LSD Restores Synaptic Plasticity in VTA of Morphine-Treated Mice and Disrupts Morphine-Conditioned Place Preference

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.