1. ©2014 American Academy of Neurology

2. Report of the Guideline Development Subcommittee of the American Academy of Neurology Systematic Review: Efficacy and Safety of Medical Marijuana (Cannabis) in Selected Neurologic Disorders

3. ©2014 American Academy of Neurology Systematic Review Endorsement This systematic review was endorsed by the American Autonomic Society, the American Epilepsy Society, the Consortium of Multiple Sclerosis Centers, the International Organization of Multiple Sclerosis Nurses, and the International Rett Syndrome Foundation. Slide 2

4. ©2014 American Academy of Neurology Authors Barbara S. Koppel, MD, FAAN John C.M. Brust, MD, FAAN Terry Fife, MD, FAAN Jeff Bronstein, MD, PhD Sarah Youssof, MD Gary Gronseth, MD, FAAN David Gloss, MD Slide 3

5. ©2014 American Academy of Neurology Sharing This Information The American Academy of Neurology (AAN) develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact guidelines@aan.com to learn about options for sharing this content beyond your personal use. guidelines@aan.com Slide 4

6. ©2014 American Academy of Neurology Presentation Objective To present the findings for the efficacy of medical marijuana (cannabis) in several neurologic conditions. Slide 5

7. ©2014 American Academy of Neurology Overview Background Gaps in care AAN systematic review process Analysis of evidence with conclusions Recommendations for future research Slide 6

8. ©2014 American Academy of Neurology Background Marijuana contains approximately 60 pharmacologically active compounds (“cannabinoids”). The presence of cannabinoid receptors in the brain led to discovery of endogenous ligands (endocannabinoids). The endocannabinoid system is widely distributed in the brain and spinal cord. 1,2 Slide 7

9. ©2014 American Academy of Neurology Background, cont. The concentration of Δ-9-tetrahydrocannabinol (THC) present in formulations and the ratio of THC to cannabidiol (CBD) (which limits THC’s psychoactive effects) play a role in therapeutic effects of cannabis products. Physiologic responses include feelings of well-being or psychosis (depending on the “dose” of THC), impaired memory and cognitive processing, slowed locomotor function, as well as antinociceptive, 3 antiemetic, antispasticity, and sleep-promoting effects. Slide 8

10. ©2014 American Academy of Neurology Background, cont. A variety of formulations with differing amounts of THC and CBD were used in studies examined for this systematic review.  Some formulations were pills, one was a mucosal spray, and some were vaporized or smoked. Slide 9

11. ©2014 American Academy of Neurology Clinical Questions 1. Spasticity in patients with multiple sclerosis (MS)? 2. Central pain and painful spasms in MS (pain from any etiology, including spasticity, but excluding neuropathic pain)? 3. Bladder dysfunction in MS? Slide 10 What is the safety and efficacy of cannabinoids in relieving/reducing:

12. ©2014 American Academy of Neurology Clinical Questions, cont. 4. Involuntary movements, including tremor, in MS? 5. Dyskinesias of Huntington disease (HD), levodopa- induced dyskinesias of Parkinson disease, cervical dystonia, and tics of Tourette syndrome? 6. Seizure frequency in epilepsy? Slide 11

13. ©2014 American Academy of Neurology AAN Systematic Review Process Clinical Question Evidence Conclusions Slide 12

14. ©2014 American Academy of Neurology AAN Systematic Review Process, cont. Rigorous, Comprehensive, Transparent Slide 13 Search Relevant Search Review abstracts Review full text Select articles

15. ©2014 American Academy of Neurology AAN Classification of Evidence All studies meeting inclusion/exclusion criteria defined a priori rated Class I, II, III, or IV Five different classification systems  Therapeutic –Randomization, control, blinding  Diagnostic –Comparison with reference standard  Prognostic  Screening  Causation Slide 14

16. ©2014 American Academy of Neurology Applying the Process to the Issue We will now turn our attention to the systematic review. Slide 15

17. ©2014 American Academy of Neurology Methods Medline (1948—Jan 2013), EMBASE, PsycINFO, Web of Science, and Scopus searched Each selected article reviewed for inclusion Risk of bias determined (classification of evidence scheme for therapeutic articles) Conflicts of interest disclosed Slide 16

18. ©2014 American Academy of Neurology Literature Search/Review Rigorous, Comprehensive, Transparent Slide 17 1,729 abstracts 34 articles met inclusion criteria Inclusion criteria: -Human randomized, controlled trials of all formulations of cannabis (pills, oral sprays, smoked cigarettes), including synthetic THC and cannabinoid extracts, alone or in combination, in the treatment of various symptoms of several neurologic illnesses -Case series (for addressing adverse effects, not efficacy) Exclusion criteria: -Surveys, case reports/series, and non–placebo-controlled trials

19. ©2014 American Academy of Neurology AAN Classification of Evidence for Therapeutic Studies Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: a.Concealed allocation b.Primary outcome(s) clearly defined c.Exclusion/inclusion criteria clearly defined d.Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias. Slide 18

20. ©2014 American Academy of Neurology AAN Classification of Evidence for Therapeutic Studies, cont. e.For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: –The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority. –The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). –The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. –The interpretation of the results of the study is based upon a per- protocol analysis that takes into account dropouts or crossovers. Slide 19

21. ©2014 American Academy of Neurology AAN Classification of Evidence for Therapeutic Studies, cont. Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a  e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b  e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.** Slide 20

22. ©2014 American Academy of Neurology AAN Classification of Evidence for Therapeutic Studies, cont. Class IV: Studies not meeting Class I, II, or III criteria, including consensus or expert opinion. *Note that numbers 1  3 in Class I, item 5, are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. **Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data). Slide 21

23. ©2014 American Academy of Neurology Clinical Question 1 Do cannabinoids relieve spasticity in patients with MS? Slide 22

24. ©2014 American Academy of Neurology Spasticity in MS Conclusions For patients with spasticity: Oral cannabis extract (OCE) is established as effective for reducing patient-reported scores (2 Class I studies 7,8 ). OCE is probably ineffective for reducing objective measures at 12 to 15 weeks (1 Class I study 7 ) but possibly effective at 1 year (1 Class II study 11 ). THC is probably effective for reducing patient-reported scores (1 Class I study 7 ). THC is probably ineffective for reducing objective measures at 15 weeks (1 Class I study 7 ) but possibly effective at 1 year (1 Class II study 11 ). Slide 23

25. ©2014 American Academy of Neurology Spasticity in MS, cont. Conclusions For patients with spasticity: Nabiximols is probably effective for reducing patient-reported symptoms at 6 weeks (1 Class I study 6 ) and probably ineffective for reducing objective measures at 6 weeks (1 Class I study 6 ). Smoked marijuana is of uncertain efficacy (insufficient evidence). Slide 24

26. ©2014 American Academy of Neurology Spasticity in MS, cont. Clinical Context More improvements were seen in subjective measures than objective measures, possibly explained in part by the overall improvements in “feelings” or well-being provided by marijuana, or by pain relief allowing improved mobility. Slide 25

27. ©2014 American Academy of Neurology Clinical Question 2 What is the efficacy of using cannabinoids to treat central pain or painful spasms in MS? Slide 26

28. ©2014 American Academy of Neurology Pain in MS Conclusions For patients with MS with central pain or painful spasms, OCE is effective for reduction of central pain (2 Class I studies 7,8 ). THC or nabiximols (1 Class I study each 7,24 ) are probably effective for treating MS-related pain or painful spasms. Smoked marijuana is of unclear efficacy for reducing pain (2 Class III studies that examined different issues 14,15 ). Slide 27

29. ©2014 American Academy of Neurology Clinical Question 3 Do cannabinoids help treat bladder dysfunction in MS? Slide 28

30. ©2014 American Academy of Neurology Bladder Dysfunction in MS Conclusions Nabiximols is probably effective for reducing the number of bladder voids per day at 10 weeks (1 Class I study 26 ). THC and OCE are probably ineffective for reducing bladder complaints (1 Class I study 7 ). Nabiximols is of unknown efficacy in reducing overall bladder symptoms (contradictory Class I studies). Slide 29

31. ©2014 American Academy of Neurology Clinical Question 4 Do cannabinoids help treat tremor in MS? Slide 30

32. ©2014 American Academy of Neurology Tremor in MS Conclusions THC and OCE are probably ineffective for treating MS-related tremor (1 Class I study 7 ). Nabiximols is possibly ineffective (1 Class II study 10 ). Slide 31

33. ©2014 American Academy of Neurology Clinical Question 5 Do cannabinoids reduce symptoms in involuntary movement disorders? Slide 32

34. ©2014 American Academy of Neurology Huntington Disease Conclusion Whereas 1 Class I study 31 and 1 Class III study 35 suggest lack of benefit, both were underpowered to detect differences, and thus no reliable conclusions can be drawn. Slide 33

35. ©2014 American Academy of Neurology Parkinson Disease Conclusion OCE is probably ineffective for treating dopa- induced dyskinesias in patients with Parkinson disease (1 Class I study 36 ). Slide 34

36. ©2014 American Academy of Neurology Tourette Syndrome Conclusion For patients with Tourette syndrome, data are insufficient to support or refute efficacy of THC for reducing tic severity (1 Class II study, 1 Class III study 39,40 ). Slide 35

37. ©2014 American Academy of Neurology Cervical Dystonia Conclusion For patients with cervical dystonia, data are insufficient to support or refute the efficacy of dronabinol. Slide 36

38. ©2014 American Academy of Neurology Clinical Question 6 Do cannabinoids decrease seizure frequency in epilepsy? Slide 37

39. ©2014 American Academy of Neurology Seizures in Epilepsy Conclusion For patients with epilepsy, data are insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency (no Class I  III studies). Slide 38

40. ©2014 American Academy of Neurology Seizures in Epilepsy, cont. Clinical Context Neither the present review, nor a Cochrane review which includes abstracts, non  peer- reviewed literature, and anecdotal reports of smoked cannabis use by patients with seizure disorders, e4 concluded there is sufficient evidence to prescribe CBDs or recommend self- treatment with smoked marijuana. Slide 39

41. ©2014 American Academy of Neurology Adverse Effects Overall, 1,619 patients were treated with cannabinoids for less than 6 months. Simple meta-analysis yielded 6.9% who stopped the medication because of adverse effects (AEs). Of the 1,118 who received placebo, 2.2% stopped because of AEs. Data on the symptom(s) that caused medication withdrawal were often incomplete. Slide 40

42. ©2014 American Academy of Neurology Adverse Effects, cont. Among patients treated with cannabinoids, the following symptoms appeared in at least 2 studies:  Nausea  Increased weakness  Behavioral or mood changes (or both)  Suicidal ideation or hallucinations (or both)  Dizziness or vasovagal symptoms (or both)  Fatigue  Feelings of intoxication Slide 41

43. ©2014 American Academy of Neurology Adverse Effects, cont. Psychosis, dysphoria, and anxiety are associated with higher concentrations of THC, which were not typical of the studies analyzed. There was 1 death "possibly related" to treatment (a seizure, followed by fatal aspiration pneumonia). 18 Slide 42

44. ©2014 American Academy of Neurology Adverse Effects, cont. Clinical Context AEs are a significant concern with marijuana use. It is especially concerning that a medication that may have an AE of suicide may be prescribed in a population such as patients with MS who already are at increased suicide risk. e7 Slide 43

45. ©2014 American Academy of Neurology Future Research Recommendations Cannabinoids should be studied as other drugs are, to determine their efficacy, and when evidence is available, should be prescribed as other drugs are. Twenty states and the District of Columbia have legalized the medical use of marijuana, and 2 have decriminalized all use. This should encourage researchers to continue seeking answers to the benefits of marijuana use in patients who have neurologic illness. Slide 44

46. ©2014 American Academy of Neurology Future Research Recommendations, cont. Future research with randomized, controlled studies is necessary in order to determine the efficacy of this medication class. Slide 45

47. ©2014 American Academy of Neurology References References cited here can be found in the published systematic review. To locate references, please access the systematic review at AAN.com/guidelines.AAN.com/guidelines Slide 46

48. ©2014 American Academy of Neurology Access Systematic Review and Summary Tools To access the complete systematic review and related summary tools, visit AAN.com/guidelines.AAN.com/guidelines Slide 47

49. ©2014 American Academy of Neurology Questions?