Regulation of nausea and vomiting by cannabinoids
Linda A Parker, Erin M Rock and Cheryl L Limebeer
British Journal of Pharmacology, 2011, 163, 1411-1422.
Doi : 10.1111/j.1476-5381.2010.01176.x
Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (D9-THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somato-dendritic 5-HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.
Keywords : emesis; vomiting; nausea; gaping; conditioned disgust; taste reactivity; cannabinoid;
cannabidiol; 5-hydroxytryptamine; serotonin
A major advance in the control of acute emesis in chemotherapy treatment was the finding that blockade of one subtype of the 5-hydroxytryptamine (5-HT) receptor, the 5-HT3 receptor, could suppress the acute emetic response (retching and vomiting) induced by cisplatin in the ferret and the shrew (Costall et al., 1986; Miner and Sanger, 1986; Ueno et al., 1987; Matsuki et al., 1988; Torii et al., 1991). In clinical trials with humans, treatment with 5-HT3 antagonists often combined with the corticosteroid dexamethasone during the first chemotherapy treatment reduced the incidence of acute vomiting by approximately 70% (e.g. Bartlett and Koczwara, 2002; Aapro et al., 2003; Ballatori and Roila, 2003; Hickok et al., 2003; Andrews and Horn, 2006). However, the 5-HT3 antagonists are less effective at suppressing acute nausea than they are at suppressing acute vomiting (Morrow and Dobkin, 1988; Bartlett and Koczwara, 2002; Hickok et al., 2003) and they are ineffective at reducing instances of delayed (24 h later) nausea and vomiting (Morrow and Dobkin, 1988; Grelot et al., 1995; Rudd et al., 1996; Rudd and Naylor, 1996; Tsukada et al., 2001; Hesketh et al., 2003) and anticipatory (conditioned) nausea and vomiting (Nesse et al., 1980; Morrow and Dobkin, 1988; Hickok et al., 2003).
More recently, NK1 receptor antagonists (e.g. aprepitant) have been developed that not only decrease acute vomiting, but also decrease delayed vomiting induced by cisplatinbased chemotherapy (Van Belle et al., 2002); however, these compounds alone and in combination with 5-HT3 antagonist/ dexamethasone treatment are also much less effective in reducing nausea (e.g. Hickok et al., 2003; Andrews and Horn, 2006; Slatkin, 2007), which is the symptom reported to be the most distressing to patients undergoing treatment with 5-HT3 antagonists (deBoer- Dennert et al., 1997). Considerable evidence suggests that another system that may be an effective target for treatment of chemotherapy-induced nausea, delayed nausea/vomiting and anticipatory nausea (AN)/vomiting is the endo-cannabinoid system (e.g. for review, Parker and Limebeer,2008).
Anti-emetic effects of cannabinoids in human clinical trials
The cannabis plant has been used for several centuries for a number of therapeutic applications (Mechoulam, 2005), including the attenuation of nausea and vomiting. Ineffective treatment of chemotherapy-induced nausea and vomiting prompted oncologists to investigate the anti-emetic properties of cannabinoids in the late 1970s and early 1980s, before the discovery of the 5-HT3 antagonists. The first cannabinoid agonist, nabilone (Cesamet), which is a synthetic analogue of D9-THC was specifically licensed for the suppression of nausea and vomiting produced by chemotherapy.
Furthermore, synthetic D9-THC, dronabinol, entered the clinic as Marinol in 1985 as an anti-emetic and
in 1992 as an appetite stimulant (Pertwee, 2009). In these early studies, several clinical trials compared the effectiveness of D9-THC with placebo or other anti-emetic drugs. Comparisons of oral D9-THC with existing anti-emetic agents generally indicated that D9-THC was at least as effective as the dopamine antagonists, such as prochlorperazine (Carey et al., 1983; Ungerleider et al., 1984; Crawford and Buckman, 1986; Cunningham et al., 1988; Tramer et al., 2001; Layeeque et al., 2006).
There is some evidence that cannabis-based medicines may be effective in treating the more difficult to control symptoms of nausea and delayed nausea and vomiting in children. Abrahamov et al. (1995) evaluated the anti-emetic effectiveness of D8-THC, a close but less psychoactive relative of D9-THC, in children receiving chemotherapy treatment. Two hours before the start of each cancer treatment and every six hours thereafter for 24 h, the children were given D8-THC as oil drops on the tongue or in a bite of food. After a total of 480 treatments, the only side effects reported were slight irritability in two of the youngest children (3.5 and 4 years old); both acute and delayed nausea and vomiting were controlled.