Medical Cannabis An overview Clinical Prof Nicholas Lintzeris

Medical Cannabis: An overview Clinical Prof Nicholas Lintzeris MBBS, Ph. D, FACh. AM Director D&A Services, SESLHD Lambert Initiative in Cannabinoid Therapeutics, University Sydney

Overview of presentation • History of medical cannabis • Understanding the cannabinoids: what are they and how do they work? • Evidence for medical cannabinoids • Medical cannabis in Australia today

History of medical cannabis • >2000 years of therapeutic use • As late as 19 th century, cannabis preparations widely prescribed by ‘Western’ doctors. – bronchitis, epilepsy, burns, hypnotic, analgesia, PMS • Prohibition since early 20 th Century led to abandonment of cannabis as therapeutic agent • Interest rekindled since 1980’s – Consumer advocacy – Scientific developments

Varieties of Cannabinoids Endocannabinoids Phytocannabinoids Synthetic cannabinoids In your brain and body In plants From the lab Anandamide, 2 -AG, Noladin ether etc. THC, CBD, CBG, CBDV, THCV, CBC, CBN, THCVA etc. Nabilone, HU-210, ABPINACA, JWH-018, etc

Brain regions that express the CB 1 cannabinoid receptor Red = abundant CB 1 receptor expression Black = moderately abundant CB 1 receptor expression Adapted from Joy JE et al, eds. Marijuana and Medicine. 1999.

CB 2 Receptors: immune system modulators • CB 2 receptors found in spleen, tonsils, thymus gland, bones, skin • Localised in monocytes, macrophages, B-cells and T-cells • Limited CB 2 in brain, except in inflammatory states (microglia) • Stimulation of CB 2 can reduce inflammation and neuropathic pain

Varieties of Cannabinoids Endocannabinoids Phytocannabinoids Synthetic cannabinoids In your brain and body In plants From the lab Anandamide, 2 -AG, Noladin ether etc. THC, CBD, CBG, CBDV, THCV, CBC, CBN, THCVA etc. Nabilone, HU-210, ABPINACA, JWH-018, etc

>100 cannabinoids in the plant. Most are non-psychoactive. Each has its own pharmacological actions and therapeutic potential. “Entourage” effects

Potency of NSW police seized cannabis: high THC and low CBD Swift et al PLo. S One 2013 40 Average THC content = 15% 35 35 30 30 25 %CONTENT 85% of samples contained <0. 1% CBD-tot 40 20 25 20 15 15 10 10 5 5 0 THC-A THCTOTAL THC: psychoactive, sedation, analgesia, antiemesis, antispasmodic 0 CBD-A CBD Total CBD: not psychoactive, anxiolytic, antipsychotic, anticonvulsant

Cannabidiol (CBD) modulates many of the effects of THC in cannabis THC and CBD = THC only =

Potential adverse events of cannabis • Cognition – Cannabis use associated with mild cognitive impairments in attention, memory, learning, psychomotor functions – Most effects reversible with abstinence, although may persist in people with early & heavy adolescent use • Mental health – Adolescent cannabis use associated with increased anxiety – Increased risk of psychoses OR = 2. 09 (95%CI 1. 54 to 2. 84) & linked to genetic predisposition • Dependence: estimated at 1 in 10 illicit users • Physical effects – Hypotension, tachycardia, dizziness, dry mouth

Preclinical research identifies a range of possible therapeutic effects from phytocannabinoids

Systematic review Cannabinoids Whiting et al JAMA June 2015 Condition # studies Conclusion Nausea & vomiting 3 RCTs THC or THC/CBD > placebo Weight gain in HIV/AIDS 1 RCT THC > placebo Spasticity in MS / paraplegia 14 RCTs THC/CBD > placebo Depression 3 RCTs Placebo > THC/CBD Anxiety 1 RCT CBD>placebo Sleep 12 RCTs THC/CBD, THC > Placebo Psychosis 1 RCT CBD = amisulpiride Tourette Syndrome 1 RCT THC > placebo Glaucoma 1 RCT THC=CBD=placebo Epilepsy Not completed CBD

Cannabinoids in chronic pain Systematic review: Whiting et al JAMA June 2015

Conditions treated with cannabis (medical marijuana. com) • • • • • Acute Gastritis; Adenomyosis; Alzheimer’s; Amyloidosis; Amyotrophic Lateral Sclerosis (ALS); Anaphylactic or Reaction; Angelman Syndrome; Anorexia; Arthritis; Arthropathy (Gout); Asperger Disorder; Asthma; Attention Deficit Disorder (ADD); Autism Back Pain; Bell's Palsy; Bipolar Disorder; Bruxism; Bulemia Cachexia; Cancer; Carpal Tunnel Syndrome; Cerebral Aneurysm; CFS; Chronic Pain; Cluster Headaches; CMT Disease; Colitis/Ulcerative Colitis; Colon Diverticulitis; Crohn's disease; CVS; Cystic Fibrosis; Cystitis/Urethritis; Darier's Disease; Depression; Diabetes; Diarrhea; Dravet Syndrome; Dupuytren's Contracture; Dyspepsia; Dystonia E. T. ; Eczema; Ehlers Danlos; Emphysema; Endometriosis; Epilepsy/Seizure Disorder Felty's syndrome; Fibromyalgia; Friedreich's Ataxia Gastro. Esophgeal Reflux Disease; Glaucoma; Graves' disease Hemophilia A; Henoch-Schonlein Purpura; Herpes; HIV / AIDS; Hydrocephalus; Hypertension (High Blood Pressure); Hyperventilation; HYPOGLYCEMIA-MMj Treatment Incontinence; Inflammatory Bowel ; Insomnia; Interstitial Pneumonia; Irritable Bowel Syndrome Limbic Rage Syndrome; Liver Disease; Lupus; Lyme Disease; Macular Degeneration; Marfan Syndrome-; mastocytosis; MD; Medical Marijuana as Pain Treatment for Patellofemoral Pain Syndrome; Medical Marijuana Treatment for Addiction; Melorheostosis; Meniere's Disease; Menopausal Syndrome; Migraines; Motion Sickness; Movement Disorders; MRSA; Multiple Sclerosis (MS); Muscle Spasms; Myofascial Pain Nausea; Nephritis; Neurodegenerative Disorders; Neurofibromatosis; Neuropathy; Nightmares; NPS Osgood-Schlatter; Osteogenesis imperfecta; Palmar Hyperhydrosis; Pancreatic Cancer; Pancreatitis; Panic Attacks; Panic Disorder; Pectus carinatum (Pigeon breast/chest); Pemphigus; Peptic Ulcer; Peutz-Jehgers; Polyarteritis Nodosa; Polycythemia vera; Porphyria—Alternative Symptom Treatments; Post Concussion Syndrome; Post Traumatic Stress Disorder; PPS-Post Polio Syndrome; Prostate Cancer; Pruritus Psoriasis; Pylorospasm reflux Radiation Therapy; Raynaud's phenomenon; Reactive Arthritis; RLS-MMj Treats Symptoms SAD; Schizophrenia(s); Scleroderma; Scoliosis; Selectivemutism; Shingles; Sinusitis; Sjogren's Syndrome; Sleep Apnea; Spina Bifida and Medical Marijuana; Sturge-Weber; Syringomyelia Tenosynovitis; Testicular Cancer; Testicular Torsion; Thoracic Outlet Syndrome; Tic Douloureux; Tietze’s Syndrome; Tinnitus; Tourette Syndrome and Cannabinoids; TTM Wolff-Parkinson-White Syndrome

Summary of evidence • Historical records • Animal data shows therapeutic potential • Anecdotal reports & case studies of patient benefit (& harms) • Psychopharmacology studies in humans showing some therapeutic potential • Few RCTs conducted, and the majority with pharmaceutical cannabinoids • Strong consumer demand for making cannabis available for medical use

Cannabinoid medications licensed internationally Cannabinoid Route Indication Nabiximols (Sativex®) Plant extracted Buccal / SL MS spasticity THC: CBD (1: 1) spray Dronabinol (Marinol®) Synthetic THC Oral Anorexia in AIDS, cancer; CINV Nabilone (Cessamet®) Synthetic THC Oral CINV CBD (Epidolex®) Plant extracted Oral CBD Cannabis plant matter Nil yet Various % THC, Vaporised Range of conditions CBD available in Holland, Israel, Canada

Vaporising cannabis • Similar to ‘e-cigarrettes’ • Vaporising heats cannabis at lower temperature than ‘smoking’. Higher bioavailability. • No side stream smoke (fewer concerns re: passive smoking) • Peak THC effects: typically 1590 min after dose, psychoactive effects for 2 -3 hours

The United States of Marijuana

Colorado dispensary

‘Medical cannabis’ in Australia today • Only illicit cannabis products – Home grown, ‘Street’ supplies, artisanal growers, imported – First legal framework (for terminal illness only) Dec 2014 • Swift et al 2005: surveyed 147 medical cannabis users – Chronic pain 57%, depression 56%, arthritis 35%, nausea 27% • Degenhardt et al 2014: 1500 CNMP patients – 6. 3% CNMP used cannabis past month for pain – Analgesic effects rated as good as / better than opioids – 25% subjects said they would use cannabis if they could! • Paediatric epilepsy: – a number of ‘artisanal’ products illegally available in Australia – CBD rich hemp products imported from USA / EU

Implications for clinicians today • Use of illicit cannabis for ‘medical’ purposes is common in some areas of medicine. • Most patients will not disclose & most doctors won’t ask • Medical cannabis to become more common in Australia – Increasing advocacy despite unclear evidence of efficacy for most conditions – What role for health providers? • Need for better understanding and education of health providers of the potential harms and therapeutic roles of cannabinoids.