The first evidence of CBD’s anxiolytic effects in humans, documented with assessment scales, was published in 1982 in a study on the interaction between CBD and THC. The study sample consisted of eight volunteers with a mean age of 27 years, no health problems and who had not used Cannabis sativa in the previous 15 days. In a double-blind procedure, the volunteers received CBD, THC, THC + CBD, diazepam, and placebo in different sequences and days. The results showed that the increased anxiety following the administration of THC was significantly attenuated with the simultaneous administration of CBD (THC + CBD).
Based on this preliminary evidence, researchers decided to investigate a possible anxiolytic action of CBD in experimentally induced anxiety in healthy volunteers using the simulated public speaking (SPS) model. The procedure consists of asking a subject to speak in front of a video camera for a few minutes, while subjective anxiety is measured with self-rated scales and physiological correlates of anxiety are recorded (heart rate, blood pressure, skin conductance). CBD (300 mg), as well as the anxiolytic drugs diazepam (10 mg) and ipsapirone (5 mg), administered in a double-blind design, significantly attenuated SPS-induced anxiety.
The SPS test may be regarded as a good model of anxiety and has apparent validity for social anxiety disorder (SAD), as the fear of speaking in public is considered a central feature in this condition. Therefore, the anxiolytic effect of CBD in healthy volunteers observed in this test led to the hypothesis that this cannabinoid could be effective to treat SAD. This hypothesis was recently tested in 24 patients with SAD who had their performance in the SPS test compared to that of a group of 12 healthy controls. The patients with SAD were divided into two groups of 12, one of which received CBD 600 mg and the other placebo, in a double-blind procedure. The results showed that the levels of anxiety, somatic symptoms, and negative self-assessment were higher in patients who took placebo than in those of the CBD group who performed similarly to healthy controls in some measures.
In another study that investigated the effects of CBD on regional cerebral blood flow (rCBF) in healthy volunteers using single photon emission computed tomography (SPECT), SPS-induced anxiety was reduced in patients receiving CBD. In that study, patients received either CBD (400 mg) or placebo, in a crossed double-blind design, in two experimental sessions with an interval of one week. CBD significantly reduced subjective anxiety as measured by rating scales, while brain activity was increased in the left parahippocampal gyrus and decreased in the left amygdala-hippocampus complex, including the fusiform gyrus. This pattern of SPECT results is compatible with an anxiolytic action.
SPECT was also used later to investigate the neural correlates of CBD’s anxiolytic effects in a sample of patients with SAD. A single dose of CBD 400 mg was able to reduce subjective anxiety measures and SPECT showed changes in the same regions previously identified in healthy volunteers.
Functional magnetic resonance imaging (fMRI), which allows the acquisition of larger series of images with better temporal and spatial resolution, was used to investigate the neural correlates of the anxiolytic effects of CBD in 15 healthy volunteers. This experiment showed that CBD (600 mg) attenuated fMRI responses during the recognition of fearful facial expressions in the amygdala and the anterior cingulate, and that this attenuation pattern correlated with skin conductance responses to the stimuli. The same group also reported that the anxiolytic action of CBD occurs by altering the subcortical prefrontal connectivity via amygdala and anterior cingulated.