Keith  Sharkey  and  Remo  Panaccione  Departments  of  Physiology  &  Pharmacology    

and  Medicine  University  of  Calgary  

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

Dr. Keith Sharkey

Consultant:  Arena  Pharmaceu,cals,  San  Diego,  USA;  LaSanta  Botanicals  Ltd.;  

Takeda  Pharmaceu,cals,  Boston,  USA.  

Research  grants:  Ironwood  Pharmaceu,cals,  Boston,  USA;  Lallemand  Health  

Solu,ons,  Montreal  Canada;  MedImmune  Inc,  Washington  DC,  USA;  NovoNordisk,  

Copenhagen,  Denmark;  Takeda,  Boston,  USA.  

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

Dr. Keith Sharkey

Member,  Health  Canada  Expert  Advisory  CommiKee  on  Informa,on  for  Physicians  on  Marihuana  for  Medical  Purposes.  

Member,  Expert  Advisory  Group  on  Cannabis,  Canadian  Centre  on  Substance  Abuse.  

Conflict of Interest Disclosures

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

hKp://movesmart.org/author/joy-­‐nalywalko/  

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

Next  Year  

hKp://www.herbmuseum.ca/files/images/Lloyd%20Brothers%20Specific%20Medicine%20Cannabis%20An,depressant%20Label%202.jpg/  

hKp://metro.co.uk/2016/03/07/7-­‐really-­‐surprising-­‐health-­‐benefits-­‐from-­‐smoking-­‐cannabis-­‐5738619/  

The  range  of  ac,on  of  this  remedy,  although  classed  as  mild,  is  quite  wide.    It  especially  controls  gastric  pain……      In  func,onal  disorders  of  the  stomach,  with  pain,  given  in  

conjunc,on  with  directly  indicated  remedies,  it  is  of  much  value.      

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?

2017 2001 1999

395 pages, ½ page on IBS,

2016

72 pages, 1 sentence with “gastrointestinal”

Oct 2018

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

https://hightimes.com/grow/beginners-how-to-grow-just-one-pot-plant-in-your-home/

https://www.leafly.com/start-exploring

Tetrahydrocannabinol (THC)

Phytocannabinoids •  THC (Tetrahydrocannabinol) •  THCA (Tetrahydrocannabinolic acid) •  CBD (Cannabidiol) •  CBDA (Cannabidiolic Acid) •  CBN (Cannabinol) •  CBG (Cannabigerol) •  CBC (Cannabichromene) •  CBL (Cannabicyclol) •  CBV (Cannabivarin) •  THCV (Tetrahydrocannabivarin) •  CBDV (Cannabidivarin) •  CBCV (Cannabichromevarin) •  CBGV (Cannabigerovarin) •  etc., etc.

Cannabidiol (CBD)

1964 – Δ9-THC isolated (Cannabis sativa) 1988 – High-affinity cannabinoid binding

sites discovered in rat brain

1992 – First endogenous cannabinoid discovered Anandamide (AEA)

1995 – Second endogenous cannabinoid discovered 2-Arachidonoyl-glycerol (2-AG)

1993 – CB2 receptor cloned

1994 – First CB1 receptor blocker characterized (Rimonabant)

The ECS modulates energy balance and metabolism, liver and gut

function and neurotransmission 21st Century

1990 –CB1 receptor cloned

E

L L M N H OH

O

O O

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)

Cannabidiol (CBD)

CB1 / CB2 receptor partial agonist

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

Synthetic cannabinoids – “spice”

HU-210

JWH-018

JWH-073 CP 55,940

WIN 55,212-2

Mukhopadhyay et al. Chem Phys Lipids 121, 91-109 (2002)

CB1 receptor

CB1/2 Ligand      (THC,  anandamide)  

- +

-

Adenylate cyclase

[cAMP]

K+ channels opened

Ca2+ entry blocked

Decreased  release  of  neurotransmiFers  or  mediators,  reduced  cell  firing  or  transmission  of  impulses  

Presynap,c  nerve    terminal,  immune  cell    

Gi/o

CB1/2

- +

-

Adenylate cyclase

[cAMP]

K+ channels opened

Ca2+ entry blocked

Gi/o

Mikkel Søes Ibsen et al. Cannabis Cannabinoid Res. 2, 48–60 (2017)

Sharkey and Wiley, Gastroenterology 151, 252-266 (2016)

AEA - Anandamide

2-AG – 2-arachidonoylglycerol

FAAH – Fatty acid amide hydrolase

 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)

Longitudinal muscle!Myenteric plexus!

Circular muscle!

Submucosa /!Submucosal plexus!

Mucosa!

Brainstem" Spinal cord!

Dorsal root!ganglion!

Nodose!ganglion!

Bacteria!CB1 receptor!Epithelium!Enteroendocrine cells!Blood vessels!

Immune cells!

VAGUS  

  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 endocannabinoid system.

  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/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

 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

Naftali et al. DDW Abstract 2018 Sa 1744

  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.

  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.

Cannabis may reduce symptoms associated with IBD, but there is little evidence to

support an anti-inflammatory role outside of animal models, and there is no evidence that it positively alters the disease course.

  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 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.

Cannabis reduces symptoms associated with IBD, but there are indications that smoked cannabis may be detrimental in

Crohn’s disease.

  Pre-clinical studies in animal models of irritable bowel syndrome (IBS) suggest that synthetic cannabinoid receptor 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 females) effects on various measures of GI motility.

  Limited evidence from one small study with dronabinol for symptoms of IBS suggests dronabinol may increase colonic compliance and decrease colonic motility index in female IBS-D/A patients, while another small study with dronabinol suggests a lack of effect on gastric, small bowel or colonic transit.

There is insufficient evidence to support or refute any benefit of dronabinol in IBS

and currently no evidence to demonstrate any benefit of cannabis in IBS or any other

GI sensory/motor disorder

  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  Dronabinol increased pain thresholds significantly

(3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04).

 No adverse effects

Malik et al. Dis. Esophagus 2017;30:1-8

There is some evidence to support a benefit of dronabinol for GI pain

and currently no evidence to demonstrate any benefit of cannabis for GI pain

 Orally active cannabinoids (nabilone 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.

Naftali et al. Dig Dis Sci 2017;62:1615-1620.

  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

Irving et al. Inflamm Bowel Dis 2018;24:714-724.

  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.

  Functional chest pain (13 patients)

 Dronabinol 5mg bid, 4 weeks  Dronabinol increased pain thresholds significantly

(3.0 vs. 1.0; P = 0.03) and reduced pain intensity and odynophagia compared to placebo (0.18 vs. 0.01 and 0.12 vs. 0.01, respectively, P = 0.04).

 No adverse effects

There is no evidence to support the use of CBD for the treatment of IBD, though in low doses it appears not to be harmful.

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

Cannabis in low to moderate amounts appears mostly safe and well tolerated.

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