Placebo effects in a RCT assessing 30 days of low dose Cannabidiol (CBD) treatment for psychological distress in stressed students at risk for depression

Cannabidiol (CBD) has been suggested to have a therapeutic role for certain mental health conditions despite a lack of empirical evidence (Khan et al. 2020; Bonaccorso et al. 2019; Kirkland et al. 2022). The aim of the RCT (DRKS00030971) was to assess the effect of a daily sublingual application of a low dose over-the-counter 10% full spectrum CBD-oil over 30 days, compared to a placebo-oil and a no-treatment control group without application of any oil on perceived stress and psychological distress in a sample of stressed students. Another goal was to assess the role of treatment expectation on the potential placebo effect. A sample of 180 highly stressed university students at risk of depression were randomized to a one-month intervention with CBD-oil or placebo-oil or a no-treatment control group. All participants received the same information about CBD. Participants took the respective oil for 30 consecutive days. Measures of psychological distress were administered 3 times (before, after intervention, 4 weeks follow-up). After 30 days of intervention, groups differed significantly in decrease of stress, depressive symptoms, and somatization, but not regarding other outcomes of psychological distress (anxiety, sleep quality, increase of wellbeing). Participants in the CBD and placebo group benefitted significantly more compared to the no-treatment control group. No significant difference in any outcome was shown between the CBD-oil and the placebo-oil group. Interestingly, treatment expectation was not correlated with the decrease of symptoms in the placebo group, but with a direct rating of treatment effects at post-treatment. While we could not find a differential efficacy of CBD treatment on perceived stress and psychological distress, the results of the study suggest a substantial placebo response in low dose CBD treatment. Explicit treatment expectation as an underlying mechanism seems to play a minor role in explaining this placebo effect, but was correlated with the a posteriori subjective rating of treatment effects at post-treatment. Pre-registered on 22/12/2022 at DRKS-ID: DRKS00030971.