Oxytocin Reduces Noradrenergic-Induced Opioid-Like Withdrawal Symptoms in Individuals on Opioid Agonist Therapy

Abstract

Background: Intranasal administration of the neuropeptide oxytocin has been explored as a potential therapeutic agent for substance use disorder including opioid use disorder (OUD). Methods: This phase 1, crossover, randomized, double-blind, placebo-controlled trial tested the safety, tolerability, and efficacy of intranasal oxytocin (80 IU) twice a day for 7 days in participants (N = 20) with OUD who were taking an opioid agonist therapy. In the laboratory, participants underwent opioid cue exposure paired with noradrenergic activation produced by yohimbine (32.4 mg) or placebo. Assessments included, 1) subjective response: craving, withdrawal, anxiety, and stress; 2) biomedical markers: hypothalamic-pituitary-adrenal axis response (cortisol) and noradrenergic activation (α-amylase); and 3) safety measures: hemodynamics and adverse event evaluation. Generalized linear model with model-based estimator in the covariance matrix was used, with medication (oxytocin/placebo) and noradrenergic activation (yohimbine/placebo) as within-subject factors. Results: Oxytocin significantly reduced opioid-like withdrawal, anxiety symptoms, and cortisol levels elicited by cue exposure under noradrenergic activation produced by yohimbine. This effect was specific because oxytocin did not reduce craving, hemodynamics, or α-amylase levels increased by yohimbine administration. A single dose of yohimbine elicited the noradrenergic stimulation, and 7-day oxytocin administration was safe and well tolerated among individuals diagnosed with OUD and taking opioid agonist therapy. Conclusions: The findings of this study suggest that oxytocin alleviates opioid-like withdrawal symptoms and anxiety by modulating the hypothalamic-pituitary-adrenal axis.

Keywords

• Noradrenergic
• Opioid use disorder
• Oxytocin
• Stress
• Yohimbine