cam therapies hass acg vgr grand rounds lecture 2.25 ......irritable bowel syndrome hypnotherapy has...

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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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American College of Gastroenterology

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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

pocket

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


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


GlutamineImproves global IBS symptom

severity Commercially available

Side effects: abdominal pain and bloating

Restoration of normal intestinal permeability


BeberineImprovement in diarrhea,

abdominal pain and urgencyCommercially available

No reported adverse effects but may interfere with drug

metabolism

Anti‐nociceptive and anti‐depressant


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


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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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


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


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


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.

[email protected]

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Questions?

Speaker: David J. Hass, MD, FACG

Moderator: Linda Anh B. Nguyen, MD

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cam therapies hass acg vgr grand rounds lecture 2.25 ......irritable bowel syndrome hypnotherapy has...

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