A German research team is preparing to peer inside the brains of adults with attention-deficit/hyperactivity disorder using a radioactive tracer that binds selectively to cannabinoid type 1 receptors. The CB1-ADHD study, a protocol paper published in EJNMMI Reports by researchers at the University Medical Center of the Johannes Gutenberg University Mainz, describes a controlled positron emission tomography trial designed to measure, for the first time, the availability of CB1 receptors in the striatum of people with ADHD. The study is registered in the German Clinical Trials Register under DRKS00037526, with recruitment that began on 1 October 2025 and a target of 114 participants within two years.
ADHD is a neurodevelopmental disorder marked by attentional deficits, hyperactivity and impulsivity that often persists into adulthood. In Germany, estimated point prevalence rates are 4 to 5 percent in children and 2 to 3 percent in adults, with males diagnosed more frequently than females. The condition is associated with comorbid disorders including depression, anxiety, personality disorders, addictive disorders and eating disorders, as well as psychosocial impairment, elevated accident risk, occupational difficulties and a substantial economic burden. According to the Global Burden of Diseases study published by the World Health Organization, the diagnostic category that includes ADHD ranks among the twenty leading causes of years lived with disability.
Current first-line pharmacotherapies, the stimulants methylphenidate and amphetamine, act on dopaminergic and noradrenergic systems, and randomised controlled trials have shown positive short-term effects. Yet the response rate is around 70 percent, stimulants are contraindicated in some adults because of sympathomimetic side effects such as increased blood pressure and pulse, and the authors argue that these drugs do not meet broader long-term clinical needs. This treatment gap motivates the study’s focus on the endocannabinoid system, a signalling network composed of CB1 and CB2 receptors, endogenous ligands such as anandamide and 2-arachidonoylglycerol, and the enzymes that synthesise and degrade them.
The rationale for targeting this system rests on anatomy and circuitry. CB1 receptors are G-protein coupled receptors found in high concentrations in the striatum, prefrontal cortex and cerebellar cortex, regions involved in attention, executive functions including impulse control, and motivation and reward. CB1 receptors sit mainly presynaptically on excitatory and inhibitory neurons, where their endogenous ligands act as retrograde messengers that modulate the release of neurotransmitters such as glutamate and GABA. Within the striatum, anandamide and 2-arachidonoylglycerol are abundant and modulate dopamine transmission, and stimulation of CB1 receptors has been shown to increase the firing rate of dopaminergic neurons and facilitate dopamine release. Evidence also runs in the reverse direction, with D2 receptors controlling anandamide production in the striatum.
The study’s hypotheses draw on prior human findings. In high novelty seekers, CB1 receptor availability was globally reduced compared with low novelty seekers and correlated negatively in the striatum with the impulsivity sub-dimension labelled extravagance. Separately, blood concentrations of anandamide and 2-arachidonoylglycerol were elevated in unmedicated participants with ADHD compared with healthy subjects, a pattern the investigators interpret as possibly triggering a compensatory downregulation of CB1 receptors. Genetic work adds another thread: polymorphisms in the CNR1 gene encoding the CB1 receptor have been linked with impulsivity-related phenotypes, particularly in the context of early-life adversity. The primary hypothesis is therefore that CB1 receptor availability will be lower in unmedicated participants with ADHD, primarily in the striatum, than in healthy controls.
The trial is monocentric, parallel-group and organised into three arms of 34 participants each: medication-naïve adults with ADHD, methylphenidate-treated adults with ADHD, and healthy controls matched for age, sex and intelligence. Participants must be between 21 and 40 years old, carry a DSM-5 diagnosis of predominantly hyperactive-impulsive or combined presentation with childhood onset, and either have been off all stimulant medication for at least six months or have been on stable methylphenidate monotherapy for at least three months. Extensive exclusion criteria screen out head injury with brain damage, neurological, endocrine or cardiovascular disorders, a range of psychiatric diagnoses, recent recreational drug use verified through hair and urine testing with defined cut-off values, pregnancy or breastfeeding, and MRI contraindications.
The experimental protocol unfolds across three appointments roughly two weeks apart, totalling about 13 hours. Before the second visit, participants complete ten questionnaires at home, covering current and childhood ADHD symptoms, self-rated trait impulsivity with the Barratt Impulsiveness Scale-11 and the UPPS scale, substance consumption, and a vocabulary-based intelligence test. The second appointment brings structural MRI, resting-state functional MRI, diagnostic interviews including the IDA-R interview for adult ADHD, the Qb-Test for objective measurement of hyperactivity, attention and impulsivity, and the stop-signal and delay discounting paradigms that quantify motor impulsivity and reward-related delay discounting. A hair sample and rapid drug test complete that visit, and a positive result ends participation.
The third appointment, lasting about seven hours, takes place at the Department of Nuclear Medicine. Each participant receives a single intravenous bolus injection of an average 250 MBq of the CB1-selective radiotracer [18F]MK-9470, an inverse agonist that binds the receptor with high selectivity and affinity. PET data are acquired on a Siemens Biograph Vision PET/CT scanner in three blocks: a first 90-minute acquisition, after a 30-minute break a second 60-minute block, and a late measurement at 360 minutes to capture the tracer’s slow kinetics. Blood samples drawn the same day will yield plasma concentrations of anandamide and 2-arachidonoylglycerol plus the related compounds arachidonic acid, palmitoylethanolamide and oleoylethanolamide, and CNR1 polymorphisms will be analysed to statistically control for genetic effects.
Quantification will go beyond simple uptake measures. The primary outcome is the distribution volume VT in the striatum, calculated with a reversible two-tissue compartment model using an arterial input function derived from image-based segmentation of the carotid artery and metabolite-corrected blood samples. The authors chose VT because it achieves higher sensitivity and specificity in detecting subtle physiological changes than semi-quantitative measures such as the standardised uptake value. Secondary outcomes include distribution volumes in other ADHD-relevant brain regions, plasma endocannabinoid concentrations, behavioural impulsivity parameters, and resting-state network connectivity measures. The primary analysis will compare VT between unmedicated participants with ADHD and healthy controls using analysis of covariance, with group and sex as fixed effects and age as a random effect, and sensitivity analyses adjusting for alcohol, tobacco and previous cannabis use, all factors known to reduce brain CB1 receptor availability.
The investigators are careful to frame expectations. As a study protocol, the paper reports no results; the authors themselves note that findings will need replication in follow-up studies before any translation into practice. Secondary hypotheses predict higher CB1 receptor availability in methylphenidate-treated than unmedicated participants, based on evidence that methylphenidate suppresses brain endocannabinoid concentrations and could drive compensatory upregulation, and correlations are anticipated between striatal receptor availability, plasma endocannabinoid levels and behavioural impulsivity measures. Exploratory questions address frontal receptor availability, the lesser-studied endocannabinoid-like compounds, and links to intrinsic network connectivity. If the hypotheses hold, the work could clarify how the endocannabinoid system participates in ADHD pathophysiology and, the authors argue, open a starting point for developing cannabinoid-based therapeutic strategies for a disorder whose current treatments leave many clinical needs unmet.
Subject of Research: A PET imaging study protocol measuring cannabinoid type 1 receptor availability in adults with ADHD
Article Title: Cannabinoid type 1 receptor availability imaging in attention-deficit/hyperactivity disorder using [18F]MK-9470 positron emission tomography: study protocol of the CB1-ADHD study
Article References: Miederer, I., Schofer, M. L., Ruckes, C., Retz, W., Schreckenberger, M., & Sebastian, A. (2026). Cannabinoid type 1 receptor availability imaging in attention-deficit/hyperactivity disorder using [18F]MK-9470 positron emission tomography: study protocol of the CB1-ADHD study. EJNMMI Reports, 10(1), Article 37. https://doi.org/10.1186/s41824-026-00322-7
Image Credits: AI Generated
DOI: 10.1186/s41824-026-00322-7
Keywords: ADHD, CB1 receptor, endocannabinoid system, PET imaging, MK-9470, striatum, methylphenidate, impulsivity, study protocol, dopamine, anandamide, neuroimaging
News Source: Ophelia Keating. (October 29, 2026). PET Study Will Image Cannabinoid Receptors in Adult ADHD Brains. Scienmag.
