Subtypes of cocaine use disorder and their neurobehavioral profiles.

Cocaine Use Disorder (CUD) afflicts over 1.4 million individuals in the United States alone. However, current treatments are largely ineffective, with up to 85% returning to use long-term. We posit that addressing functional heterogeneity underlying CUD is crucial for improving treatment success. Based on prior work, we hypothesized heterogeneity in function across three domains: approach-related behavior, executive function, and negative emotionality. We analyzed data from 109 participants (ages 22-39, 15% female, N = 61 CUD) from the SUDMEX CONN dataset. To test if distinct 'mechanism-based' subtypes exist within CUD, we conducted a Latent Profile Analysis using phenotypic data as input. The discovered subtypes were characterized regarding their use characteristics, psychiatric diagnostics, and resting-state functional connectivity (rsFC). Three distinct subtypes emerged (p < 0.05, partial eta squared: 0.19-0.51): a 'Relief Type' with high negative emotionality (N = 22); a 'Cognitive Type' with lower executive function (N = 15); and an 'Undefined Type' with no apparent impairments (N = 24). Consistent with this profile, the Relief Type had more comorbid psychiatric diagnoses. Furthermore, each subtype demonstrated a unique neurobiological profile underlying their current cocaine use (pFDR < 0.05): the Relief Type showed aberrant rsFC in Limbic/Memory and Salience networks; the Cognitive Type in Frontoparietal, higher visual, Motor Planning, Salience, and Parietal Association networks; and the 'Undefined Type', in Motor Planning, Ventral Frontoparietal, Salience, and Default-Mode networks. Importantly, despite these distinct profiles, CUD severity was equivalent between all three subtypes. Results highlight significant heterogeneity in the mechanisms underlying CUD, emphasizing the importance of mechanism-based subtyping to inform the development of targeted treatments.