Reviewed: Skelley JW, Deas CM, Curren Z, Ennis J. Use of cannabidiol in anxiety and anxiety-related disorders. J Am Pharm Assoc. January-February 2020;60(1):253-261. doi: 10.1016/j.japh.2019.11.008.

Anxiety, generally defined as a natural response to perceived threats, becomes maladaptive in excess or in the absence of threats. Neuroimaging and biochemical studies suggest that the balance between adaptive and maladaptive anxiety is modulated by regions of the brain called the limbic system, mainly the amygdala, and key neurotransmitters that act on nerve cells in the amygdala and other areas. Anxiety disorders (ADs) include social AD (SAD), generalized AD (GAD), panic disorder, specific phobias, and separation anxiety. Obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD), which can have similar symptomology, are diagnosed separately. Together, ADs and anxiety-related disorders are the most common psychiatric disorders in the United States. They are associated with decreased well-being, severe emotional distress, physical impairment, loss of productivity, and higher health care costs.

The main pharmacological treatments for anxiety and ADs modulate activity of various neurotransmitters. Less-common treatments include second-generation antipsychotics, anticonvulsants, and some antihistamines. All have limited efficacy and may cause adverse effects (AEs).

The endocannabinoid system (ECS), a biochemical signaling system, is a target for anxiolytic drugs due to its role in modulating nerve-to-nerve communication and synaptic plasticity (changes in the activity of synapses, the gaps between neurons through which electrical and chemical signals pass) in the anxiety response. The ECS includes two known cannabinoid (CB) receptors: CB1 and CB2. Cannabidiol (CBD), a psychoactive but nonintoxicating phytocannabinoid from cannabis (Cannabis sativa, Cannabaceae), has low affinity for both CB receptors. CBD is believed to indirectly affect the ECS by suppressing the inactivation of anandamide, an endogenous (internally originating) ECS neuromodulator, which in turn activates CB1 receptors. CBD also affects serotonin (5-HT) receptors.

Few studies have examined CBD’s potential for AEs and drug interactions versus other agents, but available evidence suggests that CBD has a favorable safety profile. CBD can be administered orally or topically and is available in tinctures, oils, topical creams, vaporization agents, and infused foods and beverages. Only one CBD product, Epidiolex® (GW Pharmaceuticals; Cambridge, England), a standardized oil-based CBD oral solution, is approved as a drug by the US Food and Drug Administration (FDA). Other cannabis-derived CBD products are regulated by the FDA under the 2018 Farm Bill, and, as the review authors noted, “determination of the scope of this regulation is evolving.”

The authors conducted a systematic review of evidence for CBD’s safety and efficacy in anxiety and ADs, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. An electronic database search of PubMed, Google Scholar, and International Pharmaceutical Abstracts for studies between January 1996 and June 2019 found 233 potentially relevant reports. Nine were added from references. Studies were included if they reported CBD treatment of anxiety or ADs or assessed the effects of CBD on anxiety response in healthy humans. In vivo assays and clinical studies that evaluated psychosis-related components of PTSD or OCD, or the role of CBD in modulating cannabis-related intoxication, were excluded. After screening the articles, eight met all the inclusion criteria. They included six randomized, placebo-controlled clinical trials (RCTs), a case report, and a case series (a type of observational study).

In a double-blind, crossover RCT, 10 healthy men who took a single dose of 400 mg CBD had significant reductions in anxiety (P < 0.001) assessed by visual analog scale (VAS) at all time points (30, 60, and 75 minutes after ingestion). The subjects also had significantly increased regional cerebral blood flow (rCBF) in the medial temporal cortex (P < 0.001), as assessed by single-photon emission computed tomography, a neuroimaging technique. Sedation was mentioned as an AE, but the frequency and severity of this AE were not reported.

In another double-blind RCT, 59 healthy men and women with no diagnosed AD or alcohol- or drug-related disorders were randomly assigned to one of five groups: 100 mg CBD, 300 mg CBD, 900 mg CBD, 1 mg clonazepam (a benzodiazepine), or placebo. VAS scores measuring subjective anxiety and sedation and vital signs were recorded at baseline and before, during, and after a simulated public speaking (SPS) exercise. After the speech, VAS scores were significantly lower in the 300 mg CBD group compared to the placebo and 100 mg CBD groups (P < 0.05 for both). Anxiety during the speech decreased significantly more from baseline in the 300 mg CBD group versus the 900 mg group (P < 0.05). Clonazepam was significantly more sedating than the different doses of CBD (P < 0.05 for all) during all phases of the SPS. The authors noted that the results were in line with previous findings and suggested “that CBD induces acute anxiolytic effects with an inverted U-shaped dose-response curve in humans — an effect that, at this time, is not fully understood.” In other words, increasing doses of CBD correspond to increased effects until a maximum point is reached, after which effects begin to decrease as the CBD dose continues to increase. Another double-blind RCT using VAS scores and an SPS exercise supported this inverted U-shaped dose response, with 300 mg CBD having more of an anxiolytic effect than 150 mg or 600 mg CBD in 57 healthy men.

In another double-blind RCT, 40 healthy adults were separated into four groups of 10 that received 300 mg CBD, 10 mg diazepam (a benzodiazepine), 5 mg ipsapirone (an antidepressant and anxiolytic), or placebo before an SPS exercise. VAS scores indicated that CBD significantly reduced post-SPS anxiety versus placebo (P = 0.017). Ipsapirone significantly reduced performance anxiety versus placebo (P = 0.037). Diazepam significantly reduced anxiety throughout the study when compared to placebo (P = 0.016 overall), but the authors noted that the associated physical and mental sedation limited its usefulness despite its efficacy.

A double-blind RCT evaluated 600 mg CBD versus placebo in 24 patients with SAD and compared the effects with 12 healthy controls who received no study agent. Subjective and physiological measures were used in an SPS exercise. Patients with SAD who received placebo had significantly higher anxiety than healthy controls (P value not stated). The CBD group had significantly less anxiety during the SPS exercise compared to the placebo group (P = 0.009).

An open-label case series of 72 adults with anxiety or sleep disorders in an outpatient psychiatric clinic observed the effects of prescribed daily doses of CBD (ranging from 25 mg to 175 mg) for up to three months. Anxiety was assessed at baseline and monthly follow-ups via the Hamilton Anxiety Rating Scale (HAM-A). Patients were included if they had at least one follow-up visit after CBD was prescribed. At one month, 79.2% of patients’ HAM-A scores had improved over baseline. At two months, 78.1% of those assessed had improved compared to the previous month. Third month scores did not differ significantly from second month scores. AEs included sedation, dry eyes, fatigue, and increased sexually inappropriate behavior. A few subjects with fatigue and sexual inappropriateness stopped CBD. The study concluded that CBD reduced anxiety over the period used, had a sustained effect, and was well-tolerated.

The included case report described the effects of CBD on PTSD-related anxiety in a 10-year-old girl, who did not respond to previously prescribed pharmacotherapy. The patient received 25-mg capsules of CBD oil daily for four months, after which she also received a sublingual spray to take for anxiety as needed (6-12 mg CBD per spray). Anxiety was assessed using a self-report scale at baseline and once per month for five months. From baseline to the last assessment, anxiety scores decreased by 47%. No AEs were reported.

In the eight studies reviewed, CBD regularly produced improvements in SAD, GAD, and anxiety related to PTSD. However, the small sample sizes, low statistical power of many of the studies, and use of subjective self-report measures, among other limitations, make it necessary to interpret results with caution. These authors also did not provide a quality assessment of included studies.