Does psychedelic therapy have a transdiagnostic action and prophylactic potential?

Ko and colleagues frame the paper around two interrelated problems in contemporary mental healthcare: the large, growing burden of mental illness worldwide and the limited efficacy and prophylactic reach of current treatments. They note widespread comorbidity across diagnostic categories and a renewed interest in transdiagnostic treatment targets—mechanisms or processes that traverse conventional diagnoses—and argue that interventions able to strengthen resilience and adaptability could shift care from reactive symptom management toward prevention and long-term wellness. The paper sets out to synthesise evidence that psychedelic therapy may act on such a transdiagnostic target by acutely increasing brain and psychological plasticity—defined here as an enhanced capacity for change—and, when combined with an appropriately supportive therapeutic context, enabling recalibration of maladaptive habits of mind and behaviour. Ko and colleagues present candidate psychological and neurobiological markers of this plasticity, link these to a predictive processing (Bayesian brain) account of psychedelic action, and propose a multilevel ‘‘process-of-change’’ model that implies both transdiagnostic therapeutic effects and potential prophylactic benefit for mental health. The extracted text does not report a formal, systematic review protocol; the paper is a narrative interdisciplinary synthesis integrating clinical, epidemiological, psychological and basic neuroscience evidence.

The extracted text presents a narrative, integrative review rather than a systematic meta-analysis with a declared search strategy. Ko and colleagues draw on diverse evidence types: controlled clinical trials, observational and epidemiological studies, qualitative analyses of patient reports, experimental cognitive tasks, neuroimaging and molecular/animal studies, and theoretical work in predictive processing and dynamical systems. The authors assemble findings on clinical outcomes, trait and state psychological measures (for example psychological flexibility, cognitive flexibility, mindfulness, openness), acute subjective experiences under psychedelics, and neurobiological indices of plasticity (for example synaptogenesis and markers such as brain-derived neurotrophic factor (BDNF)). Because a formal methods section or explicit inclusion/exclusion criteria is not present in the extracted text, it is not possible to provide details about literature search dates, databases searched, or structured quality/risk-of-bias assessment. Instead, the paper synthesises illustrative empirical results and theoretical perspectives to develop a unified process-of-change model, emphasising links between acute entropic brain dynamics, neuroplasticity, and psychologically mediated learning within supportive contexts.

Across clinical and epidemiological literature, the paper reports that classic serotonergic psychedelics (for example psilocybin, DMT/ayahuasca, LSD) have shown promise across a range of indications including depression, addiction, obsessive-compulsive disorder, existential distress in life‑threatening illness, and PTSD, with naturalistic evidence also suggesting benefits in eating disorders, functional neurological disorders and psychosomatic conditions. Ko and colleagues cite population-level analyses—one representative US sample of over 100,000 people—linking lifetime psychedelic use to lower rates of past-year inpatient psychiatric treatment, psychotropic medication use, serious psychological distress and suicidality. The authors also reference a recent review of 77 eligible studies (total N = 9,876) reporting aggregate improvements in various indices of mental health associated with psychedelic use across settings. On psychological processes, the review summarises evidence that psychedelics can increase constructs associated with resilience and adaptive functioning: psychological flexibility (the capacity to remain present, accept experience, and act consistently with values), cognitive flexibility (set-shifting and reduced perseveration), mindfulness-related capacities, openness to experience and aspects of creativity and prosociality. Several clinical and naturalistic studies are cited showing post‑treatment increases in experiential acceptance and reductions in experiential avoidance, with instruments such as the Acceptance and Action Questionnaire-II (AAQ-II) used in multiple samples. Acute subjective phenomena—mystical‑type or unitive experiences, ego‑dissolution, emotional breakthrough and psychological insight—are reported to reliably predict longer-term psychological and clinical outcomes in several studies. Neuroscientific findings summarised include evidence for increased neuroplasticity after psychedelic exposure: a recent study reported synaptogenesis across a range of classic psychedelics, ketamine and MDMA; two rodent studies showed about a doubling of cortical BDNF after psychedelic administration, while hippocampal results were inconsistent. Gene expression studies in cortex after psilocybin indicate upregulation of plasticity‑related genes. The 5‑HT2A receptor is emphasised as a key pharmacological locus, implicated in neurite development, progenitor proliferation and cortical plasticity; the term psychoplastogen is noted for agents that promote cortical plasticity. Behavioural and cognitive findings report increased cognitive flexibility 24 hours after ayahuasca, mixed acute cognitive effects under LSD, and accelerated associative learning in animal models under 5‑HT2A stimulation. At a systems level, the authors describe evidence for an ‘‘entropic brain’’ state under psychedelics—acute increases in neural signal complexity and desegregation of network structure—that is hypothesised to flatten the brain’s energy landscape and permit access to a broader repertoire of functional states. Within a predictive processing framing, such entropic/destabilising effects are proposed to relax excessively precise priors (rigid predictive models), facilitating relearning and de‑canalisation of maladaptive thought and behaviour. Limitations in the evidence base are noted throughout: many cited studies are observational or naturalistic, controlled trials are often small, blinding can be difficult to maintain, methodologies are heterogeneous, and some measures (for example AAQ-II) have contested construct validity. The authors also acknowledge inconsistent neurobiological findings (for example hippocampal markers) and the absence of direct longitudinal trials that would demonstrate prophylactic effects definitively.

Ko and colleagues interpret the assembled evidence as consistent with the hypothesis that psychedelic therapy produces an acute state of increased brain and mind plasticity which, when combined with psychological preparation, supportive therapeutic context and integration, can enable durable recalibration toward psychological flexibility and resilience. They present a multilevel ‘‘process-of-change’’ model grounded in predictive processing: psychedelics induce an entropic, hyperplastic state that relaxes over‑weighted priors (rigid habits of thought and behaviour), opening a therapeutic window during which learning and insight—guided by supportive context—can produce adaptive, longer‑term change. The authors situate these claims relative to earlier work on neuroplasticity, psychotherapy process, and transdiagnostic approaches, arguing that a plasticity‑centred, drug×context model bridges pharmacology and psychotherapy. They see potential for psychedelic therapy to act across diagnostic boundaries and, provisionally, as a prophylactic or health‑promoting intervention, while explicitly excluding disorders with clear organic aetiology and acknowledging elevated risk in individuals vulnerable to psychosis. Key limitations and uncertainties acknowledged in the discussion include the narrative (non‑systematic) nature of the review and potential for selective citation; a scarcity of studies that directly link acute neural plasticity, entropic brain dynamics, and subsequent psychological change within the same cohort; and debate over whether subjective acute experiences are necessary for therapeutic benefit. The authors note the plausible role of positive expectancy in outcomes and consider it a component to be harnessed rather than merely a confound. Risk and implementation concerns are emphasised: the possibility of iatrogenic reactions, although rare in controlled samples, remains; hallucinogen‑persisting perceptual disorder is possible but appears uncommon; and inappropriate use could exacerbate maladaptive processes. The importance of set, setting, psychological preparation and post‑session integration is reinforced. Ko and colleagues call for rigorous longitudinal cohort studies to test prophylactic claims, research to determine optimal dosing, frequency and delivery models, and trials that integrate third‑wave psychotherapies (for example acceptance and commitment approaches) with psychedelic treatment. They urge cautious, regulated roll‑out aligned with further scientific study and propose that the psychedelic therapy model may help reframe mental healthcare toward addressing canalised, maladaptive habits via targeted enhancement of plasticity combined with therapeutic support.