Modulation of the peripheral nervous system to restore reward circuitry in opioid use disorder: A multi-timescale...

Opioid use disorder (OUD) remains a chronic, relapsing condition; in the United States in 2024, approximately 79,000 drug-overdose deaths occurred, including about 54,000 involving opioids (NCHS Data Brief, 2026 (Centers for Disease Control and Prevention, National Center for Health Statistics, 2026)). Although current pharmacological treatments stabilize patients, residual anhedonia and relapse vulnerability may reflect persistent mesocorticolimbic dysfunction. This short review proposes a multi-timescale framework in which transcutaneous auricular vagus nerve stimulation (taVNS) serves as a non-invasive adjunct to medication-assisted treatment and psychotherapy. The proposed NTS-LC-VTA pathway may produce acute noradrenergic modulation of VTA dopamine neurons, intermediate receptor- and transcription-dependent adaptations, and longer-term BDNF/TrkB-associated synaptic remodeling. These mechanistic links remain hypotheses, and increased firing may not restore dopamine output after chronic opioid-related presynaptic adaptations. Preclinical findings and limited clinical evidence from non-invasive vagal stimulation support feasibility, but direct evidence that taVNS normalizes reward circuitry or prevents relapse in OUD remains lacking.