Medical Cannabis In the Care of the Elderly

Medical Cannabis In the Care of the Elderly April 19, 2018 Canadian Geriatrics Society Annual Scientific Meeting Michael A. Dworkind MDCM. CCFP. FCFP. Associate Professor Family Medicine and Palliative Care, McGill University

Disclosures Co-founder and medical director of Santé Cannabis, Santé Cannabis receives some funding in the form of grants from Canadian Licensed Producers of medical cannabis and is funded for the administration of clinical trials as a contract research organization by trial sponsor Tetra Bio-Pharma Inc.

Learning Objectives To better understand the complexity and controversial history of medical cannabis To learn about the Endocannabinoid System and its clinical relevance in the elderly To assess the [limited] evidence for potential efficacy and possible side effects when considering medical cannabis treatment Case study for review and discussion

Case Study: H.R. (90y F) Dx: Anorexia, attributed to major depression, mixed dementia, stroke, coronary artery disease, orthostatic hypotension, osteoarthritis, frailty Symptoms: low/no appetite, weight loss 0.5-1 lb per week, extreme fatigue, spends most days lying in bed Rx: Desipramine 10mg, oolanzapine 5mg QHS PRN, Esomeprazole 40mg QD, Rosuvastin 20mg QD, Florinef

A brief history of cannabis in medicine. Cannabis has been used as a medicine by humans for several millennia. Between 1840 and 1920-40, cannabis tinctures and other products became a mainstay of the pharmacopeia.

4000 BCE : Oldest evidence of cannabis and hemp production in China. 1550 BCE: Papyrus Ebers (Egypt) first recorded mention of cannabis in obstetrics. 19th century: Queen Victoria uses cannabis tincture for menstrual cramps.

Cannabis was prohibited in Canada in 1923, and in the United States in 1937, citing quality control issues, lack of defined chemistry, but ultimately both political and ideological auspices. This period of cannabis as planta non grata has restricted access for researchers and clinicians, stifling its full potential as a medicine.

History continued 1963-64: First isolation and synthesis of active components in cannabis THC and CBD. 1980s: Discovery of the endogenous cannabinoid system. First pharmaceutical version of THC available by prescription (Marinol). 2000: Canada legalizes medical cannabis Marihuana Medical Access Program Patients could grow their own medical supply under this program or buy from a single government supplier.

2016: Access to Cannabis for Medical Purposes Regulations (ACMPR) - Current program includes commercial sale to authorized patients and home production by patients or caregivers July?, 2018: Legalization expected via the Cannabis Act These developments, coupled with a resurgence of anecdotal accounts and renaissance of therapeutic clinical trials has cause a tsunami of interest.

Cannabis use in the senior population The fastest growing demographic of cannabis users (data from Colorado) Schauer et al., Am J Prev Med 2016

The pharmacology of medical cannabis The discovery of the endocannabinoid system (ECS) triggered an avalanche of experimental studies that have implicated the ECS in a growing number of physiological/pathological functions. Modulating the human endocannabinoid system in human health and disease: successes and failures. - Pal Pasher and George Kunos The FEBS Journal 2013 (Federation of European Biochemical Societies) http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3684164/

The Endogenous Cannabinoid System (ECS) The ECS is a system of neuromodulatory lipids (cannabinoids), their receptors, and their associated enzymes. CB1 receptors are found mainly in the brain and central nervous system. CB2 receptors are found mainly in peripheral organs and cells associated with the immune system. ECS is implicated in many physiological functions, notably: nociception, neuroprotection, homeostasis, inflammation, memory, sleep, mood, anxiety, appetite, among others.

Expression of GABA and Glutamate type receptors change as we age Hypothesized to affect brain s response to endocannabinoid phyto-cannabinoid activity

CB1 receptors implicated in essential function

Cannabinoids Cannabinoids interact with the CB1 and CB2 receptors to exert their effects; they can be endogenous, plant-based, or synthetic. More than 100 phytocannabinoids have been identified in cannabis plants. Anandamide (AEA), and 2-arachidonyl glycerol (2-AG) are endocannabinoids produced by the body. Delta-9 Tetrahydrocannabinol (THC) and Cannabidiol (CBD), are phytocannabinoids produced by the cannabis plant. Dronabinol,(THC) Nabilone (CB1 receptor agonist pharmaceutical, synthetic cannabinoids

105 publications of controlled trials included older subjects (>65 years) Only 5 reported results of older subjects separately! Found oral THC (3) and THC:CBD formulations No efficacy on levodopa induced dyskinesia, breathlessness or chemotherapy-induced nausea and vomiting THC might be useful in the anorexia and behavioural symptoms of dementia Most common adverse effect in the elderly using cannabinoids is sedation Considering the interest and increasing use rate in older persons, more study is required, especially sufficiently powered trials

Abuhasira et al Eur J Intern Med 2018

93.7% <Slight improvement> or better Abuhasira et al Eur J Intern Med 2018

Management of Chronic neuropathic Pain Moulin DE et. Al. Pain Research Management 2014, 19(6); 328-335

Safety of Cannabis for chronic pain 215 subjects and 216 controls, with chronic non-cancer pain Increased risk of non-serious adverse events in the cannabis group, however most were mild-moderate No difference in secondary safety assessment, pulmonary and neurocognitive function, hematology, biochemistry, renal, liver, endocrine function Ware MA et al. Journal of Pain. 2015 December; 16(12): 1233-42

Cancer pain Patients with advanced cancer and inadequate analgesia despite chronic opioid dosing were treated with THC extract or THC:CBD extract Both groups experienced significant pain reduction vs. placebo with twice as many patients in the THC:CBD group reporting pain reduction of 30%

Anorexia and cachexia syndrome Dronabinol: increased appetite and weight stability in HIV/AIDs and dementia Dronabinol versus megestrol acetate for cancer-associated anorexia: findings in favor of megestrol THC (2.5 mg) versus THC (2.5 mg) +CBD (1mg) versus placebo: no significant improvements in survival, weight, or other nutritional variables Improved taste, smell and food enjoyment Jatoi, A et al. J Clin Oncol 2002 Strasser F, et al. Journal of Clin Onco 2006; 24: 3394-3400 Beal JE, et al. J Pain Symptom Management 1995 10:89-97

Health Canada has aggregated relevant pre-clinical and clinical evidence for the medical use of cannabis and cannabinoids in this document. http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprofeng.php

Potential Indications Health Canada lists approximately 40 potential indications for dried cannabis. Strongest evidence base for: HIV/AIDS Multiple Sclerosis Epilepsy Spinal Cord Disease/Injury Cancer cachexia, anorexia Severe Arthritis Severe Chronic Pain Gastrointestinal disorders

THC (delta-9 tetrahydrocannabinol) Intoxicant Analgesic Anti-emetic Anti-spasmodic Anti-inflammatory Appetite Stimulant Anxiolytic (bi-phasic) Sleep Aid (bi-phasic) Apoptogenic, Anti-proliferative

CBD (cannabidiol) Non-intoxicant Anti-epileptic Anti-inflammatory Mild analgesic Anxiolytic Reduces spasticity Antipsychotic Apoptogenic, Anti-proliferative

Dosing strategy: Start low, Go slow, Stay low The efficacy of medical cannabis is directly related to strain and/or product selection and dosage. Patients typically undergo a trial period to determine which strains, methods administration and dosages are most effective.

Medical Cannabis (Phytocannabinoids) Cannabis is a plant medicine that comes in many forms: Dried cannabis flowers (aka: marijuana) Liquid oils, alcohol and glycerine tinctures Food products (aka: edibles, pot brownies) Topical oils, creams, and lotions Resins, extracts and concentrates (aka: hashish) Hundreds of cannabis strains with unique chemical profiles 100+ phytocannabinoids identified in cannabis strains from around the globe.

Pharmaceutical Cannabinoids Nabilone Synthetic THC analogue / CB1 Receptor Agonist 0.25mg, 0.5mg, 1mg formats RAMQ covers 0.5mg, 1.0mg Approved for chemotherapy induced nausea. Nabiximols Plant-derived oro-buccal spray approved for treating spasticity in Multiple Sclerosis. 2.7mg THC + 2.5mg CBD per spray Not covered by RAMQ, or most private insurance

Pharmaceutical Cannabinoids Prescribing Nabilone for geriatric patients Start with 0.25mg QHS for pain, sleep for 1 week Move to 0.5mg BID, increase to 1mg at night as needed RAMQ covers 0.5mg and multiples Effects can last up to 8 hours Cautious of sedation, dizziness, balance Small percentage find benefit for pain despite sleep improvements If not tolerated, or insufficient benefit...

Cannabis formulations in the legal framework Dried cannabis % w/w THC : CBD THC-rich THC:CBD CBD-rich Cannabis oil mg/ml (THC : CBD) Cannabis oil capsules mg (THC : CBD) per capsule

New Applications (topical, sprays, etc) to come

Clinical Model (Santé Cannabis) Specialized and patient-centred Research assistant Referral verification Screening Consent process Research Nurse Review of complete medical history. Verification of Inclusion/Excusion criteria Referring physician Referral & Supporting documentation Ongoing primary care Patient and family Report to MD Ongoing collaboration Physician Medical assessment Cannabinoid checklist Development plan Treatment Plan Cannabis Nurse-Educator Operationalization of Tx plan Education and support Follow-up 1-3 months Goal: Continuity of Care Monitoring Safety & Efficacy

Warnings and Precautions Sensitivity to THC Activities requiring co-ordination Driving, reduced mobility, vertigo, dizziness Possible interactions with other medications CNS Depressants, Opioids, Sedatives, blood thinners, SSRIs Substance abuse potential Geriatrics: restrict oral administration to BID watch for renal insufficiency Engage with your patient to reduce harms (illegal sources, unsupervised recreational use

Contraindications Uncontrolled cardiac disease Severe liver or renal dysfunction Severe respiratory disease (COPD) (inhalation) History of psychosis, schizophrenia (THC) Allergy or hypersensitivity to cannabinoids NB: Most contraindications relate only to THC, and not to more benign cannabinoids like CBD Need further research, including potential drug interactions Nothing clinically significant has been identified in the literature

Potential Adverse Effects of THC Possible Side-Effects Can often be avoided with careful titration and close followup Most Common Sedation Fatigue Somnolence Dry Mouth CBD cannabidiol Occasional Euphoria Postural, orthostatic hypotension Dizziness Vasodilation Headache Nausea, vomiting Tachycardia Rare Panic attack Dysphoria, paranoia Hallucinations Depression Cognitive impairment Ataxia Psychosis (under 25, predisposed)

Regulatory Framework

Access to Cannabis for Medical Purposes Regulations (ACMPR) Since 2016 in Canada, the production and sale of medical cannabis is overseen by Health Canada via the Access to Cannabis for Medical Purposes Regulations (ACMPR)

Licensed Producers (LPs) Only legal sources of medical cannabis Not available in the pharmacy Licensed Producers are strictly regulated by Health Canada Dried cannabis, Cannabis oils and capsules are available Many varieties of cannabis with specific concentrations of THC and CBD Cannabis is delivered via secure courier Storefront sales (ie: compassion clubs) are still illegal

Guidelines are provincially specific Dried cannabis is considered an «unrecognized treatment» Unrecognized treatments may only be prescribed under a research protocol (Quebec Cannabis Registry) Pharmaceutical options including pharmaceutical cannabinoids must be considered before prescribing dried cannabis Follow up with patients at least every 3 months Quebec Cannabis Registry currently recruited more than 2000 patients

Case Study: H.R. (90y F) Tx Objectives: Initial visit Improve appetite, stop weight loss (weight: 85 lbs) Tx: THC-rich Cannabis Oil 1mg BID, approximately 2 hours before meals CBD-rich Cannabis Oil 2mg QHS (for sleep, and bedtime anxiety) Outcomes: Almost immediate appetite improvement Increased daily activity, Improved mood Side effects: some additional cognitive effects from baseline, ie. short-term memory loss

Case Study: H.R. (90y F) Follow-up (1 month) Tx: THC-rich Oil 1mg only QAM ~2 hrs before lunch CBD-rich Oil 2mg QHS Desipramine, olazapine, esomeprazole, rosuvastin discontinued, florinef reduced Outcomes: Increase appetite maintained at 1mg THC daily Weight increasing 0.5lb per week Increased daily activity, reduced joint pain Improved mood Reducing to 1mg THC daily resolved the worsening cognitive concerns (back to baseline)

Case Study: H.R. (90y F) Follow-up (1 year) Tx: THC-rich Cannabis Oil 3mg QAM and 1mg QPM CBD-rich Oil 2mg QHS Outcomes: Weight increased back to 107 lbs Still experiences fatigue, daily THC augments energy and mood No change in cognition with increased THC (some tolerance) Reduced joint pain and inflammation Reduced caregiver burnout over spoon-feeding stress

Future Directions: Canada as a global leader in medical cannabis research?

SAFETY AND EFFICACY OF PPP001-kit FOR IMPROVING HEALTH RELATED QUALITY OF LIFE IN ADVANCED CANCER PATIENTS WITH UNCONTROLLED PAIN: A RANDOMIZED, DOUBLE-BLIND, PLACEBO- CONTROLLED, PARALLEL GROUP STUDY Principal Investigator: Antonio Vigano, MD, MSc Site: Santé Cannabis Phase III clinical trial Study duration: 6 weeks in duration including the following: A screening period of up to 2 weeks A 4-week treatment period Primary objective: To evaluate the effect of a specific formulation of dried cannabis to improve HRQoL of patients with uncontrolled cancer pain and incurable malignancy

Questions?

Some resources Email: mdworkind@santecannabis.ca Santé Cannabis www.santecannabis.ca Canadian Consortium for the Investigation of Cannabinoids www.ccic.net International Cannabinoid Research Society www.icrs.co Information for Healthcare Professionals Medical Cannabis (Health Canada) http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprof-eng.php