LSD Restores Synaptic Plasticity in VTA of Morphine-Treated Mice and Disrupts Morphine-Conditioned Place Preference.
Michael Von Gunten, Tenna Russell, Isaac Stirland, Seth Parks, Timothy Jenkins, Jeffrey G Edwards
bioRxiv : the preprint server for biology June 15, 2025 preprint DOI: 10.1101/2025.06.12.658958 (opens in new tab) via PubMed
Summary
AI-generated from the abstractA single high dose or four microdoses of LSD accelerated the extinction of morphine-induced conditioned place preference in both male and female mice. Whole-cell electrophysiology showed that excitatory synaptic plasticity in VTA GABA neurons, which was suppressed after morphine exposure, was restored 24 hours after a single high dose of LSD. Whole-brain DNA methylation analysis revealed significant differences in methylation profiles between morphine-treated mice that received LSD versus saline. These findings suggest that LSD may reverse or prevent morphine-induced changes in reward circuit plasticity and reduce measures of morphine preference.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Male and female mice |
| Intervention | Lysergic acid diethylamide (LSD) |
| Dose | a single high dose, or 4 microdoses |
| Duration | 24 hours after a single high dose |
| Topics | Psychedelic-assisted therapy |
| Keywords | Addiction treatment Neuroscience Opioid addiction |
| Key finding | LSD treatment accelerated extinction of morphine-induced conditioned place preference and restored excitatory synaptic plasticity in VTA GABA neurons that was eliminated by morphine exposure. |
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.