Cannabinoid Hyperemesis Syndrome: Lighting Up an Emergency Department Near You

Abstract

Cannabis legalization may increase the rates of emergency department presentations and hospitalizations from Cannabinoid Hyperemesis Syndrome (CHS). This syndrome was first described nearly 20 years ago and has become increasingly common. Yet, for a variety of reasons, CHS is still an underrecognized cause of recurrent abdominal pain, nausea, and vomiting. All physicians must be prepared to diagnose, manage, and counsel patients on this condition, regardless of their state’s current or future cannabis legislation.

Introduction

Amongst young adults in high-income countries such as the United States (U.S.), Australia, and Europe, cannabis, or marijuana, is the most widely used illicit drug.¹ Cannabinoid hyperemesis syndrome (CHS) was first described in a published case series in 2004.² Despite this, over the past decade and half, physician understanding of how to diagnose and treat CHS, is disproportionately low. Delayed diagnosis of CHS often leads to multiple Emergency Department (ED) evaluations including laboratory and radiologic evaluations resulting in high costs to patients and health care systems.³ The emergence of synthetic cannabinoids (SCs) makes physician awareness of the potential harmful effects and how to diagnose and treat such patients even more prudent. SCs have been found to be an important cause of CHS.⁴

Pathophysiology of CHS

In order to understand the pathophysiology and diagnosis of CHS, it is important to first understand the mechanism of action of cannabis. The primary psychoactive component of organic cannabis, delta-9-tetrahydrocannabinol (THC), produces the well known effects of cannabis via the two-types of cannabinoid (CB) receptors, CB1 and CB2 receptors.^4,5 CB1 receptors are located in the central nervous system (CNS) and enteric nervous system, while CB2 receptors are in immune/lymphoid tissues such as the spleen.⁵

The concentration of THC and other cannabinoids such as cannabidiol (CBD) used in cannabis products varies both in product and method of use. CBD moderates the psychoactive effects of THC and over time THC concentrations have risen and the ratio of THC to CBD has increased.^1,6 The potency of actual cannabis can be determined by the ratio of THC to other cannabinoidal agents, which then can influence its toxicity/effects on the body.⁵

Synthetic cannabinoids (SC) are an important consideration and contributor to cannabis-related health problems. SCs can produce the same (or greater) effects as organic cannabis (“THC-like” effects), however untoward effects are known to be more severe and relate to both THC concentration and greater affinity of the SC for the cannabinoid receptors.⁴ SCs have additional ingredients meant to enhance drug effects and make identification difficult.⁴ Use of SCs is increasing given lower cost, higher availability, and because most are not detectable on urine drug screens.^4,7 In these cases, diagnosis of CHS requires a high index of suspicion and/or disclosure of SC use by patients.

The mechanism of CHS is not entirely clear and there are a number of hypotheses published in the literature.^1,5,8 One hypothesis is metabolic enzyme variations that predispose users to accumulate cannabinoid substances. Another is that THC in high concentrations serves as an antagonist on CB1 receptors. Further, long-term THC use may cause downregulation of CB1 receptors. In recent years, it has been proposed that transient receptor potential vanilloid subtype 1 (TRPV1) receptors, which are involved in gastric motility, may be centrally involved in the pathogenesis of CHS.⁹ THC activates both CB1 and TRPV1 and over time chronic exposure to cannabis could lead to desensitization of TRPV1 signaling which leads to altered gastric motility and emesis.⁹ Some cannabinoid structures are highly lipid soluble with long half lives which mean they are more likely to accumulate with long term use and lead to negative effects.⁸ Therefore, it is hypothesized that those who are more chronic users are at increased risk of developing CHS.¹⁰

Presentation of CHS

CHS was described by Allen et al. as having a prodromal phase (not always present), hyperemetic phase, and compulsive bathing phase.² The prodromal phase can include morning nausea and/or vomiting, with or without weight loss, but with a normal appetite and eating pattern. The hyperemetic phase is often when patients present to the ED as they can suffer from intractable nausea, vomiting, sweating, coliky abdominal pain, with or without diarrhea.^1,2 The compulsive bathing phase evolves as a learned behavior over time as patients find this can relieve their symptoms temporarily. Patients often take hot baths or showers to relieve the symptoms and can present with elevated temperatures, mild leukocytosis, and even thermal burns.¹ Such episodes occur cyclically, for as long as patients are using cannabis and are often associated with weight loss. Hyperemesis episodes usually resolve upon cessation of cannabis, but the duration of sobriety from cannabis has not been found to be related to how quickly CHS will stop.⁵ CHS should not be mistaken for cyclic vomiting syndrome (CVS) although some consider it a chronic functional GI disorder and new criteria to aid in the diagnosis have been recently published, such as the Rome IV criteria.⁵

Pediatric, pregnant, diabetic ketoacidosis, and palliative care patients should be evaluated for CHS as well when presenting with intractable nausea and vomiting.^11,12 Pediatric patients should have a drug history obtained in the absence of parents or caregivers when possible.¹² Palliative care patients may not present with a classic history of taking warm baths due to physical limitations related to their disease.¹¹ Pregnant patients are another population that should be screened for CHS when presenting to the ED or clinic with hyperemesis.^13,14 Diagnosing and managing such patients proves challenging due to overlapping symptoms common in pregnancy (nausea, vomiting, abdominal cramping, etc). Further, the risks and benefits of typical therapies such as benzodiazepines and haloperidol must be considered before treating pregnant patients for CHS.¹³

Making the diagnosis of CHS is challenging, especially in its initial presentation, due to the myriad of alternative causes of nausea, vomiting, and abdominal pain. A detailed history that also includes drug use history is imperative, especially because the work up is often unremarkable. Patients often present multiple times for the same symptoms before CHS is diagnosed. In a retrospective observational study published in 2019, the average cost for the combined ED visits for 17 patients diagnosed with CHS was $76,920.92 with an average of 17.9 ED visits before the diagnosis of CHS was made.¹⁵ Although this is a small study, as cannabis use becomes more ubiquitous, the average costs of medical care may exponentially rise.

Management and Treatment

The ED management of CHS primarily consists of conservative management such as aggressive fluid repletion, antiemetics, and pain control. There is no identified antiemetic and/or regimen that has been proven to be highly effective for patients. Antiemetics that have been the most helpful act on dopaminergic, serotonergic, substance P and TRPV1 signaling.⁴ In the current literature, benzodiazepines (lorazepam mostly) have been found to be the most effective, followed by haloperidol and capsaicin cream.¹⁰ Benzodiazepines are thought to decrease activation of the CB1 receptors in the frontal cortex.¹⁶ The exact mechanism of action of haloperidol is not completely known, but it is thought that the complex interaction between dopamine receptor (D2) in the chemoreceptor trigger zone and CB1 signaling pathways may contribute to its effects on symptoms associated with CHS.¹⁷ Droperidol is starting to be used but studies are rare as droperidol use was restricted in the U.S. from 2011–2019.⁵ Capsaicin (and hot water/heat) are thought to alleviate symptoms by normalizing TRPV1 activity.⁹

Pediatric, pregnant, diabetic ketoacidosis, and palliative care patients should be evaluated for CHS as well when presenting with intractable nausea and vomiting.

Patients should be counseled and referred for substance abuse treatment. It is important to specifically address the paradox of cannabis causing cyclical vomiting despite its medically known benefits of the treatment of vomiting. Further, patients who chronically use cannabis may benefit from the physician’s explanation regarding how and why chronic use may result in “new” vomiting. Patients may be reluctant to accept the diagnosis when they have used cannabis in the past without the side effect. For palliative care patients, their symptoms may improve with decreased use of cannabis rather than complete cessation.¹¹ Lastly, patients should be counseled on the safe storage of cannabis, an important public health intervention to reduce pediatric exposures.

Legalization and its potential impact on CHS

Cannabis legalization (medical and/or recreational) and decriminalization varies by country and in the U.S., varies by state. At the time of writing, 18 states, two territories, and the District of Columbia have legalized recreational cannabis use, although federal law still technically prohibits recreational use.¹⁸ In the 2018 election, Missouri voted yes (65.5%) to legalize the use of medical marijuana.¹⁹ These individuals need physician approval, must meet one or more of the conditions that have been approved for medical cannabis use, and must have a registered and paid ($25.00) medical cannabis card in order to purchase from a Missouri licensed dispensary.^19,20 An additional $100.00 fee is required for a home cultivation card; both cards must be renewed yearly, but a physician does not need to re-approve the patient after the initial exam.^19,20 For the upcoming 2022 election, an amendment is on the ballet proposing to legalize cannabis for recreational adult use as well as expunge criminal records of Missourians who have been convicted of nonviolent cannabis offenses.¹⁹

The significance of legalization and decriminalization on public health is an area of emerging literature and study. Legalization has increased the potency, diversification, and availability of cannabis and reduced its cost.²¹ Most states with legalized recreational cannabis also legalized commercialization, meaning that in some states, the cannabis industry is free to advertise to the public with no limitations and they can sell products with little to no buyer restrictions.²² Stores have diversified their cannabis products which include beverages, edibles (gummies, candies, and other foods) extracts/tinctures etc., which has the potential to broaden the appeal. Changes to related state taxation laws and federal laws (legalization, inter-state commerce, etc.) will influence profit-seeking behavior of commercial sellers and are anticipated to affect public health impacts of cannabis use.

Published data from the U.S. suggests a possible association between cannabis legalization and rates of ED presentations for CHS. Thus far, cannabis legalization has increased regular cannabis use among existing users.^21,23 It has also increased cannabis-related ED visits for adults (psychological distress, CHS) and children (poisonings).^21,24–25 A recent study published in the American Journal of Gastroenterology compared inpatient admissions for CHS in legalized versus non-legalized states between 2011 and 2015 and found that the odds of hospitalization was higher after cannabis legalization, but they could not conclude it was the sole cause.²³ Beyond this study, there are very limited studies that have been done in the U.S. about cannabis-related ED visits following legalization outside of the state of Colorado. In a recent study published in JAMA, recreational cannabis legalization in Colorado was associated with a 29% increase in vomiting-related ED encounters.²⁶ A different study on hospitalizations in the state of Colorado in relation to cannabis legalization found a 46% increase in the incidence of CVS-related hospitalizations over a five-year period.²⁷

High quality published studies on cannabis-related ED visits, specifically for CHS, is limited for a number of reasons: a correct diagnosis must be made then documented. An appropriate International Classification of Diseases (ICD) Clinical Modification code for cannabis-induced illness should be used. Hospitals and physicians apply the ICD-10-CM (10th ICD-CM revision) codes differently. While there are numerous ICD-10-CM codes, physicians or those responsible for entering them, may be hesitant to use them. This potentially limits retrospective studies that rely on billing codes.²⁸ There is also the possibility that the symptoms such as nausea, vomiting, abdominal cramping, are documented and/or coded but that the CHS diagnosis or associated cannabis use is not. ICD-10-CM codes F12.19, F12.29 or F12.99 may be the most appropriate to use to indicate cannabis abuse, dependence, or use, respectively, associated with an “unspecified cannabis-induced disorder,” such as CHS.²⁹ Alternatively the code for nausea and/or vomiting as well as a code indicating cannabis abuse (F12.1), dependence (F12.29), or use (F12.9), or may be appropriate.²⁹

Other Considerations

At present, there is a gap between state and federal laws regarding cannabis use, which has implications for insurance coverage. The FDA is responsible for approving cannabinoid medications, however Medicare may not cover such medications.³⁰ Those who use medical cannabis face uncertainty with worker’s compensation claims and implications for employment drug screens and their consequences.³⁰ Whether or not cannabis-related ED visits, such as those due to CHS, are covered by different commercial health insurance companies, Medicaid, and Medicare is dependent on what the company deems as an emergency and the arrangement the company has with the hospital as a “fixed” rate for payment.³¹ Missouri is one of 25 states that permits licensed health insurers to exclude both diagnostic and treatment services for conditions related to use of drugs or alcohol and because of this, it is difficult to make a general assertion.³¹

Conclusion

CHS is a condition that can impact those who use cannabis. Nausea associated with abdominal pain, multiple episodes of emesis, and dehydration/starvation are some of the reasons people present to the ED for care. Pain medications, antiemetics are often needed. Patients with severe dehydration or electrolyte derangement may require hospitalization. CHS is often misdiagnosed and/or missed leading to unnecessary tests and health care costs. ED visits due to CHS are thought to increase following recreational cannabis legalization. More research needs to be done within the U.S. on whether the legalization of cannabis is impacting ED visits and costs, taking into account known limitations of such research. With the legalization of recreational cannabis in Missouri on the ballot for 2022, it is important that physicians practicing in the state be up to date on the diagnosis and management of CHS. In order to improve patient outcomes related to CHS, accurate diagnosis and documentation of CHS is critical and facilitates the study of public health consequences of cannabis use. Clinicians should document cannabis use in relation to vomiting and abdominal pain-related encounters and use appropriate billing practices.