Aim: Cannabis use disorder (CUD) typically onsets before age 22 and accounts for the majority of substance use treatment presentations by Australian youth. There are no established pharmacotherapies for CUD. Guanfacine extended-release (XR) is an alpha 2a adrenergic receptor agonist that is approved for attention deficit hyperactivity disorder in children and adolescents. Immediate-release guanfacine alleviates some cannabis withdrawal symptoms in adults. The XR formulation can be taken once daily, is well-characterised in children and adolescents, and reduces impulsivity in those with ADHD. The GRACE study – embedded within youth substance use treatment services in Victoria, Australia – will assess whether guanfacine XR added to treatment as usual (TAU) reduces the frequency of cannabis use following monitored abstinence in youth with CUD. Methods: GRACE is a pragmatic Phase 2b, double-blind, parallel-group superiority randomised controlled trial of guanfacine XR for youth aged 12-25 years seeking treatment for CUD (mild-severe). Participants (N=100) are randomly assigned in a 1:1 ratio to receive guanfacine XR (target dose 4 mg/day) or placebo plus TAU, including residential admission for supervised withdrawal for up to 14 days. The primary endpoint is efficacy, indexed by change from baseline in frequency of cannabis use (days/week) during 4-weeks in the community following discharge from residential withdrawal, measured weekly with the Timeline Follow Back. Results. GRACE commenced recruitment in August 2023; data collection is ongoing. Conclusions. The GRACE trial will investigate the efficacy of guanfacine XR – a promising candidate for CUD – in young people presenting for CUD treatment.