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Marijuana is made from a greenish-gray mixture of the dried flowers of Cannabis Sativa. The main chemical in marijuana is delta-9-tetrahydrocannabinol (THC)

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Marijuana-also called weed, herb, pot, grass, bud, ganja, Mary Jane, and a vast number of other slang terms-is a greenish-gray mixture of the dried flowers of Cannabis sativa. Some people smoke marijuana in hand-rolled cigarettes called joints; in pipes, water pipes (sometimes called bongs), or in blunts (marijuana rolled in cigar wraps). Marijuana can also be used to brew tea and, particularly when it is sold or consumed for medicinal purposes, is frequently mixed into foods ( edibles) such as brownies, cookies, or candies. Vaporizers are also increasingly used to consume marijuana. Stronger forms of marijuana include sinsemilla (from specially tended female plants) and concentrated resins containing high doses of marijuana's active ingredients, including honeylike hash oil, waxy budder, and hard amberlike shatter. These resins are increasingly popular among those who use them both recreationally and medically.

The main psychoactive(mind-altering) chemical in marijuana, responsible for most of the intoxicating effects that people seek, is delta-9-tetrahydrocannabinol (THC). The chemical is found in resin produced by the leaves and buds primarily of the female cannabis plant. The plant also contains more than 500 other chemicals, including more than 100 compounds that are chemically related to THC, called cannabinoids.

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What is marijuana? | National Institute on Drug Abuse

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Marijuana-also called weed, herb, pot, grass, bud, ganja, Mary Jane, and a vast number of other slang terms-is a greenish-gray mixture of the dried flowers of Cannabis sativa.

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People can use Marijuana medically for chronic pain. People treated with Marijuana are more likely to experience less pain. Some side effects of using Marijuana is anorexia and weight loss.

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In adults with chemotherapy-induced nausea and vomiting, oral cannabinoids are effective antiemetics.

In adults with chronic pain, patients who were treated with cannabis or cannabinoids are more likely to experience a clinically significant reduction in pain symptoms.

In adults with multiple sclerosis (MS)-related spasticity, short-term use of oral cannabinoids improves patient-reported spasticity symptoms.

For these conditions the effects of cannabinoids are modest; for all other conditions evaluated there is inadequate information to assess their effects.

CHRONIC PAIN

Relief from chronic pain is by far the most common condition cited by patients for the medical use of cannabis. For example, Light et al. (2014) reported that 94 percent of Colorado medical marijuana ID cardholders indicated "severe pain" as a medical condition. Likewise, Ilgen et al. (2013) reported that 87 percent of participants in their study were seeking medical marijuana for pain relief. In addition, there is evidence that some individuals are replacing the use of conventional pain medications (e.g., opiates) with cannabis. For example, one recent study reported survey data from patrons of a Michigan medical marijuana dispensary suggesting that medical cannabis use in pain patients was associated with a 64 percent reduction in opioid use ( Boehnke et al., 2016). Similarly, recent analyses of prescription data from Medicare Part D enrollees in states with medical access to cannabis suggest a significant reduction in the prescription of conventional pain medications ( Bradford and Bradford, 2016). Combined with the survey data suggesting that pain is one of the primary reasons for the use of medical cannabis, these recent reports suggest that a number of pain patients are replacing the use of opioids with cannabis, despite the fact that cannabis has not been approved by the U.S. Food and Drug Administration (FDA) for chronic pain.

Are Cannabis or Cannabinoids an Effective Treatment for the Reduction of Chronic Pain?

Systematic Reviews

Five good- to fair-quality systematic reviews were identified. Of those five reviews, Whiting et al. (2015) was the most comprehensive, both in terms of the target medical conditions and in terms of the cannabinoids tested. Snedecor et al. (2013) was narrowly focused on pain related to spinal cord injury, did not include any studies that used cannabis, and only identified one study investigating cannabinoids (dronabinol). Two reviews on pain related to rheumatoid arthritis did not contribute unique studies or findings ( Fitzcharles et al., 2016; Richards et al., 2012). Finally, one review ( Andreae et al., 2015) conducted a Bayesian analysis of five primary studies of peripheral neuropathy that had tested the efficacy of cannabis in flower form administered via inhalation. Two of the primary studies in that review were also included in the Whiting review, while the other three were not. It is worth noting that the conclusions across all of the reviews were largely consistent in suggesting that cannabinoids demonstrate a modest effect on pain. For the purposes of this discussion, the primary source of information for the effect on cannabinoids on chronic pain was the review by Whiting et al. (2015). Whiting et al. (2015) included RCTs that compared cannabinoids to usual care, a placebo, or no treatment for 10 conditions. Where RCTs were unavailable for a condition or outcome, nonrandomized studies, including uncontrolled studies, were considered. This information was supplemented by a search of the primary literature from April 2015 to August 2016 as well as by additional context from Andreae et al. (2015) that was specific to the effects of inhaled cannabinoids.

The rigorous screening approach used by Whiting et al. (2015) led to the identification of 28 randomized trials in patients with chronic pain (2,454 participants). Twenty-two of these trials evaluated plant-derived cannabinoids (nabiximols, 13 trials; plant flower that was smoked or vaporized, 5 trials; THC oramucosal spray, 3 trials; and oral THC, 1 trial), while 5 trials evaluated synthetic THC (i.e., nabilone). All but 1 of the selected primary trials used a placebo control, while the remaining trial used an active comparator (amitriptyline). The medical condition underlying the chronic pain was most often related to a neuropathy (17 trials); other conditions included cancer pain, multiple sclerosis, rheumatoid arthritis, musculoskeletal issues, and chemotherapy-induced pain. Analyses across 7 trials that evaluated nabiximols and 1 that evaluated the effects of inhaled cannabis suggested that plant-derived cannabinoids increase the odds for improvement of pain by approximately 40 percent versus the control condition (odds ratio [OR], 1.41, 95% confidence interval [CI] = 0.99-2.00; 8 trials). The effects did not differ significantly across pain conditions, although it was not clear that there was adequate statistical power to test for such differences.

Only 1 trial (n = 50) that examined inhaled cannabis was included in the effect size estimates from Whiting et al. (2015). This study ( Abrams et al., 2007) also indicated that cannabis reduced pain versus a placebo (OR, 3.43, 95% CI = 1.03-11.48). It is worth noting that the effect size for inhaled cannabis is consistent with a separate recent review of 5 trials of the effect of inhaled cannabis on neuropathic pain ( Andreae et al., 2015). The pooled ORs from these trials contributed to the Bayesian pooled effect estimate of 3.22 for pain relief versus placebo (95% CI = 1.59-7.24) tested across 9 THC concentrations. There was also some evidence of a dose-dependent effect in these studies.

CANCER

Cancer is a broad term used to describe a wide range of related diseases that are characterized by an abnormal, unregulated division of cells; it is a biological disorder that often results in tumor growth ( NCI, 2015). Cancer is among the leading causes of mortality in the United States, and by the close of 2016 there will be an estimated 1.7 million new cancer diagnoses ( NCI, 2016). Relevant to the committee's interest, there is evidence to suggest that cannabinoids (and the endocannabinoid system more generally) may play a role in the cancer regulation processes ( Rocha et al., 2014). Therefore, there is interest in determining the efficacy of cannabis or cannabinoids for the treatment of cancer.

Are Cannabis or Cannabinoids an Effective Treatment for Cancer?

Systematic Reviews

Using the committee's search strategy only one recent review was found to be of good to fair quality ( Rocha et al., 2014). The review focused exclusively on the anti-tumor effects of cannabinoids on gliomas. Of the 2,260 studies identified through December 2012, 35 studies met the inclusion criteria. With the exception of a small clinical trial, these studies were all preclinical studies. All 16 of the in vivo studies found an antitumor effect of cannabinoids.

Primary Literature

The committee did not identify any good-quality primary literature that reported on cannabis or cannabinoids for the treatment of cancer that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

Nausea and vomiting are common side effects of many cytotoxic chemotherapy agents. A number of pharmaceutical interventions in various drug classes have been approved for the treatment of chemotherapy-induced nausea and vomiting. Among the cannabinoid medications, nabilone and dronabinol were initially approved in 1985 for nausea and vomiting associated with cancer chemotherapy in patients who failed to respond adequately to conventional antiemetic treatments ( Todaro, 2012, pp. 488, 490).

Are Cannabis or Cannabinoids an Effective Treatment for the Reduction of Chemotherapy-Induced Nausea and Vomiting?

Systematic Reviews

Whiting et al. (2015) summarized 28 trials reporting on nausea and vomiting due to chemotherapy, most published before 1984, involving 1,772 participants. The cannabinoid therapies investigated in these trials included nabilone (14), tetrahydrocannabinol (6), levonantradol (4), dronabinol (3), and nabiximols (1). Eight studies were placebo controlled, and 20 included active comparators (prochlorperazine 15; chlorpromazine 2; dromperidone 2; and alizapride, hydroxyzine, metoclopramide, and ondansetron 1 each). Two studies evaluated combinations of dronabinol with prochlorperazine or ondansetron. The average number of patients showing a complete nausea and vomiting response was greater with cannabinoids than the placebo (OR, 3.82, 95% CI = 1.55-9.42) in 3 trials of dronabinol and nabiximols that were considered low-quality evidence. Whiting et al. (2015) concluded that all trials suggested a greater benefit for cannabinoids than for both active agents and for the placebo, although these did not reach statistical significance in all trials.

Of the 23 trials summarized in a Cochrane review ( Smith et al., 2015), 19 were crossover design and 4 were parallel-group design. The cannabinoids investigated were nabilone (12) or dronabinol (11), with 9 placebo-controlled trials (819 participants) and 15 with active comparators (prochlorperazine, 11; metoclopramide, 2; chlorpromazine, 1; domperidone, 1). In 2 trials, a cannabinoid added to a standard antiemetic was compared to the standard alone. While 2 of the placebo-controlled trials showed no significant difference in those reporting absence of nausea with cannabinoids (relative risk [RR], 2.0, 95% CI = 0.19-21), 3 showed a greater chance of having complete absence of vomiting with cannabinoids (RR, 5.7, 95% CI = 2.16-13) and 3 showed a numerically higher chance of complete absence of both nausea and vomiting (RR, 2.9, 95% CI = 1.8-4.7). There was no difference in outcome between patients who were cannabisnaïve and those who were not (P value = 0.4). Two trials found a patient preference for cannabinoids over the comparator. When compared to prochlorperazine, there was no significant difference in the control of nausea, vomiting, or both, although in 7 of the trials there was a higher chance of patients reporting a preference for the cannabinoid therapy (RR, 3.2, 95% CI = 2.2-4.7). In their review the investigators state that cannabinoids were highly effective, being more efficacious than the placebo and similar to conventional antiemetics in treating chemotherapy-induced nausea and vomiting. Despite causing more adverse events such as dizziness, dysphoria, euphoria, "feeling high," and sedation, there was weak evidence for a preference for cannabinoids over the placebo and stronger evidence for a preference over other antiemetics. Despite these findings, however, the authors concluded that there was no evidence to support the use of cannabinoids over current first-line antiemetic therapies and that cannabinoids should be considered as useful adjunctive treatment "for people on moderately or highly emetogenic chemotherapy that are refractory to other antiemetic treatments, when all other options have been tried" ( Smith et al., 2015, p. 23).

Only 3 of the 28 trials in a systematic review of antiemetic therapies in children receiving chemotherapy involved cannabinoid therapies (nabilone 2; THC 1) ( Phillips et al., 2016). The comparators were prochlorperazine in the first nabilone trial, domperidone in the second, and prochlorperazine and metoclopramide in two separate randomizations in the THC trial. In 1 trial with unclear risk of bias, THC dosed at 10 mg/m ² five times on the day of chemotherapy was superior to prochlorperazine in the complete control of acute nausea (RR, 20.7, 95% CI = 17.2-36.2) and vomiting (RR, 19.0, 95% CI = 13.7-26.3). Another trial reported better nausea severity scores for nabilone compared to domperidone (1.5 versus 2.5 on a 0 to 3 [none to worst] scale) (p = 0.01). The largest and most recent trial in this review compared THC to proclorperzine and found no benefit over the control on emesis (RR, 1.0, 95% CI = 0.85-1.17).

Primary Literature

An additional search of the primary literature since the review by Whiting et al. (2015) did not identify any additional studies. The primary literature was then searched in an effort to find studies of cannabinoids compared to the more widely used antiemetics. One trial conducted in 2007 investigated a cannabinoid therapy compared to the current generation of serotonin antagonist antiemetics, as opposed to the dopamine D2 receptor antagonists used in the earlier trials. This 64-patient study evaluated the frequently used antiemetic ondansetron versus dronabinol versus the combination of the two in delayed chemotherapy-induced nausea and vomiting ( Meiri et al., 2007). The two agents appeared similar in their effectiveness, with no added benefit from the combination. Hence, the cannabinoid again fared as well as the current standard antiemetic in this more recent investigation.

Discussion of Findings

The oral THC preparations nabilone and dronabinol have been available for the treatment of chemotherapy-induced nausea and vomiting for more than 30 years ( Grotenhermen and Müller-Vahl, 2012). They were both found to be superior to the placebo and equivalent to the available antiemetics at the time that the original trials were conducted. A more recent investigation suggests that dronabinol is equivalent to ondansetron for delayed nausea and vomiting, although no comparison to the currently more widely used neurokinin-1 inhibitors has been conducted. In the earlier trials, patients reported a preference for the cannabinoids over available agents. Despite an abundance of anecdotal reports of the benefits of plant cannabis, either inhaled or ingested orally, as an effective treatment for chemotherapy-induced nausea and vomiting, there are no good-quality randomized trials investigating this option. This is, in part, due to the existing obstacles to investigating the potential therapeutic benefit of the cannabis plant. Nor have any of the reviewed trials investigated the effectiveness of cannabidiol or cannabidiol-enriched cannabis in chemotherapy-induced nausea and vomiting. Such information is frequently requested by patients seeking to control chemotherapy-induced nausea and vomiting without the psychoactive effects of the THC-based preparations. Resolving this identified research gap may be a future research priority.

CONCLUSION 4-3 There is conclusive evidence that oral cannabinoids are effective antiemetics in the treatment of chemotherapy-induced nausea and vomiting.

ANOREXIA AND WEIGHT LOSS

Anorexia and weight loss are common side effects of many diseases, especially cancer. And prior to the availability of highly active antiretroviral therapy, a wasting syndrome was a frequent clinical manifestation in patients with human immunodeficiency virus (HIV) infection and advanced acquired immune deficiency syndrome (AIDS). The labeled indications for dronabinol were expanded in 1992 to include treatment of anorexia associated with weight loss in patients with AIDS ( IOM, 1999, p. 156).

Are Cannabis or Cannabinoids an Effective Treatment for Anorexia and Weight Loss Associated with HIV/AIDS, Cancer-Associated Anorexia-Cachexia Syndrome, and Anorexia Nervosa?

AIDS Wasting Syndrome

Systematic Reviews Two good-quality systematic reviews included trials investigating cannabinoid therapies in patients with HIV/AIDS. Four randomized controlled trials involving 255 patients were assessed by Whiting et al. (2015), who described all of the trials to be at high risk of bias (ROB) for reasons not elaborated. All four studies included dronabinol, with one investigating inhaled cannabis as well. Three trials were placebo-controlled, and one used the progestational agent megestrol acetate as the comparator. The review authors concluded that there was some evidence suggesting that cannabinoids were effective in weight gain in HIV. A second systematic review focused on morbidity and mortality in HIV/AIDS as the primary outcomes, with changes in appetite and weight as secondary endpoints ( Lutge et al., 2013). Seven RCTs conducted between 1993 and 2009 were included in the qualitative analysis. The trials compared dronabinol or inhaled cannabis with a placebo or with each other. In one study the individuals' weights increased significantly more (p <0.01) on higher doses of cannabis (3.9 percent THC) and dronabinol (10 mg) than on lower doses. In a second trial, median weight was increased with inhaled cannabis (3.5 percent) by 3.0 kg (p = 0.021) and dronabinol (2.5 mg) by 3.2 kg (p = 0.004) when compared with a placebo (a 1.1-kg increase over a 21-day exposure). In a study with 88 evaluable patients, the dronabinol group gained an average of 0.1 kg, while the placebo recipients lost a mean of 0.4 kg (p = 0.14). The proportion of patients gaining at least 2 kg was the same in both groups. Most of the weight gain was in the body fat compartment when this was investigated. Changes in appetite, food, and caloric intake were not deemed to be evaluable in any of the studies. These investigators concluded that the evidence for the efficacy and safety of cannabis and cannabinoids is lacking to support utility in treating AIDS-associated anorexia.

Primary Literature The committee did not identify any good-quality primary literature that reported on cannabis or cannabinoids as effective treatments for AIDS wasting syndrome that were published subsequently to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question. This is largely due to the virtual disappearance of the syndrome since effective antiretroviral therapies became available in the mid-1990s.

Cancer-Associated Anorexia-Cachexia Syndrome

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on cannabis or cannabinoids as effective treatments for cancer-associated anorexia-cachexia syndrome.

Primary Literature A Phase III multicenter, randomized, double-blind placebo-controlled trial was conducted by the Cannabis-In-Cachexia-Study-Group in patients with cancer-related anorexia-cachexia syndrome ( Strasser et al., 2006). Patients with advanced cancer and weight loss of greater than 5 percent over 6 months were randomized 2:2:1 to receive treatment with a cannabis extract (standardized to THC 2.5 mg and cannabidiol 1.0 mg), THC 2.5 mg, or a placebo twice daily for 6 weeks. Appetite, mood, and nausea were monitored daily. Cancer-related quality of life and cannabinoid-related toxicity were also monitored. Only 164 of the 243 patients who were randomized completed the trial. An intent-to-treat analysis yielded no difference between the groups in appetite, quality of life, or toxicity. Increased appetite was reported by 73 percent of the cannabis-extract, 58 percent of the THC group, and 69 percent of the placebo recipients. Recruitment was terminated early by the data review board because it was believed to be unlikely that differences would emerge between the treatment arms. The findings in this study reinforce the results from an earlier trial investigating dronabinol, megestrol acetate, or the combination in 469 advanced cancer patients with a loss of appetite and greater than 5 pounds weight loss over the prior 2 months ( Jatoi et al., 2002). Megestrol acetate was superior to dronabinol for the improvement of both appetite and weight, with the combination therapy conferring no additional benefit. Seventy-five percent of the megestrol recipients reported an improvement in appetite compared to 49 percent of those receiving dronabinol (p = 0.0001). Of those in the combination arm, 66 percent reported improvement. A weight gain greater than or equal to 10 percent over their baseline at some point during the course of the trial was reported by 11 percent of those in the megestrol arm, compared with 3 percent of the dronabinol recipients (p = 0.02). The combination arm reported a weight gain in 8 percent. These findings confirm a similarly designed trial that was conducted in patients with AIDS wasting syndrome ( Timpone et al., 1997).

Anorexia Nervosa

Systematic Reviews The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for anorexia nervosa.

Primary Literature Pharmacological interventions in the treatment of anorexia nervosa have not been promising to date. Andries et al. (2014) conducted a prospective, randomized, double-blind, controlled crossover trial in 24 women with anorexia nervosa of at least 5 years' duration attending both psychiatric and somatic therapy as inpatients or outpatients. In addition to their standard psychotherapy and nutritional interventions, the participants received dronabinol 2.5 mg twice daily for 4 weeks and a matching placebo for 4 weeks, randomly assigned to two treatment sequences (dronabinol/placebo or placebo/dronabinol). The primary outcome was weight change assessed weekly. The secondary outcome was change in Eating Disorder Inventory-2 (EDI-2) scores. The participants had a significant weight gain of 1.00 kg (95% CI = 0.40-1.62) during dronabinol therapy and 0.34 kg (95% CI = −0.14-0.82) during the placebo (p = 0.03). No statistically different differences in EDI-2 score changes were seen during treatment with dronabinol or the placebo, suggesting that there was no real effect on the participants' attitudinal and behavioral traits related to eating disorders. The authors acknowledged the small sample size and the short duration of exposure, as well as the potential psychogenic effects, but they concluded that low-dose dronabinol is a safe adjuvant palliative therapy in a highly selected subgroup of chronically undernourished women with anorexia nervosa.

Discussion of Findings

There is some evidence for oral cannabinoids being able to increase weight in patients with the HIV-associated wasting syndrome and anorexia nervosa. No benefit has been demonstrated in cancer-associated anorexia-cachexia syndrome. The studies have generally been small and of short duration and may not have investigated the optimal dose of the cannabinoid. In one study in HIV patients, both dronabinol and inhaled cannabis increased weight significantly compared to the placebo dronabinol. Cannabis has long been felt to have an orexigenic effect, increasing food intake ( Abel, 1975). Small residential studies conducted in the 1980s found that inhaled cannabis increased caloric intake by 40 percent, with most of the increase occurring as snacks and not during meals ( Foltin et al., 1988). Hence, the results of the clinical trials in AIDS wasting and cancer-associated anorexia-cachexia syndrome demonstrating little to no impact on appetite and weight were somewhat unexpected. One could postulate that perhaps other components of the plant in addition to THC may contribute to the effect of cannabis on appetite and food intake. There have not been any randomized controlled trials conducted studying the effect of plant-derived cannabis on appetite and weight with weight as the primary endpoint. This is, in part, due to existing obstacles to investigating the potential therapeutic benefit of the cannabis plant.

CONCLUSION 4-4

4-4(a) There is limited evidence that cannabis and oral cannabinoids are effective in increasing appetite and decreasing weight loss associated with HIV/AIDS.

4-4(b) There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for cancer-associated anorexia-cachexia syndrome and anorexia nervosa.

IRRITABLE BOWEL SYNDROME

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder commonly associated with symptoms of abdominal cramping and changes in bowel movement patterns. Irritable bowel syndrome is classified into four types based on the types of bowel movements: IBS with diarrhea, IBS with constipation, IBS mixed, and IBS unclassified ( NIDDK, 2015). Approximately 11 percent of the world's population suffers from at least one type of this disorder ( Canavan et al., 2014).

Type 1 cannabinoid (CB ₁) receptors are present in the mucosa and neuromuscular layers of the colon; they are also expressed in plasma cells and influence mucosal inflammation ( Wright et al., 2005). In animal models, endocannabinoids acting on CB ₁ receptors inhibit gastric and small intestinal transit and colonic propulsion ( Pinto et al., 2002). Studies in healthy volunteers have shown effects on gastric motility and colonic motility ( Esfandyari et al., 2006). Thus, cannabinoids have the potential for therapeutic effect in patients with IBS ( Wong et al., 2012).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms of Irritable Bowel Syndrome?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for symptoms of irritable bowel syndrome.

Primary Literature

We identified a single relevant trial ( Wong et al., 2012) evaluating dronabinol in patients with irritable bowel syndrome with diarrhea (IBS-D). This low-risk-of-bias trial enrolled 36 patients between the ages of 18 and 69 with IBS-D. Patients were randomized to dronabinol 2.5 mg BID (n = 10), dronabinol 5 mg BID (n = 13), or a placebo (n = 13) for 2 days. No overall treatment effects of dronabinol on gastric, small bowel, or colonic transit, as measured by radioscintigraphy, were detected.

EPILEPSY

Epilepsy refers to a spectrum of chronic neurological disorders in which clusters of neurons in the brain sometimes signal abnormally and cause seizures ( NINDS, 2016a). Epilepsy disorder affects an estimated 2.75 million Americans, across all age ranges and ethnicities ( NINDS, 2016a). Although there are many antiepileptic medications currently on the market, about one-third of persons with epilepsy will continue to have seizures even when treated ( Mohanraj and Brodie, 2006). Both THC and CBD can prevent seizures in animal models ( Devinsky et al., 2014).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms of Epilepsy?

Systematic Reviews

We identified two systematic reviews of randomized trials assessing the efficacy of cannabis or cannabinoids, used either as monotherapy or in addition to other therapies, in reducing seizure frequency in persons with epilepsy. Gloss and Vickrey (2014) published a systematic review of randomized controlled trials. They identified four reports (including one conference abstract and one letter to the editor) of cannabinoid trials, all of which they considered to be of low quality. Combined, the trials included a total of 48 patients. The systematic review's primary prespecified outcome was freedom from seizures for either 12 months or three times the longest previous seizure-free interval. None of the four trials assessed this endpoint. Accordingly, Gloss and Vickrey asserted that no reliable conclusions could be drawn regarding the efficacy of cannabinoids for epilepsy.

Koppel et al. (2014) published a fair-quality systematic review. They identified no high-quality randomized trials and concluded that the existing data were insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency.

Primary Literature

We identified two case series that reported on the experience of patients treated with cannabidiol for epilepsy that were published subsequent to the systematic reviews described above. The first of these was an open-label, expanded-access program of oral cannabidiol with no concurrent control group in patients with severe, intractable childhood-onset epilepsy that was conducted at 11 U.S. epilepsy centers and reported by Devinsky et al. (2016) and by Rosenberg et al. (2015). Devinsky et al. (2016) reported on 162 patients ages 1 to 30 years; Rosenberg et al. (2015) reported on 137 of these patients. The median monthly frequency of motor seizures was 30.0 (interquartile range [IQR] 11.0-96.0) at baseline and 15.8 (IQR 5.6-57.6) over the 12-week treatment period. The median reduction in motor seizures while receiving cannabidiol in this uncontrolled case series was 36.5 percent (IQR 0-64.7).

Tzadok et al. (2016) reported on the unblinded experience of Israeli pediatric epilepsy clinics treating 74 children and adolescents with intractable epilepsy with an oral formulation of cannabidiol and tetrahydrocannabinol at a 20:1 ratio for an average of 6 months. There was no concurrent control goup. Compared with baseline, 18 percent of children experienced a 75-100 percent reduction in seizure frequency, 34 percent experienced a 50-75 percent reduction, 12 percent reported a 25-50 percent reduction, 26 percent reported a reduction of less than 25 percent, and 7 percent reported aggravation of seizures that led to a discontinuation of the cannabinoid treatment.

The lack of a concurrent placebo control group and the resulting potential for regression to the mean and other sources of bias greatly reduce the strength of conclusions that can be drawn from the experiences reported by Devinsky et al. (2016), Rosenberg et al. (2015), and Tzadok et al. (2016) about the efficacy of cannabinoids for epilepsy. Randomized trials of the efficacy of cannabidiol for different forms of epilepsy have been completed, but their results have not been published at the time of this report.

SPASTICITY ASSOCIATED WITH MULTIPLE SCLEROSIS OR SPINAL CORD INJURY

Spasticity is defined as disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles ( Pandyan et al., 2005). It occurs in some patients with chronic neurological conditions such as multiple sclerosis (MS) and paraplegia due to spinal cord injury. Recent studies have shown that some individuals with MS are seeking alternative therapies, including cannabis, to treat symptoms associated with MS ( Zajicek et al., 2012).

Are Cannabis or Cannabinoids an Effective Treatment for Spasticity Associated with Multiple Sclerosis or Spinal Cord Injury?

Systematic Reviews

We identified two recent systematic reviews that assessed the efficacy of cannabis or cannabinoids in treating muscle spasticity in patients with MS or paraplegia due to spinal cord injury-the systematic review by Whiting et al. (2015) that examined evidence for a broad range of medical uses of cannabis or cannabinoids and the systematic review by Koppel et al. (2014) that focused more narrowly on neurologic conditions. Both systematic reviews examined only randomized, placebo-controlled trials. Whiting et al. (2015) excluded from their primary analysis trials that did not use a parallel group design (i.e., they excluded crossover trials) and performed a quantitative pooling of results. In contrast, Koppel et al. (2014) included crossover trials but did not perform a quantitative pooling of results.

Whiting et al. (2015) searched for studies examining the efficacy of cannabinoids for spasticity due to MS or paraplegia. They identified 11 studies that included patients with MS and 3 that included patients with paraplegia caused by spinal cord injury. None of the studies in patients with paraplegia caused by spinal cord injury were reported as full papers or included sufficient data to allow them to be included in pooled estimates. Whiting et al. (2015) reported that in their pooled analysis of three trials in patients with MS, nabiximols and nabilone were associated with an average change (i.e., improvement) in spasticity rating assessed by a patient-reported numeric rating scale of −0.76 (95% CI = −1.38 to −0.14) on a 0 to 10 scale that was statistically greater than for the placebo. They further reported finding no evidence for a difference according to type of cannabinoid (i.e., nabiximols versus nabilone). Whiting et al. (2015) also reported that the pooled odds of patient-reported improvement on a global impression-of-change score was greater with nabiximols than with the placebo (OR, 1.44, 95% CI = 1.07-1.94).

The review by Koppel et al. (2014) restricted its focus on spasticity to that due to MS. Their conclusions were broadly in agreement with corresponding conclusions from the review by Whiting et al. (2015). In particular, Koppel et al. (2014) concluded that in patients with MS, nabiximols and orally administered THC are "probably effective" for reducing patient-reported spasticity scores and that oral cannabis extract is "established as effective for reducing patient-reported scores" for spasticity ( Koppel et al., 2014, p. 1558).

A commonly used scale for rating spasticity is the Ashworth scale ( Ashworth, 1964). However, this scale has been criticized as unreliable, insensitive to therapeutic benefit, and reflective only of passive resistance to movement and not of other features of spasticity ( Pandyan et al., 1999; Wade et al., 2010). Furthermore, no minimally important difference in the Ashworth scale has been established. Whiting et al. (2015) calculated a pooled measure of improvement on the Ashworth scale versus placebo based on five parallel-group-design trials. They reported that nabiximols, dronabinol, and oral THC/CBD were associated with a numerically greater average improvement on the Ashworth scale than with a placebo but that this difference was not statistically significant. This conclusion is in broad agreement with corresponding conclusions reached by Koppel et al. (2014), who concluded in particular that nabiximols, oral cannabis extract and orally administered THC are "probably ineffective" for reducing objective measures of spasticity in the short term (6-15 weeks), although oral cannabis extract and orally administered THC are "possibly effective" for objective measures at 1 year.

Discussion of Findings

Based on evidence from randomized controlled trials included in systematic reviews, an oral cannabis extract, nabiximols, and orally administered THC are probably effective for reducing patient-reported spasticity scores in patients with MS. The effect appears to be modest, as reflected by an average reduction of 0.76 units on a 0 to 10 scale. These agents have not consistently demonstrated a benefit on clinician-measured spasticity indices such as the modified Ashworth scale in patients with MS. Given the lack of published papers reporting the results of trials conducted in patients with spasticity due to spinal cord injury, there is insufficient evidence to conclude that cannabinoids are effective for treating spasticity in this population.

CONCLUSION 4-7

4-7(a) There is substantial evidence that oral cannabinoids are an effective treatment for improving patient-reported multiple sclerosis spasticity symptoms, but limited evidence for an effect on clinician-measured spasticity.

4-7(b) There is insufficient evidence to support or refute the conclusion that cannabinoids are an effective treatment for spasticity in patients with paralysis due to spinal cord injury.

TOURETTE SYNDROME

Tourette syndrome is a neurological disorder characterized by sporadic movements or vocalizations commonly called "tics" ( NINDS, 2014). While there is currently no cure for Tourette syndrome, recent efforts have explored whether cannabis may be effective in reducing symptoms commonly associated with the disorder ( Koppel et al., 2014).

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Tourette Syndrome?

Systematic Reviews

We identified two good-quality systematic reviews ( Koppel et al., 2014; Whiting et al., 2015) that evaluated medical cannabis for Tourette syndrome. Both good-quality reviews identified the same trials, and we focus on the more recent review by Whiting et al. (2015). The two RCTs (four reports), conducted by the same research group ( Müller-Vahl et al., 2001, 2002, 2003a, b), compared THC capsules (maximum dose 10 mg daily) to a placebo in 36 patients with Tourette syndrome. Tic severity, assessed by multiple measures, and global clinical outcomes were improved with THC capsules. On a 0 to 6 severity scale, symptoms were improved by less than 1 point. These outcomes were assessed at 2 days (unclear-risk-of-bias trial) and 6 weeks (high-risk-of-bias trial). Neither trial described randomization or allocation concealment adequately, and the 6-week trial was rated high risk of bias for incomplete outcome data.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for Tourette syndrome, and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons in the spinal cord, brain stem, and motor cortex, ultimately leading to complete paralysis ( Rossi et al., 2010). The pathogenesis of ALS remains unclear, but the disease is thought to result from the interplay of a number of mechanisms, including neurofilament accumulation, excitotoxicity, oxidative stress, and neuroinflammation ( Redler and Dokholyan, 2012), all of which may be amenable to manipulation of the endocannabinoid system and cannabinoid receptors.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Amyotrophic Lateral Sclerosis?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for symptoms associated with amyotrophic lateral sclerosis.

Primary Literature

On the basis of proposed pathogenesis and anecdotal reports of symptomatic benefit from the use of cannabis in patients with ALS, two small trials of dronabinol have been conducted. In a randomized, double-blind crossover study, 19 patients with ALS were treated with dronabinol doses of 2.5 to 10 mg daily for 4 weeks ( Gelinas et al., 2002). Participants noted improvement in appetite and sleep but not in cramps or fasiculations (involuntary muscle twitches). The second study enrolled 27 patients with ALS who had moderate to severe cramps (greater than 4 on a 0-10 visual analogue scale) in a randomized, double-blind trial of dronabinol 5 mg twice daily or a placebo, each given for 2 weeks with an intervening 2-week washout period ( Weber et al., 2010). The primary endpoint was a change in cramp intensity with secondary endpoints of change in cramp number, intensity of fasciculations, quality of life, sleep, appetite, and depression. There was no difference between dronabinol and the placebo seen in any of the endpoints. The investigators reported that the dronabinol was very well tolerated and postulated that the dronabinol dose may have been too low as well as suggesting that a carryover effect in the crossover design may have obfuscated any differences in the treatment arms. The sample size was too small to discern anything but a large effect.

HUNTINGTON'S DISEASE

Huntington's disease is characterized by chorea (abnormal, involuntary movement) along with cognitive decline and psychiatric impairment ( Armstrong and Miyasaki, 2012). Worsening chorea significantly impacts patient quality of life. The pathophysiology and neurochemical basis of Huntington's disease are incompletely understood. Neuroprotective trials often investigate agents that may decrease oxidative stress or glutamatergic changes related to excitotoxic stress. There is some preclinical evidence and limited clinical evidence that suggest that changes in the endocannabinoid system may be linked to the pathophysiology of Huntington's disease ( Pazos et al., 2008; van Laere et al., 2010).

Are Cannabis or Cannabinoids an Effective Treatment for the Motor Function and Cognitive Performance Associated with Huntington's Disease?

Systematic Reviews

The systematic review from the American Academy of Neurology includes two studies on Huntington's disease ( Koppel et al., 2014). A randomized, double-blind, placebo-controlled crossover pilot trial investigated nabilone 1 or 2 mg daily for 5 weeks followed by a placebo in 22 patients with symptomatic Huntington's disease ( Curtis et al., 2009). An additional 22 patients were randomized to the placebo followed by nabilone. The primary endpoint was the total motor score of the Unified Huntington's Disease Rating Scale (UHDRS). Secondary endpoints included the chorea, cognitive performance, and psychiatric changes measured with the same instrument. No significant difference in the total motor score was seen in the 37 evaluable patients (treatment difference, 0.86, 95% CI = −1.8-3.52), with a 1-point change considered clinically significant. There was evidence of an improvement in the chorea subscore with nabilone (treatment difference, 1.68, 95% CI = 0.44-2.92). There was no difference between treatments for cognition, but there was evidence of an improvement in the two neuropsychiatric outcome measures in the nabilone arm-UHDRS behavioral assessment (4.01, 95% CI = −0.11-8.13) and neuropsychiatric inventory (6.43, 95% CI = 0.2-12.66). The small estimated treatment effect with wide confidence intervals reduces the level of evidence for nabilone's effectiveness from this pilot study. However, based on this trial, the American Academy of Neurology guideline concluded that "nabilone possibly modestly improves Huntington's disease chorea" ( Armstrong and Miyasaki, 2012, p. 601). The second study included in the systematic review was a lower-quality, 15-patient randomized, double-blind, placebo-controlled trial investigating the effect of cannabidiol capsules at a dose of 10 mg/kg/day in two divided doses ( Consroe et al., 1991). The endpoints in this study involving patients with Huntington's disease who were not on neuroleptics were chorea severity, functional limitations, and side effects. There were no statistically significant differences between cannabidiol and placebo in any outcomes, although the American Academy of Neurology considered the study to be underpowered.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the declines in motor function and cognitive performance associated with Huntington's disease that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

PARKINSON'S DISEASE

Parkinson's disease is a motor system disorder attributed to the loss of dopamine-producing brain cells. It is characterized clinically by tremor, rigidity, bradykinesia (slowness of movement), and impaired balance and coordination ( PDF, 2016a). An estimated 60,000 Americans are diagnosed with this disorder each year ( PDF, 2016b).

Although the disease is progressive and without cure, there are medications that can ameliorate some of the associated symptoms. Although levodopa has demonstrated efficacy for treating symptoms of Parkinson's disease, long-term use of levodopa is associated with the development of side effects, especially dyskinesias (involuntary movements) ( NINDS, 2015). Evidence suggests that the endocannabinoid system plays a meaningful role in certain neurodegenerative processes ( Krishnan et al., 2009); thus, it may be useful to determine the efficacy of cannabinoids in treating the symptoms of neurodegenerative diseases.

Are Cannabis or Cannabinoids an Effective Treatment for the Motor System Symptoms Associated with Parkinson's Disease or the Levodopa-Induced Dyskinesia?

Systematic Reviews

The systematic review of cannabis in selected neurologic disorders ( Koppel et al., 2014) identified two trials of cannabinoid therapies in patients with levodopa-induced dyskinesias. Nineteen patients with levodopa-induced dyskinesia greater than or equal to 2 as determined by questions 32-34 of the Unified Parkinson's Disease Rating Scale (UPDRS) were randomized in a double-blind, placebo-controlled crossover trial to receive Cannador capsules (containing THC 2.5 mg and CBD 1.25 mg) to a maximum dose of 0.25 mg/kg of THC daily or placebo ( Carroll et al., 2004). The primary endpoint was the effect of treatment on the dyskinesia score of the UPDRS. Secondary endpoints included the impact of dyskinesia on function, pathophysiologic indicators of dyskinesia, duration of dyskinesia, quality of life, sleep, pain, and overall severity of Parkinson's disease. The overall treatment effect was +0.52, which indicated a worsening with Cannador, although this worsening was not statistically significant (p = 0.09). No effects were seen on the secondary outcomes. Although there were more adverse events on the drug than on the placebo, the investigators felt that the treatment was well tolerated. The study had limited statistical power to detect anything but a large treatment effect due to its small sample size. The second study included in the systematic review was an even smaller low-quality, randomized, double-blind, placebo-controlled crossover trial involving seven patients with Parkinson's disease who had stable levodopa-induced dyskinesia present for 25-50 percent of the day ( Sieradzan et al., 2001). Nabilone dosed at 0.03 mg/kg or a placebo was administered 12 hours and 1 hour before levodopa at a dose of 200 mg. The primary endpoint was total dyskinesia disability as measured using the Rush Dyskinesia Disability Scale. The median total dyskinesia score after treatment with levodopa and nabilone was 17 (range 11-25) compared to 22 (range 16-26) after levodopa and the placebo (p <0.05). The anti-Parkinsonian actions of levodopa were not reduced by nabilone pretreatment. Although the authors stated that "nabilone significantly reduced total levodopa-induced dyskinesia compared with placebo" ( Sieradzan et al., 2001, p. 2109), the fact that the results were generated by only seven patients receiving only two doses clearly reduces the ability to draw such an enthusiastic conclusion. Koppel concludes that oral cannabis extract "is probably ineffective for treating levodopa-induced dyskinesias" ( Koppel et al., 2014, p. 1560).

Primary Literature

Cannabidiol capsules were evaluated in a randomized, double-blind, placebo-controlled trial conducted in 21 patients with Parkinson's disease ( Chagas et al., 2014). The study was an exploratory trial to assess the effect of CBD in Parkinson's disease globally with the UPDRS and the Parkinson's Disease Questionnaire-39 (PDQ-39) used to assess overall functioning and well-being. Possible CBD adverse events were evaluated by a side effect rating scale. Baseline data were collected 1 week before commencing treatment with CBD at 75 mg/day or 300 mg/day or with a placebo, and the same assessments were repeated during the sixth and final week of the trial. No statistically significant differences were seen in the UPDRS between the three study arms. There was a statistically significant difference in the variation between baseline and final assessment in the overall PDQ-39 score between the placebo (6.50 ± 8.48) and CBD 300 mg/day (25.57 ± 16.30) (p = 0.034), which suggests that there might be a possible effect of CBD on improving quality of life.

An open-label observational study of 22 patients with Parkinson's disease attending a motor disorder clinic at a tertiary medical center collected data before and 30 minutes after patients smoked 0.5 grams of cannabis ( Lotan et al., 2014). The instruments utilized included the UPDRS, the McGill Pain Scale, and a survey of subjective efficacy and adverse effects of cannabis. In addition, the effect of cannabis on motor symptoms was evaluated by two raters. The investigators found that the total motor symptoms score on the UPDRS improved from 33.1 (± 13.8) to 23.2 (± 10.5) (p <0.001). Subcategories of the UPDRS that showed statistically significant improvement included tremor, rigidity, and bradykinesia. Pain and sleep were also reported to be improved after smoking cannabis. The results from this low-quality observational study prompted the investigators to propose that their findings should be confirmed in a larger, longer, randomized, double-blind, placebo-controlled trial.

DYSTONIA

Dystonia is a disorder characterized by sustained or repetitive muscle contractions which result in abnormal fixed postures or twisting, repetitive movements ( NINDS, 2016b). Idiopathic cervical dystonia is the most common cause of focal dystonia. Oral pharmacological agents are generally ineffective, with repeated injections of botulinum toxin being the most effective current therapy. The pathophysiologic mechanisms of dystonia are poorly understood, but, as in other hyperkinetic movement disorders, underactivity of the output regions of the basal ganglia may be involved. Stimulation of the cannabinoid receptors has been postulated as a way to reduce dystonia ( Zadikoff et al., 2011). Anecdotal reports have suggested that cannabis may alleviate symptoms associated with dystonia ( Uribe Roca et al., 2005). In a 1986 preliminary open pilot study in which five patients with dystonic movement disorders received cannabidiol, dose-related improvements were observed in all five patients ( Consroe et al., 1986).

Are Cannabis or Cannabinoids an Effective Treatment for Dystonia?

Systematic Reviews

The American Academy of Neurology systematic review ( Koppel et al., 2014) identified one study that examined the effect of dronabinol on cervical dystonia. The review described the study as being underpowered to detect any differences between dronabinol and the placebo. Overall, nine patients with cervical dystonia were randomized to receive dronabinol 15 mg daily or a placebo in an 8-week crossover trial ( Zadikoff et al., 2011). The primary outcome measure was the change in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) part A subscore at the beginning and the end of each 3-week treatment phase. There was no statistically significant effect of dronabinol on the dystonia compared with the placebo as measured by the TWSTRS-A (p = 0.24).

DEMENTIA

Dementia is characterized by a decline in cognition that typically affects multiple cognitive domains such as memory, language, executive function, and perceptual motor function ( NIH, 2013). Alzheimer's disease, vascular dementia, and Parkinson's disease with dementia are three prominent dementing disorders ( NIA, n.d.). Behavioral and psychological symptoms, including agitation, aggression, and food refusal, are common in the more advanced stages of dementia. These symptoms cause distress to the patient and caregivers and may precipitate the patient being placed in institutional care. Current treatments for dementia (e.g., cholinesterase inhibitors) have only modest effects, and treatments for behavioral disturbances such as antipsychotic medications have both modest benefits and substantial adverse effects ( Krishnan et al., 2009).

CB ₁ receptors are found throughout the central nervous system, and the endogenous cannabinoid system is thought to be important in the regulation of synaptic transmission ( Baker et al., 2003), a process that is disordered in patients with dementia. Accumulating evidence suggests that cannabinoids have the potential for neuroprotective effects ( Grundy, 2002; Hampson et al., 1998; Shen and Thayer, 1998). This developing understanding of the endogenous cannabinoid system, along with cannabinoids anxiolytic and appetite-stimulating effects, provides a rationale for its study in patients with dementia.

Are Cannabis or Cannabinoids an Effective Treatment for the Symptoms Associated with Dementia?

Systematic Reviews

We identified two good-quality systematic reviews ( Krishnan et al., 2009; van den Elsen et al., 2014) that evaluated cannabis for dementia. Both reviews identified the same two RCTs, which were synthesized qualitatively. A small randomized crossover trial ( Volicer et al., 1997) evaluated dronabinol in 15 hospitalized patients with probable Alzheimer's disease who had behavior changes and were refusing food. Patients were randomized to dronabinol (2.5 mg twice daily) for 6 weeks and to a placebo for 6 weeks. Data in this trial with a high risk of bias were presented in such a way that they could not be abstracted for analysis by systematic review authors. The primary study authors reported: increased weight during the 12 weeks regardless of order of treatment (dronabinol, 7.0 [SD 1.5] pounds, and placebo, 4.6 [SD 1.3] pounds, during the first 6 weeks); decreased disturbed behavior during dronabinol treatment, an effect that persisted in patients treated first with dronabinol, then the placebo; decreased negative affect scores in both groups during the 12 weeks, more so when taking dronabinol than the placebo; and no serious adverse events attributed to dronabinol, although one patient suffered a seizure following the first dose. One other open-label pilot study ( Walther et al., 2006), which evaluated six patients with severe dementia for the effects of dronabinol on nighttime agitation, did not meet eligibility criteria for the review by Krishnan et al. (2009).

Discussion of Findings

The authors of the good-quality Cochrane systematic review concluded that the "review finds no evidence that cannabinoids are effective in the improvement of disturbed behavior in dementia or treatment of other symptoms of dementia" ( Krishnan et al., 2009, p. 8). Subsequently, a larger good-quality RCT found no benefit from low-dose THC. We agree that the evidence is limited due to the small number of patients enrolled, limits in the study design and reporting, and inconsistent effects. The current limited evidence does not support a therapeutic effect of cannabinoids.

CONCLUSION 4-13 There is limited evidence that cannabinoids are ineffective treatments for improving the symptoms associated with dementia.

GLAUCOMA

Glaucoma is one of the leading causes of blindness within the United States ( Mayo Clinic, 2015). This disorder is characterized as a group of eye conditions that can produce damage to the optic nerve and result in a loss of vision. This damage is often caused by abnormally high intraocular pressure ( NEI, n.d.). Because high intraocular pressure is a known major risk factor that can be controlled ( Prum et al., 2016, p. 52), most treatments have been designed to reduce it. Research suggests that cannabinoids may have potential as an effective treatment for reducing pressure in the eye ( Tomida et al., 2007).

Are Cannabis or Cannabinoids an Effective Treatment for Glaucoma?

Systematic Reviews

We identified one good-quality systematic review ( Whiting et al., 2015) that evaluated medical cannabis for the treatment of glaucoma. This review identified a single randomized crossover trial (six participants) in patients with glaucoma. The trial compared THC (5 mg oromucosal spray), cannabidiol (20 mg oromucosal spray), cannabidiol spray (40 mg oromucosal spray), and a placebo, examining intraocular pressure intermittently up until 12 hours after treatment. Elevated intraocular pressure is one of the diagnostic criteria for glaucoma, and lowering intraocular pressure is a goal of glaucoma treatments ( Prum et al., 2016). The trial was evaluated as "unclear" risk of bias. No differences in intraocular pressure were found between placebo and cannabinoids.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the symptoms of glaucoma and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

TRAUMATIC BRAIN INJURY/INTRACRANIAL HEMORRHAGE

Traumatic brain injury (TBI) is an acquired brain injury that can result from a sudden or violent hit to the head ( NINDS, 2016c). TBI accounts for about 30 percent of all injury deaths in the United States ( CDC, 2016). Intracranial hemorrhage (ICH), bleeding that occurs inside the skull, is a common complication of TBI which is associated with a worse prognosis of the injury ( Bullock, 2000; CDC, 2015). There is a small body of literature reporting the neuroprotective effects of cannabinoid analogues in preclinical studies of head injuries ( Mechoulam et al., 2002) as well as in observational studies in humans ( Di Napoli et al., 2016; Nguyen et al., 2014).

Are Cannabis or Cannabinoids an Effective Treatment or Prevention for Traumatic Brain Injury or Intracranial Hemorrhage?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that evaluated the efficacy of cannabinoids as a treatment or prevention for traumatic brain injury or intracranial hemorrhage.

Primary Literature

There were two fair- to high-quality observational studies found in the literature. One study (n = 446) examined the TBI presentation and outcomes among patients with and without a positive THC blood test ( Nguyen et al., 2014). Patients who were positive for THC were more likely to survive the TBI than those who were negative for THC (OR, 0.224, 95% CI = 0.051-0.991). The authors used regression analysis to account for confounding variables (e.g., age, alcohol, Abbreviated Injury Score, Injury Severity Score, mechanism of injury, gender, and ethnicity). In the only other observational study that examined the association between cannabis use and brain outcomes, a study of intracranial hemorrhage patients (n = 725) found that individuals with a positive test of cannabis use demonstrated better primary outcome scores on the modified Rankin Scale (adjusted common OR, 0.544, 95% CI = 0.330-0.895) ( Di Napoli et al., 2016). In their analysis, the authors adjusted for confounding variables that are known to be associated with worse ICH outcomes, including age, sex, Glasgow Coma Scale as continuous variables, and anticoagulant use.

ADDICTION

Drug addiction has been defined as a chronically relapsing disorder that is characterized by the compulsive desire to seek and use drugs with impaired control over substance use despite negative consequences ( Prud'homme et al., 2015). The endocannabinoid system has been found to influence the acquisition and maintenance of drug-seeking behaviors, possibly through its role in reward and brain plasticity ( Gardner, 2005; Heifets and Castillo, 2009). Furthermore, in laboratory settings orally administered dronabinol has been found to reduce cannabis withdrawal symptoms in cannabis users who were not seeking treatment to reduce cannabis use ( Budney et al., 2007; Haney et al., 2004) and therefore may be expected to be useful as a substitute to assist to achieve and maintain abstinence of cannabis.

Are Cannabis or Cannabinoids an Effective Treatment for Achieving Abstinence from Addictive Substances?

Systematic Reviews

We identified two recent published reviews that examined randomized trials evaluating the effects of cannabis or cannabinoids on the use of addictive drugs, including cannabis: one systematic review by Marshall et al. (2014) and one comprehensive review by Prud'homme et al. (2015).

The review by Marshall et al. (2014) is a high-quality systematic review of randomized and quasi-randomized trials assessing the efficacy of drug therapies specifically for cannabis dependence. They identified two trials examining THC: one published by Levin et al. (2011), examining dronabinol, and one published by Allsop et al. (2014), examining nabiximols.

The trial by Levin et al. (2011) was a randomized, placebo-controlled double-blind trial, which assigned cannabis-dependent adults to receive dronabinol (n = 79) or a placebo (n = 77) for 8 weeks, followed by a 2-week taper. Both groups received weekly individual therapy plus motivational enhancement therapy. Retention in the treatment program at the end of the maintenance phase was 77 percent in the dronabinol group and 61 percent in the placebo group (p-value for difference between groups = 0.02). Withdrawal symptoms declined more quickly in the dronabinol group than in the placebo group (p = 0.02). However, the primary outcome, the proportion of participants who achieved 2 consecutive weeks of abstinence at weeks 7 to 8, was 17.7 percent in the dronabinol group and 15.6 percent in the placebo group, which were not statistically significantly different from one another (p = 0.69).

The trial by Allsop et al. (2014) was randomized, placebo-controlled, and double-blind, and it enrolled adults seeking treatment for cannabis dependence. Subjects were patients who were hospitalized for 9 days and who received a 6-day regimen of nabiximols oromucosal spray (n = 27) or a matching placebo (n = 24) together with standardized psychosocial interventions. The primary outcome was a change in the Cannabis Withdrawal Scale, which is a 19-item scale that measures withdrawal symptom severity on an 11-point Likert scale for the previous 24 hours. Over the 6-day treatment period, subjects in the nabiximols group reported a mean 66 percent reduction from baseline in the cannabis withdrawal scale, while patients in the placebo group reported a mean increase in the cannabis withdrawal scale of 52 percent (p-value for between-group difference = 0.01). The median time between hospital discharge and relapse to cannabis use was 15 days (95% CI = 3.55-26.45) in the nabiximols group and 6 days (95% CI = 0-27.12) in the placebo group. The difference between these times was not statistically significant (p-value for between-group difference = 0.81).

Based on the Levin et al. (2011) and Allsop et al. (2014) trials, Marshall et al. (2014) concluded that there was moderate-quality evidence that users of THC preparations were more likely to complete treatment than those given a placebo (RR, 1.29, 95% CI = 1.08-1.55). However, the systematic review further concluded that, based on these two trials, the studied THC preparations were not associated with an increased likelihood of abstinence or a greater reduction in cannabis use than a placebo.

The review by Prud'homme et al. (2015) is a comprehensive review that broadly examined evidence on the effects of cannabidiol on addictive behaviors. The only randomized trial assessing the role of cannabis in reducing the use of an addictive substance was published by Morgan et al. (2013). That study was a pilot placebo-controlled trial that randomized cigarette smokers who wished to quit smoking to receive 400 µg inhaled cannabidiol (n = 12) or inhaled placebo (n = 12) for 1 week. Participants were instructed to use the inhaler when they felt the urge to smoke. The reduction in the number of cigarettes smoked per week was higher in the cannabidiol group than in the placebo group, although the difference was not statistically significant (p = 0.054). Rates of abstinence were not reported.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the reduction in use of addictive substances and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

ANXIETY

Anxiety disorders share features of excessive fear and anxiety which induce psychological and physical symptoms that can cause significant distress or interfere with social, occupational, and other areas of functioning ( APA, 2013). In a given year, an estimated 18 percent of the U.S. adult population will suffer from symptoms associated with an anxiety disorder ( NIMH, n.d.). Given the role of the endocannabinoid system in mood regulation, the committee decided to explore the relationship between anxiety and cannabis.

Are Cannabis or Cannabinoids an Effective Treatment for the Improvement of Anxiety Symptoms?

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the improvement of anxiety symptoms and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

There is limited evidence that cannabidiol improves anxiety symptoms, as assessed by a public speaking test, in patients with social anxiety disorder. These positive findings are limited by weaknesses in the study design (e.g., an inadequate description of randomization and allocation concealment), a single dose of CBD, and uncertain applicability to patients with other anxiety disorders. Limited evidence also suggests short-term benefits in patients with chronic pain and associated anxiety symptoms. In contrast, evidence from observational studies found moderate evidence that daily cannabis use is associated with increased anxiety symptoms and heavy cannabis use is associated with social phobia disorder (see Chapter 12).

CONCLUSION 4-17 There is limited evidence that cannabidiol is an effective treatment for the improvement of anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders.

DEPRESSION

Depression is one of the nation's most common mental health disorders ( ADAA, 2016). Across the many depressive disorders that exist (e.g., persistent depressive disorder, major depressive disorder, premenstrual dysphoric disorder) there are common symptomatic features of feelings of sadness, emptiness, or irritable mood, accompanied by somatic and cognitive changes that affect the individual's capacity to function ( APA, 2013, p. 155). The endocannabinoid system is known to play a role in mood regulation ( NIDA, 2015, p. 9); therefore, the committee decided to explore the association between cannabis use and depressive disorders or symptoms.

Are Cannabis or Cannabinoids an Effective Treatment to Reduce Depressive Symptoms?

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment to reduce depressive symptoms and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Although patients report using cannabinoids for depression, our search for a good-quality systematic review did not identify any RCTs evaluating the effects of medical cannabis in patients with depressive disorders. Trials in patients with chronic pain or multiple sclerosis with uncertain baseline depressive symptoms did not show an effect. There are no trial data addressing the effects of cannabinoids for major depressive disorder.

In Chapter 12 (Mental Health), the committee reviews epidemiological evidence to examine the association between cannabis use and the development of depressive disorders as well as the impact of cannabis use on the disorder's course or symptoms.

CONCLUSION 4-18 There is limited evidence that nabiximols, dronabinol, and nabilone are ineffective treatments for the reduction of depressive symptoms in individuals with chronic pain or multiple sclerosis.

SLEEP DISORDERS

Sleep disorders can be classified into major groups that include insomnia, sleep-related breathing disorders, parasomnias, sleep-related movement disorders, and circadian rhythm sleep-wake disorders ( Sateia, 2014). Fifty million to 70 million adults in the United States report having some type of sleep disorder ( ASA, 2016). In 2010, insomnia generated 5.5 million office visits in the United States ( Ford et al., 2014). There is some evidence to suggest that the endocannabinoid system may have a role in sleep. THC is associated in a dose-dependent manner with changes in slow-wave sleep, which is critical for learning and memory consolidation. Cannabis may also have effects on sleep latency, decreasing time to sleep onset at low doses and increasing time to sleep onset at higher doses ( Garcia and Salloum, 2015). Thus, cannabinoids could have a role in treating sleep disorders.

Are Cannabis or Cannabinoids an Effective Treatment for Improving Sleep Outcomes?

Systematic Reviews

The review by Whiting et al. (2015) was the most recent good-quality review. Two RCTs (54 participants) evaluated cannabinoids (nabilone, dronabinol) for the treatment of sleep problems. A trial deemed to have a high risk of bias conducted in 22 patients with obstructive sleep apnea showed a greater benefit of dronabinol (maximum dose of 10 mg daily) than with a placebo on sleep apnea/hypopnea index (mean difference from baseline −19.64, p = 0.02) at 3 weeks follow-up. A crossover trial deemed to have a low risk of bias in 32 patients with fibromyalgia found improvements for nabilone 0.5 mg daily compared with 10 mg amitriptyline in insomnia (mean difference from baseline, −3.25, 95% CI = −5.26 to −1.24) and greater sleep restfulness (mean difference from baseline, 0.48, 95% CI = 0.01-0.95) at 2 weeks follow-up. Although the antidepressant amitriptyline is an established treatment for fibromyalgia, it is not FDA approved for insomnia, and its use is limited by adverse effects.

Nineteen trials (3,231 participants) enrolled patients with other conditions (chronic pain or multiple sclerosis) and reported on sleep outcomes. Nabiximols (13 studies), THC/CBD capsules (2 studies), smoked THC (2 studies), and dronabinol or nabilone were compared to a placebo. Sleep outcomes were assessed at 2-15 weeks after randomization. Eleven of the 19 trials were judged to have a high risk of bias, 6 had an uncertain risk of bias, and the other 2 were judged to have a low risk of bias. The meta-analysis found greater improvements with cannabinoids in sleep quality among 8 trials (weighted mean difference [WMD], −0.58, 95% CI = −0.87 to −0.29) and sleep disturbance among 3 trials (WMD, −0.26, 95% CI = −0.52 to 0.00). These improvements in sleep quality and sleep disturbance were rated on a 10-point scale and would be considered small improvements. The summary estimate showing benefit was based primarily on studies of nabiximols.

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment to improve sleep outcomes and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

POSTTRAUMATIC STRESS DISORDER

Posttraumatic stress disorder (PTSD) falls within the broader trauma- and stressor-related disorders categorized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). The diagnostic criteria of PTSD include an exposure to a traumatic event (e.g., the threat of death, serious injury, or sexual violence) and exhibiting psychological distress symptoms that occur as a result of that exposure (e.g., intrusion symptoms, such as distressing memories; avoidance of stimuli that are associated with the traumatic event; negative alterations in mood and cognition; alterations in arousal and reactivity associated with the traumatic event; functional impairment) ( APA, 2013, pp. 271-272). Given the known psychoactive effects of cannabis, the committee decided to explore the association between PTSD and cannabis use.

Are Cannabis or Cannabinoids an Effective Treatment for PTSD Symptoms?

Systematic Reviews

The committee did not identify a good- or fair-quality systematic review that reported on medical cannabis as an effective treatment for PTSD symptoms.

Discussion of Findings

A single, small crossover trial suggests potential benefit from the pharmaceutical cannabinoid nabilone. This limited evidence is most applicable to male veterans and contrasts with non-randomized studies showing limited evidence of a statistical association between cannabis use ( plant derived forms) and increased severity of posttraumatic stress disorder symptoms among individuals with posttraumatic stress disorder (see Chapter 12). A search of the grey literature identified several recently initiated randomized controlled trials examining the harms and benefits of marijuana for PTSD. One trial examines the effects of four different types of cannabis with varying THC and CBD content on PTSD symptoms in 76 veterans ( Bonn-Miller, 2016). Another trial is a Canadian study that evaluates different formulations of THC and CBD in 42 adults with PTSD ( Eades, 2016). If these trials are successfully completely, they will add substantially to the knowledge base, expanding the range of cannabinoids evaluated and the opportunity to examine the consistency of effects across studies.

CONCLUSION 4-20 There is limited evidence (a single, small fair-quality trial) that nabilone is effective for improving symptoms of posttraumatic stress disorder.

SCHIZOPHRENIA AND OTHER PSYCHOSES

Schizophrenia spectrum disorders and other psychotic disorders are mental health disorders characterized by three different classes of symptoms: positive symptoms (e.g., delusions, hallucinations, or disorganized or abnormal motor behavior), negative symptoms (e.g., diminished emotional expression, lack of interest or motivation to engage in social settings, speech disturbance, or anhedonia), and impaired cognition (e.g., disorganized thinking) ( APA, 2013, p. 87; NIMH, 2015). Evidence suggests that the prevalence of cannabis use among people with schizophrenia is generally higher than among the general population ( McLoughlin et al., 2014). In most of the studies reviewed below, schizophrenia, schizophreniform disorder, schizoaffective disorder, and psychotic disorders are used as aggregate endpoints.

Are Cannabis or Cannabinoids an Effective Treatment for the Mental Health Outcomes of Patients with Schizophrenia or Other Psychoses?

Systematic Reviews

Two good-quality reviews ( McLoughlin et al., 2014; Whiting et al., 2015) evaluated cannabinoids for the treatment of psychosis. We focus on the good-quality review by Whiting et al. (2015) as it is more current. Two RCTs with high risk of bias (71 total participants with schizophrenia or schizophreniform psychosis) compared cannabidiol to the atypical antipsychotic amisulpride or a placebo. One trial reported no difference on mental health between CBD (maximum dose 800 mg/day) and amisulpride (maximum dose 800 mg/day) at 4 weeks (brief psychiatric rating scale mean difference, −0.10, 95% CI = −9.20-8.90) or on mood (positive and negative syndrome scale mean difference, 1.0; 95% CI = −12.6-14.6). A crossover trial showed no difference in effect on mood between CBD (maximum dose 600 mg/day) and placebo (positive and negative symptom scale mean difference, 1, 95% CI = −12.60-14.60; scale range 30-210).

Primary Literature

The committee did not identify any good-quality primary literature that reported on medical cannabis as an effective treatment for the mental health outcomes of patients with schizophrenia or other psychoses and that were published subsequent to the data collection period of the most recently published good- or fair-quality systematic review addressing the research question.

Discussion of Findings

Good-quality systematic reviews identified only two small, unclear-to high-risk-of-bias trials evaluating cannabinoids for the treatment of schizophrenia. These studies provide only limited evidence due to the risk of bias, the short-term follow-up, and the evaluation of a single cannabinoid. Furthermore, the larger trial was designed to detect a moderate benefit of cannabidiol compared to the antipsychotic amisulpride, but it enrolled only 60 percent of the planned sample. Thus, it did not have the statistical power to detect small or moderate differences between CBD and amisulpride. Overall, the evidence is insufficient to determine if cannabidiol is an effective treatment for individuals with schizophrenia or schiophreniform psychosis.

In Chapter 12, the committee reviews epidemiological evidence to examine the association between cannabis use and the development of schizophrenia and other psychoses, as well as the impact of cannabis use on the disorder's course or symptoms.

CONCLUSION 4-21 There is insufficient evidence to support or refute the conclusion that cannabidiol is an effective treatment for the mental health outcomes in individuals with schizophrenia or schizophreniform psychosis.

RESEARCH GAPS

In reviewing the research evidence described above, the committee has identified that research gaps exist concerning the effectiveness of cannabidiol or cannabidiol-enriched cannabis in treating the following:

treating chemotherapy-induced nausea and vomiting

symptoms of irritable bowel syndrome

spasticity due to paraplegia from spinal cord injury

symptoms associated with amyotrophic lateral sclerosis

motor function and cognitive performance associated with Huntington's Disease

motor system symptoms associated with Parkinson's disease or levodopa-induced dyskinesia

achieving abstinence or reduction in the use of addictive substances, including cannabis itself

sleep outcomes in individuals with primary chronic insomnia

posttraumatic stress disorder symptoms

mental health outcomes in individuals with schizophrenia or schizophreniform psychosis

cannabidiol short-term relief from anxiety symptoms

SUMMARY

This chapter outlines the committee's efforts to review the current evidence base for the potential efficacy of cannabis or cannabinoids on prioritized health conditions. The health conditions reviewed in this chapter include chronic pain, cancer, chemotherapy-induced nausea and vomiting, anorexia and weight loss associated with HIV, irritable bowel syndrome, epilepsy, spasticity, Tourette syndrome, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, dystonia, dementia, glaucoma, traumatic brain injury, addiction, anxiety, depression, sleep disorders, posttraumatic stress disorder, and schizophrenia and other psychoses. The committee has formed a number of research conclusions related to these health endpoints; however, it is important that the chapter conclusions be interpreted within the context of the limitations discussed in the Discussion of Findings sections above. See Box 4-1 for a summary list of the chapter's conclusions.

We found conclusive or substantial evidence (ranging in modest to moderate effect) for benefit from cannabis or cannabinoids for chronic pain, chemotherapy-induced nausea and vomiting, and patient-reported symptoms of spasticity associated with multiple sclerosis. For chemotherapy-induced nausea and vomiting and spasticity associated with multiple sclerosis, the primary route of administration examined was the oral route. For chronic pain, most studies examined oral cannabis extract, although some examined smoked or vaporized cannabis. It is unknown whether and to what degree the results of these studies can be generalized to other products and routes of administration. For many of the other conditions discussed above, there is insufficient or no evidence upon which to base conclusions about therapeutic effects. The potential efficacy of cannabinoids for several of these conditions, such as epilepsy and posttraumatic stress disorder, should be prioritized, given the substantial number of persons using cannabis for those conditions ( Cougle et al., 2011; Massot-Tarrús and McLachlan, 2016). As identified in the chapter's Discussion of Findings sections, there are common themes in the type of study limitations found in this evidence base. The most common are limitations in the study design (e.g., a lack of appropriate control groups, a lack of long-term follow-ups), small sample sizes, and research gaps in examining the potential therapeutic benefits of different forms of cannabis (e.g., cannabis plant). These limitations highlight the need for substantial research to provide comprehensive and conclusive evidence on the therapeutic effects of cannabis and cannabinoids.

REFERENCES

APA (American Psychiatric Association). Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.

Bullock R, Chesnut R, Clifton GL, Ghajar J, Marion DW, Narayan RK, Newell DW, Pitts LH, Rosner MJ, Walters BC, Wilberger JE. Management and prognosis of severe traumatic brain injury. Journal of Neurotrauma. 2000;17:451-627.

Gelinas D, Miller RG, Abood M. A pilot study of safety and tolerability of delta 9-THC (Marinol) treatment for ALS. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders. 2002;3(Suppl 2):23-24.

IOM (Institute of Medicine). Marijuana and medicine: Assessing the science base. Washington, DC: National Academy Press; 1999. [ PubMed: 25101425 ]

Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database of Systematic Reviews. 2013;(4):CD005175. [ PubMed: 23633327 ]

McLoughlin BC, Pushpa-Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, Kyprianou K. Cannabis and schizophrenia. Cochrane Database of Systematic Reviews. 2014;(10) CD004837. [ PubMed: 25314586 ]

Mechoulam R, Spatz M, Shohami E. Endocannabinoids and neuroprotection. Science's STKE. 2002;(129):re5. [ PubMed: 11972360 ]

Müller-Vahl KR, Koblenz A, Jöbges M, Kolbe H, Emrich HM, Schneider U. Influence of treatment of Tourette syndrome with Δ ⁹-tetrahydrocannabinol (Δ ⁹-THC) on neuropsychological performance. Pharmacopsychiatry. 2001;34(1):19-24. [ PubMed: 11229617 ]

Müller-Vahl KR, Schneider U, Koblenz A, Jöbges M, Kolbe H, Daldrup T, Emrich HM. Treatment of Tourette's syndrome with Δ ⁹-tetrahydrocannabinol (THC): A randomized crossover trial. Pharmacopsychiatry. 2002;35(2):57-61. [ PubMed: 11951146 ]

Müller-Vahl KR, Prevedel H, Theloe K, Kolbe H, Emrich HM, Schneider U. Treatment of Tourette syndrome with delta-9-tetrahydrocannabinol (Δ ⁹-THC): No influence on neuropsychological performance. Neuropsychopharmacology. 2003a;28(2):384-388. [ PubMed: 12589392 ]

Phillips RS, Friend AJ, Gibson F, Houghton E, Gopaul S, Craig JV, Pizer B. Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database of Systematic Reviews. 2016;(2) CD007786. [ PMC free article: PMC7073407 ] [ PubMed: 26836199 ]

Redler RL, Dokholyan NV. Progress in Molecular Biology and Translational Science. David BT, editor. Vol. 107. Cambridge, MA: Academic Press; 2012. pp. 215-262. (Chapter 7-The Complex Molecular Biology of Amyotrophic Lateral Sclerosis (ALS)). [ PMC free article: PMC3605887 ] [ PubMed: 22482452 ]

Smith LA, Azariah F, Lavender TCV, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database of Systematic Reviews. 2015;(11) CD009464. [ PMC free article: PMC6931414 ] [ PubMed: 26561338 ]

Zadikoff C, Wadia P, Miyasaki J, Char R, Lang A, So J, Fox S. Cannabinoid, CB1 agonists in cervical dystonia: Failure in a phase IIa randomized controlled trial. Basal Ganglia. 2011;1(2):91-95.

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Therapeutic Effects of Cannabis and Cannabinoids

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Cannabis sativa has a long history as a medicinal plant, likely dating back more than two millennia (Russo et al., 2007). It was available as a licensed medicine in the United States for about a century before the American Medical Association removed it from the 12th edition of the U.S.

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Marijuana is very popular and is known as the most commonly used drug in the United States. Young people today dont believe that Marijuana use is a risky behavior. This means they continue to use it and get addicted

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Marijuana is the most commonly used illegal substance in the U.S. and its use is growing. Marijuana use among all adult age groups, both sexes, and pregnant women is going up. At the same time, the perception of how harmful marijuana use can be is declining. Increasingly, young people today do not consider marijuana use a risky behavior.

But there are real risks for people who use marijuana, especially youth and young adults, and women who are pregnant or nursing. Today's marijuana is stronger than ever before. People can and do become addicted to marijuana.
Approximately 1 in 10 people who use marijuana will become addicted. When they start before age 18, the rate of addiction rises to 1 in 6.
Marijuana Risks

Marijuana use can have negative and long-term effects:

Brain health: Marijuana can cause permanent IQ loss of as much as 8 points when people start using it at a young age. These IQ points do not come back, even after quitting marijuana.

Mental health: Studies link marijuana use to depression, anxiety, suicide planning, and psychotic episodes. It is not known, however, if marijuana use is the cause of these conditions.

Athletic Performance: Research shows that marijuana affects timing, movement, and coordination, which can harm athletic performance.

Driving: People who drive under the influence of marijuana can experience dangerous effects: slower reactions, lane weaving, decreased coordination, and difficulty reacting to signals and sounds on the road.

Baby's health and development: Marijuana use during pregnancy may cause fetal growth restriction, premature birth, stillbirth, and problems with brain development, resulting in hyperactivity and poor cognitive function. Tetrahydrocannabinol (THC) and other chemicals from marijuana can also be passed from a mother to her baby through breast milk, further impacting a child's healthy development.

Daily life: Using marijuana can affect performance and how well people do in life. Research shows that people who use marijuana are more likely to have relationship problems, worse educational outcomes, lower career achievement, and reduced life satisfaction.

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Marijuana use comes with real risks that can impact a person's health and life.

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Some people that use Marijuana develop a Marijuana use disorder. This means they have a hard time not using Marijuana. Some signs of Addiction are trying to quit but failing, craving Marijuana, using Marijuana while driving or doing other tasks that would make it a high-risk situation. Other signs are experiencing withdrawl symptoms when stopping Marijuana use

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Some people who use marijuana will develop marijuana use disorder, meaning that they are unable to stop using marijuana even though it's causing health and social problems in their lives.

One study estimated that approximately 3 in 10 people who use marijuana have marijuana use disorder.¹

Another study estimated that people who use cannabis have about a 10% likelihood of becoming addicted.²

The risk of developing marijuana use disorder is greater in people who start using marijuana during youth or adolescence and who use marijuana more frequently.³

The following are signs of marijuana use disorder ⁴:

Using more marijuana than intended

Trying but failing to quit using marijuana

Spending a lot of time using marijuana

Craving marijuana

Using marijuana even though it causes problems at home, school, or work

Continuing to use marijuana despite social or relationship problems.

Giving up important activities with friends and family in favor of using marijuana.

Using marijuana in high-risk situations, such as while driving a car.

Continuing to use marijuana despite physical or psychological problems.

Needing to use more marijuana to get the same high.

Experiencing withdrawal symptoms when stopping marijuana use.

People who have marijuana use disorder may also be at a higher risk of other negative consequences, such as problems with attention, memory, and learning.

Some people who have marijuana use disorder may need to use more and more marijuana or greater concentrations of marijuana over time to experience a "high." The greater the amount of tetrahydrocannabinol (THC) in marijuana (in other words, the concentration or strength), the stronger the effects the marijuana may have on the brain. 5,6 The amount of THC in marijuana has increased over the past few decades. ⁶

In a study of cannabis research samples over time, the average delta-9 THC (the main form of THC in the cannabis plant) concentration almost doubled, from 9% in 2008 to 17% in 2017. ⁷ Products from dispensaries often offer much higher concentrations than seen in this study. In a study of products available in online dispensaries in 3 states with legal non-medical adult marijuana use, the average THC concentration was 22%, with a range of 0% to 45%. ⁸ In addition, some methods of using marijuana (for example, dabbing and vaping concentrates) may deliver very high levels of THC to the user. 6,9

Researchers do not yet know the full extent of the consequences when the body and brain are exposed to high concentrations of THC or how recent increases in concentrations affect the risk of someone developing marijuana use disorder. ⁶

1. Hasin DS, Saha TD, Kerridge BT, et al. Prevalence of marijuana use disorders in the United States between 2001-2002 and 2012-2013. JAMA Psychiatry. 2015;72(12):1235-1242.

2. Lopez-Quintero C, de los Cobos JP, Hasin DS, et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: Results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug and Alcohol Dependence. 2011;115(1-2):120-130.

3. Winters KC, Lee C-YS. Likelihood of developing an alcohol and cannabis use disorder during youth: association with recent use and age. Drug and Alcohol Dependence. 2008;92(1-3):239-247.

4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (5th ed). Washington, DC; 2013.

5. Freeman, T, Winstock, A (2015). Examining the profile of high-potency cannabis and its association with severity of cannabis dependenceexternal icon . Psychological medicine. 45(15), 3181-3189.

6. Bidwell LC, York Williams SL, Mueller RL, Bryan AD, Hutchison KE. (2018). Exploring cannabis concentrates on the legal market: User profiles, product strength, and health-related outcomesexternal icon . Addictive Behaviors Reports. 2018;8:102-106.

7. Chandra S, Radwan MM, Majumdar CG, Church JC, Freeman TP, ElSohly MA. New trends in cannabis potency in USA and Europe during the last decade (2008-2017). European Archives of Psychiatry and Clinical Neuroscience. 2019;269(1):5-15.

8. Cash MC, Cunnane K, Fan C, Romero-Sandoval EA. Mapping cannabis potency in medical and recreational programs in the United States. PloS One. 2020;15(3):e0230167.

9. Raber JC, Elzinga S, Kaplan C. Understanding dabs: contamination concerns of cannabis concentrates and cannabinoid transfer during the act of dabbingexternal icon . The Journal of Toxicological Sciences. 2015;40(6):797-803.

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Addiction | Health Effects | Marijuana | CDC

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CDC works 24/7 to protect America from health, safety and security threats, both foreign and in the U.S.

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When most people seek treatment for the use of Marijuana its because they have been using it daily for 10 years or more. They also could have tried to quit six times or more and couldnt. Currently the FDA hasnt approved any treatments for Marijuana use disorder.

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Marijuana use disorders appear to be very similar to other substance use disorders, although the long-term clinical outcomes may be less severe. On average, adults seeking treatment for marijuana use disorders have used marijuana nearly every day for more than 10 years and have attempted to quit more than six times. People with marijuana use disorders, especially adolescents, often also suffer from other psychiatric disorders ( comorbidity). They may also use or be addicted to other substances, such as cocaine or alcohol. Available studies indicate that effectively treating the mental health disorder with standard treatments involving medications and behavioral therapies may help reduce marijuana use, particularly among those involved with heavy use and those with more chronic mental disorders. The following behavioral treatments have shown promise:

Cognitive-behavioral therapy: A form of psychotherapy that teaches people strategies to identify and correct problematic behaviors in order to enhance self-control, stop drug use, and address a range of other problems that often co-occur with them.

Contingency management: A therapeutic management approach based on frequent monitoring of the target behavior and the provision (or removal) of tangible, positive rewards when the target behavior occurs (or does not).

Motivational enhancement therapy: A systematic form of intervention designed to produce rapid, internally motivated change; the therapy does not attempt to treat the person, but rather mobilize his or her own internal resources for change and engagement in treatment.

Currently, the FDA has not approved any medications for the treatment of marijuana use disorder, but research is active in this area. Because sleep problems feature prominently in marijuana withdrawal, some studies are examining the effectiveness of medications that aid in sleep. Medications that have shown promise in early studies or small clinical trials include the sleep aid zolpidem (Ambien ®), an anti-anxiety/anti-stress medication called buspirone (BuSpar ®), and an anti-epileptic drug called gabapentin (Horizant ®, Neurontin ®) that may improve sleep and, possibly, executive function. Other agents being studied include the nutritional supplement N-acetylcysteine and chemicals called FAAH inhibitors, which may reduce withdrawal by inhibiting the breakdown of the body's own cannabinoids. Future directions include the study of substances called allosteric modulators that interact with cannabinoid receptors to inhibit THC's rewarding effects.

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Available Treatments for Marijuana Use Disorders | National Institute on Drug Abuse

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Cognitive-behavioral therapy, Contingency management, and Motivational enhancement therapy are available treatments for Marijuana Use Disorder.

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Marijuana has become legalized and it makes it easier for people in Michigan to have access to it. Michigan has used medical Marijuana for years and some of the conditions you could have to use it were if you had Cancer, Glaucoma, HIV Positive, AIDS , etc.

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People all around the world have been using Marijuana for years legally or illegally. Marijuana is the most commonly used illict substance in the world and the prevalence rate have been increasing over the last decade.

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Abstract

Marijuana, behind only tobacco and alcohol, is the most popular recreational drug in America with prevalence rates of use rising over the past decade. A wide range of research has highlighted neurocognitive deficits associated with marijuana use, particularly when initiated during childhood or adolescence. Neuroimaging, describing alterations to brain structure and function, has begun to provide a picture of possible mechanisms associated with the deleterious effects of marijuana use. This chapter provides a neurodevelopmental framework from which recent data on brain structural and functional abnormalities associated with marijuana use is reviewed. Based on the current data, we provide aims for future studies to more clearly delineate the effects of marijuana on the developing brain and to define underlying mechanisms of the potential long-term negative consequences of marijuana use.

1. INTRODUCTION

Marijuana is the most commonly used illicit substance in the world and prevalence rates have been increasing over the past decade. Globally, 3-5% of the population above age 15 report current marijuana use, and in the United States 8.4% of the population above age 12 report past month use, with a peak in the 18-25-year age range in which nearly 20% of the population endorse current marijuana use ( SAMHSA, 2014; UNODC, 2014). Socially and culturally, use of marijuana has become more widely accepted and viewed as less harmful over the past decade. For example, fewer than 40% of American high school seniors (17-18 years old) reported that they believe it is risky to use marijuana regularly ( Johnston, O'Malley, Miech, Bachman, & Schulenberg, 2015), despite the fact that over 4 million Americans experience a marijuana use disorder each year ( Center for Behavioral Health Statistics & Quality, 2015). With increased use, changing perceptions of the harmfulness of use, and the movement to decriminalize and even legalize use in numerous locales, it has become crucial to characterize the effects of marijuana on human brain development and function.

Varieties of marijuana ( Cannabis sativa) contain over 70 identified cannabinoids, of which the primary psychoactive component is Δ ⁹-tetrahydrocannabinol (THC; ElSohly & Slade, 2005). THC exerts its effects on the endogenous cannabinoid system primarily via cannabinoid-1 (CB1) receptors. CB1 receptors are distributed broadly throughout the brain with particular areas of concentration in prefrontal, cerebellar, temporal, and hippocampal regions ( Burns et al., 2007; Glass, Faull, & Dragunow, 1997; cf. Fig. 1B ). These brain regions rich in CB1 receptors are instrumental for a wide range of cognitive abilities including executive functioning, reward processing, and memory; thus, the potential effects of THC on brain functioning are equally broad. During acute administration, THC decreases learning and memory ( Ranganathan & D'Souza, 2006), psychomotor performance and attention ( Ramaekers, Kauert, Theunissen, Toennes, & Moeller, 2009), and reward responsiveness ( van Hell et al., 2012), presumably through the alterations of the endocannabinoid system ( Rubino et al., 2009). Recent evidence implicates a more complex interaction of THC with both glutamate and γ-aminobutyric acid (GABA) receptors, which may alter more fundamental functions, such as neural oscillatory activity ( Raver & Keller, 2014; Rubino & Parolaro, 2016).

Animal models have demonstrated neurotoxic effects of THC (eg, cell shrinkage and damage to DNA structure) particularly in cortical areas with a high density of CB1 receptors ( Chan, Hinds, Impey, & Storm, 1998). THC appears to block synaptic plasticity and neurogenesis, particularly in hippocampal regions, which can have an effect on brain volume ( Mato et al., 2004). THC has also been shown to interfere with mesolimbic dopamine pathway functioning ( Bossong et al., 2008; Kolb, Gorny, Limebeer, & Parker, 2006). THC activation of CB1 receptors located on GABAergic interneurons in the ventral tegmental area results in increased dopamine release in the nucleus accumbens. This dopamine activity is a common mechanism among drugs of abuse ( Cass et al., 2014; Cheer, Wassum, Heien, Phillips, & Wightman, 2004; Gessa, Melis, Muntoni, & Diana, 1998) associated with feelings of reward, reinforcing effects ( Kook & Weiss, 1992; Robbin & Everitt, 2002), and drug seeking behaviors ( Aarts et al., 2010; Koepp et al., 1998; Urban et al., 2012). By contrast, continued exposure to drugs of abuse is associated with downregulation of dopamine receptors in brain reward systems ( Koob & Le Moal, 2001; Koob & Volkow, 2010).

In addition, animal models have demonstrated that exposure to THC during adolescence compared to exposure during adulthood alters maturation of neural networks, particularly in the prefrontal cortex (PFC) and hippocampus ( Renard et al., 2016; Rubino & Parolaro, 2016), and results in enduring cognitive deficits ( DiNieri & Hurd, 2012; Quinn et al., 2007). For example, exposing rats to THC repeatedly during adolescence resulted in decreased spatial memory performance in adulthood, and this effect seems to be driven by changes in the hippocampus ( Rubino et al., 2009). Specifically, rats exposed to THC during adolescence exhibited hippocampal deficits including fewer synaptic connections, less efficient connectivity, and reduced capacity for neuroplasticity ( Rubino et al., 2009). In the PFC, Cass et al. (2014) reported that exposure to cannabinoid agonists during early and middle adolescence led to frequency-dependent disinhibition (ie, repeated CB1 receptor stimulation elicits PFC network disinhibition) in adulthood, which was apparently a result of downregulation of GABA transmission. Such modulation of the functioning of the PFC could decrease synaptic plasticity that is essential for the maturation of circuits underlying a broad range of functional domains from decision making to executive functioning ( Selemon, 2013). Adolescent exposure to cannabinoid agonists, therefore, can have long lasting effects on the inhibitory and excitatory regulation of the PFC.

Direct downregulation of CB1 receptors may be a key mechanism of marijuana's effects on brain function. Relatively large magnitude adaptations in CB1 receptor functioning are central to the development of tolerance to the behavioral effects of marijuana, but the rate of downregulation and desensitization varies widely by brain region, with PFC exhibiting faster downregulation and basal ganglia exhibiting slower downregulation ( Sim-Selley, 2003). Interestingly, in studies utilizing positron emission tomography and FMPEP- d ₂, a radioligand for CB1 receptors, the adaptations in CB1 receptors in humans appear largely reversible. Chronic marijuana users exhibited a 20% decrease in cortical CB1 receptors compared to controls at baseline, but after a month of abstinence from marijuana, differences were no longer detectable between users and controls ( Hirvonen et al., 2012). In animal models, there is an inverse relationship between CB1 receptor expression in cortical and striatal regions, such that striatal regions with more CB1 receptor expression receive input from cortical regions with less expression, and critically, the expression levels of CB1 receptors in these circuits decrease from adolescence to adulthood ( Van Waes, Beverley, Siman, Tseng, & Steiner, 2012; Verdurand et al., 2011). Thus, exogenous influences of THC on these circuits could counteract typical maturational trajectories and yield changes in regions critical for decision making and addiction processes ( Volkow & Baler, 2014; Volkow, Koob, & McLellan, 2016).

Studies in humans have demonstrated a number of neurocognitive differences between marijuana users and nonusing controls including impaired verbal learning and memory, attention, psychomotor function, and decision making ( Broyd, van Hell, Beale, Yücel, & Solowij, 2016; Volkow, Swanson, et al., 2016). Evidence seems to suggest that some deficits in verbal learning and memory function may recover over time with abstinence ( Schreiner & Dunn, 2012); persistent use, however, has been associated with poor long-term neurocognitive performance ( Meier et al., 2012) and poorer health outcomes (ie, chronic bronchitis, increased risk of respiratory infections, and vascular conditions such as stroke or infarctions; Volkow, Baler, Compton, & Weiss, 2014). Taken together with animal models showing deficits in brain development when THC is administered during adolescence, it would seem that marijuana use, particularly during this critical developmental period, could negatively affect neurocognitive development. Indeed, individuals who begin using marijuana during adolescence exhibit lower IQs and seem to have less crystallized intelligence (ie, acquired knowledge through skills and experience; Jackson et al., 2016). At the same time, the direct effect of marijuana use on neurocognitive deteriorations during adolescence has not been shown to be significantly related to frequency of use, and may be attributable to genetic or familial factors that contribute to risk for both marijuana use initiation and low intellectual achievement ( Jackson et al., 2016). Therefore, characterizing changes in brain structure and function related to marijuana use may help differentiate risk factors from consequences of marijuana use. Careful study design is necessary to overcome some of the inherent challenges in illustrating specific effects of marijuana, as marijuana use often cooccurs with alcohol and nicotine consumption, and heritable factors (eg, genetics and personality traits) likely contribute to brain differences independent of marijuana use ( Hurd, Michaelides, Miller, & Jutras-Aswad, 2014).

In the current chapter, we will (1) describe a neurodevelopmental framework for understanding the effects of marijuana use on brain structure and function, (2) summarize the robust results and discuss recent findings from neuroimaging studies of the effects of marijuana use on brain structure and function, and (3) highlight remaining questions and areas of ongoing evaluation in understanding the effects of marijuana use on the human brain.

2. NEURODEVELOPMENTAL FRAMEWORK FOR UNDERSTANDING THE EFFECTS OF MARIJUANA ON BRAIN STRUCTURE AND FUNCTION

The human brain continues to mature throughout adolescence, a time during which dramatic changes occur in neurochemistry and anatomy including both cortical and hormonal alterations ( Giedd et al., 1999; Gogtay et al., 2004; Luciana, 2013; Raznahan et al., 2011). Gray matter (GM) decreases following an inverted U-shaped developmental progression-peaking in childhood and decreasing through the early 20s ( Giedd et al., 1999, 2009). The measures of GM (cortical thickness (CT), surface area (SA), and their product, cortical volume) follow different developmental trajectories with CT peaking between 2 and 4 years of age and then steadily declining through adulthood, while SA increases up to roughly age 12 before leveling off through age 30 ( Amlien et al., 2014; Walhovd, Fjell, Giedd, Dale, & Brown, 2016). The trajectories of CT and SA yield the cortical GM volumes that decrease from around ages 10-12 through adulthood. Normally, age-related decreases in GM localized to the prefrontal and temporal cortices ( Giedd et al., 1999; Gogtay et al., 2004) and in subcortical structures, including the striatum and thalamus ( Sowell, Thompson, Holmes, Jernigan, & Toga, 1999; Toga, Thompson, & Sowell, 2006), are attributed to pruning of excessive neurons and to cortical myelination ( Huttenlocher & Dabholkar, 1997; Shaw et al., 2008).

White matter (WM) volume increases linearly during adolescence through young adulthood ( Giedd et al., 1999, 2009), yielding relatively stable total brain volumes after puberty. WM maturation is associated with greater structural connectivity between brain regions and, consequently, more efficient communication between frontal and subcortical regions ( Sowell et al., 1999; Toga et al., 2006). In addition to increasing volume of WM, the quality of the microstructure continues to mature to more efficient and well-connected networks. Common measures from diffusion tensor imaging (DTI) used to infer WM microstructure include fractional anisotropy (FA), or directionally restricted diffusion of water, radial diffusivity (RD), or the perpendicular diffusion of water, and mean diffusivity (MD), or the overall magnitude of diffusion. Increasing FA is associated with more efficient and mature WM, while higher RD and MD are associated with less efficient WM. FA increases throughout adolescence and young adulthood with a relatively stable peak between 20 and 40 years, while RD and MD tend to reflect the opposite trends with decreases through adolescence and young adulthood with a relatively stable minimum between 18 and 40 years of age ( Bava et al., 2010; Lebel et al., 2012). These general developmental trajectories form the basis for understanding and interpreting potential changes associated with marijuana use.

The peak incidence of marijuana use occurs in later adolescence and early adulthood, so, it is critical to approach questions of marijuana effects on brain structure and function from a developmental perspective. Casey, Oliveri, and Insel (2014) presented a neurodevelopmental framework that is useful for conceptualizing critical questions of potential alterations to development by outside factors, such as drugs of abuse. The first concept is developmental trajectories, which is largely described by the extant literature on adolescent brain development. Starting from these well-established developmental trajectories, summarized earlier, allows us to describe alterations in terms of delays, deviations, or regressions from normal trajectories.

The second concept is sensitive periods, or windows of development in which the brain may be uniquely malleable and perhaps susceptible to influences that could alter its trajectory ( Casey et al., 2014). The changes occurring in the adolescent brain, characterized by plasticity and maturational changes, represent both opportunities and vulnerabilities that make this developmental period critical ( Dahl, 2004; Fuhrmann, Knoll, & Blakemore, 2015; Luciana, 2013). This concept is relevant to the goal of identifying developmentally defined epochs of exposure to marijuana that yield stronger and perhaps more deleterious effects on developmental trajectories.

The third concept is dynamic interaction of systems ( Casey et al., 2014). Comprehending the developmental cascades at play in determining the effects of marijuana use on brain structure and function requires sophisticated models of complex interactions. Making attempts to characterize the interaction of multiple brain systems maturing at different rates over adolescence and early adulthood will be critical for understanding how environmental events (eg, onset of marijuana use) may modulate the function or development of these systems. Furthermore, capturing synergism between genetics, behavioral traits, and experience is a vital and complex process. As we summarize results from imaging studies of the effects of marijuana use on the brain in humans, we will frequently refer to these concepts to help guide interpretations and to delineate questions and areas for future investigations.

3. STRUCTURAL CHANGES ASSOCIATED WITH MARIJUANA USE

3.1 Gray Matter

Neuroanatomic differences in GM between marijuana users and healthy controls have been reported in several specific regions, but there is very little evidence of global differences in intracranial volume or total GM volume ( Lorenzetti, Solowij, Fornito, Ian Lubman, & Yucel, 2014). Many studies have reported smaller volumes in regions rich in CB1 receptors in marijuana users, and while several studies have summarized large portions of this literature ( Batalla et al., 2013; Bhattacharyya, Atakan, Martin-Santos, Crippa, & McGuire, 2012; Lorenzetti et al., 2014; Lorenzetti, Solowij, & Yücel, 2016; Martín-Santos et al., 2010), we will summarize the most robust findings here while also highlighting recent reports (ie, since 2010; Table 1 and Fig. 1 ).

Table 1

Authors

Key Findings

Groups

n

Age Range
Mean (SD) [Range]

Sex % Male

Ashtari et al. (2011)
MJ <CON volume in right and left hippocampus;
In MJ smaller hippocampus volume =more use

MJ
abstinent 30+ days-mean 6 months

14

19.3 (0.8) [18-20]

100%

Battistella et al. (2014)
RMJ <OMJ volume in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula, and orbitofrontal cortex;
Lower age of onset =smaller volumes
RMJ >OMJ volume in cerebellum

OMJ

22

25 (2.8) a [19-29]

100%

Demirakca et al. (2011)
MJ <CON volume in right hippocampus;
Within MJ higher THC in THC/CBD ratio =smaller volume

MJ

11

NR [19-25] b

100%

CON

13

NR [19-25] b

100%

Filbey et al. (2014)
MJ =MJ only <CON volume in right middle OFC, and left superior OFC

MJ

48

28.3 (8.3) [ NR]

69%

MJ only
No alcohol use

27

28.1 (8.9) [ NR]

63%

Filbey et al. (2015)
MJ early with more use>MJ late with more use thickness in anterior dorsolateral frontal cortex (moderator effect)

MJ early onset< age 16

20

32.5 (8.01) [21-50]

55%

MJ late onset> age 16

22

30.3 (7.19) [21-47]

73%

Jacobus et al. (2015)
MJ + ALC >CON thickness across frontal and parietal regions;
MJ >CON ( controlling for alcohol) thickness in left temporal and right entorhinal cortices

MJ + ALC

30

Baseline: 18.2 (0.8) [16-19]
Year 1.5: 19.6 (0.8)
Year 3: 21.2 (0.7)

63%

CON

38

Baseline: 17.7 (0.9) [16-19]
Year 1.5: 19.1 (0.9)
Year 3: 20.8 (1.0)

76%

Lopez-Larson et al. (2011)
MJ <CON thickness in right caudal middle frontal, bilateral insula, and bilateral superior frontal regions
MJ >CON thickness in the bilateral lingual, right superior temporal, right inferior parietal and left paracentral regions
Within MJ lower age of onset =thicker right superior frontal gyrus

MJ

18

17.8 (1.0) [16-19]

94.4%

Lorenzetti et al. (2015)
MJ <CON volume in hippocampus and amygdala

MJ

15

40 (9) [ NR]

100%

Medina et al. (2010)
MJ >CON volume in inferior posterior vermis (cerebellum)

MJ

16

18.11 (0.74) [16-18]

75%

Schacht et al. (2012)
MJ <CON volume in hippocampus and left amygdala
MJ <CON CB1 receptor genetic variation (rs2023239 G allele) =lower volume hippocampus (group × time interaction)

MJ full

94

24.2 (7.4) [ NR]

34%

Weiland et al. (2015)
No volume or shape differences in subcortical structures examined (nucleus accumbens, amygdala, hippocampus, and cerebellum)

Adult MJ

29

27.4 (7.1) [19-53]

55%

Yip et al. (2014)
MJ <CON volume in putamen
Within MJ smaller putamen volume =higher probability of relapse

MJ dependent

20

26.7 (2.2) [ NR]

100%

Smaller hippocampal volumes in marijuana users relative to healthy controls have been one of the most consistently reported findings ( Ashtari et al., 2011; Demirakca et al., 2011; Lorenzetti et al., 2015; Matochik, Eldreth, Cadet, & Bolla, 2005; Schacht, Hutchison, & Filbey, 2012; Yucel et al., 2008). These studies reported cross-sectional comparisons of marijuana users and nonusing controls with varying levels of marijuana use history, and many studies examining the effect of dosage or lifetime exposure show an inverse relationship between use and hippocampal volume, with more use resulting in smaller volumes ( Ashtari et al., 2011; Matochik et al., 2005; Yucel et al., 2008). In a sample that did not exhibit group differences between marijuana users and controls, higher lifetime marijuana use within the marijuana-using group was associated with smaller hippocampal volumes ( Cousijn et al., 2012). Thus, dose and duration appear critical for effects of marijuana on hippocampal volume.

Other factors may also contribute to smaller hippocampal volumes in marijuana users. For example, in a small sample of young adults, higher levels of THC relative to cannabidiol (CBD) in a hair sample, reflecting use over the past 4-5 months, was associated with smaller hippocampal volumes ( Demirakca et al., 2011). Furthermore, an examination of genetic variants of a CB1 receptor gene (ie, rs2023239) provided evidence that genes may interact with marijuana use, as carriers of the G allele who used marijuana exhibited smaller hippocampal volumes compared with healthy controls carrying the G allele, as well as compared with marijuana-using carriers of the A allele ( Schacht et al., 2012). Identifying a genetic component that may interact with marijuana use is an important step in differentiating risk factors for marijuana use from outcomes of THC toxicity following marijuana use.

In addition to effects on hippocampal volume, several studies have reported consequences of marijuana use on the amygdala and striatum, including increased GM density (likely reflecting denser dendritic branching; Gilman et al., 2014; Matochik et al., 2005), and decreased volumes ( Lorenzetti et al., 2015; Schacht et al., 2012; Yip et al., 2014). In other structures, associations between marijuana use and brain volumes are less well delineated. For example, in marijuana users compared to controls, one study reported a slight increase in accumbens volume ( Gilman et al., 2014), another reported greater GM density in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, and amygdala ( Gilman et al., 2014), and marijuana use has also been associated with smaller and thinner insular cortex ( Battistella et al., 2014; Lopez-Larson et al., 2011).

The cerebellum, noted as a key target of marijuana exposure in imaging studies, is a region rich in CB1 receptors. Two studies that included adolescents and young adults reported larger cerebellar volumes among marijuana users compared to controls ( Cousijn et al., 2012; Medina, Nagel, & Tapert, 2010), while a study in a much older sample with a longer history of marijuana use reported smaller cerebellar volumes compared to controls ( Solowij et al., 2011). Additionally, in a large study that recruited a sample of adult marijuana users and controls and a sample of adolescent marijuana users and controls, no significant differences in volume were found in subcortical structures (eg, amygdala, hippocampus, and cerebellum) in either sample ( Weiland et al., 2015). Weiland et al. (2015) highlight that their marijuana users and controls were matched on alcohol use severity using the Alcohol Use Disorders Identification Test (AUDIT); however, characterizing marijuana use groups based on the past 2 months (for adults) and past 3 months (for adolescents) of use limited their ability to examine effects of cumulative lifetime use or age of onset.

The morphometry of PFC is also affected by marijuana use ( Fig. 1 ). Specifically, marijuana use has been associated with smaller volumes in the orbitofrontal cortex (OFC; Battistella et al., 2014; Churchwell, Lopez-Larson, & Yurgelun-Todd, 2010; Filbey et al., 2014) and with thinner cortices in caudal middle frontal regions ( Lopez-Larson et al., 2011). Interestingly, age of onset was negatively correlated with thickness in two studies ( Filbey, McQueeny, DeWitt, & Mishra, 2015; Lopez-Larson et al., 2011). In both, earlier onset of marijuana use (ie, before age 16) was associated with thicker PFC. Lopez-Larson et al. (2011) examined participants while they were still adolescents (ie, 16-19 years old) and reported a negative correlation between age of onset of regular marijuana use and the superior frontal gyrus, whereas Filbey et al. (2015) collected data on older participants (ie, 21-50 years old) and reported that those who initiated marijuana use before age 16 exhibited thicker anterior dorsolateral PFC. Taken together, these findings demonstrate that early marijuana use onset interacts with cortical development during adolescence, likely leading to the disruption of typical development (eg, pruning and plasticity).

As mentioned, the majority of currently published data on the effects of marijuana use on GM is cross-sectional; very few studies have examined changes over time using longitudinal methods. One study utilizing a single MRI acquisition at age 12 to predict substance use outcomes, at age 16 reported that smaller OFC (but not amygdala, hippocampus, or anterior cingulate cortex) volumes were associated with a greater probability of initiation of marijuana use by age 16 ( Cheetham et al., 2012). The authors controlled for other substance use and also examined whether smaller OFC volumes predicted the onset of other substance use, and reported that OFC volumes were uniquely associated with the onset of marijuana use. Thus, regional volume in the OFC appears to be specifically related to THC use, and could be a potential risk marker for initiating and maintaining marijuana use.

Some of the only studies to date that have utilized longitudinal MRI data to examine the effects of marijuana use have come out of our group (Tapert and colleagues). For example, we recently examined CT over 3 years of late adolescence (18-21 years old) in a sample of heavy marijuana and alcohol users compared to controls ( Jacobus et al., 2015). Substance users exhibited thicker cortices in all four lobes of the brain that persisted over the 3-year period, which might reflect a reduction in expected developmental pruning. Thickness measures trended downward in both groups, as expected, but the substance-using sample exhibited a shallower decline compared to controls (eg, in the paracentral lobule). Furthermore, when controlling for alcohol use, lifetime marijuana use was positively associated with CT while age of onset of marijuana use was negatively associated with CT in the temporal lobe, indicating that some of the observed differences were likely specific to marijuana use. Another recent study, examining 16-18-year-old participants over 18 months described similar attenuation of CT declines (ie, shallower slope of change) in marijuana users compared to controls ( Epstein & Kumra, 2015a). These longitudinal data largely support reports from cross-sectional studies, and underscore the concept that changes in cortical morphometry are dynamic and influenced by preexisting vulnerabilities as well as by different levels of neurotoxicity or attenuated neuroplasticity related to dose, duration, and age of onset of marijuana use.

3.2 White Matter

A majority of studies examining WM integrity in cross-sectional samples of adolescent and adult marijuana users have reported decreased FA and increased MD and RD indicating less efficient or less mature WM microstructure in users compared to controls in widely dispersed brain regions ( Table 2 ). For example, central WM regions such as the genu, rostrum, and splenium of the corpus callosum ( Arnone et al., 2008; Gruber, Dahlgren, Sagar, Gönenç, & Lukas, 2014; Gruber, Silveri, Dahlgren, & Yurgelun-Todd, 2011), as well as the superior longitudinal fasciculus and arcuate fasciculus ( Ashtari, Cervellione, Cottone, Ardekani, & Kumra, 2009; Bava et al., 2009; Thatcher, Pajtek, Chung, Terwilliger, & Clark, 2010) show higher FA in controls compared to marijuana users. Some studies report increased FA (ie, purportedly more efficient or mature WM) among users in regions such as the forceps minor ( Filbey et al., 2014) and the internal capsule and superior longitudinal fasciculus ( Bava et al., 2009), though such results are tentative since DTI findings can be affected by important covariates such as age of onset of marijuana use ( Gruber et al., 2014, 2011) and sex ( Thatcher et al., 2010).

Table 2

Authors

Key Findings

Groups

n

Age Range
Mean (SD) [Range]

Sex % Male

Ashtari et al. (2009)
MJ <CON FA in arcuate fasciculus
MJ <CON RD in arcuate fasciculus

MJ
abstinent 30+ days

14

19.3 (0.8) [18-21]

100%

Bava et al. (2013)
MJ + ALC <CON FA in right splenium, right prefrontal thalamic fibers, and right corona radiate at baseline and 18 months
MJ + ALC >CON MD & RD in superior longitudinal fasciculus, right posterior thalamic radiations, right prefrontal thalamic fibers, right superior temporal gyrus, right inferior longitudinal fasciculus, and left posterior corona radiate at baseline and 18 months

MJ + ALC

41

Time 1: 18.4 (1.2) [16-21]
Time 2: 19.8 (1.1) [17-22]

73%

Becker et al. (2015)
MJ >CON FA in genu, forceps minor;
MJ <CON growth in FA in superior longitudinal fasciculus, left superior frontal gyrus, left corticospinal tract, and right anterior thalamic radiation
Within MJ higher use =reduced longitudinal growth in FA

MJ

23

Time 1: 19.5 (0.7) [18-20]
Time 2 + 2.2 (0.5)

70%

Epstein and Kumra (2015b)a
MJ <CON FA in inferior longitudinal fasciculus over 18 months
More use over 18 months =lower FA

MJ

19

Baseline: 16.6 (1.5)
Year 1.5: +1.5 years

58%

Filbey et al. (2014)
MJ >CON FA in forceps minor
MJ <CON RD in forceps minor

MJ

48

28.3 (8.3) [ NR]

69%

MJ exc marijuana use only

27

28.1 (8.9) [ NR]

63%

Gruber et al. (2014)
MJ <CON FA in genu and left internal capsule
MJ <CON MD in genu
Within MJ earlier age onset =lower FA

MJ

25

23.1 (3.5) [ NR]

72.0%

Gruber et al. (2011)
MJ <CON FA in left frontal regions
Within MJ earlier age onset =lower FA

MJ

15

25 (8.7) [ NR]

93.3%

Jacobus, McQueeny, et al. (2009)
MJ + ALC <CON FA in corona radiate and superior longitudinal fasciculus
ALC <CON FA in corona radiata, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, cerebellar peduncle, and superior longitudinal fasciculus
MJ + ALC >ALC FA in corona radiata, inferior fronto-occipital fasciculus, cerebellar peduncle, and superior longitudinal fasciculus

MJ + ALC

14

18.2 (0.7) [16-19]

79%

Jacobus, Thayer, et al. (2013)
Within MJ + ALC lower FA in fornix and superior corona radiata at time 1 =higher substance use and risk taking at time 2

MJ + ALC

47

Time 1: 18.0 (0.9) [16-19]
Time 2: 19.5 (0.9)

59%

Jacobus, Squeglia, Infante, et al. (2013)
MJ decreased FA from time 1 to time 2 (12 clusters)
MJ decreased and ALC increased FA from time 1 to time 2 (6 clusters)

MJ initiators

8

Time 1: 18.2 (0.7) [17-19]
Time 2: 21.2 ( NR) [20-22]
NR

ALC initiators

8

Time 1: 17.5 (0.8) [17-19]
Time 2: 20.6 ( NR) [20-23]
NR

Jacobus, Squeglia, Bava, et al. (2013)

MJ + ALC =ALC <CON FA in 14 clusters
ALC <MJ + ALC <CON FA in uncinate fasciculus
MJ + ALC =MJ =decrease FA from baseline to year 3 in 12 clusters

MJ + ALC

21

Baseline: 17.9 ( NR) [16-19]
Year 1.5: 19.4 ( NR) [17-20]
Year 3: 20.9 ( NR) [19-21]

62%

ALC

17

Baseline: 17.9 ( NR) [16-19]
Year 1.5: 19.3 ( NR) [17-20]
Year 3: 20.9 ( NR) [19-22]

64%

CON

16

Baseline: 17.9 ( NR) [16-19]
Year 1.5: 19.4 ( NR) [17-20]
Year 3: 20.9 ( NR) [19-22]

50%

Zalesky et al. (2012)
MJ <CON WM connectivity in the right fimbria of the hippocampus (fornix), splenium of the corpus callosum, and commissural fibers Within MJ lower age of onset =higher RD

MJ

59

33.4 (10.9) [ NR]

47%

In order to elucidate some of complexities from the many cross-sectional studies on marijuana's effects on WM, our lab reported on a series of longitudinal studies of late adolescence. We found that over an 18-month follow-up period of continued use, heavy marijuana and alcohol use resulted in systematically lower FA and higher MD, specifically in the superior longitudinal fasciculus, right posterior thalamic radiations, right prefrontal thalamic fibers, right superior temporal gyrus, right inferior longitudinal fasciculus, and left posterior corona radiata ( Bava, Jacobus, Thayer, & Tapert, 2013). Marijuana use did not independently predict these effects, but drinking predicted decreased FA and increased MD over the follow-up period. Another recent study reported that 16-18-year-old marijuana users exhibited decreasing FA values in the inferior longitudinal fasciculus over 18 months compared to healthy controls ( Epstein & Kumra, 2015b).

In a separate longitudinal study including three groups of adolescents (heavy drinkers, heavy drinkers and heavy marijuana users, and controls) examined over 3 years (ie, 18-21), we found that controls exhibited greater FA than both user groups across the majority of regions examined and that both user groups exhibited lower FA values at each time point over the 3 years ( Jacobus, Squeglia, Bava, & Tapert, 2013). The substance-using groups differed in only one region, the right uncinate fasciculus, where the heavy drinking and marijuana-using group exhibited higher FA than the heavy drinking only group. We further examined a group of adolescents who reported little substance use at baseline (16-18 years old), but then initiated either alcohol or marijuana by the 3-year follow-up assessment (19-22 years old) to try to parse out premorbid WM differences from those related to substance use ( Jacobus, Squeglia, Infante, Bava, & Tapert, 2013). In this small study ( n=8 alcohol initiators and n=8 alcohol and marijuana initiators), we found decreasing FA in the alcohol and marijuana group, but not in the alcohol-only group across 20 different brain regions. This study, while preliminary, represents one of the only studies to date that has examined WM microstructure prior to and after the initiation of alcohol and marijuana use in adolescents and highlights a number of regions (ie, splenium of the corpus callosum, forceps minor, fronto-occipital fasciculus, superior corona radiata, posterior corona radiata, corticospinal tract, internal capsule, uncinated fasciculus, and superior longitudinal fasciculus) of interest for future studies.

Another longitudinal examination of WM over 2 years of late adolescence/early adulthood (ie, 19-21 years old) conducted by Becker, Collins, Lim, Muetzel, and Luciana (2015) compared heavy marijuana users who concurrently used alcohol, with controls who had no marijuana and limited alcohol use ( Becker et al., 2015). Their group reported higher FA and lower RD in the controls compared to substance users over 2 years in the superior longitudinal fasciculus and corticospinal tract. Marijuana users also exhibited higher FA, particularly in the right genu of the corpus callosum. Interestingly, the authors found that higher levels of marijuana use reported in the past 12 months at follow-up was negatively associated with FA in the superior longitudinal fasciculus and corticospinal tract. While the marijuana-using group also reported significantly more alcohol use than the control group, alcohol use was unrelated to the observed FA changes over the 2 years. These results are consistent with our smaller study examining the onset of marijuana and alcohol use, in that marijuana and alcohol, but not alcohol alone, were associated with greater WM deficits.

The WM alterations associated with marijuana use are likely attributable to effects on pruning and myelination processes occurring during adolescence and early adulthood ( Lebel et al., 2012) and could underlie functional alterations later in life. For example, Filbey et al. (2014) examined a sample of adult marijuana users and found they exhibited smaller OFC volumes, but greater functional connectivity in the OFC. Another group reported the same increased OFC functional connectivity in a sample of 14-20 years old adolescent and young adult marijuana users ( Lopez-Larson, Rogowska, & Yurgelun-Todd, 2015). Similar results have been reported in resting state data ( Orr et al., 2013) and in functional connectivity underlying cognitive control tasks ( Harding et al., 2012). The authors postulate that the increased functional connectivity coupled with decreased volume and structural connectivity in WM tracts (ie, decreased FA), may indicate a compensatory mechanism or "neural scaffolding" effect, wherein neurodevelopmental trajectories are modulated by exposure to marijuana and result in long-term functional alterations ( Filbey et al., 2014). To explore the functional consequences of structural differences related to marijuana use further, we will briefly review findings related to functional brain imaging studies.

4. FUNCTIONAL MRI OBSERVATIONS IN MARIJUANA USE

Several recent reviews have summarized the consequences of marijuana use on neurocognitive functioning in adolescence ( Jackson et al., 2016) and adulthood ( Auer, Vittinghoff, Yaffe, et al., 2016; Broyd et al., 2016), and have highlighted deficits in verbal memory, processing speed, and executive functioning ( Volkow, Swanson, et al., 2016). Presumably functional MRI studies reflect the brain changes underlying the long-term neurocognitive deficits; however, the connection between structural brain changes and functional manifestations has not been clearly defined. For example, our lab has described fMRI findings from spatial working memory ( Padula, Schweinsburg, & Tapert, 2007; Schweinsburg et al., 2008, 2005; Schweinsburg, Schweinsburg, Medina, et al., 2010), verbal encoding ( Schweinsburg, McQueeny, Nagel, Eyler, & Tapert, 2010), and inhibitory control tasks ( Tapert et al., 2007), and in each case marijuana users and controls demonstrated similar task performance, but the underlying brain activation patterns differed significantly. In our studies, marijuana users' relative to controls' brain function was characterized by increased activation in parietal, superior temporal, hippocampal, and posterior cingulate regions during working memory demands, and increased parietal and frontal activation during response inhibition.

Other studies in young adults have corroborated the differential activation depicted in our adolescent samples, including a study that reported hypoactivity in frontal and temporal cortices, and relative hyperactivity in the parahippocampal region during a learning task ( Nestor, Roberts, Garavan, & Hester, 2008), and a study that reported greater activation in marijuana users compared to controls in frontal and temporal regions during a visuospatial working memory task ( Smith, Longo, Fried, Hogan, & Cameron, 2010). In each of these cases, marijuana users and controls performed similarly on the tasks, but exhibited differential brain activation reflecting potential compensatory responses by the marijuana-using groups ( Filbey et al., 2015; Schweinsburg, McQueeny, et al., 2010).

Age of onset and amount of marijuana consumed appear to modulate fMRI results. Earlier onset and more intense marijuana use during adolescence was linked to less brain activation (ie, BOLD response), and users who began using marijuana in late adolescence showed notably higher brain activation compared to earlier onset users ( Jacobus, Bava, Cohen-Zion, Mahmood, & Tapert, 2009). A recent study examining performance on a Stroop task in adults showed that marijuana users performed poorly on the task compared to controls, and also exhibited a different pattern of activation in the cingulate compared to controls ( Sagar et al., 2015). Specifically, the subset of marijuana smokers with an onset of regular use prior to age 16 exhibited significant activation in the anterior cingulate, which was not evident in the late onset marijuana users or controls ( Sagar et al., 2015). Thus, the weakened capacity of marijuana users to rely on brain regions typically required for task execution (eg, executive functioning and working memory) appears to result in the recruitment of additional brain regions associated with attentional or verbal processing that are not typically utilized.

Marijuana use appears to affect the mesolimbic dopamine system, a target of many, if not all other drugs of abuse ( Filbey & DeWitt, 2012). Tasks requiring brain reward systems revealed a similar constellation of results; namely, that marijuana users and controls did not differ in their performance of the tasks, but exhibited differential activation of reward pathways, including increased activation of regions of the basal ganglia (ie, caudate, putamen, and nucleus accumbens) and the insula ( Hester, Nestor, & Garavan, 2009; van Hell et al., 2010) during reward anticipation. Additionally, marijuana users exhibited decreased activation in the insula, anterior cingulate, and putamen during loss trials in a monetary incentive delay task ( Nestor, Hester, & Garavan, 2010; Wesley, Hanlon, & Porrino, 2011). Thus, marijuana users may be more sensitive to rewards and less sensitive to negative feedback or losses.

In summary, functional MRI studies reveal relatively intact performance that is accomplished with differential activation patterns in marijuana users compared to controls. The data support a hypothesis of expanding neural recruitment that entails compensatory activation in brain regions not typically utilized to accomplish the task. Future studies with more difficult neurocognitive tasks and over a larger range of ages may provide additional evidence and clarify underlying functional changes resulting from marijuana use.

5. REMAINING QUESTIONS AND FUTURE DIRECTIONS

The literature on brain structure and function is beginning to elucidate the specific and primarily detrimental effects of marijuana use, particularly when initiated while the brain is still maturing during early to mid-adolescence. Data indicates that adolescence is indeed a sensitive period in development in which marijuana use can result in long-term negative effects. Additional research is needed to clarify the developmental trajectories of neurobiological systems including the endocannabinoid system and related neuronal systems, and to more clearly characterize the effects of marijuana use on these systems. Complex interactions between the development of the endocannabinoid system with other factors including genetics ( Schacht et al., 2012), age of use onset ( Gruber et al., 2014), and behavioral traits ( Wesley et al., 2011) will be crucial to untangle in future studies ( Hurd et al., 2014). In order to obtain data capable of addressing some of these issues, a number of methodological and conceptual advancements must also be considered in the coming years.

One such advancement is a clearer depiction of the mechanisms of action of marijuana's effects on the developing brain. Much of the neurotoxic effects of marijuana are associated with THC acting on CB1 receptors, which in turn affects a number of other neurotransmitter systems and neurodevelopmental processes (eg, synaptic plasticity and neurogenesis in the hippocampus; Lubman, Cheetham, & Yücel, 2015). THC is only one of more than 70 cannabinoids in marijuana and not all of these cannabinoids have neurotoxic effects. In fact CBD may even counteract some of the negative effects of THC ( Bhattacharyya et al., 2010; Demirakca et al., 2011). Additional studies are needed to parse out the potentially countervailing effects of different cannabinoids.

In order to better understand the complex effects of marijuana, researchers also need to improve assessment techniques. The majority of marijuana use data come from self-report and are quantified with crude measures of "days of use," "number of joints," or "grams" consumed. While it is inherently difficult to quantify an unregulated substance, it is clear that potency of marijuana has been steadily increasing and different methods of administration inevitably lead to different active doses ( ElSohly et al., 2016). Therefore, developing better and more standardized assessment techniques is essential to addressing the complexities of THC doses and potency ( Lorenzetti et al., 2016). It is possible, for example, to utilize hair samples that will provide an index of use over 3-5 months and also provide a basic ratio of THC and CBD ( Demirakca et al., 2011). As toxicology tests of urine and other bodily fluids continue to improve ( Hartman et al., 2015, 2016), researchers will need to update current methods and incorporate additional techniques to address some of these fundamental questions of pharmacokinetics and pharmacodynamics of marijuana.

Lastly, researchers must collect longitudinal data that can disentangle precursors of risk from consequences of marijuana use. Nearly, all of the existing imaging literature on the effects of marijuana on neurodevelopment is cross-sectional in nature and cannot address questions of cause and effect. Approaching these questions from a neurodevelopmental perspective requires understanding of (1) typical trajectories, (2) sensitive periods, and (3) complex interactions at multiple levels ( Casey et al., 2014). None of these aims can be sufficiently addressed solely with cross-sectional data. Fortunately, funding organizations have recently prioritized large scale, longitudinal studies, which will provide data to address some of the remaining questions. For example, in the United States, the National Institutes of Health funded the National Consortium on Alcohol and Neuro-Development in Adolescence ( http://www.ncanda.org) to examine the effects of alcohol and other drugs on neurodevelopmental trajectories in a large sample ( n=831) of adolescents including annual neuroimaging and neurocognitive assessments ( Brown et al., 2015; Pfefferbaum et al., 2015); the European Union has funded the IMAGEN project ( http://www.imagen-europe.com), which examines 2000 adolescents from age 14 to 19 with multiple imaging sessions and neurocognitive assessments ( Schumann et al., 2010). Further, the National Institutes of Health has recently approved funding for the most ambitious project to date, the Adolescent Brain Cognitive Development Study ( http://www.abcdstudy.org), which will follow 10,000 adolescents starting from ages 9 to 10 for at least 10 years, including imaging and neurocognitive assessment every 2 years and annual assessments of substance use and a multitude of other measures related to development. With the coming influx of longitudinal data, researchers will be able to address many of the gaps in understanding the effects of marijuana and other drugs on brain development and functioning.

6. CONCLUSIONS

Mounting evidence suggests that marijuana use negatively impacts brain structure and function. While there is potential recovery from some of the negative effects of prolonged use, long-term deleterious effects are present and more likely with early age of onset and protracted use. Data from both animal and human models highlight the particularly sensitive period of adolescence for adverse effects of marijuana through the modulation of the neurodevelopmental trajectories. The mechanisms that underlie such modulations are not fully understood and likely result from multiple levels of complex interactions including onset, dose, and duration of marijuana use as well as neurobiological factors including genetic risk. Prolonged marijuana use could result in persistent changes to brain structure and function that underlie the adverse cognitive outcomes associated with heavy use. Future prospective studies with enhanced assessment of marijuana use coupled with MRI assessment prior to and following marijuana use initiation will provide additional clarification of these complex effects of marijuana use on brain structure and function.

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Effects of Marijuana Use on Brain Structure and Function: Neuroimaging Findings from a Neurodevelopmental Perspective

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Marijuana, behind only tobacco and alcohol, is the most popular recreational drug in America with prevalence rates of use rising over the past decade. A wide range of research has highlighted neurocognitive deficits associated with marijuana use, particularly ...

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I think Marijuana is continuing to have increasing numbers of use. I think the only reason you should use Marijuana is medically. If not I think its really bad for you and its not helping your health in any way.