and the GI tract: Arming clinicians with evidence to speak to their paents

Keith Sharkey and Remo Panaccione Departments of Physiology & Pharmacology and Medicine University of Calgary Dr. Keith Sharkey

Conflict of Interest Disclosures - Financial (over the past 24 months)

Consultant: Arena Pharmaceucals, San Diego, USA; LaSanta Botanicals Ltd.; Takeda Pharmaceucals, Boston, USA.

Research grants: Ironwood Pharmaceucals, Boston, USA; Lallemand Health Soluons, Montreal Canada; MedImmune Inc, Washington DC, USA; NovoNordisk, Copenhagen, Denmark; Takeda, Boston, USA. Dr. Keith Sharkey

Conflict of Interest Disclosures

Member, Health Canada Expert Advisory Commiee on Informaon for Physicians on Marihuana for Medical Purposes.

Member, Expert Advisory Group on , Canadian Centre on Substance Abuse. hps://www.youtube.com/watch?v=ME-H44861cY hps://www.youtube.com/watch?v=ME-H44861cY

Next Year hp://metro.co.uk/2016/03/07/7-really-surprising-health-benefits- from-smoking-cannabis-5738619/

hp://movesmart.org/author/joy-nalywalko/ The range of acon of this remedy, although classed as mild, is quite wide. It especially controls gastric pain…… In funconal disorders of the stomach, with pain, given in conjuncon with directly indicated remedies, it is of much value.

hp://metro.co.uk/2016/03/07/7-really-surprising-health-benefits- from-smoking-cannabis-5738619/ hp://www.herbmuseum.ca/files/images/Lloyd%20Brothers%20Specific%20Medicine %20Cannabis%20Andepressant%20Label%202.jpg/ Cannabis and its derivatives have been used (legally or illegally) for the treatment of:  GI motility disorders (functional GI disorders, IBS)  Inflammatory Bowel Disease  GI Pain  Disorders of reduced appetite, such as cancer and HIV/AIDS  Emesis  Review the effects of cannabinoids and THC on the gastrointestinal tract

 Overview of the basic science evidence

 What can be translated into humans?  Does cannabis given medicinally do any good? Is cannabis an effective therapeutic for inflammatory bowel disorders?

 Does recreational cannabis do any harm, especially to patients with IBD? 395 pages, ½ page on IBS,

2017 2001 1999 72 pages, 1 sentence with “gastrointestinal”

2016 259 pages, with an extensive section on the gastrointestinal system discussing preclinical and clinical evidence for every major condition, including IBD.

Oct 2018 https://hightimes.com/grow/beginners-how-to-grow-just-one-pot-plant-in- https://www.leafly.com/start-exploring your-home/ Phytocannabinoids • THC (Tetrahydrocannabinol) (THC) • THCA (Tetrahydrocannabinolic acid) • CBD () • CBDA (Cannabidiolic Acid) • CBN () • CBG () • CBC () • CBL () Cannabidiol (CBD) • CBV () • THCV () • CBDV () • CBCV () • CBGV (Cannabigerovarin) • etc., etc. 1964 – Δ9-THC isolated () 1988 – High-affinity binding sites discovered in rat brain 1990 –CB receptor cloned O 1 1992 – First N OH M L endogenous H cannabinoid discovered (AEA) E 1993 – CB receptor cloned 2 O 1995 – Second O 1994 – First CB1 receptor blocker endogenous characterized () cannabinoid 2-Arachidonoyl-glycerol (2-AG) discovered

st The ECS modulates energy balance 21 Century and metabolism, liver and gut function and neurotransmission 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. Tetrahydrocannabinol (THC)

CB1 / CB2 receptor partial agonist

Cannabidiol (CBD)

Inhibitor of cytochrome P450, CYP3A and CYP2C Fatty acid amide hydrolase inhibitor

Negative allosteric modulator of CB1 / CB2 receptors 5-HT1A partial agonist Endocannabinoids

N-arachidonoylethanolamide (anandamide) 2-arachidonoylglycerol – “spice” JWH-018

HU-210

JWH-073 CP 55,940

WIN 55,212-2 CB1 receptor

Mukhopadhyay et al. Chem Phys Lipids 121, 91-109 (2002) Ligand (THC, anandamide) CB1/2 Gi/o - + Presynapc nerve terminal, immune cell Ca2+ entry - + blocked K channels opened Adenylate cyclase

[cAMP]

Decreased release of neurotransmiers or mediators, reduced cell firing or transmission of impulses CB1/2 Gi/o - +

Ca2+ entry - + blocked K channels opened Adenylate cyclase

[cAMP]

Mikkel Søes Ibsen et al. Cannabis Cannabinoid Res. 2, 48–60 (2017) 2-AG – 2-arachidonoylglycerol AEA - Anandamide

FAAH – Fatty acid amide hydrolase

Sharkey and Wiley, Gastroenterology 151, 252-266 (2016)  Cannabinoid receptors –CB1 and CB2  Endogenous ligands – novel lipid mediators  Specific mechanisms of biosynthesis and degradation  Produced ”on demand”  Unique mechanism of action Sharkey and Pittman, Science STKE 277, pe15 (2005)

Brainstem Spinal cord!

Dorsal root! ganglion!

Nodose! ganglion!

VAGUS Longitudinal muscle! Myenteric plexus!

Circular muscle!

Submucosa /! Submucosal plexus! Immune cells!

Mucosa!

Epithelium! CB1 receptor! Bacteria! Enteroendocrine cells! Blood vessels!  Controls gut function locally – particularly through the enteric nervous system  Controls motility by regulating transmitter release (acetylcholine) in the myenteric plexus  Controls pain transmission  Controls gut barrier function  Regulates immune activation  Cannabinoids may regulate the gut microbiota (in a diet-dependent manner)  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 .  Pre-clinical studies in animal models of inflammatory bowel disease (IBD) suggest that cannabinoids (synthetic CB1 and CB2 receptor agonists, THC, and other) may limit intestinal inflammation and disease severity.

Storr et al. Inflamm. Bowel Dis. 2009;15:1678-1685  Evidence from observational studies suggests that patients use cannabis to alleviate symptoms of IBD.  A very limited number of small clinical studies with patients having IBD reported improvement in a number of IBD-associated symptoms with smoked cannabis.  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/ = 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  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  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  Evidence from observational studies suggests that Cannabispatients use maycannabis reduce to symptoms associated alleviate symptoms of IBD. A verywith limited IBD, number but of there small is little evidence to clinicalsupport studies an with anti-inflammatory patients role outside ofhaving animal IBD reported models, and there is no evidence improvement in a number of IBD-associatedthat it positively symptoms alters the disease course. with smoked cannabis.  Prospective cohort survey study of 292 IBD patients  Cannabis users (~12% current, 39% past) reported using it for relief of symptoms associated with IBD  Abdominal pain (90%), nausea and poor appetite (73% each), and diarrhea (42%).  Most cannabis-using patients also reported cannabis as being “very helpful” or “completely relieving” in treating the symptoms of IBD.

Ravikoff Allegretti et al. Inflamm. Bowel Dis. 2013;19:2809-2814  Survey study of 319 IBD patients  Cannabis users (56 current or past) reported using it for relief of symptoms associated with IBD  Most cannabis-using patients also reported cannabis as being “helpful”  Prolonged cannabis use (>6 months) was associated with 5x odds ratio of surgery Storr et al. Inflamm. Bowel Dis. 2014;20:472-480  Evidence from observational studies suggests that patients use cannabis to alleviateCannabis symptoms reduces of IBD. symptomsA associated verywith limited IBD, number but ofthere small are indications that clinical studies with patients havingsmoked IBD reported cannabis may be detrimental in improvement in a Crohn’snumber of disease. IBD-associated symptoms with smoked cannabis.  Pre-clinical studies in animal models of irritable bowel syndrome (IBS) suggest that synthetic agonists inhibit colorectal distension-induced pain responses and slow accelerated GI transit.

Kimball et al. Front Pharmacol. 2010;1:132  Experimental clinical studies with healthy volunteers reported dose- and sex-dependent (> effects in Therefemales) is effectsinsufficient on various evidence measures of to GI support motility. or  Limitedrefute evidence any benefit from one ofsmall study with dronabinol in IBS for symptoms of IBS suggests dronabinol may increase andcolonic currently compliance no and evidence decrease colonic to demonstrate motility index anyin female benefit IBS-D/A of cannabis patients, while in anotherIBS or small any study other with dronabinolGI sensory/motor suggests a lack of disordereffect on gastric, small bowel or colonic transit.  IBS (12 healthy controls, 10 IBS patients)  Dronabinol 5mg or 10mg given 60min before testing  Sigmoid stimulation consisting of 10 high pressure distensions (60 mmHg) lasting 30 s and separated by 30s intervals of rest (5 mmHg).  No significant effects

Klooker et al. Neurogastroenterol Motil 2011;23:30-35  Functional chest pain (13 patients)  Dronabinol 5mg bid, 4 weeks There is some evidence to support a  Dronabinol increased pain thresholds significantly (3.0 benefitvs. 1.0; P of = 0.03)dronabinol and reduced for GIpain pain intensity andand currentlyodynophagia no compared evidence to placebo to demonstrate (0.18 vs. 0.01any and benefit 0.12 vs. of0.01, cannabis respectively, for PGI = 0.04).pain  No adverse effects

Malik et al. Dis. Esophagus 2017;30:1-8  Orally active cannabinoids ( and dronabinol) are effective anti-emetics and also suppress nausea in the context of cancer treatment.  They are more effective at suppressing nausea than many conventional anti-emetics.  There are no controlled trials of cannabis for nausea and vomiting.  Cannabidiol reduces experimental colitis in animal models  Cannabidiol reduces inflammatory mediators in human explant cultures from IBD patients.

Pagano et al. Front. Pharmacol 2016;7 (341):1-12.  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.  60 patients (44 men, 43 ± 14 yr) with mild to moderate ulcerative colitis  Oral CBD in a “botanic extract” with 3-5% THC), up to 500mg/day for 8 weeks  Huge problems of compliance [35% did not complete the trial; 90% of patients experienced adverse events in the CBD group and 77% in the placebo group

Irving et al. Inflamm Bowel Dis 2018;24:714-724.  No significant improvement in Mayo score  Some secondary endpoints (e.g. IBDQ) showed a trend to improvement  But the amount of THC and other molecules (flavonoids, terpenes, etc.) is such that it is hard to determine what component of the extract might have contributed positively.

Irving et al. Inflamm Bowel Dis 2018;24:714-724.  Functional chest pain (13 patients)  Dronabinol 5mg bid, 4 weeks There Dronabinol is no increased evidence pain to thresholds support significantly the use of CBD(3.0 vs. for 1.0; the P =treatment 0.03) and reduced of IBD, pain though intensity in and odynophagia compared to placebo (0.18 vs. low0.01 anddoses 0.12 it vs. appears 0.01, respectively, not to be P =harmful. 0.04).  No adverse effects Cannabis in low to moderate amounts appears mostly safe and well tolerated.

Cannabis and its derivatives have been associated with:  Cannabis hyperemesis syndrome  Acute pancreatitis (acute episodes of heavy cannabis use).  Cannabis abuse which is associated with more severe GI conditions.*

* Gubatan et al. Dig. Dis Sci. 2016;61:1844-1852 Cyclic vomiting syndrome associated with heavy consumption of cannabis, first reported in 2004.  Relieved by hot showers or baths  Typically seen in younger adults  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 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.  Does cannabis given medicinally do any good? Is cannabis an effective therapeutic for inflammatory bowel disorders?

 Does recreational cannabis do any harm, especially to patients with IBD?  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 disease, but there are suggestions that it may offer relief for certain symptoms and may improve quality of life for some patients with IBD.  Cannabis and cannabinoids have been extensively used and appear to be relatively harmless in low – moderate amounts

 Heavy cannabis use is associated with more severe GI disease

 Chronic cannabis use (smoking) is associated with cannabis hyperemesis syndrome in susceptible individuals and possibly with a greater risk of surgery in IBD patients