The dorsal raphe is one of the most extensively studied modulatory nuclei in the brain, despite being a structurally inconspicuous group of cells along the midline of the midbrain. Its serotonergic neurons were among the first to be visualised by histochemical fluorescence techniques in the 1960s (the Falck-Hillarp method), which traced their projections across the entire forebrain and revealed the diffuse nature of the monoamine projection systems.

The serotonin hypothesis of depression, dominant since the 1960s, has been substantially revised. Direct manipulations of brain 5-HT do not cleanly reproduce depression in non-depressed subjects, and the therapeutic action of SSRIs takes weeks to manifest despite immediate elevation of synaptic 5-HT. Modern frameworks emphasise neuroplasticity and BDNF signalling downstream of sustained 5-HT elevation, rather than 5-HT levels per se.

Psychedelic agonists at the 5-HT2A receptor, including psilocybin and LSD, are undergoing renewed clinical investigation for treatment-resistant depression and end-of-life distress. The therapeutic mechanism appears to involve a transient state of enhanced cortical plasticity rather than sustained pharmacological action, with single sessions producing measurable symptom reduction over weeks to months.