Cannabinoid Hyperemesis Syndrome

Etiology

The physiology of vomiting is related to multiple organ systems. When noxious stimuli are perceived (which may be anything, including a fearful sight, a foul odor, or even a distressing memory), the area postrema of the brain is activated, leading to vagal stimulation. The resultant neuro-endocrine mediated processes result in salivation, closure of the glottis to protect the person’s airway from aspiration, relaxation of the stomach’s sphincters, retroperistalsis of small intestinal contents to the stomach, and finally contraction of stomach and abdominal muscles to propel vomitus to the mouth and into the environment. The gastrointestinal tract itself has several receptors, including cannabinoids, histamine, and other chemical agents, which can serve to directly influence the process of vomiting when stimulated directly, in addition to stimulation from the nervous system.[2]

Cannabis has activity at a variety of receptors along the multiple neurologic and endocrinologic pathways, which informs its unique ability to be both a pro- and anti-emetic. For example, cannabinoid receptor (CB) 1 and 2 receptors in the brain are present in the hypothalamus, hippocampus, cerebellum, and scattered throughout the parasympathetic nervous system (including the vagus nerve, with all of its influence on the hypothalamus-pituitary-adrenal gland axis), leading to cannabis having a potent effect on a large swath of bodily processes.[1]

Epidemiology

Cannabis hyperemesis syndrome can be challenging to diagnose for a variety of factors. One matter is, by virtue of its name and potential etiology, certain patients may be hesitant to offer historical clues (e.g., illicit drug use) to clinicians, which may complicate the clinician’s ability to rule in or rule out specific diagnoses. Another barrier to diagnosis includes the close resemblance of CHS to other pathologies, such as cyclical vomiting syndrome (CVS), also known as abdominal migraine due to such patients often having concurrent migraine-like symptoms, besides the fact that occasionally cannabis is used to treat CVS.[4]

By nature of history, a necessary aspect in the diagnosis of cannabis hyperemesis syndrome is the use of cannabis, which happens to be the most used regulated substance in the world. Between 3 and 5% of the world's population has used cannabis at least once, with the majority of usages having been for non-prescribed purposes. Age is a significant correlation of cannabis smoking, and different countries vary in terms of age of the earliest use of cannabis. Approximately fifty percent of people in the United States have their first use of marijuana around the age of 20 years old. In the United States, there is male to female parity during adolescent years for the age of first marijuana usage. The ethnicity of cannabis users has changed from the 20th into the 21st century, with peoples identified as Hispanics representing a majority of cannabis users while in the modern era, non-Hispanic Whites make up the majority.[5]

Pathophysiology

Due to the prevalence of receptors through which cannabis can act along the neurological and gastrointestinal organ systems to mediate vomiting, it seems paradoxical that a drug used as an antiemetic for a variety of conditions, including multiple sclerosis, chemotherapy-induced vomiting, and even cyclic vomiting syndrome could cause such distressing episodes of vomiting. The present hypothesis is that CHS may result from chronic overstimulation of endocannabinoid receptors, leading to derangements in the body’s intrinsic control of nausea and vomiting.[2] Another receptor system recently elucidated, transient receptor potential vanilloid-1 (TRPV1) nociceptor system in the peripheral nervous system, is also influenced by cannabinoids. 

Probably, a crucial factor in the genesis of CHS is the composition of cannabis. Since the 1990s, there has been a progressive change in the composition of the plant, with increases in the tetrahydrocannabinol (THC) and a reduction of cannabidiol (CBD).[6] This trend correlates with increased cannabis use. Some individuals, for instance, also admitted to smoking 2000 mg of THC per day.

History and Physical

With the recognition of potential etiologies come diagnostic criteria for CHS.[7] Multiple checklists have been proposed, including the latest known as the Rome IV criteria: 

1. Criteria fulfilled for at minimum three months, with symptomatic onset occurring at least six months before diagnosis
2. Stereotypical episodic vomiting resembling cyclical vomiting syndrome in onset, duration, and frequency
3. Presentation after prolonged, excessive cannabis use
4. Relief of vomiting by a sustained cessation of cannabis use
5. May be associated with “pathologic” bathing behavior, e.g., prolonged hot baths and showers. 

While diagnostic criteria can be helpful to tease out similar appearing disease processes, the Rome IV criteria suffer from a lack of data granularity, especially in terms of the specifics regarding number of vomiting episodes, amount of cannabis use, number of pathologic bathing episodes per day for however much time, period of time of sustained cessation of cannabis.[4]

An intriguing point to keep in mind is that the Rome IV criteria include the phrase "resembling cyclical vomiting syndrome." In that regard, it is important to distinguish between the two. Per the Nelson Textbook of Pediatrics, cyclic vomiting syndrome is defined by having sudden onset episodes of vomiting, having at least four bouts of vomiting per hour, and often having 12 to 15 episodes of vomiting per day. These episodes of vomiting are often separated by weeks or months, and there is a return to baseline between episodes. Importantly, for the definition of cyclic vomiting syndrome, these episodes of vomiting cannot be attributed to other disorders. This factor is a key distinguishing feature from cannabis hyperemesis syndrome, where the toxicokinetics of cannabis itself influence the course of the disease. 

Regardless, specific recommended historical points to keep in mind include demographics and associated risk factors (age, gender, medical and surgical history), the onset, frequency, and progression of the patient’s vomiting, as well as any associated symptoms (notably headaches), the use of hot showers or baths, the duration of vomiting-free intervals, medication as well as illicit drug use, prior treatments and efficacies, periods of abstinence from various medications and illicit drugs, ability to follow up with a primary care provider, and any comorbidities, especially anxiety, depression, panic disorder, and migraine headaches.[4] Appropriate history and a detailed physical exam can avoid a costly workup, inappropriate referrals to specialists, and, with recognition of this syndrome, a proper disposition, and recommendation for these patients.[3]

Evaluation

Leaving aside risk factors dependent on the basis of age (e.g., cardiac markers for atypical presentations of coronary syndromes in the elderly, vasculopathy, or neuropathology in patients with diabetes), an appropriate workup in the emergency department includes a metabolic panel to assess for electrolyte derangements as well as degree of dehydration in the form of a prerenal azotemia.[8] Furthermore, a complete blood count (which, paired with an appropriate history, including travel history, which can assess for infectious etiologies), and a urinalysis to determine the presence of a urinary tract infection as well as ketones as a marker for metabolism and nutrition status, are required. An electrocardiogram may be useful to assess the patient’s QTc interval, especially in the context of antipsychotic medication use, as well as before the administration of certain antiemetics, which may prolong the QTc interval to extreme lengths. In women, a pregnancy test is necessary to assess for any pregnancies, especially ectopic pregnancies. Imaging is up to the discretion of the clinician, depending on various specific factors of history or physical exam, which may be concerning for surgical processes. 

Treatment / Management

A key difficulty in treating CHS is its classic resistance to mainstay antiemetic therapy in both the emergency and primary care setting such as ondansetron and metoclopramide.[1] In the last several years, case studies and reviews have come out recommending a variety of medical therapies, such as benzodiazepines in the short term, tricyclic antidepressants for long term control, and even antiepileptics such as levetiracetam and antipsychotics such as haloperidol, though these recommendations come from small case studies.[9][10][11]. The emergency medicine and toxicology literature have explored dopamine (D2 and D3) and serotonin (5HT) antagonists.[10][2] D2 and D3 antagonism in the medulla is believed to target emesis provocation from the area postremia and is the mechanism of action for metoclopramide, prochlorperazine, promethazine, and haloperidol, with various levels of efficacy.(A1)

Serotonin antagonism in the gastrointestinal tract from medications such as ondansetron, dolasetron, and granisetron likewise have varying levels of efficacy. Tricyclic antidepressants also antagonist serotonin receptors and may limit nausea due to this mechanism, though their extensive side effect profile such as transaminitis and predisposition to various dysrhythmias via QTc prolongation and QRS widening make appropriate dosing of these medications a priority. Drugs with an anticholinergic effect may likewise block medullary mediated vomiting, though they may have minimal impact on visceral stimulation, including the crippling abdominal cramping pain that patients with CHS experience. Opioids, while often prescribed for the patient’s debilitating abdominal pain, are not appropriate for CHS, as they may, in fact, worsen nausea and vomiting. 

The historical feature of CHS patients having their symptoms partially or even fully relieved through hot baths or showers raises the consideration of heat therapy for relief. A 2014 anonymous internet survey sought to obtain information regarding hot shower usage amongst nearly five hundred marijuana users, who were predominantly Caucasian women from the United States of America with a mean age of 34 years and all recruited from a cyclical vomiting referral center in the United States at the Medical College of Wisconsin. This population had a high proportion of comorbid conditions, including anxiety, depression, migraine, and bipolar disorder. Sixty-seven percent of respondents noted that hot showers relieved their symptoms, though whether symptoms were merely ameliorated or fully resolved is unknown. Of note, this survey took place before the widespread legalization of cannabis, and a fear of litigation may have influenced respondent answers.[12](B2)

Capsaicin has been put forward as a potential analgesic with many hypotheses regarding its mechanism of action.[1][10][2] The aforementioned transient receptor potential vanilloid-1 nociceptor system becomes activated by both acidic pH and high temperatures, which use sodium and calcium channels to regulate the release of substance P, a mediator involved in the perception of pain, and hence may undergo modulation through the use of topical capsaicin as well as exposure to hot water.(A1)

As of 2018, twenty published cases of CHS demonstrated significant relief of both pain and vomiting with capsaicin cream, though, due to various difficulties including the nascent age of this diagnosis, differing diagnostic criteria, and the lack of recruitment for large case series and randomized control trials, have not fully legitimized capsaicin use as definitive therapy for CHS.[13] However, its easy acquisition and application, besides lack of notable adverse reactions excepting a localized sensation of warmth, stinging, and itching, make it a useful adjunct to nausea and pain control in the patient suspected to have CHS.

Differential Diagnosis

Before anchoring on the diagnosis of CHS, it is important to rule in or rule out other important diseases against the patient’s age and other risk factors, many of which may require urgent surgical and medical management. Certainly, when discussing abdominal pain associated with nausea and vomiting, gastrointestinal pathologies often leap to the forefront of one’s mind, including:

• Gastritis
• Gastrointestinal reflux disease (GERD)
• Peptic ulcer disease (PUD)
• Appendicitis
• Diverticulitis
• Sigmoid volvulus
• Biliary colic
• Pancreatitis
• Nephrolithiasis
• Urinary tract infection

In female patients of reproductive age additional diagnoses in the differential include:

• Ectopic pregnancy
• Ovarian torsion

In older patients, especially those with hypertension, cardiovascular illnesses such as aortic pathology and atypical coronary artery syndromes may present as vague abdominal pain, nausea, and vomiting.

A variety of toxidromes and infectious etiologies, as well as non-penetrating traumatic injuries, will have this presentation. Neurologic syndromes such as strokes to the area postrema may result in nausea and vomiting, compounded by abdominal pain from forceful vomiting, which a patient may report as abdominal cramping. Psychiatric causes, likewise, may cause vomiting syndromes, as well as a variety of self, reported aggravating and relieving factors which the astute clinician must dissect.[14]

Pertinent Studies and Ongoing Trials

A study examining nearly ninety veterans in a Veterans Affairs medical center reviewed the role of physical activity as a part of a self-guided cannabis cessation program, demonstrating that among primarily male veterans with a mean age of nearly 51 years old, after being matched for age, medical and psychiatric conditions, and psychiatric assessment for stated desire to halt cannabis use, participants that performed lower levels of physical activity, measured in metabolic equivalents (METS) had more significant risks for relapsing to cannabis in the first four days after cessation, a particularly important period for acute withdrawal.[15]

The ACCENT trial (Achieving Cannabis Cessation: Evaluating N-Acetylcysteine Treatment), which began enrollment in 2014 and is now in Phase 3 under the purview of UCLA, which examined the use of N-Acetylcysteine as a potential tool for cannabis cessation in adult participants. Its material is presently undergoing review and is unpublished at this time. 

Prognosis

The prognosis is generally good as long as the diagnosis is made early and the patient commits to cannabinoid cessation. The morbidity associated with this disease is related to poor control of symptoms due to ongoing cannabinoid use and frequent hospitalizations. 

Complications

There are several potential complications of CHS. Indeed, with any syndrome that results in frequent vomiting, there is a concern for a disorder of electrolytes and fluid balance in the body. Patients who fail to respond to antiemetic therapy are at high risk for dehydration and resulting in nutritional deficiencies. Other known complications of forceful and uncontrolled vomiting include aspiration and subsequent pneumonitis or aspiration pneumonia as well as injury to the esophageal wall such as Boerhaave's syndrome.