Cannabinoid Hyperemesis Syndrome: A Review of Potential Mechanisms

Abstract

Introduction: Cannabinoids have long been known for their ability to treat nausea and vomiting. Recent reports, however, have highlighted the paradoxical proemetic effects of cannabinoids. Cannabinoid hyperemesis syndrome (CHS) is characterized by cyclical episodes of nausea and vomiting, accompanied by abdominal pain following prolonged, high-dose cannabis use, which is alleviated by hot baths and showers. Little is known about the cause of this syndrome.

Discussion: Cannabinoids produce a biphasic effect on nausea and vomiting, with low doses having an antiemetic effect and high doses producing emesis. Presentation and treatment of CHS are similar to cyclical vomiting syndrome as well as chemotherapy-related anticipatory nausea and vomiting, suggesting that these phenomena may share mechanisms. The prevalence of CHS is not known because of the symptomatic overlap with other disorders and the lack of knowledge of the syndrome by the public and physicians. Treatment with typical antiemetic drugs is ineffective for CHS, but anxiolytic and sedative drugs, along with hot showers, seem to be consistently effective at reducing symptoms. The only known way to permanently end CHS, however, is abstinence from cannabinoids. Case studies and limited pre-clinical data on CHS indicate that prolonged high doses of the main psychotropic compound in cannabis, Δ⁹-tetrahydrocannabinol (THC), result in changes to the endocannabinoid system by acting on the cannabinoid 1 (CB₁) receptor. These endocannabinoid system changes can dysregulate stress and anxiety responses, thermoregulation, the transient receptor potential vanilloid system, and several neurotransmitters systems, and are thus potential candidates for mediating the pathophysiology of CHS.

Conclusions: Excessive cannabinoid administration disrupts the normal functioning of the endocannabinoid system, which may cause CHS. More clinical and pre-clinical research is needed to fully understand the underlying pathophysiology of this disorder and the negative consequences of prolonged high-dose cannabis use.

Introduction

The plant Cannabis Sativa has been used for centuries recreationally and medicinally, and remains one of the most commonly used drugs worldwide.^1,2 Cannabis has several chemical constituents, termed cannabinoids, but the only compound that produces psychotropic effects is Δ⁹-tetrahydrocannabinol (THC).³ THC is a partial agonist of the cannabinoid 1 (CB₁) receptor of the endocannabinoid system.⁴ These receptors are located throughout the brain and body, and are activated by endogenous ligands known as endocannabinoids, including anandamide (AEA)⁵ and 2-arachidonoylglycerol (2-AG).⁶ AEA and 2-AG are degraded by fatty acid amide hydrolase (FAAH)⁷ and monoacylglycerol lipase (MAGL),⁸ respectively. To better understand the endocannabinoid system, highly potent, synthetic full agonists of the CB₁ receptor have been synthesized (i.e., JWH-018 and HU210). Slight modifications to their chemical structures have led to the development of synthetic cannabinoid designer drugs, including Spice and K2, and are becoming increasingly popular.⁹

One of the first approved medical uses of a synthetic version of THC was to treat chemotherapy-induced nausea and vomiting.¹⁰ Even though considerable pre-clinical and clinical evidence suggests that cannabinoids reduce nausea and vomiting,^11,12 recent evidence suggests that high doses of cannabinoids can produce nausea and vomiting in laboratory animals^13–19 and humans,^20–22 and can lead to cannabinoid hyperemesis syndrome (CHS) in the latter.²³

It is perhaps not surprising that cannabinoids produce seemingly paradoxical effects on nausea and vomiting because cannabinoids are known to produce biphasic effects, where low and high doses typically produce opposite effects.^24–27 Information regarding the adverse effects of high-dose CB₁ agonists is of particular importance because THC content in cannabis has been consistently increasing,^28,29 and high potency THC concentrates^30–32 and designer synthetic cannabinoids⁹ are becoming increasingly popular. This article will discuss the seemingly contradictory effects of cannabinoids on nausea and vomiting, and the prevailing theories about CHS' mechanisms.

Cannabinoid Hyperemesis Syndrome

In certain individuals, long-term cannabis use may induce CHS. This syndrome is characterized by cyclical nausea and vomiting, accompanied by abdominal pain following prolonged, high-dose cannabis use.²³ The symptoms associated with CHS can be alleviated by high temperature baths or showers, sometimes resulting in burns.²³ CHS can also develop following the long-term use of synthetic cannabinoid designer drugs,^33–36 which tend to be full agonists at the CB₁ receptor, as opposed to THC, which is a partial agonist, and can cause adverse effects at lower doses.³⁷ Indeed, nausea and vomiting are common side effects of acute synthetic cannabinoid intoxication.^37–39

CHS presents in three stages: the prodromal, the hyperemetic, and the recovery phase.^23,40 The prodromal stage of CHS is characterized by anxiety, severe nausea, and an array of autonomic symptoms, such as, sweating, flushing, and increased thirst, with symptoms being more severe in the morning. The prodromal stage can last for months before any vomiting attacks occur. The hyperemetic phase follows with debilitating abdominal pain, nausea, and vomiting. It is during this stage that patients typically develop compulsive hot bathing or showering behaviors. The emetic phase will last until prolonged abstinence from cannabis has occurred and CHS patients enter a recovery phase where vomiting and bathing behavior subsides. Full recovery from symptoms can be weeks or months following the cessation of cannabis use.²³ These phases of CHS follow a cyclical repetitive pattern, usually initiated by the reoccurrence of cannabis use.⁴⁰

Diagnosis

The Rome IV criteria list CHS as a subset of cyclical vomiting syndrome (CVS). Table 1 represents the diagnostic criteria of CVS and CHS. Analogous to CHS, CVS is characterized by reoccurring episodes of nausea and vomiting.⁴¹ Due to the commonalities with CVS, CHS is often misdiagnosed.^42,43 Some argue that these syndromes may not be distinct disorders, but rather CHS is a variant of CVS brought on by excessive cannabis use.⁴¹ Subtle differences may help with accurate diagnosis to guide treatment.

Table 1.

Rome IV Diagnostic Criteria for Cyclical Vomiting Syndrome and Cannabinoid Hyperemesis Syndrome⁴¹

Cyclical vomiting syndrome (CVS)	Cannabinoid hyperemesis syndrome (CHS)
Acute onset of stereotypical vomiting episode that lasts less than 1 week	Stereotypical vomiting episodes similar to CVS
At least three episodes in the previous year, two episodes in the last 6 months at least 1 week apart	Presentation following sustained excessive cannabis use
No vomiting between episodes	Relief from vomiting after abstinence from cannabis
Symptoms must be present for 3 months with onset 6 months earlier	Symptoms must be present for 3 months with onset 6 months earlier
Supportive criteria: history of migraine headaches	Supportive criteria: pathological bathing behavior (prolonged hot baths or showers)

Individuals with CHS will recover following sustained abstinence from cannabis, but this is not the case for CVS.⁴⁴ It is of note that a high proportion of individuals with CVS are also cannabis users.^45,46 Interestingly, Venkatesan et al.⁴⁵ found that among 437 CVS patients surveyed, 81% were cannabis users. Yet, the information is not available to discern if CVS patients concurrently use cannabis to relieve emetic symptoms or if these are individuals with CHS.

The main distinction between CHS and CVS is the resolution of symptoms for CHS following the termination of cannabis use. Ongoing follow-up of patients after stopping cannabis use would help with accurate diagnosis. Other distinguishing features have been proposed to properly diagnose CHS and CVS. For example, individuals with CVS tend to have rapid gastric emptying, whereas CHS is associated with delayed gastric emptying.^23,44,47,48 Delayed gastric emptying in CHS is not surprising given that THC and other CB₁ receptor agonist have an inhibitory effect on gastric motility.^49–52 Gastric emptying studies could, therefore, improve diagnosis.

Treatment

The only effective way to permanently alleviate symptoms of CHS is stopping cannabis use; however, during acute emetic phases, both CVS and CHS symptoms are managed in similar ways.⁴⁴ It is important to note that typical antiemetic drugs, such as the 5-HT₃ receptor antagonist ondansetron, are not effective at alleviating nausea and vomiting from CHS.⁵³ Anxiolytic and sedative drugs, such as benzodiazepines (i.e., diazepam) and antipsychotics (i.e., haloperidol), seem to be the most effective for emetic phases of CVS and CHS^44,53–55; yet it is still unclear whether these drugs are effective because they interfere with the mechanism of CHS or because of their sedating effects. Acute management of symptoms is important for preventing dehydration and adrenal injury, common complications of CHS that can be fatal.^56,57

Following acute symptom management, physicians should encourage cannabis abstinence in patients; however, abstaining from cannabis use can be difficult if the individual has cannabis use disorder (CUD). Currently, there is no information on the percentage of CHS individuals with concurrent CUD. If CHS is suspected, it could be beneficial to assess individuals for CUD to determine appropriate treatment. There are research groups investigating the benefits of early detection and addiction therapy intervention for individuals with CHS showing promising results.⁵⁸ Treating CUD in this population could aid in preventing reoccurrence of CHS. In addition to addiction therapies, current pharmacological treatment options that are under investigation for CUD include the following: antidepressants, CB₁ receptor agonists, and FAAH inhibitors.^59–61 While CB₁ agonists can be beneficial at reducing withdrawal symptoms, they should be used cautiously in CHS as they may exacerbate symptoms by increasing CB₁ receptor activation.

Prevalence of CHS

Prevalence of CHS among the general population is difficult to determine because of the clinical similarities between CHS and CVS. Moreover, individuals may be unwilling to disclose their cannabis use to physicians or be unaware of the emetic effects of cannabis, leading to misdiagnosis and underreporting of CHS. Therefore, there is a lack of recognition and knowledge of the syndrome by sufferers and physicians.

Publications about CHS have been consistently increasing since 2004 when the syndrome was coined.^53,62 Several groups have tried to establish the prevalence of CHS by retrospective analyses of reports from hospitals or urgent care centers.^62–65 Kim et al.⁶⁵ found that CVS diagnosis, including CHS, has nearly doubled since the legalization of cannabis in Colorado, United States. It is unclear, however, if this was due to an increase in cannabis use or an increase in cannabis use reporting due to the increased acceptance and legalization of cannabis. Schreck et al.⁶² determined that the rate of reporting in France is similar to that reported in international literature. These studies only provide estimates, and rely on accurate diagnosis and disclosure of cannabis use; therefore, they are likely underestimations of the actual prevalence. Indeed, Habboushe et al.⁶⁴ acknowledge the limitations of their estimation and conclude that CHS is much more prevalent than is recognized in society. Prevalence cannot accurately be determined until accurate diagnosis and classification are agreed upon. Most studies regarding the epidemiology of CHS lack information about patient histories, comorbid psychiatric illnesses, possible re-disposing factors, and type of cannabis consumed (i.e. THC percentage), which may aid the understanding of the etiology of CHS.

CHS: Potentially a Dysfunctional Endocannabinoid System

Most research to date regarding CHS is limited to case studies (e.g.,^{23,42,66–70}). While these reports provide information about how the syndrome manifests and what treatments are effective for some patients, they do not provide information about the underlying neurobiological mechanism. However, we can make informed speculations about the pathophysiology of CHS by considering information from case studies and the pharmacology of cannabinoids. The prevailing theory about how CHS develops is that extended activation of the CB₁ receptor by prolonged exposure to THC leads to desensitization and/or downregulation of the CB₁ receptor and changes to endocannabinoid-related enzymes, resulting in endocannabinoid system dysregulation.⁷¹

Many studies have shown dose-dependent CB₁ receptor desensitization and/or downregulation in rodents following administration of high doses of CB₁ agonists.^72–75 Similar findings in humans using positron emission tomography find that daily cannabis smokers had fewer CB₁ receptors compared to nonsmokers in cortical regions, including the insular cortex,⁷⁶ a brain region implicated in nausea.⁷⁷ CB₁ receptor downregulation was positively correlated with years of cannabis use.⁷⁶ There was, however, no self-report data about side-effects of cannabis, medical history, or follow-up of the participants; therefore, it cannot be known if any of the participants had, or went on to develop CHS. It remains unknown how changes to the endocannabinoid system could lead to the development of CHS and more empirical research is needed to identify the mechanism.

Given the ubiquitous nature of the endocannabinoid system, dysregulation of its normal functioning can have dramatic and potentially adverse outcomes. Indeed, along with acute and long-term high doses of CB1 agonists,^13–22 CB₁ antagonism/inverse agonism can also result in nausea and vomiting in humans⁷⁸ and animals.^13,79,80 Therefore, disrupting normal endocannabinoid signaling can influence nausea and vomiting. Figure 1 presents a schematic representation of factors that may contribute to CHS. Changes in the endocannabinoid system may lead to alterations in other systems that have the potential to promote nausea and vomiting. The impact of endocannabinoid system dysregulation on various neurobiological systems and their possible contribution to nausea and vomiting, and consequently CHS, are discussed in the following section.

FIG. 1.

Schematic representation of factors that may contribute to CHS. CHS, cannabinoid hyperemesis syndrome.

Acute cannabinoid-induced nausea and vomiting

One of the first approved and recognized medical uses of cannabis in modern medical history was for treatment of chemotherapy-induced nausea and vomiting.¹⁰ Recent research suggests that low doses of THC inhibit nausea by acting on CB₁ receptors in the interoceptive insular cortex,^81,82 and inhibit vomiting by activating CB₁ receptors in the dorsal vagal complex (DVC).^83,84 Despite the vast body of literature indicating that cannabinoids prevent nausea and vomiting, there are instances where higher doses of THC can produce vomiting in several species, including shrews,^13,14 cats,¹⁵ dogs,^16,17 monkeys,¹⁸ and humans.^{20–22,85–87}

Work in our laboratory has investigated the anti-nauseating and pro-nauseating effects of cannabinoids using a pre-clinical rat model of nausea, conditioned gaping in the taste reactivity test.^12,88 When a novel flavor, delivered intraorally, is paired with an emetic agent, such as Lithium Chloride (LiCl) or chemotherapy drugs, rats display a conditioned gaping response, characterized by the wide triangular opening of the mouth, when re-exposed to that flavor.⁸⁹ Rats lack the motor output of vomiting, but do detect toxins the same way as species that can vomit.^90–94 Therefore, rats provide an excellent model for studying neurobiological mechanism of nausea, without the confound of vomiting.

A low dose of THC prevents conditioned gaping produced by a flavor paired with LiCl in the taste reactivity paradigm.⁹⁵ However, when THC is paired with a flavor in the taste reactivity paradigm, high doses of THC, but not low doses of THC, produce conditioned gaping reactions, indicating nausea.^19,96 Pre-treatment with a CB₁ antagonist prevented THC-induced nausea in rats¹⁹ and vomiting in shrews,¹⁴ further implicating the endocannabinoid system. We also found that repeated administration of the high dose that produced conditioned gaping in rats, also produced an upregulation of the gene for endocannabinoid degrading enzymes (both FAAH and MAGL,) in the hypothalamus.¹⁹ The resulting reduction in AEA and 2-AG, respectively (currently being evaluated), may produce dysregulation in processes regulated by the hypothalamus, such as stress and thermoregulation, in THC-induced nausea.

Dysregulated stress response in nausea and vomiting

Emesis is associated with an altered stress response (Fig. 1); however, this relationship is correlational and role of stress as an antecedent or a consequence of nausea and vomiting is unknown.^97,98 Stress is hypothesized to be involved in the pathophysiology of various nausea and vomiting disorders, including CVS,^55,99–101 and anticipatory nausea and vomiting associated with chemotherapy.¹⁰² CVS and anticipatory nausea and vomiting is correlated with anxiety and mood disorders.^99,102 During the emetic phase of CVS in cannabis users and nonusers, there is an increase in circulating endocannabinoids,⁹⁷ which is also seen during times of stress.¹⁰³ There is also activation of the hypothalamic-pituitary-adrenal (HPA) axis during CVS, shown by elevated levels of glucocorticoid hormones and corticotropin-releasing hormone (CRH) during vomiting episodes.¹⁰¹ Anticipatory nausea and vomiting are the result of classically conditioned associations between the context where patients receive treatment and the nauseating and emetic effects of chemotherapy agents.¹⁰⁴ Despite receiving first-line antiemetic therapy, ∼20% of chemotherapy patients still experience anticipatory nausea, and these individuals tend to have higher trait and state anxiety and experience more emotional distress than patients who do not experience anticipatory nausea.^102,105

As with CHS and CVS, typical 5-HT₃ receptor antagonists, which are effective in preventing acute vomiting and somewhat effective in preventing acute nausea in chemotherapy treatment,^106,107 are ineffective at reducing the expression of anticipatory nausea and vomiting.^108,109 For CHS, CVS, and anticipatory nausea and vomiting in chemotherapy, benzodiazepines are the most common treatment.^110,111 Anticipatory nausea can be studied in pre-clinical models as well.¹⁰⁹ Similar to conditioned gaping produced by a flavor paired with an emetic drug,¹² rats and shrews gape when placed in a distinctive context paired with emetic agents.^112–114 Low-dose cannabinoids, endocannabinoid manipulations, and benzodiazepines, but not ondansetron (5-HT₃ antagonist), reduce contextually elicited conditioned gaping in rats and shrews, mirroring findings in humans with CHS.^113–118

While stress and anxiety are common occurrences for many people, there are clear relationships between stress, anxiety, and several nausea and vomiting disorders. The direction and causality of these correlations have yet to be established and need to be investigated to understand how this might contribute to the development CHS in certain individuals.

Hypothalamic pituitary adrenal axis dysregulation

Nausea and vomiting are associated with dysregulated hypothalamic pituitary adrenal (HPA) axis activation,^97,98,119 as well as changes in the endocannabinoid system (Fig. 1).^97,119 The endocannabinoid system is essential for the allostasis of the HPA axis.^120,121 Briefly, during basal stress, the hypothalamus becomes active and triggers the pituitary to send neuroendocrine signals to the adrenal glands to release glucocorticoid stress hormones.¹²² These hormones then provide negative feedback to the hypothalamus to terminate this process. When glucocorticoid hormones provide feedback to the hypothalamus, 2-AG is released to terminate the stress response by acting on CB₁ receptors and inhibiting glutamate release.^123–125 Conversely, AEA is tonically released in the hypothalamus to suppress the HPA axis and is reduced following exposure to a stressor, disinhibiting the stress response.¹²⁴

Changes to the endocannabinoid system in the hypothalamus from cannabinoid use could lead to a dysregulated stress response, and perhaps contribute to the development of CHS. Alterations of the endocannabinoid system produced by exogenous cannabinoids are known to be dose-dependent and region-specific in the brain.^76,126 Indeed, our laboratory has shown that repeated administration of a high dose of THC that produces nausea in rats, but not a lower antinausea dose, also causes an upregulation of the genes for the degrading enzymes of 2-AG, (MAGL) and of AEA(FAAH) in the hypothalamus, but not any other brain regions sampled (insular cortex, hippocampus, DVC, and nucleus accumbens).¹⁹ It is also intriguing that Tai et al.¹²⁷ found that chronic exposure to THC or the full CB₁ agonist JWH-018 produced downregulation, and reduced functionality in the hypothalamic, but not cortical, CB₁ receptors in mice. This suggests that high doses of THC can lead to low levels of endocannabinoids within the hypothalamus, which may prevent inhibitory control of the HPA axis. More research is still needed to understand the impact of cannabinoids on hypothalamic endocannabinoid and endocannabinoid-related enzymes.

Endocannabinoids in the amygdala, specifically the basolateral amygdala (BLA), play a similar role for regulation of the stress response by inhibiting hypothalamic activity.^122,128 Agonism of CB₁ receptors on glutamatergic BLA neurons decreases glutamate release and inhibits HPA axis and autonomic activation.¹²² Stress-induced release of CRH from the hypothalamus causes an upregulation of FAAH in the BLA, leading to a reduction in AEA,¹²⁹ which disinhibits this region, further activating the HPA axis.^128,130 Under acute stress conditions, glucocorticoids provide feedback to increase 2-AG after a delay in the BLA^129,131,132 and hypothalamus.^123,124 Reduction of 2-AG in the BLA promotes anxiety behaviors¹³⁰; therefore, it is possible that disruption of this mechanism by overactivation of the CB₁ receptor could increase BLA excitability, and consequently promote stress and anxiety,¹³³ potentiating nausea and vomiting in response to high-dose, long-term THC exposure.

High doses of cannabinoids are known to activate the stress response in humans and laboratory animals and cause increased CRH production^75,134 and circulating glucocorticoid levels,^135–137 and produce anxiety behavior.¹³⁸ Research regarding HPA axis function in long-term cannabis users is less clear. Cuttler et al.¹³⁹ demonstrated that when compared with nonusers, chronic cannabis users display a blunted cortisol increase in response to an acute stressor. Similarly, Somaini et al.¹⁴⁰ found that cannabis users had a limited increase in plasma cortisol and adrenocorticotropin hormone (ACTH) compared to nonusers when shown unpleasant visual stimuli. On the other hand, some studies show that chronic cannabis users have higher basal cortisol and ACTH levels, and increased ratings of anxiety compared to nonusers.^140,141 The authors suggest that altered stress reactivity in chronic cannabis users may be mediated by alterations in the endocannabinoid system required for regulation of HPA axis activation.^121,122 Chronic cannabinoid administration alters endocannabinoid content in rodents^142,143 and in humans, which differs between light and heavy users.¹⁴⁴ Therefore, the blunted stress responses in chronic cannabis users may be the result of alterations in endocannabinoid signaling. More research is needed, however, to assess if the blunted stress response is an impairment in HPA activation or impaired negative feedback of the HPA axis. Moreover, research is needed to determine the impact of THC dose, length of use, and genetic or other pre-disposing factors on stress reactivity in cannabis users.^140,145

Sympathetic nervous system dysregulation

Activation of the sympathetic nervous system (SNS) is also implicated in nausea and vomiting as indicated in Figure 1.⁷⁷ Indeed, aberrant sympathetic activation is associated with CVS and CHS.^99,146 Symptoms of CVS and CHS are more prominent in the morning, which is also when SNS and HPA axis activity is at its highest.^99,146 CVS and CHS are often accompanied by sympathetic symptoms, including, sweating, flushing, thirst, hypertension, and tachycardia.^40,99 Venkatesan et al.⁹⁷ found that salivary alpha-amylase, a biomarker of SNS activity, was significantly higher in CVS patients who use cannabis compared to those who do not use cannabis, during the emetic phase. This finding suggests that cannabis potentiates the SNS dysfunction during emesis.

Prolonged cannabinoid use may dysregulate basal sympathetic signaling.⁹⁹ Acutely, it is well established that THC increases heart rate and blood pressure.^147,148 Studies have shown that chronic cannabis users have increased blood pressure and heart rate,^149,150 and an increased skin conductance response in a fear conditioning paradigm¹⁵¹ compared to nonusers. Similarly, Schmid et al.¹⁵² found that cannabis users have greater heart rate variability than nonusers. Withdrawal from cannabis also leads to an increase in heart rate and blood pressure.¹⁵³ These findings implicate the endocannabinoid system in SNS regulation.

Several brain structures send GABAergic projections that have CB₁ receptors¹⁵⁴ to the brainstem regions involved in SNS activation, the rostral ventrolateral medulla (rVLM), and vomiting, the nucleus tractus solitarius (NTS) located in the DVC.^99,155,156 Disinhibition of the rVLM and NTS by CB₁ receptor activation could increase the likelihood of SNS activation and vomiting. Similarly, CB₁ receptor agonists increase NE release by activating CB₁ receptors on GABAergic terminals in the locus coeruleus (LC), reducing GABA release, and disinhibiting this region.^157,158 This effect is dose-dependent, with higher doses of THC producing greater LC activity.¹⁵⁸ Indeed, THC dose-dependently activates the SNS through altered NE signaling, with larger doses producing greater activation through its effects on NE transmission, an important neurotransmitter for SNS activity.^{147,148,152,159,160}

Propranolol, a β-adrenergic receptor antagonist that reduces SNS activity and inhibits HPA activation by high-dose cannabinoids,¹³⁵ is also effective in alleviating CHS symptoms in human case studies.¹⁶¹ Other anxiolytic and sedating drugs, such as benzodiazepines and antipsychotics, can alleviate the nausea and vomiting associated with CHS as well.⁵³ Given the link between SNS and nausea and vomiting, the sympathetic symptoms (i.e., hypertension, tachycardia, and sweating) associated with CHS episodes, the impact of THC on the SNS, and acute treatments, it is possible that a dysregulated SNS may contribute to the pathophysiology of CHS (Fig. 1).

TRPV1 and temperature regulation

The endocannabinoid system in the hypothalamus is a critical brain region involved in thermoregulation.^162,163 Low doses of THC cause hyperthermia, whereas high doses produce hypothermia^26,164 by activating CB₁ receptors in the hypothalamus.¹⁶⁵ As previously mentioned, hot baths and showers consistently decrease nausea and vomiting symptoms for individuals experiencing CHS.^23,43,66,166 Nausea and vomiting are associated with a decline in body temperature in humans^167–169 and animals.¹⁷⁰ The hot bathing behavior associated with CHS could be overcoming the combined hypothermia of nausea and high doses of THC, improving symptoms.

High temperatures, such as during a hot shower, also activate transient receptor potential vanilloid 1 (TRPV1) receptors located on nociceptive neurons. These receptors are activated by noxious stimuli, high heat, or agonists like capsaicin,¹⁷¹ the chemical in chili peppers that makes them spicy, to send pain signals to the brain.¹⁷² The TRPV1 receptors are also implicated in nausea and vomiting pathways, where TRPV1 activity in the NTS leads to nausea and vomiting.¹⁷³ Likewise, the endocannabinoid system is interconnected with TRPV1 systems. AEA and 2- AG are endogenous agonists of the TRPV1 receptor, and CB₁ and TRPV1 receptors are often co-expressed on neurons, but have opposite effects, whereby CB₁ receptors inhibit neuronal activity and TRPV1 receptor activates neuronal activity.¹⁷¹ While THC has minimal efficacy at the TRPV1 receptors, other cannabinoids found in the cannabis plant, such as cannabidiol and cannabinol, along with AEA and 2-AG, activate and desensitize the TRPV1 receptor.^174,175

There is also a relationship between TRPV1 signaling and stress. While chronic stress leads to a downregulation of CB₁ receptors, there is an upregulation of TRPV1 receptors, which can lead to visceral hyperalgesia.¹⁷¹ Dysregulation of the endocannabinoid system could lead to dysregulation of TRPV1 receptors, and their associations with nausea, vomiting, and stress could indicate why individuals with CHS experience relief from symptoms when they take hot baths or use capsaicin cream.

Topical capsaicin cream applied to the abdomen is reported to be effective and safe for alleviating symptoms of CHS.^176–178 Topical capsaicin activates and then desensitizes the TRPV1 receptor, thus inhibiting pain signals, resulting in analgesic and anti emetic effects.^171,173 Therefore, capsaicin could be beneficial in an emergency room setting to prevent dehydration and kidney failure.^171,178 A retrospective chart analysis by Wagner et al.¹⁷⁸ found that capsaicin cream reduced the overall number of medications used to treat individuals with CHS in the emergency room, but did not reduce the overall length of stay in the hospital. While it is effective, other medications are still needed in conjunction with topical capsaicin for total symptom resolution.¹⁷⁸ The mechanism of how capsaicin reduces CHS symptoms is not known; therefore, its exact role in CHS treatment is not yet clear.

It is unclear if the relief felt by individuals with CHS by these therapies is because of direct alteration of TRPV1 receptors or because of alternative indirect mechanisms. Given the relationships between TRPV1 receptors, the endocannabinoid system, stress, pain, nausea, and the benefits of capsaicin cream and hot baths in CHS, it is possible that endogenous activation and function of TRPV1 receptors could be altered due to dysregulation of the endocannabinoid system, contributing to the development of CHS. Alternatively, high-temperature baths and capsaicin cream may produce a “cutaneous steal” syndrome.¹⁴⁶ Topical capsaicin and hot baths cause vasodilation in the skin and may cause redirection of blood flow from the gut to the skin, alleviating abdominal pain and nausea.¹⁷¹ This theory would explain why symptom relief with these methods is only temporary with capsaicin and hot baths. Information regarding changes to the TRPV1 system and function of capsaicin following chronic cannabis exposure, and TRPV1 receptor function in individuals with CHS is still needed to confirm its contribution to CHS symptoms.

Gut motility regulation

Another possible contributing factor to the pathophysiology of CHS is the effect of cannabinoids on gastrointestinal function.¹⁷⁹ Patients with CHS typically have delayed gastric emptying,^23,47,66 which, as discussed earlier, could help to distinguish CHS from CVS, which typically presents with an increase in gastric emptying.⁴⁸ Delayed gastric emptying without an obstruction, known as gastroparesis, produces nausea and vomiting.^180,181 The proemetic effects of inhibiting gut motility by cannabinoids may override the antiemetic effects of cannabinoids. This could be another contributing factor in the pathophysiology of CHS (Fig. 1). THC and synthetic designer cannabinoids have been shown to inhibit gut motility and gastric emptying in rats by acting on CB₁ receptors in the gut.^51,52,182 The inhibitory gastric effects are dose-dependent, where higher doses have a greater inhibitory effect on gastric motility and emptying,^51,52,182 and tolerance does not develop.^183,184 This is also seen in humans.^49,50 Furthermore, CRH released from the hypothalamus also inhibits gastrointestinal function.^101,185 These data highlight the connection between cannabinoids, endocannabinoid system, stress, and nausea and vomiting.

Pre-disposing factors

One characteristic of CHS that remains unresolved is that not every cannabis user develops CHS; therefore, it is likely that certain individuals are pre-disposed to develop CHS. Yet the prevalence of CHS among cannabis users is unknown. Genome-wide association studies may be beneficial in determining genetic anomalies in individuals with CHS. Indeed, polymorphisms of the CB₁ receptor gene are linked to an increased likelihood for individuals to develop CVS,¹⁸⁶ and differences in the FAAH gene are associated with an increased likelihood of irritable bowel syndrome,¹⁸⁷ addiction,¹⁸⁸ and anxiety disorders.^128,188

Individuals with pre-existing heightened or dysregulated stress responses may be at a higher risk of developing CHS. Mood disorders, such as anxiety and depression, are associated with dysregulated stress responses, and are linked to an increased likelihood of developing nausea and vomiting disorders.^{55,99,101,102} In addition, there is a correlation between mood disorders and excessive cannabis use,¹⁸⁹ as well as excessive cannabis use in CVS,⁴⁵ which may provide a link to CHS. Some studies have indicated that CHS is more common in males than females.^43,45,46 Sex differences should also be investigated to further understand what pre-disposes individuals to CHS. Also, some evidence suggests that most individuals with CHS began using cannabis in their teenage years.⁴³ Expression of CB₁ receptors is high during adolescence, and plays a very important role in this critical period for neuronal development. Heavy cannabis use in adolescence has been implicated in endocannabinoid system dysregulation to possibly impair proper neuronal development,¹⁹⁰ potentially influencing the development of CHS later in life. More research is needed, however, to understand how genetics, mood disorders, sex, and other pre-disposing factors contribute to the development of CHS.

Cannabis contamination

It is sometimes thought, often from anecdotal reports in popular media, that CHS is a result of poisoning from contaminants such as pesticides on cannabis and not from the actual plant constituents themselves. However, support is lacking for this hypothesis in the empirical literature.^191,192 Contaminants can be detected on cannabis plant samples^32,193 and in smoke.¹⁹⁴ The bioavailability of contaminants in smoked cannabis is still unknown¹⁹² and a significant amount of smoke is often lost in side stream. Indeed, the symptoms of pesticide poisoning are different than the symptoms of CHS. Pesticide poisoning typically leads to nausea and vomiting, pulmonary and cardiovascular symptoms, convulsions, and hepatic toxicity.^195,196 The only symptoms that are consistently seen with CHS are nausea and vomiting.²³Most markedly, compulsive hot bathing, a symptom used as supportive criteria for CHS diagnosis,^23,66,166 is not present in instances of pesticide poisoning.¹⁹⁶ The limited pre-clinical research on CHS does indicate that cannabis-induced nausea and vomiting is mediated by the action of THC at the CB₁ receptor.^14,19 Moreover, synthetic cannabinoids, which are produced in laboratories and therefore do not have pesticides, can also lead to CHS,^34–36 further undermining the notion of contamination contributing to CHS. In addition, since pesticides are not exclusive to cannabis, there would be many similar cases that would not be solved with cannabis abstinence. While pesticides can lead to adverse health problems, this is likely not the cause of CHS.

Conclusions

Low doses of THC are effective antiemetic treatments, but high doses paradoxically produce nausea and vomiting, and may lead to the development of CHS.²³ This complex syndrome may have many contributing factors, including downregulation of CB₁ receptors, a dysfunctional stress response, altered thermoregulatory and TRPV1 systems, inhibited gastric motility, and genetic factors.⁷¹ The evidence regarding the mechanisms responsible for cannabinoid-induced nausea and vomiting is limited, and there is much left to investigate.

Despite the possible pharmacological and behavioral therapies, the only way to eliminate CHS is abstaining from cannabinoids. Acute treatment is necessary to avoid dehydration, renal failure, and death, but long-term treatments need to emphasize that sustained abstinence is required to permanently cease symptoms. Education regarding the potential effects of long-term high doses of cannabinoids should be disseminated to physicians and the public to better detect and manage this debilitating syndrome. Future research, both clinical and pre-clinical, should continue to investigate the underlying mechanism and pre-disposing factors of CHS, to further understand the consequences of high-dose cannabinoid use and dysregulation of the endocannabinoid system.

Abbreviations Used

2-AG

2-arachidonoylglycerol

ACTH

adrenocorticotropin hormone

AEA

anandamide

BLA

basolateral amygdala

CB₁

cannabinoid 1

CHS

cannabinoid hyperemesis syndrome

CRH

corticotropin-releasing hormone

CUD

cannabis use disorder

CVS

cyclical vomiting syndrome

DVC

dorsal vagal complex

FAAH

fatty acid amide hydrolase

HPA

hypothalamic-pituitary-adrenal

LC

locus coeruleus

LiCl

lithium chloride

MAGL

monoacylglycerol lipase

NTS

nucleus tractus solitarius

rVLM

rostral ventrolateral medulla

SNS

sympathetic nervous system

THC

Δ⁹-tetrahydrocannabinol

TRPV1

transient receptor potential vanilloid 1

Author Disclosure Statement

The authors have no conflicts of interest to disclose.

Funding Information

This research was supported by a research grant from the Natural Sciences and Engineering Reserch Council of Canada (NSERC: 03629) to L.A.P. and an NSERC CGS D Scholarship to M.V.K.

Cite this article as: DeVuono MV, Parker LA (2020) Cannabinoid hyperemesis syndrome: a review of potential mechanisms, Cannabis and Cannabinoid Research 5:2, 132–144, DOI: 10.1089/can.2019.0059.