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Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD's potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.
Cannabidiol as a Potential Treatment for Anxiety Disorders
Esther M. Blessing
&Maria M. Steenkamp
&Jorge Manzanares
Charles R. Marmar
#The American Society for Experimental NeuroTherapeutics, Inc. 2015
Abstract Cannabidiol (CBD), a Cannabis sativa constituent,
is a pharmacologically broad-spectrum drug that in recent
years has drawn increasing interest as a treatment for a range
of neuropsychiatric disorders. The purpose of the current re-
view is to determine CBDs potential as a treatment for
anxiety-related disorders, by assessing evidence from preclin-
ical, human experimental, clinical, and epidemiological stud-
ies. We found that existing preclinical evidence strongly sup-
ports CBD as a treatment for generalized anxiety disorder,
panic disorder, social anxiety disorder, obsessivecompulsive
disorder, and post-traumatic stress disorder when adminis-
tered acutely; however, few studies have investigated chronic
CBD dosing. Likewise, evidence from human studies sup-
ports an anxiolytic role of CBD, but is currently limited to
acute dosing, also with few studies in clinical populations.
Overall, current evidence indicates CBD has considerable po-
tential as a treatment for multiple anxiety disorders, with need
for further study of chronic and therapeutic effects in relevant
clinical populations.
Keywords Cannabidiol .Endocannabinoids .Anxiety .
Generalized anxiety disorder .Post-traumatic stress disorder
Fear and anxiety are adaptive responses essential to coping
with threats to survival. Yet excessive or persistent fear may
be maladaptive, leading to disability. Symptoms arising from
excessive fear and anxiety occur in a number of neuropsychi-
atric disorders, including generalized anxiety disorder (GAD),
panic disorder (PD), post-traumatic stress disorder (PTSD),
social anxiety disorder (SAD), and obsessivecompulsive dis-
order (OCD). Notably, PTSD and OCD are no longer classi-
fied as anxiety disorders in the recent revision of the Diagnos-
tic and Statistical Manual of Mental Disorders-5; however,
excessive anxiety is central to the symptomatology of both
disorders. These anxiety-related disorders are associated with
a diminished sense of well-being, elevated rates of unemploy-
ment and relationship breakdown, and elevated suicide risk
[13]. Together, they have a lifetime prevalence in the USA
of 29 % [4], the highest of any mental disorder, and constitute
an immense social and economic burden [5,6].
Currently available pharmacological treatments include sero-
tonin reuptake inhibitors, serotoninnorepinephrine reuptake in-
hibitors, benzodiazepines, monoamine oxidase inhibitors, tricy-
clic antidepressant drugs, and partial 5-hydroxytryptamine (5-
receptor agonists. Anticonvulsants and atypical antipsy-
chotics are also used to treat PTSD. These medications are asso-
ciated with limited response rates and residual symptoms, partic-
ularly in PTSD, and adverse effects may also limit tolerability
and adherence [710]. The substantial burden of anxiety-related
disorders and the limitations of current treatments place a high
priority on developing novel pharmaceutical treatments.
Cannabidiol (CBD) is a phytocannabinoid constituent of
Cannabis sativa that lacks the psychoactive effects of Δ
rahydrocannabinol (THC). CBD has broad therapeutic prop-
erties across a range of neuropsychiatric disorders, stemming
from diverse central nervous system actions [11,12]. In recent
*Esther M. Blessing
New York University School of Medicine, New York, NY, USA
Instituto de Neurociencias de Alicante, Universidad Miguel
Hernández and Consejo Superior deInvestigaciones Científicas,
Alicante, Spain
DOI 10.1007/s13311-015-0387-1
years, CBD has attracted increasing interest as a potential
anxiolytic treatment [1315]. The purpose of this review is
to assess evidence from current preclinical, clinical, and epi-
demiological studies pertaining to the potential risks and ben-
efits of CBD as a treatment for anxiety disorders.
A search of MEDLINE (PubMed), PsycINFO, Web of Science
Scopus, and the Cochrane Library databases was conducted for
English-language papers published up to 1 January 2015, using
the search terms Bcannabidiol^and Banxiety^or Bfear^or
Bstress^or Banxiety disorder^or Bgeneralized anxiety disorder^
or Bsocial anxiety disorder^or Bsocial phobia^or Bpost-trau-
matic stress disorder^or Bpanic disorder^or Bobsessive com-
pulsive disorder^. In total, 49 primary preclinical, clinical, or
epidemiological studies were included. Neuroimaging studies
that documented results from anxiety-related tasks, or resting
neural activity, were included. Epidemiological or clinical stud-
ies that assessed CBDs effects on anxiety symptoms, or the
potential protective effects of CBD on anxiety symptoms in-
duced by cannabis use (where the CBD content of cannabis is
inferred via a higher CBD:THC ratio), were included.
CBD Pharmacology Relevant to Anxiety
General Pharmacology and Therapeutic Profile
Cannabis sativa,aspeciesoftheCannabis genus of flowering
plants, is one of the most frequently used illicit recreational
substances in Western culture. The 2 major phyto- cannabinoid
constituents with central nervous system activity are THC, re-
sponsible for the euphoric and mind-altering effects, and CBD,
which lacks these psychoactive effects. Preclinical and clinical
studies show CBD possesses a wide range of therapeutic prop-
erties, including antipsychotic, analgesic, neuroprotective, anti-
convulsant, antiemetic, antioxidant, anti-inflammatory, antiar-
thritic, and antineoplastic properties (see [11,12,1619]for
reviews). A review of potential side effects in humans found
that CBD was well tolerated across a wide dose range, up to
1500 mg/day (orally), with no reported psychomotor slowing,
negative mood effects, or vital sign abnormalities noted [20].
CBD has a broad pharmacological profile, including inter-
actions with several receptors known to regulate fear and
anxiety-related behaviors, specifically the cannabinoid type
1 receptor (CB
R), the serotonin 5-HT
receptor, and the
transient receptor potential (TRP) vanilloid type 1 (TRPV1)
receptor [11,12,19,21]. In addition, CBD may also regulate,
directly or indirectly, the peroxisome proliferator-activated
receptor-γ, the orphan G-protein-coupled receptor 55, the e-
quilibrative nucleoside transporter, the adenosine transporter,
additional TRP channels, and glycine receptors [11,12,19,
21]. In the current review of primary studies, the following
receptor-specific actions were found to have been investigated
as potential mediators of CBDs anxiolytic action: CB
TRPV1 receptors, and 5-HT
receptors. Pharmacology rele-
vant to these actions is detailed below.
The Endocannabinoid System
Following cloning of the endogenous receptor for THC,
namely the CB
R, endogenous CB
R ligands, or
Bendocannabinoids^(eCBs) were discovered, namely anan-
damide (AEA) and 2-arachidonoylglycerol (reviewed in [22]).
The CB
R is an inhibitory G
protein-coupled receptor that is
mainly localized to nerve terminals, and is expressed on both
γ-aminobutryic acid-ergic and glutamatergic neurons. eCBs
are fatty acid derivatives that are synthesized on demand in
response to neuronal depolarization and Ca
influx, via
cleavage of membrane phospholipids. The primary mecha-
nism by which eCBs regulate synaptic function is retrograde
signaling, wherein eCBs produced by depolarization of the
postsynaptic neuron activate presynaptic CB
Rs, leading to
inhibition of neurotransmitter release [23]. The BeCB system^
includes AEA and 2-arachidonoylglycerol; their respective
degradative enzymes fatty acid amide hydroxylase (FAAH)
and monoacylglycerol lipase; the CB
R and related CB
ceptor (the latter expressed mainly in the periphery); as well as
several other receptors activated by eCBs, including the
TRPV1 receptor, peroxisome proliferator-activated
receptor-γ, and G protein-coupled 55 receptor, which func-
tionally interact with CB
R signaling (reviewed in [21,24]).
Interactions with the TRPV1 receptor, in particular, appear to
be critical in regulating the extent to which eCB release leads
to inhibition or facilitation of presynaptic neurotransmitter re-
lease [25]. The TRPV1 receptor is a postsynaptic cation chan-
nel that underlies sensation of noxious heat in the periphery,
with capsacin (hot chili) as an exogenous ligand. TRPV1 re-
ceptors are also expressed in the brain, including the amygdala,
periaqueductal grey, hippocampus, and other areas [26,27].
The eCB system regulates diverse physiological functions,
including caloric energy balance and immune function [28].
The eCB system is also integral to regulation of emotional
behavior, being essential to forms of synaptic plasticity that
determine learning and response to emotionally salient, par-
ticularly highly aversive events [29,30]. Activation of CB
produces anxiolytic effects in various models of uncondi-
tioned fear, relevant to multiple anxiety disorder symptom
domains (reviewed in [3033]). Regarding conditioned fear,
the effect of CB
R activation is complex: CB
R activation
may enhance or reduce fear expression, depending on brain
locus and the eCB ligand [34]; however, CB
R activation
potently enhances fear extinction [35], and can prevent
fear reconsolidation. Genetic manipulations that impede
Blessing et al.
R activation are anxiogenic [35], and individuals with
eCB system gene polymorphisms that reduce eCB tone
for example, FAAH gene polymorphismsexhibit physio-
logical, psychological, and neuroimaging features consis-
tent with impaired fear regulation [36]. Reduction of
R signaling in the amygdala mediates the
anxiogenic effects of corticotropin-releasing hormone
[37], and CB
R activation is essential to negative feedback
of the neuroendocrine stress response, and protects against
the adverse effects of chronic stress [38,39]. Finally,
chronic stress impairs eCB signaling in the hippocampus
and amygdala, leading to anxiety [40,41], and people
with PTSD show elevated CB
R availability and reduced
peripheral AEA, suggestive of reduced eCB tone [42].
Accordingly, CB
R activation has been suggested as a tar-
get for anxiolytic drug development [15,43,44]. Proposed
agents for enhancing CB
R activation include THC, which
is a potent and direct agonist; synthetic CB
R agonists; FAAH
inhibitors and other agents that increase eCB availability, as
well as nonpsychoactive cannabis phytocannabinoids, includ-
ing CBD. While CBD has low affinity for the CB
R, it func-
tions as an indirect agonist, potentially via augmentation of
R constitutional activity, or via increasing AEA through
FAAH inhibition (reviewed in [21]).
Several complexities of the eCB system may impact upon
the potential of CBD and other CB
R-activating agents to serve
as anxiolytic drugs. First, CB
R agonists, including THC and
AEA, have a biphasic effect: low doses are anxiolytic, but
higher doses are ineffective or anxiogenic, in both preclinical
models in and humans (reviewed in [33,45]). This biphasic
profile may stem from the capacity of CB
R agonists to
also activate TRPV1 receptors when administered at a high,
but not low dose, as demonstrated for AEA [46]. Activation
of TRPV1 receptors is predominantly anxiogenic, and thus a
critical balance of eCB levels, determining CB1 versus TRPV1
activation, is proposed to govern emotional behavior [27,47].
CBD acts as a TRPV1 agonist at high concentrations, poten-
tially by interfering with AEA inactivation [48]. In addition to
dose-dependent activation of TRPV1 channels, the anxiogenic
versus anxiolytic balance of CB
R agonists also depends on
dynamic factors, including environmental stressors [33,49].
The 5-HT
receptor (5-HT
R) is an established anxiolytic
target. Buspirone and other 5-HT
R agonists are approved
for the treatment of GAD, with fair response rates [50]. In
preclinical studies, 5-HT
R agonists are anxiolytic in animal
models of general anxiety [51], prevent the adverse effects of
stress [52], and enhance fear extinction [53]. Both pre- and
postsynaptic 5-HT
Rs are coupled to various members of the
protein family. They are expressed on serotonergic neurons
in the raphe, where they exert autoinhibitory function, and
various other brain areas involved in fear and anxiety
[54,55]. Mechanisms underlying the anxiolytic effects
of 5-HT
R activation are complex, varying between
both brain region, and pre- versus postsynaptic locus,
and are not fully established [56]. While in vitro studies
suggest CBD acts as a direct 5-HT
R agonist [57],
in vivo studies are more consistent with CBD acting
as an allosteric modulator, or facilitator of 5-HT
signaling [58].
Preclinical Evaluations
Generalized Anxiety Models
Relevant studies in animal models are summarized in chro-
nological order in Table 1. CBD has been studied in a wide
range of animal models of general anxiety, including the
elevated plus maze (EPM), the Vogel-conflict test (VCT),
and the elevated T maze (ETM). See Table 1for the anxi-
olytic effect specific to each paradigm. Initial studies of
CBD in these models showed conflicting results: high
(100 mg/kg) doses were ineffective, while low (10 mg/kg)
doses were anxiolytic [59,60]. When tested over a wide
range of doses in further studies, the anxiolytic effects of
CBD presented a bell-shaped doseresponse curve, with an-
xiolytic effects observed at moderate but not higher doses
[61,90]. All further studies of acute systemic CBD without
prior stress showed anxiolytic effects or no effect [62,65],
the latter study involving intracerebroventricular rather than
the intraperitoneal route. No anxiogenic effects of acute sys-
temic CBD dosing in models of general anxiety have yet
been reported. As yet, few studies have examined chronic
dosing effects of CBD in models of generalized anxiety.
Campos et al. [66] showed that in rat, CBD treatment for
21 days attenuated inhibitory avoidance acquisition [83].
Long et al. [69] showed that, in mouse, CBD produced
moderate anxiolytic effects in some paradigms, with no ef-
fects in others.
Anxiolytic effects of CBD in models of generalized anxiety
have been linked to specific receptor mechanisms and brain
regions. The midbrain dorsal periaqueductal gray (DPAG) is
integral to anxiety, orchestrating autonomic and behavioral
responses to threat [91], and DPAG stimulation in humans
produces feelings of intense distress and dread [92]. Microin-
jection of CBD into the DPAG produced anxiolytic effects in
the EPM, VGC, and ETM that were partially mediated by
activation of 5-HT
Rs but not by CB
Rs [65,68]. The bed
nucleus of the stria terminalis (BNST) serves as a principal
output structure of the amygdaloid complex to coordinate
sustained fear responses, relevant to anxiety [93]. Anxiolytic
effects of CBD in the EPM and VCT occurred upon microin-
jection into the BNST, where they depended on 5-HT
Cannabidiol as a Potential Treatment for Anxiety Disorders
Tab l e 1 Preclinical studies
Study Animal Route Dose Model Effect Receptor Involvement
Silveira Filho et al. [59]WR i.p. 100 mg/kg,
GSCT No effect NA
Zuardi et al. [60]WR i.p. 10mg/kg,
CER Anxiolytic NA
Onaivi et al. [61] ICR mice i.p. 0.01, 0.10, 0.50,1.00,2.50,5.00,
10.00,50.00, 100.00 mg/kg, acute
EPM Anxiolytic Effects by IP flumazenil,
unchanged by naloxone
Guimaraes et al. [61]WR i.p. 2.5,5.0,10.0 and
20.0 mg/kg, acute
EPM Anxiolytic NA
Moreira et al. [62]WR i.p. 2.5,5.0and10.0 mg/kg, acute VCT Anxiolytic Effect unchanged by IP
Resstel et al. [63]WR i.p. 10 mg/kg, acute CFC Anxiolytic NA
Campos et al. [64] WR dlPAG 15.0, 30.0, 60.0 nmol/0.2 μl, acute EPM Anxiolytic Both effects by intra-dlPAG
WAY100635 but not
intra-dlPAG AM251
VCT Anxiolytic
Bitencourt et al. [65]WR i.c.v. 2.0 μg/μl
5 min before extinction, acute
Anxiolytic Extinction effect by
SR141716A but not
capsazepineEPM before and
24 h after CFC
No effect before CFC
Anxiolytic following CFC
Campos et al. [66]WR dlPAG 30, 60 mg/kg, acute EPM Anxiolytic Intra-dlPAG capsazepine
renders 60 mg/kg anxiolytic
Resstel et al. [67]WR i.p. 1,10 or 20 mg/kg, acute RS Anxiolytic,
All effects by systemic
EPM 24 h
following RS
Soares et al. [68] WR dlPAG 15, 30 or 60nmol, acute ETM Anxiolytic
All effects by intra-dlPAG
WAY100635 but not AM251
PAG E-stim Panicolytic
Long et al. [69] C57BL/6 J mice i.p. 1, 5, 10, 50mg/kg, chronic, daily/21 d EPM No effect NA
L-DT 1 mg/kg
SI No effect
OF 50 mg/kg anxiolytic
Lemos et al. [70]WR i.p.
10mg/kg IP, 30nmol intra-PL and
intra-IL, acute
CFC IP and PL anxiolytic IL
Casarotto et al. [71] C57BL/6 J mice i.p. 15, 30, and 60 mg/kg,
acute, or subchronic, daily/7 d
MBT Anticompulsive Effect by IP AM251 but not
Gomes et al. [72] WR BNST 15, 30, and 60 nmol, acute EPM Anxiolytic Both effects by intra BNST
WAY100635VCT Anxiolytic
Granjeiro et a l. [73] WR Intracisternal 15, 30, and 60 nmol, acute RS Anxiolytic, Pressor Tachycardia NA
EPM 24 h after RS Anxiolytic
Deiana et al. [74]SM i.p.
120mg/kg, acute MBT Anticompulsive NA
Uribe-Marino et al. [75]SM i.p. 0.3,3.0,30.0mg/kg, acute PS Panicolytic NA
Blessing et al.
Tab l e 1 (continued)
Study Animal Route Dose Model Effect Receptor Involvement
Stern et al. [76]WR i.p. 3,10, 30 mg/kg
immediately after retrieval,
Reconsolidation blockade Anxiolytic
Effect by AM251 but not
Campos et al. [77]WR i.p. 5mg/kg, subchronic, daily/7 d EPM following PS Anxiolytic Effects by IP WAY100635
Hsiao et al. [78]WR CeA1μg/μl REM sleep time REM sleep suppression NA
EPM Anxiolytic
OF Anxiolytic
Gomes et al. [79]WR BNST15,30,60nmol, acute CFC Anxiolytic Both effects by intra-BNST
El Batsh et al. [80] LE-H R i.p. 10mg/kg, chronic,
daily/14 d
CFC Anxiogenic NA
Campos et al. [81] C57BL/6 mice i.p. 30mg/kg2 hafterCUS,
chronic daily/14 d
EPM Anxiolytic Both effects by AM251
NSF Anxiolytic
Do Monte et al. [82] L-E HR IL 1 μgor0.4μg/0.2 μl
5 min before extinction
daily/4 d
Extinction of CFC Anxiolytic Effect by IP rimonabant
Campos et al. [83]Rat i.p. 5mg/kg, chronic,
daily/21 d
ETM Anxiolytic
Panicolytic effect by
intra-dlPAG WAY100635
Almeida et al. [84]Rat i.p. 1, 5, 15 mg/kg, acute SI Anxiolytic NA
Gomes et al. [85]WR BNST30 and 60 nmol, acute RS Anxiogenic
Effect by WAY100635
Twardowschy et al. [86]SM i.p. 3mg/kg, acute PS Panicolytic Effects by IP WAY100635
Focaga et al. [87] WR PL 15, 30, 60 nmol, acute EPM Anxiogenic All effects by intra PL
Anxiolytic EPM effect
post-RS by IP metyrapone
EPM after RS Anxiolytic
CFC Anxiolytic
Nardo et al. [88]SM i.p. 30 mg/kg, acute MBT Anticompulsive NA
da Silva et al. [89]WR SNpr 5μg/0.2μl GABA
in dlSC
Panicolytic Both effects by AM251
Effective doses are in bold
Receptor specific agents: AM251 = cannabinoid receptor type 1 (CB
R) inverse agonist; WAY100635 = 5-hydroxytryptamine 1A antagonist; SR141716A = CB
R antagonist; rimonabant = CB
antagonist; capsazepine = transient receptor potential vanilloid type 1 antagonist; naloxone = opioid antagonist; flumazenil = GABA
receptor antagonist
Anxiolytic effects in models used: CER = reduced fear response; CFC = reduced conditioned freezing; CFC extinction = reduced freezing following extinction training; EPM = reduced % time in open arm;
ETM = decreased inhibitory avoidance; L-DT = increased % time in light; VCT = increased licks indicating reduced conflict; NSF = reduced latency to feed; OF = increased % time in center; SI = increased
social interaction
Anticomplusive effects: MBT = reduced burying
Panicolytic effects: ETM = decreased escape; GABA
blockade in dlSC = defensive immobility, and explosive escape; PAG-E-Stim = increased threshold for escape; PS = reduced explosive escape
WR=Wistarrats;SM=Swissmice;L-EHR=LongEvans hooded rats; i.p. = intraperitoneal; dlPAG = dorsolateral periaqueductal gray; i.c.v. = intracerebroventricular; PL = prelimbic; IL = infralimbic;
BNST = bed nucleus of the stria terminalis; CeA = amygdala central nucleus; SNpr = substantia nigra pars reticularis; CUS = chronic unpredictable stress; GSCT = GellerSeifter conflict test; CER =
conditioned emotional response; EPM = elevated plus maze; VCT = Vogel conflict test; CFC = contextual fear conditioning; RS = restraint stress; ETM = elevated T maze; PAG E-stim = electrical
stimulation of the dlPAG; L-DT = lightdark test; SI = social interaction; OF = open field; MBT = marble-burying test; PS = predator stress; NSF = novelty suppressed feeding test; GABA
aminobutyric acid receptor A; dlSC = deep layers superior colliculus; REM = rapid eye movement; NA = not applicable
Cannabidiol as a Potential Treatment for Anxiety Disorders
activation [79], and also upon microinjection into the cen-
tral nucleus of the amygdala [78]. In the prelimbic cortex,
which drives expression of fear responses via connections
with the amygdala [94], CBD had more complex effects: in
unstressed rats, CBD was anxiogenic in the EPM, partially
via 5-HT
R receptor activation; however, following acute
restraint stress, CBD was anxiolytic [87]. Finally, the anxi-
olytic effects of systemic CBD partially depended on
receptor activation in the EPM model but not in
the VCT model [61,62].
As noted, CBD has been found to have a bell-shaped re-
sponse curve, with higher doses being ineffective. This may
reflect activation of TRPV1 receptors at higher dose, as block-
ade of TRPV1 receptors in the DPAG rendered a previously
ineffective high dose of CBD as anxiolytic in the EPM [66].
Given TRPV1 receptors have anxiogenic effects, this may
indicate that at higher doses, CBDs interaction with TRPV1
receptors to some extent impedes anxiolytic actions,
although was notably not sufficient to produce anxiogenic
Stress-induced Anxiety Models
Stress is an important contributor to anxiety disorders, and
traumatic stress exposure is essential to the development of
PTSD. Systemically administered CBD reduced acute in-
creases in heart rate and blood pressure induced by restraint
stress, as well as the delayed (24 h) anxiogenic effects of stress
in the EPM, partially by 5-HT
R activation [67,73]. How-
ever intra-BNST microinjection of CBD augmented stress-
induced heart rate increase, also partially via 5-HT
tion [85]. In a subchronic study, CBD administered daily 1 h
after predator stress (a proposed model of PTSD) reduced the
long-lasting anxiogenic effects of chronic predator stress, par-
tially via 5-HT
R activation [77]. In a chronic study, system-
ic CBD prevented increased anxiety produced by chronic un-
predictable stress, in addition to increasing hippocampal
AEA; these anxiolytic effects depended upon CB
R activation
and hippocampal neurogenesis, as demonstrated by genetic
ablation techniques [81]. Prior stress also appears to modulate
CBDs anxiogenic effects: microinjection of CBD into the
prelimbic cortex of unstressed animals was anxiogenic in the
EPM but following restraint stress was found to be anxiolytic
[87]. Likewise, systemic CBD was anxiolytic in the EPM
following but not prior to stress [65].
PD and Compulsive Behavior Models
CBD inhibited escape responses in the ETM and increased
DPAG escape electrical threshold [68], both proposed models
of panic attacks [95]. These effects partially depended on 5-
R activation but were not affected by CB
R blockade.
CBD was also panicolytic in the predatorprey model, which
assesses explosive escape and defensive immobility in re-
sponse to a boa constrictor snake, also partially via 5-HT
activation; however, more consistent with an anxiogenic ef-
fect, CBD was also noted to decrease time spent outside the
burrow and increase defensive attention (not shown in
Table 1)[75,86] . Finally, CBD, partially via CB
Rs, de-
creased defensive immobility and explosive escape caused
by bicuculline-induced neuronal activation in the superior
colliculus [89]. Anticompulsive effects of CBD were investi-
gated in marble-burying behavior, conceptualized to model
OCD [96]. Acute systemic CBD reduced marble-burying be-
havior for up to 7 days, with no attenuation in effect up to high
(120 mg/kg) doses, and effect shown to depend on CB
Rs but
not 5-HT
Rs [71,74,88].
Contextual Fear Conditioning, Fear Extinction,
and Reconsolidation Blockade
Several studies assessed CBD using contextual fear condition-
ing. Briefly, this paradigm involves pairing a neutral context,
the conditioned stimulus (CS), with an aversive unconditioned
stimulus (US), a mild foot shock. After repeated pairings, the
subject learns that the CS predicts the US, and subsequent CS
presentation elicits freezing and other physiological re-
sponses. Systemic administration of CBD prior to CS
re-exposure reduced conditioned cardiovascular re-
sponses [63], an effect reproduced by microinjection of
CBD into the BNST, and partially mediated by 5-
R activation [79]. Similarly, CBD in the prelimbic
cortex reduced conditioned freezing [70], an effect
Rblockade[87]. By contrast,
CBD microinjection in the infralimbic cortex enhanced
conditionedfreezing[70]. Finally, El Batsh et al. [80]
reported that repeated CBD doses over 21 days, that is
chronic as opposed to acute treatment, facilitated condi-
tioned freezing. In this study, CBD was administered
prior to conditioning rather than prior to re-exposure
as in acute studies, thus further directly comparable
studies are required.
CBD has also been shown to enhance extinction of
contextually conditioned fear responses. Extinction train-
ing involves repeated CS exposure in the absence of the
US, leading to the formation of a new memory that
inhibits fear responses and a decline in freezing over
subsequent training sessions. Systemic CBD administra-
tion immediately before training markedly enhanced ex-
tinction, and this effect depended on CB
R activation,
without involvement of TRPV1 receptors [65]. Further
studies showed CB
Rs in the infralimbic cortex may be
involved in this effect [82].
CBD also blocked reconsolidation of aversive memo-
ries in rat [76]. Briefly, fear memories, when reactivated
by re-exposure (retrieval), enter into a labile state in
Blessing et al.
which the memory trace may either be reconsolidated or
extinguished [97], and this process may be pharmacolog-
ically modulated to achieve reconsolidation blockade or
extinction. When administered immediately following re-
trieval, CBD prevented freezing to the conditioned con-
text upon further re-exposure, and no reinstatement or
spontaneous recovery was observed over 3 weeks, con-
sistent with reconsolidation blockade rather than extinc-
tion [76]. This effect depended on CB
R activation but
not 5-HT
Summary and Clinical Relevance
Overall, existing preclinical evidence strongly supports
the potential of CBD as a treatment for anxiety disor-
ders. CBD exhibits a broad range of actions, relevant to
multiple symptom domains, including anxiolytic,
panicolytic, and anticompulsive actions, as well as a
decrease in autonomic arousal, a decrease
in conditioned fear expression, enhancement of fear ex-
tinction, reconsolidation blockade, and prevention of the
long-term anxiogenic effects of stress. Activation of 5-
Rs appears to mediate anxiolytic and panicolytic
effects, in addition to reducing conditioned fear expres-
sion, although CB
R activation may play a limited role.
By contrast, CB
R activation appears to mediate CBDs
anticompulsive effects, enhancement of fear extinction,
reconsolidation blockade, and capacity to prevent the
long-term anxiogenic consequences of stress, with in-
volvement of hippocampal neurogenesis.
While CBD predominantly has acute anxiolytic ef-
fects, some species discrepancies are apparent. In addi-
tion, effects may be contingent on prior stress and vary
according to brain region. A notable contrast between
CBD and other agents that target the eCB system, in-
cluding THC, direct CB
R agonists and FAAH inhibi-
tors, is a lack of anxiogenic effects at a higher dose.
Further receptor-specific studies may elucidate the recep-
tor specific basis of this distinct dose response profile.
Further studies are also required to establish the efficacy
of CBD when administered in chronic dosing, as rela-
tively few relevant studies exist, with mixed results, in-
cluding both anxiolytic and anxiogenic outcomes.
Overall, preclinical evidence supports systemic CBD
as an acute treatment of GAD, SAD, PD, OCD, and
PTSD, and suggests that CBD has the advantage of
not producing anxiogenic effects at higher dose, as dis-
tinct from other agents that enhance CB
R activation. In
particular, results show potential for the treatment of
multiple PTSD symptom domains, including reducing
arousal and avoidance, preventing the long-term adverse
effects of stress, as well as enhancing the extinction and
blocking the reconsolidation of persistent fear memories.
Human Experimental and Clinical Studies
Evidence from Acute Psychological Studies
Relevant studies are summarized in Table 2. The anxiolytic
effects of CBD in humans were first demonstrated in the con-
text of reversing the anxiogenic effects of THC. CBD reduced
THC-induced anxiety when administered simultaneously with
this agent, but had no effect on baseline anxiety when admin-
istered alone [99,100]. Further studies using higher doses
supported a lack of anxiolytic effects at baseline [101,107].
By contrast, CBD potently reduces experimentally induced
anxiety or fear. CBD reduced anxiety associated with a simu-
lated public speaking test in healthy subjects, and in subjects
with SAD, showing a comparable efficacy to ipsapirone (a 5-
Ragonist)ordiazepam[98,105]. CBD also reduced the
presumed anticipatory anxiety associated with undergoing a
single-photon emission computed tomography (SPECT) im-
aging procedure, in both healthy and SAD subjects [102,104].
Finally, CBD enhanced extinction of fear memories in healthy
volunteers: specifically, inhaled CBD administered prior to or
after extinction training in a contextual fear conditioning par-
adigm led to a trend-level enhancement in the reduction of
skin conductance response during reinstatement, and a signif-
icant reduction in expectancy (of shock) ratings during rein-
statement [106].
Evidence from Neuroimaging Studies
Relevant studies are summarized in Table 3. In a SPECT study
of resting cerebral blood flow (rCBF) in normal subjects,
CBD reduced rCBF in left medial temporal areas, including
the amygdala and hippocampus, as well as the hypothalamus
and left posterior cingulate gyrus, but increased rCBF in the
left parahippocampal gyrus. These rCBF changes were not
correlated with anxiolytic effects [102]. In a SPECT study,
by the same authors, in patients with SAD, CBD reduced
rCBF in overlapping, but distinct, limbic and paralimbic areas;
again, with no correlations to anxiolytic effects [104].
In a series of placebo-controlled studies involving 15
healthy volunteers, Fusar-Poli et al. investigated the effects
of CBD and THC on task-related blood-oxygen-level depen-
dent functional magnetic resonance imaging activation, spe-
cifically the go/no-go and fearful faces tasks [109,110]. The
go/no-go task measures response inhibition, and is associated
with activation of medial prefrontal, dorsolateral prefrontal,
and parietal areas [111]. Response activation is diminished
in PTSD and other anxiety disorders, and increased activation
predicts response to treatment [112]. CBD produced no
changes in predicted areas (relative to placebo) but reduced
activation in the left insula, superior temporal gyrus, and trans-
verse temporal gyrus. The fearful faces task activates the
amygdala, and other medial temporal areas involved in
Cannabidiol as a Potential Treatment for Anxiety Disorders
Tabl e 2 Human psychological studies
Study Subjects,
CBD route,
Measure Effect
Karniol et al. [99]HV,
Oral, 15, 30, 60 mg, alone
or with THC,
acute, at 55, 95, 155, and
185 min
Anxiety and pulse rate after
THC and at baseline
THC-induced increases in
subjective anxiety and
pulse rate
No effect at
Zuardi et al., [100]HV,
Oral 1 mg/kg alone or with
THC, acute, 80 min
STAI score after THC THC-induced increases in
STAI scores
Zuardi et al. [98]HV,
Oral 300 mg,
acute, 80 min
following SPST
STAI scores
VA M S s c o r e s
Martin-Santos et al. [101]HV,
Oral 600 mg,
acute, 1, 2, 3 h
Baseline anxiety and
pulse rate
No effect
Crippa et al. [102]10HV,
Oral 400 mg,
acute, 60 and 75 min
VA M S s c o r e s
Bhattacharyya et al. [103]15HV
Oral 600 mg,
acute, 1, 2, 3 h
STAI scores
VAMS scores
STAI scores
VA M S s c o r e s
Crippa et al. [104] SAD and HC
Oral 400 mg,
acute, 75 and 140 min
VA M S s c o r e s
Bergamaschi et al. [105] SAD and HC DBP Oral 600 mg, acute,
1, 2, 3 h
VAMS, SSPS-N, cognitive
impairment, SCR, HR
after SPST
VAMS, SSPS-N and cognitive
impairment, no effect on SCR
or HR
Das et al. [106]HV
Inhaled, 32 mg, acute,
immediately following,
before, after extinction
SCR and shock expectancy
following extinction
CBD after extinction training
produced trend level reduction
Hindocha et al. [107] Varying in schizotypy and
cannabis use, DBP
Inhaled, 16 mg, acute Baseline VAS anxiety No significant effect of CBD
HV = healthy volunteers; DBP = double-blind placebo; SAD = social anxiety disorder; HC = healthy controls; THC =
9-tetrahydrocannabinol; STAI =
Spielbergers state trait anxiety inventory; VAMS = visual analog mood scale; BP = blood pressure; SPST = simulated public speaking test; SCR = skin
conductance response; SPECT = single-photon emission computed tomography; SSPS-N = negative self-evaluation subscale; HR = heart rate; VAS =
visual analog scale, CBD = cannabidiol
Tabl e 3 Neuroimaging studies
Study Subjects, design CBD route, dose, timing Measure Effect of CBD
Crippa et al. [102]10HV,
Oral 400 mg,
acute, 60 and 75 min
SPECT, resting (rCBF) rCBF in left medial temporal cluster,
including amygdala and HPC, also rCBF
in the HYP and posterior cingulate gyrus
rCBF in left PHG
Borgwardt et al. [108]15HV,
Oral 600 mg,
acute, 12h
fMRI during oddball and
go/no-go task
Activation in left insula, STG and MTG
Fusar-Poli et al. [109]15HV,
Oral 600 mg,
acute, 12h
fMRI activation during
fearful faces task
Activation in left medial temporal region,
including amygdala and anterior PHG, and
in right ACC and PCC
Fusar-Poli et al. [110]15HV,
Oral 600 mg,
acute, 12h
fMRI functional connectivity
during fearful faces task
Functional connectivity between L) AMY
and ACC
Crippa et al. [104] SAD and HC
Oral 400 mg,
acute, 75 and 140 min
SPECT, resting (rCBF) rCBF in the left PHG, HPC and ITG.
rCBF in the right posterior cingulate gyrus
CBD = cannabidiol; HV = healthy controls; DBP = double-blindplacebo; SAD= social anxiety disorder; HC = healthy controls; SPECT = single-photo
emission computed tomography; rCBF = regional cerebral blood flow; fMRI = functional magnetic resonance imaging; HPC = hippocampus; HYP =
hypothalamus; PHG = parahippocampal gyrus; STG = superior temporal gyrus; MTG = medial temporal gyrus; ACC = anterior cingulate cortex; PCC =
posterior cingulate cortex
Blessing et al.
emotion processing, and heightened amygdala response acti-
vation has been reported in anxiety disorders, including GAD
and PTSD [113,114]. CBD attenuated blood-oxygen-level
dependent activation in the left amygdala, and the anterior
and posterior cingulate cortex in response to intensely fearful
faces, and also reduced amplitude in skin conductance fluctu-
ation, which was highly correlated with amygdala activation
[109]. Dynamic causal modeling analysis in this data set fur-
ther showed CBD reduced forward functional connectivity
between the amygdala and anterior cingulate cortex [110].
Evidence from Epidemiological and Chronic Studies
Epidemiological studies of various neuropsychiatric disorders
indicate that a higher CBD content in chronically consumed
cannabis may protect against adverse effects of THC, includ-
ing psychotic symptoms, drug cravings, memory loss, and
hippocampal gray matter loss [115118] (reviewed in [119]).
As THC acutely induces anxiety, this pattern may also be
evident for chronic anxiety symptoms. Two studies were iden-
tified, including an uncontrolled retrospective study in civilian
patients with PTSD patients [120], and a case study in a pa-
tient with severe sexual abuse-related PTSD [121], which
showed that chronic cannabis use significantly reduces PTSD
symptoms; however, these studies did not include data on the
THC:CBD ratio. Thus, overall, no outcome data are currently
available regarding the chronic effects of CBD in the treat-
ment of anxiety symptoms, nor do any data exist regarding the
potential protective effects of CBD on anxiety potentially in-
duced by chronic THC use.
Summary and Clinical Relevance
Evidence from human studies strongly supports the potential
for CBD as a treatment for anxiety disorders: at oral doses
ranging from 300 to 600 mg, CBD reduces experimentally
induced anxiety in healthy controls, without affecting baseline
anxiety levels, and reduces anxiety in patients with SAD.
Limited results in healthy subjects also support the efficacy
of CBD in acutely enhancing fear extinction, suggesting po-
tential for the treatment of PTSD, or for enhancing cognitive
behavioral therapy. Neuroimaging findings provide evidence
of neurobiological targets that may underlie CBDs anxiolytic
effects, including reduced amygdala activation and altered
medial prefrontal amygdala connectivity, although current
findings are limited by small sample sizes, and a lack of inde-
pendent replication. Further studies are also required to estab-
lish whether chronic, in addition to acute CBD dosing is an-
xiolytic in human. Also, clinical findings are currently limited
to SAD, whereas preclinical evidence suggests CBDspoten-
tial to treat multiple symptom domains relevant to GAD, PD,
and, particularly, PTSD.
Preclinical evidence conclusively demonstrates CBDseffica-
cy in reducing anxiety behaviors relevant to multiple disor-
ders, including PTSD, GAD, PD, OCD, and SAD, with a
notable lack of anxiogenic effects. CBDs anxiolytic actions
appear to depend upon CB
Rs and 5-HT
Rs in several brain
regions; however, investigation of additional receptor actions
may reveal further mechanisms. Human experimental find-
ings support preclinical findings, and also suggest a lack of
anxiogenic effects, minimal sedative effects, and an excellent
safety profile. Current preclinical and human findings mostly
involve acute CBD dosing in healthy subjects, so further stud-
ies are required to establish whether chronic dosing of CBD
has similar effects in relevant clinical populations. Overall,
this review emphasizes the potential value and needfor further
study of CBD in the treatment of anxiety disorders.
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Blessing et al.
... The two main endocannabinoids, N-arachidonylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) are synthesized as required by cleavage of membrane phospholipids, which is usually induced by depolarization (neurons) and/or Ca +2 influx. In the nervous system, synthesis occurs in the post-synaptic terminals and AEA and 2-AG feedback in a retrograde manner to CB 1/2 on presynaptic membranes, inhibiting further neurotransmitter release (Blessing et al. 2015;Morena et al. 2016). ...
... Clinically, CBD does antagonize some actions of THC. However, CBD has different clinical effects to recombinant and other antagonists of CB 1/2 (McPartland et al. 2015), and the overall clinical effect of CBD is to increase CB 1/2 signaling (Blessing et al. 2015;Campos et al. 2013;Fogaça et al. 2018). CBD is also an antagonist of GPR55, which is an endocannabinoid receptor with multiple putative clinical actions (de Almeida and Devi 2020). ...
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Combination tetrahydrocannabinol (THC)/cannabidiol (CBD) medicines or CBD-only medicines are prospective treatments for chronic pain, stress, anxiety, depression, and insomnia. THC and CBD increase signaling from cannabinoid receptors, which reduces synaptic transmission in parts of the central and peripheral nervous systems and reduces the secretion of inflammatory factors from immune and glial cells. The overall effect of adding CBD to THC medicines is to enhance the analgesic effect but counteract some of the adverse effects. There is substantial evidence for the effectiveness of THC/CBD combination medicines for chronic pain, especially neuropathic and nociplastic pain or pain with an inflammatory component. For CBD-only medication, there is substantial evidence for stress, moderate evidence for anxiety and insomnia, and minimal evidence for depression and pain. THC/CBD combination medicines have a good tolerability and safety profile relative to opioid analgesics and have negligible dependence and abuse potential; however, should be avoided in patients predisposed to depression, psychosis and suicide as these conditions appear to be exacerbated. Non-serious adverse events are usually dose-proportional, subject to tachyphylaxis and are rarely dose limiting when patients are commenced on a low dose with gradual up-titration. THC and CBD inhibit several Phase I and II metabolism enzymes, which increases the exposure to a wide range of drugs and appropriate care needs to be taken. Low-dose CBD that appears effective for chronic pain and mental health has good tolerability and safety, with few adverse effects and is appropriate as an initial treatment.
... However, non-psychoactive phytocannabinoids, such as cannabidiol (CBD) and cannabigerol (CBG), have also received noteworthy attention from the scientific community ( Figure 1). CBD is one of the most intensively researched cannabinoids owing to its positive therapeutic effects on several medical conditions, i.e., epilepsy [15], schizophrenia [16], anxiety [17], and sepsis [18]. It is also used for the treatment of several skin conditions, including psoriasis, atopic dermatitis, skin cancer, and hair growth disorders [19][20][21]. ...
In this study, drug carrier nanoparticles comprised of Pluronic-F127 and cannabidiol (CBD) or cannabigerol (CBG) were developed, and their wound healing action was studied. They were further incorporated in 3D printed films based on sodium alginate. The prepared films were characterized morphologically and physicochemically and used to evaluate the drug release profiles of the nanoparticles. Additional studies on their water loss rate, water retention capacity, and 3D-printing shape fidelity were performed. Nanoparticles were characterized physicochemically and for their drug loading performance. They were further assessed for their cytotoxicity (MTT Assay) and wound healing action (Cell Scratch Assay). The in vitro wound-healing study showed that the nanoparticles successfully enhanced wound healing in the first 6 h of application, but in the following 6 h they had an adverse effect. MTT assay studies revealed that in the first 24 h, a concentration of 0.1 mg/mL nanoparticles resulted in satisfactory cell viability, whereas CBG nanoparticles were safe even at 48 h. However, in higher concentrations and after a threshold of 24 h, the cell viability was significantly decreased. The results also presented mono-disperse nano-sized particles with diameters smaller than 200 nm with excellent release profiles and enhanced thermal stability. Their entrapment efficiency and drug loading properties were higher than 97%. The release profiles of the active pharmaceutical ingredients from the films revealed a complete release within 24 h. The fabricated 3D-printed films hold promise for wound healing applications; however, more studies are needed to further elucidate their mechanism of action.
... CBD potentially has high medicinal value and has been reported to be of therapeutic benefit in many types of disease, such as cancer, anxiety, schizophrenia, and immune system disorders [106,[146][147][148][149]. However, the oral bioavailability of CBD is limited by its poor water solubility and substantial hepatic first pass metabolism, whereby it is metabolised by oxidation predominantly by CYP3A4 and CYP2C19 [150,151]. ...
Lipid-based formulations play a significant role in oral delivery of lipophilic drugs. Previous studies have shown that natural sesame oil promotes the intestinal lymphatic transport and oral bioavailability of highly lipophilic drug cannabidiol (CBD). However, both lymphatic transport and systemic bioavailability were also associated with considerable variability. The first aim of this thesis was to test the hypothesis that pre-digested lipid formulations (oleic acid, linoleic acid, oleic acid with 2-oleoylglycerol, oleic acid with 2-oleoylglycerol and oleic acid with glycerol) could reduce variability and increase the extent of the intestinal lymphatic transport and oral bioavailability of CBD. In vivo studies in rats showed that pre-digested or purified triglyceride did not improve the lymphatic transport and bioavailability of CBD in comparison to sesame oil. Moreover, the results suggest that both the absorption of lipids and the absorption of co-administered CBD were more efficient following administration of natural sesame oil vehicle compared with pre-digested lipids or purified trioleate. However, this natural oil-based formulation also leads to considerable variability in absorption of CBD [1]. Therefore, the second approach in this thesis was to test the performance of lipid-based formulations with the addition of medium-chain triglyceride (MCT) or surfactants to the sesame oil vehicle in vitro and in vivo using CBD as a model drug. The in vitro lipolysis has shown that addition of the MCT leads to a higher distribution of CBD into the micellar phase. Further addition of surfactants to MCT-containing formulations did not improve distribution of the drug into the micellar phase. In vivo, formulations containing MCT led to lower or similar concentrations of CBD in serum, lymph and mesenteric lymph nodes (MLN), but with reduced variability. MCT improves the emulsification and micellar solubilisation of CBD, but surfactants did not facilitate further the rate and extent of lipolysis. Even though addition of MCT reduces the variability, the in vivo performance for the extent of both lymphatic transport and systemic bioavailability remains superior with a pure natural oil vehicle [2]. These results lead to the hypothesis that differences in composition of vegetable oils lead to differences in promotion of intestinal lymphatic transport of lipophilic drugs. Therefore, the differences in composition of sesame, sunflower, peanut, soybean, olive and coconut oils and their corresponding role as vehicles in promoting CBD lymphatic targeting and bioavailability were investigated in this thesis. The comparative analysis suggested that the fatty acids profile of vegetable oils is overall similar to the fatty acids profile in the corresponding chylomicrons in rat lymph. However, arachidonic acid (C20:4), was introduced to chylomicrons from endogenous nondietary sources in all cases. Overall, fatty acid composition of natural vegetable oils vehicles affected the intestinal lymphatic transport and bioavailability of CBD following oral administration in this work. Olive oil led to the highest concentration of CBD in the lymphatic system and systemic circulation and low variability in comparison to other natural vegetable oils following oral administration in rats. The natural rapeseed oil bodies also used as lipid-based vehicles to facilitate CBD oral bioavailability and lymphatic transport in this thesis. The oral bioavailability of CBD was 1.7-fold higher in oil bodies-based formulation than rapeseed oil-based formulation in rats. This finding indicates that oil bodies could potentially to improve lipophilic drug systemic exposure and lymphatic targeting in comparison to simple oils, and their other pharmaceutical properties as a drug delivery carrier needs to be further investigated. Overall in this thesis, olive oil and oil bodies are preferred lipid vehicles for improving intestinal lymphatic transport and bioavailability of co-administered CBD following oral administration.
... D-9-THC is a partial agonist at both the type 1 and type 2 cannabinoid (CB) receptors [8,9] and is believed to be the primary driver of most behavioral effects associated with acute cannabis administration (e.g., euphoria, "high," increased appetite, memory impairment; [10]). CBD has increased in popularity in recent years due to its purported therapeutic effects for myriad health conditions (e.g., autism, anxiety, posttraumatic stress disorder; pain; [8,11,12]). CBD has multiple mechanisms of action, with evidence that CBD interacts with GPR55, TRPV1, and 5-HT1A receptors [8,9]. ...
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Purpose of Review With cannabis legalization expanding throughout the world, an unprecedented number of people now have access to legal cannabis. This expanded legalization has also created an extensive retail market that includes a litany of cannabis products, which vary on factors such as chemical profile (i.e., chemotype), formulation, and intended route of administration. Despite increases in cannabis access and product variety, research on the effects of product and user characteristics on drug effect profiles is limited. Recent Findings Controlled laboratory studies are important because they can reveal what factors influence the pharmacokinetic (PK) and pharmacodynamic (PD; e.g., subjective, cognitive, psychological) effects of cannabis and its principal constituents D-9-tetrahydrocannbinol (D-9-THC) and cannabidiol (CBD). In this review, we describe the various product (e.g., chemotype, route of administration) and user factors (e.g., frequency of use, sex, and age) that influence the PK and PD effects of cannabis. Summary Understanding the factors that impact the PK/PD profile of cannabis could be used to promote more consistency in drug effects, as well as cannabinoid delivery for medical purposes. Furthermore, such knowledge is key to informing eventual regulatory actions and dosing guidelines for cannabis products.
... Contrary to THC, CBD attenuates anxiety in both pre-clinical and clinical studies. [67][68][69] The addition of CBD to THC might even prevent serious adverse effects from THC, such as paranoid psychosis. 70,71 An optimal dose of THC or CBD has not been established. ...
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Background: Cannabinoids have been suggested to alleviate frequently experienced symptoms of reduced mental well-being such as anxiety and depression. Mental well-being is an important subdomain of health-related quality of life (HRQoL). Reducing symptoms and maintaining HRQoL are particularly important in malignant primary brain tumor patients, as treatment options are often noncurative and prognosis remains poor. These patients frequently report unprescribed cannabinoid use, presumably for symptom relieve. As studies on brain tumor patients specifically are lacking, we performed a meta-analysis of the current evidence on can-nabinoid efficacy on HRQoL and mental well-being in oncological and neurological patients. Methods: We performed a systematic PubMed, PsychINFO, Embase, and Web of Science search according to PRISMA guidelines on August 2 and 3, 2021. We included randomized controlled trials (RCTs) that assessed the effects of tetrahydrocannabinol (THC) or cannabidiol (CBD) on general HRQoL and mental well-being. Pooled effect sizes were calculated using Hedges g. Risk of bias of included studies was assessed using Cochrane's Risk of Bias tool. Results: We included 17 studies: 4 in oncology and 13 in central nervous system (CNS) disease. Meta-analysis showed no effect of cannabinoids on general HRQoL (g = À0.02 confidence interval [95% CI À0.11 to 0.06]; p = 0.57) or mental well-being (g = À0.02 [95% CI À0.16 to 0.13]; p = 0.81). Conclusions: RCTs in patients with cancer or CNS disease showed no effect of cannabinoids on HRQoL or mental well-being. However, studies were clinically heterogeneous and since many glioma patients currently frequently use cannabinoids, future studies are necessary to evaluate its value in this specific population.
Habits are inflexible behaviors that persist despite changes in outcome value. While habits allow for efficient responding, neuropsychiatric diseases such as drug addiction and obsessive-compulsive disorder are characterized by overreliance on habits. Recently, the commercially popular drug cannabidiol (CBD) has emerged as a potential treatment for addictive behaviors, though it is not entirely clear how it exerts this therapeutic effect. As brain endocannabinoids play a key role in habit formation, we sought to determine how CBD modifies goal-directed behaviors and habit formation. To explore this, mice were administered CBD (20 mg/kg i.p.) or vehicle as a control and trained on random interval (RI30/60) or random ratio (RR10/20) schedules designed to elicit habitual or goal-directed lever pressing, respectively. Mice were tested for habitual responding using probe trials following reinforcer-specific devaluation as well as omission trials, where mice had to withhold responding to earn rewards. We found that while CBD had little effect on operant behaviors or reward devaluation, CBD inhibited goal-directed behavior in a sex-specific and contextdependent manner during the omission task. Beyond drug treatment, we found an effect of sex throughout training, reward devaluation, and omission. This work provides evidence that CBD has no effect on habit formation in a reward devaluation paradigm. However, the omission results suggest that CBD may slow learning of novel actionoutcome contingencies or decrease goal-directed behavior. This work calls for further examination of sex-dependent outcomes of CBD treatment and highlights the importance of investigating sex effects in habit-related experiments.
Zusammenfassung Die medizinische Verwendung von Cannabis hat in den letzten Jahren in Europa und Nordamerika an Popularität gewonnen. Cannabinoide sind sowohl als Fertigarzneimittel als auch in Blüten- und Extraktform verfügbar. Der vorliegende Artikel legt den Fokus auf die supportive Therapie onkologischer Patienten. Mögliche Indikationen sind Schmerzen, Chemotherapie-bedingte Übelkeit und Erbrechen, Appetitlosigkeit und Geschmacksveränderungen. Trotz des enormen Hypes um Cannabis als Medizin ist die Evidenz für dessen Anwendung bei onkologischen Patienten unzureichend. Palliativpatienten mit refraktären Symptomen könnten jedoch geeignete Kandidaten für einen Therapieversuch darstellen. Der entscheidende Parameter für die Auswahl eines Cannabis-Arzneimittels ist die THC/CBD-Ratio. Orale Einnahmeformen bieten sich gerade für Cannabis-naive und ältere Patienten an. Psychische und kardiovaskuläre Nebenwirkungen sind nicht zu unterschätzen.
In psychostimulant drug addiction, relapse is the most concerning outcome to be managed, considering there is no approved treatment for this neuropsychiatric condition. Here, we investigated the effects of the CBD treatment on the relapse behavior triggered by stress, after being submitted to the amphetamine (AMPH)-induced conditioned place preference (CPP) in rats. To elucidate the mechanisms of action underlying the CBD treatment, we evaluated the neuroadaptations on dopaminergic and endocannabinoid targets in the ventral striatum (VS) and ventral tegmental area (VTA) of the brain. Animals received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the CPP paradigm for 8 days. Following the first CPP test, animals were treated with CBD (10 mg/kg, i.p.) or its vehicle for 5 days and subsequently submitted to forced swim stress protocol to induce AMPH-CPP relapse. Behavioral findings showed that CBD treatment prevented AMPH-reinstatement, also exerting anxiolytic activity. At the molecular level, in the VTA, CBD restored the CB1R levels decreased by AMPH-exposure, increased NAPE-PLD, and decreased FAAH levels. In the VS, the increase of D1R and D2R, as well as the decrease of DAT levels induced by AMPH were restored by CBD treatment. The current outcomes evidence a substantial preventive action of the CBD on the AMPH-reinstatement evoked by stress, also involving neuroadaptations in both dopaminergic and endocannabinoid systems in brain areas closely involved in the addiction. Although further studies are needed, these findings support the therapeutic potential of CBD in AMPH-relapse prevention.
Background: An oral route of administration for tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) eliminates the harmful effects of smoking and has potential for efficacious cannabis delivery for therapeutic and recreational applications. We investigated the pharmacokinetics of CBD, Δ9-THC, 11-OH-THC, and 11-nor-9-carboxy-Δ9-THC (THC-COOH) in a novel oral delivery system, Solutech™, compared to medium-chain triglyceride-diluted cannabis oil (MCT-oil) in a healthy population. Materials and Methods: Thirty-two participants were randomized and divided into two study arms employing a comparator-controlled, parallel-study design. To evaluate the pharmacokinetics of Δ9-THC, CBD, 11-OH-THC, and THC-COOH, blood was collected at pre-dose (t=0) and 10, 20, 30, and 45, min and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, and 48 h post-dose after a single dose of Solutech (10.0 mg Δ9-THC, 9.76 mg CBD) or MCT (10.0 mg Δ9-THC, 9.92 mg CBD). Heart rate and blood pressure were measured at 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 h. Relationships between cannabis use history, body mass index, sex, and pharmacokinetic parameters were investigated. Safety was assessed before and at 48 h post-acute dose. Results: Acute consumption of Solutech provided a significantly greater maximum concentration (Cmax), larger elimination and absorption rate constants, faster time to Cmax and lag time, and half-life for all analytes compared to MCT-oil (p<0.001). In addition, cannabis use history had a significant influence on the pharmacokinetic parameters of CBD, Δ9-THC, 11-OH-THC, and THC-COOH. On average, participants with later age of first use had higher Δ9-THC, CBD, and THC-COOH Cmax and later time-to-Cmax and half-life for Δ9-THC, CBD, THC-COOH, and 11-OH-THC than those with earlier age of first use (p≤0.032). Those with more years of recreational cannabis use had higher area under the curve for Δ9-THC and CBD, Cmax for CBD, and longer 11-OH-THC half-life than those with less (p≤0.048). Conclusion: This study demonstrated that consumption of Solutech enhanced most pharmacokinetics parameters measured compared to MCT-oil. Participant's cannabis use history, including their age of first use and number of years using cannabis significantly impacted pharmacokinetic parameters investigated. Acute consumption of both products was found to be safe and well tolerated. The results suggest that Solutech may optimize bioavailability from cannabis formulations.
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The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.
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Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses. Interestingly, neither AM251, JZL184, nor PF3845 affected CB1-positive dendritic interneuron synapses. Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity. Tonic cannabinoid signaling plays a critical role in the regulation of synaptic transmission. However, the mechanistic details of how persistent CB1 cannabinoid receptor activity inhibits neurotransmitter release have remained elusive. Therefore, electrophysiological recordings, lipid measurements, and super-resolution imaging were combined to elucidate those signaling molecules and mechanisms that underlie tonic cannabinoid signaling. The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions. Copyright © 2015 Lee et al.
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The contribution of two major endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), in the regulation of fear expression is still unknown. We analyzed the role of different players of the endocannabinoid system on the expression of a strong auditory-cued fear memory in male mice by pharmacological means. The cannabinoid receptor type 1 (CB1) antagonist SR141716 (3 mg/kg) caused an increase in conditioned freezing upon repeated tone presentation on three consecutive days. The cannabinoid receptor type 2 (CB2) antagonist AM630 (3 mg/kg), in contrast, had opposite effects during the first tone presentation, with no effects of the transient receptor potential vanilloid receptor type 1 (TRPV1) antagonist SB366791 (1 and 3 mg/kg). Administration of the CB2 agonist JWH133 (3 mg/kg) failed to affect the acute freezing response, whereas the CB1 agonist CP55,940 (50 μg/kg) augmented it. The endocannabinoid uptake inhibitor AM404 (3 mg/kg), but not VDM11 (3 mg/kg), reduced the acute freezing response. Its co-administration with SR141716 or SB366791 confirmed an involvement of CB1 and TRPV1. AEA degradation inhibition by URB597 (1 mg/kg) decreased, while 2-AG degradation inhibition by JZL184 (4 and 8 mg/kg) increased freezing response. As revealed in conditional CB1-deficient mutants, CB1 on cortical glutamatergic neurons alleviates whereas CB1 on GABAergic neurons slightly enhances fear expression. Moreover, 2-AG fear-promoting effects depended on CB1 signaling in GABAergic neurons, while an involvement of glutamatergic neurons remained inconclusive due to the high freezing shown by vehicle-treated Glu-CB1-KO. Our findings suggest that increased AEA levels mediate acute fear relief, whereas increased 2-AG levels promote the expression of conditioned fear primarily via CB1 on GABAergic neurons.
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Introduction: Posttraumatic stress disorder (PTSD) is a prevalent, chronic and disabling anxiety disorder that may develop following exposure to a traumatic event. There is currently no effective pharmacotherapy for PTSD and therefore the discovery of novel, evidence-based treatments is particularly important. This review of potential novel treatments could act as a catalyst for further drug investigation. Areas covered: In this review, the authors discuss the heterogeneity of PTSD and why this provides a challenge for discovering effective treatments for this disorder. By searching for the neurobiological systems that are disrupted in individuals with PTSD and their correlation with different symptoms, the authors propose potential pharmacological treatments that could target these symptoms. They discuss drugs such as nabilone, d-cycloserine, nor-BNI, 7,8-dihydroxyflavone and oxytocin (OT) to target systems such as cannabinoids, glutamate, opioids, brain-derived neurotrophic factor and the OT receptor, respectively. While not conclusive, the authors believe that these brain systems include promising targets for drug discovery. Finally, the authors review animal studies, proof-of-concept studies and case studies that support our proposed treatments. Expert opinion: A mechanism-based approach utilizing techniques such as in vivo neuroimaging will allow for the determination of treatments. Due to the heterogeneity of the PTSD phenotype, focusing on symptomology rather than a categorical diagnosis will allow for more personalized treatment. Furthermore, there appears to be a promise in drugs as cognitive enhancers, the use of drug cocktails and novel compounds that target specific pathways linked to the etiology of PTSD.
Independent discoveries in several laboratories suggest that the midbrain periaqueductal gray (PAG), the cell-dense region surrounding the midbrain aqueduct, contains a previously unsuspected degree of anatomical and functional organization. This organization takes the form of longitudinal columns of afferent inputs, output neurons and intrinsic interneurons. Recent evidence suggests: that the important functions that are classically associated with the PAG--defensive reactions, analgesia and autonomic regulation--are integrated by overlapping longitudinal columns of neurons; and that different classes of threatening or nociceptive stimuli trigger distinct co-ordinated patterns of skeletal, autonomic and antinociceptive adjustments by selectively targeting specific PAG columnar circuits. These findings call for a fundamental revision in our concept of the organization of the PAG, and a recognition of the special roles played by different longitudinal PAG columns in co-ordinating distinct strategies for coping with different types of stress, threat and pain.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
In order to compare the effects of cannabidiol (CBD) and diazepam, both drugs were tested on neophobia, food-intake and conflict behavior. CBD was ineffective to show an anti-neophobic action, to increase food intake, or to attenuate conflict behavior. On the other hand, diazepam produced clear antineophobic effects, increased food intake above control levels, and elevated conflict response rates. Judging from the present results, CBD may not be considered a benzodiazepine-like drug, although it have showed, in other experimental situations, pharmacological properties resembling those of the benzodiazepines. However, a possible anti-anxiety action of CBD could not be discarded, as its generalized depressor effects on behavior might be interfering with such an action in the present experiments.
Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and endocannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-endocannabionoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. This explosive escape behaviour was followed by significant antinociception. Cannabidiol microinjection into the SNpr had a clear anti-aversive effect, decreasing the duration of defensive alertness, the frequency and duration of defensive immobility, and the frequency and duration of explosive escape behaviour, expressed by running and jumps, elicited by transitory GABAergic dysfunction in dlSC. However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signaling in cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways. Copyright © 2015. Published by Elsevier B.V.
Although the medial subdivision of the central nucleus of the amygdala (CeM) and serotonin-1A (5-HT1A) receptors are involved in the regulation of anxiety, their roles in Parkinson's disease (PD)-associated anxiety are still unknown. Here we assessed the importance of CeM 5-HT1A receptors for anxiety in rats with unilateral 6-hydroxydopamine (6-OHDA) lesion of the medial forebrain bundle (MFB). The lesion induced anxiety-like behaviors, increased the firing rate and burst-firing pattern of CeM γ-aminobutyric acid (GABA) neurons, as well as decreased dopamine (DA) levels in the striatum, medial prefrontal cortex (mPFC), amygdala and ventral part of hippocampus (vHip). Intra-CeM injection of the selective 5-HT1A receptor agonist 8-OH-DPAT produced anxiolytic effects in the lesioned rats, and decreased the firing rate of CeM GABAergic neurons in two groups of rats. Compared to sham-operated rats, the duration of the inhibitory effect on the firing rate of GABAergic neurons was shortened in the lesioned rats. The injection increased DA levels in the mPFC and amygdala in two groups of rats and the vHip in the lesioned rats, and increased 5-HT level in the lesioned rats, whereas it decreased NA levels in the mPFC in two groups of rats and the vHip in the lesioned rats. Moreover, the mean density of 5-HT1A receptor and GABA double-labeled neurons in the CeM was reduced after the lesioning. These results suggest that activation of CeM 5-HT1A receptor produces anxiolytic effects in the 6-OHDA-lesioned rats, which involves decreased firing rate of the GABAergic neurons, and changed monoamine levels in the limbic and limbic-related brain regions. Copyright © 2015. Published by Elsevier Ltd.