Introduction: One of the most common adverse effects of habitual cannabis use is hyperemesis—recurrent bouts of protracted vomiting, retching and abdominal pain superimposed on a baseline of daily nausea and anorexia. Largely anecdotal evidence supports the use of haloperidol, benzodiazepines or topical capsaicin over traditional antiemetics, yet little is known about the cause or optimal treatment of this newly recognized disorder. We report the results of one of the first clinical trials on so-called cannabis hyperemesis syndrome (NCT03056482). Methods: We approached adults with a working diagnosis of hyperemesis due to cannabis, provided they had ongoing emesis for >2 hours, a cyclic pattern of 3+ episodes in the last 2 years, and near daily use of cannabis by inhalation. We excluded those who were pregnant, deemed unreliable, or using opioids. Subjects provided written consent to be randomized during the index or any subsequent visit to either haloperidol (with a nested randomization to either 0.05 mg/kg or 0.1 mg/kg) or ondansetron 8 mg intravenously in a quadruple-blind fashion, and to be followed for 7 days. The primary outcome was the average reduction from baseline in abdominal pain and nausea (each measured on a 10-cm VAS) at 2 hours. While the original trial design allowed for crossover, the primary analysis used only the first treatment period since fewer than the prespecified threshold of 20% of subjects crossed over. Results: We enrolled 33 subjects, of whom 30 (16 men, 29+/-11 years old, using 1.5+/-0.9 g/day since age 19+/-2 years) were treated at least once (haloperidol 13, ondansetron 17). Haloperidol at either dose was superior to ondansetron (difference 2.3 cm [95%CI 0.6, 4.0]; p = 0.01), with similar improvements in both pain and nausea, as well as less rescue antiemetics (27% vs 61%; p = 0.04), and shorter time to ED departure (3.1+/-1.7 vs 5.6+/-4.5 hours; p = 0.03 Wilcoxon rank sum). There were two (haloperidol) vs six (ondansetron) return visits for ongoing nausea/vomiting, as well as two return visits for acute dystonia, both in the higher dose haloperidol group. Conclusion: Haloperidol is superior to ondansetron for the acute symptomatic treatment of patients with ongoing hyperemesis attributed to habitual cannabis use. The efficacy of this agent over ondansetron provides insight into the mechanism of this new disorder, now almost a daily diagnosis in many Canadian emergency departments.

Introduction: Emergency physicians increasingly encounter young patients with protracted, forceful hyperemesis associated with heavy cannabis use, previously termed “cyclic vomiting.” The national discourse on liberalization of cannabis has largely ignored this poorly understood condition. We wondered to what degree hyperemesis cannabis is an idiosyncratic reaction, like motion sickness or migraine, versus a more predictable dose-response effect of heavy, prolonged use. Methods: As part of a larger case-control study using structured interviews, we measured cannabinoid concentrations in scalp hair of both cases and controls. Cases were required to have an emergency visit for vomiting, 2+ episodes of severe vomiting in the previous year, history of near-daily use of cannabis for 6+ months, positive urine Δ9-tetrahydrocannabinol (THC) and age 16-55 years; exclusion criteria were chronic opioid use, synthetic cannabinoid use, or established alternative diagnosis. Age- and sex-matched chronic cannabis-using controls without vomiting were identified via social referral primarily from the cases themselves. Scalp hair was analyzed for THC, cannabinol (CBN), cannabidiol (CBD) and 11-nor-9-carboxy-THC (THC-COOH) by LC-MS/MS (limit of quantification ~15 pg/mg hair; accuracy <5%) in an independent laboratory blinded to subject classification. Results: We obtained satisfactory hair and urine samples from 18 cases (median [IQR] age 27 [20,31] years; 12 male) and 13 controls. THC and CBN concentrations were higher in cases than controls (THC 240 [120,820] vs 99 [73, 290] pg/mg; CBN 63 [33, 260] vs 15 [negative, 76] pg/mg; each P<0.05). CBD and THC-COOH were often unquantifiable to undetectable in both cases and controls. Conclusion: Hyperemesis cannabis patients have substantially higher hair cannabinoid concentrations than their peers without vomiting, although there is some overlap. The association cannot demonstrate a direct dose-response with THC--confounding (e.g. other cannabinoids, external smoke deposition), altered metabolism and reverse causation (e.g. seeking temporary symptom relief by using more cannabis) could also yield a positive association. Nevertheless, these findings support counselling patients with hyperemesis to reduce or discontinue using cannabis. They also support national regulatory initiatives including education, labelling, and progressive taxation based on potency intended to discourage excessive use.