Curr Gastroenterol Rep (2015) 17: 9
DOI 10.1007/s11894-015-0429-1
NEUROGASTROENTEROLOGY AND MOTILITY DISORDERS OF THE GASTROINTESTINAL TRACT (S RAO, SECTION EDITOR)
The Role of Cannabinoids in Regulation of Nausea and Vomiting,
and Visceral Pain
Zubair Malik & Daniel Baik & Ron Schey
Published online: 26 February 2015
# Springer Science+Business Media New York 2015
Abstract Marijuana derived from the plant Cannabis sativa
has been used for the treatment of many gastrointestinal (GI)
disorders, including anorexia, emesis, abdominal pain, diar-
rhea, and others. However, its psychotropic side effects have
often limited its use. Several cannabinoid receptors, which
include the cannabinoid receptor 1 (CB1), CB2, and possibly
GPR55, have been identified throughout the GI tract. These
receptors may play a role in the regulation of food intake,
nausea and emesis, gastric secretion and gastroprotection, GI
motility, ion transport, visceral sensation, intestinal inflamma-
tion, and cell proliferation in the gut. However, the regulation
of nausea and vomiting by cannabinoids and the
endocannabinoid system has shed new knowledge in this
field. Thus far, despite evidence of visceral sensitivity inhibi-
tion in animal models, data in irritable bowel syndrome (IBS)
patients is scarce and not supportive. Furthermore, many com-
pounds that either act directly at the receptor or increase (or
reduce) ligand availability have the potential to affect other
brain functions and cause side effects. Novel drug targets such
as FAAH and monoacylglycerol lipase (MAGL) inhibitors
appear to be promising in animal models, but more studies
are necessary to prove their efficiency. The promise of emerg-
ing drugs that are more selective and peripherally acting sug-
gest that, in the near future, cannabinoids will play a major
role in managing an array of GI diseases.
Keywords Cannabis . CB1 . CB2 . Endocannabinoids .
Nausea and vomiting . Visceral pain
This article is part of the Topical Collection on Neurogastroenterology
and Motility Disorders of the Gastrointestinal Tract
Z. Malik : D. Baik : R. Schey (*)
Section of Gastroenterology, Department of Medicine, Temple
University School of Medicine, Philadelphia, PA, USA
e-mail: Ron.schey@tuhs.temple.edu
Introduction
The marijuana plant Cannabis sativa is one of the most com-
monly used illicit drug today with over 16 million users in the
USA; the largest demographic group is the 18–25 year olds
[1]. The plant contains at least 70 different cannabinoids that
are a class of diverse chemical compounds of Cannabis that
act on cannabinoid receptors located on cells that repress neu-
rotransmitter release in the brain. These receptor proteins in-
clude 1. endocannabinoids, which are produced naturally in
the body by humans and animals and are a part of the
endocannabinoid system that also consists of cannabinoid re-
ceptors and the enzymes that synthesize and degrade the li-
gands, 2. phytocannabinoids, which are found in cannabis and
some other plants (Cannabis delta-9-tetrahydrocannabinol
(Δ9-THC) and cannabidiol), and 3. synthetic cannabinoids,
which are manufactured chemically (Table 1) [2].
Cannabinoids have been used to treat many health prob-
lems, including anorexia, emesis, abdominal pain, and diar-
rhea. Their role in the treatment of gastrointestinal (GI) disor-
ders particularly visceral pain, nausea, and vomiting will be
the focus of this review.
The Cannabinoid Receptors
Cannabinoid receptors are present throughout the GI tract,
including the liver, pancreas, stomach, and the small and large
intestines. In 1990, the first cannabinoid receptor was cloned
by Matsuda et al. and named it as cannabinoid receptor 1
(CB1) [3]. Subsequently, a second receptor (CB2) was iden-
tified [4]. The discovery of the endogenous ligands for these
receptors provided the basis for the establishment of the
endocannabinoid system [3, 5]. The established CB receptors
show a distinct distribution in the gastrointestinal tract with
CB1 and CB2 receptors found on macrophages, plasma cells,
9 Page 2 of 9
Table 1 Cannabinoid receptor compounds
Agonists
Plant derived
Δ9-THC Main psychoactive cannabinoid in the marijuana
plant
Δ8-THC Slightly less potent than Δ9-THC
11-OH-Δ9-THC Bioactive compound formed when the body
breaks down Δ9-THC
Animal derived
Anandamide 2-AG
THC analogues
Dronabinol Nabilone CP 55,940 HU-210 Levonantradol
Different chemical structure
WIN-55,212 Binds to both cannabinoid receptors.
Antagonists (receptor blockers)
SR 141716A Synthetic CB1 antagonist
SR 144528 Synthetic CB2 antagonist
enteric neurons, nerve fibers, and terminals throughout the
enteric nervous system [6–9]. CB1 receptors are also localized
on epithelial cells, and CB2 receptors are present on immune
cells [6, 10]. Both receptors are coupled negatively through
Gi/Go-type G proteins to adenylate cyclase and positively to
mitogen-activated protein kinase (MAP kinase), but little is
known regarding the exact cellular mechanisms involved after
their activation in the gastrointestinal tract [10]. CB1 receptors
are mainly expressed in the central and peripheral nervous
system, including the enteric nervous system, whereas the
CB2 re ce pto rs a re s ee n in immu ne cell s [7 , 8 ].
Endocannabinoid and CB1 receptors have been identified in
key areas of the GI tract, such as the cholinergic neurons. The
endogenous arachidonate-based lipids, anandamide (N-
arachidonoylethanolamide, AEA) and 2-
arachidonoylglycerol (2-AG), are known as
“endocannabinoids” and are physiological ligands for the can-
nabinoid receptors. The endocannabinoid system has been
shown to have a role in regulation of food intake, nausea
and emesis, gastric secretion and gastroprotection, GI motility,
ion transport, visceral sensation, intestinal inflammation, and
cell proliferation in the gut [9, 11]. Unlike traditional neuro-
transmitters, endogenous cannabinoids are not stored in vesi-
cles after synthesis but are synthesized on demand. However,
some evidence suggests that a pool of synthesized
endocannabinoids (namely 2-AG) may exist without the re-
quirement of on-demand synthesis. CB2 receptors are thought
to serve as an important role in immune function and inflam-
mation, but it has been shown that they also have a role in
regulating abnormal motility, modulating intestinal inflamma-
tion, and reducing visceral sensitivity and pain [12, 13].
Curr Gastroenterol Rep (2015) 17: 9
The recently discovered G-protein-coupled receptor,
GPR55, has been proposed to be the ‘third’ cannabinoid re-
ceptor. Although gene expression of GPR55 is evident in the
gut, functional evidence for GPR55 in the gut is lacking. A
recent study found that GPR55 activation inhibits neurogenic
contractions in the gut [14].
Effects of Cannabinoids: Activation of CB1 and CB2
receptors may play a role in the regulation of GI function.
CB1 receptor activation has been shown to inhibit the
peristaltic reflex and slow down GI and colonic transit,
while endocannabinoids may play a role in transient lower
esophageal sphincter relaxations (TLESRs) [15]. The en-
dogenous cannabinoid system also modulates the nerve
growth factor-mediated components of inflammatory re-
sponse [16]. A recent study demonstrated that Δ9-THC
blocks diclofenac-induced gastric inflammatory damage
in rats at doses insufficient to cause common cannabinoid
side effects [17].
Cannabinoid receptor agonists inhibit gastric emptying and
intestinal motility in humans. There is good evidence to sup-
port the role of CB1 receptors in the control of gastrointestinal
sensation, since these receptors have been identified in the
neuronal circuitry of the transmission of visceral pain. CB2
receptor activation reduces nociception in a variety of preclin-
ical models, including those involved in tactile and thermal
allodynia, mechanical and thermal hyperalgesia, and writhing
[18]. Experimental data show that cannabinoid receptor ago-
nists have a visceral anti-receptive effect. In general, the phar-
macological effects of cannabis consumption on the GI tract
include decreased motility and secretion and slowing of
gastric/colonic emptying as well as anti-inflammatory [9].
The m ajor constituent of cannabis is delta-9-
tetrahydrocannabinol (Δ9-THC) which acts as a partial ago-
nist at of both cannabinoid receptors. Its prototypes are
nabilone and dronabinol. Dronabinol is marketed as an appe-
tite stimulant and as an anti-emetic in many countries. One
study has shown that it also activates non-CB receptors, and
this may be responsible for the psychoactive effects mainly
through its actions on the CB1 receptor [19, 20]. Other com-
pounds have also been identified that may play a role as phar-
macologic agents, such as cannabidiol, oleoylethanolamide
(OEA), and salvinorin [21]. It has been suggested that these
other compounds interact in a complex manner to modulate
pain [22].
The use of cannabinoids is often limited by their side ef-
fects, which can include tachycardia, hypotension, muscle re-
laxation, bloodshot eyes, gastroparesis, dizziness, depression,
hallucinations, and paranoia, and these often occur at higher
doses [23–28].
Cannabis may exacerbate psychiatric disorders and de-
crease motivation. Other side effects may include moderate
driving impairment, gynecomastia, impairment of fetal
growth, and reduction in fertility and immune function.
Curr Gastroenterol Rep (2015) 17: 9
Coadministration of opioids should be done cautiously be-
cause cannabinoids may increase the synthesis or release of
endogenous opioids and may upregulate opioid gene expres-
sion in the brain and spinal cord and regions that regulate pain
sensation, motor activity, and pituitary secretion. A systematic
review of safety studies of medical cannabinoids reported that
the most common serious adverse event was relapse of mul-
tiple sclerosis, vomiting, and urinary tract infections as well as
cyclical vomiting-like syndrome also called cannabinoid
hyperemesis. Dizziness was the most commonly non-serious
adverse event among people exposed to cannabinoids [29,
30].
Cannabinoids and Visceral Pain
Visceral pain results from the activation of nociceptors located
in the thoracic, pelvic, or abdominal viscera, which are sensi-
tive to distension, ischemia, and inflammation. The pain is
diffuse, often difficult to localize, and usually accompanied
by referred pain. Patients with visceral pain often fall into
the category of functional GI disorders, with the two major
disorders being functional dyspepsia and irritable bowel syn-
drome (IBS). IBS is the most common disorder seen in the GI
outpatient practice [31]. The mechanism of pain in IBS is
attributed to visceral hypersensitivity or enhanced perception
to distention of colon or rectosigmoid, in approximately 70 %
of patients [32, 33]. It is estimated that there are approximately
3.65 million physician visits annually for IBS with a direct
cost of $1.5 billion and an indirect cost of $20 billion annually
[34, 35].
Cannabis may be used for its analgesic properties, but its
use is limited by its psychotropic side effects. Cannabinoids
have been demonstrated to have an analgesic effect at both the
spinal and peripheral levels in both the GI tract as well as other
areas of the body [36, 37, 38•].
Intestinal peristalsis is mediated by intrinsic sensory neu-
rons and interneurons, as well as by excitatory and inhibitory
motor neurons. Acetylcholine (ACh) acting through both
muscarinic and nicotinic receptors and tachykinins serve as
excitatory neurotransmitters for peristalsis, whereas VIP, nitric
oxide (NO), and ATP (or related purine) acts as inhibitory
mediators. Cannabinoids may affect the intrinsic sensory neu-
rons. CB1 receptor immunoreactivity was identified on the
intrinsic sensory neurons, ascending neurons, as well as the
excitatory motor neurons that project into the longitudinal and
circular muscles (Fig. 1) [28]. Brusberg et al. showed that CB1
receptors, but not CB2, are involved in the modulation of
basal visceral sensation in a rodent model of visceral pain
induced by colorectal distension [7]. This did not support a
previous study that demonstrated an anti-nociceptive effect of
a putative CB2 receptor agonist in a rat model [39]. Another
rat model showed that transient receptor potential vanilloid
Page 3 of 9 9
type 1 receptor (TRPV1), which plays a pivotal role in the
development of inflammatory heat hyperalgesia and visceral
hyperreflexia, can be activated by cannabinoids (Fig. 1) [40•].
In other rat models of acid-induced colitis, CB1 and CB2
antagonists resulted in an increased visceral hypersensitivity
to rectal distension, whereas CB1 and CB2 agonists reduced
basal sensitivity and colitis-induced hypersensitivity [39, 41].
Bingham et al. showed that a CB2 agonist was effective in the
relief of visceral pain in rats [42]. Put together, these studies
provide evidence for a role of cannabis in visceral sensation.
Few clinical trials have studied the role of cannabinoids in
the control of intestinal motility and sensory function in pa-
tients. Dronabinol decreased fasting colonic motility and in-
creased compliance to colorectal distention in healthy volun-
teers. However, IBS patients who received dronabinol report-
ed increased pain during colorectal distention. It was hypoth-
esized that this phenomenon was possibly due to the central
side effect of increased awareness [43].
Klooker et al. examined the effect of Δ9-THC on rectal
sensitivity. They compared the effect of placebo and a Δ9-
THC agonist (5 and 10 mg) on rectal sensitivity using a rectal
barostat in 10 patients with IBS and 12 healthy volunteers.
The cannabinoid agonist did not alter baseline rectal percep-
tion to distension compared to placebo in both groups. Simi-
larly, after sigmoid stimulation, there was no significant dif-
ference compared to placebo. The authors concluded that Δ9-
THC agonist does not modify visceral rectal perception and
suggested that CB agonists are not useful for treatment of
visceral hypersensitivity in IBS patients [44•]. This study is
hampered by the fact that anxiety was not evaluated, although
all participants reported central side effects including in-
creased awareness of the surrounding, light-headedness, and
sleepiness with the highest dose of Δ9-THC agonist
(dronabinol 10 mg), whereas no side effects were reported
with placebo. Although BP was stable, the heart rate increased
in both groups, substantially more in IBS patients. As men-
tioned, the central activation of CB1 receptor induces anxiety
and increased awareness of physical stimuli. All medications
were given in a single oral administration 30–100 min prior to
evaluation. These results are disappointing given the evidence
in animal models for an analgesic role of cannabinoids. In
addition, these patients were noted to have central side effects
such as drowsiness and heightened awareness [44•].
Wong et al. demonstrated that dronabinol decreased fasting
colonic motility and increased colonic compliance selectively
in patients with IBS-D or IBS-A. Participants were random-
ized to one oral administration of placebo, dronabinol 2.5 mg
or dronabinol 5 mg, taken at the study center under supervi-
sion of a study staff. The effects were influenced by the pres-
ence of genetic polymorphisms in fatty acid amide hydrolase
(FAAH) or CB1. However, pain scores during colorectal dis-
tention were unaffected [45]. Overall, these data suggest that
the endocannabinoid system does play a role in the
9 Page 4 of 9
Fig. 1 Sites of action of
cannabinoids in the enteric
nervous system (adapted with the
permission from Aviello G et al.,
Verducci publishers [28])
pathophysiology of IBS in animal models: further studies are
needed to determine whether pharmacologic manipulation of
this system can be clinically beneficial [7, 38•, 39, 40•, 41, 43,
44•, 45].
Recently, we evaluated visceral pain thresholds in patients
with non-GERD-related non-cardiac chest pain (NCCP). Thir-
teen patients were randomized to receive a Δ9-THC agonist
(dronabinol 5 mg bid) or placebo for 4 weeks. An esophageal
balloon distention test (EBDT) was performed by incremental
balloon distension with water in the mid esophagus. First sen-
sation and maximum tolerance on a 0–4 scale were assessed at
baseline and on the last day of treatment (day 28). Chest pain
symptoms and esophageal sensorimotor properties were
assessed pre and on day 28 of treatment using questionnaires
and a symptom diary. The threshold for the first sensation was
significantly higher after treatment compared to pretreatment
in the dronabinol group and non-significant in the placebo
group. In addition, the dronabinol group demonstrated a sig-
nificant improvement in pain frequency and intensity on day
28 when compared to pretreatment. Interestingly, no signifi-
cant adverse effects were noted despite the fact that the med-
ication was given twice daily for a period of 4 weeks [46•].
Fichna et al. reported that PF-3845 (selective FAAH inhib-
itor) significantly inhibited mouse colonic motility in vitro and
in vivo. It reversed hypermotility and reduced pain in mouse
Curr Gastroenterol Rep (2015) 17: 9
models mimicking functional GI disorders. The effects of PF-
3845 were mediated by endogenous CBs and non-CB lipo-
philic compounds via classical CB1 and atypical CB recep-
tors. The anti-nociceptive action of PF-3845 was evaluated on
the basis of behavioral pain models [47•].
Cannabinoids and Nausea and Vomiting
Nausea is an aversive experience that often precedes
emesis, which is a forceful expulsion of gastric and up-
per intestinal contents. Nausea and vomiting (N&V) are
important defense mechanisms that protect the gut from
the ingestion of potentially harmful substance [48]. How-
ever, the sensitivity of this reflex is extremely low and
triggered with marginal stimuli, leading to improper
stimulation in many disease states [48]. Similarly, N&V
are some of the most common adverse effects of medi-
cations, notoriously associated with many chemothera-
peutic agents [48]. Other common causes of N&V in-
clude pregnancy (with the extreme health-compromising
situation of hyperemesis gravidarum) and motion sick-
ness (caused by conflict between the vestibular, visual,
and other proprioceptive systems) [49, 50].
The brain centers that control nausea are located in the
forebrain, and the receptors which are located in the floor of
Curr Gastroenterol Rep (2015) 17: 9
the fourth ventricle of the brain represent a chemoreceptor
trigger zone that, when stimulated, leads to vomiting. The
chemoreceptor trigger zone has dopamine D2 receptors, sero-
tonin 5-HT3 receptors, opioid receptors, acetylcholine recep-
tors, and receptors for substance P (Fig. 2). The pathophysi-
ology for most cases of emesis are well studied and include a
trigger (serotonin e.g., 5-HT) released from enterochromaffin
cells in the GI epithelium, activating 5-HT3/5-HT4 receptors
on vagal primary afferent nerves [51]. These stimulate circuits
to the dorsal vagal complex (DVC) of the brainstem, which
includes the nucleus of the solitary tract, area postrema, and
dorsal motor nucleus of the vagus. The solitary nucleus acti-
vates the motor responses that elicit the characteristic emesis
[48].
The brain circuitry responsible for evoking nausea is not
well understood. A recent study triggered nausea by visual
stimulation and performed functional magnetic resonance im-
aging simultaneously. This study revealed an elaborate net-
work in the brain activated by nausea, including areas respon-
sible for interceptive, limbic, somatosensory, and cognitive
processing [52].
As mentioned previously, CB1 receptors are widely distrib-
uted in virtually all brain regions, including the DVC involved
in emesis and the brain regions described above [53]. The
highest density of CB1 receptors are in the cortex, amygdala,
and basal ganglia, with lower densities in the nucleus accum-
bens, ventral tegmental area, and brainstem regions [54]. CB1
receptors are also located on dopaminergic, noradrenergic,
and other transmitter-containing neurons in the brain regions
involved in the control of nausea and vomiting [55].
CB1-
D2+
NK-1+
5-HT3+
Fig. 2 Chemoreceptor trigger zone agonists and antagonists
Page 5 of 9 9
Cannabis prevents N&V triggered by many causes [56].
However, its therapeutic value is overshadowed by its central
nervous system side effects. Recent research has focused on
finding selective ligands for the CB2 receptor or on develop-
ing peripherally restricted CB1/CB2 ligands [57]. Many stud-
ies have confirmed that cannabinoids block both acute and
delayed emesis, mediated by its effects of the CB1 receptors
in the DVC [58–61]. Additionally, the administration of CB1
receptor antagonists in humans has actually evoked nausea
and emesis in multiple studies [62–64].
I n t e r e s t i n g l y, C h o u k e r e t a l . r e v i e w e d b l o o d
endocannabinoid levels in humans undergoing parabolic
flight maneuvers and noted that those who experienced mo-
tion sickness had lower levels of anandamide and 2-AG, while
those who did not experience motion sickness had higher
levels of the endocannabinoids [65]. In addition, CB1 receptor
expression was also reduced in those experiencing more
symptoms, and the level of arachidonic acid, the downstream
metabolite of endocannabinoids, was significantly increased
in patients experiencing N&V upon acceleration than those
who did not [61, 65, 66].
Conversely, the role of CB2 receptors in preventing N&V
is ill defined, although one study did show that there are CB2
receptors in the DVC of a ferret [61]. CB2 receptors are post-
synaptically localized and may regulate neuronal excitability
by unique mechanisms, as well as through more traditional
cannabinoid signaling. CB2 receptors in the prefrontal cortex
are intracellular and regulate neuronal excitability through
calcium-activated chloride channels and are recently reported
to form functional heteromers with the CB1 receptor [67]. The
distribution of endocannabinoid biosynthesis enzymes needs
further evaluation, though FAAH and monoacylglycerol li-
pase (MAGL) are present in some of these regions, such as
the nucleus accumbens and the amygdala [68].
The CB2 receptor’s role in anti-emesis merits further re-
search because of its lack of psychotropic effects [48]. It is
also important to note that the entire endocannabinoid system
likely communicates with other receptor systems, including
the 5-HT3 and the TRPV1 systems, and their interactions
require further study.
Chemotherapy-induced nausea and vomiting (CINV) is as-
sociated with a significant deterioration in quality of life [51].
The orally active, synthetic analogue of Δ9-THC, nabilone,
has been shown to lower the vomiting episodes compared
with D2 receptor antagonists such as domperidone and
metoclopramide in patients taking moderately toxic chemo-
therapy treatments [69]. However, there was no advantage
over D2 antagonists when given to cancer patients receiving
cisplatin (highly emetogenic agent) chemotherapy. The same
effect was seen with another synthetic analogue of Δ9-THC,
dronabinol [70]. Namisol is a novel oral formulation of pure
Δ9-THC that has shown promising pharmacokinetic and
pharmacodynamic characteristics. Variability and t (max) of
9 Page 6 of 9
THC plasma concentrations were smaller than reported for
studies using oral dronabinol and nabilone [71].
A recent study evaluated the safety and pharmacokinetic
profile of Namisol in healthy older subjects and found it to be
safe and well tolerated by healthy older individuals [72]. Pre-
viously, Meiri et al. compared dronabinol alone versus
ondansetron (5-HT3 receptor antagonist) versus a combina-
tion in the treatment of CINV. In this study, dronabinol or
ondansetron were similarly effective (although dronabinol
had an advantage in mild-moderately severe nausea), but the
combination of both was no more effective than either one
alone [73]. Recently, a non-selective cannabinoid agonist
WIN 55 212-2 (WIN) aggravated gastric dysmotility caused
by cisplatin but did prevent induced neuropathy in a rat model
[74]. Another study used cannabidiolic acid in rats, which also
showed improvement in nausea-induced behavior and
vomiting [75].
The current CINV prevention strategy includes a combina-
tion of serotonin (5-HT3) receptor antagonists, corticoste-
roids, and/or neurokinin-1 receptor antagonists. Current
guidelines recommend that D2 receptor antagonists be re-
served for patients intolerant of or refractory to 5-HT3 recep-
tor antagonists, but this study may cause extrapyramidal
symptoms, which limits the use of these agents. Thus far, a
clinical trial which compares the effect of cannabinoids versus
dopamine/serotonin receptor combination has not been done.
A phase II trial compared Sativex (combination of Δ9-THC
and cannabidiol) taken with 5-HT3 receptor antagonists ver-
sus a combination of placebo and 5-HT3 receptor antagonists
in patients with CINV. The addition of Sativex reduced the
incidence of delayed nausea and vomiting and was well toler-
ated. This combination may be useful in managing delayed
nausea and vomiting in humans [76].
The “cannabinoid hyperemesis syndrome” (CHS) was first
described in 2004 [77]. CHS is a syndrome of cyclic episodes
of nausea and vomiting and abdominal pain, due to chronic
cannabis usage. Patients adopt a learned behavior of hot baths
or showers to improve symptoms [78]. Interestingly, standard
anti-emetics are markedly ineffective in its treatment [77, 79,
80]. The mechanism of this syndrome is entirely unknown,
although some believe a toxic metabolite from the cannabis
plant may be responsible. Another hypothesis is that the high
exposure to the ligand may lead to the downregulation of
cannabinoid receptors [48].
Conclusions
Cannabinoids are increasingly being prescribed for GI condi-
tions, particularly nausea and vomiting, as an appetite stimu-
lant and anecdotally for visceral pain. However, treatment of
visceral pain has yet to be proven in humans, with some prom-
ising early results. It seems that direct or indirect CB1 receptor
Curr Gastroenterol Rep (2015) 17: 9
activation as well as direct CB2 receptor activation inhibit
visceral sensitivity and pain in rodents. Thus far, despite these
promising results in animal models, data in IBS patients is
scarce and not supportive. Furthermore, central side effects
such as drowsiness and heightened awareness were reported
in these studies. The development of new CB2 ligands as well
as peripherally acting CB1/CB2 ligands has the potential to
alleviate symptoms without central nervous system side ef-
fects. Overall, further studies are needed to validate whether
pharmacologic manipulation of this system is clinically useful
in treating IBS.
Cannabinoids have a more proven role in N&V, with the
recent progress in understanding the regulation of nausea and
vomiting by cannabinoids and the endocannabinoid system.
However, much research is needed regarding the fact that
compounds that either act directly at the receptor or increase
(or reduce) ligand availability have the potential to effect brain
functions besides nausea and vomiting and lead to side effects,
worsen GI motility disorders, and potentially to induce can-
nabinoid hyperemesis syndrome. Novel drug targets such as
FAAH and MAGL inhibitors seem to be promising in animal
models, and more studies are necessary.
In conclusion, our review suggests that cannabinoids have
the potential to play a vital role in the modulation of nausea,
vomiting, and possibly visceral pain. Although the jury is still
out on determining the “magic drug,” it seems that with the
development of newer ligands, the future appears promising.
Compliance with Ethics Guidelines
Conflict of Interest Zubair Malik, Daniel Baik, and Ron Schey declare
no conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with animal subjects performed by any of the
authors. With regard to the authors’ research cited in this paper, all pro-
cedures were followed in accordance with the ethical standards of the
responsible committee on human experimentation and with the Helsinki
Declaration of 1975, as revised in 2000 and 2008.
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