MAHVASH KHAN, MUHAMMAD OMAR MALIK, AYYAZ AHMED, NIMRA FARID4, BUSHRA RIAZ, MEHVISH ASHFAQ, MUHAMMAD ISMAIL
DOI: https://doi.org/Psilocybin, a naturally occurring psychedelic compound derived from mushrooms, has emerged as a promising therapeutic agent in psychiatric research. As conventional antidepressants often fall short for many patients with major depressive disorder (MDD), interest has grown in psilocybin for its potential to provide rapid and sustained symptom relief. This study aimed to systematically evaluate and quantify the effect of psilocybin on key hypothalamic-pituitary-adrenal (HPA) axis biomarkers cortisol, ACTH, and corticosterone in both human and animal models, better to understand its role in stress regulation and depression treatment. This research follows the PRISMA 2020 guidelines systematic review and meta-analysis. A comprehensive search of PubMed, Scopus, PsycINFO, and Google Scholar was performed up to April 2025 using predefined search terms related to psilocybin, HPA axis, and depression. Studies were included to determine whether they involved psilocybin or ayahuasca administration in human or animal models and reported outcomes related to cortisol, ACTH, or corticosterone. Two reviewers independently screened titles, abstracts, and full texts for eligibility, and extracted data using a standardized form. The meta-analyses were conducted in RevMan 5.4 using a random-effects model to compute the standardized mean differences (SMDs) with corresponding 95% confidence intervals. The I² statistic was used to evaluate heterogeneity, whereas funnel plots and Egger's regression test were utilized to assess publication bias. Seven clinical and preclinical studies that determined eligibility were selected. The results showed that psilocybin significantly influenced all three biomarkers, suggesting it may restore HPA axis balance through mechanisms distinct from traditional antidepressants. Despite the encouraging findings, significant heterogeneity was observed, likely due to differences in dosing, timing of biomarker measurement, and study designs. The findings suggest that psilocybin may modulate the HPA axis and influence stress hormone levels, which could underlie its antidepressant effects. However, the study variability highlights the need for more uniform, large-scale trials to determine its therapeutic utility and physiological mechanisms.
