The goal of this clinical trial is to learn if administering a high dose stimulant with Contingency Management reduces days of use in adults who use methamphetamine better than the usual treatment provided by the clinic.

The main questions the trial aims to answer are:

Is a high dose stimulant better than a placebo and usual treatment at helping reduce the number of days they use methamphetamine? Is a high dose stimulant with contingency management better than placebo and usual treatment at helping people reduce the number of days they use methamphetamine?

Participants will be placed randomly into one of four groups:

1. Usual treatment and placebo
2. Usual treatment, placebo and contingency management
3. Usual treatment and high dose stimulant
4. Usual treatment, high dose stimulant and contingency management

Participation includes the following:

1. Participants will receive medication or placebo weekly for 15 weeks.
2. Participants will attend the clinic for weekly treatment
3. Participants will attend the clinic once every 2 weeks for study visits. Each visit will take about an hour to complete. At these visits, participants will be asked to provide a urine sample and complete questionnaires.

The ASCME trial is a multi-centre, randomized double blind (lisdexamfetamine-01 component), open label (Contingency Management component), dose-ascending, placebo controlled trial. Participants will be enrolled in one of the 4 treatment arms:

Arm 1: treatment as usual plus placebo Arm 2: treatment as usual plus placebo and contingency management Arm 3: treatment as usual plus lisdexamfetamine (LDX-01) Arm 4: treatment as usual plus lisdexamfetamine (LDX-01) and contingency management

The trial will enroll 440 participants, and will be conducted in 5-7 treatment centres across Canada.

Participants will be enrolled in the trial for 20 weeks altogether.

Inclusion Criteria:

• Participant must meet all the following criteria:

  1. Between 18 and 55 years of age;

  2. Diagnosed with a moderate to severe methamphetamine (MA) use disorder as defined by the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) criteria;

  3. Active MA use at screening measured via self-reported MA use ≥14 days in the past 28 days AND verified by urine drug metabolite testing;

  4. Interested in reducing/stopping MA use;

  5. If female:

     1. Be of non-childbearing potential, defined as (i) postmenopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age); or (ii) documented surgically sterilized (i.e., tubal ligation, hysterectomy, or bilateral oophorectomy); or
     2. Be of childbearing potential, have a negative pregnancy test at screening, and agree to use an acceptable method of birth control throughout the study;

  6. Willing to be randomized to one of the 4 study arms and followed for the duration of the trial;

  7. Able to provide informed consent;

  8. Willing to comply with study procedures;

  9. Able to communicate in English or French.

Exclusion Criteria:

• 1. Symptomatic or advanced cardiovascular disease (e.g., advanced arteriosclerosis), moderate hypertension; current hyperthyroidism confirmed via blood test; known hypersensitivity or idiosyncrasy to the sympathomimetic amines or glaucoma or any disabling, severe, OR unstable medical condition that, in the opinion of the study physician, precludes safe participation or the ability to provide fully informed consent; 2. Any severe or unstable co-morbid substance use disorder that, in the opinion of the study physician, precludes safe participation in the study; 3. Participants with Opioid Use Disorder (OUD) who have been on Opioid Agonist Therapy (OAT) for < 12 weeks, and not yet at stabilization dose, or at stabilization dose < 4 weeks; 4. Current or history of any serious psychiatric disorder (e.g., bipolar disorder, pre-existing psychosis, schizophrenia) that, in the opinion of the study physician, precludes safe participation in the study; 5. History of a severe adverse event, hypersensitivity or known allergic reaction to LDX or other amphetamine drugs OR hypersensitivity to the sympathomimetic amines; 6. Pregnant, nursing, or planning to become pregnant during the study period; 7. Planned extended absence during study period (e.g., pending legal action, surgery, incarceration, inpatient residential program) in the opinion of the study physician that might prevent completion of the study; 8. Use of an investigational drug for stimulant use disorder during the 30 days prior to screening, confirmed via self-report OR pharmacy records; 9. Currently receiving contingency management for the treatment of stimulant use disorder in the 4 weeks prior to screening, confirmed via self-report OR site records; 10. Use of prescribed amphetamine-type medication OR medication for the treatment of stimulant use disorder (e.g., methylphenidate, modafinil, bupropion) in the 4 weeks prior to screening; 11. Current or anticipated need for treatment with any medication that may interact with LDX (e.g., proton pump inhibitors, monoamine oxidase inhibitors [MAOIs]) used currently or within the past 14 days AND that would preclude study participant at the discretion of the study physician

All participants will receive identical capsules (i.e., smell, taste, and colour), reducing bias by blinding participants, providers, and research staff to the study drug.

To maintain the blinding of the study medication, dose adjustments will be known by Qualified Investigators and the Pharmacy team according to the Induction Phase schedule and at the Investigator's discretion, without unblinding the study medication (i.e., LDX-01 versus placebo) except for some limited safety related reasons. Access to the randomization code will be strictly controlled by the Data Management Centre. Each participant's assignment will be kept so that an individual code may be broken without unblinding the randomization allocation of other participants.