Psilocybin, a serotonergic psychedelic, is being reexamined for treating depression resistant to conventional antidepressants. Recent clinical trials suggest therapeutic potential, though its mechanisms remain unclear. Psilocybin's active metabolite, psilocin, primarily activates serotonin 5-HT2A receptors, which mediate its psychedelic effects, but its role in antidepressant effects is debated. Preclinical work explores neurotransmitter systems, neuroplasticity, and neural circuits involved. Understanding these mechanisms is crucial for validating psilocybin's use alongside SSRIs/SNRIs in mood disorders, especially as depression is projected to become the leading cause of disability by 2030.
Ketamine's rapid antidepressant effects in depressed patients may depend on a specific metabolite, (2R,6R)-hydroxynorketamine ((6)-HNK). In male BALB/cJ mice with high anxiety, blocking liver enzymes that break down ketamine (using fluconazole) raised ketamine and norketamine levels in blood and brain but sharply reduced (6)-HNK levels. This blockade prevented ketamine's sustained antidepressant-like effects 24 hours later in behavioral tests and stopped the increase in cortical GABA levels. Giving a single dose of (2R,6R)-HNK alone restored the antidepressant-like activity. The findings indicate that (6)-HNK is essential for ketamine's lasting antidepressant effects and suggest that drug interactions affecting ketamine metabolism could matter in patients.