1. Medical Marihuana: Clearing the Air Sara Feinauer, PharmD, BCPS November 2014 Google: Smoke. http://campbellpropertymanagement.com/blog/2014/08/05/159-new-laws-go-smoke-quick-look-medical-marijuana-smoke-foul/

2. Disclosure No disclosures concerning a conflict of interest with commercial entities that may be referenced in this presentation.

3. Objectives 1. Describe how medical marihuana may provide medicinal benefits 2. Compare and contrast the benefits versus risks of using medical marihuana 3. List usages and restrictions as applicable to the state of Michigan in regards to the use of medical marihuana

4. Overview Medical Marihuana LawsRisksUses

5. Marijuana vs. Marihuana 1 Per Initiated Law 1 of 2008 and administrative rules: – “Marihuana is one of two acceptable spellings in the dictionary and is consistent with the spelling in the Michigan Public Health Code, Act 368 of 1978, and Initiated Law 2008.”

6. Marihuana: A History 2,3 Prior to 1937, marihuana was commonly used as a bronchodilator – Used most often for asthma in the 1800s Dropped from the US pharmacopeia in 1941 Most commonly used illicit substance worldwide – 3.9% of adult population (15-64 years old)

7. Marihuana: A Controversy 2,3 DEA states that there are legal products available AMA supports rescheduling to schedule II – “Known medicinal value, while acknowledging the importance of proper medical supervision and accepting that more research is necessary into the side effects and possible dangers of medical marijuana use”

8. Limitation to Uses 2 Relief of symptoms, not cure Evidence often anecdotal Route of use Amount for use

9. How does it work? 2,4 Tetrahydrocannabinol (THC) is a partial agonist at cannabinoid receptors (CB1, CB2) in the endocannabinoid system – THC primary effect on CB1

10. How does it work? 2,4 CB1 Brain PNS ANS Psychoactive CB2 Neurons Immune cells

11. CB1 Effects 2,4 SedationAnalgesicPsychiatric Anxiolytic Appetite Stimulant

12. Uses Appetite Stimulant Chronic Pain Multiple Sclerosis Glaucoma Nausea and Vomiting Medical Marijuana. Pharmacist’s Letter. January 2013.

13. Appetite Stimulant 2 Dronabinol < megestrol Oral cannabis ≠ placebo Cancer Smoking stimulates appetite Dronabinol and THC (2% and 3.9%) > placebo HIV

14. Chronic Pain 5,6 >45 studies – Cancer, diabetes, fibromyalgia, MS, HIV, rheumatoid arthritis, spinal injuries – Majority show benefit – Quarter of studies showed no improvement No benefit in acute pain

15. Chronic Pain 4,6,7 THC 10 mg was better than placebo – Analgesically similar to 60mg codeine 3.56% THC cigarettes TID x 5 days decreased pain intensity over placebo – 3.56% and 7% studied – 9 cumulative “puffs” (240 minutes) = ½ cigarette – 19mg (3.56%) 34mg (7%) THC consumed

16. Multiple Sclerosis 2,5 Benefit shown from both oral intake and smoking – PO may reduce urge incontinence >24 studies – Relax rigid muscles – Decrease pain

17. Nausea and Vomiting 2,7 Modest anti-emetic Different mechanism than commercially available products Possible adjunctive treatment Most studies available look at commercial products vs. medical marihuana Smoking 8.4-16.9 mg THC had limited benefit compared to 8 mg ondansetron

18. Glaucoma 2,7 Smoking marihuana reduces intraocular pressure short-term – 60-65% decrease for open angle glaucoma – Decreases blood flow to optic nerve – Linear relationship to amount smoked – Benefit for 3-4 hours = 8-10 marihuana cigarettes smoke/day for continual benefit Unknown benefit to visual function

19. Possible Benefit Alzheimer’s Disease AutismCancerEpilepsy Digestive Disorders Schizophrenia Vaida B. Medical Marijuana: What the Research Shows. April 02, 2014. http://www.medscape.com/viewarticle/822942

20. Alzheimer’s Disease 5,8 1 trial from 1997 showed THC could ease symptoms Participants showed less agitation and better appetites Decrease amyloid beta at low concentrations Potential neuroprotective effect – Memory impairment only seen at “abuse” concentrations

21. Autism 5 2 animal studies show possible symptom benefit Study at University of California in progress

22. Cancer 5 Several human and animal studies Small study (9 participants) showed THC and other cannabinoids may slow brain cancer growth Lab studies of human cells show potential to slow breast and leukemia cancer cells

23. Epilepsy 5 Anecdotal and animal studies show cannabidiol (CBD) may help seizures in children New York University to begin studying marihuana benefit for epilepsy in children

24. Digestive Disorders 5 Anecdotal, early studies – Smoking marihuana can help with: colitis, irritable bowel syndrome, and Crohn’s disease – Reduces bowel inflammation and decrease acid reflux – Some patients retained more nutrients – Some had disease remission

25. Schizophrenia 5 2 trials THC and cannabidiol could help psychotic and other symptoms Possible link to causing schizophrenia in adolescents who start National Institute of Health funding clinical trial to study ease of symptoms

26. Other possibilities 7 Tourette’s – Oral THC helped decrease tics after 6 weeks compared to placebo Levodopa-induced dyskinesias in Parkinson’s Disease

27. Question 1 Which of the following properties is an example of the possible beneficial aspects of using medical marihuana? a.Anxiolytic b.Analgesic c.Appetite stimulant d.All of the above

28. Risks 9 “What the data are showing is for the majority of the population, cannabis is not associated with severe, long-term adverse outcomes, but there is a misconception that this means it is safe for nearly everyone, which is not true.”

29. Limitations to Risks Recreational use is not the same as medicinal use No consensus on definitions of low vs. heavy use Most studies use oral commercial forms

30. Abuse 9-11 States with legalized marihuana have higher rates of use/abuse/dependence Clinical and epidemiologic studies show link between early cannabis use and increased exposure to heavier drugs – No true causal relationship – genetic and environmental influences – Screening processes Addiction potential 9-10% – Highest when starting as a teenager

31. Withdrawal Irritability Anger Depression Insomnia Craving Decreased appetite

32. Side Effects 2 Serious side effect risks low compared to many other prescription drugs

33. Common Side Effects 6 Dry mouth, red eyesNausea/VomitingSedationDizzinessAltered sense of timeDecreased GI motilityConfusionIncreased heart rate and BP fluctuationsIncreased well-beingMuscle relaxationIncreased appetiteCough

34. Chronic Use 6 ApathyImpaired memorySexual dysfunctionBullous emphysemaIncreased risk of MI in middle ageIschemic stroke

35. Unknown Risks 2 Lung cancer Testicular cancer Increased risk of psychosis

36. Other risks 6,9 “Motivational syndrome” Intoxicating doses impair reaction time, motor coordination, and visual perceptions – Driving may be impaired for up to 8 hours Dependency similar to other pain medications

37. Lung Disease 3 Marihuana smoke contains 70% more carcinogenic ingredients than cigarette smoke Similar compounds to cigarette smoke Research with lung cancer is conflicting Combustive marihuana is a respiratory irritant

38. Lung Disease 3 Meta-analysis Tetrault et al. – Consistent association between short-term use and bronchodilation Increase FEV1, peak flow, and airway conductance – Also found no consistent association with long- term smoking and airflow obstruction – Benefit is non-linear, increase FEV1 with low levels of exposure, but decrease FEV1 at high levels

39. Lung Disease 3 CARDIA (Coronary Artery Risk Development in Young Adults) – 20 year follow up with no airflow obstruction with occasional or low cumulative marihuana smokers NHANES III (National Health and Nutrition Examination Survey) – Both marihuana and tobacco increase respiratory symptoms Fligiel et al. suggests physical exam and spirometry may not be sensitive enough in asymptomatic smokers

40. Lung Disease 3 Associated with chronic bronchitis symptoms and airway inflammation, however low cumulative doses are not a risk factor for COPD Apical bullous lung disease – Linked to heavy smoking in young adults – Deeper and longer inhalations – Related to technique – Very rare and possibly coincidental

41. Lung Cancer 3 Research is conflicting – THC effects on cytokines suggest cancer cell growth but cannabinoids seem to inhibit cell proliferation in vitro Histopathologic and immunohistologic evidence suggested molecular markers of pretumor progression, Moir et al. – Epidemiologic evidence linking is rare

42. Lung Cancer 3 Swedish study – > 50,000 men, 18-20 years old – Extended follow-up – Heavy cannabis smoking = >50 uses Two-fold greater risk in developing lung cancer Article conclusion: “Any toxicity pales when compared to the greatest legalized killer in the world – tobacco.”

43. Study Flaws 3 Most people who smoke marihuana also smoke tobacco Most studies lack power to associate marihuana with COPD Under-reporting Wide variety of definitions for “heavy” use

44. Question 2 True or False: Smoking marijuana has been conclusively linked to lung cancer. True False

45. Pharmacist stuff… Medical Marijuana. Google. saintpetersblog.com

46. Drug Interactions 6 CYP450 3A4 and 2C inhibitor Little evidence of clinically significant interactions at medicinal doses Unclear if risk equivalent when smoking (undergoes less hepatic first-pass metabolism) Use caution with anti-cholinergics and CNS depressants (additive effects)

47. Contraindications/Precautions 6 Contraindication Abnormal sensitivity to marihuana Precautions Severe personality disorders/psychoses Pregnant/breastfeeding Children/adolescents Elderly Cardiovascular disease Addictive disorders

48. Pharmacokinetics 6,7 THC immediately in plasma following inhalation – Rapidly absorbed within seconds, peak concentration 3-10 minutes Low oral bioavailability improved when in oil- based formulation Active metabolites higher after oral use than smoking

49. Pharmacokinetics 7 Cannabidiol (CBD) has extensive first-pass metabolism – Oral: peak 30-120 minutes and detected for 180- 240 minutes after ingestion Rapid onset and predictable decay allow for self-titration Overdose is rare

50. Medical Marihuana 9,12 “Not your parents’ pot” – Current cannabis more potent – Higher levels of THC 1960-1970’s: <5% THC Last 10 years: 15-20% THC Prescriptions should specify THC concentrations not greater than 9%

51. Types of Medical Marihuana SativaIndica Leung L. Cannabis and its derivatives: Review of medical use. J Am Board Fam Med 2011;24:425-462.

52. Routes SmokingVaporizingEatingDrinkingTinctureTopical Methods, Forms and Routes of Medical Marijuana Administration. http://svphyto.org/wp-content/uploads/2013/06/Methods-Forms- and-Routes-of-Medical-Marijuana-Administration.pdf

53. Smoking 3,4,6,13 Pros Most immediate relief Refined control Self-titration Cons Respiratory irritation Combustion creates additional byproducts Possible contaminants Amount delivered depends on individual techniques/lung capacity

54. Smoking 13 Potentially greater benefit in: – Tourette’s Syndrome – Glaucoma – Pain – HIV-induced neuropathic pain

55. Smoking 2,3 No FDA approved drug is available administered by smoking – Most studied route for medical marihuana Despite lack of marihuana standardization, smoking is an unpredictable route of administration – Dependent on user: time of inhale, method of inhale, time of exhale

56. Vaporizing 13 Smokeless alternative – Considered safest route – Not the same as water pipes – Heat cannabis below point of combustion producing less byproducts but allowing essential oils to volatize Similar effects to smoking Marijuana Vaporizer. Google. lelandkim.com

57. Eating 13 Cannabinoids extracted into fats (butter/oils) Ingested via baked goods/candy-like products Active ingredients must be metabolized by liver – Can take 30 minutes – 2 hours before effects – Effects last 2-8 hours Side effects typically stronger than smoking More difficult to regulate doses Oral use potentially more beneficial in: MS spasticity, peripheral/central neuropathic pain

58. Drinking 13 Tea – Boil water and pour over cannabis – Steep for 1.5 hours – not readily water soluble – Effects similar to eating

59. Tinctures 13 Alcohol used to extract cannabinoids Effects similar to eating Faster onset and quicker offset than eating – Effects in 5 minutes – 1 hour – Last up to 4 hours May drop or spray into mouth and absorb through mucous membranes Can drop in hot water to burn off alcohol

60. Topical 13 Can be absorbed through skin Ideal for ointments

61. Commercially Available 2 Dronabinol (Marinol®) – schedule III Nabilone (Cesamet®) – schedule II – Use: nausea with chemotherapy agents Nabiximols (Sativex®) – Buccal spray approved in Canada, currently studied in US for neuropathic pain in adults with MS Epidiolex® – FDA approved in 2013 for children’s epilepsy – Highly restricted use

62. Commercially Available 2,13 Typically these agents are too psychoactive – Narrow gap between therapeutic dose and adverse effects Euphoria, cognitive clouding, drowsiness Only based off of THC (psychoactive component) A combination of cannabinoids (cannabidiol and THC) as found in medicinal marihuana can have affect over benefit and side effect profile

63. Michigan Medical Marihuana Act 9 Department of Justice: Will not challenge state laws that legalize marihuana – Focus on: Preventing distribution to minors Stop drug trafficking by gangs/cartels Prevent drugged driving Prohibit public lands for growing

64. Michigan Medical Marihuana Act 14 Patient MI Resident Debilitating qualifying medical condition Registered with MMMP

65. “Usable” Marihuana 14 LeavesFlowers

66. Michigan Medical Marihuana Act 14 Caregivers Must meet state requirements for protection May care for up to 5 patients Physicians Must meet state requirements for protection Bona fide physician – patient relationship

67. MMMA: Updates 14 Limit transportation Public Act 460 Define bona fide physician-patient relationship Further definitions: enclosed, locked facility, primary caregiver Public Act 512 Proof of residency Further definitions Add confidentiality Public Act 514

68. Debilitating Medical Condition 14 CancerGlaucomaPositive HIV statusAIDSHepatitis CAmyotrophic Lateral SclerosisCrohn’s diseaseAgitation of Alzheimer’s diseaseNail patella syndrome

69. Debilitating Medical Condition 14 Cachexia or wasting syndromeSevere and chronic painSevere nauseaSeizuresSevere and persistent muscle spasmsAny other medical condition or its treatment approved by the department

70. Debilitating Medical Condition 14 Approved Parkinson’s Disease PTSD Denied Asthma Autism Insomnia Bipolar disorder

71. Question 3 Which of the following is NOT a valid use for medical marihuana in Michigan? a.Glaucoma b.Crohn’s Disease c.Nail patella d.Schizophrenia

72. Updates 15 Dispensaries shutdown in February 2013 as “public nuisance” – House legislation to add new rules and limitations for reopening Michigan Court of Appeals in July 2013 said “pot brownies” are not “usable marihuana” under the law, unless contain actual plant material – Legislation also to redefine to include edibles

73. Conclusions Marihuana has shown possible medicinal benefit in multiple indications Marihuana use does not come without risks Further studies need to be done

74. Resources 1.Michigan Medical Marihuana Program. LARA. http://www.michigan.gov 2.Medical Marijuana. Pharmacist’s Letter. January 2013. 3.Manish J et al. Marijuana and Lung Diseases. Curr Opin Pulm Med. 2014;20(2):173-197. 4.Leung L. Cannabis and its derivatives: Review of medical use. J Am Board Fam Med 2011;24:425-462. 5.Vaida B. Medical Marijuana: What the Research Shows. April 02, 2014. http://www.medscape.com/viewarticle/822942 6.Zanni GR. Medical marijuana potential and pitfalls. http://www.pharmacytimes.com 7.Medical Marijuana. Clinical Pharmacology. 2014. 8.Harrison P. Marijuana Compound a Novel Treatment for Alzheimer’s? September 05, 2014. http://www.medscape.com/viewarticle/831199 9.Melvil NA. Public in a haze about marijuana safety. September 04 2013. http://www.medscape.com/viewarticle/810427 10.Alcohol and Drug Information. National Council on Alcoholism and Drug Dependence, Inc. https://ncadd.org/for-the-media/alcohol-a-drug-information. 11.Nicotine Addiction: Past and Present. How Tobacco Smoke Causes Disease. 2010. Available from: http://www.ncbi.nlm.nih.gov/books/NBK53018/ 12.Collier R. MediData: How potent is medical marijuana. CMAJ. Aug 26, 2014. 13.Methods, Forms and Routes of Medical Marijuana Administration. http://svphyto.org/wp- content/uploads/2013/06/Methods-Forms-and-Routes-of-Medical-Marijuana-Administration.pdf 14.Michigan Medical Marihuana Program. LARA. http://www.michigan.gov 15.Oosting J. Michigan medical marihuana rule changes hit speed bump. October 01, 2014. http://www.mlive.com/lansing-news/index.ssf/2014/10/michigan_medical_marijuana_rul.html

75. Questions? Smoke. Google. http://textures8.com/smoke-abstract-background-sixty-five/