Current pharmacological treatments for major depressive disorder (MDD) are often only partially effective, with many patients experiencing no significant benefit, leading to treatment-resistant depression (TRD). Psilocybin, a classical serotonergic psychedelic, has emerged as a notable emerging treatment for such disorders. The aim of this systematic review and meta-analysis is to summarize and discuss the most recent evidence about the therapeutic effects of single-dose and two-dose psilocybin administration on the severity of depressive symptoms, as well as compare the efficacy of these interventions among patients with a primary diagnosis of MDD or TRD. Articles were collected from EBSCOhost and PubMed following the PRISMA guidelines, yielding 425 articles with 138 duplicates. After screening 287 records, 12 studies met the eligibility criteria and were included in the review. A quantitative analysis of the studies indicates that psilocybin is highly effective in reducing depressive symptoms severity among patients with primary MDD or TRD. Both single-dose and two-dose psilocybin treatments significantly reduced depressive symptoms severity, with two-dose administration sometimes yielding more pronounced and lasting effects. However, it is unclear if this was solely due to dosage or other factors. Future research should include standardized trials comparing these dosing strategies to better inform clinical practice.

Background: Metacognition refers to the ability to reflect on and regulate cognitive processes. Despite advances in neuroimaging and lesion studies, its neural correlates, as well as their interplay with other cognitive domains, remain poorly understood. The orbitofrontal cortex (OFC) is proposed as a potential substrate for metacognitive processing due to its contribution to evaluating and integrating reward-related information, decision-making, and self-monitoring. Methods: This study examined OFC involvement in metacognition using transcranial direct current stimulation (tDCS) while participants performed a two-alternative forced choice task with confidence ratings to assess their metacognitive sensitivity. Before stimulation, the subjects completed the Metacognitions Questionnaire-30 and a monetary intertemporal choice task for the quantification of delay discounting. Results: Linear mixed-effects models showed that anodal tDCS over the left OFC reduced participants’ metacognitive sensitivity compared to sham stimulation, leaving perceptual decision-making accuracy unaffected. Moreover, real stimulation increased self-reported confidence ratings compared to the sham. Significant correlations were found between metacognitive sensitivity and negative beliefs about thinking. Conclusions: These results highlight the potential involvement of the OFC in the processing of retrospective second-order judgments about decision-making performance. Additionally, they support the notion that OFC overstimulation contributes to metacognitive dysfunctions detected in clinical conditions, such as difficulties in assessing the reliability of one’s thoughts and decision outcomes.