Steph’s Note: You’re working on the general medicine floor, and you overhear the nurses talking about the patient in Room 101A. “The guy just won’t get out the shower! He’s steaming it up practically ALL day. What on earth is going on?!” Guess what, it may not just be a case of someone wanting to relive their vacation in Mexico. Those frequent hot showers may actually be a huge clue for cannabinoid hyperemesis syndrome, which is the topic of today’s post.

Josef Nissan, our resident critical care writer extraordinaire of previous tl;dr posting fame (most recently on pre-eclampsia), is here to shed light on this increasingly common syndrome so that you are able to recognize, understand, and treat your patients appropriately. Take it away, Joe!

Would you believe me if I told you that cannabis (AKA marijuana) is the most used psychoactive substance worldwide. That’s right, worldwide.

In fact, the Centers for Disease Control and Prevention reported that an estimated 48.2 million people used cannabis in 2019. And the crazy part is that use of cannabis will only continue to increase. As of April 2024, 38 states have legalized medical marijuana, and 24 states have legalized recreational marijuana. Check out the map distribution of legality below:

Naturally, as cannabis use continues to increase, so will the prevalence of cannabinoid hyperemesis syndrome (CHS). As a matter of fact, the prevalence of treatment for CHS in the ED doubled between 2017 and 2021 in North America, with the highest treatment prevalence among the 16-34 year olds.

So, what exactly is cannabinoid hyperemesis syndrome (CHS)? Keep on reading, and I’ll tell ya all about it :).

Cannabis vs. THC vs. Cannabidiol (CBD) vs. Marijuana

Seriously, what the heck is the difference between all these substances? Are they the same thing? Is that one hippie surf shop with the sign that says, “We Sell CBD” practically selling marijuana? Wait, don’t some dogs get CBD oil? Is that the same thing as THC?

Yeah, it’s pretty confusing lol. Now by no means am I a cannabis expert. But I can give you the scientific differences between these products.

For starters, cannabis (marijuana) is a plant (scientific name is Cannabis sativa) that has more than 400 chemicals. The most important constituents include tetrahydrocannabinol (THC) and cannabidiol (CBD). Of these, THC is the psychoactive ingredient, while CBD does NOT have psychoactive properties.

Slight, but crucial, chemical structure difference. (Image)

THC comes in three common forms: herbs or flowers, hash/hashish, and hash oil. CBD comes in many forms, including oils, extracts, patches, vapes, and topical lotions. Despite having different pharmacological effects, both CBD and THC share a similar chemical structure. Are you ready for me to geek out?

Well, both substances contain 21 carbon atoms, 30 hydrogen atoms, and 2 oxygen atoms. However, a slight difference in how the atoms are arranged accounts for the difference between CBD and THC. Pretty neat right?

What is Cannabinoid Hyperemesis Syndrome (CHS)?

As with any substance, there are a handful of adverse effects associated with chronic cannabis use. One of the most prevalent adverse effects is cannabinoid hyperemesis syndrome. As the name clearly suggests, CHS is a subtype of cyclical vomiting syndrome that is associated with chronic (typically years) and heavy (typically daily or near-daily) cannabis use. It is observed predominantly in males.

Of note, CHS is primarily associated with THC, the main psychoactive compound of cannabis, and rarely with cannabidiol, which has no abuse potential. So can your patient develop CHS if they take CBD? Most likely not.

Symptoms of CHS typically come on several years after the start of chronic marijuana use. Common symptoms include the following:

persistent nausea,
repeated vomiting and retching,
intense abdominal pain and discomfort, and
loss of appetite.

Specifically, symptoms of CHS and their severity depend on the phase of the syndrome. Take a look at this figure below for a better explanation:

The biggest risk factor for developing CHS is long-term marijuana use (typically 10 to 12 years). In addition, it is more common in men and in those who’ve been using cannabis since their adolescent years.

CHS is a diagnosis of exclusion. This means there is no real confirmatory testing. However, the Rome IV Criteria is commonly used as a diagnostic tool for cyclic vomiting syndrome in adults. A patient meets the Rome IV Criteria if ALL of the following are present for the last three months with symptom onset at least six months prior to diagnosis:

Presentation after prolonged use of cannabis
Relief of vomiting episodes by sustained cessation of cannabis use
Stereotypical episodes of vomiting regarding onset (acute) and duration (<1 week)
At least 3 discrete episodes in the previous year and 2 episodes in the past 6 months, occurring at least 1 week apart
Supportive criteria: personal or family history of migraine headaches

Pathophysiology of Cannabinoid Hyperemesis Syndrome (CHS)

Ok, now this can be really confusing. Aren’t cannabinoids such as dronabinol and nabilone anti-emetics? So aren’t they supposed to induce the opposite of nausea/vomiting? Wait, aren't these agents also approved by the FDA for the treatment of chemotherapy-associated nausea and vomiting?

Yes, yes, and yes.

So how the heck does an anti-emetic lead to hyperemesis?! Confusing, right?

Alright, let’s start with the basics. Both endogenous and exogenous cannabinoids bind to Cannabinoid 1 (CB1) and TRPV1 receptors. CB1 receptors are primarily found in the brain, while TRPV1 receptors are mostly found in the nociceptive neurons of the peripheral nervous system. Stimulation of CB1 receptors inhibits the hypothalamic-pituitary-adrenal (HPA) axis and sympathomimetic nervous system. In addition, agonism of CB1 receptors leads to the non-competitive inhibition of emetogenic serotonin receptors, resulting in the inhibition of gastric function and proemetic dopamine activity.

Voila, the end result is an anti-emetic effect.

Anyone else received this look because of too much of a good thing? (Image)

However, as I’ve stated many times already, CHS generally occurs in those with chronic (typically years) and heavy (near-daily) cannabis use. As you may suspect at this point, chronic cannabis use can lead to the downregulation, desensitization, and internalization of the CB1 and TRPV1 receptors. Downregulation of these receptors diminishes the endogenous anti-emetic mechanisms, leading to abdominal pain, nausea, and emesis.

Make sense? This is the perfect example that too much of a good thing can be bad.

Acute Management of Cannabinoid Hyperemesis Syndrome (CHS)

On to the pharmacy phun part ;).

As with all patients presenting with moderate/severe episodes of emesis, our number one goal is to make sure we maintain hydration. Cyclic vomiting can lead to large volume losses and electrolyte imbalances. And the most crucial step in acute management of CHS is the treatment/prevention of hypovolemia.

Therefore, the first step in CHS treatment should always be IV fluids, preferably a crystalloid fluid such as normal saline or lactated ringers. In terms of volume replenishment, it is patient specific. Someone with more clear signs of dehydration may need more volume than someone who presents with mild emesis. A good starting point is generally 1 liter of crystalloid fluid, followed by reassessment.

After replenishing fluid/electrolytes, the next step in the acute management of CHS is to treat ongoing emesis. There are quite a few antiemetics to choose from. However, in CHS, the common antiemetics such as ondansetron, promethazine, chlorpromazine, and metoclopramide are generally ineffective. In fact, a small case series found that 87.5% of patients with CHS did NOT respond to standard antiemetic therapy.

So what else can we give?

Haloperidol or droperidol! Why do we use these two first-generation antipsychotics? Primarily for their significant dopamine antagonism effects in the chemoreceptor trigger zone.

There’s not much data, but one trial of 33 adults with CHS compared the use of haloperidol versus ondansetron as a first approach. Two hours after drug administration, haloperidol was more effective in improving abdominal pain and nausea compared to ondansetron.

How do we dose? Any clinical pearls you should know about? I’m glad you asked! Take a look:

Haloperidol (IV): 0.5 to 1 mg every 6 hours as needed
Droperidol (IV): 0.625 to 1.25 mg every 6 hours as needed
Clinical Pearls:
- Risk of QTc prolongation should always be considered when administering these agents (especially in patients with electrolyte disturbances as a result of excessive vomiting)
- Increased chance for extrapyramidal side effects (EPS) with higher doses
- Black box warning for increased mortality in elderly patients with dementia-related psychosis

Ok, now let’s say you gave appropriate fluids and a dopamine antagonist but the patient is still experiencing severe emesis. What’s the next step?

In patients with persistent symptoms despite IV fluids and dopamine antagonists, our next step is capsaicin cream. (Like the over-the-counter pain cream? Mmmhmm. That’s right.) Remember how we said that chronic exposure to cannabis can desensitize and downregulate the CB1 and TRPV1 receptors leading to emesis? Well, capsaicin (as well as those hot showers we intro’d with) is thought to activate the TRPV1 receptors, leading to the reactivation of anti-emetic effects. In terms of dosing, take a look below:

Capsaicin cream 0.025 to 0.1% applied as a thin film over the abdomen
Clinical Pearls:
- Overall, capsaicin cream is generally well-tolerated. Most common adverse reaction is local application-site burning.

If a patient continues to have persistent symptoms despite IV fluids, dopamine antagonists, and capsaicin, then trialing other antiemetics is your last option. Realistically, there’s literature that proves these agents to likely be ineffective. However, it is worth a trial in patients with severe persistent symptoms.

There are many options including ondansetron, metoclopramide, prochlorperazine, and diphenhydramine. There are no clinical guidelines that recommend one agent over the other for the management of CHS. Each agent may be preferred depending on patient-specific factors and institutional policy.

Chronic Management of Cannabinoid Hyperemesis Syndrome (CHS)

Cannabis cessation is the only treatment that relieves and prevents symptoms associated with CHS as it allows for the upregulation of the CB1 and TRPV1 receptors. However, immediate and abrupt cessation of cannabis (“cold turkey”) may be associated with significant withdrawal symptoms and high frequency of recidivism.

Although cannabis-specific resources to help with withdrawal are limited, observational experience suggests that a tricyclic antidepressant, such as amitriptyline, escalated from a starting dose of 25 mg and maintained at a dose of 75-100 mg at bedtime, is efficacious in approximately 70% of patients.

Appropriate patient education can play a vital role in preventing and recognizing CHS. Common patient education points to emphasize are include:

What is cannabis hyperemesis syndrome?
- CHS is a condition that causes frequent vomiting. It can happen in people who have been using cannabis (marijuana) regularly for at least a year.
- Almost all people with CHS use cannabis at least weekly, and most report daily use.
What are the symptoms of CHS?
- The main symptom is repeated, severe episodes of vomiting (sometimes up to 6 to 8 times per hour during an episode). These episodes can last for up to a few days. Then, the cycle repeats every few weeks or months.
- Other symptoms include nausea, belly pain, fatigue, pale skin, and diarrhea.
When should I see a doctor?
- Patients should see a doctor if they have any signs of dehydration, including fatigue, dry mouth, muscle cramps, dizziness, confusion, and oliguria.
How is CHS treated?
- The long-term treatment is complete cessation of cannabis products and symptoms generally improve within days to weeks of cessation.
- Medicines such as IV fluids, dopamine antagonists, and capsaicin can be utilized to treat an acute episode of CHS.
Can CHS be prevented?
- The only way to prevent CHS is to avoid using cannabis products.

The tl;dr of Cannabinoid Hyperemesis Syndrome (CHS)

Cannabis (marijuana) is a plant (scientific name is Cannabis sativa) that has more than 400 chemicals. The most important constituents include tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive ingredient, while CBD does NOT have psychoactive properties.

CHS is a subtype of cyclical vomiting syndrome that is associated with chronic (typically years) and heavy (typically daily or near-daily) cannabis use and is observed predominantly in males. IV fluids and electrolyte supplementation remain the mainstays of therapy in patients with CHS showing signs of dehydration.

Dopamine antagonists, specifically haloperidol and droperidol, are the first-line antiemetics of choice for the treatment of CHS. Common antiemetics such as ondansetron, promethazine, chlorpromazine, and metoclopramide are generally ineffective in the majority of patients experiencing CHS. Capsaicin cream can be utilized for patients with persistent symptoms that have already received IV fluids and dopamine antagonists.

Cannabis cessation is the only long-term treatment that relieves and prevents symptoms associated with CHS as it allows for the upregulation of the CB1 and TRPV1 receptors. Tricyclic antidepressants, such as amitriptyline, can be utilized to help relieve cannabis withdrawal symptoms and aid in the prevention of CHS. Appropriate patient education can play a vital role in preventing and recognizing CHS.

What Every Pharmacist Should Know about Cannabinoid Hyperemesis Syndrome (CHS)