Psilocybin as Transformative Fast-Acting Antidepressant: Pharmacological Properties and Molecular Mechanisms

In the 1950s-60s, serotonergic psychedelic drugs were studied as potential adjuvants to psychotherapy to treat addiction and alcoholism. However, starting in the 70s, preclinical and clinical studies on psychedelics stopped for decades because legislation controlled its recreational use, citing their hallucinogenic and psychotomimetic effects, as well as their abuse potential. Amazingly, we are witnessing an impressive return of these drugs due to recent clinical trials suggesting a therapeutic potential of psychedelics, among them psilocybin, for treating patients with depression resistant to conventional antidepressant drugs. Yet, their underlying mechanisms of action remain incompletely elucidated. This review provides an update on seminal clinical trials using psilocybin, as well as preclinical work uncovering the pharmacological properties and experimental pharmacology of psilocybin and its active metabolite psilocin. These drugs are primarily serotonin 5-HT_2A receptor (5-HT2AR) agonists. Although there is a consensus that 5-HT2AR activation mediates its psychedelic effects in human and rodent models of anxiety/depression, its role in psilocin's antidepressant effects remains controversial. This review also provides an overview of neurotransmitter systems, neuroplasticity, and neural circuits activated by psilocin. Further research in developing effective antidepressants for depression is prescient now more than ever, as according to the World Health Organization (WHO), depression will be the main cause of disability in 2030. Understanding the mechanisms through which psilocybin/psilocin would be an effective antidepressant is crucial to ultimately validate its therapeutic potential when combined with SSRIs/SNRIs in mood disorders.