Cannabinoid Hyperemesis Syndrome

Cannabinoid Hyperemesis Syndrome – 14 Interesting Facts

Cannabinoid hyperemesis syndrome involves abdominal discomfort, nausea, and cyclic vomiting in the setting of chronic heavy cannabis use¹²
Marijuana is the most commonly-used illicit xenobiotic used in the world³
Cannabinoid hyperemesis syndrome can be conceptualized as a functional gut-brain axis disorder similar to cyclic vomiting syndrome⁴
Factors that have been associated with the development of cannabinoid hyperemesis syndrome in epidemiologic studies include male sex and weekly or daily cannabis use²
Cannabinoid hyperemesis syndrome is a clinical diagnosis suggested by hyperemesis in the setting of heavy, chronic cannabis use often relieved by hot water bathing⁴
ROME IV criteria for diagnosis of cannabinoid hyperemesis syndrome require all criteria to be present
Symptoms present for past 3 months (with onset at least 6 months before)
Episodes last for less than 1 week
At least 3 episodes in the last year and 2 episodes in the last 6 months, occurring at least 1 week apart
No emesis between episodes
Treatment is largely supportive; pharmacologic interventions show varied success
Trial of various pharmacotherapies may be attempted including antiemetics, benzodiazepines, dopamine antagonists, and substance P modulators¹²⁴
Cessation of cannabis use is considered the mainstay of treatment and typically results in complete recovery¹²
Avoidance of cannabis is preventive of cannabinoid hyperemesis syndrome; a harm reduction approach includes less than weekly use

Alarm Signs and Symptoms

Significant volume depletion requires attentive fluid replacement and electrolyte management to maintain hemodynamic stability
Gastrointestinal bleeding indicates need for emergent identification, management, and intervention of bleeding source

Introduction

“Cannabis” refers to all parts and products derived from Cannabis spp, a flowering plant
“Marijuana” refers to a psychoactive drug derived from Cannabis spp that contains THC (delta-9-tetrahydrocannabinol), the prototypical cannabinoid thought to be responsible for the majority of marijuana’s psychoactive effects
The term “cannabinoid” refers to exogenous or endogenous compounds which bind cannabinoid receptors
CHS (cannabinoid hyperemesis syndrome) involves abdominal discomfort, nausea, and cyclic vomiting in the setting of chronic heavy cannabis use¹²
- CHS is not limited to smoked forms of cannabis, other forms (eg, edibles, “dabs,” tinctures) may also cause the development/continuation of CHS

Epidemiology

Cannabis use by men exceeds that by women¹
Marijuana is the most commonly-used illicit xenobiotic used in the world³

Etiology

CHS can be conceptualized as a functional gut-brain axis disorder similar to cyclic vomiting syndrome⁴
Pathophysiology is unclear but proposed mechanisms include:
- Downregulation of cannabinoid receptors type 1 (CB₁) receptors/other modulation of the endocannabinoid system
- Desensitization of transient receptor potential vanilloid 1 (TRPV1) receptors and resultant substance P modulation
- THC-induced splanchnic vascular dilation¹²⁴
The quality of evidence supporting any of these hypotheses is very low²

Risk Factors

Factors that have been associated with the development of CHS in epidemiologic studies include male sex and weekly or daily cannabis use²

Diagnosis

Approach to Diagnosis

CHS is a clinical diagnosis
- Suggestive history includes:
  - Hyperemesis in the setting of heavy, chronic cannabis use⁴
  - Repetitive hot water bathing (which often provides relief) is highly suggestive of CHS, although studies have shown variable positive and negative predictive values of such¹²⁴
- Suggestive symptoms include:
  - Abdominal discomfort, nausea, and cyclic vomiting¹²
  - Symptoms are often refractory to pharmacologic treatment but near-immediate relief is found with a hot shower or bath
No definitive testing exists; instead, use laboratory and imaging studies to exclude other diagnostic considerations and evaluate for CHS sequelae/complications

Diagnostic Criteria

The Rome IV committee characterizes CHS as a variant of cyclic vomiting syndrome (which is designated as a subset of functional gastrointestinal disorders); Rome IV diagnostic criteria are provided in Table 1⁵

Table 1. Rome IV criteria for diagnosing CHS; all criteria should be present with chronic cannabis use and cease with abstinence.


Symptoms present for past 3 months (with onset at least 6 months before)
Episodes last for less than 1 week
At least 3 episodes in last year and 2 episodes in last 6 months, occurring at least 1 week apart
No emesis between episodes

Caption: Data from Perisetti A et al. Cannabis hyperemesis syndrome: an update on the pathophysiology and management. Ann Gastro. 2020; 33(6):571-578.

Workup

History

CHS is a clinical diagnosis; a detailed history is key to correct identification (Table 2)
- Assess demographic factors
  - CHS more typically occurs in male patients aged younger than 50 years²
- Determine frequency and duration of cannabis use; data show²
  - 97.4% of patients reported at least weekly cannabis use
  - Daily cannabis use was reported by 76.6% of patients
  - Regular cannabis use for longer than 1 year was found in 74.8% of patients
- Assess presence of symptoms, pattern of illness, and precipitating/alleviating factors; a large systemic review found²:
  - Severe nausea and vomiting are present in 100% of cases
  - Abdominal pain was reported by 85.1% of patients
  - Vomiting that recurs in a cyclic pattern over months was also present in all cases
  - 92.3% of patients claimed that their symptoms were alleviated by hot showers or baths
  - Symptom resolution after cannabis cessation was reported by 96.8% of patients
- Determine if ROME IV criteria (see Table 1) have been met:
  - All criteria should be present with cannabis use and resolve with abstinence
    - Symptoms must be present for the past 3 months, with onset 6 months before
    - Episodes last for less than 1 week
    - At least 3 episodes in the last year and 2 episodes in the last 6 months, each occurring at least 1 week apart
    - No emesis between episodes
Determine if history and symptoms suggest alternative diagnoses which require further evaluation to differentiate the illness; for example:
- Nausea, vomiting, and abdominal pain with localized right upper quadrant discomfort may indicate gallbladder pathology
- Nausea, vomiting, and abdominal pain with localized right lower quadrant discomfort may indicate appendicitis
- Nausea, vomiting, and abdominal pain in early pregnancy may indicate ectopic pregnancy

Table 2. Epidemiologic, historical, and examination factors associated with CHS.

Characteristic	Frequency observed in literature
Severe nausea and vomiting	100%
Vomiting that recurs in a cyclic pattern over months	100%
Age less than 50 at time of evaluation	100%
At least weekly cannabis use	97.4%
Symptom resolution after cannabis cessation	96.8%
Compulsive hot baths/showers with symptom relief	92.3%
Abdominal pain	85.1%
Daily cannabis use	76.6%
Regular cannabis use for longer than 1 year	74.8%
Male predominance	72.9%

Caption: Data from Sorensen CJ et al. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment – a systematic review. J Med Toxicol. 2017;13(1):71-87.

Physical Examination

No specific physical examination findings are indicative of CHS; however, typical findings may include¹²⁶:
- Vital signs: tachycardia is common due to distress and dehydration
- General distress:
  - Patient may be moaning, writhing in the bed
  - Patient may be diaphoretic and actively vomiting/dry-heaving
- Abdominal examination:
  - Patient may have diffuse tenderness of the abdomen; no peritoneal signs should be evident
  - Focal tenderness suggests that alternative etiologies should be evaluated

Laboratory Tests

No laboratory tests are diagnostic for CHS
Obtain laboratory studies to evaluate for complications of CHS and evaluate alternative diagnoses
- CBC
  - Leukocytosis with neutrophilia is common, but may also indicate alternative diagnosis such as infectious process⁷
- Basic metabolic panel
  - Mild hypokalemia may be present⁷
  - BUN and creatinine may be elevated in cases associated with volume depletion due to vomiting¹³
- Liver function tests, pancreatic enzymes
  - Lipase, bilirubin fractionation, and transaminases are typically normal in CHS¹³

Imaging Studies

No imaging studies are required for diagnosis of CHS; however, imaging is often useful in excluding other diagnoses, particularly at a patient’s first presentation
Abdominal radiographs should demonstrate normal findings without obstruction and no free intraperitoneal air¹⁴
Abdominal ultrasound should display no findings explaining the patient’s symptoms (eg, gallstones/thickened gallbladder wall, abdominal aortic aneurysm)
CT scan should reveal no alternative cause for the patient’s symptoms (eg, bowel obstruction/ischemia, pancreatitis, gallbladder pathology)

Diagnostic Procedures

Endoscopy is sometimes recommended to exclude other diagnoses; no specific endoscopic findings are present in CHS
Gastric emptying studies are sometimes used to differentiate CHS from gastroparesis and other gastric motility disorders
Obtain ECG to evaluate cardiac intervals before administration of QT-prolonging medications

Differential Diagnosis

Table 3. Differential Diagnosis: Cannabinoid hyperemesis syndrome.

Condition	Description	Differentiated by
Cyclic vomiting syndrome	Cyclic nausea and vomiting lasting for several hours to several days without known trigger	Often begins in childhood, not specifically associated with cannabis use, CHS can be considered a sub-category of CVS
Psychogenic vomiting	Recurrent emesis without any organic cause identified	Often related to psychological stress, not specifically associated with cannabis use
Gastroparesis	Delayed gastric emptying causing early and prolonged satiety, nausea, vomiting	Often associated with diabetes mellitus, not specifically associated with cannabis use
Gastritis/Peptic ulcer disease	Inflammation of the gastric mucosal lining resulting in nausea, vomiting, and abdominal pain	Typically associated with H. pylori infection, nonsteroidal anti-inflammatory drug use, or ethanol use; not specifically associated with cannabis use
Pancreatitis	Inflammation and necrosis of the pancreas causing nausea, vomiting, and abdominal pain	Often associated with ethanol consumption or autoimmune processes, not specifically associated with cannabis use
Hepatobiliary pathology (eg, symptomatic cholelithiasis, cholecystitis, choledocholithiasis)	Gallbladder inflammation leading to nausea/vomiting, abdominal (typically right upper quadrant) pain, and jaundice/icterus	Often associated with localized right upper quadrant/right hemi-abdominal tenderness on examination and Murphy sign, imaging findings will typically confirm diagnosis; not specifically associated with cannabis use
Genitourinary pathology (eg, cystitis, pyelonephritis, ureterolithiasis)	Bladder/kidney infection or inflammation leading to nausea/vomiting, abdominal/flank pain, dysuria, or hematuria	Often associated with flank (pyelonephritis/ureterolithiasis) or suprapubic (cystitis) tenderness on examination; not specifically associated with cannabis use
Pelvic organ pathology (eg, tubo-ovarian abscess, ovarian torsion, ovarian cyst, ectopic pregnancy)	Infection or inflammation of adnexal structures leading to nausea/vomiting, abdominal/flank pain, dysuria, or pyuria	Often associated with adnexal tenderness on examination, imaging findings will typically be positive; not specifically associated with cannabis use
CNS pathology (eg, stroke, brain mass)	Brain mass, insult, ischemia, or hemorrhage that may result in nausea and vomiting	Often associated with focal neurologic signs and symptoms (eg, focal weakness, aphasia); not specifically associated with cannabis use

Caption: CHS, cannabinoid hyperemesis syndrome; CNS, central nervous system; CVS, cyclic vomiting syndrome.

Treatment

Approach to Treatment

Treatment is largely supportive, pharmacologic interventions show varied success
- Hot showering and bathing are anecdotally effective therapies, but difficult to employ in the emergency setting
- Provide fluid repletion with normal saline or lactated Ringers
- Consider trial of various pharmacotherapies including antiemetics, benzodiazepines, dopamine antagonists, and substance P modulators¹²⁴
Cessation of cannabis use is considered the mainstay of treatment and typically results in complete recovery¹²
- Continued cannabis usage typically results in return of symptoms despite treatment¹²⁴

Nondrug and Supportive Care

Provide intravenous fluid repletion with normal saline or lactated Ringer solution; convert to oral rehydration once able to tolerate fluids without emesis
Hot showering and bathing have been reported, both anecdotally and in case reports/series, to be effective treatments
- Mechanism of relief is incompletely understood, the following are thought to possibly be contributory:
  - Cannabinoid receptors’ role in thermoregulatory processes
  - Cannabinoids’ and hot showering’s possible alterations in splanchnic vascular tone

Drug Therapy

A variety of pharmacologic therapies have been employed with varying degrees of anecdotal and published success
- Evidence supporting all acute pharmacologic treatments is low-quality and very heterogeneous¹²⁴⁶⁸
Substance P modulator (eg, topical capsaicin)¹²⁴⁸
- Applied to cover the abdomen in a thin layer of cream
- Likely carries a favorable risk-benefit ratio and side-effect profile
Serotonin receptor antagonists (eg, ondansetron)
- Demonstrate variable efficacy in alleviating CHS-associated nausea and vomiting⁸
- Consider trial of 4mg to 8 mg of ondansetron PO⁹
  - Before administration ensure that the patient does not display any QTc prolongation on their ECG
Dopamine antagonists (eg, haloperidol, droperidol)
- Anecdotally used with significant success and demonstrated reasonable efficacy in low-quality case report data⁸
- Consider trial of 2 mg to 5 mg IM haloperidol every 8 hours
Serotonin-dopamine receptor antagonist (eg, olanzapine)
- Anecdotally used with reasonable success
- Consider 5 mg IM/IV⁶¹⁰¹¹
Benzodiazepines
- Variably effective in treating CHS-associated gastrointestinal symptoms⁸
- Consider trial of 1 mg to 2 mg oral lorazepam (or 0.05 mg/kg IV [maximum 4 mg per dose])¹²
NMDA (N-methyl-D-aspartate) receptor antagonist (eg, ketamine)
- Variably effective in treating CHS-associated distress and gastrointestinal symptoms
- Consider a dose of 0.1 mg/kg IV to 0.5 mg/kg IV¹³¹⁴
Cyclic antidepressants
- Case reports have demonstrated some degree of success in controlling long-term symptoms with
- The most frequently used agents include amitriptyline, nortriptyline, and doxepin⁸¹⁵
  - Described dosing is extremely variable; most case reports started at the lowest possible dose of the selected agent and titrated upward¹⁵
Opioids have not demonstrated benefit and are not indicated¹²⁴

Table 4. Selected drugs used to acutely treat CHS symptoms.

Drug	Mechanism of action	Common dose	Adverse effects
5-HT₃ Antagonists – Ondansetron⁹ – Granisetron	5-HT₃ antagonism in the area postrema	– 4 mg to 8 mg PO or 0.15 mg/kg IV, (maximum 16 mg per dose) – 2 mg PO or 1 mg IV	QTc prolongation, risk of serotonin toxicity with multiple other serotonergic agents
Benzodiazepines – Lorazepam¹² – Midazolam – Diazepam	GABA_A agonism	– 1 mg to 2 mg PO or 0.05 mg/kg IV – 0.05 mg/kg IV, maximum 5 mg per dose – 5 mg to 10 mg IV	Sedation and associated risks (ie, aspiration)
Dopamine antagonists – Haloperidol¹⁶ – Droperidol¹⁷	Postsynaptic D₂ antagonism	– 2 mg to 5 mg IM – 1 mg to 2.5 mg IM or IV	Extrapyramidal symptoms, antimuscarinic toxicity, sedation, orthostatic hypotension, QT prolongation
Dopamine + Serotonin antagonist – Olanzapine¹⁰	5HT_2A/2C, 5HT₆, dopamine D_1-4, histamine H₁ and adrenergic α₁ antagonism	– 2.5 mg to 10 mg IM/IV	Postural hypotension, somnolence
NMDA antagonist – Ketamine¹¹¹⁴	Non-competitive NMDA antagonist	– 10 mg to 25 mg IV	Dissociation, agitation, hypertension
Substance P modulators – Capsaicin cream	TRPV-1 modulation	– Apply a thin coating of 0.075% capsaicin cream to the anterior abdominal wall – Do not cover with occlusive dressing – Do not place on mucous membranes or sensitive areas (perineum, etc)	Cutaneous burning sensation, pruritus

Caption: GABA, gamma-aminobutyric acid; IM, intramuscular; IV, intravenous; NMDA, N-methyl-D-aspartate; TRPV, transient receptor potential vanilloid.

Data from Lapoint JM et al. Cannabinoid hyperemesis syndrome: public health implications and a novel model treatment guideline. West J Emerg Med. 2017;19(2):380-386 and Richards JR et al. Pharmacologic treatment of cannabinoid hyperemesis syndrome: a systematic review. Pharmacotherapy. 2017;37(6):725-734.

Follow-Up

Complications

Volume depletion with resultant renal injury has been reported¹²⁴
Vomiting-related complications may include aspiration pneumonitis and Mallory-Weiss tears

Prognosis

Cessation of cannabis use is considered the mainstay of treatment and typically results in complete recovery¹²
- Full recovery is expected in 10 to 14 days after cessation of cannabis use¹²
  - Some reports describe recovery requiring much longer (3 months to 4 years of self-reported abstinence), possibly due to THC’s long half-life due to storage in fat tissue⁴
Continued use is likely to continue to precipitate episodes

Screening and Prevention

Avoidance of cannabis is completely preventative
Harm reduction approach may be employed by suggesting decreased frequency of use
- A systemic review demonstrated that 97.4% of CHS cases were associated with at least weekly cannabis use

Author Affiliations

Steven J. Walsh, MD
Core Faculty, Division of Medical Toxicology
Department of Emergency Medicine
Division of Medical Toxicology
Jefferson Einstein Philadelphia Hospital, Jefferson Health

References

1.Lapoint JM. Cannabinoids. Editors. Nelson L.S., & Howland M, & Lewin N.A., & Smith S.W., & Goldfrank L.R., & Hoffman R.S.(Eds.), (2019). Goldfrank’s Toxicologic Emergencies, 11e. McGraw Hill.

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2.Sorensen CJ, DeSanto K, Borgelt L, Phillips KT, Monte AA. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review. J Med Toxicol. 2017 Mar;13(1):71-87.