To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).

Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatmentresistant depression. Preclinical and clinical studies have suggested that serum brainderived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood. Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo. In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms. This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at http://clinicaltrials.gov (NCT02914769).

Background: Mental health burden has been massively reported during the COVID-19 pandemic period. Aiming to summarise these data, we present a meta-review of meta-analyses that evaluated the impact of COVID-19 pandemic on anxiety, depressive and stress symptoms, psychological distress, post-traumatic stress disorder/symptoms (PTSD), and sleep disturbance, reporting its prevalence on general public (GP) and health care workers (HCW).Methods: A search was performed in the PubMed, EMBASE, and the Web of Science. Sleep disturbances, psychological distress, stress, and burnout were grouped as “Psychophysiological stress,” and anxiety, depression, and PTSD were grouped as “Psychopathology.” A random-effects model, calculating the pooled prevalence together with 95% confidence interval was performed for each domain. Subgroup analyses were performed for each population type (GP and HCW) and for each mental health outcome. For anxiety and depression, subgroup analysis for population type was performed. Heterogeneity is reported as I2. Publication bias was assessed through visual inspection of the funnel plot, and further tested by Egger's test and trim and fill analyses.Results: A total of 18 meta-analyses were included. The prevalence of psychophysiological stress was 31.99% (CI: 26.88–37.58, I2 = 99.9%). HCW showed a higher prevalence (37.74%, CI: 33.26–42.45, I2 = 99.7%) than the GP (20.67%, 15.07–27.66, I2 = 99.9%). The overall prevalence of insomnia, psychological distress, and stress were, respectively, 32.34% (CI: 25.65–39.84), 28.25% (CI: 18.12–41.20), and 36% (CI: 29.31–43.54). Psychopathology was present at 26.45% (CI: 24.22–28.79, I2 = 99.9%) of the sample, with similar estimates for population (HCW 26.14%, CI: 23.37–29.12, I2 = 99.9%; GP: 26.99%, CI: 23.41–30.9, I2 = 99.9%). The prevalence of anxiety, depression, and PTSD was 27.77% (CI: 24.47–31.32), 26.93% (CI: 23.92–30.17), and 20% (CI: 15.54–24.37), respectively. Similar proportions between populations were found for anxiety (HCW = 27.5%, CI: 23.78–31.55; GP = 28.33%, CI: 22.1–35.5) and depression (HCW = 27.05%, CI: 23.14–31.36; GP = 26.7%, CI: 22.32–31.59). Asymmetry in the funnel plot was found, and a slight increase in the estimate of overall psychopathology (29.08%, CI: 26.42–31.89) was found after the trim and fill analysis.Conclusions: The prevalence of mental health problems ranged from 20 to 36%. HCW presented a higher prevalence of psychophysiological stress than the general population.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=252221, identifier: CRD42021252221.