscarriages, as well as neural tube defects and low birth weight.

How Cannabinoids Affect Embryo Development:

THC crosses the placenta, enters fetal blood circulation, passes through the blood brain barrier, and is found at the highest levels in fetal fat tissue. The brain is 60% fat and therefore stores THC following maternal ingestion. The brain is also densely populated with CB1 receptors which mediate THC's psychoactive properties.

1. Folic Acid Uptake: As stated above, THC interferes with fetal folic acid uptake. Low levels of folic acid during pregnancy are known to be associated with neural tube defects and low birth weight.

2. Cellular Growth: Exogenous cannabinoids may interfere with critical pathways for cellular growth and angiogenesis (formation of new blood vessels).

3. Neural Development: Cannabinoids acting upon the CB1 receptor have the ability to influence the differentiation of neural cells from stem cells in the brain. This has tremendous potential to negatively affect learning and memory as well as developmental processes such as limb development.

Risk/Benefit Analysis:

Usually we take a balanced approach to the use of medications during pregnancy: Does the potential benefit of taking a particular drug outweigh the risks of fetal exposure to that drug or the effects of untreated disease in the mother? At this point, there is no compelling evidence to suggest that marijuana is an effective treatment for any mental health disorders. Given that a number of adverse outcomes are associated with marijuana use during pregnancy , the risk benefit decision seems straightforward: the benefits do not outweigh the risks.

Why Do Women Use Marijuana During Pregnancy?

Many women view marijuana as a relatively benign drug and are not aware that its use poses any health risks. Given the dearth of information on the reproductive safety of cannabis and the potential risk for adverse outcomes, the American College of Obstetricians and Gynecologists (ACOG) has issued a committee opinion on the use of marijuana in pregnant and nursing women, calling for OB-GYNs to educate and urge their patients who are pregnant or contemplating pregnancy to discontinue marijuana use.

But what about the women who use marijuana to help them manage various psychiatric symptoms, including depression and anxiety? Some of these women may choose to use marijuana over traditional psychiatric medications during pregnancy. Is it because women want to avoid psychiatric medications during pregnancy? Is psychiatric care too difficult to find or too expensive? My guess is that there a number of factors at work here.

If the issue is wanting to avoid pharmacologic treatments during pregnancy - that's a personal choice, to be made ideally with medical supervision. However, if that is the case, marijuana cannot be viewed as a substitute. Some women mistakenly believe that marijuana is safer than psychiatric medications because it is 'natural'. Conventional antidepressants, including SSRIs, have a plethora of efficacy and reproductive safety data to support their use during pregnancy, marijuana does not. A lack of information does not make marijuana safe nor do recent changes in legislation.

Wanting to avoid pharmacologic treatment for mental health disorders during pregnancy is common. If that is the case, we can encourage women to explore non-pharmacologic treatment modalities, such as cognitive behavioral therapy which has so much efficacy data at this point and has no side effects.

If the barriers are due to provider access and cost, that is much more difficult to rectify. We have an obligation to offer effective and safe treatments for mental health disorders so that we can have healthier moms and babies. While we can't control the direction of federal funding for healthcare or medical research, efforts are being made that bypass these traditional pathways. One approach is to empower primary care physicians to deliver effective mental health care, and technology is being leveraged to offer free or low cost web-based therapy that may allow people to access care they couldn't have before.
Conclusion:
As legislation for medical and recreational marijuana is changing, marijuana is becoming more accessible and acceptable. Unfortunately, it will take years for research to catch up with use. The information available now warrants a cautious approach with regard to marijuana use during pregnancy and underscores an urgent need for more human data.

Alexandra Z. Sosinsky

References:

1. Friedrich J, Khatib D, Parsa K, Santopietro A, Gallicano GI. The grass isn't always greener: The effects of cannabis on embryological development. BMC Pharmacol Toxicol . 2016 Sep 29; 17(1):45.

2. Martin BR, Dewey WL, Harris LS, Beckner JS. 3H-delta9-tetrahydrocannabinol distribution in pregnant dogs and their fetuses. Res Commun Chem Pathol Pharmacol. 1997;17(3):357-70.

3. Bailey JR, Cunny HC, Paule MG, Slikker WJ. Fetal disposition of delta-9-tetrahydrocannabinol (THC) during late pregnancy in the rhesus monkey. Toxicol Appl Pharmacol. 1987;90(2):315-21.

4. Psychoyos D, Hungund B, Cooper T, Finnell RH. A Cannabinoid Analogue of 3H-delta9-tetrahydrocannabinol Disrupts Neural Development in Chick. Birth Defects Research. 2008;83:477-488.

5. Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;1:10-4.

6. Paria BC, Song H, Wang X, Schmid PC, Krebsbach RJ, Schmid HH, Bonner TI, Zimmer A, Dey SK. Dysregulated cannabinoid signaling disrupts uterine receptivity for embryo implantation. J Biol Chem. 2001;276(23):20523-8.

7. Schmid PC, Paria BC, Krebsbach RJ, Schmid HH, Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci USA. 1997;94(8):4188-92.

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The Effects of Marijuana on Fetal Development

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Given that many states have or are now moving forward with the legalization of medical and recreational marijuana, it should be no surprise that we are seeing an increasing number of women in our clinic who are using marijuana on a regular basis. According to a nationwide survey, 7.3% of

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Medical cannabis has been legal in the UK since 2018, but it is not available on the NHS and is rarely prescribed. Project Twenty21 is taking steps to improve access to medical cannabis and one of the most common indications for medical cannabis is pain. One in 11 people in the UK suffer from chronic neuropathic pain but most doctors continue to prescribe drugs which can cause a significant reduction in quality of life due to negative side effects.

In this new paper, we report the results of a Multi-Criteria Decision Analysis (MCDA) which found that medical cannabis is among the most effective treatments for people with long term, problematic neuropathic pain.

The MCDA compares medical cannabis with the nine drugs that are most commonly prescribed for neuropathic pain in the UK, and evaluates them across 17 criteria.

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Medical Cannabis Improves Patients' Quality of Life More Than Any Other Treatment For Chronic Neuropathic Pain | drugscience.org.uk

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Authors David J. Nutt, Lawrence D. Phillips, Michael P. Barnes, Brigitta Brander, Helen Valerie Curran, Alan Fayaz, David P. Finn, Tina Horsted, Julie Moltke, Chloe Sakal, Haggai Sharon, Saoirse E. O'Sullivan, Tim Williams, Gregor Zorn, and Anne K. Schlag Published March 17, 2021 Medical cannabis has been legal in the UK since 2018, but it ...

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1. Using Spice

2. What Are the Signs of Addiction?

3. Am I Addicted to K2/Spice?

4. How to Encourage Someone to Get Treatment

5. Support Groups for Families and Friends

6. Spice Addiction Treatment

Using Spice

Most people start using Spice because:

Spice has a high addictive potential because of its intense psychoactive effects-which can be more potent than regular marijuana due to the presence of other chemicals.

Continued Spice use has been associated with psychiatric emergencies and medical complications like:

What Are the Signs of Addiction?

Substance addictions have a characteristic pattern of symptoms. Here's how you can determine whether there might be an issue:

Development of tolerance, such that a higher amount is needed to achieve the same effects.

Development of withdrawal symptoms after stopping use.

Am I Addicted to K2/Spice?
If you are looking for an inpatient treatment facility, click here to search for rehabs.

Here are a few signs and symptoms of addiction to K2/Spice you should not ignore:

Denial. Are you trying to hide something by using K2/Spice? It is a popular alternative to marijuana because it eludes detection in urine tests. Remember, no one is judging you for this. It is a sign of needing some support, not a sign of moral failure.

Tolerance. Do you find that you consistently need a higher amount to experience desired effects?

Withdrawal. Do you vomit, have diarrhea, violent headaches, when you go without the drug? Do you have cramping pain or muscle twitching especially in your feet and legs?

Craving. When you don't have the drug, do you crave it? Does it occupy your time so much that friends, family and work obligations are ignored? Are you getting into risky behaviors such as driving under the influence?

How to Encourage Someone to Get Treatment

Educate Yourself: The first step to encouraging a loved one in the direction of treatment is understanding that they may have developed defense mechanisms related to their drug use.This inhibits them from fully understanding the damage they are doing to themselves and to others. As you probably know by now, making them feel guilty or shaming them into abstinence does not work. Instead, be compassionate and approach them in a nonconfrontational way. You can learn about CRAFT strategies, which help improve communication skills for concerned loved ones.

Improve Family Life:
Family dynamics have a direct impact on the motivation to use-particularly for adolescents-because of the presence of both protective and risk factors which impact drug using behavior. The quality of family bonding can have a direct impact on behavior, so consider if there is something here that you can improve.

Encourage adjunct treatment: Helping your loved one visit a family physician may be a good first step. Telling them that they don't look their best, or that you are concerned about their insomnia, is encouraging and not confrontational; it's an observation which can tap into their motivation, not a judgment to tap into their defenses. Referral to addiction treatment may be more acceptable when your loved one discovers that the health problems they're experiencing are caused by their drug use. This may motivate them to acknowledge the problem and consider getting help.

Seek outside assistance: If your loved one has a good relationship with a drug-free peer at work or school, or with someone whose opinion they value, encourage a meeting between the two. An informal chat with a respected individual can motivate them towards recovery.

Staging an Intervention

An intervention, as used here, is defined as "a systematic process to encourage an individual with a psychoactive substance use disorder to seek treatment."

The Johnson Model is a traditional intervention model in which friends and family of the individual struggling with addiction confront him/her about the substance abuse behavior. To break through denial, the strategy involves mentioning specific incidents that illustrate how the addiction caused the loved one's pain, embarrassment, or fear.

Here are a few things to consider:

Involve an addiction counselor or 'interventionist' to coordinate the intervention.

The people present should genuinely care for the individual and have been impacted by the substance abuse, such as: spouses, children, significant others, teachers, employers, or friends.

Figure out the available treatment options, and plan for immediate enrollment if the intervention goes well. Also, consider making travel arrangements to the treatment location or facility.

Rehearse the sequence of events.

Choose an appropriate venue.

Carefully consider the consequences; they need to be serious enough to impact the individual.

Community Reinforcement and Family Training (CRAFT) is an alternative model for communicating your concerns to your loved one and encouraging treatment.

Support Groups for Families and Friends

Family Education Groups provide information on the drug itself, the effects of the addiction on the family, and the nature of relapse and recovery. These groups motivate families to be involved and engaged in the treatment/recovery process. Groups such as Nar-Anon ( www.naranon.com ) and Families Anonymous ( www.familiesanonymous.org ) are available in many locations.

Some providers offer family retreats or "family days" at the treatment center. Some participants have described these retreats as the most important part of their recovery, healing broken relationships with family members. These events also help reestablish roles and healthy boundaries, while creating realistic expectations.

Spice Addiction Treatment

To date, there are no FDA-approved drug treatments for spice addiction.

ER treatment with benzodiazepines, such as lorazepam, are effective for temporary relif from anxiety and prevention of seizures.

Psychosocial Interventions such as Motivational Interviewing (MI), Cognitive Behavioral Therapy (CBT), and Contingency Management (CM) are effective treatment strategies.

An intervention combining Motivational Enhancement Therapy (MET) and Cognitive-Behavioral Therapy (CBT), referred to as , is specifically designed to treat adolescent marijuana abuse. MET/CBT has demonstrated success in improving adolescent substance abuse in a number of studies.

Finding the Best K2/Spice Treatment

In looking for the best treatment rehabilitation services, keep in mind the following key points:

The treatment center should address co-occurring mental health disorders, given that addiction is often coupled with mental health struggles.

The use of evidence-based treatment.

Culturally-competent staff.

Access to medical treatment.

The program environment.

Since spice addiction seems to be mainly prevalent in adolescents and young adults, the amenities provided by the treatment program should be developmentally appropriate and effective.

Opportunities for family education and level of family involvement.

Well-developed after-care protocols.

Treatment continuity, e.g., access to peer recovery support systems.

Sources

American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5 Edition). Arlington, VA: American Psychiatric Publishing.

Auwarter, V., Dargan, P., and Wood, M. (2013). Synthetic Cannabinoid Receptor Agonists. In Dargan, P., and Wood, D., editors. Novel Psychoactive Substances: Classification, Pharmacology and Toxicology. Boston: Elsevier. 317-343.

Baker, M.D., (2009). Mechanisms of motivational interviewing: The influence of social acceptance self-esteem on adolescent substance use. Dissertation Abstracts International 69(10b), 6399.

Baumeister, D., Tojo, L.M., and Tracy, D.K., (2015). Legal highs: staying on top of the flood of novel psychoactive substances. Ther Adv Psychopharmacol 5(2):97-132.

Blonigen, D.M., Finney, J.W., et al., (2015). Psychosocial treatments for substance use disorders. In Nathan, P.E., and Gorman, J.M. editors. Treatments that work. Fourth Edition. New York, NY: Oxford University Press, 731-761.

Castenato, M.S., Gorelick, D.A., Desrosiers, N.A., et al., (2015). Synthetic Cannabinoids: Epidemiology, Pharmacodynamics, and Clinical Implications. Drug Alcohol Depend 1:0:12-41.

Center for Substance Abuse Treatment. Substance Abuse: Clinical Issues in Intensive Outpatient Treatment. Treatment Improvement Protocol (TIP) Series 47. DHHS Publication No. (SMA) 06-4182. Rockville, MD: Substance Abuse and Mental Health Services Administration (SAMHSA), 2006.

DeBruyne, D., and Le Boisselier, R., (2015), Emerging drugs of abuse: current perspectives on synthetic cannabinoids. Subst Abuse Rehabil 6:113-129.

Dennis ML, Godley SH, Diamond GS, Babor T, Donaldson J, Liddle H, et al. The Cannabis Youth Treatment (CYT) Study: Main findings from two randomized trials. Journal of Substance Abuse Treatment. 2004;27:197-213.

Hunter, S. B., Ramchand, R., Griffin, B. A., Suttorp, M. J., McCaffrey, D., & Morral, A. (2012). The effectiveness of community-based delivery of an evidence-based treatment for adolescent substance use. Journal of substance abuse treatment, 43(2), 211-220.

Kilwer, W., Zaharakis, N., (2014). Family-based models of drug etiology. In Scheier, L.M., and Hansen, W.B., (editors). Parenting and teen drug use: the most recent findings from research, prevention, and treatment. New York, NY: Oxford University Press, pp.214-242.

Landry, M.J., (1994). Understanding Drugs of Abuse: The Processes of Addiction, Treamtent, and Recovery. Washington, DC: American Psychiatric Press, Inc.

Lopez-Gon᷉i, J.J., Fernández-Montalvo, J., and Arteaga, A. (2015). Differences Between Cocaine Addicts and Alcoholics Seeking Treatment. Span J Psychol 18.

Miller, W.R., Meyers, R. J., and Tonigan, J.S., (1999). Engaging the unmotivated in treatment for alcohol problems: a comparison of 3 strategies for intervention through family members. J Consult Clin Psychol 67(5):688-697.

Mee-Lee, D., Shulman, G.D., Fishman, M.J., et al. (2013). The ASAM Criteria: Treatment Criteria for Addictive, Substance-Related, and Co-Occurring Conditions. Third Edition. Chevy Chase, MD: The Change Companies.

NAADAC, The Association for Addiction Professionals (2009). Basics of Addiction Counseling: Desk Reference and Study Guide. (Tenth Edition). Alexandria, VA: NAADAC

NAADAC, The Association for Addiction Professionals (2010). Integrating Treatment for Co-occurring Disorders: An Introduction to What Every Addiction Counselor Needs to Know. Alexandria, VA: NAADAC

Ramchand, R., Griffin, B. A., Suttorp, M., Harris, K. M., & Morral, A. (2011). Using a cross-study design to assess the efficacy of motivational enhancement therapy-cognitive behavioral therapy 5 (MET/CBT5) in treating adolescents with cannabis-related disorders. Journal of studies on alcohol and drugs, 72(3), 380.

Schaub, S.P., Haug, S., Wenger, A., et al. (2013). Can reduce - the effects of chat counseling and web-based self-help alone, and web-based self-help alone and a waiting list control program on cannabis use in problematic cannabis users: A randomized controlled trial. BMC Psychiatry 13. Article 305.

Tse, R., Kodur, S., Squires, B., and Collins, N., (2014). Sudden cardiac death complicating acute myocardial infarction following synthetic cannabinoid use. Internal Medicine Journal 44(9):934-936.

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Using Spice What Are the Signs of Addiction? Am I Addicted to K2/Spice? How to Encourage Someone to Get Treatment Support Groups for Families and Friends Spice Addiction Treatment Most people start using Spice because: Spice has a high addictive potential because of its intense psychoactive effects-which can be more potent than regular marijuana due to the presence of other chemicals.

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Resources for professionals and service users

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He began to find the experience of selling drugs very frightening as people would regularly try and assault him to steal his drugs, or would refuse to pay, leaving him in debt to the local crime group. Lee decided that he wanted to stop dealing, however the people he was doing it for made serious threats of violence against him and his family, and he could not see any way out. Eventually with the support of his Wise worker and other professionals, he was able to protect himself by leaving the area. However, he felt a great sense of loss at having to completely remove himself from his local area and family. Lee has had the opportunity to start a fresh, but many other young people are trapped in criminal exploitation, suffering violence and intimidation on a regular basis with little hope of getting out.

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WiSE Up To Exploitation - YMCA DownsLink Group

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He began to find the experience of selling drugs very frightening as people would regularly try and assault him to steal his drugs, or would refuse to pay, leaving him in debt to the local crime group.