This is not a clinical trial. The aim of this study is to understand the mechanism of action of two recently licensed drugs for ADHD on brain function. We will compare the brain activation changes elicited by Guanfacine extended release (GXR; a non-stimulant drug) with the brain activation changes elicited by Lisdexamfetamine (LISDEX; a stimulant drug) and by placebo in 20 drug-free patients with ADHD using functional Magnetic Resonance Imaging (fMRI). For this purpose we intend to scan participants during their performance of tasks of attention, working memory, and inhibition, which we know from previous studies to elicit abnormal brain activation patterns in ADHD patients (Rubia et al., 2005; Smith et al., 2006).

Twenty ADHD patients between 8 and 20 years of age will participate in the double-blind, randomised, active drug condition, within-group, placebo-controlled experimental fMRI study. Each participant will be assessed in baseline measures during a pre-assessment visit. Then the patient will be scanned 3 times under each of these 3 drug conditions: GXR, LISDEX, and placebo. Every patient will receive a single typical clinical weight-adjusted dose of GXR (0.05mg/kg rounded down to the closest dose of 1mg, 2mg, or a maximum of 3mg), LISDEX (for participants aged 8-9 years 20mg regardless of weight; for participants aged 10-20 years the dose will be calculated at 0.5mg/kg rounded to the closest 30, 40, or 50mg, middle doses, e.g. 35mg, will be rounded down) and placebo (10mg Vit C) in one of the scans, in a randomised order. Patients will perform a battery of cognitive tests 3.5 hours after drug administration, after which the will undergo an fMRI scan. The scan will start 4.5 hours after drug administration where drugs have shown to have maximum plasma concentration. Participants will be scanned 3 times, one week apart, under each drug condition.

Inclusion Criteria:

• Age range: 8-20 years
• Medication-naïve or non-medicated for two weeks or on stimulant medication, and willing to take the medication off for 48 hours before scans.
• Meeting DSM-5 diagnosis of ADHD
• Score above clinical cut-off on the ADHD module of the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) (Kaufman et al., 1997)
• Score above clinical cut-off for ADHD on the short forms of the Conners Parent Rating Scales, CPRS (Conners et al., 2008)
• Score above cut-off on the ADHD Rating Scale, ADHD-RS (DuPaul, et al., 1998)
• IQ > 70 as tested on the WASI-II (Wechsler et al., 1999)
• Mood and depression symptoms will be allowed as long as they are not the primary diagnosis.

Exclusion Criteria:

• IQ < 70 (Wechsler et al., 1999).
• Comorbidity with schizophrenia, bipolar disorder, learning disability, OCD, severe depression with current suicidal behaviour (as assessed by a clinical interview)
• Neurological problems, i.e. a history of severe neurological illness, e.g. brain tumour, epilepsy or a history of symptomatic seizures, polyneuropathy etc.
• Substance abuse history
• Other illness (cardiovascular, renal, hepatic, metabolic) that would impact the data integrity or safety of the subject (i.e. contraindicated to any of the treatments) as determined by the investigators
• Contraindication to MRI. i.e., previous implantation of metallic material, pacemaker, implanted medication pumps, neural stimulators, claustrophobia
• Unable to give informed assent or consent in the case of the parent
• Contraindications for LISDEX and GXR use (i.e. advanced arteriosclerosis, agitated states, hyperexcitability, hyperthyroidism, moderate or severe hypertension, symptomatic cardiovascular disease)