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What you need to know about Cannabinoid Hyperemesis Syndrome

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15-year-old AJ presents to the Emergency Department with abdominal pain and vomiting. He hasn’t been able to go to school for the last week because his symptoms were so bad. He admits to using more and more cannabis over the last year.

You prescribe IV fluids, ondansetron and analgesia whilst waiting for test results.

Introduction

Cannabis use is increasing in all age groups. It is the third most used recreational drug in adolescents (after alcohol and tobacco) and its widespread use means that accidental ingestion in younger children is also increasing. Although it is well known for its anti-emetic properties it may also induce nausea and cyclical vomiting. This can lead to them presenting to the Emergency Department (ED) for help.

What is Cannabinoid Hyperemesis?

Cannabinoid hyperemesis syndrome [CHS] was first described in 2004 and was thought to be either related to cyclical vomiting syndrome, or an independent diagnosis. CHS can be debilitating. It is characterised by intractable vomiting, nausea, and generalized abdominal pain. Presentations to emergency departments have been increasing in number and this may be due to the availability of more potent cannabis.

How does this happen?

Cannabis’ ability to have both pro- and anti-emetic effects is unique. It acts at a number of receptors that have neurological, gastrointestinal and endocrine effects. These include CB1, CB2 and transient receptor potential vanilloid-1 (TRPV1). CB1 receptors are located in both the central (CNS) and peripheral (PNS) nervous systems, as well as the gastrointestinal tract. They affect pain transmission, gastric secretions and intestinal motility and it is thought that these receptors are responsible for the anti-emetic properties of cannabis. CB2 receptors are concentrated in the lymphoid cells and modulate immune cell migration and cytokine release. Finally, the TRPV1 receptors are located in the peripheral nervous system and have an effect on pain modulation and thermoregulation.

It’s not entirely clear how cannabis hyperemesis syndrome occurs though there are several theories. One is that since cannabinoids have long-half lives and are lipid soluble, they accumulate in the brain and over time cause symptoms, particularly in young people who may have genetic variations in enzymes which lead to further accumulation. Another theory is that there is a thermoregulatory and autonomic imbalance in the limbic system caused by chronic use. Other suggestions are that with long-term consumption cannabis becomes a receptor antagonist, or that they become down-regulated or de-sensitised over time. This reverses the antiemetic effect of cannabis. It seems that chronic over-stimulation of receptors leads to dysregulation of the body’s control of nausea and vomiting, leading to CHS.

What are the clinical features of Cannabinoid Hyperemesis Syndrome?

Most young people who smoke cannabis regularly do not go on to develop CHS.

It appears in three distinct phases, a prodromal phase, hyperemetic phase, and a recovery phase.

The prodromal phase can be really long, occurring months to years before the hyperemetic phase. During this phase the patient may feel nauseated, have abdominal discomfort and develop a fear of vomiting (emetophobia). Symptoms occur on one or more days of the week and patients often increase their cannabis consumption to self-medicate.

The proportion of people who progress to the hyperemetic phase is unclear. Here, young people experience intractable vomiting, abdominal pain and resultant weight loss. Symptoms may be relieved with prolonged hot baths and showers so these behaviours can become compulsive. Patients can alternate between prodromal and hyperemetic phases as attacks occur and subside.

The recovery phase begins when the young person stops using cannabis. Symptoms can improve within 24 to 48 hours. Unfortunately, people in this phase may experience a return of symptoms if they start using again.

How is this different to cyclical vomiting?

The similarity between CHS and Cyclical Vomiting Syndrome (CVS) is a barrier to diagnosis – a diagnosis made even trickier when some young people with CVS self-medicate with cannabis.

Cyclical vomiting is characterized by the sudden onset of bouts of vomiting, often up to 12-15 episodes a day. These episodes may be separated by weeks or months without symptoms. It is often associated with psychiatric disorders and a history of migraines.  One key diagnostic feature of CVS is that it cannot be attributed to any other disorder, whereas CHS is always related to cannabis use. Symptomatic relief by hot showering is specific to cannabis hyperemesis.

What can we see on investigation in the Emergency Department?

It can be quite tricky to diagnose CHS as so much of the diagnosis is based on the clinical history and having a high index of suspicion. The HEEADSSS assessment is a good way of asking about recreational drug use and can provide good opportunities to support struggling young people.

Appropriate investigation in the ED involves evaluation for complications and ruling out potential differentials. It is important to assess for electrolyte disturbance and for acute kidney injury. Equally, ketones are a useful marker of metabolism and starvation status.  A raised white cell count is often seen and is of uncertain significance. An ECG may also be useful to assess the patient’s QTc interval, and before the administration of specific antiemetics.

Based upon clinical assessment other investigations can be helpful in ruling out differentials such as infection, pregnancy (especially ectopic pregnancies) or brain tumours.

How can we treat it and what is the evidence?

Treating CHS is particularly challenging as the vomiting is resistant to common antiemetics. There is a lack of paediatric data, which means there isn’t an agreed-upon treatment algorithm. A systematic review involving 13 case reports and 1 retrospective cohort study explored treatment strategies for young people. Outcomes were limited by the small number of cases, reflecting a lack of data, and a lack of recognition of the syndrome, in young people. The review mirrored the broader adult evidence and supports the extrapolation of these treatments to young people.

In addition to the more specific treatments for CHS, the review looked at different strategies for the use of ondansetron, promethazine, metoclopramide, and dimenhydrinate. They were all found to be ineffective. Similarly, opioids and acid suppression treatments (such as PPI’s and Histamine-2-receptor antagonists) were also ineffective. Combination treatments did not work either, demonstrating just how difficult CHS can be to treat.

Of the studies and reports reviewed, six mentioned effective treatments, detailed below.

Benzodiazepines

These were the most commonly prescribed therapy. As GABA agonists they are thought to work by inhibiting central neurotransmitters, decreasing the activation of CB1 receptors in the brain, leading to an antiemetic effect.

The dosage varied between reports with no specific drug or dose recommended.

One study of just ten patients recommended a maximum treatment duration of 2 weeks, in an effort to help with withdrawal symptoms from cannabis.

Haloperidol

Haloperidol works as an anti-dopaminergic agent at D2 receptors in the chemoreceptor trigger zone of the brain.

It appears to be an effective treatment in adult patients but despite this, only one report evaluated its use in young people.

Capsaicin cream

Capsaicin is thought to modulate thermoregulatory TRPV1 receptors which are activated by cannabis and involved in the perception of pain.

Application of capsaicin cream to the abdomen appeared to be a reasonably effective treatment. The cream comes in 0.025% and 0.075% formulations though only the 0.025% formulation was evaluated in young people despite there being evidence for the effectiveness of the stronger formulation in adults. Equally, application of the cream to other sites on the body has not been explored.

Hot baths and showers

Compulsive bathing or showering is commonly seen in patients with CHS. It is not entirely clear how this works though perhaps peripheral vasodilation causes re-distribution of blood from the gastrointestinal tract thus reducing the adverse effects of CB1 directed gastrointestinal vasodilation.

There are case reports of burns in patients with over-enthusiastic use of the hot tap.

Common Pitfalls

  • Not asking about cannabis use
  • Not considering other differentials
  • Only using conventional anti-emetics when you suspect CHS
  • Not providing cessation advice

Conclusion

Although there is limited data in young people, we know that cannabis hyperemesis syndrome is an emerging problem. It is important to consider this in the differential diagnosis, of young people with persistent vomiting. It is resistant to traditional anti-emetic and analgesic treatments and the only treatments that have been demonstrated to be effective are benzodiazepines, haloperidol, capsaicin, and hot baths or showers. Patients often present with debilitating symptoms so consultation and treatment is an opportunity to promote cannabis cessation in a non-judgmental manner. This is the only long-term effective treatment.

AJ’s investigations come back as normal but he is still in pain and vomiting despite treatment. A colleague diagnoses cannabis hyperemesis syndrome and recommends that you try a low dose of a benzo. AJ’s symptoms improve in the department, and he is prescribed a short course of diazepam to help with withdrawal symptoms.

References

Chu F, Cascella M. Cannabinoid Hyperemesis Syndrome. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 5, 2022.

Dosani K, Koletic C, Alhosh R. Cannabinoid Hyperemesis Syndrome in Pediatrics: An Emerging Problem. Pediatr Rev. 2021;42(9):500-506. doi: 10.1542/pir.2019-0097.

Lonsdale H, Kimsey KM, Brown JM, Dey A, Peck J, Son S, Wilsey M. Pediatric Cannabinoid Hyperemesis: A Single Institution 10-Year Case Series. J Adolesc Health. 2021;68(2):255-261. doi: 10.1016/j.jadohealth.2020.09.024.

Reinert JP, Niyamugabo O, Harmon KS, et al. Management of Pediatric Cannabinoid Hyperemesis Syndrome: A Review. J Pediatr Pharmacol Ther. 2021;26(4):339-345. doi:10.5863/1551-6776-26.4.339

About the authors

  • Owen Hibberd is an Emergency Medicine Trainee in Cambridge, currently studying on the QMUL PEM MSc. Interested in Paediatric Emergency Medicine, Pre-Hospital Emergency Medicine and Medical Education. He/him.

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