Cannabinoid hyperemesis syndrome (CHS) is an enigmatic constellation of symptoms and signs first reported in 2004 in Australia, consisting of intractable vomiting, abdominal pain and hot water bathing behavior that represents one of the few true contraindications to cannabis usage. CHS solely occurs in the context of heavy chronic use of cannabis or products containing high amounts of tetrahydrocannabinol (THC) or other CB1 receptor agonists. The syndrome is increasingly identified, particularly in the USA, where estimates of its prevalence range from 350K to 2.5M affected patients. It is associated with frequent emergency visits for treatment and diagnosis, with high diagnostic expense ($30-90K) and general resistance to treatment with anti-emetics and analgesics. Considerable morbidity and even some fatalities related to hyponatremia-associated vomiting have been reported. The definitive treatment is abstention from cannabis usage, but cutaneous application of capsaicin ointment (TRPV1 agonist/desensitizer) can provide symptomatic relief. Prior studies hypothesized that the pathophysiology/biochemical basis of CHS might relate to biphasic dose responses to THC, a paradoxical shift of THC from partial agonist to antagonist of CB1, or to changes in the TRPV1 receptor. In 2021, the authors were part of a team with EndocannaDNA that investigated a possible genetic basis for CHS that could explain its pathophysiology (Russo et al, 2021).