Experience, plasticity, and context: Beyond single-level models of antidepressant action

The re-emergence of serotonergic psychedelics has introduced rapid-acting antidepressant effects and has been widely described as a paradigmatic shift in depression treatment. Recently, there has been intense debate about whether the acute subjective effects of psychedelics are necessary for their therapeutic efficacy or merely byproducts of underlying neuroplastic processes. Recent conceptualizations of "psychoplastogens" emphasize rapid induction of neuroplasticity as a potential common pathway across mechanistically diverse rapid-acting antidepressants. Here, some argue that the psychedelic experience itself may not be required for enduring therapeutic change while others highlight the clinical and existential significance of the subjective experience and its integration within structured psychotherapeutic settings. This Perspective argues that the debate is often framed too narrowly as a binary opposition between experience and mechanism and opts for a complementary model in which receptor-level signalling, network reorganization, subjective experience, and psychotherapeutic context represent interacting dimensions of a single intervention architecture. Within this framework, subjective experience may be clinically meaningful without being biologically indispensable, while neuroplasticity may constitute an enabling condition without being sufficient in isolation. Rather than asking whether experience or mechanism is primary, the clinically relevant question becomes under which conditions, for which patients, and within which care structures different plasticity-inducing interventions, hallucinogenic or non-hallucinogenic, are most appropriate. This question is further complicated by methodological challenges in isolating those contributions empirically. Psychedelic research thus challenges not only neurobiological models of depression but also existing assumptions about how pharmacological and psychotherapeutic processes converge in antidepressant treatment.