Cannabinoid Hyperemesis Syndrome: A Case Report and Literature Review Robert A. Beech, DDS,* David R. Sterrett, DMD,y James Babiuk, DDS,z and Henry Fung, DDSx Purpose:
As society has seen an increase in rates of cannabis abuse, largely related to an increase in legalization of the substance, a new clinical condition deemed cannabinoid hyperemesis syndrome has been recognized. This syndrome of idiopathic etiology is stimulated from chronic marijuana usage and produces cyclic episodes of nausea, vomiting, and epigastric pain often alleviated with compulsive hot water bathing. Patient and Methods: A 42-year-old woman with a medical history of hypertension and myasthenia gravis was admitted to the authors’ institution with a mandibular fracture. Results:
Her laboratory work showed her to be extremely hypokalemic and with slight metabolic alkalosis. This was attributed to her reports of chronic vomiting, multiple times daily, over several weeks’ duration. After her medical workup, cannabinoid hyperemesis syndrome was diagnosed and treated by fluid resuscitation, antiemetic medications, and marijuana cessation. After correction of her clinical symptoms and laboratory work, she was able to undergo open reduction and internal fixation of her mandibular fracture.
Conclusions: The dental community is well aware of the positive antiemetic and appetite-stimulating effects of marijuana, but they might be unaware of some of the paradoxical effects it can produce as shown in this newly documented clinical condition. As society is seeing an increase in the legalization of marijuana for medical and recreational usage in the United States, the dental community should be aware of this condition and its implications. Ó 2015 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 73:1907-1910, 2015
Marijuana use has been a popular recreational drug for thousands of years and is currently the third most common drug of abuse after alcohol and tobacco.1 It is the most commonly used illicit drug in the United States, with more than 16 million users, and is most prevalent in the 18- to 25-year-old group.2 Epidemiologic risk factors for abuse include male gender, low economic status, residing in the Western hemisphere, and patients with strained relationship statuses. In 2004, Allen et al3 discussed a new disorder associated with marijuana use that displayed signs and symptoms of episodic and recurrent vomiting, abdominal pain, and learned behavior of compulsory hot water bathing. These symptoms are contrary to the
well-known positive effects of marijuana, such as antiemesis and appetite stimulation.1,2,4 This syndrome is commonly broken down into 3 phases: prodromal, hyperemetic, and recovery. The prodromal and recovery phases occur with varying duration, whereas the more seriously symptomatic hyperemetic phase will commonly resolve within 48 hours if treated with appropriate supportive therapy. This report describes a case in which the patient’s treatment of a routine mandibular fracture was complicated by this syndrome. The authors discuss a clinical description of the symptoms associated with cannabinoid hyperemesis syndrome (CHS), the differential diagnosis, pharmacologic factors that can
Received from the Department of Oral and Maxillofacial Surgery,
tal of Cook County, 1900 W Polk Street, Suite 611, Chicago, IL 60612;
John H. Stroger Hospital of Cook County, Chicago, IL. *Resident.
e-mail: [email protected]
Received January 22 2015
Accepted March 28 2015
Ó 2015 American Association of Oral and Maxillofacial Surgeons
xChairman, Residency Program Director.
Address correspondence and reprint requests to Dr Beech:
Department of Oral and Maxillofacial Surgery, John H. Stroger Hospi-
1908 contribute to the condition, and a proposed algorithm for treatment.
Report of Case A 42-year-old woman presented to the emergency department at John H. Stroger Hospital of Cook County (Chicago, IL) 1 month after blunt head trauma. She denied loss of consciousness, but noted having a malocclusion and pain during function. A maxillofacial computed tomographic (CT) scan without contrast showed a partially healed right mandibular parasymphysis fracture. Her medical history was noteworthy for myasthenia gravis and hypertension. Initially, her social history was noteworthy for regular tobacco and marijuana use and infrequent alcohol consumption. She was admitted and placed on appropriate medications, including carvedilol and pyridostigmine. During her workup, it was noted she was hypokalemic at 2.9 mEq/L, with a slight metabolic alkalosis showing a CO2 value of 32 mEq/L. Electrocardiogram showed a sinus bradycardia at 57 beats/minute with otherwise normal rhythm and normal waveform. When the patient was questioned further about her medical history, she noted that she had vomited 6 times during the past 24 hours. Then, the pyridostigmine was discontinued, because she was asymptomatic to her myasthenia gravis and its ability to cause emesis. Her electrolytes were corrected and re-evaluated the next day. The following day, the patient’s nausea and vomiting continued. Her potassium level was still 2.9 mEq/L and a repeat electrocardiogram was found to be normal. The patient was questioned further and admitted to smoking 6 to 7 marijuana cigarettes a day and that she had intractable vomiting periodically during the past 8 years. Her nausea and vomiting had worsened with the patient subjectively stating 5/10 epigastric pain, and she noted taking habitual frequent hot showers that relieved her nausea. With this new history, the authors consulted the medicine service to assist in their medical management of this patient. According to their recommendations, she underwent multiple tests to identify a possible organic cause to explain this cyclic vomiting pattern. Esophagogastroduodenoscopy (EGD) and CT scanning with and without contrast of the head, abdomen, and pelvis were performed. All findings were unremarkable. With the assistance of their medical colleagues, through a process of exclusion, the authors came to a diagnosis of CHS. This was supported by her symptomatic improvement with hot water bathing and eventual recovery after cessation of marijuana. Once stabilized with supportive therapy, she underwent open reduction and internal fixation of her right
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mandibular symphysis fracture. Because frequent emesis is a contraindication to a closed reduction, this treatment allowed her to have immediate mobilization and function in case of another acute episode.
Discussion CHS was first documented during this past decade. The first article describing this syndrome was by Allen et al3 in 2004. They noticed a correlation with chronic cannabis use causing a paradoxical effect of intractable vomiting that was relieved with compulsory hot water bathing. With cessation of marijuana use, the patient’s symptoms resolved. Since then, other case studies and reports have been published supporting the syndrome. In 2012, Simonetto et al4 performed a case series of 98 patients, in which they expanded on the original findings for a diagnosis of CHS. From their findings, they broke down the criteria for diagnosis into 3 categories. These categories included essential, major, and supportive features (Table 1), which included the main features that Allen et al3 and others had discussed previously.1-10 The timeframe that was most commonly attributed to a diagnosis of chronic cannabis use was 1 to 5 years, with 32% of patients having less than 1 year of use.4 Ninety-one percent of patients reported that hot water baths alleviated the symptoms during the acute phase.4 No other vomiting syndrome shares this unique characteristic.4 Cannabis is traditionally associated with antiemetic effects in relation to acute ingestion. Any documented cases of hyperemesis related to tetrahydrocannabinol (THC) had traditionally been associated with acute toxicity in the face of Table 1. PROPOSED CLINICAL CRITERIA FOR CANNABINOID HYPEREMESIS SYNDROME
Essential for diagnosis Long-term cannabis use Major features Severe cyclic nausea and vomiting Resolution with cannabis cessation Relief of symptoms with hot showers or baths Abdominal pain, epigastric or periumbilical Weekly use of marijuana Supportive features Age 5 kg Morning predominance of symptoms Normal bowel habits Negative laboratory, radiographic, and endoscopic test results Beech et al. Cannabinoid Hyperemesis Syndrome. J Oral Maxillofac Surg 2015.
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intravenous injection of crude marijuana extract.11 However, since these initial studies, CHS is being more readily identified. CLINICAL PRESENTATION
Presentation of CHS occurs with cycles of symptomfree intervals. This syndrome has been broken down to 3 phases: pre-emetic or prodromal, hyperemetic, and recovery. The prodromal phase can last for months to even years, with patients enduring morning sickness, anxiety, and abdominal pain.12 In this stage, patients usually can maintain normal eating habits and will continue their marijuana usage because they believe it is helping alleviate their nausea. The hyperemetic phase can last as few as 48 hours if treated with appropriate therapy. It is characterized by paroxysms of intense and persistent cyclic vomiting, upward of 5 times an hour, sometimes without warning.12 Patients also can have weight loss, abdominal pain, and dehydration. It is within this phase that patients typically begin to take compulsory hot water showers or baths. Patients find this to be the only alleviating measure to control symptoms and this readily becomes a learned behavior.2 The recovery phase can extend from days to months and is associated with general patient wellness, weight gain, regular frequency of bathing, and return of normal eating patterns. DIFFERENTIAL DIAGNOSIS AND MEDICAL WORKUP
CHS is frequently confused with cyclic vomiting syndrome (CVS). CVS is a chronic functional condition of unknown etiology characterized by recurring attacks of intense nausea, vomiting, abdominal pain, headaches, and migraines. CVS typically develops during childhood, usually at 3 to 7 years of age; although it often remits during adolescence, it can persist into adulthood. Patients with CHS are frequently labeled as having CVS and vice versa; however, this is frequently in part from failure to recognize the patient’s chronic marijuana usage. Migraines are not commonly found in patients with CHS; furthermore, patients with CVS will commonly exhibit accelerated gastric emptying times in contrast to delayed emptying seen in CHS.13 Patients with CHS typically will go misdiagnosed for an extended period. In 1 study, patients were documented to undergo on average 7.1 to 11.4 emergency room visits and a delay in diagnosis upward of 9 years before proper identification of CHS.12 With such delays in diagnosis, timely identification of CHS can greatly decrease patient morbidity and associated costs of hospital visits. The initial approach to the hyperemetic patient should start with a thorough evaluation of the patient’s medical history and review of systems. It is pertinent to rule out potential pathologic
conditions of the gastrointestinal tract, peritoneal cavity, central nervous system, endocrine, and metabolic functions. Laboratory tests, including complete blood cell count with differential, basic metabolic panel, pancreatic and hepatic enzymes, pregnancy test, urinalysis, and urine toxicology screen, should be considered, among others.13 Imaging studies, including an abdominal flat panel film, possible abdominal CT scan, and other invasive testing such as upper endoscopy might be warranted to rule out other pathologic conditions.13 CHS is a diagnosis of exclusion, supported by patient symptomology and further supported by recovery after marijuana cessation. PHARMACOLOGIC CONSIDERATIONS
The specific etiology of CHS is unknown. However, it is believed to stem from an inherited reaction to cannabis after several years of exposure. It has been documented to resurface in heavy users within weeks of cannabis resumption, even after lengthy periods of abstinence.3 This toxicity occurs because cannabinoids have a long half-life. The true elimination halflife of THC is difficult to calculate, but many studies have estimated it to be 20 to 30 hours.2 THC is excreted mainly as acid metabolites, with 60 to 80% cleared through the feces and 20 to 35% excreted in the urine.2 THC accumulates within body fat, which serves as an extended storage site of the drug. This characteristic allows for a ‘‘re-intoxication effect’’ secondary to increased lipolysis during times of stress or food deprivation.2 Therefore, THC levels continue to stay elevated with chronic use, building on previous exposures and leading to toxic levels.7 There are 2 cannabinoid receptors that have been identified in human and animal models: CB1 and CB2. These receptors function as G-coupled protein receptors and act by inhibiting adenylate cyclase.7 CB1 cells can be found in the brain, spleen, heart, liver, uterus, bladder, and vas deferens. Much less is known about CB2 receptors. They are expressed primarily by immune cells, such as lamina propria plasma cells, and macrophages. CB2 receptors are thought to be involved in the inhibition of inflammation, visceral pain, and intestinal motility in the inflamed gut.2 There are many hypotheses to explain the contradictory effects of cannabis resulting in CHS. This paradox is believed to occur when cannabinoids that usually work through a mediator, THC, stimulate CB1 receptors, causing antiemetic effects, but lead to acute vomiting.14 One proposal suggests that chronic use leads to toxic levels affecting the CB1 receptors in the brain, thus leading to delayed gastric emptying and thermoregulatory and autonomic disequilibrium.7 Another proposal theorizes that chronic use leads to a
1910 disruption of the hypothalamic-pituitary-adrenal axis, leading to autonomic instability.4 CB1 receptors in the preoptic area have been reported to be involved in physiologic thermoregulation owing to cannabis use, which could explain the hot shower relief.4 Another hypothesis suggests that the toxic effects of THC might affect the CB1 receptors in the gastric mucosa, leading to a decrease in peristalsis, decreasing gastric emptying, and eventually leading to vomiting. Although the true pathophysiology is unknown, the known cure or prevention occurs with the cessation of cannabis use.1-10 TREATMENT
The treatment of CHS is mainly supportive in nature. Patients might require hospitalization during the hyperemetic phase for acute signs of abdominal pain, volume depletion, and severe nausea and vomiting. Aggressive resuscitation with intravenous fluids is required in the initial phases. Antiemetic agents might provide minimal relief from nausea and vomiting. Narcotics and opioids can be given for abdominal pain relief. However, patients report that their compulsory hot water bathing provides the greatest relief. The exact mechanism of how hot showers provide relief from symptoms is not understood, but it is hypothesized that it might correct the cannabis-induced disequilibrium of the thermoregulatory capacity of the hypothalamus.7 Once beyond the hyperemetic stage, relief of symptoms relies on cessation from marijuana intake. Relapse in chronic marijuana users remains high. Patient education and outpatient therapy can prove paramount in patient cessation success. CHS is a new and often misdiagnosed condition.15 The authors believe the present case displays the growing prevalence of CHS in this society and the difficulty in diagnosis. The present patient’s presentation was complicated by her medical history of myasthenia gravis. The more obvious cause for her intractable vomiting would have been her pyridostigmine medication. Even when that medication was withheld, her electrolyte imbalance and symptoms continued. Moreover, organic causes were ruled out with multiple CT scans and an EGD. It was only at her admission of extensive daily chronic cannabis use combined with a recurrent history of severe vomiting and abdominal
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pain relieved by hot showers that the authors could confidently arrive at the diagnosis of CHS. Cannabis use is becoming more accepted in contemporary society. Initially, it was made legal solely for its medicinal purposes. As of early 2015, 23 states allow the usage of marijuana medically, and the states of Alaska, Oregon, Washington, and Colorado have legalized its recreational use. As this trend continues, the dental field should be aware of the paradoxical presentation of chronic marijuana use and its implications toward treatment.
References 1. Sontineni SP, Chaudhary S, Sontineni V, et al: Cannabinoid hyperemesis syndrome: Clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse. World J Gastroenterol 15:1264, 2009 2. Gallli JA, Sawaya RA, Friedenberg FK: Cannabinoid hyperemesis syndrome. National Institutes of Health. Curr Drug Abuse Rev 4: 241, 2011 3. Allen JH, de Moore GM, Heddle R, et al: Cannabinoid hyperemesis; cyclical hyperemesis in association with chronic cannabis abuse. Gut 53:1566, 2004 4. Simonetto DA, Oxentenko AS, Herman ML, et al: Cannabinoid hyperemesis: A case series of 98 patients. Mayo Clin Proc 87: 114, 2012 5. Cox B, Chhabra A, Adler M, et al: Cannabinoid hyperemesis syndrome: Case report of a paradoxical reaction with heavy marijuana use. Case Rep Med 2012:757696, 2012 6. Wild K, Wilson H: Cannabinoid hyperemesis [published online ahead of print September 7, 2010]. BMJ Case Rep. http://dx. doi.org/10.1136/bcr.01.2010.2605 7. Price SL, Fisher C, Kumar R, et al: Cannabinoid hyperemesis syndrome as the underlying cause of intractable nausea and vomiting. J Am Osteopath Assoc 111:166, 2011 8. Donnino M, Cocchi M, Miller J, et al: Cannabinoid hyperemesis: A case series. J Emerg Med 40:e63, 2011 9. Ashton CH: Adverse effects of cannabis and cannabinoids. Br J Anaesth 83:637, 1999 10. Budney JA, Hughes JR: The cannabis withdrawal syndrome. Curr Opin Psychiatry 19:233, 2006 11. Vaziri ND, Thomas R, Sterling M, et al: Toxicity with intravenous injection of crude marijuana extract. Clin Toxicol 18:353, 1981 12. Soriano-Co M, Batke M, Cappell MS: The cannabis hyperemesis syndrome characterized by persistent nausea and vomiting, abdominal pain, and compulsive hot water bathing associated with chronic marijuana use: A report of eight cases in the U.S. Dig Dis Sci 55:3113, 2010 13. Quigley E, Hasler W, Parkman H: AGA technical review on nausea and vomiting. Gastroenterology 120:263, 2001 14. Chang YH, Windish DM: Cannabinoid hyperemesis relieved by compulsive bathing. Mayo Clin Proc 84:76, 2009 15. Schmid SM, Lapaire O, Huang DJ, et al: Cannabinoid hyperemesis syndrome: An underreported entity causing nausea and vomiting of pregnancy. Arch Gynecol Obstet 284: 1095, 2011