# Fentanyl, Methamphetamine and Polysubstance Use Differentially Affect Locomotor Sensitisation and Social Behaviour in Rats: Psychedelic Treatment Reverses Social Deficits

## TL;DR

This study shows that using fentanyl and methamphetamine together harms social behavior in rats, but a psychedelic drug can reverse these effects.

## Contribution

The study reveals that psychedelic treatment can reverse social deficits caused by polysubstance use in rats.

## Key findings

- Polysubstance use causes unique social deficits compared to single substance use.
- Acute DOI treatment reverses withdrawal-induced social deficits in rats.
- DOI enhances social interactions in female rats after withdrawal.

## Abstract

Polysubstance use of opioids and stimulants is increasingly common among individuals with a substance use disorder, yet most researchers examine these substances in isolation. This gap limits our understanding of the effects of polysubstance use and how these differ from single substance use. Here, we examined the impact of single versus polysubstance exposure of fentanyl and methamphetamine on locomotor sensitisation and social behaviour in male and female rats. In addition, as recent evidence has suggested the potential for psychedelic compounds to decrease facets of both opioid and stimulant use disorders, we tested whether the psychedelic R‐(−)2,5‐dimethoxy‐4‐iodoamphetamine (DOI) can reverse drug withdrawal‐induced social deficits. Baseline sociability was assessed in male and female Sprague–Dawley rats using DeepLabCut and Simple Behavioral Analysis (SimBA). Rats then received injections of saline, methamphetamine (1 mg/kg) and/or fentanyl (20 μg/kg) for 14 days, and locomotion was measured. All rats then underwent 10 days of withdrawal followed by a reassessment of sociability. The following day, all subjects received DOI (0.3 mg/kg; 30 min) and were reassessed for sociability. Our results indicate that the development of locomotor sensitisation and drug withdrawal‐induced social deficits vary as a function of drug class, drug history and sex. In addition, acute DOI treatment is sufficient to reverse social deficits as well as enhance social interactions in females. The findings from these experiments suggest a potential therapeutic role of psychedelics in mitigating the social deficits that are associated with withdrawal from polysubstance use of opioids and stimulants.

Polysubstance opioid–stimulant use is increasingly prevalent, yet its behavioral consequences remain poorly understood. We compared single versus combined fentanyl and methamphetamine exposure in male and female rats, assessing locomotor sensitization and sociability during withdrawal. Polysubstance exposure uniquely disrupted social preference, and acute treatment with the psychedelic 5‐HT2A agonist DOI reversed these withdrawal‐induced social deficits, supporting serotonergic psychedelics as potential interventions for social dysfunction in polysubstance use disorder.