The purpose of this study is to test the effects of a medication called metformin (Glucophage®) on smoking behavior. This medication is FDA-approved for treatment of type-2 diabetes. It is being used for research purposes in this study. Participants will be randomized to one of 3 treatment groups: low dose of metformin, high dose of metformin, or placebo.

There is a need for novel approaches to optimize smoking cessation treatment to help more smokers quit. Mood disturbance and cognitive deficits during nicotine withdrawal may be important treatment targets given their association with smoking relapse. In addition, factors such as HIV-1 infection may exacerbate abstinence effects on mood and cognitive deficits and thus should be measured and controlled for. The investigators hypothesize that the FDA-approved medication, metformin, will attenuate withdrawal-related mood disturbance and cognitive deficits, controlling for HIV status. Using a well-validated abstinence challenge paradigm, the investigators propose a placebo-controlled double-blind parallel arm study with one between-subjects factor of medication (low dose: 500 mg, high dose: 1500 mg, and placebo). Non-treatment seeking smokers (HIV-: n=54; 18 per group) will complete this 23 day study.

Inclusion Criteria

Eligible subjects will be males and females:

1. 18 years of age or older who self-report smoking at least 5 cigarettes (menthol and non-menthol) per day, on average for the past 6 months.

2. HIV status

   1. HIV-infected smokers: diagnosed with HIV infection and exhibiting viral load of less than or equal to 1000 copies/mL and CD4+ counts of greater than or equal to 200 cells/mm3 within 6 months prior to enrollment.
   2. HIV-uninfected smokers: no diagnosis of HIV, either via blood test or self-report.

3. Must not currently be interested in quitting smoking.

4. Women of childbearing potential (based on medical history) must consent to use a medically accepted method of birth control (e.g., condoms and spermicide, oral contraceptive, Depo-Provera injection, contraceptive patch, tubal ligation) or abstain from sexual intercourse during the time they are in the study and using transdermal nicotine.

5. If current or past diagnosis of bipolar disorder, eligible if:

   1. No psychotic features
   2. MADRS: total score less than 8 (past 4 weeks), suicidal item score less than1 (past 4 weeks)
   3. Y-MRS: total score less than 8 (past 4 weeks), irritability, speech content, disruptive or aggressive behavior items score less than 3 (past 4 weeks)
   4. No psychiatric hospitalization or Emergency Room visits for psychiatric issues in the past 6 months
   5. No aggressive or violent acts or behavior in the past 6 months

6. Able to communicate fluently in English.

7. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the combined consent/HIPAA form.

Exclusion Criteria

Smoking Behavior:

1. Current enrollment in a smoking cessation program, or use of other smoking cessation medications in the last month or plans to do either in the next 2 months.
2. Daily use of chewing tobacco, snuff and/or snus, or electronic cigarettes.

Alcohol/Drugs:

1. Self-report current alcohol consumption that exceeds 25 standard drinks/week over the past 6 months. Subjects will be told to limit or avoid the use of alcohol while in the study to avoid any adverse reactions to the study medication.
2. Current untreated and unstable diagnosis of substance dependence (eligible if past use and if receiving treatment and stable for at least 30 days). Current untreated and unstable diagnosis of substance abuse requires Study Physician approval.
3. A positive urine drug screen for cocaine, amphetamines, methamphetamines, PCP, barbiturates and ecstasy (MDMA)at Intake, or any testing session (see Measures and Table 1 for details). Participants believed to have a false-positive result may continue in the study, with investigator approval.

Medical:

1. Females who self-report current pregnancy, planning a pregnancy during the study, or currently breastfeeding/lactating. All female subjects of child-bearing potential shall undergo a urine pregnancy test at the Intake, Baseline, PQ-Testing and 24-H Testing sessions.

2. Current diagnosis of unstable and untreated major depression, as determined by self-report & MINI (eligible if stable for at least 30 days).

3. Current or past diagnosis of psychotic disorder, as determined by self-report or MINI.

4. Suicide risk as indicated by at least one of the following on the MINI/CSSRS (the PI &/or PM [LCSW] will be consulted to assess safety and determine eligibility in cases close to the eligibility cutoffs):

   1. Current suicidal ideation (within 30 days of enrollment)
   2. Two or more lifetime suicide attempts or episodes of suicidal behavior
   3. Any suicide attempt or suicidal behavior within 2 years of enrollment

5. Self-reported kidney and/or liver disease or transplant untreated/unstable or within the past 6 months.

6. Heart/Cardiovascular disease (e.g., angina, coronary heart disease, stroke, etc.) in the past 6 months.

7. Type-1 or type-2 diabetes.

8. Uncontrolled hypertension (BP systolic greater than 159 and/or diastolic greater than 99)*.

9. Liver function tests more than 20% outside of the normal range; Gamma-glutamyl Transpepsidase (GGT) values more than 20% outside of the normal range. If Albumin/Globulin ratios are 20% outside of normal range the abnormal value will be evaluated for clinical significance by the Study Physician and eligibility will determined on a case-by-case basis.

10. Renal disease or renal dysfunction (e.g., serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females]).

11. A blood glucose level less than 70 mg/dl at any visit.

    • Participants presenting with SBP greater than 159 mmHg and/or DBP greater than 99 mmHg at the Intake visit will be instructed to sit quietly for 10 minutes. Then the participant will have a second blood pressure reading taken after a 10 minute period. If, after the second reading the SBP greater than 159 mmHg and the DBP greater than 99 mmHg, the individual will be ineligible to participate, unless determined otherwise by the Study PI or Study Physician, upon review.

Medication:

1. Current use or recent discontinuation (within the past 14 days) of any of the following medications:

   1. Anti-anxiety or panic disorder medications (e.g., clonazepam, alprazolam).
   2. Anti-psychotic medications as assessed on a case-by-case basis
   3. Glucophage/metformin
   4. Glyburide
   5. Furosemide or digoxin
   6. Nifedipine
   7. Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin)

2. Participants who report taking prescription opiate-containing medications (Duragesic/fentanyl patches, Percocet, Oxycontin) will require physician approval prior to confirming final eligibility.

3. Current use of any smoking cessation medications (e.g., Chantix/varenicline, Zyban/bupropion, nicotine replacement therapy/gum/patch).

4. For safety reasons, HIV-infected smokers taking dolutegravir (Tivicay) or drugs that contain dolutegravir (e.g., Triumeq) should not take more than 1000 mg of metformin per day. Therefore, individuals taking dolutegravir will be force randomized to either the placebo condition or the low dose condition.

Subjects will be instructed to refrain from using any study prohibited drugs/medications (both recreational and prescription) throughout their participation in the study. After final eligibility is confirmed, subjects who report taking contraindicated medication(s) over the course of the study period may only remain eligible if the Study Physician and/or Principal Investigator determines that the contraindicated medication(s) do/did not impact the study design, data quality, and/or subject safety/welfare. Subjects are permitted to take necessary prescription medications not included within the exclusion list during the study.

General Exclusion:

1. Current, anticipated, or pending enrollment in another research program over the next 2-3 months that could potentially affect subject safety and/or the study data/design as determined by the Principal Investigator and/or Study Physician.
2. Not planning to live in the area for the next two months.
3. Color blindness.
4. Any impairment (physical and/or neurological) including visual or other impairment preventing cognitive task performance.
5. Known allergy to study medication.
6. Planned radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials) during the course of study participation.
7. Inability to provide informed consent or complete any of the study tasks as determined by the Principal Investigator.
8. Not able to effectively communicate in English (reading, writing, speaking).
9. Missing 3 or more doses during the medication period determined by self-report.

Individuals who started study medication

Through study completion, an average of 30 days