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Substance use disorders (SUDs) and anxiety disorders (ADs) are highly comorbid, a co-occurrence linked to worse clinical outcomes than either condition alone. While the neurobiological mechanisms involved in SUDs and anxiety disorders are intensively studied separately, the mechanisms underlying their comorbidity remain an emerging area of interest. This narrative review explores the neurobiological processes underlying this comorbidity, using the Research Domain Criteria (RDoC) framework to map disruptions in positive valence, negative valence, and cognitive systems across the three stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Anxiety and substance use play a reciprocal role at each stage of addiction, marked by significant psychosocial impairment and dysregulation in the brain. A more thorough understanding of the neural underpinnings involved in comorbid SUDs and anxiety disorders will contribute to more tailored and effective therapeutic interventions and assessments.

Abstract The faster a drug enters the brain, the greater its addictive potential, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. With simultaneous PET-fMRI we linked dynamics of dopamine signaling, brain activity/connectivity, and self-reported ‘high’ in 20 adults receiving methylphenidate orally (results in slow delivery) and intravenously (results in fast delivery) (trial NCT03326245). We estimated speed of striatal dopamine increases to oral and IV methylphenidate and then tested where brain activity was associated with slow and fast dopamine dynamics (primary endpoint). We then tested whether these brain circuits were temporally associated with individual ‘high’ ratings to methylphenidate (secondary endpoint). A corticostriatal circuit comprising the dorsal anterior cingulate cortex and insula and their connections with dorsal caudate was activated by fast (but not slow) dopamine increases and paralleled ‘high’ ratings. These data provide evidence in humans for a link between dACC/insula activation and fast but not slow dopamine increases and document a critical role of the salience network in drug reward.

Combined PET imaging and mathematical simulations reveal that the rate of dopamine increase in the striatum underlies self-reports of drug “high” in response to oral and intravenous methylphenidate challenges in humans