What is cannabinoid hyperemesis syndrome?

Cannabinoid hyperemesis syndrome (CHS) is a condition in which patients who have been using cannabis or synthetic cannabinoids for a prolonged period of time develop a pattern of episodic, severe vomiting (usually accompanied by abdominal pain) interspersed with prolonged asymptomatic periods.

When should you consider cannabinoid hyperemesis syndrome as a diagnosis?

The diagnostic criteria for CHS require evidence of relief of symptoms with sustained cessation from cannabis, which makes them of limited utility in the Emergency Department (ED) [1]. However, a number of ED-based diagnostic criteria have been proposed with overlapping features [1,2]. There are 3 key components to assess for when making a presumed diagnosis:

1. An episodic pattern of vomiting
   • Episodes of vomiting should last < 7 consecutive days
   • Asymptomatic periods often last > 1 month between episodes
2. Prolonged cannabis use
   • Criteria vary: normally >1 time per week (often daily) for at least 1 year
   • Importantly, this is not an intoxication effect from a single large ingestion
3. Exclusion of alternative diagnoses
   • Look for atypical features on history & exam including abnormal vital signs, diarrhea, focal abdominal pain, peritonitis, and jaundice
   • It is important to exclude pregnancy in all female patients
   • If a patient has never had an esophagogastroduodenoscopy (EGD), it is reasonable to refer newly diagnosed patients to gastroenterology for a non-emergent EGD to assess for a structural cause of the patient’s symptoms

What causes cannabinoid hyperemesis syndrome?

There is no singular theory that fully explains CHS. Importantly, the pattern of illness does not correlate well with the amount of cannabis consumed acutely, suggesting it is not related to a direct effect of the delta-9-tetrahydrocannabinol (THC) or a withdrawal effect. There are two prevailing theories related to changes in neuro-signaling and receptor expression with chronic THC exposure:

Theory #1: Downregulation of the cannabinoid receptor type 1 (CB-1) receptor which occurs with chronic THC use causing dysregulation of the hypothalamic-pituitary-adrenal stress axis. This theory supports why medications that have sedative or anxiolytic properties, such as haloperidol and benzodiazepines, have reported efficacy.

Theory #2: Changes in central nervous system dopamine signaling pathways with chronic THC exposure leading to a hypersensitive emesis response to dopamine. This theory is less well supported but has been used to explain the beneficial effects of dopamine antagonists such as haloperidol, droperidol, and olanzapine.

How should we treat cannabinoid hyperemesis syndrome in the ED?

Ondansetron, Metoclopramide, and Antihistamines

Traditional antiemetics have had low rates of success in treating CHS based on reported cases (ondansetron = 1.75%, metoclopramide = 4.35%) [3]. Antihistamines such as dimenhydrinate, diphenhydramine, and meclizine have no studies supporting their use, and the limited case reports available suggest they are ineffective [3]. While cases of treatment failure are more likely to be published which contributes to a reporting bias, clinical experience supports that CHS often does not respond well to these antiemetics. These medications may still have a role as an adjunct for patients who are refractory to other treatments, but given the evidence available supporting other agents, they can no longer be recommended as first-line therapy. Drawbacks to using a “traditional antiemetics first” strategies include a delay to effective treatment, prolonged ED length of stay, and prolongation of the QT interval.

Haloperidol

The HaVOC trial showed haloperidol was twice as effective as ondansetron at reducing nausea (change from baseline = -5.0 vs. -2.4) and abdominal pain (change from baseline = -4.3 vs. -2.1). Haloperidol also decreased rescue medication use (31% vs. 76%) and time from medication administration to ED discharge (3.1 hours vs. 5.6 hours) [4].

Lower doses of haloperidol were recommended (0.05 mg/kg) due to higher rates of adverse reactions with larger doses. Weight-band based dosing may be a more practical approach:

• Haloperidol 2.5 mg IV for adults < 80 kg
• Haloperidol 5 mg IV for adults > 80 kg

Olanzapine

There is very limited evidence supporting olanzapine specifically in CHS (6 reported cases) [3]. However, olanzapine has strong evidence supporting its antiemetic properties in oncology literature [5,6]. Unlike haloperidol, olanzapine does not prolong the QT interval and it has much lower rates of extrapyramidal side effects. Therefore, olanzapine may be a reasonable substitution for haloperidol in the following cases: documented allergy to haloperidol, prolonged QT interval, or previous extrapyramidal effects with haloperidol.

Capsaicin

While capsaicin is often discussed as a treatment [ALiEM trick of the trade], the evidence supporting its use is limited to a small case series and a small RCT with some significant limitations. The small RCT published in support of capsaicin had large baseline differences between the capsaicin and placebo groups. The placebo group was “more sick”, having higher baseline nausea which was not corrected for in the analysis [7].

The trial reported a significant reduction in nausea scores with capsaicin (60-minute nausea score: Placebo = 6.4 vs. Capsaicin = 3.2, p = 0.007) which looks impressive, but the change in nausea from baseline was much less substantial (change in nausea: Placebo = -2.1 vs. Capsaicin = -2.8). Overall, the evidence supporting capsaicin is limited, so its use should be a shared decision.

Benzodiazepines

Lorazepam has no studies assessing its utility in CHS, but a summary of case reports suggests an efficacy of 58.3% in 19 patients [3]. Despite the lack of evidence, clinical experience has led to lorazepam being recommended as an adjunct in recent cyclic vomiting syndrome guidelines for patients who have an anxiety component to their presentation [8]. Since 40-50% of traditional cyclic vomiting syndrome patients were chronic cannabis users, it is reasonable to extrapolate these guidelines to CHS until more specific literature is published.

Overall Approach to Treatment

Based on the currently available research outlined above and clinical experience, the following is a reasonable approach to acute symptomatic management of CHS in the ED:

What should we be considering at the time of discharge?

Like other chronic episodic illnesses (eg. migraines) the long-term management of CHS can be conceptualized to have three components: avoidance of triggers, management of acute episodes, and episode prevention (prophylaxis).

Avoidance of Triggers

• The only cure for CHS is the prolonged cessation of cannabis. It is important to emphasize that it may take 6 months of cannabis cessation before symptoms improve, and to recognize that the challenges in stopping cannabis use are often underestimated. Professional addictions support is encouraged.

Management of Acute Episodes

• Medications at home to abort acute episodes are a logical management strategy and may be a safe option to reduce recurrent ED visits in some patients. This will depend on which medications work for the patient, their comorbidities, and the patient’s access to reliable follow-up.
• There is no current evidence to guide outpatient treatment. Traditionally, many gastroenterologists have used a combination of sublingual lorazepam and ondansetron which may be reasonable if a patient has responded to these medications in the ED.
• The use of oral haloperidol at home is currently being studied, but there are no good protocols published to guide practice.

Episode Prevention

• There have been no studies on using medications to reduce the frequency of CHS episodes. However, amitriptyline is recommended as a first-line prophylactic treatment for adults with cyclic vomiting syndrome as it reduces subjective symptoms scores, episode frequency, and ED utilization [9,10].
• Using amitriptyline for CHS would be considered experimental and amitriptyline has several well-recognized side effects, requires slow up-titrated, and necessitates close follow-up. It may be reasonable for a patient to discuss with their primary care provider.

References

1. Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterology & Motility. 2019 Jun;31(Suppl 2):e13606.
2. Sorensen CJ, DeSanto K, Borgelt L, Phillips KT. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment – a systematic review. Journal of Medical Toxicology. 2017;13:71-87.
3. Richards JR, Gordon BK, Danielson AR, Moulin AK. Pharmacologic treatment of cannabinoid hyperemesis syndrome: a systematic review. Pharmacotherapy. 2017;37(6):725-34.
4. Ruberto AJ, Sivilotti ML, Forrester S, et al. Intravenous haloperidol versus ondansetron for cannabis hyperemesis syndrome (HaVOC): a randomized, controlled trial. Annals of Emergency Medicine. 202 Nov;S0196-0644(20)30666-1.
5. Hashimoto H, Abe M, Tokuyama O, Mizutani H, Uchitomi Y, Yamaguchi T, Hoshina Y, Sakata Y, Takahashi TY, Nakashima K, Nakao M, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology. 2020;21:242-49.
6. Naravi RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. New England Journal of Medicine. 2016 Jul;375(2):134-42.
7. Dean DJ, Sabagha N, Rose K, et al. A pilot trial of topical capsaicin cream for treatment of cannabinoid hyperemesis syndrome. Academic Emergency Medicine. 2020;27:1166-72.
8. Venkatesan T, Levinthal DJ, Tarbell SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American neurogastroenterology and motility society and the cyclic vomiting syndrome association. Neurogastroenterology & Motility. 2019;31(Supp 2):e13604.
9. Hejazi RA, Reddymasu SC, Namin F, et al. Efficacy of tricyclic antidepressant therapy in adults with cyclic vomiting syndrome: a two year follow up study. Journal of Clinical Gastroenterology. 2010;44:18-21.
10. Namin F, Patel J, Lin Z, et al. Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy. Neurogastroenterology & Motility. 2007;19:196-202.