The impact of cannabidiol placebo on amygdala-based neural responses to an acute stressor

Abstract

Background: Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD's anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress.

Method: Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA.

Results: CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC (p = 0.042), but did not systematically alter amygdala-AI rsFC (p-values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context.

Conclusion: CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity.

Keywords: Cannabidiol; amygdala; anterior cingulate cortex; neuroimaging; placebo.

Figure 1.

Experimental session timeline. T1–T6 refer to the time points for subjective assessments, which included ratings of stress, anxiety, energy, and sedation, all measured on a scale from 1 (not at all) to 10 (extremely); CO: carbon monoxide; rs: resting state; EPI: echo planar imaging; Baseline and Post-Stressor rs MRI scans are bolded, as these reflect the two primary time points of interest for the rsFC analyses. Gray and Blue shadings differentiate measures taken outside versus inside the MRI scanner, respectively. Task difficulty was rated on a scale from 1 (not at all) to 10 (extremely).

Figure 2.

ROIs in MNI152 template space. (a) Bilateral amygdala (R: 24.1, −8.05, −20.06; L: −23.5, −6.73, −19.7). (b) Bilateral dACC (R: 7.35, 19.98, 29.06; L: −6.8, 21.32, 28.29). (c) Bilateral AI (R: −38.97, 12, −8.11; L: 44.54, 13.44, −7.51). Six millimeters Seed Regions of Interest (ROI) were used for the rsFC analyses. R: right; L: left; dACC: dorsal anterior cingulate cortex; AI: anterior insula; Each seed ROI was defined as a 6 mm sphere created using NiftiSphereMasker from Nilearn 0.9.0 in standard MNI152 template space.

Figure 3.

Group differences in post-stressor rsFC between the Amygdala and pairwise ROIs. rsFC: resting state functional connectivity, measured as Pearson r correlations between pairwise ROIs; ROIs: regions of interests; dACC: dorsal anterior cingulate cortex; AI: anterior insula; R: right, L: left; Results correspond to a sample of N = 32. *p < 0.05.

Figure 4.

Estimated marginal means (±standard error) for subjective outcomes. Subjective results presented in panels (a–d) correspond to a more restricted head motion sample of N = 32. Stress, anxiety, sedation, and energy were rated on a scale from 1 (not at all) to 10 (extremely). T1–T6 refer to the time-points for subjective assessments (i.e., T1: Baseline; T2: in scanner; T3: post-oil; T4: post-stressor; T5: anticipation; T6: recovery). All panels show the pairwise breakdown of subjective ratings by time, within each of the two expectancy conditions (Told CBD vs Told CBD-free). For panels (a) and (b), time point 4 was significantly different from all other time points within each expectancy condition, indicating that the counting task effectively increased subjective stress and anxiety. Time-varying covariates specified in each model are shown as baseline values. **p < 0.001, *p < 0.05.