Polysubstance use of opioids and stimulants is common, but most research examines each drug alone. In rats, the effects of fentanyl and methamphetamine—alone or combined—on movement sensitization and social behavior depended on drug class, drug history, and sex. After withdrawal, social deficits emerged. A single dose of the psychedelic DOI reversed those social deficits and even boosted social interaction in females. The findings suggest psychedelics might help treat social impairments linked to withdrawal from combined opioid and stimulant use.
Withdrawal from repeated use of methamphetamine and fentanyl together reduces social preference in rats, confirming earlier findings that polysubstance withdrawal impairs social behavior. A single dose of psilocybin did not restore sociability within 24 hours. In the medial prefrontal cortex, psilocybin had opposite effects on CRHR1 gene expression depending on drug history: it decreased expression in control rats but increased it in polysubstance-treated rats. In the nucleus accumbens, polysubstance treatment reduced CRHR1 expression. OPRM1 expression was sex-dependent, with a marked reduction in the nucleus accumbens of females after polysubstance treatment and sex-dependent effects in the medial prefrontal cortex.