In search of finding the neurobiological underpinnings by which cannabidiol (CBD) could possibly exert an anxiolytic effect on the brain, Jose Crippa et. al. designed what they state is the first study to investigate CBD’s effect on anxiety disorders. In addition to identifying which brain regions are impacted by cannabidiol, the authors also suggest two physiological functional mechanisms by which CBD could be initiating these changes. They were able to produce statistically significant but modest findings with important potential implications.
The research was conducted through the University of São Paulo, Brazil. Ten participants were ultimately selected to take part in the experiment based on a survey on anxiety. These ten were all right-handed males with a mean age of 24.2 who had an average of 14.8 years of history with generalized social anxiety. The severity of their social anxiety was rated using the Brief Social Phobia Scale (BSPS) which gives an overall social anxiety score from 0-76 and the Social Phobia Inventory (SPIN) which gives an overall social anxiety score of 0-68. The average BSPS score was 61 and the average SPIN 57.9, classifying these individuals as having severe social anxiety.
The obvious issues with this sample are the lack of sample size, no gender diversity, and too broad of an age range (20-33) as to be generalizable to either a larger population or a specific demographic. Also, it is not stated why only ten subjects were selected – whether because of a limited amount of the drug or because only so many responded and still met the criteria. While the authors claim that the participants were treatment naive, they qualified treatment naive as not having ingested marijuana in the past year or not more than five times in their life and as not having any medical treatment for their anxiety disorder in the past three months.
The primary statistic being studied was ratings of subjective anxiety based on the Visual Analogue Mood Scale (VAMS) as a factor of time and drug interaction. Ratings on the VAMS scale consists of pointing on a spectrum of feelings, e.g. calm – agitated, while under examination. The anxiety provoking event in the experimental design was the SPECT (Single Photon Emission Computed Tomography) procedure itself which included injections of 99mTc-ECD which was used to measure blood flow as a function of brain activity. VAMS evaluations were conducted at five points during the experiment; 30 minutes prior to drug intake, at the time of drug intake, 60 minutes after drug intake, and at 140 minutes after drug intake. Tubes were hooked up at 60 minutes, 99mTc-ECD injected at 90 minutes, and brain imaging taken at 110 minutes. Participants were trained on VAMS evaluation prior to the beginning of the experiment.
The timing of VAMS evaluation and stress markers were chosen based on the plasma peak of CBD having been identified by the authors as being anywhere from one to two hours. Brain imaging was performed using Statistical Parametric Mapping software (SPM2) with particular attention paid to the voxels in the limbic and paralimbic systems. The results, as discussed below, will have to be analyzed under scrutiny of what was a big experimental flaw. The authors were researching a hypothesis based on social anxiety disorders but did not test for social situations, instead using the SPECT imaging procedure itself as the anxiety provoking stimulus.
It initially seemed like the right idea to rigorously train subjects on the VAMS evaluation as to control for only one anxiety event (SPECT procedures). However being as it was a study on social anxiety, presenting the subjects with an unfamiliar examination and forcing them to respond based on only having a rudimentary understanding of the rules would have elicited emotional response networks in the brain more akin to those provoked in anxiety and fear responses.
The authors compared the effects of CBD and placebo on resting regional cerebral blood flow (rCBF) of social anxiety disorder patients in a double-blind, randomized, repeated measures, within-subject crossover design. VAMS factors were submitted to a two-way repeated-measures analysis of variance (ANOVA). They found that compared to placebo (p<0.001), the CBD group had decreased rCBF activity in the left parahippocampal gyrus and hippocampus based on reduced ECD uptake. They found increased rCBF in the right posterior cingulate gyrus (p<0.001) based on increased ECD uptake. The anxiety scale for VAMS was a factor analysis including ratings of calm-excited, relaxed-tense, and tranquil-troubled and was taken at the five intervals. The results for CBD vs. placebo at these phases were measured in centimeters as a function of space between the options on a spectrum VAMS scale, the results are summarized here; +1.4 at pre-drug -30mins, +1.9 at drug intake 0mins, -8.3 at pre-stress 60mins, -7.6 at adaptation 75mins, and -11.3 at post-stress 140mins. Statistical significance was shown at the 60, 75, and 140 minute time intervals.
The VAMS scores show definitively that the CBD group exhibited significantly less anxiety when compared to the placebo group from the stress onset, plasma peak point onward. Other factors of the VAMS (physical sedation, mental sedation, and other feelings) showed no statistical significance. Although the CBD group did show increased mental sedation at the post-stress 140 minute evaluation whereas the placebo remained at essentially the same level of mental sedation from -30 minutes to 140 minutes after drug intake. These findings make sense when considering the decreased parahippocampal activity. The findings do need to be considered in light of the within-subject crossover design and the absence of individual VAMS scores. Since that information is not available and because of the design, it is not possible to tell how much prior experience on the SPECT procedure impacted the CBD group or placebo group. Participants were tested twice, one week apart. Half received CBD the first trial, half received placebo and then vice versa. Being double blind, the results for rCBF are valid however the authors couldn’t find correlations between VAMS scores and ECD measurements, in part, because of the extraneous variable role that experience could have played.
Discussion and Integration
In addition to their research, the authors spend a good deal of time discussing two potential physiological functional mechanisms through which CBD could be influencing anxiolytic effects. The first mechanism is through the enhancement of the endogenous anandamide feedback system in the amygdala by which increased cannabinoid activity keeps the fear response from getting out of control and modulates the anxious state. The second suggested mechanism is through the agonist role of CBD on the 5-HT1A receptor (a subtype of serotonin). Since these mechanisms affect CB1 and CB2 receptors as noncompetitive ligands and don’t rely on benzodiazepine receptors, there is an inference that anxiolytics effects can be accomplished safely.
The researcher’s findings of increased posterior cingulate gyrus activity is interesting when one considers the existing evidence that social rejection activates the anterior cingulate cortex. This relation shows the potential relationships in different areas of the cingulate cortex and how CBD could impact the region. As increased happiness and lowered social inhibition associated with increased right posterior cingulate cortex activity becomes more salient, left anterior cingulate cortex activity associated with anger and social rejection becomes less salient.
In light of the fact that the limbic system plays a role in modulating emotion and mood, it is important to look at the hippocampal formation and the endocannabinoid anandamide’s role as a retrograde messenger. The parahippocampal gyrus has been implicated in the context encoding aspect of social learning. Therefore it can be inferred that overstimulation in this region could be associated with the over generalization of the fear response in generalized social anxiety disorder. Additionally the dentate gyrus of the hippocampal formation is thought to be one of the very few locations which can experience neurogenesis in adulthood. If CBD, as implicated in the study, is decreasing parahippocampal activity it could mean that the overgeneralizing of the fear response is being reduced. This would explain the retrograde neuromodulating effects associated with improved anandamide function. Long-term potentiation of neurons in the hippocampus then, can be seen as being a rewiring of the fear response as a function of altered parahippocampal activity. Providing a mechanism by which CBD could have an anxiolytic effect and provide long-term relief from social anxiety.
While many of these potential benefits are exciting, it is important to keep in mind, as the authors note, to wait until double-blind placebo long-term studies can be conducted. Additionally, the study being discussed did not provide experimental parameters involving actual social interaction and did not observe dramatic changes in the amygdala. This is in part because of the software they chose to use but also because of the conditions that were not created in the current experimental design. Situations which would trigger the emotional network in the limbic system where social rejection and fear would be prominent and amygdala stimulation salient, require future studies of how CBD could mediate this more complex emotional response.
* Crippa, J. A., Derenusson, G. N., Ferrari, T. B., Wichert-Ana, L., Duran, F. L., Martin-Santos, R., . . . Hallak, J. E. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology, 25(1), 121-130. doi:10.1177/0269881110379283
** Breedlove, S. M., & Watson, N. V. (2013). Biological psychology: an introduction to behavioral, cognitive, and clinical neuroscience. Sunderland, MA: Sinauer Associates, Inc., .