CBD use in anxiety disorders

Over-the-counter (OTC) CBD products have become very popular in the health and wellness markets globally. One of the features most often proclaimed for CBD is its ability to reduce stress and anxiety. A cross-sectional study of OTC CBD users found that the top three medical conditions for which CBD is used were pain, anxiety and depression . A more recent study found that the top reasons OTC CBD was used were stress relief, relaxation and sleep improvement . A 2020 analysis of social media content revealed that CBD is most discussed as a therapeutic option for anxiety disorders and pain . Supporting the widespread use of OTC CBD for stress and anxiety, there is a growing body of clinical studies demonstrating the anxiolytic effects of CBD across various patient cohorts.

Clinical studies with CBD in anxiety and related disorders

Several randomised controlled clinical trials and case series report on the ability of CBD to have positive effects on anxiety in healthy volunteers or patients with various diagnoses, and these studies are summarised in Table 2.
In healthy volunteers in randomised controlled studies, acute doses of 300 or 600mg given orally reduce the anxiety caused by public speaking , and reduce the blood pressure and cardiovascular response to physical and mental stress (600mg, . Such anxiolytic effects of acute CBD treatment are associated with altered brain activity in corticolimbic regions (e.g. cingulate cortex, amygdala) that mediate cognition and emotional regulation . In healthy volunteers, 7 days of treatment with CBD (600mg/day) also reduced the haemodynamic response to physical stress .
In medication–naive patients with generalised social anxiety disorder (SAD), acute oral doses of 300 or 600mg reduce anxiety caused by public speaking in a randomised, controlled study . Similarly, in teenagers with SAD, a randomised controlled trial showed that 4 weeks CBD (300 mg/day) treatment decreased anxiety measures using the Fear of Negative Evaluation Questionnaire and the Liebowitz Social Anxiety Scale . As with healthy volunteers, the anxiolytic effects of CBD in anxiety disorders are also linked to alterations in corticolimbic activity . Moreover, in medication–naive participants at clinical high risk of psychosis, CBD (600 mg) partially normalised the alterations in limbic, striatal, and midbrain function in a randomised controlled trial . A follow up study by the same group showed 7 days of treatment with CBD (600 mg/day) in patients at clinical high risk of psychosis partially restored the cortisol response elicited during the Trier Social Stress Test to that observed in the control group . In this study, the experience of anxiety in response to the stress test was greatest in the high-risk patients and lowest in the healthy controls, with those at high risk who were treated with CBD for 7 days exhibiting an intermediate response.
Anxiety is often comorbid with other presentations, and the anxiolytic effects of CBD in other pathologies has also been tested in randomised controlled studies. In patients with Parkinson’s disease (PD), a single dose of CBD (300 mg) attenuated the anxiety experimentally induced by a Simulated Public Speaking Test in a randomised, double-blinded, placebo-controlled, crossover trial . In drug-abstinent individuals with heroin use disorder, CBD (either 400 or 800mg for 3 days) also reduced the anxiety and cortisol responses to the presentation of a drug cue in a double-blind randomized placebo-controlled .
Several case reports also document the anxiolytic effects of CBD. In adults with concerns of anxiety or poor sleep, CBD treatment (25-175 mg per day) improved anxiety and sleep improved for most patients in a recent case series . For a 16-year-old patient with multiple substance use disorder, severe depression, social phobia and narcissistic personality disorder, treatment with CBD (100-600mg/day for 8 weeks) improved depressive and anxiety symptoms . CBD treatment (up to 600mg per day over 19 weeks) in a 14-year-old patient with Crohn’s disease and anxiety disorder (social phobia) reduced the severity of anxiety symptoms . A case report and case series in PTSD patients treated with CBD (2-100 mg/day for 8 weeks) reported improvements in anxiety and sleep quality . A recently published study of an audit of CBD-prescribed patients was completed on 253 patients . Patients with non-cancer pain and mental-health symptoms achieved significant improvements to patient-reported pain, depression and anxiety symptoms.

CBD’s mechanism of action in anxiety

Many preclinical studies have investigated the anxiolytic and mnemonic effects of CBD in animal models of anxiety and learned fear when CBD is administered systemically or directly into the brain, revealing potential mechanisms of action for CBD in these models . Several receptors have been implicated to be molecular sites of action of CBD. The 5HT1A receptor and transient receptor potential vanilloid 1 (TRPV1) channel have been implicated in the anxiolytic effects of CBD . Peroxisome proliferator-activated receptor gamma (PPARγ) activation is also thought to be involved in the underpinning anti-inflammatory/anti-oxidant effects that help resolve the pathological effects that can lead to anxiety . Activation of the cannabinoid receptor type 1 (CB1) has been implicated in the facilitatory effect of CBD on fear extinction, possibly as an indirect consequence of enhancing endocannabinoids within the brain . Fear extinction is a form of inhibitory learning that suppresses learned fear and forms the theoretical basis for exposure therapy in the treatment of certain anxiety disorders . Interestingly, a study in humans showed that CBD also enhanced fear extinction in healthy volunteers , raising the possibility that CBD might enhance the therapeutic effects of psychological treatments.
In preclinical studies, CBD has also been shown to decrease dopamine (DA) transmission , 5HT transmission and to modulate synaptic plasticity in the amygdala and hippocampus . CBD can also block the formation of associative, fear-related memories in specific neural regions, including the nucleus accumbens (NAc) and ventral hippocampus (vHIPP). Thus, reported that direct infusions of CBD into the rodent NAc potently blocked the formation of associative fear memories through a 5HT1A-receptor dependent mechanism. These effects of CBD on fear-memory formation were also dependent on its ability to dampen the activity of DA neurons directly in the ventral tegmental area , an effect that is similarly thought to underlie the putative anti-psychotic properties of CBD . Interestingly, CBD has also been reported to mitigate the anxiogenic effects of delta-9-tetrahydrocannabinol (THC). For example, co-administration of CBD with THC in the rodent vHIPP was shown to block the ability of THC alone to induce potentiation of fear-related memory formation. This effect was dependent on CBD’s ability to block hyperstimulation of extracellular-signal-related kinase 1-2 phosphorylation states (ERK-1-2) induced by THC . Thus, the therapeutic ability of CBD in anxiety and stress management are not reliant on a single molecular target and may involve many biological processes. Accordingly, there is an urgent need to map and validate these preclinical molecular biomarkers associated with CBD’s anxiolytic properties onto translational studies in human populations.