Cannabinoids effects on vomiting and nausea in animal models

Linda A. Parker, Cheryl L. Limebeer and Magdalena Kwiatkowska

Department of Psychology, Wilfrid Laurier University, Waterloo, Ontario, Canada N2L 3C5

Introduction

The development of chemotherapy treatment has prolonged the lives of many cancer patients. However, use of these powerful drugs presents a serious challenge to both clinicians and patients. Significant side effects of cancer chemotherapy include nausea and vomiting which may last for several days. These symptoms come to be dreaded by patients, often interfering with successful completion of treatment. The emetic reflex is conventionally considered to include vomiting, retching and the more subjective sensation of nausea. However, the organization of the reflex is very complex, because although nausea, retching and vomiting usually occur in a temporal sequence, they can be separated experimentally [1].

Vomiting is a widespread protective reflex that serves to expel accidentally ingested toxins from the upper gastrointestinal tract. The sensation of nausea serves as a warning (as does pain), and usually results in the cessation of ingestion and an associative aversion to the ingestant in the future. The act of vomiting is often followed by a feeling of well-being which may serve to reinforce that behavior [1]. In the case of chemotherapy patients, however, the vomiting reflex does not remove the perceived toxin; therefore, in contrast to the removal of an ingested toxin from the gut, vomiting is not self-limiting [1].

Chemotherapy patients experience three separate types of emetic episode: (1) acute nausea and/or vomiting occurs within minutes to hours of receiving a dose of a toxic chemotherapy drug, (2) delayed nausea and/or vomiting that has been arbitrarily defined as emesis begins or persists more than 24 h after chemotherapy, and (3) anticipatory nausea and/or vomiting (ANV) occurs when the patient is re-exposed to cues associated with the toxin. ANV occurs in nearly half of patients treated, frequently during later cycles of chemotherapy [2]. The more intense the initial acute emetic episode, the worse the resultant ANV.

A major advance in the control of emesis 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 [3-7]. In clinical trials with humans, treatment with

5-HT3 antagonists often combined with the corticosteroid, dexamethasone, during the first chemotherapy treatment has reduced the incidence of acute vomiting by 70-90% [1, 8-14]. If acute vomiting is prevented, the incidence of delayed and anticipatory vomiting is reduced [2, 8-11, 20]. However, the 5-HT3 antagonists are less effective at suppressing acute nausea than they are at suppressing acute vomiting [1, 9, 10, 14, 20] and they are ineffective in reducing instances of delayed nausea/vomiting [13, 15-20] and ANV [1, 10, 11, 14, 20-22] when they do occur. Therefore, it is likely that another system may be involved in chemotherapy-induced nausea, delayed nausea/vomiting and ANV. Two such systems include the neurokinin 1 (NKj) tachykinin receptors for substance P (e.g. [16,17, 23]) and the endocannabinoid system [24-39]. The effect of cannabinoids on nausea and vomiting is the subject of this review.

Cannabinoids as anti-emetics

The marijuana plant has been used for several centuries for a number of therapeutic results, including nausea and vomiting [40]; however, it was only recently that Gaoni and Mechoulam [41] isolated the major psychotropic component, A9-tetrahydrocannabinol (A9-THC). Twenty-five years later, the specific brain receptors for this compound, cannabinoidi (CBj) and cannabinoid2 (CB2), were identified (for review see [42]) and cloned [43]. Therefore, it was only natural to start the search for an endogenous ligand for the cannabinoid receptor, which was discovered 2 years later [44]. This ligand was the ethanolamide of arachidonic acid, and called anandamide. A second type of endocannabioid was discovered in 1995 [45], also a derivative of arachidonic acid, but its ester, 2-aracidonoyl glycerol (2-AG). Both anandamide and 2-AG are rapidly inactivated after their formation and release by the enzyme fatty acid amide hydrolase (FAAH) [46].

The anti-emetic effects of cannabinoids appear to be mediated by action at the CB1 receptor. CB1 receptors are found in the gastrointestinal tract and its enteric nervous system [47] as well as within the emetic system of the brain [34, 35] in the dorsal vagal complex, consisting of the area postrema (AP), nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMNX) in the brainstem of rats, ferrets and the least shrew [33, 34]. Recent reviews on the gastrointestinal effects of cannabinoids have concluded that cannabinoid agonists act mainly via peripheral CB1 receptors to decrease intestinal motility [47], but act centrally to attenuate emesis [34, 35]. The dorsal vagal complex is involved in the nausea and/or vomiting reactions induced by either vagal gastrointestinal activation or several humoral cytotoxic agents. It is considered the starting point of a final common pathway for the induction of emesis in vomiting species. CBj receptors in the NTS are activated by A9-THC and this activation is blocked by the selective CB1 antagonists SR-141716 [28] and AM-251 [35]. Indeed, c-Fos expression induced by cisplatin in the DMNX, specific subnuclei of the NTS and AP is significantly reduced by A9-THC [34, 35]. Endogenous cannabinoid ligands, such as anan-damide, as well as synthetic cannabinoids, such as WIN-55,212-2, also act on these receptors [33].

Recent findings indicate that the cannabinoid system interacts with the serotonergic system in the control of emesis. The dorsal vagal complex not only contains CBj receptors, but is also densely populated with 5-HT3 receptors [48, 49], potentially a site of anti-emetic effects of 5-HT3 antagonists. Anandamide has also been reported to interact with serotonin [50]. Cannabinoid receptors are co-expressed with serotonin 5-HT3 receptors in some neurons in the central nervous system [51] and inhibitory functional interactions have been reported between cannabinoid CBj and 5-HT3 receptors [52, 53]. Additionally, canabi-noids reduced the ability of 5-HT3 agonists to produce emesis [28] and this effect was prevented by pretreatment with the selective cannabinoid CBj receptor antagonist SR-141716. Cannabinoids may act at CBj presynaptic receptors to inhibit release of newly synthesized serotonin [28, 54, 55].

Anti-emetic effects of cannabinoids in human clinical trials

The potential for marijuana to suppress nausea and vomiting produced by chemotherapy is of considerable therapeutic interest. Indeed, three canna-bis-based medicines are available: dronabinol, nabilone and levonantradol. Tramer et al. [56] present a thorough systematic review of 30 clinical trial comparisons of cannabis (oral nabilone, dronabinol (THC) and intramuscular levo-nantradol) with a placebo or other anti-emetics (predominantly dopamine antagonists). Tramer et al. [56] conclude that the cannabinoids were superior to the conventional dopaminergic antagonists in the treatment of nausea and vomiting.

There has been only one [57] comparison of cannabis with a 5-HT3 antagonist using the short-acting emetic agent syrup of ipecac. Human participants compared the effectiveness of a single dose of ondansetron (8 mg) with one of two doses of smoked marijuana (8.4 and 16.9 mg A9-THC) in attenuating nausea and vomiting produced by syrup of ipecac. Unlike cisplatin, ipecac produces short-lasting nausea and vomiting with a fast onset. They report that within the limited dose range tested, ondansetron was considerably more effective than smoked marijuana in attenuating vomiting and nausea and nausea produced by the ipecac. There have been no clinical trials comparing the relative efficacy of marijuana and 5-HT3 antagonists in suppressing long-lasting nausea and vomiting produced by chemotherapy treatment.

Cannabinoids produce psychotropic side effects, which partially accounts for their lack of popularity in clinical use [58]. Patients who have not had any experience with cannabis often find the psychotropic effects unpleasant and disturbing. Most importantly, the development of 5-HT3 antagonist anti-emetic drugs, with few side effects, has limited clinical use of cannabis-based medicines. The 5-HT3 antagonist anti-emetic agents are highly effective at preventing chemotherapy-induced vomiting, but are much less effective at inhibit ing nausea, as well as delayed nausea and vomiting and ANV when they do occur. There is some evidence that cannabis-based medicines may be effective in treating these intractable symptoms. Abrahamov et al. [59] evaluated the anti-emetic effectiveness of A8-THC, a close but less psychoactive relative of A9-THC, in children receiving chemotherapy treatment. Two hours before the start of each cancer treatment and every 6 h thereafter for 24 h, the children were given A8-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.

Furthermore, Tramer et al. [56] conclude that many patients have a strong preference for smoked marijuana over the synthetic cannabinoids delivered orally. This could be for various reasons: (1) possible advantages of self-titra-tion with the smoked marijuana, (2) the difficulty of swallowing the pills while experiencing emesis, (3) faster speed of onset for the inhaled or injected A9-THC than oral delivery, or (4) a combination of the action of other cannabi-noids with A9-THC that are found in marijuana. Although many marijuana users have claimed that smoked marijuana is a more effective anti-emetic than oral A9-THC, no controlled studies have yet been published that evaluate this possibility. Most of the evidence is based upon anecdotal testimonials, such as that of the late Stephen Jay Gould [60]: "I was miserable and came to dread the frequent treatments with an almost perverse intensity. ...Absolutely nothing in the available arsenal of medications worked at all. Marijuana, on the other hand, worked like a charm."

Smoking marijuana may represent a more efficient and rapid route of administration. However, it is also possible that as marijuana contains over 60 other compounds, some of these additional consitutents may contribute to the anti-emetic/anti-nausea effect. Another major cannabinoid found in marijuana is cannabidiol (CBD); however, unlike A9-THC, CBD does not produce psy-chomimetic effects [61]. CBD, unlike A9-THC, does not bind to the known cannabinoid receptors. It may act by blocking the reuptake of anandamide (an endogenous cannabinoid), or by inhibiting enzymatic hydrolysis of anan-damide, or bind with some as-yet-unknown cannabinoid receptor [61-63]. In mice, CBD is a highly effective anti-inflammatory agent [63], as well as a neu-roprotective antioxidant [64]. In shrews, CBD inhibits cisplatin-induced [32] and lithium-induced [31] emesis and in rats CBD inhibits nausea [38]. These effects are described more fully below.

Effects of cannabinoids on emesis in animals

In order to understand the pathways involved in the response to anti-cancer therapies to develop appropriate drug therapies, animal models have been developed. Since rats and mice do not vomit in response to a toxin challenge, it was necessary to develop other animal models of emesis. As indicated in

Table 1, there is considerable evidence that cannabinoids attenuate vomiting in emetic species. Cannabinoids have been shown to reduce vomiting in cats [30], pigeons [65, 66], ferrets [33-35], least shrews, Cryptotis parva [24-29] and the house musk shrew, Suncus murinus [31, 32].

Table 1. Effect of cannabinoid on emesis across species

Species

Emetogen

Cannabinoid

Effect on emesis

Cat

Cisplatin (7.5 mg/kg, iv)

N-Methyllevonantradol (0.003-0.02 mg/kg, iv)

i [30] i [30]

Dog

Cisplatin (3 mg/kg, iv)

Nabilone (0.1 mg/kg, iv)

- [67]

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