DOX as a Potential Treatment for Methamphetamine Dependence

Inclusion Criteria: 1. Be English-speaking volunteers who are not seeking treatment at the time of the study 2. Be between 18-55 years of age 3. Meet DSM-IV TR criteria for methamphetamine dependence; participants may or may not meet criteria for nicotine dependence. Nicotine dependence is allowed but not required because most methamphetamine users smoke cigarettes. 4. Have a self-reported history of using methamphetamine by the smoked or IV route 5. Have vital signs as follows: supine blood pressure \> 100/65 mm Hg, a seated blood pressure of \> 90/60 mm Hg, and an orthostatic change \< 20 mm Hg systolic or \<10 mm Hg diastolic on standing. To ensure that subjects will not be at risk from methamphetamine, the resting pulse must be \< 90 bpm and the blood pressure must be \< 150 mmHg systolic and \< 90 mmHg diastolic. 6. Have hematology and chemistry laboratory tests that are within normal (+/- 10%) limits with the following exceptions: a) liver function tests (total bilirubin, ALT, AST, and alkaline phosphatase) \< 3 x the upper limit of normal, and b) kidney function tests (creatinine and BUN) within normal limits 7. Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant arrhythmias 8. Have a medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the principal investigator. Exclusion Criteria: 1. Meet DSM IV TR criteria for dependence on drugs other than methamphetamine or nicotine. 2. Have any history or evidence suggestive of seizure disorder or brain injury 3. Have any previous medically adverse reaction to methamphetamine, including loss of consciousness, chest pain, or epileptic seizure 4. Have neurological or psychiatric disorders, such as: * psychosis, bipolar illness or major depression as assessed by MINI * organic brain disease or dementia assessed by clinical interview * history of any psychiatric disorder which would require ongoing treatment or which would make study compliance difficult * history of suicide attempts within the past year and/or current suicidal ideation/plan 5. Have evidence of clinically significant heart disease or hypertension, as determined by the PI 6. Have evidence of untreated or unstable medical illness including: neuroendocrine, autoimmune, renal, hepatic, or active infectious disease 7. Have symptomatic HIV or are taking antiretroviral medication 8. Be pregnant or nursing. Other females must either be unable to conceive (i.e., surgically sterilized, sterile, or post-menopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, upon hospital admission, and at the end of study participation 9. Have asthma or currently use theophylline or other sympathomimetics 10. Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study. Criteria for Discontinuation Following Initiation Participants will be discharged if they have a positive breath test indicating use of alcohol or a urine test indicating illicit use of drugs while in the MED-VAMC, if they do not comply with study procedures, or if they do not tolerate the study drugs. Stopping criteria are detailed below. Subject Selection Criteria Rationale Route of administration. Participants are required to have used MA by the IV or smoked route to avoid exposing participants to drugs by routes of administration that produce more intensive interoceptive effects than usually used by the participants. Prior experience with smoked MA is allowed (rather than restricting the population to those with experience with IV MA) because smoked MA reaches brain sites of action as rapidly as does intravenously administered MA and smoked MA produces effects that are comparable to IV MA. Speed of administration (and rate of delivery to brain) of stimulant drugs likely impacts subjective and cardiovascular effects, so smoked and intravenously administered MA produce similar subjective effects (22-26).