Cannabis and Cannabinoid Research

Volume X, Number X, 2020

ª Mary Ann Liebert, Inc.
DOI: 10.1089/can.2020.0083

Cannabidiol Interferes with Establishment

of D9-Tetrahydrocannabinol-Induced Nausea
Through a 5-HT1A Mechanism
Marieka V. DeVuono,1 Olivia La Caprara,1 Gavin N. Petrie,2,3 Cheryl L. Limebeer,1 Erin M. Rock,1
Matthew N. Hill,2,3 and Linda A. Parker1,*

Abstract
Introduction: Cannabinoid hyperemesis syndrome (CHS) is characterized by intense nausea and vomiting
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brought on by the use of high-dose D9-tetrahydrocannabinol (THC), the main psychotropic compound in can-
nabis. Cannabidiol (CBD), a nonpsychotropic compound found in cannabis, has been shown to interfere with
some acute aversive effects of THC. In this study, we evaluated if CBD would interfere with THC-induced nausea
through a 5-HT1A receptor mechanism as it has been shown to interfere with nausea produced by lithium chlo-
ride (LiCl). Since CHS has been attributed to a dysregulated stress response, we also evaluated if CBD would in-
terfere with THC-induced increase in corticosterone (CORT).
Materials and Methods: The potential of CBD (5 mg/kg, ip) to suppress THC-induced conditioned gaping
(a measure of nausea) was evaluated in rats, as well as the potential of the 5-HT1A receptor antagonist, WAY-
100635 (WAY; 0.1 mg/kg, ip), to reverse the suppression of THC-induced conditioned gaping by CBD. Last, the
effect of CBD (5 mg/kg, ip) on THC-induced increase in serum CORT concentration was evaluated.
Results: Pretreatment with CBD (5 mg/kg, ip) interfered with the establishment of THC-induced conditioned
gaping ( p = 0.007, relative to vehicle [VEH] pretreatment), and this was reversed by pretreatment with
0.1 mg/kg WAY. This dose of WAY had no effect on gaping on its own. THC (10 mg/kg, ip) significantly increased
serum CORT compared with VEH-treated rats ( p = 0.04). CBD (5 mg/kg, ip) pretreatment reversed the THC-
induced increase in CORT.
Conclusions: CBD attenuated THC-induced nausea as well as THC-induced elevation in CORT. The attenuation of
THC-induced conditioned gaping by CBD was mediated by its action on 5-HT1A receptors, similar to that of LiCl-
induced nausea.
Keywords: cannabidiol; cannabinoid hyperemesis; corticosterone; D9-tetrahydrocannabinol; 5-HT1A receptor;
nausea

Introduction dose-dependent acute nausea and vomiting in hu-

Cannabinoid hyperemesis syndrome (CHS), an ad- mans6–8 and laboratory animals.9–15 The mechanism
verse event related to high-dose chronic cannabis use, of the nauseating effects of high-dose THC is not
is characterized by cyclical episodes of intense nausea well understood, but is thought to be the result of dys-
and vomiting with severe abdominal pain that is alle- regulated endocannabinoid and stress systems.4,16,17
viated by high-temperature baths or showers and Rats are useful animal models for studying the nau-
abstinence from cannabis.1–4 There are several reports seating effects of cannabis. Although they do not vomit,
that the main intoxicating component of the cannabis rats detect toxins the same way as emetic species, but
plant, D9-tetrahydrocannabinol (THC),5 produces lack the motor output for vomiting.18–21 Considerable
1
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada.
Departments of 2Cell Biology and Anatomy and 3Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.

*Address correspondence to: Linda A. Parker, PhD, Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1,
Canada, E-mail: parkerl@uoguelph.ca

1
 2 DEVUONO ET AL.
evidence suggests that rats display the unique behavior
of gaping (wide open mouth with lower incisors ex-
posed)22 when exposed to a flavor previously paired
with an emetic drug such as lithium chloride (LiCl)
in the taste reactivity (TR) paradigm.23 Therefore, con-
ditioned gaping provides a unique tool for investigating
the neurobiology of nausea in rats. We have previously
demonstrated that THC and the synthetic cannabinoid
1 (CB1) receptor agonist, JWH-018, produce dose-
dependent conditioned gaping where high, but not
low, doses produce conditioned gaping in rats through
their action on the CB1 receptor.15,24
Cannabidiol (CBD) is another main nonintoxicating
compound found in cannabis that is touted for its ther-
apeutic potential.25 Evidence suggests that CBD pro-
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tects against pain, inflammation, epilepsy, depression,
and anxiety, as well as nausea and vomiting.26–38 More-
over, CBD is thought to antagonize many of the ad-
verse effects associated with THC. For example, CBD
counteracts the effects of THC on conditioned place
aversion39 and social interaction40 and attenuates para-
noia,41 psychosis,42,43 and anxiety44,45 elicited by THC.
Therefore, it is possible that CBD may interfere with
THC-induced nausea as well.
Unlike THC, CBD only has minimal efficacy as a CB1
receptor agonist and produces its effects through several
different mechanisms.46 One such mechanism is the se-
rotonin 5-HT1A receptor, where CBD acts as an indirect
agonist of somatodendritic 5-HT1A autoreceptors in the
dorsal raphe nucleus (DRN),33,47 which reduces seroto-
nin release in the forebrain.48 Many of the effects of
CBD mentioned above can be prevented by administra-
tion of the 5-HT1A receptor antagonist, WAY-100635
(WAY).29,31,33–35,49,50 For example, Rock et al.33 demon-
strated that systemic and intra-DRN administration of
WAY blocks CBD’s ability to interfere with LiCl-induced
conditioned gaping in rats, suggesting CBD’s action at
the 5-HT1A receptor that mediates its antinausea effects.
Therefore, CBD may interfere with THC-induced nausea
by a 5-HT1A receptor mechanism as well.
It is hypothesized that CHS is the result of a dysregu-
lated hypothalamic–pituitary–adrenal (HPA) axis due
to high doses of THC producing endocannabinoid sys-
tem alterations.4,17,51 Relatively high doses of THC are
known to activate the HPA axis, as indicated by an in-
crease in the corticotropin-releasing hormone (CRH),
adrenocorticotropic hormone (ACTH), and the gluco-
corticoid stress hormone corticosterone (CORT).52–55
Circulating ACTH and CORT are also elevated during
nausea and vomiting.56–58 Indeed, we have previously
shown that a CRH receptor antagonist, which inhibits
the neuroendocrine response to stress and stress-
induced anxiety,59 also interferes with THC-induced
nausea in rats.52 Given that CBD is anxiolytic and
may counteract the adverse effect of high-dose THC,
it may also interfere with THC-induced stress and
consequently THC-induced nausea. CBD has been
demonstrated to reduce the increased transcription
of HPA axis-related genes following restraint stress,
including the genes for CRH and proopiomelanocor-
tin (POMC), which are both elevated in times of
stress.60 The effect of CBD on THC-induced CORT
release, however, is unknown.
The current study evaluated the potential of CBD to
interfere with THC-induced conditioned gaping. Fur-
thermore, the ability of the 5-HT1A antagonist, WAY,
to block the effect of CBD on THC-induced condi-
tioned gaping was tested to determine its mechanism
of action. Last, the potential of CBD to interfere with
THC-induced serum CORT release was evaluated.
Materials and Methods
Subjects
Animal procedures were conducted in accordance with
the Canadian Council on Animal Care (CCAC) and
the National Institutes of Health guidelines. All proto-
cols were approved by the Institutional Animal Care
Committee at the University of Guelph, which is
accredited by the CCAC. A total of 63 (n = 32 for exper-
iment 1 and n = 31 for experiment 2) naı̈ve, male
Sprague-Dawley rats (Charles River Laboratories) were
used in all experiments. Rats were single-housed and
maintained as described by DeVuono et al.15 All exper-
imental manipulations occurred during the dark phase
of the cycle.
Drugs
The method of injection for all drugs used was intraper-
itoneal (ip). THC, CBD, and WAY-100635 (WAY) were
dissolved in ethanol, then Tween 80 (Sigma) was added
to the solution in a graduated cylinder. Using a nitrogen
stream, the ethanol was then evaporated off. Saline
(SAL) was then added to the solution. The final vehicle
(VEH) solution comprised 1:9 Tween:SAL. THC was
mixed at a concentration of 10 mg/mL and administered
intraperitoneally at 1 mL/kg (10 mg/kg). CBD was pre-
pared as a 5 mg/mL solution of the vehicle and admin-
istered at volumes of 1 mL/kg (5 mg/kg). WAY-100635
(WAY) was mixed at concentrations of 0.1 mg/mL and
administered at 1 mL/kg (0.1).
 CBD AND THC-INDUCED NAUSEA
TR apparatus
The TR chamber was a clear Plexiglas chamber
(25 · 25 · 12.5 cm) with a removable, opaque Plexiglas
lid, which was placed on top of a table with a clear glass
top, and a mirror beneath the chamber at a 45 angle
was used to record the rat’s ventral surface. The intrao-
ral infusions were delivered by an infusion pump
(Model KDS100; KD Scientific, Holliston, MA) at-
tached to intraoral cannulae. A video camera pointing
toward the mirror below the chamber recorded the
rat’s behavior during conditioning and test trials.
Intraoral cannulation surgery
Rats in experiment 1 were implanted with intraoral
cannulae, as described by Limebeer et al.61 For 3 days
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following surgery, indices of recovery were assessed
(body weight, facial swelling, and activity, etc.) and
the cannula was flushed daily with an oral cleansing so-
lution (Nolvadent; Ayerst, Fort Dodge, IA).
Behavioral procedures
Experiment 1: effects of WAY and CBD on THC-induced
conditioned gaping and conditioned taste avoid-
ance. As reported by DeVuono et al.,15 following
3 days of recovery from intraoral surgery, the rats
were adapted to the TR chamber. Water was infused
into their intraoral cannulae using an infusion pump
for 2 min at the rate of 1 mL/min. Following the adap-
tation trial, the rats received a series of three consecu-
tive conditioning trials occurring 24 h apart. In each of
the three trials (24 h apart), rats were injected intraper-
itoneally with either VEH or 0.1 mg/kg WAY 15 min
before being injected intraperitoneally with either
VEH or 5 mg/kg CBD and 30 min before being infused
with 0.1% saccharin for 2 min at a rate of 1 mL/min,
according to their random group assignment, creating
four treatment groups (VEH-VEH, VEH-CBD, WAY-
VEH, and WAY-CBD; n = 8 rats per group). During
this time, the orofacial responses were video recorded
from the mirror beneath the chamber. Immediately fol-
lowing saccharin infusion, rats were then injected with
10 mg/kg THC. The test trial occurred 24 h after the
third conditioning trial and followed the same proce-
dure as the conditioning trial, except rats were not
injected before or after the saccharin infusion. Video
recordings were later scored using the Observer (Noldus,
NL) event-recording program. Since the pretreatment
drugs were on board during the three conditioning trials,
only the gaping reactions from the drug-free test were
analyzed to assess if they altered the establishment of
3
conditioned gaping produced by THC. The number of
gaping reactions (defined by the rapid large-amplitude
opening of the mouth to expose the lower incisors)
that occurred in each 2-min drug-free test was counted
by an observer blind to group assignment.
The day following the test trial, rats received a one-
bottle, conditioned taste avoidance (CTA) test to deter-
mine if the pretreatment interfered with learning per se
rather than THC-induced nausea.23 Rats were deprived
of water for 17 h before the start of the 6-h taste avoid-
ance test. A bottle filled with the saccharin solution was
placed in the rat’s home cage, and consumption mea-
sures were taken at 30, 120, 240, and 360 min of testing.
Experiment 2: effect of CBD on THC-induced increase in
serum CORT concentrations. Rats were randomly
assigned to one of four treatment conditions (VEH-
VEH, n = 8; VEH-THC, n = 8; CBD-VEH, n = 8; and
CBD-THC, n = 7) and injected intraperitoneally with
their treatment every 24 h for 3 consecutive days to
match the injection procedure from experiment 1.
Rats were injected intraperitoneally with either VEH
or 5 mg/kg CBD 30 min before being injected with
VEH of 10 mg/kg THC according to their random
group assignment to mirror the procedure used in
experiment 1. On the third day of injection, rats were
sacrificed 30 min following their last respective injection
by rapid decapitation (restrained in a DecapiCone;
Braintree Scientific).62 Trunk blood was collected fol-
lowing decapitation, separated by centrifugation, and
the resulting serum was stored at 80C before analysis.
Serum samples were analyzed with the ELISA kit (Arbor
Assays) by following the manufacturer’s instructions.
Samples were tested in triplicate and diluted 1:1000 to
make sure levels fit into the standard curve. Results
are reported in nanograms per milliliter (ng/mL).
Statistical analyses
For experiment 1, the number of gaping reactions during
the drug-free test was entered into a one-way ANOVA
with the between-group factor of pretreatments (VEH-
VEH, VEH-CBD, WAY-VEH, or WAY-CBD). CTA
test results were entered into a 4 · 4 mixed factor
ANOVA with the between-group factor of pretreatment
drug (VEH-VEH, VEH-CBD, WAY-VEH, or WAY-
CBD) and the within-group factor of minutes of testing.
For experiment 2, mean serum CORT levels (ng/mL)
were entered into a one-way ANOVA with the between-
group factor of drug treatment (VEH-VEH, CBD-VEH,
VEH-THC, and CBD-THC). Subsequent Bonferroni
 4 DEVUONO ET AL.

post hoc tests were conducted for significant main effects

where appropriate. For all statistical analyses, signifi- A
cance was defined as p < 0.05.

Results
Experiment 1: effects of WAY and CBD
on THC-induced conditioned gaping and CTA
Conditioned gaping. WAY (0.1 mg/kg) reversed
CBD’s ability to interfere with THC-induced condi-
tioned gaping. Figure 1A shows the mean number of
gapes elicited by THC-paired saccharin during the
drug-free test for the different pretreatment groups.
The one-way ANOVA revealed a significant effect of
the pretreatment group, F(3, 28) = 5.47; p = 0.004. Bon- B
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ferroni post hoc analysis revealed that rats that received

VEH-CBD during conditioning gaped significantly less
at test than rats treated with VEH-VEH ( p = 0.007),
WAY-VEH ( p = 0.03), or WAY-CBD ( p = 0.025).
Rats in the VEH-VEH, WAY-VEH, and WAY-CBD
groups did not differ significantly at test ( p = 1.00).

Conditioned taste avoidance. Pretreatment condition

did not have an effect on CTA. Figure 1B shows the
mean cumulative amount (mL) of saccharin solution
consumed over the 6 h of testing. The 4 · 4 ANOVA
only revealed a significant effect of time, F(3, 84) =
39.45; p < 0.001.

Experiment 2: effect of CBD on THC-induced
increase in serum CORT concentrations
THC significantly increased serum CORT concentra-
tions, and this effect was attenuated by pretreatment
with CBD. Figure 2 represents the mean serum CORT
levels in rats treated with different drug treatments.
The one-way ANOVA revealed a significant main effect
of drug treatment, F(3, 27) = 6.60, p = 0.002. Bonferroni
post hoc analysis revealed that rats treated with VEH-
THC had significantly increased serum CORT levels
compared with rats treated with VEH-VEH ( p = 0.04),
CBD-VEH ( p = 0.001), or CBD-THC ( p = 0.05). Rats
treated with VEH-VEH, CBD-VEH, and CBD-THC
did not differ significantly.
FIG. 1. (A) Mean ( – sem) number of gapes
elicited by THC-paired saccharin solution by
the different pretreatment conditions during
the drug-free test trial. The VEH-CBD group
gaped significantly less than all other groups
(VEH-VEH, WAY-VEH, and WAY-CBD).
Pretreatment with WAY reversed the
suppression of THC-induced gaping by CBD.
(B) Mean ( – sem) mL of saccharin consumed
in a 360-min taste avoidance test. Pretreatment
condition had no effect on the amount of
saccharin consumed. n = 8 for all groups,
**p < 0.01 compared with VEH. CBD, cannabidiol;
THC, D9-tetrahydrocannabinol; VEH, vehicle.

Discussion
Pretreatment with 5 mg/kg CBD (ip) suppressed condi-
tioned gaping reactions produced by a flavor paired
with a high dose of THC (10 mg/kg, ip), a rat model
of nausea. Additionally, suppression of conditioned
gaping by CBD was attenuated by administration of
the 5-HT1A receptor antagonist, WAY (0.1 mg/kg,
ip), before CBD. There was no effect of pretreatment
condition on CTA, indicating that CBD and WAY
did not impact the learning of the association between
saccharin and THC. These findings mirror the effect of
CBD on LiCl-induced conditioned gaping, which is
 CBD AND THC-INDUCED NAUSEA
FIG. 2. Mean ( – sem) serum levels of
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corticosterone (ng/mL) of rats in different
treatment groups. Rats in the VEH-THC group
had significantly elevated serum corticosterone
compared with all other groups. Rats in the
VEH-VEH, CBD-VEH, and CBD-THC groups do not
differ significantly. n = 8 for VEH-VEH, VEH-THC,
and CBD-VEH groups and n = 7 for the CBD-THC
group. *p < 0.05 compared with the VEH-VEH
group. {p = 0.05 and {{{p = 0.001 for CBD-VEH
and CBD-THC groups compared with the
VEH-THC group.
also reversed by pretreatment with WAY.33 Interest-
ingly, blockade of the 5-HT1A receptor also reverses
the anxiolytic effect of CBD34,49 and the ability of
CBD to attenuate the autonomic response to a stressor
and subsequent stress-induced anxiety.27,36 In addition
to nausea and vomiting, in humans, CHS is often ac-
companied by anxiety and autonomic symptoms,4
and anxiolytic drugs, such as benzodiazepines, are the
most commonly used treatment for CHS patients in
the hospital setting.63,64 This makes the effects of
CBD on anxiety and nausea and vomiting particularly
noteworthy.
One potential mechanism for development of CHS
and THC-induced nausea is a dysregulated stress re-
sponse due to high-dose THC, leading to cyclical nau-
sea and vomiting.4,17 We have previously shown that
THC produces dose-dependent conditioned gaping15
and a dose-dependent increase in serum CORT.52
Indeed, CBD was shown in the current experiment to
not only interfere with conditioned gaping produced
by a high dose of THC (10 mg/kg) but also to prevent
THC-induced increase in circulating CORT. CBD ad-
5
ministered before THC was able to inhibit the CORT
increase to where the CBD-THC group did not differ
significantly from rats treated with VEH control.
Viudez-Martı́nez et al.60 found that CBD prevented
stress-induced upregulation of stress-related gene ex-
pression in mice and attributed the effect to CBD’s ac-
tion on 5-HT1A receptors. CBD’s ability to inhibit
CORT increase by THC is therefore likely mediated
by its action on the 5-HT1A receptor. Indeed, a higher
dose of the 5-HT1A receptor antagonist, WAY, has
been shown to attenuate the increase in circulating
CORT produced by a high dose of the CB1 receptor ag-
onist, HU210.65
High doses of THC can increase 5-HT release by act-
ing on CB1 receptors on GABAergic terminals in the
DRN, resulting in disinhibition of 5-HT neurons.66,67
The increase in 5-HT produced by high doses of
THC may contribute to stress, anxiety, and nausea
associated with CHS. The ability of CBD to act on
5-HT1A autoreceptors in the DRN and reduce seroto-
nin release33,47,48 may be interfering with the aversive
effects of high-dose THC, ultimately reducing circulat-
ing CORT and attenuating THC-induced nausea.
Conclusions
In this study, we demonstrate that CBD reduces THC-
induced nausea by acting on 5-HT1A receptors and
inhibits the serum CORT increase produced by THC.
These findings suggest that serotonin and 5-HT1A re-
ceptors are involved in the mechanism of THC-
induced nausea as well as THC-induced stress.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
This research was supported by research grants from
the Natural Sciences and Engineering Research Council
of Canada (NSERC-03629) and the Canadian Institutes
of Health Research (CIHR-388239) to L.A.P.
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Abbreviations Used
and endocrine responses to stress. Endocrinology. 1999;140:79–86. ACTH ¼ adrenocorticotropic hormone
60. Viudez-Martı́nez A, Garcı́a-Gutiérrez MS, Manzanares J. Cannabidiol reg- CB1 ¼ cannabinoid 1
ulates the expression of hypothalamus-pituitary-adrenal axis-related CBD ¼ cannabidiol
genes in response to acute restraint stress. J Psychopharmacol. 2018;32: CCAC ¼ Canadian Council on Animal Care
1379–1384. CHS ¼ cannabinoid hyperemesis syndrome
61. Limebeer CL, Vemuri VK, Bedard H, et al. Inverse agonism of cannabinoid CORT ¼ corticosterone
CB 1 receptors potentiates LiCl-induced nausea in the conditioned gap- CRH ¼ corticotropin-releasing hormone
ing model in rats. Brit J Pharmacol. 2010;161:336–349. CTA ¼ conditioned taste avoidance
62. Rock EM, Moreno-Sanz G, Limebeer CL, et al. Suppression of acute and DRN ¼ dorsal raphe
anticipatory nausea by peripherally restricted fatty acid amide hydrolase HPA ¼ hypothalamic–pituitary–adrenal
inhibitor in animal models: role of PPARa and CB1 receptors. Br J Phar- LiCl ¼ lithium chloride
macol. 2017;174:3837–3847. POMC ¼ proopiomelanocortin
63. Richards JR, Gordon BK, Danielson AR, et al. Pharmacologic treatment of SAL ¼ saline
cannabinoid hyperemesis syndrome: a systematic review. Pharmaco- THC ¼ D9-tetrahydrocannabinol
therapy. 2017;37:725–734. TR ¼ taste reactivity
64. Khattar N, Routsolias JC. Emergency department treatment of cannabi- VEH ¼ vehicle
noid hyperemesis syndrome: a review. Am J Ther. 2017;5:1–5.