Shared neurobiological mechanisms and behavioral strategies contribute to elevated substance use disorder risk in comorbid autism and ADHD

The clinical landscape of neurodevelopmental psychiatry has fundamentally shifted following the formal recognition that autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) frequently cooccur. While historically viewed as distinct entities, the comorbid "AuDHD" phenotype is now understood to represent a unique neurobiological state characterized by high susceptibility to substance use disorders (SUD). This integrative review synthesizes a decade of research, including pivotal 2024 and 2025 findings, to delineate the mechanisms underlying this vulnerability. We identified a synergistic interaction between shared genetic risk loci, convergent frontostriatal dysfunction, and a mesolimbic "reward deficiency" that predisposes individuals to seek external chemical regulation. Furthermore, we examine how behavioral adaptation strategies, such as social masking and functional self-medication, exacerbate this risk by creating chronic cognitive exhaustion. Our findings demonstrate that substance use in this population often emerges as a functional attempt at self-regulation rather than simple impulsivity. By integrating genomic architecture with circuit-level dynamics and social coping mechanisms, this report provides a comprehensive model for understanding addiction in neurodivergent populations. These insights advocate for concurrent, neuroaffirming treatment models that move beyond traditional diagnostic silos to address the specific needs of the comorbid individual.