CASE REPORT

Cannabinoid Hyperemesis Syndrome as the Underlying Cause of Intractable Nausea and Vomiting

Stephanie L. Price, DO; Cynthia Fisher, DO; Ravinder Kumar, MD; and Alan Hilgerson, DO

Recently, reports have suggested that chronic cannabis abuse The diagnosis and management of cannabinoid hyper - can result in cyclical vomiting, or cannabinoid hyperemesis emesis syndrome is of clinical importance because cannabis use syndrome. With the increasing prevalence of cannabis use is so widespread. Marijuana is the most commonly used illegal in the United States, this syndrome may be encountered in drug in the United States, 6 with a prevalence rate of roughly the emergency department. The authors describe a case of a 4%. 2 In 2009, 16.7 million US individuals aged 12 years or 30-year-old man who presented to the emergency depart - older had used marijuana at least once in the month prior to ment with diffuse abdominal pain, nausea, and intractable being surveyed. 7 In the absence of other possible causes, vomiting. He reported symptomatic relief with prolonged hot including pancreatitis, gastroenteritis, nephrolithiasis, showers. Results of a urine drug screen were positive for pyelonephritis, cholecystitis, peptic ulcer disease, pyloric cannabis, and the patient admitted to chronic cannabis use obstruction, gastroparesis, and pregnancy, this syndrome for years. Results of the drug screen, combined with the should be considered in treating patients with cyclical vomiting patient’s symptomatic relief with hot showers, led to the as it may be underrecognized. diagnosis of cannabinoid hyperemesis syndrome. The patient We describe the case of a man who sought emergency care was admitted to the hospital and underwent pharmaceu - for uncontrolled nausea and vomiting. We also provide a brief tical treatment. However, hot showers continued to be the review of the literature on cannabinoid hyperemesis syn - mainstay of the patient’s symptomatic relief. Four days after drome. presentation, the patient’s symptoms resolved and he was discharged from the hospital. Report of Case J Am Osteopath Assoc. 2011;111(3):166-169 A 30-year-old previously healthy man with a white collar job presented to the emergency department with diffuse abdom - inal pain accompanied by nausea, intractable vomiting, and everal mechanisms have been proposed to explain the decreased oral intake of food and drink. The patient was dehy - Spathophysiology of cyclical vomiting, but the etiology drated at presentation and indicated his symptoms had lasted remains unclear. 1,2 Although cannabinoids have long been for 3 days. The patient denied any previous episodes and recognized for their therapeutic potential as antiemetics, 3,4,5 reported symptomatic onset with ingestion of “several Bud - chronic cannabis use has recently been associated with recur - weisers.” He also reported symptomatic relief with prolonged rent vomiting. 3 Patients with this disorder, termed cannabi - hot showers. He denied eating anything out of the ordinary, noid hyperemesis syndrome, also experience abdominal encountering other unhealthy individuals, traveling recently, pain, polydipsia, and a desire to take repeated hot showers. 1 or feeling sick prior to symptom onset. His past medical and surgical histories were unremarkable, and he had no reported allergies. He denied tobacco or other illicit drug use. He noted a subjective weight loss of 10 lbs. On physical examination, the patient’s vital signs included a temperature of 35.2°C, heart rate of 52 beats per minute, res - piratory rate of 16 breaths per minute, blood pressure of 135/76 mm Hg, oxygen saturation of 98% on room air, and weight of 80 kg. He was irritable and agitated with intractable hiccupping. From Broadlawns Medical Center in Des Moines, Iowa. Dr Price was a student He had mild flushing of the integument on the anterior thorax. at Des Moines University College of Osteopathic Medicine at the time of the His pupils were equal in diameter and reactive to light, and study. extraocular movements were intact. Examination of the Financial Disclosure : None reported. Address correspondence to Stephanie Price, DO, 502 Belinda Alley, patient’s mouth and oropharynx revealed moist mucous mem - Columbia, MO 65203-3860. branes. No discernable lymphadenopathy or thyromegaly E-mail: [email protected] was present. The patient’s cardiovascular examination was Submitted July 10, 2010; accepted November 4, 2010. unremarkable and his chest was clear on auscultation. Exam - ination of the abdomen revealed soft tissue with diffuse ten -

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derness, positive bowel sounds, and no signs of organomegaly, rebound tenderness, or guarding. Extremities showed no signs Table. of clubbing, cyanosis, or edema. Findings of a neurologic Laboratory Findings for a 30-Year-Old Man examination were unremarkable. With Cannabinoid Hyperemesis Syndrome Laboratory findings revealed an elevated anion gap, hyponatremia, hypochloremia, elevated bicarbonate levels, Laboratory Test Finding Reference Range and acute renal insufficiency with elevated blood urea nitrogen ◾ White Blood Cell Count, × 10 9/μL 19.0 4.0-11.0 (Table ). Fractional excretion of Na was 2.27%. Liver transam - ◾ Red Blood Cell Count, × 10 6/μL 5.89 4.60-6.20 inase, lipase, and amylase levels were normal. Urinalysis ◾ Hemoglobin, g/dL 17.7 14.0-18.0 results were positive for trace ketones from decreased food ◾ Hematocrit, % 49.1 42.0-52.0 intake. Ultrasonography of the kidneys showed no evidence ◾ Blood Platelet Count, × 10 3/μL 492 150-450 of hydronephrosis or obstruction. ◾ Segmented Neutrophils, K/ μL 14.3 1.8-8.0 Results of the patient’s urine drug screen were positive for ◾ Anion Gap, mmol/L 24 8-16 cannabis. When confronted with the positive urine drug screen, ◾ Osmolality, mmol/kg the patient admitted to last using cannabis 3 days prior to ◽ Measured 288 275-295 admission, with history of chronic daily use for years. Results ◽ Calculated 290 275-295 of the drug screen, combined with the patient’s description of ◾ Basic Metabolic Panel symptomatic relief with hot showers, led to the diagnosis of ◽ Sodium, mmol/L 130 132-146 cannabinoid hyperemesis syndrome due to chronic cannabis ◽ Chloride, mmol/L 67 99-109 abuse. ◽ Bicarbonate, mmol/L 39 20-31 The patient was admitted to the hospital and immedi - ◽ Nitrogen, mg/dL 67 9-23 ately treated with intravenous fluids, including normal saline ◽ Creatinine, mg/dL 3.2 0.5-1.3 (2 L bolus and then 200 mL/hr) and famotidine (20 mg). Within the next 2 hours, the patient experienced minimal relief as we administered ondansetron hydrochloride for nausea and vomiting (4 mg as needed), morphine for pain (4 mg as hydrochloride and lorazepam. Ondansetron hydrochloride needed), droperidol (5 mg), diphenhydramine hydrochloride was not administered, despite being available in the instance (50 mg), promethazine hydrochloride (12.5 mg as needed), that the patient needed it. chlorpromazine hydrochloride for resolution of intractable Hot showers—19 throughout the course of hospitaliza - hiccups (25 mg as needed), and acetaminophen for headache tion—were the mainstay of the patient’s symptom relief. He (650 mg as needed). Except for the acetaminophen, all drugs had episodes of perspiration, extreme thirst, flushing, and were administered intravenously. episodes of low-grade fever after showering. The patient did The patient vomited several times overnight and nausea not respond well to antiemetics but intravenous fluids and was still present the next morning. However, the patient hot showers seemed to calm the active phase of his disease pro - reported that his headache had resolved and abdominal pain cess. Results of his blood and chemistry panels further sup - was improving. In addition, the patient’s dehydration, relative ported this improvement. Liver, pancreas, and renal patholo - polycythemia, and leukocytosis had improved, and his hiccups gies were dismissed as potential causes because of normal had resolved. The patient took multiple hot showers on this enzyme levels and ultrasonography readings. day. We conducted research simultaneously with presentation The next day, the patient continued to vomit despite con - of this obscure case, which helped us determine the patient’s tinued treatment with ondansetron hydrochloride. He also treatment. The patient was discharged on the fourth day of reported continued abdominal pain. At this point, we switched hospitalization, at which point his symptoms had resolved. his nausea treatment to promethazine hydrochloride (first Before discharge, the patient was educated about symptoms of line, 12.5 mg as needed), lorazepam (second line, 1 mg every cannabinoid toxicity and how abstaining from cannabis could 4 hours as needed), and ondansetron hydrochloride (third resolve his symptoms. He was also informed that, while the dis - line, 4 mg as needed). We administered another 1 L bolus and ease takes years to develop, it would resurface within weeks of resumed intravenous fluids at 150 mL per hour. We let the resuming cannabis, even after considerable periods of absti - patient continue to take hot showers as needed. nence. 1,8 The patient was not followed up. By the next morning (the fourth day of hospitalization), patient felt much better. His abdominal pain had resolved Comment and he denied any nausea or vomiting; the last episode of Clinical Presentation vomiting had occurred the previous night. Pain was controlled Cannabinoid hyperemesis syndrome is a new and emerging with morphine, and nausea was controlled with promethazine clinical diagnosis that is often overlooked in the emergency

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department because adverse effects of chronic cannabinoid decreasing the emetic response. 9,11,12 In patients who develop use are not always recognized. The syndrome, characterized hyperemesis, the enteric emetic effects of cannabis, such as by a triad of chronic cannabis use, cyclical vomiting, and com - decreased gastrointestinal motility, may promote emesis by pulsive hot bathing, is divided into 3 phases: prodrome, recur - overriding antiemetic effects mediated by the central nervous rent vomiting, and recovery. 2 system. 2,13 As previously mentioned, patients with cannabinoid Prodromal phase 2—The prodromal phase is variable in dura - hyperemesis syndrome shower or bathe in hot water to tion and manifests with nausea, fear of vomiting, and abdom - decrease the intensity of the nausea and vomiting. A series of inal discomfort. Symptoms are most common in early middle- cases in South Australia, Australia, demonstrated that simul - aged adults who have consistently been using cannabis since taneous with hot bathing, patients lost 10 to 15 lbs of body adolescence. weight, which they regained after they abstained from cannabis and their symptoms resolved. They also displayed a variety of Vomiting phase 2—The vomiting phase is characterized by autonomic symptoms including sweating, flushing, thirst, intense, persistent nausea, vomiting, and retching that can alteration in body temperature, and colicky abdominal pain. 8 occur up to 5 times per hour and is often described by patients This effect might arise from the modulation of the hypotha - as overwhelming. In addition, patients experience concomitant lamic-pituitary-adrenal axis by endocannibinoids. 8,14 Cannabis abdominal pain and a compulsive need to bathe in hot water. toxicity may disrupt the balanced equilibrium of satiety, thirst, Patients typically visit hospitals numerous times throughout digestion, and the thermoregulatory systems of the hypotha - this phase, which can lead to escalating healthcare costs. Results lamus. This disruption may be settled with hot bathing or of esophagogastroduodenoscopy, colonoscopy, radiologic showering. 8 abdominal imaging, ultrasonography, and further workup are generally unremarkable. Routine blood tests are often Conclusion unrevealing as well. Cannabinoid hyperemesis syndrome is a newly recognized diagnosis related to cannabis toxicity. The adverse effects of Recovery phase 2—The recovery phase begins with cannabis chronic cannabis use are still under investigation, and the cessation. Within 1 week, patients will experience a substan - mechanism of cannabis leading to intractable nausea and vom - tial decrease in and eventual resolution of vomiting. Symptoms iting is still unclear. 1,2 With the widespread use of this sub - are further alleviated with 24 to 48 hours of intravenous fluid stance, both recreationally and therapeutically, the paradoxical administration. Despite reports of patients with this condi - effect of cannabinoid hyperemesis syndrome deserves fur - tion being refractory to supportive antiemetic regimens (such ther attention. as in the present report), pharmaceutical management can The goal of the present case report is to raise awareness relieve symptoms of pain and nausea in some cases. The ten - of the potential adverse effects of cannabis and the impor - dency to take hot showers also subsides during the recovery tance of obtaining a thorough history, including questions phase. Return to cannabis use at any time will lead to recur - regarding illicit substance abuse. When questioning a patient’s rence of cannabinoid hyperemesis syndrome. social history, it may be worthwhile to inquire about hot show - ering patterns, especially in those who deny or minimize their Etiology use of illicit drugs. Clinicians should have heightened aware - Despite proposed mechanisms of cannabinoid hyperemesis ness when intractable nausea and vomiting is unresponsive to syndrome, the etiology remains unclear. 1,2 Cannabis has been antiemetics but relieved with hot showering. When encoun - used to treat chemotherapy-induced nausea and vomiting, tering this unusual presentation, clinicians should consider anorexia, anxiety, and glaucoma. 9 The antiemetic effect of illicit cannabis abuse in addition to organic disease as a possible cannabinoids is mediated by cannabinoid type 1 receptors in cause. This consideration may prevent further unnecessary the brain by means of Δ9-tetrahydrocannabinol, the active workup and healthcare costs for patients with cannabinoid compound in cannabis. 4,10 Proposed mechanisms of cannabi - hyperemesis syndrome. noid hyperemesis syndrome include toxicity because of mar - ijuana’s long half-life, cumulative lipophilic effects in the brain, References delayed gastric emptying, and thermoregulatory and auto - 1. Wallace D, Martin AL, Park B. Cannabinoid hyperemesis: marijuana puts nomic disequilibrium in the limbic system. 8,4,10 patients in hot water. Australas Psychiatry . 2007;15(2):156-158. Vomiting is coordinated by the brainstem in response to 2. Soriano-Co M, Batke M, Cappell MS. The cannabis hyperemesis syndrome noxious stimuli involving many neurotransmitters. Metoclo - characterized by persistent nausea and vomiting, abdominal pain, and com - pulsive bathing associated with chronic marijuana use: a report of eight pramide, an antiemetic agent, acts as an antagonist to the same cases in the United States [published online ahead of print February 4, 2010]. chemoreceptor trigger zone in the brainstem that inhibits the Dig Dis Sci . 2010;55(11):3113-3119. vomiting reflex. It also increases gastric motility, further (continued)

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3. Donnino MW, Cocchi MN, Miller J, Fisher J. Cannabinoid hyperemesis: a case 9. Chang YH, Windish DM. Cannabinoid hyperemesis relieved by compulsive series [published online ahead of print September 16, 2009]. J Emerg Med . bathing. Mayo Clin Proc . 2009;84(1):76-78. doi:10.1016/j.jemermed.2009.07.033. 10. Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut. 2001;48(6): 4. Sontineni SP, Chaudhary S, Sontineni V, Lanspa SJ. Cannabinoid hyper - 859-867. emesis syndrome: clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gatroenterol . 2009;15(10):1264-1266. 11. Albibi R, McCallum RW. Metoclopromide: pharmacology and clinical application. Ann Intern Med . 1983;98(1):86-95. 5. Pagotto U, Marsicano G, Fezza F, et al. Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize 12. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain con - endogenous cannabinoids: first evidence for a direct role of cannabinoids on stituent that binds to the cannabinoid receptor. Science . 1992;258(5090):1946- hormone modulation at the human pituitary level. J Clin Endocrinol Metab . 1949. 2001;86(6):2687-2696. 13. Walsh D, Nelson KA, Mahmoud FA. Established and potential therapeutic 6. Compton WM, Grant BF, Colliver JD, Glantz MD, Stinson FS. Prevalence of applications of cannabinoids in oncology. Support Care Cancer. 2003;11(3):137- marijuana use disorders in the United States: 1991-1992 and 2001-2002. 143. JAMA . 2004;291(17): 2114-2121. 14. Howlett AC, Barth F, Bonnie TI, et al. International Union of Pharma - 7. National Institute on Drug Abuse. NIDA info facts: marijuana. National cology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. Institutes of Health Web site. http://www.drugabuse.gov/infofacts/mari - 2002;54(2):161-202. juana.html. Accessed February 4, 2011. 8. Allen JH, de Moore GM, Heddle R, Twartz JC. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse. Gut. 2004;53(11):1566-1570.

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