Evaluating cannabidiol (CBD) expectancy effects on acute stress and anxiety in healthy adults: a randomized crossover study

Abstract

Rationale: Cannabidiol (CBD) has been reported to attenuate stress and anxiety, but little is known about the extent to which such effects result from pharmacological versus expectancy factors.

Objectives: We evaluated whether CBD expectancy alone could influence stress, anxiety, and mood, and the extent to which beliefs regarding CBD effects predicted these responses.

Methods: In this randomized crossover study, 43 health adults (23 women) attended two experimental laboratory sessions, where they self-administered CBD-free hempseed oil sublingually. During one session, they were (incorrectly) informed that the oil contained CBD and in the other session, that the oil was CBD-free. Following administration, participants engaged in the Maastricht Acute Stress Test (MAST). Heart rate variability (HRV) was assessed continuously, and subjective state was assessed at baseline, 90-min following oil administration, immediately following the MAST, and after a 10-min recovery period.

Results: The CBD expectancy condition was associated with increased sedation as well as with changes in HRV that were consistent with heightened anticipatory stress regulation. Overall, there were no systematic changes in subjective stress, or anxiety, according to expectancy condition. However, participants who endorsed strong a priori beliefs that CBD has anxiolytic properties reported significantly diminished anxiety in the CBD expectancy condition.

Conclusions: CBD expectancy alone impacted several subjective and physiological responses. Additionally, expectancy-related factors were implicated in anxiolytic effects of CBD for those who believed it was helpful for such purposes, emphasizing the need to measure and control for CBD-related expectancies in clinical research that involves the administration of CBD.

Keywords: Affect; Anxiety; Anxiolytic; CBD; Cannabidiol; Cannabis; Expectancy; Placebo; Stress; Subjective response.

Fig. 1

Estimated marginal mean (± standard error). a Stress [Numeric Rating Scale “Stress”; score range 1–10], b Anxiety [State-Trait Anxiety Inventory- State Version, Short Form; total score range: 20–80]. c Negative affect [International Positive Negative Affect Schedule- Short Form; total score range: 5–25]. d Positive affect [International Positive Negative Affect Schedule- Short Form; total score range: 5–25] ratings over Time by Expectancy condition. No significant Time by Expectancy condition interactions were observed for any of the subjective ratings. Baseline (T1): +00; Post-absorption (T2): +95; Post-stress (T3): +110; Recovery (T4): +120

Fig. 2

Estimated marginal mean (± standard error) RMSSD, an index of heart rate variability, over Time by Expectancy condition. RMSSD is a measure of vagal tone, thus higher RMSSD is thought to represent more parasympathetic output. A decrease in RMSSD is thought to represent a greater physiological stress response. In the CBD expectancy condition, RMSSD changed sequentially over time, and was higher at recovery relative to baseline. In the CBD-free expectancy condition, RMSSD was lower during stress relative to recovery, and higher at recovery relative to baseline. RMSSD root mean square of successive differences. Baseline (T1): +00 − + 70; Anticipation (T2): +95; Stress (T3): +100; Recovery (T4): +110

Fig. 3

Plot of generalized estimating equation (GEE) model predicted values for ratings of anxiety [State-Trait Anxiety Inventory-State Version, Short Form; total score range: 20–80] (adjusted for baseline scores) by expectancy condition at a post-absorption, b post-stress, and c recovery. Darker points indicate higher endorsement of belief that CBD reduces anxiety, whereas lighter points indicate lower endorsement of belief [Numeric Rating Scale “CBD reduces anxiety”; score range 1–10]. A belief by expectancy condition interaction was observed such that participants who endorsed the highest beliefs that CBD reduces anxiety (third tercile; 9–10) had significantly lower anxiety ratings in the CBD expectancy condition relative to CBD-free condition (across all three time points post-administration). Baseline (T1): +00; Post-absorption (T2): +95; Post-stress (T3): +110; Recovery (T4): +120