There is substantial need to improve treatment for opioid use disorder (OUD). Buspirone is a mechanistically supported medication with robust preclinical and preliminary clinical support for treating opioid withdrawal and decreasing relapse. Buspirone has the utility to treat both acute and protracted withdrawal periods. We are experts in the measurement, evaluation and treatment of opioid withdrawal symptoms and have recently completed an RCT pilot study (n=16) which provides the initial safety, feasibility, and efficacy data to support a more thorough evaluation of buspirone to mitigate withdrawal when administered as an adjunct to a residential stepwise opioid taper. We propose a rigorous, Phase II, three-group, placebo-controlled double-blind RCT to evaluate the efficacy of buspirone for (1) acute withdrawal as an adjunctive pharmacotherapy to a residential opioid stepwise taper and (2) protracted withdrawal during an outpatient phase following taper completion. During the 12-day residential phase, 100 participants with OUD will be enrolled, stabilized on morphine, undergo a morphine stepwise taper, and complete a post-taper observation period where they will have the opportunity to initiate long-term buprenorphine or extended-release naltrexone. The outpatient phase will take place over the course of a 4-week period and will consist of weekly in-person visits and daily diary reports of their withdrawal and craving severity and anxiety. Individuals with OUD (n=100) will be randomized to one of three groups (1) buspirone during both residential and outpatient phases, (2) buspirone during the residential phase and placebo during the outpatient phase, and (3) placebo during both the residential and outpatient phases. We aim to complete 90 participants (30/group). We will collect measures of withdrawal, craving (acute and tonic), anxiety, medication acceptability, and biochemical measures of opioid use. Primary Aim 1 evaluates the impact of buspirone on acute and protracted withdrawal. We hypothesize participants who receive buspirone during both the residential and outpatient phases of the study will have the lowest overall opioid withdrawal severity. Primary Aim 2 evaluates the impact of buspirone on acute and tonic craving. We hypothesize participants that receive buspirone during both residential and outpatient phases will have the lowest tonic craving and that participants will show significantly lower acute craving when they are actively receiving buspirone. Primary Aim 3 evaluates whether retention and relapse prevention are impacted by buspirone. We hypothesize that buspirone used during a residential opioid taper will increase treatment retention and that buspirone used during the outpatient phase will decrease rates of relapse. Primary Aim 4 evaluates whether buspirone mitigates anxiety during residential and outpatient treatment for opioid use disorder. We hypothesize that buspirone will show modest reductions in anxiety during residen...