1. Marijuana: What Does The Evidence Show? Allen C. Bowling, MD, PhD Physician Associate Colorado Neurological Institute (CNI)

2. Marijuana and Neurological Disease  Increasing legalization and availability  Neurologically relevant medical studies  BUT huge challenges for public and professionals: –Emotional response –Political/media/business interests –Difficult to find objective safety and effectiveness information

3. Marijuana Information   “Cannabis is effective for treating epilepsy, Parkinson’s disease, depression, and migraine.”   “[In MS], numerous studies have reported improvement in tremor, sexual dysfunction,…vision dimness, dysfunctions of walking and balance (ataxia), and memory loss.”   “Research has shown that medical marijuana…can alleviate symptoms of Tourette’s.”

4. Summary  Basics of Marijuana  The Evidence –Scientific studies –Clinical studies MS, epilepsy, Parkinson’s disease and other movement disordersMS, epilepsy, Parkinson’s disease and other movement disorders Pain, anxiety, sleepPain, anxiety, sleep –Safety  Information Resources

5. States with Medical/Recreational Marijuana (Illegal at Federal Level)

6. Proposed Marijuana Bills/Initiatives in 2014

7. Medical Marijuana in Colorado: “Approved Conditions”  “persistent muscle spasms, including those that are characteristic of multiple sclerosis”  “seizures, including those that are characteristic of epilepsy”  “severe pain”

8. Variability of Marijuana Plants and Products  Two major “subspecies” –Cannabis sativa: mainly THC –Cannabis indica: THC and CBD   Many different hybrids   Other variables – –Growing and storage – –State of maturity – –Processing/formulation

9. Forms of Marijuana  Leaf –Smoked, eaten (“edibles”), vaporized  Plant resin: “hashish” –Smoked, eaten  Oil extracts –Nabiximols (Sativex), Cannador, many others that are unregulated and non-standardized  Single molecule preparations –THC: Marinol, dronabinol –Chemical variant of THC: Cesamet, nabilone

10. “Cannabinoids”   Many different potentially active molecules: – –THC: delta-9- tetrahydrocannabinol – –CBD: cannabidiol – –About 60 others

11. Marijuana  Actions –CB1 receptors Nerve cellsNerve cells “Homeostasis”“Homeostasis” –CB2 receptors Immune cellsImmune cells –Multiple other effects - Antioxidant, excitotoxicity, calcium flux

12. “Endocannabinoids”  Analagous to endorphins  Two main endocannabinoids –Anandamide 100 times less potent100 times less potent than THC ? “endorphin high”? “endorphin high” –2-AG  Full range of functions unknown

13. “Endocannabinoids”  Analagous to endorphins  Two main endocannabinoids –Anandamide 100 times less potent100 times less potent than THC ? “endorphin high”? “endorphin high” –2-AG  Full range of functions unknown THC

14. “Endocannabinoids”  Analagous to endorphins  Two main endocannabinoids –Anandamide 100 times less potent100 times less potent than THC ? “endorphin high”? “endorphin high” –2-AG  Full range of functions unknown THC Anandamide

15. Summary  Basics of Marijuana  The Evidence –Scientific studies –Clinical studies MS, epilepsy, Parkinson’s disease and other movement disordersMS, epilepsy, Parkinson’s disease and other movement disorders Pain, anxiety, sleepPain, anxiety, sleep –Safety  Information Resources

16. Neurological Relevance: Scientific Studies  Nerve Cell Function –Normalizes release of many different neurotransmitters  Nerve Cell Survival –Promotes survival by many mechanisms  Immune System Function –Anti-inflammatory effect

17. Neurological Relevance: Clinical Studies  Multiple Sclerosis  Epilepsy  Parkinson’s Disease and Other Movement Disorders  Pain  Sleep Disorders  Anxiety

18. AAN Classification Scheme: Classes of Controlled Trials  Class I –Randomized, controlled, objective outcome –Extra criteria: concealed allocation, primary outcome clearly defined, exclusion and inclusion criteria clearly defined, adequate accounting for dropouts and crossovers  Class II: lacks one criterion  Class III: all other controlled trials with independent outcome assessment

19. Review of Alternative Medicine and MS  Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis. Neurology 2014;82:1-10.  Report of the Guideline Development Committee of the American Academy of Neurology –Yadav, Bever, Bowen, Bowling, Weinstock-Guttman, Cameron, Bourdette, Gronseth, Narayanaswami  Medline search: 1970-Sept 2013

20. Review of Marijuana and Neurological Disorders  Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders. Neurology 2014;82:1556-1563.  Report of the Guideline Development Committee of the American Academy of Neurology –Koppel, Brust, Fife, Bronstein, Youssof, Gronseth, Gloss  Medline search: 1948-Jan 2013  Disorders –MS: spasticity, pain, bladder dyfunction, tremor –Dyskinesias: Huntington’s disease, levodopa-induced in Parkinson’s disease –Cervical dystonia, tics of Tourette syndrome, epilepsy

21. Studies of Marijuana and Neurologic Conditions Class IClass IIClass III TOTAL MS649 19 Epilepsy000 0 Parkinson’s101 2 Huntington’s111 3 Tourette011 2 Dystonia001 1

22. MS: Two Recent Reviews   The largest and most convincing research   Formulations – –THC: 4 – –Oral cannabis extract (Cannador): 8 – –Nabiximols (Sativex): 8 – –Smoked: 2

23. MS: Two Recent Reviews   Some level of effectiveness – –“Subjective spasticity,” pain Cannador, Nabiximols, THC – –Urinary frequency Nabiximols   Probably ineffective – –Objective spasticity, tremor Cannador, Nabiximols, THC   Insufficient data: smoked

24. Epilepsy  Marijuana and THC: anti-convulsant or pro-convulsant?  CBD: appears anti-convulsant  No Class I, II, or III studies  2 Class IV with no benefit, many anecdotes  Survey of 19 parents, CBD-enriched –84% improved: 11% seizure-free, 42% with more than 80% decrease –Porter, Epilepsy & Behav 2013;29:574-577.

25. Parkinson’s Disease  2 studies: one class I, one class III  CBD extract not effective for “dyskinesia”  Class IV study –“Open label,” smoked –Improvement in tremor, rigidity, and bradykinesia

26. Huntington’s Disease and Others  Huntington’s –3 studies: Classes I, II, III –Nabilone possibly effective for chorea, but inconsistent results and limited studies  Tourette and Dystonia –Very limited studies –No conclusions possible

27. Pain  18 controlled trials in pain –Classes I, II, and III  Formulations –Smoked: 4 –Extract: 7 –THC: 2 –Nabilone: 4 –Unique molecule: 1 Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Brit J Clin Pharmacol 2011;72:735-744.

28. Pain  15/18 reported improvement in pain –Especially central and peripheral nerve pain –For painful HIV neuropathy, possibly the most effective treatment –Also fibromyalgia and rheumatoid arthritis  4/18 also reported improvement in sleep  No controlled studies in headache, including migraine

29. Sleep Disorders  39 clinical studies –Quality: extremely variable, generally poor  Formulations –Smoked: 7 –THC or Nabilone: 14 –Cannador or Nabiximols: 14 –Other oral form: 4 Gates PJ, et al. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev 2014;1-11.

30. Sleep Disorders  Impossible to make firm conclusions –Many different conditions and formulations  General observations –“Recreational use” May interrupt sleep cycle and cause non- restful sleepMay interrupt sleep cycle and cause non- restful sleep –Use with condition that interrupts sleep May improve sleep quality and decrease night- time disturbancesMay improve sleep quality and decrease night- time disturbances

31. Anxiety  A very complicated story!  Marijuana use is significantly higher in those with anxiety  Paradoxes –Limited use: may cause relaxation but also panic, paranoia, and psychosis –Regular use Short-term: may decrease anxietyShort-term: may decrease anxiety Long-term: may increase anxiety and decrease effectiveness of anxiety medsLong-term: may increase anxiety and decrease effectiveness of anxiety meds Tambaro S, et al. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives. Recent Patents CNS Drug Discov 2012;7:25-40.

32. Anxiety  Variable effects may be due to different components –Marijuana and THC Modest doses: decreased anxietyModest doses: decreased anxiety High doses: panic, psychosis, phobiaHigh doses: panic, psychosis, phobia –CBD More consistent anti-anxiety effectMore consistent anti-anxiety effect

33. Marijuana: Side Effects  Generally well tolerated in neurological clinical trials  No risk of lethal overdose (unlike alcohol)  No clear increase in risk of COPD or cancer of lung, head, and neck (?anti- cancer effect)

34. Marijuana:Side Effects CONFIDENCE AddictionHigh Decreased achievementHigh Motor vehicle accidentsHigh Chronic bronchitisHigh Abnormal brain developmentMedium Progression to other drugsMedium SchizophreniaMedium Depression or anxietyMedium Volkow et al, Adverse health effects of marijuana use. New Eng J Med 2014;370:2219-2227.

35. Marijuana: Neurologically Relevant Side Effects  Dizziness, impaired balance, incoordination, visual difficulties, seizures, leg weakness, sedation, lightheadedness, psychosis, hallucinations, associated with strokes (and heart attacks)  Also, interactions with many neurological meds

36. MRI Changes: Cognition  Recent MS study –Users had more cognitive impairment and more abnormalities on functional MRI –Limitations of study –Pavisian B, et al. Effects of cannabis on cognition in patients with MS. Neurol 2014;82:1879-1887.

37. MRI Changes: Cognition  ?Neurotoxicity –“Meta-analysis”--14 studies –Consistently smaller hippocampus size in users Is cannabis neurotoxic for the healthy brain? A meta- analytic review of structural brain alterations in non- psychotic users, Rocchetti et al, Psych Clin Neurosci 2013;67:483-492.Is cannabis neurotoxic for the healthy brain? A meta- analytic review of structural brain alterations in non- psychotic users, Rocchetti et al, Psych Clin Neurosci 2013;67:483-492.

38. MRI Changes: Addiction?  Amygdala and Nucleus Accumbens: emotion and motivation Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational user, Gilman et al, J Neurosci 2014;34:5529-5538.Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational user, Gilman et al, J Neurosci 2014;34:5529-5538.

39. Marijuana: Uncertain Potency and Purity   Study of edibles in Colorado (2014) N=13 No products contained the amount of THC on label 1 product with 50% more 3 products with 0.2-0.4%   Colorado labelling “Warning: There may be health risks associated with the consumption of this product…The product was produced without regulatory oversight for health, safety, or efficacy…The marijuana product contained within this package has not been tested for potency, consume with caution. The marijuana product contained within this package has not been tested for contaminants.”

40. Unanswered Questions, Unresolved Issues  Many studies are with standardized preparations—not available in the US  Products that are available –Many are non-standardized, non-regulated, and high in THC  How to translate research studies with oral preparations to smoked products?

41. Unanswered Questions, Unresolved Issues  Are some hybrids more effective or safer?  What dose, frequency, and preparation?  “Combination therapy” with meds?  Relative safety and effectiveness of marijuana vs conventional meds or procedures?

42. Future Directions  Studies of specific strains –Low, medium, and high THC –Significant differences: anxiety, appetite, others –Brunt et al, 2014, J Clin Psychopharm  Increase endocannabinoid levels –Many possibilities –Promising studies in animals –Pryce et al, 2013, Mult Scler J

43. Summary  Thousands of years of human use, but scientific understanding and evidence- based medical use is in its infancy  Extremely complex pharmacology  Dozens of potentially active compounds  Complex neurological conditions  Limited safety information  Thoughtful, evidence-based risk:benefit analysis

44. Summary: Examples of Use  MS –Reasonable?—moderate-severe disability with severe pain and/or spasticity –Unreasonable—college student, rare spasms  Epilepsy –Reasonable?—severe seizure disorder not treatable with meds, surgery is next option –Unreasonable—2 seizures, never taken meds

45. Information Sources  Objective, updated, user-friendly information resource for general public and professionals

46. Information Sources  Objective, updated, user-friendly information resource for general public and professionals –DOES NOT EXIST!

47. States with Medical/Recreational Marijuana (Illegal at Federal Level)

48. Information Resources  Lay articles –King ME. Medical marijuana: hype or hope? Momentum Fall 2014, pp. 28-35. –Bowling AC. Marijuana and MS—an unfinished story. Momentum Fall 2010, pp. 33-35.  Book –Iversen LL. The Science of Marijuana. Oxford Univ. Press: 2010.

49. References   Books – –Bowling AC. Optimal Health With Multiple Sclerosis: A Guide to Integrating Lifestyle, Alternative, and Conventional Medicine. New York: Demos, 2014. – –Bowling AC. Complementary and alternative medicine: practical considerations. In Rae-Grant A, Fox R, Bethoux F, eds. Multiple Sclerosis and Related Disorders: Diagnosis, Medical Management, and Rehabilitation. New York: Demos, 2013, 243-249. – –Iversen LL. The Science of Marijuana. New York: Oxford University Press, 2008. – –Jellin JM, Gregory PJ, Batz F, et al. Pharmacist’s Letter/ Prescriber’s Letter Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty, 2014.

50. References   Journal Articles – –Aggarwal SK. Cannabinergic pain medicine. Clin J Pain 2013;29:162- 171. – –Anon. Adverse effects of marijuana. Prescrire Int 2011;20:18-23. – –Baca R. Labels fudge THC levels: with no standard for testing, buyers can’t trust items’ potency. Denver Post 2014 March 9:1A, 17A. – –Baker D, et al. The therapeutic potential of cannabis. Lancet Neurol 2003;2:291–298. – –Borgelt LM, et al. The pharmacologic and clinical effects of medical cannabis. Pharmacother 2013;33:195-209. – –Bowling AC. Cannabinoids in MS—are we any closer to knowing how best to use them? Mult Scler 2006; 12:523-525. – –Bowling AC. Worthless weed or pot of gold? Int J MS Care 2004;5:138,166. – –Bowling AC. Marijuana and MS—an unfinished story. Momentum, Fall 2010, 33-35.

51. References – –Corey-Bloom J, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ 2012;184:1143- 1150. – –Devinsky O, et al. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric conditions. Epilepsia 2014;55:791-802. – –Gates PJ, et al. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev 2014;1-11. – –Gilman JM, et al. Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users. J Neurosci 2014;34:5529-5538. – –Gordon AJ, et al. Medical consequences of marijuana use: a review of current literature. Curr Psych Rep 2013;15:419. – –Greenberg HS, et al. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clin Pharmacol Ther 1994;55:324-328. – –Kedzior KK, Laeber LT. A positive association between anxiety disorders and cannabis use or cannabis use disorders in the general population—a meta-analysis of 31 studies. BMC Psychiatr 2014;14:136. – –King ME. Medical marijuana: hype or hope? Momentum Fall 2014:28-35.

52. References – –Koppel BS, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurol 2014;82:1556-1563. – –Lotan I, et al. Cannabis (medical marijuana) treatment of motor and non- motor symptoms of Parkinson disease: an open-label observational study. Clin Neuropharm 2014;37:41-44. – –Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Brit J Clin Pharmacol 2011;72:735-744. – –Pavisian B, et al. Effects of cannabis on cognition in patients with MS. Neurol 2014;82:1879-1887. – –Porter BE, Jacobson C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epil Behav 2013;29:574-577. – –Pryce G, et al. Control of experimental spasticity by targeting the degradation of endocannabinoids using selective fatty acid amide hydrolase inhibitors. Mult Scler J 2013;19:1896-1904. – –Rocchetti M, et al. Is cannabis neurotoxic for the healthy brain? A meta- analytical review of structural brain alterations in non-psychotic users. Psychiatr Clin Neurosci 2013;67:483-492.

53. References – –Secades-Villa R, et al. Probability and predictors of the cannabis gateway effect: a national study. Int J Drug Policy 2014; 10.1016/j.drugpo.2014.07.011 – –Tambaro S, et al. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives. Recent Patents CNS Drug Discov 2012;7:25-40. – –Thomas G, et al. Adverse cardiovascular, cerebrovascular, and peripheral vascular effects of marijuana inhalation: what cardiologists need to know. Amer J Cardiol 2014;113:187-190. – –Volkow ND, et al. Adverse health effects of marijuana use. New Eng J Med 2014;370:2219-2227. – –Yadav V, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurol 2014;82:1-10. – –Zajicek JP, Apostu VI. Role of cannabinoids in multiple sclerosis. CNS Drugs 2011;25:187-201. – –Zajicek J, et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomized, placebo-controlled trial. Lancet Neurol 2013;12:857-865.

54. References – –Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 2003;362:1517–1526. – –Zajicek J, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neursurg Psych 2005;76:1664–1669.