Medical Marijuana: The Doctor’s Dilemma

1. Medical Marijuana: The Doctor’s Dilemma Michael Craine, Ph.D. Chief, Health Psychology Section Denver Veterans Affairs Medical Center VA Eastern Colorado Health Care System

2. Disclosures • None

3. Learning Objectives • Understand complex and changing history of marijuana in the U.S. and differences between State and Federal status. • Recognize how marijuana is marketed to medical patients. • Understand current systematic reviews of cannabis for pain. • Understand risks associated with cannabis use. • Understand VHA Directive 1315. • Review issues to address with pain patients about medical marijuana.

4. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S,Donaghe H: Low-dose vaporized cannabis significantlyimproves neuropathic pain. J Pain 14:136-148, 2013 • Cannabis isn’t just another experimental medication or treatment. It has a cultural and scientific context that is unique in our society, and new data are needed to move beyond emotional based discussions. Stacey, BR and Moller, JL The Journal of Pain, Vol 14, No 10 (October), 2013: pp 1250-1251 • We appreciate the authors’ interest in the study and belief that rigorous studies are needed to address the potential role, or not, of cannabinoids in pain research, particularly in the area of neuropathic pain, where upwards of 40–60% of patients fail to get relief from current treatments. We agree that much is still unknown regarding the potential use of cannabis as medicine, such as How frequently would it need to be administered? Is any benefit sustainable? What are the short- and long-term effects on daily functioning (positive and negative)? What is the therapeutic window? Wilsey, B and Marcotte,T The Journal of Pain, Vol 14, No 10 (October), 2013: pp 1252-1253

5. History in Western Medicine • Cannabis use for medicinal purposes in China dates back at least 3,000 years. • 1839 - W.B. O’Shaughnessy, an Irish physician who worked in India for the British East India Company, brought it to Western Medicine for analgesic, sedative, anti-inflammatory, antispasmodic, and anticonvulsant effects. Concurrently, a French physician, Jean-Jacques Moreau de Tours explored use in mental problems. • 1850 – listed in U.S. Pharmacopeia for neuralgia, tetanus, typhus, cholera, rabies, dysentery, alcoholism, opiate addiction, anthrax, leprosy, incontinence, gout, convulsive disorders, tonsillitis, insanity, excessive menstrual bleeding, and uterine bleeding, etc.

6. U.S. Legislative History • 1911-1927 Starting with Massachusetts, 11 states pass marijuana prohibition. • 1936 – Reefer Madness released. • 1937 - U.S. Treasury Dept. Marihuana Tax Act imposed a levy of $1 per ounce for medicinal use and $100 per ounce for nonmedical use. • AMA testimony in hearings said evidence that Cannabis was harmful was lacking and the tax would block research into medical applications. Prescriptions declined after tax enacted.

7. Legislative History • 1942 - Cannabis removed from U.S. Pharmacopoeia due to concerns about its potential to cause harm. • 1951 - Boggs Act includes Cannabis with narcotic drugs and sets prison sentence. • 1970 - Controlled Substances Act classified it as a Schedule Drug I indicating no accepted medical use. • 1976 – Federal Court approves medical necessity for glaucoma patient.

8. Legislative History • 1972 –National Bipartisan Commission recommends decriminalization. Rejected by President Nixon. • 1978 - Compassionate Use Investigational New Drug program allowed case-by-case distribution under Government control. • 1985 – Marinol (dronabinol) approved by FDA.

9. Legislative History • 1992 – Compassionate Use program closed to new patients. 13 patients remained on the program. • 1996 - Proposition 215 in California permits patients and primary caregivers to cultivate and possess marijuana with physician recommendation. • 1997 – NEJM and NIH seek rescheduling to support medical research.

10. Legislative History • 1998 - • Congress stops enactment of Medical Marijuana Law in District of Columbia. • Alaska, Oregon and Washington Legalize Medical Marijuana. • 1999 – Maine legalizes Medical Marijuana. • 2000 – Hawaii, Colorado, Nevada legalize medical use. • 2001- Supreme Court rules against medical necessity exception – denies use.

11. Legislative History • 2004 – Montana, Vermont, • 2006 – Rhode Island, • 2007 – New Mexico, • 2008 – Michigan. • 2009 – Department of Justice memo states that DOJ will not prioritize medical marijuana. • 2010 – New Jersey, D.C, Arizona, Delaware legalize and South Dakota rejects legalization.

12. Legislative History • 2010 – VA Issues 2010-035 Medical Marijuana Directive. • 2011 – VA issues 2011-04 Access to Clinical Programs for Veterans Participating in State Approved Marijuana Programs. • 2012 – Connecticut, Massachusetts, • 2013 – New Hampshire, Illinois, • 2014 – Maryland, Minnesota, New York.

13. Legislative History • 2015 – Puerto Rico, • 2016 – Pennsylvania,Ohio,Arkansas,Florida,North Dakota, • 2017 – West Virginia, Louisiana. 30 states, D.C., Guam and Puerto Rico. 16 more with Low THC/ CBD access. • 2017 – VA Directive 1315 Access to Clinical Programs for Veterans Participating in State-Approved Marijuana Programs • 2018 – Attorney General rescinds DOJ non-priority policy.

14. http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx National Council of State Legislatures.

15. Cannabis Facts • 22.2 million Americans (12 years of age and older) report using cannabis in the past 30 days. (2015) • 21% of High School Seniors • Highest use in males ages 18-34. • Colorado Marijuana Sales - Total to date $4,724,523,425 • $1 Billion In Marijuana Taxes Is Addictive To State Governors – Forbes 4/11/17 • (DEA) seizures record a substantial increase in average potency (THC) , from 3.8 percent in 1995 to roughly 12.2 percent in 2014. Often as high as 20%in current seizures.

17. Cannabis Facts • 89% of users report recreational, 10.5% medical and 36% mixed use (Schauer et al., 2016) • Adults are more likely to use daily compared to youth users. • Multiple means of delivery: • Smoking, vaping similar rates of onset with maximum in 30 minutes lasting 1 to 4 hours. • Eating edibles slower onset and longer lasting 5-8 hours or longer. • Also applied in salves, sprays, oils, and creams. • In 2015, between 498,170 and 721,599 units of medical and recreational cannabis edibleswere sold per month in Colorado. (Colorado DOR, p. 12)

20. Recreational Synthetic Cannabinoids • Synthetic cannabinoids are sprayed on plant materials like herbs and spices marketed as “natural” substances. • Strong affinity and long binding to CB1 receptors. • Examples - K2, Spice, Eclipse, Joker, Kush, Cloud Nine, Vitamin K, AK47. • Illinois April 2018 – 3 men died and 107 people experienced severe bleeding due to brodifacoum poisoning in synthetic cannabinoid.

21. Cannabis - a complicated plant • Three main species: sativa, indica, ruderalis, strains are mixed in cultivation resulting in a variety of phenotypes. • 537 chemical constituents of which 107 different cannabinoids have been identified. • Two constituents of primary interest: THC and CBD • Delta-9-Tetrahydrocannabinol (THC) is a psychoactive substance with partial agonist activity at CB1 (central and peripheral nervous system) and CB2 receptors (mostly peripheral nervous system). • Medical THC reported to reduce pain, spasticity, nausea, increase appetite, improve mood and treat cancer. • THC responsible for psychoactive effects of cannabis.

22. Cannabis - a complicated plant • Cannabidiol (CBD) Non-psychoactive component of marijuana that is of interest for potential health benefits. • CBD has low affinity for CB1 and CB2 receptors. • Multiple direct and indirect mechanisms of action: • Serotonin 5-HT1A agonist, inhibits deactivation of endocannabinoid anandamide (CB1 ) . • Inhibits inactivation of adenosine (possible anti-inflammation mechanism).

24. Cannabinoids in Pain ModulationRichardson, 2000 J of Pain • Anti-nociception and anti-hyperalgesia demonstrated in animal models, mostly rats. • Cannabinoids act on peripheral, spinal and supraspinal sites. • Actions include inhibition of mast cell degranulation, primary afferent activity, and modulation of nociceptive neurons. • Tonic activity cannabinoid receptors modulates nociceptive thresholds and may be important in etiology of chronic pain. • Cannabinoids and opioids potentiate each other.

25. Endocannabinoid Exocannabinoid Image by the NIDA

26. Cannabis for Chronic Pain • Most users of medical marijuana cite pain as the condition treated – 94% of Coloradoans in 2014. (Light, et al., 2014) • Medical marijuana use might lead to reduced opioid use. (Boehnke, et al., 2016; Bradford and Bradford, 2016). • Useful Reviews: • Cannabinoids for Medical Use: A Systematic Review and Meta-analysis, Whiting, et al. 2015, JAMA. • Cannabis-based medicines for chronic neuropathic pain in adults, Mucke, et al. 2018, Cochrane Database Syst Rev. • National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research.

27. Cannabis for Chronic Pain Whiting, et al. 2015 • 28 studies, N=2454 • 13 nabiximols, 4 smoked THC, 5 nabilone, 3 THC/CBD oromucosal spray, 2 dronabinol, 1 vaporized cannabis, 1 ajuvenic acid capsules, 1 oral THC. • Neuropathic pain (12 studies), 3 cancer pain, 3 diabetic peripheral neuropathy, 2 fibromyalgia, 2 HIV sensory neuropathy, 1 of each: MS or other neurological condition, rheumatoid arthritis, non-cancer pain, central pain, musculoskeletal, and chemotherapy-related.

28. Cannabis for Chronic Pain Whiting, et al. 2015 • Only two studies were graded as low risk for bias. • Number of patients reporting at least 30% improvement in pain favored cannabinoids compared with placebo (OR, 1.41 [95% CI, 0.99-2.00), but many individual studies did not show significant difference. • One smoked THC trial reported the greatest beneficial effect (OR, 3.43 [95% CI, 1.03-11.48]). • Nabiximols (6 trials) was associated with best improvement across several measures, NRS, BPI, Global Change compared to placebo.

29. Cannabis for Chronic Pain Whiting, et al. 2015 • Summary – moderate-quality evidence to support use of cannanbinoids in chronic pain. • Cannabinoids were associated with increased risk of short-term adverse events. • Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

30. Cannabis for Chronic Neuropathic Pain Mucke, et al. 2018 Cochrane Review • 16 studies, N = 1750 • 10 THC/CBD oromucosal spray, 2 nabilone, 2 dronabionol and 2 inhaled herbal cannabis. • MS neuropathy (5), mixed peripheral neuropathy (3), diabetic neuropathy (3), plexus injury (1), spinal cord injury (1), HIV-neuropathy (1), chemotherapy-induced (1), mixed central or peripheral pain (1). • Nine studies were high risk for bias for study size. • Twice as many participants withdrew from cannabinoid for AE than with placebo 10.4% vs 4.7%.

31. Cannabis for Chronic Neuropathic Pain Mucke, et al. 2018 Cochrane Review • Studies overall found benefit for cannabis treatment of pain but were of low quality and suffered from bias. • Concluded that there is no high-quality evidence for efficacy of cannabis-based medication reviewed: herbal cannabis, dronabinol, nabilone, THC/CBD oromucosal spray. • Adverse events – somnolence, dizziness, sedation, confusion, headache, and psychiatric disorders may limit usefulness of cannabis-based medication.

32. Cannabis for Chronic Pain National Academy of Science Report 2017 • Reviewed Whiting, et al. 2015 and Andreae, et al. 2015 systematic review and other primary sources. • Concluded there is substantial evidence that cannabis is effective for chronic pain in adults. • Noted most studies evaluated nabiximols outside of U.S. • Lack of studies investigating medical marijuana, edibles, topicals, or dosing of these means of cannabis use, leaves many questions.

33. Adverse Effects, Risks and Safety • Short-term effects: • Memory impairment • Impaired motor coordination • Increased heart rate • Somnolence • Fatigue • Confusion • Disorientation

34. Image by NIDA

35. Adverse Effects, Risks and Safety • Long term effects: • Chronic use associated with chronic cough and bronchitis. • Smoking during pregnancy associated with lower birth rate. • Frequent and heavy use associated with psychosis in severe users and genetically vulnerable, and with use beginning in adolescence. (Marconi et al. 2016, Auther, 2015). • Daily use associated with increased incidence of social anxiety.

36. Adverse Effects, Risks and Safety • Impaired educational achievement in adolescents who use regularly. • Risk of developmental impact on youth including neurological development. • Increased risk of driving accidents. • Subtle cognitive impairment with long-term use, even if infrequent. • Risk of overdose by children in states with legal cannabis. • Risk of mood or other behaviors disorders in children with prenatal and perinatal exposure.

37. Adverse Effects, Risks and Safety • SAMHSA estimated that in 2015, 4 million persons met criteria for a marijuana use disorder. • Regular use may lead to reduced production of endocannabinoids and dependence. • Withdrawal syndrome is recognized - restlessness, insomnia, irritability, anxiety, depression, low appetite, headache, sweating, chills, tremor, fever, GI discomfort. • Estimated that 9% will develop a dependency with rate as high as 17% associated with use in early teens.

38. Adverse Effects, Risks and Safety • Risk of use disorder associated with: • Male • Genetics • Other substance use (alcohol, tobacco, other) • Mental Health Disorders • Parental divorce or death before age 15 • Positive experience of cannabis in early adolescence • Unclear risk of acute myocardial infarction. • Unclear risk of ischemic stroke.

39. Medical Marijuana and Pain • Lack of Regulation and Standards: • No accurate dose control. • No dosing guidelines for treatment. • No guidance on target conditions to be treated. • No guidance on drug-drug interactions. • No guidance on effect on illness or disease state. • No guidance on expected side-effects or side-effect management. • Psychoactive effects confound analgesic response. • No PDR for Medical Marijuana

40. Research Needs • Long-term health effects in broad range of socio-demographic and health risk populations. • Cannabinoid dose-response relationships and pharmacodynamics in different forms of delivery. • Benefits and harms of different forms of use. • Increase general quality of research.

41. Research Barriers in USA • Schedule I classification – deems no medical use. • Funding – State – Federal Conflict • Difficulty obtaining substance. • Need standardized sources of Cannabis with consistent measures of cannabinoids. • Social stigma to investigators, participants.

43. The Doctor’s Dilemma - Uncertainty • How frequently would it need to be administered? • Is any benefit sustainable? • What are the short- and long-term effects on daily functioning (positive and negative)? • What is the therapeutic window?

44. Savage, SR, Romero-Sandoval, A, Schatman, M, Wallace, M, Gaciullo, G, McCarberg, B, Ware, M. Cannabis in Pain Treatment: Clinical and Research Considerations, J of Pain, Vol 17, No 6, 2016: pp654-668

45. Should doctors prescribe cannabinoids? Farrell, et al. BMJ 2014;348:g2737 doi: 10.1136/bmj.g2737 • Legality, Physician’s ability to prescribe. • Provide information about possible adverse effects such as development of dependence. • Avoid non-approved or off-label use, refer to specialist for trial when possible. • When patient is using medical marijuana, discuss in a non-judgmental, supportive manner the advisability of using cannabis for the problem. • Advise there is clear evidence that putative benefits outweigh possible harms. • Assess for symptoms of cannabis dependence and address as indicated.

46. VHA Directive 1315 December 2017 Access to VHA Clinical Programs for Veterans Participating in State-Approved Marijuana Programs • Veterans are not prohibited from participation in VA healthcare programs solely due to use of state-authorized marijuana. • Clinical staff should discuss relevant clinical information regarding marijuana. This includes how use of marijuana to treat medical or psychiatric conditions may impact overall care including pain, PTSD or substance abuse treatment. Discussions should be documented in the medical record. • Providers need to make decisions to modify treatment plans based on marijuana use on a case-by-case basis, such decisions need to be made in partnership with the Veteran and must be based on concerns regarding Veteran health and safety and documented in treatment plan.

47. Clinical Practice with Chronic Pain • Two teams: • Interdisciplinary CARF-accredited team: PM&RS Physician, PharmD, Psychologist, DPT, RN Case Manager. • Chronic Pain Care Clinic: PharmD and Psychologist work conjointly with primary care provider. • Patients asked about cannabis use and screened by UDT prior to initiating pain medications. • Hard to track or reliably identify use of topicals. • Psychology assessment includes assessment of cannabis use disorder as well as other SA and referred to SATP as indicated.

48. Clinical Practice with Chronic Pain • Patients using marijuana are informed that teams will not provide concurrent opioid treatment due to safety concerns. • Patients are provided assistance tapering and discontinuing either or both. • Patients who continue to use marijuana are instructed not to use on Cognitive Behavioral Therapy treatment days. • Reviewing program evaluation data to examine marijuana and outcomes.

49. Marijuana slide from CPCC Patient Orientation • VHA policy is that you can still get health care/ treatment at the VA if you use a Colorado State authorized “medical marijuana”. • However, your VA providers may not want to include certain medications in your treatment plan. • If you are in this clinic and use marijuana, it will be recommended that we use non-opioid medications for safety reasons.