Cannabinoid hyperemesis syndrome

Cannabinoid hyperemesis syndrome (CHS) is recurrent nausea, vomiting, and cramping abdominal pain due to cannabis use.[3] These symptoms may improve temporarily by taking a hot shower or bath.[1] Complications may include kidney failure, electrolyte problems, and skin burns from hot water.[1] At least two deaths have been associated with CHS.[1][4][5]

Cannabinoid hyperemesis syndrome (CHS)
People with CHS often find some relief with hot showers[1]
SpecialtyToxicology
SymptomsNausea, vomiting, stomach pain[2]
ComplicationsKidney failure, electrolyte problems, skin burns from hot water[1]
CausesLong term cannabis use[2]
Diagnostic methodBased on the symptoms[1]
Differential diagnosisCyclical vomiting syndrome[1]
TreatmentStopping cannabis, hot showers[2]
MedicationCapsaicin cream[1]
Frequency2.7 million per year (US)[1]

Weekly cannabis use is generally required for the syndrome to occur.[1] The underlying mechanism is unclear, with several possibilities proposed.[1] Diagnosis is based on the symptoms.[1] The condition is typically present for some time before the diagnosis is made.[1] Another condition that may present similarly is cyclic vomiting syndrome.[1]

Definitive treatment involves stopping use of cannabis.[1] Up to two weeks may be required to see a benefit.[1] Treatments during an episode of vomiting is generally supportive in nature.[1] There is tentative evidence for the use of capsaicin cream on the abdomen during an acute episode.[1]

The number of people affected is unclear.[6] Of those who go to the emergency department in the United States with recurrent vomiting, about 6% have the condition.[1] The syndrome was first described in 2004, and simplified diagnostic criteria published in 2009.[7][8]

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 physiological states.[8] CHS is a paradoxical syndrome characterized by hyperemesis (persistent vomiting), as opposed to the better known antiemetic properties of cannabinoids.[9] Specifically, CHS takes the pattern of cyclical nausea, vomiting, and abdominal pain in the setting of chronic cannabinoid use.[9] The abdominal pain tends to be mild and diffused.[10] There are three phases of CHS: the prodromal phase, the hyperemetic phase, and the recovery phase.[11]

Prodromal phase

The prodromal phase is characterized by subsyndromal symptoms of CHS, 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.[11]

Hyperemetic phase

The hyperemetic phase is characterized by the full syndromal symptoms of CHS, including persistent nausea, vomiting, abdominal pain, and retching.[11] Retching can occur up to 5 times per hour.[10] The symptoms experienced in this phase are cyclical, and can recur unpredictably in intervals of weeks to months.[12] 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.[11] 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 CHS are likely to present to the emergency department of the hospital for treatment.[11]

Recovery phase

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.[11] If a person in this phase consumes cannabis again, their symptoms tend to come back.[12]

Complications

Individual attacks can lead to complications, such as acute kidney injury.[13] In the setting of CHS, this may be defined as cannabinoid hyperemesis acute renal failure (CHARF).[13] CHARF occurs through dehydration secondary due to persistent vomiting and hot showers, leading to prerenal azotemia.[13] A case report of acute renal failure, albeit in the setting of rhabdomyolysis, has been reported with the use of synthetic cannabinoids.[14]

Pathogenesis

Cannabis contains more than 400 different chemicals, of which about 60 are cannabinoids.[9] The chemical composition of cannabis may vary between cannabis products, making it difficult to identify the specific chemical(s) responsible for the syndrome.[15] The pathophysiology of CHS is complicated by the complex action of these chemicals throughout the body, both in the central nervous system and in the gastrointestinal system.[9] Cannabis-related factors, such as the potency of THC in the cannabis, the amount of use, and the duration of use likely play a role, but are not yet well understood.[15] Other factors, such as chronic stress, genetics, and emotional factors, may influence the risk for CHS.[15]

Various pathogenic mechanistic theories attempting to explain symptoms have been put forward:[12]

  • dose dependent buildup of cannabinoids and related effects of cannabinoid toxicity
  • the functionality of cannabinoid receptors in the brain and particularly in the hypothalamus (which regulates body temperature and the digestive system)
  • direct stimulation of cannabinoid receptors in the gut

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.[10] During periods of stress or food deprivation, a person's fat stores can be mobilized (lipolysis) for energy consumption, releasing the previously stored THC back into the blood.[10] The mechanism can be characterized as a "reintoxication effect."[10] 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.[10]

Hypothalamic theory

Cannabidiol, a cannabinoid found in cannabis, can increase the expression of the CB1 receptors in the hypothalamus of the brain.[10] Additionally, THC acts at the CB1 receptors to induce a hypothermic effect, lowering body temperature.[10] This might explain how exposure to hot water can relieve symptoms of CHS, reversing the decrease in the thermoregulatory set point induced by cannabinoids.[9]

TRPV1 theory

Alterations in the transient receptor potential vanilloid subtype 1 (TRPV1) receptor, which is involved in gastric motility and is activated by cannabinoids, nociceptive heat (temperatures above 43°C), and capsaicin, has been proposed as potential mechanism of CHS.[16] In vitro cannabinoids mediate dephosphorylation of TRPV1 and desensitize the receptor.[17] The TRPV1 theory posits that chronic exposure to cannabinoids down regulates TRPV1 signaling, and that compulsive hot-water bathing is a learned behavior to normalize diminished TRPV1 activity by exposure to nociceptive heat. This may also explain the salubrious effects of topical capsaicin in treating CHS.

Diagnosis

Various diagnostic frameworks for CHS have been proposed.[3] As of 2015, the modified criteria by Simonetto et al. are the most frequently used.[9] The most important feature is detecting a history of cannabinoid use, the denial of which can delay proper diagnosis.[11] A urine drug screen can be useful for objectively determining the presence of cannabinoids in a person's system.[11] 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.[18]

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.[10]

Sontineni criteria[8]
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 gallbladder or pancreatic inflammation
Modified criteria[19]
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[3]
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 the third decade of life

Differential diagnosis
Cyclic vomiting syndrome versus cannabinoid hyperemesis syndrome[9][10]
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

Prior to diagnosing and treating for a presumed CHS, more serious medical conditions need to be ruled out.[3] Medical conditions that may present similarly to CHS include cyclic vomiting syndrome,[10] 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.[3][11] In general, CHS is most often misdiagnosed as cyclic vomiting syndrome.[10] 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).[3] A complete history of the person's use of cannabinoids is important in establishing the correct diagnosis.[3]

CHS is sometimes left undiagnosed, even for years.[9] 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.[9] Identifying the correct diagnosis saves money for the healthcare system and reduces morbidity associated with the condition.[10]

Treatment

Many traditional medications for nausea and vomiting are ineffective. Treatment is otherwise supportive and focuses on stopping cannabis use.[20] With the cessation of cannabinoid use, complete symptomatic relief can take between 7–10 days.[21] 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.[21] Clinical pharmacists can play a role in administering this education, as well as encouraging patients to seek the assistance of mental health providers.[11] Abstinence from cannabinoids currently remains the only definitive treatment.[3] Cognitive behavioral therapy and motivational enhancement therapy are evidence-based outpatient treatment options for patients with cannabis use disorder.[10]

Symptomatic relief is noted with exposure to hot water (greater than 41 degrees C), which is mediated by TRPV–the capsaicin receptor.[21] 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.[13] If dehydration is severe, hospitalization may be required.[10] Based on the mechanism of the effect, some clinicians have used topical capsaicin cream applied to the periumbilical area in the treatment of acute CHS.[21] The use of capsaicin as first-line treatment for CHS has been well tolerated, though the evidence for efficacy is limited.[21] 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.[21]

The use of antipsychotics, such as haloperidol and olanzapine, have provided complete relief of symptoms in case-reports.[21][22] The evidence for the use of benzodiazepines, such as lorazepam,[22] has shown mixed results.[21] Other drug treatments that have been tried, with unclear efficacy, include neurokinin-1 receptor antagonists,[10] first-generation antihistamines (e.g. diphenhydramine), 5-HT3 receptor antagonists (e.g. ondansetron), and non-antipsychotic antidopaminergics (e.g. metoclopramide).[21]

Acetaminophen has shown some benefit in case reports for alleviating headaches associated with CHS.[11] Opioids can provide some relief of abdominal pain, but their use is discouraged due to the risk of worsening nausea and vomiting.[10]

Prognosis

Acute episodes of cannabinoid hyperemesis typically lasts 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.[11]

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.[10]

Epidemiology

The number of people affected is unclear as of 2015,[6] though one estimate puts the number at about 2.7 million people in the United States a year.[1] Among users smoking 20 or more days per month, about one-third might experience symptoms.[23] CHS 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).[3] A significant increase in the incidence of CHS (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.[21] As the use of marijuana continues to be legalized at the state level, the prevalence of CHS is expected to increase in the US.[3]

A 2018 surveyed of 155 heavy cannabis users in hospital found 51 of them experienced CHS.[1] This ratio was used to estimate that in the United States, 2.7 million out of 8.3 million heavy cannabis users should be experiencing the syndrome.[1] The same study found that of those who go to the emergency department in the United States with recurrent vomiting, about 6% have the condition.[1] In 2018 a 17 year old died of the condition.[24]

History

Cannabinoid hyperemesis was first reported in the Adelaide Hills of South Australia in 2004.[7]

The name cannabinoid hyperemesis syndrome was also coined at this time. The report focused on nine patients who were chronic cannabis users who presented with cyclical vomiting illness. One woman in the study reported that warm baths provided the only relief from the nausea, severe vomiting, and stomach pain and reportedly burned herself in a hot water bath three times trying to get relief.[25]

Society and culture

CHS is not very well known. [26] Some emergency room physicians have referred to the symptoms as "scromiting," a portmanteau of "screaming" and "vomiting."[27] In lieu of a correct diagnosis, the average patient in the US may be charged $100,000 or more in medical bills through emergency department visits.[26] 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.[28] 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.[28]

Research directions

It is unclear why CHS 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 CHS. 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 CHS is unknown.[10]

References
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