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Educational videos about the endocannabinoid system 

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Educational videos about the endocannabinoid system 

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Cannabis and the endocannabinoid system - English

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The endocannabinoid system and the revolution of one | Rachel Knox | TEDxPortland

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Demystifying the endocannabinoid system 

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Demystifying the endocannabinoid system 

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Demystifying the endocannabinoid system. | Ruth Ross | TEDxMississauga

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Is Your Endocannabinoid System in Balance?

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This article is sponsored by PlusCBD Oil , a product line from CV Sciences (formerly CannaVest). CV Sciences is one of the leading suppliers and manufacturers of agricultural hemp-derived CBD bulk and finished products. Many of us realize the important of "balance" in our daily lives.

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An over activation of CB2 receptors can cause body function failure such as decreased immune function and improper wound healing.

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When there is over activation of CB1 receptors in the body this can cause affects on the body such as increased psycho-activity, systemic inflammation, cardiovascular risk and diabetes.

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What happens when your endocannabinoid system is not balanced?

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What happens when your endocannabinoid system is not balanced?

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When referring to an imbalance of the endocannabinoid system we are referring to an imbalance between CB1 and CB2 activation in the body

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Increased levels of CB2 in the body it will have its of effects on the body such as; decreased inflammation, decreased tissue damage from inflammation, improvements in metabolic health,  improvements in insulin signaling and increased energy balance.

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Through research it has been discovered that an increased amount of CB1 receptors is associated with increased stress levels, anxiety, paranoia and augmented appetite. Increased CB1 receptors are also shown by decreased nausea and vomiting as well as pain.

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When thinking about balance of the endocannabinoid system this refers to balance between CB1 and CB2 reseptors in the body at any given time

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Is your endocannabinoid system balanced? 

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Is your endocannabinoid system balanced? 

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The endocannabinoid system is an ancient, evolutionary and ubiquitous lipid signaling system which plays an important role in the regulatory functions of the body. The ECS plays a very important role in the body which include physiological and pathophysiological processes in the body. The ECS has a direct impact on many functions of the body such as nervous system development, immune function, inflammation, appetite, metabolism, energy, homeostasis, cardiovascular function, digestion, bone development, bone density and many more.

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

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

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

Prepared by Health Canada

Date of latest version: Spring 2018

Reporting Adverse Reactions to Cannabis (marihuana, marijuana) Products

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

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

1. Report online

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

3. Complete a Canada Vigilance Reporting Form and:

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

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

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

Table of contents

List of figures and tables

Figures

Tables

List of abbreviations

2-AG:

2-arachidonoylglycerol

5-ASA:

5-aminosalicylic acid

5-HT:

5-hydroxytryptamine

2-OG:

2-oleoylglycerol

AA:

arachidonic acid

AB:

Alberta

ACCESS:

AIDS Care Cohort to evaluate Exposure to Survival Services

ACE:

angiotensin-converting enzyme

ACMPR:

Access to Cannabis for Medical Purposes Regulations

ACTH:

adrenocorticotropic hormone

AD:

Alzheimer's disease

AED:

anandamide

AIDS:

acquired immune deficiency syndrome

AKT1:

AKT Serine/Threonine Kinase 1

ALS:

amyotrophic lateral sclerosis

ALSPAC:

Avon Longitudinal Study of Parents and Children

ALT:

alanine transaminase

AMP:

adenosine monophosphate

AOR:

adjusted odds ratio

ApoE:

apolipoprotein E

APP:

amyloid precursor protein

APRI:

AST-to-platelet ratio index

ART:

anti-retroviral therapy

AST:

aspartate transaminase

AUC:

area-under-the-curve

12-hour AUC

Aβ:

amyloid-beta

b.i.d.:

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

BAC:

blood alcohol concentration

BC:

British Columbia

BCOS:

Bipolar Comprehensive Outcomes Study

BDNF:

brain-derived neurotrophic factor

BDS:

botanical drug substance

BHO:

butane hash oil

BMI:

body mass index

BPI:

Brief Pain Inventory

calcium

CADUMS:

Canadian Alcohol and Drug Use Monitoring Survey

CAMPS:

Cannabis Access for Medical Purposes Survey

CAMS:

Cannabis in Multiple Sclerosis

CAPS:

Clinician-Administered PTSD Scale

CARDIA:

Coronary Artery Risk Development In young Adults

CB:

cannabinoid

CBC:

cannabichromene

CBD:

cannabidiol

CBDA:

cannabidiolic acid

CBDV:

cannabidivarin

CBG:

cannabigerol

CBN:

cannabinol

CCL:

chemokine (C-C motif) ligand

CDAI:

Crohn's disease activity index

CDKL5:

cyclin-dependent kinase-like 5 gene

CHS:

cannabis hyperemesis syndrome

CI:

confidence interval

CINV:

chemotherapy-induced nausea and vomiting

CGI-I:

clinical global impression improvement

CGI-S:

clinical global impression scale

cMAS:

combined modified Ashworth score

Cmax:

Maximal concentration of a drug in the blood

CNR1:

cannabinoid receptor 1

CNR2:

cannabinoid receptor 2

CNS:

central nervous system

COMT:

catechol-O-methyltransferase

COX:

cyclo-oxygenase

CRP:

C-reactive protein

CRPS:

complex regional pain syndrome

CSF:

cerebrospinal fluid

CUD:

cannabis use disorder

CUPID:

Cannabinoid Use in Progressive Inflammatory Brain Disease

CYP:

cytochrome P450

D:

duration of action

DAG:

diacylglycerol

DAGL:

diacylglycerol lipase

DAT1:

dopamine active transporter 1

DIO:

diet-induced obesity

DNA:

deoxyribonucleic acid

DNBS:

dinitrobenzene sulfonic acid

DSM-5:

diagnostic and statistical manual of mental disorders (fifth edition)

DSM-IV:

diagnostic and statistical manual of mental disorders (fourth edition)

DUIA:

driving under the influence of alcohol

DUIC:

driving under the influence of cannabis

ECS:

endocannabinoid system

median effective dose

EDSP:

Early Developmental Stages of Psychopathology

EDSS:

expanded disability status scale

EEG:

electroencephalogram

e.g.:

for example

EMBLEM:

European Mania in Bipolar Longitudinal Evaluation of Medication

EORTC QLQ-C30:

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

EQ-5D:

EuroQoL five dimensions questionnaire

ESM:

experience sampling methodology

ETA:

ethanolamine

FAACT:

Functional Assessment of Anorexia-Cachexia Therapy

FAAH:

fatty acid amide hydrolase

forced expiratory volume in one second

fMRI:

functional magnetic resonance imaging

FSH:

follicle stimulating hormone

FVC:

forced vital capacity

g:

gram

GABA:

gamma-aminobutyric acid

GAD:

generalized anxiety disorder

GI:

gastrointestinal

GnRH:

gonadotropin-releasing hormone

GPR55:

G protein-coupled receptor 55

GRADE:

Grading of Recommendations, Assessment, Development and Evaluation

GVHD:

graft-versus-host disease

h:

hour

proton magnetic resonance spectroscopy

HD:

Huntington's disease

HDL:

high density lipoprotein

HIV:

human immunodeficiency virus

HMG-CoA:

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

HMO:

health maintenance organization

HOMA-IR:

homeostatic model assessment of insulin resistance

HPA:

hypothalamic-pituitary-adrenal

HPO:

hypothalamic-pituitary-ovarian

HRQoL:

health-related quality of life

I.M.:

intramuscular

I.P.:

intraperitoneal

I.V.:

intravenous

IBD:

inflammatory bowel disease

IBS:

irritable bowel syndrome

IBS-A:

alternating pattern (alternation constipation/diarrhea) IBS

IBS-C:

constipation-predominant IBS

IBS-D:

diarrhea-predominant IBS

median inhibitory concentration

ICAM-1:

intercellular adhesion molecule-1

ICD:

International Classification of Diseases

ICM:

inner cell mass

IFN:

interferon

IL:

interleukin

IND:

investigational new drug

iNOS:

inducible nitric oxide synthase

IOP:

intraocular pressure

IQ:

intelligence quotient

IQR:

interquartile range

IRR:

incident rate ratio

potassium

kg:

kilogram

L:

liter

LCT:

lipid long-chain triglyceride

median lethal dose

LDL:

low density lipoprotein

LH:

luteinizing hormone

LOX:

lipo-oxygenase

MAGL:

monoacylglycerol lipase

MB:

Manitoba

Met:

methionine

mg:

milligram

min:

minute

miRNA:

micro ribonucleic acid

mL:

milliliter

MMP:

matrix metalloproteinase

MOVE 2:

Mobility Improvement in MS-Induced Spasticity Study

mRNA:

messenger ribonucleic acid

MS:

multiple sclerosis

MSIS-29:

MS Impact Scale 29

MUSEC:

Multiple Sclerosis and Extract of Cannabis trial

N/A:

not applicable

sodium

NAFLD:

non-alcoholic fatty liver disease

NAPE:

N-arachidonoylphosphatidylethanolamine

NASEM:

National Academy of Sciences, Engineering and Medicine

NB:

New Brunswick

NCS:

National Comorbidity Survey

NCS-R:

National Comorbidity Survey-Replication

NEMESIS:

Netherlands Mental Health Survey and Incidence Study

NESARC:

National Epidemiological Survey on Alcohol and Related Conditions

ng:

nanogram

NHANES:

National Health and Nutrition Examination Survey

NK:

natural killer

NK-1:

neurokinin 1

NL:

Newfoundland and Labrador

nM:

nanomolar

NMDA:

N-methyl-D-aspartic acid

nmol:

nanomole

NNT:

number needed to treat

NRG1:

neuregulin 1

NRS:

numerical rating scale

NRS-PI:

numerical rating scale for pain intensity

NS:

Nova Scotia

NSAIDs:

nonsteroidal anti-inflammatory drugs

NSDUH:

National Survey on Drug Use and Health

NT:

Northwest Territories

NU:

Nunavut

O:

onset of effects

OA:

osteoarthritis

OEA:

oleoylethanolamide

ON:

Ontario

OR:

odds ratio

P:

peak effects

PE:

Prince Edward Island

P.O.:

oral administration

PD:

Parkinson's disease

PDQ-39:

39-Item Parkinson Disease Questionnaire

PEA:

palmitoylethanolamide

PLD:

phospholipase-D

pNRS:

pain numerical rating score

PPAR:

peroxisome proliferator-activated receptor

PRISMA:

Preferred Reporting Items for Sytematic Reviews and Meta-Analyses

PTSD:

post-traumatic stress disorder

PWID:

people who inject drugs

QC:

Quebec

q.i.d.:

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

QoL:

quality of life

RA:

rheumatoid arthritis

RCT:

randomized controlled trial

REM:

rapid eye movement

RNA:

ribonucleic acid

Rx:

prescription

s:

second

SAFTEE:

Systematic Assessment of Treatment Emergent Events

s.c.:

subcutaneous

SCI:

spinal cord injury

SD:

standard deviation

SDLP:

standard deviation of lateral position

SF-36:

36-Item Short Form Health Survey

SIBDQ:

short IBD questionnaire

SIV:

simian immunodeficiency virus

SK:

Saskatchewan

SNP:

single nucleotide polymorphism

sNRS:

subjective numerical rating spasticity scale

S-TOPS:

Short-Form Treatment Outcomes in Pain Survey

SYS:

Saguenay Youth Study

t.i.d.:

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

TGCT:

testicular germ cell tumours

THC:

delta-9-tetrahydrocannabinol

THCA:

tetrahydrocannabinolic acid

THCV:

tetrahydrocannabivarin

TIA:

transient ischemic attack

Tmax:

Time to maximal blood concentration of a drug

TNBS:

trinitrobenzene sulfonic acid

TNF:

tumor necrosis factor

TRH:

thyrotropin-releasing hormone

TRP:

transient receptor potential

TRPV1:

transient receptor potential vanilloid channel 1

TS:

Tourette's syndrome

TWSTRS:

Toronto Western Spasmodic Torticollis Rating Scale

U.K.:

United Kingdom

UPDRS:

Unified Parkinson's Disease Rating Scale

Val:

valine

VAS:

visual analogue scale

VCAM-1:

vascular cellular adhesion molecule-1

w/w:

weight/weight

WHO:

World Health Organization

YT:

Yukon

delta-9-tetrahydrocannabinol

µg:

microgram

μM:

micromolar

Authorship and acknowledgements

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

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

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

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

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

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

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

Overview of Summary Statements

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4.7.2.3 Cancer pain

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

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

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

4.7.2.5 Headache and migraine

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

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

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

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

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

4.9 Other diseases and symptoms 4.9.1 Movement disorders 4.9.1.1 Dystonia

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

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

4.9.1.2 Huntington's disease

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

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

4.9.1.3 Parkinson's disease 4.9.1.4 Tourette's syndrome

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

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

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

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

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

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

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

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

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

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

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

4.9.5.5 Schizophrenia and psychosis

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

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

4.9.6 Alzheimer's disease and dementia

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

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

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

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

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

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

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

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

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

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

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

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

4.9.8.4 Metabolic syndrome, obesity, diabetes

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

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

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

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

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

7.0 Adverse effects 7.1 Carcinogenesis and mutagenesis

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

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

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

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

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

7.7 Central nervous system 7.7.1 Cognition

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

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

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

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

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

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

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

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

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

1.0 The Endocannabinoid System

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

Components of the endocannabinoid system

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

Endocannabinoid synthesis

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

Genetics and signaling through the cannabinoid receptors

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

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

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

Cannabinoid receptor expression and receptor distribution

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

Other molecular targets for cannabinoids

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

Signal termination

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

Role of the endocannabinoid system in nervous system development

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

Figure 1. The Endocannabinoid System in the Nervous System

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

1.1 Cannabis

1.1.1 Chemistry and composition

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

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

1.1.2 Other constituents

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

1.1.3 Stability and storage

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

2.0 Clinical Pharmacology

2.1 Pharmacodynamics

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

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

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

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

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

Phytocannabinoid-phytocannabinoid interactions and phytocannabinoid differences among cannabis strains

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

Factors affecting the nature of the potential phytocannabinoid-phytocannabinoid interactions

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

Pharmacokinetic vs. pharmacodynamic interactions

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

Psychological and physiological effects associated with varying phytocannabinoid concentrations

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

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

Overview of pharmacological actions of cannabis

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

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

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

Body System/Effect

Detail of Effects

Central Nervous System (CNS)

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

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

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

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

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

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

Cardiovascular and Cerebrovascular System

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

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

Carcinogenesis/mutagenesis

(Section 7.1)

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

Respiratory System

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

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

Gastrointestinal System

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

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

Musculoskeletal system

(Section 4.9.2)

Limited evidence for decreased intraocular pressure.

Immune System

Reproductive System

2.2 Pharmacokinetics

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

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

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

2.2.1 Absorption

2.2.1.1 Smoked cannabis

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

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

2.2.1.2 Vapourized cannabis

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

2.2.1.3 Oral

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

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

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

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

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

2.2.1.4 Oro-mucosal and intranasal

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

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

2.2.1.5 Rectal

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

2.2.1.6 Topical

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

2.2.2 Distribution

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

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

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

2.2.3 Metabolism

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

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

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

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

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

2.2.3.1 Inhalation

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

2.2.3.2 Oral

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

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

2.2.4 Excretion

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

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

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

2.3 Pharmacokinetic-pharmacodynamic relationships

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

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

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

Smoked cannabis

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

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

Vapourized cannabis

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

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

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

Oral and oro-mucosal cannabinoids

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

2.4 Tolerance, dependence, and withdrawal symptoms

Tolerance

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

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

Dependence and withdrawal

Psychological dependence

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

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

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

Physical dependence

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

Cannabidiol for cannabis and other drug dependence

2.5 Special populations

Pediatric/Adolescent

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

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

Geriatric

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

Clinical Studies

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

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

Sex-dependent effects

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

3.0 Dosing

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

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

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

Minimal therapeutic dose and dosing ranges

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

Prescription cannabinoids

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

Survey and clinical data

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

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

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

Dosing and threshold of psychotropic effects

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

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

1. Take a medical history and perform a physical examination

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

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

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

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

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

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

8. Develop a treatment plan incorporating these goals

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

10. Discuss the risks of addiction

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

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

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

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

15. Maintain an ongoing relationship with the patient

3.1 Smoking

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

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

Relationship between a smoked/vapourized dose and an oral dose

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

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

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

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

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

Cannabinoid
(Generic name)

Brand/Registered name

Principal constituents/Source

Official status in Canada

Approved indications

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

Route of administration

Availability on provincial/ territorial formulary

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

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

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

3.2 Oral

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

Marinol

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

Cesamet

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

Epidiolex

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

Cannabis oil

3.3 Oro-mucosal

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

3.4 Vapourization

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

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

4.0 Potential Therapeutic Uses

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

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

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

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

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

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

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

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

Percent and dose of Δ⁹-THC (if known)

Trial duration; and number of patients/participants

Reference

HIV/AIDS-associated weight loss

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

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

Central and peripheral chronic neuropathic pain (various etiologies)

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

1 day total;
38 patients

HIV-associated chronic neuropathic pain refractory to other medications

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

5 days total;
28 patients

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

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

5 days total; 21 patients

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

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

3 sessions total;
39 patients

Neuropathic pain of various etiologies

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

One session only;
10 patients

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

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

4 sessions total;
16 patients

Neuropathic pain from spinal cord injury or disease

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

3 sessions total;
42 patients

4.1 Palliative care

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

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

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

Data from observational studies

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

4.2 Quality of life

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

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

Clinical studies with dronabinol

Clinical studies with cannabis extract

Clinical studies with nabilone

Clinical studies with nabiximols

Clinical and observational studies with smoked cannabis

4.3 Chemotherapy-induced nausea and vomiting

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

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

Pre-clinical studies

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

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

Cannabinoid acids and other cannabinoids

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

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

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

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

Clinical studies

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

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

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

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

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

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

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

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

4.4.1 To stimulate appetite and produce weight gain in AIDS patients

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

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

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

4.4.2 To stimulate appetite and produce weight gain in cancer patients

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

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

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

4.4.3 Anorexia nervosa

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

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

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

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

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

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

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

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

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

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

4.5.1 Multiple sclerosis

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

Pre-clinical studies

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

Historical and survey data

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

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

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

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

Nabiximols

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

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

CUPID and MUSEC clinical studies

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

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

Clinical studies with smoked cannabis

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

Cannabis/cannabinoid tolerability in multiple sclerosis

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

Bladder dysfunction associated with multiple sclerosis or spinal cord injury

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

4.5.2 Amyotrophic lateral sclerosis

4.5.3 Spinal cord injury (or spinal cord disease)

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

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

4.6 Epilepsy

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

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

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

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

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

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

The endocannabinoid system and epilepsy

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

Pre-clinical studies

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

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

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

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

Data from observational studies and patient surveys

Treatment-resistant, childhood-onset epilepsy

Clinical studies

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

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

Treatment-resistant, childhood-onset epilepsy

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

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

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

4.7 Pain

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

Role of CB₁ and CB₂ receptors

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

Role of endocannabinoids, anandamide and 2-AG

Considerations and caveats

Animal vs. human studies

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

Experimental models of acute pain vs. chronic pain

Placebo effect

Patient/study subject population

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

Other considerations

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

4.7.1 Acute pain

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

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

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

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

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

4.7.2 Chronic pain

4.7.2.1 Experimentally-induced inflammatory and chronic neuropathic pain

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

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

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

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

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

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

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

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

Figure 3 - Text description

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

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

b At least 30% reduction in pain intensity.

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

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

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

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

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

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

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

4.7.2.3 Cancer pain

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

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

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

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

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

4.8 Arthritides and musculoskeletal disorders

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

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

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

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

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

Information from surveys

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

4.8.1 Osteoarthritis

Pre-clinical studies

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

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

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

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

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

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

Clinical studies

4.8.2 Rheumatoid arthritis

Pre-clinical studies

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

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

Clinical studies

There are no published clinical studies of cannabis for RA.

4.8.3 Fibromyalgia

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

Clinical studies with smoked or orally ingested cannabis

Clinical studies with prescription cannabinoid medications

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

Dronabinol

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

Nabilone

4.8.4 Muscular pain

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

4.8.5 Osteoporosis

Pre-clinical studies

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

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

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

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

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

4.9 Other diseases and symptoms

4.9.1 Movement disorders

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

4.9.1.1 Dystonia

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

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

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

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

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

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

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

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

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

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

4.9.1.4 Tourette's syndrome

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

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

4.9.1.5 Spinocerebellar ataxias

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

4.9.2 Glaucoma

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

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

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

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

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

4.9.3 Asthma

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

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

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

4.9.4 Hypertension

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

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

4.9.5 Stress and psychiatric disorders

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

The endocannabinoid system, stress and psychiatric disorders

4.9.5.1 Anxiety and depression

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

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

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

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

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

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

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

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

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

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Nick Jikomes December 12, 2016

Some of us consume cannabis for its mind-altering effects, while others seek symptom relief. But cannabis wouldn't get us high or have some of its therapeutic benefits if our bodies didn't already contain a biological system capable of interacting with its active chemical compounds, like THC.

Our endocannabinoid system (ECS) does just that. But it isn't there just to allow us to enjoy the effects of our favorite strain. It serves a vital purpose for our health and well-being because it regulates key aspects of our biology.

So, what's it doing, and how does it work?

What is the endocannabinoid system and what does it do?

The endocannabinoid system (ECS) is a biological system first discovered in the late '80s and early '90s, although much remains unknown about the system today.

The ECS is largely comprised of endocannabinoids, receptors, and enzymes that are believed to help regulate a variety of functions in human including sleep, mood, memory, appetite, reproduction, and pain sensation. Scientists still have plenty of questions about the human endocannabinoid system and how it functions.

Homeostasis: Staying in the Goldilocks zone

To understand the human endocannabinoid system, it's helpful to know a little about one of the most fundamental concepts in biology: homeostasis. And the best way to understand homeostasis is to think of Goldilocks and the Three Bears.

The classic fairy tale illustrates the idea that the best outcome often lies somewhere in the middle, between two extremes. We don't want things too hot or too cold, but just right.

Homeostasis is the concept that most biological systems are actively regulated to maintain conditions within a narrow range. Our bodies don't want temperature to be too hot or too cold, blood sugar levels too high or too low, and so on. Conditions need to be just right for our cells to maintain optimum performance, and exquisite mechanisms have evolved to draw them back to the Goldilocks zone if they move out.

The body's endocannabinoid system (ECS) is a vital molecular system for helping maintain homeostasis-it helps cells stay in their Goldilocks zone.

Key pieces of the endocannabinoid system (ECS)

Because of its crucial role in homeostasis, the ECS is widespread throughout the animal kingdom. Its key pieces evolved a long time ago, and the ECS can be found in all vertebrate species.

The three key components of the human endocannabinoid system are:

Cannabinoid receptors found on the surface of cells

Endocannabinoids, small molecules that activate cannabinoid receptors

Metabolic enzymes that break down endocannabinoids after they are used

Why do we have cannabinoid receptors and what are they?

Cannabinoid receptors sit on the surface of cells and "listen" to conditions outside the cell. They transmit information about changing conditions to the inside of the cell, kick-starting the appropriate cellular response.

There are two major cannabinoid receptors: CB1 and CB2. These aren't the only cannabinoid receptors, but they were the first ones discovered and remain the best-studied.

CB1 receptors are one of the most abundant receptor types in the brain. These are the receptors that interact with THC to get people high.

CB2 receptors are more abundant outside of the nervous system, in places like the immune system. However, both receptors can be found throughout the body (Figure 1).

What are endocannabinoids?

Endocannabinoids are molecules that, like the plant cannabinoid THC, bind to and activate cannabinoid receptors. However, unlike THC, endocannabinoids are produced naturally by cells in the human body ("endo" means "within," as in within the body).

There are two major endocannabinoids: anandamide and 2-AG (Figure 2). These endocannabinoids are made from fat-like molecules within cell membranes, and are synthesized on-demand. This means that they get made and used exactly when they're needed, rather than packaged and stored for later use like many other biological molecules.

Anandamide. Derived from the Sanskrit word "ananda," which translates to "joy," "bliss," or "delight," anandamide is sometimes called "the bliss molecule." More scientifically known as N-arachidonoylethanolamine (AEA), this fatty acid neurotransmitter is the subject of several scientific studies that try to determine its effects on humans. First identified and named in 1992 by Raphael Mechoulam, anandamide is believed to have an impact on working memory and early stage embryo development.

2-AG. 2-ArachidonoylGlycerol (2-AG) was first described in 1994-1995 by Raphael Mechoulam and his student Shimon Ben-Shabat. While it was previously a known chemical compound, this is when scientists first became aware of its affinity for cannabinoid receptors. Present at high levels in the central nervous system, 2-ArachidonoylGlycerol (2-AG) has been identified in maternal bovine as well as human milk.

Metabolic enzymes

The third piece of the endocannabinoid triad includes the metabolic enzymes that quickly destroy endocannabinoids within the ECS once they are used. The two big enzymes are FAAH, which breaks down anandamide, and MAGL, which breaks down 2-AG (Figure 3).

These enzymes ensure that endocannabinoids get used when they're needed, but not for longer than necessary. This process distinguishes endocannabinoids from many other molecular signals in the body, such as hormones or classical neurotransmitters, which can persist for many seconds or minutes, or get packaged and stored for later use.

These three key components of the endocannabinoid system can be found within almost every major system of the body. When something brings a cell out of its Goldilocks zone, these three pillars of the ECS are often called upon to bring things back, thus maintaining homeostasis.

Because of its role in helping bring things back to their physiological Goldilocks zone, the ECS is often engaged only when and where it's needed. Dr. Vincenzo Di Marzo, Research Director at the Institute of Biomolecular Chemistry in Italy, put it to us this way:

"With the 'pro-homeostatic action of the ECS' we mean that this system of chemical signals gets temporarily activated following deviations from cellular homeostasis. When such deviations are non-physiological, the temporarily activated ECS attempts, in a space- and time-selective manner, to restore the previous physiological situation (homeostasis)."

In other words, the endocannabinoid system helps bring things back to the biological Goldilocks zone.

Below we will consider examples of how the ECS helps maintain homeostasis in two areas: the firing of brain cells in the nervous system and the inflammatory response of the immune system.

Endocannabinoid regulation of brain cell firing

Brain cells (neurons) communicate by sending electrochemical signals to each other. Each neuron must listen to its partners to decide whether it will fire off its own signal at any given moment. However, neurons don't like to get too much input-there's a Goldilocks zone. If they get overloaded by signals, it can be toxic.

That's where endocannabinoids come in.

Consider a simplified scenario with one neuron listening to two others.

One of the two outputting neurons might become overactive and send too many signals to the neuron that's listening. When that happens, the neuron that's listening will make endocannabinoids specifically where it's connected to the overactive neuron. Those endocannabinoids will travel back to the "loud" neuron where they bind to CB1 receptors, transmitting a signal that instructs it to quiet down. This brings things back to the Goldilocks zone, maintaining homeostasis (Figure 4).

As the example above illustrates, endocannabinoids travel backward, which is why they're known as retrograde signals. Most of the time, information flow between neurons is strictly in one direction, from sender neurons that release neurotransmitter signals to receiver neurons that listen to those signals. Endocannabinoids allow receiver neurons to regulate how much input they're getting, and they do this by sending retrograde signals (endocannabinoids) back to overactive sender neurons.

But the brain isn't the only organ that needs to maintain homeostasis. Every other system of the body, the digestive, immune, ECS system, etc., needs to carefully regulate how its cells are functioning. Proper regulation is crucial for ensuring survival.

Endocannabinoid regulation of inflammation

Inflammation is a natural protective reaction the immune system has in response to infection or physical damage. The purpose of inflammation is to remove pathogens (germs) or damaged tissue. The inflamed area is produced by fluid and immune cells moving into the area to do the dirty work and return things to their Goldilocks zone.

It's important that inflammation be limited to the location of damage and doesn't persist longer than needed, which can cause harm. Chronic inflammation and autoimmune diseases are examples of the immune system getting activated inappropriately. When that happens, the inflammatory response lasts too long, which results in chronic inflammation, or gets directed toward healthy cells, which is known as autoimmunity.

In general, endocannabinoids seem to suppress or limit the immune system's inflammatory signals. Professor Prakash Nagarkatti, Vice President for Research at the University of South Carolina whose laboratory studies endocannabinoid regulation of immune responses, told us how tweaking the endocannabinoid system might be a good way to treat inflammatory diseases.

"Most of our research demonstrates that endocannabinoids are produced upon activation of immune cells and may help regulate the immune response by acting as anti-inflammatory agents. Thus, interventions that manipulate the metabolism or production of endocannabinoids may serve as a novel treatment modality against a wide range of inflammatory disease."

Consider a normal immune response triggered by a bacterial infection. First, immune cells detect the presence of bacteria and release pro-inflammatory molecules that tell other immune cells to come and join the fight.

Endocannabinoids get released as well (Figure 4), which also signal to other immune cells for assistance and likely help limit the inflammatory response so it isn't excessive. By tightly regulating inflammation, the immune system can destroy germs or remove damaged tissue, and then stop. This prevents excessive inflammation, allowing cells, and thus the body, to return to the Goldilocks zone.

Other treatment potential of cannabinoids

While much remains to be discovered about the endocannabinoid system and the various medical uses and treatment potential of cannabinoids, certain conditions have been identified as key areas of research potential. In particular, cannabinoids may be used to treat:

Acute and chronic kidney disease

Alzheimer's disease

Autoimmune diseases

Cardiovascular disease

Chronic pain conditions

With increased research, this list is likely to grow significantly.

How do plant cannabinoids like THC and CBD interact with the endocannabinoid system?

The reason that plant cannabinoids have psychoactive and medicinal effects within the body is, in large part, because we have an endocannabinoid system (ECS) that they can interact with. For example, THC gets you high because it activates the CB1 receptor within the brain. Endocannabinoids like anandamide also activate CB1.

So why aren't we constantly high?

A couple big reasons. First, THC doesn't interact with CB1 receptors in exactly the same fashion as the body's natural endocannabinoids. Second, the metabolic enzymes that quickly break down endocannabinoids like anandamide don't work on THC, so THC lingers around for much longer.

It's important to remember that molecules like cannabinoids and other neurotransmitters rarely interact with only one receptor type; they often interact with many. The plant-based cannabinoid CBD illustrates this nicely, as it interacts with numerous receptor types in the brain.

So while plant cannabinoids may activate the same cannabinoid receptors as endocannabinoids, they will likely interact with several other receptors and therefore have distinct effects.

CBD is also interesting because it can affect overall levels of endocannabinoids in the brain, referred to as "endocannabinoid tone." CBD inhibits the FAAH enzyme, which breaks down anandamide. Thus, CBD can increase anandamide levels by preventing FAAH from breaking it down. Inhibiting the FAAH enzyme has been shown to be a useful strategy for treating anxiety disorders, and some of CBD's anti-anxiety properties may come from its ability to inhibit this enzyme and thereby increase endocannabinoid tone.

Endocannabinoid system summary

The endocannabinoid system (ECS), comprised of cannabinoid receptors, endocannabinoid molecules, and their metabolic enzymes, is a crucial molecular system that the body uses to help maintain homeostasis. Because of its vital role in making sure that cells and systems remain in their physiological Goldilocks zone, the ECS is tightly regulated; it gets deployed exactly when and where it's needed. However, this doesn't mean that activating the ECS, through consumption of cannabis or by any other means, will always make things just right.

Like any other complex biological system, the ECS can go awry. "If deviation from physiological homeostasis is prolonged, due to either external factors or chronic pathological conditions, the ECS can lose its time- and space-selective mode of action and start affecting inappropriate cells," Dr. Di Marzo explained. "In these cases, the ECS, instead of being beneficial, may actually contribute to disease progression."

It's important to remember that activating the ECS, through cannabis consumption or by any other means, isn't a cure-all. Like most of biology, it's complicated.

By understanding the biological Goldilocks principle (homeostasis), and how the ECS illustrates this at the cellular level, we can more deeply appreciate why we have an ECS to begin with, and how a variety of cannabis-based therapies might actually work. The presence and critical function of the ECS across many systems of the body, including the nervous and immune systems, explains why such a wide variety of ailments and disease states are responsive to cannabis-based interventions.

References

Gunduz-cinar O, Hill MN, Mcewen BS, Holmes A. Amygdala FAAH and anandamide: mediating protection and recovery from stress. Trends Pharmacol Sci. 2013;34(11):637-44. [PDF]

Ligresti A, De petrocellis L, Di marzo V. From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology. Physiol Rev. 2016;96(4):1593-659. [PDF]

Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333-49. [PDF]

Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215. [PDF]

Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296(5568):678-82. [PDF]

Zlebnik NE, Cheer JF. Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation? Annu Rev Neurosci. 2016;39:1-17. [PDF]

Nick is Leafly's principal research scientist and holds a PhD in neuroscience from Harvard University and a B.S. in genetics from the University of Wisconsin-Madison. He has been a professional cannabis researcher and data scientist since 2016.

More on endocannabinoids

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What is the endocannabinoid system and what is its role?

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Nick Jikomes December 12, 2016 Some of us consume cannabis for its mind-altering effects, while others seek symptom relief. But cannabis wouldn't get us high or have some of its therapeutic benefits if our bodies didn't already contain a biological system capable of interacting with its active chemical compounds, like THC.

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According to research, endocannabinoids suppress and limit the body's immune reaction of inflammation.  Professor Prakash Nagarkatti, Vice President for Research at the university of South Carolina shared: “Most of our research demonstrates that endocannabinoids are produced upon activation of immune cells and may help regulate the immune response by acting as anti-inflammatory agents. Thus, interventions that manipulate the metabolism or production of endocannabinoids may serve as a novel treatment modality against a wide range of inflammatory disease.”

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When speaking of inflammation, we know that inflammation is a natural reaction from the body in attempts to prevent damage or infection to the physical body. It is important that the inflammation stays localized to the site of damage and doesn't persist longer than required. If inflammation occurs for longer than required, this can cause additional damage and chronic inflammation.

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How Does The Endocannabinoid System Effect The Inflammatory response ?

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How Does The Endocannabinoid System Effect The Inflammatory response ?

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The endocannabinoid system (ECS) is a complex cell-signaling system identified in the early 1990s by researchers exploring THC, a well-known cannabinoid. Cannabinoids are compounds found in cannabis.

Experts are still trying to fully understand the ECS. But so far, we know it plays role in regulating a range of functions and processes, including:

The ECS exists and is active in your body even if you don't use cannabis.

Read on to learn more about the ECS including how it works and interacts with cannabis.

The ECS involves three core components: endocannabinoids, receptors, and enzymes.

Endocannabinoids

Endocannabinoids, also called endogenous cannabinoids, are molecules made by your body. They're similar to cannabinoids, but they're produced by your body.

Experts have identified two key endocannabinoids so far:

anandamide (AEA)

2-arachidonoylglyerol (2-AG)

These help keep internal functions running smoothly. Your body produces them as needed, making it difficult to know what typical levels are for each.

Endocannabinoid receptors

These receptors are found throughout your body. Endocannabinoids bind to them in order to signal that the ECS needs to take action.

There are two main endocannabinoid receptors:

CB1 receptors, which are mostly found in the central nervous system

CB2 receptors, which are mostly found in your peripheral nervous system, especially immune cells

Endocannabinoids can bind to either receptor. The effects that result depend on where the receptor is located and which endocannabinoid it binds to.

For example, endocannabinoids might target CB1 receptors in a spinal nerve to relieve pain. Others might bind to a CB2 receptor in your immune cells to signal that your body's experiencing inflammation, a common sign of autoimmune disorders.

Enzymes

Enzymes are responsible for breaking down endocannabinoids once they've carried out their function.

There are two main enzymes responsible for this:

fatty acid amide hydrolase, which breaks down AEA

monoacylglycerol acid lipase, which typically breaks down 2-AG

The ECS is complicated, and experts haven't yet determined exactly how it works or all of its potential functions.

has linked the ECS to the following processes:

appetite and digestion

metabolism

chronic pain

inflammation and other immune system responses

mood

learning and memory

motor control

sleep

cardiovascular system function

muscle formation

bone remodeling and growth

liver function

reproductive system function

skin and nerve function

These functions all contribute to homeostasis, which refers to stability of your internal environment. For example, if an outside force, such as pain from an injury or a fever, throws off your body's homeostasis, your ECS kicks in to help your body return to its ideal operation.

Today, experts believe that maintaining homeostasis if the primary role of the ECS.

Tetrahydrocannabinol (THC) is one of the main cannabinoids found in cannabis. It's the compound that gets you "high."

Once in your body, THC interacts with your ECS by binding to receptors, just like endocannabinoids. It's powerful partly because it can bind to both CB1 and CB2 receptors.

This allows it to have a range of effects on your body and mind, some more desirable than others. For example, THC may help to reduce pain and stimulate your appetite. But it can also cause paranoia and anxiety in some cases.

Experts are currently looking into ways to produce synthetic THC cannabinoids that interact with the ECS in only beneficial ways.

The other major cannabinoid found in cannabis is cannabidiol (CBD). Unlike THC, CBD doesn't make you "high" and typically doesn't cause any negative effects.

Experts aren't completely sure how CBD interacts with the ECS. But they do know that it doesn't bind to CB1 or CB2 receptors the way THC does.

Instead, many believe it works by preventing endocannabinoids from being broken down. This allows them to have more of an effect on your body. Others believe that CBD binds to a receptor that hasn't been discovered yet.

While the details of how it works are still under debate, research suggests that CBD can help with pain, nausea, and other symptoms associated with multiple conditions.

Some experts believe in a theory known as clinical endocannabinoid deficiency (CECD). This theory suggests that low endocannabinoid levels in your body or ECS dysfunction can contribute to the development of certain conditions.

A 2016 article reviewing over 10 years of research on the subject suggests the theory could explain why some people develop migraine, fibromyalgia, and irritable bowel syndrome.

None of these conditions have a clear underlying cause. They're also often resistant to treatment and sometimes occur alongside each other.

If CECD does play any kind of role in these conditions, targeting the ECS or endocannabinoid production could be the missing key to treatment, but more research is needed.

The ECS plays a big role in keeping your internal processes stable. But there's still a lot we don't know about it. As experts develop a better understanding of the ECS, it could eventually hold the key to treating several conditions.

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Endocannabinoid System: A Simple Guide to How It Works

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The endocannabinoid system (ECS) is a complex cell-signaling system identified in the early 1990s by researchers exploring THC, a well-known cannabinoid. Cannabinoids are compounds found in cannabis. Experts are still trying to fully understand the ECS.

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The main function of enzymes is to break down the endocannabinoids once they have completed their initial function.

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Endocannabinoid receptors are receptors that are naturally found throughout the human body. The receptors that are found in the body can be divided into two main receptors. CB1 receptors are found in the central nervous system. CB2 receptors are found in the peripheral nervous system, with a wide range of receptors being imune cells.

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Endocannabinoids are molecules that are made by the human body.

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The endocannabinoid system is a complex body system. The ECS consists of three primary components which are; endocannabinoids, receptors and enzymes.