Medical Cannabis: An overviewClinical Prof Nicholas Lintzeris MBBS, PhD, FAChAMDirector D&A Services, SESLHDLambert 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 cannabinoidsMedical cannabis in Australia today

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, PMSProhibition since early 20th Century led to abandonment of cannabis as therapeutic agentInterest rekindled since 1980sConsumer advocacy Scientific developments

Varieties of CannabinoidsEndocannabinoidsPhytocannabinoidsSyntheticcannabinoidsIn your brain and bodyIn plantsFrom the labAnandamide, 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 expressionAdapted 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

EndocannabinoidsPhytocannabinoidsSyntheticcannabinoidsIn your brain and bodyIn plantsFrom the labAnandamide, 2-AG, Noladin ether etc.THC, CBD, CBG, CBDV, THCV, CBC, CBN, THCVA etc. Nabilone, HU-210, AB-PINACA, JWH-018, etcVarieties of Cannabinoids

>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 CBDSwift et al PLoS One 201385% of samples contained

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

Potential adverse events of cannabisCognition 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 healthAdolescent 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 usersPhysical effectsHypotension, 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 # studiesConclusionNausea & vomiting3 RCTsTHC or THC/CBD > placeboWeight gain in HIV/AIDS1 RCTTHC > placeboSpasticity in MS / paraplegia14 RCTsTHC/CBD > placeboDepression3 RCTsPlacebo > THC/CBDAnxiety1 RCTCBD>placeboSleep12 RCTsTHC/CBD, THC > PlaceboPsychosis1 RCTCBD = amisulpirideTourette Syndrome1 RCTTHC > placeboGlaucoma1 RCTTHC=CBD=placeboEpilepsyNot completed CBD

Cannabinoids in chronic painSystematic review: Whiting et al JAMA June 2015

Conditions treated with cannabis (medical marijuana.com)Acute Gastritis; Adenomyosis; Alzheimers; Amyloidosis; Amyotrophic Lateral Sclerosis (ALS); Anaphylactic or Reaction; Angelman Syndrome; Anorexia; Arthritis; Arthropathy (Gout); Asperger Disorder; Asthma; Attention Deficit Disorder (ADD); AutismBack Pain; Bell's Palsy; Bipolar Disorder; Bruxism; BulemiaCachexia; 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; DystoniaE. T.; Eczema; Ehlers Danlos; Emphysema; Endometriosis; Epilepsy/Seizure DisorderFelty's syndrome; Fibromyalgia; Friedreich's AtaxiaGastroEsophgeal Reflux Disease; Glaucoma; Graves' diseaseHemophilia A; Henoch-Schonlein Purpura; Herpes; HIV / AIDS; Hydrocephalus; Hypertension (High Blood Pressure); Hyperventilation; HYPOGLYCEMIA-MMj TreatmentIncontinence; Inflammatory Bowel ; Insomnia; Interstitial Pneumonia; Irritable Bowel SyndromeLimbic 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 PainNausea; Nephritis; Neurodegenerative Disorders; Neurofibromatosis; Neuropathy; Nightmares; NPSOsgood-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; PorphyriaAlternative Symptom Treatments; Post Concussion Syndrome; Post Traumatic Stress Disorder; PPS-Post Polio Syndrome; Prostate Cancer; PruritusPsoriasis; Pylorospasm refluxRadiation Therapy; Raynaud's phenomenon; Reactive Arthritis; RLS-MMj Treats SymptomsSAD; Schizophrenia(s); Scleroderma; Scoliosis; Selectivemutism; Shingles; Sinusitis; Sjogren's Syndrome; Sleep Apnea; Spina Bifida and Medical Marijuana; Sturge-Weber; SyringomyeliaTenosynovitis; Testicular Cancer; Testicular Torsion; Thoracic Outlet Syndrome; Tic Douloureux; Tietzes Syndrome; Tinnitus; Tourette Syndrome and Cannabinoids; TTMWolff-Parkinson-White Syndrome

Summary of evidence Historical recordsAnimal 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

CannabinoidRouteIndicationNabiximols (Sativex)Plant extracted THC:CBD (1:1)Buccal / SL sprayMS spasticityDronabinol (Marinol)Synthetic THCOralAnorexia in AIDS, cancer; CINV Nabilone (Cessamet)Synthetic THCOralCINVCBD (Epidolex)Plant extracted CBD Oral Nil yet Cannabis plant matterVarious % THC, CBD available VaporisedRange of conditions in Holland, Israel, Canada

Vaporising cannabis Similar to e-cigarrettesVaporising 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 todayOnly illicit cannabis productsHome 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 painAnalgesic 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 AustraliaCBD rich hemp products imported from USA / EU

Implications for clinicians todayUse of illicit cannabis for medical purposes is common in some areas of medicine. Most patients will not disclose & most doctors wont askMedical 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.

Galen: greek physician prescribed cannabis 150 ADWilliam 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. **Brain Regions That Express the CB1 Receptor

CB1 receptors are among the most abundant G proteincoupled 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

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Cannabinoid receptors are G proteincoupled receptors consisting of 7 transmembrane-spanning domains The CB1 receptor is among the most abundant G proteincoupled 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

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