Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

Abstract

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.

Full text

doi: 10.1098/rstb.2011.0389 , 3364-3378367 2012 Phil. Trans. R. Soc. B
Francisco Silveira Guimarães
Alline Cristina Campos, Fabricio Araújo Moreira, Felipe Villela Gomes, Elaine Aparecida Del Bel and
therapeutic potential of cannabidiol in psychiatric disorders
Multiple mechanisms involved in the large-spectrum
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Review
Multiple mechanisms involved in the
large-spectrum therapeutic potential of
cannabidiol in psychiatric disorders
Alline Cristina Campos1,2, Fabricio Arau
´jo Moreira3,
Felipe Villela Gomes4, Elaine Aparecida Del Bel5
and Francisco Silveira Guimara
˜es4,*
1
Group of Neuroimmunology, Laboratory of Immunopharmacology, Institute of Biological Sciences,
Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
2
Infectious Diseases and Tropical Medicine Program, Medical School, and
3
Department of Pharmacology,
Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenue Antonio Carlos 6627,
31270-901, Belo Horizonte, Minas Gerais, Brazil
4
Department of Pharmacology, School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo,
Avenue Bandeirantes 3900, 14049-900, Ribeira˜o Preto, Sa˜ o Paulo, Brazil
5
Faculty of Odontology of Ribeira˜o Preto, Department of Morphology, Physiology and Stomatology,
University of Sa˜ o Paulo, Avenue Cafe
´s/n, 14040-904, Ribeira˜ o Preto, Sa˜ o Paulo, Brazil
Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psy-
chotomimetic and other psychotropic effects that the main plant compound D
9
-tetrahydrocannabinol
(THC) being able, on the contrary, to antagonize these effects. This property, together with its safety
profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear
that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such
as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different bio-
logical systems have been extensively investigated by in vitro studies, the mechanisms responsible for
its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that
these mechanisms are not unitary but rather depend on the behavioural response being measured.
Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-
mediated neurotransmission in key brain areas related to defensive responses, including the dorsal
periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects,
such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories,
and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-
mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the
antipsychotic effectand the bell-shaped dose-response curves commonlyobserved with CBD. Consid-
ering its safety profile and wide range of therapeutic potential, however, further studies are needed to
investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse
agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARgreceptors agonism,
intracellular (Ca
2þ
) increase, etc.), on CBD behavioural effects.
Keywords: cannabidiol; anxiety; depression; psychosis; serotonin; anandamide
1. HISTORY
Cannabidiol (CBD) is the main non-psychotropic
phytocannabinoid present in the Cannabis sativa
plant, constituting up to 40 per cent of its extract.
The chemical characterization of the main cannabi-
noids present in this plant by Mechoulam’s group in
the 1960s [1] originated the first wave of scientific
interest in this compound. With the discovery of the
endocannabinoid (eCB) system in the early 1990s
and the rise, in the words of Bill Devane [2], of the
new dawn of cannabinoid pharmacology, there was a
renewed interest in CBD, with the number of related
published studies growing exponentially since then.
Recent comprehensive reviews suggest that this
compound is one of the most promising candidates
for a therapeutic tool in a wide range of disorders
[3,4]. In the present paper, we will review the evidence
that supports its use in psychiatric disorders and the
proposal mechanisms that try to explain it.
2. CANNABIDIOL AND ANXIETY
Early reports describing the effects of CBD in animal
models of anxiety were inconsistent. Silveira Filho &
*Author for correspondence (fsguimar@fmrp.usp.br).
One contribution of 15 to a Theme Issue ‘Endocannabinoids in
nervous system health and disease’.
Phil. Trans. R. Soc. B (2012) 367, 3364–3378
doi:10.1098/rstb.2011.0389
3364 This journal is q2012 The Royal Society
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from

Tufik [5] did not find any effect of CBD
(100 mg kg
21
) in rats tested in the classical Geller-
Seifter conflict model of anxiety, whereas Zuardi &
Karniol [6] described that a much lower CBD dose
(10 mg kg
21
) attenuated conditioned emotional
responses. These apparent contradictory results were
subsequently explained by Guimara
˜es et al.[7].
Using an ethologically based model of anxiety, the
elevated plus maze, they showed that CBD promotes
anxiolytic-like effects with an inverted U-shaped
dose-response curve, higher doses (more than
20 mg kg
21
in rats) being ineffective (table 1).
The anti-anxiety properties of CBD in rats were
later confirmed in different species (mice) and
animal models, including the Vogel conflict test and
contextual fear conditioning [8–10]. More recently,
CBD was shown to decrease defensive behaviours
evoked by predator exposure, a proposed model of
panic attacks and posttraumatic stress disorder
(PTSD) [11,13]. CBD also reduces marble burying
behaviour in mice, suggesting that this compound
could be effective in obsessive-compulsive disorder
(OCD) [14]. Moreover, CBD can interfere in learning
and/or memory of aversive events, processes that have
Table 1. Preclinical and clinical studies investigating the anxiolytic properties of CBD. , anxiolytic effect; , anxiogenic
effect; CFC, contextual fear conditioning; EPM, elevated plus maze; ETM, elevated T maze; GAD, generalized anxiety
patients; OF, open field; VCT, Vogel conflict test; i.p., intraperitoneal injection; i.c.v., intracerebroventricular injection;
DPAG, dorsal periaqueductal grey; BNST, bed nucleus of the stria terminalis; PL, prelimbic cortex; IL, infralimbic cortex;
CeA, central amygdala.
model species effective doses CBD effect references
studies with laboratory animals
Geller-Seifter conflict model rat 100 mg kg
21
i.p. no effect [5]
conditioned emotional responses rat 10 mg kg
21
i.p. [6]
EPM rat 2.5–10 mg kg
21
i.p [7]
EPM mouse 1 – 10 mg kg
21
i.p. [8]
VCT rat 10 mg kg
21
[9]
CFC rat 10 mg kg
21
i.p. ; decreased autonomic responses [10]
predator exposure (Cat)þEPM rat 5 mg kg
21
[11]
restraint stress þEPM rat 30 nmol intra-cisterna
magna
decreased autonomic and delayed
anxiogenic effect
[12]
predator exposure (snake) mouse 3 – 30 mg kg
21
i.p. panicolytic [13]
marble burying mouse 30 mg kg
21
i.p decreased compulsive behaviour [14]
CFC/fear memory extinction rat 6.35 nmol i.c.v. ; facilitated extinction [15]
ETM/DPAG electric stimulation rat 30 – 60 nmol intra-
DPAG
, panicolytic [16]
restraint stress þEPM rat 10 mg kg
21
i.p. decreased autonomic and delayed
anxiogenic effect
[17]
EPM/VCT rat 15–30 nmol intra-
DPAG
[18]
EPM/VCT rat 30–60 nmol intra-
BNST
[19]
CFC rat 30–60 nmol intra-
BNST
, decreased autonomic responses [20]
CFC rat 30 nmol intra-PL [21]
CFC rat 30 nmol intra-IL [21]
CFC rat 10 mg kg
21
i.p./daily/
14 days
[22]
CFC/fear reconsolidation rat 10 mg kg
21
i.p. ; memory reconsolidation
impairment
[23]
model/measures subjects dose (mg, p.o.) CBD effect references
clinical studies
simulated public-speaking healthy
volunteers
400 mg [24]
neuroimaging study healthy
volunteers
400 mg [25]
fearful facial stimuli healthy
volunteers
600 mg [26]
fearful facial stimuli healthy
volunteers
600 mg [27]
anxiety symptoms (visual
analogue mood scale)
GAD 400 mg [28]
simulated public speaking social phobics 400 mg [29]
Review.Cannabidiol and psychiatric disorders A. C. Campos et al. 3365
Phil. Trans. R. Soc. B (2012)
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been associated with PTSD pathophysiology [30].
Intracerebroventricular administration of CBD facili-
tates extinction in a contextual aversive conditioning
model [15]. In this same paradigm, it can also
impair reconsolidation, resulting in the attenuation of
the aversive memory trace. In this study, the impair-
ment of contextual fear memory did not show
reinstatement and was long-lasting (22 days) [23].
Contrasting with these results, Elbatsh et al.[22]
have recently reported that repeated (14 days) admin-
istration of CBD increases freezing in a contextual fear
conditioning test. The reasons for this difference is
unknown, but may involve the distinct conditioning
protocols and drug administration regime (chronic
versus acute) used compared with other studies that
investigated the effects of CBD in this model
[15,21,23]. Moreover, in this study, it is also possible
that CBD could have interfered in learning/memory
mechanisms, because the animals were conditioned
under the drug effect [22].
(a)Clinical anxiolytic effects of cannabidiol
In agreement with the results obtained in animal
models, clinical studies confirmed that CBD has anxio-
lytic properties (table 1). Following the initial report
that it blocks the anxiogenic effects of high doses of
the main psychoactive compound present in the Canna-
bis sativa plant, D
9
-tetrahydrocannabinol (THC) [31],
it was demonstrated that CBD can also reduce anxiety
in healthy volunteers during a neuroimaging study or
after a simulated public-speaking procedure [24,25].
More recently, using the latter procedure, Bergamaschi
et al.[29] showed that CBD (600 mg p.o.) decreases
anxiety in treatment-naive social phobic patients.
(b)Brain sites of cannabidiol anxiolytic effects
Neuroimaging studies show that CBD changes the
activity of brain regions related to the control of
emotional process [25,27]. It attenuates blood oxygen-
ation in the amygdala and the anterior and posterior
cingulate cortex in subjects exposed to fearful faces
[27], impairs the connectivity between the pre-frontal
and subcortical regions [27] and decreases the acti-
vation of left-amygdala– hippocampal complex and
left posterior cingulate gyrus [25].
These clinical findings were complemented by
studies in rodents, using direct administration into
brain sites related to anxiety- or panic-like responses
(figure 1). Microinjection of CBD into the dorsal por-
tions of the periaqueductal grey (DPAG) promoted
anxiolytic-like effects in the elevated plus maze, elev-
ated T maze and Vogel conflict tests. It also
decreased escape latency in a model of panic attacks,
electrical stimulation of the DPAG [16,18]. Anxiolytic
effects were also found after CBD injection into the
bed nucleus of the stria terminalis (BNST) in rats
tested in the elevated plus maze, Vogel conflict test
and contextual fear conditioning [19,20]. This latter
effect corroborates results showing that the effects of
CBD in a contextual fear conditioning model is associ-
ated with decreased neuronal activation (measure by
cFos expression) in this area [21]. This same treatment
attenuated the activation of the pre- and infra-limbic
cortical regions. In these two brain areas, however,
CBD produced opposite effects, decreasing and facili-
tating, respectively, conditioned emotional responses
[10]. Recently, Hsiao et al.[26] showed anxiolytic
effects of CBD injection into the central nucleus of
the amygdala. Other possible brain sites of CBD
anxiolytic effect have not yet been investigated (e.g.
the hippocampus).
(c)Mechanisms of the anxiolytic effects of
cannabidiol
CBD can produce multiple pharmacological actions
over a wide range of drug concentrations (table 2)
[3,4]. CBD is proposed to activate or modify the func-
tion of several receptors in the central nervous system
(CNS), including CB1, CB2, GPR55, TRPV1 and 5-
HT1A receptors (table 2)[32,33,35,42]. Moreover, it
could inhibit the anandamide hydrolysing enzyme
(fatty acid amide hydrolase, FAAH) and the adenosine
hippocampus: neurogenesis (CB1, CB2?)
PL: CER (5-HT1A)
IL:
BNST: CER, anxiety
anxiety/panic (5-HT1A)
anxiety (TRPV1?)
DPAG:
CER (?)
(5-HT1A)
Figure 1. Possible brain sites and mechanisms of CBD effects on anxiety. BNST, bed nucleus of the stria terminalis; CeA,
central nucleus of the amygdala; CER, conditioned emotional response; DPAG, dorsal periaqueductal grey; IL, infralimbic
prefrontal cortex; PL, prelimbic prefrontal cortex.
3366 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
Phil. Trans. R. Soc. B (2012)
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transporter [33,43,50], indirectly increasing the levels
of these neurotransmitters.
Some of CBD effects involve intracellular pathways
that play fundamental roles in neuronal physiology.
For example, in hippocampal neurons, CBD increases
intracellular calcium concentrations via mitochon-
drial uptake and release and/or activation of type-L
voltage-gated calcium channels [38,39]. CBD has
also a potent action in inhibiting oxidative and nitrosa-
tive stress, a mechanism that has been related to its
neuroprotective effects with implications for the treat-
ment of Alzheimer’s, Huntington’s and Parkinson’s
diseases. It decreases the neuronal damage pro-
moted by b-amyloid protein deposit [47,51] and
attenuates the depletion of tyrosine hydroxylase, dopa-
mine and GABA levels by modulating the expression
of the inducible nitric oxide synthase and reducing
the production of reactive oxygen species (ROS)-gen-
erating NADPH oxidases [47,52–54]. Moreover,
CBD pretreatment attenuated high-glucose-induced
mitochondrial superoxide generation and NF-kB
activation, along with the expression of adhesion
molecules ICAM-1 and VCAM-1 [48]. Together,
these results suggest that CBD can exert CB1- and
Table 2. Possible mechanisms of CBD behaviour effects. Evidence from in vitro studies. CHO, Chinese hamster ovary cells.
biological system mechanism biological system concentration range references
endocannabinoid/
endovanilloid related
mechanisms
CB1 receptor antagonist mouse brain membranes 4.9 mM(K
i
)
a
[32]
CB2 receptor inverse agonist CHO transfected cells 4.2 mM(K
i
)
b
[32]
TRPV1 agonist HEK-293 transfected cells 3.2 mM (EC
50
)[33]
FAAH/anandamide
transporter inhibition
HEK-293 transfected
cells, rat brain
membranes
7.5– 8.6/22 mM (IC
50
)[33,34]
serotonin-related
mechanisms
5-HT1A receptor agonist CHO transfected cells 16 mM (increases
receptor response by
67%)
[35]
5-HT2A receptor agonist CHO transfected cells 32 mM (IC
50
)[35]
5-HT3 receptor antagonist Xenopus laevis oocytes 10–30 mM[36]
suppression of mitogen-
induced IDO activity
(decreasing tryptophan
metabolism)
human blood cells 8.9 mM (IC
50
)[37]
others intracellular (Ca
2þ
) increase hippocampal cell cultures/
hippocampal
preparations
approximately 1 mM
(effective
concentration)
[38,39]
allosteric modulation of m
and dopioid receptors
cerebral cortex
preparations
100 mM[40]
PPArgreceptors agonist aorta preparations 5 mM (IC
50
)[41]
GPR55 antagonist cell membranes of
transfected cells
445 nM (IC
50
)[42]
blockade of adenosine
uptake/indirect A2 agonist
microglia and
macrophages cell
cultures
less than 250 nM (K
i
)/
500 nM (effective
concentration)
[43,44]
TRPV2 agonist HEK-293 transfected
cells/rat dorsal root
ganglia (DRG) sensory
neurons
3.7 mM (EC
50
)[45]
TRPM8 antagonist HEK-293 transfected
cells/rat dorsal root
ganglia (DRG) sensory
neurons
80–140 nM(IC
50
)[46]
TRPA1 agonist HEK-293 transfected
cells/rat dorsal root
ganglia (DRG) sensory
neurons
96 nM(EC
50
)[46]
P38 MAPKinase inhibition PC12 cells 10
26
–10
24
M (effective
concentrations)
[47]
NF-kB activation PC12 cells 10
26
–10
24
M (effective
concentrations)
[47]
inhibition of mitochondrial
superoxide production
vascular endotelial cells 4 mM (effective
concentration)
[48]
inhibition of inducible nitric
oxide synthase (iNOS)
expression
kidney 10 mg kg
21
[49]
a
CBD was able to antagonize the effects of the CB1 agonist CP55940-induced stimulation of [35S]GTPgS binding to mouse brain
membranes at a much lower concentration (K
B
¼79 nM) than the K
i
for displacement of the CB1 ligand.
b
CBD acts as an inverse agonist with a lower concentration (K
B
¼65 nM) than the K
i
for displacement of the CB2 ligand.
Review.Cannabidiol and psychiatric disorders A. C. Campos et al. 3367
Phil. Trans. R. Soc. B (2012)
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CB2-independent neuroprotective/antioxidant/anti-
inflammatory effects [48].
The large majority of these possible mechanisms
have been unveiled by in vitro studies. Their associ-
ation to the behaviour effects of CBD is still not
clear, a topic that is further complicated by the
common bell-shaped dose-response curves produced
by this compound in distinct biological systems [4].
In the last decade, however, several in vivo studies
have helped us to understand the mechanisms of
CBD central effects.
(d)In vivo mechanisms of cannabidiol anxiolytic
effects: 5-HT1A receptors
Russo et al.[35] were the first to suggest that CBD
could act as a 5HT1A receptor agonist. They observed
that, at mM range, this drug displaces 8-OH-DPAT,
a 5-HT1A receptor agonist, from cloned human
5-HT1A receptors expressed in cultured cells obtained
from Chinese hamster ovary. In vivo experiments gave
further support to the involvement of 5-HT1A recep-
tors in the effects of CBD [18 –20,55]. For instance,
the neuroprotective effects of CBD in hepatic ence-
phalopathy or cerebral infarction are mediated by
these receptors [55,56]. Regarding the behavioural
studies, the effects of CBD in a PTSD model (preda-
tor exposure) were prevented by WAY100635, a
5HT1A receptor antagonist [11]. This same antagon-
ist prevented the anxiolytic- and panicolytic-like effects
of CBD after injections into the DPAG [16,18], bed
nucleus of the stria terminalis [19,20] and prefron-
tal cortex (M. V. Fogac¸a & F. S. Guimara
˜es 2012,
unpublished data; figure 1). In humans, although no
study so far has investigated the involvement of 5-
HT1A mechanisms in CBD effects, the anxiolytic pro-
file of this drug in the public speaking model was
remarkably similar to the positive control ipsapirone,
a 5HT1A receptor partial agonist [24].
Other CBD effects also involve 5-HT1A receptors.
It decreases nausea and vomiting probably by an indir-
ect agonism at these receptors. Although the
mechanism of this indirect action is unclear, it may
involve interactions with allosteric sites or changes in
different systems that would result in a facilitation of
5-HT1A-mediated responses [57]. Adding to the evi-
dence that the interaction of CBD with 5-HT1A
receptors could be complex, it was recently shown
that this compound antagonizes food intake induced
by 8-OH-DPAT [58]. Therefore, additional research
is clearly needed to clarify how CBD facilitates
5-HT1A-mediated neurotransmission.
(e)In vivo mechanisms of cannabidiol effects:
the endocannabinoid system
CBD could facilitate eCB-mediated neurotrans-
mission by blocking the metabolism and uptake of
anandamide [33]. However, AM251, a CB1 receptor
antagonist, failed to prevent the anxiolytic effects of
CBD injected into the DPAG observed in the elevated
plus maze at the same dose that antagonized the anxio-
lytic effects of anandamide [18,59].
On the other hand, CB1, but not 5-HT1A, receptor
antagonism was able to prevent CBD effects on both
extinction and reconsolidation, indicating that its
interference on aversive memories involves eCB-
mediated mechanisms [15,23]. These results agree
with the well-described facilitation of extinction by
endogenous cannabinoids [60], suggesting that CBD
interferes with aversive memories by facilitating the
effects of eCBs [45].
Finally, AM251 blocked CBD effects in the marble
burying model [14], whereas 5-HT1A-receptor antag-
onism was ineffective. This result corroborates the
proposal that anxiety and OCD models engage distinct
brain mechanisms, with the marble burying beha-
viour being related to repetitive behaviours instead of
anxiety [61].
How facilitation of eCB-mediated neurotrans-
mission decreases repetitive behaviour is unknown,
but may involve attenuation of glutamate-mediated
neurotransmission. eCBs can reduce the release of
several neurotransmitters, including glutamate [62],
a major neurotransmitter of the cortico-striato-
thalamo-cortical circuitry that has been implicated in
the pathophysiology of OCD [63]. Anti-glutamatergic
drugs such as riluzole and memantine decrease marble
burying behaviour [64,65] and are proposed to be
clinically useful for OCD treatment [66,67].
An indirect anti-glutamatergic action via increased
eCB neurotransmission may also be involved in other
central effects of CBD such as anticonvulsant [3], an
effect that could also be related to indirect CB1-
mediated inhibition of glutamate release. Corroborating
this proposal, anticonvulsant effects of other inhibitors
of anandamide metabolism/uptake have recently been
described [3]. Moreover, epileptic patients present a
significant reduction in the fraction of CB1-positive
glutamatergic, but not GABAergic, axon terminals,
probably resulting in increased neural excitability [68].
(f)In vivo mechanisms of cannabidiol effects:
adult hippocampal neurogenesis
Impairment in adult hippocampal neurogenesis has
been associated with the pathogenesis of anxiety dis-
orders and depression [69] and at least some of the
behavioural effects of prototype antidepressant drugs
depend on facilitation of this process [70]. CBD can
also increase adult hippocampal neurogenesis, as first
demonstrated by Wolf et al.[71]. They also showed
that the proneurogenic effect of CBD was absent in
CB1-knockout mice [71]. Because CBD is not
a CB1-receptor agonist, this result suggested that
CBD effect was mediated by an indirect activation of
these receptors, possibly by inhibition of anandamide
metabolism/uptake [33]. Corroborating this latter
possibility, recent results from our group showed that
CBD increases proliferation of hippocampal progeni-
tor cells in culture, an effect mimicked by CB
1
or
CB
2
receptor agonists and prevented by antagonists
of these receptors [72]. Moreover, CBD effects were
also inhibited by overexpression of the FAAH, reinfor-
cing the proposal of anandamide involvement. These
results agree with those previously reported by Jiang
et al.[73] showing that a synthetic CB1 agonist is
able to promote embryonic and adult hippocampus
neurogenesis, an effect associated with the anxiolytic
3368 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
Phil. Trans. R. Soc. B (2012)
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and antidepressant properties of the drug. Similar
to prototype antidepressants, the anxiolytic effect
of repeated administered CBD (30 mg/daily for 14
days) in mice submitted to a chronic unpredictable
stress model disappeared when hippocampal neuro-
genesis was inhibited [72], suggesting a causal link
between its proneurogenic and anxiolytic effect after
repeated administration (figure 1).
Other mechanisms could also be involved in CBD
effects on adult hippocampal neurogenesis—for
example, activation of peroxisome proliferator-
activated receptors. This particular mechanism seems
to be important during neuroinflammation and neuro-
degenerative process related to b-amyloid protein
deposits in CNS [51]. Although the pro-neurogenic
effect of CBD has not yet been studied in rats, it
could help us to explain the recent report that repeated
CBD treatment enhances contextual fear conditioning
[22]. Immature newborn neurons are selectively acti-
vated by this task [74], and neurogenesis suppression
impairs contextual fear memory [75]. Considering
the important role proposed for hippocampal neuro-
genesis in several brain functions [76,77], the effects
and mechanisms of CBD on this process is another
important research venue to be pursued.
(g)Cannabidiol and the vanilloid system
CBD can activate transient receptor potential (TRP)
channels [33]. These channels comprise a family of
over 50 members and are present in different species,
including yeast, worms, insects, fish and mammals [78].
The vanilloid receptor 1 or TRPV1 is one of the first
identified members of the family, being a non-selective
cation channel with a preference for calcium. It is acti-
vated by noxious stimuli, heat, protons (pH ,5.9) and
various, mostly noxious, natural products such as cap-
saicin [79]. TRPV1 receptors are present in the brain,
where anandamide has been proposed to act as an
endogenous agonist or an endovanilloid [80]. These
receptors can facilitate the release of glutamate [81], a
neurotransmitter that induces defensive responses in
brain areas such as the DPAG [82]. On the basis of
these pieces of evidence, we hypothesized that TRPV1
activation could be at least partially responsible for the
inverted U-shaped dose-response curves commonly
observed with CBD. Accordingly, using intra-DPAG
injections, we showed that local pretreatment with an
ineffective dose of the TRPV1 antagonist capsazepine
turned a higher, ineffective dose (60 nmol) of CBD
into an anxiolytic one [83]. TRPV1 receptors are also
involved in the bell-shaped dose responses curves of
anandamide analogues [84,85].
In addition to TRPV1, CBD could also interfere with
other members of the TRP family, activating TRPV2
and ankyrin type 1 (TRPA1) channels and antagonizing
melastatin type 8 (TRPM8) channels [45,46]. The role
played by these mechanisms on CBD behavioural
effects, however, is unknown at the moment.
3. CANNABIDIOL AND PSYCHOSIS
Initial studies with laboratory animals suggested that
CBD prevents some of the effects produced by THC
[86]. Similar antagonism was also found in humans,
where CBD attenuated the impairment of time pro-
duction tasks and the euphoria induced by THC in
healthy volunteers [87,88]. Confirming and extending
these results, Zuardi et al. [31] demonstrated that
CBD inhibits THC-induced anxiety and psychotic-
like symptoms such as disconnected thoughts,
perceptual disturbance, depersonalization and resist-
ance to communication. In the same year, it was
observed that patients admitted to a psychiatric hospi-
tal in South Africa after the use of a variety of Cannabis
virtually devoid of CBD showed a much higher fre-
quency of acute psychotic episodes than in other
countries [89], suggesting that the presence of CBD
in Cannabis samples protects users against the occur-
rence of THC-induced acute psychotic episodes.
Because experimental evidence indicates that the
antagonistic effect of CBD did not result from a phar-
macokinetic interaction between the two cannabinoids
[90], these initial observations led to the hypothesis
that CBD could possess antipsychotic properties.
An initial study in rats investigated whether this
compound could attenuate stereotypies induced by
the dopaminergic agonist apomorphine. CBD effects
were compared with those of haloperidol [91]. Both
drugs reduced apomorphine-induced stereotyped be-
haviour in a dose-related manner. Even though they
increased plasma levels of prolactin, CBD had much
lower potency, with significant increases only seen
after the doses of 120 and 240 mg kg
21
. Moreover,
contrary to haloperidol, CBD did not induce cata-
lepsy, even at doses as high as 480 mg kg
21
. These
results suggest that CBD exhibits a profile similar to
atypical antipsychotic drugs. In another study, CBD
was compared with haloperidol and clozapine, an aty-
pical antipsychotic drug. The drug inhibited the
hyperlocomotion induced by amphetamine and keta-
mine, an NMDA receptor antagonist, in mice [92].
As expected, while both haloperidol and clozapine
inhibited hyperlocomotion, only haloperidol induced
catalepsy. These results extend CBD antipsychotic-
like effects to a glutamate-based model. In agreement
with these results, CBD, similar to clozapine, reversed
the disruption of prepulse inhibition (PPI) in mice and
the hyperactivity and reduction of social interaction in
rats caused by MK-801, another NMDA receptor
antagonist [93,94]. Typical antipsychotics, on the
other hand, are usually unable to restore the deficits
in PPI and social interaction induced by NMDA
receptor antagonists [95,96].
Extending findings from studies using single drug
administration, chronic treatment with CBD attenu-
ated amphetamine-induced hyperlocomotion [97].
Preliminary results from our group indicate that this
treatment regime is also able to decrease the impair-
ments in PPI and object recognition induced by
repeated administration of MK-801 (F. V. Gomes,
E. A. Del Bel & F. S. Guimara
˜es, unpublished data).
Despite these findings, there are also negative results
regarding the possible antipsychotic effects of CBD.
Chronic treatment with this drug failed to change be-
havioural changes such as locomotor hyperactivity and
PPI deficits observed in transmembrane domain neur-
egulin 1 mutant (Nrg1) mice, a proposed model for a
schizophrenia susceptibility gene [98]. A summary of
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the studies investigating the antipsychotic-like effects
of CBD in animal models can be seen in table 3.
(a)Cannabidiol and psychosis: clinical studies
The antipsychotic-effects of CBD have also been demon-
strated in humans (table 3). In healthy volunteers,
Leweke et al. [100] observed that the decrease of the
perception of illusory image induced by nabilone, a
synthetic cannabinoid drug with THC-like properties,
was reduced by CBD. Another model used to evaluate
antipsychotic-like activity of drugs in humans is the
administration of sub-anaesthetic doses of ketamine.
This drug induces psychotic symptoms that mimic
both positive and negative symptoms of schizophrenia.
An initial investigation in healthy subjects showed
that CBD induced a non-significant trend to reduce
ketamine-induced dissociative effects, but, at the same
time, augmented the activating effects of ketamine
Table 3. Preclinical and clinical studies investigating the antipsychotic properties of CBD. , antipsychotic-like effects;
BPRS, brief psychiatric rating scale; CADSS, clinician administered dissociative states scale; PANSS, positive and negative
syndrome scale; PPQ, Parkinson psychosis questionnaire.
model species effective doses CBD effects references
studies with laboratory animals
apomorphine-induced
stereotyped behaviour
rat 60 mg kg
21
[91]
D-amphetamine- and
ketamine-induced
hyperlocomotion
mouse 15–60 mg kg
21
[92]
MK-801-induced disruption
of PPI
mouse 5 mg kg
21
[93]
D-amphetamine-induced
hyperlocomotion
mouse 50 mg kg
21
(chronic – 21
days)
[97]
MK-801-induced social
withdrawal and isruption of
PPI
rat 3 – 30 mg kg
21
[99]
MK-801-induced
hyperlocomotion and
deficits in social interaction
and
rat 3 mg kg
21
[94]
locomotor hyperactivity and
PPI
Nrg 1 mutant mouse 1, 50 and 100 mg kg
21
no effects [98]
model/measures subjects (n) doses CBD effects references
clinical studies
THC-induced impairment of
time production task
healthy male volunteers
(40)
15–60 mg (acute) [87]
THC-induced euphoria healthy male volunteers
(15)
0.15 mg kg
21
(inhalation;
acute)
[88]
THC-induced psychotic
symptoms
healthy male volunteers
(eight)
1mgkg
21
(acute) [31]
nabilone-induced impairment
of perception of binocular
depth inversion
healthy male volunteers
(nine)
200 mg (acute) [100]
THC-induced psychotic
symptoms (PANSS)
healthy male and female
volunteers (six)
5 mg (iv, acute) [101]
ketamine-induced psychotic
symptoms (BPRS and
CADSS)
healthy male volunteers
(10)
600 mg (acute) (trend) [102]
psychotic symptoms (BPRS) schizophrenic female
patient (one)
increasing oral doses of CBD,
reaching 1500 mg d
21
(four
weeks)
[103]
psychotic symptoms (BPRS) male patients with
treatment-resistant
schizophrenia (three)
increased from 40 up to
1280 mg d
21
(30 days)
one patient
showed mild
improvement
[104]
L-dopa-induced psychosis
(BPRS and PPQ)
Parkinson’s disease
patients (six)
increased from 150 up to
600 mg d
21
depending on
the clinical response (four
weeks)
[105]
psychotic symptoms (BPRS
and PANSS)
acute paranoid
schizophrenia patients
(42)
600 mg d
21
(four weeks) [34]
Stroop Colour Word Test schizophrenic patients
(28)
300 and 600 mg (acute) no effect [106]
3370 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
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[102]. Because only a single dose of CBD was used,
additional studies are needed to characterize the effects
of CBD in this model [102].
The therapeutic use of CBD in psychotic patients
was tested for the first time in 1995. In an open, case-
report study, a 19-year-old black schizophrenic female
patient, who presented serious side effects after treat-
ment with conventional antipsychotics, received
increasing oral doses of CBD (up to 1500 mg d
21
) for
four weeks [103]. A significant improvement with no
side effects was observed in all items of the standard
brief psychiatric rating scale (BPRS) during CBD treat-
ment, with an efficacy similar to that of haloperidol.
Symptom worsening was observed when the adminis-
tration was interrupted. In another case study, CBD
was administered to three 22- or 23-year-old male
schizophrenic patients who had not responded to typical
antipsychotic drugs for 30 days [104]. The dose of CBD
was increased from 40 up to 1280 mg d
21
. One patient
showed mild improvement, but only slight or no change
was observed in the other two, suggesting that CBD may
not be effective for the treatment of resistant schizo-
phrenia. Moreover, CBD had no beneficial effects on
the performance of schizophrenic patients in the
Stroop colour word test, which can be used to assess
attentional processes frequently impaired in schizo-
phrenia [106]. It is still unknown whether chronic
administration of CBD could improve the cognitive def-
icits in the disorder. No significant side effects were
observed during CBD treatment in these clinical
studies, suggesting that CBD is safe and well tolerated
in schizophrenic patients.
In an open-label study evaluating CBD effects on
psychotic symptoms associated with L-dopa use in Par-
kinson’s patients [105], the drug decreased scores of a
questionnaire developed to assess psychotic symptoms
in Parkinson’s disease (Parkinson psychosis question-
naire), improved total BPRS scores as well as scores
specifically related to positive and negative symptoms.
Confirming the lack of motor effects observed in
animal studies, CBD did not affect motor function.
On the contrary, it decreased the total scores of the
unified Parkinson’s disease rating scale, suggesting an
improvement of this function.
Overall, therefore, even if there are negative results,
most clinical studies with normal subjects or schizo-
phrenic patients suggest that CBD has antipsychotic
properties. Corroborating this possibility, a four-week
double-blind controlled clinical trial in 42 acute
schizophrenic and schizophreniform psychosis patients
comparing the effects of CBD with those of amisul-
pride, an atypical antipsychotic, showed that both
treatments were equally effective in reducing acute
psychotic symptoms after two and four weeks of treat-
ment [34]. Moreover, compared with amisulpride,
CBD caused a lower incidence of extrapyramidal
symptoms and increases in prolactin and weight gain.
The presence of antipsychotic properties in CBD is
also supported by convergent evidence linking the
habitual use of Cannabis to the risk of developing schizo-
phrenia or schizophrenia-like psychosis, especially in
vulnerable subjects [107]. This effect has been attribu-
ted to THC. In agreement with the initial reports
showing antagonism of THC-induced psychotomimetic
effects [31,87,88], the presence of CBD in Cannabis
strains has been shown to be protective against the
occurrence of psychotic-like reactions and cognitive
impairment [108–110]. In this context, Di Forti et al.
[111] found that the use of Cannabis containing high
THC- and low CBD concentration was associated with
a higher risk of a first psychotic episode. Furthermore,
the presence of CBD protects from Cannabis-associated
decrease in hippocampal volume [112]. This neuropro-
tective effect of CBD has also been reported in the
human basal ganglia, where there was a strong positive
correlation between N-acetylaspartate/total creatine
ratio and the amount of CBD (as measured by its
presence in hair samples) in the putamen/globus palli-
dum of recreational Cannabis users. This finding could
reflect a CBD-induced enhancement of neuronal and
axonal integrity in these regions [113]. More recently,
Bhattacharyya et al. [114], investigating the effects
of THC and CBD during attentional salience proces-
sing, have also showed that these two cannabinoids
produce opposite effects on prefrontal, striatal and
hippocampal functions.
(b)Brain sites and mechanisms of cannabidiol
antipsychotic effects
Few studies in laboratory animals have investigated
the possible brain sites and mechanisms of CBD antipsy-
chotic effects. Consistent with the behavioural data
described earlier, both CBD and clozapine, but not halo-
peridol, increased neuronal activation (measured by
cFos-protein expression) in the prefrontal cortex. Prob-
ably reflecting its motor side effects, only haloperidol
increased cFos in the dorsal striatum. CBD, and, in
addition, increased cFos in the nucleus accumbens
[115], an effect shared by typical and atypical antipsycho-
tic drugs [116]. Intracerebroventricular administration of
CBD (10 mg) also enhanced cFos expression in waking-
related brain areas such as hypothalamus and dorsal
raphe nucleus [117], but the relation between this finding
and its antipsychotic properties is unclear.
A number of neuroimaging studies in healthy
volunteers have compared the effects of CBD and
high doses of THC. Consistent with the behavioural
findings in humans and rodents, these drugs caused
opposite effects on brain activity in the striatum,
anterior cingulate, prefrontal cortex, parahippocampal
gyrus, amygdala, right posterior superior temporal
gyrus, middle occipital gyrus and cerebellum [27,
101,114,118–120]. Behavioural measurements in
these studies indicated that some of these changes
(decreased activation of ventral and dorsal striatum,
anterior cingulate gyrus, right temporal lobe) are associ-
ated with the psychotic-like effects of THC, suggesting
that these regions could be possible brain suites of CBD
action [121]. No study using direct injections into key
brain regions associated with the pathophysiology of
schizophrenia, such as the prefrontal cortex and nucleus
accumbens, has been performed so far to investigate
CBD antipsychotic properties.
Regarding the pharmacological mechanisms, intra-
cerebroventricular administration of CBD enhanced
extracellular levels of dopamine in the nucleus
accumbens [122]. A similar finding was found after
Review.Cannabidiol and psychiatric disorders A. C. Campos et al. 3371
Phil. Trans. R. Soc. B (2012)
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microdialysis perfusion of CBD (30, 60 or 90 nM) into
the rat lateral hypothalamus [117], a procedure that
also enhanced alertness. It is unclear how this effect
would relate to the antipsychotic properties of CBD
because usual antipsychotic drugs act by antagonizing
dopamine-2 receptors [123]. Moreover, studies with
animal models that involve dopaminergic stimulation
suggest that the antipsychotic-like doses of CBD
(60–120 mg kg
21
) are higher than those needed to
induce anxiolytic-like effects [7,91,92] and reverse be-
havioural deficits induced by the NMDA receptor
antagonist MK-801 [93,94,99]. These findings indicate
that the mechanisms of CBD effects on glutamate-
or dopamine-based models could be at least partially
distinct. This possibility needs to be further explored.
Recently, Leweke et al.[34] showed that schizo-
phrenic patients treated with CBD present higher
anandamide serum levels compared with those receiv-
ing the antipsychotic amisulpride. Moreover, in the
CBD group, there was a significant association between
anandamide levels and improvement of psychotic
symptoms. In the same study, they confirmed, in vitro,
that CBD inhibits FAAH activity in a concentration
(10 mM) that does not interact with receptors (dopa-
mine, GABA, serotonin and glutamate) commonly
associated with schizophrenia. However, by indirectly
activating CB1 receptors via increased levels of
anandamide, CBD could potentially modulate neuro-
transmitters systems related to these receptors [121,
124]. Moreover, as previously discussed, facilitation
of CB1-mediated neurotransmission by CBD also
increases adult hippocampal neurogenesis, a mechan-
ism that could be related to the cognitive deficits
found in schizophrenic patients [124].
As discussed already, CBD and anandamide can
also activate TRPV1 channels. This mechanism,
probably by facilitating the pre-synaptic release of glu-
tamate [80], is involved in the ability of CBD to
reverse the disruption of PPI induced by the NMDA
receptor antagonist MK-801 [93].
Other mechanisms that could also help us to explain
CBD anti-psychotic effects are facilitation of 5-HT1A-
mediated neurotransmission, an effect shared by the
atypical anti-psychotic aripiprazole, which acts as a par-
tial agonist at these receptors, and anti-inflammatory/
neuroprotective action [124].
4. CANNABIDIOL AND DEPRESSION
Cannabis sativa exerts significant effects upon humour,
which include euphoria and mood elevation [125].
THC may account for most of these effects through
activation of CB1 receptors. Considering these obser-
vations, as well as the effects of synthetic cannabinoids
and drugs that increase eCB levels, a putative role
for the eCB system in mood disorders has been pro-
posed [126]. The effects of CBD, however, have
been scarcely investigated (table 4). The fact that
this compound, in addition to facilitating eCB activity
[33], may facilitate the activation of 5-HT1A receptors
[35] suggests that it might also have antidepressant-
like properties. 5HT1A receptors modulate responses
to stressful stimuli and are proposed to mediate the
effects of antidepressant drugs [129].
Stress exposure is a key aetiological factor in
depression [130] and animal models used to study
antidepressant-like effects are generally based on acute
responses to inescapable aversive stimuli, which are
prevented by antidepressants [131]. Alternatively, con-
sidering the nature of depression as a chronic
psychiatric disorder, some models investigate drug
effects upon the diverse consequences of chronic
stress, including anhedonia and changes in exploratory
activity [132].
One of the first studies that indicate the presence of
antidepressant-like properties in CBD focused on its
ability to prevent the autonomic and behavioural conse-
quences of inescapable stress [17]. Rats were submitted
to restraint stress during 60 min, which increases heart
rate and blood pressure and caused anxiogenic-like
responses in rats exposed to the elevated plus maze
24 h later. CBD was injected 30 min before the stress
at the doses of 1, 10 or 20 mg kg
21
. The doses of 10
and 20 mg kg
21
attenuated the changes in autonomic
parameters, whereas at 10 mg kg
21
CBD also prevented
the late anxiogenic-like effect of stress. There were no
changes in motor activity or basal cardiovascular par-
ameters, discarding any possible confounding factor
[17]. Similar effects were observed after intra-cisterna
magna administration of CBD [12], thus suggesting
that these effects are centrally mediated.
Another behavioural model widely used to assess
antidepressant-like effects, mainly due to its pharmaco-
logical predictability, is the forced swim test. In this
assay, rats or mice exposed to inescapable swimming
assume a posture of immobility, which is reversed by
antidepressants [131]. We tested in mice the effects of
CBD (3– 100 mg kg
21
) injected 30 min prior to the
test [128]. The drug produced an inverted U-shaped
dose-response curve. At the dose of 30 mg kg
21
,it
reduced immobility similar to the tricyclic antide-
pressant imipramine (30 mg kg
21
). Our behavioural
Table 4. Antidepressant-like effects of CBD. Studies with laboratory animals. FST, forced swimming test; TST, tail
suspension test.
model species effective doses CBD effects references
restraint stress rat 10–20 mg kg
21
cardiovascular and behavioural effects of stress [17]
FST mouse 200 mg kg
21
immobility [127]
TST mouse 20 – 200 mg kg
21
no effect [127]
FST mouse 30 mg kg
21
immobility [128]
chronic unpredictable
stress
mouse 30 mg kg
21
(daily,
chronic treatment)
the behavioural consequences of stress through
enhancement of hippocampal neurogenesis
[72]
3372 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
Phil. Trans. R. Soc. B (2012)
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findings in the forced swimming test were confirmed by
another study, published in the same year. CBD was
tested at the doses of 20, 100 and 200 mg kg
21
[127],
with the higher dose being effective. The drug had no
effect, however, in the mouse tail suspension test. One
drawback common to all these studies is that the animals
received only acute injections. Depression, however, is a
chronic disorder that requires long-lasting drug treat-
ment [130]. CBD has been recently tested against the
consequences of chronic unpredictable stress, which
includes anhedonia and anxiety-like behaviour [130].
Chronic treatment with CBD was able to prevent
these behavioural changes, an effect that depends on
hippocampal neurogenesis, similar to antidepressant
drugs [72]. This observation further strengthens the
notion that this natural cannabinoid should be con-
sidered as a potential approach for the treatment of
mood disorders.
Despite this body of evidence, no clinical study has
investigated whether CBD can decrease depressive
symptoms in patients. This compound has been
tested, however, in patients suffering from bipolar dis-
orders, a subtype of mood disorder, in whom it was
not effective in treating manic episodes [133]. Actu-
ally, this is in line with animal models, in which
CBD failed to prevent hyperactivity in rodents [134].
To summarize, although the data are scarce, preclini-
cal studies so far do provide evidence that this
compound could induce antidepressant-like effects.
Clinical studies are important to confirm this possibility.
(a)Mechanisms of cannabidiol
antidepressant effects
Similar to findings with animal models of anxiety, the
attenuation of the behavioural consequences of restraint
stress and the antidepressant-like effects of CBD in
the forced swimming test were attenuated by a
5-HT1A receptor antagonist [17,128]. In the latter
model, despite the association between increased
expression of neurotrophic factors and antidepressant
activity [130], CBD failed to modify brain-derived
neurotrophic factor hippocampal levels [128].
As discussed earlier, CBD can also facilitate hippo-
campal neurogenesis, probably by facilitation of eCB
neurotransmission [72]. The involvement of this
mechanism on its antidepressant-like properties after
repeated administration remains to be investigated.
5. CONCLUSIONS
CBD is a safe compound with a wide range of
therapeutic applications, including the treatment of
psychiatric disorders [3,4]. These findings make this
drug an attractive candidate for future clinical use.
Its therapeutic use, however, has some limiting factors.
In addition to its low and variable oral bioavailability in
humans [135], it causes bell-shaped dose-response
curves and, judging from the studies with laboratory
animals, possesses a narrow therapeutic dose range.
A clear target of future research, therefore, is to try
to develop compounds with similar safety and clini-
cal profile but with larger effective dose ranges. To
this aim, a better understanding of the mechanisms
responsiblefortheuniquepropertiesofCBDisessential.
The behaviour studies reviewed here clearly indicate
that more than one mechanism is involved, depending
on the effects being measured (anxiolytic, anti-
compulsive, antidepressant or antipsychotic-like) and
the drug regime (single versus repeated administration).
Facilitation of 5-HT1A-mediated neurotransmission in
key brain areas related to defensive responses, including
the dorsal periaqueductal grey, bed nucleus of the
stria terminalis and medial prefrontal cortex, seems
responsible for CBD acute anxiolytic-like effects. Other
CBD effects, such as anti-compulsive, increased extinc-
tion and impaired reconsolidation of aversive
memories, facilitation of adult hippocampal neurogen-
esis and blockade of the anxiogenic consequences of
chronic unpredictable stress could depend on poten-
tiation of anandamide-mediated neurotransmission.
Finally, activation of TRPV1 channels may help us to
explain the antipsychotic effect and the bell-shaped
dose-response curves commonly observed with CBD.
In addition to these mechanisms, CBD can interfere in
several other important biological processes (e.g. inhi-
bition of adenosine uptake, inverse agonism at CB2
receptor, CB1 receptor antagonism, GPR55 antagon-
ism, PPARgreceptors agonism, intracellular (Ca
2þ
)
increase, etc.). Additional in vivo studies are clearly
needed to investigate their possible involvement on
CBD behavioural effects.
This work was supported by grants from CNPq, CAPES,
NAPNA-USP and FAPESP.
REFERENCES
1 Gaoni, Y. & Mechoulam, R. 1964 Isolation, structure
and partial synthesis of an active constituent of
hashish. J. Am. Chem. Soc. 86, 1646. (doi:10.1021/
ja01062a046)
2 Devane, W. A. 1994 New dawn of cannabinoid pharma-
cology. Trends Pharmacol. Sci. 15, 40 – 41. (doi:10.1016/
0165-6147(94)90106-6)
3 Hill, A. J., Williams, C. M., Whalley, B. J. & Stephens,
G. J. 2012 Phytocannabinoids as novel therapeutic
agents in CNS disorders. Pharmacol. Ther. 133,79–
97. (doi:10.1016/j.pharmthera.2011.09.002)
4 Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V. &
Mechoulam, R. 2009 Non-psychotropic plant cannabi-
noids: new therapeutic opportunities from an ancient
herb. Trends Pharmacol. Sci. 30, 515 –527. (doi:10.
1016/j.tips.2009.07.006)
5 Silveira Filho, N. G. & Tufik, S. 1981 Comparative
effects between cannabidiol and diazepam on neo-
phobia, food intake and conflict behavior. Res.
Commun. Psychol. Psychiatr. Behav. 6, 251– 266.
6 Zuardi, A. W. & Karniol, I. G. 1983 Changes in the
conditioned emotional response of rats induced by D9-
THC, CBD and mixture of the two cannabinoids.
Braz. Arch. Biol. Technol. 26, 391–397.
7 Guimara
˜es, F. S., Chiaretti, T. M., Graeff, F. G. &
Zuardi, A. W. 1990 Antianxiety effect of cannabidiol
in the elevated plus-maze. Psychopharmacology (Berl.)
100, 558–559. (doi:10.1007/BF02244012)
8 Onaivi, E. S., Green, M. R. & Martin, B. R. 1990
Pharmacological characterization of cannabinoids in
the elevated plus maze. J. Pharmacol. Exp. Ther. 253,
1002–1009.
9 Moreira, F. A., Aguiar, D. C. & Guimara
˜es, F. S.
2006 Anxiolytic- like effect of cannabidiol in the rat
Review.Cannabidiol and psychiatric disorders A. C. Campos et al. 3373
Phil. Trans. R. Soc. B (2012)
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from

Vogel conflict test. Prog. Neuropsychopharmacol. Biol.
Psychiatry 30, 1466 – 1471. (doi:10.1016/j.pnpbp.
2006.06.004)
10 Resstel, L. B., Joca, S. R., Moreira, F. A., Correa, F. M. &
Guimara
˜es, F. S. 2006 Effects of cannabidiol and
diazepam on behavioural and cardiovascular respon-
ses induced by contextual conditioned fear in rats.
Behav. Brain Res. 172, 294– 298. (doi:10.1016/j.bbr.
2006.05.016)
11 Campos, A. C. & Guimara
˜es, F. S. 2009 Activation of
5HT1A receptors mediates the anxiolytic effects of can-
nabidiol in a PTSD model. Behav. Pharmacol. 20, S54.
12 Granjeiro, E. M., Gomes, F. V., Guimara
˜es, F. S., Correa,
F. M. & Resstel, L. B. 2011 Effects of intracisternal
administration of cannabidiol on the cardiovascular and
behavioral responses to acute restraint stress. Pharmacol.
Biochem. Behav. 99, 743 – 748. (doi:10.1016/j.pbb.
2011.06.027)
13 Uribe-Marino, A., Francisco, A., Castiblanco-Urbina,
M. A., Twardowschy, A., Salgado-Rohner, C. J.,
Crippa, J. A., Hallak, J. E., Zuardi, A. W. & Coimbra,
N. C. 2012 Anti-aversive effects of cannabidiol on
innate fear-induced behaviors evoked by an ethological
model of panic attacks based on a prey vs the wild
snake Epicrates cenchria crassus confrontation paradigm.
Neuropsychopharmacology 37, 412 – 421. (doi:10.1038/
npp.2011.188)
14 Casarotto, P. C., Gomes, F. V., Resstel, L. B. &
Guimara
˜es, F. S. 2010 Cannabidiol inhibitory effect
on marble-burying behaviour: involvement of CB1
receptors. Behav. Pharmacol. 21, 353– 358. (doi:10.
1097/FBP.0b013e32833b33c5)
15 Bitencourt, R. M., Pamplona, F. A. & Takahashi, R. N.
2008 Facilitation of contextual fear memory extinction
and anti-anxiogenic effects of AM404 and cannabidiol
in conditioned rats. Eur. Neuropsychopharmacol.18,
849–859. (doi:10.1016/j.euroneuro.2008.07.001)
16 Soares, V. de P., Campos, A. C., Bortoli, V. C.,
Zangrossi Jr, H., Guimara
˜es, F. S. & Zuardi, A. W.
2010 Intra-dorsal periaqueductal gray administration
of cannabidiol blocks panic-like response by activating
5-HT1A receptors. Behav. Brain Res. 213, 225–229.
(doi:10.1016/j.bbr.2010.05.004)
17 Resstel, L. B., Tavares, R. F., Lisboa, S. F., Joca, S. R.,
Corre
ˆa, F. M. & Guimara
˜es, F. S. 2009 5-HT1A recep-
tors are involved in the cannabidiol-induced attenuation
of behavioural and cardiovascular responses to acute
restraint stress in rats. Br. J. Pharmacol. 156,
181–188. (doi:10.1111/j.1476-5381.2008.00046.x)
18 Campos, A. C. & Guimara
˜es, F. S. 2008 Involvement of
5HT1A receptors in the anxiolytic-like effects of canna-
bidiol injected into the dorsolateral periaqueductal gray
of rats. Psychopharmacology (Berl.)199, 223 – 230.
(doi:10.1007/s00213-008-1168-x)
19 Gomes, F. V., Resstel, L. B. & Guimara
˜es, F. S. 2011
The anxiolytic-like effects of cannabidiol injected into
the bed nucleus of the stria terminalis are mediated by
5-HT1A receptors. Psychopharmacology (Berl.)213,
465–473. (doi:10.1007/s00213-010-2036-z)
20 Gomes, F. V., Reis, D. G., Alves, F. H., Correa, F. M.,
Guimara
˜es, F. S. & Resstel, L. B. 2012 Cannabidiol
injected into the bed nucleus of the stria terminalis
reduces the expression of contextual fear condition-
ing via 5-HT1A receptors. J. Psychopharmacol. 26,
104–113. (doi:10.1177/0269881110389095)
21 Lemos, J. I., Resstel, L. B. & Guimara
˜es, F. S.
2010 Involvement of the prelimbic prefrontal cortex
on cannabidiol-induced attenuation of contextual con-
ditioned fear in rats. Behav. Brain Res. 207, 105–111.
(doi:10.1016/j.bbr.2009.09.045)
22 Elbatsh, M. M., Assareh, N., Marsden, C. A. & Kendall,
D. A. 2012 Anxiogenic-like effects of chronic cannabidiol
administration in rats. Psychopharmacology (Berl.)221,
239–247. (doi:10.1007/s00213-011-2566-z)
23 Stern, C. A. J., Gazarini, L., Takahashi, R. N.,
Guimara
˜es, F. S. & Bertoglio, L. J. 2012 On disruption
of fear memory by reconsolidation blockade: evidence
from cannabidiol treatment. Neuropsychopharmacology
37, 2132– 2142. (doi:10.1038/npp.2012.63)
24 Zuardi, A. W., Cosme, R. A., Graeff, F. G. &
Guimara
˜es, F. S. 1993 Effects of ipsapirone and
cannabidiol on human experimental anxiety. J. Psycho-
pharmacol. 7, 82 – 88.
25 Crippa, J. A. et al. 2004 Effects of cannabidiol (CBD)
on regional cerebral blood flow. Neuropsychopharmacol-
ogy 29, 417 – 426. (doi:10.1038/sj.npp.1300340)
26 Hsiao, Y. T., Yi, P. L., Li, C. L. & Chang, F. C.
2012 Effect of cannabidiol on sleep disruption
induced by the repeated combination tests consisting
of open field and elevated plus-maze in rats. Neurophar-
macology 62, 373–384. (doi:10.1016/j.neuropharm.
2011.08.013)
27 Fusar-Poli, P. et al. 2010 Modulation of effective
connectivity during emotional processing by Delta
9-tetrahydrocannabinol and cannabidiol. Int. J.
Neuropsychopharmacol. 13, 421 – 432. (doi:10.1017/
S1461145709990617)
28 Crippa, J. A. et al. 2011 Neural basis of anxiolytic effects
of cannabidiol (CBD) in generalized social anxiety dis-
order: a preliminary report. J. Psychopharmacol. 25,
121–130. (doi:10.1177/0269881110379283)
29 Bergamaschi, M. M. et al. 2011 Cannabidiol reduces
the anxiety induced by simulated public speaking in
treatment-naive social phobia patients. Neuropsychophar-
macology 36, 1219– 1226. (doi:10.1038/npp.2011.6)
30 Yehuda, R., Joe¨ls, M. & Morris, R. G. 2010 The
memory paradox. Nat. Rev. Neurosci. 11, 837– 839.
(doi:10.1038/nrn2957)
31 Zuardi, A. W., Shirakawa, I., Finkelfarb, E. & Karniol,
I. G. 1982 Action of cannabidiol on the anxiety and
other effects produced by delta 9-THC in normal sub-
jects. Psychopharmacology (Berl.)76, 245 – 250. (doi:10.
1007/BF00432554)
32 Thomas, A., Baillie, G. L., Phillips, A. M., Razdan, R. K.,
Ross, R. A. & Pertwee, R. G. 2007 Cannabidiol displays
unexpectedly high potency as an antagonist of CB1 and
CB2 receptor agonists in vitro.Br. J. Pharmacol. 150,
613– 623. (doi:10.1038/sj.bjp.0707133)
33 Bisogno, T. et al. 2001 Molecular targets for cannabi-
diol and its synthetic analogues: effect on vanilloid
VR1 receptors and on the cellular uptake and enzymatic
hydrolysis of anandamide. Br. J. Pharmacol. 134,
845–852. (doi:10.1038/sj.bjp.0704327)
34 Leweke, F. M., Piomelli, D., Pahlisch, F., Muhl, D.,
Gerth, C. W., Hoyer, C., Klosterko¨ tter, J., Hellmich,
M. & Koethe, D. 2012 Cannabidiol enhances anada-
mide signilling and alliviates psychotic symptoms of
schizoprenia. Transl. Psychiatry 2, e94. (doi:10.108/tp.
2012.15)
35 Russo, E. B., Burnett, A., Hall, B. & Parker, K. K. 2005
Agonistic properties of cannabidiol at 5-HT1a recep-
tors. Neurochem. Res. 30, 1037–1043. (doi:10.1007/
s11064-005-6978-1)
36 Xiong, W., Koo, B. N., Morton, R. & Zhang, L. 2011
Psychotropic and nonpsychotropic cannabis derivatives
inhibit human 5-HT(3A) receptors through a receptor
desensitization-dependent mechanism. Neuroscience
184, 28– 37. (doi:10.1016/j.neuroscience.2011.03.066)
37 Jenny, M., Santer, E., Pirich, E., Schennach, H. &
Fuchs, D. 2009 D9-tetrahydrocannabinol and
3374 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
Phil. Trans. R. Soc. B (2012)
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from

cannabidiol modulate mitogen-induced tryptophan
degradation and neopterin formation in peripheral
blood mononuclear cells in vitro.J. Neuroimmunol.
207, 75– 82. (doi:10.1016/j.jneuroim.2008.12.004)
38 Dr ysdale, A. J., Ryan, D., Pertwee, R. G. & Platt, B.
2006 Cannabidiol-induced intracellular Ca
2þ
elevations
in hippocampal cells. Neuropharmacology 50, 621 – 631.
(doi:10.1016/j.neuropharm.2005.11.008)
39 Ryan, D., Drysdale, A. J., Pertwee, R. G. & Platt, B.
2007 Interactions of cannabidiol with endocan-
nabinoid signalling in hippocampal tissue. Eur.
J. Neurosci. 25, 2093– 2102. (doi:10.1111/j.1460-
9568.2007.05448.x)
40 Kathmann, M., Flau, K., Redmer, A., Tra¨ nkle, C. &
Schlicker, E. 2006 Cannabidiol is an allosteric modu-
lator at mu- and delta-opioid receptors. Naunyn
Schmiedebergs Arch. Pharmacol. 372, 354 – 361. (doi:10.
1007/s00210-006-0033-x)
41 O’Sullivan, S. E., Sun, Y., Bennett, A. J., Randall, M. D. &
Kendall, D. A. 2009 Time-dependent vascular actions
ofcannabidiolintherataorta.Eur. J. Pharmacol. 612,
61–68. (doi:10.1016/j.ejphar.2009.03.010)
42 Ryberg, E. et al. 2007 The orphan receptor GPR55 is a
novel cannabinoid receptor. Br. J. Pharmacol. 152,
1092–1101. (doi:10.1038/sj.bjp.0707460)
43 Carrier, E. J., Auchampach, J. A. & Hillard, C. J. 2006
Inhibition of an equilibrative nucleoside transporter by
cannabidiol: a mechanism of cannabinoid immunosup-
pression. Proc. Natl Acad. Sci. USA 103, 7895 – 7900.
(doi:10.1073/pnas.0511232103)
44 Liou, G. I., Auchampach, J. A., Hillard, C. J., Zhu, G.,
Yousufzai, B., Mian, S., Khan, S. & Khalifa, Y. 2008
Mediation of cannabidiol anti-inflammation in the
retina by equilibrative nucleoside transporter and A2A
adenosine receptor. Invest. Ophthalmol. Vis. Sci. 49,
5526–5531. (doi:10.1167/iovs.08-2196)
45 Qin, N., Neeper, M. P., Liu, Y., Hutchinson, T. L.,
Lubin, M. L. & Flores, C. M. 2008 TRPV2 is activated
by cannabidiol and mediates CGRP release in cultured
rat dorsal root ganglion neurons. J. Neurosci. 28, 6231–
6238. (doi:10.1523/JNEUROSCI.0504-08.2008)
46 De Petrocellis, L., Vellani, V., Schiano-Moriello, A.,
Marini, P., Magherini, P. C., Orlando, P. & Di Marzo,
V. 2008 Plant-derived cannabinoids modulate the activity
of transient receptor potential channels of ankyrin type-1
and melastatin type-8. J. Pharmacol. Exp. Ther. 325,
1007– 1015. (doi:10.1124/jpet.107.134809)
47 Esposito, G., De Filippis, D., Maiuri, M. C., De
Stefano, D., Carnuccio, R. & Iuvone, T. 2006 Cannabi-
diol inhibits inducible nitric oxide synthase protein
expression and nitric oxide production in beta-amyloid
stimulated PC12 neurons through p38 MAP kinase
and NF-kappaB involvement. Neurosci. Lett. 399,
91– 95. (doi:10.1016/j.neulet.2006.01.047)
48 Rajesh, M., Mukhopadhyay, P., Ba
´tkai, S., Hasko
´, G.,
Liaudet, L., Drel, V. R., Obrosova, I. G. & Pacher, P.
2007 Cannabidiol attenuates high glucose-induced
endothelial cell inflammatory response and barrier dis-
ruption. Am. J. Physiol. Heart. Circ. Physiol. 293,
H610– H619. (doi:10.1152/ajpheart.00236.2007)
49 Pan, H., Mukhopadhyay, P., Rajesh, M., Patel, V.,
Mukhopadhyay, B., Gao, B., Hasko
´, G. & Pacher, P.
2009 Cannabidiol attenuates cisplatin-induced nephro-
toxicity by decreasing oxidative/nitrosative stress,
inflammation, and cell death. J. Pharmacol. Exp. Ther.
328, 708–714. (doi:10.1124/jpet.108.147181)
50 Pandolfo, P., Silveirinha, V., dos Santos-Rodrigues, A.,
Venance, L., Ledent, C., Takahashi, R. N., Cunha,
R. A. & Ko¨ falvi, A. 2011 Cannabinoids inhibit the
synaptic uptake of adenosine and dopamine in the rat
and mouse striatum. Eur. J. Phar macol. 655, 38 – 45.
(doi:10.1016/j.ejphar.2011.01.013)
51 Esposito, G. et al. 2011 Cannabidiol reduces a beta-
induced neuroinflammation and promotes hippocampal
neurogenesis through PPARgamma involvement. PLoS
ONE 6, e28668. (doi:10.1371/journal.pone.0028668)
52 Esposito, G., Scuderi, C., Savani, C., Steardo Jr, L., De
Filippis, D., Cottone, P., Iuvone, T., Cuomo, V. &
Steardo, L. 2007 Cannabidiol in vivo blunts beta-
amyloid induced neuroinflammation by suppressing
IL-1beta and iNOS expression. Br. J. Phar macol. 151,
1272–1279. (doi:10.1038/sj.bjp.0707337)
53 Sagredo, O., Pazos, M. R., Satta, V., Ramos, J. A.,
Pertwee, R. G. & Fernandez-Ruiz, J. 2011 Neuroprotec-
tive effects of phytocannabinoid-based medicines in
experimental models of Huntington’s disease.
J. Neurosci. Res. 89, 1509– 1518. (doi:10.1002/jnr.22682)
54 Garcia-Arencibia, M., Gonza
´lez, S., de Lago, E.,
Ramos, J. A., Mechoulam, R. & Ferna
´ndez-Ruiz, J.
2007 Evaluation of the neuroprotective effect of canna-
binoids in a rat model of Parkinson’s disease:
importance of antioxidant and cannabinoid receptor-
independent properties. Brain Res. 1134, 162–170.
(doi:10.1016/j.brainres.2006.11.063)
55 Mishima, K., Hayakawa, K., Abe, K., Ikeda, T.,
Egashira, N., Iwasaki, K. & Fujiwara, M. 2005
Cannabidiol prevents cerebral infarction via a seroto-
nergic 5-hydroxytryptamine1A receptor-dependent
mechanism. Stroke 36, 1077– 1082. (doi:10.1161/01.
STR.0000163084.16505.e3)
56 Magen, I., Avraham, Y., Ackerman, Z., Vorobiev, L.,
Mechoulam, R. & Berry, E. M. 2010 Cannabidiol ame-
liorates cognitive and motor impairments in bile-duct
ligated mice via 5-HT1A receptor activation.
Br. J. Phar macol. 159, 950 – 957. (doi:10.1111/j.1476-
5381.2009.00589.x)
57 Rock, E. M., Bolognini, D., Limebeer, C. L., Cascio,
M. G., Anavi-Goffer, S., Fletcher, P. J., Mechoulam,
R., Pertwee, R. G. & Parker, L. A. 2012 Cannabidiol,
a non-psychotropic component of cannabis, attenuates
vomiting and nausea-like behaviour via indirect agon-
ism of 5-HT(1A) somatodendritic: autoreceptors in
the dorsal raphe nucleus. Br. J. Pharmacol. 165,
2620–2634. (doi:10.1111/j.1476-5381.2011.01621.x)
58 Scopinho, A. A., Guimara
˜es, F. S., Correa, F. M. &
Resstel, L. B. 2011 Cannabidiol inhibits the hyperpha-
gia induced by cannabinoid-1 or serotonin-1A receptor
agonists. Pharmacol. Biochem. Behav. 98,268– 272.
(doi:10.1016/j.pbb.2011.01.007)
59 Moreira, F. A., Aguiar, D. C. & Guimara
˜es, F. S.
2007 Anxiolytic-like effect of cannabinoids injected
into the rat dorsolateral periaqueductal gray. Neurophar-
macology 52, 958–965. (doi:10.1016/j.neuropharm.
2006.10.013)
60 Marsicano, G. et al. 2002 The endogenous cannabinoid
system controls extinction of aversive memories. Nature
418, 530–534. (doi:10.1038/nature00839)
61 Thomas, A., Burant, A., Bui, N., Graham, D., Yuva-
Paylor, L. A. & Paylor, R. 2009 Marble burying reflects
a repetitive and perseverative behavior more than
novelty-induced anxiety. Psychopharmacology (Berl.)
204, 361–373. (doi:10.1007/s00213-009-1466-y)
62 Piomelli, D. 2003 The molecular logic of endocannabi-
noid signalling. Nat. Rev. Neurosci. 4, 873– 884.
(doi:10.1038/nrn1247)
63 Pittenger, C., Krystal, J. H. & Coric, V. 2006 Gluta-
mate-modulating drugs as novel pharmacotherapeutic
agents in the treatment of obsessive-compulsive dis-
order. Neurotherapeutics 3, 69– 81. (doi:10.1016/j.nurx.
2005.12.006)
Review.Cannabidiol and psychiatric disorders A. C. Campos et al. 3375
Phil. Trans. R. Soc. B (2012)
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from

64 Egashira, N., Okuno, R., Harada, S., Matsushita, M.,
Mishima, K., Iwasaki, K., Nishimura, R., Oishi, R. &
Fujiwara, M. 2008 Effects of glutamate-related drugs
on marble-burying behavior in mice: implications for
obsessive-compulsive disorder. Eur. J. Pharmacol. 586,
164–170. (doi:10.1016/j.ejphar.2008.01.035)
65 Iijima, M., Kurosu, S. & Chaki, S. 2010 Effects of
agents targeting glutamatergic systems on marble-bury-
ing behavior. Neurosci. Lett. 471, 63–65. (doi:10.1016/j.
neulet.2009.12.048)
66 Aboujaoude, E., Barry, J. J. & Gamel, N. 2009
Memantine augmentation in treatment-resistant obses-
sive-compulsive disorder: an open-label trial. J. Clin.
Psychopharmacol. 29, 51 – 55. (doi:10.1097/JCP.
0b013e318192e9a4)
67 Grant, P., Lougee, L., Hirschtritt, M. & Swedo, S. E. 2007
An open-label trial of riluzole, a glutamate antagonist, in
children with treatment-resistant obsessive-compulsive
disorder. J. Child Adolesc. Psychopharmacol. 17, 761–767.
(doi:10.1089/cap.2007.0021)
68 Luda
´nyi, A. et al. 2008 Downregulation of the CB1 can-
nabinoid receptor and related molecular elements of the
endocannabinoid system in epileptic human hippo-
campus. J. Neurosci. 28, 2976– 2990. (doi:10.1523/
JNEUROSCI.4465-07.2008)
69 Samuels, B. A. & Hen, R. 2011 Neurogenesis and affec-
tive disorders. Eur. J. Neurosci. 33, 1152 – 1159. (doi:10.
1111/j.1460-9568.2011.07614.x)
70 Santarelli, L. et al. 2003 Requirement of hippocampal
neurogenesis for the behavioral effects of antidepress-
ants. Science 301, 805–809. (doi:10.1126/science.
1083328)
71 Wolf, S. A. et al. 2010 Cannabinoid receptor CB1 med-
iates baseline and activity-induced survival of new
neurons in adult hippocampal neurogenesis. Cell
Commun. Signal. 8, 12. (doi:10.1186/1478-811X-8-12)
72 Campos, A. C., Palazuelos, J., Aguado, T., Aguiar,
D. C., Guzma
´n, M., Galve-Roperh, I. & Guimara
˜es,
F. S. 2011 Hippocampal proliferative processes are
needed for behavioral effects of cannabidiol. Revista de
Neuroscie
ˆncias 19(Suppl.), 81.
73 Jiang, W., Zhang, Y., Xiao, L., Van Cleemput, J., Ji, S. P.,
Bai, G. & Zhang, X. 2005 Cannabinoids promote
embryonic and adult hippocampus neurogenesis and
produce anxiolytic- and antidepressant-like effects.
J. Clin. Invest. 115, 3104– 3116. (doi:10.1172/JCI25509)
74 Kirby, E. D., Friedman, A. R., Covarrubias, D., Ying,
C., Sun, W. G., Goosens, K. A., Sapolsky, R. M. &
Kaufer, D. 2012 Basolateral amygdala regulation of
adult hippocampal neurogenesis and fear-related acti-
vation of newborn neurons. Mol. Psychiatry 17, 527 –
536. (doi:10.1038/mp.2011.71)
75 Saxe, M. D. et al. 2006 Ablation of hippocampal neuro-
genesis impairs contextual fear conditioning and
synaptic plasticity in the dentate gyrus. Proc. Natl
Acad. Sci. USA 103, 17 501–17 506. (doi:10.1073/
pnas.0607207103)
76 Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. &
Cameron, H. A. 2011 Adult hippocampal neurogenesis
buffers stress responses and depressive behaviour.
Nature 476, 458–461. (doi:10.1038/nature10287)
77 Sahay, A., Scobie, K. N., Hill, A. S., O’Carroll, C. M.,
Kheirbek, M. A., Burghardt, N. S., Fenton, A. A.,
Dranovsky, A. & Hen, R. 2011 Increasing adult hippo-
campal neurogenesis is sufficient to improve pattern
separation. Nature 472, 466– 470. (doi:10.1038/
nature09817)
78 Nilius, B. & Voets, T. 2005 TRP channels: a TR(I)P
through a world of multifunctional cation channels. Pflu-
gers Arch. 451, 1– 10. (doi:10.1007/s00424-005-1462-y)
79 Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen,
T. A., Gilbert, H., Skinner, K., Raumann, B. E., Basbaum,
A. I. & Julius, D. 1998 The cloned capsaicin receptor
integrates multiple pain-producing stimuli. Neuron 21,
531– 543. (doi:10.1016/S0896-6273(00)80564-4)
80 Zygmunt, P. M., Petersson, J., Andersson, D. A.,
Chuang, H., Sørga
˚rd, M., Di Marzo, V., Julius, D. &
Ho¨ gesta¨tt, E. D. 1999 Vanilloid receptors on sensory
nerves mediate the vasodilator action of anandamide.
Nature 400, 452– 457. (doi:10.1038/22761)
81 Xing, J. & Li, J. 2007 TRPV1 receptor mediates gluta-
matergic synaptic input to dorsolateral periaqueductal
gray (dlPAG) neurons. J. Neurophysiol. 97, 503 – 511.
(doi:10.1152/jn.01023.2006)
82 Molchanov, M. L. & Guimara
˜es, F. S. 2002 Anxiolytic-
like effects of AP7 injected into the dorsolateral or ven-
trolateral columns of the periaqueductal gray of rats.
Psychopharmacology (Berl.)160, 30 – 38. (doi:10.1007/
s00213-001-0941-x)
83 Campos, A. C. & Guimara
˜es, F. S. 2009 Evidence for a
potential role for TRPV1 receptors in the dorsolateral
periaqueductal gray in the attenuation of the anxiolytic
effects of cannabinoids. Prog. Neuropsychopharmacol.
Biol. Psychiatry 33, 1517 – 1521. (doi:10.1016/j.pnpbp.
2009.08.017)
84 Rubino, T. et al. 2008 Role in anxiety behavior of the
endocannabinoid system in the prefrontal cortex. Cereb.
Cortex 18, 1292 – 1301. (doi:10.1093/cercor/bhm161)
85 Casarotto, P. C., Terzian, A. L., Aguiar, D. C.,
Zangrossi, H., Guimara
˜es, F. S., Wotjak, C. T. &
Moreira, F. A. 2012 Opposing roles for cannabinoid
receptor type-1 (CB
1
) and transient receptor potential
vanilloid type-1 channel (TRPV1) on the modulation
of panic-like responses in rats. Neuropsychopharmacology
37, 478–486. (doi:10.1038/npp.2011.207)
86 Karniol, I. G. & Carlini, E. A. 1973 Pharmacological
interaction between cannabidiol and delta 9-tetrahydro-
cannabinol. Psychopharmacologia 33, 53 – 70. (doi:10.
1007/BF00428793)
87 Karniol, I. G., Shirakawa, I., Kasinski, N., Pfeferman,
A. & Carlini, E. A. 1974 Cannabidiol interferes with
the effects of delta 9-tetrahydrocannabinol in man.
Eur. J. Phar macol. 28, 172– 177. (doi:10.1016/0014-
2999(74)90129-0)
88 Dalton, W. S., Martz, R., Lemberger, L., Rodda, B. E. &
Forney, R. B. 1976 Influence of cannabidiol on D-9-
tetrahydrocannabinol effects. Clin. Pharmacol. Ther. 19,
300–309.
89 Rottanburg, D., Robins, A. H., Ben-Arie, O., Teggin, A. &
Elk, R. 1982 Cannabis-associated psychosis with hypoma-
nic features. Lancet 2, 1364– 1366. (doi:10.1016/S0140-
6736(82)91270-3)
90 Hunt, C. A., Jones, R. T., Herning, R. I. & Bachman, J.
1981 Evidence that cannabidiol does not significantly
alter the pharmacokinetics of tetrahydrocannabinol in
man. J. Pharmacokinet. Biopharm. 9, 245 – 260.
91 Zuardi, A. W., Rodrigues, J. A. & Cunha, J. M. 1991
Effects of cannabidiol in animal models predictive of
antipsychotic activity. Psychopharmacology (Berl.)104,
260–264. (doi:10.1007/BF02244189)
92 Moreira, F. A. & Guimara
˜es, F. S. 2005 Cannabidiol
inhibits the hyperlocomotion induced by psychotomi-
metic drugs in mice. Eur. J. Pharmacol. 512, 199– 205.
(doi:10.1016/j.ejphar.2005.02.040)
93 Long, L. E., Malone, D. T. & Taylor, D. A. 2006
Cannabidiol reverses MK-801-induced disruption of
prepulse inhibition in mice. Neuropsychopharmacology
31, 795–803. (doi:10.1038/sj.npp.1300838)
94 Gurujan, A., Taylor, D. A. & Malone, D. T. 2012.
Cannabidiol and clozapine reverse MK-801-induced
3376 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
Phil. Trans. R. Soc. B (2012)
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from

deficits in social interaction and hyperactivity in
Sprague-Dawle rats. J. Psychophar macol. 26, 1317 –
1332 (doi:10.1177/0269881112441865)
95 Curzon, P. & Decker, M. W. 1998 Effects of phencyclidine
(PCP) and (þ)MK-801 on sensorimotor gating in CD-1
mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 22,
129– 146. (doi:10.1016/S0278-5846(97)00184-X)
96 Geyer, M. A., Krebs-Thomson, K., Braff, D. L. &
Swerdlow, N. R. 2001 Pharmacological studies of
prepulse inhibition models of sensorimotor gating
deficits in schizophrenia: a decade in review. Psycho-
pharmacology (Berl.)156, 117 – 154. (doi:10.1007/
s002130100811)
97 Long, L. E., Chesworth, R., Huang, X. F., McGregor,
I. S., Arnold, J. C. & Karl, T. 2010 A behavioural
comparison of acute and chronic D9-tetrahydrocanna-
binol and cannabidiol in C57BL/6JArc mice.
Int. J. Neuropsychopharmacol. 13, 861– 876. (doi:10.
1017/S1461145709990605)
98 Long, L. E., Chesworth, R., Huang, X. F., Wong, A.,
Spiro, A., McGregor, I. S., Arnold, J. C. & Karl, T.
2012 Distinct neurobehavioural effects of cannabidiol
in transmembrane domain neuroregulin 1 mutante
mice. PLoS ONE 7, e34129. (doi:10.1371/journal.
pone.0034129)
99 Gururajan, A., Taylor, D. A. & Malone, D. T. 2011
Effect of cannabidiol in a MK-801-rodent model
of aspects of schizophrenia. Behav. Brain Res. 222,
299–308. (doi:10.1016/j.bbr.2011.03.053)
100 Leweke, F. M., Schneider, U., Radwan, M., Schmidt,
E. & Emrich, H. M. 2000 Different effects of nabilone
and cannabidiol on binocular depth inversion in man.
Pharmacol. Biochem. Behav. 66, 175–181. (doi:10.
1016/S0091-3057(00)00201-X)
101 Bhattacharyya, S. et al. 2010 Opposite effects of D-9-
tetrahydrocannabinol and cannabidiol on human brain
function and psychopathology. Neuropsychopharmacol-
ogy 35, 764 – 774. (doi:10.1038/npp.2009.184)
102 Hallak, J. E. et al. 2011 The interplay of cannabinoid
and NMDA glutamate receptor systems in humans:
preliminary evidence of interactive effects of cannabi-
diol and ketamine in healthy human subjects. Prog.
Neuropsychopharmacol. Biol. Psychiatry 35, 198 – 202.
(doi:10.1016/j.pnpbp.2010.11.002)
103 Zuardi, A. W., Morais, S. L., Guimara
˜es, F. S. &
Mechoulam, R. 1995 Antipsychotic effect of cannabi-
diol. J. Clin. Psychiatry 56,485–486.
104 Zuardi, A. W., Hallak, J. E., Dursun, S. M., Morais,
S. L., Sanches, R. F., Musty, R. E. & Crippa, J. A.
2006 Cannabidiol monotherapy for treatment-resistant
schizophrenia. J. Psychopharmacol. 20, 683– 686.
(doi:10.1177/0269881106060967)
105 Zuardi, A. W., Crippa, J. A., Hallak, J. E., Pinto, J. P.,
Chagas, M. H., Rodrigues, G. G., Dursun, S. M. &
Tumas, V. 2009 Cannabidiol for the treatment of psy-
chosis in Parkinson’s disease. J. Psychopharmacol. 23,
979–983. (doi:10.1177/0269881108096519)
106 Hallak, J. E., Machado-de-Sousa, J. P., Crippa, J. A.,
Sanches, R. F., Trzesniak, C., Chaves, C., Bernardo,
S. A., Regalo, S. C. & Zuardi, A. W. 2010 Performance
of schizophrenic patients in the Stroop Color Word Test
and electrodermal responsiveness after acute adminis-
tration of cannabidiol (CBD). Rev. Bras. Psiquiatr. 32,
56–61. (doi:10.1590/S1516-44462010000100011)
107 Murray, R. M., Morrison, P. D., Henquet, C. & Di
Forti, M. 2007 Cannabis, the mind and society: the
hash realities. Nat. Rev. Neurosci. 8, 885– 895.
(doi:10.1038/nrn2253)
108 Morgan, C. J. & Curran, H. V. 2008 Effects of cannabi-
diol on schizophrenia-like symptoms in people who use
cannabis. Br. J. Psychiatry 192, 306 – 307. (doi:10.1192/
bjp.bp.107.046649)
109 Morgan, C. J. et al. 2012 Sub-chronic impact of canna-
binoids in street cannabis on cognition, psychotic-like
symptoms and psychological well-being. Psychol. Med.
42, 391–400. (doi:10.1017/S0033291711001322)
110 Schubart, C. D., Sommer, I. E., van Gastel, W. A.,
Goetgebuer, R. L., Kahn, R. S. & Boks, M. P. 2011
Cannabis with high cannabidiol content is associated
with fewer psychotic experiences. Schizophr. Res. 130,
216–221. (doi:10.1016/j.schres.2011.04.017)
111 Di Forti, M. et al. 2009 High-potency cannabis and the
risk of psychosis. Br. J. Psychiatry 195, 488 – 491.
(doi:10.1192/bjp.bp.109.064220)
112 Demirakca, T., Sartorius, A., Ende, G., Meyer, N.,
Welzel, H., Skopp, G., Mann, K. & Hermann, D.
2011 Diminished gray matter in the hippocampus of
cannabis users: possible protective effects of cannabi-
diol. Drug Alcohol Depend. 114, 242 – 245. (doi:10.
1016/j.drugalcdep.2010.09.020)
113 Hermann, D., Sartorius, A., Welzel, H., Walter, S.,
Skopp, G., Ende, G. & Mann, K. 2007 Dorsolateral
prefrontal cortex N-acetylaspartate/total creatine
(NAA/tCr) loss in male recreational cannabis users.
Biol. Psychiatry 61, 1281 – 1289. (doi:10.1016/j.
biopsych.2006.08.027)
114 Bhattacharyya, S. et al. 2012 Induction of psychosis by
delta9-tetrahydrocannabinol reflects modulation of pre-
frontal and striatal function during attentional salience
processing. Arch. Gen. Psychiatry 69, 27 – 36. (doi:10.
1001/archgenpsychiatry.2011.161)
115 Guimara
˜es, V. M., Zuardi, A. W., Del Bel, E. A. &
Guimara
˜es, F. S. 2004 Cannabidiol increases Fos
expression in the nucleus accumbens but not in the
dorsal striatum. Life Sci. 75, 633 – 638. (doi:10.1016/j.
lfs.2004.01.015)
116 Robertson, G. S. & Fibiger, H. C. 1992 Neuroleptics
increase c-fos expression in the forebrain: contrasting
effects of haloperidol and clozapine. Neuroscience 46,
315–328. (doi:10.1016/0306-4522(92)90054-6)
117 Murillo-Rodrı
´guez, E., Palomero-Rivero, M., Milla
´n-
Aldaco, D., Mechoulam, R. & Drucker-Colı
´n, R.
2011 Effects on sleep and dopamine levels of micro-
dialysis perfusion of cannabidiol into the lateral
hypothalamus of rats. Life Sci. 88, 504–511. (doi:10.
1016/j.lfs.2011.01.013)
118 Borgwardt, S. J. et al. 2008 Neural basis of D-9-tetrahy-
drocannabinol and cannabidiol: effects during response
inhibition. Biol. Psychiatry 64, 966 –967. (doi:10.1016/j.
biopsych.2008.05.011)
119 Bhattacharyya, S. et al. 2009 Modulation of medio-
temporal and ventrostriatal function in humans by
D9-tetrahydrocannabinol: a neural basis for the effects
of Cannabis sativa on learning and psychosis. Arch.
Gen. Psychiatry 66, 442 – 451. (doi:10.1001/archgenpsy
chiatry.2009.17)
120 Winton-Brown, T. T. et al. 2011 Modulation of auditory
and visual processing by D-9-tetrahydrocannabinol and
cannabidiol: an FMRI study. Neuropsychopharmacology
36, 1340– 1348. (doi:10.1038/npp.2011.17)
121 Zuardi, A. W., Crippa, J. A., Hallak, J. E., Bhatacharyya,
S., Atakan, Z., Martin-Santos, R., McGuire, P. K.,
Fusar-Poli, P. & Guimara
˜es, F. S. In press. A critical
review of the antipsychotic effects of cannabidiol: 30
years of a translational investigation. Curr. Pharmac. Des.
122 Murillo-Rodrı
´guez, E., Milla
´n-Aldaco, D., Palomero-
Rivero, M., Mechoulam, R. & Drucker-Colı
´n, R.
2006 Cannabidiol, a constituent of Cannabis sativa,
modulates sleep in rats. FEBS Lett. 580,4337–4345.
(doi:10.1016/j.febslet.2006.04.102)
Review.Cannabidiol and psychiatric disorders A. C. Campos et al. 3377
Phil. Trans. R. Soc. B (2012)
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from

123 Kapur, S. 2004 How antipsychotics become anti-‘psy-
chotic’—from dopamine to salience to psychosis.
Trends Pharmacol. Sci. 25, 402 – 406. (doi:10.1016/j.
tips.2004.06.005)
124 Zuardi, W. A., Guimara
˜es, F. S., Hallak, J. E. C. &
Crippa, J. A. 2011 Is the highest density of CB1 recep-
tors in paranoid schizophrenia a correlate of
endocannabinoid system functioning? Exp. Rev.
Neurother. 11, 1111– 1114. (doi:10.1586/ERN.11.89)
125 Hall, W. & Degenhardt, L. 2009 Adverse health effects
of non-medical cannabis use. Lancet 374, 1383– 1391.
(doi:10.1016/S0140-6736(09)61037-0)
126 Hill, M. N., Hillard, C. J., Bambico, F. R., Patel, S., Gor-
zalka, B. B. & Gobbi, G. 2009 The therapeutic potential
of the endocannabinoid system for the development of a
novel class of antidepressants. Trends Pharmacol. Sci. 30,
484– 493. (doi:10.1016/j.tips.2009.06.006)
127 El-Alfy, A. T., Ivey, K., Robinson, K., Ahmed, S.,
Radwan, M., Slade, D., Khan, I., ElSohly, M. &
Ross, S. 2010 Antidepressant-like effect of D9-tetrahy-
drocannabinol and other cannabinoids isolated from
Cannabis sativa L. Pharmacol. Biochem. Behav. 95,
434–442. (doi:10.1016/j.pbb.2010.03.004)
128 Zanelati, T. V., Biojone, C., Moreira, F. A., Guimara
˜es,
F. S. & Joca, S. R. 2010 Antidepressant-like effects of
cannabidiol in mice: possible involvement of 5-HT1A
receptors. Br. J. Phar macol. 159, 122 – 128. (doi:10.
1111/j.1476-5381.2009.00521.x)
129 Lowry, C. A., Lightman, S. L. & Nutt, D. J. 2009 That
warm fuzzy feeling: brain serotonergic neurons and
the regulation of emotion. J. Psychopharmacol. 23,
392–400. (doi:10.1177/0269881108099956)
130 Krishnan, V. & Nestler, E. J. 2010 Linking molecules to
mood: new insight into the biology of depression.
Am. J. Psychiatry 167, 1305–1320. (doi:10.1176/appi.
ajp.2009.10030434)
131 Cryan, J. F., Markou, A. & Lucki, I. 2002 Assessing
antidepressant activity in rodents: recent developments
and future needs. Trends Pharmacol. Sci. 23, 238 – 245.
(doi:10.1016/S0165-6147(02)02017-5)
132 Willner, P. 2005 Chronic mild stress (CMS) revisited:
consistency and behavioural-neurobiological concor-
dance in the effects of CMS. Neuropsychobiology 52,
90–110. (doi:10.1159/000087097)
133 Zuardi, A. W., Crippa, J., Dursun, S., Morais, S.,
Vilela, J., Sanches, R. & Hallak, J. 2010 Cannabidiol
was ineffective for manic episode of bipolar affective
disorder. J. Psychopharmacol. 24, 135– 137. (doi:10.
1177/0269881108096521)
134 Valvassori, S. S. et al. 2011 Effects of cannabidiol on
amphetamine-induced oxidative stress generation in
an animal model of mania. J. Psychopharmacol. 25,
274–280. (doi:10.1177/0269881109106925)
135 Agurell, S., Carlsson, S., Lindgren, J. E., Ohlsson, A.,
Gillespie, H. & Hollister, L. 1981 Interactions of
delta 1-tetrahydrocannabinol with cannabinol and
cannabidiol following oral administration in man.
Assay of cannabinol and cannabidiol by mass fragmen-
tography. Experientia 37, 1090 – 1092. (doi:10.1007/
BF02085029)
3378 A. C. Campos et al. Review.Cannabidiol and psychiatric disorders
Phil. Trans. R. Soc. B (2012)
on October 29, 2012rstb.royalsocietypublishing.orgDownloaded from