Cannabinoid Hyperemesis Syndrome

Is Cannabinoid Hyperemesis Syndrome a new condition? Or is it Cyclical Vomiting Syndrome triggered by cannabis use? Perhaps its the outcome of a negative pesticide synergy? We take a deep dive and explore the research...

Cannabis is often used for its anti-emetic and anxiolytic properties. Paradoxically, cannabis use has also been associated with a condition resembling cyclical vomiting syndrome (CVS), named cannabinoid hyperemesis syndrome (CHS). The term first appeared in the medical literature during November 2004 in a paper titled ‘Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis abuse.’

Looking at the origins and parameters of the initial report, the study was based on 19 subjects which concluded with only 9 remaining subjects participating. No blinds were used. The paper concluded that “chronic cannabis abuse was the cause of the cyclical vomiting illness in all cases, including the previously described case of psychogenic vomiting,” and has been cited by almost 100 peer-reviewed articles since.

Another mention of CHS in the medical literature came 2 years later in the paper ‘Cannabis hyperemesis causation questioned’, which concluded that the original paper was ‘unduly presumptive’, stating ‘the proposed biological explanation is weak’ and ‘this syndrome should not be accepted as being caused by cannabis without additional reports and other evidence.’

The next significant paper came in January 2009, titled ‘Cannabinoid Hyperemesis Relieved by Compulsive Bathing’ by Yoon Hee Chang and Donna M. Windish, which, despite being a study of only 2 subjects, has now been cited by over 30 subsequent studies and concluded, ‘when confronted with these unusual symptoms, the physician should consider not only organic disease but also illicit marijuana use as a possible cause.’

In March 2009 a follow up paper titled ‘Cannabinoid hyperemesis syndrome: Clinical diagnosis of an under-recognised manifestation of chronic cannabis abuse’ was published. Based on a study of only 1 subject, it concluded ‘in the setting of chronic cannabis abuse, patients presenting with chronic severe nausea and vomiting that can sometimes be accompanied by abdominal pain and compulsive hot bathing behaviour, in the absence of other obvious causes, a diagnosis of cannabinoid hyperemesis syndrome should be considered.’

2 months later Yoon Hee Chang and Donna M. Windish published the following throw back:

‘When we saw our first patient with hyperemesis in June 2007, we were immediately intrigued by the patient's symptoms of refractory nausea and vomiting that were relieved only with hot showers. We immediately performed PubMed and Google searches and learned about cannabinoid hyperemesis. When we saw a second patient with a similar presentation in January 2008, we decided to write about our patients because, to the best of our knowledge at that time, they would be the first cases to be reported in the United States.’

Important to note here, Yoon Hee Chang and Donna M. Windish wrote some of the very first published papers on CHS, a condition they learned about through Pubmed and Google searches, where they would have read the initial study which ended only 9 subjects participating, and another study of only 2 subjects.

With one researcher following on from the other, the next year another paper titled ‘Cannabinoid Hyperemesis’ was published, again, based on a study of only 1 subject with unexplained cyclical vomiting. It stated:

‘Cannabinoid hyperemesis syndrome is characterized by chronic, heavy use of cannabis, recurrent episodes of severe nausea and intractable vomiting, and abdominal pain. Temporary relief of symptoms is achieved by taking a hot bath or shower, and resolution of the problem when cannabis use is stopped. Failure to recognize the syndrome leads to misdiagnoses such as psychogenic vomiting, the cyclic vomiting syndrome, an eating disorder or ‘drug-seeking behaviour’, and may lead to extensive, expensive and unproductive investigations, psychiatric referrals and ineffective treatments. Other than stopping cannabis use, there is no proven treatment.’

Many more papers based on single subjects were published with little more connection to cannabis other than ‘urine toxicology was positive for cannabinoids’ and ‘patient has a history of using cannabis’.

In 2010 Nissar A. Darmani reviewed other hypothesises that may explain Cannabinoid Hyperemesis Syndrome.

“These encompass: (1) pharmacokinetic factors such as long half-life, chronic exposure, lipid solubility, individual variation in metabolism/excretion leading to accumulation of emetogenic cannabinoid metabolites, and/or cannabinoid withdrawal; and (2) pharmacodynamic factors including switching of the efficacy of Δ9-THC from partial agonist to antagonist, differential interaction of Δ9-THC with Gs and Gi signal transduction proteins, CB1 receptor desensitization or downregulation, alterations in tissue concentrations of endocannabinoid agonists/inverse agonists, Δ9-THC-induced mobilization of emetogenic metabolites of the arachidonic acid cascade, brainstem versus enteric actions of Δ9-THC, and/or hypothermic versus hyperthermic actions of Δ9-THC. In addition, human and animal findings suggest that chronic exposure to cannabis may not be a prerequisite for the induction of vomiting but is required for the intensity of emesis.”

We’ll come back to pharmacodynamic factors later in the article…

More than 16 years after CHS was first reported, things are not much clearer. As the December 2020 study, ‘Cannabinoid hyperemesis syndrome: the conundrum is here to stay’, concluded: ‘The current Rome IV criteria for CHS diagnosis are limited and need to be revisited and updated. Future research in CHS focused on pathophysiology, clinical presentation and natural history is still in great need.

Cannabis cultures around the world have expressed doubt to the validity of the claim that cannabis is responsible for a newly diagnosed cyclical vomiting condition, and one which wasn’t heard of in cannabis communities prior to 2004. This remains unexplained. Long before the results of randomised controlled trials, cannabis communities have been familiar with the range of benefits, and side-effects, associated with consuming cannabis. An ongoing cyclical vomiting syndrome, relieved by hot showers, does not appear in the learned experience and shared wisdoms of cannabis cultures.

When we evaluate the evidence of the initial reports, studies based on 1 or 2 subjects, researchers who first learned about CHS through Google and wrote one of the earliest papers on it, and over 16 years later ‘the criteria for CHS diagnosis are limited and need to be revisited and updated,’ its not clear whats actually going on.

Between 2004 and 2010, the studies published on CHS were based on the following case numbers:

2004 - Australia (9)

2005 - UK (1)

2006 - USA (1)

2007 - Australia (1)

2008 - USA (8)

2009 - Australia (1)

2009 - New Zealand (1)

2009 - USA (1)

2010 - Switzerland (1)

2009 - USA (3)

2009 - USA (2)

2010 - USA (2)

2010 - USA (8)

2010 - USA (4)

50% of the initial papers were based on a case report of 1 person. Quite surprising how a new condition can be diagnosed, cited, and recognised in medical literature based on the extremely limited numbers of subjects across these studies.

Some have felt CHS was the current 'Reefer Madness de jour', with the lack of due diligence to produce respectable studies, and conclusions based on sketchy evidence.

A 2019 review article on Cyclical Vomiting Syndrome highlighted the following:

‘There are significant gaps in our understanding of the pathophysiology, clinical features, comorbidities, and effective management options of CVS. Recommendations for treating CVS are based on limited clinical data, as no placebo‐controlled, randomized trials have yet been conducted. Diseases associated with CVS, including migraine, mitochondrial disorders, autonomic dysfunction, and psychiatric comorbidities, provide clues about pathophysiologic mechanisms and suggest potential therapies.’

In a cross-sectional study of 140 patients with CVS, 41% of patients were current cannabis users, with 21% reporting cannabis use more than 4x per week. Most users reported that cannabis helped to control cyclical vomiting syndrome. 88% of the cannabis users had abstained for longer than 1 month at some point, with only 1 user reporting resolution of their cyclical vomiting episodes during the abstinence period.

A 2015 cross-sectional study of 2574 emergency department visits due to cyclical vomiting syndrome in Colorado, noted a doubling of ‘reported cannabis use’ amongst CVS patients since legalisation. Its unclear whether this is due to more accurate cannabis use reporting, increased cannabis use post-legalisation, or both.

In 2012 the largest case-series review of 1571 patients diagnosed with CHS was carried out. To meet conclusion criteria patients had to;

have a history of recurring vomiting with no other explanation, and, that cannabis use preceded symptom onset.

Of the 1571 patients diagnosed with Cannabinoid Hyperemesis, only 98 of the patients (6%) actually met the criteria for ‘unexplained recurring vomiting with a history of cannabis use that preceded symptom onset.’

Of those 98 patients, only 10 were available for follow up study. 7 of the 10 had stopped using cannabis with 6 of the 7 reporting relief of symptoms following cessation.

Despite starting with a total 1571 patients diagnosed with Cannabinoid hyperemesis, this conclusion was made from those 7 remaining patients in the follow up study:

‘Cannabinoid hyperemesis should be considered in younger patients with long-term cannabis use and recurrent nausea, vomiting, and abdominal pain. On the basis of our findings in this large series of patients, we propose major and supportive criteria for the diagnosis of CH.’

It makes you wonder, is it actually anything to do with cannabis at all?

While many papers have claimed that hot water bathing for relief is not associated with CVS, instead being a hallmark feature of CHS, others have disputed this. As highlighted by the Cyclical Vomiting Syndrome Association, the ‘phenomenon of this behaviour was also seen in Cyclical Vomiting Syndrome patients who denied any use of (cannabis), and this kind of bathing should not be interpreted as being pathognomonic of cannabis use.’

Under Rome IV Criteria for diagnosing CVS it is noted that a history or family history of migraines is often present. Dr Ethan Russo hypothesised that migraines may come under a wider group of disorders which could be known as ‘clinical endocannabinoid deficiency syndrome’.

‘…disorders that may overlap in their affected populations and whose sufferers have all endured the stigma of a psychosomatic label, as well as the failure of endless pharmacotherapeutic interventions with substandard benefit.’

Psychiatric cormorbidities are often preset in CVS, and avoiding 'triggers’ is often a central part of treatment. Which may explain some of the following scenarios reported by some patients diagnosed with cannabinoid hyperemesis syndrome. Patients have noted their sensitivity towards cannabis going from tolerant, to feeling nauseous, to being unable to tolerate 2nd hand cannabis smoke, to even a whiff of 2nd hand smoke from a colleagues clothing being enough to trigger vomiting. While overstimulation of the CB1 receptor is thought to be one possible mechanism to explain CHS, as has been noted with synthetic cannabinoids, for vomiting to be triggered by the smell of cannabis from someones clothing would suggest a psychological trigger, as no aerosolised cannabinoids were inhaled or entered the bloodstream but vomiting was induced.

Possible pharmacodynamic factors. If interference with cannabinoid signalling is a mechanism of action in CVS and CHS, we need to talk about pesticides and pesticide synergists .

Could a ‘negative entourage’ effect be to blame?

While some CHS patients feel they have excluded pesticide contamination in cannabis, unless very strict checks have been made sourcing food products there is still the potential for accumulated pesticides in the food chain, combined with any exposure in cannabis, to produce a negative entourage effect. Others have reported a connection with a particular source of cannabis and finding resolution of symptoms following stopping or changing source. The majority of pesticides in our food supply are only tested individually to decide a ‘safe residue level’, but in real world practice are used in combination with multiple other pesticides and synergists that haven’t been tested in combination. There is very little evidence regarding the safety of inhaled/vaporised/combusted pesticides with producers typically following what is considered ‘food safe’ levels of residue.

First up, piperonyl butoxide, a synthetic pesticide synergist that was patented in 1947 and described as ‘a new and safe insecticide for the household and field’.

‘Despite never being listed in the organic regulation, the use of piperonyl butoxide has been tolerated in EU organic farming for a long time. The first version of regulation 2092/91 listed pyrethrins with the comment ‘possibly containing a synergist’. Its use in organic farming is tolerated, if it is authorised at member state level. Under pesticide legislation, piperonyl butoxide is considered as a ‘synergist’. Synergists are substances or preparations which, while showing no or only weak activity [...], can give enhanced activity to the active substance(s) in a plant protection product (Reg. 1107/2009, Art 2.3(b)).

No Maximum Residue Level for piperonyl butoxide is fixed within EU.

‘Piperonyl butoxide contains the functional group methylenedioxyphenyl, which inhibits enzymatic breakdown (detoxification) of pyrethrin within the insect body.

Because piperonyl butoxide is not considered to be an active substance, no EFSA evaluation report is available. Toxicological data were summarised in 1999 by the Veterinary Medicines Evaluation Unit (EMEA 1999). Acute toxicity is low, but long-term exposure may lead to liver damage. The WHO has set an acceptable daily intake of 0.2 mg/kg, which indicates no major toxicological concerns.

The use of piperonyl butoxide is not in line with the objectives, criteria and principles of organic farming. It should therefore not be included in Annex II, and the tolerance of its use should be phased out.’

‘It is possible that in some EU member states, all registered pyrethrin products contain piperonyl butoxide at the moment. In order to ensure continuous use of pyrethrin by organic farmers, an adequate transition period should be allowed, during which the manufacturers can modify their pyrethrin products (to substitute piperonyl butoxide), and register the new formulations.’

Reflections of the Group / Balancing of arguments in the light of organic farming principles

Piperonyl butoxide blocks CB1 signalling.

Its activity as a CB1 antagonist was described in a 2014 study as ‘may have potential to modify CB1-receptor-dependent behavioral/physiological outcomes in the whole animal.’

For context, it fairly common to get up to 20mg of Piperonyl Butoxide per kg of wheat as a maximum accepted residue, while leafy greens may contain up to 50mg per kg!

The action of Piperonyl Butoxide as an insecticide synergist is to prevent the breakdown other pesticides in the liver therefore increasing toxicity, while inhibiting the CB1 receptor.

From a 2017 study in Greece into the safety of Piperonyl Butoxide:

‘Piperonyl Butoxide is a potent inhibitor of cytochrome P450 enzymes (and of esterases). This is the proposed mechanism of acting as a synergist together with pyrethrins and synthetic pyrethroids, inhibiting the enzymatic degradation of these. Upon repeated exposure, Piperonyl Butoxide induces hepatic cytochrome P450 enzymes. This results, at high dose levels, in hepatocellular hypertrophy, cell proliferation and hepatotoxicity. This has been demonstrated in mechanistic studies in rodents.’

In Oregon, the following consideration is given to pesticides in cannabis, describing Piperonyl Butoxide as having a ‘potential for misuse.’

‘Piperonyl butoxide and pyrethrins may be allowed for use on cannabis. However, they remain on the target analyte list because of potential for misuse. OHA counterparts in Colorado, where some marijuana has already been tested for pesticide residues, reported to OHA that they have found very high concentrations of piperonyl butoxide (up to 50 parts per million [ppm]) in cannabinoid concentrates. They also report that piperonyl butoxide and pyrethrins are typically used together. The actionable level is 2ppm.’

‘Oregon Health Authority Issues Another Pesticide Residue Alert’ after two dispensaries sold flower tainted with piperonyl butoxide and spinosad.

‘Effects of smoking marijuana containing spinosad or piperonyl butoxide are not known. Those concerned about exposure to spinosad or piperonyl butoxide, or anyone experiencing health problems after using affected marijuana strains, should contact the Oregon Poison Center’

Another correlated symptom of CB1 inhibition and Piperonyl Butoxide exposure is reduced exploratory behaviour in mice.

With the same results being reported in genetically modified mice that lack CB1 receptors (CB1 knock-out mice)

‘CB1-knockout mice showed a reduced exploration of the open arms of the plus-maze apparatus, thus appearing more anxious than the wild-type animals’

From Washington: Pesticides that May Be Used and Health Effects

‘The use of pesticides not specifically registered for use on a crop raises health and safety issues. An allowance of a pesticide use and exposure pattern not evaluated for its potential health impacts remains a concern among health advocates.

WSDA has compiled a list of 271 allowed pesticide products that fit the criteria it developed in its opinion on cannabis production. A review of the list finds pesticides exempt from tolerances by EPA, such as pyrethrins, sulfur, and essential oils. However, it appears that WSDA does allow a material (sodium lauryl sulfate) that is not exempt from a tolerance. On the other hand, the synthetic piperonyl butoxide (PBO), frequently used as a synergist to enhance the toxicity of a pesticide product’s active ingredient, is allowed by WSDA because its use in crop production is exempt from a tolerance.

Between April 2019 and May 2020 the United States imported 20 tons of pure Piperonyl Butoxide. This number does not include the piperonyl butoxide contents imported in other pre-mixed pesticide formulations.

Organophosphates:

‘Organophosphates (OPs) are esters of phosphoric acid that covalently bind to Acetylcholinesterase (AChE), causing over-stimulation of neurons. More recently, some OPs are recognized to have off-target toxicities at concentrations below the inhibition of AChE. For example, some OPs can inhibit or activate serine hydrolases and inhibit cannabinoid receptor 1 (CNR1)

To get an idea of some of the potential downstream effects, from ‘Acetylcholinesterase Inhibitors: Pharmacology and Toxicology’

‘enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission.’

Whether its from a medication such as donepezil or rivastigmine, or a pesticide such an organophosphates, nausea is a known side effect of AChE inhibtion.

Chlorpyrifos:

The 2011 study, ‘Effect of Developmental Chlorpyrifos Exposure, on Endocannabinoid Metabolizing Enzymes, in the Brain of Juvenile Rats’, showed that:

Chlorpyrifos inhibited the hydrolysis of endogenous cannabinoids 2-AG and AEA in a dose-related manner, and the effects of repeated exposure of Chlorpyrifos on the brains endocannabinoid metabolism was not yet known.

Spinosad:

‘The specific mode of action of spinosad is to alter the function of nicotinic and GABA-gated ion channels, causing rapid excitation of the insect nervous system, leading to involuntary muscle contractions, tremors, paralysis, and death.’

Mode(s) of Action:

‘The mechanism of action of spinosad and other spinosynson insecticides is not entirely clear, but they are known to act on both GABA and nicotinic acetylcholine receptors of the membranes of nerve cells of insects through pathways distinct from those of other insecticides.

The mechanism or mechanisms of mammalian toxicity are not known.

During tests on dogs, the most common clinical sign of spinosad toxicity was vomiting.’

Cannabis samples with spinosad at 100x the legal limit have been found for sale on the US market.

Neem oil:

Neem oil has been well covered in the CHS discussion prior but is worth mentioning. While neem poisoning does not match exactly with CHS symptoms, there are unidentified pharmacodynamic factors within neem oil due to lack of regulation surrounding its production. Neem products will often contain piperonyl butoxide as a synergist, and may contain other traces of pesticides used during growth and storage due to varying regulations in production.

Looking through the 2020 permitted pesticide list for use on cannabis and hemp in Colorado, there are 9 products containing Piperonyl Butoxide, with 5 of the 9 containing more that 60% concentration of Piperonyl Butoxide and one approved for use at over 91% concentration. Being a known CB1 inhibitor, this is clearly something that warrants further study.

Genetic polymorphisms:

Another factor to consider is cannabinoid receptor polymorphisms. A 2017 study found for the first time that certain CB1 polymorphisms are associated with an increased risk of CVS, while others appear to reduce the risk.

‘Our results show for the first time that the variations in CNR1 and OPRM1 genes are associated with CVS and that different genotypes may contribute to the risk of CVS.’

If you would like to participate in further research into cannabinoid hyperemesis syndrome, Dr Ethan Russo, MD and associates, and Endocannahealth are (at time of press) currently looking for volunteers to take part in a study. Using DNA analysis, the aim is to find genetic variants and their correlation with cannabinoid hyperemesis syndrome. More information on participating in the study can be found here.

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