Medical Marijuana - Does it Have a Role in the Treatment of Cancer Patients?

1. Medical marijuana Does it have a role in the treatment of cancer patients? Paul Daeninck, MD MSc FRCPC Departments of Internal & Family Medicine University of Manitoba and CancerCare Manitoba

2. Objectives At the end of this event, participants will learn about: 1. Basic facts about medical cannabis in Canada 2. The role of medical cannabis for cancer patients 3. How to access medical cannabis under the current Health Canada process

3. Ma-fen is used for waste diseases and injuries; it clears blood and…it undoes rheumatism. If taken in excess it produces hallucinations and a staggering gait. If taken over a long term it causes one to communicate with spirits and lightens one’s body Ancient Chinese Herbal, c. 2700 BC

4. Russo et al, 2008 Cannabis in History Food and oil (seeds) Fibre (stems) Drug / Medicine (flowers)

5. A few definitions… Cannabis: plant material, cannabis sativa, cannabis indica, hemp, marijuana Cannabinoid: group of active compounds found in cannabis (e.g., THC, CBD, CBG, etc) Endocannabinoid system: includes receptors (CB1, CB2), ligands (2-AG), enzymes (FAAH)

6. Time Nov 22/2010 How does cannabis work?

7. Cannabis sativa Marijuana (dried leaves / flowering heads) Isolated pure compounds Non-cannabinoids Cannabinoids Psychoactive Δ9-THC Δ8-THC cannabinol (weak) Active, not psychoactive cannabidiol Inactive > 80 compounds > 400 chemical compounds > 70 types of cannabinoids Most potent psychoactive ingredient Cannabis: What’s in it? Kalant H. Pain Res Manage 2001;6:80-91 active in several conditions

8. 1) Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron 2) Activation of postsynaptic neuron leads to synthesis and release of endocannabinoid 3) The endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor 4) The CB1 receptor activates a G-protein, which lead to presynaptic events that result in inhibition of NT release 5) Exogenous drugs directly activate CB1 receptors to stimulate the endogenous cannabinoid system, enhancing its function 5 1 2 4 3 Cappendijk S Modulators of Drug Dependence Phenomena 2010 Mackie K Ann Rev Pharmacol Toxicol 2006,46:101-122

9. Endocannabinoids Immune function Inflammation Appetite Metabolism and energy homeostasis Cardiovascular function Digestion Bone development and bone density Pain Reproduction Psychiatric disease Psychomotor behavior Memory Wake/sleep cycles Regulation of stress and emotional state Learning Evidence supports the role of endocannabinoids in:

10. Who is using medical cannabis?

11. Who uses cannabis as medicine? 2% use cannabis for medical purposes (2000) >37,000 people registered with MMAR (Mar 2013) approx 6% cancer Dx >50,000 people registered with MMPR (Mar 2016) >98,000 registrants with ACMPR (Sept 2016) No epidemiology studies done in cancer or palliative care patients Ogborne, CMAJ 2000 Health Canada information

12. Market data from Health Canada

13. Hazekamp et al, J Psycho Drugs, 2013

14. Hazekamp et al, J Psycho Drugs, 2013

15. Time Nov 22/2010 Why are people asking for cannabis? What is the evidence?

16. On-label indications: Nausea and vomiting from chemotherapy Chronic pain (neuropathic pain in MS and cancer) Anorexia associated with HIV / AIDS Off-label indications/emerging evidence for: Neuropathic / mixed pain Chronic daily headache Anorexia / cachexia Spasticity Epilepsy Cannabinoid indications PTSD Anxiety Insomnia Spasticity (MS) Bladder spasms (MS) Fibromyalgia

17. Symptom prevalence in cancer patients Pain Depression Anxiety Confusion (delirium) Fatigue Breathlessness (dyspnea) Nausea Constipation Anorexia 35 - 96% 3 - 77% 13 - 79% 6 - 93% 32 - 90% 10 - 70% 6 - 68% 23 - 65% 30 - 92% Solano et al, JPSM 2006; 31: 58-69

18. Symptoms responsive to cannabinoids Pain Depression Anxiety Confusion (delirium) Fatigue Breathlessness (dyspnea) Nausea Constipation Anorexia

19. What is the evidence? Pain Pre-clinical Clinical Evidence ++ +++

20. Pre-clinical data: Pain Robust in vitro evidence cancer pain responds to cannabinoid treatment Use in bone pain/neuropathic pain has strongest evidence Direct use of agonists/antagonists and prevention of enzyme degradation Peripheral application effective, few A/E

21. Clinical data: Pain Trial evidence supports oral use in cancer pain, in addition to usual therapy Small studies using smoking/vaporization None using edibles or oils Reduction in use of pain meds noted Few A/E

22. Conclusions of reviews Studies small, short in duration, modest effect size “cannabinoids are safe, demonstrate a modest analgesic effect and provide a reasonable treatment option for chronic non-cancer pain”

23. CPS neuropathic pain guideline revision Add additional agents sequentially if partial but inadequate pain relief Tramadol or Controlled-release opioid analgesic Fourth-line agents† Cannabinoids TCA Gabapentin or pregabalin SNRI ‡ †methadone, lamotrigine, topiramate, valproic acid, lidocaine. ‡Do not add SNRIs to TCAs Pain Res Manage 2014;19(6):328-335

24. What is the evidence? Nausea Pre-clinical Clinical Evidence ++ +++

25. Martin BR & Willey JL. J Support Onc 2004;2: 305-16 Cannabinoids in nausea

26. CBs may be superior to conventional therapies in low- medium emetogenic setting Patient preference for CBs ranged from 38-90% (P 4-20%) CBs produced significantly more A/E effects (good & bad), more pt withdrawals “In selected patients, cannabinoids may be useful as mood enhancing adjuvants for the control of chemotherapy related sickness” BMJ 2001, 323:1-8

27. Inhaled marijuana Three studies, associated with chemo administration Some new users, many previous cannabis users All studies showed benefit, but high incidence of side effects 25-35% pts prefer marijuana Vinciguerra et al, N Y State J Med 1988 88:525 Chang et al, Ann Int Med 1979 91:819 Levitt et al, JCO 1984 abstract C-354

28. What is the evidence? Appetite/wt loss Pre-clinical Clinical Evidence ++ +

29. Marijuana flips appetite switch in brain Sudden attacks of 'the munchies’ triggered by changes in hormone pro- opiomelanocortin (POMC) release by neurons doi:10.1038/nature.2015.16957 doi: 10.1038/nature14260

30. Jatoi A et al. J Clin Oncol 2002;20:567-573 Nelson K et al. J Pall Care 1994;10:14-18 Timpone JG et al. AIDS Res Hum Retroviruses 1997;13:305-15 Struwe M et al. Ann Pharmacother 1993;27:827-31 Beal JE et al. J Pain Symptom Manage 1995;10:89-97 Beal JE et al. J Pain Symptom Manage 1997;14:7-14 Appetite and weight loss

31. Dronabinol: taste alterations Pilot trial to improve taste, smell changes in advanced cancer patients THC 2.5 mg BID or TID vs placebo x 18 days, n=21 Questionnaires / interviews revealed significant improvement in taste / smell, increased appetite and protein intake QoL measures found improved relaxation, quality of sleep Adverse effects same in both groups TD Brisbois Clarkson et al, Ann Oncol 2011; 22: 2086-93

32. What is the evidence? Neuroprotection Pre-clinical Clinical Evidence +/- +

33. What is the evidence? Insomnia Pre-clinical Clinical Anxiety Pre-clinical Clinical Evidence - ++* ++ - *secondary finding

34. Cannabinoids and anxiety Oral cannabinoids used for nausea produces sedation and reduces anxiety Very low dose cannabis can produce sedation, diminish anxiety without getting high Cannabidiol can exert anti-anxiety effects, although only demonstrated in acute, experimentally-induced anxiety Tramer et al, BMJ 2001; 323:1-8 Graham and Li, Cannabis and Health, 1976 Bergamaschi et al, Neuropsychopharmcol 2011; 36: 1219-26

35. 20 Medical Studies That Prove Cannabis Can Cure Cancer http://www.collective-evolution.com/2013/08/23/20-medical-studies-that-prove- cannabis-can-cure-cancer/#sthash.H5ypYS6a.dpuf Cannabis Cures Cancer https://dl.dropboxusercontent.com/u/27713298/Web/cure/How_It_Works.html Run From The Cure: How Cannabis Cures Cancer And Why No One Knows Cannabis sativa hemp, the miracle plant, contains the cure for cancer and other ailments By Rick Simpson - Friday, March 7 2008 http://www.cannabisculture.com/articles/5169.html

36. What is the evidence? Cancer Pre-clinical Clinical Clinical trials Evidence +++ nil - In Progress Cannabis is not a cure for cancer

37. What should one know about obtaining medical cannabis in Canada?

38. Prescription cannabinoids Dronabinol (Δ-9 tetrahydrocannabinol – THC) (2.5 - 10mg) Oral capsule Approved for chemotherapy-induced nausea and vomiting and anorexia associated with HIV/AIDS Nabilone (0.25 - 1.0mg) Oral capsule Approved for chemotherapy-induced nausea and vomiting Nabiximols (2.5mg THC + 2.7mg CBD) Oromucosal spray Approved in Canada for multiple sclerosis-associated neuropathic pain, spasticity and advanced cancer pain

39. Female flowers (“buds”) are rich in cannabinoids (e.g. THC) Smoked Herbal cannabis-joints, pipes Vaporized Herbal cannabis heated to release cannabinoids but prevent burning Oral / buccal Tinctures (alcoholic extracts) Oils and edible products (cookies, brownies, etc.) Sublingual spray (nabiximols by prescription) Topical Balms, lotions and salves Medicinal cannabis products

40. Health Canada website 36 Licensed Producers to date Patient confusion over who to choose What distinguishes one LP over another? Is the product safe? What does “Jack the Ripper” and “Green Kush” mean? Supply availability? http://www.hc-sc.gc.ca/dhp- mps/marihuana/info/list-eng.php

41. Cannabis strains Thousands of cannabis strains exist 34 licensed producers listed >300 strains Most strains were developed for recreational use and still use common names high THC (15-20%), very low CBD (<1%) mod CBD (9-15%), low THC (1-4%) THC=CBD Oils (THC>CBD, THC=CBD, THC<CBD) Varying amounts of minor cannabinoids (CBC, THCV, etc.), terpenoids, flavonoids Page, 2014

42. Medical cannabis: Is it different than street marijuana? Grown under strict Good Production Practices (GPP) guidelines enforced by Health Canada Most producers have industrial size “grow-ops” Products tested for microbials, mycotoxins, metals and pesticides Delivered to the patient in a safe and secure manner Concentrations of cannabinoids captured on label (usually THC and CBD) Recall ability given lot designation

43. Precautions and contraindications Contraindications: Psychosis/schizophrenia Unstable heart disease Pregnancy Age under 21-25 (cognitive development) Ask about: History of legal issues/criminal charges Screening for other drug use Prior recreational cannabis use

44. Adverse effects Drowsiness Dry mouth Delirium/psychosis Cognition Hyperemesis Dependence Interactions Respiratory effects Spermatogenesis Neurodevelopment

45. Patient Symptoms where conventional treatments have failed Compassionate end- of-life care or specified medical conditions Current ACMPR process

46. PatientCompassionate end- of-life care or specified medical conditions A physician completes a medical document on behalf of patient for access to medicinal marijuana Current ACMPR process

47. Patient Current ACMPR process The patient sends an application form to the Licensed Producer of their choice.

48. Patient Current ACMPR process The Licensed Producer validates the client’s medical document / application form and adds them as a client. Once the client orders product, it is then shipped via secured courier to their door.

49. Licensed Producer Mailing Address Product choice Health Care Practitioner Information Patient Information Written Order Physician Attestation, Signature

50. Summary Cannabis & cannabinoids active in supportive care for cancer patients Clinical benefits in: pain, nausea, appetite More research is needed

Medical Marijuana - Does it Have a Role in the Treatment of Cancer Patients?

Canadian Cancer Survivor Network

Medical Marijuana - Does it Have a Role in the Treatment of Cancer Patients?