Is there a role for medical marijuana in the management of IBD? Jami A. Kinnucan, MD Division of Gastroenterology University of Michigan Hospital

Is there a role for medical marijuana in the management of IBD? Jami A. Kinnucan, MD Division of Gastroenterology University of Michigan Hospital

Disclosures No relevant financial or relationship disclosures

Outline Get to know Cannabis sativa A brief history lesson Physician and patient views What we know about use in IBD patients What does the literature really tell us? What can you tell your patients?

Why should we care about medical marijuana? Medical marijuana legalization is of increasing interest to the public Majority in favor of legalization for medical purposes 1 Google trends data since 2010 2 Legal medical cannabis Dr. Sanjay Gupta says you should We should legalize medical marijuana. We should do it nationally. And, we should do it now 1. http://www.people-press.org/2013/04/04/majority-now-supports-legalizing-marijuana/ accessed June 11, 2015. 2. https://www.google.com/trends/explore#q=legal%20cannabis&cmpt=q&tz= accessed June 11, 2015.

Cannabis sativa Generically known as marijuana or cannabis Composed of hundreds of active compounds or phytocannabinoids Delta-9-tetrahydrocannabinoil (THC) Cannabidiol (CBD) Image courtesy of Wikipedia Cannabinoids act at multiple endocannabinoid receptors Two synthetic FDA approved THC cannabinoids Dronabinol Nabilone Image adapted from Peak Pharma

Synthetic Cannabinoids Dronabinol Marketed as Marinol Schedule III Capsule FDA approved: 1. AIDS cachexia 2. Chemo nausea/vomiting Studied in IBS-D with decreased colonic motility 1 No studies in IBD Nabilone Marketed as Cesamet Schedule II Capsule FDA approval 1985, marketed in US 2006 1. Chemo nausea/vomiting Alterative uses -Chronic pain, fibromyalgia No studies in IBD 1. Wong et al. Gastroenterology 2011 Nov;141(5):1638-47.

What are the clinical effects of cannabinoids? Direct GI effects -Alteration of permeability? -Immune cell trafficking? -Alteration of gut motility IBD Effects? -Potent anti-inflammatory in mouse model -Appetite stimulant -Bowel relaxation/anti-cholinergic effects -Unknown in humans Image adapted from www.the-human-solution.org, accessed June 12, 2015

Medical marijuana timeline 8/2013 Law signed 1/2014 Program eff. 11/2015 Product? 12/2017 Expiration

Where is medical marijuana legal? Accessed http://www.governing.com/gov-data/state-marijuana-laws-map-medicalrecreational.html on June 1, 2015

Accessed http://www.governing.com/gov-data/state-marijuana-laws-map-medicalrecreational.html on June 1, 2015 Where is medical marijuana legal? DISCLAIMER: It is still considered Schedule I drug under he Federal Controlled Substance Act

Practitioner s legalization uncertainty The Minnesota Office of Medical Cannabis conducted a survey of both patients and physicians 70% of eligible patients would register for the program, majority of were patients with cancer The Minnesota Medical Association surveyed about 500 of registered physicians 9% planned to participate in the program 68% would not participate Large group of physicians surveyed expressed concern for potential physical and mental risks and limited evidence for use in various conditions http://www.minnesotamedicine.com/portals/mnmed/may_2015/medicalcannabis_specialissue.pdf accessed June 12, 2015. Kondrad E, Reid A. J Am Board Fam Med 2013;26:52-60.

http://medicalmarijuana.procon.org/view.source.php?sourceid=000412 accessed July 17, 2015 CCFA Statement The CCFA does not endorse the smoking of marijuana by IBD patients, any current state-based medical marijuana programs, or the legalization of marijuana. The CCFA does support the calls by the various health organizations urging review of marijuana s status as a federal Schedule I controlled substance, with the goal of facilitating the conduct of clinical research and the potential development of cannabanoid-based medications."

Are IBD patients using marijuana? A Spanish study reports use in 10% of IBD patients 1 A large Canadian study found 50% with prior use, 15% with current use of marijuana 2 Majority using to relieve IBD-related symptoms Use associated with lower quality of life scores Canadian study found that cannabis use in the last 6- months was a strong predictor for surgery in patients with Crohn s disease 3 OR= 5.03, 95% CI 1.45-17.46 1. Garcia-Planella et al. Med Clin (Barc) 2007;128:45-8. 2. Lal S et al. European journal of gastroenterology & hepatology 2011;23:891-6. 3. Storr et al. Inflamm Bowel Disease 2014 Mar;20(3):472-80.

Marijuana use in IBD in the United States Survey of 292 patients at single center in Boston 1 61% Crohn s disease, 35% UC Mean age 39.3 years Marijuana use patterns Current users 12% Past users 39% Never users 49% Majority cited that marijuana was very helpful in relieving abdominal pain, nausea, diarrhea Marijuana use associated with younger age and chronic abdominal pain Prospective survey of 88 patients at tertiary referral centers 2 60% Crohn s disease, 40% UC Mean age 38 years 45% 25% 30% Current cannabis Previous cannabis Never cannabis Marijuana use was associated with younger age, male gender, single marital status, daily abdominal pain No association with disease or severity of disease 1. Ravikoff Allegretti J et al. Inflamm Bowel Dis 2013; 19(13):2809-2814. 2. Kinnucan JA et al. Abstract presented at DDW 2015.

Is there a role for marijuana in digestive diseases? Significant preclinical data evaluating effects of cannabinoids on digestive health Randomized controlled trials are limited 1 Gerich M et al. Am J Gastroenterol 2015; 110: 208-214.

Is there a role for marijuana in management of IBD?

Is there a role for marijuana in management of IBD? Small observational studies show benefit in Crohn s disease Improvement in symptoms, overall well-being and need for steroids 1,2 Naftali and colleagues performed only RCT of marijuana in the management of IBD 3 Small study with only 21 active Crohn s disease pts (CDAI 200-450) Failure of prior therapy (5ASAs, steroids, IM, MTX or anti-tnf) Randomized 1:1 to receive smoked cannabis vs. placebo 1º: Clinical remission at 8 weeks 2º: Clinical response (CDAI Δ 100), CRP, quality of life 1. Nafatali T et al. Isr Med Assoc J 2011; 13:455-458. 2. Lahat A et al. Digestion 2012; 85:1-8. 3. Naftali T et al. Clin Gasteroenterol Hepatol 2013; 11: 1276-1280.

Is there a role for marijuana in management of IBD? Study (n=11) Placebo (n=10) p-value Clinical remission (CDAI <150) 45% 10% 0.43 Mean CDAI (8 weeks) ± SD 152±109 306±143 <0.05 Clinical response (CDAI Δ >100) 90% 40% <0.05 Mean CDAI reduction ± SD 177 ± 80 66 ± 98 0.005 Failure to meet primary endpoint- clinical remission at 8 weeks Some secondary endpoints met No changes in objective markers of inflammation

Study Summary + Large percentage of patients in clinical remission + Improvement in quality of life scores + Patients able to stop steroids or opiate therapy - No differences in objective markers of inflammation - All patients relapse after stopping treatment/placebo - Small study numbers Based on available data, one cannot argue that cannabis is a successful treatment for the inflammatory process in Crohn s disease

Can marijuana be harmful? Overall marijuana has good safety profile, although there are concerns with long-term use Acute adverse effects Anxiety Psychotic No symptoms deaths have been associated with Chronic adverse effects marijuana use alone Increased risk of motor vehicle accidents Decreased fertility Altered adolescent psychosocial development and mental health Chronic smoke inhalation effects Withdrawal symptoms Hyperemesis syndrome

Cannabis hyperemesis syndrome (CHS) First described 7 years ago among chronic cannabis users Symptoms include cyclic vomiting, abdominal pain, nausea Risk factors include early onset of use, chronic/daily use, males Cause is not clearly understood Treatment Cessation of cannabis use, rehydration Psychological counseling Hot bath and showers Wallace EA et al. South Med J 2011;104:659 664.

There are still so many unanswered questions Are there high quality studies evaluating long term outcomes? Does the strain of marijuana matter used matter? Does route of administration matter? How often should patients use cannabis to obtain effect? How can we apply controlled trial data to real-life use? Are there indications (ie chronic pan) where it might be helpful? Why are patients not asking for FDA approved synthetic derivatives? What are the legal implications for physicians? Patients? We need more high quality studies evaluating efficacy (mucosal healing?) and outcomes

Bottom line There is clearly not enough robust controlled data to suggest role for treatment in all patients with IBD There might be an adjuvant role to approved medical therapy in a select group of patients with Crohn s disease

Illinois Medical Cannabis Patient Program Supplemental Slides kinnucan@med.umich.edu