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Disclosures:
Speaker: David J. Hass, MD, FACGDr. Hass has no conflicts of interest related to this talk.
Moderator: Linda Anh B. Nguyen, MDAdvisory Board: Gemelli Biotech; Consultant: Eli Lilly, Takeda, Ironwood, Pendulum, Neurogastrx, Phathom, Alnylam; Research Grant Funding: Bold Health, Vanda
David J. Hass, MD, FACG
Associate Clinical Professor of Medicine
Yale University School of Medicine
PACT Gastroenterology Center
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WHAT IS COMPLEMENTARY AND ALTERNATIVE
MEDICINE?
Medical interventions not taught widely in medical schools
Not generally available in U.S. hospitals
‐ But this is rapidly changing……
Some examples…. Relaxation techniques
Herbal Medicine
Massage therapy
Chiropractic therapy
Megavitamins
Homeopathy
Fecal microbial
therapy
Hypnosis
Biofeedback
Acupuncture
Art therapy
Energy healing
Lifestyle diets
Medical cannabis
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Some demographics….Women > Men
Caucasians > other ethnicities
Age group of 35‐49 years old reported highest rates
Correlation between income level and CAM use
Correlation between education level and CAM use
Cost of therapy
Majority of patients who implement CAM pay out of
Estimated $30 billion dollars spent per year
Estimated $35 billion dollars spent per year on supplements
Exceeds total out of pocket expenditures for
hospitalizations
Washington Post, January 2020.
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Non‐Disclosure
Less than 40% of CAM therapies are reported to PCPs
Danger of non‐disclosure
Common conditions
Neck and back problems
Depression
Anxiety
Digestive problems
Arthritis
Allergies
Headaches
Fatigue
Hypertension
Terminal illness
Chronic Pain
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Which of the following has been reliably well studied for the treatment of nausea and emesis?
A. Ginger (Zingiber officinale)
B. Ayurvedic medicine
C. Homeopathy
D. Psyllium
Ginger Enhances GI motility and acts as a 5‐HT3 receptor antagonist
RCTs demonstrate efficacy in postoperative, chemotherapy, morning sickness
Medication interactions
Ernst E, Pittler MH. Br J Anaesth 2000; 84:367-71.
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Irritable Bowel Syndrome
Hypnotherapy has been proposed as an effective complementary therapy in the treatment of Irritable Bowel Syndrome. Through “gut–related imagery,” what percentage of patients report initial overall symptom improvement with this modality?
A. 10%
B. 40%
C. 60%
D. 80%
Supplements/Natural Products
Treatment PROS CONS Comments
Peppermint Oil
Improves global symptoms Commercially available (e.g. IBGard™ – non‐prescription, ultrapurified peppermint oil)
Side effects: diarrhea, nausea, vomiting, allergic reactions, atrial fibrillation, dyspepsia,
GERD
Acts by direct blockade of smooth muscle calcium
channels (esophagus, distal stomach and duodenal bulb)Allosteric effect on 5‐HT3
receptorLow quality of evidence
TurmericImproves symptom severity via
anti‐spasmodic effectCommercially available
Side effects: nausea, vomiting, fatigue, headache and diarrhea
Increases GI motility and activates hydrogen producing
bacteria in the colon Very low quality of evidence
Cannabis Presumed analgesic effect
Many adverse effects including hepatotoxicity, hyperemesis
and paradoxical exacerbation of abdominal pain, sedation
Not consistently available with variable dosing
Very low quality of evidence
Ford et al. N Engl J Med. 2017;376(26):2566-2578. Chey et al. JAMA. 2015;313(9):949-958. Deutsch J and Hass DJ. Am J Gastroenterol. 2020;115(3):350-364.
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Supplements/Natural Products
Treatment PROS CONS Comments
Aloe Vera
Anti‐inflammatory and analgesic effect and can also
act as a laxative Commercially available
Side effect: diarrheaCan decrease absorption of
certain medications
Dosing ranges from 1 tablespoon to 1/3 cup dailyVery low quality of evidence
STW‐5(Iberogast™)
Improves global symptoms and abdominal pain
Commercially available
Hepatoxicity, increased bleeding, altered absorption
of medications
Promotes fundic relaxation and antral contraction
Very low quality of evidence
GlutamineImproves global IBS symptom
severity Commercially available
Side effects: abdominal pain and bloating
Restoration of normal intestinal permeability
Very low quality of evidence
BeberineImprovement in diarrhea,
abdominal pain and urgencyCommercially available
No reported adverse effects but may interfere with drug
metabolism
Anti‐nociceptive and anti‐depressant
Very low quality of evidence
Ford et al. N Engl J Med. 2017;376(26):2566-2578. Chey et al. JAMA. 2015;313(9):949-958. Deutsch J and Hass DJ. Am J Gastroenterol. 2020;115(3):350-364.
Mind/Body
Treatment PROS CONS Comments
Cognitive Behavioral Therapy
Management of stress surrounding IBS symptoms One meta‐analysis reported
NNT of 3No reported adverse effects
Could be costly, but some insurance will
cover
Appropriate for patients who report that stressors make GI symptoms worseHigh quality of evidence
Gut‐directed hypnotherapy
Overall symptom improvement of 50‐80%
One meta‐analysis reported NNT of 4
No reported adverse effects
Could be costly, but some insurance will
cover
Mechanism of action unknown
Moderate quality of evidence
Deutsch J and Hass DJ. Am J Gastroenterol. 2020;115(3):350-364.
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“Long‐term Follow‐up of Gut Directed Hypnotherapy Self‐Exercises at Home Using CD vs. Individual Therapy by Qualified Therapists In Children With Irritable Bowel Syndrome or Functional Abdominal Pain”
Non‐inferiority
144 patients from previous RCT
5.8 years of follow up
80% CD group vs. 83% iHT group reported relief
Supports the use of low cost home treatment that can be widely distributed
R. Rexwinkel et al. Netherlands DDW 2019 Abstract1608
Is Hypnotherapy Equally Effective Self-directed at Home vs. with a Therapist?
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Inflammatory Bowel Disease
Turmeric (Curcuma longa)
Prevents formation of free radical species
Decreases TNF alpha and IL 1β production
Inhibits NF‐κB activation
Inhibits synthesis of pro‐inflammatory prostaglandins and leukotrienes through inhibition of arachidonic acid pathway
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Turmeric (Curcuma longa)
Used in Indian and Chinese herbal medicine
Prospective RCT of UC pts in remission (4.6% vs. 20.5% relapsed in turmeric vs. placebo)
RCT of curcumin 3gm demonstrated that over 53% achieved clinical and endoscopic remission in conjunction with mesalamine
Hanai et al. CGH 2006. Lang et al. CGH 2015.
Curcumin Use in Ulcerative Colitis ‐ Is it Ready for Primetime? A Systematic Review and Meta‐Analysis of Clinical Trials ‐Chandan et al.” Abstract 1871, DDW 2019
“Meta‐analysis of RCTs evaluating the efficacy of adjunctive therapy with curcumin in treating pts with UC
380 pts total included
Overall pooled OR of 3.13 for clinical response
Overall pooled OR of 3.33 for endoscopic response
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Highly Bioavailable Curcumin for Crohn’s Disease ‐ RDBPCT
360mg daily vs. placebo or 12 weeks
Mild to moderate CD pts (<180 CDAI <450)
CDAI significantly improved at week 12 (149 vs.210) p=0.005 in Theracumin® group
Clinical remission in Theracumin® group at week 12 compared with placebo ‐ 40% vs. 0%. (p=0.02)
Endoscopic remission noted, but not statistically significant.
Bommelaer et al. Abstract 1716, DDW 2019
Turmeric (Curcuma longa)
Safe even in high doses
No evidence of mutagenicity or chromosomal damage
Turmeric does exhibit an inhibitory effect on platelet aggregation
Patients who are maintained on agents such as aspirin, clopidogrel, or ticlopidine should be closely monitored
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Screening Anti‐Fibrotic Agents: Exploration of Promising Therapies to Reduce or Reverse Intestinal Fibrosis in Crohn’s Disease
Assessed novel anti‐fibrotic agents’ effects on myofibroblasts stimulated with TGF‐B
Measured profibrotic markers expression after exposure to novel agent.
Curcumin significantly reduced expression of every pro‐fibrotic measured (ACTA2, procollagen, tissue inhibitor metalloproteases.)
Broxson et al. Abstract 1035, DDW 2019.
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The History of Cannabis
The History of Cannabis
1600 A.D. ‐> As trade routes expanded, cannabis made its way to Europe
Rumored that Queen of England used hemp for maladies
Colonization of America from England – hemp brought to the eventual United States
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John Hudak – Marijuana: A Short History
The History of Cannabis
Marijuana Tax Act of 1937
Controlled Substances Act (1970) – Schedule I
National Commission on Marijuana (1972) ‐ Nixon
“Just Say No” Campaign ‐ Nancy and Ronald Reagan
California Compassionate Use Act (1996) – Prop. 215
Statistics
10.7 % of individuals regularly use cannabis in U.S. age 15‐64
Up to 50% of IBD pts have used cannabis in their lifetime
50% of IBD pts report interest in cannabis trials
Eur J Gastro Hep 2011;23(10):891-896
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Indications for Medical Marijuana Malignancy
Glaucoma
Parkinson’s Disease
HIV/AIDS
Epilepsy
Spinal cord injury/ Muscle Spasticity
Cerebral Palsy
Cystic Fibrosis
Cachexia
Wasting Syndrome
Spinal cord injury
PTSD
Crohn’s Disease
Ulcerative Colitis
Intractable Seizure Disorder
Terminal Illness
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Sifting through the “weeds”
Phytocannabinoids
Δ9‐tetahydrocannabinol main component (THC)
Cannabidiol (CBD)
Up to 130 other phytocannabinoids (CBG, CBDa, THCa)
Three main subspecies of Cannabis
Cannabis sativa (higher THC content)
Cannabis indica (couchlock)
Cannabis ruderalis (low THC content, allows flowering more quickly)
Currently nearly 800 different Cannabis strains
Endocannabinoid System
Two endogenous endocannnabinoids
Anandamide
2‐arachidonoylglycerol (2‐AG)
Two receptors: CB1 and CB2
CB1 expressed principally in the enteric nervous system of the gut (submucosal and myenteric plexus) and also on mucosal epithelium.
CB2 mainly expressed on surface of immune cells
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Endocannabinoid System – CB1
CB1 modulates central functions including pain control, nausea/vomiting center.
CB1 promotes inhibitory effect on motility and secretory function via reduced acetylcholine release.
CB1 receptors seen on colonic epithelium and enhance wound healing.
Endocannabinoid System – CB2
CB2 receptors are found on inflamed colonic epithelium.
In vitro evidence to suggest that activation of CB2 receptors inhibits TNF‐α , IL‐1 , IL‐8 and prostaglandin release.
Evidence of cannabinoid receptor expression in injured liver and pancreas.
Antifibrotic effect in liver, apoptotic and anti‐proliferative effect on GI cancer cell lines.
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Ways to ingest…
Edibles
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Physiology – “The Buzz”
Inhalation Ingestion
Onset 1 minute 30‐90 minutes
Peak 30 minutes 2‐3 hours
Duration 2‐3 hours 4‐12 hours
Adverse effects
Anxiety
Psychosis
Decreased fertility
Hyperemesis Syndrome
Withdrawal Syndrome (irritability, sleep disturbance, anorexia, depressed mood)
Pancreatitis
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Cannabis Hyperemesis Syndrome
First described by Singh and Coyle in 2004 in Australia
Hypothesis is that the TRPV1 receptors located in area postrema of medulla and skin are desensitized from chronic exposure to cannabis
Leads to decrease in anti‐emetic physiology
Hot water may augment cutaneous TRPV1 receptor function and thus increase anti‐emetic properties
The data….. Little clinical evidence demonstrating efficacy
Majority of controlled human studies with synthetic cannabinoids – not medical marijuana
5 RCT on marijuana and GI disease
Appetite, HIV (2), cancer‐related anorexia‐cachexia, and Crohn’s disease
Cannabis use common in IBD
50% of IBD patients admit to marijuana use; 16‐50% use it to control symptoms of IBD
Improved symptoms and QOL in 2 small observational studies
Storr et al. Inflamm Bowel Dis 2014Allegretti et al, Inflamm Bowel Dis 2013
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Randomized “Placebo” Controlled Trial of Cannabis (THC) in Crohn’s Disease
Inclusion: CD patients with CDAI>200 failing at least 1 therapy for CD (including mesalamines) (n=21)
RCT of Δ9-tetrahydrocannabinol (THC) Cigarettes with 115mg THC vs no THC
Primary endpoint complete remission (CDAI < 150)
Clinical Outcomes
THC (n=11) Placebo (n=10)
P‐value
Clinical remission
45% (5/11) 10% (1/10) 0.43
Clinical response(CDAI↓ >100)
90% (10/11) 40% (4/10) 0.028
Naftali T et al. Clin Gastroenterol Hepatol 2013;11:1276‐1280.
What about data for UC?
RDBPCT
Once daily CBD rich extract for 10 weeks
Active UC patients
N = 60
Adjunct to mesalamine therapy
Improved quality of life
Failure of primary endpoint of remission
Irving et al. Inflamm Bowel Dis 2018
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“Epidemiology, National Trends and Outcomes of Cannabis Use in Hospitalized Patients With IBD in US 2002‐2014”
Hospitalized IBD patients (both CD and UC) have increased prevalence of cannabis use
Inpatient mortality lower with cannabis use
Length of stay shorter ‐1/2 day (p<0.001)
Lower rate of colectomy 2.8% v. 6.7% with cannabis (p<0.001)
Elkafrawy et al. Abstract 1800, DDW 2019
“The Association of Hepatocellular Carcinoma and Cannabis Use”
To determine association between HCC and Cannabis use
Identified patients with HCC and Cannabis use
996,290 patients identified vs. controls
Cannabis users were younger, more males, higher % of HBV, HCV, Cirrhosis, tobacco use
OR of HCC =0.58 (40% less likely to develop HCC) compared
with controls
Khoudari et al. Abstract 1502, DDW 2019.
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“Dude, what’s the law?”
Still a Federal Schedule I substance
State laws vary widely
Most states that allow for medical marijuana have systems to protect physicians
Conant vs. Walters – Ninth Circuit Court of Appeals
Permanent injunction
Supreme Court refused to hear
“Cole Memo” ‐ Obama administration stated that resources will generally not be used to prosecute individuals who comply with state marijuana law.
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THE BUZZ Kill?...
Rescinded The Cole Memo
Regulation
Medical Use Approved in 36 states, D.C., Guam, Puerto Rico and U.S. Virgin Islands
Recreational Use in 15 states and D.C.
Different states have different regulations and laws
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Dollars….
All out of pocket expense for patients
Average $500/month spent per patient
2025 US revenue from marijuana sales is estimated to be 13 billion dollars
Nationwide legalization of marijuana could generate up to $28 billion in tax revenues for federal, state, and local governments.
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Resources
Association of Cannabis Specialists
https://cannabis‐specialists.org/
United Patients Group
https://unitedpatientsgroup.com/
Practice, H., Division, M., & Academies, N. (2017). The Health Effects of Cannabis and Cannabinoids. https://doi.org/10.17226/24625
Conclusions Knowledge of CAM therapies is lacking amongst gastroenterologists both in training and in practice.
Medical cannabis is an emerging modality that with large prevalence amongst GI patients, specifically IBD patients.
Research is ongoing with phytocannabinoids and in vitro evidence and physiology is promising.
A thorough knowledge base of CAM therapies will help us care for our patients in a more comprehensive and responsible manner.
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References Hass DJ. Complementary and Alternative Medicine Therapies in Gastrointestinal and Hepatic Disease. In: Sleisenger
and Fordtran’s Gastrointestinal and Liver Disease, Chapter 131, 2192‐2205; 11th Edition (Feldman M, Friedman LS, and Brandt LJ eds.), Philadelphia, PA. 2021.
Deutsch JK and Hass DJ. Am J Gastroenterol. 2020;115(3):350‐364.
Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990‐1997. JAMA;1998 280:1569‐75.
Koretz RL, Rotblatt M. Complementary and alternative medicine in gastroenterology: The good, the bad, and the ugly. Clin Gastroenterol Hepatol 2004;2:957‐67.
Ernst E, Pittler MH. Efficacy of ginger for nausea and vomiting: A systematic review of randomized clinical trials. Br J Anaesth 2000; 84:367‐71.
Coon JT, Ernst E. Systematic review: Herbal medicinal products for non‐ulcer dyspepsia. Aliment Pharmacol Ther2002; 16:1689‐99.
Forster HB, Niklas H, Lutz S. Antispasmodic effects of some medicinal plants. Planta Med 1980 40:309‐19.
Melzer J, RoschW, Reichling J, et al. Meta‐analysis: Phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther 2004; 20:1279‐1287.
Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97(Suppl 11):S7.
Madisch A, Holtmann G, Plein K, Hotz J. Treatment of irritable bowel syndrome with herbal preparations: Results of a double‐blind, randomized, placebo‐controlled, multi‐center trial. Aliment Pharmacol Ther 2004; 19:271.
Brenner DM, Moeller M, CheyWD, Schoenfeld P. The utility of probiotics in the treatment of irritable bowel syndrome: a systematic review. Abstract S1040. Presented at American College of Gastroenterology Conference, Philadelphia PA 2007.
Whorwell PJ, Prior A, Colgan SM. Hypnotherapy in severe irritable bowel syndrome: Further experience. Gut 1987; 28:423‐25.
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References Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: A pilot study. Dig Dis Sci 2005;50(11):2191‐2193.
Chainani‐Wu N. Safety and anti‐inflammatory activity of curcumin: A component of turmeric (curcuma longa). J Alt Comp Med 2003;9(1): 161‐168.
Levy C, Seeff LD, Lindor KD. Use of herbal supplements for chronic liver disease. Clin Gastroenterol Hepatol 2004;2:947‐56.
Lindfors P, et al. Effects of gut‐directed hypnotherapy on IBD in different clinical settings – Results from two randomized controlled trials. Am J Gastro 2012;107:276‐285.
Mawdsley J, et al. The effect of hypnosis on systemic and rectal mucosal measures on inflammation in ulcerative colitis. Am J Gastro 2008;103:1460‐1469.
Thank you for your attention.
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Questions?
Speaker: David J. Hass, MD, FACG
Moderator: Linda Anh B. Nguyen, MD
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