EVIDENCE AND USE OF MEDICAL MARIJUANA. Jennifer Pitman Island Health Pharmacy Resident November 15 th 2017

Transcription

1 EVIDENCE AND USE OF MEDICAL MARIJUANA Jennifer Pitman Island Health Pharmacy Resident November 15 th 2017

2 OUTLINE Background on medical marijuana Pharmacology of medical marijuana Evidence for the use if medical marijuana Dosing, drug interactions, and adverse effects of medical marijuana How to get access to medical marijuana

3 BACKGROUND ON MARIJUANA Comes from cannabis sativa (a hemp plant) Contains at least 489 distinct compounds from 18 chemical classes Principle compounds are tetrahydrocannabinol (THC) and cannabidiol (CBD) Other cannabinoids: Cannabinol (CBN) Cannabigerol (CBG) Average THC content: 10% in illicit products 12.5% in Health Canada products Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

4 MEDICAL MARIJUANA Health Canada products are composed of the mature flowering heads of the female cannabis plant (highest THC content) The product is irradiated to remove contaminants such as toxic spores The finished lots are based on results of bacterial, fungal, and moisture testing Kept in sterile pouches in cold storage Stability: Ideal storage is 2-6 degrees with shelf life of 12 months When kept >18 degrees 33% of THC content is lost over 5 years Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

5 THE CANNABINOIDS Tetrahydrocannabinol (THC) Activates CB1 receptors Responsible for psychoactive and therapeutic effects Cannabidiol (CBD) Activates various ion channels, receptors and enzymes (not CB1 or CB2) Many possible therapeutic effects Cannabinol (CBN) 10% of the activity of THC Possible immunosuppressive effects Cannabigerol (CBG) Partial activates CB1 and CB2 receptors Possibly anti-inflammatory and pain relief properties Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

6 CB1 Receptors Most abundant in the central and peripheral nervous system Also expressed in fat tissues, immune cells, spleen, heart, lungs, GI tract, kidney, bladder, reproductive organs, skeletal muscle, bone and joints CB2 Receptors Most abundant in immune system such as white blood cells and spleen Also found in bone, liver, and neurons Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

7 PRESCRIPTION CANNABINOIDS Dronanbinol (Marinol) Oral capsule Synthetic THC Not available in Canada Nabilone (Cesamet) Oral pill THC analog (similar structure) Indicated for nausea/vomiting in cancer Nabiximols (Sativex) Buccal Spray Contains THC and Cannabidiol extracts Indicated for spasticity/neuropathic pain in MS and adjunctive pain treatment in cancer

8 ENDOCANNABINOID SYSTEM Endocannabinoids are made as needed from post synaptic terminal lipid membranes Primary endocannabinoids: Anandamide and 2-AG They diffuse retrograde to pre-synaptic terminals to bind and activate CB1 receptors The CB1 receptor activation triggers an inhibitory response, preventing the release of excitatory and inhibitory neurotransmitters from the neuron The endocannabinoids then diffuse back to the post-synaptic neuron and are degraded by enzymes FAAH and MAGL to yield arachidonic acid and ethanolamine or glycerol Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

9 THC ON THE BRAIN Output dopaminergic neuron locations: Amygdala (emotion) & Hippocampus (memory) Nucleus Accumbens (reward) Ventral Tegmental Area (reward) Panlilio et al. Clin Pharmacol Ther Jun;97(6):

10 PHARMACOKINETICS OF THC Absorption Smoking: onset 5 mins, duration 2-4h, high peak concentration; F~25% Vaporization: similar to smoking but faster onset Oral: onset min, duration 8-12h, lower peak blood levels; F~10-20% Distribution Taken up by fatty and highly perfused (brain, heart, lungs, liver) tissues Heart and adipose reach 10 and 1000 x higher levels than plasma V D =10 L/kg Plasma protein binding 97% Metabolism Cannabinoid oxidation via CYP2C9, 2C19, 3A4 Polyaromatic hydrocarbons in smoke induce expression of CYP1A2 THC, CBD and CBN inhibit CYP1A1, 1A2, 1B1 Elimination 65% Feces, 20% Urine Terminal Half life estimate of 96 hours Low levels detected in urine & feces for up to 5 weeks Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

11 HOW CANNABIS AFFECTS THE BODY System CNS Cardiovascular Respiratory Effects Euphoria or dysphoria Anxiety Aggravation or precipitation of psychosis Heightened sensory perception, hallucinations Sedation Impaired cognition and motor functioning Analgesia Anti-emetic and anti-nausea; increased appetite Tolerance & dependence Tachycardia (tolerance develops), arrhythmias Peripheral vasodilationà hypotension, conjunctival reddening Histopathological lung changes (when smoked) Cough Phlegm production Bronchodilation

12 HOW CANNABIS AFFECTS THE BODY System Gastrointestinal Musculoskeletal Eye Immune Reproduction Effects Decreased motility and secretions Hepatic steatosis (especially with Hepatitis C) Pancreatitis (heavy use) Pain relief Decreased IOP Suppressive and stimulatory effects Anti-androgenic properties Decrease sperm count, motility and morphology Changes in menstrual cycle, ovulation suppression Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

13 COMMON MEDICAL INDICATIONS Severe refractory nausea and vomiting from chemotherapy Loss of appetite and body weight in cancer and HIV patients Pain and muscle spasms from multiple sclerosis Chronic non-cancer pain (mainly neuropathic) Severe refractory cancer associated pain Insomnia and depression associated with chronic disease (HIV, chronic non-cancer pain) Palliation and end of life care *All other indications have very limited evidence Health Canada. Consumer Information-Cannabis (Marijuana, marijuana). 2007;29 76

14 OTHER STUDIED USES OF CANNABIS System CNS Musculoskeletal GI Other Disease Amyotrophic lateral sclerosis (ALS) Spinal Chord Injury Epilepsy Acute Pain Headache and migraine Alzheimer s Disease and Dementia Movement Disorders: Dystonia, Huntington s Disease, Parkinson s Disease, Tourette s Syndrome Psychiatric disorders: Anorexia Nervosa, Anxiety, depression, sleep disorders, PTSD, alcohol and opioid withdrawal symptoms, schizophrenia and psychosis Osteoarthritis Rheumatoid Arthritis Fibromyalgia Osteoporosis IBS, IBD Liver disease, pancreatic disease Metabolic syndrome, obesity, diabetes Glaucoma Asthma Hypertension Anti-neoplastic properties

15 WHEN CANNABIS SHOULD NOT BE USED Under age 25 Allergy Serious liver, kidney, heart or lung disease Personal family history of mental illness such a schizophrenia, psychosis, depression, bipolar disorder History of substance abuse Concomitant use of sedative-hypnotics Pregnancy or breastfeeding Both men and women attempting to conceive Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

16 EVIDENCE: CHEMO INDUCED NAUSEA & VOMITING Cochrane Database of Systematic Reviews Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy (Review) Smith LA, Azariah F, Lavender VTC, Stoner NS, Bettiol S 23 RCTs between Most were cross-over design None compared cannabinoids to newer anti-emetic drugs such as ondansetron Most at risk of bias due to allocation concealment or attrition Interventions included nabilone and dronabinol (use of THC cigarettes if oral dose was vomited in 2 studies) Smith LA et al. Cochrane database Syst Rev. 2015;11(11):CD

17 Analysis 1.1. Comparison 1 Cannabinoid versus placebo, Outcome 1 Absence of nausea. Review: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy Comparison: 1 Cannabinoid versus placebo Outcome: 1 Absence of nausea Study or subgroup Cannabinoid Placebo Risk Ratio Weight Risk Ratio n/n n/n IV,Random,95% CI IV,Random,95% CI Chang 1979a 2/32 1/ % 2.00 [ 0.19, ] Chang /16 0/16 Not estimable Total (95% CI) % 2.00 [ 0.19, ] Total events: 2 (Cannabinoid), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.58 (P = 0.56) Test for subgroup differences: Not applicable Favours placebo Favours cannabinoid Smith LA et al. Cochrane database Syst Rev. 2015;11(11):CD

18 Analysis 1.2. Comparison 1 Cannabinoid versus placebo, Outcome 2 Absence of vomiting. Review: Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy Comparison: 1 Cannabinoid versus placebo Outcome: 2 Absence of vomiting Study or subgroup Cannabinoid Placebo Risk Ratio Weight Risk Ratio 1Nabilone n/n n/n IV,Random,95% CI IV,Random,95% CI Levitt /36 4/ % 7.25 [ 2.84, ] Subtotal (95% CI) % 7.25 [ 2.84, ] Total events: 29 (Cannabinoid), 4 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 4.14 (P = ) 2Dronabinol Chang 1979a 6/32 2/ % 3.00 [ 0.65, ] Chang /16 0/16 Not estimable Subtotal (95% CI) % 3.00 [ 0.65, ] Total events: 6 (Cannabinoid), 2 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 1.41 (P = 0.16) Total (95% CI) % 5.69 [ 2.56, ] Total events: 35 (Cannabinoid), 6 (Placebo) Heterogeneity: Tau 2 =0.0;Chi 2 =0.93,df=1(P=0.33);I 2 =0.0% Test for overall effect: Z = 4.27 (P = ) Test for subgroup differences: Chi 2 =0.93,df=1(P=0.33),I 2 =0.0% Smith LA et al. Cochrane database Syst Rev. 2015;11(11):CD Favours placebo Favours cannabinoid

19 Efficacy of Crude Marijuana and Synthetic Delta-9-Tetrahydrocannabinol as Treatment for Chemotherapy-Induced Nausea and Vomiting: A Systematic Literature Review Jayme Cotter, RN, MS, OCN Pts admitted after failing phenothiazine antiemetics Smoked cannabis resulted in % relief of nausea & vomiting THC capsule resulted in 76-88% relief of nausea & vomiting Plasma THC levels >10 ng/ml were associated with best efficacy Source Purpose Sample Design Treatment Instrument Results U New Mexico Health and Environment Department, 1983 as cited in Musty & Rossi, 2001 Vinciguerra et al., 1988 Michigan Cancer Foundation, 1982 as cited in Musty & Rossi, 2001 THC capsule versus marijuana cigarette for treatment of CINV in patients refractory to traditional antiemetics Smoked marijuana for CINV in patients refractory to standard antiemetics; patients acceptance of inhalation route Smoked marijuana versus thiethylperazine for CINV 142 total patients Randomized THC capsule or marijuana cigarette before chemotherapy and for five days after chemotherapy 74 patients participated; 56 were evaluated. Nonrandomized, no placebo 165 patients Randomized, crossover Marijuana starting six to eight hours prior to chemotherapy and every four to six hours thereafter for a total of four doses Marijuana cigarette or thiethylperazine If the treatment failed in 24 hours, patients were crossed over to the other treatment group. Self-report using the Target Problem Rating Scale Patient evaluations using scales 1 5 to evaluate nausea, vomiting, appetite, and mood Self-report and physician and nurse observations of nausea severity Both effective at decreasing CINV, but no significant difference between the two treatments Marijuana found to be effective for CINV; 24% of patients dropped out of the study because they did not accept the inhalation route. No significant difference between drugs Cotter J. Oncol Nurs Forum. 2009;36(3): Musty RE and Rossi R. J Cannabis Ther. 2001;1(1):29 56.

20 The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS (Review) EVIDENCE: LOSS OF APPETITE & WEIGHT IN HIV/AIDS Lutge EE, Gray A, Siegfried N 7 randomized controlled trials included Duration ranging from days Lutge EE et al. Cochrane Database Syst Rev. 2013;(4)CD

21 RESULTS Haney 2007 Population: N=10 Interventions: Marijuana cigarettes (0%, 2%, and 3.9% THC)and dronabinol (0mg, 5mg and 10mg) x days Outcomes: Participants on marijuana 3.9% and dronabinol 10mg had significant weight increase vs those on lower doses (P<0.01) Higher doses also increased number of daily eating occasions and daily caloric intake Haney 2005 Population: N=30 Interventions: Marijuana cigarettes (0%, 1.8%, 2.9%, 3.9% THC) and dronabinol (0mg, 10mg, 20mg, 30mg) during 8 sessions over 3-4 weeks Outcomes: Pts with significant wt loss showed increased daily caloric intake for both treatments Lutge EE et al. Cochrane Database Syst Rev. 2013;(4)CD

22 RESULTS Abrams 2003 Population: N=62 Intervention: 3.95% THC marijuana cigarette or 2.5mg dronabinol capsule or placebo TID before meals x 21 days Outcomes: Marijuana arm gained median of 3kg (P=0.021), dronabinol arm gained median of 3.2kg (P=0.004), while placebo arm gained 1.1kg Beal 1995 Population: N=139 Intervention: 2.5mg dronabinol vs placebo1 hour before lunch and supper x 6 weeks Outcomes: Dronabinol group gained mean of 0.1kg while placebo lost 0.4kg (P=0.14) Significant increase in appetite in dronabinol group with 37% on VAS vs 17% in placebo (P=0.05) Lutge EE et al. Cochrane Database Syst Rev. 2013;(4)CD

23 EVIDENCE: LOSS OF APPETITE & WEIGHT IN CANCER Effects of smoking cannabis on appetite and weight gain in this population have not been studied Effects of THC capsules (dronabinol) or oral cannabis have mixed results

24 Comparison of Orally Administered Cannabis Extract and Delta-9-Tetrahydrocannabinol in Treating Patients With Cancer-Related Anorexia-Cachexia Syndrome: A Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial From the Cannabis-In- Cachexia-Study-Group Florian Strasser, Diana Luftner, Kurt Possinger, Gernot Ernst, Thomas Ruhstaller, Winfried Meissner, You-Dschun Ko, Martin Schnelle, Marcus Reif, and Thomas Cerny A B S T R A C T Population: N=243, average wt loss of 11.9% Intervention: Patients assigned to cannabis extract (CE) capsules (2.5mg THC + 1mg cannabidiol), THC capsules (2.5mg) or placebo BID x 6 weeks Outcome: Appetite, mood, and nausea were monitored daily with visual analog scale Results: No significant difference in outcomes Appetite increase was reported by 75% in CE group, 60% in THC group, and 72% in placebo group (P=0.068) Strasser F et al. J Clin Oncol. 2006;24(21):

25 EVIDENCE: MULTIPLE SCLEROSIS CMAJ Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial Jody Corey-Bloom MD PhD, Tanya Wolfson MA, Anthony Gamst PhD, Shelia Jin MD MPH, Thomas D. Marcotte PhD, Heather Bentley BA, Ben Gouaux BA Research Placebo controlled cross over trial Population: 30 adult patients with MS and spasticity (Ashworth 3) Intervention: smoked cannabis (800mg, 4% THC) vs placebo cigarettes once daily x 3 days with 11 day washout Outcome: Change in spasticity on modified Ashworth scale, pain perception by visual analog scale (VAS), timed walk, changes in cognition via Paced Auditory Serial Addition Test Corey-Bloom et al. Can Med Assoc J. 2012;184(10):

26 MODIFIED ASHWORTH SCALE Authors combined ratings for elbows, hips, and knees for a total of 30 possible points. Points were assed before and 45 minutes after treatment administration for 3 visits. Corey-Bloom et al. Can Med Assoc J. 2012;184(10):

27 11 RESULTS Modified Ashworth scale, combined score Before treatment After treatment Smoked cannabis reduced Ashworth Score for spasticity by an average of 2.74 points (P<0.0001) Smoked Cannabis reduced pain scores on VAS by average 5.28 points (P=0.008) Scores for timed walk did not differ Smoked Cannabis reduced Paced Auditory Serial Addition Test for cognition by 8.67 points (P=0.003) Visit (placebo) Visit (cannabis) Corey-Bloom et al. Can Med Assoc J. 2012;184(10):

28 EVIDENCE: CHRONIC NEUROPATHIC PAIN Research CMAJ Smoked cannabis for chronic neuropathic pain: a randomized controlled trial Mark A. Ware MBBS, Tongtong Wang PhD, Stan Shapiro PhD, Ann Robinson RN, Thierry Ducruet MSc, Thao Huynh MD, Ann Gamsa PhD, Gary J. Bennett PhD, Jean-Paul Collet MD PhD Population: 23 adults with posttraumatic or post surgical neuropathic pain for at least 3 months, average pain >4 pts Intervention: 25mg of smoked cannabis of varying potencies (THC 0%, 2.5%, 6% and 9.4%) three times daily x 5 days followed by 9 day washout (cross-over trial) Outcomes: Pain intensity on 11-point scale, mood, sleep, quality of life, adverse events Ware MA et al. CMAJ. 2010;182(14).

29 Outcome Pain intensity Average daily pain 6.1 (1.6) 5.9 (1.9) 6.0 (1.8) 5.4 (1.7) No difference in mood or quality of life Most Feeling Getting frequent on to waking-up sleep AEs: headache, dry eyes, burning sensation, dizziness, numbness, cough RESULTS Highest daily pain 7.1 (1.4) 7.0 (1.6) 7.0 (1.5) 6.5 (1.6) Lowest daily pain 5.1 (2.1) 5.0 (2.4) 4.8 (2.4) 4.4 (2.2) McGill Pain Questionnaire Sensory 17.2 (10.5) 17.1 (9.9) 14.8 (9.2) 15.6 (8.7) Table 3: Effects of smoked cannabis and secondary outcomes, by potency of tetrahydrocannabinol (THC) received Affective 3.5 (3.0) 3.8 (3.6) 3.3 (3.4) 3.0 (3.1) Evaluative 2.2 (1.5) Potency of THC, 2.8 (1.3) %; outcome measure, 2.1 (1.5) mean (SD)* 1.7 (1.5) Miscellaneous 6.2 (4.3) 6.8 (4.4) 5.5 (2.9) 4.5 (3.6) Outcome Total score 29.1 (17.0) 30.4 (18.1) 25.8 (14.5) 24.8 (14.7) Present Pain intensity pain intensity Leeds Average Sleep daily Evaluation pain Questionnaire 2.8 (1.2) 6.1 (1.6) 3.0 (1.0) 5.9 (1.9) 2.8 (1.0) 6.0 (1.8) 2.5 (1.1) 5.4 (1.7) Getting Highest to daily sleep pain 7.1 (1.4) 7.0 (1.6) 7.0 (1.5) 6.5 (1.6) Harder easier than usual 5.4 (1.5) 5.5 (1.6) 6.1 (1.5) 6.8 (1.8) Slower faster than usual 5.3 (1.3) 5.6 (1.4) 6.2 (1.7) 6.9 (1.7) Less more drowsy than usual 5.3 (1.1) 5.9 (1.4) 5.7 (1.3) 6.6 (1.5) Quality of sleep More restless more restful 5.5 (1.6) 5.4 (1.7) 5.9 (2.0) 6.5 (2.1) More less period wakefulness than usual 5.3 (1.5) (1.5) (4.4) 5.5 (2.9) (1.7) (3.6) (1.8) Awakening Total score this morning 29.1 (17.0) 30.4 (18.1) 25.8 (14.5) 24.8 (14.7) Present More difficult pain intensity easier (1.2) (0.8) (1.0) (1.0) (1.4) (1.1) (1.0) Leeds Took longer Sleep Evaluation shorter Questionnaire 4.4 (0.8) 4.4 (0.9) 1.7 (1.1) 5.0 (1.0) Tired Harder alert easier than usual (1.9) (1.5) (1.5) (1.6) (1.5) (1.9) (1.8) (1.9) Feeling Slower now faster than usual 5.3 (1.3) 5.6 (1.4) 6.2 (1.7) 6.9 (1.7) Tired Less more alert drowsy than usual (1.5) (1.1) (1.7) (1.4) (1.3) (2.0) (1.5) (1.7) Sense Quality of of balance sleep Ware MA et al. CMAJ. 2010;182(14).

30 EVIDENCE: CHRONIC NEUROPATHIC PAIN The Journal of Pain, Vol 9, No 6 (June), 2008: pp Available online at A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain Barth Wilsey,* Thomas Marcotte, Alexander Tsodikov, Jeanna Millman, Heather Bentley, Ben Gouaux, and Scott Fishman Population: 38 patients with central and peripheral neuropathic pain (with previous cannabis exposure) Interventions: 7%, 3.5%, or placebo cannabis cigarettes x 3 six hour sessions Outcomes: Pain intensity, evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance Wilsey B et al. J Pain. 2008;9(6):

31 PROCEDURES Figure 1. Experimental procedures. THC, tetrahydrocannabinol; VAS, visual analog scale. Wilsey B et al. J Pain. 2008;9(6):

32 RESULTS Figure 2. Visual analog scale (VAS) pain intensity. Significant response occurred only after a cumulative dose of 9 puffs at time 240 minutes (P=0.02) No effect on evoked pain Psychoactive effects were minimal Patients felt significantly more high, stoned or impaired on the 7% THC marijuana cigarettes Wilsey B et al. J Pain. 2008;9(6):

33 EVIDENCE: CHRONIC PAIN ARTICLES See COMMENTARY page 769 nature publishing group Cannabinoid Opioid Interaction in Chronic Pain DI Abrams 1, P Couey 1, SB Shade 2, ME Kelly 1 and NL Benowitz 3 Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential Population: 21 adult inpatients with chronic pain, on a regimen of BID sustained release morphine (MS Contin) or oxycodone (OxyContin) Intervention: Vaporized cannabis (3.56%, 0.9g) HS on day one, followed by TID on days 2-4, and the morning of day 5 Outcomes: Daily questionnaire evaluating: Pain, stimulation, anxiety, sedation, feeling down, hunger, mellowness, confusion, irritation, depression, withdrawn, dizziness, nausea, dry mouth (VAS 0-100) Pharmacokinetic parameters Abrams DI et al. Clin Pharmacol Ther. 2011;90(6):

34 RESULTS Table 2 Pain by study day Day 1 Day 5 Difference Percentage change n Mean (95% CI) Mean (95% CI) Mean (95% CI) Mean (95% CI) Overall (35.8, 43.3) 29.1 (25.4, 32.8) 10.7 ( 14.4, 7.3) 27.2 ( 45.5, 8.9) Morphine (29.4, 40.1) 24.1 (18.8, 29.4) 11.2 ( 16.5, 6.0) 33.7 ( 63.8, 3.5) Oxycodone (38.6, 49.1) 33.6 (28.5, 38.6) 10.3 ( 14.8, 5.8) 21.3 ( 47.0, 5.3) CI, confidence interval. Participants in both groups reported significant reductions in pain ratings Abrams DI et al. Clin Pharmacol Ther. 2011;90(6):

35 EVIDENCE: CANCER PAIN Table 6 Results of the systematic reviews of randomized controlled trials of cannabis-based medicines for cancer pain included in the systematic reviews Reference Databases and period covered by search of literature Results for efficacy (95% CI) Number of studies/patients in case of quantitative synthesis Results for tolerability and safety (95% CI) Number of studies/patients in case of quantitative synthesis Conclusions of the authors M ucke et al. (2016) Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, PubMed, Scopus and Clinicaltrials.gov up to April 2015 Twenty-eight databases and grey literature sources were searched from inception to April 2015 RD 30% and more pain relief 0.07 (95% CI: 0.0 to 0.16) 2/387 RD Drop-out due to adverse events 1.15; 95% CI: 0.80 to 1.6) a ; 4/825 RD Serious adverse events 1.12 (95% CI: 0.86 to 1.46) 4/825 Due to the sparse amount of data, it is not possible to recommend a favoured use of cannabis or cannabinoids at this time Whiting et al. (2015) OR 30% and more pain relief 1.41 [95% CI: 0.99 to 2.00]; 2/387 No separate analysis for cancer pain No separate statement for cannabis-based medicines in cancer pain CO, confidence interval; OR, odds ratio; RD, risk difference. a Two additional studies with cancer patients included which did not measure pain but other outcomes. *No clinical trials with smoked marijuana Whiting PF et al. JAMA. 2015;313(24):2456 Mücke M et al. Cochrane Database Syst Rev. 2016;2016(5).

36 EVIDENCE: CANCER PAIN One study tested dronabinol (range: 5 to 20 mg/day) vs placebo One study test THC/CBD oromucosal spray (Sativex) (range: 30/32 to 43/40 mg/day) versus placebo. Both reviews of this evidence concluded from quantitative analysis that cannabinoids were not statistically superior to placebo in 30% and more pain relief Whiting PF et al. JAMA. 2015;313(24):2456 Mücke M et al. Cochrane Database Syst Rev. 2016;2016(5).

37 EVIDENCE: EPILEPSY Cannabinoids for epilepsy (Review) Gloss D, Vickrey B Four randomized trials (48 patients total) using cannabidiol as an adjunct to anti-epileptic drugs Cunha 1980: 15 pts with temporal lobe epilepsy with secondary generalized seizures on cannabidiol mg daily vs placebo. Ames 1985: 12 pts with uncontrolled seizures on 300mg cannabidiol daily vs placebo x1 week, then 200mg daily. No difference found. Mechoulam 1978: 9 pts on cannabidiol 200mg daily vs placebo x 3 months. Two pts were seizure free vs none in placebo. Trembly 1990 (abstract): 12 pts on 300mg cannabidiol vs placebo x 6 months. Suggested reduction in seizures. Gloss D et al. Cochrane Database Syst Rev. 2014;(3).

38 EVIDENCE: SCHIZOPHRENIA Cannabis and schizophrenia (Review) McLoughlin BC, Pushpa-Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, Kyprianou K Cannabidiol vs Amisulpride No data reported for mental state using BPRS and PANSS No overall differences in mental state Conclusions: No evidence that cannabidiol has antipyschotic effect McLoughlin BC et al. Cochrane database Syst Rev. 2014;(10):CD

39 EVIDENCE: PALLIATIVE CARE Gaining ground in settings where the focus is on individual choice, autonomy, empowerment, comfort and especially quality of life May be be useful in alleviating a wide variety of single concurrent symptoms often encountered in the palliative setting such as nausea and vomiting with chemo and radiation, anorexia, severe pain, depression, insomnia Effects on Quality of life: RCT in adult patients with advanced cancer and anorexia Cannabis extract and THC did not provide any significant benefit RCT in chronic neuropathic pain (post traumatic or post-surgical etiology) Smoked cannabis did not provide significant benefit Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

40 Can affect proper mental functioning PATIENT WARNINGS/PRECAUTIONS Use involves risks to health which are not fully known or understood Does not meet standards required by Food and Drug regulations for marketed drugs in Canada Smoking cannabis is not recommended Cannabis can impair concentration, decision making, coordination, and reaction time, affecting your ability to drive It can increase anxiety and cause panic attacks, and in some cases paranoia and hallucinations Cognitive impairment may be greatly increased when consumed with alcohol or other psychoactive drugs Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

41 Highly individualized and relies greatly on titration Most individuals use < 3g /day of dried marijuana whether oral, inhaled or combination of both Max supply from health Canada is 150g per 1 month (5g/day) Smoking/Vaporizing: Onset within minutes, shorter duration Wait 30 min between puffs/ inhalations to gauge effect DOSING Edibles/oils: Slow and erratic absorption, delayed onset Dosing less well established (more overdoses) Wait 2 h between administration of single doses of oral products to gauge effect Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

42 DOSING CONVERSION Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

43 OVERDOSE Signs and Symptoms: Sleepiness, confusions, disorientation, loss of coordination, fainting, dizziness, chest pain, fast or slow heart rate, panic attacks, loss of contact with reality, seizures Estimated lethal dose: 30mg/kg (approx. 21g for 70kg person) There is no documented evidence of death exclusively attributable to cannabis overdose to date Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

44 INTERACTIONS Most Important Interaction: CNS Depressants (e.g. alcohol, sedative-hypnotics) Drug That Increase THC Levels: Antiretroviral drugs ritonavir Antibiotics & Antifungals clarithromycin, erythromycin, itraconazole, fluconazole, ketoconazole, miconazole Certain antidepressants fluoxetine, fluvoxamine, nefazodone Proton Pump Inhibitors Omeprazole, cimetidine Certain heart meds diltiazem, verapamil, amiodarone Drugs that Decrease THC Levels: Antibiotics: Rifampicin, rifabutin Anticonvulsants: Carbamazepine, phenobarbital, phenytoin, primidone Natural Health Products St. John s wort Drugs Increased by THC: Amitriptyline, theophylline, granisetron, dacarbazine, flutamide Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

45 ADVERSE EFFECTS System CNS Mouth & Throat CV GI Adverse Effect Dizziness, sedation, fatigue, headache Impaired memory, concentration, decision making Disorientation, confusion, feeling high Anxiety, paranoid, hallucination Motor skill impairment, falls Seizures Dry mouth, throat irritation, cough Tachycardia Nausea/Vomiting Cannabis Hyperemesis Syndrome

46 Table 3. Summary Estimates From Meta-analyses for Each AE Assessed: Odds of Participants Experiencing AE With Cannabinoid vs Placebo or Active Comparison No. of Studies (No. of Patients) Summary OR (95% CI) I 2,% General Dizziness AE categories 41 (4243) 5.09 ( ) 18 Dry mouth 36 (4181) 3.50 ( ) 28 Nausea 30 (3579) 2.08 ( ) 0 Fatigue 20 (2717) 2.00 ( ) 0 Somnolence 26 (3168) 2.83 ( ) 27 Euphoria 27 (2420) 4.08 ( ) 49 Depression 15 (2353) 1.32 ( ) 0 Vomiting 17 (2191) 1.67 ( ) 0 Diarrhea 17 (2077) 1.65 ( ) 15 Disorientation 12 (1736) 5.41 ( ) 0 Asthenia 15 (1717) 2.03 ( ) 0 Drowsiness 18 (1272) 3.68 ( ) 44 Anxiety 12 (1242) 1.98 ( ) 54 Confusion 13 (1160) 4.03 ( ) 0 Balance 6 (920) 2.62 ( ) 0 Hallucination 10 (898) 2.19 ( ) 0 Dyspnea 4 (375) 0.83 ( ) 0 Paranoia 4 (492) 2.05 ( ) 0 Psychosis 2 (37) 1.09 ( ) 25 Seizures 2 (42) 0.91 ( ) 0 Whiting PF et al. JAMA. 2015;313(24):2456

47 LONG TERM EFFECTS Aggravation of psychiatric disorders Risk of lung infections Decrease in fertility (males and females) Behavioral and cognitive development issues from exposure in utero Reduced cognitive function Tolerance and Withdrawal (physical dependence) Addiction (psychologic dependence) Compulsive and continued used despite harm Cravings Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

48 DSM-V: CANNABIS WITHDRAWAL Cessation of cannabis use that has been heavy and prolonged 3 of the follow signs and symptoms (within 1 week of cessation): Irritability, anger, or aggression Nervousness or anxiety Sleep difficulty (insomnia, disturbing dreams) Decreased appetite/ weight loss Restlessness Depressed mood At least one of the follow symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache Among adults and adolescents enrolled in treatment or heavy cannabis users, 50% 95% report cannabis withdrawal

49 CANNABIS WITHDRAWAL SCALE Commonly used in studies to quantify cannabis withdrawal Allsop 2014 & Levin 2011 Developed from the Marijuana Withdrawal Checklist (Budney et al. 1999) Not yet a validated assessment tool, but in the works Allsop et al. Drug Alcohol Depend 2011 Dec 1;119(1-2):123-9.

50 HOW TO GET ACCESS FROM HEALTH CANADA 1. Consult with Health Care Practitioner (Physician or Nurse Practitioner) 2. Obtain a medical document from your health care practitioner 3. Registered and order from a licensed producer (must submit document) 4. Cannabis is sent directly to patient from licensed producer via mail a) Maximum allowable quantity is 150g/month

51 LICENSED PRODUCERS Only licensed producers may sell or provide: Dried marijuana Fresh marijuana Cannabis oil Starting materials to eligible persons

52 CANNABIS DISPENSARIES Not operating under the government s approved distribution system Free Skype Consultation with a medical practitioner OR have a MMPR (Medical Marijuana Purposes Regulation) Card Marijuana and THC/CBD products are shipped to your address Formulations: Cannabis Flowers Concentrates Capsules Phoenix Tears Shatter Hash Cannabis Tinctures THC Distillate CO2 (for vaping) Suppositories Pure CBD Products (including oils) Topical Products

53 CANNABIS DISPENSARY PRODUCTS

54 QUESTIONS?

55 REFERENCES 1. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther [Internet]. 2011;90(6): Available from: 2. Chang AE, Shiling DJ, Stillman RC, Goldberg NH, Seipp CA, Barofsky I, et al. Delta-9-Tetrahydrocannabinol as an Antiemetic in Cancer Patients Receiving High-Dose Methotrexate: A prospective, Randomized Evaluation. Ann Intern Med. 1979;91(6): Cirone S, Kahan M, Ware M, Dubin R. Authorizing Dried Cannabis for Chronic Pain or Anxiety. Can Fam Physician. 2014;(September). 4. Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. Can Med Assoc J. 2012;184(10): Cotter J. Efficacy of Crude Marijuana and Synthetic Delta-9-Tetrahydrocannabinol as Treatment for Chemotherapy-Induced Nausea and Vomiting: A Systematic Literature Review. Oncol Nurs Forum [Internet]. 2009;36(3): Available from: 6. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev [Internet]. 2014;(3). Available from: 7. Häuser W, Petzke F, Fitzcharles M-A. Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management - An overview of systematic reviews. Eur J Pain [Internet]. 2017; Available from: 8. Health Canada. Access to Cannabis for Medical Purposes Regulations Règlement sur l accès au cannabis à des fins médicales Health Canada. Consumer Information-Cannabis (Marijuana, marijuana). 2007; Health Canada. Information for Health Care Professionals: Cannabis (Marihuana, marijuana) and the cannabinoids. 2009;(888).

56 REFERENCES CONTINUED 1. Kramer JL. Medical Marijuana for Cancer. Ca Cancer J Clin. 2015;65(2): Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev [Internet]. 2013;(4). Available from: 3. Mücke M., Phillips T., Radbruch L., Petzke F., Häuser W. Cannabinoids for chronic neuropathic pain. Cochrane Database Syst Rev. 2016;2016(5). 4. McLoughlin BC, Pushpa-Rajh JA, Gillies D, Rathbone J, Variend H, Kalakouti E. Cannabis and schizophrenia. Cochrane database Syst Rev. 2014;(10):CD. 5. Musty RE, Rossi R. Effects of Smoked Cannabis and Oral 9 -Tetrahydrocannabinol on Nausea and Emesis After Cancer Chemotherapy : A Review of State Clinical Trials. J Cannabis Ther [Internet]. 2001;1(1): Available from: JCANT.pdf 6. Smith LA, Azariah F, Lavender VTC, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane database Syst Rev. 2015;11(11):CD Strasser F, Luftner D, Possinger K, Ernst G, Ruhstaller T, Meissner W, et al. Comparison of orally administered cannabis extract and delta-9- tetrahydrocannabinol in treating patients with cancer-related anorexia-cachexia syndrome: A multicenter, phase III, randomized, double-blind, placebo-controlled clinical trial from the Cannabis-In-Cachexia-Study-Group. J Clin Oncol. 2006;24(21): Tafelski S, Häuser W, Schäfer M. Efficacy, tolerability, and safety of cannabinoids for chemotherapy-induced nausea and vomiting a systematic review of systematic reviews. Der Schmerz [Internet]. 2016;30(1): Available from: 9. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic neuropathic pain: A randomized controlled trial. Cmaj. 2010;182(14). 10. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez A V., et al. Cannabinoids for Medical Use. Jama [Internet]. 2015;313(24):2456. Available from: Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. J Pain. 2008;9(6):