The power of placebo: Does cannabidiol (CBD) expectancy alone impact acute stress and anxiety?
Authors: Spinella Toni , Stewart Sherry , Naugler Julia , Yakovenko Igor , Barrett Sean 
Published: September 2022

Background. There have been notable increases in the use of cannabidiol (CBD) for therapeutic purposes, such as in the treatment of stress- and anxiety- related disorders. Preliminary research has demonstrated that CBD decreases indices of stress and anxiety. However, drug effects in humans are thought to be comprised of both pharmacological properties as well as a placebo response. Little is known about the extent to which the purported therapeutic effects of CBD result from pharmacological versus expectancy factors. Aims. The aim of this study was to evaluate whether (i) CBD expectancy alone could influence stress, anxiety, and mood, and (ii) the extent to which beliefs regarding CBD effects predicted these responses. Generalized estimating equations (GEE) were used to evaluate the research questions of interest. Methods. In this randomized crossover study, 43 health adults (23 women) attended three laboratory sessions. During the first session, they were oriented to the study and rated the extent to which they believed that CBD helped with stress, anxiety, and mood. They then participated in two identical 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) to induce moderate levels of stress and anxiety. Heart rate variability (HRV) was assessed continuously, and subjective state (i.e., stress, anxiety, mood, other subjective states) 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 significant fluctuations in HRV that could indicate heightened anticipatory stress regulation. Overall, there were no observed changes in subjective stress, or anxiety, according to expectancy condition. However, participants who endorsed the strongest a priori beliefs about CBD possessing anxiolytic properties reported significantly lower anxiety in the CBD expectancy condition and higher anxiety the CBD-free expectancy condition. Conclusions. Results from this study indicated that CBD expectancy alone impacted several subjective and physiological responses. Additionally, expectancy-related factors were implicated in anxiolytic effects of CBD for those who strongly believed it was helpful for such purposes, suggesting that expectation plays some role in the purported stress- and anxiety- reducing effects of CBD. Findings from this study emphasize the need to measure and control for CBD-related expectancies in clinical research that involves the administration of CBD. Future investigations would benefit from replicating these findings and using a full balanced-placebo research design to elucidate the relative contributions of pharmacology and expectancy.