Methamphetamine-Fentanyl Polysubstance Administration Produces Social Deficits and Corticolimbic Stress-Reward Circuit Adaptations

Rationale and Objectives: Polysubstance use involving psychostimulants and opioids is increasingly prevalent and associated with elevated overdose risk, relapse vulnerability, and poor treatment outcomes. However, the neurobehavioral consequences of opioid-stimulant use remain poorly understood. We evaluated whether repeated methamphetamine-fentanyl polysubstance treatment disrupts social preference during withdrawal, whether psilocybin treatment restores sociability, and whether these manipulations alter corticolimbic expression of stress- and opioid-related genes. Methods Male and female rats received injections of methamphetamine and fentanyl or saline and were assessed for social preference at baseline and following 10 days of withdrawal. On withdrawal day 10, rats received psilocybin or saline and were reassessed for sociability 24 h later. CRHR1 and OPRM1 expression in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) were quantified by RT-qPCR. Results Withdrawal from 14-days of polysubstance treatment reduced social preference, replicating prior findings of withdrawal-associated social dysfunction. Psilocybin pretreatment did not restore social preference at the time point examined. In the mPFC, psilocybin bidirectionally altered CRHR1 expression depending on drug history, decreasing expression in saline-treated controls, while increasing expression following polysubstance treatment. In the NAc, polysubstance administration reduced CRHR1 expression. OPRM1 expression showed sex-dependent regulation with a marked reduction in the NAc of females following polysubstance treatment and evidence of sex-dependent effects in the mPFC. Conclusions Methamphetamine-fentanyl treatment produces persistent social deficits during withdrawal and region- and sex-dependent corticolimbic transcriptional adaptations in vivo . Although psilocybin did not restore sociability, it produced drug history-dependent regulation of cortical CRHR1 .