Medical Cannabis: An overview Clinical Prof Nicholas Lintzeris MBBS, PhD, FAChAM 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

Galen: greek physician prescribed cannabis 150 AD William Oshaunnessy: Irish physician in Br East India company: documented medical cannabis use in India Hua Tuo: Han dynasty: 2nd century AD: first anaesthetic for surgery: combination of cannabis and wine.

History of medical cannabis >2000 years of therapeutic use As late as 19th century, cannabis preparations widely prescribed by ‘Western’ doctors. bronchitis, epilepsy, burns, hypnotic, analgesia, PMS Prohibition since early 20th 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, AB-PINACA, JWH-018, etc

Brain regions that express the CB1 cannabinoid receptor Red = abundant CB1 receptor expression Black = moderately abundant CB1 receptor expression Brain Regions That Express the CB1 Receptor CB1 receptors are among the most abundant G protein–coupled receptors in the brain, present in almost every brain region and on many different types of neurons. CB1 receptors are particularly abundant in brain regions such as the hippocampus, cortex, cerebellum, and basal ganglia The study of the ECS in these brain areas has implicated this system in modulating motor function in the cerebellum and basal ganglia. In the hippocampus, the ECS plays a role in pathways related to learning and memory, and in the cerebral cortex the system is implicated in cognitive information processing. In the amygdala the ECS modulates emotionality and in the brain stem and spinal cord the ECS is involved in nociception Furthermore, studies of CB1 receptors within the mesolimbic dopaminergic system indicate that the ECS plays a role in reward and motivational processes. Finally, it is now clear that the ECS directly modulates the activity of neuronal circuits regulating food intake, both within the hypothalamus and the limbic system The density of CB1 receptors in different brain areas is similar to levels of -aminobutyric acid (GABA)- and glutamate-gated ion channels An important role for CB1 receptors in the brain is to mediate retrograde signaling. This is defined as the communication by signaling molecules (in this case, endocannabinoids) derived from postsynaptic cells that diffuse to presynaptic cells Joy JE, Watson SJ, Benson JA, Institute of Medicine (US). Division of Neuroscience and Behavioral Health. Marijuana and Medicine: Assessing the Science Base. Washington, DC: National Academy Press; 1999. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47(suppl 1):345-358. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389-462. Fernandez-Ruiz J, Gonzales S. Cannabinoid control of motor function at the basal ganglia. Handb Exp Pharmacol. 2005:479-507. Rodriguez de Fonseca F, Del Arco I, Martin-Calderon JL, Gorriti MA, Navarro M. Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol Dis. 1998;5(6 Pt B):483-501. Lutz B. The endocannabinoid system and extinction learning. Mol Neurobiol. 2007;36:92-101. Egerton A, Allison C, Brett RR, Pratt JA. Cannabinoids and prefrontal cortical function: insights from preclinical studies. Neurosci Biobehav Rev. 2006;30:680-695. Solinas M, Justinova Z, Goldberg SR, Tanda G. Anandamide administration alone and after inhibition of fatty acid amide hydrolase (FAAH) increases dopamine levels in the nucleus accumbens shell in rats. J Neurochem. 2006;98:408-419. Cota D, Woods S. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351. Kawamura Y, Fukaya M, Maejima T, et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci. 2006;26:2991-3001. Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:678-682. Adapted from Joy JE et al, eds. Marijuana and Medicine. 1999.

CB2 Receptors: immune system modulators CB2 receptors found in spleen, tonsils, thymus gland, bones, skin Localised in monocytes, macrophages, B-cells and T-cells Limited CB2 in brain, except in inflammatory states (microglia) Stimulation of CB2 can reduce inflammation and neuropathic pain Cannabinoid Receptors Cannabinoid receptors are G protein–coupled receptors consisting of 7 transmembrane-spanning domains The CB1 receptor is among the most abundant G protein–coupled receptors in the brain, present in almost every brain region and on many different types of neurons CB1 receptors receptors are also located in a variety of peripheral tissues such as adipose tissue, liver, muscle, the GI tract, and pancreas Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161-202. Devane WA et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605-613. Munro S et al. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61-65. Ameri A. The effects of cannabinoids on the brain. Prog Neurobiol. 1999;58:315-348. Osei-Hyiaman D, DePetrillo M, Pacher P, et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005;115:1298-1305. Cota D, Woods SC. The role of the endocannabinoid system in the regulation of energy homeostasis. Curr Opin Endocrinol Diabetes. 2005;12:338-351.

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, AB-PINACA, 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 PLoS One 2013 - A O L 5 1 2 3 4 % N E % C O N T E B D - A o t a l 5 1 2 3 4 Average THC content = 15% 85% of samples contained <0.1% CBD-tot CBD uniformly low on the most part THC: psychoactive, sedation, analgesia, antiemesis, antispasmodic 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 Placebo > THC/CBD Anxiety CBD>placebo Sleep 12 RCTs THC/CBD, THC > Placebo Psychosis CBD = amisulpiride Tourette Syndrome Glaucoma 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; 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 GastroEsophgeal 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 Spasm; 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 Route Indication Nabiximols (Sativex®) Plant extracted THC:CBD (1:1) Buccal / SL spray MS spasticity Dronabinol (Marinol®) Synthetic THC Oral Anorexia in AIDS, cancer; CINV Nabilone (Cessamet®) CINV CBD (Epidolex®) Plant extracted CBD Nil yet Cannabis plant matter Various % THC, CBD available Vaporised Range of conditions 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 15-90 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.