Expert Opinion on Pharmacotherapy

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What role do cannabinoids have in modern

medicine as gastrointestinal anti-inflammatory
drugs?

Adrian Szczepaniak & Jakub Fichna

To cite this article: Adrian Szczepaniak & Jakub Fichna (2020): What role do cannabinoids
have in modern medicine as gastrointestinal anti-inflammatory drugs?, Expert Opinion on
Pharmacotherapy, DOI: 10.1080/14656566.2020.1795129

To link to this article: https://doi.org/10.1080/14656566.2020.1795129

Published online: 31 Jul 2020.

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EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2020.1795129
EDITORIAL
What role do cannabinoids have in modern medicine as gastrointestinal
anti-inflammatory drugs?
Adrian Szczepaniak and Jakub Fichna
Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
ARTICLE HISTORY Received 26 April 2020; Accepted 7 July 2020
KEYWORDS Inflammatory bowel disease; endocannabinoid system; cannabinoids; cannabis
1. Introduction
Inflammatory bowel disease (IBD) is a type of relapsing and
remitting disease which is associated with disturbance of
immune cell hemostasis, also in the intestinal mucosa. There
are three main types of IBD: Crohn’s disease (CD), ulcerative
colitis (UC), and unclassified IBD (IBD-U). IBD is becoming an
increasingly common problem because its incidence and
prevalence have increased significantly over the past few
decades. Several methods are currently being used to con­
trol symptoms and improve patients’ quality of life, but
new, more effective treatment options are still being sought
[1].
Cannabis sativa, also known as marijuana, has been cul­
tivated and used forcenturies for recreational and medicinal
purposes. Cannabis plant contains at least 60 cannabinoids
and several other compounds such as terpenoids, flavo­
noids, or alkaloids [2]. The main psychoactive substance in
C. sativa is Δ9-tetrahydrocannabinol (THC) but it also con­
tains pharmacologically relevant cannabidiol (CBD), tetrahy­
drocannabivarin, cannabichromene, and cannabigerol.
Cannabis extracts have been used throughout centuries for
a variety of diseases due to their anti-inflammatory, antie­
metic, antidiarrheal, and analgesic properties. In addition to
plant-derived compounds, there are two other classes of
cannabinoids – synthetic (e.g. WIN55212-2) and endogenous
such as anandamide (AEA) and 2-arachidonoylglycerol
(2-AG) [3]. Overall, cannabinoid-based drugs are used mainly
in chronic diseases where standard treatment does not have
positive effects [4]. Cannabinoids can be administered in
many ways, including oral, sublingual, inhaled, or local.
Cannabinoids affect the cells by interacting with canna­
binoid receptors coupled with G protein (‘classical’ – CB1
and CB2 and ‘non-classical’ – e.g. GPRs and TRPs), which
are part of the endocannabinoid system (ECS). In general,
ECS, apart from receptors, includes their endogenous
ligands as well as enzymes synthesizing (diacylglycerol
lipase, DAGL, and N-acylphosphatidyl ethanolaminopho­
spholipase D, NAPE-PLD) and degrading (fatty acid amide
hydrolase, FAAH, and monoacylglycerol lipase, MAGL) can­
nabinoid ligands.
CONTACT Jakub Fichna jakub.fichna@umed.lodz.pl
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2. Endocannabinoid system in a pre-clinical setting
Maintenance of intestinal homeostasis is possible through ECS.
It is important to note that both centrally- and peripherally
mediated effects are essential to maintain gut in good
health [5].
Studies using animal models of dextran sulfate sodium
(DSS)- or trinitrobenzene sulfonic acid (TNBS)-induced colitis
have shown increased expression of ECS components, namely
CB1, CB2 and AEA, thus suggesting the involvement of canna­
binoid signaling in inflammation [6,7]. In addition, the FAAH
expression, which is responsible for the degradation of AEA, is
lowered in the early stages of colitis [8]. Furthermore, several
studies have observed changes in the expression of ECS ele­
ments in the human inflamed tissue compared to non-
inflamed colons. The data are summarized in Table 1.
Concurrently, it was showed that the activation of canna­
binoid receptors protects against colitis, and inhibition of
degrading enzymes (FAAH or MAGL) relieves inflammation
[5] (Table 2). Moreover, cannabinoids reduce the degree of
visceral sensitivity by activating CB1 and CB2 [11]. In contrast,
a selective CB1 antagonist rimonabant intensifies hyperalgesia
caused by colitis, confirming the involvement of ECS in inflam­
matory hyperalgesia [12].
Research has revealed a strong link between the microbiome
and ECS. Gut microbiota were found to modulate CB1, FAAH, and
MAGL expression in the mouse colon [14]. In addition,
Lactobacillus acidophilus was shown to induce CB2 receptor
expression in the intestinal epithelial cells and rodent intestinal
mucosa [15]. On the other hand, the growth of the Akkermansia
municiphila strain, which has beneficial effects in the mouse
model of colitis, is associated with the action of CB1 antagonists.
Namely, the blockade of CB1 has significantly increased the
relative abundance of these bacteria [16]. Moreover, it has been
shown that AEA stimulates the myeloperoxidase activity in the
intestine, which is a marker of intestinal inflammation and is also
involved in the inflammatory process caused by Clostridium
difficile toxin A [17]. To sum up, since intestinal microbiota has
important metabolic and host-protective functions and plays
a key role in the etiopathogenesis of IBD, its interaction with
cannabinoids could be employed in IBD treatment [18].
Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz 92-215, Poland
2 A. SZCZEPANIAK AND J. FICHNA

Table 1. Expression of ECS and ECS-related elements in human colon in Crohn’s

disease (CD) and ulcerative colitis (UC) compared to non-inflamed tissue [9,10].
ECS elements CD UC a significant improvement in general well-being, ability to
AEA ↓ ↓ work, and pain reduction. They were able to gain weight
CB1 ↑ or - ↑ to a normal body mass index. The only randomized study
CB2 - (PCR) -
or
[21] which assessed the effects of marijuana on CD showed
↑ (immunohistochemistry) induction of clinical remission after 8 weeks of treatment,
FAAH ↑ ↑ which allowed discontinuation of steroid treatment while
NAPE-PLD ↓ ↓
OEA ↑ ↑
using cannabis. However, there were no differences in
PEA - - biochemical parameters, including hemoglobin and CRP
– (no changes in expression), ↑ (increase in expression), ↓ (decrease in levels between cannabis and placebo groups. Importantly,
expression) cannabis has reduced abdominal pain and improved qual­
AEA, anandamide; CB1, cannabinoid receptor type 1; CB2, cannabinoid receptor ity of life. It should be noted that all patients reported
type 2; FAAH, fatty acid amide hydrolase; NAPE-PLD, N-acylphosphatidyl
ethanolaminophospholipase D; OEA, oleoylethanolamide; PEA, deterioration of health within 2 weeks after stopping can­
palmitoylethanolamide nabis use [21].
Many scientists are currently looking for substances among
the ingredients of cannabis that can be used as anti-IBD agents.
Studies have confirmed the importance of CBD as a promising
3. Cannabinoids as anti-inflammatory drugs
drug in the treatment of IBD and preclinical colitis models
Current IBD therapy is based on anti-inflammatory agents, [22,23]. CBD normalizes in vivo induced hypermotility and can
corticosteroids as well as biological agents such as anti-TNF, inhibit FAAH, showing anti-inflammatory effects in the intestine.
vedolizumab, or ustekinumab, which are used in severe forms Moreover, CBD reduces the severity of intestinal inflammation by
of IBD. However, treatment with biological agents may involve controlling the neuroimmune axis [24]. In a randomized placebo-
side effects; moreover, the success rate of IBD therapies ranges controlled study, Naftali et al. [25] evaluated the effect of CBD on
only from 40% to 60%. New, low-toxicity therapeutic options CD. They showed that the administration of CBD was safe, but
are thus being sought to support the pharmacological treat­ had no beneficial effects. The lack of any therapeutic effect in this
ment of IBD and – when combined with conventional anti-IBD case may have resulted from a low dose of CBD or a small
drugs – to increase its effectiveness. number of patients in the study, so further studies are recom­
IBD patients often use cannabis to combat the disease mended [25].
symptoms such as abdominal pain, nausea, diarrhea and to
improve their mood and consequently their quality of life.
Due to legal restrictions, it is difficult to estimate the
4. Side effects of cannabis and cannabinoid use
number of IBD patients who use this therapeutic option, Storr et al. reported that 36% of IBD patients who were
but several studies indicate that between 6.8% and 17.6% afraid of using cannabis were worried about its side effects
of IBD patients actively take cannabis [19]. Similarly, no [26]. Long-term use of cannabis raises concerns about the
reliable data is available to demonstrate the effectiveness development of addiction. Lal et al. showed that almost
of cannabis in IBD. In one of many studies, patients with a third of the patients with IBD reported significant side
CD took cannabis in the form of prepared cigarettes in the effects, from euphoria and increased awareness to dry
dose of 50 g dry processed plant per month. They used mouth, palpitations, anxiety, and memory loss [27]. On
marijuana whenever they felt pain, taking up to three the other hand, Wang et al. reported the occurrence of
inhalations each time from prepared cigarettes to avoid almost 5,000 adverse events as complications, while
psychiatric side effects [20]. Patients reported approximately 97% were not considered as serious [28].

Table 2. The role of cannabinoids in preclinical models of colitis [13].

Cannabinoid Effects
AM841 (CB1 and CB2 agonist) Anti-inflammatory effect, reduction in gastric emptying and intestinal transit
HU210 (nonselective cannabinoid receptor agonist) Amelioration of inflamed colon in colitis, protective effect on the intestinal barrier function
ACEA (CB1 agonist) Attenuation of inflammation in OM and DSS-induced colitis models
WIN 55,212–2 (CB1 agonist) Reduction in diarrhea
AM1241 (CB2 agonist) Reduction in murine colitis
JWH-133 (CB2 agonist) Reduction in murine colitis
O-1966 (CB2 agonist) Increased percentage of T regulatory cells, decrease in pro-inflammatory cytokines
O-1602 Protection against experimentally induced colitis and inhibition of neutrophil recruitment
URB597 (FAAH inhibitor) Significant reduction in macroscopic alterations of the colon
Cannabichromene Reduction of inflammation-induced hypermotility in vivo, altered mRNA expression of TRPA1
Cannabigerol Attenuation of murine colitis, reduction in nitric oxide production in macrophages
Cannabis sativa extract with high content of cannabidiol Reduction in intestinal hypermotility, attenuation of motility in DNBS model of inflammation
Tetrahydrocannabivarin Inhibition of nitrate production in macrophages
THC and cannabinol Attenuation of serum IgE, IL-2, IL-4, IL-5 and IL-13 mRNA level

Concurrently, the safety of cannabis and cannabinoid use
versus the intestines is questionable. For example, for many
years CBD was considered to have anticonvulsant properties,
but due to a lack of sufficient research and reports, it was
not used for this purpose. It is currently estimated that
around one-third of epilepsy patients do not respond well
to commonly used antiepileptic drugs [29]. Recently,
a randomized, controlled, double-blind study was conducted
for the first time to assess the effect of CBD on seizure
control in patients with Lennox-Gastaut syndrome (child­
hood seizure disorder associated with encephalopathy). It
was found that CBD caused a 43.9% reduction in drop
seizures. However, one of the most common complications
was diarrhea and decreased appetite, which occurred in 86%
of patients in the CBD group. In this case, cannabis plant
ingredients can help treat epilepsy, but their long-term use
contributes to gastrointestinal disorders [30].
5. Expert opinion
IBD is becoming a common problem in many countries
around the world. In 2017, there were 6.8 million new
cases of IBD worldwide, and the incidence of IBD increased
significantly in the years 1990–2017, which can be a social
and economic burden in the coming years. Currently,
plant-derived drugs are being developed, which may be
an alternative treatment method or an important element
complementing standard therapy [31].
The ECS is involved in the intestinal inflammatory pro­
cess, therefore, it becomes a potential therapeutic target in
the treatment of IBD. Despite reports confirming the
potential positive effects of components of Cannabis sativa
on IBD, additional studies are required to determine the
mechanisms of action of (endo)cannabinoids in inflamma­
tory diseases. Moreover, extensive clinical trials are needed
to determine the efficacy, doses, best administration meth­
ods and side effects of long-term use of (endo)cannabi­
noids. In reference to the latter, all we know so far is that
short-term cannabis use leads to dizziness or hallucina­
tions, while its long-term use causes mental disorders
and impaired liver and bile duct function [32]. However,
questions like whether the synthetic cannabinoid agonists
are safer than phytocannabinoids or what their off target
side effects remain unanswered. With cost-effectiveness
already better understood for natural ligands, these issues
need to be addressed in the future.
In conclusion, there is a potential in cannabinoid use in
IBD. Currently, the main objective is to create effective
medicinal products based on cannabinoids that do not
cause serious adverse effects.
Declaration of interest
The authors have no other relevant affiliations or financial involve­
ment with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
EXPERT OPINION ON PHARMACOTHERAPY 3
Reviewer disclosures
One referee declares that they act as a consultant for STERO, a company that
develops CBD for clinical use. Peer reviewers on this manuscript have no
other relevant financial relationships or otherwise to disclose.
Funding
The authors are supported by the Medical University of Lodz, Poland (via
grant number #503/1-156-04/503-11-001).
References
1. Nemati S, Teimourian S. An overview of inflammatory bowel disease:
general consideration and genetic screening approach in diagnosis of
early onset subsets. Middle East J Dig Dis. 2017;9:69–80.
2. Atakan Z. Cannabis, a complex plant: different compounds and
different effects on individuals. Ther Adv Psychopharmacol. SAGE
Publications. 2012;2(6):241–254
3. Freeman TP, Hindocha C, Green SF, et al. Medicinal use of cannabis
based products and cannabinoids. BMJ. 2019 Apr 4;365:
l1141. DOI:10.1136/bmj.l1141.
4. Hazekamp A, Ware MA, Muller-Vahl KR, et al. The medicinal use of
cannabis and cannabinoids-an international cross-sectional survey
on administration forms. J Psychoactive Drugs. 2013;45:199–210.
5. Hasenoehrl C, Storr M, Schicho R. Cannabinoids for treating inflam­
matory bowel diseases: where are we and where do we go? Expert
Rev Gastroenterol Hepatol. 2017;11:329–337.
6. Massa F, Marsicano G, Hermann H, et al. The endogenous canna­
binoid system protects against colonic inflammation. J Clin Invest.
2004;113:1202–1209.
7. D’Argenio G, Valenti M, Scaglione G, et al. Up-regulation of ana­
ndamide levels as an endogenous mechanism and
a pharmacological strategy to limit colon inflammation. Faseb J.
2006;20:568–570.
8. Storr MA, Keenan CM, Emmerdinger D, et al. Targeting endocanna­
binoid degradation protects against experimental colitis in mice:
involvement of CB1 and CB2 receptors. J Mol Med.
2008;86:925–936.
9. Grill M, Högenauer C, Blesl A, et al. Members of the endocannabinoid
system are distinctly regulated in inflammatory bowel disease and
colorectal cancer. Sci Rep. 2019;9:1–13.
10. Ambrose T, Simmons A. Cannabis, Cannabinoids, and the endocan­
nabinoid system-is there therapeutic potential for inflammatory
bowel disease? J Crohns Colitis. 2019;13:525–535.
11. Sharkey KA, Wiley JW. The role of the endocannabinoid system in
the Brain–Gut Axis. Gastroenterology. W.B. Saunders. 2016;151
(2):252–266.
12. Izzo AA, Camilleri M. Cannabinoids in intestinal inflammation and
cancer. Pharmacol Res. 2009;60:117–125.
13. Leinwand KL, Gerich ME, Hoffenberg EJ, et al. Manipulation of the
endocannabinoid system in colitis: a comprehensive review.
Inflamm Bowel Dis. Lippincott Williams and Wilkins. 2017;23
(2):192–199
14. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid
system links gut microbiota to adipogenesis. Mol Syst Biol.
2010;6:392.
15. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus
modulates intestinal pain and induces opioid and cannabinoid
receptors. Nat Med. 2007;13:35–37.
16. Mehrpouya-Bahrami P, Chitrala KN, Ganewatta MS, et al. Blockade
of CB1 cannabinoid receptor alters gut microbiota and attenuates
inflammation and diet-induced obesity. Sci Rep. 2017;7:1–16.
17. McVey DC, Schmid PC, Schmid HHO, et al. Endocannabinoids induce
ileitis in rats via the capsaicin receptor (VR1). J Pharmacol Exp Ther.
2003;304:713–722.
4 A. SZCZEPANIAK AND J. FICHNA
18. Kienzl M, Storr M, Schicho R. Cannabinoids and opioids in the
treatment of inflammatory bowel diseases. Clin Transl
Gastroenterol. 2020;11:e00120.
19. Weiss A, Friedenberg F. Patterns of cannabis use in patients with
inflammatory bowel disease: a population based analysis. Drug
Alcohol Depend. 2015;156:84–89.
20. Lahat A, Lang A, Shomron BH. Impact of cannabis treatment on the
quality of life, weight and clinical disease activity in inflammatory
bowel disease patients: A pilot prospective study. Digestion.
2012;85(1):1–8.
21. Naftali T, Bar-Lev Schleider L, Dotan I, et al. Cannabis induces a clinical
response in patients with Crohn’s disease: a prospective placebo-
controlled study. Clin Gastroenterol Hepatol. 2013;11:1276–1280.
•• Describes the effect of cannabis in Crohn's disease patients.
22. Irving PM, Iqbal T, Nwokolo C, et al. A randomized, double-blind,
placebo-controlled, parallel-group, pilot study of cannabidiol-rich
botanical extract in the symptomatic treatment of ulcerative
colitis. Inflamm Bowel Dis. 2018;24:714–724.
23. Schicho R, Storr M. Topical and systemic cannabidiol improves
trinitrobenzene sulfonic acid colitis in mice. Pharmacology.
2012;89:149–155.
24. Esposito G, De Filippis D, Cirillo C, et al. Cannabidiol in inflammatory
bowel diseases: A brief overview. Phyther Res. 2013;27(5):633–636.
25. Naftali T, Mechulam R, Marii A, et al. Low-dose cannabidiol is
safe but not effective in the treatment for Crohn’s disease,
a randomized controlled trial. Dig Dis Sci. 2017;62:1615–1620.
26. Storr M, Devlin S, Kaplan GG, et al. Cannabis use provides
symptom relief in patients with inflammatory bowel disease
but is associated with worse disease prognosis in patients with
Crohn’s disease. Inflamm Bowel Dis. 2014;20:472–480.
•• Describes the effect of cannabis in Crohn's disease patients.
27. Lal S, Prasad N, Ryan M, et al. Cannabis use amongst patients
with inflammatory bowel disease. Eur J Gastroenterol Hepatol.
2011;23:891–896.
•• Describes the effect of cannabis in IBD patients.
28. Wang T, Collet JP, Shapiro S, et al. Adverse effects of medical
cannabinoids: A systematic review. Cmaj Cmaj. 2008;178
(13):1669–1678.
29. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients
with treatment-resistant epilepsy: an open-label interventional
trial. Lancet Neurol. 2016;15(3):270–278.
30. Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients
with seizures associated with Lennox-Gastaut syndrome
(GWPCARE4): a randomised, double-blind, placebo-controlled
phase 3 trial. Lancet. 2018;391:1085–1096.
31. Alatab S, Sepanlou SG, Ikuta K, et al. The global, regional, and
national burden of inflammatory bowel disease in 195 coun­
tries and territories, 1990–2017: a systematic analysis for the
global burden of disease study 2017. Lancet Gastroenterol
Hepatol. 2020;5:17–30.
32. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for
medical use: A systematic review and meta-analysis. J Am
Med Assoc. American Medical Association. 2015;313
(24):2456–2473.
•• A systematic review and meta analysis on cannabinoids in
medical use.