Effects of Psychedelics Lysergic Acid Diethylamide and <i>R</i> (–)-2,5-Dimethoxy-4-Iodoamphetamine on Oral Opioid Consumption and Naloxone-Precipitated Withdrawal in Male C57Bl/6J Mice

Background: There are currently three FDA-approved medications for opioid use disorder (OUD), but none of them are especially effective, some can precipitate withdrawal in dependent individuals, and all of them require daily administration. In the appropriate settings, single administrations of psychedelics can elicit persistent anti-addiction effects in humans and in laboratory animals, but very few studies have assessed the potential therapeutic utility of psychedelics in OUD. Methods: We have recently established a model of oral opioid consumption in mice that captures an “addiction-like” phenotype characterized by induction of physical dependence and defense of opioid consumption when drug solutions are devalued. In these studies, we used this procedure to assess the effects of two different psychedelics on abuse-related effects of two distinct fentanyl analogs. Results: Mice consumed solutions of water, acryl fentanyl (AF), or 4-fluoroisobutyryl fentanyl (4-FIBF) for 2 h per day, 7 days per week, demonstrating postsession antinociceptive effects and becoming physically dependent. Four days after a single treatment with saline, lysergic acid diethylamide (LSD), or R (–)-2,5-dimethoxy-4-iodoamphetamine (DOI), mice were given access to their maintenance solutions, which were now adulterated with bitter quinine. In mice drinking water, quinine significantly decreased consumption, but mice consuming AF or 4-FIBF solutions defended their consumption despite the bitter taste. In all cases, treatment with LSD or DOI did not alter the defense of consumption observed with opioid solutions, suggesting no effects on opioid taking. Fifteen days after psychedelic treatment, mice were injected with the opioid antagonist naloxone, and withdrawal-associated jumping, restlessness, and thermal hyperalgesia were measured. Neither LSD nor DOI treatment altered naloxone-precipitated jumping or restlessness, but both psychedelics significantly attenuated withdrawal-associated thermal hyperalgesia. Conclusions: These data do not strongly support the use of a single exposure to psychedelics in the treatment of OUD but may suggest persistent effects of psychedelics on heightened pain perception typically observed in opioid withdrawal.