OPINION PAPER: “Persistent hyperemesis with cannabis and its synthetic derivatives”

 

Ilia A Petrou

Carlo Berti

Abstract:

Cannabinoid Hyperemesis Syndrome (CHS) is a syndrome of severe cyclic vomiting in susceptible individuals, mainly young male adults, with chronic and regular use of cannabis. Traditional antiemetic treatments don’t seem to be beneficial. The only consistent  relief is by frequent hot baths.

Despite the increased awareness of the condition, its recognition remains difficult in clinical and in particular in Psychiatric Liaison Services. We propose a review of the evidence and we add this evidence to the expected tolerability of cannabis and cannabinoids as there is a social debate over its use for both recreational and medicinal purposes.

 

Introduction

DEFINITION: Cannabinoid Hyperemesis Syndrome (CHS) is a syndrome of severe cyclic vomiting in susceptible individuals with chronic, regular use of cannabinoids. Compulsive hot baths/showers which provide symptom relief are a major characteristic of the clinical presentation [1], while traditional antiemetic treatments don’t seem to be beneficial.

DESCRIPTION OF SYNDROME: It was initially described by Allen et al, in 2004. The authors described a series of nine cases in South Australia and summed up the common features of this newly recognised syndrome [2]. They compared the clinical presentation of their patients with the presentation of a previously published case report by Moore et al, in 1996. Originally, the syndrome had been described as psychogenic vomiting, but cannabis hadn’t been recognised as a possible etiology of illness [3]. . It was later approved as a syndrome and it was included in the ROME IV criteria of May 2016. CHS was placed under the Gastroduodenal Functional Disorders and more specifically in the nausea and vomiting disorders subcategory (B3), together with Chronic Nausea Vomiting Syndrome (CNVS) and Cyclical Vomiting Syndrome (CVS) [4].

CANNABIS: The main psychoactive substance of cannabis is Δ9 tetrahydrocannabinol (THC) [5]. Other phytocannabinoids are cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG).

In the human body, cannabinoids bind to endocannabinoid G-protein coupled receptors (CB1 and CB2). Endocannabinoids (anandamide and 2-AG), phytocannabinoids and synthetic cannabinoids are all capable of binding to cannabinoid receptors [6]. CB1 receptors are mainly expressed in  the central and peripheral nervous system (including the enteric nervous system) and they mediate the antiemetic properties of cannabis [1].CB2 receptors are expressed mainly in immune system cells [1].

IMPORTANCE OF SYNDROME: According to the latest World Drug Report 2019 from the United Nations Office on Drug and Crime (UNODC), cannabis continues to be the most frequently used recreational drug globally, having been used by approximately 188 million people in 2017. The annual prevalence of cannabis use in England and Wales was 7.18% in 2017, among the 16-59 age group. [5]

During the last two decades, cultivation techniques of cannabis have changed [5]. Via selective breeding and plant management, different varieties with both high THC content and lower levels of CBD have been achieved. [5].

Among the other medical uses, cannabis is used for various therapeutic indications, including treatment of  nausea and emesis (chemotherapy-induced, Cyclic Vomiting Syndrome=CVS), appetite stimulation in HIV patients with cachexia, peripheral neuropathy, chronic pain [1], spasticity in Multiple Sclerosis [7], cases of severe epilepsy.

 

Methods

Our aim was to focus to address a relatively new emerging medical syndrome. To achieve our objective we performed a literature review using the  MEDLINE database; the keywords were “cannabinoid” and “hyperemesis”. We considered the evidence from 2004, the date of the first report and citation, to 2019. The majority of the evdience comes from case reports and we tried to summarise the available evidence so far. Therefore, we selected the articles pertaining to CHS. The data were extracted from literature reviews, case reports and other articles and were combined in the cumulative synthesis presented in this paper. The emerging evidence from the use of cannabinoids prescribed in the management of intractable epilepsy are not part of this review.

 

Results

EPIDEMIOLOGY: Current epidemiologic data regarding CHS mainly come from systematic reviews of reported case series [1].

CHS presents more commonly in young males. 72.9% of the reported CHS cases were in male patients, while the median age at symptom onset is 24 years old and the median age at diagnosis is 28 years old [1]. Patients are commonly less than 50 years old at time of evaluation (100%) [1].  .

In all cases cannabis use preceeded the onset of symptoms but the duration of use was variable. More specifically,  25.1% of patients have been using cannabis for less than 1 year and 36.3% of patients were found to have used cannabis for 2-5 years. 16.8% and 21.8% of patients used cannabis for 6-10 years and more than 10 years respectively [1].

As for the frequency of cannabis use, its daily use was reported in 47.9% of cases, whereas, in 23.7% of cases, cannabis use was found to be greater than daily [1]. Most patients did not make use of other psychoactive substances besides cannabis [7]. The key epidemiological findings are summarised in Table 1.

Table. 1 EPIDEMIOLOGIC DATA  [1,7]

Gender

Predominantly Males

Median Age at Symptom Onset

24 yrs old

Median Age at Diagnosis

28 yrs old

Duration of Cannabis Use

74.1% more than 1 year

Frequency of Cannabis Use

47.9% daily use, 23.7% greater than daily use

SYMPTOMS: Various diagnostic frameworks have been recommended since the first description of the syndrome.

The major diagnostic characteristics reported by most authors are as follows:

Severe nausea and vomiting incidents (100%) [1], with each crisis lasting for approximately one week [2] and with episodes recurring in a cyclic pattern over months (100%) [1] are basic characteristcs of the syndrome. There is resolution of symptoms after stopping cannabis (96.8%) [1]. An interesting clinical finding is that symptom relief is achieved with compulsive hot baths/ showers (92.3%) [1]. This is a consistent finding, although it may not be present during the first few episodes. Patients would take multiple baths daily, during the active phase of illness, but not during the prodromal stage. The relief of symptoms was temperature dependent. Hence, some patients might even end up scalded because of the hot water temperatures. This is a learned behaviour and, although it would become a major preoccupation for patients, it could not be attributed to a concomitant psychosis or obsessive-compulsion disorder. This behaviour resolves after cessation of cannabis and cessation of the emesis episodes [2]. Associated with emesis there is atypical abdominal (epigastric or peri-umbilical) pain (85.1%) [1]. CHS has been described in patients using synthetic cannabinoids as well. The main characteristics of CHS are summarised in Table 2.

Table. 2 MAJOR CHARACTERISTICS OF CHS [1,2]

Severe nausea and vomiting

Vomiting that recurs in a cyclic pattern

Resolution of symptoms after stopping cannabis

Symptom relief with compulsive hot baths/ showers

Abdominal pain

History of cannabis use for >1 year

At least weekly cannabis use

History of daily cannabis use

Male predominance

Age < 50 years old

 

Other reported symptoms: Reliable return of symptoms within weeks of resuming use, weight loss >5kg [1], symptoms predominant in the morning, normal gastrointestinal transit (in cases of gastric emptying studies) [7] have all been described. Common antiemetic treatments are not beneficial [2]. Allen et al also documented a series of autonomic symptoms like alternating body temperature (low grade pyrexia), sweating, flushing, thirst, colicky abdominal pain [2]. Prodromal phase of illness has been described with occasional morning nausea or emesis, fear of vomiting and nausea when seeing or smelling food. These prodromal episodes tend to occur once or twice weekly, during the past few weeks to years prior to the cyclical vomiting onset [2].

In terms of clinical examination and workup, there have been no specific findings in the cases reported [7]. Patients were found to have normal bowel habits and negative medical work-up [1]. The only occasionally reported findings were leucocytosis with neutrophilia (without increased C-Reactive Protein in cases where it was addtionally measured) and electrolyte balance disorders [1], [2].

COMPLICATIONS: In most cases symptoms resolve following cannabinoid cessation. However, there is a series of major medical complications in the literature frequently associated with CHS, typical of persistent vomiting: Dehydration (secondary to constant vomiting and hot showers) [8], electrolytic abnormalities (hyponatraemia, hypochloraemia) [9], Acute Renal Failure due to severe dehydration  [8], Acute Coronary Syndrome secondary to coronary vasospasm, Takotsubo Cardiomyopathy [10], hypoglycaemia secondary to food intolerance on the grounds of intractable CHS [9], pneumomediastinum [6], oesophagitis [2], injuries in the gastrointestinal tract [6].

INVESTIGATIONS: A basic medical  workup is indicated for those patients. This can include basic laboratories, abdominal ultrasound (US), computerised tomography (CT) as well as oesophagogastroduodenoscopy (OGD) in case of hospital admission [1].

DIFFERENTIAL DIAGNOSIS:  Cyclical vomiting syndromes are physical health conditions and entities of unknown etiology. For example, there are  Hyperemesis Gravidarum, forms of porphyria, as well as Addison’s disease.

Other entities to be considered are Paediatric Cyclic Vomiting, Cannabis Withdrawal Syndrome, Chronic Nausea Vomiting Syndrome (CNVS) and Psychogenic vomiting/ Cyclical Vomiting Syndrome (CVS) [2].

Psychogenic vomiting/ Cyclical Vomiting Syndrome (CVS) shares more similarities with CHS. CVS is a medical condition described in adulthood characterised by cyclical vomitng, commonly with a tendency to vomit since childhood [2]. In CVS other vomiting triggers, like physical stress/illness, menstruation  or emotional stress, are usually present [7]. Patients will commonly use cannabis or other illicit drugs and alcohol in an attempt to control the cyclical vomiting [2]. It is arguable that some cases previously described as CVS, are possibly misdiagnosed cases of CHS, as patients were chronic cannabis users and they presented with compulsive bathing behaviour.

The exclusion of other major medical conditions, prior to the diagnosis of CHS is necessary.

Co-existence of other mental health illnesses should also be explored.

In particular, anorexia nervosa (Binge-purge type) and bulimia nervosa would need to be excluded [2], [11]. In CHS, patients have a normal appetite and they do not present with [2] morbid fear of fatness, body image distortion, body size overestimation, sharply defined weight threshold. Other mental illnesses like psychosis and Obsessive-Compulsion Disorder should be excluded as a possible cause of the compulsive bathing behaviour [2]. In this case, the positive urine drug screen as well as the cessation of symptoms following cessation of cannabis would favour the diagnosis of CHS over the above entities.

PATHOPHYSIOLOGY: The exact pathophysiologic mechanisms of CHS remain unknown.

The role of cannabinoids:

A.Cannabinoids have a long half life and are lipophilic, binding to cerebral fat. Cannabis accumulation, via regular use, in susceptible individuals, can lead to toxicity in the brain [2].

B.Cannabinoids bind to CB1 and CB2 receptors which seem to demonstrate complex pharmacological effects:

1.CB1 brain receptors mediate the antiemetic effect of cannabis. Downregulation of those receptors, on the grounds of chronic regular cannabis use, could account for the hyperemesis symptoms. Cessation of cannabis would then lead to cessation of emesis [1].

2.Endocannabinoids play a role in homeostasis and recovery from stressful stimuli [6]. Hence, the described downregulation of CB1 receptors would lift the inhibitory effect of endocannabinoids on hypothalamic-pituitary-adrenal (HPA) axis and Sympathetic Nervous System (SNS) [6]. This could result in increased ACTH hormone, enhancing HPA activity and stress- related autonomous system responsiveness [6], [7]. This may eventually lead to release of neurotransmitters which are involved in emesis [6].

3.Additional binding of cannabinoids to CB1 receptors in the gastrointestinal tract could decrease GI mobility, overriding the central antiemetic effect [1].

4.CB1 receptors mediate intestinal vasodilation, contributing to the symptoms [7].

C.Genetic variations in p450 enzymes involved cannabis metabolism could explain the susceptibility of certain individuals to the syndrome.

The role of hot showers:

One of the effects of hot showers is possibly the parasympathetic activation which compensates for the increased HPA axis activity [7]. The relieving effect of hot baths could also possibly be explained by considering that the CB1 receptors are involved in the thermoregulatory systems in the hypothalamus [2,7]. Moreover, hot showers are hypothesised to cause skin vasodilation, divertion of splanchnic circulation and relief of abdominal discomfort [7] (“cutaneous steal” syndrome [6]).

MANAGEMENT: Cessation of cannabis has been identified as the only effective treatment for CHS, resolving symptoms in 96.8% of cases [1]. Hot baths/showers provide only temporary symptom relief. Patients are supported with intravenous fluids and correction of electrolyte disturbances, during the acute phase of illness. Short-term use of benzodiazepines has been suggested both for symptom relief [7] and as a supportive measure, to control the symptoms cannabinoid withdrawal syndrome, during the first two weeks of cessation of cannabis [2].

In scientific literature, various pharmacological treatments have been researched. However, the evidence to recommend any of them for routine clinical use is insufficient. Capsaicin cream applied topically on the abdomen has been reported to relieve symptoms and this could hypothetically be attributed to capsaicin’s binding to the TRVP-1 receptor which interacts with the endocannabinoid system [1]. Dopamine antagonist agents have also been tried. Interestingly, haloperidol (i.e.5mg PO [1]) was the only dopamine antagonist that has been reported to relieve symptoms in isolated cases.The concept behind its use is that Δ9-THC increases dopamine synthesis, turnover and efflux, as well as dopamine cell- firing [1]. Haloperidol has adrenolytic properties which could hypothetically explain its unique efficacy [7]. Metoclopramide as well as analgesics (WHO steps 1 & 2) seem to be unsuccessful, while proton pump inhibitors have variable efficacy [7]. Opiates should be avoided as analgesics, as they are related to nausea, emesis and bowel dysfunction [1].

 

Discussion

THE PARADOX OF CANNABIS: Given the impact of this cannabis-related syndrome, the concomitant use of cannabis for the treatment of nausea and vomiting- a common practice for drug-induced nausea in patients under chemotherapy- seems at least paradoxical. Consequently, one might wonder why cannabis treats vomiting under specific circumstances and elicits it under different ones. The prevalence of the syndrome seems to be low, taking into consideration the widespread use of cannabis [1]. Is there a dose transition point after which the effect of cannabis is reversed? Is there a genetic predisposition component? In addition, it remains unknown why the syndrome develops after years of cannabis use but recurs only within weeks of cannabis continuation [2].

CHALLENGES: It seems that, for the time being, CHS syndrome is frequently under-recognised. Most patients are often discharged without a conclusive diagnosis and present in various emergency departments prior to the final diagnosis of the syndrome. They end up going through not one but multiple CT scans, OGDs or even exploratory operations. The accumulative cost of such practices can be significant [1], while the median delay between onset of symptoms and diagnosis of CHS has been estimated as 4.1 years [1]. Patients commonly deny that cannabis is the cause of their symptoms and can often be missed during follow-up [1]. There is also significant under-reporting of cannabis use, due to the stigma around its use as well as its illegal status in many regions [1]. Nowadays, the cannabis market has diversified so that currently a variety of products are available with varying modes of administration potency and effects [5], making the estimation of the amount of substances, each individual is exposed to challenging. Patients may report small amounts of cannabis used but the real potency of them usually remains unknown.

RECOMMENDATIONS:

The differential diagnosis of  CHS should be considered in cases of unexplained vomiting or “compulsive bathing”.

The recognition of this syndrome might prompt questions within the scientific community and legislative bodies to review the safe use of cannabis.

RECOMMENDATIONS FOR RESEARCH:

Further basic science research focused on the pathophysiologic mechanisms behind this particular syndrome is required, as the current evidence for any suggested mechanisms is only minimal [1]. Most of the knowledge around CHS currently originates from case reports and systematic reviews, but there are not any controlled studies. Therefore, a prospective cohort study, where the amount of cannabis used would be homogeneously reported, would contribute to our better understanding of the syndrome and the recognition of risk factors. It is necessary for evaluating the already proposed diagnostic criteria and for the establishment of guidelines for the management of the condition [1]. Acknowledgement of any possible triggers before crisis onset would be useful and it must become common place in acute medicine review and in liaison psychiatry.

References

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[9] Nourbakhsh MMiller AGofton JJones GAdeagbo B, Cannabinoid Hyperemesis Syndrome: Reports of Fatal Cases. J Forensic Sci. 2019 Jan;64(1):270-274. doi: 10.1111/1556-4029.13819. Epub 2018 May 16.

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About the authors

Ilia Anna Petrou is an F2 WAST doctor working in Old Age Psychiatry at Kent and Medway NHS and Social Care Partnership Trust.

Carlo Berti is a Consultant Psychiatrist who had senior appointments in Medical Education and NHS management. He has a keen  interest in Novel Psychoactive Substances and the safety of psychotropics. He is a member of the Technology Appraisal Committee for NICE and the Training Committee of the Academy of the Medical Royal Colleges.