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.