Clinical Toxicology

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Cannabinoid hyperemesis syndrome: potential

mechanisms for the benefit of capsaicin and hot
water hydrotherapy in treatment

John R. Richards, Jeff M. Lapoint & Guillermo Burillo-Putze

To cite this article: John R. Richards, Jeff M. Lapoint & Guillermo Burillo-Putze
(2018) Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of
capsaicin and hot water hydrotherapy in treatment, Clinical Toxicology, 56:1, 15-24, DOI:
10.1080/15563650.2017.1349910

To link to this article: https://doi.org/10.1080/15563650.2017.1349910

Published online: 21 Jul 2017.

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CLINICAL TOXICOLOGY, 2018
VOL. 56, NO. 1, 15–24
https://doi.org/10.1080/15563650.2017.1349910

REVIEW

Cannabinoid hyperemesis syndrome: potential mechanisms for the benefit of

capsaicin and hot water hydrotherapy in treatment
John R. Richardsa , Jeff M. Lapointb and Guillermo Burillo-Putzec
a
Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CA, USA; bDepartment of Emergency


Medicine, Southern California Permanente Medical Group, San Diego, CA, USA; cArea de Toxicolog
ıa Cl
ınica, Servicio de Urgencias,
Universidad Europea de Canarias, Tenerife, Spain

ABSTRACT ARTICLE HISTORY

Introduction: Cannabinoid hyperemesis syndrome is a clinical disorder that has become more preva- Received 7 April 2017
lent with increasing use of cannabis and synthetic cannabinoids, and which is difficult to treat. Accepted 28 June 2017
Standard antiemetics commonly fail to alleviate the severe nausea and vomiting characteristic of the Published online 14 July
syndrome. Curiously, cannabinoid hyperemesis syndrome patients often report dramatic relief of symp- 2017
toms with hot showers and baths, and topical capsaicin. KEYWORDS
Objectives: In this review, we detail the pharmacokinetics and pharmacodynamics of capsaicin and Cannabinoid hyperemesis;
explore possible mechanisms for its beneficial effect, including activation of transient receptor potential cannabis; capsaicin; heat;
vanilloid 1 and neurohumoral regulation. Putative mechanisms responsible for the benefit of hot water hot shower; TRPV1
hydrotherapy are also investigated.
Methods: An extensive search of PubMed, OpenGrey, and Google Scholar from inception to April 2017
was performed to identify known and theoretical thermoregulatory mechanisms associated with the
endocannabinoid system. The searches resulted in 2417 articles. These articles were screened for rele-
vant mechanisms behind capsaicin and heat activation having potential antiemetic effects. References
from the selected articles were also hand-searched. A total of 137 articles were considered relevant
and included.
Capsaicin: Topical capsaicin is primarily used for treatment of neuropathic pain, but it has also been
used successfully in some 20 cases of cannabinoid hyperemesis syndrome. The pharmacokinetics and
pharmacodynamics of capsaicin as a transient receptor potential vanilloid 1 agonist may explain this
effect. Topical capsaicin has a longer half-life than oral administration, thus its potential duration of
benefit is longer.
Capsaicin and transient receptor potential vanilloid 1: Topical capsaicin binds and activates the
transient receptor potential vanilloid 1 receptor, triggering influx of calcium and sodium, as well as
release of inflammatory neuropeptides leading to transient burning, stinging, and itching. This elicits a
novel type of desensitization analgesia. Transient receptor potential vanilloid 1 receptors also respond
to noxious stimuli, such as heat (>43
C), acids (pH <6), pain, change in osmolarity, and endovanilloids.
The action of topical capsaicin may mimic the effect of heat-activation of transient receptor potential
vanilloid 1.
Endocannabinoid system and transient receptor potential vanilloid 1: Cannabinoid hyperemesis
syndrome may result from a derangement in the endocannabinoid system secondary to chronic
exogenous stimulation. The relief of cannabinoid hyperemesis syndrome symptoms from heat and use
of transient receptor potential vanilloid 1 agonists suggests a complex interrelation between the endo-
cannabinoid system and transient receptor potential vanilloid 1.
Temperature regulation: Hot water hydrotherapy is a mainstay of self-treatment for cannabinoid
hyperemesis syndrome patients. This may be explained by heat-induced transient receptor potential
vanilloid 1 activation.
“Sensocrine” antiemetic effects: Transient receptor potential vanilloid 1 activation by heat or capsa-
icin results in modulation of tachykinins, somatostatin, pituitary adenylate-cyclase activating polypep-
tide, and calcitonin gene-related peptide as well as histaminergic, cholinergic, and serotonergic
transmission. These downstream effects represent further possible explanations for transient receptor
potential vanilloid 1-associated antiemesis.
Conclusions: These complex interactions between the endocannabinoid systems and transient recep-
tor potential vanilloid 1, in the setting of cannabinoid receptor desensitization, may yield important
clues into the pathophysiology and treatment of cannabinoid hyperemesis syndrome. This knowledge
can provide clinicians caring for these patients with additional treatment options that may reduce
length of stay, avoid unnecessary imaging and laboratory testing, and decrease the use of potentially
harmful medications such as opioids.

CONTACT John R. Richards jrrichards@ucdavis.edu Department of Emergency Medicine, U.C. Davis Medical Center, 4150 V Street, PSSB 2100, Sacramento,
CA 95817, USA
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
16 J. R. RICHARDS ET AL.
Introduction
Cannabis is the most commonly used drug both in the US
and worldwide [1,2]. Legalized cannabis use has increased in
recent years, and modern-day cannabis strains have tripled in
potency over the past two decades [3,4]. In this period of
time, cannabinoid hyperemesis syndrome has become more
prevalent [5,6]. In 2004, Allen and colleagues [7] described
cannabinoid hyperemesis syndrome as a variant of cyclic
vomiting syndrome in a case series of 19 chronic cannabis
users with episodic, intractable nausea and vomiting relieved
only by showering and bathing in hot water. Patients with
cannabinoid hyperemesis syndrome often present to the
emergency department for antiemetics, rehydration, and
electrolyte replacement, and they are frequently subjected to
unnecessary laboratory testing and imaging [8,9].
Cannabinoid hyperemesis syndrome has three phases: pro-
drome, hyperemesis, and recovery [10,11]. The prodromal
phase is characterized by nausea, anorexia, and vague abdom-
inal discomfort. The hyperemetic phase presents with bouts of
emesis and diffuse abdominal pain that can last for hours. This
is followed by a recovery phase with resolution of all symp-
toms. In 2012, Simonetto et al. [12] refined the diagnostic cri-
teria of cannabinoid hyperemesis syndrome to include long-
term cannabis use with the major features of: cyclic nausea
and vomiting; resolution with cannabis cessation; relief of
symptoms with hot showers or baths; abdominal pain; and fre-
quent use of marijuana. Other features supporting the diagno-
sis of cannabinoid hyperemesis syndrome include: age less
than 50 years; weight loss >5 kg; morning predominance of
symptoms; normal bowel habits; negative laboratory, radio-
graphic, and endoscopic test results.
The pharmacologic treatment of cannabinoid hyperemesis
syndrome has been systematically reviewed recently by
Richards et al. [13], and routinely-prescribed antiemetics such
as prochlorperazine, metoclopramide, and ondansentron are
often ineffective. Clinicians must then experiment with off-
label agents to control hyperemesis [11]. Benzodiazepines,
haloperidol, and topical capsaicin are most commonly associ-
ated with resolution of cannabinoid hyperemesis syndrome
[13]. Hot showering/bathing and cessation of cannabis use
appear to be the only consistent short- and long-term treat-
ment for cannabinoid hyperemesis syndrome [11].
Lapoint and associates [14–16] described the successful
use of capsaicin for cannabinoid hyperemesis syndrome in
three abstracts in 2014. Together they described eight
patients with cannabinoid hyperemesis syndrome symptoms
resolving usually within 45 min of topical application of cap-
saicin to the abdomen, back, and arms. One of these patients
had failed treatment with ondansetron prior to receiving top-
ical capsaicin. Two years later, Burillo-Putze and colleagues
[17,18] reported successful resolution of symptoms in a
patient with cannabinoid hyperemesis syndrome from appli-
cation of 0.075% topical capsaicin cream after metoclopra-
mide and granisetron failed. In 2017, Dezieck et al. [19]
detailed a case series of 13 cannabinoid hyperemesis syn-
drome patients successfully treated with topical capsaicin for
whom multiple rounds of antiemetics failed. These represent
the only published sources describing capsaicin treatment of
cannabinoid hyperemesis syndrome to date.
Objectives
In this paper, we detail the pharmacokinetics and pharmaco-
dynamics of capsaicin and explore possible mechanisms for its
beneficial effect, including activation of transient receptor
potential vanilloid 1 (TRPV1) receptors, neurohumoral regula-
tion, and modulation of the emetogenic neurotransmitters his-
tamine, acetylcholine, and serotonin. We also review potential
physiological mechanisms behind hot water hydrotherapy.
Methods
An extensive search of PubMed, OpenGrey, and Google Scholar
from inception to May 2017 was performed to identify known
and theoretical thermoregulatory mechanisms associated with
the endocannabinoid system. The initial PubMed search string
utilizing medical subject headings (MeSH) and text words (TW)
((“capsaicin”[MeSH] OR “hot temperature”[MeSH] OR
“hyperthermia, induced”[MeSH] OR “hydrotherapy”[MeSH])
AND (“TRPV1”[TW] OR “endovanilloid”[TW] OR “vanilloid”[TW]
OR “endocannabinoid”[TW] OR “cannabinoid”[TW] OR
“cannabis”[TW] OR “marijuana”[TW])) resulted in 2417 articles.
These articles were screened for relevant mechanisms behind
capsaicin and heat activation having potential antiemetic
effects. References from the selected articles were also hand-
searched. A total of 137 articles were considered relevant and
included. All three authors were involved in the review process
and analysis.
Capsaicin
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an alkaloid
extract from Capsicum, a genus of flowering plants in the night-
shade family Solanaceae. It is a vanilloid, a group that includes
vanillin from vanilla, zingerone from ginger, and eugenol from
cloves [20,21]. Capsaicin, first extracted in impure form in 1816,
was later isolated and named by John Thresh in 1876 [22].
Capsicum species are native to the Americas and have been
detected in microfossils dating from 6000 years BC [23].
Capsaicin is the main ingredient responsible for the hot,
pungent taste of chili peppers, and ranks high on the
Scoville scale, a measure of pungency, or spicy heat [24]. The
bell pepper rates zero Scoville units, a habanero pepper up
to 350,000 units, and pure capsaicin 16 million units [20].
Resiniferatoxin, extracted from the cactus Euphorbia resinifera,
has the highest Scoville ranking at 16 billion units [25].
Capsaicin is present in the placental tissue surrounding seeds
in Capsicum and likely serves as a teleological deterrent
against herbivores. After its introduction by Europeans to
Asia and Africa, the chili pepper became an essential ingredi-
ent of cuisines unique to those regions [26].
Capsaicin pharmacokinetics
Topical capsaicin absorbed into the epidermal and dermal
layers can be detected in the blood in quantifiable

concentrations even 24 h after removal from the skin [27]. It
is metabolized by the cytochrome P450 system, and its
metabolites are excreted by the kidney [27,28]. In contrast to
topical capsaicin (plasma half-life of 1.64 h), oral capsaicin has
a half-life of only 25 min from hepatic first-pass effects [29].
Capsaicin pharmacodynamics
Topical capsaicin was first noted to have analgesic properties
in the mid-1800s [30]. Since that time, topical capsaicin has
been used in the treatment of nociceptive and neuropathic
musculoskeletal pain, such as arthritis, migraine, post-herpetic
neuralgia, and diabetic neuropathy [31]. Since capsaicin is
lipophilic, organic solvents, and alcohols are used to solubil-
ize the compound for topical use. Capsaicin is available in
some countries as a 0.025, 0.075, and 0.1% topical cream,
and a high concentration (8%) patch (QutenzaV, Acorda
R
Therapeutics, Ardsley, New York) [32]. Over-the-counter oral
and topical formulations are also widely available. A recent
Cochrane review on topical capsaicin for treatment of chronic
neuropathic pain concluded that high concentration products
were more effective than lower concentration formulations,
although the number of high-quality studies was limited [33].
Application on the skin results in a sensation of local heat
and burning.
Capsaicin adverse effects
Skin irritation, burning, and cough are the most common
adverse effects reported by patients. Personal defense sprays
containing capsaicin causes disabling irritation to the skin
and eyes.
Capsaicin and transient receptor potential
vanilloid 1
In the 1940s, Jancso
et al. [34] observed that topical capsaicin
elicited a novel type of desensitization analgesia. Capsaicin-
treated animals did not react to inflammation from noxious
chemicals but retained responsiveness to physical stimuli
[35]. The transient receptor potential channels were discov-
ered in Drosophila in 1989 and have several subfamilies [36].
In the 1980s, evidence suggested the existence of a dedi-
cated capsaicin receptor [37]. In 1997, this receptor was suc-
cessfully cloned and named “vanilloid receptor 1,” later
renamed “transient receptor potential vanilloid 1” (TRPV1) by
the International Union of Basic and Clinical Pharmacology
Committee (IUPHAR) Nomenclature Committee [35,38].
The TRPV1 receptor is an outwardly rectifying, nonselec-
tive cation channel located on C and Ad peripheral nocicep-
tive neurons and in the brain, gastrointestinal tract, airways,
bladder, and kidney [25]. Capsaicin binding activates the
TRPV1 receptor triggering influx of calcium and sodium, as
well as release of inflammatory neuropeptides leading to
transient burning, stinging, and itching [39]. TRPV1 receptors
are also expressed on the endoplasmic reticulum and regu-
late intracellular calcium concentrations [40]. In addition to
TRPV1, capsaicin-sensitive receptors express several other
CLINICAL TOXICOLOGY 17
members of the transient receptor potential channel family.
These receptors respond to noxious stimuli, such as heat
(>43
C), acids (pH <6), pain, and change in osmolarity, as
well as endogenous lipid compounds, termed endovanilloids
[41]. The endovanilloids, which include anandamide and N-
arachidonoyl-dopamine, induce TRPV1 currents much smaller
than those evoked by topical capsaicin [42]. The action of
topical capsaicin may mimic the effect of heat-activation of
TRPV1.
The endocannabinoid system and TRPV1
The endocannabinoid system is involved in myriad physio-
logical and emotional processes including nausea/emesis,
nociception, motor function, thermoregulation, analgesia,
cognition, memory, energy, mood, hunger, stress, sleep,
addiction, and immune function [43]. Two primary cannabin-
oid receptors have been identified, CB1 and CB2. Both recep-
tor subtypes are present in the central and peripheral
nervous system, as well as in muscle, adipose cells, skin, kid-
neys, and the gastrointestinal tract. CB2 receptors are also
found in peripheral immune tissues such as the spleen, ton-
sils, and thymus. Both subtypes are G protein-coupled recep-
tors located on the pre-synaptic membrane. Activation by
endocannabinoids causes a decrease in cyclic adenosine
monophosphate (cAMP) by inhibition of adenylyl cyclase and
a rise in mitogen-activated protein kinase (MAP kinase) [44].
The endocannabinoid and endovanilloid systems are
highly synergistic from a functional and anatomical stand-
point [45]. Anandamide, considered both an endocannabi-
noid and endovanilloid, interacts with TRPV1, CB1, and CB2
receptors [46]. Anandamide is able to inhibit trigeminal neu-
rons, act as a vasodilator of dural blood vessels, and modu-
late calcitonin gene-related peptide release from its
activation of TRPV1 receptors [47–50]. TRPV1 and CB1 recep-
tors are widely co-expressed, and anandamide can bind to
TRPV1 and CB1 receptors of the same neuron [51].
Anandamide binding to TRPV1 elevates calcium concentra-
tions with potentiation of synaptic transmission, whereas
binding to CB1 has the opposite effect. This counter-regula-
tory interplay between TRPV1 and CB1 receptors appear to
play a role not only in nausea, emesis, and nociception, but
also in anxiety-related behaviors and stress maladaptation
which are associated with cyclic vomiting syndrome and can-
nabinoid hyperemesis syndrome [52–55]. Chronic stress is fre-
quently accompanied by visceral hyperalgesia and altered
bowel function, possibly from down-regulation of CB1 recep-
tors and up-regulation of TRPV1 receptors [56–58]. As with
cyclic vomiting syndrome and irritable bowel syndrome, can-
nabinoid hyperemesis syndrome may represent a disorder of
allostatic or epigenetic regulation of response to stress that
is mediated by endocannabinoid and endovanilloid syner-
gism [10,11,52,53,59–61].
Cannabis, which contains over 100 phytocannabinoids,
has been used by humans for centuries for its medicinal and
psychotropic properties [62,63]. These phytocannabinoids
and their metabolites bind not only to CB1 and CB2 recep-
tors, but to transient receptor potential receptors as well
18 J. R. RICHARDS ET AL.
[64,65]. Tetrahydrocannabinol is the phytocannabinoid
mimetic to anandamide, and cannabidiol is the phytocanna-
binoid mimetic to the other main endocannabinoid, 2-arachi-
donoylglycerol [64]. One theory regarding the precipitation
of an acute episode of cannabinoid hyperemesis syndrome is
that chronic cannabis users experience acute elevations of
plasma cannabinoids during periods of stress and fasting,
which may overwhelm the endocannabinoid system. It is
possible TRPV1 receptor activation from hot showers or top-
ical capsaicin may counter this effect.
Temperature regulation
According to reports, hot showers and baths consistently
mitigate cannabinoid hyperemesis syndrome symptoms
[10,11,65]. Several theories have been proposed to explain
this phenomenon (Table 1). Endogenous cannabinoids and
CB1 cannabinoid receptors in the hypothalamus play an
important role in thermoregulation. Cannabinoids regulate
body temperature in a dose-dependent manner, with high
doses decreasing heat production and causing hypothermia
[67]. High doses might result from chronic or excessive acute
intake of phytocannabinoids or release of stored cannabi-
noids from lipids during periods of fasting or stress. Warm
water hydrotherapy decreases sympathetic nervous system
activation resulting in decreased heart rate and blood pres-
sure in human subjects [68,69]. A “cutaneous steal” syndrome
is another theory, in which cutaneous vasodilation from
external heating alters core temperature and diverts splanch-
nic circulation, lessening abdominal discomfort [70].
In the 1970s, Szolcs
anyi [35] reported that application of
capsaicin resulted in a decrease in body temperature in cats.
This response was absent in capsaicin-desensitized animals.
This hypothermic effect was due to a coordinated physio-
logical response consisting of vasodilation, salivation, pant-
ing, and reduced metabolic rate. These results were
confirmed in several later studies using different species
[71–73]. Certain experimental TRPV1 antagonists, such as
AMG 517, cause hyperthermia, which in some cases may
reach dangerous levels in humans [74]. Based on the hypo-
thermic effect of TRPV1 activation, it seems unlikely that the
improvement in symptoms of cannabinoid hyperemesis syn-
drome from hot showers or baths represents a solely tem-
perature-related effect to counter cannabinoid-induced
hypothermia.
Table 1. Hydrotherapy (>43
C) for cannabinoid hyperemesis syndrome: sum-
mary of potential molecular and neurohumoral effects.
Cutaneous thermoceptor and TRPV1 activation [25,39,41,42,75,84]
Reversal of hypothalamic cannabinoid-induced hypothermia [10,11,66,67]
Decreased HPA-axis and sympathetic nervous system activation [68,69]
Restoration of DNIC balance [90–96]
“Cutaneous steal” syndrome [70]
Stimulation of somatostatin [24,107–112]
Stimulation of PACAP [113–119]
Depletion/inhibition of CGRP [120–130]
Restoration of CB1/TRPV1 balance [45–65]
TRPV1: transient receptor potential vanilloid-1; HPA: hypothalamic–pituitary–
adrenal; DNIC: diffuse noxious inhibitory controls; PACAP: pituitary adenylate-
cyclase activating polypeptide; CGRP: calcitonin gene-related peptide; CB1:
cannabinoid receptor 1.
Pro-inflammatory mediators lower the temperature activa-
tion threshold of TRPV1 [75]. Topical capsaicin reverses this
process and leads to “desensitization” or “defunctionalization”
of the dorsal root ganglion sensory nerves to heat and capsa-
icin [37,39]. Several mechanisms are responsible for this
effect. Topical capsaicin activation of the TRPV1 nociceptor
results in an influx of calcium ions. This, in turn, triggers cal-
cium-dependent protease enzymes causing microtubule
depolymerization, which diminishes or eliminates fast axonal
transport [76]. Influx of calcium, sodium, and chloride ions
results in osmotic swelling of the nerve fiber [35]. Capsaicin
inhibits the electron-transfer activity of nicotinamide adenine
dinucleotide (NADH)-coenzyme Q oxidoreductase, resulting
in mitochondrial dysfunction [77]. This chain of events initi-
ated by topical capsaicin effectively leads to a non- or
limited-functional state of the nociceptor nerve fibers.
Other possible mechanisms include capsaicin-induced
depletion of tachykinin peptides substance P and neurokinin
A, after which sensory nerves become insensitive to heat and
noxious chemical stimuli and lose their ability to release pro-
inflammatory mediators [75]. Depletion of membrane
phospholipid phosphatidylinositol 4,5-bisphosphate results
from capsaicin-associated TRPV1 activation of Phospholipase
C [78,79]. Activation of TRPV1 from capsaicin results in
receptor down-regulation from endocytosis and lysosomal
degradation. Desensitization is also enhanced by increased
calcium-dependent calmodulin and calcineurin activity
[80–82]. Capsaicin causes degeneration of nociceptive fibers,
leading to desensitization [83].
Thermal hyperalgesia, or increased sensitivity to heat, is
commonly associated with inflammatory pain. In animal
models, genetic deletion of TRPV1 eliminates thermal hyper-
algesia induced by inflammation [84]. Thermal hyperalgesia
may result from higher expression of TRPV1 at the RNA and
protein level, and increased sensitivity or activity of TRPV1
receptors [75,85–88]. Based on these findings, cannabinoid
hyperemesis syndrome patients may have lower than normal
expression of TRPV1 receptors from gene polymorphisms and
feel cold even when normothermic. Genetic polymorphisms
of CB1 increase the likelihood of cyclic vomiting syndrome
[89]. These effects of these abnormal genotypes may be syn-
ergistic with excessive cannabinoid stimulation of CB1 recep-
tors in the temperature-regulating areas of the
hypothalamus. Genetic polymorphisms such as these may
also explain why only a minority of chronic cannabis users
develop cannabinoid hyperemesis syndrome.
The concept of diffuse noxious inhibitory controls repre-
sents another potential explanation for the beneficial effect
of heat and topical capsaicin on acute episodic cannabinoid
hyperemesis syndrome. Diffuse noxious inhibitory controls
are central nervous system mechanisms controlling spinal–
medullary–spinal inhibition of noxious stimuli, such as pain
and itch, in which these stimuli are suppressed by stimuli
remote from the origin [90]. Diffuse noxious inhibitory con-
trols are triggered by activation of peripheral nociceptors
transmitting sensation via C- and Ad-fibers, inhibiting noxious
stimuli from any part of the body [90]. Clinical studies indi-
cate that fibromyalgia and irritable bowel syndrome patients
have dysfunctional diffuse noxious inhibitory controls [91,92].

The application of heat >43
C or topical capsaicin can evoke
diffuse noxious inhibitory controls in human subjects
[90,93–95]. Endocannabinoids enhance diffuse noxious inhibi-
tory controls, especially during periods of stress [96]. Excessive
phytocannabinoids and associated metabolites released during
periods of stress and fasting in cannabinoid hyperemesis syn-
drome patients may overwhelm this intrinsic balance, leading
to diffuse noxious inhibitory controls impairment in the form
of nausea and abdominal discomfort. It is possible hot show-
ers or topical capsaicin may reverse this imbalance.
“Sensocrine” antimetic effects
Nausea and emesis may be initiated by calcium-dependent
release of multiple neurotransmitters from the gastrointes-
tinal tract or the brainstem, activating several different pro-
emetic receptors, such as dopaminergic D2, histaminergic H1,
serotonergic 5-HT3, cholinergic M1, and tachykininergic NK1
[97,98]. Capsaicin may also be effective for treatment of can-
nabinoid hyperemesis syndrome from antiemetic effects
unrelated to thermosensation (Table 2).
Activation of capsaicin-sensitive nociceptors is associated
with a novel neurohumoral regulatory “sensocrine” function,
with subsequent release of several other neuropeptides such
as substance P, neurokinin A, somatostatin, pituitary adenyl-
ate-cyclase activating polypeptide, and calcitonin gene-
related peptide [99]. There is a complex interdependence
and synergism in the antiemetic and nociceptive mechanisms
mediated by transient receptor potential receptors for these
neuropeptides, as well as histamine, acetylcholine, and sero-
tonin (Figure 1) [100,101].
Tachykinins
Capsaicin and other TRPV1 agonists have antiemetic effects
from depletion and inhibition of the tachykinin peptides sub-
stance P and neurokinin A in the spinal cord, vagus nerve,
and medulla oblongata [102,103]. The medulla oblongata is
especially important in this regard, as it contains several
nuclei involved in the regulation of nausea and emesis, such
as the chemoreceptor trigger zone (area postrema), nucleus
tractus solitarius, and central pattern generator [97]. In sev-
eral trials, capsaicin applied at acupressure points prevented
post-operative nausea and vomiting for patients undergoing
abdominal, thyroid, and middle ear surgery [103–106].
Table 2. Topical capsaicin treatment for cannabinoid hyperemesis syndrome:
summary of potential molecular and neurohumoral effects.
Shift in TRPV1 temperature activation threshold [25,26,28,75]
“Desensitization” or “defunctionalization” of nociceptors [22,23,25,35,74–78]
TRPV1 and CB1 polymorphisms and down-regulation [70,80–89]
Restoration of DNIC imbalance [90–96]
Depletion/inhibition of substance P, neurokinin A [101–106]
Stimulation of somatostatin [25,107–112]
Stimulation of PACAP [113–119]
Depletion/inhibition of CGRP [120–130]
Inhibition of histamine, acetylcholine, and serotonin [131–147]
Restoration of CB1/TRPV1 balance [45–65]
TRPV1: transient receptor potential vanilloid-1; DNIC: diffuse noxious inhibitory
controls; PACAP: pituitary adenylate-cyclase activating polypeptide; CGRP: calci-
tonin gene-related peptide; CB1: cannabinoid receptor-1.
CLINICAL TOXICOLOGY 19
The authors of these studies postulated capsaicin may block
the transport and synthesis of substance P from sensory C-
and Ad-fibers leading to the medullary chemoreceptor trigger
zone. This antiemetic effect from TRPV1 activation also repre-
sents the most logical explanation for improvement in canna-
binoid hyperemesis syndrome symptoms from hot showers/
baths greater than 43
C and topical capsaicin treatment.
Somatostatin
TRPV1 receptors appear to be involved in gastric protection
and modulation of inflammation [25]. Capsaicin stimulation
of these receptors results in the release of somatostatin, a
peptide hormone with anti-nociceptive and anti-inflammatory
properties [107]. Somatostatin suppresses the release of
gastrointestinal hormones gastrin, cholecystokinin, secretin,
ghrelin, motilin, vasoactive intestinal peptide, gastric inhibi-
tory polypeptide, and the pancreatic hormones insulin and
glucagon [108–110]. Somatostatin increases the rate of gas-
tric emptying, and reduces gastrointestinal smooth muscle
contraction and blood flow [106]. Capsaicin protects against
indomethacin- and ethanol-associated gastropathy, reduces
gastric acid output, and increases gastric emptying [111].
Capsaicin-induced release of somatostatin may be beneficial
in cannabinoid hyperemesis syndrome patients because of
these inhibitory effects on the gastrointestinal tract.
Capsaicin improves esophageal peristalsis and reduces dis-
tention in healthy human subjects, which may mitigate nau-
sea and emesis [112].
Pituitary adenylate-cyclase activating polypeptide
Pituitary adenylate-cyclase activating polypeptide is another
peptide hormone released from capsaicin-sensitive receptors.
Pituitary adenylate-cyclase activating polypeptide stimulates
enterochromaffin-like cells in the gastrointestinal tract
[113,114]. It also modulates psychogenic and metabolic stress
response by activating catecholamine secretion and biosyn-
thesis in the adrenal medulla [115]. Pituitary adenylate-
cyclase activating polypeptide acts as an emergency
response peptide and is required for survival by promoting
gluconeogenesis to counter life-threatening hypoglycemia
[116]. Genetic variations in the pituitary adenylate-cyclase
activating polypeptide receptor have been implicated in mal-
adaptive responses to stress, anxiety, and fear, and are
believed to be important factors in the development of post-
traumatic stress disorder [117–119]. Thus, stimulation of pitu-
itary adenylate-cyclase activating polypeptide may be
another benefit of capsaicin treatment, in that fasting and
emotional stress has been reported as a common precipitant
of acute episodes of cannabinoid hyperemesis syndrome in
genetically predisposed individuals [10,11,53].
Calcitonin gene-related peptide
Calcitonin gene-related peptide, a potent peptide vasodilator,
is produced in peripheral and central neurons and is involved
in pain transmission. Although not found to have a direct
20 J. R. RICHARDS ET AL.

Figure 1. Potential therapeutic neurohumoral effects of hydrotherapy (>43
C) and topical capsaicin for cannabinoid hyperemesis syndrome at anatomic structures
involved in nausea and emesis. TRPV1: transient receptor potential vanilloid-1; SNS: sympathetic nervous system; HPA: hypothalamic–pituitary–adrenal; DNIC: diffuse
noxious inhibitory controls; PACAP: pituitary adenylate-cyclase activating polypeptide; CGRP: calcitonin gene-related peptide; (þ): activation; (): inhibition; ":
increase; #: decrease; ?: unclear. (Adapted from medical images freely available through creative commons license from Blausen Medical Communications,
WikiJournal of Medicine.)

pro-emetic effect, calcitonin gene-related peptide is an
important factor in the genesis and duration of migraine and
cluster headaches, which are frequently accompanied by nau-
sea and emesis [120]. Topical and intranasal capsaicin has
been used successfully for prophylaxis and treatment of
migraine and cluster headaches [121–124]. There is a high
prevalence of concomitant migraine headache in patients
with cyclic vomiting syndrome [52]. Cannabinoid hyperemesis
syndrome is considered to be a variant of cyclic vomiting
syndrome, which some researchers describe as an
“abdominal migraine” [52,125,126]. TRPV1 receptors are
expressed by inner ear ganglion cells, and intracranial blood
vessels are innervated by trigeminal sensory nerve fibers,
which store and release calcitonin gene-related peptide, sub-
stance P, and neurokinin A [127–129]. Trigeminal nerve fibers
leading to the vestibular-cochlear system have been impli-
cated in basilar and vestibular migraine, in which nausea,
vomiting, imbalance, and hearing changes may occur. De
Tomasso et al. [130] found that topical capsaicin applied to
the hand increased the blink reflex, an experimental measure
of diffuse noxious inhibitory controls, in chronic migraine
versus non-migraine subjects [130]. This further demonstrates
that topical capsaicin has both local and systemic effects
which may explain its potential benefit for treatment of can-
nabinoid hyperemesis syndrome. It is possible that capsaicin-
induced depletion of calcitonin gene-related peptide and
tachykinins may also have a role in its antiemetic effect in
cannabinoid hyperemesis syndrome [10,11,52,53].
Histamine, acetylcholine, and serotonin
Histamine and TRPV1 receptors are co-expressed in sensory
neurons, and primary afferent C-fibers are sensitive to hista-
mine and capsaicin [131,132]. One-time topical capsaicin
application often evokes pruritus, whereas repeated applica-
tion of capsaicin or heat may alleviate this associated pruritus
through TRPV1 desensitization and diffuse noxious inhibitory
controls [133–138]. This effect appears to result from
increased blood flow to the midbrain region, especially the
periaqueductal gray matter [139]. As histamine is a pro-
emetic substance, inhibition by topical capsaicin and heat
may have an antiemetic effect.

Afferent cholinergic vagal neurons from the gastrointes-
tinal tract contribute to nausea and emesis by sensing nox-
ious chemical, infectious, and physical events and conducting
this information to the medullary vomiting center [98,140].
TRPV1 receptors have been detected in the afferent vagal
nerve [141]. Capsaicin in blood can inhibit afferent vagal cho-
linergic transmission from desensitization of nerve conduc-
tion in C-, Ad-, and Aab-fibers [142–145]. Serotonin (5-HT) is
released from enterochromaffin cells in the gastrointestinal
tract and initiates emesis via this same pathway [146,147].
Serotonin is another emetogenic substance, and the 5-HT3
serotonin subtype receptor antagonists, such as ondansetron,
are widely utilized antiemetics [98]. For these reasons, it is
possible that capsaicin inhibition of afferent vagal transmis-
sion may also mitigate cannabinoid hyperemesis syndrome-
associated nausea and emesis.
Conclusions
As legalization and availability of high-potency cannabis and
synthetic cannabinoids continues to increase in the United
States and worldwide, cannabinoid hyperemesis syndrome-
related emergency department visits and hospital admissions
will undoubtedly rise in step. There is limited research detail-
ing the pathophysiology and best pharmacologic treatment
of cannabinoid hyperemesis syndrome. Serotonin antagonists
are often ineffective. Dopamine antagonists, such as pheno-
thiazines and butyrophenones, appear to be somewhat more
effective than 5-HT3 antagonists. Hot showers and baths
often provide transient relief of cannabinoid hyperemesis
syndrome-associated nausea, vomiting, and abdominal pain.
Topical capsaicin can be administered rapidly and has been
utilized to successfully treat acute attacks of cannabinoid
hyperemesis syndrome. Future studies are needed to further
define the role of topical capsaicin for cannabinoid hyperem-
esis syndrome. Recognition of cannabinoid hyperemesis syn-
drome and its resistance to routine antiemetics is important
to help reduce emergency department visits, hospital admis-
sions, unnecessary diagnostic testing, ineffective treatment,
morbidity, and health care costs.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
John R. Richards http://orcid.org/0000-0003-1251-3877
Jeff M. Lapoint http://orcid.org/0000-0002-1780-3614
Guillermo Burillo-Putze http://orcid.org/0000-0001-5679-7846
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