Cannabis Hyperemesis Syndrome (CHS) has become a well-documented syndrome since 2004 and is expected to increase in prevalence with continuing liberalization of marijuana and recognition of the disease. Regardless of whether the association with heavy cannabis use is recognized, there is well-documented resistance to traditional anti-emetic treatment. Given promising reports of the use of intravenous haloperidol, a randomized controlled trial comparing it to the commonly administered anti-emetic ondansetron will contribute to the management of CHS

This is a double-blinded, randomized, cross-over clinical trial that will enroll approximately 80 subjects from at least four different research sites. Patients who have been diagnosed with CHS and enrolled in our study will act as their own controls upon their return to the ED for a subsequent bout of CHS for up to 3 visits per subject. Each patient will be allocated in a 1:1:1 fashion into one of three treatment groups: high- or low-dose haloperidol, or ondansetron, with a minimum 7-day washout period between treatments. As CHS tends to be a recurrent syndrome (presumably given the continued use of cannabis despite recommendations to taper and abstain), it is expected that most subjects will return at least once again, and a substantial subset of the study population will complete all three treatment visits during the trial.

Inclusion Criteria:

1. Age > 18 years
2. Self-report of ≥3 episodes of emesis occurring in a cyclic pattern for greater than 1 month in the preceding 2 years
3. Current episode >2 hours of emesis
4. At least one episode of emesis/forceful retching witnessed (including products of emesis at bedside) or heard by an independent observer (healthcare provider or family/friend) in the emergency department
5. Self-reported frequent (near daily to daily x at least 6 months) use of cannabis by inhalation.
6. Working diagnosis of cannabis hyperemesis syndrome in the opinion of the treating emergency physician

Exclusion Criteria:

1. Chronic, daily use of opioid equivalent to ≥10mg morphine/day
2. Inability to comprehend study consent or instructions
3. Unreliable follow-up/unlikely to return for cross-over
4. Administration of an intravenous antiemetic, anticholinergic or antipsychotic (other than up to 100mg dimenhydrinate) in the previous 24 hours
5. Allergy or intolerance to haloperidol or ondansetron
6. Pregnancy
7. Any other medical or psychiatric condition that in the opinion of the enrolling physician would interfere with participation in the trial
8. Current active participation in an investigational drug trial

Participants will be allocated to an intervention via a sealed, opaque envelope system to be opened by an unblinded nurse not otherwise involved in patient care or research procedures will prepare the intervention. The Attending physician, Research personnel and Investigator(s) will all remain blinded to the allocation.