Smoke, dust or ashes? Therapeutic use of medical marijuana in IBD management
Peter L. Lakatos
McGill University Health Center, Department of Gastroenterology, Montreal, Canada Semmelweis University, First Department of Medicine, Budapest, Hungary
Conflict of interest:
NON-USER
Cannabis
Objectives
• Review the „basic” data on cannabinoids • Mechanism of ac:on • An:-‐inflammatory effect
• Data on clinical use of cannabinoids in IBD • THC or CBD • Symptom or an:-‐inflammatory effect • Side effects
~ 50 cita:ons in pubmed by Oct 6, 2018
Cannabis is a complex mixture of potential active compounds
Cannabinoids: discovered in the 40s
Defined by Mechoulam and Gaoni 1967:
A group of C21 compounds typical of
and present in Cannabis spp.
Endocannabinoid-‐ endogenous substances
Tuning of key biological processes:
Memory, movement, appeIte, pain
Phytocannabinoids – Cannabis plant-‐
Over 120 reported
A wide variety of biological effects-‐
mimicking endocannabinoids
Hanus LO, Natural Product Reports 2016,
Endocannabinoid system
• Endocannabinoids: • anandamide • 2-‐arachidonoyl glycerol (2-‐AG)
• Endocannabinoid Synthesis: • DAGL: diacylglycerol lipase • NAPE:N-‐acyl phosphaIdylethanolamine
• Cannabinoid receptors: • CB1 CB2 TRPV1, GPR55
• Cannabinoid degrada:on: • faYy acid amide hydrolase (FAAH) • monoacylglycerol lipase (MAGL)
Hillard C . Neuropsychopharmacol rev, 2018
CB1 & CB2 are widely distributed in the GI tract
Gastroenterol Hepatol, 2016
Pain control AppeIte Nausea VomiIng
CB1
CB2
Decrease LES relaxaIon Delayed gastric emptying Reduced acid secreIon
Improved epithelial wound healing Decreased intesInal permeability
Decrease intesInal moIlity Decreased gut secreIons
InhibiIon of cytokine producIon InducIon of apoptosis T cell inhibiIon
Cannabinoid system in normal human colon
Plos One, 2009
Cannabinoids anti inflammatory effect Therapeu:c targe:ng of the ECS in murine coli:s
KL Leinwand., Inflamm Bowel Dis 2017 TurcoYe C., J Leukoc Biol 2015
Phytocannabinoids are synthesized in the plant as acids and can undergo decarboxylaIon by heat (proacIvely or by smoking)
Different cannabis strains vary in chemical composiIon depending on parameters such as: geneIcs, growth condiIons (nutriIon, humidity, light), harvest Ime, storage, extracIon
method
HepaIc Vs. extrahepaIc metabolism of cannabinoids results in different pharmacologically acIve metabolites (HuesIs M.A., Chem Biodivers. 2007)
Diverse strains and routes of administration determine activity
Cannabis in IBD, „meta”analysis of basic and clinical studies
Couch DG et al Inflamm Bowel Dis 2018
• N=51 publica:ons • heterogeneity in
• design, compound, dose
Cannabis in IBD, „meta”analysis of basic and clinical studies
Couch DG et al Inflamm Bowel Dis 2018
Cannabis in IBD, uncontrolled observations
Hasenoehrl C Expert Rev Gastroenteorl Hepatol 2017
Cannabis in IBD, „meta”analysis of basic and clinical studies
Couch DG et al Inflamm Bowel Dis 2018
Cannabis in CD ClinicalTrials.gov: NCT01037322
• Moderate/severe ac:ve CD (n=21)
• 8 weeks + 2 weeks “wash out”
• Moderate/severe acIve CD (n=20)
• Oral CBD vs placebo, 10mgX2/day
• 8 weeks
• Comparable CDAI Study before Study aier Placebo before Placebo aier
Naiali T et al Dig Dis Sci 2017
Prospec:ve, double-‐blind placebo-‐controlled studies
CDAI
Before A[er CDAI: CBD 337 ± 108 220 ± 122
placebo 308 ± 96 216 ± 121
Cannabis in CD
• Moderately ac:ve CD
• THC-‐rich cannabis Vs THC-‐extracted (placebo), 2 CigareYes of Cannabis (=230mg THC)/day*
• Complete remission-‐5/11 (45%) vs. 1/10 (10%)
• 3 steroid dependent paIents could taper steroids
*supplied by “Tikun Olam”
A prospec:ve, double-‐blind placebo-‐controlled study
Naiali T et al. Clin Gastroenterol Hepatol 2013
ClinicalTrials.gov: NCT01040910
Monitoring long term safety
Naiali T et al. Personal communicaIon
13
62
13
33
10 8
80
34
100 79
103 104
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120
Irritated eyes Dry mouth Dizziness Memory decline
Confusion Restlessness
Yes No
• Extract safety data from Registered cannabis users (Meir Data base, n=127)
• Effect of long term (>2mos) use on paIents funcIon and wellbeing
• Monitor effect on disease acIvity
Cannabis in UC
• Moderately ac:ve UC (4<Mayo<10, endoscopic subscore >1)
• CBD-‐rich cannabis extract vs placebo (n=75)
• Endpoint: clinical remission
Irving et al Inflamm Bowel Dis 2018
A prospec:ve, double-‐blind placebo-‐controlled, parallel group study
Cannabis in UC
Irving et al Inflamm Bowel Dis 2018
A prospec:ve, double-‐blind placebo-‐controlled, parallel group study
• Remission at 10 weeks was 28% in CBD, 26% in placebo group*
*Mayo <3, no subscore >1
Mayo score „Total impression” IBDQ score
Cannabis in UC
Irving et al Inflamm Bowel Dis 2018
BUT……
CBD and THC in CD 46 CD pa:ents (62% males), RCT cannabis oil with 15% Cannabidiol (CBD) and 4% tetrahydrocannabinol (THC) or placebo for 8 weeks
Bar Lev Schlieder L UEG 2018, OP 196
Cannabis treatment in Crohn's disease could be considered for temporary symptom relief. The poten:al an:-‐inflammatory proper:es of Cannabis treatment in IBD/Crohn's disease requires further inves:ga:on.
Disclosure: , Bar-‐Lev Schlieder Lihi is an employee of Tikun Olam , a supplier of medical cannabis,
0
50
100
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250
300
350
CDAI control CDAI CDB/THC FCAL control FCAL CBD/THC before aier
0
2
4
6
8
10
12
CRP control CRP CDB/THC SES-‐CD control SES-‐CD CBD/THC before aier
Remission rate (CDAI < 150): 65% vs 35%, p< 0.05
Cannabis in UC OP196 - CANNABIS INDUCES CLINICAL RESPONSE BUT NO ENDOSCOPIC RESPONSE IN CROHN´S DISEASE PATIENTS Naftali T, Bar-Lev Schlieder L, Konikoff F, Benjaminov F, Lish I, Sergeev I, Ringel Y. Introduction: Many patients with Crohn's disease (CD) report that the use of medical cannabis improves their symptoms, however studies evaluating objective disease parameters including inflammatory markers and endoscopic score are lacking. Aims and Methods: To assess the effect of cannabis treatment on Crohn´s disease patients. Methods: In a double blind, randomized, placebo-controlled trial on CD patients with active disease Patients were randomized to receive either cannabis oil with 15%Cannabidiol (CBD) and 4%tetrahydrocannabinol (THC) or placebo for eight weeks. All other medications remained unchanged. Disease-related outcome measures including Crohn´s disease activity index (CDAI), C-reactive protein (CRP), fecal calprotectin, simple endoscopic score for Crohn’s disease (SES-CD) and SF-36 quality of life (QOL) were assessed before, during and after treatment. Results: A total of 46 patients, 31 males (62%), mean age 35±12, were investigated. Each study group included 23 patients. CDAI before the treatment was 288.4±78.0 and 298.5±112.2 (p=0.71), after eight weeks of treatment the CDAI was143.1±96.0 and 209.5±113.0 in the cannabis and placebo groups, respectively (p< 0.05). Remission rate (defined as CDAI < 150) was achieved in 65% of the cannabis group and 35% of the placebo group (p< 0.05). Median quality of life score after 8 weeks was 90.1(IQR 83-102) in the cannabis group and 76 (IQR 68-92) in the placebo group (p< 0.05). CRP before treatment was 3.1±4.4mg/dl and 3.6±5.4mg/dl (p=0.62), after treatment it was 2.4±8mg/dl and 4.1±8.8mg/dl in the cannabis and placebo groups, respectively (p=0.40). Calprotectin before treatment was 182±133 and 122±91 (p=0.37), after treatment it was 170±115.6 and 137±115 (p=0.76) in the cannabis and placebo groups, respectively. SES-CD was 9.5±6.511.9±6 (p=0.93) before treatment and 7.17±6 and 9.8±5.4 (p=0.17) after treatment in the cannabis and placebo groups, respectively. Conclusion: Eight weeks of CBD rich Cannabis treatment induced significant clinical improvement but no change in inflammatory parameters or endoscopic score. Cannabis treatment in Crohn's disease could be considered for temporary symptom relief. The potential anti-inflammatory properties of Cannabis treatment in IBD/Crohn's disease requires further investigation. Disclosure: Bar-Lev Schlieder Lihi is an employee of Tikun Olam, a supplier of medical cannabis.
Cannabis in UC: side effects
Irving et al Inflamm Bowel Dis 2018
…and the reality before legalization in Canada • US: 292 (94% response rate)
• 12.3% acIve marijuana users
• 39.0% past users
• 48.6% never users
• 16.4% of current or past users felt that marijuana
was “very helpful” for relief of abdominal pain,
nausea, and diarrhea.
• Age and chronic abdominal pain were associated
with current marijuana use
• OR: 0.93; 95%CI: 0.89–0.97; P < 0.001
• OR: 3.5; 95% CI: 1.24-‐9.82; P = 0.02
Allegres JR et al Inflamm Bowel Dis 2013
…and the reality before legalization in Canada
• CAN: 291 (Toronto)
• CD/UC: 12/16% acIve marijuana users
• 51/48% ever users
• 33/50% of ever users felt that marijuana was “very
helpful” for relief of abdominal pain, appeIte and
diarrhea.
• Surgery, analgesic use, CAM use and lower sIBDQ
were associated with current marijuana use
Lal S et al Eur J Gastroenteorl Hepatol 2011 Storr M et al Inflamm Bowel Dis 2014
• CAN: 313 (Calgary)
• 17.6% acIve marijuana users
• marijuana improved abdominal pain (83.9%),
abdominal cramping (76.8%), joint pain (48.2%),
and diarrhea (28.6%)
• Cannabis use > 6 months at any Ime for IBD
symptoms was a strong predictor for surgery in CD
• OR: 5.03, 95% CI: 1.45-‐17.46
…current medical therapy in an IBD center from Canada
Restellini S et al UEG 2018
5-‐ASA Steroid Immunomodulators
an:-‐TNF other
biological therapy
clinical trial
narco:cs anxyoli:c/
an:-‐depressant
Maximal treatment steps 16.8 15.1 15.6 41.1 7.7 0.8
Current strategy in CD 21.3 18.7 25.9 43.2 8.6 0.8 6.9 19.5
Current strategy in UC 70.8 10.8 14.5 21.3 4.9 0.6 1.3 12.8
16.8 15.1 15.6
41.1
7.7
0.8
21.3 18.7 25.9
43.2
8.6 0.8 6.9
19.5
70.8
10.8 14.5
21.3
4.9 0.6 1.3
12.8
0
10
20
30
40
50
60
70
80
Steroid dependent
6.6%
Biological therapy CD 51.8% UC 26.2%
Narco:cs/anxyoli:cs*
• Montreal, MUHC
• Quality of Care cohort
• N=1357
• CD/UC 874/483
*Marijuana use could not be captured reliably
Cannabis Get used to using it…?
Policy principles of cannabis for medical use
Over 30,000 licenses for medical cannabis in Israel
~half for non-‐oncological reasons
Personal communica:on by I Dotan
The chain of medical cannabis in Israel
PaIent training kits for use of Cannabis for medical purposes
Research and development to create smoking alternaIves
Feasibility of Export
Supervision – complying with security standards IMC-‐GSP for security
Availability of Standardized Cannabis Medicinal products in the pharmacies
DistribuIon to pharmacies IMC-‐GDP grade
Manufacturers that will produce generic and uniform Medicinal Cannabis products IMC-‐GMP grade
CulIvaIon farm for Medical Cannabis IMC-‐GAP grade
Personal communica:on by I Dotan
Summary
• Basic science evidence on cannabinoids support an: inflammatory and pain control effect
• A significant propor:on of IBD pa:ents use(d) cannabinoids
• Current evidence from clinical trials is mainly nega:ve
• There is a need for high quality RCTs • THC versus CBD • Mode of delivery • Length of study • Endpoints • Safety
• CBD/THC can help to decrease opioid/major analgesic use
