The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses Ineffective treatment of chemotherapy-induced nausea and vomiting from the Natural Sciences and Engineering Research Council of Canada. THC reduces vomiting by binding to cannabinoid CB1 receptors. Laura was a physician who spent much of her clinical time treating. But because of the extraordinary price for the prescription, the treatment is cost- prohibitive for Many people also appreciate that cannabis is a natural choice.
Treatment Nausea Natural and Cannabis
If the patient can tolerate it, oral intake of fluids is recommended for hydration. Some patients cannot tolerate oral hydration owing to excessive vomiting, so IV fluids may be indicated for volume depletion associated with dehydration. Compulsive hot bathing is a hallmark learned behavior that patients may use to minimize symptoms associated with CHS. As was discussed previously, hot bathing may help with thermoregulation. Another theory is that peripheral vasodilation and redistribution from splanchnic circulation may reduce blood flow to the stomach, resulting in decreased vomiting.
Antiemetics have been used without success to relieve symptoms of CHS. Lack of response to antiemetics should cause the clinician to suspect CHS. In case reports, patients have had no therapeutic relief from nausea and vomiting with ondansetron, promethazine, chlorpromazine, or metoclopramide.
Haloperidol exerts antipsychotic effects by antagonizing dopamine D 2 receptors in the mesolimbic and mesocortical pathways. Haloperidol is traditionally used to treat agitation; however, it has been used successfully as an antiemetic in general surgery and oncology.
D 2 receptors are also present in the chemoreceptor trigger zone, which may account for these antiemetic properties. Animal studies suggest that CB 1 may be affected by haloperidol, rendering this agent a potential treatment option. Cessation of cannabis is the only treatment that relieves and prevents symptoms associated with CHS. In the study that first described CHS, abstinence from cannabis resulted in cessation of nausea and vomiting in seven of 10 patients, whereas the others continued to suffer ongoing illness.
Three of the seven patients later rechallenged themselves with cannabis, and symptoms returned within a few months. As cannabis is legalized in more states, it is likely that its use will increase and more cases of CHS will be reported. Clinicians should suspect CHS in patients who present with a history of cannabis or synthetic cannabinoid use and symptoms including intractable nausea and vomiting, along with reports of the use of hot bathing for symptom control.
This conjecture could prevent extensive and costly workups for other conditions. Pharmacists have a role in counseling patients about the risks associated with cannabis use and referring patients with CHS symptoms for appropriate follow-up care. Case reports in the literature have identified risk factors for CHS. Unfortunately, CHS is relatively underreported, and its exact mechanism is unknown. Diagnosis and treatment of CHS is currently based on small case reports.
Information should continue to be evaluated as it becomes available in order to ensure appropriate treatment. Accessed August 25, What is the scope of marijuana use in the United States? Colorado cannabis legalization and its effect on emergency care. Medical marijuana laws in 50 states: Where pot is legal. Accessed November 13, How does marijuana produce its effects?
Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Drug Abuse Rev. Eur J Gastroenterol Hepatol. The cannabis hyperemesis syndrome characterized by persistent nausea and vomiting, abdominal pain, and compulsive bathing associated with chronic marijuana use: A gut gone to pot: Case Rep Emerg Med.
A case of cannabinoid hyperemesis syndrome caused by synthetic cannabinoids. Cleve Clin J Med. Habboushe J, Sedor J. Cannabinoid hyperemesis acute renal failure: Am J Emerg Med. Cannabinoid hyperemesis syndrome associated with compulsive showering and acute kidney injury.
Cannabinoid hyperemesis syndrome and the onset of a manic episode. Waning effect of compulsive bathing in cannabinoid hyperemesis. Haloperidol, a novel treatment for cannabinoid hyperemesis syndrome. Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys. J Pharmacol Exp Ther. Haloperidol for treatment of cannabinoid hyperemesis syndrome. However, to the best of our knowledge, the effectiveness of this compound in reducing nausea and vomiting has not been evaluated.
Many patients have a strong preference for smoked marijuana over the synthetic cannabinoids delivered orally Tramer et al. Several reasons for this have been suggested: Although many marijuana users have claimed that smoked marijuana is a more effective anti-emetic than oral THC, no controlled studies have yet been published that evaluate this possibility.
To evaluate the anti-emetic potential of drug therapies, animal models have been developed. Since rats and mice do not vomit in response to a toxin challenge, it is necessary to use other animal models of vomiting.
There is considerable evidence that cannabinoids attenuate vomiting in emetic species reviewed in Parker et al. Cannabinoid agonists have been shown to reduce vomiting in cats McCarthy and Borison, , pigeons Feigenbaum et al. The mechanism of action of the suppression of nausea and vomiting produced by cannabinoids has recently been explored with the discovery of the endocannabinoid system and the development of animal models of nausea and vomiting. Recent reviews on the gastrointestinal effects of cannabinoids have concluded that cannabinoid agonists act mainly via peripheral CB 1 receptors to decrease intestinal motility Pertwee, , but may act centrally to attenuate emesis Van Sickle et al.
The dorsal vagal complex DVC is involved in the vomiting reactions induced by either vagal gastrointestinal activation or several humoral cytotoxic agents. The DVC is considered to be the starting point of a final common pathway for the induction of emesis in vomiting species.
Endogenous cannabinoid ligands, such as anandamide and 2-arachidonyol glycerol 2-AG , as well as synthetic cannabinoids, such as WIN 55,—2, also act on these receptors Simoneau et al. Although anandamide has been reported to have anti-emetic properties in the ferret Van Sickle et al. Darmani found that 2-AG 2. An evaluation of changes in endocannabinoid levels elicited by cisplatin revealed that cisplatin increased levels of 2-AG in the brainstem, but decreased intestinal levels of both 2-AG and anandamide Darmani et al.
On the other hand, Van Sickle et al. CB 2 receptors in the brainstem may play a role in the regulation of emesis by 2-AG, at least when CB 1 receptors are co-stimulated.
The anti-emetic effects of 2-AG 0. Although inhibition of FAAH elevates multiple endocannabinoid-like molecules that show activity at multiple target receptors, the anti-emetic effects of URB were reversed by pretreatment with rimonabant, indicating a CB 1 mechanism of action.
In experiments with the S. A relative of the cannabinoid system, vanilloid TRPV1 receptors have recently been shown to regulate emesis in the ferret Sharkey et al. The TRPV1 receptor is targeted by capsaicin the burning component of chili peppers as well as resiniferatoxin, which can produce pro-emetic and anti-emetic effects at similar doses in S.
Recent findings indicate that the cannabinoid system interacts with the 5-hydroxytryptaminergic system in the control of emesis e. The first evidence of an interaction between cannabinoids and 5-HT 3 receptors was revealed by the finding that anandamide, WIN55 and CP inhibit 5-HT 3 receptor-mediated inward currents with IC 50 values in the nanomolar concentration range in rat nodose ganglion cells Fan, Since WIN 55,—2 did not displace a 5-HT 3 antagonist [ 3 H]-GR from the ligand binding site, the results suggest that cannabinoids inhibit 5-HT 3A receptors noncompetitively by binding to an allosteric modulatory site of the receptor Barann et al.
Additionally, cannabinoids have been shown to reduce the ability of 5-HT 3 agonists to produce emesis Darmani and Johnson, and this effect was prevented by pretreatment with rimonabant. Cannabinoids may act at CB 1 presynaptic receptors to inhibit the release of newly synthesized 5-HT Schlicker and Kathmann, ; Howlett et al.
Indeed, Darmani et al. Another major cannabinoid found in marijuana is CBD. As has been reported by others e. A wide range of doses was not effective in reducing motion-induced emesis in the S. The anti-emetic effect of CBD does not appear to be mediated by its action at CB 1 receptors, because it is not reversed by the CB 1 antagonist, rimonabant Kwiatkowska et al.
Indeed, Russo et al. Recently, our laboratory has investigated the mechanism of action for the anti-emetic effects of CBD. This activation of the 5-HT 1A receptors results in a reduction of the rate of firing of 5-HT neurones, ultimately reducing the release of forebrain 5-HT Blier and de Montigny, In addition, a recent finding suggests that CBD may also act as an allosteric modulator of the 5-HT 3 receptor Yang et al.
These findings suggest that allosteric inhibition of 5-HT 3 receptors by CBD may also contribute to its role in the modulation of emesis. Nausea is more resistant to effective treatment with new anti-emetic agents than is vomiting e. Andrews and Horn, and therefore remains a significant problem in chemotherapy treatment and as a side effect from other pharmacological therapies, such as anti-depressants.
Even when the cisplatin-induced emetic response is blocked in the ferret by administration of a 5-HT 3 receptor antagonist, c-fos activation still occurs in the AP, suggesting that an action here may be responsible for some of the other effects of cytotoxic drugs, such as nausea or reduced food intake Reynolds et al.
In rats, the gastric afferents respond in the same manner to physical and chemical intragastric copper sulphate and cisplatin stimulation that precedes vomiting in ferrets, presumably resulting in nausea that precedes vomiting Hillsley and Grundy, ; Billig et al. Furthermore, 5-HT 3 antagonists that block vomiting in ferrets also disrupt this preceding neural afferent reaction in rats. That is, in the rat the detection mechanism of nausea is present, but the vomiting response is absent.
Nauseogenic doses of cholecystokinin and LiCl induce specific patterns of brainstem and forebrain c-fos expression in ferrets that are similar to c-fos expression patterns in rats Reynolds et al. In a classic review paper, Borrison and Wang suggest that the rats' inability to vomit can be explained as a species-adaptive neurological deficit and that, in response to emetic stimuli, the rat displays autonomic and behavioural signs corresponding to the presence of nausea, called the prodromata salivation, papillary dilation, tachypnoea and tachycardia.
The typical measure used in the literature to evaluate the nauseating potential of a drug is conditioned taste avoidance. However, taste avoidance is not only produced by nauseating doses of drugs, it is also produced by drugs that animals choose to self-administer or that establish a preference for a distinctive location e. Berger, ; Wise et al. In fact, when a taste is presented prior to a drug self-administration session, the strength of subsequent avoidance of the taste is a direct function of intake of the drug during the self-administration session Wise et al.
This paradoxical phenomenon was initially interpreted as another instance of taste aversion learning. Because Garcia et al. However, in an animal capable of vomiting, the S. Since rats are incapable of vomiting, it is likely that conditioned taste avoidance produced by rewarding drugs in this species is based upon a learned fear of anything that changes their hedonic state e.
Gamzu, when that change is paired with food previously eaten. Another approach to understanding the role that nausea plays in the establishment of taste avoidance in rats is to evaluate the potential of anti-nausea treatments to interfere with avoidance of a flavour paired with an emetic treatment.
Early work suggested that anti-nausea agents interfered with the expression of previously established taste avoidance produced by LiCl Coil et al. Furthermore, there is considerable evidence that anti-nausea treatments either do not interfere with the establishment of conditioned taste avoidance learning Rabin and Hunt, ; Rudd et al. Two prominent anti-nausea treatments include drugs that reduce 5-HT availability and drugs that elevate the activity of the endocannabinoid system in rats see Parker et al.
Over the past number of years, our laboratory has provided considerable evidence that conditioned nausea in rats may be displayed as conditioned disgust reactions Parker, ; ; ; ; Limebeer and Parker, ; ; Limebeer et al. Rats display a distinctive pattern of disgust reactions including gaping, chin rubbing and paw treading when they are intraorally infused with a bitter tasting quinine solution. Rats also display this disgust pattern when infused with a sweet tasting solution that normally elicits hedonic reactions of tongue protrusions that has previously been paired with a drug that produces vomiting such as LiCl or cyclophosphamide in species capable of vomiting.
Only drugs with emetic properties produce this conditioned disgust reaction when paired with a taste. The most reliable conditioned disgust reaction in the rat is that of gaping Breslin et al.
If conditioned gaping reflects nausea in rats, then anti-nausea drugs should interfere with this reaction. Limebeer and Parker demonstrated that when administered prior to a saccharin-LiCl pairing, the 5-HT 3 antagonist, ondansetron, prevented the establishment of conditioned gaping in rats, presumably by interfering with LiCl-induced nausea.
Since ondansetron did not modify unconditioned gaping elicited by bitter quinine solution, the effect was specific to nausea-induced gaping. Subsequently, Limebeer and Parker demonstrated a very similar pattern following pretreatment with the 5-HT 1A autoreceptor antagonist, 8-OH-DPAT, that also reduces 5-HT availability and serves as an anti-emetic agent in animal models.
Most recently, Limebeer et al. The orofacial characteristics of the rat gape are very similar to those of the shrew retch just before it vomits Parker, Indeed, Travers and Norgren suggest that the muscular movements involved in the gaping response mimic those seen in species capable of vomiting. Using the conditioned gaping response as a measure of nausea in rats, we have demonstrated that a low dose 0. The potent agonist, HU 0.
When administered 30 min prior to the conditioning trial, rimonabant did not produce conditioned gaping on its own, but it did potentiate the ability of LiCl to produce conditioned gaping.
This same pattern has been reported in the emesis literature Van Sickle et al. Van Sickle et al. More compelling evidence that the endocannabinoid system may serve as a regulator of nausea is the recent finding that prolonging the duration of action of anandamide by pretreatment with URB, a drug that inhibits the enzyme FAAH, also disrupts the establishment of LiCl-induced conditioned gaping reactions in rats Cross-Mellor et al.
Rats pretreated with URB 0. Rats given the combination of URB 0. Although inhibition of FAAH produces an elevation of a variety of fatty acids that act at different receptors, the effect of URB on conditioned nausea was reversed by AM, indicating that it was mediated by CB 1 receptors. On the other hand, the silent CB 1 antagonists, AM and AM, which do not have inverse agonist properties, do not produce conditioned gaping Sink et al. In addition, the peripherally restricted silent CB 1 antagonist, AM, which also suppresses feeding at equivalent doses of AM Cluny et al.
Finally, neither the silent antagonist, AM which crosses the blood—brain barrier nor AM with limited CNS penetration , potentiate LiCl-induced nausea, an effect evident with low doses 2. AMinduced conditioned nausea is thus mediated by inverse agonism of the CB 1 receptor.
Recent research Rock et al. Research aimed at determining the forebrain regions e. AN often develops over the course of repeated chemotherapy sessions Nesse et al. For instance, Nesse et al. He experienced the same nausea when returning for routine follow-up visits, even though he knew he would not receive treatment. The nausea gradually disappeared over repeated follow-up visits. AN is best understood as a classically conditioned response CR Pavlov, Control over AN could be exerted at the time of conditioning or at the time of re-exposure to the conditioned stimulus CS.
If an anti-emetic drug is presented at the time of conditioning, then a reduction in AN would be the result of an attenuated unconditioned response UCR ; that is, reduced nausea produced by the toxin at the time of conditioning thereby attenuating the establishment of the CR. Indeed, when administered during the chemotherapy session, the 5-HT 3 antagonist, granisetron, has been reported to reduce the incidence of AN in repeat cycle chemotherapy treatment Aapro et al.
On the other hand, if a drug is delivered prior to re-exposure to cues previously paired with the toxin-induced nausea, then suppressed AN would be the result of attenuation of the expression of the CR conditioned nausea ; the 5-HT 3 antagonists are ineffective at this stage Nesse et al.
Although there has been considerable experimental investigation of unconditioned retching and vomiting in response to toxins, there have been relatively few reports of conditioned retching; that is, emetic reactions elicited by re-exposure to a toxin paired cue.
Conditioned retching has been observed to occur in coyotes, wolves and hawks upon re-exposure to cues previously paired with lithium-induced toxicosis Garcia et al. This effect was replicated more recently and extended to demonstrate that CBD also interferes with the expression of conditioned retching in the shrew, but the 5-HT 3 antagonist ondansetron was completely ineffective Parker et al. The doses employed were selected on the basis of their potential to interfere with toxin-induced vomiting in the S.
Rats also display conditioned gaping reactions when re-exposed to a context previously paired with LiCl-induced nausea Limebeer et al. Following four pairings of a distinctive, vanilla odour-laced chamber with LiCl-induced illness, rats were returned to the context for 30 min and received a 1 min intraoral infusion of novel saccharin solution every 5 min. During the infusions, the rats displayed gaping reactions.
Surprisingly, the rats also gaped during intervals when they were not being infused with saccharin while in the LiCl-paired context. The finding that rats express conditioned gaping responses when re-exposed to an odour-laced context previously paired with LiCl during inter-infusion intervals Limebeer et al.
Meachum and Bernstein had previously shown the re-exposure to a lithium-paired odour cue elicited gaping reactions in rats.
Recently, Limebeer et al. Most recently, Rock et al. Indeed, inhibition of FAAH by URB also prevented the establishment of LiCl-induced conditioned gaping elicited by the contextual cues when administered 2 h prior to each conditioning trial. These results suggest that cannabinoid compounds may be effective agents in the treatment of AN in chemotherapy patients. Since the discovery of the mechanism of action of cannabinoids, our understanding of the role of the endocannabinoid system in the control of nausea and vomiting has greatly increased.
In the ferret and shrew models, the site of action has been identified in the emetic area of the brainstem, the DVC. The shrew model, in particular, is cost effective for the evaluation of the anti-emetic properties of agents. The conditioned gaping response in the rat has provided a glimpse into the anti-nausea mechanisms of action of cannabinoids, in the absence of a vomiting response. Since nausea is a more difficult symptom to control than vomiting, the gaping model may serve as a useful tool for the development of new anti-nausea treatments, as well as for the evaluation of the potential side effects of nausea in newly developed pharmacological treatments.
Recent work has also supported anecdotal reports that cannabis may attenuate AN. Although chemotherapy-induced vomiting is well controlled in most patients by conventionally available drugs, nausea acute, delayed and anticipatory continues to be a challenge. Nausea is often reported as more distressing than vomiting, because it is a continuous sensation e.
Both preclinical and human clinical e. Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex e. Hornby, ; however, the neural mechanisms of nausea are still not well understood Andrews and Horn, One limitation in the preclinical screening of the nauseating side effect of compounds and the potential of compounds to treat nausea has been the lack of a reliable preclinical rodent model of nausea.
For years researchers have been using conditioned taste avoidance in rats as a model of nausea, but it has been well documented that non-nauseating treatments also produce taste avoidance — it is not a selective measure of nausea e. However, the considerable amount of evidence reviewed above indicates that conditioned disgust in rats elicited by an illness-paired flavour e.
This model may be a useful tool for elucidating the neurobiology of nausea and the role that the endocannabinoid system plays in the regulation of this distressing condition. This research was supported by a research grant to L. National Center for Biotechnology Information , U. Journal List Br J Pharmacol v.
Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. Introduction 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-HT 3 receptor, could suppress the acute emetic response retching and vomiting induced by cisplatin in the ferret and the shrew Costall et al.
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, , including the attenuation of nausea and vomiting. Effects of cannabinoids on vomiting in animal models To evaluate the anti-emetic potential of drug therapies, animal models have been developed.
Anti-emetic effect of cannabinoids: Effects of cannabinoids on nausea in animal models Nausea is more resistant to effective treatment with new anti-emetic agents than is vomiting e. Effects of cannabinoids on nausea in rats Using the conditioned gaping response as a measure of nausea in rats, we have demonstrated that a low dose 0. Cannabinoids and AN in rats and shrews AN often develops over the course of repeated chemotherapy sessions Nesse et al.
Conclusions Since the discovery of the mechanism of action of cannabinoids, our understanding of the role of the endocannabinoid system in the control of nausea and vomiting has greatly increased. Acknowledgments This research was supported by a research grant to L. The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: An efficient new cannabinoid antiemetic in pediatric oncology. Resiniferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in the ferret.
Signals for nausea and emesis: The pharmacology of the emetic response to upper gastrointestinal tract stimulation in Suncus murinus. The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus , the house musk shrew.
Impact of nausea and vomiting on quality of life in cancer patients during chemotherapy. Health Qual Life Outcomes. Direct inhibition by cannabinoids of human 5-HT 3A receptors: Control of nausea and vomiting after chemotherapy: Conditioning of food aversions by injections of psychoactive drugs. J Comp Phys Psychol. Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin. Physiology and pharmacology of vomiting. A quantitative comparison of taste reactivity behaviors to sucrose before and after lithium chloride pairings: Deltatetrahydrocannabinol in cancer chemotherapy: A neutral CB 1 receptor antagonist reduces weight gain in rat.
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