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Cannabinoid hyperemesis syndrome: Marijuana is both antiemetic and proemetic

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ABSTRACT

Although marijuana is sometimes used to treat chemotherapy-induced nausea and vomiting, when used long-term it can have a paradoxical hyperemetic effect known as cannabinoid hyperemesis syndrome. Knowledge of this phenomenon may reduce the ordering of unnecessary and expensive investigations, as well as inappropriate medical and surgical treatment in patients presenting with recurrent vomiting of unknown cause. This article reviews the pathophysiology, clinical presentation, diagnosis, and management of this emerging condition.

KEY POINTS

  • The prodromal phase is characterized by severe anxiety and agitation. Patients display a spectrum of autonomic symptoms such as sweating, flushing, constantly sipping water due to thirst, and colicky abdominal pain.
  • In the second phase, patients develop incapacitating nausea and vomiting that may occur without warning and is usually resistant to conventional antiemetics such as ondansetron and promethazine. During this phase, patients learn the immediate relieving effects of taking hot baths.
  • After 24 to 48 hours of conservative management, intravenous fluid replacement, and, most importantly, cessation of cannabis use, patients experience marked resolution of symptoms. The compulsive hot-bathing behavior subsides. However, eventually, patients go back to using marijuana, and the cycle of symptoms recurs.


 

References

With the growing use of marijuana, reports have appeared of a newly recognized condition in long-term heavy users termed cannabinoid hyperemesis syndrome.1

This syndrome is interesting for at least two reasons. First, paradoxically, marijuana appears to have an emetic effect with chronic use, whereas it usually has the opposite effect and is used as an antiemetic in patients undergoing chemotherapy. Second, patients develop a compulsion to bathe or shower in extremely hot water to relieve the symptoms.

In this article, we review the pathophysiology, clinical presentation, diagnosis, and management of this emerging condition.

MARIJUANA USE ON THE RISE

Marijuana is the most widely used illicit drug worldwide. Although statistics on its use vary, a report from the Pew Research Center2 stated that 49% of Americans say they have tried it. Several states now allow the use of marijuana for medicinal purposes, and Colorado and Washington have legalized it for recreational use. This marks a major turning point and may accelerate the slow-growing acceptance of marijuana use in the United States.

Marijuana has been used to treat HIV-associated anorexia and wasting, convulsions, glaucoma, headache, and chemotherapy-induced nausea and vomiting.3–5

Cannabinoid hyperemesis syndrome was first described in 2004 in South Australia.1 Since its recognition, an increasing number of cases have been identified worldwide. However, there are still no population-based studies to estimate its exact prevalence.

THC PREVENTS VOMITING—AND CAUSES IT

Delta-9-tetrahydrocannabinol (THC) is the principal psychoactive component in marijuana.6,7 There are two types of cannabinoid receptors in humans: CB1 and CB2. Both are found in the central nervous system and autonomic nervous system. Activation of CB1 receptors is responsible for the psychoactive effects of cannabinoids such as altered consciousness, euphoria, relaxation, perceptual disturbances, intensified sensory experiences, cognitive impairment, and increased reaction time. The physiologic role of CB2 is not known.

THC as an antiemetic

The antiemetic property of THC is not well understood but has been linked to activation of CB1 receptors found on the enteric plexus, presynaptic parasympathetic system, and central nervous system, particularly the cerebellum, hypothalamus, and vomiting center in the medulla.1,8–12 Stimulation and blockade of CB1 receptors can inhibit and induce vomiting in a dose-dependent manner, implicating endogenous cannabinoids in emetic circuits.12

THC as a proemetic

The mechanism of the paradoxical hyperemetic effect of THC is unknown, but several concepts have been proposed.

Chronic cannabis use can lead to down-regulation of CB1 receptors.13 Simonetto et al10 suggested that the central effects of long-term cannabis use on the hypothalamic-pituitary-adrenal axis may play a central role in the development of hyperemesis.10

Cannabinoids have a long half-life and are lipophilic.1 When used infrequently, they prevent vomiting. But with chronic use, high concentrations of THC can accumulate in the body, including cerebral fat, and can cause severe nausea and vomiting.8,9 This paradoxic hyperemesis was observed in people using intravenous crude marijuana extract.7 The same response was also noted in ferrets injected with 2-arachidonoylglycerol, a potent cannabinoid agonist.11

Patients who experience hyperemesis from chronic cannabis use may also have a genetic variation in their hepatic drug-transforming enzymes that results in excessive levels of cannabis metabolites that promote emesis.1,14

Delayed gastric emptying has also been linked to the proemetic effect of THC. However, this association became controversial when a large case series study showed that only 30% of patients with cannabinoid hyperemesis syndrome had delayed emptying on gastric scintigraphy.10

It is also possible that excessive stimulation of cannabinoid receptors in the gut can cause diffuse splanchnic vasodilation and contribute to the abdominal pain.13

DIAGNOSING CANNABINOID HYPEREMESIS SYNDROME

Cannabinoid hyperemesis syndrome is a clinical diagnosis typically seen in young patients (under age 50) with a long history of marijuana use. They present with severe, cyclic nausea and vomiting and admit to compulsively taking extremely hot showers or baths. Most patients report using marijuana for more than a year before developing episodes of severe vomiting. However, one study found that as many as 32% of patients had used it less than 1 year before experiencing symptoms.10

Other associated nonspecific symptoms are diaphoresis, bloating, abdominal discomfort, flushing, and weight loss. Symptoms are relieved with long, hot showers or baths and cessation of marijuana use. Taking a complete history is key to making the diagnosis.

In 2004, Allen et al1 first defined cannabinoid hyperemesis as excessive marijuana use associated with cyclical vomiting and abdominal pain.1 In 2012, Simonetto et al10 proposed diagnostic criteria (Table 1). Although not yet validated, these criteria are based on the largest series of cases of cannabinoid hyperemesis syndrome to date (98 patients).10

THE THREE PHASES OF CANNABINOID HYPEREMESIS

The clinical presentation of cannabinoid hyperemesis syndrome can be divided into three phases: prodromal, vomiting, and resolution.

Prodromal phase

During this phase, patients often appear anxious and agitated and display a spectrum of autonomic symptoms such as sweating, flushing, and constantly sipping water due to thirst. They may sometimes have abdominal pain that is usually epigastric but may also be diffuse. Their symptoms are associated with severe nausea, usually early in the morning or when they see or smell food. Appetite and eating patterns remain normal. Compulsive hot bathing or showering is minimal at this phase.

Vomiting phase

In this next phase, patients experience incapacitating nausea and vomiting that may occur without warning and are resistant to conventional antiemetics such as ondansetron and promethazine.14 However, patients eventually learn that hot baths or showers relieve the symptoms, and this behavior eventually becomes a compulsion. The higher the temperature of the water, the better the effect on symptoms.1 Low-grade pyrexia, excessive thirst, orthostasis, abdominal tenderness, weight loss, and sometimes even superficial skin burns have been reported.1,9,15–18

Recovery phase

During the final phase of cannabinoid hyperemesis syndrome, most patients experience marked resolution of symptoms after 24 to 48 hours of conservative management (bowel rest until symptoms resolve, slowly advancing diet as tolerated, intravenous fluids, and electrolyte monitoring and repletion as necessary), and most importantly, cessation of cannabis use. However, the time from cessation of marijuana use to resolution of symptoms may be as long as 1 week to 1 month.1,10,14 Patients begin to resume their normal diet and daily activities. The bathing-showering compulsion subsides, and patients regain lost weight after 3 to 6 months.1

In all case series and reports, resumption of cannabis use causes the symptoms to recur. This recurrence is compelling evidence that cannabis is the cause of the hyperemesis and should be part of the essential criteria for the diagnosis of cannabinoid hyperemesis syndrome.

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