A PET protocol examining CB1 receptors in people with ADHD

BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by attentional deficits, hyperactivity and impulsivity that often persists into adulthood. While dysfunction of dopaminergic neurotransmitter systems has been observed, underlying mechanisms remain incompletely understood. Current treatments with methylphenidate and amphetamines show limited long-term effectiveness and do not address broader clinical needs. The endocannabinoid system represents a promising therapeutic target. Cannabinoid type 1 (CB1) receptors are highly concentrated in the prefrontal cortex and striatum, brain regions central to ADHD pathophysiology. The "dual pathway model of ADHD" describes deficits in inhibition-related executive functions and reward-related functions, both mediated by fronto-striatal networks. Striatal CB1 receptor availability correlates negatively with impulsivity. Given the interaction between dopaminergic and endocannabinoid systems, CB1 receptors may play a key role in ADHD pathogenesis. METHODS: This controlled study will investigate CB1 receptor availability in ADHD using positron emission tomography (PET) with the CB1-selective radiotracer [18F]MK-9470. The primary outcome is the CB1 receptor distribution volume (VT) in the striatum. Secondary outcomes include CB1 receptor availability in prefrontal cortex and other ADHD-relevant brain regions, plasma concentrations of endocannabinoids (anandamide, 2-arachidonoylglycerol), and validated neuropsychological assessments of attention and impulsivity. We will compare three groups (n = 34 each): medication-naïve participants with ADHD, methylphenidate-treated participants with ADHD, and healthy controls. Statistical analysis will employ ANOVA with post-hoc comparisons and correlation analyses between neuroimaging and behavioral measures. RESULTS: N/A, as this is a study protocol. CONCLUSIONS: This first investigation of the endocannabinoid system in ADHD will provide crucial insights into disease mechanisms and identify potential therapeutic targets. Results may inform development of novel cannabinoid-based treatments and improve evidence-based therapeutic strategies for ADHD management. TRIAL REGISTRATION: German Clinical Trials Register (DRKS-ID: DRKS00037526, Registration date: 25 September 2025).