Out of the box: A psychedelic model to study the creative mind

Rather than reporting original empirical data, the paper sets out a mechanistic experimental approach to test the proposed model. The central experimental design advocated is placebo-controlled pharmaco-imaging studies in healthy volunteers who receive psilocybin, with additional conditions that combine psilocybin with pharmacological blockers targeting the serotonin 5-HT2A receptor, the dopamine D2 receptor and oxytocin receptors. The primary behavioural endpoints are measures of flexible divergent thinking, mood states, trait openness and empathy; timing and specific psychometric instruments are not detailed in the extracted text. Neuroimaging methods recommended include proton magnetic resonance spectroscopy (1H MRS) to quantify glutamate-related metabolites in targeted brain regions and functional connectivity analyses of resting-state and task-related networks to characterise interactions among the default mode network (DMN), central executive network (CEN) and salience network (SN). The paper formulates explicit mechanistic hypotheses to be tested: for example, that blockade of 5-HT2A receptors will abolish psilocybin-induced changes in glutamatergic signalling and the enhancement of divergent thinking, and that blockade of D2 or oxytocin receptors will prevent increases in oxytocin and the associated improvements in divergent thinking. The extracted text does not report details on sample size, randomisation, dosing regimens, timing of measurements, psychological support procedures or statistical analysis plans.

The paper does not present new experimental results. Instead, it synthesises prior findings from neuroimaging, pharmacology and behavioural studies to build the proposed model. Key empirical observations cited include: reductions in functional connectivity within parts of the DMN following psychedelic administration; increased frontal activation and altered prefrontal–subcortical activation patterns under psychedelics; and the SN becoming active shortly before the attainment of an insightful solution during creative tasks. Resting-state connectivity in vmPFC and posterior cingulate cortex (PCC) has been positively associated with divergent thinking in earlier work, and shifts in coupling among DMN, SN and CEN are reported during stages of divergent idea generation. On the neurochemical side, the paper summarises evidence that dopamine (DA) influences divergent thinking, with very high DA linked to impaired performance and medium-to-high levels associated with better flexible thinking. Reduced D2 receptor densities are suggested to lower thalamic gating thresholds and increase thalamo-cortical information flow, which could enhance divergent thinking. The authors note that 5-HT2A receptors in prefrontal cortex exert excitatory control over ventral tegmental area DA neurons and that psychedelics act primarily via 5-HT2A receptors while also affecting glutamatergic, dopaminergic and noradrenergic pathways. Behavioural and personality correlates compiled in the paper include reliable links between positive mood, increased openness and empathy, and higher divergent thinking; oxytocin is offered as a converging biological candidate, given associations between oxytocin, empathy, openness and, in one reported study, improved divergent thinking. The text also cites the concept of reduced latent inhibition—less filtering of familiar stimuli—as associated with creativity and potentially modulated by striatal DA changes.

Kuypers interprets the assembled evidence to propose a testable model in which psychedelics facilitate flexible, divergent thinking by perturbing interactions among large-scale brain networks (DMN, CEN and SN) and by modulating neurotransmitter systems including 5-HT2A-mediated glutamatergic signalling, dopamine pathways and oxytocin-related mechanisms. The model emphasises that network shifts—such as reduced DMN integrity and altered thalamo-cortical gating—combined with changes in mood, openness and empathy, could jointly account for the enhanced cognitive flexibility observed after psychedelic use. In this framing, the therapeutic effects reported in anxiety and depression may reflect a shift away from rigid cognitive patterns toward greater flexibility that enables psychotherapeutic change. To substantiate these claims the authors advocate placebo-controlled pharmacological challenge studies with receptor-specific antagonists, combined with 1H MRS and functional connectivity analyses, in healthy volunteers. Such experiments are presented as necessary to isolate the contributions of 5-HT2A, D2 and oxytocin systems to both the neurochemical and network-level changes and to the behavioural phenotype of enhanced divergent thinking. The paper notes that psilocybin produces a controllable altered state marked by affective stimulation, introspection and increased empathy and that it has been widely used in psychopharmacological research without reports of severe adverse events, supporting its suitability as an experimental tool. The extracted text does not provide a detailed discussion of methodological limitations, sample considerations or potential confounds beyond the general acknowledgement that the mechanisms remain to be empirically established.