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.