Cannabis is currently the most widely produced and consumed drug worldwide. According to the United Nations Office on Drugs and Crime, approximately 183 million people (or 3.8% of the global population) used cannabis in 2014.1 In the United States, an increasing number of jurisdictions are passing laws to allow for production, distribution, and sale of cannabis for both medicinal and recreational use.2 As a result, the prevalence of cannabis use is steadily increasing, whereas the age of first cannabis use is decreasing. According to the 2015 National Survey on Drug Use and Health, the prevalence of past-month cannabis use among those aged 12 years and older increased from 6% to 8% over the past 10 years, with past-month prevalence increasing even more rapidly in jurisdictions that legalized recreational cannabis use.3 Therefore, it is becoming increasingly important to understand the adverse effects of frequent and chronic cannabis use. An increasingly common adverse effect that challenges clinicians and consumes significant resources is cannabinoid hyperemesis syndrome (CHS). We will review the most up-to-date literature on CHS and focus on the best available treatment strategies for this clinical problem.
CHS is a syndrome of cyclic vomiting in the setting of chronic high-dose cannabis use. Much remains to be understood about CHS, and thus, it is often diagnosed only after repeated emergency department (ED) visits, hospital admissions, consultations, and expensive tests. As the prevalence of cannabis use grows, the overall costs associated with managing CHS also increase.4 The cost per patient combined with the increasing patient population makes it that much more important to understand the syndrome of CHS, diagnose it early, and treat it as efficiently as possible.
Areas of Uncertainty
As a relatively recently recognized entity that was first reported in 2004, much still remains to be learned about CHS. Current research comes primarily from case reports, rather than from randomized control trials. Thus, various specialists in different settings have repeatedly described the syndrome, and common characteristics have been identified. But a true understanding of its etiology is still lacking. There are many suggested mechanisms, but the exact pathophysiology is still incompletely understood. As a result, it is not yet known how this syndrome occurs in some chronic cannabis users but not others. In addition, marijuana has long been used as a remedy for nausea and vomiting in certain patient populations (eg, cancer patients, patients affected with human immunodeficiency virus), so it is not entirely clear why its use is causing the opposite effect in CHS patients.
A literature search was conducted through PubMed, Embase, and Google Scholar from inception to June 2017. Search terms included “cannabinoid hyperemesis syndrome,” “CHS,” and “cannabis hyperemesis.” Case reports, review articles, and clinical trials investigating animals and humans published only in English were included. Publications discussing the epidemiology, pathophysiology, diagnostic criteria, and treatments for CHS were incorporated after thorough evaluation. In addition, national government surveys examining the use of cannabis worldwide were referred to for current information about the CHS patient population.
CHS has largely been a diagnosis of exclusion, made only after years of visits to different hospitals and extensive workups entailing imaging studies, consultation by various specialists, and inpatient hospitalizations.5,6 Given its increasing prevalence and clear precipitants, this syndrome should now be in the differential diagnosis of any patient presenting with intractable nausea and vomiting. Life-threatening conditions should still be ruled out at the discretion of the examining physician, if the patient's presentation is concerning for other diagnoses. However, CHS should be considered if the presentation does not suggest another intraabdominal process.7
In diagnosing CHS, details about the current and past cannabis use of the patients are significant. In addition, compulsive hot water bathing that relieves the symptoms of nausea/vomiting should be considered pathognomonic. Certain common characteristics have been found to have the highest sensitivities for identifying patients with CHS. They are at least weekly cannabis use for more than 1 year (74.8%), severe nausea/vomiting (100%), vomiting that recurs in a cyclic pattern over months (100%), resolution of symptoms after stopping cannabis use (96.8%), compulsive hot baths/showers with symptom relief (92.3%), and abdominal pain (85.1%).8
Although the basics of delta-9-tetrahydrocannabinol (THC) mechanisms of action are widely understood, many differing explanations exist regarding the pathophysiology of CHS. THC is the main active cannabinoid in marijuana, and it has been shown to act on cannabinoid receptor type 1 (CB1) and CB2 receptors, namely CB1 receptors located in the central nervous system (CNS) and enteric plexus. This is thought to be where the antiemetic effect of cannabinoids comes from.9 One school of thought is that CHS is a withdrawal-type syndrome, as a result of long-standing agonism in the CNS and enteric receptors. However, the presence of a strong withdrawal response has not been well supported in studies thus far.10 Another line of reasoning suggests that chronic agonism of CB1 receptors produces a paradoxical emetic response in certain patients. THC has also been shown to affect CB1 receptors to alter gastrointestinal motility (ie, to slow motility in a dose-dependent manner) and delay gastric emptying, and so, another possible explanation is that THC is inducing symptoms through one or a combination of these effects.6,9,11 Furthermore, the potency of cannabinoid material has been consistently increasing over the past 10 years.12 This change in plant material may be causing stronger adverse effects on CB1 receptors. In addition, the higher potency of the drug is likely contributing to increased dependence on cannabis and therefore a higher risk of sequela from chronic use.
Many treatment options have been explored for symptom resolution and disease management. In the ED setting, intravenous hydration, electrolyte repletion, and antiemetics are initially given for symptom relief. This improves the volume and electrolyte deficiencies that CHS patients develop from repeated vomiting. However, antiemetics, such as ondansetron, promethazine, prochlorperazine, and metoclopramide, are commonly used, but they are infrequently effective in relieving the nausea and vomiting of CHS patients.6,9 As a result, alternative therapies are now being used for symptomatic management.
CHS patients invariably turn to hot showers and baths for symptomatic relief before seeking medical care.6 Thus, hot water should be considered as one of the standard therapies for CHS. Hot water bathing has provided significant relief in a multitude of case reports, so much so that showers/baths are now considered a learned behavior pattern of CHS.6,13,14 This is often the only treatment that patients can rely on in the outpatient setting, and as a result, patients will spend hours in the bath or shower, repeat this behavior for the majority of their day, and then present to a hotel, motel, or finally the ED only after the option of bathing has been exhausted or they have developed scald burns requiring treatment.13,14 Chang and Windish6 reported one CHS patient who presented to the ED only after running out of hot water in his home, and another who refused to leave the shower in her room until her shower stall broke. The effect of hot water seems to be temperature dependent, as patients report that they have more symptom alleviation with hotter water. It is not yet understood how hot water alleviates the symptoms of CHS. One theory is that hot water is disrupting the hypothalamic thermoregulatory system in such a way to counteract marijuana's effect on the hypothalamus.6 Another line of reasoning states that hot water causes local histamine release and vasodilation, thereby counteracting the redistributory effects of marijuana, redistributing blood flow from the gut to the skin, and ultimately causing systemic relief.15,16 Although the mechanism is unclear, the effectiveness of hot water is recognized by the majority of CHS patients.
Topical capsaicin has been tried as an alternative therapy for the nausea and emesis of CHS with some success. This was initially demonstrated in a case series by Lapoint17 who described 5 patients with complete symptom resolution after the administration of capsaicin cream to the abdomen. More recently, Dezieck et al18 found that 13 patients treated with capsaicin cream experienced symptom relief after failure of other treatments. The effect of capsaicin is thought to be via hyperstimulation and desensitization of the cannabinoid transient receptor potential vanilloid receptor 1 (TRPV1). Interestingly, TRPV1 is a modulator of various pain stimuli, and it is therefore activated by extremes of temperature and by substances that modulate sensations of hot, cold, and burning pain. Agonists of this receptor have been found to cause desensitization, neuronal ablation, and alleviation of pain.19 This provides a possible explanation for the soothing effects of not only capsaicin but also hot water baths in CHS patients.
Haloperidol (Haldol) has also been used to relieve the nausea and emesis of CHS patients. Haloperidol has traditionally been used as an antipsychotic to treat agitation in patients with schizophrenia and other illnesses. However, it has also long been used by anesthesiologists in the management of postoperative nausea and vomiting.20 Its efficacy is so well established in the anesthesia literature that it is even included in consensus guidelines for the management of postoperative nausea and vomiting.21 Multiple case reports are now finding that haloperidol has significant antiemetic effects on CHS patients in both the ED and outpatient settings.22–24 Administration of haloperidol has led to resolution of intractable nausea, vomiting, and abdominal pain that had not improved with standard therapies. In a case report by Inayat et al,25 a hospitalized patient's symptoms proved refractory to fluids, ondansetron and even lorazepam; only after receiving haloperidol, his gastrointestinal symptoms subsided. Additional case reports show that patients have seen resolution of their symptoms within just 2 hours of receiving haloperidol and are discharged within 8 hours of the initial dosing.23 The exact mechanism of haloperidol's antiemetic efficacy is still unclear, but it is likely related to its antagonism at D2 dopamine receptors in the CNS, specifically the chemoreceptor trigger zone.23
In addition to capsaicin and antipsychotics, many other medications have been used in CHS management with varying success. Benzodiazepines, most commonly lorazepam, are frequently administered early in presentation. In a case report by Cox et al,26 a patient with CHS was given 1 mg of intravenous lorazepam after developing extreme anxiety about tolerating oral intake. This led to improvement in all symptoms and gradual transition to oral intake. The patient was successfully discharged home with 1-mg lorazepam tablets; however, the time to discharge was notably longer than that in patients given haloperidol. In another case report by Baron et al,27 a young patient was unable to abstain from marijuana use and continued to present with emesis and renal failure, despite prescription of oral benzodiazepines. The sedating effect of benzodiazepines likely plays a role in the subjective improvement in patient's symptoms, but any direct effect on emesis and pain is uncertain. Propranolol has also been recently described as an effective treatment for CHS. As described by Richards and Dutczak,28 the prior success of propranolol in treating cyclic vomiting syndrome led to its use for the mentioned CHS patient. Although the mechanism of propranolol's effect is unclear, its established use in other patients with intractable vomiting could mean further success for CHS relief. In addition, clinicians often administer opioids to alleviate the abdominal pain that usually accompanies intractable emesis. This is generally ineffective because pain medication has little effect on the causative nausea and vomiting; furthermore, opioids are associated with a risk of bowel dysfunction and can themselves bring about more gastrointestinal irritation.8
Despite the ever-increasing number of therapies being explored, the only definitive treatment for CHS continues to be abstinence from marijuana. In virtually all patients studied thus far, abstinence has led to complete resolution of symptoms; however, this has often taken years to accomplish due to underrecognition of the syndrome and patient reluctance to abstain from their chronic marijuana use. Furthermore, ED visits and hospital stays are often aimed at symptom resolution rather than eradication of the etiology. To truly reduce the prevalence and morbidity associated with CHS, providers must focus on the identification of the syndrome and proper counseling for affected patients. CHS is a diagnosis made in chronic substance abusers and should be treated with counseling and referral just as other addictive problems are. In addition, marijuana is commonly perceived as a benign drug without the addiction risk and medical side effects associated with other drugs and many do not recognize the potential for CHS. Many patients unknowingly turn to marijuana use to ease the nausea and vomiting of CHS. Therefore, proper education must aim at dispelling myths about marijuana and the syndrome of CHS. Pelissier et al29 described a pilot study aimed at increasing the early recognition of CHS and referral to addiction specialists. Studies such as this will provide valuable information regarding the benefit of addiction resources for CHS patients specifically.
Due to the increased prevalence of cannabis usage and no universally accepted standard treatment regimens, CHS continues to challenge clinicians. Moving forward, research needs to be aimed at developing empiric treatment for CHS. Medical management should be explored further, with studies comparing different types of treatment between established CHS patient groups. Perhaps, even more importantly, the undisputed value of abstinence should be emphasized, and patients should be educated as soon as their diagnosis is made. The effects of counseling and education should also be explored, so that patients can receive the optimal therapy for their addiction. Ultimately, CHS should be treated as any other substance abuse problem, with early recognition, symptomatic management, and a support system to help end the addiction.
The authors are grateful to Mark Mycyk, MD, for his assistance with this systematic review.
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