Cannabinoid hyperemesis syndrome

Cannabinoid hyperemesis syndrome
People with cannabinoid hyperemesis syndrome often find some relief with hot showers
Classification and external resources
Specialty	Toxicology

Cannabinoid hyperemesis syndrome can occur with cannabis use and is characterized by recurrent nausea, vomiting, and crampy abdominal pain. These symptoms have been reported to be improved temporarily by taking a hot shower or bath, or more fully by stopping the use of cannabis. It is important that cannabinoid hyperemesis syndrome be distinguished from other causes of nausea and vomiting, such as cyclic vomiting syndrome.

The pathogenesis of cannabinoid hyperemesis syndrome is unclear, but it may involve accumulation of exogenous cannabinoids or alterations in the brain's regulation of body temperature. While definitive treatment involves abstinence from cannabinoids, various drug therapies have been studied for symptomatic relief in the acute presentation of a patient suffering from cannabinoid hyperemesis syndrome, often in the setting of a hospital emergency department.

The syndrome was described by Allen and colleagues (2004) and Sontineni and colleagues (2009) who offer simplified diagnostic criteria. A subsequent, larger study reported a case series of 98 subjects with cannabinoid hyperemesis syndrome, confirming the earlier reported findings.

Signs and symptoms

The long-term and short-term effects of cannabis use are associated with behavioral effects leading to a wide variety of effects on the body systems and physiologic states. Cannabinoid hyperemesis syndrome is a paradoxical syndrome characterized by hyperemesis (persistent vomiting), as opposed to the better known antiemetic properties of cannabinoids. Specifically, cannabinoid hyperemesis syndrome takes the pattern of cyclical nausea, vomiting, and abdominal pain in the setting of chronic cannabinoid use. The abdominal pain tends to be mild and diffused. There are three phases of cannabinoid hyperemesis syndrome: the prodromal phase, the hyperemetic phase, and the recovery phase.

The prodromal phase is characterized by subsyndromal symptoms of cannabinoid hyperemesis syndrome, including mild discomfort and nausea upon waking. Prior to the use of compensatory exposure to hot water to treat symptoms, people sometimes increase their intake of cannabinoids in an effort to treat the persistent nausea they experience. This phase can last for months or even years.

The hyperemetic phase is characterized by the full syndromal symptoms of cannabinoid hyperemesis syndrome, including persistent nausea, vomiting, abdominal pain, and retching. Retching can occur up to 5 times per hour. It is very difficult to take food or medicine by mouth during this stage, and patients may develop a fear of eating. Weight loss and dehydration due to decreased oral intake and vomiting are possible. Compensatory exposure to hot water, even for hours at a time, may be attempted for symptomatic relief, resulting in compulsive bathing/showering. People have described the hot water relief as "temperature-dependent," meaning that hotter temperatures provide greater relief. It is during this phase that people with cannabinoid hyperemesis syndrome are likely to present to the emergency department of the hospital for treatment.

The recovery phase begins after the patient abstains from cannabinoids, and can last days to months. Lost weight can be regained due to a restoration of normal oral intake, and compulsive bathing/showering can give way to normal patterns of behavior.

Complications

Individual attacks can lead to complications, such as acute kidney injury. In the setting of cannabinoid hyperemesis syndrome, this may be defined as cannabinoid hyperemesis acute renal failure (CHARF). CHARF occurs through dehydration secondary due to persistent vomiting and hot showers, leading to prerenal azotemia. A case report of acute renal failure, albeit in the setting of rhabdomyolysis, has been reported with the use of synthetic cannabinoids.

Pathogenesis

Cannabis contains more than 400 different chemicals, of which about 60 are cannabinoids. The pathophysiology of cannabinoid hyperemesis syndrome is complicated by the complex action of these chemicals throughout the body, both in the central nervous system and in the gastrointestinal system.

Various pathogenic mechanistic theories attempting to explain symptoms have been put forward. These theories follow two themes: (1) dose dependent buildup of cannabinoids and related effects of cannabinoid toxicity or (2) the functionality of cannabinoid receptors in the brain and particularly in the hypothalamus (which regulates body temperature and the digestive system). However, the mechanisms by which cannabis causes or controls nausea and the adverse consequences of long-term cannabis toxicity remain unknown and organic disease should not be ruled out as a possible cause.

Cannabinoid buildup theory

Tetrahydrocannabinol (THC) is a fat-soluble cannabinoid that can be deposited into a person's fat stores, accounting for the long elimination half-life of THC. During periods of stress or food deprivation, a person's fat stores can be mobilized (lipolysis) for energy consumption, releasing the previously stored THC as well. THC can then leach back into the blood stream, leading to progressively higher concentrations in the blood. The mechanism can be characterized as a "reintoxication effect." Another cannabinoid called cannabigerol acts as an antagonist at cannabinoid 1 (CB1) and serotonin 1A receptors, antagonizing the anti-emetic effects of cannabidiol that occurs through its effects on serotonin.

Hypothalamic theory

Cannabidiol, a cannabinoid found in cannabis, can increase the expression of the CB1 receptor in the hypothalamus of the brain. Additionally, THC acts at the CB1 receptor to induce a hypothermic effect, lowering body temperature. This might explain how exposure to hot water can relieve symptoms of cannabinoid hyperemesis syndrome, reversing the decrease in the thermoregulatory set point induced by cannabinoids.

Diagnosis

Various diagnostic frameworks for cannabinoid hyperemesis syndrome have been proposed. As of 2015, the modified criteria by Simonetto et al. are the most frequently used. The most important feature is detecting a history of cannabinoid use, the denial of which can delay proper diagnosis. A urine drug screen can be useful for objectively determining the presence of cannabinoids in a person's system. Cannabinoid metabolites (specifically 11-nor-Δ9-carboxylic acid) can be detected in urine for about 2–8 days with short-term use, and for 14–42 days of chronic use.

Other commonly used diagnostic tests include laboratory blood tests (complete blood count and differential, blood glucose, basic metabolic panel, pancreatic and liver enzymes), pregnancy test, urinalysis, and plain flat radiographic series.

Sontineni criteria

Essential	Cannabis use for years
Major	Severe nausea and vomiting Vomiting that recurs in a cyclic pattern over months Resolution of symptoms after stopping cannabis use
Supportive	Compulsive hot baths with symptom relief Colicky abdominal pain No evidence of gall bladder or pancreatic inflammation

Modified criteria

Essential	Long-term cannabis use
Major	Severe cyclic nausea and vomiting Resolution with cannabis cessation Relief of symptoms with hot showers or baths Abdominal pain, epigastric or periumbilical Weekly use of marijuana
Supportive	Age less than 50 y Weight loss of >5 kg Morning predominance of symptoms Normal bowel habits Negative laboratory, radiographic, and endoscopic test results

Sorensen et al. 2017 systematic review

Criteria	Severe cyclic vomiting usually accompanied by abdominal pain Symptom onset preceded by at least weekly cannabis use Temporary relief of symptoms with hot bathing Resolution of symptoms with cannabis cessation Supportive features: male gender, cannabis use onset in teenage years, symptom onset in third decade of life

Differential diagnosis

It is important to ensure that, prior to diagnosing and treating for a presumed cannabinoid hyperemesis syndrome, that more serious, medical conditions be ruled out. Medical conditions that may present similarly to cannabinoid hyperemesis syndrome include cyclic vomiting syndrome, bowel perforation or obstruction, gastroparesis, cholangitis, pancreatitis, nephrolithiasis, cholecystitis, diverticulitis, ectopic pregnancy, pelvic inflammatory disease, heart attack, acute hepatitis, adrenal insufficiency, and ruptured aortic aneurysm. In general, cannabinoid hyperemesis syndrome is most often misdiagonsed as cyclic vomiting syndrome. However, if simple laboratory tests and imaging have excluded more serious conditions, it is reasonable to monitor for a worsening of the patient's status to prevent the unnecessary application of more invasive, and potentially dangerous, diagnostic procedures (e.g. exploratory surgery). A complete history of the patient's use of cannabinoids is important in establishing the correct diagnosis.

Cyclic vomiting syndrome versus cannabinoid hyperemesis syndrome

Clinical features	Cyclic vomiting syndrome	Cannabinoid hyperemesis syndrome
Hypothesized cause	mtDNA mutations	Exogenous cannabinoid ingestion
Trigger (e.g. infection, stress)	Frequently	Absent
Prodromal phase	Common	Common
Cannabis use	Infrequently	Universal
Sex	Females > Males	Males > Females
Vomiting	Universal	Universal
Abdominal pain	Frequent; moderate-severe	Frequent; mild-moderate
Dehydration and increased drinking	Frequent	Frequent
Weight loss	Frequent	Frequent
Frequent and compulsive hot showers or baths	Absent	Universal
Psychiatric disorders	Frequent	Rare
Migraine headache	Frequent	Rare
Leukocytosis or neutrophilia	Occasionally	Occasionally
Low blood potassium	Occasionally, due to hyperemesis	Occasionally, due to hyperemesis
Gastric emptying study result	Accelerated or normal	Delayed or normal
Urine cannabinoid screen	Typically negative	Typically positive
Endoscopy result	Normal	Frequently esophagitis or gastritis

Cannabinoid hyperemesis syndrome is sometimes left undiagnosed, even for years. This may be due to reluctance on behalf of patients to fully disclose their use of cannabis to healthcare professionals, especially when another person is accompanying the partner to an appointment or emergency department visit. Identifying the correct diagnosis saves money for the healthcare system and reduces morbidity associated with the condition.

Treatment

Many traditional medications for nausea and vomiting are ineffective. Treatment is otherwise supportive and focuses on stopping cannabis use. With the cessation of cannabinoid use, complete symptomatic relief can take between 7–10 days. Proper patient education includes informing patients that their symptoms are due to their use of cannabis/cannabinoids, and that exposure to cannabinoids in the future are likely to cause their symptoms to return. Clinical pharmacists can play a role in administering this education, as well as encouraging patients to seek the assistance of mental health providers. Abstinence from cannabinoids currently remains the only definitive treatment. Cognitive behavioral therapy and motivational enhancement therapy are evidence-based outpatient treatment options for patients with cannabis use disorder.

Symptomatic relief is noted with exposure to hot water (greater than 41 degrees C), which is mediated by TRPV–the capsaicin receptor. Assessing for dehydration due to vomiting and hot showers is important as it can lead to acute kidney failure, and this is easily treated with IV fluids. If dehydration is severe, hospitalization may be required. Based on the mechanism of the effect, some clinicians have used topical capsaicin cream in the treatment of acute cannabinoid hyperemesis syndrome. The use of capsaicin as first-line treatment for cannabinoid hyperemesis syndrome has been well-tolerated, though the evidence for efficacy is limited. The use of hot water showers in the emergency department setting has been advocated in situations where topical capsaicin cream is unavailable, though the same precautions to hot water use (dehydration, burn injury) are required.

The use of antipsychotics, such as haloperidol and olanzapine, have provided complete relief of symptoms in case-reports. The evidence for the use of benzodiazepines, such as lorazepam, has shown mixed results. Other drug treatments that have been tried, with unclear efficacy, include neurokinin-1 receptor antagonists, first-generation antihistamines (e.g. diphenhydramine), 5-HT₃ receptor antagonists (e.g. ondansetron), and non-antipsychotic antidopaminergics (e.g. metoclopramide).

Acetaminophen has shown some benefit in case reports for alleviating headaches associated with cannabinoid hyperemesis syndrome. Opioids can provide some relief of abdominal pain, but their use is discouraged due to the risk of worsening nausea and vomiting.

Prognosis

Acute episodes of cannabinoid hyperemesis typically last for 24–48 hours and the problem often resolves with long term stopping of cannabis use. Improvement can take one to three months to occur.

Relapses are common, and this is thought to be possibly secondary to a lack of education as many people use or increase their use of cannabis due to their symptoms of nausea and vomiting.

Epidemiology

The number of people affected is unclear as of 2015, though the prevalence may be in the millions. Among users smoking 20 or more days per month, about one-third might experience symptoms. Cannabinoid hyperemesis syndrome has been reported more frequently in people that use cannabis daily (47.9% of patients) and greater than daily (23.7% of patients), compared to once weekly users (19.4% of patients) and less frequent users (2.4% of patients). A significant increase in the incidence of cannabinoid hyperemesis syndrome (and other marijuana-related visits to the emergency department) has been noted in U.S. states that have legalized marijuana, with the incidence of cyclic vomiting prominently doubling in the US state of Colorado after legalization. As the use of marijuana continues to be legalized at the state level, the prevalence of cannabinoid hyperemesis syndrome is expected to increase in the US.

History

Cannabinoid hyperemesis was first reported in the Adelaide Hills of South Australia in 2004.

Society and culture

Cannabinoid hyperemesis syndrome is not very well known, and some healthcare providers may view it as a "rare, kind of funny disease." Some emergency room physicians have referred to the symptoms as "scromiting," a portmanteau of "screaming" and "vomiting." In lieu of a correct diagnosis, the average patient in the US may owe $100,000 USD or more in medical bills through emergency department visits. An emergency department physician in 2018 commented that the condition wasn't on their "radar" in the 5 years prior, though the condition was being diagnosed more often now. Many people are struck by the notion that cannabis could induce symptoms of nausea and vomiting, given the common perception that cannabis can be used to prevent nausea and vomiting.

Research directions

It is unclear why cannabinoid hyperemesis syndrome is disproportionately uncommon in recognition of how widely used cannabis is throughout the world. There may be genetic differences between cannabis users that affect one's risk for developing cannabinoid hyperemesis syndrome. The pathophysiology of the syndrome is also unclear, especially with regards to the effect of cannabinoids on the gut. The long-term outcomes of patients that have suffered from cannabinoid hyperemesis syndrome is unknown.