1. Medical Marijuana: Risks and Benefits Malcolm P. Rogers, M.D. Portland VA Clinic malcolm. rogers@va.gov

2. Brief History Long History of Use as Herbal Medicine 1937: Severely Restricted – Medical Marijuana Tax Act 1970 : Controlled Substances Act – Places marijuana into Schedule 1 1996: California law sanctions medical use of marijuana and protects patients and providers from prosecution

3. History (continued) 2005 US Supreme Court (Gonzales v Raich) overturns California’s law by 6-3 vote About a dozen other states allow medical marijuana October 2009: Obama Administration discourages US Attorneys from taking enforcement actions in medical marijuana states November 2009: Maine votes yes on medical marijuana dispensaries

4. Medical Community Response February 2009: American College of Physicians calls for “evidence-based review of marijuana’s status as Schedule 1 controlled substance to determine whether” to reclassify November 2009: AMA voted to change classification, affirming therapeutic benefits for neuropathic pain, improving appetite and relieving spasticity and pain in MS patients

5. Biology of Cannabis Cannabis is complex: plant contains over 60 cannabinoid molecules and 500 total compounds 1964: Active substance in herbal marijuana found to be delta-9-tetrohydrocannabinol (THC) 1990: CB1 & CB2 receptors binding THC & endocannabinoids soon discovered Receptors primarily in frontal regions of cortex but also in basal ganglia, cerebellum, hypothalamus, pituitary, anterior cingulate gyrus, spinal cord and peripheral nervous system

6. Biology of Cannabis CB1 receptors also found in fat and muscle cells CB1 most abundant G protein-coupled receptor in brain THC acts by inhibiting the release of neurotransmitters: L-glutamate, GABA, noradrenaline, dopamine, serotonin and acetylcholine

7. Potential Therapeutic Role Regulation of hunger and weight Regulates fat cells, lipids and glucose Preventing action of CB1 receptor reduces nicotine dependence Rimonabant trials were not successful and drug withdrawn from European market HPA axis: – potential effect on stress response, fertility and sexual response

8. Benefits - Cancer Chemotherapy Tramer et al: BMJ 323: 16, 2001 – 30 randomized comparisons with other antiemetics, 1336 patients: reduced nausea and vomiting more than other agents Good side effects: high, euphoria, sedation Bad side effects: dizziness, dysphoria, paranoia Machado-Rocha FC, et. Al: Eur. J. Cancer Care 17:431, 2008 – Systematic review and meta-analyses showed superiority of cannabis over placebo and conventional drugs - but more adverse effects

9. Stimulates Appetite Anorexia in chemotherapy treated cancer patients Wasting in HIV/AIDS – One of the oral preparations dronabinol (Marinol) is approved for anorexia associated with AIDS

10. MS and Neuropathic Pain MS Spasticity – relieves muscle spasticity and related pain Ghaffar et al. Neurology 71:164, 2008. Neuropathic Pain – both central and peripheral Abrams D et al. Neurology 68:515, 2007.

11. Possible Benefits Reduction of anxiety and anger in occasional, non-medical users – anecdotal evidence for as well as against in terms of panic attacks and paranoia Arthritis, asthma, migraine, motor tics, ALS, cerebral palsy, gastrointestinal (Crohn’s), glaucoma, hepatitis C, neuroprotection and chronic pain

12. Adverse Effects – Psychosis Risk Systematic review of longitudinal and population based studies 7 studies Risk of developing psychosis – 2.58 times more likely if ever used – Confounding factors : Reverse causation, intoxication Suggestion that risk higher if use occurs before age 16 – Moore et al, Lancet 370: 319,2007 – Moore et al. Lancet 370: 319, 2007

13. Adverse Effects – Psychosis Risk Only small percentage of people using marijuana develop psychosis In existing psychosis, marijuana use can exacerbate symptoms, worsen course, trigger relapse Insufficient alone to cause psychosis but interacts with other risk factors – Family hx, neurobehavioral deficits, social withdrawal – Moore et al. Lancet 370: 319, 2007

14. Adverse Effects – Mood & Affect Affective dysregulation in adolescents Amotivational Syndrome Limited support from systematic meta- analyses for increased depression risk Anxiety – case reports of panic disorder but overall data unclear.

15. Adverse Effects – Cognition and Memory Acute effects on visuo-spatial working memory Impairs executive function in short term abstinent cannabis users Memory problems can persist for one month after last use but long term effects unclear fMRI suggests that neurodevelopment might be altered in adolescents with persistent neurocognitive deficits

16. Other Adverse Effects Addictive Potential Association with relapse in other substance abuse, for example, opioid abuse in suboxone patients Risks associated with legal prohibition Marijuana smoke and medical risk

17. Adverse Effects - Medical Potential increased risk of cancer and cardiovascular disease – Cannabis smoke delivers 50-70% more carcinogenic hydrocarbons than tobacco smoke – Higher risk of cardiac arrhythmias Oral (Marinol) or sublingual preparations (Sativa) alternatives but might not be as effective

18. Summary Benefits: – nausea and appetite in cancer – spasticity in MS – neuropathic pain Risks: (mostly in high frequency recreational users): – psychosis – cognitive impairment – mood and motivation – medical