LSD Restores Synaptic Plasticity in VTA of Morphine-Treated Mice and Disrupts Morphine-Conditioned Place Preference.
bioRxiv : the preprint server for biology – June 15, 2025
Source: PubMed
Summary
Could psychedelics unlock new addiction treatments? One study shows LSD can reverse brain changes caused by opioids. In mice, a single dose or microdoses of LSD quickly reduced morphine preference. It also restored vital brain cell connections, previously damaged by morphine, and induced beneficial epigenetic shifts. These findings suggest LSD can positively reshape reward circuits, attenuating drug-seeking behaviors.
Abstract
Psychedelics are emerging as a promising treatment option for a range of neuropsychiatric disorders, including substance use disorders. One potential mechanism underlying their therapeutic benefits may involve a reversal of maladaptive plasticity induced by drug exposure. Here, we identify physiological, behavioral, and epigenetic impacts of lysergic acid diethylamide (LSD) on morphine-treated male and female mice. Morphine was selected due to the high leverage capacity to address the opioid epidemic. A single treatment of LSD, or 4 microdoses of LSD, cause accelerated extinction of morphine-induced conditioned place preference. Whole-cell electrophysiology revealed that excitatory synaptic plasticity, which was eliminated in VTA GABA neurons following morphine exposure, was restored 24 hours after a single high dose of LSD. To explore the impact of LSD treatment on potential epigenetic changes, whole-brain DNA methylation analysis in morphine-treated mice that received either saline or LSD post-morphine treatment revealed significant differences in methylation profiles associated with LSD treatment. Collectively, these findings suggest that LSD may reverse or prevent morphine-induced changes in reward circuit plasticity and attenuate measures of morphine-preference.