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.
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.
What happened when I took CBD for a week to help with my anxiety
Steven Phan: You gotta lean back. No, tongue back!
Benji Jones: That’s me, trying CBD at a shop in New York City. Lately, I’ve seen this stuff everywhere: At the local health food store, but also at Urban Outfitters, Sephora, and CBD shops like this one. And if you look at some of the branding, it kind of makes sense.
CBD products claim to help with everything from anxiety to insomnia to muscle pain. It almost sounds too good to be true. And maybe it is. To find out, I set up a little experiment. For one week, I took CBD three times a day, while tracking my anxiety with a scorecard. I also chatted with an expert before and after to sort through the results. Here’s what I learned.
CBD is a distant cousin of THC, the psychoactive chemical in marijuana. They both come from the cannabis plant, but CBD isn’t psychoactive. Meaning it doesn’t get you high. Now, of course, getting high isn’t the only reason why cannabis is popular. People also use it to relieve pain, control seizures, and lessen anxiety. But as researchers like Dr. Yasmin Hurd are discovering, it’s likely CBD, not THC, that’s behind these benefits.
Dr. Hurd: “It can activate some serotonin receptors, and the serotonin system is associated with alleviating anxiety.”
Jones: Hurd has been studying the effects of CBD for over 10 years. And she’s found that it can reduce anxiety in people with a history of heroin addiction. Now, fortunately, I don’t have a history of addiction, but I do see a therapist for chronic anxiety. And CBD could still help.
Dr. Hurd: “Both under normal conditions and in people who have anxiety disorders, enough research has started to show that it does have an anti-anxiety effect.”
Jones: So, back at the shop, I tried all kinds of product. From sweets to lotions and sprays. And while Hurd couldn’t recommend a specific dose for me, she did say that 300 milligrams a day should be enough to feel something. Because participants in clinical trials typically take anywhere from 300 to 600 milligrams. So, those chocolates and sprays? They weren’t going to cut it. Instead, I went for something else.
Phan: The tinctures, right? This is where you really get into the higher-strength things.”
Jones: I decided to err on the side of caution and take 250 milligrams each day, broken out into three doses: 50 milligrams in the morning, 100 milligrams at midday, and another 100 milligrams at night. That way, it wouldn’t hit me all at once.
Jones: All right, today is the day! I have my CBD here. I’m kind of nervous. All right, here we go.
Now, mind you, this was a Wednesday. A workday. Side note: The reason I’m taking CBD this way is that there are tons of capillaries under your tongue. So, anything you put there can be absorbed directly into your bloodstream. Whereas when you ingest CBD, like with that chocolate, a lot of it is broken down by your stomach. Which means you probably won’t feel much.
Anyway, several hours later, I took my last dose of the day.
If anything, I just feel extremely tired.
That was the first thing I noticed: that CBD was making me drowsy. Really drowsy. Which Hurd said is a pretty normal side effect at high doses. Though we’re not exactly sure why. But as I discovered the next night, it’s also great for hangovers.
I had some alcohol, and I’m certainly not going to have trouble sleeping. I think I’m going to eat a slice of pizza.
The next morning, I felt…great. And according to Hurd, that’s because CBD also has some anti-inflammatory effects. But what about anxiety, what I was really in this for? Each morning, I filled out the anxiety scorecard that Hurd gave me. It was a rough estimate of my daily emotional state, based on numbered responses to statements like, “I feel at ease.” But day to day, it was harder to figure out whether CBD was helping.
Just walking home on Friday night after three days of CBD, and I’m reporting that I’m mostly just tired and feeling lethargic. Not in a bad way; it kind of feels like I have a warm blanket around me, so I don’t hate it.
But over the weekend, I finally got the relief I was looking for, even more quickly than I had expected.
So, I happened to take CBD right before I had to do something stressful. It’s Sunday, but I had a task that I was not looking forward to. And I took 100 milligrams, and I pretty quickly felt my nerves calming down. And I was like, OMG, this is totally working, which is really great because I’m looking for that quick relief like everyone is.
Now, of course, this could have been a placebo. I mean, all of this could have been placebo. So, a few days later, I tried it again in a similar high-stress situation.
Not going to lie, I actually feel a little bit more calm. It kind of puts me into a dissociative state, where I’m slowing down a little bit. I actually get physical pain in my heart region when I’m anxious, which I know sounds terrible. But just 30 minutes after taking my 100-milligram dose for the evening, I feel an absence of that. I will say that I’ve also been listening to the “Lion King” soundtrack, so there are confounding variables. But yeah, I feel a lot better right now.
At that point, I had just one day left.
All right, I’m about to take my last dose of CBD! I must say, I’m kind of excited to stop having to take this three times a day. I think part of it is scheduling and remembering. But also, yeah, I’ve also just been so much more tired. I don’t feel like my anxiety was just washed away. I felt like there were a few times where it really helped in certain instances. And, overall, kind of lowered the intensity of how I was feeling because I felt lethargic. But yeah, I don’t want to be tired anymore.
Afterward, I looked over my anxiety scorecards. And sure enough, it showed that I was feeling slightly less anxious on my last day, compared to my first. Especially when I looked at statements like this. Yeah, that’s a big one for me. I wanted to run these results by Hurd.
Dr. Hurd: “How do you feel?”
Jones: Um, to be honest, I don’t feel that different. I think that the biggest change that I noticed is…I was just tired all the time. I feel this kind of slo-mo lethargia that makes me feel, like, a little bit disassociated with reality. And I think that is what made me feel a little less anxious at times.
Dr. Hurd: So, perhaps…taking it at night only might be best because it can make you a bit sleepy, and everyone has a different sensitivity. If you take it at night you get past the initial sedative effects… and then you don’t have to worry about taking other things like caffeine to try to stay awake.
Jones: And what about those moments of instant relief? Was that in my head, or could CBD act that fast?
Dr. Hurd: “Yeah, absolutely. It can act that quickly. For us, in our studies, people did — shortly after getting CBD — report reduced anxiety.”
Jones: But if there was one takeaway from our conversations, it was this:
Dr. Yasmin Hurd: Ironically, even though it’s now this huge fad in our society, we still don’t have a very good handle on how it’s working.
Jones: In other words, we don’t know: what size dose you should take, how, exactly, it changes your brain, or how it impacts different people in different ways. That’s because until late 2018, nearly all CBD was classified as an illegal substance. Which made it really difficult for scientists to study. And while research is starting to catch up… in some ways, it’s too late.
Dr. Hurd: It’s one of the first times in history that the public is determining whether something is medicine, not scientists and physicians.
Jones: As for me, will I continue using CBD? Yes — but likely only for those moments when I need instant relief. Because, while it seems to benefit a lot of people … I’m not yet fully convinced. But also because, this bottle? It costs more than $130! And if I’m going to spend that much, I want to be absolutely sure it works.
EDITOR’S NOTE: This video was originally published on August 20, 2019.
CBD Oil for Anxiety & Depression: The Pros & Cons
Everyone’s talking about it, so we’re here to help you weigh up the pros and cons, without bias.
The pros & cons of taking CBD oil:
1. Depression & Anxiety
With symptoms like excessive worry, extreme self-consciousness, chest pain, and panic attacks, anxiety can be a debilitating condition. Depression can be equally destructive—feeling sad, with little interest in the activities you once enjoyed.
Fortunately, there are a wide variety of options for treating anxiety and depression. Selective serotonin reuptake inhibitors (SSRIs) are popular, but they come with a host of side effects. Others have the risk of addiction.
Many people search for a safer, more natural way to treat anxiety and depression, so new options are being developed and researched all the time.
One emerging treatment is CBD oil. It’s becoming more popular with each passing day, but there are still major questions about how effective it is at treating anxiety and depression—and how exactly it helps.
As a fairly new and little-understood product, it’s important to learn as much as you can about CBD oil for anxiety and depression—and speak to your mental health provider—before you decide to try it.
2. What Is CBD Oil?
Cannabidiol (CBD) oil is a type of cannabinoid. Cannabinoids are chemicals that occur naturally in the cannabis plant. Cannabidiol is extracted from the plant and made into an oil.
Tetrahydrocannabinol, or THC, is another type of cannabinoid. It’s the chemical responsible for the “high” one feels after using marijuana. Because CBD is not THC, you cannot get high from using CBD oil.
CBD oil is suggested to have positive effects for people with:
- and other mental health disorders
- in addition to depression and anxiety
- Studies have shown inconclusive results for most of these uses, with the exceptions of epilepsy, anxiety, and depression
3. How Does CBD Oil Work?
CBD oil for depression and anxiety is still being studied and doesn’t have as much research to back it up as many other treatments do. Make sure you talk to your doctor about whether it’s a good fit for you and how to incorporate it into your treatment plan.
4. CBD for anxiety
It isn’t known exactly how CBD oil combats anxiety, but it’s thought to work with a receptor in your brain called CB1. Researchers believe the interactions between CBD oil and CB1 alter serotonin signals.
The core problem at the heart of anxiety disorders is low serotonin—a neurotransmitter related to mood and well-being. SSRIs, for instance, work by blocking the absorption of serotonin in your brain, meaning you get more serotonin. CBD oil may do something similar.
Studies have shown that CBD oil can be effective in treating various types of anxiety, including:
- Social anxiety disorder (PTSD)
Behavioral symptoms of anxiety and physiological symptoms of anxiety, like rapid heartbeat, were reduced in some studies. It’s also been shown to be effective against anxiety-related insomnia.
5. CBD for Depression
CBD oil works similarly for people suffering from depression because depression happens when serotonin levels are low. Increasing the amount of serotonin in your brain has a positive effect on your emotions and motor skills.
CBD oil may also affect the hippocampus, which plays a large role in regulating your emotions. When you have depression, your hippocampus doesn’t function as well. CBD oil may help promote neurogenesis or the formation of new neurons in the hippocampus.
6. How to use CBD
You take CBD oil by either putting a few drops under your tongue with a dropper or mixing it with food. CBD gummies are also becoming popular.
7.Disadvantages of CBD Oil
While CBD oil for anxiety and depression holds promise, there are significant disadvantages to its use.
First, it isn’t widely available. You can only buy CBD oil in states where medical marijuana is legal.
Second, no CBD oil products are approved by the FDA for the treatment of anxiety or depressive disorders. Only one CBD oil product is FDA-approved, and that is for the treatment of epilepsy.
Without the oversight and regulation of the FDA, CBD oils vary widely in quality. Manufacturers can more or less put whatever they want on labels.
According to Marcel Bonn-Miller, adjunct assistant professor of psychology at the University of Pennsylvania School of Medicine, 43% of CBD oil products contain too little CBD, while about 26% contain too much.
Due to its lack of regulation, approximately one in five CBD products contain THC, meaning they could give you a high. THC can increase anxiety instead of reducing it. The additional risk in taking CBD oil is that even if the product contains trace amounts of THC, you could still test positive for marijuana on a drug test.
Quality CBD oil is considered safe, but it does come with a few side effects.
- Dry mouth
- Sleeping problems
- Gastrointestinal discomfort
More concerning than these side effects is the potential harm CBD oil can inflict on your liver. About 10% of people taking CBD in studies showed increases in liver enzymes. This increase could indicate potential liver damage. These concerns were severe enough for 2% to 3% of participants in the study to drop out due to concerns from the people running the study.
There is also the potential for dangerous drug interactions when taking CBD oil with another medication. If you are taking an antidepressant or any other medications, be sure to consult with your doctor before taking CBD oil.
8. Other Alternative Anxiety & Depression Treatments
Although CBD oil as a treatment for anxiety disorders and depression is a potentially viable option, there are alternative treatments—besides medication—that are safe and effective.
Transcranial magnetic stimulation, or TMS, is one such treatment. It offers hope for patients with anxiety disorders by restoring the neurons in the amygdala—the part of your brain involved in the fight-or-flight response—to a normal level of functioning. In those with depression, TMS stimulates the thalamus and hippocampus, which work to control the brain’s emotional responses.
TMS does this by stimulating your brain using electromagnetic pulses. It has very few side effects, and results can be felt in just two weeks.
Explore TMS side effects
Many people are searching for natural treatments for anxiety and depression, and it isn’t hard to see why.
It’s always a good idea to be open-minded to new treatments, especially when there is clinical evidence to back them up. The most important things to do are conduct thorough research and discuss any options you’re considering with your doctor.