Benefits of Medical Cannabis for Cancer Patients

1. Benefits of Medical Cannabis for Cancer Patients Diana Martins-Welch, MD Northwell HealthMay 28, 2019

2. DISCLOSURES None

3. OBJECTIVES Understand the history of medicinal cannabis Learn the basics of the human endocannabinoid system Review the major phytocannabinoids and learn their medicinal properties Review the evidence, and lack thereof, for cannabis’ therapeutic effects Learn about the NY State Medical Marijuana Program

5. CANNABIS • A genus of flowering plant native to Asia with 3 subspecies: • Sativa, Indica, Ruderalis • Over 400 chemical compounds are produced, 65 are unique to the cannabis plant – Phytocannabinoids • The phytocannabinoids of most therapeutic interest are tetrahydrocannabinol (THC) and cannabidiol (CBD). • Marijuana is made from a mixture of dried and shredded flowers of the plant and is greenish-gray in appearance. • Hashish is made from the resins of the plant, high THC content. • Common street names: pot, herb, Mary Jane, grass, reefer, dope, weed, ganja, bud, chronic andskunk.

6. BIOLOGICAL COMPONENTS OF CANNABIS • Cannabinoids THC, CBD • Minor Cannabinoids CBC, CBG, CBN, THC-V, CBD-V, CBC-V • Terpenes trans-caryophyllene, α-caryophyllene, α-pinene, β-pinene, terpinolene, myrcene, limonene, linalool, phytol, squalene • Carotenoids β-carotene • Fatty Acids Linoleic acid, palmitoleic acid, linolenicacid, palmitic acid, oleic acid, stearic acid, myristic acid, arachidonic acid • Sterols β-sitosterol, campesterol, stigmasterol • Vitamin E • Triglycerides

7. PHYTOCANNABINOIDS Gaoni Y, MechoulamR. J Am ChemSoc1964;86:1646–7.

8. PHYTOCANNABINOIDS • Phytocannabinoids have pharmacological activity due to their receptor-based effects on the endocannabinoidsystem • Additional pharmacological effects, such as anti-inflammatory mechanisms may be non-receptor mediated.  

10. History of Cannabis

11. HISTORY OF CANNABIS • 2900BC – Chinese emperor Fu Hsi references “Ma” (cannabis) as a “popular medicine” • 2700 BC – Father of Chinese medicine Emperor ShenNung discovers healing properties of cannabis • 1213 BC – Egyptians use cannabis for glaucoma, inflammation • 1000 BC – Bhang (mix of cannabis and milk) used as medicine in India • 200 BC – Medical cannabis used in ancient Greece

12. HISTORY OF CANNABIS • 1500s– The Spanish brought cannabis to the Americas • 1839 – Sir William O’Shaughnessy researched cannabis in India • 1850– United States Pharmacopeia classifies marijuana as a legitimate medical compound • 1936 – The American propaganda film Reefer Madness was made to scare American youth away from using cannabis. • 1937 – Marijuana Tax Act banned cannabis use and sales • 1970 – Controlled Substances Act – Schedule I

13. CANNABIS PROHIBITION IN THE U.S. • Harry Anslinger • First director of the Federal Bureau of Narcotics in 1930 • Launched a vigilant campaign against cannabis over the 3 decades he remained in office. • The term “marihuana” (Spanish in origin) was used in anti-cannabis propaganda to make it sound more foreign. There are 100,000 total marijuana smokers in the US, and most are Negroes, Hispanics, Filipinos and entertainers. Their Satanic music, jazz and swing, result from marijuana usage. This marijuana causes white women to seek sexual relations with Negroes, entertainers and any others.” –Harry Anslinger, testifying before Congress in 1937

14. Back to the science…

15. ENDOCANNABINOID SYSTEM • Ubiquitous network in the nervous system that regulates synaptic neurotransmission in both excitatory and inhibitory circuits • Humans naturally produce cannabinoids - endocannabinoids • Endocannabinoids interact with specific receptors found on neurons and immune cells • Act to reduce excess nerve activity and suppress inflammation • Functions in parallel and in conjunction with adrenergic, cholinergic, and dopaminergic systems in both the central and autonomic nervous systems

16. ENDOCANNABINOID SYSTEM • Three main components: • Endocannabinoids– (endogenous lipid ligands) • Anandamide & 2-AG • Receptors– CB1 & CB2 (G-protein coupled), TRPV1 • Regulatory Enzymes– Synthesis and hydrolysis of endocannabinoids (ex: fatty acid amidohydrolase, FAAH; monoacylglycerol lipase, MAGL)

17. ENDOCANNABINOIDS • Anandamide (AEA) – Partial agonist of CB1 receptors, low affinity to CB2 (1992) • 2-AG – Fully efficacious agonist of both CB1 and CB2 receptors (1995)

18. CANNABINOID RECEPTORS • CB1 receptor - G protein receptor that serves as a target for both endocannabinoidsandphytocannabinoids. • 10 times more prevalent in the CNS as compared to the μ-opioid receptor. • Found in high densities in the neuron terminals of the basal ganglia (affecting motor activity), cerebellum (motor coordination), hippocampus (short-term memory), neocortex (thinking), and hypothalamus and limbic cortex (appetite and sedation). • To a lesser extent, the CB1 receptors are found in periaqueductal gray dorsal horn (pain), immune cells, liver, thyroid, uterus, bones and testicular tissue

20. CANNABINOID RECEPTORS • CB2 receptor (CB2r) – Found on immune cells and tissues, is primarily immunomodulatory and anti-inflammatory • Expressed on the cell membranes of B and T cells, macrophages and spleen. • When signaled, CB2r are generally inhibitory to immune cell activation. • CB2r expression is inducible, their number is increased by inflammation. • Reduced CB2r signaling results in increased severity of inflammation as found in studies in mice.

22. Medicinal effects of Cannabis

23. “Modulating endocannabinoid activity may have therapeutic potential in almost all diseases affecting humans, including obesity/metabolic syndrome, diabetes and diabetic complications, neurodegenerative, inflammatory, cardiovascular, liver, gastrointestinal, skin diseases, pain, psychiatric disorders, cachexia, cancer, chemotherapy-induced nausea and vomiting, among many others.” Pacher and Kunos FEBS J. 2013 May; 280(9): 1918–1943

24. REASONS FOR MEDICAL CANNABIS USE Reinarman et al., 2011

25. POTENTIAL THERAPEUTIC BENEFITS OF CANNABIS • Nausea and Vomiting • Anorexia and Cachexia • Spasticity • Movement Disorders • Pain • Glaucoma • Epilepsy • Asthma • Autoimmune Diseases and Inflammation • Psychiatric Symptoms • Miscellaneous, Mixed Syndromes: Pruritus, Chronic Fatigue Syndrome, Attention Deficit Disorder, Restless Leg Syndrome, Hiccups

26. PHARMACOLOGIC EFFECTS OF THC • Psychotropic • Initial euphoria and relaxation followed by depressant period • Alterations in memory and cognitive perceptual abilities • Immunosuppressive/immunomodulatory • Cardiovascular • Tachycardia, orthostatic hypotension, peripheral vasodilation • Analgesic • Anti-emetic • Appetite stimulation

27. PHARMACOLOGIC ACTIONS OF CBD • Anticonvulsive • Analgesic • Anti-anxiety • Anti-depressant • Anti-psychotic • Anti-inflammatory • Immunosuppressive • Inhibits FAAH enzyme • Potential benefit in Parkinson’s, Alzheimer’s disease, Diabetes mellitus, Cancer

28. CANNABINOID MEDICINES • Dronabinol (Schedule III) • Chemo-induced nausea/vomiting (1985) • Anorexia associated with weight loss from AIDS (1992) • Nabilone(Schedule II) • Chemo-induced nausea/vomiting (1985) • Nabiximols(not FDA-approved) Cannabis-derived liquid extract formulated from 2 strains of Cannabis sativa into an oromucosal spray. Approved in 10 countries for: • Spasticity from MS • Neuropathic pain in MS patients • Intractable cancer pain • Rimonabant(CB1 antagonist) – Anorectic antiobesity drug • Taken off market due to serious psychiatric effects

29. 2015 • Dronabinol, nabiximols, nabilone, CBD. • Only 2 studies evaluated cannabis • 79 trials included (6462 participants) • Most trials showed improvement in symptoms (not all statistically significant) • Compared with placebo, cannabinoids were associated with a greater average number of patients showing: • a complete nausea and vomiting response; 3 trials, • reduction in pain; 8 trials, • a greater average reduction in numerical rating scale pain assessment; 6 trials, • average reduction in the Ashworth spasticity scale; 5 trials, • There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

30. 2011 • Included neuropathic pain, fibromyalgia, RA and mixed chronic pain • 18 RCTs (2003- 2010), 766 total participants • “Overall quality of trials was excellent” • “15 or the 18 trials that met inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared to placebo, several reported significant improvements in sleep. There were no serious adverse side effects.” • “This systematic review of 18 recent good quality randomized trials demonstrates that cannabinoids are a modestly effective and safe treatment option for chronic non-cancer (predominantly neuropathic) pain. Given the prevalence of chronic pain, its impact on function and the paucity of effective therapeutic interventions, additional treatment options are urgently needed. More large scale trials of longer duration reporting on pain and level of function are required.”

31. SYNERGY WITH OPIOIDS • Abrams et al (2011) studied 21 individuals with chronic pain, on a regimen of twice-daily doses of sustained-release Morphine or Oxycodone • Admitted participants for 5-day inpatient stay • Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2–4, and in the morning of day 5. • Blood sampling was performed at 12-h intervals on days 1 and 5. • Extent of chronic pain was assessed daily. • Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration–time curves for either morphine or oxycodone after exposure to cannabis. • Pain was significantly decreased (average 27%) after the addition of vaporized cannabis. • Concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects

32. NEUROPATHIC PAIN - FIVE RCTs • Wilsey et al: A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. J Pain. 2008 June ; 9(6): 506–521. • Ellis et al: Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial. 2009 February ; 34(3): 672–680. • Wallace et al: Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. J Pain. 2015 July ; 16(7): 616–627. • Ware et al: Smoked Cannabis for Chronic Neuropathic Pain: A randomized controlled trial. CMAJ. 2010 Oct 5;182(14):E694-701. • Abrams et al: Cannabis in Painful HIV-Associated Sensory Neuropathy: a randomized placebo-controlled trial. Neurology. 2007 Feb 13;68(7):515-21.

33. CANNABIS FOR NAUSEA AND VOMITING • Central regulation of emesis occurs via the: • Dorsal Vagal Complex (DVC) • Area Postrema – located outside BBB, provides communication between blood-borne signals • Nucleus of the solitary tract • Dorsal motor nucleus of the vagus } Contain CB1 receptors • Meta-analysis of 3 RCTs (Machado, et al, 2008) showed statistically significant benefit of Dronabinol on CINV. • Scarcity of data comparing cannabis to first-line anti-emetics

34. CANNABIS FOR CANCER-ASSOCIATED PAIN • The CB1r is found in the CNS and in peripheral nerve terminals. Elevated levels of the CB1r (like opioid receptors) are found in areas of the brain that modulate nociceptive processing. • Cannabinoids may contribute to pain modulation through an anti-inflammatorymechanism—a CB2 effect with cannabinoids acting on mast cell receptors to attenuate the release of inflammatory agents such as histamine and serotonin and on keratinocytes to enhance the release of analgesic opioids.

35. CANNABIS FOR CANCER-ASSOCIATED PAIN • Johnson, et al (2010) performed a placebo-controlled RCT comparing THC:CBD extract to THC only extract to placebo. • 2x as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain numerical rating scale (NRS) score when compared with placebo • The number of THC-only group responders was similar to placebo and did not reach statistical significance. • No change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. • THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids

36. CANNABIS FOR ANOREXIA/CACHEXIA SYNDROME • Numerous nuclei in the medulla are involved in the regulation of appetite and nausea  coordinate sensory input from the brainstem, vagal complex, vestibular organs, and peripheral organs. • CB1r are present in the hypothalamus (controls food intake) and in mesolimbic reward system which may be involved in the motivational/reward aspects of eating. • Endocannabinoidsand CB1 agonists inhibit vagal fibers to promote eating and CB1 antagonists to decrease or inhibit food intake. • Trials conducted in the 1970s in healthy controls found thatsmoked cannabis (especially when used in a social/communal setting) led to an increase in caloric intake, predominantly in the form of between-meal snacks, (mainly fatty and sweet foods). •  Lack of clinical studies showing benefit in cancer patients

37. CANNABIS AS AN ANTI-CANCER AGENT • Antiproliferative effects were originally reported in 1975 by Munson et al. who demonstrated that delta-9-THC, delta-8-THC, and cannabinol inhibited Lewis lung adenocarcinoma cell growth in vitro as well as in mice. • Cannabinoids may exert their antitumor effects by a number of different mechanisms, including: • direct induction of transformed cell death, • direct inhibition of transformed-cell growth, • inhibition of tumor angiogenesis and metastasis • Research on cannabis as an anti-neoplastic medication in humans is lacking

38. THE ENTOURAGE EFFECT • The enhancement of cannabinoid effects by non-cannabinoid components.

39. FACTORS INFLUENCING CANNABIS’ EFFECTS • Dose of cannabis consumed • Ratio of the various cannabinoids in the cannabis product • Route of administration • Time since consumption • Health status of the patient • Age of the patient • Co-administration of other drugs/medicines • Whether or not the patient has been using cannabis recreationally (or receiving cannabis therapy) long-term or if the patient is cannabis naïve

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41. CONTRAINDICATIONS • Absolute Contraindications • Acute psychosis and other unstable psychiatric conditions • Relative Contraindications • Severe cardiovascular, immunological, liver or kidney disease • Cannabis may exacerbate arrhythmia or a history of arrhythmias

42. SIDE EFFECTS/ADVERSE EFFECTS OF CANNABIS USE • Distorted perception • Loss of motor coordination • Difficulty with concentration/problem solving • Dry mouth • Tachycardia • Psychosis and Schizophrenia (increased risk with personal/family hx) • Infertility • In vivo and in vitro studies have shown that cannabis may disrupt the hypothalamus pituitary-gonadal axis, spermatogenesis, and sperm function • Cannabinoid hyperemesis syndrome • Impaired driving

43. CANNABIS USE DISORDER • A problematic pattern of cannabis use leading to clinically significant impairment or distress. Manifested by at least 2 of the following within a 12-month period (DSM-V): • Cannabis is often taken in larger amounts or over a longer period than was intended. • Persistent desire or unsuccessful efforts to cut down or control cannabis use. • Great deal of time spent obtaining, using or recovering from effects of cannabis. • Craving, or a strong desire or urge to use cannabis. • Recurrent cannabis use resulting in a failure to fulfill major obligations. • Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis. • Important activities are given up or reduced because of cannabis use. • Recurrent cannabis use in situations in which it is physically hazardous. • Continued use despite knowledge of problems caused or exacerbated by cannabis. • Tolerance • Withdrawal symptoms

44. CANNABIS WITHDRAWAL SYNDROME • Includes restlessness, irritability, mild agitation, insomnia, strange dreams, appetite loss, nausea, and cramping. • Regular cannabis intake is related to a desensitization and downregulation CB1 receptors. • Starts to reverse within the first 2 days of abstinence; receptors return to normal functioning within 4 weeks of abstinence. • CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Bonnet U, et al. 2017

45. New York State Medical Marijuana Program

46. COMPASSIONATE CARE ACT • Governor Cuomo passed bill (Compassionate Care Act) on June 19, 2014 • Program launched on January 7, 2016 • Five registered organizations, 4 dispensaries each • Bloomfield Industries Inc. • Columbia Care NY LLC • Etain, LLC • PharmaCann LLC • Vireo Health of New York LLC

47. COMPASSIONATE CARE ACT • Five new organizations added (Aug 2017): • NYCANNA, LLC • Phiorello Pharmaceuticals, Inc • Valley Agriceuticals, LLC • Citiva Medical, LLC • PalliaTech NY, LLC

48. PRACTITIONER QUALIFICATIONS • Be qualified to treat patients with one or more of the serious conditions. • Be licensed, in good standing as a physician/NP/PA and practicing medicine • Have completed a four-hour course approved by the Commissioner • Have registered with the New York State Department of Health (NYSDOH).

49. ELIGIBILITY CRITERIA • Serious Medical Condition • Cancer • HIV +/- AIDS • ALS • Parkinson’s • MS • Spinal cord injury with spasticity • Epilepsy • IBD • Neuropathy • Huntington’s Disease • Chronic Pain • PTSD • Pain that degrades health/function as an alternative to opioid use • Substance Use Disorder

50. ELIGIBILITY CRITERIA • Clinically Associated Condition • Seizures • Severe nausea • Severe or persistent muscle spasms • Severe or chronic pain resulting in substantial limitation of function • Cachexia or wasting syndrome • PTSD • Opioid use disorder, but only if enrolled in a treatment program certified pursuant to Article 32 of the Mental Hygiene Law