C H A P T E R

72
The Role of 5-HT1A Receptor, and
Nausea and Vomiting Relief by
Cannabidiol (CBD), Cannabidiolic Acid
(CBDA), and Cannabigerol (CBG)
E.M. Rock, L.A. Parker
Department of Psychology and Collaborative Neuroscience Program,
University of Guelph, Guelph, ON, Canada

SUMMARY POINTS KE Y FA CTS O F CA NNA B I D O L A N D

• Cannabidiol and cannabidiolic acid reduce acute CA NNA B I D I O L I C A CI D ’ S E F F E C T S
vomiting, acute nausea, and anticipatory nausea I N A NI M A L M O D E L S O F NAUS E A
in animal models. A ND E M E S I S
• Cannabidiol and cannabidiolic acid’s effects • Cannabidiol and cannabidiolic acid reduce acute
are mediated by indirect agonism of the 5-HT1A vomiting, acute nausea, and anticipatory nausea in
receptor. animal models.
• Cannabidiolic acid is much more potent than
• Cannabigerol acts as a 5-HT1A receptor
cannabidiol in these animal models.
antagonist, as it blocks the antinausea and
• These effects are mediated via the
antiemetic effects of cannabidiol
5-hydroxytryptamine 1A (5-HT1A) receptor, as
• Cannabidiol and/or cannabidiolic acid may be administration of a 5-HT1A antagonist blocks these
potential treatments for chemotherapy-induced effects.
nausea and vomiting. • As these phytocannabinoids do not exert their actions
• Human clinical trials need to evaluate the efficacy via the cannabinoid 1 receptor, these compounds are
of cannabidiolic acid to reduce chemotherapy- nonpsychoactive.
induced nausea and vomiting, especially for • Cannabidiol and/or cannabidiolic acid may be
the reduction of anticipatory nausea, because promising therapeutics for cancer patients undergoing
there is currently no selective treatment for this chemotherapy.
symptom.

Handbook of Cannabis and Related Pathologies. http://dx.doi.org/10.1016/B978-0-12-800756-3.00083-1

Copyright © 2017 Elsevier Inc. All rights reserved.
703
704 72.  CBD, CBDA, AND CBG
KEY FA C T S OF CANNAB IGEROL’ S
EFFECTS I N ANIMAL MODELS O F
N AU SEA A ND EMESIS
• Cannabigerol blocks cannabidiol’s antiemetic effects,
suggesting that cannabigerol acts as a 5-HT1A receptor
antagonist.
• Cannabigerol also blocks cannabidiol’s antinausea
effects, suggesting that cannabigerol acts as a 5-HT1A
receptor antagonist.
• These two phytocannabinoids may be acting in
opposition at the 5-HT1A receptor to modulate nausea
and vomiting
• This finding has important implications for the
potential therapeutic effects of various Cannabis sativa
strains.
• A C. sativa strain with higher cannabidiol relative to
cannabigerol may be more effective in reducing nausea
and vomiting in human patients.
LIST OF ABBREVIATIONS
AN Anticipatory nausea
CB1 Cannabinoid receptor 1
CB2 Cannabinoid receptor 2
CBD Cannabidiol
CBDA Cannabidiolic acid
CBG Cannabigerol
DRN Dorsal raphe nucleus
5-HIAA 5-Hydroxyindoleacetic acid
5-HT Serotonin
5-HT1A 5-Hydroxytryptamine 1A
5-HT3 5-Hydroxytryptamine 3
LiCl Lithium chloride
MRN Median raphe nucleus
NK-1 Neurokinin-1
8-OH-DPAT 8-Hydroxy-2-(di-n-propylamino) tetralin
THC ∆9-Tetrahydrocannabinol
INTRODUCTION
Cannabis sativa has been used for medicinal purposes
for more than 5000 years. Although the psychoactive can-
nabinoid ∆9-tetrahydrocannabinol (THC) was isolated in
1964, and extensively studied thereafter, only recently
have other cannabinoid compounds been investigated.
This chapter reviews recent findings on the potential of
the phytocannabinoids cannabidiol, cannabidiolic acid,
and cannabigerol, to modulate nausea and vomiting via
5-hydroxytryptamine1A (5-HT1A) receptors. First, we de-
scribe chemotherapy-induced nausea and vomiting, the
preclinical animal models that are used to evaluate these
VI.  Effects of specific natural and synthetic cannabinoids
potential treatments, and the involvement of the 5-HT1A
receptors in nausea and vomiting.
NAUSEA AND VOMITING
Emesis (vomiting), the act of eliminating poisonous
or toxic contents via expulsion through the mouth, can
be observed and quantified objectively. In contrast, nau-
sea, a subjective experience, is less easily defined. It has
been characterized as “an unpleasant, but not painful,
sensation associated with a heightened awareness of the
upper gut, cold sweating and the expectation that vomit-
ing is imminent” (Andrews, Rapeport, & Sanger, 1988).
Nausea and vomiting are distressing symptoms associ-
ated with pharmacological treatments, such as with an-
ticancer drug therapies.
Chemotherapy-Induced Nausea and Vomiting
Cancer patients undergoing chemotherapy treatment
often experience the distressing side effects of acute nau-
sea and vomiting, as well as delayed nausea and vomit-
ing (Fiore & Gralla,  1984). If posttreatment nausea and
vomiting are not properly managed, anticipatory nausea
(AN) and vomiting—a conditioned response elicited by
reexposure to the illness-paired context of the clinic—
can result (Morrow,  1982). Please refer to Table  72.1
for a description of the three phases of chemotherapy-
induced nausea and vomiting. Although acute vomiting
has become relatively well managed since the advent of
the 5-hydroxytryptamine 3 (5-HT3) receptor antagonists
such as ondansetron, and the neurokinin-1 (NK-1) recep-
tor antagonists, such as aprepitant (Hickok et al., 2003),
delayed nausea and AN are still unmanaged (Hickok
et al., 2003). Nausea is often identified as one of the most
distressing symptoms experienced by cancer patients un-
dergoing chemotherapy treatment (Aapro, Molassiotis,
TABLE 72.1 Three Phases of Chemotherapy-Induced Nausea
and Vomiting
Phase Description
Acute Occurring within 24 h after treatment (day 1 of
the chemotherapy cycle)
Delayed Occurring 24 h to 7 days after treatment (days
2–7 of the chemotherapy cycle)
Anticipatory A conditioned response, whereby patients feel
ill upon simply returning (or preparing to
return) to the clinic where they have received
chemotherapy
Occurring when acute and delayed phases are not
properly managed
This table describes the three phases of chemotherapy-induced nausea and
vomiting experienced by cancer patients, as discussed by Bender et al. (2002).
 Serotonin1A (5-hydroxytryptamine; 5-HT1A) receptors and nausea and vomiting 705
& Olver, 2005). With some 76% of patients reporting nau-
sea, and up to 43% of patients reporting vomiting after
their first treatment cycle (Morrow et al., 1998), the need
for effective pharmacotherapies is apparent.
ANIMAL MODELS OF NAUSEA
In order to assess the efficacy of novel pharmaco-
therapies, reliable preclinical animal models are neces-
sary. While the neural mechanisms of the emetic reflex
have been well established using animal models, such
as the ferret and the shrew (Hornby,  2001), the central
mechanisms regulating nausea are not well understood
(Andrews & Horn, 2006). In contrast to vomiting, nausea
is subjective, making development of an animal model
difficult. Further, we summarize the current selective
models (for a comprehensive review refer to Sharkey,
Darmani, & Parker, 2014) used to determine the nauseat-
ing potential of compounds, and to determine the poten-
tial of antinausea agents that can block or reduce nausea.
Conditioned Gaping
Conditioned Gaping to a Nausea-Paired
Flavor (Acute Nausea)
Recent evidence suggests that conditioned disgust
(gaping) reactions elicited by exposure to a flavor that has
been previously paired with an illness-inducing agent,
such as lithium chloride (LiCl), is a sensitive and selective
model of nausea-induced behavior in rats (Parker, Rana,
& Limebeer,  2008). Conditioned gaping reactions (see
Fig. 72.1) are only produced by drugs capable of produc-
ing vomiting (in emetic species), and antiemetic drugs
suppress conditioned gaping (see Parker et  al.,  2008).
Using this model, if a rat is pretreated with a compound,
resulting in a reduction of nausea-induced conditioned
gaping reactions (relative to vehicle-pretreated controls),
then this compound may be a potential therapeutic for
reducing acute nausea.
FIGURE 72.1  Conditioned gaping. Conditioned gaping in rats, de-
scribed as a wide, triangular opening of the mouth and jaw, exposing
the incisors, is the most sensitive and reliable rodent model of nausea.
VI.  Effects of specific natural and synthetic cannabinoids
Conditioned Gaping to a Nausea-Paired
Context (Anticipatory Nausea)
Interestingly, in addition to displaying conditioned
gaping reactions to a LiCl-paired flavor, rats also display
conditioned gaping reactions to a LiCl-paired context
(Limebeer et al., 2008; Rock, Limebeer, Mechoulam, Pio-
melli, & Parker, 2008). Like the chemotherapy patient who
feels nauseous upon returning to the clinic (where they
have previously experienced nausea-inducing chemother-
apy treatments), these contextually elicited conditioned
gaping reactions serve as a rodent model of AN. Indeed,
once AN develops in human chemotherapy patients, it is
refractive to classic antiemetic treatments such as ondan-
setron (Hickok et al., 2003). Similarly, pretreatment with
ondansetron is ineffective in suppressing conditioned
gaping responses elicited by a LiCl-paired context, in rats
(Limebeer, Hall, & Parker, 2006; Rock et al., 2014).
The conditioned gaping model is a useful tool for as-
sessing the therapeutic potential of a compound, as a re-
duction in acute nausea (conditioned gaping to a LiCl-
paired flavor) or AN (conditioned gaping to a LiCl-paired
context) can be assessed. The work reviewed here em-
ploys the conditioned gaping model to assess the antin-
ausea properties of the phytocannabinoids that exert their
action via 5-hydroxytryptamine 1A (5-HT1A) receptors.
SEROTONIN1A
(5-HYDROXYTRYPTAMINE; 5-HT1A)
RECEPTORS AND NAUSEA AND
VOMITING
5-HT1A Receptors
5-HT1A receptors, coupled to Gi/o, are distributed
throughout the central nervous system (see Hannon
& Hoyer,  2008), with high levels expressed in limbic
areas such as the raphe nuclei of the brainstem (Verge
et al., 1986). 5-HT1A autoreceptors, found on the cell bod-
ies and dendrites of serotonin (5-HT) containing neurons
(Riad et al., 2000) in the rat median raphe nucleus (MRN)
and dorsal raphe nucleus (DRN), regulate 5-HT release
(Verge et al., 1986) to terminal forebrain regions by de-
creasing the rate of neuronal firing (see Blier, Pineyro,
el Mansari, Bergeron, & de Montigny, 1998). Activation
of these somatodendritic 5-HT1A autoreceptors leads to a
reduction in neuronal firing (Blier & de Montigny, 1987).
Local 5-HT release in the raphe nuclei reduces neuronal
firing, producing negative feedback regulation of neu-
rotransmitter release (Adell & Artigas,  1991). Indeed,
5-HT receptor agonists inhibited release of 5-HT from in
vitro preparations of rodent brain tissue (Chase, Katz, &
Kopin, 1969). In addition, in vivo, 5-HT receptor agonists
reduced the electrical activity of serotonergic neurons in
the DRN (Aghajanian,  1972). Therefore, stimulation of
706 72.  CBD, CBDA, AND CBG
somatodendritic 5-HT1A autoreceptors results in a de-
crease of available 5-HT.
Classic 5-HT1A Receptor
Agonists and Antagonists
8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)
is a highly selective and centrally active potent ligand
(Arvidsson et  al.,  1981) preferentially binding to the so-
matodendritic (Hjorth & Magnusson, 1988) 5-HT1A auto-
receptor (Middlemiss & Fozard,  1983). 8-OH-DPAT has
traditionally been utilized as the standard receptor ago-
nist to evaluate behavioral effects of the 5-HT1A receptor.
Indeed, systemically administered 8-OH-DPAT dose-
dependently reduces the 5-HT synthesis rate, decreases
5-hydroxyindoleacetic acid (5-HIAA), the main metabo-
lite of 5-HT (Sharp, Bramwell, & Grahame-Smith, 1989),
and inhibits 5-HT neuronal firing in the DRN (Blier,
Steinberg, Chaput, & de Montigny,  1989), ultimately
reducing release of 5-HT in the brain (Hjorth et al., 1982).
WAY100135, a 5-HT1A receptor antagonist, has been
used to investigate this receptor, however, WAY100135
has since been shown to act at both presynaptic and
postsynaptic 5-HT1A receptors (Fletcher et  al.,  1993).
More recently, the highly selective and potent 5-HT1A
receptor antagonist WAY100635 has replaced the use of
WAY100135 (Forster et al., 1995). These 5-HT1A receptor
antagonists effectively block the effects of 8-OH-DPAT
on extracellular levels of 5-HT in the rat hippocampus
(Assie & Koek, 1996) and, when given alone, WAY100135
but not WAY100635 decreases 5-HT levels, indicating
possible partial agonist properties of WAY100135 at so-
matodendritic 5-HT1A receptors (Assie & Koek, 1996).
Classic 5-HT1A Receptors, and
Nausea and Vomiting in Humans
With the advent of the antiemetic 5-hydroxytryptamine
3 (5-HT3) receptor antagonists, most nausea and vomiting
research has focused on the involvement of this recep-
tor, rather than the 5-HT1A receptor, in mediating these
effects. Although a great deal of animal literature sup-
ports the involvement of the somatodendritic 5-HT1A
autoreceptors in the regulation of emesis and nausea,
little human literature exists. Chial et al. (2003) reported
that administration of the 5-HT1A receptor partial ago-
nist buspirone selectively suppressed self-report nausea
scores in the nutrient drink test (an assessment of gastric
functioning).
Classic 5-HT1A Receptors and
Nausea and Vomiting in Animals
5-HT1A receptor agonists such as 8-OH-DPAT, buspi-
rone, and LY228729 suppress vomiting in emetic species,
VI.  Effects of specific natural and synthetic cannabinoids
such as pigeons (Wolff & Leander, 1994, 1995, 1997), Sun-
cus murinus (house musk shrew; Javid & Naylor,  2006;
Okada, Torii, Saito, & Matsuki,  1994), cats (Lucot &
Crampton,  1987a,b,  1989; Lucot,  1990a,b) and dogs
(Gupta & Sharma, 2002). In the rat acute nausea model,
8-OH-DPAT reduces conditioned gaping (Limebeer
& Parker,  2003; Limebeer, Litt, & Parker,  2009). Please
refer to Table 72.2 for a summary of the involvement of
5-HT1A receptor ligands in nausea and vomiting using
animal models. This evidence indicates that agonism of
the 5-HT1A receptor via classic 5-HT1A ligands reduces
toxin-induced nausea and vomiting. The remainder of
this chapter will focus on the constituents of the canna-
bis plant (phytocannabinoids) that exert their antinau-
sea and antiemetic effects via activation of the 5-HT1A
receptor.
PHYTOCANNABINOIDS AND
NAUSEA AND VOMITING
C. sativa has been used for centuries as a therapeu-
tic for many ailments (Mechoulam,  2005), such as the
alleviation of nausea and vomiting. In fact, in the 19th
century, C. sativa was used in British medical practice to
treat nausea and vomiting (O’Shaughnessy, 1843). In the
1970s, young chemotherapy patients anecdotally report-
ed experiencing less (or none) of their nausea and vom-
iting when they were “high” from smoking cannabis
(Sweet, Miller, Weddington, Senay, & Sushelsky,  1981),
prompting early clinical trials demonstrating the effi-
cacy of THC, the psychoactive component in cannabis,
to reduce chemotherapy-induced nausea and vomiting
(Sweet et  al.,  1981). Due to the unsuccessful control of
chemotherapy-induced nausea and vomiting, oncolo-
gists began to investigate cannabinoids for their thera-
peutic potential. Recently, the mechanisms by which
cannabinoids reduce chemotherapy-induced nausea and
vomiting have been investigated (see Sharkey et al., 2014
for review) using animal models.
Cannabidiol
A major nonpsychoactive component in cannabis,
cannabidiol (CBD), was isolated from Lebanese hash-
ish in 1963 by Mechoulam and coworkers (Mechoulam
& Hanus, 2002). CBD has a very low affinity (in the mi-
cromolar range) for the cannabinoid 1 (CB1) and can-
nabinoid 2 (CB2) receptors (Pertwee,  2008). Although
CBD exerts its therapeutic effects via a number of
mechanisms, CBD’s antiemetic and antinausea effects
seem to be mediated by action at the 5-HT1A receptor.
For a summary of the antinausea and antiemetic ef-
fects of cannabidiol in animal models, please refer to
Table 72.3.
 Phytocannabinoids and nausea and vomiting 707
TABLE 72.2 Summary of Classic 5-HT1A Receptor Ligand Modulation of Nausea and Vomiting in Animal Models
Compound Species Effect References

8-OH-DPAT Pigeon Eliminated ditolyguanidine-induced emesis Wolff and Leander (1994)

Suncus murinus Eliminated motion-induced emesis Brame and Lucot (2011); Javid and Naylor
(2006); Okada et al. (1994)

Eliminated nicotine-, veratrine-, cisplatin-, or copper Brame and Lucot (2011); Okada et al. (1994)
sulfate-induced emesis

Cat Reduced motion-, cisplatin- or xylazine-induced emesis Lucot and Crampton (1989)

Eliminated RU 24969-induced emesis Lucot (1990b)

Rat Reduced acute nausea Limebeer and Parker (2003); Limebeer et al.
(2009); Rock et al. (2011, 2012)

Buspirone S. murinus Eliminated motion-induced emesis Okada et al. (1994)

Cat Reduced motion-, xylazine-induced emesis Lucot (1990a); Lucot and Crampton (1987b)

Eliminated cisplatin-induced emesis Lucot and Crampton (1987a)

Dog Reduced cisplatin-induced emesis Gupta and Sharma (2002)

Eliminated apomorphine-induced emesis Gupta and Sharma (2002)

LY228729 Pigeon Eliminated ditolyguanidine-induced emesis Wolff and Leander (1994)

Eliminated cisplatin-, ipecac-, emetine- and Wolff and Leander (1995)

m-(chlorophenyl)-biguanide-induced emesis

Eliminated cyclophosphamide-induced emesis Wolff and Leander (1997)

SUN8399 S. murinus Eliminated motion-induced emesis Okada et al. (1994)

Eliminated nicotine-, veratrine-, cisplatin-, copper
sulfate-induced emesis

Ipsapirone S. murinus Eliminated motion-induced emesis Okada et al. (1994)

Tandospirone S. murinus Eliminated motion-induced emesis Okada et al. (1994)

Gepirone S. murinus Eliminated motion-induced emesis Okada et al. (1994)

WAY100635 S. murinus No effect alone on motion-induced emesis Javid and Naylor (2006)
Unable to block 8-OH-DPAT-induced attenuation of
motion-induced emesis
This table summarizes the published effects of classic 5-HT1A receptor ligands in animal models of nausea and emesis.

CBD Reduces Nausea and Vomiting
in Human Patients
In a phase II clinical trial, when added to the standard
therapy, the oromucosally administered cannabis-based
medicine Sativex (containing approximately 50/50 THC
and CBD) was effective (57% of Sativex patients vs 22% of
placebo patients reporting no delayed emesis, and 71% of
Sativex patients vs 22% of placebo patients reporting no
delayed emesis) in suppressing delayed nausea and vom-
iting (Duran et al., 2010). To date, there are no published
human clinical trials evaluating the ability of CBD alone
to reduce chemotherapy-induced nausea and vomiting.
CBD Reduces Vomiting in Animal Models
In S. murinus, CBD produces a biphasic effect, at
low doses (5  mg/kg) suppressing, and at higher doses
(40 mg/kg) potentiating acute cisplatin-induced vomit-
ing (Kwiatkowska et al., 2004). In addition, acute LiCl-
induced vomiting has been suppressed by low doses (5–
10  mg/kg) of CBD, while higher doses (20–40  mg/kg)
of CBD were found to facilitate (rather than reduce) Li-
Cl-induced vomiting (Parker et  al.,  2004). Interestingly,
CBD is ineffective in reducing motion-induced vomiting
(Cluny et al., 2008). Consistent with the low binding af-
finity of CBD to the CB1 receptor (Pertwee, 2008), the CB1
receptor antagonist SR141716 did not block the CBD-
induced suppression of vomiting (Parker et  al.,  2004).
WAY100135 effectively blocked the CBD- (5 mg/kg) in-
duced suppression of acute nicotine-, LiCl- and cisplatin-
(20  mg/kg, but not 40  mg/kg) induced vomiting in
S. murinus, indicating a 5-HT1A receptor mediated anti-
emetic effect (Rock et al., 2012).
CBD Reduces Acute Nausea in Animal Models
In rats, CBD (5  mg/kg) has been shown to reduce
conditioned gaping to a LiCl-paired flavor, when

VI.  Effects of specific natural and synthetic cannabinoids

708 72.  CBD, CBDA, AND CBG

TABLE 72.3 Summary of Cannabidiol’s Effects in Animal Models of Nausea and Vomiting

Phytocannabinoid Animal model Effect Mechanism of action References

Cannabidiol Emesis in Suncus Reduced cisplatin-induced emesis 5-HT1A receptor Kwiatkowska, Parker,
murinus (5 mg/kg) Burton, and Mechoulam (2004);
Rock et al. (2012)

Potentiated cisplatin-induced Not evaluated Kwiatkowska et al. (2004)

emesis (40 mg/kg)

Reduced LiCl-induced emesis 5-HT1A receptor Parker, Kwiatkowska,

(5–10 mg/kg) Burton, and Mechoulam (2004);
Rock et al. (2012)

Potentiated LiCl-induced emesis Not evaluated Parker et al. (2004)

(20–40 mg/kg)

Reduced nicotine-induced emesis 5-HT1A receptor Rock et al. (2012)

Ineffective for motion-induced Not evaluated Cluny, Naylor, Whittle,

emesis and Javid (2008)

Acute nausea Reduced conditioned gaping 5-HT1A receptor Rock et al. (2012)
in rats
Enhanced 8-OH-DPAT-induced Not evaluated Rock et al. (2012)
reduction of conditioned gaping

Anticipatory Reduced conditioned gaping Not evaluated Rock et al. (2008)

nausea in rats
This table summarizes the published effects of cannabidiol (CBD) in animal models of nausea and emesis, as well as whether these effects are mediated by the
5-HT1A receptor.

administered systemically (Rock et al., 2012) or centrally
to the DRN (Rock et al., 2012). In addition, at a subthresh-
old dose (0.5  mg/kg), CBD systemically enhances the
antinausea effect of a subthreshold dose (0.005 mg/kg)
of 8-OH-DPAT (Rock et al., 2012).
The antinausea effect of CBD has been blocked by
WAY100635, when it is systemically or centrally (intra-
DRN) administered (Rock et  al.,  2012). In fact, when
WAY100635 was infused outside of the DRN, CBD’s
antinausea effects were not blocked, indicating that
the effect was selective to the DRN. Since the DRN is
a site of somatodendritic 5-HT1A autoreceptors, activa-
tion of which decreases the firing rate of 5-HT afferents
projecting to terminal brain regions (Verge et al., 1985),
these results suggest that CBD may be exerting its an-
tinausea effects by reducing the firing rate of 5-HT af-
ferents which project to terminal forebrain areas. CBD
enhanced the action of 8-OH-DPAT in vitro (% stimu-
lation of [35S]GTPγS binding above basal) and in vivo
(conditioned gaping), without acting as a direct agonist
at the 5-HT1A receptor in brainstem preparations (Rock
et al., 2012). Therefore, CBD may be acting as an indi-
rect agonist, thereby augmenting endogenous 5-HT ac-
tivation of the 5-HT1A receptor to reduce toxin-induced
acute nausea.
CBD Reduces Anticipatory Nausea
in Animal Models
CBD (1 and 5, but not 10  mg/kg) reduced condi-
tioned gaping to a LiCl-paired context (Rock et al., 2008);
however, CBD’s mechanism of action in AN has not yet
been evaluated. As there are currently no specific treat-
ments for AN, this nonpsychoactive component in can-
nabis could be a promising therapeutic option; however,
its limited effective dose range may prove difficult.
Conclusions
It is unfortunate that CBD has not yet been investigat-
ed in published human clinical trials with chemotherapy
patients, despite its efficacy in reducing acute vomiting,
acute nausea, and anticipatory nausea in animal mod-
els (via indirect 5-HT1A receptor agonism). Indeed, CBD
has also been shown to inhibit paclitaxel-induced neuro-
pathic pain (through 5-HT1A receptors), without dimin-
ishing chemotherapeutic efficacy (Ward et al., 2014), and
has even been shown to have antitumor action itself (De
Petrocellis et al., 2013).
Cannabidiolic Acid
Cannabidiolic acid (CBDA) is the nonpsychoac-
tive carboxylic acidic precursor of CBD. It is present
in the fresh cannabis plant, and decarboxylates upon
heating, such as when cannabis is smoked or dried.
In comparison to CBD, much less work has focused
on this acidic precursor. Studies in our laboratory
indicate that it is a highly potent antiemetic and an-
tinausea agent. For a summary of the antinausea and
antiemetic effects of CBDA in animal models, please
refer to Table 72.4.

VI.  Effects of specific natural and synthetic cannabinoids

 Phytocannabinoids and nausea and vomiting 709
TABLE 72.4 Summary of Cannabidiolic Acid’s Effects in Animal Models of Nausea and Vomiting
Phytocannabinoid Animal model Effect Mechanism of action References

Cannabidiolic acid Emesis in Suncus Reduced motion-, LiCl-, or Not evaluated Bolognini et al. (2013)
murinus cisplatin-induced emesis

Acute nausea in rats Reduced conditioned gaping 5-HT1A receptor Bolognini et al. (2013)

Enhanced ondansetron- or Not evaluated Rock and Parker (2013a,b)

metoclopramide-induced
suppression of conditioned gaping

Anticipatory nausea Reduced conditioned gaping 5-HT1A receptor Bolognini et al. (2013)
in rats
Enhanced tetrahydrocannabinolic 5-HT1A receptor and Rock et al. (2014)
acid-induced suppression of CB1 receptor
conditioned gaping
This table summarizes the published effects of cannabidiolic acid (CBDA) in animal models of nausea and emesis, as well as whether these effects are mediated by
the 5-HT1A receptor.

CBDA Reduces Vomiting in Animal Models
Recent evidence indicates that CBDA (0.1 and/or
0.5  mg/kg, i.p.) potently reduces motion-, LiCl-, and
cisplatin-induced vomiting in S. murinus (Bolognini
et  al.,  2013). Unfortunately, the 5-HT1A receptor media-
tion of these effects has not yet been investigated.
CBDA Reduces Acute Nausea in Animal Models
CBDA (0.1  mg/kg) also reduced LiCl-induced acute
nausea, an effect that was blocked by WAY100635, but not
SR141716 (Bolognini et al., 2013). CBDA also increased the
ability of the 5-HT1A receptor agonist, 8-OH-DPAT, to po-
tently stimulate [35S]GTPγS binding to rat brainstem mem-
brane, without activating CB1 receptors in vitro (Bolognini
et al., 2013). CBDA, like CBD, seems to inhibit nausea in
rats by enhancing the activation of 5-HT1A receptors. More
recently, CBDA has been shown to reduce acute nausea at
a dose as low as 0.5 µg/kg (Rock & Parker, 2013a). As well,
a subthreshold dose of CBDA (0.1 µg/kg) enhanced the
ability of a mildly effective dose of ondansetron (1 µg/kg),
or a subthreshold dose of metoclopramide (0.3 mg/kg, a
dopamine antagonist) to reduce LiCl-induced acute nau-
sea (Rock & Parker, 2013a,b).
CBDA Reduces Anticipatory Nausea
in Animal Models
CBDA suppressed contextually elicited conditioned
gaping (at doses as low as 0.001  mg/kg) in the rodent
model of AN (Rock et  al.,  2014), and this effect was
blocked by the 5-HT1A receptor antagonist, WAY100635
(Bolognini et  al.,  2013). In addition, coadministration
of subthreshold doses of CBDA (0.1  µg/kg) and tetra-
hydrocannabinolic acid (the acidic precursor of THC,
5  µg/kg) enhanced the suppression of AN, over that
of either agent alone (Rock et  al.,  2014), indicating
that these acidic precursors potently reduce AN. Pre-
treatment with SR141716 (CB1 receptor antagonist) or
WAY100635 blocked the combined effect of CBDA and
THCA, indicating the involvement of both receptors in
this effect (Rock et al., 2014).
Conclusions
CBDA suppresses nausea and vomiting in rats, in
a 5-HT1A receptor dependent manner, suggesting that
CBDA could be developed as a treatment for nausea and
vomiting because of its potency. CBDA could be a par-
ticularly interesting candidate treatment for AN, as there
is no current selective therapeutic available, once AN
develops. CBDA is also promising for development as a
treatment for acute nausea, because, unlike CBD, it does
not potentiate nausea and/or vomiting at high doses. In
fact, CBDA is active at much lower doses than CBD, but
at high doses CBDA is merely ineffective. As well, CBDA
does not modify overall activity level of rats (Bologini
et al., 2013; Rock et al., 2014). In addition to its antiemetic
and antinausea properties, CBDA (5, 10, 25  mM) inhib-
its highly aggressive human breast cancer cell migration,
a factor crucial in the prevention of cancer metastasis
(Takeda et al., 2012). These results highlight the need for
clinical trials with cancer patients undergoing chemo-
therapy, perhaps especially in breast cancer patients, in
order to prevent metastasis.
Cannabigerol
Cannabigerol (CBG), a nonpsychoactive component
of cannabis (Gaoni & Mechoulam, 1964) has been shown
to act as a 5-HT1A receptor antagonist (Cascio, Gauson,
Stevenson, Ross, & Pertwee, 2010), and recent work in our
laboratory has confirmed a 5-HT1A mediated effect in our
animal models. For a summary of CBG’s effects in animal
models of nausea and vomiting, please refer to Table 72.5.
CBG Blocks CBD-Induced Antiemetic
Effects in Animal Models
CBG (5 mg/kg, i.p.) blocked the CBD- (5 mg/kg, i.p.)
induced suppression of LiCl-induced acute vomiting in

VI.  Effects of specific natural and synthetic cannabinoids

710 72.  CBD, CBDA, AND CBG

TABLE 72.5 Summary of Cannabigerol’s Effects in Animal Models of Nausea and Vomiting

Phytocannabinoid Animal model Effect Mechanism of action References

Cannabigerol Emesis in Suncus Blocked the CBD-induced reduction of LiCl-induced 5-HT1A receptor Rock et al. (2011)
murinus emesis

Acute nausea in Blocked the CBD- or 8-OH-DPAT-induced reduction 5-HT1A receptor Rock et al. (2011)
rats of conditioned gaping (5 or 10 mg/kg)

Reduced conditioned gaping (1 mg/kg) Not evaluated Rock et al. (2011)

This table summarizes the published effects of cannabigerol (CBG) in animal models of nausea and emesis, as well as whether these effects are mediated by the
5-HT1A receptor.

S. murinus, suggesting that CBG exerts its action at the
5-HT1A receptor to block the effect of CBD at this receptor
(Rock et al., 2011).
CBG Blocks CBD-Induced Antinausea
Effects in Animal Models
CBG (5 or 10 mg/kg, i.p.) blocked the CBD- (5 mg/kg,
i.p.) and 8-OH-DPAT- (0.01  mg/kg, s.c.) induced sup-
pression of acute nausea (Rock et al., 2011), again suggest-
ing that CBG is acting on the 5-HT1A receptor to block the
5-HT1A mediated effects of CBD and 8-OH-DPAT. Also
of interest is the finding that CBG (1 mg/kg, i.p.) actually
suppressed acute nausea on its own (Rock et  al.,  2011).
This result is in line with the in vitro concentration spe-
cific effects of CBG, such that low concentrations of CBG
stimulate GTPγS binding to mouse brain membranes, but
this effect disappears at higher concentrations where CBG
acts as a 5-HT1A receptor antagonist (Cascio et al., 2010).
Summary
Interestingly, CBG and CBD, two constituents found
in the cannabis plant, both target 5-HT1A receptors, al-
though with opposite actions, to modulate the effects of
these receptors on nausea and vomiting. Therefore, the
concentration of these opposing cannabinoids in a spe-
cific strain of cannabis may be important in its efficacy
to reduce chemotherapy-induced nausea and vomiting.
CONCLUSIONS
It is only recently that the therapeutic potential of phy-
tocannabinoids (other than THC) has been investigated.
Here we provide evidence that several nonpsychoac-
tive phytocannabinoids (CBD, CBDA, CBG), which act
at 5-HT1A receptors, are potential treatment options for
chemotherapy-induced nausea and vomiting.
MINI-DICTIONARY
Anticipatory nausea  A classically conditioned response to the
hospital context that becomes associated with the chemotherapy-
induced illness experienced by patients (see Table 72.1). This
condition is modeled in rats with conditioned gaping to a lithium
chloride-paired context.
Cannabidiol (CBD)  A nonpsychoactive phytocannabinoid
exhibiting a low binding affinity for the CB 1 and 2 receptors.
Its antinausea and antiemetic effects are mediated by the
5-HT1A receptor, as the CBD-induced effects can be blocked
by a 5-HT1A receptor antagonist.
Cannabidiolic acid (CBDA)  The acidic precursor to cannabidiol,
found in the fresh Cannabis sativa plant. CBDA potently reduces
nausea and vomiting through a 5-HT1A receptor mediated
mechanism, as the CBDA-induced effects can be blocked by a
5-HT1A receptor antagonist.
Cannabigerol (CBG)  A nonpsychoactive phytocannabinoid that
acts as a 5-HT1A receptor antagonist, in contrast to CBD. In fact,
CBG blocks CBD’s antiemetic and antinausea effects.
Conditioned gaping  Although rats cannot vomit, they exhibit
conditioned disgust reactions (gaping), in response to the
delivery into their oral cavity of a flavor that has been previously
paired with illness (see Fig. 72.1). This is considered a rodent
model of acute nausea. Gaping, described as a wide, triangular
opening of the mouth and jaw exposing the incisors, is the most
sensitive and reliable rodent model of nausea. Indeed, rats also
exhibit gaping in response to a context that has been previously
paired with illness—a rodent model of anticipatory nausea.
Emesis  Also known as vomiting, it is the body’s means of
rejecting noxious or toxic substances via the oral cavity. Therefore,
antiemetic compounds prevent (or reduce) vomiting.
5-Hydroxytryptamine 1A (5-HT1A) receptors  A serotonin (5-HT)
receptor subtype binding the endogenous 5-HT neurotransmitter,
mediating inhibitory neurotransmission. The 5-HT1A receptors
located in the dorsal raphe nucleus are largely somatodendritic
(located on the soma and dendrites of serotonergic neurons).
Phytocannabinoid  Cannabinoids derived from C. sativa.
S. murinus  Also known as the house musk shrew, these
insectivores vomit in response to toxins such as lithium chloride.
Therefore, S. murinus are an animal model to assess whether
certain compounds can reduce (or eliminate) vomiting, indicating
an antiemetic effect.
Acknowledgments
We would like to thank NSERC (Grant #92057) and GW Pharmaceuti-
cals for their support of this work, and in particular GW Pharmaceu-
ticals for supply of several compounds that we have evaluated in the
experiments reviewed here.

Acute nausea  Chemotherapy-induced nausea that occurs within

24 h of the initial chemotherapy administration (see Table 72.1).
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VI.  Effects of specific natural and synthetic cannabinoids

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