This project will evaluate the ability of Mirtazapine (MZP), a pharmacologically unique medication with a growing body of evidence to support its efficacy and safety for the treatment of methamphetamine (MA) use among medication for opioid use disorder (MOUD) patients, to significantly decrease MA use and related health-impairing behaviors. MZP has already successfully been used in the treatment of methamphetamine (detailed further below and in the Appendices).

The investigators hypothesize that those assigned to the MZP plus treatment as usual (TAU) MZP+TAU arm will demonstrate significantly increased rates of biochemically verified abstinence from MA and other substances of abuse and experience improvements in health impairing behaviors relative to the placebo (PLO)+TAU arm across the 10-week treatment and follow-up periods.

Inclusion Criteria:

• Enrollment at medication for opioid use disorder (MOUD) treatment at Oregon Recovery & Treatment Center/clinics in Spokane, WA.
• Verification of a DSM-5104 diagnosis of an methamphetamine (MA) use disorder (i.e. mild, moderate, or severe),
• Aged 18+ years,
• Ability to provide written informed consent,
• Demonstration of 78% adherence rate during the induction period and
• Provision of at least one MA positive urinalysis at baseline or during induction.
• Baseline complete blood cell count (CBC), total protein, albumin, glucose, alkaline phosphatase, creatinine, BUN, and electrolytes without clinically significant abnormalities as determined by clinician in conjunction with symptoms, physical exam, and medical history.
• No current acute illness requiring prolonged medical care.
• No serious chronic illnesses that are likely to progress clinically during trial participation.
• Vital signs are within the normal ranges (i.e., Blood pressure: 90/60 mm Hg to 120/80 mm Hg; breathing: 12-18 breaths per minute; pulse: 60-100 beats per minute; temperature: 97.8 - 99.1 degrees Fahrenheit.

Exclusion Criteria:

• Inability to demonstrate competency to provide informed consent because of cognitive or psychiatric disorders or limited English proficiency,
• Prior diagnosis of dementia,
• Medically or psychiatrically unsafe to participate as determined by Dr. Layton (Medical Director),
• Documented suicide attempt in the past 30 days and/or serious suicide intention or plan as assessed by the Structured Clinical Interview for DSM-5 (SCID-5; clinical trials version)105
• Suicide attempt in the last 2 years
• Moderate or severe liver disease (AST, ALT, and total bilirubin >= 5 times upper limit of normal),
• Impaired renal function (estimated GFR <40 ml/min),
• Current severe cocaine, amphetamine, or alcohol use disorder as defined by DSM-5 criteria which Drs Layton and McPherson deem their participation as unsafe.
• History of bipolar disorder or psychotic disorder, as determined by Structured Clinical Interview for DSM Disorders (SCID,
• Currently taking 1) any type of opioid use disorder medication other than methadone or buprenorphine/naloxone, or 2) phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) and CYP enzyme inhibitor cimetidine.
• Taking an anti-depressant medication within the past 30 days, including mirtazapine or a monoamine oxidase inhibitor,
• Prescribed MZP in the least year, or
• History of violent criminal behavior or being on parole,.
• Currently pregnant or intending to become pregnant,.
• Final determination of eligibility will be made by Dr. Layton in consultation with the PI.