Mechanisms of Psychedelic Metaplasticity: Intracellular Receptor Pharmacology, Epigenomic Priming and Candidate Substrates of Persistence—A Narrative Review
- 1IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy
- 2Department of Biomedical and Dental Sciences and Morpho Functional Imaging, University of Messina, 98125 Messina, Italy
Abstract
A single dose of a serotonergic psychedelic produces benefits that persist for weeks beyond drug elimination, yet the substrate holding that capacity across the days-to-weeks consolidation window is undefined. Psychedelics are described as metaplastogens, agents that durably modulate the capacity for subsequent plasticity rather than sustaining a plastic state. This review assembles the candidate substrates and grades the evidence as established, indirectly supported or hypothetical. Intracellular serotonin 2A (5-HT2A) receptor pools and neurotrophin convergence are reviewed. Cortical histone H3 lysine 27 acetylation (H3K27ac) data show a persistent bidirectional change at seven days: elevated elements enriched for rhythmic processes alongside depotentiated enhancers annotated to synaptic plasticity. Because acetylation turns over within minutes to hours where it has been measured—a premise untested at these elements—we propose, as a framework rather than a demonstrated mechanism, that the signal reflects a displaced regulatory set-point, not a retained mark. The evidence base is narrow: one compound, frontal cortex of adult male mice, bulk neuronal nuclei, nothing beyond seven days and no causal test. Claims of persistence over weeks therefore concern the behavioural phenotype, not the chromatin state. The review closes with six falsifiable criteria and a matrix discriminating competing accounts.
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BibTeX
@article{anchesi2026mechanisms,
title = {{Mechanisms of Psychedelic Metaplasticity: Intracellular Receptor Pharmacology, Epigenomic Priming and Candidate Substrates of Persistence—A Narrative Review}},
author = {Ivan Anchesi and Veronica Argento and Alessia Floramo and Maria Francesca Astorino and Sara Spinelli and Marco Calabrò and Giovanni Luca Cipriano},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms272110010},
url = {https://www.mdpi.com/1422-0067/27/21/10010},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanisms of Psychedelic Metaplasticity: Intracellular Receptor Pharmacology, Epigenomic Priming and Candidate Substrates of Persistence—A Narrative Review
AU - Ivan Anchesi
AU - Veronica Argento
AU - Alessia Floramo
AU - Maria Francesca Astorino
AU - Sara Spinelli
AU - Marco Calabrò
AU - Giovanni Luca Cipriano
PY - 2026
DA - 2026/11/08
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms272110010
UR - https://www.mdpi.com/1422-0067/27/21/10010
AB - A single dose of a serotonergic psychedelic produces benefits that persist for weeks beyond drug elimination, yet the substrate holding that capacity across the days-to-weeks consolidation window is undefined. Psychedelics are described as metaplastogens, agents that durably modulate the capacity for subsequent plasticity rather than sustaining a plastic state. This review assembles the candidate substrates and grades the evidence as established, indirectly supported or hypothetical. Intracellular serotonin 2A (5-HT2A) receptor pools and neurotrophin convergence are reviewed. Cortical histone H3 lysine 27 acetylation (H3K27ac) data show a persistent bidirectional change at seven days: elevated elements enriched for rhythmic processes alongside depotentiated enhancers annotated to synaptic plasticity. Because acetylation turns over within minutes to hours where it has been measured—a premise untested at these elements—we propose, as a framework rather than a demonstrated mechanism, that the signal reflects a displaced regulatory set-point, not a retained mark. The evidence base is narrow: one compound, frontal cortex of adult male mice, bulk neuronal nuclei, nothing beyond seven days and no causal test. Claims of persistence over weeks therefore concern the behavioural phenotype, not the chromatin state. The review closes with six falsifiable criteria and a matrix discriminating competing accounts.
SN - 1422-0067
ER -