Neurotherapeutics

, Volume 12, Issue 4, pp 825–836 | Cite as

Cannabidiol as a Potential Treatment for Anxiety Disorders

  • Esther M. Blessing
  • Maria M. Steenkamp
  • Jorge Manzanares
  • Charles R. Marmar
Review

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 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.

Keywords

Cannabidiol Endocannabinoids Anxiety Generalized anxiety disorder Post-traumatic stress disorder 

Introduction

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 neuropsychiatric disorders, including generalized anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and obsessive–compulsive disorder (OCD). Notably, PTSD and OCD are no longer classified as anxiety disorders in the recent revision of the Diagnostic 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 unemployment and relationship breakdown, and elevated suicide risk [1, 2, 3]. 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 serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, benzodiazepines, monoamine oxidase inhibitors, tricyclic antidepressant drugs, and partial 5-hydroxytryptamine (5-HT)1A receptor agonists. Anticonvulsants and atypical antipsychotics are also used to treat PTSD. These medications are associated with limited response rates and residual symptoms, particularly in PTSD, and adverse effects may also limit tolerability and adherence [7, 8, 9, 10]. 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 ∆9-tetrahydrocannabinol (THC). CBD has broad therapeutic properties across a range of neuropsychiatric disorders, stemming from diverse central nervous system actions [11, 12]. In recent years, CBD has attracted increasing interest as a potential anxiolytic treatment [13, 14, 15]. The purpose of this review is to assess evidence from current preclinical, clinical, and epidemiological studies pertaining to the potential risks and benefits of CBD as a treatment for anxiety disorders.

Methods

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 “cannabidiol” and “anxiety” or “fear” or “stress” or “anxiety disorder” or “generalized anxiety disorder” or “social anxiety disorder” or “social phobia” or “post-traumatic stress disorder” or “panic disorder” or “obsessive compulsive 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 studies that assessed CBD’s effects on anxiety symptoms, or the potential protective effects of CBD on anxiety symptoms induced 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, a species of the Cannabis 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, responsible 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 properties, including antipsychotic, analgesic, neuroprotective, anticonvulsant, antiemetic, antioxidant, anti-inflammatory, antiarthritic, and antineoplastic properties (see [11, 12, 16, 17, 18, 19] 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 interactions with several receptors known to regulate fear and anxiety-related behaviors, specifically the cannabinoid type 1 receptor (CB1R), the serotonin 5-HT1A receptor, and the transient receptor potential (TRP) vanilloid type 1 (TRPV1) receptor [1112, 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 equilibrative nucleoside transporter, the adenosine transporter, additional TRP channels, and glycine receptors [1112, 19, 21]. In the current review of primary studies, the following receptor-specific actions were found to have been investigated as potential mediators of CBD’s anxiolytic action: CB1R, TRPV1 receptors, and 5-HT1A receptors. Pharmacology relevant to these actions is detailed below.

The Endocannabinoid System

Following cloning of the endogenous receptor for THC, namely the CB1R, endogenous CB1R ligands, or “endocannabinoids” (eCBs) were discovered, namely anandamide (AEA) and 2-arachidonoylglycerol (reviewed in [22]). The CB1R is an inhibitory Gi/o 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 Ca2+ influx, via cleavage of membrane phospholipids. The primary mechanism by which eCBs regulate synaptic function is retrograde signaling, wherein eCBs produced by depolarization of the postsynaptic neuron activate presynaptic CB1Rs, leading to inhibition of neurotransmitter release [23]. The “eCB system” includes AEA and 2-arachidonoylglycerol; their respective degradative enzymes fatty acid amide hydroxylase (FAAH) and monoacylglycerol lipase; the CB1R and related CB2 receptor (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 functionally interact with CB1R 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 release [25]. The TRPV1 receptor is a postsynaptic cation channel that underlies sensation of noxious heat in the periphery, with capsacin (hot chili) as an exogenous ligand. TRPV1 receptors 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, particularly highly aversive events [29, 30]. Activation of CB1Rs produces anxiolytic effects in various models of unconditioned fear, relevant to multiple anxiety disorder symptom domains (reviewed in [30, 31, 32, 33]). Regarding conditioned fear, the effect of CB1R activation is complex: CB1R activation may enhance or reduce fear expression, depending on brain locus and the eCB ligand [34]; however, CB1R activation potently enhances fear extinction [35], and can prevent fear reconsolidation. Genetic manipulations that impede CB1R activation are anxiogenic [35], and individuals with eCB system gene polymorphisms that reduce eCB tone—for example, FAAH gene polymorphisms—exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation [36]. Reduction of AEA–CB1R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [37], and CB1R 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 CB1R availability and reduced peripheral AEA, suggestive of reduced eCB tone [42].

Accordingly, CB1R activation has been suggested as a target for anxiolytic drug development [15, 43, 44]. Proposed agents for enhancing CB1R activation include THC, which is a potent and direct agonist; synthetic CB1R agonists; FAAH inhibitors and other agents that increase eCB availability, as well as nonpsychoactive cannabis phytocannabinoids, including CBD. While CBD has low affinity for the CB1R, it functions as an indirect agonist, potentially via augmentation of CB1R 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 CB1R-activating agents to serve as anxiolytic drugs. First, CB1R 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 CB1R 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, potentially by interfering with AEA inactivation [48]. In addition to dose-dependent activation of TRPV1 channels, the anxiogenic versus anxiolytic balance of CB1R agonists also depends on dynamic factors, including environmental stressors [33, 49].

5-HT1A Receptors

The 5-HT1A receptor (5-HT1AR) is an established anxiolytic target. Buspirone and other 5-HT1AR agonists are approved for the treatment of GAD, with fair response rates [50]. In preclinical studies, 5-HT1AR 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-HT1ARs are coupled to various members of the Gi/o 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-HT1AR 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-HT1AR agonist [57], in vivo studies are more consistent with CBD acting as an allosteric modulator, or facilitator of 5-HT1A signaling [58].

Preclinical Evaluations

Generalized Anxiety Models

Relevant studies in animal models are summarized in chronological 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 1 for the anxiolytic 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 dose–response curve, with anxiolytic 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 systemic 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 effects in others.
Table 1

Preclinical studies

Study

Animal

Route

Dose

Model

Effect

Receptor Involvement

Silveira Filho et al. [59]

WR

i.p.

100 mg/kg,

acute

GSCT

No effect

NA

Zuardi et al. [60]

WR

i.p.

10 mg/kg,

acute

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, 5.0 and 10.0 mg/kg, acute

VCT

Anxiolytic

Effect unchanged by IP flumazenil

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

CFC

extinction

Anxiolytic

Extinction effect ↓ by SR141716A but not capsazepine

EPM 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,

↓ Pressor

↓ Tachycardia

All effects ↓ by systemic WAY100635

EPM 24 h

following RS

Anxiolytic

Soares et al. [68]

WR

dlPAG

15, 30 or 60 nmol, acute

ETM

Anxiolytic

Panicolytic

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, 50 mg/kg, chronic, daily/21 d

EPM

No effect

NA

L-DT

1 mg/kg

anxiolytic

SI

No effect

OF

50 mg/kg anxiolytic

Lemos et al. [70]

WR

i.p.

PL

IL

10 mg/kg IP, 30 nmol intra-PL and intra-IL, acute

CFC

IP and PL anxiolytic IL anxiogenic

NA

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 WAY100635

Gomes et al. [72]

WR

BNST

15, 30, and 60 nmol, acute

EPM

Anxiolytic

Both effects ↓ by intra BNST WAY100635

VCT

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.

Oral

120 mg/kg, acute

MBT

Anticompulsive

NA

Uribe-Marino et al. [75]

SM

i.p.

0.3, 3.0, 30.0 mg/kg, acute

PS

Panicolytic

NA

Stern et al. [76]

WR

i.p.

3, 10, 30 mg/kg

immediately after retrieval, acute

Reconsolidation blockade

Anxiolytic

1 and 7 d old fear memories disrupted

Effect ↓ by AM251 but not WAY100635

Campos et al. [77]

WR

i.p.

5 mg/kg, subchronic, daily/7 d

EPM following PS

Anxiolytic

Effects ↓ by IP WAY100635

Hsiao et al. [78]

WR

CeA

μg/μl

REM sleep time

↓ REM sleep suppression

NA

EPM

Anxiolytic

OF

Anxiolytic

Gomes et al. [79]

WR

BNST

15, 30, 60 nmol, acute

CFC

Anxiolytic

Both effects ↓ by intra-BNST WAY100635

El Batsh et al. [80]

LE-H R

i.p.

10 mg/kg, chronic,

daily/14 d

CFC

Anxiogenic

NA

Campos et al. [81]

C57BL/6 mice

i.p.

30 mg/kg 2 h after CUS,

chronic daily/14 d

EPM

Anxiolytic

Both effects ↓ by AM251

NSF

Anxiolytic

Do Monte et al. [82]

L-E HR

IL

1 μg or 0.4 μg/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.

5 mg/kg, chronic, daily/21 d

ETM

Anxiolytic

Panicolytic

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

BNST

30 and 60 nmol, acute

RS

Anxiogenic

↑ Tachydardia

Effect ↓ by WAY100635

Twardowschy et al. [86]

SM

i.p.

3 mg/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 WAY100635

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

5 μg/0.2 μl

GABAA blockade in dlSC

Panicolytic

Both effects ↓ by AM251

Effective doses are in bold

Receptor specific agents: AM251 = cannabinoid receptor type 1 (CB1R) inverse agonist; WAY100635 = 5-hydroxytryptamine 1A antagonist; SR141716A = CB1R antagonist; rimonabant = CB1R antagonist; capsazepine = transient receptor potential vanilloid type 1 antagonist; naloxone = opioid antagonist; flumazenil = GABAA 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; GABAA blockade in dlSC = defensive immobility, and explosive escape; PAG-E-Stim = increased threshold for escape; PS = reduced explosive escape

WR = Wistar rats; SM = Swiss mice; L-E HR = Long–Evans 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 = Geller–Seifter 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 = light–dark test; SI = social interaction; OF = open field; MBT = marble-burying test; PS = predator stress; NSF = novelty suppressed feeding test; GABAA = γ-aminobutyric acid receptor A; dlSC = deep layers superior colliculus; REM = rapid eye movement; NA = not applicable

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]. Microinjection of CBD into the DPAG produced anxiolytic effects in the EPM, VGC, and ETM that were partially mediated by activation of 5-HT1ARs but not by CB1Rs [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 microinjection into the BNST, where they depended on 5-HT1AR activation [79], and also upon microinjection into the central 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-HT1AR receptor activation; however, following acute restraint stress, CBD was anxiolytic [87]. Finally, the anxiolytic effects of systemic CBD partially depended on GABAA 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 response curve, with higher doses being ineffective. This may reflect activation of TRPV1 receptors at higher dose, as blockade 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, CBD’s interaction with TRPV1 receptors to some extent impedes anxiolytic actions, although was notably not sufficient to produce anxiogenic effects.

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 increases 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-HT1AR activation [67, 73]. However intra-BNST microinjection of CBD augmented stress-induced heart rate increase, also partially via 5-HT1AR activation [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, partially via 5-HT1AR activation [77]. In a chronic study, systemic CBD prevented increased anxiety produced by chronic unpredictable stress, in addition to increasing hippocampal AEA; these anxiolytic effects depended upon CB1R activation and hippocampal neurogenesis, as demonstrated by genetic ablation techniques [81]. Prior stress also appears to modulate CBD’s 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-HT1AR activation but were not affected by CB1R blockade. CBD was also panicolytic in the predator–prey model, which assesses explosive escape and defensive immobility in response to a boa constrictor snake, also partially via 5-HT1AR activation; however, more consistent with an anxiogenic effect, 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 CB1Rs, decreased defensive immobility and explosive escape caused by bicuculline-induced neuronal activation in the superior colliculus [89]. Anticompulsive effects of CBD were investigated in marble-burying behavior, conceptualized to model OCD [96]. Acute systemic CBD reduced marble-burying behavior for up to 7 days, with no attenuation in effect up to high (120 mg/kg) doses, and effect shown to depend on CB1Rs but not 5-HT1ARs [71, 74, 88].

Contextual Fear Conditioning, Fear Extinction, and Reconsolidation Blockade

Several studies assessed CBD using contextual fear conditioning. 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 responses. Systemic administration of CBD prior to CS re-exposure reduced conditioned cardiovascular responses [63], an effect reproduced by microinjection of CBD into the BNST, and partially mediated by 5-HT1AR activation [79]. Similarly, CBD in the prelimbic cortex reduced conditioned freezing [70], an effect prevented by 5-HT1AR blockade [87]. By contrast, CBD microinjection in the infralimbic cortex enhanced conditioned freezing [70]. Finally, El Batsh et al. [80] reported that repeated CBD doses over 21 days, that is chronic as opposed to acute treatment, facilitated conditioned 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 training 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 administration immediately before training markedly enhanced extinction, and this effect depended on CB1R activation, without involvement of TRPV1 receptors [65]. Further studies showed CB1Rs in the infralimbic cortex may be involved in this effect [82].

CBD also blocked reconsolidation of aversive memories in rat [76]. Briefly, fear memories, when reactivated by re-exposure (retrieval), enter into a labile state in which the memory trace may either be reconsolidated or extinguished [97], and this process may be pharmacologically modulated to achieve reconsolidation blockade or extinction. When administered immediately following retrieval, CBD prevented freezing to the conditioned context upon further re-exposure, and no reinstatement or spontaneous recovery was observed over 3 weeks, consistent with reconsolidation blockade rather than extinction [76]. This effect depended on CB1R activation but not 5-HT1AR activation [76].

Summary and Clinical Relevance

Overall, existing preclinical evidence strongly supports the potential of CBD as a treatment for anxiety disorders. 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 extinction, reconsolidation blockade, and prevention of the long-term anxiogenic effects of stress. Activation of 5-HT1ARs appears to mediate anxiolytic and panicolytic effects, in addition to reducing conditioned fear expression, although CB1R activation may play a limited role. By contrast, CB1R activation appears to mediate CBD’s anticompulsive effects, enhancement of fear extinction, reconsolidation blockade, and capacity to prevent the long-term anxiogenic consequences of stress, with involvement of hippocampal neurogenesis.

While CBD predominantly has acute anxiolytic effects, some species discrepancies are apparent. In addition, 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, including THC, direct CB1R agonists and FAAH inhibitors, is a lack of anxiogenic effects at a higher dose. Further receptor-specific studies may elucidate the receptor 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 relatively few relevant studies exist, with mixed results, including 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 distinct from other agents that enhance CB1R 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 context 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 administered 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 simulated public speaking test in healthy subjects, and in subjects with SAD, showing a comparable efficacy to ipsapirone (a 5-HT1AR agonist) or diazepam [98, 105]. CBD also reduced the presumed anticipatory anxiety associated with undergoing a single-photon emission computed tomography (SPECT) imaging 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 paradigm led to a trend-level enhancement in the reduction of skin conductance response during reinstatement, and a significant reduction in expectancy (of shock) ratings during reinstatement [106].
Table 2

Human psychological studies

Study

Subjects,

design

CBD route,

dose

Measure

Effect

Karniol et al. [99]

HV,

DBP

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 baseline

Zuardi et al., [100]

HV,

DBP

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,

DBP

Oral 300 mg,

acute, 80 min

VAMS, STAI and BP following SPST

↓ STAI scores

↓ VAMS scores

↓ BP

Martin-Santos et al. [101]

HV,

DBP

Oral 600 mg,

acute, 1, 2, 3 h

Baseline anxiety and pulse rate

No effect

Crippa et al. [102]

10 HV,

DBP

Oral 400 mg,

acute, 60 and 75 min

VAMS before SPECT

SPECT

↓ VAMS scores

Bhattacharyya et al. [103]

15 HV

DBP

Oral 600 mg,

acute, 1, 2, 3 h

STAI scores

VAMS scores

↓ STAI scores

↓ VAMS scores

Crippa et al. [104]

SAD and HC

DBP

Oral 400 mg,

acute, 75 and 140 min

VAMS before SPECT

SPECT

↓ VAMS scores

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

DBP

Inhaled, 32 mg, acute, immediately following, before, after extinction

SCR and shock expectancy following extinction

CBD after extinction training produced trend level reduction in SCR and decreased shock expectancy

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 = Δ9-tetrahydrocannabinol; STAI = Spielberger’s 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

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].
Table 3

Neuroimaging studies

Study

Subjects, design

CBD route, dose, timing

Measure

Effect of CBD

Crippa et al. [102]

10 HV,

DBP

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]

15 HV,

DBP

Oral 600 mg,

acute, 1–2 h

fMRI during oddball and go/no-go task

↓ Activation in left insula, STG and MTG

Fusar-Poli et al. [109]

15 HV,

DBP

Oral 600 mg,

acute, 1–2 h

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]

15 HV,

DBP

Oral 600 mg,

acute, 1–2 h

fMRI functional connectivity during fearful faces task

↓ Functional connectivity between L) AMY and ACC

Crippa et al. [104]

SAD and HC

DBP

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-blind placebo; 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

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 dependent functional magnetic resonance imaging activation, specifically 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 transverse temporal gyrus. The fearful faces task activates the amygdala, and other medial temporal areas involved in emotion processing, and heightened amygdala response activation 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 fluctuation, which was highly correlated with amygdala activation [109]. Dynamic causal modeling analysis in this data set further 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, including psychotic symptoms, drug cravings, memory loss, and hippocampal gray matter loss [115, 116, 117, 118] (reviewed in [119]). As THC acutely induces anxiety, this pattern may also be evident for chronic anxiety symptoms. Two studies were identified, including an uncontrolled retrospective study in civilian patients with PTSD patients [120], and a case study in a patient 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 treatment of anxiety symptoms, nor do any data exist regarding the potential protective effects of CBD on anxiety potentially induced 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 potential for the treatment of PTSD, or for enhancing cognitive behavioral therapy. Neuroimaging findings provide evidence of neurobiological targets that may underlie CBD’s 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 independent replication. Further studies are also required to establish whether chronic, in addition to acute CBD dosing is anxiolytic in human. Also, clinical findings are currently limited to SAD, whereas preclinical evidence suggests CBD’s potential to treat multiple symptom domains relevant to GAD, PD, and, particularly, PTSD.

Conclusions

Preclinical evidence conclusively demonstrates CBD’s efficacy in reducing anxiety behaviors relevant to multiple disorders, including PTSD, GAD, PD, OCD, and SAD, with a notable lack of anxiogenic effects. CBD’s anxiolytic actions appear to depend upon CB1Rs and 5-HT1ARs in several brain regions; however, investigation of additional receptor actions may reveal further mechanisms. Human experimental findings 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 studies are required to establish whether chronic dosing of CBD has similar effects in relevant clinical populations. Overall, this review emphasizes the potential value and need for further study of CBD in the treatment of anxiety disorders.

Notes

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2015_387_MOESM1_ESM.pdf (523 kb)
ESM 1(PDF 523 kb)
13311_2015_387_MOESM2_ESM.pdf (506 kb)
ESM 2(PDF 505 kb)
13311_2015_387_MOESM3_ESM.pdf (532 kb)
ESM 3(PDF 532 kb)
13311_2015_387_MOESM4_ESM.pdf (515 kb)
ESM 4(PDF 514 kb)

References

  1. 1.
    Kroenke K, Spitzer RL, Williams JB, Monahan PO, Lowe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med 2007;146:317-325.PubMedCrossRefGoogle Scholar
  2. 2.
    Khan A, Leventhal RM, Khan S, Brown WA. Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database. J Affect Disord 2002;68:183-190.PubMedCrossRefGoogle Scholar
  3. 3.
    Olatunji BO, Cisler JM, Tolin DF. Quality of life in the anxiety disorders: a meta-analytic review. Clin Psychol Rev 2007;27:572-581.PubMedCrossRefGoogle Scholar
  4. 4.
    Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:593-602.PubMedCrossRefGoogle Scholar
  5. 5.
    Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:629-640.PubMedCrossRefGoogle Scholar
  6. 6.
    Gustavsson A, Svensson M, Jacobi F, et al. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011;21:718-779.PubMedCrossRefGoogle Scholar
  7. 7.
    Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiary 2001;158:1989-1992.CrossRefGoogle Scholar
  8. 8.
    Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004;65:1696-1707.PubMedCrossRefGoogle Scholar
  9. 9.
    Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial. JAMA 2011;306:493-502.PubMedCrossRefGoogle Scholar
  10. 10.
    Shin HJ, Greenbaum MA, Jain S, Rosen CS. Associations of psychotherapy dose and SSRI or SNRI refills with mental health outcomes among veterans with PTSD. Psychiatr Serv 2014;65:1244-1248.PubMedCrossRefGoogle Scholar
  11. 11.
    Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009;30:515-527.PubMedCrossRefGoogle Scholar
  12. 12.
    Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimaraes FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci 2012;367:3364-3378.CrossRefGoogle Scholar
  13. 13.
    Schier ARD, Ribeiro NP, Silva AC, et al. Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Rev Bras Psiquiatr 2012;34:S104-S117.PubMedCrossRefGoogle Scholar
  14. 14.
    Schier ARD, de Oliveira Ribeiro NP, Coutinho DS, et al. Antidepressant-like and anxiolytic-like effects of cannabidiol: A chemical compound of Cannabis sativa. CNS Neurol Disord Drug Targets 2014;13:953-960.CrossRefGoogle Scholar
  15. 15.
    Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F. Endocannabinoid system and mood disorders: priming a target for new therapies. Pharmacol Ther 2013;138:18-37.PubMedCrossRefGoogle Scholar
  16. 16.
    Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO. Cannabidiol—recent advances. Chem Biodivers 2007;4:1678-1692.PubMedCrossRefGoogle Scholar
  17. 17.
    Marco EM, Garcia-Gutierrez MS, Bermudez-Silva FJ, et al. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects. Front Behav Neurosci 2011;5:63.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014;55:791-802.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Robson PJ, Guy GW, Di Marzo V. Cannabinoids and schizophrenia: therapeutic prospects. Curr Pharm Design 2014;20:2194-2204.CrossRefGoogle Scholar
  20. 20.
    Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 2011;6: 237-249.PubMedCrossRefGoogle Scholar
  21. 21.
    McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Delta(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 2015;172:737-753.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Di Marzo V, Bisogno T, De Petrocellis L. Anandamide: Some like it hot. Trends Pharmacol Sci 2001;22:346-349.PubMedCrossRefGoogle Scholar
  23. 23.
    Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science 2002;296: 678-682.PubMedCrossRefGoogle Scholar
  24. 24.
    Battista N, Di Tommaso M, Bari M, Maccarrone M. The endocannabinoid system: An overview. Front Behav Neurosci 2012;6:9.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Lee SH, et al. Multiple forms of endocannabinoid and endovanilloid signaling regulate the tonic control of GABA release. J Neurosci 2015;35:10039-10057.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Kauer JA, Gibson HE. Hot flash: TRPV channels in the brain. Trends Neurosci 2009;32:215-224.PubMedCrossRefGoogle Scholar
  27. 27.
    Aguiar DC, Moreira FA, Terzian AL, et al. Modulation of defensive behavior by transient receptor potential vanilloid type-1 (TRPV1) channels. Neurosci Biobehav Rev 2014;46:418-428.PubMedCrossRefGoogle Scholar
  28. 28.
    Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 2013;17:475-490.PubMedCrossRefGoogle Scholar
  29. 29.
    Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron 2012;76:70-81.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Riebe CJ, Pamplona FA, Kamprath K, Wotjak CT. Fear relief-toward a new conceptual frame work and what endocannabinoids gotta do with it. Neuroscience 2012;204:159-185.PubMedCrossRefGoogle Scholar
  31. 31.
    McLaughlin RJ, Hill MN, Gorzalka BB. A critical role for prefrontocortical endocannabinoid signaling in the regulation of stress and emotional behavior. Neurosci Biobehav Rev 2014;42:116-131.PubMedCrossRefGoogle Scholar
  32. 32.
    Moreira FA, Lutz B. The endocannabinoid system: emotion, learning and addiction. Addict Biol 2008;13:196-212.PubMedCrossRefGoogle Scholar
  33. 33.
    Ruehle S, Rey AA, Remmers F, Lutz B. The endocannabinoid system in anxiety, fear memory and habituation. J Psychopharmacol 2012;26:23-39.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Llorente-Berzal A, Terzian AL, di Marzo V, Micale V, Viveros MP, Wotjak CT. 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons. Psychopharmacology 2015;232: 2811-2825.PubMedCrossRefGoogle Scholar
  35. 35.
    Marsicano G, Wotjak CT, Azad SC, et al. The endogenous cannabinoid system controls extinction of aversive memories. Nature 2002;418:530-534.PubMedCrossRefGoogle Scholar
  36. 36.
    Dincheva I, Drysdale AT, Hartley CA. FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun 2015;6:6395.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Gray JM, Vecchiarelli HA, Morena M, et al. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci 2015;35:3879-3892.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Evanson NK, Tasker JG, Hill MN, Hillard CJ, Herman JP. Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling. Endocrinology 2010;151:4811-4819.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Abush H, Akirav I. Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory. Neuropsychopharmacology 2013;38:1521-1534.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Hill MN, Patel S, Carrier EJ, et al. Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress. Neuropsychopharmacology 2005;30;508-515.PubMedCrossRefGoogle Scholar
  41. 41.
    Qin Z, Zhou X, Pandey NR, et al. Chronic stress induces anxiety via an amygdalar intracellular cascade that impairs endocannabinoid signaling. Neuron 2015;85:1319-1331.PubMedCrossRefGoogle Scholar
  42. 42.
    Neumeister A. The endocannabinoid system provides an avenue for evidence-based treatment development for PTSD. Depress Anxiety 2013;30:93-96.PubMedCrossRefGoogle Scholar
  43. 43.
    Papini S, Sullivan GM, Hien DA, Shvil E, Neria Y. Toward a translational approach to targeting the endocannabinoid system in posttraumatic stress disorder: a critical review of preclinical research. Biol Psychol 2015;104:8-18.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Ragen BJ, Seidel J, Chollak C, Pietrzak RH, Neumeister A. Investigational drugs under development for the treatment of PTSD. Exp Opin Invest Drugs 2015;24:659-672.CrossRefGoogle Scholar
  45. 45.
    Viveros MP, Marco EM, File SE. Endocannabinoid system and stress and anxiety responses. Pharmacol Biochem Behav 2005;81:331-342.PubMedCrossRefGoogle Scholar
  46. 46.
    Rubino T, Realini N, Castiglioni C, et al. Role in anxiety behavior of the endocannabinoid system in the prefrontal cortex. Cereb Cortex 2008;18:1292-1301.PubMedCrossRefGoogle Scholar
  47. 47.
    Moreira FA, Aguiar DC, Terzian AL, Guimaraes FS, Wotjak CT. Cannabinoid type 1 receptors and transient receptor potential vanilloid type 1 channels in fear and anxiety-two sides of one coin? Neuroscience 2012;204:186-192.PubMedCrossRefGoogle Scholar
  48. 48.
    Bisogno T, Hanus L, De Petrocellis L, et al. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001;134:845-852.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Haller J, et al. Interactions between environmental aversiveness and the anxiolytic effects of enhanced cannabinoid signaling by FAAH inhibition in rats. Psychopharmacology 2009;204:607-616.PubMedCrossRefGoogle Scholar
  50. 50.
    Chessick CA, Allen MH, Thase M, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev 2006;CD006115.Google Scholar
  51. 51.
    Roncon CM, Biesdorf C, Coimbra NC, et al. Cooperative regulation of anxiety and panic-related defensive behaviors in the rat periaqueductal grey matter by 5-HT1A and mu-receptors. J Psychopharmacol 2013;27:1141-1148.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhou J, Cao X, Mar AC, et al. Activation of postsynaptic 5-HT1A receptors improve stress adaptation. Psychopharmacology 2014;231:2067-2075.PubMedCrossRefGoogle Scholar
  53. 53.
    Saito Y, Matsumoto M, Yanagawa Y, et al. Facilitation of fear extinction by the 5-HT(1A) receptor agonist tandospirone: possible involvement of dopaminergic modulation. Synapse 2013;67:161-170.PubMedCrossRefGoogle Scholar
  54. 54.
    Sprouse JS, Aghajanian GK. Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists. Synapse 1987;1:3-9.PubMedCrossRefGoogle Scholar
  55. 55.
    Sun YN, Wang T, Wang Y, et al. Activation of 5-HT receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease. Neuropharmacology 2015;95:181-191.PubMedCrossRefGoogle Scholar
  56. 56.
    Celada P, Bortolozzi A, Artigas F. Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: rationale and current status of research. CNS Drugs 2013;27:703-716.PubMedCrossRefGoogle Scholar
  57. 57.
    Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 2005;30:1037-1043.PubMedCrossRefGoogle Scholar
  58. 58.
    Rock EM, Bolognini D, Limebeer CL, et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol 2012;165:2620-2634.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Silveira Filho NG, Tufik S. Comparative effects between cannabidiol and diazepam on neophobia, food intake and conflict behavior. Res Commun Psychol Psychiatry Behav 1981;6:25-26.Google Scholar
  60. 60.
    Zuardi AW, Finkelfarb E, Bueno OF, Musty RE, Karniol IG. Characteristics of the stimulus produced by the mixture of cannabidiol with delta 9-tetrahydrocannabinol. Arch Int Pharmacodyn Ther 1981;249:137-146.PubMedGoogle Scholar
  61. 61.
    Onaivi ES, Green MR, Martin BR. Pharmacological characterization of cannabinoids in the elevated plus maze. J Pharmacol Exp Ther 1990;253:1002-1009.PubMedGoogle Scholar
  62. 62.
    Moreira FA, Aguiar DC, Guimaraes FS. Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1466-1471.PubMedCrossRefGoogle Scholar
  63. 63.
    Resstel LB, Joca SR, Moreira FA, Correa FM, Guimaraes FS. Effects of cannabidiol and diazepam on behavioral and cardiovascular responses induced by contextual conditioned fear in rats. Behav Brain Res 2006;172:294-298.PubMedCrossRefGoogle Scholar
  64. 64.
    Campos AC, Guimaraes FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 2008;199:223-230.CrossRefGoogle Scholar
  65. 65.
    Bitencourt RM, Pamplona FA, Takahashi RN. Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats. Eur Neuropsychopharmacol 2009;18:849-859.CrossRefGoogle Scholar
  66. 66.
    Campos AC, Guimaraes FS. 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 2009;33:1517-1521.PubMedCrossRefGoogle Scholar
  67. 67.
    Resstel LB, Tavares RF, Lisboa SF, et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 2009;156:181-188.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Soares Vde P, Campos AC, Bortoli VC, et al. Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav Brain Res 2010;213:225-229.PubMedCrossRefGoogle Scholar
  69. 69.
    Long LE, Chesworth R, Huang XF. A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol 2010;13:861-876.PubMedCrossRefGoogle Scholar
  70. 70.
    Lemos JI, Resstel LB, Guimaraes FS. Involvement of the prelimbic prefrontal cortex on cannabidiol-induced attenuation of contextual conditioned fear in rats. Behav Brain Res 2010;207:105-111.PubMedCrossRefGoogle Scholar
  71. 71.
    Casarotto PC, Gomes FV, Resstel LB, Guimaraes FS. Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behav Pharmacol 2010;21:353-358.PubMedCrossRefGoogle Scholar
  72. 72.
    Gomes FV, Resstel LB, Guimaraes FS. The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology (Berl) 2011;213:465-473.CrossRefGoogle Scholar
  73. 73.
    Granjeiro EM, Gomes FV, Guimaraes FS, Correa FM, Resstel LB. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress. Pharmacol Biochem Behav 2011;99:743-748.PubMedCrossRefGoogle Scholar
  74. 74.
    Deiana S, Watanabe A, Yamasaki Y. Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl) 2012;219:859-873.CrossRefGoogle Scholar
  75. 75.
    Uribe-Marino A, et al. 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 2012;37:412-421.PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Stern CA, Gazarini L, Takahashi RN, Guimaraes FS, Bertoglio LJ. On disruption of fear memory by reconsolidation blockade: evidence from cannabidiol treatment. Neuropsychopharmacology 2012;37:2132-2142.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Campos AC, Ferreira FR, Guimaraes FS. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors. J Psychiatr Res 2012;46:1501-1510.PubMedCrossRefGoogle Scholar
  78. 78.
    Hsiao YT, Yi PL, Li CL, Chang FC. Effect of cannabidiol on sleep disruption induced by the repeated combination tests consisting of open field and elevated plus-maze in rats. Neuropharmacology 2012;62:373-384.PubMedCrossRefGoogle Scholar
  79. 79.
    Gomes FV, Resstel LB, Guimaraes FS, et al. Cannabidiol injected into the bed nucleus of the stria terminalis reduces the expression of contextual fear conditioning via 5-HT1A receptors. J Psychopharmacol 2012;26:104-113.PubMedCrossRefGoogle Scholar
  80. 80.
    El Batsh MM, Assareh N, Marsden CA, Kendall DA. Anxiogenic-like effects of chronic cannabidiol administration in rats. Psychopharmacology (Berl) 2012;221:239-247.CrossRefGoogle Scholar
  81. 81.
    Campos AC, Ortega Z, Palazuelos J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 2013;16:1407-1419.PubMedCrossRefGoogle Scholar
  82. 82.
    Do Monte FH, Souza RR, Bitencourt RM, Kroon JA, Takahashi RN. Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors. Behav Brain Res 2013;250:23-27.PubMedCrossRefGoogle Scholar
  83. 83.
    Campos AC, de Paula Soares V, Carvalho MC, et al. Involvement of serotonin-mediated neurotransmission in the dorsal periaqueductal gray matter on cannabidiol chronic effects in panic-like responses in rats. Psychopharmacology (Berl) 2013;226:13-24.CrossRefGoogle Scholar
  84. 84.
    Almeida V, Levin R, Peres FF, et al. Cannabidiol exhibits anxiolytic but not antipsychotic property evaluated in the social interaction test. Prog Neuropsychopharmacol Biol Psychiatry 2013;41:30-35.PubMedCrossRefGoogle Scholar
  85. 85.
    Gomes FV, Alves FH, Guimaraes FS, et al. Cannabidiol administration into the bed nucleus of the stria terminalis alters cardiovascular responses induced by acute restraint stress through 5-HT(1)A receptor. Eur Neuropsychopharmacol 2013;23:1096-1104.PubMedCrossRefGoogle Scholar
  86. 86.
    Twardowschy A, Castiblanco-Urbina MA, Uribe-Marino A, et al. The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae). J Psychopharmacol 2013;27:1149-1159.PubMedCrossRefGoogle Scholar
  87. 87.
    Fogaca MV, Reis FM, Campos AC, Guimaraes FS. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience. Eur Neuropsychopharmacol 2014;24:410-419.PubMedCrossRefGoogle Scholar
  88. 88.
    Nardo M, Casarotto PC, Gomes FV, Guimaraes FS. Cannabidiol reverses the mCPP-induced increase in marble-burying behavior. Fundam Clin Pharmacol 2014;28:544-550.PubMedCrossRefGoogle Scholar
  89. 89.
    da Silva JA, Biagioni AF, Almada RC, et al. Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: The role of CB-cannabinoid receptor in the ventral mesencephalon. Eur J Pharmacol 2015;758:153-163.PubMedCrossRefGoogle Scholar
  90. 90.
    Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW. Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 1990;100:558-559.CrossRefGoogle Scholar
  91. 91.
    Bandler R, Shipley MT. Columnar organization in the midbrain periaqueductal gray: modules for emotional expression? Trends Neurosci 1994;17:379-389.PubMedCrossRefGoogle Scholar
  92. 92.
    Nashold BS, Jr, Wilson WP, Slaughter DG. Sensations evoked by stimulation in the midbrain of man. J Neurosurg 1969;30:14-24.PubMedCrossRefGoogle Scholar
  93. 93.
    Walker DL, Miles LA, Davis M. Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:1291-1308.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Sierra-Mercado D, Padilla-Coreano N, Quirk GJ. Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 2011;36:529-538.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Schenberg LC, Bittencourt AS, Sudre EC, Vargas LC. Modeling panic attacks. Neurosci Biobehav Rev 2001;25;647-659.PubMedCrossRefGoogle Scholar
  96. 96.
    Thomas A, Burant A, Bui N, Graham D, Yuva-Paylor LA, Paylor R. Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl) 2009;204;361-373.CrossRefGoogle Scholar
  97. 97.
    Suzuki A, Josselyn SA, Frankland PW, et al. Memory reconsolidation and extinction have distinct temporal and biochemical signatures. J Neurosci 2004;24:4787-4795.PubMedCrossRefGoogle Scholar
  98. 98.
    Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl) 1982;76:245-250.CrossRefGoogle Scholar
  99. 99.
    Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9 - tetrahydrocannabinol in man. Eur J Pharmacol 1974;28:172-177.PubMedCrossRefGoogle Scholar
  100. 100.
    Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. J Psychopharmacol 1993;7:82-88.PubMedGoogle Scholar
  101. 101.
    Martin-Santos R, Crippa JA, Batalla A, et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr Pharm Design 2012;18:4966-4979.CrossRefGoogle Scholar
  102. 102.
    Crippa JA, Zuardi AW, Garrido GE, et al. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 2004;29:417-426.PubMedCrossRefGoogle Scholar
  103. 103.
    Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 2010;35:764-774.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol 2011;25:121-130.PubMedCrossRefGoogle Scholar
  105. 105.
    Bergamaschi MM, Queiroz RH, Chagas MH, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 2011;36:1219-1226.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Das RK, Kamboj SK, Ramadas M, et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology 2013;226:781-792.PubMedCrossRefGoogle Scholar
  107. 107.
    Hindocha C, Freeman TP, Schafer G, et al. Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur Neuropsychopharmacol 2015;25:325-334.PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Borgwardt SJ, Allen P, Bhattacharyya S, et al. Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biol Psychiatry 2008;64:966-973.PubMedCrossRefGoogle Scholar
  109. 109.
    Fusar-Poli P, Crippa JA, Bhattacharyya S. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch Gen Psychiatry 2009;66:95-105.Google Scholar
  110. 110.
    Fusar-Poli P, Allen P, Bhattacharyya S. Modulation of effective connectivity during emotional processing by Delta 9-tetrahydrocannabinol and cannabidiol. Int J Neuropsychopharmacol 2010;13:421-432.PubMedCrossRefGoogle Scholar
  111. 111.
    Rubia K, Russell T, Overmeyer S, et al. Mapping motor inhibition: conjunctive brain activations across different versions of go/no-go and stop tasks. Neuroimage 2001;13:250-261.Google Scholar
  112. 112.
    Falconer E, Allen A, Felmingham KL, Williams LM, Bryant RA. Inhibitory neural activity predicts response to cognitive-behavioral therapy for posttraumatic stress disorder. J Clin Psychiatry 2013;74:895-901.PubMedCrossRefGoogle Scholar
  113. 113.
    Mochcovitch MD, da Rocha Freire RC, Garcia RF, Nardi AE. A systematic review of fMRI studies in generalized anxiety disorder: evaluating its neural and cognitive basis. J Affect Disord 2014;167:336-342.PubMedCrossRefGoogle Scholar
  114. 114.
    Patel R, Spreng RN, Shin LM, Girard TA. Neurocircuitry models of posttraumatic stress disorder and beyond: a meta-analysis of functional neuroimaging studies. Neurosci Biobehav Rev 2012;36:2130-2142.PubMedCrossRefGoogle Scholar
  115. 115.
    Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of Delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology 2010;35:1879-1885.PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry 2008;192:306-307.PubMedCrossRefGoogle Scholar
  117. 117.
    Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study: naturalistic study [corrected]. Br J Psychiatry 2010;197:285-290.PubMedCrossRefGoogle Scholar
  118. 118.
    Demirakca T, Sartorius A, Ende G, et al. Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol. Drug Alcohol Depend 2011;114:242-245.PubMedGoogle Scholar
  119. 119.
    Niesink RJ, van Laar MW. Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry 2013;4:130.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Greer GR, Grob CS, Halberstadt AL. PTSD symptom reports of patients evaluated for the New Mexico Medical Cannabis Program. J Psychoactive Drugs 2014;46:73-77.PubMedCrossRefGoogle Scholar
  121. 121.
    Passie T, Emrich HM, Karst M, Brandt SD, Halpern JH. Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug Test Anal 2012;4:649-659.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2015

Authors and Affiliations

  • Esther M. Blessing
    • 1
  • Maria M. Steenkamp
    • 1
  • Jorge Manzanares
    • 1
    • 2
  • Charles R. Marmar
    • 1
  1. 1.New York University School of MedicineNew YorkUSA
  2. 2.Instituto de Neurociencias de AlicanteUniversidad Miguel Hernández and Consejo Superior de Investigaciones CientíficasAlicanteSpain

Personalised recommendations