Cannabis What's Hot What's New & What All Pharmacists Ought to Know

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1 Cannabis 2017 What's Hot What's New & What All Pharmacists Ought to Know Andrew J Smith, MDCM Staff Physician, Pain and Addiction Medicine Medical Lead, Interprofessional Pain and Addiction Recovery Clinic Centre for Addiction and Mental Health, Toronto Toronto Academic Pain Medicine Institute

2 + Faculty/Presenter Disclosure Faculty: Andrew J Smith, MDCM Relationship with commercial interests None

+ Discussion of Off-Label/Investigational Use of Commercial Products This activity contains information about clinical and experimental uses of drugs that are not currently approved by Health

3 + Discussion of Off-Label/Investigational Use of Commercial Products This activity contains information about clinical and experimental uses of drugs that are not currently approved by Health Canada and/or other national regulatory agencies in Canada. Participants are encouraged to consult the Health Canada approved product labelling for any drug mentioned in this program before use.

4 Learning Objectives By the end of the session, participants will be able to: 1. Understand the main arguments in support of medical cannabis use 2. Name at least 3 common acute adverse effects of cannabis use 3. List at least 2 components of the endocannabinoid system

5 + Medical Cannabis Pros and Cons Getting Beyond the Smoke and Mirrors of Stigma, Lack of High Quality Evidence and Various Political and Economic Agendas

6 + Medical Use of Herbal Cannabis: Arguments PRO Cannabis contains numerous cannabinoids and other active constituents that combine to make whole plant cannabis and its extracts more clinically effective than currently available cannabinoid medications Cannabis has very low or no potential for overdose and relatively low rates of addiction and harmful use compared to opioid analgesics and may clinically replace opioids in some contexts and there-by reduce opioid-related harm Cannabis is an ancient medication with millennia of experience supporting its use as a safe and effective treatment Cannabis is relatively inexpensive to grow and produce

7 + Medical Use of Herbal Cannabis: Arguments CON The chemically active content of herbal cannabis is complex, variable and often unknown, making dosing and predictability of effects uncertain; it would not meet FDA criteria for approval as a medication Cannabis is widely used recreationally with associated harm to individual and public health; making cannabis available as a medication will increase general availability and associated harm Few patients cannot be managed well clinically without cannabis; the push for medical cannabis is part of a well-structured and funded strategy to legalize cannabis for general use Smoking cannabis may be harmful due to products of combustion and other delivery systems are not well studied

8 OSDUHS 2015 PAST YEAR USE TOP 10 Alcohol 45.8% (54.9 %) Cannabis 21.3% (22.0 %) Binge Drinking 24.7 % (17.6%) Vape pens (e-cigarettes) 11.7% Opioid Pain Relievers (NM) 10% (14.0%, 17.8%) Cigarettes Tobacco 8.6 % (8.7 %) OTC Cough/Cold Medication 6.4 % Solvents 2.8% (5.6 % ) Hallucinogens other than LSD, PCP 5.4% (3.8 %) Stimulants (NM) 2.1 % (4.8 %) Salvia Divinorum 3.7 % (

+ MJ Consumption Patterns in Ontario Vast majority of harms are concentrated among the daily / near-daily users (20 30% of users) About 9% of cannabis users develop

9 + MJ Consumption Patterns in Ontario Vast majority of harms are concentrated among the daily / near-daily users (20 30% of users) About 9% of cannabis users develop dependence Nicotine: 68% probability of developing dependence Alcohol: 23% Cocaine: 21% Long-term frequent users have a higher risk of dependence than occasional users

10 + Endocannabinoid System and Addiction CB1 receptor agonists are rewarding Activate endogenous DA system Cannabinoids have strong interactions with the opioid system: THC increase B-endorphin in NAcc & VTA Involved in rewarding effects of Alcohol Synergistic with Nicotine rewarding effects Solinas, et al: The endocannabinoid system in brain reward processes, Br J Pharmacol v.154(2); May 2008

+ Adverse Effects: Short-term Anxiety, panic attacks Distorted perception, hallucinations Increased heart rate and blood pressure Decreased memory & learning Difficulty thinking & problem

11 + Adverse Effects: Short-term Anxiety, panic attacks Distorted perception, hallucinations Increased heart rate and blood pressure Decreased memory & learning Difficulty thinking & problem solving Decreased coordination Disuomotor skills deficit *Effects transient, resolve without intervention.* *Actual impairment persists past perceived impairment* *Effects primarily associated with THC*

12 Increases over Time in the Potency of Tetrahydrocannabinol (THC) in Marijuana and the Number of Emergency Department Visits Involving Marijuana, Cocaine, or Heroin. Volkow ND et al. N Engl J Med 2014;370:

13 Health Risks and Chronic Harms Early Use + Strong and growing body of evidence that regular cannabis use in adolescence can seriously harm the developing brain Early regular cannabis use is associated with Low levels of educational attainment Diminished life satisfaction Higher likelihood of developing cannabis use disorder Increased risk of developing mental health problems Cannabis use before the age of 18 increases the risk of developing schizophrenia Adolescent-onset frequent use IQ loss (8 pts) 3% of Ontario s high school students = estimated 26,000 adolescents use cannabis daily

14 Volkow ND et al. N Engl J Med 2014;370:

15 + Harm Reduction: Low Risk Cannabis Use Guidelines Cannabis-related harm mainly concentrated among limited sub-group of users who Use heavily Start young Although abstinence is the only way to completely avoid the health risks of cannabis use, for those who do use it, the risks are expected to be reduced if: Use is delayed until early adulthood Frequent (daily or near daily) use is avoided Users shift away from smoking cannabis towards less harmful (smokeless) delivery systems such as vaporizers Less potent products are used, or THC dose is titrated Driving is avoided for 3 to 4 hours after use, or longer if needed People with higher risk of cannabis related problems (e.g. people with a personal or family history of psychosis, people with cardiovascular problems, and pregnant women) abstain altogether

16 + Cannabinoids Endogenous and Exogenous: The Ins and Outs of Cannabinoid Mechanism of Action

17 + What is Medical Marijuana Cannabis sativa and indica More than 80 terpenophenolic compounds cannabinoids Lipophilic 2 main neuroactive components d-9 THC = psychoactive CBD = cannabidiol Sativa: Higher THC: CBD ratio more activating Indica: Lower THC:CBD ratio more sedating THC activates ENDOCANNABINOID system THC isolated and characterized in 1964 focus of research d/t psychotropic effects CBD isolated in 1940 characterized in 1963 THC found to bind to CB1 and CB2 G-protein coupled cell mb receptors CB1 endo ligand = anandamine CB2 endo-lingand = arachidonoylglycerol

19 + Endocannabinoid System 3 major components: CB1 receptors in central nervous system involved in Modulation of mood, motor tone, and coordination, and cognition (such as concentration, short-term memory, attention, and tracking behavior) Abuse potential and dependence CB1 receptors in peripheral nervous system modulate Energy metabolism fat deposition and insulin resistance Food intake, visceral sensation, gastrointestinal motility, gastric secretion, intestinal inflammation, and cell proliferation CB2 receptors found in periphery (mainly on immune cells) function to regulate Cellular and humoral response to neuroinflammation and pain GI functions of digestion and host defense

20 Cannabinoid mechanisms

21 Cannabinoids as immune modulators Nature Rev Drug Disc 2008;7:

22 + Endocannabinoid System 3 major components: Endocannabinoids at other receptors capsaicin receptor (TRPV1) and G protein-coupled receptors 55 and 119 Enzymes and uptake systems involved in endocannabinoid metabolism and includes COX-2 and fatty acid amide hydrolase-1

23 Cannabinoids as synaptic circuitbreakers Nat Med 2008;14(9):923-30

24 Delta-9-tetrahydrocannabinol (THC) Partial agonist activity at CB1 and CB2 receptors Yields psychoactive effects of cannabis (euphoria and feeling "high" Other effects: muscle relaxation, analgesia, antiemesis, psychosis, anxiety, and sedation Lethal overdose in humans has not been reported THC spares autonomic nervous system (CB1 receptors nearly absent in brainstem)

25 CBD Antagonist/inhibitor at CB1 or CB2 Multi-target molecule: activates 5HT1a receptor, alpha3-3 and alpha-1 glycine receptors, TRPA1, nuclear peroxisome proliferator-activated receptor gamma, TRPV1, and TPRV2 Anticonvulsant effects (Trials also in LGS and Dravet syndrone) Antipsychotic effects Reverses THC-induced psychotic sx in humans Reverses ketamine-induced depersonalization (human glutamate model of schizophrenia) CBD vs D2 antagonist Rx: comparable, significant improvement with superior outcomes of negative sx, better safety profile, superior cognition Anxiolytic Analgesic NMDA antagonism; TRPV1 agonist

26 CBD Neonatal HIE (neuroprotective) rodent models Close Ca++ channels prevent toxic ic[ca] buildup reduce glutamate release Anti-inflammatory Modulate toxic NO production Vasodilators Show neuroproliferative and remyelinating effects Addiction risk modulator In rats: THC potentiates heroin self-administration, CBD inhinits Normalizes drug-induced changes in AMPA and CB1 receptors in nucleus accumbens reduces drug-seeking behaviours in rats 2 weeks after administration (neural resilience to prevent relapse) Human studies: Higher CBD:THC ratio less attentional bias to drug-stimuli; less liking of cannabis

27 + Natural Antagonism THC euphoria anxiety psychosis cognitive impairment tachycardia CBD no (or less) euphoria anti-anxiety anti-psychotic neuroprotective bradycardia Loss of antagonism may lead to increased side effects and poor tolerability.

28 Non-psychoactive phytocannabinoids

29 + Medical Cannabis - Efficacy Cannabis has been cultivated for >3,000 years but we lack high quality data for its effectiveness for any medical indications

30 What About Medical Marijuana??? First use probably in Central Asia ~5000 years ago Prescribed by Chinese emperor Shen-Nung ~ 2700 BCE Menstrual disorders, gout, rheumatism, malaria, constipation, absent-mindedness Islamic physicians in medieval times: n/v, epilepsy, inflammation, pain, fever Dr. WB O'Shaughnessy (1830s) Irish physician working in Calcutta On Indian Hemp: pain, vomiting, convulsions and spasticity US Dispensatory listing 1854: tinctures, extracts, cigarettes, plasters for insomnia, headaches, anorexia, sexual dysfunction, pain, whooping cough, asthma common analgesic drug before ASA

fishermen Impoverished Mexicans ( opium of the poor) Mid-20 th Century African Americans and Hispanics Lack of

31 Stigmatization of Cannabis Psychoactive qualities tightly controlled religious adjunct Before mid-20 th Century recreational use restricted to fringe and marginalized groups Literary intellectuals Rural Brazilian blacks and fishermen Impoverished Mexicans ( opium of the poor) Mid-20 th Century African Americans and Hispanics Lack of standardized product Rise of synthetic drugs: ASA, penicillin Hypodermic needle Schedule 1 listing despite AMA objections

32 + Cannabis: Self-Medication 1.3% of adults ( 18 years old) in United States reported medical marijuana use over 1 year based on crosssectional study of 96,100 adults in the United States participating in National Survey on Drug Use and Health (NSDUH) 12.9% of all participants reported past-year marijuana use 11.6% reported nonmedical use only 0.8% reported medical use only, and 0.5% reported combined medical and nonmedical use In users of marijuana 90.2% reported nonmedical use only 6.2% reported medical use only 3.6% reported medical and nonmedical use JAMA, 2017 Jan 10;317(2): doi: /jama

33 + Cannabis: Self-Medication 14%-21% of patients with IBD reported to selfmedicate with marijuana, based on cross-sectional study of 100 patients with ulcerative colitis and 191 patients with Crohn disease attending tertiary care clinic 13% of patients referred to tertiary care for fibromyalgia pain reported to self-medicate with marijuana based on cross-sectional study of %-50% of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) reported medicinal use of cannabis somewhat/very effective in 57-63% of respondents (cross sectional survey) Eur J Gastroenterol Hepatol Oct;23(10): doi: /MEG.0b013e328349bb4c. Can Urol Assoc J Nov;8(11-12):E doi: /cuaj.2268.

34 + Medical Use of Herbal Cannabis: The Evidence Evidence for efficacy varies by potential indication Limited by variations in cannabinoids used in clinical trials Lack of randomized trials for evaluating most conditions Most RCT data uses standardized preparations rather than herbal cannabis Benefit for herbal cannabis extrapolated from data from other cannabinoids

35 Medical Use of Herbal Cannabis: The Evidence Medical Marijuana Indications Malignant neoplasm -chemotherapy-induced N/V -loss of appetite Glaucoma Supporting Evidence Low quality data. Mixed results, effective. Low quality data. Megestrol superior. Insufficient data. Other tx options superior. HIV or AIDS -loss of appetite Agitation d/t Alzheimer Disease PTSD Medical condition that produces: -cachexia -severe pain -severe nausea -seizures (+/- epilepsy) -persistent muscle spasms (+/- MS) *Crohn s disease, hepatitis C, renal failure requiring hemodialysis, traumatic brain injury Low quality data; favors efficacy. Insufficient data. Insufficient data. Low quality data. Mixed results. Low to moderate quality. Mixed results. Low quality data. Mixed results. PONV favors efficacy; operative N/V ineffective. Insufficient data. (CBD studies in progress.) Low to moderate quality data. Inconclusive. Insufficient data. Whiting PF et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015; 313(24):

36 Cannabinoids: Neurological Conditions Multiple Sclerosis: symptoms of pain and spasm (weak) Oromucosal cannabinoid spray (nabiximols) Oral cannabis extract (OCE) Delta-9 tetrahydrocannabinol (THC) to reduce patient reported symptoms of spasticity and pain, except for neuropathic pain Huntington Disease: Nabilone for the short-term treatment of chorea (weak) For children with severe refractory epilepsy disorders: CBD-rich cannabinoids For HIV-associated neuropathic pain consider smoked cannabis as a treatment option For chronic neuropathic pain (not HIV or multiple sclerosis-related), consider cannabinoids for pain relief

37 Cannabinoids: Other Conditions Chemotherapy-induced nausea and vomiting consider cannabinoids for patients intolerant or refractory to 5HT3 receptor antagonists, NK-1 receptor antagonists, and dexamethasone For fibromyalgia, consider cannabinoids (such as nabilone), especially in patients with significant sleep problems For glaucoma, marijuana can lower intraocular pressure but marijuana is not currently recommended in any form for treatment of glaucoma

38 + Multiple Sclerosis American Academy of Neurology recommendations: Oral cannabis extract (OCE) may be offered to reduce patient-reported symptoms of spasticity and pain, except for neuropathic pain (AAN Level A) delta-9-tetrahydrocannabinol (THC) may be offered to reduce patient-reported symptoms of spasticity and pain, except for neuropathic pain (AAN Level B) Oromucosal cannabinoid spray (nabiximols) may be offered to reduce symptoms of spasticity, pain, or urinary frequency (AAN Level B)

39 + Childhood Epilepsy Addition of CBD to current antiepileptic therapy decreases convulsive seizure frequency in children and adolescents with Dravet syndrome and drug-resistant seizures Frequency of sz: cannabidiol vs. placebo during 14-week treatment period : median monthly frequency of convulsive seizures 5.9 vs (no p value reported) Median reduction in convulsive seizure frequency 38.9% vs. 13.3% (median difference 22.8%, 95% CI 5.4%- 41.1%, p = 0.01) Most common adverse events with cannabidiol ( 15% frequency): somnolence, diarrhea, decreased appetite, elevated liver aminotransferase enzyme levels, fatigue, vomiting, and pyrexia In patients with other epilepsy syndromes insufficient evidence from randomized trials to evaluate cannabinoids for epilepsy Systematic review of 4 RCTs evaluating CBD monotherapy or add-on N Engl J Med May 25;376(21): doi: /NEJMoa

40 + HIV / AIDS Smoked cannabis may reduce HIV-associated neuropathic pain (level 2 [mid-level] evidence) based on 2 randomized trials Marijuana might increase weight gain in patients with HIV infection or AIDS, but megestrol acetate might be more effective than dronabinol (level 2 [mid-level] evidence) Based on systematic review of mostly low-to-moderatequality trials: 79 randomized trials comparing cannabinoids vs. usual care, placebo, or no treatment in 6,462 patients with 1 of 10 indications 1 trial included assessment of MJ

41 Can Fam Physician Aug;61(8):e Whiting PF et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015; 313(24): Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA. 2015;313(24): Chronic Pain Low-dose medical marijuana smoked or vaporized may reduce pain in conjunction with traditional analgesics in patients with chronic noncancer pain, but may be associated with adverse effects Systematic review of 6 randomized trials evaluating medical marijuana for pain relief for patients with chronic noncancer pain (CNCP) with 226 patients 3 trials in patients with neuropathic pain, 2 trials in patients with HIV-associated neuropathy, and 1 trial in patients with multiple sclerosis Meta-analysis not performed due to heterogeneity of dosing and outcomes Comparing marijuana to placebo Clinically meaningful pain reduction found in 3 trials Pain reduction not reaching clinical significance found in 3 trials Compared with placebo, smoking cannabis associated with greater incidence of adverse events in all trials

42 Since then Ware MA, et al. Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The Journal of Pain. 2015;15(12): Prospective cohort study, chronic non-cancer pain Primary endpoint: adverse effects Secondary endpoints: neurocognition, pulmonary function, efficacy, labs Limitations: Powered for n = 350. Starting n = 215. Finishing n = 138. Study and control groups not matched for age, gender, disability, tobacco, alcohol, opioids, antidepressants, anticonvulsants, etc. High drop out rate (30%) Dose ranged grams/day despite regulated product (11-14% THC) Inconsistent mechanism of consumption Didn t administer all screening to all pts

43 COMPASS: Pain Results Changes in pain intensity over 1 yr for those w/ all 7 data points (n = 145 (study) and 157 (control)). VAS = visual analog scale Ware MA, et al. Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The Journal of Pain. 2015;15(12):

44 + Messages from The Literature Wide dose ranges Adverse effects at higher doses No tolerance develops Sleep and mood (anxiety) often also improved Few randomized controlled trials Poor study design Small n Short duration Difficult to blind Wide range of products, doses, routes of administration Poor tolerability, high drop out rates

45 + GI Conditions Cannabis may reduce symptom severity and appears to increase remission in patients with refractory Crohn disease Based on small randomized trial 21 patients with Crohn disease (Crohn disease activity index [CDAI] score points) : Cannabis (115 mg delta-9 tetrahydrocannabinol [THC]) vs. placebo (cannabis flowers without THC) cigarettes and followed for 8 weeks during use and after a 2-week washout period All patients had been refractory to 1 standard therapy (includes steroids, immunomodulators, or anti-tumor necrosis factoralpha agents) Clinical response defined as CDAI reduction > 100 points Comparing cannabis vs. placebo, cannabis associated with clinical response in 90% vs. 40% (p = 0.028, NNT 2) mean CDAI reduction 177 points vs. 66 points (p = 0.005) In cannabis group, 3 patients with steroid-dependence weaned off steroids and 2 patients receiving opiates for severe abdominal pain stopped opiate Clin Gastroenterol Hepatol Oct;11(10): e1. doi: /j.cgh Epub 2013 May 4.

46 + Fibromyalgia Nabilone may improve pain and anxiety in patients with fibromyalgia J Pain Feb;9(2): Epub 2007 Nov 5 Nabilone may improve pain and anxiety in patients with fibromyalgia Cannabis associated with improvement in some fibromyalgia symptoms Based on cross-sectional study 28 patients with fibromyalgia who used cannabis and 28 patients with fibromyalgia who did not use cannabis were surveyed Cannabis use associated with reduced pain and stiffness, enhancement of relaxation, and increased somnolence and feeling of well-being after 2 hours (each p < 0.05) Comparing quality of life scores in cannabis users vs. nonusers mean mental health score 29.6 vs (p < 0.05) physical health score vs (not significant) sleep score 14.1 vs (not significant) No patients reported worsening of any symptoms after cannabis use PLoS One Apr 21;6(4):e doi: /journal.pone

47 + Psychiatric Conditions Cannabidiol may reduce anxiety during public speaking in patients with social anxiety disorder 4 patients with social anxiety disorder randomized to cannabidiol 600 mg capsule orally vs. placebo taken once about 90 minutes prior to a simulated public speaking test 12 healthy controls also participated in simulated public speaking test Outcomes measured included Visual Analog Mood Scale (VAMS) and Negative Self-Statement scale (SSPS-N) and physiological measures (blood pressure, heart rate, and skin conductance) Compared to placebo, cannabidiol associated with decreased anxiety level (p < 0.001), cognitive impairment (p = 0.009), and discomfort (p = 0.029) during simulated public speaking test Neuropsychopharmacology May;36(6): doi: /npp Epub 2011 Feb 9

48 Thank You!

Medical Marijuana Martin P. Eason MD, JD Associate Chief of Staff for Education Mountain Home VA Medical Center. Disclosure.

Medical Marijuana Martin P. Eason MD, JD Associate Chief of Staff for Education Mountain Home VA Medical Center Controversies in Pain Management Conference Johnson City, TN November 13, 2015 Disclosure