Project Summary The prevailing neuroscientific characterization of addiction is that of evolving neuro-behavioral responses to chronic drug use that are initially motivated by increasing pleasure (impulsive drug use) that over time causes neuro-adaptations such that drug use is increasingly motivated by relief from negative affect (compulsive use). The compulsive stage of addiction can be seen as a “vicious cycle” since the short-term relief from negative affect through drug use ultimately exacerbates negative affect through neuroadaptations to chronic use. Our early work demonstrated that the vicious cycle was a primary factor in maintaining comorbidity between alcohol use disorder (AUD) and internalizing disorders (anxiety and depression). This provided the ground work for the development and validation of a cognitive-behavioral therapy program for AUD comorbidity that directly targeted the vicious cycle of addiction (VC-CBT). Further, we developed a fully autonomous and easily scaled digital platform to deliver VC-CBT that has proved to be as effective as the therapist-delivered version. The intervention is premised on educating individuals about the reversibility of the vicious cycle, and training them to use proven coping skills to manage negative affect without drugs can significantly aid them in achieving desired treatment goals. In this project, we leverage the trans-addiction status of the neuroscientific underpinnings of the VC-CBT intervention and its flexibility as a digital therapeutic to develop and test a digital treatment for comorbidity in opioid use disorder (OUD). Relative to other drugs of abuse, the progression from initial impulsive use to negatively reinforced compulsive use is known to be truncated and nearly universal among those who routinely use opioids, and those with co-occurring internalizing disorders are especially susceptible. This, along with the relatively high lethality of OUD, makes it an ideal near-term target for this trans-addiction therapy. To achieve this, we propose to test the clinical efficacy of digitally-delivered VC-CBT for OUD-INTD comorbidity in a UG3/UH3 program consisting of two phases. The overarching aim of Phase 1 is the modification and pilot testing of the established digitally-delivered negative affect VC-CBT for application in OUD. The overarching aim of Phase 2 is to conduct a scientifically rigorous clinical trial of the modified VC- CBT for OUD. The impact of this work would be to provide a scalable and inexpensive means of improving the otherwise poor OUD treatment outcomes among those with co-occurring anxiety or depression. Moreover, the project would support the viability of trans-addiction interventions that target processes common to multiple addiction types.

Project Narrative This project aims to develop and test a fully-autonomous (no-human operator) CBT-based digital therapeutic for comorbid opioid use disorder (OUD) and internalizing (anxiety and depression) disorders that targets compulsive opioid use motivated by relief of unpleasant emotions. We will modify an existing digital therapeutic in the project's first phase and test it in a clinical trial in the second phase. The success of this project would provide a relatively cheap and easily scaled intervention for OUD based on a well-developed neuro-behavioral model of addiction.