Gastroenterology 2020;159:62–80
REVIEWS IN BASIC AND CLINICAL GASTROENTEROLOGY
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AND HEPATOLOGY
Role of Cannabis and Its Derivatives in Gastrointestinal and
Hepatic Disease
Jonathan Gotfried,1 Timna Naftali,2 and Ron Schey3
1
Section of Gastroenterology, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia,
Pennsylvania; 2Division of Gastroenterology and Hepatology, Meir Medical Center, affiliated with the Sackler School of
Medicine, Tel Aviv University, Tel Aviv, Israel; and 3Division of Gastroenterology/Hepatology Department of Internal Medicine,
University of Florida College of Medicine, Jacksonville, Florida
Medical and recreational cannabis use has increased
dramatically over the last decade, resulting from main-
stream cultural acceptance and legalization in several
countries worldwide. Cannabis and its derivatives affect
many gastrointestinal processes via the endocannabinoid
system (ECS). The ECS influences gastrointestinal homeo-
stasis through anti-inflammatory, anti-nociceptive, and anti-
secretory effects. Some gastrointestinal disorders might
therefore be treated with cannabinoids. Despite numerous
studies in cell lines and animals, few human studies have
evaluated the therapeutic effects of cannabinoids. Cannabis’
schedule 1 drug status has limited its availability in
research; cannabis has been legalized only recently, in some
states, for medicinal and/or recreational use. Cannabinoids
can alleviate chemotherapy-induced nausea and emesis and
chronic pain. Studies have demonstrated the important
roles of the ECS in metabolism, obesity, and nonalcoholic
fatty liver disease and the anti-inflammatory effects of
cannabis have been investigated in patients with inflam-
matory bowel diseases. Despite its potential benefits, un-
desired or even detrimental effects of cannabis can limit its
use. Side effects such as cannabinoid hyperemesis syndrome
affect some users. We review the ECS and the effects of
cannabis and its derivatives on gastrointestinal and hepatic
function in health and disease.
Keywords: CHS; NAFLD; drug; THC.
C annabis contains numerous chemically active com-
pounds, including cannabinoids, terpenoids, flavo-
noids, and alkaloids. The most prominent and best
characterized are D9-tetrahydrocannabinol (THC) and can-
nabidiol (CBD). There are, however, more than 100 active
cannabinoids, each with capacity to modulate the endo-
cannabinoid system (ECS).1 The ECS is a network of canna-
binoid receptors, their ligands, and regulating synthesizing
and degrading enzymes that function on demand (Figure 1).
Ligands include arachidonic acid-derived lipids anandamide
and 2-arachidonoylglycerol, although others exist.2 Corre-
sponding receptors are cannabinoid receptor 1 (CNR1, also
called CB1) and cannabinoid receptor 2 (also called CB2), as
well as transient receptor potential cation channel subfamily
V member 1, peroxisome proliferator–activated receptor-a,
and the orphan G-protein coupled receptors GPR55 and
GPR119.3 Enzymes that synthesize endocannabinoids include
diacylglycerol lipase, which synthesizes anandamide, and N-
acyl-phosphatidylethanolamine-specific phospholipase D,
which synthesizes 2-arachidonoylglycerol. The enzymes fatty
acid amide hydrolyase (FAAH) and monoacylglycerol lipase
degrade endocannabinoids.4 The ECS can be activated by
exogenous cannabis or other phytocannabinoids, or synthetic
compounds.
Cannabis affects many gastrointestinal processes
through its actions on the ECS (Figure 2). Cannabinoid re-
ceptors and their ligands are distributed throughout the
human gastrointestinal tract with regional variations in
expression.3 CB1 is expressed in the enteric nervous system
in epithelial cells and myenteric and submucosal plexuses,
and is found adjacent to motoneurons, interneurons, and
primary afferent neurons. CB2 is frequently expressed by
immune cells and the peripheral nervous system.5,6 The ECS
maintains gut homeostasis by modulating immune toler-
ance,7 gastrointestinal motility,5 and visceral pain and
inflammation.8 Activation leads to increased food intake and
other metabolic processes that affect energy balance,
including lipolysis and glucose metabolism.3,8,9
Medical and recreational cannabis use has increased
nationwide, especially after legalization in several states.
Although cannabis can have beneficial effects in patients
with some disorders, there has also been a commensurate
increase in treatment of cannabis-use disorders.10 It is
therefore important to review cannabis’ salutary and po-
tential harmful side effects.
Abbreviations used in this paper: AP, acute pancreatitis; CBD, cannabi-
diol; CDAI, Crohn’s Disease Activity Index; CHS, cannabinoid hyperemesis
syndrome; CI, confidence interval; CNR1, cannabinoid receptor 1; CNS,
central nervous system; CP, chronic pancreatitis; CVS, cyclical vomiting
syndrome; ECS, endocannabinoid system; FAAH, fatty acid amide
hydrolyase; GE, gastric emptying; GERD, gastroesophageal reflux dis-
ease; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome;
IBS-D, irritable bowel syndrome with diarrhea; IL, interleukin; LES, lower
esophageal sphincter; LPS, lipopolysaccharide; NAFLD, nonalcoholic fatty
liver disease; STC, slow transit constipation; THC, D9-tetrahydrocannab-
inol; WAT, white adipose tissue.
Most current article
© 2020 by the AGA Institute
0016-5085/$36.00
https://doi.org/10.1053/j.gastro.2020.03.087
July 2020 Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease 63

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Figure 1. ECS. The major
receptors, ligands, and
synthesizing and degrading
enzymes in the ECS. AEA,
arachidonoylethanolamide;
2-AG, 2-
arachidonoylglycerol; DAGL,
diacylglycerol lipase; ER,
endoplasmic reticulum;
MGL, monoacylglycerol
lipase; NAPE, N-arach-
idonoylphosphatidylethanol-
amine. Adapted from Vemuri
and Makriyannis,145 with
permission.

Gastrointestinal Motility
In animal studies, CB1 agonists reduced motility,
whereas CB1 antagonists had promotility effects.11 CB1 is
found on presynaptic neurons in the myenteric plexus and
submucosal neurons. Agonists inhibit excitatory cholinergic
neurons, leading to reduced contractile activity subse-
quently decreasing peristalsis.12 This occurs through a
dampening effect on the spread of junction potentials by
inhibiting interneuron-mediated neurotransmission.13
Furthermore, CB1 modulates peristaltic reflexes by inhibit-
ing substance P and VIP release.5,12,13 These actions seem to
occur in a dose-dependent manner, independently from
pacemaker cells (such as interstitial cells of Cajal).13 Less is
known about the roles of CB2 in health, and its effects on
motility are better studied in inflammatory conditions.
Esophageal Function
Few studies have evaluated cannabis’ effects on
esophageal motility and gastroesophageal reflux disease
(GERD) pathogenesis. Two studies in humans found lower
esophageal sphincter (LES) relaxation to be affected by
cannabinoids; short-term THC administration relaxed LES
pressures, whereas the CB1 antagonist rimonabant
increased postprandial LES pressures.14,15 Conversely, a
limited retrospective study reported higher prevalence of
hypertensive LES in chronic cannabis users, and further
 64 Gotfried et al
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research is needed to understand its effects on LES
pressure as it relates to GERD.16 Cannabis might also
affect GERD through action on rates of transient LES
relaxation.
THC administration transiently reduced transient LES
relaxation frequency and acid reflux episodes, although this
reduction was not statistically significant.14 There are
limited data on cannabinoids’ role in functional chest pain.
In a prospective study, 4 weeks’ administration of the CB1
agonist dronabinol increased pain thresholds and reduced
pain intensity and odynophagia, compared to placebo,
without significant side effects.17 Cannabis might therefore
improve esophageal function, reduce symptoms of GERD
and noncardiac chest pain, but further studies are needed.
Gastric Emptying and Gastroparesis
Gastric emptying (GE) decreases after cannabinoid
administration, based on findings from animal and limited
human studies, mainly via the effects of CB1 agonists on
peripheral and central nervous system (CNS) pathways.18
THC and dronabinol delayed GE in 2 placebo-controlled
trials. Patients given THC had delayed GE compared to pa-
tients given placebo, especially at 120 minutes, determined
by scintigraphy.19 Similar findings occurred with dronabi-
nol.20 Notably, sex-specific responses in the dronabinol
group were observed; women had longer times of GE and
men had higher fasting gastric volumes, possibly due to
hormonal differences.
Unexpectedly, despite evidence that cannabis delays GE,
a recent survey of patients with gastroparesis symptoms
found cannabis use was associated with symptom
improvement.21 This was not as pronounced in
Gastroenterology Vol. 159, No. 1
Figure 2. Effects of
cannabis and its de-
rivatives on gastrointes-
tinal organs and functions.
TLESR, transient lower
esophageal sphincter
relaxation.
gastroparetics using oral dronabinol, potentially from
decreased bioavailability compared to inhaled cannabis.
These findings indicate that dose and cannabis’ effects on
pathways beyond GE might contribute to development of
gastroparesis.22 Further studies are needed to determine
benefits in certain subgroups (idiopathic vs diabetes vs
postsurgical) before recommendations for clinical use.
Colon Transit
Cannabinoid administration delays colonic transit as
shown in animal and human studies.20 These studies
postulate increased ECS tone inhibits cholinergic contrac-
tility, subsequently decreasing colonic transit.23 Human
studies have evaluated exogenous cannabinoid derivatives
on colonic motility. In a randomized, placebo-controlled
trial, dronabinol reduced colonic contractile activity in
fasting and postprandial periods.20 Additionally, in a retro-
spective case series of 6 patients with refractory diarrhea,
patients receiving CB1 agonist nabilone experienced
decreased stool frequency and improved weight gain. Only 1
patient experienced significant side effects, which resolved
after nabilone cessation.24 By extension, CB1 antagonists
would be expected to increase colonic motility, as confirmed
through a meta-analysis demonstrating increased incidence
of diarrhea from rimonabant or taranabant in clinical
trials.25
Dysregulation of enzymes that synthesize and degrade
endocannabinoids, such as FAAH, monoacylglycerol lipase,
and diacylglycerol lipase, might contribute to colonic
motility disorders.26 Inhibiting these enzymes increases
availability of endocannabinoids, thereby decreasing colon
transit.27 A recent case series evaluated FAAH activity in
July 2020 Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease
patients with slow transit constipation (STC). Compared
with controls, serum samples from patients with STC had
higher amounts of anandamide, 2-arachidonoylglycerol, and
palmitoylethenolamide (inversely associated with FAAH),
indicating that low FAAH contributes to STC. Additionally,
patients with STC have increased CB1 expression in myen-
teric nerve fibers, indicating increased sensitivity to endo-
cannabinoid action. CB2 appears to have anti-kinetic effects
during intestinal inflammation, observed in patients with
inflammatory bowel disease (IBD), or immune activation.
Rats with intestinal hypermotility, induced by administra-
tion of lipopolysaccharide (LPS), had slower motility after
CB2R activation.6
Despite these findings, cannabis use was associated with
decreased constipation in a nationwide database survey.28
This discrepancy could be attributed to the survey not
evaluating delivery method (inhaled or ingested) or dose.
Additionally, CBD could inhibit CB1, whereby different for-
mulations with altered CBD/THC ratios might attenuate
CB1-mediated activities. Overall, data indicate that the ECS
affects colonic motor activity and might be targeted for
treatment of colonic motility disorders, although further
research is needed.
Irritable Bowel Syndrome
IBS involves changes in gastrointestinal motility,
inflammation and immune dysregulation, visceral hyper-
sensitivity, and possibly dysbiosis.29 Considering the in-
teractions of the ECS with many of these processes,
alterations in ECS tone might affect IBS pathogenesis.
Visceral hypersensitivity is an important feature of IBS.
Studies of rodents have found direct or indirect activation of
CB1R and likely CB2R, which might inhibit visceral sensi-
tivity and pain.30,31 Accordingly, expression of CB1 de-
creases in stress-induced states and visceral hyperalgesia
occurs after administration of CB1 antagonist (WIN 55,212-
2).32,33 CB1 activation also affects other pain pathways
outside the ECS. Low expression of CB1R in the dorsal root
ganglion results in increased expression of transient re-
ceptor potential cation channel subfamily V member 1.32
This finding indicates that there are interactions between
the ECS and vanilloid system—a pathway that senses
noxious stimuli and pain, indicating a role for CB1 in pain
sensation.
The ECS appears to become sensitized during inflam-
matory or hyperalgesic states through modulation of CB2
expression. This is important because patients with IBS have
been reported to have low-level inflammation. Studies of
rats with colitis support this observation; administration of
a CB2 agonist (PF-03,550,096) increased pain thresholds,
measured by colonic-distension, in a dose-dependent
manner.30 Activation of CB2 might down-regulate other in-
flammatory mediators, including bradykinin, indicating its
role in pain mediation during inflammation.34
In addition to direct action on cannabinoid receptors,
modification of degrading enzymes may also affect IBS
symptoms. In mice with visceral inflammation (induced
with acetic acid) and distension-induced pain, inhibitors of
65
FAAH and monoacylglycerol lipase had analgesic effects,
reducing pain from inflammation, and increased distension-
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induced visceral pain thresholds after FAAH inhibition.34
The ECS therefore controls pain sensation in physiologic
and inflammatory states.
Humans
There have been few studies of the role of the ECS in
patients with IBS. Small bowel and colonic transit were
studied, using scintigraphy and sensation to isobaric
distension, in patients with IBS with 2 variants in CNR1 and
subjects without IBS (controls). The researchers found a
significant association between CNR1 rs806378 and
increased colonic transit in patients with IBS and diarrhea
(IBS-D).35 There was also an association between these gene
variants and gas sensation, but not pain, indicating roles for
cannabinoid receptors in motility and sensation. ECS mod-
ulation by dronabinol was evaluated in 75 patients with
different IBS subtypes and polymorphisms in ECS genes.36
Regardless of IBS subtype, dronabinol decreased fasting
proximal left colonic motility index compared with placebo,
with the largest effects in patients with IBS-D or IBS-
alternating. Interestingly, dronabinol did not significantly
alter sensation or tone among subjects. Based on those
findings, a randomized trial evaluated single nucleotide
polymorphisms CNR1 rs806378 and FAAH rs324420 in
patients with IBS-D.37 However, dronabinol did not produce
statistically significant effects on transit. In persons without
IBS, dronabinol reduced postprandial colonic motility, as
previously observed in patients with IBS, but the subjects
had increased thresholds for pain and distension.38 So there
seems to be a difference between patients with IBS and
controls in response to cannabinoids.
CB2 might modulate inflammation and pain in patients
with IBS. The CB2 ligand PF-03550096 increased the
visceral pain threshold in rats. In a functional, human cell-
based assay, PF-03550096 bound CB2 with a similar affin-
ity as in the rat studies.30 CB2 has been evaluated in only 1
animal study, which investigated the effects of the dietary
compounds polydatin and palmithoylethanolamide (struc-
turally related to anandamide). These compounds have
synergistic effects on mast cells.39 Patients with IBS given
these compounds for 12 weeks had lower severity of
abdominal pain compared with placebo. These patients had
higher mucosal mast cell counts and higher levels of CB2R
expression.
A recent study by Dothel et al40 reported increased
levels of m-opioid receptor, CB2 messenger RNA and protein,
and b-endorphin in colon mucosal biopsies from patients
with IBS compared with asymptomatic individuals; biopsy
tissues from women had higher levels of CB2 messenger
RNA than men. In contrast, in the asymptomatic control
group, men had higher expression than women. These
findings indicate that cannabinoids, via CB2, contribute to
immune-related compensatory action in visceral pain.
Although cannabinoids could have promising effects, they
are not used in the management of dysmotility-associated
conditions—further studies are needed (Table 1).
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Table 1.Studies of Functional Gastrointestinal Disorders

66
Patients

Gotfried et al
Study Study, first
Study design duration n Age and sex Interventions Key results author

IBS-C, IBS-D, IBS-M Single dose 75 Approximately 40 y, Assessed left colonic IBS-D or IBS-mixed, Wong36
Double-blind, randomized, placebo-controlled, 92% women compliance, motility index, dronabinol reduced
parallel-group study tone, and sensation during fasting colonic motility
Dronabinol (2.5 mg or 5 mg) or placebo fasting and after a meal FAAH and CNR1 variants
Analyzed the single nucleotide could influence the
polymorphisms CNR1 effects of this drug on
rs806378, FAAH rs324420, colonic motility
MGLL rs11538700
IBS-D 2d 36 Approximately 41 y, Gastric, small bowel, and Dronabinol had no effect Wong37
Double-blind, randomized, placebo-controlled, 2% men colonic transit on gut transit in patients
parallel-group study Genotype, the single with IBS-D, dronabinol
Dronabinol (2.5 mg or 5 mg) twice daily for 2 d vs nucleotide polymorphisms delayed colonic transit
placebo CNR1 rs806378, FAAH in patients with the CB1
rs324420 rs806378 CT/TT
polymorphism
Healthy volunteers Single dose 52 34 y, 42% men Volonic compliance, motility, Significant increase in Esfandyari38
Double-blind, randomized, placebo-controlled, tone, and sensation 1 h colonic compliance,
parallel-group study before and after a 1000- borderline effect of
Dronabinol (7.5 mg) vs placebo kcal meal relaxation in fasting
colonic tone, inhibition
of postprandial colonic
tone and fasting and
postprandial phasic
pressure
IBS 12 wk 68 40 y, 41.2% men Questionnaires, biopsy, and Did not significantly modify Cremon39
Randomized, double-blind, placebo-controlled trial IBS biologic profile (ELISA, IBS biological profile,
palmithoylethanolamide or polydatin vs placebo immunoblot, including mast cell
immunohistochemistry) count
Reduced severity of
abdominal pain
IBS-C, IBS-D, or IBS-M vs healthy individuals 1 injection 63 Age not available, Left colon mucosal biopsies IBS patients had increased Dothel40
Expression of MOR ligand b-endorphin, CB2R 55% men colonic mucosal
Correlation with sex and symptom perception expression of MOR,

Gastroenterology Vol. 159, No. 1

b-endorphin, and
CB2R, localized
to immune cells

ELISA, enzyme-linked immunsorbent assay; IBS-C, IBS with constipation; IBS-D, IBS with diarrhea; IBS-M, IBS mixed.
July 2020 Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease
Salutary Effects Against Nausea and
Emesis
Cannabinoid receptors are found along emetic pathways
in peripheral and CNS, involving areas associated with
generation of nausea and emesis, including area postrema
and dorsal vagal complex. Cannabinoid agonists likely sup-
press the emetic reflex. Studies of animals have shown that
ECS activation down-regulates enterochromaffin release of
serotonin and inhibits substance P-induced neurokinin
pathways, indicating anti-emetic properties.41,42 Enzymes
that regulate the ECS, such as FAAH, diacylglycerol lipase,
and N-acyl-phosphatidylethanolamine-specific phospholi-
pase D, might also affect CNS processes, although data to
support this come from only animal studies.41
Use of cannabis and cannabinoids as anti-emetics has
been mostly studied in patients with chemotherapy-induced
nausea and vomiting. Different formulations and delivery
methods have been used to treat chemotherapy-induced
nausea and vomiting, sometimes with other anti-emetics,
with varying results. In a meta-analysis of 28 studies
(including nabilone [n ¼ 14]; dronabinol [n ¼ 3]; and lev-
onantradol [n ¼ 4], cannabis extract nabiximols [n ¼ 1], and
THC [n ¼ 6]), use of cannabinoids appeared superior to
placebo and active comparators (alizapride, hydroxyzine,
metoclopramide, and ondansetron), although the results
were not statistically significant.43 Importantly, pharmaco-
dynamics and pharmacokinetics of these compounds might
influence their effectiveness—newer formulations might
have better outcomes.44,45 Recent oncology guidelines
recommend dronabinol as rescue therapy for
chemotherapy-induced nausea and vomiting, but not THC or
CBD, citing insufficient data and potential side effects.46,47
There have been fewer studies of cannabis as an anti-
emetic agent during pregnancy. Obstetric guidelines
discourage cannabis use during pregnancy, citing lack of
evidence for benefits and safety.48 Nonetheless, a recent
phone survey found that many medical dispensaries in
Colorado still recommend cannabis—clinicians with preg-
nant patients should be aware of this activity.49
Cannabinoid Hyperemesis Syndrome
Increased incidence of cannabinoid hyperemesis syn-
drome (CHS) has been reported in states after state-wide
legalization of medicinal and recreational cannabis, high-
lighting potential side effects in some users.50,51 CHS likely
occurs in long-term users (near daily use for 1 year), most
often in adolescent males or young adults.52 Cannabis and
synthetic formulations can cause CHS53 by unknown
mechanisms. Chronic use might down-regulate CB1 in per-
sons with specific genetic variants, lowering emetic pathway
thresholds. Other theories attribute relative potency or
formulation differences of cannabis products (THC/CBD
ratio).51 Lastly, delayed GE from cannabis use is described
but the extent this contributes to CHS is unknown.
Patients with CHS present with features similar to
cyclical vomiting syndrome (CVS), so CHS might be a CVS
subtype.51,54 However, unlike CHS, CVS is associated with
psychologic comorbidities, anxiety and dysphoria, migraine
67
headaches, lack of hot water symptom relief, and female
predilection. It is important to note some patients with CVS
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have improvement after self-medication with cannabis.
Furthermore, abortive anti-emetics used for CVS have been
tried in CHS with varying results.52
In patients with CHS, symptoms are episodic and may
cease, classically, after a hot shower. Symptom resolution
after cannabis cessation strongly supports the diagnosis and
is recommended first-line therapy. There is no defined time
for resolution of symptoms after cessation. By the authors’
experience, symptoms resolve several days and up to
months after cannabis weaning. It is imperative to caution
patients that symptoms may return with re-exposure.
Tricyclic antidepressants are the most commonly pre-
scribed long-term treatment in patients requiring medical
therapy.55 Benzodiazepines, haloperidol, and capsaicin are
preferred acute treatments. The rationale for capsaicin use
follows similar physiologic response to exposure to hot
water relieving symptoms in CHS. Capsaicin affects transient
receptor potential cation channel subfamily V member 1
receptors, found adjacent to CB1, and may modulate nausea
and emesis through action on the medullary vomiting center
and gastrointestinal tract, possibly through release of sub-
stance P.3,56,57 However, a recent systematic review
concluded that the quality of data for capsaicin treatment of
CHS is low, although the limited availability of alternative
antiemetic therapies and capsaicin’s favorable risk-to-
benefit profile make it a reasonable, adjunctive treatment
option.58 Clinicians should be vigilant eliciting patient’s
history of cannabis use when evaluating patients with
episodic emesis and recognize the varying response to
available therapies in CHS.
Gut Microbiome
Cannabis has been reported to modify intestinal micro-
biome, so it might be used in treatment of various condi-
tions. For example, in an analysis of a nationwide inpatient
database using ICD-9-CM codes, cannabis use (including
dependent and nondependent use) was associated with a
significant reduction in risk (28%) of Clostridioides difficile
infection in hospitalized patients compared with nonuse.59
However, there are few data on its overall effects on the
microbiome, especially because preclinical studies of
cannabinoid receptor agonists and antagonists have pro-
duced inconsistent results.60–62 Furthermore, due to limited
oversight and lack of standardization among dispensaries,
there have been reports of medicinal cannabis contaminated
with bacterial and fungal pathogens, which have raised
concerns about its negative effects on microbiome
composition.63
Despite barriers and limitations of its study, several
studies of the microbiome and its association with cannabis
are worth noting. The ECS could have an important role in
modulating visceral pain sensation in patients with dys-
biosis, a hallmark feature of some patients with functional
gastrointestinal disorders.64 Ingestion of Lactobacillus aci-
dophilus strains increased endocannabinoid (CB2) and
m-opioid receptor expression in intestinal epithelial cells in a
 68 Gotfried et al
rat model of induced colonic hypersensitivity.65 Microbes
might therefore potentiate or modify visceral pain pathways
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through the ECS and be included in treatment strategies for
functional gastrointestinal disorders.
Studies of mice have shown that the gut microbiota af-
fects metabolism through effects on intestinal ECS tone.
Dysbiosis resulting from high-fat diet can increase ECS tone,
modulating gut permeability and subsequently increasing
plasma level of LPS, which promotes metabolic disorders
and inflammation.66 The proposed endocannabinoid–LPS
regulatory loop is likely to be affected by genetic and
environmental factors, such as diet; the ECS might link
dysbiosis with obesity.67 This theory is supported by the
increased ratio of Firmicutes to Bacteroidetes observed in
mice with diet-induced obesity given THC. These findings
indicate that THC might affect the intestinal microbiome and
obesity, but further research is needed.62
Endocannabinoid System in Obesity
The ECS regulates energy intake and appetite through
central and peripheral metabolic pathways. ECS activation
seems to favor net-positive anabolic processes and energy
storage. Within the CNS, tight control of metabolism occurs
through on demand endocannabinoid production based on
energy needs, increasing and decreasing endocannabinoid
levels in fasting and fed states, respectively.68 The effects of
the ECS on metabolism might be regulated by retrograde
neuromodulation of presynaptic CB1 in excitatory and
inhibitory pathways, depending on energy needs.69 ECS af-
fects homeostatic pathways in the hypothalamus and
brainstem through modification of anorexigenic (such as
leptin) and orexigenic hormones (such as ghrelin). Obese
individuals have impaired production of leptin, resulting in
diminished inhibition of endocannabinoid levels, which
might also contribute to insulin resistance.1
The CNS also affects energy intake occurs through
behavior–reward pathways of the mesolimbic system.70
Levels of endocannabinoid increase after ingestion of
palatable food. Consequently, the ECS inhibits GABAergic
neurons, leading to disinhibition of dopamine and activation
of the hedonic drive toward further food consumption.70
Concomitant orosensory input activates CB1R enhancing
olfaction and taste circuits, thereby increasing food
intake—especially sweet food.71
The ECS also modulates peripheral metabolism and in-
sulin sensitivity through actions in digestive organs and
skeletal muscle. ECS stimulation increases insulin resis-
tance, dyslipidemia, and increased adiposity.1,5 Additional
ECS activation occurs in obese patients from aberrant
plasma and intestinal endocannabinoid signaling leading to
inhibition of gut–brain satiation signaling, ultimately
contributing to hyperphagia and weight gain.72,73
Cannabinoid Therapy for Obesity
CB1 might be targeted for treatment of weight-related
disorders. Dronabinol increases body mass index values in
patients with cancer-related cachexia or advanced acquired
immunodeficiency syndrome, probably through appetite
Gastroenterology Vol. 159, No. 1
stimulation, typically at higher doses.74,75 Although cannabis
use benefit these patients, its effects vary, due to unreliable
dosing and pharmacokinetics.76
In obese individuals, CB1 antagonists have been found to
promote weight loss, but there were negative side effects. A
meta-analysis of randomized trials of rimonabant showed
that patients lost an average 4.7 kg compared with placebo
at 1 year (95% confidence interval [CI], 4.1–5.3 kg; P <
.0001).77 However, patients receiving rimonabant had high
rates of depression and anxiety and, more concerning, a 1.4-
fold increase in risk of serious adverse events (P ¼ .03;
number needed to harm ¼ 59), which included suicidal
thoughts, leading to its withdrawal. Taranabant had similar
effects on weight loss; the highest dose (2 mg, once daily)
resulted in loss of 6.7 kg after 52 weeks. However, similar
concerns about side effects lead to discontinuation.78,79 To
avoid side effects, researchers evaluated peripherally
restricted CB1 antagonists.67,80 Compared with rimonabant,
the second-generation CB1 antagonist TM38837 had
decreased CNS penetration, but also lower peripheral ac-
tivity.81 Other methods, such as targeting non-CB1 path-
ways, are being evaluated, most recently in preclinical and
phase 2 trials. The peripherally restricted agent tetrahy-
drocannabivarin significantly decreased fasting plasma
glucose and improved pancreatic b-cell function in subjects
with noninsulin-treated type 2 diabetes and was well tol-
erated.82–84
Cannabinoid Receptor 2 and Energy Metabolism
CB2 is expressed in tissues with high levels of meta-
bolism, such as liver, pancreas, and adipose tissue, so it
might be involved in development of obesity or metabolic
disorders, although it is less well-characterized than CB1.
The CB2 agonist JWH-133 increases the activity of UCP1, a
mitochondrial protein involved in energy balance.85 CB2
agonist stimulation of UCP1 promotes white adipose tissue
(WAT) browning, converting WAT to beige adipose (an
inducible form of WAT that functions similar to brown ad-
ipose tissue). WAT browning stimulates thermogenesis and
caloric expenditure during rest and exercise, indicating that
cannabinoids might modulate energy utilization (Figure 3).
The effects are reversed after administration of CB2 antag-
onists, leading to increased food intake.85 These and other
studies showed that CB2 is involved in energy
homeostasis.86
Cannabis Use in Obese Patients
Epidemiology studies have reported decreased rates of
obesity among chronic cannabis users.87,88 Lower expres-
sion of CB1, either from long-term cannabis use or different
phenotypic expression across populations, might account
for this observation.87,89,90 Alternatively, although there is
overwhelming evidence that CB1 promotes energy meta-
bolism, other ECS components, such as CB2, could have
under-recognized effects on metabolic processes, leading to
net weight loss. Studies of this pathway are needed and
might lead to therapies (Table 2).
July 2020 Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease
Figure 3. Effects of cannabinoids on fat metabolism. Activation of CB2 or blockade of CB1 might shift white adipose tissue
(principally for fat storage and hormone secretion) to transitional adipocytes (beige) that, when stimulated, can lead to
development of brown adipose tissue, involved in energy expenditure and thermogenesis.
Nonalcoholic Fatty Liver Disease
CB1 signaling might affect lipid metabolism, insulin
sensitivity, and development of hepatic steatosis.91 In mice,
activation of CB1 in hepatocytes increases de novo fatty acid
synthesis and increases expression of lipogenic enzymes,
such as fatty acid synthase, leading to lipid accumulation
and steatosis.92 This was confirmed in CB1-knockout mice,
which did not develop hepatic steatosis after placement on a
high-fat diet.93 Studies of patients indicted a role for CB1 in
development of NAFLD. In a randomized trial, patients given
rimonabant for 48 weeks had decreased hepatic steatosis,
measured by the ratio of liver to spleen attenuation.94
However, rimonabant was withdrawn due to psychotropic
side effects.
Interestingly, chronic use of cannabis can lower body
weight and decrease hepatic steatosis.95 In a post-hoc
analysis of heavy users of cannabis treated for depen-
dence, subjects were found to have normal levels of liver
enzymes, which did not correlate with levels of THC or THC
metabolites.96 In a cross-sectional, population-based study,
a lower prevalence of NAFLD was found in cannabis users
compared with nonusers (adjusted odds ratio, 0.82; 95% CI,
0.76–0.88; P < .0001).95 Among chronic cannabis users,
NAFLD prevalence was 43% lower in dependent users
compared with nondependent users, defined as moderate to
severe consumption through ICD-10 coding (adjusted odds
ratio, 0.57; 95% CI, 0.42–0.77; P < .0001). These findings
seem to contradict the physiologic effects of endocannabi-
noids on cannabinoids receptors. One potential reason,
proposed by Dibba et al,97 is that THC tolerance, with re-
petitive use, leads to decreased CB1 density and subsequent
lower CB1 activity overall. Another potential mechanism
includes the entourage effect, whereby other constituents in
cannabis, such as CBD and tetrahydrocannabivarin,
decrease CB1 activation, causing decreased hepatic steatosis
and inflammation. This theory is supported by the finding
that CBD and tetrahydrocannabivarin (at high doses) are
antagonists of CB1 and CB2.98
The role of CB2 in hepatic steatosis and its relationship
with CB1 are complex and not fully understood. Human
hepatocytes incubated with oleic acid had dose-dependent
69
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REVIEWS AND
increases in steatosis after administration of CB1 and CB2
agonists.99 Moreover, CB2 agonists increased expression of
CB1, increasing lipid accumulation in hepatocytes.
Interestingly, exocannabinoids in cannabis have anti-
inflammatory effects and prevent NAFLD, by inhibiting cy-
tokines.100 This likely occurs via the antagonist effects of
CBD on CB2R.98 However, studies of the effects of rimona-
bant in patients with nonalcoholic steatohepatitis hepatic
inflammation were discontinued due to safety concerns.101
Namacizumab, a negative allosteric antibody against CB1
that is intended to down-regulate the receptor is the first
peripherally restricted biologic agent designed to target the
ECS , and currently evaluated in treatment of nonalcoholic
steatohepatitis.68
Effects of Endocannabinoid System on Liver
Fibrosis in Patients With Chronic Liver Disease
The ECS is up-regulated in patients with advanced liver
disease, cirrhosis, nonalcoholic steatohepatitis, alcoholic liver
disease, autoimmune hepatitis, and viral hepatitis.102,103 The
ECS might affect progression from fibrosis to cirrhosis in
patients with these conditions. Additionally, CB1 might in-
fluence the circulatory sequelae observed in patients with
chronic liver disease, including portal hypertension.102
Liver biopsies from patients with acute and chronic liver
injury have increased expression of CB1 and CB2.104–106
CB1 and CB2 were expressed in liver tissues from all pa-
tients with hepatitis examined. Furthermore, a significant
increase in cells positive for both CB1 and CB2 was detected
in stage 3 and stage 4 disease compared to stage 1 and stage
2 disease. There was a strong positive association between
CB1 expression and a-SMA expression. Moreover, double
immunofluorescence staining for CB1 and a-SMA demon-
strated that activated hepatic stellate cells express CB1.107
However, the exact effects of cannabis and its derivates
are not clear in patients with chronic liver diseases,
including alcoholic and viral hepatitis, and little is known
about their effects on fibrogenesis. There are conflicting
data from studies of animal models as to whether cannabis
contributes to or protects against fibrosis.102,108 In
 PERSPECTIVES
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Table 2.Studies of Nonalcoholic Fatty Liver Disease and Obesity

70
Patients

Gotfried et al
Study, first
Study design Study duration n Age and sex Interventions Key results author

Double-blind, randomized, placebo-
controlled study
Body mass index, 27–43 kg/m2, 51%
with metabolic syndrome
Taranabant 2 mg (n ¼ 414), 4 mg (down-
dosed for year 2 to 2 mg) (n ¼ 415), or
6 mg (down-dosed during year 1 to 2
mg) (n ¼ 1256) or placebo
(n ¼ 417) daily
Multicenter, double-blind randomized
placebo-controlled study
Body mass index, 27–43 kg/m2
Taranabant 0.5 mg (n ¼ 207), 1 mg
(n ¼ 208), or 2 mg (n ¼ 417) daily
Meta-analysis of 4 randomized
controlled trials, rimonabant 20 mg,
or placebo daily
Evaluation of metabolic parameters
(includes NAFLD and weight)
104 wk 2,502 Approximately 48 y, Measured body weight, Mean changes in body weight for Aronne78
44% men waist circumference, taranabant 2 mg, 4 mg, and 6
lipid, and glycemic end mg group were –2.6 kg, –6.6
points kg, –8.1 kg, respectively, at 52
wk
Mean changes in body weight for
taranabant 2 mg, 4 mg (down-
dosed to 2 mg during year 2),
and 6 mg (down-dosed to 2
mg during year 1) were –8.1 kg
at 52 wk with, respectively,
–1.4 kg, –8.1 kg at 52 wk with,
respectively, 6.4 kg, –8.1 kg at
52 wk with, respectively, 7.6
kg at 104 wk, respectively
2-wk lifestyle 832 Approximately 49 y, Measured change in body Mean changes in body weight for Proietto79
interventions, 66% men weight, waist taranabant 0.5 mg, 1 mg, and
followed by 52-wk circumference, lipid end 2 mg, and placebo were 5.4
treatment points, and glycemic kg, 5.3 kg, 6.7 kg, and
4-wk follow-up end points 1.7 kg, respectively (P < .001
vs placebo)
Increased gastrointestinal
(nausea, diarrhea) and
psychiatric-related (anger,
irritability) in taranabant group
52 wk 4105 44–55 y Effects on weight after 1 y Significant weight loss 4.7 kg Christensen77
27% men and 73% compared with placebo Increased adverse events (odds
men Evaluation of side effects ratio, 1.4; number needed to
harm, 25); 2.5-fold more likely
to have depressive mood
disorders and anxiety
13 wk 62 Approximately 59 y, Measured absolute weight No significant effects on any Jadoon82
68% men loss primary end points between

Gastroenterology Vol. 159, No. 1

Randomized, double-blind placebo- Measure of liver treatment groups
controlled study triglycerides by Overall safe and tolerated without
Nonpsychotropic cannabinoids: magnetic resonance significant side effects
5 groups: imaging or magnetic Potential influence of THCV on
CBD 100 mg twice daily, resonance glycemic control in patients
THCV 5 mg twice daily, spectroscopy with type 2 diabetes
CBD and THCV 5 mg each twice daily,
CBD 100 mg and 5 mg twice daily,
or placebo
 July 2020 Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease 71

population-level studies, cannabis has been shown to

Study, first possibly be protective against fibrosis progression, likely

PERSPECTIVES
REVIEWS AND
author

Bergholm94
through anti-inflammatory pathways, via CB2, or other
pathways.109 Further research is needed in this topic.
Cannabis and its derivates have been investigated in
other liver disorders, including cholestatic liver disease and
pruritus, autoimmune hepatitis, and hepatic encephalopa-
Weight loss averaged 8.5 ± 1.4 kg

thy—for reviews, see references.110–112

rimonabant and hypocaloric

hypocaloric diet group (P <

placebo; nonsignificant for

rimonabant vs hypocaloric
placebo, and 7.5 ± 0.2 kg
rimonabant, 1.7 ± 1.0 kg

.001 for rimonabant vs

Overall decrease liver fat

comparable between
Key results

Cannabis and Pancreatic Diseases

CB1 and CB2 are expressed in the pancreas and there
has been increased attention to cannabis’ role in acute
diet group pancreatitis (AP) and chronic pancreatitis (CP). AP is char-
acterized by inflammation, which might be affected by
diet)

cannabis use. However, it is not clear whether cannabis

contributes to or attenuates episodes of AP. A recent sys-
tematic review of case reports of AP found cannabis to be a
causative agent for previously classified idiopathic pancre-
atitis.113 A cohort study of 460 patients with a first episode
assessed by magnetic
Absolute weight loss with

of AP found a high prevalence of cannabis use for all etiol-

Interventions

ogies of AP (10%), including in cases labeled idiopathic.114

Change in liver fat

spectroscopy

The authors suggested cannabis may be the inciting

rimonabant

resonance

source in previously labeled idiopathic AP and additional

investigation into its role in AP is warranted. In mice with
cerulein-induced AP, infusion of the CB1 agonist ananda-
mide increased the severity of pancreatitis. CB1 might
activate an inflammatory response in the pancreas by
increasing production of TNF, unlike its anti-TNF effects
Approximately 57 y,

elsewhere in the gastrointestinal tract.115 Conversely, find-

Age and sex

ings from other studies showed that cannabis might protect

32% female

against AP.116 In the largest database study to date, which

Patients

evaluated 10 years of inpatient hospital data, patients with

cannabis exposure (defined using ICD-9-CM) had lower age-
NAFLD, nonalcoholic fatty liver disease; TCHV, tetrahydrocannabivarin.

adjusted disease severity and mortality and fewer compli-

cations (such as acute respiratory distress syndrome and
acute kidney injury) compared to non–cannabis-exposed
n

37

group.117 Cannabis was also reported to reduce risk of

alcohol-induced CP and AP.118 There might be altered CB
Study duration

expression in inflamed tissues, leading to a net anti-

inflammatory effect of cannabis.95 In mice, CB2 agonists
had anti-inflammatory effects, via cytokine inhibition and
decreased oxidative stress.119,120
There is limited evidence of cannabis’ analgesic prop-
48 wk

erties in patients with CP-associated pain. In a randomized

trial of patients with chronic pancreatitis, 1 dose of THC did
not significantly alter pain compared with placebo.121
NAFLD or hepatic steatosis randomized,

rimonabant 20 mg or placebo daily

However, longer-term use might improve pain control. In

double-blind, placebo-controlled,

a small, retrospective cohort study, cannabis use for 34–297

weeks (based on state registry data) decreased levels of
opiate requirement for CP pain, indicating a role for pain
control.122 The visceral inflammatory process in pancreatitis
Table 2. Continued

is likely associated with activation of the ECS. There is a

basis for testing the therapeutic value of cannabinoids as
Study design

supplements to conventional analgesics, as well as their

anti-inflammatory effects. Conflicting findings might be the
results of differences in dosing or delivery methods; further
research is needed to better understand cannabis’ effects on
pancreatitis.
 72 Gotfried et al Gastroenterology Vol. 159, No. 1
PERSPECTIVES
REVIEWS AND

Figure 4. The ECS in

Crohn’s disease and ul-
cerative colitis.
Figure shows receptors
and synthesizing and
degrading enzymes and
relative levels reported
from studies of IBD. AEA,
arachidonoylethanolamide;
2AG, 2-arachidonoylglycerol;
DAGL, diacylglycerol
lipase; MGLL, mono-
acylglycerol lipase;
NAPE-PLD, N-arach-
idonoylphosphatidyletha-
nolamine phospholipase D;
PEA, palmitoylethanolamide.

There have been only 2 studies of the effects of
cannabidiol in patients with gastrointestinal disorders
(IBD and NAFLD)—each produced equivocal re-
sults.123,124 CBD affects enzymes involved in drug meta-
bolism, including CYP450. Many CBD products are not
supervised by the US Food and Drug Administration and
little is known about interactions of other drugs with
CBD, so caution is advised for patients who consume
these products.
Inflammatory Bowel Disease
The ECS can modulate IBD pathogenesis, based on cor-
relations between cannabinoid receptor genotypes and IBD
characteristics (Figure 4). The CB2 complementary DNA
188–189 GG/GG polymorphism is associated with a 2-fold
reduction in endocannabinoid-induced inhibition of T-cell
proliferation.125 The CB2 R63 variant was significantly
associated with IBD, particularly with Crohn’s disease.126
The CB1 p.Thr453Thr polymorphism appears to modulate
susceptibility to ulcerative colitis and Crohn’s disease
phenotype.127 Patients with Crohn’s disease who are ho-
mozygous for the FAAH p.Pro129Thr polymorphism were
more likely to develop severe disease, associated with fis-
tulas and extra-intestinal manifestations, and patients with
ulcerative colitis homozygous for that mutation have earlier
onset of disease.128
There have been many studies of the anti-inflammatory
effects of cannabinoids in various tissues—for reviews, see
Ambrose et al.129 Synthetic and endogenous cannabinoids
inhibit LPS-induced release of TNF from rat microglial
cells.131 Exposure of the mast cell line RBL2H3 to cannabi-
noid altered transcription of many genes; CB2 agonists
activated extracellular signal-regulated kinase, AKT, and a
subset of AKT targets.130
Mice with knockout of CB1 and/or CB2 developed more
severe colitis after administration of dinitrobenzene sulfonic
acid or dextran sulfate sodium than wild-type mice.131 In
mice with dinitrobenzene sulfonic acid–induced induced
colitis, CBD reduced colon injury, expression of inducible
nitric oxide synthase (but not cyclooxygenase-2), and
changes in interleukin (IL)1beta, IL10, and endocannabi-
noids associated with 2,4,6-dinitrobenzene sulfonic acid
administration. So CBD reduces colitis in mice.132 In rats,
THC and CBD each reduced myeloperoxidase activity,
reduced colonic motility (measured in vitro), and protected
Table 3.Studies of Inflammatory Bowel Disease

July 2020
Patients
Study, first
Study design Study duration n Age and sex Interventions Key results author

Crohn’s disease double-blind, 8 wk treatment, 2 wk 21 Approximately 40 y Assessed patients with Primary end point of Naftali142
randomized, placebo-controlled after therapy and 62% men CDAI scores >200 induction of remission
smoked cannabis flowers without response to was not achieved
11.5 mg or placebo, twice daily steroids, 10 of 11 had significant
immunomodulators, or clinical and steroid free
anti-TNF agents benefit
Decrease in CDAI score by
more than 100 patients,
P ¼ .028
Crohn’s disease; double-blind, 8 wk treatment and 2 22 Approximately 39 y Assessed patients with No significant reduction in Naftali123
randomized, placebo-controlled; wk after therapy and 50% men moderately active CD CDAI concluded that
CBD oil (10 mg) vs placebo twice and assessed CBD was safe but not
daily nonresponders to beneficial for patients
steroids, immune- with Crohn’s disease

Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease

modulators, or anti-TNF
agents
Ulcerative colitis; double-blind, 10 wk 60 (39 Approximately 45 y Assessed remission (by Primary end point not Irving143
randomized, placebo-controlled, completed and 79% men Mayo score) after 10 wk achieved, no significant
parallel group trial; the study) effect on rate of
CBD-rich botanical extract (50–250 remission, according to
mg) and 0.7% THC or placebo, per-protocol analysis of
twice daily total or partial Mayo
scores indicated effects
of CBD-THC group (P ¼
.068 vs P ¼ .038 in
placebo group)
Ulcerative colitis; randomized, 8 wk 28 33 y and 52% men Assessed response to THC THC-rich cannabis is safe Naftali146
placebo-controlled trial; inhaled in patients with and led to clinical and
cannabis (cigarettes) moderately severe endoscopic
0.5 g cannabis (11.5 mg THC) vs ulcerative colitis by improvement
placebo (extracted THC), 2 disease activity index Decrease in CDAI scores of
cigarettes daily and Mayo score approximately 6
patients and decrease
in Mayo score of
approximately 1 patient

73
REVIEWS AND
PERSPECTIVES
 74 Gotfried et al
cholinergic nerves. The effects of these 2 phytocannabinoids
were additive.133 In mice with dinitrobenzene sulfonic acid–
PERSPECTIVES
REVIEWS AND
induced colitis, cannabigerol, a non-psychotropic cannabis-
derived cannabinoid, reduced colon weight to length ratios,
myeloperoxidase activity, and levels of inducible nitric oxide
synthase; increased superoxide dismutase activity; and
normalized levels of IL1B, IL10, and interferon gamma.134
For reviews of these studies, see Couch et al.135
Cannabis Use by Patients With
Inflammatory Bowel Disease
Despite improvements in IBD therapy, many patients do
not respond to treatment and some have turned to alter-
native therapies, including cannabis. Data from a nationwide
health survey support this, showing increased use of
cannabis among patients with IBD compared to participants
without IBD.136
Several observational studies have shown improvement
in both symptoms and clinical outcomes with cannabis use.
In a retrospective, observational study of the effects of
cannabis on disease activity, use of medication, need for
surgery, and hospitalization were examined in 30 patients
with Crohn’s disease. A significant improvement was
observed in 21 of 30 patients, with reduction in the average
Harvey Bradshaw index from 14 ± 6.7 to 7.0 ± 4.7 (P <
.001). The need for other medication was reduced signifi-
cantly.137 Observational data from a national inpatient
sample of patients with Crohn’s disease–related complica-
tions compared 615 cannabis users and nonusers hospital-
ized from 2012 through 2014. Cannabis users were
significantly less likely to have had active fistulizing disease
and intra-abdominal abscess, blood product transfusion,
colectomy, and parenteral nutrition requirement.138 Lastly,
a survey of 313 patients with IBD investigating motives,
patterns of use, and subjective beneficial and adverse effects
of cannabis use found that cannabis had been used by
17.6% of respondents, who reported reduced abdominal
pain (83.9%), abdominal cramping (76.8%), joint pain
(48.2%), and diarrhea (28.6%). Interestingly, despite
improvement in these subject symptoms, patients with
Crohn’s disease, cannabis use for longer than 6 months for
symptoms was associated with requirement for surgery. It
is not clear whether cannabis use increases risk for surgery
or if cannabis is used more frequently in patients with se-
vere, perhaps fibrostenotic, disease.139
Although there are data to support cannabis use for
subjective symptoms in patients with IBD, these were from
observational studies, and results should be interpreted
with caution. Although patients might have subjective
improvement in their symptoms, there is no evidence for
reductions in disease progression or severity.
Trials of Cannabis Use for Inflammatory
Bowel Disease
Despite abundant preclinical evidence that cannabinoid
drugs can reduce intestinal inflammation, few clinical
studies have been completed. There were 2 Cochrane
Gastroenterology Vol. 159, No. 1
reviews of randomized trials of patients with Crohn’s dis-
ease (3 studies)140 and ulcerative colitis (2 studies).141 In
the first trial, 21 patients with Crohn’s Disease Activity In-
dex (CDAI) scores >200 were randomly assigned to groups
given either cannabis flowers containing THC or placebo.
Complete remission (CDAI score <150) was achieved by 5
of 11 subjects in the cannabis group (45%) and 1 of 10
subjects in the placebo group (10%; P ¼ .43), not achieving
the primary end point of the study. However, clinical re-
sponses (decrease in CDAI score by >100 points) were
observed in 10 of 11 subjects in the cannabis group (90%;
from a mean 330 ± 105 to 152 ± 109) and 4 of 10 in the
placebo group (40%; from a mean 373 ± 94 to 306 ± 143;
P ¼ .028). Patients reported improved appetite and sleep
without significant adverse events.142
Due to the lack of central effect and the anti-
inflammatory activity observed in animal models, CBD is
an attractive treatment option. A randomized trial evaluated
the effects of low-dose CBD in 19 patients with CDAI scores
>200 who were randomly assigned to groups given 10 mg
oral CBD or twice daily placebo for 8 weeks. Mean CDAI
scores before CBD consumption were 337 ± 108 and 308 ±
96 in the CBD and placebo groups, respectively. After 8
weeks of treatment, CDAI scores were 220 ± 122 and 216 ±
121 in the CBD and placebo groups, respectively (not
significantly different). The negative result of this study
could be attributed to inefficacy of CBD in patients with
Crohn’s disease or inadequate dosing.123
A randomized trial of 50 patients with active Crohn’s
disease compared the effects of cannabis oil (15% CBD and
4% THC) vs placebo for 8 weeks. At study completion, the
mean CDAI scores were 118.6 in the cannabis oil group vs
212.6 in the placebo group (P < .05). Quality of life scores
were 96.3 in the cannabis oil group vs 79.9 in the placebo
group (P < .05).140
In a study of patients with ulcerative colitis, participants
were randomly assigned to groups that received CBD-rich
botanical extract (also containing THC) for 10 weeks or pla-
cebo capsules. At the end of the study, the proportion of
patients in remission did not differ significantly between the
CBD (28%) and placebo (26%) groups. However, many pa-
tients were intolerant to the CBD capsules, so 40% of patients
in this group had a protocol deviation. Per-protocol analysis
revealed that patients in the CBD group had significant re-
ductions in total and partial Mayo scores (P ¼ .068 and P ¼
.038, respectively), indicating clinical and endoscopic
improvement. Quality of life also improved in patients given
CBD. Although this study did not reach its primary end point,
the findings indicate some beneficial effects of cannabis for
patients with ulcerative colitis.143 A separate study compared
the effects of cannabis cigarettes (23 mg THC/day) vs pla-
cebo in 30 patients with active ulcerative colitis. This study
found that after 8 weeks, mean disease activity index scores
in patients taking cannabis was 4 compared with 8 for pa-
tients in the placebo group (P ¼ .001).140
Olorinab (APD371), a peripherally restricted, selective
agonist of CB2, reduced pain scores in patients with Crohn’s
disease and has a favorable safety profile, specifically
without CNS effects.144 Studies are planned to evaluate its
July 2020 Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease
effects on chronic abdominal pain in patients with Crohn’s
disease. There have been no studies of the ability of
cannabis to maintain remission in patients with Crohn’s
disease or ulcerative colitis (Table 3).
Future Directions
The ECS helps maintain gastrointestinal homeostasis and
might be manipulated therapeutically. There is abundant
evidence for the anti-inflammatory and anti-nociceptive ef-
fects of cannabinoids. Many patients with gastrointestinal
conditions could benefit from cannabis or cannabinoids.
Findings from several small studies support use of cannabis
or cannabinoids in patients with IBD. Interestingly, results
from epidemiologic studies contradict results from animal
and human studies of cannabis and cannabinoids—especially
their effects on obesity and fatty liver, relief from symptoms
of gastroparesis, and IBS. These discordant results indicate
the complicated pathways and interactions of the ECS with
other organ systems. The ECS is far more complex than we
appreciate, and most studies have evaluated CB1 and CB2
only. Targeting individual receptors is beneficial, but future
studies, such as those evaluating synthesizing and degrading
enzymes and their effects on endocannabinoids, as well as
new, peripherally restricted agents, could lead to new ther-
apeutic avenues for cannabis and its derivatives in treatment
of gastrointestinal disease. Importantly, cannabinoids are far
from the panacea that some claim—additional investigation
is needed to further our understanding of their sometimes
detrimental effects.
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144. Yacyshyn B, Ginsberg DC, Gilder K, et al.

Received August 8, 2019. Accepted March 29, 2020.
Su1930—Safety and efficacy of olorinab, a peripherally
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restricted, highly selective, cannabinoid receptor 2 Correspondence

agonist in a phase 2A study in chronic abdominal pain Address correspondence to: Ron Schey, MD, FACG, Division of
Gastroenterology/Hepatology, Department of Internal Medicine, University of
associated with Crohn’s disease. Gastroenterology Florida College of Medicine, Jacksonville, Florida. e-mail:
2019;156:S-665. Ron.Schey@jax.ufl.edu.
145. Vemuri VK, Makriyannis A. Medicinal chemistry of can-
CRediT Authorship Contributions
nabinoids. Clin Pharmacol Ther 2015;97:553–558. Siyuan Ding, PhD (Writing – original draft: Equal; Writing – review & editing:
146. Naftali T, Bar-lev Schleider L, Sklerovsky Benjaminov F, Equal); T. Jake Liang, M.D. (Writing – original draft: Equal; Writing – review &
et al. Cannabis induces clinical and endoscopic editing: Equal).
improvement in moderately active ulcerative colitis. Conflicts of interest
Gastroenterology 2018;154:S378; Abstract Suppl 1. The authors disclose no conflicts.