Cannabidiol as a Potential Treatment for Anxiety Disorders
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-015-0387-1) contains supplementary material, which is available to authorized users.
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 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 [1–3]. Together, they have a lifetime prevalence in the USA of 29 % , 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 [7–10]. 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 [13–15]. 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.
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, 16–19] 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 .
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 [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 equilibrative 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 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 ). 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 Ca 2+ 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 . 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 . 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 . 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 [30–33]). 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 ; however, CB1R activation potently enhances fear extinction , and can prevent fear reconsolidation. Genetic manipulations that impede CB1R activation are anxiogenic , 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 . Reduction of AEA–CB1R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone , 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 .
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 ).
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 . 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 . 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].
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 . In preclinical studies, 5-HT1AR agonists are anxiolytic in animal models of general anxiety , prevent the adverse effects of stress , and enhance fear extinction . 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 . While in vitro studies suggest CBD acts as a direct 5-HT1AR agonist , in vivo studies are more consistent with CBD acting as an allosteric modulator, or facilitator of 5-HT1A signaling .
Generalized Anxiety Models
Relevant studies in animal models are summarized in chronological order in Table Table1. 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 Table1 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.  showed that in rat, CBD treatment for 21 days attenuated inhibitory avoidance acquisition . Long et al.  showed that, in mouse, CBD produced moderate anxiolytic effects in some paradigms, with no effects in others.
|Silveira Filho et al. ||WR||i.p.||100 mg/kg,
|Zuardi et al. ||WR||i.p.||10 mg/kg,
|Onaivi et al. ||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. ||WR||i.p.||2.5, 5.0, 10.0 and 20.0 mg/kg, acute||EPM||Anxiolytic||NA|
|Moreira et al. ||WR||i.p.||2.5, 5.0 and 10.0 mg/kg, acute||VCT||Anxiolytic||Effect unchanged by IP flumazenil|
|Resstel et al. ||WR||i.p.||10 mg/kg, acute||CFC||Anxiolytic||NA|
|Campos et al. ||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|
|Bitencourt et al. ||WR||i.c.v.||2.0 μg/μl
5 min before extinction, acute
|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. ||WR||dlPAG||30, 60 mg/kg, acute||EPM||Anxiolytic||Intra-dlPAG capsazepine renders 60 mg/kg anxiolytic|
|Resstel et al. ||WR||i.p.||1, 10 or 20 mg/kg, acute||RS||Anxiolytic,
|All effects ↓ by systemic WAY100635|
|EPM 24 h
|Soares et al. ||WR||dlPAG||15, 30 or 60 nmol, acute||ETM||Anxiolytic
|All effects ↓ by intra-dlPAG WAY100635 but not AM251|
|Long et al. ||C57BL/6 J mice||i.p.||1, 5, 10, 50 mg/kg, chronic, daily/21 d||EPM||No effect||NA|
|OF||50 mg/kg anxiolytic|
|Lemos et al. ||WR||i.p.
|10 mg/kg IP, 30 nmol intra-PL and intra-IL, acute||CFC||IP and PL anxiolytic IL anxiogenic||NA|
|Casarotto et al. ||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. ||WR||BNST||15, 30, and 60 nmol, acute||EPM||Anxiolytic||Both effects ↓ by intra BNST WAY100635|
|Granjeiro et a l. ||WR||Intracisternal||15, 30, and 60 nmol, acute||RS||Anxiolytic, ↓Pressor ↓Tachycardia||NA|
|EPM 24 h after RS||Anxiolytic|
|Deiana et al. ||SM||i.p.
|120 mg/kg, acute||MBT||Anticompulsive||NA|
|Uribe-Marino et al. ||SM||i.p.||0.3, 3.0, 30.0 mg/kg, acute||PS||Panicolytic||NA|
|Stern et al. ||WR||i.p.||3, 10, 30 mg/kg
immediately after retrieval, acute
1 and 7 d old fear memories disrupted
|Effect ↓ by AM251 but not WAY100635|
|Campos et al. ||WR||i.p.||5 mg/kg, subchronic, daily/7 d||EPM following PS||Anxiolytic||Effects ↓ by IP WAY100635|
|Hsiao et al. ||WR||CeA||1 μg/μl||REM sleep time||↓ REM sleep suppression||NA|
|Gomes et al. ||WR||BNST||15, 30, 60 nmol, acute||CFC||Anxiolytic||Both effects ↓ by intra-BNST WAY100635|
|El Batsh et al. ||LE-H R||i.p.||10 mg/kg, chronic,
|Campos et al. ||C57BL/6 mice||i.p.||30 mg/kg 2 h after CUS,
chronic daily/14 d
|EPM||Anxiolytic||Both effects ↓ by AM251|
|Do Monte et al. ||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. ||Rat||i.p.||5 mg/kg, chronic, daily/21 d||ETM||Anxiolytic
|Panicolytic effect ↓ by intra-dlPAG WAY100635|
|Almeida et al. ||Rat||i.p.||1, 5, 15 mg/kg, acute||SI||Anxiolytic||NA|
|Gomes et al. ||WR||BNST||30 and 60 nmol, acute||RS||Anxiogenic
|Effect ↓ by WAY100635|
|Twardowschy et al. ||SM||i.p.||3 mg/kg, acute||PS||Panicolytic||Effects ↓ by IP WAY100635|
|Focaga et al. ||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|
|Nardo et al. ||SM||i.p.||30 mg/kg, acute||MBT||Anticompulsive||NA|
|da Silva et al. ||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 , and DPAG stimulation in humans produces feelings of intense distress and dread . 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 . Anxiolytic effects of CBD in the EPM and VCT occurred upon microinjection into the BNST, where they depended on 5-HT1AR activation , and also upon microinjection into the central nucleus of the amygdala . In the prelimbic cortex, which drives expression of fear responses via connections with the amygdala , 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 . 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 . 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 . 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 . 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 . 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 . Likewise, systemic CBD was anxiolytic in the EPM following but not prior to stress .
PD and Compulsive Behavior Models
CBD inhibited escape responses in the ETM and increased DPAG escape electrical threshold , both proposed models of panic attacks . 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 Table1) 1 ) [75, 86] . Finally, CBD, partially via CB1Rs, decreased defensive immobility and explosive escape caused by bicuculline-induced neuronal activation in the superior colliculus . Anticompulsive effects of CBD were investigated in marble-burying behavior, conceptualized to model OCD . 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 , an effect reproduced by microinjection of CBD into the BNST, and partially mediated by 5-HT1AR activation . Similarly, CBD in the prelimbic cortex reduced conditioned freezing , an effect prevented by 5-HT1AR blockade . By contrast, CBD microinjection in the infralimbic cortex enhanced conditioned freezing . Finally, El Batsh et al.  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 . Further studies showed CB1Rs in the infralimbic cortex may be involved in this effect .
CBD also blocked reconsolidation of aversive memories in rat . 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 , 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 . This effect depended on CB1R activation but not 5-HT1AR activation .
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 Table2. 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 .
Human psychological studies
|Karniol et al. ||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 baseline
|Zuardi et al., ||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. ||HV,
|Oral 300 mg,
acute, 80 min
|VAMS, STAI and BP following SPST||↓ STAI scores
↓ VAMS scores
|Martin-Santos et al. ||HV,
|Oral 600 mg,
acute, 1, 2, 3 h
|Baseline anxiety and pulse rate||No effect|
|Crippa et al. ||10 HV,
|Oral 400 mg,
acute, 60 and 75 min
|VAMS before SPECT
|↓ VAMS scores|
|Bhattacharyya et al. ||15 HV
|Oral 600 mg,
acute, 1, 2, 3 h
|↓ STAI scores
↓ VAMS scores
|Crippa et al. ||SAD and HC
|Oral 400 mg,
acute, 75 and 140 min
|VAMS before SPECT
|↓ VAMS scores|
|Bergamaschi et al. ||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. ||HV
|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. ||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 = Δ 9-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 Table3. 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 . 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 .
|Study||Subjects, design||CBD route, dose, timing||Measure||Effect of CBD|
|Crippa et al. ||10 HV,
|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. ||15 HV,
|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. ||15 HV,
|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. ||15 HV,
|Oral 600 mg,
acute, 1–2 h
|fMRI functional connectivity during fearful faces task||↓ Functional connectivity between L) AMY and ACC|
|Crippa et al. ||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-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 . Response activation is diminished in PTSD and other anxiety disorders, and increased activation predicts response to treatment . 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 . Dynamic causal modeling analysis in this data set further showed CBD reduced forward functional connectivity between the amygdala and anterior cingulate cortex .
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 [115–118] (reviewed in ). 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 , and a case study in a patient with severe sexual abuse-related PTSD , 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.
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.
I Took CBD Oil Every Day for My Anxiety—Here’s What Went Down
Dana Myers, LCSW is a licensed clinical social worker and life coach based in Philadelphia. She has a special interest in how race, sex, gender, ethnicity, social status and competencies impact those in marginalized communities and aims to help her clients find purpose and peace in life.
Michelle Regalado is a seasoned editor, fact-checker, and content strategist with expertise in women’s lifestyle news.
When I first learned about CBD oil, I’ll admit I was a bit skeptical. My mind immediately turned to weed and the unnerving experiences I’d had with heightened anxiety in college. For me, a person who’s already predisposed to overthinking, marijuana, no matter what the form, would typically put my mind into overdrive and result in a common yet dreaded side effect: Paranoia. But, let’s back up a bit. What even is CBD?
What is CBD?
A bit of online digging led me to realize that the active ingredient in Charlotte’s Web Everyday Plus Hemp Oil, the product I’d been offered to test, was the chemical compound CBD, which stands for cannabidiol. Unlike THC, the other crucial compound in hemp and marijuana plants, CBD (when derived from the hemp plant) does not produce the psychoactive effects that make you feel “high”; instead, emerging science has hinted that CBD may actually ease anxiety, and therefore, makes you less likely to freak out.
For example, one study comparing the effects of THC and CBD found that, while THC increased anxiety by activating the neurotransmitters involved in the “fight or flight” response, CBD actually repressed autonomic arousal—or the nervous system response associated with sudden increases in heart rate or respiration. In other words, CBD may be ideal for people looking to relax and unwind.
While the science behind CBD’s effectiveness for treating anxiety, pain, and insomnia is still in its infancy, Charlotte Figi’s inspiring story sounds promising. Figi, a 6-year-old girl diagnosed with a rare and resistant form of epilepsy known as Dravet syndrome, was placed on hospice care and given a “do not resuscitate” order when her parents, desperate and frustrated with pharmaceutical medication, considered medical marijuana; specifically, a strain low in THC and high in CBD. Charlotte is now nearly seizure-free since she began supplementing with Charlotte Web’s CBD oil, which the brand named after Figi.
Legal and Safety Things To Know About CBD
The current CBD industry is like the internet’s early years. the Wild West. Legally, speaking, a Harvard Medical School blog post reads, “All 50 states have laws legalizing CBD with varying degrees of restriction, and while the federal government still considers CBD in the same class as marijuana, it doesn’t habitually enforce against it.” With heightened interest around CBD, it’s important to note that because CBD is currently unregulated, it’s difficult to know what you’re getting (whether that’s a tincture—commonly referred to as CBD oil, which is often combined with a carrier oil like coconut oil—topical products like creams and balms, sprays, or capsules), despite product labels and brand promises, the blog post further reads. It’s also important to note that people experience CBD differently. For the most part, the National Institute of Medicine says that while most people can tolerate CBD, side effects do exist. They might include dry mouth, drowsiness, and reduced appetite, among others.
That said, those interested in exploring the potential benefits of CBD should consult with their doctor (especially if you are pregnant, nursing, or currently taking medication) and be mindful of your dosage, writes Consumer Reports. And before you buy, Megan Villa, co-founder of the hemp-focused website and shop Svn Space, told Shape magazine to seek out a certificate of analysis. “Ask for a COA for the batch number of the product you have, since these products are made in batches,” she said. “You need to match the batch number to the COA that pertains to it.” Then, scan the report for potency (i.e. does the number of milligrams of CBD that the product label touts match the lab report?), contaminants and pesticides, and mold (which should live under the “Microbiological Testing” part of the report). Go a step further and note whether the testing lab is GMP (Good Manufacturing Principles) certified, and whether the lab is registered with the Food and Drug Administration (FDA). Shape magazine also suggests purchasing CBD products made from domestically-grown hemp, and reading up on the difference between full- and broad-spectrum and CBD isolate.
With that, I threw caution to the wind and asked for a sample. Here’s what happened—including what it feels like—when I took one full dropper of Charlotte’s Web’s Everyday Plus Hemp Oil in the mint chocolate flavor every morning for seven days.
My First Impression
It was actually a bad bout of jet lag after a trip to California that inspired me to finally test out the CBD oil (I’ll admit that my weed-based reservations kept me from trying it for the first few months). Knowing that the oil had also helped people with sleep issues, I squeezed one full dropper of the Everyday Plus oil onto my tongue, per the instructions, and waited.
Thirty minutes later, I was surprised by how subtle the effect was. While I expected a hazy nodding-off effect similar to melatonin’s, the oil simply relaxed my body ever so slightly—my heart stopped pounding against my chest, my legs stopped kicking beneath my sheets, my mind stopped racing. I wasn’t sure if it was the oil or the late hour, but eventually, physical relaxation gave way to mental relaxation, and I drifted off to sleep.
Reflecting the next morning, I was most surprised by the fact that I never felt “high” in any way—there was never a moment of It’s kicking in; I can feel it now like with pain medications or even anti-anxiety drugs. Considering it takes time, consistency, and the right dosage to experience the full effect, I continued taking the oil once a day for the next six days. Here’s what went down.
It Made Me Less Anxious and Edgy
Rather than overthinking a sternly worded email or analyzing a social interaction, I found it easier to recognize the irrationality of these thoughts and actually let them go.
While normally I’d be slightly tripped up by little things like an overly crowded subway car or a full inbox at work, the CBD oil seems to have taken the edge off of my anxiety a bit. Rather than overthinking a sternly worded email or analyzing a social interaction, I found it easier to recognize the irrationality of these thoughts and actually let them go. In some ways, I feel more like myself. With that said, I’ve still experienced some social anxiety when meeting new groups of people—I’d be interested to see what taking the full recommended dose would do.
I’m More Focused At Work
I work well under pressure, but being extremely busy at work has almost made me less productive—I’m constantly distracted by email, Slack, and the people around me, to the point where getting my work done becomes difficult. This week, however, I’ve found it easier to put my blinders on, block out all distractions (especially social distractions), and focus on one task at a time. I think this is partly related to the lessened anxiety—I feel more frazzled and off task when my anxiety is running high. It almost feels like a newfound sense of clarity and calm that enables me to focus.
I’m Falling Asleep Faster
I assume this is also a side effect of feeling less anxious, but I seem to fall asleep faster; within the 20-30-minute range rather than my normal 45 minutes to one hour (or longer). Not only do I seem to be skipping or at least shortening the whole tossing-and-turning phase of my sleep cycle, but I’m able to snap out of the overthinking that often keeps me up at night. Of course, there’s no telling whether a big life event would disrupt this newfound bliss, but I’d like to think it’s helped on a day-to-day basis.
My Experience With CBD
Would I say that CBD oil has fundamentally changed my life? No. But per the Charlotte’s Web website, this is the typical first experience. “Anyone who has ever started a new vitamin or supplement routine knows the short answer to how long it takes to kick in is—’it depends.’ For many newcomers, they’re not sure what to imagine, or some anticipate a huge change right away. For most of us, though, dietary supplements take time.”
With that said, I’m definitely intrigued enough by the subtle effects to continue taking the oil and to possibly up the dosage to the recommended two full droppers of the 30mL bottle per day. Plus, I take comfort in knowing that it’s an all-natural product that’s responsibly grown on family farms in Colorado. Something that’s safe, legal, requires no prescription, and makes me less anxious, less scatterbrained, and more focused? I’m definitely on board.
Explore the World of CBD
Looking to learn more about CBD? These are some of my favorite products to help get you started.
For those new to CBD, Charlotte’s Web recommends this hemp oil. Containing 17mg of CBD per 1mL serving, this CBD oil is also U.S. Hemp Authority Certified. Choose from four different flavors including Lemon Twist, Mint Chocolate, Orange Blossom, and Olive Oil.
Go deep on the subject of CBD with this book that includes case studies, interviews with doctors, an overview of the latest cannabis research, and how scientists are exploring cannabis for various medical uses. There is also an explainer about the difference between CBD products made from industrial hemp versus in a lab, and products made from the whole marijuana plant.
Charlotte’s Web inaugural CBD oil product comes in two flavors; Olive Oil and Mint Chocolate. It’s also its most potent. According to its website, its Original Formula Hemp Extract Oil comes with 50mg CBD per mL.
Gretchen Lidicker puts a lifestyle spin on the world of CBD as the author draws on the “knowledge of leaders in the health and wellness world” to explain why CBD has become a top beauty and wellness trend for top athletes and celebrities. The book also includes recipes and recommendations for how to choose a top-quality CBD product.
This travel-friendly roll-on is packed with CBD and fragrant essential oils, including lavender, bergamot, and chamomile, for an easy de-stress quick fix. The result? “That elusive feeling of wakeful calm,” reads the Sagely Naturals website.
With this book, CBD is explained from A to Z and breaks down the good, bad, and ugly of a fledgling industry that is poised for rapid growth. CBD: 101 Things You Need to Know About CBD Oil covers what it is, why people take it, who it’s for (and who it isn’t for), its myriad forms, and more.
Lord Jones’ High CBD Formula Body Oil combines CBD with organic avocado, jojoba and safflower oils for smooth, hydrated skin. Each bottle has 100mg of CBD.
Charlotte’s Web’s Extra Strength Capsules feature 25 mg of CBD per capsule. The website offers capsules as a convenient and precise way to take CBD—on the go, stash them in your gym bag, pocket, etc.
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Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in anxiety and sleep: A large case series. Perm J. 2019;23:18-041. doi:10.7812/TPP/18-041