Neurobiological Dysfunctional Substrates for the Self-Medication Hypothesis in Adult Individuals with Attention-Deficit Hyperactivity Disorder and Cocaine Use Disorder: A Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography Study

Objectives: Attention-deficit hyperactivity disorder (ADHD) in adulthood shows high co-occurrence rates with cocaine use disorder (CoUD). The self-medication hypothesis (SMH) provides a theoretical explanation for this comorbidity. This study investigates the neurobiological mechanisms that could support SMH in adult patients with attention-deficit hyperactivity disorder with cocaine use disorder (ADHD-CoUD).Materials and Methods: We included 19 ADHD-CoUD patients (84.2% male; age: 32.11 years [7.18]) and 16 CoUD patients (68.7% male; age: 36.63 years [8.12]). All subjects underwent a fluorine-18-fluorodeoxyglucose positron emission tomography (F-18-FDG PET) brain scan. We tested brain metabolism differences between ADHD-CoUD and CoUD patients using voxel-based and regions of interest (ROIs)-based analyses. The correlation between dependence/abstinence duration and regional brain metabolism was also assessed in the two groups. Lastly, we investigated the integrity of brain metabolic connectivity of mesocorticolimbic and nigrostriatal dopaminergic systems, and large-scale brain networks involved in ADHD and addictions.Results: The voxel-wise and ROIs-based approaches showed that ADHD-CoUD patients had a lower metabolism in the thalamus and increased metabolism in the amygdala and parahippocampus, bilaterally, than CoUD subjects and healthy controls (HCs). Metabolism in the thalamus negatively correlated with years of dependence in ADHD-CoUD patients. Moreover, connectivity analyses revealed that ADHD-CoUD patients had a more preserved metabolic connectivity than CoUD patients in the dopaminergic networks and large-scale networks involved in self-regulation mechanisms of attention and behaviors (i.e., anterior default mode network [ADMN], executive network [ECN], and anterior salience network [aSAN]).Conclusions: We demonstrated distinct neuropathological substrates underlying substance-use behaviors in ADHD-CoUD and CoUD patients. Furthermore, we provided neurobiological evidence in support of SMH, demonstrating that ADHD-CoUD patients might experience short-term advantages of cocaine assumption (i.e., compensation of dopaminergic deficiency and related cognitive-behavioral deficits). Impact statementThis study provides neurobiological evidence for self-medication hypothesis (SMH) in adults with attention-deficit hyperactivity disorder with cocaine use disorder (ADHD-CoUD). The current results suggest differential treatment approaches, namely pharmacological approaches for cocaine use disorder (CoUD) individuals with and without attention-deficit hyperactivity disorder (ADHD), to improve functional adjustment and reduce the risk of relapse in addictive behaviors. Specifically, stimulant pharmacological treatments (e.g., methylphenidate- and amphetamine-based stimulants) with a long-acting formulation should be considered the first line of intervention for adults with ADHD-CoUD. Furthermore, these pharmacological treatments could be combined with evidence-based behavioral interventions for emotional dysregulation in patients with substance use disorders and ADHD.

Automated summary

This study investigates the neurobiological mechanisms underlying the comorbidity of attention-deficit hyperactivity disorder (ADHD) and cocaine use disorder (CoUD), supporting the self-medication hypothesis (SMH). The findings provide important clinical implications for treatment approaches in adults with ADHD-CoUD and suggest considering stimulant pharmacological treatments as the first line of intervention. The study is rated with a score of 8 out of 10 for its significance.