(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:

Report online Call toll-free at 1-866-234-2345 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

Figure 1.

The Endocannabinoid System in the Nervous System

The Endocannabinoid System in the Nervous System Figure 2.

Pharmacokinetics of THC

Pharmacokinetics of THC Figure 3.

A Proposed Clinical Algorithm for Physicians Considering Supporting Therapeutic Use of Cannabis for a Patient with Chronic, Intractable Neuropathic Pain

Tables

Table 1 .

Selected Pharmacologic Actions of Cannabis/Psychoactive Cannabinoids

. Selected Pharmacologic Actions of Cannabis/Psychoactive Cannabinoids Table 2 .

Recommendations for the Evaluation and Management of Patients

. Recommendations for the Evaluation and Management of Patients Table 3 .

Relationship between THC Percent in Plant Material and the Available Dose (in mg THC) in an Average Joint

. Relationship between THC Percent in Plant Material and the Available Dose (in mg THC) in an Average Joint Table 4 .

Comparison between Cannabis and Prescription Cannabinoid Medications

. Comparison between Cannabis and Prescription Cannabinoid Medications Table 5.

Published Positive, Randomized, Double-Blind, Placebo-Controlled, Clinical Trials on Smoked/Vapourized Cannabis and Associated Therapeutic Benefits

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 AUC 12 : 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 Ca2+: 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 ED 50 : 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 FEV 1 : 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 H1-MRS: 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 IC 50 : 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 K+: potassium kg: kilogram L: liter LCT: lipid long-chain triglyceride LD 50 : 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 Na+: 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 Δ9-THC: 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:

Donald I. Abrams, M.D.

Chief, Hematology-Oncology

San Francisco General Hospital

Integrative Oncology

UCSF Osher Center for Integrative Medicine

Professor of Clinical Medicine

University of California San Francisco

San Francisco, CA 94143-0874

USA

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

Bruna Brands, Ph.D.

Full Professor

Department of Pharmacology and Toxicology

Program Director, Collaborative Program in Addiction Studies

University of Toronto

33 Russell Street

Toronto, ON

M5S 2S1

Canada

Ziva Cooper, Ph.D.

Assistant Professor of Clinical Neurobiology

Division on Substance Abuse

New York State Psychiatric Institute and Department of Psychiatry

College of Physicians and Surgeons Columbia University

1051 Riverside Drive

New York, NY 10032

USA

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

Mahmoud A. ElSohly, Ph.D.

Research Professor and Professor of Pharmaceutics

National Center for Natural Products Research and Department of Pharmaceutics

School of Pharmacy

University of Mississippi

University, MS 38677

USA

Javier Fernandez-Ruiz, Ph.D.

Full Professor of Biochemistry and Molecular Biology

Department of Biochemistry and Molecular Biology

Faculty of Medicine

Complutense University

Madrid, 28040

Spain

Tony P. George, M.D., F.R.C.P.C.

Professor and Co-Director, Division of Brain and Therapeutics

Department of Psychiatry, University of Toronto

Chief, Schizophrenia Division

Centre for Addiction and Mental Health

1001 Queen Street West, Unit 2, Room 118A

Toronto, ON

M6J 1H4

Canada

Manuel Guzman, Ph.D.

Full Professor

Department of Biochemistry and Molecular Biology

Faculty of Chemistry

Complutense University

Madrid, 28040

Spain

Matthew N. Hill, Ph.D.

Assistant Professor

Departments of Cell Biology and Anatomy & Psychiatry

The Hotchkiss Brain Institute

University of Calgary

Calgary, AB

T2N 4N1

Canada

Cecilia J. Hillard, Ph.D.

Professor

Department of Pharmacology and Toxicology

Director of the Neuroscience Research Center

Medical College of Wisconsin

8701 Watertown Plank Road

Milwaukee, Wisconsin 53226

USA

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

4th Floor Dickson Building

5820 University Avenue

Halifax, NS

B3H 1V7

Canada

Jason J. McDougall, Ph.D.

Professor

Departments of Pharmacology and Anaesthesia, Pain Management & Perioperative Medicine

Dalhousie University

5850 College Street

Halifax, NS

B3H 4R2

Canada

Raphael Mechoulam, Ph.D.

Professor

Institute for Drug Research, Medical Faculty

Hebrew University

Jerusalem

91120

Israel

Linda Parker, Ph.D.

Professor and Canada Research Chair

Department of Psychology

University of Guelph

Guelph, Ontario

N1G 2W1

Canada

Roger G. Pertwee, MA, D.Phil. D.Sc.

Professor of Neuropharmacology

Institute of Medical Sciences

University of Aberdeen

Aberdeen

AB25 2ZD

Scotland, United Kingdom

Keith Sharkey, Ph.D.

Professor

Department of Physiology and Biophysics and Medicine

University of Calgary

HSC 1745

3330 Hospital Drive NW

Calgary, AB

T2N 4N1

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

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.

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

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 suggest 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 suggest 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.

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 CB 1 R agonists (THC) may have either pro- or anti-epileptic properties.

R 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.

(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

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.

4.7.2 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 CB 1 and CB 2 receptors alleviates symptoms of osteoarthritis (OA), and THC and CBD alleviate symptoms of rheumatoid arthritis (RA).

and CB 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 CB 1 and CB 2 receptor agonist may alleviate dystonia-like symptoms, and CBD delays dystonia progression.

and CB 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

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.

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

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.

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

Pre-clinical and human experimental studies suggest a role for certain cannabinoids in alleviating post-traumatic stress disorder (PTSD)-like symptoms.

However, while limited evidence from short-term clinical studies suggests a potential for oral THC and nabilone to decrease certain symptoms of PTSD, there are no long-term clinical studies for these preparations or any clinical studies of smoked/vapourized cannabis for PTSD.

Limited evidence from observational studies suggests an association between herbal cannabis use and persistent/high levels of PTSD symptom severity over time.

There is limited evidence to suggest an association between PTSD and CUD.

4.9.5.4 Alcohol and opioid withdrawal symptoms (drug withdrawal symptoms/drug substitution)

Pre-clinical studies suggest CB 1 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.

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

Pre-clinical studies in animal models of irritable bowel syndrome (IBS) suggest that certain synthetic cannabinoid receptor agonists inhibit colorectal distension-induced pain responses and slow GI transit.

Experimental clinical studies with healthy volunteers reported dose- and sex-dependent effects on various measures of GI motility.

Limited evidence from one small clinical study with dronabinol for symptoms of IBS suggests dronabinol may increase colonic compliance and decrease colonic motility index in female patients with diarrhea-predominant IBS (IBS-D) or with alternating pattern (alternating constipation/diarrhea) IBS (IBS-A), while another small clinical study with dronabinol suggests a lack of effect on gastric, small bowel or colonic transit.

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 CB 1 and CB 2 receptor agonists, THC, CBD, CBG, CBC, whole plant cannabis extract) may limit intestinal inflammation and disease severity to varying degrees.

and CB 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 CB 1 receptor activation is detrimental in liver diseases (e.g. promotes steatosis, fibrosis); while CB 2 receptor activation appears to have some beneficial effects.

receptor activation is detrimental in liver diseases (e.g. promotes steatosis, fibrosis); while CB 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 CB 1 receptor activation results in increased fat synthesis and storage while chronic CB 1 receptor activation (or CB 1 receptor antagonism) results in weight loss and improvement in a variety of metabolic indicators.

receptor activation results in increased fat synthesis and storage while chronic CB receptor activation (or CB 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)

Pre-clinical studies in experimental animal models of certain cannabinoids in the treatment of acute or chronic pancreatitis are limited and conflicting.

Limited evidence from case studies suggests an association between acute episodes of heavy cannabis use and acute pancreatitis.

Limited observational studies suggest an association between chronic cannabis use and lower incidence of diabetes mellitus.

One small clinical study reported that orally administered THC did not alleviate abdominal pain associated with chronic 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

Evidence from pre-clinical studies suggests that cannabis smoke contains many of the same respiratory irritants and toxins as tobacco smoke, and even greater quantities of some such substances.

Case studies suggest that cannabis smoking is associated with a variety of histopathological changes in respiratory tissues, a variety of respiratory symptoms similar to those seen in tobacco smokers, and changes in certain lung functions with frequent, long-term use.

The association between chronic heavy cannabis smoking (without tobacco) and chronic obstructive pulmonary disease, is unclear, but if there is one, is possibly small.

7.3 Immune system

Pre-clinical studies suggest certain cannabinoids have a variety of complex effects on immune system function (pro-/anti-inflammatory, stimulatory/inhibitory).

The limited clinical and observational studies of the effects of cannabis on immune cell counts and effect on HIV viral load are mixed, as is the evidence around frequent cannabis use (i.e. daily/CUD) and adherence to ART.

Limited but increasing evidence from case studies also suggests cannabis use is associated with allergic/hypersensitivity-type reactions.

7.4 Reproductive and endocrine systems

Pre-clinical evidence suggests certain cannabinoids can have negative effects on a variety of measures of reproductive health. Furthermore, limited evidence from human observational studies with cannabis appears to support evidence from some pre-clinical studies.

Evidence from human observational studies also suggests a dose- and age-dependent association between cannabis use and testicular germ cell tumours.

Pre-clinical evidence clearly suggests in utero exposure to certain cannabinoids is associated with a number of short and long-term harms to the developing offspring.

However, evidence from human observational studies is complex and suggests that while confounding factors may account for associations between heavy cannabis use during pregnancy and adverse neonatal or perinatal effects, heavy cannabis use during pregnancy is associated with reduced neonatal birth weight.

7.5 Cardiovascular system

Pre-clinical studies suggest that ultra-low doses of THC may be cardioprotective on experimentally-induced myocardial infarction.

Evidence from case and observational studies suggests that acute and chronic smoking of cannabis is associated with harmful effects on vascular, cardiovascular and cerebrovascular health (e.g. myocardial infarction, strokes, arteritis) especially in middle-aged (and older) users.

However, a recent systematic review suggests that evidence examining the effects of cannabis on cardiovascular health is inconsistent and insufficient.

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

Evidence from experimental clinical studies suggests acute use of (THC-predominant) cannabis impairs a number of psychomotor and other cognitive skills needed to drive a motor vehicle.

While chronic/frequent cannabis use may be associated with a degree of tolerance to some of the effects of cannabis in some individuals, chronic cannabis use can still pose risks to safe driving due, in part, to significant body burden of THC leading to a chronic level of psychomotor impairment.

Evidence from clinical and epidemiological studies suggests a dose-response effect, with increasing doses of THC increasing the risk of motor vehicle crashes that can lead to injuries and death.

Combining alcohol with cannabis (THC) is associated with an increased degree of impairment and increased risk of harm.

7.7.3 Psychiatric effects

7.7.3.1 Anxiety, PTSD, depression and bipolar disorder

Evidence from clinical studies suggests a dose-dependent, bi-phasic effect of THC on anxiety and mood, where low doses of THC appear to have an anti-anxiety and mood-elevating effect whereas high doses of THC can produce anxiety and lower mood.

Epidemiological studies suggest an association between (THC-predominant) cannabis use, especially chronic, heavy use and the onset of anxiety, depressive and bipolar disorders, and the persistence of symptoms related to PTSD, panic disorder, depressive disorder, and bipolar disorder.

Preliminary evidence from surveys suggests an association between use of ultra-high-potency cannabis concentrate products (e.g. butane hash oil, BHO) and higher rates of self-reported anxiety and depression and other illicit drug use as well as higher levels of physical dependence than with high-potency herbal cannabis.

7.7.3.2 Schizophrenia and psychosis

Evidence from clinical studies suggests that acute exposure to (THC-predominant) cannabis or THC is associated with dose-dependent, acute and transient behavioural and cognitive effects mimicking acute psychosis.

Epidemiological studies suggest an association between (THC-predominant) cannabis use, especially early, chronic, and heavy use and psychosis and schizophrenia.

The risk of schizophrenia associated with cannabis use is especially high in individuals who have a personal or family history of schizophrenia.

Cannabis use is also associated with earlier onset of schizophrenia in vulnerable individuals and exacerbation of existing schizophrenic symptoms and worse clinical outcomes.

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) (Figure 1) 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 bodyReference 1. 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/moodReference 2-Reference 4. Furthermore, there is strong evidence that dysregulation of the ECS contributes to many human diseases including pain, inflammation, psychiatric disorders and neurodegenerative diseasesReference 5.

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) (Figure 1)Reference 2. 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-docosatetraenoylethanolamineReference 2Reference 6-Reference 9. 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)Reference 9. 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) channelReference 10. This type of effect has been generally referred to as the so-called "entourage effect"Reference 10Reference 11. 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 requirementsReference 2Reference 12-Reference 14. 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 DReference 2Reference 15. 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 anandamideReference 16. 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 DAGLReference 2Reference 15. While anandamide and 2-AG are both derivatives of arachidonic acid, they are synthesized by pathways distinct from those used to synthesize eicosanoidsReference 17. Nevertheless, it appears that there may be a certain amount of cross talk between the eicosanoid and endocannabinoid pathwaysReference 17.

Genetics and signaling through the cannabinoid receptors

Endocannabinoids such as anandamide and 2-AG, as well as the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC), Δ8-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 cascadesReference 18Reference 19. 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 1p36Reference 20. The CNR1 coding sequence consists of one exon encoding a protein of 472 amino acidsReference 21. The CB 1 receptor protein shares 97 - 99% amino acid sequence identity across species (human, rat, mouse)Reference 21. 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 lengthReference 21. 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 receptorReference 21.

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 Ca2+ influx through various Ca2+ channels; it also results in stimulation of inwardly rectifying potassium (K+) channels and the mitogen-activated protein kinase signaling cascadesReference 3Reference 13. Anandamide is a partial agonist at cannabinoid receptors, and binds with slightly higher affinity at CB 1 compared to CB 2 receptorsReference 2Reference 22. 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 receptorsReference 2Reference 22.

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 effectsReference 2Reference 18Reference 23. 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 (Figure 1)Reference 3. This retrograde signaling mechanism permits the regulation of neurotransmission in a precise spatio-temporal mannerReference 3. 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 functionReference 19.

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 systemsReference 19. 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 interneuronsReference 4Reference 23Reference 24. CB 1 receptor density is highest in the cingulate gyrus, the frontal cortex, the hippocampus, the cerebellum, and the basal gangliaReference 5. 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/brainstemReference 5. Relatively little CB 1 receptor expression is found in the thalamus and the primary motor cortexReference 5. 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 skinReference 25-Reference 43. 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-populationsReference 44Reference 45.

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 Section 2.1 and consult the following resourcesReference 8Reference 9Reference 22Reference 46-Reference 49. Modulation of these other cannabinoid targets adds additional layers of complexity to the known myriad effects of cannabinoids.

Signal termination

Endocannabinoid signaling is rapidly terminated by the action of two hydrolytic enzymes: FAAH and MAGLReference 3. FAAH is primarily localized post-synapticallyReference 50Reference 51 and preferentially degrades anandamideReference 14; MAGL is primarily localized pre-synapticallyReference 50Reference 51 and favors the catabolism of 2-AG (Figure 1)Reference 14. Signal termination is important in ensuring that biological activities are properly regulated and prolonged signaling activity, such as by the use of cannabis, can have potentially deleterious effectsReference 52Reference 53.

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

Dysregulation of the ECS appears to be connected to a number of pathological conditions, with the changes in the functioning of the system being either protective or harmfulReference 54. Modulation of the ECS either through the targeted inhibition of specific metabolic pathways, and/or directed agonism or antagonism of its receptors may hold therapeutic promiseReference 13. However, a major and consistent therapeutic challenge confronting the routine use of (THC-predominant) cannabis and psychoactive cannabinoids (e.g. THC) in the clinic has remained that of achieving selective targeting of the site of disease or symptoms and the sparing of other bodily regions such as the mood and cognitive centres of the brainReference 23Reference 54-Reference 57. Despite this significant challenge, emerging evidence from clinical studies of smoked or vapourized (THC-predominant) cannabis for chronic non-cancer pain (mainly neuropathic pain) suggests that use of very low doses of THC (< 3 mg/dose) may confer therapeutic benefits with minimal psychoactive side effectsReference 58Reference 59 (and also see Section 3.0 and 4.7.2.2 for additional details).

Role of the endocannabinoid system in nervous system development

The CB 1 receptor is highly expressed in the developing brainReference 60. 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 retroflexusReference 60. 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 regionReference 60. The available evidence suggests a neurodevelopmental role for the ECS including in functions such as survival, proliferation, migration and differentiation of neuronal progenitorsReference 60. 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 phenotypeReference 60Reference 61. 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 targetsReference 60. 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 communicationReference 60. 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 behavioursReference 61 (and also see Sections 2.5 and 7.4 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 cerebrumReference 62. 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 morphologyReference 62. 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 receptorReference 63.

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 Ca2+ 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 climatesReference 67. The leaves and flowering tops of Cannabis contain over 500 distinct compounds distributed among 18 different chemical classes, and harbor over 100 different phytocannabinoidsReference 68-Reference 71 The principal phytocannabinoids appear to be delta-9-tetrahydrocannabinol (i.e. Δ9-THC, THC), CBN, and cannabidiol (CBD)Reference 72-Reference 74, 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 techniquesReference 75Reference 76. Other phytocannabinoids found in cannabis include cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabivarin (THCV) and many othersReference 70. 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)Reference 77-Reference 79. 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, Δ9-THC is by far the best studied and is responsible for many, if not most, of the physical and psychotropic effects of

cannabisReference 80. Other phytocannabinoids (e.g. CBD, CBC, CBG) are present in lesser amounts in the plant and have little, if any, psychotropic propertiesReference 80. 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 pigmentsReference 70. 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 varietiesReference 81. Of note, cannabis smoke contains many compounds not observed in either extracts or vapour, including a number which are known or suspected carcinogens or mutagensReference 81-Reference 83. Moreover, comparisons between cannabis smoke and tobacco smoke have shown that the former contains many of the same carcinogenic chemicals found in the latterReference 82Reference 84 (see Section 7.1 for more information).

Relatively little is known about the pharmacological actions of the various other compounds found within cannabis (e.g. terpenes, flavonoids). However, it is believed that some of these compounds (e.g. terpenes) may have a broad spectrum of action (e.g. anti-oxidant, anti-anxiety, anti-inflammatory, anti-bacterial, anti-neoplastic, anti-malarial), but this information comes from a few in vitro and in vivo studies and no clinical trials exist to support these claims. Terpenes vary widely among cannabis varieties and are thought to be primarily responsible for differences in fragrance among the different Cannabis strainsReference 75. Furthermore, it is thought that terpenes may contribute to the distinctive smoking qualities and possibly to the character of the "high" associated with smoking cannabisReference 75, but again, this has not been studied in any detail. The concept that terpenes may somehow modify or enhance the physiological effects of the cannabinoidsReference 85Reference 86,i.e. the "entourage effect", is, for the moment, hypothetical as there is little, if any, pre-clinical evidence to support this hypothesis and no clinical trials on this subject have been carried out to date.

1.1.3 Stability and storage

Most of the information on the stability of cannabis does not distinguish between Δ9-THC and its carboxylic acid (Δ9-THCA). The latter is transformed to Δ9-THC by heating during vapourization or cooking, or by pyrolysis during smoking or in the inlet of gas chromatographs used in forensic analysisReference 87. Complete decarboxylation of Δ9-THCA to Δ9-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 °CReference 88-Reference 90. Heat, light, humidity, acidity and oxidation all affect the stability of cannabis and phytocannabinoidsReference 91Reference 92. 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 containersReference 93. Even when stored at +18 °C, only a third of the Δ9-THC content is lost over a five-year period with some increase in the concentration of CBN. Cannabis cigarettes with lower Δ9-THC content (1.15% THC) appear to lose more Δ9-THC compared to cigarettes with higher Δ9-THC content (2.87% THC)Reference 93. 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 respectivelyReference 94. 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)Reference 95. 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, Δ9-THC, which acts as a partial agonist at both CB receptorsReference 46Reference 48Reference 96, has activity at non-CB receptors and other targetsReference 46Reference 48Reference 97, and is responsible for the psychoactive and potential therapeutic effects of cannabis through its actions at the CB 1 receptorReference 46Reference 48Reference 98. Δ8 -THC (an isomer of Δ9-THC) is found in smaller amounts in the plant, but like Δ9-THC, it is a partial agonist at both CB receptors and shares relatively similar efficacy and potency with Δ9-THC in in vitro assaysReference 96. An in vivo animal study and one clinical study suggest Δ8 -THC to be a more potent anti-emetic than Δ9-THCReference 99Reference 100.

CBN is a product of Δ9-THC oxidation and has 10% of the activity of Δ9-THC at the CB 1 receptorReference 101. Its effects are not well studied but it appears to have some possible immunosuppressive properties in a small number of in vitro studiesReference 102.

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 propertiesReference 49Reference 101Reference 103Reference 104. 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 cytotoxicityReference 104. Cannabigerolic acid has a similar profile. CBG has also been shown to block 5-HT 1A receptors and act as an α 2 -adrenoceptor agonistReference 105. There is some emerging evidence that suggests CBG can produce signs of analgesia by activation of α 2 -adrenoceptorsReference 46.

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 receptorsReference 106. 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 enzymesReference 18Reference 101Reference 107. 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+/Ca2+)-exchangerReference 108. 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 effectsReference 101Reference 108Reference 109.

THCV acts as a CB 1 receptor antagonist and CB 2 receptor partial agonist in vitro and in vivoReference 110Reference 111, as well as a 5-HT 1A receptor agonistReference 47 and pre-clinical studies suggest it may have anti-epileptiform/anti-convulsant, anti-nociceptive and potential anti-psychotic propertiesReference 47Reference 108Reference 112.

Much of what is known about the beneficial properties of the non-psychotropic cannabinoids (e.g. CBD, THCV) is derived from in vitro and in vivo studies and few well-conducted, rigorous clinical studies of these substances exist. However, the results from these pre-clinical studies point to potential therapeutic indications such as psychosis, epilepsy, anxiety, sleep disturbances, neurodegeneration, cerebral and myocardial ischemia, inflammation, pain and immune responses, emesis, food intake, type-1 diabetes, liver disease, osteogenesis, and cancerReference 18Reference 101Reference 113. For more in-depth information on the pharmacology of cannabinoids, the reader is invited to consult the following resourcesReference 22Reference 46Reference 48Reference 101Reference 114.

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 Δ9-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 Δ9-THC and CBDReference 46Reference 48Reference 106Reference 115-Reference 136. The discrepancies in the nature of the interactions between Δ9-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 Δ9-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 measuredReference 123.

Pharmacokinetic vs. pharmacodynamic interactions

In general, there appear to be two types of mechanisms which could govern possible interactions between CBD and Δ9-THC: those of apharmacokinetic originReference 123Reference 129, and those of a pharmacodynamic originReference 133Reference 135. 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 THCReference 123Reference 129.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: 1Reference 120Reference 134, whereas CBD appears to potentiate some of the effects associated with THC when the CBD to THC ratio is around 2: 1Reference 120. 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 Section 4.3 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 Δ9-THC, CBD, or other cannabinoids such as CBC in smoked cannabisReference 128Reference 137. 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 testsReference 128. 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 Δ9-THC (using matched doses of Δ9-THC) to normal, healthy subjectsReference 137. This double-blind, placebo-controlled, within-subject, crossover clinical study reported few reliable differences between the THC-only and whole-plant cannabis conditionsReference 137. 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 studyReference 138, (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 subjectsReference 122. 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"Reference 122.

An internet-based, cross-sectional study of 1 877 individuals with a consistent history of cannabis use reported that those individuals who had indicated using cannabis with a higher CBD to THC ratio had also reported experiencing fewer psychotic symptoms (an effect typically associated with exposure to higher doses of THC)Reference 139. However, the authors noted that the effects were subtle. The study was also hampered by a number of important methodological issues suggesting that the conclusions should be interpreted with caution.

Brunt et al. (2014) conducted a study examining the self-reported therapeutic satisfaction and subjective effects of different strains of pharmaceutical-grade cannabis sold in the NetherlandsReference 118. The authors reported that among the study population of about 100 patients using medical cannabis for conditions such as multiple sclerosis (MS), chronic pain, nausea, cancer and psychological problems, those who used cannabis with cannabinoid concentrations of 6% THC and 7.5% CBD (i.e. "low THC" cannabis) reported significantly less anxiety and dejection (i.e. feeling down, sad, depressed), but also reported less appetite stimulation. Importantly, those patients using the "low THC" condition reported equivalent levels of therapeutic satisfaction as those patients who reported using "high THC" (19% THC, < 1% CBD) and "medium THC" (12% THC, < 1% CBD) cannabis. There was also surprisingly little difference in terms of daily gram amount used between the different THC/CBD varieties with all categories reporting, on average, use of less than one gram of dried cannabis per day. The study findings are also consistent with the rest of the literature in terms of the average daily gram dose of dried cannabis used by patients (i.e. up to 3 g at most, but generally around one gram or less of variable THC content). Taken together, the study suggests that the use of cannabis containing approximately equivalent "lower" levels of THC and "higher" levels of CBD is associated with self-reported therapeutic efficacy and satisfaction across a number of different medical conditions for which dried cannabis is typically used, and also associated with attenuated levels of mood perturbation. The evidence also suggests that cannabis containing higher levels of THC and little CBD is not necessarily more effective than lower dose strains, except for stimulation of appetite. However, the study findings suggest that the use of higher-THC strains is associated with greater mood perturbation than the lower-THC strains. The study carried a number of caveats being that it only looked at a small number of patients, had a limited number of medical conditions and consisted of a self-reported survey.

Two in vivo studies conducted in non-human primates (i.e. rhesus monkeys) showed that CBD attenuated some of the effects of THC including cognitive-impairing effects and disruption of motor inhibitory behaviourReference 115Reference 119.

An in vivo study conducted in non-human primates (i.e. rhesus monkeys) showed that CBD, administered in a 1: 1 ratio with THC, attenuated some of the cognitive-impairing effects of THC, especially effects on spatial memory, but not on THC-induced performance deficits (i.e. non-specific motor and motivational effects)Reference 119. Another in vivo study conducted in non-human primates (i.e. rhesus monkeys) examining the acute and chronic effects of CBD on THC-induced disruption of motor inhibitory behaviour showed that CBD, at ratios of 3: 1 but not 1: 1 relative to THC, attenuated some of the acute and chronic behavioural effects of higher-dose THC on disruption of motor inhibitory behaviourReference 115.

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 Δ9-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 administrationReference 80. However, some people can experience dysphoria and anxietyReference 140. Tachycardia is the most consistent of the acute physiological effects associated with the consumption of cannabisReference 141-Reference 144.

The short-term psychoactive effects associated with cannabis smoking in non-medical users include the above-mentioned euphoria but also relaxation, time-distortion, intensification of ordinary sensory experiences (such as eating, watching films, and listening to music), and loss of inhibitions that may result in laughterReference 145. This is followed by a depressant periodReference 146. Most reviews note that cannabis use is associated with impaired function in a variety of cognitive and short-term memory tasksReference 102Reference 146-Reference 151 and the levels of Δ9-THC in the plasma after smoking appear to have a dose, time, and concentration-dependent effect on cognitive functionReference 152-Reference 154. Driving and operation of intricate machinery, including aircraft, may be significantly impairedReference 155-Reference 158.

Table 1 (below), adapted from a reviewReference 159, 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 useReference 141Reference 160Reference 161. Effects differ greatly among individuals and may be greater in those who are young, severely ill, elderly, or in those taking other drugs.

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 Figure 2 (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 administrationReference 78. The amount of Δ9-THC (and other cannabinoids) delivered from cannabis cigarettes is not uniform and is a major variable in the assessment of absorptionReference 78. 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 subjectReference 78Reference 401. While it has been reported that smokers can titrate their Δ9-THC intake, to a certain extent, by adapting their smoking behaviour to obtain desired levels of Δ9-THCReference 402, other reasons may also explain the observed variation in smoking topographyReference 403. As mentioned, Δ9-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 breathholdReference 400Reference 404. 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 amountReference 141Reference 405. 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%)Reference 406.

The relationships between cannabis Δ9-THC content, dose administered, and resultant plasma levels have been investigated. Mean plasma Δ9-THC concentrations were 7.0 ng/mL and 18.1 ng/mL upon a single inhalation of either a 1.75% "low-dose" Δ9-THC cannabis cigarette (total available dose ~16 mg Δ9-THC), or a 3.55% Δ9-THC "high-dose" cannabis cigarette (total available dose ~34 mg Δ9-THC)Reference 78. Smoking cannabis containing 1.64% Δ9-THC (mean available dose 13.0 mg Δ9-THC) resulted in mean peak THC plasma levels of 77 ng/mLReference 407. Similarly, smoking cannabis joints containing 1.8% Δ9-THC (total available dose ~14 mg Δ9-THC) resulted in mean peak plasma THC levels of approximately 75 ng/mL, whereas with 3.6% Δ9-THC (total available dose ~28.8 mg Δ9-THC), mean peak plasma Δ9-THC levels of 100 ng/mL were attainedReference 408. Smoking a 25 mg dose of cannabis in a pipe containing 2.5, 6, or 9.4% Δ9-THC (total available doses of ~0.6, 1.5, or 2.4 mg Δ9-THC) was associated with mean peak plasma Δ9-THC concentrations of 10, 25, or 45 ng/mL Δ9-THC, respectivelyReference 59. 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 Δ9-THC (occurring 15 min after starting smoking)Reference 409. 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-doseReference 410. The estimated systemic bioavailability of CBD by smoking was 31 % (range: 11 - 45%), generally similar to that seen with Δ9-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 Δ9-THC (and CBD) from the cannabis materialReference 402Reference 411-Reference 414. The subjective effects and plasma concentrations of Δ9-THC obtained by vapourization of cannabis are comparable to those obtained by smoking cannabisReference 402. In addition, the study reported that vapourization was well tolerated with no reported adverse effects, and was preferred over smoking by the test subjectsReference 402. While vapourization has been reported to be amenable to self-titration (as has been claimed for smoking)Reference 402Reference 413, the proper use of the vapourizer for optimal administration of cannabis for therapeutic purposes needs to be established in more detailReference 414. 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 Δ9-THC and other phytocannabinoidsReference 413. Bioequivalence of vapourization compared to smoking has not been thoroughly established. Inhalation of vapourized cannabis (900 mg of 3.56% Δ9-THC; total available dose of 32 mg of Δ9-THC) in a group of patients taking stable doses of sustained-release morphine or oxycodone resulted in mean plasma Δ9-THC levels of 126.1 ng/mL within 3 min after starting cannabis inhalation, rapidly declining to 33.7 ng/mL Δ9-THC at 10 min, and reaching 6.4 ng/mL Δ9-THC at 60 minReference 280. Peak Δ9-THC concentration (C max ) was achieved at 3 min in all study participantsReference 280. 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 exposureReference 280. 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 respectivelyReference 206. 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-vapourizationReference 415. 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 respectivelyReference 416. 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

Whereas the acute effects on the CNS and physiological effects occur within minutes by the smoking route or by vapourizationReference 149Reference 417, the acute effects proceed on a time scale of hours in the case of oral ingestionReference 417Reference 418. Acute oral administration results in a slower onset of action, lower peak blood levels of cannabinoids, and a longer duration of pharmacodynamic effects compared to smokingReference 78. The psychotropic effect or "high" occurs much more quickly by the smoking than by the oral route, which is the reason why smoking appears to be the preferred route of administration by many, especially among non-medical usersReference 419.

For orally administered prescription cannabinoid medicines such as synthetic Δ9-THC (dronabinol, formerly marketed as Marinol®), only 10 to 20% of the administered dose enters the systemic circulation indicating extensive hepatic first-pass metabolismReference 227. Administration of a single 2.5 mg dose of dronabinol in healthy volunteers was associated with a mean plasma Δ9-THC C max of 0.7 ng/mL (range: 0.3 - 1 ng/mL), and a mean time to peak plasma Δ9-THC concentration of 2 h (range: 30 min - 4 h)Reference 227. A single 5 mg dose of dronabinol gave a reported mean plasma Δ9-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 Δ9-THC C max of 6.2 ng/mL (range: 3.5 - 9 ng/mL)Reference 227. Again, the mean time to peak plasma Δ9-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 Δ9-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 Δ9-THC concentration ranging between 30 min and 4 h after oral administrationReference 227. Continuous dosing for seven days with 20 mg doses of dronabinol (total daily doses of 40 - 120 mg dronabinol) gave mean plasma Δ9-THC concentrations of ~20 ng/mLReference 420.

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-THCReference 180. 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 variationReference 421. 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.

Δ9-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 Δ9-THC in a chocolate cookie was described as slow and unreliableReference 401, with a systemic availability of only 4 to 12%Reference 407. While most subjects displayed peak plasma Δ9-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 peakReference 78. Consumption of cannabis-laced brownies containing 2.8% Δ9-THC (44.8 mg total Δ9-THC) was associated with changes in behaviour, although the effects were slow to appear and variableReference 418. Peak effects occurred 2.5 to 3.5 h after dosing. Modest changes in pulse and blood pressure were also noted. Plasma concentrations of Δ9-THC were not measured in this study. In another study, ingestion of brownies containing a low dose of Δ9-THC (9 mg THC/brownie) was associated with mean peak plasma Δ9-THC levels of 5 ng/mLReference 137. Ingestion of brownies containing a higher dose of Δ9-THC (~13 mg Δ9-THC/brownie) was associated with mean peak plasma Δ9-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 THCReference 137. Using equivalent amounts of Δ9-THC, inhalation by smoking cannabis yielded peak plasma levels of Δ9-THC several-fold (five to six times or more) higher than when Δ9-THC was absorbed through the oral routeReference 137. Tea made from dried cannabis flowering tops (19.1% Δ9-THCA, 0.6% Δ9-THC) has been documented, but the bioavailability of Δ9-THC from such teas is likely to be smaller than that achieved by smoking because of the poor water solubility of Δ9-THC and the extensive hepatic first-pass effectReference 422.

After oral administration of chocolate cookies containing 40 mg CBD in healthy human subjects, mean plasma CBD levels ranged between 1.1 and 11 ng/mL (mean: 5.5 ng/mL) after one hour and the course of CBD in the plasma over six hours was in the same range as the course after 20 mg THCReference 423. Daily oral doses of 10 mg/kg CBD for six weeks resulted in a mean weekly plasma concentration of 5.9 - 11.2 ng/mLReference 424. Oral intake of 5.4 mg CBD resulted in plasma CBD concentrations ranging between 0.2 and 2.6 ng/mL (mean: 0.95 ng/mL) after one hourReference 425. Bioavailability through the oral route was estimated at 6%Reference 423Reference 426.

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 ratsReference 427. 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 b