HCV New Drug Research

Nausea and vomiting, and abdominal pain associated with chronic marijuana use
The Digestive Diseases & Sciences investigate the cannabis hyperemesis syndrome characterized by persistent nausea and vomiting, abdominal pain, and compulsive bathing.

The cannabis hyperemesis syndrome, which is associated with chronic cannabis use, was recently reported in seven case reports and one clinical series of ten patients from Australia.

Dr Maria Soriano-Co and colleagues further characterized this syndrome with 8 well-documented cases in the United States and report results of cannabis discontinuation and cannabis rechallenge.

Patients were identified by the 3 investigators in gastroenterology clinic or inpatient wards at William Beaumont Hospital from 2009 based on chronic cannabis use, and recurrent vomiting, and compulsive bathing.

Charts were retrospectively analyzed with follow-up data obtained from subsequent physician visits and patient interviews.

7 patients took hot baths or showers
Digestive Diseases & Sciences

The 8 patients on average were 32 years old, and 5 were male.

The mean interval between the onset of cannabis use and development of recurrent vomiting was 19 years.

Patients had a mean of 7 emergency room visits, 5 were clinic visits, and 3 were admissions for this syndrome.

The team noted that all patients had visited at least one other hospital in addition to Beaumont Hospital.

The research team found that all patients had vomiting, compulsive bathing, and abdominal pain.

The team noted that 7 patients took hot baths or showers, and 7 patients experienced polydipsia.

The researchers observed that 4 out of 5 patients who discontinued cannabis use recovered from the syndrome, while the other 3 patients who continued cannabis use, despite recommendations for cessation, continued to have this syndrome.

Among those 4 who recovered, 1 patient had recurrence of vomiting and compulsive bathing with cannabis resumption.

Dr Soriano-Co's team, "Cannabis hyperemesis is characterized by otherwise unexplained recurrent nausea and vomiting, compulsive bathing, abdominal pain, and polydipsia associated with chronic cannabis use."

"This syndrome can occur in the United States as well as in Australia."

"Cannabis cessation may result in complete symptomatic recovery."

Dig Dis Sci 2010; 55(11):3113-9

17 November 2010

Original Article

The Cannabis Hyperemesis Syndrome Characterized by Persistent Nausea and Vomiting, Abdominal Pain, and Compulsive Bathing Associated with Chronic Marijuana Use: A Report of Eight Cases in the United States

Maria Soriano-Co, Mihaela Batke and Mitchell S. Cappell
Original Article

(1) Department of Medicine, William Beaumont Hospital, Royal Oak, MI, USA
(2) Division of Gastroenterology, William Beaumont Hospital, Royal Oak, MI, USA
(3) Division of Gastroenterology, William Beaumont Hospital, MOB 233, 3535 W. Thirteen Mile Road, Royal Oak, MI 48073, USA

Mitchell S. Cappell
Email: mscappell@yahoo.com

Received: 4 December 2009 Accepted: 11 January 2010 Published online: 4 February 2010

Abstract
Goals/Background

The cannabis hyperemesis syndrome, which is associated with chronic cannabis use, was recently reported in seven case reports and one clinical series of ten patients from Australia. We further characterize this syndrome with eight well-documented cases in the United States and report results of cannabis discontinuation and cannabis rechallenge.

Study Methods
Patients were identified by the three investigators in gastroenterology clinic or inpatient wards at William Beaumont Hospital from January to August 2009 based on chronic cannabis use; otherwise unexplained refractory, recurrent vomiting; and compulsive bathing. Charts were retrospectively analyzed with follow-up data obtained from subsequent physician visits and patient interviews.
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Results
The eight patients on average were 32.4 ± 4.1 years old. Five were male. The mean interval between the onset of cannabis use and development of recurrent vomiting was 19.0 ± 3.7 years. Patients had a mean of 7.1 ± 4.3 emergency room visits, 5.0 ± 2.7 clinic visits, and 3.1 ± 1.9 admissions for this syndrome. All patients had visited at least one other hospital in addition to Beaumont Hospital. All patients had vomiting (mean vomiting episodes every 3.0 ± 1.7 h), compulsive bathing (mean = 5.0 ± 2.0 baths or showers/day; mean total bathing time = 5.0 ± 5.1 h/day), and abdominal pain. Seven patients took hot baths or showers, and seven patients experienced polydipsia. Four out of five patients who discontinued cannabis use recovered from the syndrome, while the other three patients who continued cannabis use, despite recommendations for cessation, continued to have this syndrome. Among those four who recovered, one patient had recurrence of vomiting and compulsive bathing with cannabis resumption.

Conclusions
Cannabis hyperemesis is characterized by otherwise unexplained recurrent nausea and vomiting, compulsive bathing, abdominal pain, and polydipsia associated with chronic cannabis use. This syndrome can occur in the United States as well as in Australia. Cannabis cessation may result in complete symptomatic recovery.
Keywords Cannabis hyperemesis syndrome - Marijuana use - Nausea - Cyclic vomiting - Functional GI disorders

Abbreviations CB Cannabinoid receptor - CVS Cyclic vomiting syndrome

- BMI Body mass index - HPA Hypothalamic pituitary adrenal
- THC Tetrahydrocannabinol

Current knowledge:

Limited quantitative information on the newly described cannabis hyperemesis syndrome with only seven published case reports and one clinical series of ten patients from Australia; This syndrome is potentially clinically much more common than reported or realized due to the high prevalence of chronic marijuana use and dependence in the United States and other Western countries.

Report of eight cases of this syndrome occurring in the United States within a 9-month period at a single large hospital in the United States; Quantitative description of syndrome: All patients had vomiting (mean vomiting episodes every 3.0 ± 1.7 h), compulsive bathing (mean = 5.0 ± 2.0 baths or showers/day, mean total bathing time = 5.0 ± 5.1 h/day), and abdominal pain. Seven of the eight patients took hot baths or showers, and seven patients experienced polydipsia. Patients had a mean of 7.1 ± 4.3 ER visits, 5.0 ± 2.7 clinic visits, and 3.1 ± 1.9 admissions for this syndrome; Evidence is presented of a specific association of syndrome with cannabis use: cessation of syndromic symptoms in four of five patients who ceased cannabis use, and recurrence of syndrome in one patient who subsequently resumed cannabis use (drug rechallenge).

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Introduction

Cannabis hyperemesis is a recently described syndrome of hyperemesis and compulsive bathing associated with chronic cannabis use. This syndrome has been reported in seven case reports [1–6] and in one clinical series of ten patients from Australia [7]. However, there is only scant data about this syndrome in patients from the United States. The present study extends the clinicoepidemiologic description of this syndrome by comprehensive analysis of a series of eight patients from the United States. This syndrome could potentially be much more common than reported or recognized, and may therefore be important clinically because cannabis is so widely used: it is the most commonly used illicit drug in the United States and Europe with a prevalence of 4% of cannabis use in American adults [8] and a prevalence of cannabis dependence of .3%, as defined by DSM-IV [9].


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Methods
Eight adult patients (minimum age >21 years) were identified in the gastroenterology clinic and inpatient wards of William Beaumont Hospital at Royal Oak, Michigan from January through August 2009 that satisfied the diagnostic criteria for cannabis hyperemesis, which included: (1) chronic cannabis use for at least 1 year; (2) recurrent episodes of intractable nausea and vomiting in association with abdominal discomfort or pain; (3) absence of other demonstrable causes of nausea or vomiting and (4) presence of other stereotypical symptoms, of either compulsive bathing or polydipsia. Patients were identified among the three investigators’ own patients. This hospital with 1,065 licensed inpatient beds has the second largest number of annual hospital admissions in the United States. Data were extracted from the medical charts and supplemented by patient interviews by the investigators. This study was approved by the Human Investigation Committee/Institutional Review Board at William Beaumont Hospital.


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Results
The epidemiology, previous cannabis usage, medical history, symptoms, and medical evaluation of the individual study patients are reported in Table 1. The aggregate data on epidemiology, previous medical history, and symptoms of the eight study patients are summarized and compared to the data on previously reported cases in Table 2. The eight adults averaged 32.4 ± 4.1 years at diagnosis (range 26–38 years). Five patients were male. The age of onset of cannabis use averaged 13.4 ± 3.4 years (range 9–20 years). Average duration of cannabis use prior to onset of recurrent vomiting was 19.0 ± 3.7 years. Two patients had a cyclical presentation of nausea and vomiting, often occurring every 2–3 months.

Table 1 Clinical characteristics of eight study patients with the cannabis hyperemesis syndrome

Enlarge Table 1.

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n number * Reference [7] ** References [1–6]

All patients had a prodromal disorder characterized by abdominal discomfort and nausea, without vomiting, followed by an active phase, characterized by persistence of these prodromal symptoms and development of severe, persistent vomiting. The average frequency of vomiting or retching episodes was every 3.0 ± 1.7 h (range 0.2–6 h).

Vomiting was unrelated to meals. The vomitus was typically whitish and watery. Only one patient had an episode of bloody vomitus. All patients had abdominal pain or discomfort. Seven patients (87.5%) had increased thirst and polydipsia. The average BMI (body mass index) was 26.2 ± 1.4 kg/m2 (normal range 18.5–25). Six patients (75%) lost ≥5 kg of weight during the emetic phase.

All patients exhibited compulsive bathing.

Patients averaged 5.0 ± 2.0 baths or showers per day, with each bath or shower lasting 57.0 ± 30.9 min. The total duration of bathing averaged 5.0 ± 5.1 h per day! Seven (87.5%) of the patients took hot baths or showers, and the eighth patient took warm baths. All patients believed the baths provided comfort and decreased the sensation of nausea and the intensity of vomiting, but this relief ceased as soon as they stopped bathing.

All patients had visited or had been admitted to at least two hospitals. The mean number of emergency room visits was 7.1 ± 4.3 (range 5–15), hospital admissions was 3.1 ± 1.9 (range 2–6), and clinic visits was 5.0 ± 2.7 (range 2–10).

The vomiting was refractory to prescribed antiemetic medications of ondansetron or promethazine in 87.5%. The abdominal pain or other symptoms was not relieved in seven patients (87.5%) by prescribed proton pump inhibitors.

The patients had no other demonstrable etiology for the vomiting. Two patients had a prior history of pancreatitis or nephrolithiasis, but did not have these disorders when experiencing the hyperemesis. None had a history of pyelonephritis, cholelithiasis, diabetes mellitus, gastroparesis, migraines, or hyperemesis gravidarum.

Two patients (25%) had headaches. All patients were neurologically intact, without focal deficits. None of the patients exhibited delusions or hallucinations. One patient was receiving duloxetine hydrochloride for clinical depression and one patient was receiving olanzapine for a panic disorder. None of the patients had any other concurrent illnesses at the time of presentation.

Abnormal physical findings and laboratory tests in the study patients and in the previously reported cases are summarized in Table 3. Routine blood tests including the hemogram, serum electrolytes, lipase, and liver function tests were within normal limits in seven tested patients. All five patients tested for cannabinoids in the urine had positive results. Seven patients had one or more abdominal imaging studies, including abdominal flat plate in five, abdominal ultrasound in six, and abdominal CT in two; all these tests were within normal limits. Six patients underwent esophagogastroduodenoscopy (EGD). All six patients had only minimal-to-mild distal esophagitis or mild gastritis. One patient underwent a gastric emptying study that revealed borderline normal gastric emptying of solids and liquids.
Table 3 Abnormal physical findings and laboratory tests in patients with cannabis hyperemesis syndrome: currently reported patients versus previously reported patients

Enlarge :Table 3

EGD esophagogastroduodenoscopy; β HCG beta human chorionic gonadotropin; LFTs liver function tests
* Reference [7]
** References [1–6]

All patients were reluctant to accept that cannabis played a role in their symptoms. Five patients ceased cannabis use. Four of them experienced complete cessation of the syndrome, with elimination of the symptoms of hyperemesis and compulsive bathing. These four patients had an average weight gain of approximately 5 kg (mean = 3.3 ± 2.6 months of follow-up). One patient redeveloped the syndrome with resumption of cannabis use. Three patients refused to stop cannabis use, despite medical recommendations for abstention. They all had persistent symptoms of nausea, vomiting, and compulsive bathing.

Discussion
The main active ingredient of cannabis—whether in marijuana (the dried material of the hemp plant) or in hashish (the dried resin of the hemp flowers)—is delta-9-tetrahydrocannabinol (THC). THC and other cannabinoids are responsible for the psychoactive properties and adverse effects [6, 10]. Cannabis contains at least 66 cannabinoids, including cannabinidiol and tetrahydrocannabivarin, many of which may play a role in the symptoms [11, 12].
Recurrent vomiting due to chronic cannabis use is an emerging clinical syndrome that typically occurs in early middle-aged adults who have been using cannabis since their teenage years [4, 7, 13]. It may indeed be high in the differential diagnosis of recurrent vomiting in patients with chronic, long-standing cannabis use. The illness is classically divided into three phases: prodrome, recurrent vomiting, and recovery. Recognition of these phases helps diagnostically and therapeutically. The prodromal phase, which manifests with nausea, fear of vomiting, and abdominal discomfort, is variable in duration. Patients are still able to eat and retain food or oral medications at this stage.

The vomiting phase is characterized by intense, persistent nausea, vomiting, and retching that patients typically describe as overwhelming and incapacitating. Patients can vomit and retch up to five times per hour. The vomitus typically consists of whitish watery secretions because patients cannot tolerate solid food. Patients frequently have abdominal pain. Concomitant stereotypical behaviors include compulsive hot bathing and polydipsia. The currently reported patients, incredibly, averaged 5.0 baths or showers per day! Seven patients reported hot baths or showers, and the eighth patient took just a warm bath. Previously reported cases presented similarly. No patient exhibited delusions or hallucinations regarding bathing or other daily activities.

Patients typically visit hospitals and physicians multiple times during this phase. The currently reported patients averaged about 15 visits to the hospital, emergency room, or clinic, with at least one admission to two or more hospitals. Health-care costs associated with these numerous physician contacts were exorbitant. The symptoms were refractory to all administered antiemetic medications. Investigations—including routine blood tests, EGD, and radiologic abdominal imaging—were generally unremarkable. Among conditions that can cause emesis, the most frequently investigated and excluded were pancreatitis, cholecystitis, nephrolithiasis, pyelonephritis, and pregnancy in female patients [3, 5]. Comparison with the case series from Australia and the sporadic case reports in the United States showed a similar clinical presentation as currently reported (Tables 2, 3).

The recommended treatment is cannabis cessation, with supportive adjunctive therapy of fluid replacement and counseling. The recovery phase begins with acceptance of cannabis cessation. In contrast to previous studies, the currently reported patients required a mean of 1 week after cannabis cessation to experience a significant decrease (to less then 5 episodes) of vomiting per day. The single patient who resumed cannabis use had recurrence of the syndrome. This criterion (recurrence with rechallenge) is considered the strongest evidence that a drug or other agent causes the observed effect

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Cannabis is known to decrease nausea and vomiting from chemotherapy. The mechanism for the paradoxical cannabis hyperemesis is unknown. As a conjecture, subjects exhibiting this syndrome may have a genetic variation in their hepatic drug transforming enzymes that results in excessive levels of cannabis metabolites that promote emesis. Alternatively, the emesis after long-term exposure might be due to chronic accumulation of THC in the brain due to binding of this lipophilic compound to cerebral fat [1, 15], which might be toxic in sensitive patients.

THC binds to the cannabinoid receptors CB-1 and CB-2 [16, 17]. CB-1 receptors exert a neuromodulatory role in the central nervous system and enteric plexus, manifested by gastric mucosal cytoprotection, decreased gastrointestinal motility, and decreased intestinal secretion [18–20], while CB-2 receptors have an immunomodulatory effect [21, 22]. Nausea and vomiting are influenced by the balance between the enteric and central nervous system effects. The enteric pro-emetic effects of cannabis, such as decreased gastrointestinal motility, may override its central nervous system-mediated antiemetic effects, to promote emesis [23].
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Patients generally consider hot baths as a comforting maneuver to decrease the intensity of the nausea and vomiting. This effect might arise from modulation of the hypothalamic-pituitary-adrenal (HPA) axis by endocannabinoids. Cannabinoid receptor type 1 is present in brain areas that regulate HPA axis function and cannabis may modulate the thermoregulatory system of the hypothalamus and may be associated with voluntary initiation of hot baths [2, 24].

Endocannabinoids are, moreover, involved in the regulation of anxiety-related behaviors, which represent part of the physiological responses to stressful stimuli [25, 26]. Endocannabinoids may also stimulate thirst. Hot baths can also produce relaxation in response to stress. We cannot, therefore, completely exclude that the observed frequent bathing and polydipsia are nonspecific neurotic or compulsive responses to anxiety or psychological stress induced by the symptom of severe nausea and vomiting.

Episodic vomiting associated with cannabis has been related to the cyclical vomiting syndrome (CVS), which was first described in the English literature in 1882 by McGee, who reported on nine children ranging in age from 4 to 8 years old [27, 28]. CVS has also been reported in adults with an onset ranging from childhood to middle age. It has four phases—inter-epidosic, prodrome, emetic, and recovery phases—similar to the phases of cannabis hyperemesis, and it is characterized by recurrent episodes of incapacitating nausea, vomiting, and other symptoms, separated by relatively asymptomatic intervals of comparative wellness. It is believed to be primarily a disorder of function that arises in the central nervous system and not the digestive tract [29, 30]. CVS may be a manifestation of a migraine diathesis [31].

Patients with cannabis hyperemesis, however, do not generally complain of headaches and do not respond to medications that usually abort migraine episodes. While investigated as a subset of CVS, cannabis hyperemesis is unlikely to be a form of migraine-associated CVS. Further studies are warranted to investigate a possible link between cannabis hyperemesis and CVS.

Study limitations include the relatively small number of reported cases, the retrospective nature of the series, and the lack of a control group. The small sample size limits the quantitative description of this syndrome. Study strengths include that this is the largest series from the United States of a recently described syndrome, and the comprehensive, quantitative patient description due to our involvement in all the patients’ care.

Conclusions
A newly recognized syndrome related to chronic cannabis use has been identified in Australia and the United States manifesting with recurrent nausea and vomiting, compulsive bathing, abdominal pain, and polydipsia. Eight well-characterized cases are currently reported. A strong association between the syndrome and cannabis use is suggested by the current report of syndrome cessation in four of five patients who discontinued cannabis administration, and by the current report of syndrome recurrence in one patient with cannabis rechallenge. This syndrome may be underdiagnosed because of failure to question patients with cyclic vomiting or refractory nausea and vomiting about marijuana use or compulsive bathing.

This syndrome may potentially be moderately common—as indicated by our diagnosis of eight cases during 8 months at one large hospital—due to the prevalence of marijuana use in the general population. All patients with cyclic vomiting or persistent vomiting of undetermined etiology should therefore be questioned about marijuana use and compulsive bathing to exclude the cannabis hyperemesis syndrome. Syndrome recognition should lead to cannabis cessation, which may result in symptomatic recovery.

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