Endocannabinoid signaling in stress, nausea, and vomiting

Abstract

Background

Classical antiemetics that target the serotonin system may not be effective in treating certain nausea and vomiting conditions like cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome (CHS). As a result, there is a need for better therapies to manage the symptoms of these disorders, including nausea, vomiting, and anxiety. Cannabis is often used for its purported antiemetic and anxiolytic effects, given regulation of these processes by the endocannabinoid system (ECS). However, there is considerable evidence that cannabinoids can also produce nausea and vomiting and increase anxiety in certain instances, especially at higher doses. This paradoxical effect of cannabinoids on nausea, vomiting, and anxiety may be due to the dysregulation of the ECS, altering how it maintains these processes and contributing to the pathophysiology of CVS or CHS.

Purpose

The purpose of this review is to highlight the involvement of the ECS in the regulation of stress, nausea, and vomiting. We discuss how prolonged cannabis use, such as in the case of CHS or heightened stress, can dysregulate the ECS and affect its modulation of these functions. The review also examines the evidence for the roles of ECS and stress systems' dysfunction in CVS and CHS to better understand the underlying mechanisms of these conditions.

Key points.

• The endocannabin old system (ECS)plays an important role in regulating nausea, vomiting, stress and anxiety.

• Chronic stress and/or cannabis use can alter endocannabinoidsignaling and impair its ability to modulate these functions.

• Endocannabinoid system dysfunction maycontribute to the development of Cyclic Vomiting Syndrome (CVS) or Cannabinoid Hyperemesis Syndrome (CHS).

1. INTRODUCTION

The first‐line treatments for nausea and vomiting are typically serotonin 5‐HT3 receptor antagonists, which effectively prevent acute vomiting and are partially effective at preventing acute nausea associated with chemotherapy. ¹ , ² These classic antiemetics are sometimes ineffective at alleviating symptoms associated with certain nausea and vomiting disorders, such as cyclic vomiting syndrome (CVS) or cannabinoid hyperemesis syndrome (CHS). ³ , ⁴ , ⁵ Neurokinin 1 (NK1) receptor antagonists have improved the management of nausea and vomiting; however, there is a need for better therapies that can treat both nausea and vomiting, as well as the anxiety that is associated with disorders such as CVS and CHS. ⁶ , ⁷ , ⁸ Cannabis has historically been used as an effective antiemetic treatment for chemotherapy‐induced nausea and vomiting. ⁹ The antiemetic effects are attributed to the primary psychoactive constituent of cannabis, ∆⁹‐tetrahydrocannabinol (THC), ¹⁰ which has led to the development of synthetic derivatives of THC (i.e., dronabinol and nabilone) for the treatment of chemotherapy‐induced nausea and vomiting. ¹¹ In addition to the anti‐nausea and antiemetic effects, acutely in humans, THC generally produces subjective effects such as elevated mood, reduced anxiety, and increased sociability. ¹² There is growing evidence, however, that cannabinoids can also produce nausea and vomiting and increase anxiety in certain instances, particularly at higher doses. ¹³ , ¹⁴ The biphasic effects of exogenous cannabinoids on nausea, vomiting, and anxiety suggest that the endocannabinoid system's role in modulating these processes could also be biphasic.

Cannabis exerts most of its effects through modulation of the endocannabinoid system (ECS). THC is a partial agonist of the Cannabinoid 1 (CB1) receptor of the ECS. ¹⁵ Synthetic derivatives can be more potent and efficacious at CB1 than THC. ¹⁶ The CB1 receptor is an inhibitory G protein‐coupled receptor found on presynaptic axon terminals, and when bound by endogenous ligands (i.e., endocannabinoids), such as 2‐arachidonoylglycerol (2‐AG) and N‐arachidonylethanolamine (anandamide; AEA), can inhibit neurotransmitter release. ¹⁷ Unlike classical neurotransmitters, endocannabinoids are not packaged in presynaptic vesicles awaiting release. Instead, endocannabinoid synthesis is triggered “on‐demand” in postsynaptic neurons by neuronal activity that initiates enzymatic cascades to drive endocannabinoid synthesis from phospholipid precursors. Endocannabinoids synthesized in postsynaptic compartments travel retrogradely through poorly understood mechanisms to act on presynaptic CB1 receptors and modulate synaptic transmission. Hydrolyzing enzymes quickly terminate ECS signaling; 2‐AG is catabolized by monoacylglycerol lipase (MAGL) and AEA by fatty acid amide hydrolase (FAAH). ¹⁸ Thus, the activity of AEA and 2‐AG as CB1 receptor agonists is greatly dependent on the activity of synthesizing and degrading enzymes. CB1 receptors are highly abundant in the central nervous system, ¹⁹ , ²⁰ and endocannabinoid CB1‐mediated signaling is crucial for regulating the balance of synaptic activity. ECS signaling has widespread effects, particularly related to the modulation of mood, anxiety, stress, nausea, and vomiting. ⁹ , ²¹

2. ECS REGULATION OF STRESS AND ANXIETY

One of the most commonly reported reasons for cannabis use is stress relief and anxiety management. ²² A cross‐sectional study of 140 patients with CVS showed that of 41% who used cannabis, 80% reported feeling more relaxed because of its use and reported a reduction in nausea, vomiting, and abdominal pain, which are characteristic of a CVS attack. ²³ Another internet survey of 437 patients with CVS showed that, of the 81% who used cannabis, 90% stated that cannabis reduced stress levels. ²⁴

There is compelling evidence that the ECS is a stress effector that acts to regulate responses to acute stressors. ²⁵ Stressors are challenges to homeostasis, the balance of biological activity which supports survival, and include events such as tissue injury, starvation, pain, psychological stress, and exercise. ²⁶ , ²⁷ Signaling in the ECS is altered by stressors, producing changes in synaptic activity, which regulate the initiation and recovery of central stress pathways and mediate or modulate stress‐associated behaviors and return to homeostasis.

Stress exposure directs activation of central stress pathways, including the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic branch of the autonomic nervous system, and promotes stress‐associated behaviors, such as fear and anxiety, to cope with stressors. ²⁶ , ²⁸ Acute stress activates the hypothalamus and, as a result of the release of corticotropin releasing hormone (CRH), triggers pituitary release of adrenocorticotropin hormone (ACTH) to signal the adrenal glands to release glucocorticoid stress hormones. ²⁷ The release of CRH also stimulates norepinephrine (NE) release and initiates an autonomic response generated by the sympathetic nervous system (SNS), promoting arousal, attention, changes in heart rate, blood pressure, blood vessel dilation, and changes in gastrointestinal function. ²⁹ Glucocorticoids provide negative feedback to the hypothalamus and other brain regions to terminate these processes. ²⁷

CRH and glucocorticoids alter endocannabinoid signaling during the initiation and termination of the stress response, respectively. ²⁵ The elevation of CRH produced by stress increases the activity of the hydrolyzing enzyme for the endocannabinoid AEA, FAAH, and augments AEA breakdown. The reduction in AEA reduces CB1 signaling, promoting excitatory glutamate release in the hypothalamus and amygdala, and activation of the stress response. ³⁰ , ³¹ In the prefrontal cortex, where CB1 receptors are mainly present on inhibitory GABAergic neurons, CRH‐induced AEA reductions raise GABA release, thus inhibiting the PFC negative control of stress pathways. The disinhibition further enhances hypothalamus and amygdala excitability and further contributes to the activation of the stress response. ³² These findings suggest that basal AEA concentrations constrain the stress response, and the CRH‐FAAH‐mediated reduction of AEA allows the stress response to become active. ²⁵ This mechanism is consistent with data demonstrating that decreased AEA concentrations are associated with susceptibility to stress, elevated circulating glucocorticoid, and anxiety‐related behaviors. ³¹ , ³³ , ³⁴ , ³⁵ , ³⁶ , ³⁷ Likewise, elevating AEA by inhibiting the enzymatic activity of FAAH is anxiolytic and reduces glucocorticoid levels in humans and laboratory animals. ³³ , ³⁵ , ³⁶ , ³⁸

In contrast to the response of AEA, 2‐AG synthesis is increased following stress through a glucocorticoid‐mediated mechanism. ³⁹ After a delay following stress, glucocorticoids feedback to the hypothalamus and bind to glucocorticoid receptors to drive 2‐AG synthesis and release. ⁴⁰ 2‐AG can then bind to CB1 receptors, restoring ECS signaling to terminate the stress response and inhibit anxiety. Reduced brain 2‐AG is associated with enhanced stress susceptibility, anxiety behaviors, and increased glucocorticoids. ³³ , ⁴¹ , ⁴² , ⁴³ Accordingly, increased levels of 2‐AG are associated with stress resiliency and blocking 2‐AG breakdown by inhibiting MAGL activity can also protect against stress‐induced anxiety behaviors. ⁴² , ⁴³ , ⁴⁴

The ECS can also interact with transient receptor potential vanilloid 1 (TRPV1) channels. While primarily implicated in pain and temperature sensation, TRPV1 also participates in stress and anxiety signaling. ⁴⁵ Endocannabinoids, in particular AEA, are endogenous ligands of TRPV1, ⁴⁶ and CB1 and TRPV1 receptors are often co‐expressed on neurons throughout the brain, including the amygdala. ⁴⁷ Similar to stress‐induced FAAH activation, TRPV1 expression is increased following acute and chronic stress, likely through a glucocorticoid‐CB1 mechanism. ⁴⁸ , ⁴⁹ , ⁵⁰ Increased TRPV1 signaling is associated with enhanced stress activation and related behaviors. ⁵¹ Additionally, TPRV1 deletion leads to stress resiliency in mice, ⁵² and antagonism of TRPV1 and dual inhibition of FAAH/TRPPV1 inhibit stress‐induced anxiety‐like behavior and glucocorticoid release. ⁵³ , ⁵⁴ Overall, these findings suggest TRPV1 channels interact with the ECS systems to properly regulate the stress response.

2.1. ECS dysregulation and effects of CB1 receptor agonism

Despite relaxation being the most popular reason for cannabis use and considerable evidence that the ECS signaling is anxiolytic, a common adverse side effect of cannabis use is heightened anxiety. ¹⁴ Interestingly, while ECS signaling typically inhibits stress, high doses of CB1 receptor agonists (i.e., THC or synthetic cannabinoids), but not lower doses can acutely activate stress, as indexed by increased levels of ACTH, CRH, circulating glucocorticoids and enhanced SNS activity. ⁵⁵ , ⁵⁶ , ⁵⁷ , ⁵⁸ , ⁵⁹ Baseline cortisol levels tend to be higher in heavy regular cannabis users than nonusers, yet cannabis users display a blunted glucocorticoid response to acute stressors suggesting HPA axis impairment. ⁶⁰ , ⁶¹ Chronic cannabis users also tend to have increased blood pressure, heart rate and an increased skin conductance response during fear, ⁵⁷ , ⁶¹ , ⁶² indicative of SNS activation. In patients with CVS, Venkatesan et al. ⁶³ measured peripheral endocannabinoids, as well as salivary cortisol and alpha‐amylase, markers of HPA and SNS activity, respectively, and found that cannabis users had significantly higher salivary cortisol and alpha‐amylase concentrations during an acute CVS episode compared to nonusers. ⁶³ Additionally, Shah et al. ⁶⁴ found in a retrospective chart review that patients with CHS had higher blood pressure than patients with CVS. These findings are consistent with loss of ECS signaling and support the hypothesis that high doses of and/or prolonged exposure to CB1 agonists can enhance stress.

Consistent with other behavioral effects and the impact on stress hormones, CB1 receptor agonists exhibit dose‐dependent effects on anxiety behaviors, with low doses being anxiolytic and higher doses being anxiogenic. ⁶⁵ , ⁶⁶ These studies suggest that ECS can regulate fear and anxiety circuits at multiple sites. Mouse models in which CB1 receptors have been selectively deleted from either excitatory glutamatergic or inhibitory GABAergic neurons align with this hypothesis as deletion produces opposite effects on anxiety. Specifically, CB1 deletion on glutamatergic neurons interferes with the anxiolytic effects of low doses, and deletion of CB1 on GABAergic neurons blocks anxiogenic responses to high doses of CB1 agonists. ⁶⁶

The pro‐anxiety effects of CB1 receptor agonists at high doses could also be explained by ECS dysregulation. When CB1 receptor signaling is high, as occurs in the presence of high concentrations of agonists or prolonged exposure, receptors recruit ß‐arrestin to initiate receptor desensitization, which can then lead to receptor internalization and downregulation. ¹⁶ , ⁶⁷ , ⁶⁸ Such receptor adaptations result in loss of inhibitory control provided by the CB1 receptor, dampening ECS signaling (Figure 1). This mechanism could underlie the increase in stress and anxiety in the face of chronic high‐dose THC exposure.

FIGURE 1.

Representation of the influences of stress and cannabis use on Cannabinoid 1 (CB1) receptor endocannabinoid system (ECS) signaling. CB1 receptor signaling is high when endocannabinoids are available, which typically translates to reduced stress activation, suppressed anxiety, and inhibition of nausea and vomiting. When CB1 receptor signaling is low, there is often impaired stress regulation, increased anxiety, nausea, and vomiting. Healthy endocannabinoid signaling would allow for flipping between these two states and appropriate regulation of stress, nausea and vomiting; however, chronic stress exposure (orange lighting bolt) and prolonged cannabis use (green cannabis leaf) can dysregulate the ECS. Chronic stress and cannabis use alter endocannabinoid synthesis and degradation, affecting their availability. While THC itself activates the CB1 receptor, prolonged exposure can lead to desensitization and subsequent downregulation of CB1 receptors and, ultimately, reduced signaling. Chronic stress can also contribute to these receptor adaptations, thus deregulating the system to favor the low CB1 receptor signaling state and potentially contribute to the pathophysiology of cyclic vomiting syndrome (CVS) and cannabinoid hyperemesis syndrome (CHS).

Chronic administration of high doses of CB1 agonists in rodents has also been shown to reduce CB1 receptor availability and alter levels of endocannabinoids and their synthetic and catabolic enzymes. ⁶⁷ , ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷² , ⁷³ CB1 receptor changes are dose dependent with higher doses of CB1 agonists resulting in greater downregulation. ¹⁶ , ⁷⁴ , ⁷⁵ Moreover, ECS alterations following chronic CB1 agonism and subsequent functional recovery, are region and time‐dependent as they occur at different rates and amplitudes in different brain regions. ⁶⁷ , ⁶⁸ , ⁷⁶ Longer CB1 receptor agonism is also associated with a more prolonged time to functional recovery. ⁷⁷ Correspondingly, human neuroimaging studies have demonstrated that heavy, frequent/daily cannabis use is associated with less CB1 receptor availability, which was negatively correlated with years of cannabis use, and altered endocannabinoid levels, which differed between light and heavy users. ⁷⁸ , ⁷⁹ , ⁸⁰ , ⁸¹ The preclinical and clinical findings suggest that long‐term, high‐dose cannabis use as is typical in individuals with CHS, may result in profound and widespread ECS dysregulation that is resilient to recovery. Given the importance of ECS signaling in stress regulation, these changes likely contribute to the disrupted stress regulation and enhanced anxiety observed in chronic cannabis users. ⁶⁰

Chronic stress itself is associated with similar effects on ECS signaling and stress responsiveness (Figure 1). ²⁵ , ⁸² Prolonged stress can lead to maladaptations of the stress response and the development of psychiatric illnesses, which are often associated with impaired glucocorticoid signaling. ⁸³ ECS dysregulation may mediate these consequences of chronic stress. Acute stress results in transient changes to the ECS to allow regulation of the stress response; however, chronic stress produces more enduring ECS adaptation, including changes to AEA and 2‐AG levels and ECS enzyme activity, resulting in lowered CB1 receptor availability and reduced ECS signaling. ³² , ⁴⁴ , ⁸⁴ Prolonged glucocorticoid exposure can also elevate TRPV1 expression and potentially further impair stress regulation through interaction with the ECS. ⁴⁸ Given the importance of the ECS in stress homeostasis, dysregulation of its normal functioning by cannabis use or chronic stress has the potential to have profound effects that likely contribute to the adverse outcomes of chronic stress and cannabis use.

3. ECS REGULATION OF EMESIS

One of the first recognized medicinal uses of cannabinoids was for treating chemotherapy‐induced nausea and vomiting. ¹¹ Cannabis and synthetic CB1 agonists in small amounts effectively reduce acute vomiting in humans, ⁸⁵ , ⁸⁶ suggesting ECS modulation of emesis.

The brainstem's dorsal vagal complex (DVC) has been identified as a vital brain region for initiating the vomiting reflex. ⁸⁷ The DVC consists of the nucleus tractus solitarius (NTS), area postrema (AP), and dorsal motor nucleus (DMNX). These regions contain significant densities of serotonin 5‐HT3 receptors and NK1 receptors that are necessary in emetic species for acute and delayed vomiting, respectively. ⁸⁸ , ⁸⁹ Stimuli that produce vomiting, such as chemotherapy drugs, lithium chloride (LiCl), or electrical stimulation of abdominal vagal afferents, increase serotonin (5‐HT) levels in the AP and NTS which excites DMNX neurons, which produce the motor output of vomiting. ⁸⁹ There is also a delayed increase in NK1 activation by substance P that results in a prolonged delayed phase of vomiting. ⁷ Thus, the DVC is the region where antiemetics such as the 5‐HT3 antagonist ondansetron interfere with acute vomiting and NK1 antagonists such as aprepitant interfere with delayed vomiting.

The DVC also contains CB1 receptors. Activation of the CB1 receptors in the DVC reduces neuronal activation induced by emetic stimuli. ¹⁰ Low doses of THC or synthetic CB1 receptor agonists prevent vomiting caused by chemotherapy drugs, LiCl, radiation, and motion sickness in animals capable of vomiting, such as ferrets and shrews. ⁹⁰ , ⁹¹ , ⁹² , ⁹³ , ⁹⁴ Moreover, exogenously administered endocannabinoids, 2‐AG, and AEA, and enhancing ECS signaling by inhibiting 2‐AG and AEA breakdown, prevent toxin‐induced emesis through a CB1 receptor mechanism. ⁴⁷ , ⁹⁵ , ⁹⁶ , ⁹⁷ CB1 receptors have been identified on the terminals of 5‐HT‐releasing neurons. ⁹⁸ , ⁹⁹ Therefore, endocannabinoids may bind to inhibitory presynaptic CB1 receptors in the DVC to suppress 5‐HT release to alleviate acute emesis.

The antiemetic effect of elevated AEA signaling may be, in part, mediated by TRPV1 channels in the NTS that co‐localize with CB1 receptors. This suggests an overlap between CB1 receptors and TRPV1 channels in vomiting regulation. Enhanced AEA levels lead to activation and rapid desensitization of TRPV1 channels, resulting in an antiemetic effect. ⁴⁷ TRPV1 antagonism has also been shown to be antiemetic; thus, increased TRPV1 signaling likely contributes to vomiting. ⁴⁵ , ¹⁰⁰ TPRV1 activation also increases substance P release, a neuropeptide involved in pain processing, which could further contribute to vomiting through NK1 receptor activation. ⁴⁵ CB1 receptor mechanism can prevent vomiting initiated by NK1 receptor agonists or exogenous substance P, ¹⁰¹ suggesting the ECS signaling may inhibit delayed vomiting through interaction with substance P/NK1. However, the roles of specific endocannabinoids in the relationship have yet to be established. Taken together, these findings strongly implicate the ECS in the regulation of emesis in the brain and that cannabinoid‐based treatments exploit the ECS innate antiemetic mechanisms to alleviate vomiting effectively.

4. ECS REGULATION OF NAUSEA

In contrast to emesis, nausea is not well controlled by available antiemetics. ⁷ , ¹⁰² Nausea is an intense adverse experience that typically accompanies vomiting but can occur independently. Indeed, distinct neuronal mechanisms underlie nausea and vomiting. ¹⁰³ , ¹⁰⁴ Cannabinoid‐based antiemetics are more effective than 5‐HT3 receptor antagonists and can enhance the anti‐nausea effects of NK1 antagonists, especially to alleviate chemotherapy‐induced nausea. ⁸⁵ , ¹⁰⁵ , ¹⁰⁶ , ¹⁰⁷ Therefore, the ECS likely plays a role in regulating nausea in addition to emesis.

The neurobiological mechanisms of nausea are less understood than vomiting, in part because nausea is challenging to measure in laboratory animals. However, rats display a conditioned gaping behavior in the taste reactivity test that offers a preclinical method to quantify nausea. ¹⁰⁸ Rats lack the motor output of vomiting; however, they do receive the same gastrointestinal and DVC signals that precede vomiting in species capable of vomiting. ⁸⁹ When given a novel flavor paired with an emetic agent, such as LiCl, chemotherapy drugs, or radiation, rats display a conditioned gaping response, characterized by the wide triangular opening of the mouth, when reexposed to that flavor. ¹⁰⁸ , ¹⁰⁹ The conditioned gaping behavior also engages the same orofacial muscles as vomiting in species capable of vomiting. ¹¹⁰ Manipulations that produce nausea in species that can vomit also consistently produce conditioned gaping in rats, and treatments that alleviate nausea in emetic species also reduce conditioned gaping in rats. ¹⁰⁸ Therefore, rats provide a valuable model for studying the mechanism of nausea without the confound of vomiting, and have been used to investigate the neurobiological mechanisms responsible for nausea and the involvement of the ECS.

Although the DVC is essential for the vomiting reflex, the insular cortex has been identified as a crucial region for generating sensations of nausea and disgust. ¹¹¹ , ¹¹² , ¹¹³ 5‐HT3, NK1, and CB1 receptors are expressed in the insular cortex. ¹¹⁴ , ¹¹⁵ In rats, the posterior interoceptive insular cortex (IIC) receives visceral sensory input, and the anterior gustatory insular cortex (GIC) receives gustatory signals and is where the majority of output signals to autonomic brainstem structures are located. ¹¹⁶ , ¹¹⁷ Emetic stimuli increase neuronal activation and elevate 5‐HT in the IIC while producing conditioned gaping behaviors, without affecting 5‐HT in the GIC. ¹¹⁸ Additionally, blocking 5‐HT3 receptors in the IIC, but not the GIC, interferes with LiCl‐induced conditioned gaping reactions suggesting IIC 5‐HT3 activity is involved in establishing acute nausea. ¹¹⁹

The ECS in the IIC also modulates nausea. ¹¹⁸ At low doses, systemic and direct administration of THC and synthetic CB1 receptor agonists into the IIC prevents nausea in rats. ¹²⁰ , ¹²¹ CB1 receptor activity in the GIC does not affect conditioned gaping, ¹²² supporting the importance and selectivity of the CB1 receptor in the IIC. Elevating 2‐AG signaling with MAGL inhibition and exogenously administered 2‐AG, systemically and intra‐IIC, also interfere with nausea through CB1‐dependent mechanisms. ⁹⁷ , ¹²³ , ¹²⁴ , ¹²⁵ Interestingly, unlike vomiting, FAAH inhibition in the IIC does not reduce LiCl‐induced conditioned gaping. ¹²⁴ , ¹²⁵ Systemic FAAH inhibition and peripherally restricted FAAH inhibition can interfere with LiCl nausea in rats, however, through a peroxisome proliferator‐activated receptor α (PPARα) mechanism, not CB1 signaling. ¹²⁶ , ¹²⁷ Therefore, the anti‐nausea effects of FAAH inhibition are unlikely to be mediated by AEA but by other FAAH substrates that are PPARα agonists, including oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). ¹²⁶ , ¹²⁷ Indeed, systemic and intra‐IIC MAGL inhibition elevates 2‐AG in the IIC, but systemic and intra‐IIC FAAH inhibition does not elevate AEA in this region, but does elevate levels of OEA and PEA. ¹²⁴

The selective role of 2‐AG in the IIC to reduce nausea is further supported by acute episodes of nausea elevating 2‐AG, but not AEA in the IIC. ¹²⁴ Enhancing 2‐AG signaling with MAGL inhibition also reduced neuronal activation and 5‐HT release in the IIC caused by LiCl treatment. ¹¹⁸ , ¹²⁴ These preclinical findings suggest that nauseating stimuli increase 5‐HT release in IIC, which acts on postsynaptic 5‐HT3 receptors to produce acute nausea. Activation of the 5‐HT3 receptors also promotes the synthesis and release of 2‐AG, which turns off the serotonergic activity via its action on presynaptic CB1 receptors in a negative feedback loop and alleviates nausea.

While the interaction between the ECS, TRPV1, substance P, and NK1 receptors have begun to be investigated in vomiting, less is known about this relationship in terms of nausea circuits specifically and remains an avenue of future research regarding the ECS signaling in nausea.

5. CANNABINOID‐INDUCED NAUSEA AND VOMITING: ASSOCIATION BETWEEN ECS, STRESS, NAUSEA, AND VOMITING

Despite the vast body of literature indicating that CB1 receptor activation prevents nausea and vomiting, there are certain instances where cannabinoids can produce nausea and vomiting. Humans commonly report nausea and vomiting as an adverse side effect associated with high doses of THC or synthetic cannabinoids. ¹⁴ , ¹²⁸ , ¹²⁹ , ¹³⁰ , ¹³¹ , ¹³² Perhaps, the most striking example of cannabinoid‐induced nausea and vomiting is the phenomenon of CHS seen in some cannabis users. ¹³ CHS is characterized by episodes of severe nausea, vomiting, and often abdominal pain that closely mimics the symptoms of CVS and is diagnosed using Rome IV criteria. While there have been multiple case reports and case series describing CHS, not all heavy cannabis users develop CHS; therefore, how or whether cannabis directly causes hyperemesis and if cessation leads to complete resolution of symptoms is unclear. ¹³³ A systematic review of 376 cases of CHS published in the literature demonstrated significant heterogeneity in diagnostic criteria and inadequate follow‐up of cases except for the study by Allen et al. In this review, only 16% of cases met Rome IV criteria for CHS. ¹³³ Experts have postulated that CHS is a subset of CVS where chronic cannabis use exacerbates symptoms or can contribute to the development of hyperemesis in patients who are genetically predisposed to CVS or otherwise susceptible. For example, a case–control study of patients with CVS showed that polymorphisms of the gene for the CB1 receptors, CNR1, are associated with risk of CVS. ¹³⁴ The AG and GG genotypes of CNR1 rs806380 are associated with an increased risk of CVS, whereas the CC genotype of CNR1 rs806368 is associated with a decreased risk of CVS. Of note, the CT and CC genotypes of CNR1 rs2023239 are associated with a positive response to therapy. ¹³⁴ Cannabis may also interact with other yet be established variables such as genetics, age of cannabis use onset, or lifestyle factors such as nutrition and environmental stress that may aggravate symptoms further. Taken together, these data support the involvement of ECS signaling in the pathophysiology of CVS and CHS, and in nausea and vomiting regulation.

Comparable to the effect of THC on anxiety, the antiemetic and pro‐emetic effects of CB1 receptor agonists are dose dependent. Low doses of CB1 receptor agonists produce antiemetic effects and offer therapeutic results for nausea and vomiting in humans and animals. ⁸⁵ , ⁹² , ¹²⁰ However, when administered at high doses, CB1 agonists produce vomiting in several species capable of vomiting, including shrews, cats, dogs, and nonhuman primates. ⁹⁰ , ⁹⁴ , ¹³⁵ , ¹³⁶ , ¹³⁷ Using the taste reactivity paradigm to investigate nausea preclinically, low doses of THC and synthetic CB1 agonists prevent LiCl‐induced conditioned gaping in rats. ¹²⁰ , ¹²² However, when cannabinoids are themselves paired with a flavor in the taste reactivity test, high but not low doses produce conditioned gaping reactions on their own, indicating nausea. ⁵⁹ , ⁷³ , ¹³⁸ In contrast to findings with nausea produced by LiCl and cisplatin, 5‐HT3 antagonism with ondansetron is not effective at preventing THC‐induced nausea in rats. ⁵⁸ These results are consistent with the treatment of CVS and CHS in humans, where typical antiemetics are usually ineffective at alleviating symptoms, particularly nausea and anxiety. ⁴ , ¹³⁹ Nausea and vomiting associated with CVS and CHS are regularly managed with anxiolytic drugs like benzodiazepines, and the beta blocker propranolol has been shown to have some efficacy in treating symptoms of CHS. ¹³⁹ , ¹⁴⁰ , ¹⁴¹ Indeed, the benzodiazepine, chlordiazepoxide, and ß‐adrenergic receptor antagonist, propranolol, interfere with THC‐induced conditioned gaping in rats. ⁵⁸ Other treatments that show promise in humans with CVS and CHS such as NK1 antagonists (i.e., aprepitant), tricyclic antidepressant (i.e., amitriptyline), or antipsychotic drugs (i.e., haloperidol or olanzapine), have yet to be investigated against cannabinoid‐induced conditioned gaping in rats. The similarities in effective treatments between humans with CHS and cannabinoid‐induced conditioned gaping in rats support using this preclinical model to investigate central mechanisms of nausea and effective treatments.

Stress and anxiety have also been hypothesized to be involved in the pathophysiology of several functional nausea and vomiting disorders including CVS and CHS. ¹⁴² , ¹⁴³ , ¹⁴⁴ , ¹⁴⁵ , ¹⁴⁶ , ¹⁴⁷ , ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ Given that treatments for CVS and CHS in humans and cannabinoid‐induced nausea in rats are often anxiolytic, ECS dysregulation of stress and anxiety could contribute to a loss of the anti‐nausea effects of ECS signaling. It remains unclear, however, if the benefits of such pharmacotherapies are due to their general sedative effect independent of their impact on stress and anxiety. It is noteworthy that non‐pharmacological treatments such as psychotherapy, which target anxiety and psychological distress, can also be beneficial for CVS and CHS, ¹⁵¹ , ¹⁵² , ¹⁵³ , ¹⁵⁴ supporting that anxiety reduction could be part of the treatment mechanism of anxiolytic. However, this relationship requires additional investigation. Nausea, anxiety, and autonomic symptoms frequently co‐occur in a prodromal phase that precedes vomiting episodes in CVS and CHS. ¹³ , ¹⁵⁵ There is some evidence that preexisting anxiety or higher trait anxiety increases the likelihood of developing nausea and vomiting disorders irrespective of cannabis use, including anticipatory, postoperative, chronic unexplained nausea and vomiting, and even increases the chance of experiencing motion sickness or nausea following endurance exercise. ¹⁴² , ¹⁴⁶ , ¹⁴⁷ , ¹⁴⁸ , ¹⁴⁹ , ¹⁵⁰ Nausea and vomiting are also associated with changes in stress reactivity and sympathetic symptoms, including sweating, flushing, thirst, hypertension, and tachycardia. ⁶³ , ¹¹² , ¹⁵⁶ , ¹⁵⁷ It has also been shown that cannabis use potentiates HPA and SNS dysfunction during vomiting, highlighting the interaction between the ECS, stress, and nausea, and vomiting. ⁶³ Therefore, the effect of excessive ECS signaling on stress could contribute to nausea and vomiting and increase the likelihood that cannabis use leads to nausea and vomiting; however, a causal relationship cannot be fully determined.

ECS dysregulation and altered stress homeostasis by extended CB1 receptor activation could, in turn, impair mechanisms controlling nausea and vomiting and potentially contribute to the pathophysiology of certain nausea and vomiting disorders like CHS or CVS in vulnerable individuals (Figure 1). ¹³³ , ¹⁴³ Allostasis is the act of maintaining stability and coping with assaults to homeostasis. ²⁶ Therefore, the ECS can be considered an allostatic mechanism. When allostatic mechanisms fail or are overwhelmed by prolonged or multiple stressors, adaptations occur leading to imbalances which are associated with biological and psychiatric illnesses. ¹⁵⁸ Dysregulation of the ECS allostatic mechanisms could make it more difficult to cope with threats to homeostasis such as further cannabis use, diet changes or life stressors, and prolong the return to baseline and contribute to the cyclical nature of CVS and CHS. For example, episodes of CVS are triggered by negative stresses (loss of a loved one or examinations) in 67% and by positive events (birthdays or vacations) in 59% of patients. ¹⁵⁹ External life stressors, including the resumption of cannabis use, may also trigger CHS emetic episodes. ¹³ Levels of peripheral endocannabinoid and related lipids have also been shown to be differentially altered between emetic and well phases in CVS patients. ⁶³ , ¹⁶⁰ Exploring the dynamics of the ECS alterations across different phases of CVS and CHS could help identify how dysfunctional ECS signaling participates in the initiation and recovery from emetic episodes.

The involvement of ECS and stress dysfunction in cannabinoid‐induced nausea has been investigated further using the taste reactivity test in rats. ¹⁴³ Elevating ECS signaling by blocking endocannabinoid breakdown by inhibiting either MAGL or FAAH interferes with THC‐induced conditioned gaping in rats. ⁵⁸ This is opposed to the findings with LiCl‐induced nausea, where AEA signaling in the IIC does not seem to be central in acute nausea regulation. ¹²⁴ However, central AEA signaling is vital for stress and anxiety regulation. ²⁷ For example, as stress triggers CRH release to enhance FAAH activity and reduce AEA's inhibitory control in several stress‐related brain regions, inhibition of FAAH reduced HPA axis activation by opposing the effect of CRH. ³⁰ Therefore, FAAH inhibition could elevate AEA in other brain centers to inhibit stress activation and, ultimately, produce an anti‐nausea effect. In accordance with this hypothesis, CRH receptor antagonism also interferes with THC‐induced nausea in rats. ⁵⁸ Thus, AEA augmentation is ineffective for acute nausea, where 2‐AG signaling dominates, but is effective in cannabinoid‐induced nausea, which is proposed to be related to stress systems where AEA is dominant in the ECS regulation.

5.1. Potential interplay between ECS and other neuromodulator systems in stress, nausea, and vomiting

Many patients with CHS report that topical cutaneous capsaicin cream applied to the abdomen and hot baths and/or showers produce temporary symptom relief of CHS. ¹⁶¹ These treatments are not specific to CHS and also beneficial in CVS, and other nausea and vomiting conditions. ²⁴ , ¹⁶² , ¹⁶³ Capsaicin, a compound responsible for spiciness in chili peppers, high temperatures, and AEA all activate TRPV1 channels. ⁴⁵ TRPV1 channels are increased in response to chronic stress, partially mediated by the ECS and contribute to stress‐induced visceral hyperalgesia. ⁴⁸ , ⁴⁹ ECS dysregulation caused by prolonged CB1 receptor activation or stress could indirectly alter TRPV1 signaling by affecting AEA levels. It is unknown if the relief felt by patients with CHS using these therapies is due to direct activation and rapid desensitization of TRPV1 channels correcting dysregulated channel function. An alternative explanation, consistent with the transient therapeutic effects of the TRPV1‐related stimuli, is an acute episode of abdominal vasodilation that reduces visceral hyperalgesia. ¹⁶¹

Activation of TRPV1 can also lead to the release of the neuropeptide substance P that binds to NK1 receptors and can contribute to pain signaling, but also nausea and vomiting. ⁷ The availability of NK1 receptors in the amygdala has been associated with anxiety behaviors in humans. ¹⁶⁴ NK1 antagonism, like with a common antiemetic agent aprepitant, can produce antidepressant and anxiolytic effects in animal models and humans. ¹⁶⁵ , ¹⁶⁶ , ¹⁶⁷ Chronic administration of NK1 antagonists elevates AEA and 2‐AG in brain regions involved in emotional regulation, and this elevation is blocked by a CB1 receptor antagonist. ¹⁶⁵ CB1 receptors facilitate NK1 receptor internalization, likely as a result of ECS‐mediated increase of substance P release from TRPV1‐containing neurons and highlighting the connections between these systems. ¹⁶⁸ Less is known regarding the effects of chronic stress and chronic cannabis use on NK1, which, in addition to TRPV1, warrants exploration to better understand ECS regulation of stress, nausea, and vomiting.

Antagonism of dopamine type 2 (D2) receptors with antipsychotic drugs like haloperidol produces antiemetic effects and is demonstrated to be effective at alleviating CHS symptoms in an emergency room setting. ¹³⁹ , ¹⁶⁹ However, the sedative effects of D2 antagonists may complicate the interpretation of these findings. D2 receptors present in the DVC have been suggested to be the site of antiemetic action of D2 antagonism. ¹⁷⁰ Further investigation is required to clarify the role of D2 receptors in nausea and the involvement of the ECS. The ECS modulates dopamine signaling indirectly through inhibition of glutamatergic and GABAergic inputs. ¹⁷¹ It is well recognized that ECS dysregulation impacts dopaminergic signaling as well. ¹⁷² Therefore, it is possible that interactions between dopamine and ECS signaling potentially contributes to symptoms associated with CHS and CVS.

6. CONCLUSIONS

All together, these findings emphasize the relationship between the ECS, stress, nausea, and vomiting. Considerable evidence supports the associations between these systems, but further investigation is necessary to clarify the direction and causality of the correlations described in this review. Given its key modulatory role, dysregulation of the ECS can have drastic consequences for the neurobiological control of these processes. As such, the resulting ECS dysfunction produced by heightened stress, fear or anxiety, or chronic cannabis use, as is the case with CHS, may accumulate and likely play a role in the pathophysiology of nausea and vomiting disorders like CVS and CHS.

AUTHOR CONTRIBUTIONS

M.V.D., T.V., and C.J.H. all completed the literature review, prepared the manuscript, and reviewed and approved the final manuscript.

CONFLICT OF INTEREST STATEMENT

C.J.H. is a member of the Scientific Advisory Committee and has equity in Formulate Biosciences.

DeVuono MV, Venkatesan T, Hillard CJ. Endocannabinoid signaling in stress, nausea, and vomiting. Neurogastroenterology & Motility. 2025;37:e14911. doi: 10.1111/nmo.14911

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.