Towards an understanding of psychedelic-induced neuroplasticity

Recent renewed interest in classic psychedelics — including LSD, psilocybin, DOI, 5-MeO-DMT and DMT — follows observations that a small number of doses, typically combined with psychotherapy, can produce relatively long-lasting improvements in mood, anxiety and addiction. Calder and Hasler frame these enduring effects in terms of neuroplasticity: the nervous system's capacity to reorganise structure and function in response to experience. They note that neuroplasticity encompasses molecular changes (for example in gene and protein expression such as brain-derived neurotrophic factor, BDNF), morphological changes (dendritogenesis, synaptogenesis) and, in some regions like the hippocampus, neurogenesis, and that dysfunction in these processes is implicated in depression and addiction. This review sets out to evaluate evidence that psychedelics enhance neuroplasticity, to describe likely mechanisms, to identify brain regions and dose ranges involved, to characterise the temporal dynamics of any plasticity window, and to consider behavioural and clinical consequences. The authors aim to synthesise preclinical and human data to clarify which aspects of plasticity are reliably affected by different psychedelics and to highlight key open questions for future research and therapeutic application.

The extracted text indicates that this article is a narrative review synthesising animal and human studies rather than reporting new empirical data. Calder and Hasler structure the review around a set of specific questions: whether psychedelics enhance neuroplasticity, by what molecular mechanisms, in which brain regions, at what doses, how long effects last, and what the behavioural and clinical consequences may be. The extraction does not report a formal search strategy, inclusion criteria, databases searched, dates, or explicit risk-of-bias assessment, so the review should be understood as a targeted synthesis of existing preclinical and clinical findings rather than a systematic review with a reproducible literature search. Where available, the authors integrate molecular, cellular, neuroimaging and peripheral-biomarker data from animal experiments and human studies to address each focal question.

Do psychedelics enhance neuroplasticity? Animal studies provide moderately strong evidence that classic psychedelics (LSD, psilocybin, DMT, DOI) upregulate plasticity-related transcripts (including immediate early genes and BDNF), promote dendritic and synaptic growth, and can enhance long-term potentiation (LTP). Findings on adult neurogenesis are mixed: LSD and DOI showed no effect in some rat studies and psilocybin slightly reduced neurogenesis in mice, whereas DMT and 5-MeO-DMT increased neurogenesis in other mouse studies. Human evidence relying on peripheral BDNF is inconsistent: some studies report increases after ayahuasca, LSD or psilocybin, while others report no change. The authors caution that peripheral BDNF is an imperfect proxy for central plasticity and note supporting human neuroimaging findings of altered connectivity after psilocybin and ayahuasca. Molecular mechanisms. The weight of evidence implicates the 5-HT2A receptor as central to psychedelic-enhanced plasticity. Functional blockade with higher doses of the antagonist ketanserin abolishes plasticity effects, affinity for 5-HT2A predicts psychoplastogenic potency, and 5-HT2A knockout mice do not show enhanced plasticity after psychedelics. Downstream circuitry appears to involve increased cortical glutamate and AMPA receptor stimulation, with a putative positive feedback loop linking AMPA activation, BDNF secretion, TrkB and mTOR signalling to sustained synaptogenesis and dendritic growth. Other receptors can be relevant for particular compounds: DMT has functional affinity for the sigma-1 receptor (linked to neurogenesis and neuroprotection), and 5-MeO-DMT acts preferentially at 5-HT1A receptors, which may explain some hippocampal neurogenic effects. Regional specificity. Because 5-HT2A receptor density is highest in the neocortex, the cortex — and in particular the prefrontal cortex (PFC) — shows relatively robust psychoplastogenic changes in animal studies: upregulation of plasticity genes, increased spinogenesis, and, in pigs, greater presynaptic density after psilocybin. Human PET studies report increased glutamate signalling in the PFC after psilocybin. By contrast, the hippocampus often shows smaller or inconsistent effects; some studies report fewer upregulated transcripts or no immediate-early gene induction, DOI sometimes reduces BDNF in the dentate gyrus, and a PET study found reduced hippocampal glutamate after psilocybin. Preliminary data suggest c-Fos induction in several subcortical areas (claustrum, locus coeruleus, lateral habenula, thalamus, amygdala, brainstem), but the authors caution that c-Fos is a non-specific marker. Mesolimbic structures implicated in addiction express relatively few 5-HT2A receptors and are therefore less likely to be directly impacted, though enhanced dendritic growth in PFC neurons projecting to the mesolimbic pathway could mediate anti-addictive effects. Dose-response and chronic dosing. Animal data generally show dose-dependent psychoplastogenic effects (examples: LSD effects from 0.2 mg/kg to 1 mg/kg; psilocybin required ~4 mg/kg to induce gene-expression changes; DOI dose-dependent). A sub-hallucinogenic dose of 1 mg/kg DMT altered synaptic currents in cortical slices. Human studies on dose effects are inconsistent: sub-hallucinogenic 'microdoses' of 5–20 µg LSD produced short-term plasma BDNF increases in one report, whereas another study found BDNF effects only at 200 µg and yet another found no change. Chronic dosing findings are mixed: repeated LSD enhanced learning in rodents and reversed stress-induced synaptogenesis deficits, but chronic DMT may cause dendritic retraction and chronic LSD upregulated some plasticity genes while also being linked to schizophrenia-related genes in one study. Many preclinical studies do not clearly distinguish microdosing from repeated hallucinogenic dosing. Temporal dynamics. Markers of enhanced plasticity emerge rapidly: plasticity-related transcripts can be upregulated within 1–1.5 hours, BDNF mRNA may rise by 2–3 hours, and early morphological changes are detectable from about 6 hours. Synaptogenesis and spinogenesis often peak later — at 24–72 hours — and rates of dendritic spine formation remain elevated for several days (e.g. elevated for 3 days in mice, returning toward baseline by day 5). Crucially, new dendrites and synapses formed during this window can persist: some new spines survive for at least a month in mice, and human functional changes after psilocybin have been observed at least 1 month post-treatment. Different molecular markers follow different time courses, so the ‘‘window of plasticity’’ is multi-phasic rather than a single uniform period. Behavioural and clinical correlates. A limited number of studies link plasticity changes to behavioural outcomes. In chronically stressed mice, psilocybin strengthened cortico-hippocampal synapses and reduced anhedonia; DMT-associated neurogenesis was accompanied by memory improvements; other animal studies report enhanced fear extinction and reduced anxiety alongside dendritic changes. In humans, one study found ayahuasca-induced BDNF increases that correlated with clinical improvement, and psilocybin-induced increases in PFC connectivity coincided with reduced negative affect and anxiety. The authors emphasise that causal mediation by neuroplasticity is not established. Potential broader outcomes and risks. The review argues that PFC dendritic and synaptic growth plausibly underlies improved emotional regulation, cognitive flexibility and mindfulness reported after psychedelic experiences, and might restore top-down control in depression, PTSD and addiction. Conversely, drug-induced plasticity in sensory regions could plausibly contribute to undesirable outcomes such as flashbacks or the rarer hallucinogen persisting perceptual disorder (HPPD).

Calder and Hasler interpret the collected evidence as supporting the view that classical psychedelics act as psychoplastogens: they stimulate dendritogenesis, synaptogenesis and the upregulation of plasticity-related genes in a manner dependent largely on 5-HT2A receptor activation, with the cortex appearing particularly affected. The authors emphasise that the plasticity window appears to open within hours and may last a few days, yet structural changes formed during that window can persist for at least a month, which offers a plausible mechanism for long-lasting clinical effects that outlast the drug's pharmacokinetic presence. They also underscore the importance of experience-dependence: because the plastic window overlaps with the subjective psychedelic state, the content and valence of experiences, and accompanying psychotherapy, are likely to shape ultimate neural and behavioural outcomes. Key limitations and uncertainties acknowledged include the heavy reliance on preclinical data, the inconsistency of peripheral BDNF as a biomarker in humans, and the absence of a clear, reproducible dose–response characterisation in people — particularly regarding microdosing and chronic regimens. The authors note that many human studies use indirect or peripheral proxies for central plasticity and call for direct human measures such as LTP-like paradigms, tetanic sensory stimulation, and PET imaging with synaptic-density markers (for example SV2A). They also flag unresolved questions about compound-specific receptor contributions (for example sigma-1 or 5-HT1A roles), regional heterogeneity of effects, and potential adverse long-term plastic changes in sensory circuits. For future research and clinical translation, the paper recommends confirming preclinical findings in humans, clarifying the minimum and optimal doses for different compounds, delineating temporal dynamics in humans to optimise timing of psychotherapy or rehabilitation, and investigating whether chronic microdosing has distinct effects. The authors propose that combining psychedelics with psychotherapeutic or neurorehabilitative interventions may leverage the plastic window to enhance learning and recovery, but they caution that adverse experiences during heightened plasticity or inappropriate dosing regimens could have negative consequences.

The authors conclude that current data support the hypothesis that classic psychedelics promote cortical dendritogenesis, synaptogenesis and upregulation of plasticity-related genes via mechanisms centred on 5-HT2A receptor activation, with a plasticity window emerging within hours and lasting days, while structural changes may endure for at least a month. They call for targeted human studies using direct measures of central plasticity, clearer dose-response investigations including microdosing and chronic schedules, and research linking neuroplastic alterations causally to clinical and behavioural outcomes to inform safe and effective therapeutic applications.