Serotonergic psychedelics for depression: A comprehensive overview

Depressive disorders continue to pose a major clinical challenge worldwide, particularly given the high prevalence and increasing number of treatment-resistant cases. Over the past decade, advances in research have elucidated the antidepressant potential of psilocybin and other 5-HT₂A receptor agonists in patients with major depressive disorder (MDD) and treatment-resistant depression (TRD). Phase I and II clinical trials have consistently demonstrated that even a single administration can yield rapid and sustained symptom reduction. These effects compare favourably with conventional pharmacotherapies such as SSRIs and ketamine. The distinctive pharmacological profile and robust safety data associated with serotonergic psychedelics make them particularly promising candidates, especially for patients who do not respond to standard treatments. Nonetheless, several challenges impede their integration into routine clinical practice, including the resource-intensive nature of psychedelic-assisted therapy, which demands specialized training and controlled settings. Despite those limitations, some countries including Australia, Switzerland or Canada are paving the way by allowing the use of psilocybin in TRD cases. This chapter reviews the antidepressant potential of psilocybin, DMT, ayahuasca and 5-MeO-DMT based on modern clinical trial data, comparing effect sizes of psychedelics to conventional treatments like SSRIs and ketamine, and provides a brief overview of their potential neurobiological mechanisms.