Psychedelics, which have been used for centuries, can dramatically alter conscious experience. Recent research indicates that certain psychedelics promote neural plasticity by stimulating neurite growth and synapse formation. This review concentrates on classical serotonergic psychedelics and their role in neural plasticity, discussing how this mechanism may underlie their therapeutic potential.
Classic psychedelics such as psilocybin, LSD, DMT, 5-MeO-DMT, mescaline, and DOI work primarily by activating 5-HT2A receptors, causing widespread brain and behavior changes relevant to psychiatric research. Evidence from rodent studies shows that these effects differ by sex across pharmacokinetics, physiology, neuroplasticity, behavior, and disease models. Females often show stronger or qualitatively distinct behavioral responses, including head twitch, locomotor activity, prepulse inhibition, stress reactivity, and social behavior, with ovarian cycle phase further modulating some effects. Disease model studies also find sex-dependent outcomes, such as psilocybin's effects on alcohol consumption and DMT microdosing on mood and neuroplasticity. The review concludes that sex is a critical biological variable shaping psychedelic effects in rodents, and integrating sex-specific analyses is essential for improving translational validity and guiding clinical applications.
Psilocybin promotes the formation and maturation of synapses while accelerating the elimination of pre-existing synapses. Signaling through serotonin 2A receptors in cortical layer 5 pyramidal neurons is necessary and sufficient for this synaptic remodeling but is not required for the head-twitch response, a rodent proxy for hallucination.