Contingency management plus deep transcranial magnetic stimulation for the treatment of cocaine use disorder

The National Institute on Drug Abuse awarded a $6.239 million Cooperative Agreement to the University of Texas Health Science Center at Houston on September 15, 2025, under the Drug Use and Addiction Research Programs (CFDA 93.279).

The award funds development and evaluation of a novel treatment combining contingency management behavioral therapy with deep transcranial magnetic stimulation (H4 coil) to improve outcomes in treatment-resistant cocaine use disorder. The study employs a two-stage design with 130 participants, using high-magnitude contingency management in the initial four weeks to identify treatment-refractory cases, then pairing deep TMS targeting the insula and lateral prefrontal cortex bilaterally with continued behavioral intervention. The research aims to address phenotypic characteristics in cognition, reward, and negative emotionality that correlate with poor treatment response, by modulating brain circuitry alterations associated with contingency management effects.

Performance occurs in Houston, Texas, with a period of performance through June 30, 2029. The University of Texas Health Science Center at Houston, operating through its Sponsored Projects Administration Division, is a child entity within the University of Texas System. The award obligates $6.239 million against the total authorized amount.

Abstract

The prevalence of cocaine use disorder (CUD) in the united states is increasing, now affecting approximately 1.4 million, alongside a significant rise in the rate of cocaine-involved overdoses. In the absence of FDA- approved medications, treatment options for CUD are limited to behavioral approaches, with contingency management (CM) considered the most effective. However, research by our group and others has shown that responses to CM vary considerably, with poorer treatment outcomes associated with phenotypic characteristics in the domains of cognition, reward, and negative emotionality. This study aims to develop a novel treatment combination by pairing behavioral therapy (CM) with transcranial magnetic stimulation (TMS) that targets brain circuity alterations associated with CM effects, with the goal of improving treatment refractoriness. Basic behavioral neuroscience research has indicated that the anterior insular (AIN) - amygdala pathway plays a key role in psychostimulant abstinence and relapse in rodent models of CM. Until recently, traditional TMS devices could only stimulate a focal area directly under the skull. Recent advances in brain stimulation techniques allow for targeting these deeper structures. Specifically, the 'deep TMS' H4 coil stimulates the insula and lateral prefrontal cortex (PFC) bilaterally, making IT possible to target CM-critical pathways. Further, the insula and PFC are critical hubs for cognition, reward, and negative emotionality phenotypes associated with CM, such that H4-delivered TMS could potentially correct these phenotypic characteristics linked to treatment refractoriness. This study will use a novel two-stage design to evaluate the effects of CM plus H4 TMS for treating CUD. In the first 4 weeks of treatment, all participants (n = 130) will receive high-magnitude CM to identify treatment refractoriness, with initial 'response' to CM defined as achieving two weeks of consecutive cocaine-negative urines. Participants who do not respond ('non-responders') will enter the TMS augmentation protocol and be randomized to receive either active or sham deep H4 TMS therapy, in addition to CM, for another 8 weeks. The accelerated TMS protocol will consist of three sessions of intermittent theta burst stimulation (itbs), delivered thrice weekly for six weeks then once weekly for two weeks. Primary outcomes will include abstinence (proportion of responders), reduced cocaine use (percent negative urines), and change in craving as assessed through self-report and CUE-induced electroencephalogram brain responses (aim 1). Resting-state functional connectivity (rsfc) and the nida phenotyping assessment battery (phab) will be conducted at three timepoints to explore treatment mechanisms associated with the proposed pathway (aim 2). Machine learning techniques will integrate data across modalities (rsfc; phab) to preliminarily develop a predictive model aimed at identifying initial non-responders who are most likely to benefit from CM+TMS treatment (exploratory aim). If successful, the results of this study could pave the way toward FDA clearance of a combination (CM+TMS) product tailored to individuals with treatment-refractory phenotypes.