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Psychedelics have emerged as a promising novel therapeutic approach for major depressive disorder (MDD). Altered activity and structural atrophy of the prefrontal cortex, hippocampus, and limbic structures are associated with depressive disorders. Psilocybin may reverse the loss of synaptic connections and restore the function of these brain regions. In this study, we investigated the effects of psilocybin on rat behavior, hippocampal neurogenesis, expression level of brain-derived neurotrophic factor (BDNF) and hypothalamic-pituitary-adrenal (HPA) axis activity. Psilocybin administered in two doses (0.6 mg/kg, s.c., 7 days apart) reversed anhedonia in stressed rats, produced antidepressant-like effects in the forced swim test (FST), and exerted anxiolytic activity in the light/dark box (LDB), elevated plus maze (EPM), and open field (OF) tests in stressed animals. Psilocybin induced hippocampal neurogenesis as evidenced by increasing the number of BrdU-positive cells (an exogenous marker of cell proliferation and survival), DCX-positive cells (a marker of immature neurons), and Ki-67-positive cells (an endogenous marker of cell proliferation) in stressed animals. Stress-induced reductions in BDNF expression levels appeared to be associated with normalization of HPA axis activity. These findings underscore the role of psilocybin-induced neuroplasticity in the antidepressant and anxiolytic mechanisms of psychedelics. Show less

Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT Show less

Serotonergic psychedelics are re-emerging as therapeutic candidates across psychiatry, particularly for treatment-resistant depression. Their rapid and sustained antidepressant effects, alongside evidence for neuroplastic, dopaminergic, and glutamatergic modulation, have prompted interest in whether they could address depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). This narrative review summarizes mechanistic, preclinical, and early clinical findings relevant to psychedelic use in SSDs. Schizophrenia and major depressive disorder share disturbances in dopamine, glutamate, and neuroplasticity, and both involve large-scale network abnormalities. Schizophrenia is associated with widespread dysconnectivity, mesocortical hypodopaminergia, and striatal hyperdopaminergia linked to NMDA receptor hypofunction. Depression is characterized by fronto-limbic and default mode network hyperconnectivity, mesolimbic hypodopaminergia, and reduced cortical glutamatergic tone. Depressive symptoms within SSDs may reflect an intermediate phenotype combining depressive-like hyperconnectivity with schizophrenia-related global dysconnectivity, suggesting that psychedelics' capacity to transiently increase network flexibility and recalibrate maladaptive connectivity may be clinically relevant. Preclinical studies show increased dendritic spine density, enhanced BDNF expression, restored reward sensitivity, and modulation of network dynamics after psychedelic administration. Clinically, uncontrolled exposure appears associated with increased psychosis-related presentations, whereas limited case reports suggest controlled administration may be tolerated in carefully selected, clinically stable individuals with SSDs. To date, only one early-phase trial (MDMA in schizophrenia) is ongoing, and no randomized trials have evaluated psilocybin or LSD in SSDs. Overall, psychedelics are biologically and mechanistically plausible but remain unproven for depressive and negative symptoms in SSDs, which partially overlap. Carefully designed, safety-focused early-phase studies in clinically stable patients are therefore a prerequisite for broader clinical application. Show less

Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT Show less

Neuroplasticity refers to the ability of the brain to modify synaptic connections and reorganize neural circuits, underpinning cognitive function, emotional regulation, and recovery from injury. Recent advances have redefined adult neuroplasticity as more dynamic and therapeutically accessible than previously thought, spurring investigation into pharmacological interventions that can augment these adaptive processes. This review dissects current evidence for drug strategies targeting synaptic modulators (NMDA, AMPA, and GABA receptors), neuropeptide systems (including BDNF, oxytocin, vasopressin), and psychedelic compounds (psilocybin, LSD, ketamine), integrating insights from cellular, preclinical, and clinical studies. We detail how these agents modulate molecular pathways governing synaptic transmission, dendritic remodeling, and gene expression linked to neuronal growth and resilience. Highlighted findings include the rapid-acting antidepressant effects of NMDA antagonists, the structural and functional reorganization induced by classic psychedelics via 5-HT2A receptor activation, and the neurorestorative roles of neuropeptides in synaptic and network adaptation. Alongside these advances, we critically address safety, ethical considerations, and the risk of maladaptive plasticity, underscoring the importance of dosing, patient selection, and controlled therapeutic environments. Non-hallucinogenic neuroplastogens and combinatorial approaches that are still emerging offer new avenues to fine-tune plasticity with an improved safety profile. The collective evidence positions neuroplasticity-targeting pharmacology as a promising and complex frontier for the treatment of neuropsychiatric and neurodegenerative disorders in adulthood. Show less