Post by: D. Evan Mulvihill
PGY2 Emergency Medicine Pharmacy Resident

Sharp Chula Vista Medical Center/Touro University California


Cannabinoid Hyperemesis Syndrome (CHS) is a sequela of long-term heavy cannabis use that involves cyclic bouts of nausea, vomiting, and diffuse abdominal pain. The treatment of CHS is unique in that your traditional anti-emetics and GI cocktails like Zofran, metoclopramide, and acid reducers, are fairly ineffective in controlling symptoms. CHS patients often receive extensive gastrointestinal (GI) work-ups in the ED, and may even be admitted when there are much simpler treatments to attempt first.

Case in point: the New York Times described one CHS patient named Thomas Hodorowski who received many unnecessary therapies and invasive procedures because CHS was not diagnosed early. They write: “[Hodorowski] had been to the emergency room dozens of times, tried anti-nausea drugs, anti-anxiety medications, and antidepressants, endured an upper endoscopy procedure and two colonoscopies, seen a psychiatrist and had his appendix and gallbladder removed.”

This blog post is intended to give you a quick and dirty introduction to CHS, and to implement strategies that will educate providers to cast a wider umbrella for diagnosis, so that effective pharmaceutical treatment is delivered in a timely fashion.

Introduction to CHS

Heavy use of cannabis for extended periods of time (usually on the scale of years) can lead to a cyclic vomiting syndrome known as CHS, which is characterized by nausea, vomiting, and diffuse abdominal pain.  Patients report that hot showers or baths relieve symptoms, and long bathing often becomes a compulsive behavior. Estimates on the prevalence of CHS are difficult to find, but a 2009 study at a Colorado found that the incidence of CHS doubled from 41 per 113,262 visits to 87 per 129,095 visits in the year after legalization of marijuana, although absolute numbers of ED visits were low.

CHS are frequent utilizers of ED care and often receive extensive GI/abdominal pain work-ups. Episodes typically last 24-48 hours but can last up to 7-10 days. The condition will resolve with cannabis cessation.

Pathophysiology

The exact pathological mechanism of CHS is poorly understood, but current literature implicates a receptor called TPRV1 (transient receptor potential vanilloid subtype 1) most heavily. Cannabis has classically been known to activate 2 types of receptors: CB1 and CB2. CB1 receptors are found in the central nervous system (CNS) and are responsible for the sensations of being “stoned” (euphoria, relaxation, sedation, those intractable munchies, possible anxiety/paranoia, etc.). CB2 receptors are located in the peripheral nervous system and immune system, especially the GI tract, and is responsible for the antiemetic effect endorsed by users. CB2 receptors were originally considered to be the most likely culprit for CHS, however, more evidence now points to TPRV1 based on successful treatment of CHS using TPRV1 agonists, including capsaicin and heat (hot showers/baths).

TPRV1 is expressed in the GI tract, CNS, and dermis. It is known to promote gastric mobility and has potent anti-emetic effects when activated, which may involve depletion of substance P (SP) in neural circuits. SP is known to activate neurokinin 1 (NK1) receptors and cause nausea, hence the anti-emetic effect of direct NK1 antagonists such as aprepitant. Other currently described agonists of TPRV1 include cannabinoids, capsaicin, nociceptive heat above 43 C, and acid.

Chronic cannabis use is thought to lead to decreased levels of TPRV1 in the body based on desensitization and downregulation. Lower levels of TPRV1 receptors may thus result in impaired ability to deplete SP, and effects such as emesis and altered gastric motility. It is unclear why the syndrome is cyclic rather than constant but may have to do with increased sensitivity to fluctuations in endogenous SP levels.

Management of CHS

There is only one published guideline on the management of CHS, which was created by the San Diego Emergency Medicine Oversight Committee. The expert panel stated that cannabis cessation is the only failproof treatment. The panel also recommended to avoid opioids for abdominal pain due to addiction potential and to avoid advanced imaging, radiation, and invasive procedures during work-up.

The supportive therapies endorsed by the panel included IV fluids for dehydration, traditional antiemetics (ondansetron, promethazine, metoclopramide), benzodiazepines (lorazepam, diazepam), diphenhydramine, antipsychotics (haloperidol, olanzapine), and lastly capsaicin cream. The panel does not privilege one treatment over the others but states that topical capsaicin is the first-line treatment in cases of a clear diagnosis. They recommend a dose of 0.075% strength cream applied topically 3 times daily to the abdomen or back of arms, although there is little evidence to privilege one strength over another. 

Capsaicin

Ashkan Khabazian, an EM pharmacist at Sharp Memorial Hospital in San Diego, CA, says that the concentration matters little compared to the total quantity used. “Physicians tend to order 0.1% for CHS, but the actual concentration is a moot point,” he wrote in an email to us. “More depends on the quantity used.” To that point, we recommend applying a small quarter-sized portion to the abdomen, and then add more if the drug produces a reduction in emetic symptoms and is well tolerated (i.e. no severe dermatological reaction).

Multiple case reports and case series have documented the success of capsaicin therapy, usually after the failure of other therapies. A patient described by Moon, Buckley, and Mark failed IV fluids, ondansetron,

metoclopramide, prochlorperazine, fentanyl, a GI cocktail, and pantoprazole. The patient’s nausea and abdominal pain was reported to be completely resolved after application of capsaicin 0.075% cream to a 15 x 25 cm area in the periumbilical region every 4 hours for 4 doses.

A case series published by Dezieck and colleagues found that capsaicin facilitated discharge for 13 patients who failed other therapies. They noted that there was no obvious difference in response between 7 patients who received 0.25% and 6 who received 0.075%.

Caption: Eight of 13 patients in the Dezieck study were given capsaicin as the last drug prior to discharge, usually only staying 1 to 4 hours afterward. Source: Dezieck 2016

Lastly, a report from Lapoint (the lead author on the San Diego Emergency Medicine Committee expert panel paper) showed that 5 patients saw rapid and significant decreases in abdominal pain scores after administration of capsaicin.

Haloperidol

The evidence for haloperidol use in CHS is also limited to case reports. The mechanism of action is unclear but may relate to D2 receptor antagonism in the chemoreceptor trigger zone.

In a case published by Hickey, a patient failed morphine, ondansetron, and normal saline bolus but haloperidol 5mg IV once resolved his symptoms. Witsil and Mycyk described 4 patients who failed standard therapy but improved with haloperidol. Jones and Abernathy described a patient who failed ondansetron, promethazine, prochlorperazine, metoclopramide, lorazepam, and omeprazole. However, the patient reported that a trial of haloperidol 5mg PO daily completed resolved her symptoms within 1 day of starting treatment, but was subsequently lost to follow-up.

A Canadian randomized clinical trial is in progress to compare 3 pharmacologic interventions for CHS: ondansetron 8mg IV, haloperidol 0.05 mg/kg IV, and haloperidol 0.1 mg/kg IV. Patients will serve as their own controls with a minimum 7-day washout period.

Conclusions and Clinical Pearls

This table is compiled from the existing evidence and my personal opinion on which therapies are most effective. The treatments are arranged from top to bottom in the order of what I would try first, and then move on if it failed.

DrugRecommended Starting DoseAdverse EffectsComments
CapsaicinAny strength cream topically TID-q4h prn (0.075% if stocked), test with a quarter-sized area first then apply to larger areaRedness, stinging at the administration siteLittle evidence to say any particular strength is more efficacious
Haloperidol5 mg PO or IV prnQTc prolongation, sedation, EPSCan trial haloperidol 5 mg po daily in an outpatient setting if capsaicin fails, or if there is concomitant psychiatric disease
Lorazepam1 mg PO or IV prnSedation, the addiction potential
Ondansetron4-8 mg PO or IVQTc prolongation
IV Fluids0.5-1 L NS IV x 1Fluid overload

I recommend against: placing an IV line unless it is necessary for other medical needs, giving IV or PO opioids, and invasive work-ups.

Future Research Questions 

A few questions have come up for me while studying CHS. First, why is the syndrome cyclic instead of constant? The cyclic nature of it may have something to do with increased TRPV1 receptor sensitivity to fluctuations in SP. But, if the syndrome is indeed caused by TRPV1 downregulation and subsequent SP excess, why isn’t there at least a mild undercurrent of constant nausea?

I also wonder about what risk factors are needed so that we can more accurately rule in and rule out CHS. Approximately how many years of heavy marijuana use are needed to put patients at risk for CHS? Can it happen with lighter use over a longer period of time? Will the effect be seen in edibles and new cannabis products like CBD?

Another question I have is if CHS can eventually become resistant to capsaicin or haloperidol. What other treatment options are there then besides hot showers and baths?