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, diarrhea, 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 inflammation, 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 inhibition in animal models, data in irritable bowel syndrome (IBS) patients is scarce and not supportive. Furthermore, many compounds 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 emerging drugs that are more selective and peripherally acting suggest 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: [email protected]

Introduction The marijuana plant Cannabis sativa is one of the most commonly 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 neurotransmitter release in the brain. These receptor proteins include 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 receptors and the enzymes that synthesize and degrade the ligands, 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 problems, including anorexia, emesis, abdominal pain, and diarrhea. Their role in the treatment of gastrointestinal (GI) disorders 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 identified [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 (Narachidonoylethanolamide, AEA) and 2arachidonoylglycerol (2-AG), are known as “endocannabinoids” and are physiological ligands for the cannabinoid 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 neurotransmitters, endogenous cannabinoids are not stored in vesicles after synthesis but are synthesized on demand. However, some evidence suggests that a pool of synthesized endocannabinoids (namely 2-AG) may exist without the requirement of on-demand synthesis. CB2 receptors are thought to serve as an important role in immune function and inflammation, but it has been shown that they also have a role in regulating abnormal motility, modulating intestinal inflammation, 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 receptor. 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 endogenous cannabinoid system also modulates the nerve growth factor-mediated components of inflammatory response [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 support 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 preclinical models, including those involved in tactile and thermal allodynia, mechanical and thermal hyperalgesia, and writhing [18]. Experimental data show that cannabinoid receptor agonists have a visceral anti-receptive effect. In general, the pharmacological 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-9tetrahydrocannabinol (Δ9-THC) which acts as a partial agonist at of both cannabinoid receptors. Its prototypes are nabilone and dronabinol. Dronabinol is marketed as an appetite 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 compounds have also been identified that may play a role as pharmacologic 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 effects, which can include tachycardia, hypotension, muscle relaxation, bloodshot eyes, gastroparesis, dizziness, depression, hallucinations, and paranoia, and these often occur at higher doses [23–28]. Cannabis may exacerbate psychiatric disorders and decrease 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 because cannabinoids may increase the synthesis or release of endogenous opioids and may upregulate opioid gene expression 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 multiple 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 sensitive 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 syndrome (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 neurons 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 neurons. 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 patients. Dronabinol decreased fasting colonic motility and increased compliance to colorectal distention in healthy volunteers. However, IBS patients who received dronabinol reported increased pain during colorectal distention. It was hypothesized 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 Δ9THC 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 perception to distension compared to placebo in both groups. Similarly, after sigmoid stimulation, there was no significant difference compared to placebo. The authors concluded that Δ9THC 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 increased 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 mentioned, 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 randomized to one oral administration of placebo, dronabinol 2.5 mg or dronabinol 5 mg, taken at the study center under supervision of a study staff. The effects were influenced by the presence of genetic polymorphisms in fatty acid amide hydrolase (FAAH) or CB1. However, pain scores during colorectal distention were unaffected [45]. Overall, these data suggest that the endocannabinoid system does play a role in the

9 Page 4 of 9

Curr Gastroenterol Rep (2015) 17: 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). Thirteen 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 sensation 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 significant improvement in pain frequency and intensity on day 28 when compared to pretreatment. Interestingly, no significant adverse effects were noted despite the fact that the medication was given twice daily for a period of 4 weeks [46•]. Fichna et al. reported that PF-3845 (selective FAAH inhibitor) significantly inhibited mouse colonic motility in vitro and in vivo. It reversed hypermotility and reduced pain in mouse

models mimicking functional GI disorders. The effects of PF3845 were mediated by endogenous CBs and non-CB lipophilic compounds via classical CB1 and atypical CB receptors. 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 upper intestinal contents. Nausea and vomiting (N&V) are important defense mechanisms that protect the gut from the ingestion of potentially harmful substance [48]. However, 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 medications, notoriously associated with many chemotherapeutic agents [48]. Other common causes of N&V include pregnancy (with the extreme health-compromising situation of hyperemesis gravidarum) and motion sickness (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

Page 5 of 9 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, serotonin 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P (Fig. 2). The pathophysiology 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 activates 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 imaging simultaneously. This study revealed an elaborate network in the brain activated by nausea, including areas responsible for interceptive, limbic, somatosensory, and cognitive processing [52]. As mentioned previously, CB1 receptors are widely distributed 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 accumbens, 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].

CB1D2+ NK-1+

5-HT3+ Fig. 2 Chemoreceptor trigger zone agonists and antagonists

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 developing peripherally restricted CB1/CB2 ligands [57]. Many studies 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 motion 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 postsynaptically 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 lipase (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 research 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 associated 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 chemotherapy 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]. Previously, Meiri et al. compared dronabinol alone versus ondansetron (5-HT3 receptor antagonist) versus a combination 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 combination of serotonin (5-HT3) receptor antagonists, corticosteroids, and/or neurokinin-1 receptor antagonists. Current guidelines recommend that D2 receptor antagonists be reserved for patients intolerant of or refractory to 5-HT3 receptor 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 versus 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 tolerated. 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].

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 effects. 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 cannabinoid 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 procedures 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.

References Papers of particular interest, published recently, have been highlighted as: • Of importance

Conclusions Cannabinoids are increasingly being prescribed for GI conditions, particularly nausea and vomiting, as an appetite stimulant and anecdotally for visceral pain. However, treatment of visceral pain has yet to be proven in humans, with some promising early results. It seems that direct or indirect CB1 receptor

1.

2.

United States Department of Health and Human Services. Substance Abuse and Mental Health Services Administration. Office of Applied, Studies. Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3): 389–462.

Curr Gastroenterol Rep (2015) 17: 9 3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13. 14.

15.

16.

17.

18. 19.

20.

21.

Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561–4. doi:10.1038/ 346561a0. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441): 61–5. doi:10.1038/365061a0. Di Marzo V, Fontana A. Anandamide, an endogenous cannabinomimetic eicosanoid: ‘killing two birds with one stone’. Prostaglandins Leukot Essent Fat Acids. 1995;53(1):1–11. Wright K, Rooney N, Feeney M, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005;129(2):437–53. Brusberg M, Arvidsson S, Kang D, Larsson H, Lindstrom E, Martinez V. CB1 receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents. J Neurosci. 2009;29(5):1554–64. doi:10.1523/JNEUROSCI. 516608.2009. Kulkarni-Narla A, Brown DR. Localization of CB1-cannabinoid receptor immunoreactivity in the porcine enteric nervous system. Cell Tissue Res. 2000;302(1):73–80. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21– 38. doi:10.1016/j.pharmthera.2009.12.005. Gruber SA, Rogowska J, Yurgelun-Todd DA. Altered affective response in marijuana smokers: an FMRI study. Drug Alcohol Depend. 2009;105(1–2):139–53. doi:10.1016/j.drugalcdep.2009. 06.019. Moreno-Sanz G, Sasso O, Guijarro A, et al. Pharmacological characterization of the peripheral FAAH inhibitor URB937 in female rodents: interaction with the Abcg2 transporter in the bloodplacenta barrier. Br J Pharmacol. 2012;167(8):1620–8. doi:10. 1111/j.1476-5381.2012.02098.x. Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;153(2):263–70. Izzo AA. The cannabinoid CB(2) receptor: a good friend in the gut. Neurogastroenterol Motil. 2007;19(9):704–8. Ross GR, Lichtman A, Dewey WL, Akbarali HI. Evidence for the putative cannabinoid receptor (GPR55)-mediated inhibitory effects on intestinal contractility in mice. Pharmacology. 2012;90(1–2):55– 65. doi:10.1159/000339076. Fioramonti J, Bueno L. Role of cannabinoid receptors in the control of gastrointestinal motility and perception. Expert Rev Gastroenterol Hepatol. 2008;2(3):385–97. doi:10.1586/17474124. 2.3.385. Farquhar-Smith WP, Jaggar SI, Rice AS. Attenuation of nerve growth factor-induced visceral hyperalgesia via cannabinoid CB(1) and CB(2)-like receptors. Pain. 2002;97(1–2):11–21. Kinsey SG, Cole EC. Acute delta(9)-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice. Eur J Pharmacol. 2013;715(1–3): 111–6. doi:10.1016/j.ejphar.2013.06.001. Beltramo M. Cannabinoid type 2 receptor as a target for chronic pain. Mini-Rev Med Chem. 2009;9(1):11–25. Govaerts SJ, Hermans E, Lambert DM. Comparison of cannabinoid ligands affinities and efficacies in murine tissues and in transfected cells expressing human recombinant cannabinoid receptors. Eur J Pharm Sci. 2004;23(3):233–43. Pertwee RG. Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr Med Chem. 2010;17(14):1360–81. Di Marzo V, Piscitelli F. Gut feelings about the endocannabinoid system. Neurogastroenterol Motil. 2011;23(5):391–8. doi:10.1111/ j.1365-2982.2011.01689.x.

Page 7 of 9 9 22.

23.

24.

25.

26.

27.

28.

29.

30.

31. 32.

33.

34.

35.

36.

37.

38.•

39.

40.•

Booker L, Naidu PS, Razdan RK, Mahadevan A, Lichtman AH. Evaluation of prevalent phytocannabinoids in the acetic acid model of visceral nociception. Drug Alcohol Depend. 2009;105(1–2):42– 7. doi:10.1016/j.drugalcdep.2009.06.009. Saez-Cassanelli JL, Fontanella GH, Delgado-Garcia JM, Carrion AM. Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia. J Neurochem. 2007;103(6): 2629–39. doi:10.1111/j.1471-4159.2007.05000.x. Gregg JM, Small EW, Moore R, Raft D, Toomey TC. Emotional response to intravenous delta9tetrahydrocannabinol during oral surgery. J Oral Surg. 1976;34(4):301–13. Bisogno T, Ligresti A, Di Marzo V. The endocannabinoid signalling system: biochemical aspects. Pharmacol Biochem Behav. 2005;81(2):224–38. Battista N, Di Tommaso M, Bari M, Maccarrone M. The endocannabinoid system: an overview. Front Behav Neurosci. 2012;6:9. doi:10.3389/fnbeh.2012.00009. Sugiura T, Kishimoto S, Oka S, Gokoh M. Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand. Prog Lipid Res. 2006;45(5):405–46. Aviello G, Romano B, Izzo AA. Cannabinoids and gastrointestinal motility: animal and human studies. Eur Rev Med Pharmacol Sci. 2008;12 Suppl 1:81–93. Anthony JC, Warner L, Kessler R. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the national comorbidity survey. Exp Clin Psychopharmacol. 1994;2:224–68. Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. CMAJ. 2008;178(13):1669–78. doi:10.1503/cmaj.071178. Camilleri M. Management of the irritable bowel syndrome. Gastroenterology. 2001;120(3):652–68. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology. 1995;109(1):40–52. Posserud I, Syrous A, Lindstrom L, Tack J, Abrahamsson H, Simren M. Altered rectal perception in irritable bowel syndrome is associated with symptom severity. Gastroenterology. 2007;133(4):1113–23. Talley NJ. Functional gastrointestinal disorders as a public health problem. Neurogastroenterol Motil. 2008;20 Suppl 1:121–9. doi: 10.1111/j.1365-2982.2008.01097.x. Cash B, Sullivan S, Barghout V. Total costs of IBS: employer and managed care perspective. Am J Manage Care. 2005;11(1 Suppl): S7–S16. Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fat Acids. 2002;66(2–3):243–56. doi:10.1054/plef.2001.0362. Farquhar-Smith WP, Rice AS. Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder. Anesthesiology. 2001;94(3):507–13. discussion 6A. Jaggar SI, Hasnie FS, Sellaturay S, Rice AS. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain. 1998;76(1–2):189–99. The first study to demonstrate anti-nociceptive effect of a CB2 receptor agonist. Sanson M, Bueno L, Fioramonti J. Involvement of cannabinoid receptors in inflammatory hypersensitivity to colonic distension in rats. Neurogastroenterol Motil. 2006;18(10):949–56. Mahmud A, Santha P, Paule CC, Nagy I. Cannabinoid 1 receptor activation inhibits transient receptor potential vanilloid type 1 receptor-mediated cationic influx into rat cultured primary sensory neurons. Neuroscience. 2009;162(4):1202–11. doi:10.1016/j. neuroscience.2009.05.024. Demonstrated that potential vanilloid

9 Page 8 of 9

41.

42.

43.

44.•

45.

46.•

47.•

48.

49.

50. 51.

52.

53.

54.

55.

type 1 receptor (TRPV1), which plays a pivotal role in the development of inflammatory heat hyperalgesia and visceral hyper-reflexia, can be activated by cannabinoids. Kikuchi A, Ohashi K, Sugie Y, Sugimoto H, Omura H. Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity. J Pharmacol Sci. 2008;106(2):219–24. Bingham B, Jones PG, Uveges AJ, et al. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. Br J Pharmacol. 2007;151(7):1061–70. Esfandyari T, Camilleri M, Busciglio I, Burton D, Baxter K, Zinsmeister AR. Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study. Am J Physiol Gastrointest Liver Physiol. 2007;293(1):G137–45. Klooker TK, Leliefeld KE, Van Den Wijngaard RM, Boeckxstaens GE. The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients. Neurogastroenterol Motil. 2011;23(1):30–5, e2. doi: 10.1111/j.1365-2982.2010.01587.x. This study concluded that the CB agonists are not a useful drug for treatment of visceral hypersensitivity in IBS patients. Wong BS, Camilleri M, Busciglio I, et al. Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology. 2011;141(5):1638–47.e1-7. doi:10.1053/j. gastro.2011.07.036. Malik Z, Bayman L, Valestin J, Schey R. Dronabinol increases pain threshold in non-cardiac chest pain: A double blind placebo controlled trial. 2014. First study to demonstrate that dronabinol increases NCCP pain threshold using an objective parameter (EBDT). Fichna J, Salaga M, Stuart J, et al. Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol Motil. 2014;26(4):470–81. doi:10.1111/nmo. 12272. One of the first studies evaluating the effect of selective FAAH inhibitor on mouse colonic motility and pain. Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol. 2014;722:134–46. doi:10.1016/j.ejphar.2013.09.068. Patil CL, Abrams ET, Steinmetz AR, Young SL. Appetite sensations and nausea and vomiting in pregnancy: an overview of the explanations. Ecol Food Nutr. 2012;51(5):394–417. doi:10.1080/ 03670244.2012.696010. Brainard A, Gresham C. Prevention and treatment of motion sickness. Am Fam Physician. 2014;90(1):41–6. Rutkowska M, Gliniak H. The influence of ACEA—a selective cannabinoid CB1 receptor agonist on whole blood and plateletpoor plasma serotonin concentrations. Pharmazie. 2009;64(9): 598–601. Napadow V, Lee J, Kim J, et al. Brain correlates of phasic autonomic response to acupuncture stimulation: an event-related fMRI study. Hum Brain Mapp. 2013;34(10):2592–606. doi:10.1002/ hbm.22091. Sharkey KA, Cristino L, Oland LD, et al. Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur J Neurosci. 2007;25(9):2773–82. Mackie K. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005;(168): 299–325. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic

Curr Gastroenterol Rep (2015) 17: 9

56. 57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

transmission. Physiol Rev. 2009;89(1):309–80. doi:10.1152/ physrev.00019.2008. Mechoulam R. Plant cannabinoids: a neglected pharmacological treasure trove. Br J Pharmacol. 2005;146(7):913–5. Nevalainen T. Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands. Curr Med Chem. 2014;21(2):187–203. Darmani NA. Delta(9)-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB(1) receptor antagonist/inverse agonist SR 141716A. Neuropsychopharmacology. 2001;24(2):198–203. Darmani NA. Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB(1) receptors in the least shrew. Pharmacol Biochem Behav. 2001;69(1–2):239–49. Ray AP, Chebolu S, Darmani NA. Receptor-selective agonists induce emesis and fos expression in the brain and enteric nervous system of the least shrew (Cryptotis parva). Pharmacol Biochem Behav. 2009;94(1):211–8. doi:10.1016/j.pbb.2009.08.010. Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310(5746):329–32. Despres JP, Ross R, Boka G, Almeras N, Lemieux I, ADAGIOLipids Investigators. Effect of rimonabant on the high-triglyceride/ low-HDL-cholesterol dyslipidemia, intraabdominal adiposity, and liver fat: the ADAGIO-lipids trial. Arterioscler Thromb Vasc Biol. 2009;29(3):416–23. doi:10.1161/ATVBAHA.108.176362. Kipnes MS, Hollander P, Fujioka K, et al. A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes. Diabetes Obes Metab. 2010;12(6):517–31. doi:10.1111/j.14631326.2009.01188.x. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-north america: a randomized controlled trial. JAMA. 2006;295(7):761–75. Chouker A, Kaufmann I, Kreth S, et al. Motion sickness, stress and the endocannabinoid system. PLoS One. 2010;5(5):e10752. doi:10. 1371/journal.pone.0010752. Mo FF, Qin HH, Wang XL, et al. Acute hyperglycemia is related to gastrointestinal symptoms in motion sickness: an experimental study. Physiol Behav. 2012;105(2):394–401. doi:10.1016/j. physbeh.2011.08.024. Callen L, Moreno E, Barroso-Chinea P, et al. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J Biol Chem. 2012;287(25):20851–65. doi:10.1074/jbc.M111.335273. Gulyas AI, Cravatt BF, Bracey MH, et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004;20(2):441–58. doi:10.1111/j.1460-9568. 2004.03428.x. Dalzell AM, Bartlett H, Lilleyman JS. Nabilone: an alternative antiemetic for cancer chemotherapy. Arch Dis Child. 1986;61(5):502– 5. Lane M, Vogel CL, Ferguson J, et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manag. 1991;6(6):352–9. Klumpers LE, Beumer TL, van Hasselt JG, et al. Novel delta(9)tetrahydrocannabinol formulation Namisol(R) has beneficial pharmacokinetics and promising pharmacodynamic effects. Br J Clin Pharmacol. 2012;74(1):42–53. doi:10.1111/j.1365-2125.2012. 04164.x. Ahmed AI, van den Elsen GA, Colbers A, et al. Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older

Curr Gastroenterol Rep (2015) 17: 9 subjects: a randomized controlled trial. Eur Neuropsychopharmacol. 2014. 73. Meiri E, Jhangiani H, Vredenburgh JJ, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007;23(3):533–43. doi:10.1185/ 030079907X167525. 74. Abalo R, Cabezos PA, Vera G, Lopez-Perez AE, Martin MI. Cannabinoids may worsen gastric dysmotility induced by chronic cisplatin in the rat. Neurogastroenterol Motil. 2013;25(5):373. doi: 10.1111/nmo.12073. –82, e292. 75. Bolognini D, Rock EM, Cluny NL, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol. 2013;168(6):1456–70. doi:10.1111/bph.12043. 76. Duran M, Perez E, Abanades S, et al. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in

Page 9 of 9 9 chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol. 2010;70(5):656–63. doi:10.1111/j.1365-2125.2010. 03743.x. 77. Galli JA, Sawaya RA, Friedenberg FK. Cannabinoid hyperemesis syndrome. Curr Drug Abus Rev. 2011;4(4): 241–9. 78. Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004;53(11):1566–70. 79. Nicolson SE, Denysenko L, Mulcare JL, Vito JP, Chabon B. Cannabinoid hyperemesis syndrome: a case series and review of previous reports. Psychosomatics. 2012;53(3):212–9. doi:10.1016/ j.psym.2012.01.003. 80. Simonetto DA, Oxentenko AS, Herman ML, Szostek JH. Cannabinoid hyperemesis: a case series of 98 patients. Mayo Clin Proc. 2012;87(2):114–9. doi:10.1016/j.mayocp. 2011.10.005.