Herbs and Weeds: Evidence-Based Complementary Therapy for IBD. Robert Isfort, M.D. TriHealth Digestive Institute

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1 Herbs and Weeds: Evidence-Based Complementary Therapy for IBD Robert Isfort, M.D. TriHealth Digestive Institute CCF Family Education Day March 4, 2018

2 Disclosures No relevant financial disclosures, but Much of what is discussed today is not FDA-approved for the treatment of IBD Some of what is discussed today is considered illegal under federal law

3 Learning Objectives Understand complementary therapy in general and as it pertains to IBD Use clinical trials to help guide which therapies could be safe and effective for IBD Herbal / Extracts Probiotics Mind-body Review evidence around medical marijuana use and Ohio s implementation

4 Complementary Medicine

5 What is Complementary Medicine? Also referred to as CAM (complementary and alternative medicine) Complementary if used with traditional therapy Alternative if used instead of traditional therapy Group of diverse therapies or healthcare practices that are not commonly utilized in allopathic Western medicine Many have been used for hundreds of years

6 Who uses CAM? 30-68% of IBD patients utilize a CAM therapy Fewer than half discuss this with their physician Concerns over negative reaction Use of CAM has increased over time Only 13% of IBD patients reported use in 1980s Characteristics of those using CAM Side effects or dissatisfaction with traditional treatment Female sex Higher education Friends or relatives also use Long and progressive disease course Prolonged need for steroid medications Gastroenterology 2017;152: Aliment Pharmacol Ther 2012;35:

7 What CAM is used most often in IBD? Aliment Pharmacol Ther 2012;35:

8 Why doctors are uncomfortable with CAM Lack of FDA approval Dietary Supplement Health and Education Act-1994 Categorizes supplements as foods Cannot claim to diagnose, treat, cure, or prevent disease Can market for effects on bodily structure or function No requirement for rigorous safety or efficacy testing Burden falls on the FDA to prove a product is unsafe Risks to patients Direct toxicity Adulterants Dosage variability Drug interactions Lack of data for special populations Children, pregnant women Lack of familiarity or training PT 2010 Sept;35(9):

9 Herbals and Extracts

10 Drugs come from plants Aspirin Etoposide Willow Mayapple Colchicine Morphine Autumn crocus Opium poppy

11 Tumeric / Curcumin Tumeric (Curcuma longa) Commonly used Asian spice Curcumin is active ingredient One of the best studied herbs for IBD Proposed mechanism of action Reduces inflammatory chemical signaling Inhibits abnormal blood vessel growth

12 Curcumin in IBD Ulcerative colitis-active (mild to moderate) 50 patients on maximal dose mesalamine received either curcumin 3 g per day or placebo for 4 weeks 54% of the curcumin group vs. 0% in placebo in clinical remission 38% vs 0% achieved endoscopic remission Ulcerative colitis-maintenance of remission 89 patients given mesalamine/sulfasalazine and curcumin (50%, 2 grams per day) or placebo 5% of curcumin group relapsed within 6 months vs 21% of placebo Significant improvement in clinical activity index and endoscopy Gastroenterology 2017;152:

13 Curcumin side effects Bloating and diarrhea in clinical studies Yellow stool Increased gas in children if taking more than 4g/day Curcumin enemas Studied as complement to other therapies for mildmoderate UC No statistically significant improvement; though trend in this direction Harder to obtain and administer Gastroenterology 2017;152:

14 Fish Oil Found in oily fish (tuna, salmon, mackerel, sardines) Active ingredients are omega-3 polyunsaturated fatty acids Eicosapentaenoic acid (EPA) Docosahexaenoic acid Reduces lipid based inflammatory molecule Generally safe with fishy breath and nausea as main side effects

15 Fish Oil in IBD Crohn s disease Relatively large studies (363 patients-epic 1, 375 patients-epic 2) with no benefit compared to placebo Addition of 8 week prednisone taper first made no difference Ulcerative colitis No difference in rate of relapse or colonoscopy findings If steroids given at same time as fish oil for flare, lower doses of steroids were needed Gastroenterology 2017;152:

16 Other Herbal Preparations Aloe vera Succulent plant with complex antioxidant and antiinflammatory properties 1oomg oral gel used twice daily in mild-moderate ulcerative colitis (44 patients) compared to placebo Clinical remission in 37% vs 7% with placebo (ns) Clinical response in 47% vs 14% No change in endoscopy or biopsy findings No reported side effects in trials Diarrhea at high doses Cases of liver injury Gastroenterology 2017;152:

17 Other Herbal Preparations Wormwood (Artemisia absinthe) Found in absinthe Studied in Crohn s disease 500mg three times daily for 10 weeks In patients on prednisone (study of 40 patients) Disease activity index improved in 65% vs 0% in placebo 90% able to wean from steroids vs. 45% placebo (ns) Improved depression significantly No documented side effects Gastroenterology 2017;152:

18 Other Herbal Preparations Andrographis panniculata (HMPL 004) Mild-mod UC in 108 patients 1200mg/d ethanol extracted. Similar response as mesalamine, better than placebo Safe in IBD study (rash), concerning side effects in HIV study Green chiretta

19 Probiotics

20 What are probiotics? Single or multiple cultures of bacteria and/or yeast used for beneficial effects on microbiome Most used complementary therapy in IBD Mechanism is unclear, but evolving Anti-inflammatory and immune modulatory Increases barrier function of the gut

21 Probiotics in IBD Crohn s disease No consistent benefit, including after surgery Ulcerative colitis VSL#3: Bifidobacteria, Lactobacillus, and Streptococcus species Capsules 112 billion CFU vs. Packets 450 or 900 billion CFU Improved symptom scores and clinical remission compared with placebo Improved pediatric endoscopic scores and clinical remission rates when used in combination with other therapies Rates of remission higher with balsalazide vs. balsalazide alone Side effect of rare bloating and diarrhea E coli Nissle 1917: As effective as mesalamine in maintenance of remission Gastroenterology 2017;152:

22 Probiotics in Pouchitis Pouchitis Aberrant immune response to bacterial dysbiosis and genetic factors in ileal pouch 40 patient study showed VSL#3 led to 15% relapse rate at 9 months vs 100% with placebo after antibiotics Real world experience may be less impressive When given after pouch creation, 1 year follow up 40% of patients in placebo with pouchitis vs. 10% in VSL#3 High doses (3600 bil CFU/d) may treat pouchitis Gastroenterology 2017;152:

23 Parasites In areas with high prevalence of parasite infection there is low incidence of IBD Parasites suppress an immune response pathway (Th1) that is important in driving IBD inflammation Trichuris suis Pig whipworm Colonizes human host, does not cause disease In ulcerative colitis when eggs given every 2 weeks for 12 weeks 43% of patients responded symptomatically vs 17% with placebo In Crohn s disease no significant difference noted for response or remission Gastroenterology 2017;152:

24 Mind-Body

25 Acupuncture and Moxibustion Acupuncture Inserting needles into the skin at therapeutic acupoints Moxibustion Burning or placement of herbs at acupoints Several promising studies for Crohns and colitis, but generally small and with methodological limitations Generally used with mild-mod disease

26 Mind-Body Stress plays an important role in inflammatory bowel disease Stimulation of the vagus nerve has anti-inflammatory effects Vagus nerve tone is reduced in Crohn s disease Multiple modalities tested in IBD Relaxation programs, yoga, psychodynamic therapy Generally improve psychological scores and QOL, not disease activity Hypnotherapy with some promise Exercise Up to moderate exercise three times per week studied and is safe Improves psychological and QOL scores Other benefits Gastroenterology 2017;152:

27 Marijuana

28 What is Marijuana? Marijuana refers to components of the Cannabis plant, Flowering buds of the female plants, harvested for their chemically-rich trichromes. C. sativa: Generally THC>CBD; used for hemp (minimal THC) C. indica: Higher relative CBD content C. ruderalis: Limited THC content; industrial uses Trichromes

29 Active Ingredients Marijuana contains over 420 chemical compounds including over 60 phytocannabinoids. The most extensively studied to date include 9 - tetrahydrocannabinol (THC), cannabidiol (CBD) Marijuana s use dates to at least 2737 B.C. in China. Used as a patent medicine for various GI diseases in the US. THC Huestis Chem Biodivers (2007) 4: Hi Econ Bot (1974) 28: CBD

30 Epidemiology -Warner LA, Kessler RC, Hughes M, et al. Prevalence and correlates of drug use and dependence in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1995;52: Smoking-attributable mortality, years of potential life lost, and productivity losses--united States, MMWR Morb Mortal -Wkly Rep 2008;57: Murphy SL, Xu J, Kochanek KD. Deaths: Final data for Natl Vital Stat Rep 2013;61. -Minino AM, Anderson RN, Fingerhut LA, et al. Deaths: injuries, Natl Vital Stat Rep 2006;54: Gable RS. The toxicity of recreational drugs. American Scientist 2006;94:

31 Marijuana pharmacology Phytocannabinoids bind to receptor molecules on the body s endocannabinoid system Found in intestinal cell and nerve cells Effects in IBD Reduced immune cell response, reduced inflammatory chemicals, improved wound healing Reduction in nausea Reduced diarrhea through Increased appetite Reduced visceral pain In survey study 1/3 of IBD patient state marijuana more effective than steroids 2/3 would give up driving to continue marijuana use Gastroenterology 2017;152:

32 Pomahacova Inhalational Tox (2009) 21: Marijuana Delivery Systems Joint/Blu nt Bowl Bong Vaporizer or Dabs Oils/ Edibles How it Works MJ rolled in cigarette paper/ciga r wrap Metal, wood, or glass pipe Smoke filtered through water MJ heated to just below combustion Ingested without burning. Variable strength. Comments Higher carcinogen s to THC Similar effect to joint/blunt Cooled smoke. Lose cannabinoid(?) Higher THC, less carcinogen No combustion products. Variable kinetics

33 Clinical Trials Low dose cannabidiol (CBD) 10mg twice daily Safe in Crohn s but no benefit in 20 patient trial Marijuana use Reduced symptom severity, need for steroids, and surgery (retrospective study) Improvement in QOL, symptom severity, and weight gain of 8-10lbs (prospective observational study) 5x higher risk of needing surgery (prospective survey study) Clinical response in 90% vs 40% with placebo in RCT of 21 Crohn s patients for 8 weeks Remission in 45% vs 10% but not statistically significant No difference in inflammation markers, no endoscopy Dig Dis Sci 2017Jun;62(6):

34 Risks of Marijuana Use Elevated heart rate, dizziness, drymouth, anxiety / paranoia at time of use Increased cardiovascular events have been reported Driving impairment Heavy and chronic use can affect memory, cognition, and motivation Cannabis hyperemesis syndrome Pancreatitis No consistent risk of lung injury No apparent risk of cancer

35 Marijuana and the Law Marijuana is categorized by DEA as schedule I No currently accepted medical use and a high potential for abuse Illegal under federal law Medical marijuana can be recommended by a physician but not prescribed 30 states and Washington DC with medical / recreational marijuana Leniency by federal government may change over time

36 Medical Marijuana in Ohio Lgalized 2016 for select medical conditions Crohn s and ulcerative colitis included Affirmative defense registration cards to be issued by 9/2018, valid for 1 year Ohio laws surrounding MMJ Cannot cultivate at home Registration with state board of pharmacy required. Private information. All forms of marijuana available except flower for smoking; vaporizers permitted Marijuana will be available at dispensaries Minors permitted to use with parental consent

37 Closing Thoughts

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39 Questions? Thank you!