Improving cognitive functioning in major depressive disorder with psychedelics: a dimensional approach

Magaraggia and colleagues frame major depressive disorder (MDD) as a heterogeneous syndrome in which cognitive dysfunction—particularly decreased ability to think, indecisiveness and psychomotor retardation—contributes substantially to functional impairment. The paper argues that categorical diagnostic systems such as the DSM and ICD obscure biologically meaningful targets, and that a dimensional, Research Domain Criteria (RDoC) approach focused on cognitive and valence domains may better guide therapeutic development. Structural and functional abnormalities in the prefrontal cortex (PFC), hippocampus and amygdala, together with reduced neuroplasticity and lower neurotrophic support (notably BDNF), are highlighted as core biological substrates of the cognitive deficits observed in MDD. The authors set out to explore whether serotonergic psychedelics (for example psilocybin, LSD and DMT) could constitute a novel class of therapeutics for MDD by reversing impaired neuroplasticity and improving cognitive processes. They propose a translational, dimensional framework that links drug-induced changes at molecular and cellular levels to circuit function and cognitive outcomes, in particular by targeting negativity bias and cognitive inflexibility. Pattern separation—a hippocampal-dependent mnemonic process that reduces interference between similar inputs—is introduced as a measurable cognitive construct that may bridge preclinical and clinical investigation of these mechanisms.

The extracted text does not present a distinct Methods section or an explicit systematic search strategy; the paper is a narrative, translational review synthesising preclinical and clinical literature to develop a mechanistic hypothesis. The authors integrate findings from human clinical trials (randomised and open-label), experimental studies of acute subjective and network-level brain effects, and animal and cellular studies addressing neuroplasticity, neurogenesis and molecular signalling. Rather than reporting original experimental data, the paper constructs a mechanistic model by triangulating evidence across units of analysis: behavioural and psychometric outcomes in humans, neuroimaging measures of network activity (notably default mode network and hippocampal subfields), and (sub)cellular measures from animal and in vitro work such as neuritogenesis, spinogenesis, synaptogenesis, newborn neuron counts in the dentate gyrus, and BDNF/trkB and mTOR pathway involvement. Where available, the authors draw attention to specific experimental manipulations (for example pharmacological blockade of TrkB or mTOR in preclinical preparations) that inform causal interpretation. The extraction does not report pre-specified inclusion/exclusion criteria, databases searched, quality assessment procedures, or quantitative meta-analytic methods, so the review should be understood as a theory-driven synthesis rather than a formal systematic review or meta-analysis.

Clinical evidence reviewed indicates that acute, hallucinogenic doses of serotonergic psychedelics can produce clinically meaningful reductions in depressive symptoms. The authors summarise early cancer-related trials and more recent second-wave studies: an open-label trial in 20 treatment-resistant depression patients found sustained improvements on psychometric depression and anhedonia measures up to 6 months after two psilocybin doses; a randomised, waiting-list controlled trial in 27 MDD patients reported clinical response (>50% reduction in GRID-HAMD) in 67% at week 1 and 71% at week 4, with remission (GRID-HAMD <7) in 58% at week 1 and 54% at week 4. Preliminary reports also suggest antidepressant effects of other serotonergic agents such as DMT and LSD. At the cognitive and systems level, acute psychedelic administration is associated with reductions in rigidity of thought, increased environmental sensitivity and transient disruption of default mode network (DMN) activity and connectivity. Reduced DMN integrity and altered thalamic gating are proposed to create a state of “unconstrained cognition” in which entrenched self-referential beliefs can be challenged. Behaviourally, longer-term increases in indices of cognitive flexibility have been observed, including enhanced divergent and convergent thinking and openness; one ayahuasca study reported improved performance on a cognitive flexibility task (details of task metrics are not fully reported in the extracted text). Preclinical and translational findings supporting neuroplastic effects are presented in some detail. In frontocortical preparations, psychedelics increase neuritogenesis, spinogenesis and synaptogenesis in vitro and in vivo, and induce expression of neuroplasticity-related genes. In the hippocampus, several studies report increased numbers and dendritic complexity of newborn granule cells in the dentate gyrus after psychedelic exposure; DMT additionally increased astrocyte and oligodendrocyte numbers and influenced neural stem cell proliferation and differentiation. Human data indicate acute increases in peripheral BDNF after LSD and ayahuasca, and rodent studies report region-specific BDNF protein increases in hippocampus and cortex. Mechanistic experiments show that antagonism of TrkB or inhibition of mTOR blocks psychedelic-induced neuroplastic changes in primary cortical cultures, and that mTOR activation may engage a positive feedback BDNF signalling loop. The authors also note evidence that psychedelics modulate immune and hypothalamic–pituitary–adrenal (HPA) axis activity, which could indirectly influence neuroplasticity. Specific to the translational hypothesis, preliminary data are highlighted linking psychedelics to pattern separation: psilocybin reversed developmental-stress–induced pattern separation deficits in rats when administered one month before testing, and this effect correlated with antidepressant behaviour in a forced swim test. Additional rodent studies connect psychedelic-induced plasticity with improved fear extinction and learning outcomes. Quantitative effect sizes, pooled estimates, and formal heterogeneity or risk-of-bias metrics are not provided in the extracted text.

Magaraggia and colleagues interpret the assembled evidence to propose a tripartite "translational fingerprint" for therapies that reduce negativity bias in MDD. First, an increase in neuroplasticity markers (for example increased BDNF, synaptogenesis, spinogenesis and adult-born neurons) provides the cellular substrate. Second, these (sub)cellular adaptations are predicted to restore hippocampal-dependent pattern separation and modulate activity in emotion-related circuits including amygdala, hippocampus and PFC. Third, circuit restoration should translate into reduced fear and stress reactivity, improved executive functions and reduced anhedonia, thereby lowering depressive symptoms. The authors position this model relative to prior work by noting parallels with other antidepressant strategies that stimulate neuroplasticity, such as vortioxetine and ketamine, and by emphasising the potential utility of pattern separation as a translational biomarker to bridge animal and human studies. They also discuss therapeutic implications, including the pursuit of psychedelic-like molecules that retain neuroplastic benefits without hallucinogenic effects, and the possibility of microdosing or intermittent low-dose regimens to provide sustained biological stimulation with greater practicality and lower acute distress. Key limitations and uncertainties are acknowledged. The review highlights gaps in the evidence base: regional and temporal specificity of BDNF and neuroplastic responses (for example mature BDNF versus pro-BDNF; PFC versus hippocampus), dose- and time-dependent effects on neurogenesis, and the incomplete characterisation of pharmacology beyond 5-HT2A receptors (roles for 5-HT1A and sigma-1 receptors are discussed). The relationship between the acute subjective/hallucinogenic experience and long-term plasticity and clinical outcome remains unresolved; set and setting appear to influence outcomes but biological effects have also been reported with subhallucinogenic dosing paradigms. Pharmacokinetic–pharmacodynamic relationships that could serve as biomarkers (for example plasma exposure predicting BDNF changes) are not yet established. The authors call for targeted, multi-level studies assessing transcriptional, protein and receptor-level BDNF measures, detailed neurogenesis staging, circuit-level imaging, standardised cognitive endpoints (including pattern separation) and rigorous PK/PD characterisation to validate the model. Finally, they note that application of the framework to COVID-19–related cognitive and mood disturbances is speculative and requires empirical testing. Overall, the discussion presents the translational framework as heuristic and potentially useful for guiding mechanistic and drug development work, while emphasising that the model is provisional and that further experimental validation is necessary.