Psychedelic-Induced Neural Plasticity: A Comprehensive Review and a Discussion of Clinical Implications

The review addresses whether classic serotonergic psychedelics (5-HT2A agonists: psilocybin/psilocin, LSD, mescaline, DMT and related tryptamines) induce neural plasticity and how such effects relate to their emerging antidepressant and therapeutic properties. Context: Since the 1970s–2000s, antidepressant mechanisms expanded from acute monoamine actions to downstream neurotrophic and neuroplastic adaptations (e.g., BDNF/TrkB), supporting the network hypothesis of depression. Rapid-acting antidepressants (ketamine, scopolamine) also rely on plasticity mechanisms. Purpose: To comprehensively synthesize preclinical and clinical evidence specifically on the psychoplastogenic effects of classic psychedelics, clarifying mechanisms, behavioral correlates, and clinical implications. Importance: Psychedelics show therapeutic promise but remain controversial due to potential harms and methodological limitations; understanding their plasticity mechanisms is critical for safe, effective, and precise clinical applications.

Preclinical literature (majority of included studies) consistently shows that classical psychedelics induce immediate early gene expression (e.g., c-Fos, Egr1/Egr2), upregulate plasticity-related genes and proteins (BDNF, TrkB, Arc, synaptic markers like SV2A, synaptophysin, GAP43), and promote structural plasticity (neuritogenesis, spinogenesis, synaptogenesis) across cortical and limbic regions. Psilocybin/psilocin increase dendritic spine size and density in mouse cortex persisting for weeks; decrease 5-HT2A receptor density and increase SV2A in pig hippocampus; reverse stress-induced anti-plastic changes; and facilitate fear extinction. DMT/5-MeO-DMT/ayahuasca upregulate synaptic plasticity proteins in human cerebral organoids; intensify dendritic spine formation; facilitate fear extinction and reduce ischemic injury while modulating BDNF and inflammatory cytokines; effects often require 5-HT2A activation, including intracellular 5-HT2A. LSD increases transcription of plasticity genes, elevates signaling entropy, and alters proteomic and epigenomic profiles implicating mTOR; brief exposures suffice to trigger persistent growth phases via TrkB/mTOR/AMPA signaling. Some evidence indicates direct binding of LSD and psilocin to TrkB as positive allosteric modulators, suggesting 5-HT2A-independent contributions. Synthetic 5-HT2A agonists (DOI, 25C-NBOMe) enhance structural plasticity, modulate cortical synchronization and cognitive flexibility, and engage MAPK/CaMKII/CREB pathways. Clinical literature, while inferential, shows macroscopic and functional changes consistent with plasticity: reduced PCC cortical thickness in ayahuasca users; increased brain entropy predicting trait openness after LSD; psilocybin-induced DMN desynchronization and uncoupling with anterior hippocampus; subacute modulation of amygdala responses; EEG theta increases relating to symptom improvement; and acute plasma BDNF increases after low-dose LSD. Case reports suggest plasticity-mediated benefits in phantom limb pain and olfactory deficits, potentially via facilitated cortical reorganization.

Systematic literature search on MEDLINE/PubMed and Web of Science from inception to 26 June 2024 using: (psychedelic OR dmt OR dimethyltryptamine OR lsd OR lysergic acid diethylamide OR psilocybin OR psilocin OR mescaline) AND (plasticity OR neuroplasticity OR metaplasticity). Inclusion: original data studies (clinical and preclinical). Exclusion: non-English articles; reviews (narrative/systematic, pooled analyses, meta-analyses); books/chapters; expert opinions/consensus; editorials, guidelines, protocols, and other non-original data. Screening managed in Rayyan; abstract screening and eligibility assessment by four authors independently with conflicts resolved by a fifth. Records: 1083 identified (813 PubMed; 270 Web of Science); 180 duplicates removed; 903 screened; 331 excluded on formal grounds; 572 assessed for eligibility; 1 not retrieved; 501 non-relevant excluded; 69 included initially plus 1 via snowballing (total 70). Studies were categorized by compound (psilocybin/psilocin, DMT-related, LSD, mescaline/related, synthetic 5-HT2A agonists) and clinical methodology (neuroimaging, electrophysiology, biohumoral, behavioral, case reports).

- Screening outcomes: 1083 records initially (813 PubMed; 270 Web of Science); 903 after duplicates; 572 eligible for full assessment; 70 included (55 preclinical, 15 clinical). - Psilocybin/psilocin: Increased SV2A and decreased 5-HT2A receptor density in pig hippocampus/PFC; persistent increases in cortical dendritic spine size/density in mice (≥1 month); dose-dependent upregulation of plasticity genes (e.g., c-Fos, BDNF, Psd95) predominantly in PFC; reversal of glucocorticoid-induced anti-plastic changes; facilitation of fear extinction; region-specific c-Fos signatures. - DMT/5-MeO-DMT/ayahuasca: Upregulation of synaptic and cytoskeletal plasticity proteins in human organoids; increased dendritic complexity and proliferation in dentate gyrus; reopening of plasticity windows and facilitation of extinction; reduced ischemic lesion volume with increased BDNF and anti-inflammatory cytokines; intracellular 5-HT2A-mediated structural plasticity; requirement of 5-HT2A for neuroplastic and antidepressant-like effects. - LSD: Upregulates plasticity-related genes (c-fos, arc, krox-20, MKP-1, C/EBPβ, ILAD-1) via 5-HT2A; increases transcriptional entropy (stem-cell-like profile); proteomics implicate mTOR, synaptic vesicle cycling, axon guidance; transient exposure triggers lasting growth via TrkB/mTOR/AMPA; epigenomic changes in enhancers; evidence of direct TrkB binding and BDNF potentiation independent of 5-HT2A. - Synthetic 5-HT2A agonists: DOI induces Arc, Bdnf1, Egr1/2 via MAPK/CaMKII/CREB; increases transitional dendritic spine density and LTP; enhances cognitive flexibility; 25C-NBOMe augments glutamatergic transmission. - Critical period reopening durations (sCPP): ketamine ~48 h; psilocybin/MDMA ~2 weeks; LSD ~3 weeks; ibogaine >4 weeks. - Clinical imaging/electrophysiology: Ayahuasca users show reduced PCC thickness and altered morphometric similarity (transmodal vs sensorimotor); LSD increases brain entropy predicting openness; psilocybin desynchronizes DMN and uncouples with anterior hippocampus; reduced amygdala responsiveness subacutely; psilocybin increases EEG theta power correlating with symptom reduction; polysomnography shows increased REM latency and reduced first-cycle delta; microdose LSD did not modulate visual ERPs. - Biohumoral: Low-dose LSD (5 and 20 µg) acutely increases plasma BDNF at 6 h. - Case reports: Psilocybin combined with mirror therapy relieved phantom limb pain; microdosing psilocybin benefited chronic pain (durations 2–8 weeks, potentiated by exercise); psilocybin or LSD improved olfactory deficits in two cases and transiently in an idiopathic anosmia case.

Findings across gene expression, protein, microscopy, electrophysiology, behavior, and clinical imaging converge on psychedelics as psychoplastogens that acutely elevate metaplastic potential and induce sustained structural and functional neuroplasticity. Mechanistically, a central role for 5-HT2A emerges (including intracellular pools), with downstream AMPA/mTOR growth pathways and immediate early gene activation. Additional evidence indicates a 5-HT2A-independent component via direct TrkB binding (psilocin, LSD), suggesting multiple convergent routes to BDNF/TrkB signaling. Clinically, alterations in DMN (PCC thickness reductions, desynchronization and uncoupling with hippocampus) align with ego-dissolution and relaxed priors frameworks (REBUS), potentially enabling updating of maladaptive generative models. However, these macroscopic and functional changes pose questions about long-term impacts on self-referential networks, with implications for populations vulnerable to self-disruption (e.g., psychosis risk, borderline traits). Behavioral correlates (fear extinction, reduced depressive-like immobility, enhanced cognitive flexibility) support therapeutic relevance but highlight sex- and receptor-specific dependencies. Overall, evidence supports psychedelic-induced BDNF-mediated hyperplasticity via indirect (glutamatergic/AMPA), direct (5-HT2A), and hyperdirect (TrkB) pathways, with acute stimulation phases followed by growth phases. Clinical findings are largely inferential but consistent, indicating translational promise and safety considerations.

This comprehensive review consolidates robust preclinical evidence and supportive clinical indications that classic psychedelics induce neural plasticity via 5-HT2A-dependent and TrkB-mediated mechanisms, producing structural, molecular, and behavioral changes relevant to therapeutic action. The work highlights convergent pathways to BDNF/TrkB activation, critical period reopening, and network-level modulation (particularly DMN). Future research should: clarify the necessity and sufficiency of psychedelic phenomenology versus non-hallucinogenic psychoplastogens; determine whether beneficial plasticity can be dissociated from psychodysleptic effects; refine precision medicine indications and contraindications based on baseline self/DMN integrity and psychopathology; assess long-term structural-functional outcomes; and explore direct TrkB agonism or modulators downstream of diverse antidepressant mechanisms. Rigorous clinical trials with improved methodology and safety monitoring are essential.

The clinical evidence synthesized is less exhaustive and largely inferential relative to preclinical findings due to methodological constraints and limited direct clinical measures of neuroplasticity. Many included clinical studies assess proxies (e.g., DMN connectivity, entropy, EEG) rather than direct plasticity markers, complicating causal attribution. Additional limitations include heterogeneity of paradigms, dosages, and models; small sample sizes; potential biases in case reports; and unresolved questions about long-term safety, the dissociability of plasticity from acute psychodysleptic effects, and the outcome-agnostic nature of plasticity (plastic paradox).