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Cannabinoid Hyperemesis Syndrome Survey
and Genomic Investigation
Ethan B. Russo,
1,
*
,i
Chris Spooner,
2
Len May,
3
Ryan Leslie,
3
and Venetia L. Whiteley
1
Abstract
Background: Cannabinoid hyperemesis syndrome (CHS) is a diagnosis of exclusion with intractable nausea, cy-
clic vomiting, abdominal pain, and hot bathing behavior associated with ongoing tetrahydrocannabinol (THC)
exposure. Increasing cannabis use may elevate CHS prevalence, exacerbating a public health issue with atten-
dant costs and morbidity.
Objective, Design, and Data Source: This study, the largest contemporaneous database, investigated genetic
mutations underlying CHS. Patients with CHS diagnosis and ongoing symptoms were compared with current
cannabis users lacking symptoms.
Target Population: A screening questionnaire was posted online. Of 585 respondents, 205 qualified as the CHS
pool and 54 as controls; a reduced pool of 28 patients and 12 controls ultimately completed genomic testing.
Results: Patients and controls were high-frequency users of cannabis flower or concentrates (93%), using mul-
tiple grams/day of THC-predominant material. Among patients, 15.6% carried diagnoses of cannabis depen-
dency or addiction, and 56.6% experienced withdrawal symptoms. About 87.7% of patients improved after
cannabis cessation, most suffering recurrence rapidly after resumption. Findings in patients included mutations
in genes COMT {odds ratio, 12 (95% confidence limit [CL], 1.3–88.1) p=0.012}, transient receptor potential vanil-
loid receptor 1 (TRPV1) (odds ratio, 5.8 [95% CL, 1.2–28.4] p=0.015), CYP2C9 (odds ratio, 7.8 [95% CL, 1.1–70.1]
p=0.043), gene coding dopamine-2 receptor (DRD2) (odds ratio, 6.2 [95% CL, 1.1–34.7] p=0.031), and ATP-
binding cassette transporter gene (ABCA1) (odds ratio, 8.4 [95% CL, 1.5–48.1] p=0.012).
Limitations: Some participants were reluctant to undergo genetic testing; only 28 of 99 CHS patients who
agreed to testing ultimately returned a kit.
Conclusion: This is the largest patient cohort of CHS examined to date, and first to note associated mutations in
genes affecting neurotransmitters, the endocannabinoid system, and the cytochrome P450 complex associated
with cannabinoid metabolism. Although the sample size was smaller than desired, these preliminary findings
may contribute to the growing body of knowledge, stimulate additional investigation, help elucidate the path-
ophysiology of CHS, and, ultimately, direct future treatment.
Keywords: cannabinoid hyperemesis syndrome; cannabinoids; tetrahydrocannabinol; cannabis; nausea; vomit-
ing; abdominal pain; substance abuse; genomics
Introduction
Cannabinoid hyperemesis syndrome (CHS) is an enig-
matic constellation of signs and symptoms comprising
nausea, vomiting, abdominal pain, and unusual hot
bathing behavior in the context of heavy and chronic
exposure to tetrahydrocannabinol (THC), the primary
intoxicating agent of Cannabis sativa. It was first
reported in Australia in nine patients in 2004, but the
1
CReDO Science, Vashon, Washington, USA.
2
Paradigm Naturopathic Medicine, Vernon, Canada.
3
Endocanna Health, Los Angeles, California, USA.
i
ORCID ID (https://orcid.org/0000-0003-4715-515X).
*Address correspondence to: Ethan B. Russo, MD, CReDO Science, 20402 81st Avenue SW, Vashon, WA 98070, USA, E-mail: ethanrusso@comcast.net
ªEthan B. Russo et al.; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution
Noncommercial License [CC-BY-NC] (http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and
reproduction in any medium, provided the original author(s) and the source are cited.
Cannabis and Cannabinoid Research
Volume X, Number X, 2021
Mary Ann Liebert, Inc.
DOI: 10.1089/can.2021.0046
1
index case dated to 1996.
1
Subsequently, CHS has been
frequently reported in the literature, especially in the
United States, where access to high potency cannabis
and derivatives is widespread. The largest case study
from Mayo Clinic described 98 patients,
2
and Pergo-
lizzi et al. collected the literature through May 2018,
uncovering 105 journal citations
3
in some hundreds
of patients. Current authors’ queries to emergency de-
partment personnel and gastroenterologists suggest
that the problem is burgeoning, and now rarely
reported despite its public health relevance.
CHS is remarkably stereotyped in its presentation
4
:
history of regular cannabis use for over 1 year (74.8%),
severe nausea and vomiting (100%), vomiting recurring
in cyclic patterns over months (100%), resolution of
symptoms after stopping cannabis (96.8%), compulsive
hot baths/showers with symptom relief (92.3%), male
predominance (72.9%), abdominal pain (85.1%), at
least weekly cannabis use (97.4%), and history of daily
cannabis use (76.6%). Patients tend to be younger, likely
reflecting cannabis use patterns rather than predilection.
CHS is associated with frequent hospitalizations, nega-
tive workups as a ‘‘diagnosis of exclusion’’ whose median
costs may exceed $95,000 per patient.
5
At least two
deaths have been documented with hyponatremia,
hypochloremia, and elevated urea in the vitreous fluid.
6
The phenomenology and theoretical pathophysiol-
ogy of CHS have been expertly reviewed.
7
Asine qua
non is exposure to high, chronic doses of THC, a partial
agonist of the cannabinoid receptor 1 (CB
1
) prevalent
in the brain, gut, and throughout the body. Cannabi-
noids display biphasic dose–response effects
8
; whereas
THC is well recognized as an antiemetic in cancer
chemotherapy, high doses are proemetic. CHS presents
in phases: a prolonged prodrome with morning
nausea, anxiety, diaphoresis, and flushing, followed
by a hyperemetic phase with abdominal pain, nausea,
vomiting, and hot-water bathing that becomes compul-
sive, eventually monopolizing the patient’s activity.
This stage is prolonged until abstinence from cannabis.
A recovery phase follows abstinence but may require a
long interval before total subsidence. Re-exposure initi-
ates the cycle de novo. Administration of serotonin
type-3 (5-HT
3
) antagonists is usually ineffective in con-
trolling nausea, while intravenous haloperidol has pro-
ven superior in a small randomized controlled trial,
9
although with associated akathisia and dystonia.
CHS has been characterized as a downregulation of
the CB
1
receptor and endocannabinoid system (ECS),
the basic homeostatic regulator of vertebrate physiology,
as a result of chronic THC exposure.
10
CHS is also
accompanied by sympathetic nervous system dysregula-
tion and activation of the hypothalamic–pituitary–
adrenal axis.
11
In addition to disturbances of CB
1
func-
tion, CHS seems to encompass changes in transient
receptor potential vanilloid receptor 1 (TRPV1) activity.
Heat and acid stimulate TRPV1, as does capsaicin, the
caustic agent of capsicum. Cutaneous capsaicin tempo-
rarily abrogates symptoms, and has a longer half-life
and better bioavailability than oral administration.
12
Capsaicin desensitizes TRPV1, thereby reducing gut
pain
12
and counteracting nausea through depletion of
substance P in the brainstem nucleus tractus solitarius.
13
Many CHS sufferers disbelieve THC overexposure as
its etiology,
9
and the necessity of abstinence to achieve
remission, prompting alternative hypotheses, such as
pesticide contamination of cannabis. Organophosphate
exposure symptoms or that for neem (Azadirachta ind-
ica), a botanical insecticide, are inconsistent with those
of CHS, which may also appear with chronic use of
synthetic CB
1
agonists (e.g., ‘‘K2’’ and ‘‘Spice’’).
CHS is frequently misdiagnosed as cyclic vomiting
syndrome (CVS), recently labeled a ‘‘functional’’ gas-
trointestinal (GI) disorder, or ‘‘disorder of gut–brain
interaction’’ in the Rome IV criteria,
14,15
but CVS
often appears in childhood as a forme fruste of mi-
graine, which is less often associated with compulsive
hot bathing behavior. Confusion has arisen due to
the increasing adoption of cannabis as treatment for
CVS.
16
Interestingly, CVS is associated with AG and
GG genotypes of the CB
1
receptor, gene coding CB
1
re-
ceptor (CNR1) rs806380.
17
This study is the largest survey of CHS patients
available to date, and the first to examine genetic ab-
normalities systematically. A working hypothesis was
that mutations could be identified in genes coding
the CB
1
,CB
2
, TRPV1 receptors, or those coding for
catabolic THC enzymes.
Materials and Methods
Study design and participants
This study was approved by the Western Institu-
tional Review Board November 8, 2019 (Protocol
#20192689). A detailed questionnaire for prospective
CHS patient candidates was distributed through
cannabis-related list-serves, websites, the Society of
Cannabis Clinicians, and direct solicitations directed
to previous investigators of published studies, open
for 1 year November 2019–October 2020. Ultimately,
585 people responded (CONSORT diagram, Fig. 1).
2 RUSSO ET AL.
All CHS Qualified Participants displayed the constel-
lation of symptoms of CHS,
4
were diagnosed by phy-
sicians and had ongoing symptoms, N=205. Of
these, 99 patients, primarily from the United States
and Canada, but with one patient each from Scotland
and Hungary, agreed to accept genomic test kits.
Control patients fulfilled three criteria: (1) never di-
agnosed with CHS; (2) used cannabis regularly; and
(3) lacked vomiting, nausea, and abdominal pain.
CHS patients and controls were offered genomic
FIG. 1. CONSORT style diagram and flow sheet of CHS patients and controls. CHS, cannabinoid
hyperemesis syndrome.
CHS GENOMIC INVESTIGATION 3
testing. Ultimately, only 28 CHS patients and 12 con-
trols returned test kits (Fig. 1), due to some dissent
from the online CHS community (v.i, Limitations
section for additional information). The demograph-
ics of the two groups are compared (Table 1).
Genotyping methods
Genotyping was undertaken using the Illumina
Infinium high-throughput screening (HTS assay),
18,19
using Infinium probes and a dual-color channel ap-
proach. Multiplexing was accomplished by combining
whole-genome amplification sample preparation with
direct, array-based capture and enzymatic scoring of
the single nucleotide polymorphism (SNP) loci.
Locus discrimination or copy number variation was
determined from a combination of high bead-type rep-
resentation, sequence-specific hybridization capture,
and array-based, single-base primer extension. Perfect
matches were extended and a signal generated. Mis-
matches produce no extension or signal generation.
Allele-specific, single-base extension of the primer
incorporates a biotin nucleotide or a dinitrophenyl-
labeled nucleotide. C and G nucleotides are biotin la-
beled. A and T nucleotides are dinitrophenyl labeled.
Signal amplification of the incorporated label further
improves the overall signal-to-noise ratio of the assay.
The genomic analysis of the DNA samples submit-
ted for this study was obtained utilizing the Infinium
HTS assay and the automated workflow for 4 Bead-
Chips. DNA samples were plated, denatured, and neu-
tralized to prepare them for amplification. Reagents
were applied robotically, then incubated for >20 h.
DNA was then enzymatically fragmented. An endpoint
fragmentation was used to prevent overfragmentation.
One hundred percent 2-propanol and PM1 was
employed to precipitate the DNA. Precipitated DNA
was resuspended using RA1 reagent and incubated
for 1 h. The fragmented, resuspended DNA was dis-
pensed onto BeadChips, incubated, then hybridized.
BeadChips were washed in PB1 solution and assembled
into flow-through chambers. Labeled nucleotides were
added to extend primers hybridized to the samples be-
fore staining. After the flow-through chambers were
disassembled, the BeadChips were coated for protec-
tion. BeadChips were subsequently scanned using the
Illumina iScanSystem.
Statistical analysis
Using an analysis software, the subject’s DNA files were
grouped, compared, and searched. Genetic variants
with potential to impact CHS pathologies were used
as a base to find common variants among the pa-
tients. Visible associations with Enliter software were
recorded for statistical analysis. Fisher’s exact test was
used to evaluate significant differences in genetic vari-
ants. Odds ratio with 95% confidence was applied to
confirm significance.
Results
Survey findings
The survey yielded 585 respondents (Fig. 1). Two
hundred five respondents were eligible for genomic
testing fulfilling criteria of (1) current cannabis use;
(2) periodic nausea and vomiting, abdominal pain
alleviated by hot showers or baths; and (3) diagnosis
of CHS. Complete questionnaire responses of CHS
Qualified Participants are available (Supplementary
Appendix S1).
About 62.1% of the cohort were not on CYP2C19-
inhibitor medications. A slight majority were female.
Table 1. Demographic Comparison of Cannabinoid Hyperemesis Syndrome Patients and Controls
CHS patients Control subjects
Age Mean: 33.8 SD: 12 Mean: 43.8 SD: 13.8
Sex Female: 53.6% Male: 46.4% Female: 60% Male: 40%
Smoking habit 85.7% daily consumers 70% daily consumers
Prescribed SSRI 10.7% 20%
Prescribed PPI 28.6% 0%
Diagnosed w/CVS 38.3% 0%
a
Diagnosed w/IBD 28.6% 0%
Diagnosed w/gallbladder disease/removal 32.1% 0%
Symptomatic abdominal pain 89.3% 0%
Symptomatic nausea/vomiting 82.1% 0%
Related hospitalization 75% 0%
a
Control screening criteria removed any subjects with bolded conditions or symptoms.
CHS, cannabinoid hyperemesis syndrome; CVS, cyclic vomiting syndrome; IBD, inflammatory bowel disease; PPI, proton pump inhibitor; SD, stan-
dard deviation; SSRI, selective serotonin reuptake inhibitor.
4 RUSSO ET AL.
In all, 85.7% were daily or greater-than-daily cannabis
users, 97.1% smoked cannabis, 53.7% vaporized. About
90.7% utilized flower primarily by smoking, while
58.5% employed cannabis concentrates, primarily by
vaporization. As depicted in Supplementary Appendix
S1, usage rates were high, with 4 g and many inhala-
tions/day as the most frequent responses. About
89.1% employed THC-predominant cannabis, and
56.1% considered their usage recreational versus 5.9%
medical, and 38% both. Associated complaints in-
cluded chronic pain 50%, sleep 53.3%, and nausea
35.6%. Only 22.2% had tried cannabidiol (CBD)-
predominant cannabis. About 21.5% carried cannabis
dependency or addiction diagnoses; 91.5% had been
told at some point to stop cannabis usage for health
reasons. Seventy-five percent reported withdrawal
symptoms: anxiety, depression, insomnia, and irritabil-
ity. None were pregnant, but of 107 female respondents
who had been pregnant, 57.9% acknowledged history
of severe morning sickness or hyperemesis gravidarum.
About 48.8% had been labeled as having CVS, 32.45%
migraine, and 28.3% irritable bowel syndrome.
All had nausea and vomiting history, often lasting
days to years. Attacks were weekly in 14% and more
often in 16%. There were no clear patterns related to
menstrual cycles. Abdominal pain extended days to
years, with 16% weekly and 27% more often. About
86.8% had been medically evaluated for their symp-
toms, with 78.7% requiring hospitalization. About
90.1% reported improvement of symptoms after absti-
nence from cannabis, while 100% were better after hot-
water exposure.
Patients experienced long delays before CHS diagno-
sis: 21% after several months and 61% after >1 year.
Most had been tried on multiple drug treatments, but
heat was cited as most effective. For 69%, attacks lasted
several days, but for 15.2% they remained ongoing.
Alleviation of symptoms required days to weeks post-
abstinence. About 79.4% resumed cannabis usage
with recrudescent symptoms, 69% after a more than
a week, and after increasing intake rates or develop-
ment of THC tolerance in 75.9%. When queried as to
their opinions of the etiology of CHS, 30% cited a prob-
lem in the ECS, 6% blamed pesticides, and 2% blamed
neem exposure.
Among controls (Supplementary Appendix S2),
the pool encompassed 54 respondents (Fig. 1), whose
usage patterns were quite similar to CHS patients
(Table 1 and Supplementary Appendix S2): 100%
used cannabis within 1 year, 70% daily or greater
than daily, mostly by smoking. In marked contrast to
the CHS cohort, only 3.7% had historical labels of can-
nabis addiction/dependency, 76% had never experi-
enced withdrawal symptoms, and only 11.1% had
been told to stop for health reasons.
Identification of genetic variants predicted
to relate to CHS pathophysiology
Primary findings of genomic testing are summarized
(Table 2):
CNR1. SNP in the CNR1 gene coding for CB
1
receptor
has been associated with cannabis usage,
20
but was not
significant in the CHS cohort, contrary to the initial
hypothesis and to the findings in CVS.
17
COMT. ACOMT mutation was observed on the
intron in CHS patients {odds ratio, 12 (95% confidence
limit [CL], 1.3–88.1) p=0.012}.
COMT (catechol-o-methyltransferase) catabolizes
catecholamines, especially dopamine. Conditions of
dopamine excess, encountered in pharmacotherapy
Table 2. Summary of Genomic Testing Results of Cannabinoid Hyperemesis Syndrome Patients Versus Controls
Gene RSID Mutation Allele Zygosity Diplotype Haplotype p
a
Odds ratio
(confidence
interval)
Control
displaying
variant (%)
CHS patients
displaying
variant
COMT rs4646316 Intron C >T Heterozygous CGGC/TGGC CGGC 0.012 12 (1.3–98.1) 10 57.1%
ABCA1 rs2230806 Synonymous C >T Homozygous CTTG/CTTG CTTG 0.012 8.4 (1.5–48.1) 20 67.9%
TRPV1 rs879207 Downstream A >G Heterozygous ATGG/GTGG ATGG 0.015 5.8 (1.2–28.4) 30 71.5%
DRD2 rs4648318 Intron T >C Heterozygous TCCC/CCCC TCCC 0.031 6.2 (1.1–34.7) 20 60.7%
CYP2C9 rs1934967 Intron C >T Homozygous CTTG/CTTG CTTG 0.043 (0.011
b
) 7.8 (1.1–70.1) 10 46.4% (60%
b
)
TRPV1 rs11655540 Intron T >G Heterozygous TCAA/GCAA TCAA 0.066 4.2 (0.8–19.9) 30 64.3%
COMT rs165656 Intron C>T Heterozygous CCGG/TCGG CCGG 0.069 4.6 (0.8–25.7) 20 53.6%
CYP2C19 rs4494250 Intron G >A Heterozygous GCTT/ACTT GCTT 0.069 (0.007
b
) 4.6 (0.8–25.7) 20 53.6% (75%
b
)
CRY1 rs2287161 Downstream G >C Heterozygous GTCG/CTCG GTCG 0.091 3.7 (0.8–16.9) 50 78.6%
a
p-Values were obtained through a Fisher exact test. Odds ratios are shown with a 95% confidence interval.
b
Genes CYP2C9 and CYP2C19 have a second set of values showing when patients on PPI medications were excluded from the data. This was due to
suspected interactions of CYP2C9 and CYP2C19 and PPI medication.
CHS GENOMIC INVESTIGATION 5
with dopamine agonists such as L-dopa and bromo-
criptine, are associated with compulsive behavior, in-
cluding gambling, sex addiction, and substance abuse,
particularly alcoholism.
Mutations of COMT have been investigated, and
specifically including this RSID (reference SNP cluster
ID [identification]), rs4646316. A Finnish group inves-
tigated the relationship of monoamines to depression
in a birth cohort of 5225 patients.
21
This COMT muta-
tion was associated with depression based on Hopkins
Symptom Checklist-25 (HSCL) score ( p=0.026).
Other COMT mutations have been associated with
poor antidepressant responses.
Patients with COMT haplotypic variants showed sta-
tistically significant impulsivity.
22
COMT inactivates dopamine in the prefrontal cortex
(PFC), as there is a dearth of dopamine transporter in
that location. Enzymatic hypofunction can be linked
to deficits in working memory, executive functions,
cognitive flexibility, and the ability to inhibit behav-
ioral impulses. COMT has additionally been linked
to attention-deficit hyperactivity disorder, obsessive-
compulsive behavior, addiction, anxiety, and psychosis.
Such PFC hypofunction attributable to excessive dopa-
minergic activity would explain some CHS phenome-
nology such as compulsive behavior traits.
In a related study,
23
COMT mutations were linked to
ruminative behavior and depression. The rs4646316
variant correlated strongly to Ruminative Response
Scale scores ( p=0.028). Dopamine dysfunction in the
PFC, amygdala, striatum, and hippocampus could
lead to an ‘‘impulsive cognitive style.’’ Hypoactive
COMT mutations were hypothesized to increased
dopamine in the PFC and promote rumination, in-
creasing rigidity and inflexibility that parallel the obser-
vations of fixed behaviors in CHS patients: prolonged
employment of high-THC cannabis despite medical
warnings against its continued usage, compulsive hot-
water bathing, etc.
An additional study examined 193 in-patient
alcoholics for mood disturbances and tendency toward
relapse.
24
COMT rs4646316 was associated with onset
of heavy alcohol intake at a younger age in female
patients.
COMT is said to moderate THC effects on memory
and attention,
20
and a genotype with CHS in position
c.472 increased likelihood of cognitive impairment
with cannabis.
25
The Val158Met mutation in COMT
has been associated with psychotic symptoms and de-
velopment of schizophrenia in cannabis users.
26,27
Haloperidol, a dopamine antagonist (mostly D2),
has proven more effective as an antiemetic in treatment
of CHS as compared with 5-HT
3
antagonist agents,
9
but is inferior to topical capsaicin. Given evidence
above of excessive dopaminergic activity in CHS,
with dopamine as a known proemetic,
28
the superiority
of haloperidol to first-line antiemetics is sensible.
TRPV1. A mutation was observed downstream in CHS
patients (odds ratio, 5.8 [95% CL, 1.2–28.4] p=0.015).
TRPV1 receptor responds to heat, ethanol, and low
pH, which is strongly associated with pain responses.
Capsaicin is a natural agonist/desensitizer of TRPV1,
as is CBD.
29
While endocannabinoids anandamide and
2-arachidonylglycerol (2-AG) are ligands, THC is not.
TRPV1 has been linked to anxiety and pain responses
in the brain, mediates long-term synaptic depression
in the hippocampus, and controls glutamate release in
the brainstem solitary tract nucleus affecting gut motility
and secretion.
30
No previous studies have associated
TRPV1 polymorphism with cannabis dependency.
20
Although this rs879207 mutation was not found in
National Library of Medicine-listed publications, its
identification in the CHS cohort suggests its observed
roles in anxiety, pain, and gut motility disturbances,
and the fact that hot-water bathing and clinical re-
sponse to cutaneous capsaicin application are critical
factors of CHS phenomenology. Topical capsaicin
absorption likely reaches the GI tract and brain, ame-
liorating propulsion, nausea, anxiety, and pain engen-
dered by this mutation through some yet to be
explained mechanism, possibly mediated through the
brainstem nuclei, as hypothesized in relation to a single
case report of apreptitant alleviating a CHS attack.
31
Alternatively, CBD without concomitant THC con-
tent might achieve the same end as a TRPV1 agonist/
desensitizer without caustic effects.
29
CYP2C9. A mutation was observed in the intron of
CYP2C9 in CHS patients (odds ratio, 7.8 [95% CL,
1.1–70.1] p=0.043), but 0.0011 with exclusion of pa-
tients on proton pump inhibitors (PPIs).
Cytochrome P450 isozyme 2C9 is a catalyst for ca-
tabolism of various drugs, and endogenous vitamin
D, steroids, and fatty acids, especially arachidonic
acid,
32
the latter a precursor to the endocannabinoids,
anandamide and 2-AG. Although primarily located in
the liver, CYP2C9 is also found in the vasculature.
Some P450 enzymes are also expressed in the brain,
sometimes in greater concentrations than the liver,
6 RUSSO ET AL.
and can be important in responses to pharmaceuticals
and expressed adverse event profiles,
33
particularly tox-
icities associated with neurological disorders and be-
havioral abnormalities.
34
CYP2C9 is the main catabolic enzyme for THC
breakdown in the liver, as well as that of its psychoac-
tive metabolite, 11-OH-THC. Concentrations of the
latter were increased in carriers of CYP2C9*3 alleles
and calculated intrinsic clearances 33% compared
with CYP2C9*1 carriers,
35
suggesting that slow metab-
olizers would experience prolonged exposure to psy-
choactive effects and might consider genomic testing
before THC exposure.
Deficits in CYP2C9 function could lead to accumu-
lation of THC in the brain, resulting in toxicity ascrib-
able to the biphasic dose-response, that is, a reversal of
effect at elevated doses. Antiemetic THC becomes
proemetic at higher doses. Similarly, if catabolism of
11-hydroxy-THC becomes impaired due to hypoactiv-
ity of CYP2C9, it also could exert toxic effects. All
known metabolites downstream of 11-hydroxy-THC
are inactive, but an additional possibility is that an al-
tered enzyme catalyzes production of a yet-unidentified
proemetic THC metabolite.
A remaining explanation is that overexposure to
THC produces a downregulation of the CB
1
receptor,
causing it to turn from a partial agonist to an antago-
nist,
36
a phenomenon that could be hastened by im-
paired metabolism.
The rs1934967 mutation was identified as homozy-
gous in our study cohort, increasing the likelihood
that it has relevance to the pathophysiology of the syn-
drome. Further support derives from a recent case re-
port of a patient with CHS, cannabis dependency,
and personality disorder with a mutation in CYP2C9
and CYP2C19.
37
Mutations of CYP2C9 have been asso-
ciated with synthetic THC metabolism.
38
The haplotype CCAC of this mutation has been
linked to coronary artery disease risk in Han women
in Xinjiang ( p=0.016).
32
CYP2C19. CYP2C19 is an accessory catabolic enzyme
for THC. A mutation was observed in CHS patients
just missing statistical significance (odds ratio, 4.6
[95% CL, 0.8–25.7] p=0.0690), but 0.007 when pa-
tients on PPI were excluded.
DRD2. A mutation was observed in the intron of gene
coding dopamine-2 receptor (DRD2) in CHS patients
(odds ratio, 6.2 [95% CL, 1.1–34.7] p=0.031).
DRD2 gene codes for the type-2 dopamine receptor,
target for most antipsychotic drugs through its antago-
nism. It has a primary role in fear memories in the pre-
limbic areas,
39
and has been associated with depression
and anxiety.
21
Stimulants of this receptor have gut
motility and clear proemetic effects.
28
Among the strongest statistical associations of
genomic findings in a Finnish cohort were related to
the rs4648318 intron mutation: HSCL ( p=0.00005)
regardless of early environmental factors, HSCL de-
pression subscore ( p=0.0015), and HSCL anxiety sub-
score ( p=0.02312).
21
Other DRD2 mutations have
been associated with nicotine dependence, Tourette
syndrome, tanning addiction, and persistent pain.
The combination of dopamine-2 receptor and dopa-
mine metabolism mutations in the cohort highlights its
importance in CHS pathophysiology and phenomenol-
ogy with respect to nausea and vomiting, as well as
associated psychiatric challenges.
ABCA1. A mutation was observed in synonymous
areas of ATP-binding cassette transporter gene
(ABCA1) in CHS patients (odds ratio, 8.4 [95% CL,
1.5–48.1] p=0.012).
ABCA1 is the gene coding the ATP-binding cassette
transporter, previously known as the cholesterol efflux
regulatory protein, which affects cholesterol and phos-
pholipid homeostasis, key to Alzheimer’s disease (AD)
and problems associated with apoE accumulation and
Abdeposition.
40
Comparison of 431 AD patients
with 302 elderly cognitively normal controls revealed
that a rs2230806 mutation was over-represented in de-
mented patients in a ‘‘recessive model’’ ( p=0.048).
Homozygosity in our cohort could imply increased
risk of dementia. Additional correlations for mutations
of this gene include associations with coronary artery
disease and type-2 diabetes mellitus.
Polymorphisms in a different gene, ABCB1, have
been demonstrated to alter drug pharmacokinetics,
and increased cannabis dependency was noted in the
3435C allele over controls.
41
CRY1. CRY1, cryptochrome 1 (photolyase-like), is a
gene involved in the circadian rhythm regulation,
42
mood disorders, and alcoholism.
43
Whereas no statisti-
cally significant differences were seen in our sampling
between CHS patients and controls, it is included
here as possibly relating to the pathophysiology of
the disorder.
CHS GENOMIC INVESTIGATION 7
Discussion
Limitations
CHS remains an under-recognized diagnosis with a few
hundred case reports in the literature. The survey re-
sults for the 205 patients in the CHS pool were based
on current and ongoing symptoms plus medical diag-
nosis, and represent a valid dataset concordant with
prior reviews.
The primary limitation of this study was the reduced
number of returned kits from eligible CHS patients.
Whereas 99 patients from the CHS pool agreed to
receive genomic test kits, only 28 (28.3%) actually
returned them. It is certainly possible that a larger data-
set would present different results. Unfortunately, this
study was the center of considerable controversy in
the online CHS community, with some members
actively questioning its motives and dissuading partic-
ipation. Similar reticence in patient recruitment, com-
pliance, and follow-up has been noted in a recent CHS
study.
9
Hesitation might also be attributed to suspicion
in patients with CHS, coupled with long-standing and
increasing concerns that the general public harbors
with respect to provision of their genetic information
and how it might be a threat to health insurance cover-
age,
44
employment, or legal exposure. It is the authors’
hope that the results to date, although possibly prelim-
inary, may stimulate additional interest and investiga-
tion to corroborate and expand current findings.
Conclusions
Five mutations with plausible etiological roles in the
phenomenology of CHS symptoms and signs have
been identified with statistical significance from a
small dataset. Pending corroboration from future test-
ing in CHS patients, this constellation of genetic sus-
ceptibilities may represent a valid diagnostic battery
for diagnosis of the syndrome that would identify at-
risk individuals and provide an alternative to more ex-
pensive invasive testing in this previous diagnosis of
exclusion. CHS can contemporaneously be conceived
of, not as a ‘‘functional’’ GI disorder, but rather as a
manifestation of gene–environment interaction in a
rare genetic disease
19
unmasked by a toxic reaction to
excessive THC exposure.
Authors’ Contributions
E.B.R. provided study idea; E.B.R., L.M., C.S., and
V.L.W. performed conceptualization and design;
E.B.R., L.M., C.S., R.L., and V.L.W. contributed to ac-
quisition, analysis, and interpretation of data; E.B.R.,
L.M., C.S., and R.L. contributed to drafting of the arti-
cle; R.L. performed statistical analysis; E.B.R., L.M.,
C.S., and V.L.W performed supervision.
Author Disclosure Statement
E.B.R. is a scientific advisor to Endocanna Health
(uncompensated). L.M. is CEO of EndocannaHealth.
C.S. is medical director of Endocanna Health. R.L. is
employee of Endocanna Health. An application for a
patent on the genomic test battery has been submitted.
Funding Information
This study was funded by CReDO Science and Endo-
canna Health independent of any grant support.
Supplementary Material
Supplementary Appendix S1
Supplementary Appendix S2
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Cite this article as: Russo EB, Spooner C, May L, Leslie R, Whiteley VL
(2021) Cannabinoid hyperemesis syndrome survey and genomic
investigation, Cannabis and Cannabinoid Research X:X, 1–9, DOI:
10.1089/can.2021.0046.
Abbreviations Used
ABCA1 ¼ATP-binding cassette transporter gene
2-AG ¼2-arachidonylglycerol
5-HT ¼5-hydroxytryptamine (serotonin)
AD ¼alzheimer disease
CB ¼cannabinoid
CB
1
/CB
2
¼cannabinoid receptor 1 or 2
CBD ¼cannabidiol
CHS ¼cannabinoid hyperemesis syndrome
CL ¼confidence limit
CNR1 ¼gene coding CB
1
receptor
COMT ¼catechol-o-methyltransferase
CRY1 ¼cryptochome-1 gene
CVS ¼cyclic vomiting syndrome
CYP ¼cytochrome P450
DRD2 ¼gene coding dopamine-2 receptor
ECS ¼endocannabinoid system
GI ¼gastrointestinal
HSCL ¼Hopkins Symptom Checklist-25
HTS ¼high-throughput screening
IBD ¼inflammatory bowel disease
PFC ¼prefrontal cortex
SD ¼standard deviation
SNP ¼single nucleotide polymorphism
SSRI ¼selective serotonin reuptake inhibitor
THC ¼tetrahydrocannabinol
TRPV ¼transient receptor potential vanilloid receptor
CHS GENOMIC INVESTIGATION 9
