Short answer: possibly, in blood. An exploratory analysis in people with alcohol use disorder found that psilocybin was associated with small DNA methylation changes in peripheral blood, but the evidence is preliminary.
In a randomized, double-blind, placebo-controlled study of 37 abstinent participants, researchers collected blood at baseline, 24 hours after a 25 mg psilocybin dose or placebo, and about one month later. They reported one CpG site linked to TLE4 and a differentially methylated region in RASGRP4, plus nominal signals in HTR2A and TNF, and co-methylation modules related to psilocybin exposure, depressive symptoms, and drinking behavior. Details are in this Translational Psychiatry study.
Important caveats: the original trial showed no significant improvement on primary alcohol outcomes, the methylation data come from blood not brain tissue, the sample was small, and some signals may reflect abstinence or recovery rather than drug effects. I cannot verify whether these blood-based methylation shifts translate to brain changes or durable clinical impacts.
Bottom line: psilocybin may be linked to modest, exploratory DNA methylation changes in this setting, but stronger, replicated evidence is needed.