This is a randomized, double-blind, sham-controlled, partial crossover study investigating LIFU targeting the NAc and VC for participants with severe, treatment refractory OUD.

The overall objective of this study is to assess the safety, tolerability, and feasibility of using Low Intensity Focused Ultrasound (LIFU) to treat opioid use disorder (OUD) as well as investigate the potential impact on substance use and risk factors associated with drug use recurrence.

Inclusion Criteria:

• Aged 22 - 60 years at time of enrollment.
• Fulfill current DSM-5 (American Psychiatric Association diagnostic and statistical manual of mental disorders, 5th ed, 2013) diagnostic criteria for severe OUD with at least a 2-year history.
• Women of reproductive potential must have negative pregnancy test and agree to use acceptable forms of contraception.

Exclusion Criteria:

• Unable to undergo MR-imaging because of non-MR compatible implants (e.g., pacemakers, medication pumps, aneurysm clips, metallic prostheses (including metal pins and rods, heart valves or cochlear implants), shrapnel fragments, permanent make-up or small metal fragments in the eye that welders and other metal workers may have), or if candidates are uncomfortable in small spaces (have claustrophobia) or cannot lie comfortably on their back for 2-3 hours.
• History of any clinically significant neurological disorder (e.g., brain surgery, tumors, uncontrolled epilepsy, or any others deemed clinically significant by the investigator).
• History of stroke or brain lesion in the targeted brain region (the NAc, ventral striatum, or VC).
• Implanted neurostimulators (e.g., vagus nerve stimulator, spinal cord stimulator, DBS).
• Documentation of clinically significant MRI abnormality indicative of a neurological condition or abnormality that may jeopardize the participant's safety, study conduct, or confound the participant's diagnostic assessments.
• More than 30% of the skull area traversed by the sonication pathway is covered by scars, scalp disorders (e.g., eczema), or atrophy of the scalp.
• Subject with chronic pulmonary disorders e.g. severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area.
• Subject with impaired renal function with estimated glomerular filtration rate <30 mL/min/1.73m2
• Hepatic function laboratory values which are > 1.5 times the upper limit of normal unless deemed not clinically significant by a study investigator.
• Past or present diagnosis of schizophrenia or psychotic disorder.
• Subject unwilling to attempt abstinence from illicit substance use during the course of the study.
• Unable to speak, read and understand English.
• Subject is considered to be a poor surgical or study candidate, which may include, but is not limited to the following: any medical, social, or psychological problem that could complicate the required procedures and evaluations of the study in the judgment of the investigator.

Randomization will occur after all inclusion criteria have been met at which time participants will be randomized 1:1 to either the Active or the Sham arm.This study will be performed in a double-blind manner, with participants as well as investigators and study staff involved with assessments unaware of treatment assignment.