and in Gastrointestinal and Liver Disease

Keith Sharkey1 and Christian Turbide2 Departments of 1Physiology & Pharmacology and 2Medicine University of Calgary Dr. Keith Sharkey Conflict of Interest Disclosures - Financial (over the past 24 months) No relevant financial relationships with any commercial interests

Consultant: Arena Pharmaceuticals, San Diego, USA; LaSanta Botanicals Ltd., Calgary, Canada.

Research grants: Ironwood Pharmaceuticals, Boston, USA; Lallemand Health Solutions, Montreal, Canada; MedImmune Inc, Washington DC, USA; NovoNordisk, Copenhagen, Denmark; Takeda Pharmaceuticals, Boston, USA. Dr. Christian Turbide Conflict of Interest Disclosures - Financial (over the past 24 months)

Financial relationships with any commercial interests

Consultant: Lupin Pharma Advisory Board, Abbott Advisory Board

Medical Director: True North Cannabis Drs. Keith Sharkey and Christian Turbide

Mitigating Potential Bias

No specific cannabis products will be discussed.

The presentation contains no advocacy; the potential harms of cannabis and its derivatives are clearly identified and discussed. Cannabis in Canada!

https://www.youtube.com/watch?v=ME-H44861cY Cannabis in Canada!

https://www.youtube.com/watch?v=ME-H44861cY

Oct 2019 http://metro.co.uk/2016/03/07/7-really-surprising-health-benefits- from-smoking-cannabis-5738619/

http://movesmart.org/author/joy-nalywalko/ Objectives

 Review what is cannabis, how cannabis is consumed and the differences between recreational and medicinal cannabis.  Review the mechanisms of action of cannabis  Discuss the and cannabidiol in GI and liver disease  Consider harms of cannabis  Engage in an in depth discussion of physician experience with cannabis and cannabidiol What is cannabis?

https://hightimes.com/grow/beginners-how-to-grow-just-one-pot-plant-in- your-home/ https://www.leafly.com/start-exploring The effects of cannabis are mediated by Phytocannabinoids • THCA (Tetrahydrocannabinolic acid) (THC) • THC (Tetrahydrocannabinol) • CBD (Cannabidiol) • CBDA (Cannabidiolic Acid) • CBN () • CBG () • CBC () • CBL () Cannabidiol (CBD) • CBV () • THCV () • CBDV () • CBCV (Cannabichromevarin) • CBGV (Cannabigerovarin) • etc., etc. The effects of cannabis may also be mediated by other molecules found in the flowers

 Terpenes • Limonene, Myrcene, Pinene, β-, Linalool, etc.

 Flavonoids • Cannaflavin A, Orientin, Quercetin, Silymarin, , etc. How is cannabis consumed? Cannabis: recreational vs medicinal

The range of action of this remedy, although classed as mild, is quite wide. It especially controls gastric pain…… In functional disorders of the stomach, with pain, given in conjunction with directly indicated remedies, it is of much value.

http://metro.co.uk/2016/03/07/7-really-surprising-health-benefits- from-smoking-cannabis-5738619/ http://www.herbmuseum.ca/files/images/Lloyd%20Brothers%20Specific%20Medicine%2 0Cannabis%20Antidepressant%20Label%202.jpg/ Recreational vs Medicinal Cannabis

The drug is the same!

The intent is different….

Considerations: cannabis strains (lower vs higher THC and/or CBD content), quantity, timing and route of consumption. How do different routes of administration alter the duration of action of cannabis?

Inhaled cannabis

(smoked / vaped) Intensity Intensity response of

0 1 2 3 4 5 6 7 Duration (hours) How do different routes of administration alter the duration of action of cannabis?

Edible cannabis Intensity Intensity response of

0 1 2 3 4 5 6 7 Duration (hours) PROS CONS Inhaled Rapid onset “pothead” stigma – Pros and Smell, smoke, etc. High Potentially uncertain bioavailability dosing cons of and limited initial metabolism different Harder to Cough, irritation to the overdose throat and lungs cannabis Includes terpenes consumption Ingested Discrete, Slow onset of action carrying no methods “pothead” stigma Measured dosing Lower bioavailability and more rapid metabolism

Slow onset of Terpenes may be lost action Easier to overdose Accidental ingestion How does cannabis work? Cannabis acts on the receptors of the

1964 – 9-THC isolated (Cannabis sativa) 1988 – High-affinity binding sites discovered in rat brain

O 1990 –CB1 receptor cloned 1992 – First N OH M L endogenous H cannabinoid discovered (AEA) E

1993 – CB2 receptor cloned O OH 1995 – Second O 1994 – First CB1 receptor blocker endogenous characterized () OH cannabinoid 2-Arachidonoyl-glycerol (2-AG) discovered

21st Century

Devane WA et al. Science. 1992;258:1946-1949.; Munro S et al. Nature. 1993;365:61-65.; Rinaldi-Carmona M et al. FEBS Lett. 1994;350:240-244. Sugiura T et al. Biochem Biophys Res Commum. 1995;215:89-97. Endocannabinoid system of the brain-gut- microbiota axis: the conductor and the orchestra!

=== Cannabinoid receptors in the GI tract and liver

Maccarrone et al., Trends Pharmacol Sci 2015, 36, 277-296 Cannabis can impact the brain-gut axis to alter gut function

 Through actions in the enteric nervous system  By altering pain transmission  Possibly by altering gut barrier function  Through the control of immune activation  Possibly through actions on the gut microbiota Medicinal cannabis and GI disorders

 GI motility disorders  Inflammatory Bowel Disease  GI Pain  Disorders of reduced appetite, such as cancer and HIV/AIDS  Emesis

The use of medicinal cannabis for the treatment of these conditions “makes sense”, based on the physiology of the endocannabinoid system. Cannabis and cannabidiol in GI and liver disease Inflammatory Bowel Disease

 21 patients (40 ± 14; 13 men) with moderate to severe Crohn’s disease)  Not cannabis smokers  Smoked cannabis 2x daily – 23% THC, 0.5% CBD, 0.5g/joint = 115mg THC  Complete remission (CDAI of <150) in 5/11 vs 1/10 THC vs placebo - NS

Naftali et al. Clin. Gastroenterol. Hepatol. 2013;11:1276-1280 Inflammatory Bowel Disease

 Clinical response (CDAI drop of >100 pts) in 10/11 vs 4/10 THC vs placebo – p<0.05  No significant change in CRP  Reduced pain, better appetite and better sleep  No significant side effects  No lasting clinical improvement  NB - No endoscopic assessment

Naftali et al. Clin. Gastroenterol. Hepatol. 2013;11:1276-1280 Inflammatory Bowel Disease

 28 patients (33 yr; 17 men) with moderate to severe ulcerative colitis)  Smoked cannabis 2x daily – 23% THC, 0.5% CBD, 0.5g/joint = 115mg THC  DAI 10±3 to 4±3.2 and from 10±2.7 to 8±2 (p<0.01)  Mayo endoscopic score median of 2 (IQR2-2.5) to 1 (IQR 0-2) (p=0.01) and from 2 (IQR2-2) to 2 (IQR 1.25-2) (p=0.059) in the THC and placebo groups, respectively.

Naftali et al. DDW Abstract 2018 Sa 1744 IBD – Clinical data

Kafil et al., Cochrane Database Syst Rev. 2018 Nov 8;11:CD012853 and CD012954. Systematic review - conclusions

 Evidence from observational Thestudies effects suggests of that cannabis and cannabis oil on patients use cannabis to alleviateCrohn’s symptoms disease of IBD. (CD) A / ulcerative colitis very limited(UC) number are uncertain. of small Thus no firm clinical studies with patients havingconclusions IBD reported regarding the efficacy and safetyimprovement of cannabis in a number and of cannabis oil in adults IBD-associatedwith active symptoms CD/ UC can be drawn. with smoked cannabis.

Kafil et al., Cochrane Database Syst Rev. 2018 Nov 8;11:CD012853 and CD012954. Inflammatory Bowel Disease

 Nationwide inpatient survey (USA), using ICD-9 codes from 2002-2014.  3.3 million patients with IBD. 0.9% had cannabis use disorder/dependence. ◦ Cannabis users increased from 0.3% to 1.8% over time (>CD vs UC) ◦ Mortality: 1.4% non-users, 0.3% users ◦ Colectomy: 6.7% non-users, 2.8% users ◦ Blood transfusions: 9.6% non-users, 4.5% users ◦ Hospital stay: 5.6 days non-users, 5.2 days users

Elkafrawy et al. DDW Abstract 2019 Sa1800 CBD in Inflammatory Bowel Disease

 19 patients (11 men, 18- 75yr) with moderate to severe Crohn’s disease  Oral CBD oil, 20mg/day in two doses sublingually for 8 weeks  No adverse effects  No benefits

Naftali et al. Dig Dis Sci 2017;62:1615-1620. CBD and Intestinal Permeability

 10 healthy male (18-50yr) controls/group  Oral CBD, 600mg ± 600 mg aspirin, as a single dose 1h before sugar test.  No adverse effects reported

Couch et al. Infl. Bowel Dis. 2019;25:1006-1018. CBD in Inflammatory Bowel Disease

 Functional chest pain (13 patients) There is currently no evidence to support  theDronabinol use of5mg CBD bid, for 4 weeks the treatment of IBD.  increased pain thresholds significantly In(3.0 low vs. doses 1.0; P it= appears0.03) and reducednot to painbe harmful intensity in and odynophagia IBDcompared patients. to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04). In higher doses acutely (in healthy controls)  No adverse effects it may reduce intestinal permeability. GI motility Disorders

 Experimental clinical studies with healthy volunteers reported dose- and sex-dependent (> effects in females) effects on various measures of GI motility.  LimitedThere’s evidence currently from one small nostudy evidence with dronabinol to for symptoms of IBS suggests dronabinol may increase demonstratecolonic compliance any and benefit decrease ofcolonic cannabis motility indexin IBS inor female any IBSother-D/A GIpatients, sensory/motor while another small disorderstudy with dronabinol suggests a lack of effect on gastric, small bowel or colonic transit. Recreational cannabis and bowel function – paradoxical effects!

 NHANES (USA) from 2005-2010. Drug use, bowel function questionnaires.  9,645 respondents - Cannabis users 12% ◦ Constipation: 10.2% non-users, 7.5% users (P=0.03) ◦ Diarrhea: 6.9% non-users, 6.5% users ◦ ~30% reduction in OR for constipation adjusted for age, sex, BMI, education, SES, tobacco use, alcohol use, and other factors.

Adejumo et al. DDW Abstract 2019 26 Cannabidiol attenuates alcohol- induced liver steatosis, metabolic dysregulation, inflammation and injury disease

Wang et al., Scientific Rep 2017, 7, 12064 Cannabis and Liver Disease

Pooled OR with 95% confidence intervals for prevalence of fibrosis in the setting of marijuana use in NAFLDHCV was was 1.96 0.80 (0.78 (0.75–4.92)–0.85)

Goyal et al., Eur J Gastroenterol Hepatol 2018, 30, 1283-1290 Hepatocellular carcinoma

 Nationwide inpatient survey (USA), using ICD-9 codes from 2002-2014.  Cannabis users had an odds ratio of 0.58 (CI 0.54- 0.63) for having hepatocellular carcinoma. ◦ Age difference? Average age of users 34 vs 48 for non-users ◦ Race? African-Americans – users 30%, non-users 14% ◦ Smoking, Hep B, Hep C, cirrhosis – all > in users, obesity and gallstones < in users?

Khoudari et al. DDW Abstract 2019 Mo1502 Potential harms of cannabis Potential harms of cannabis

Pattern and age of consumption increase harms

 Early onset use (before age of ~16/17)

 Heavy use (daily or more frequent)

 Chronic use –use over long periods of time Potential harms of cannabis

 Consumption in pregnancy (~2-5%, but likely more)  Addiction (~8-10%, but doubles with early onset)  Cannabis use disorder is associated with 2x odds of having IBS *  Mental health concerns (family history, heavy use)  Driving when impaired  Respiratory (if smoked or vaped)  Cognitive dysfunction (likely transient, increased in youth and with heavy use)

* Adejumo et al., Eur J Gastroenterol Hepatol 2019, In press Potential harms of cannabis

 Cannabis hyperemesis syndrome  Overdose – particularly when eaten, due to delayed onset and psychoactive of actions  Deaths (of the consumer and of bystanders) have been reported from the consumption of edible cannabis products. Cannabis hyperemesis syndrome Cyclic vomiting syndrome associated with heavy consumption of cannabis, first reported in 2004.  Typically seen in younger adults with normal bowel habits  No radiological abnormalities

Consists of three phases:  Early morning prodromal phase of nausea, anorexia and diffuse abdominal pain  Emetic phase of nausea and cyclic vomiting accompanied by abdominal pain  Recovery of all symptoms Cannabis hyperemesis syndrome

Paradoxical syndrome whose pathogenesis remains to be determined.

 Downregulation of CB1 receptors in the brainstem emetic centres.  Disorder of the HPA axis and sympathetic nervous system caused by disrupted endocannabinoid regulation leading to abnormal processing in stressful signals in genetically predisposed individuals. Cannabis hyperemesis syndrome

 Relieved by hot showers or baths  Relieved by capsaicin cream applied to abdomen and back of arms  Traditional anti-emetics are usually ineffective  Haloperidol and benzodiazepines have been reported to relieve acute symptoms. Cessation / substantial reduction of cannabis use is recommended

Lapoint et al., Western J Emerg Med 2018, 19, 380-386 Cannabis hyperemesis syndrome

 State inpatient data from Colorado and Washington, ICD- 9/10 codes.  Significantly increased rates of hospitalization for hyperemesis (0.26% before to 0.31% in CO, 0.39% WA)  Higher odds of presenting with hyperemesis: 4.2 in CO, 3.3 in WA when adjusted for cannabis use after legalization.  Female, African-American racial group and cannabis users were all associated with higher admissions for hyperemesis.

Nemer et al. DDW Abstract 2019 1001 Cannabis in GI and Liver Disease

 The endocannabinoid system is important for the physiological regulation of the gut.

 Currently there is very little evidence to support the use of cannabis/cannabinoids in GI and liver disease, but there are suggestions that it may offer relief for certain GI symptoms and may improve quality of life for some patients with IBD.

 Cannabis does not seem to worsen fibrotic liver diseases and may improve NAFLD (possibly by reducing the degree of obesity and/or systemic inflammation). Cannabis in GI and Liver Disease

 Cannabis and cannabinoids (including cannabidiol) have been extensively used and appear to be relatively harmless in low – moderate amounts.

 Heavy cannabis use may be associated with more severe GI disease.

 Chronic cannabis use is associated with cannabis hyperemesis syndrome in susceptible individuals and possibly with a greater risk of surgery in IBD patients. Audience engagement

 What is your experience with medical cannabis?

 What patients do you feel would benefit from a medical marijuana prescription?

 What is the process to be authorized to prescribe medical cannabis?

 Who should not get medical cannabis?