New Treatment for Alcohol and Nicotine Dependence

High and Low Dose Topiramate for the Treatment of Alcohol-Dependent Smokers

This research study aims to test whether topiramate (a drug that is being used for seizure) will help individuals who have problems with both alcohol and nicotine. The investigators believe that individuals taking topiramate will be more successful at abstaining from both alcohol and nicotine than individuals taking placebo.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence; Nicotine Dependence
• Intervention / Treatment: Drug: Low-Dose Topiramate; Drug: High-Dose Topiramate; Drug: Placebo

Detailed Description

We propose a novel pharmacological strategy for treating alcohol and nicotine dependence concomitantly.

The reinforcing effects of both alcohol and nicotine are mediated through the cortico-mesolimbic dopamine (CMDA) system, and the concomitant use of both drugs enhances their pharmacological effects. We propose a better approach to control dopamine (DA) effects by contemporaneous indirect modulation of DA release and its functional expression. Both DA release from its cell bodies in the ventral tegmental area and the expression of its reinforcing effects through the cortico-mesolimbic system are modulated by gamma-aminobutyric acid (GABA) efferents under the tonic control of glutamate-mediated excitatory amino acid pathways. Thus, it is reasonable to hypothesize that a medication that facilitates cortico-mesolimbic GABAergic function and inhibits glutamate action should diminish both nicotine's and alcohol's reinforcing effects by inhibiting the release of midbrain DA and its functional expression through pathways projecting from the nucleus accumbens to the cortex. The promise of this novel approach is exemplified by our recent proof-of-concept demonstration that topiramate compared with placebo significantly improved smoking abstinence rates and decreased serum cotinine levels among alcohol dependent smokers. An important clinical effect of topiramate in alcohol-dependent individuals appears to be that its anti-withdrawal effects promote the gradual tapering of drinking. Hence, due to this unique anti-withdrawal effect of topiramate, we propose to adopt the same methodology for treating alcohol-dependent individuals, as is common practice with smokers, of setting a target quit date (TQD) after which relapse to either drug can be measured. We propose an 18-week, double-blind clinical trial with follow-up visits at 1 month and 3 months, in which alcohol-dependent smokers will receive brief behavioral compliance enhancement treatment (BBCET) plus a smoking self-help manual as their psychosocial treatment, and will be randomized to receive placebo,high-dose topiramate (up to 250 mg/day), or low-dose topiramate (up to 125 mg/day) to prevent relapse to heavy drinking and smoking. Each of the 3 treatment arms shall contain 98 individuals, with a total N of 294.

The TQD will occur at the beginning of the 6th week of treatment. Our primary objective is to determine whether both low- and high-dose topiramate will be more efficacious than placebo at reducing the percentage of heavy drinking days and increasing the continuous abstinence rate for smoking determined by a combination of self-report and carbon monoxide (CO) monitoring after the TQD and in the last 4 weeks of treatment. We also will be able to determine whether a lower dose of topiramate is as efficacious as the higher dose and, therefore, is associated with a lower adverse profile. Our secondary objectives are to test whether topiramate will be more efficacious than placebo at improving quality of life and reducing craving after the TQD and in the last 4 weeks of treatment and whether this improvement will be sustained in the follow-up phase.

• Study Type: Interventional
• Enrollment (Actual): 236
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • La Jolla, California, United States, 92093
      • University of California, San Diego
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas MD Anderson Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • University of Virginia Center for Addiction Research & Education
    • Richmond, Virginia, United States, 23294
      • University of Virginia Center for Addiction Research & Education

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males and females who have given written informed consent
• Subjects must be above the age of 18
• Good physical health
• Diagnostic and Statistical Manual (DSM)-IV diagnosis of mild to severe alcohol use disorder
• Smoking ≥ 5 cigarettes/day
• Currently drinking at least 8 standard drink units (SDUs) per week for women and at least 15 SDUs per week in the 30 days prior to randomization
• Subjects must provide evidence of stable residence
• The pregnancy test for females of child-bearing potential at screen and prior to randomization must be negative. Additionally, women of child-bearing potential must be using an acceptable form of contraception.
• Literate in English and able to read, understand, and complete the rating scales and questionnaires accurately, follow instructions, and make use of the behavioral treatments
• Willing to participate in a treatment program for alcohol and nicotine dependence

Exclusion Criteria:

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Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo with brief behavioral enhancement therapy	Drug: Placebo; Placebo with brief behavioral enhancement therapy; Other Names: sugar pill
Experimental: Low-Dose Topiramate; Low-dose topiramate (125 mg) with brief behavioral enhancement therapy	Drug: Low-Dose Topiramate; Low-dose topiramate (up to 125 mg/day) with brief behavioral enhancement therapy; Other Names: Topamax
Experimental: High-Dose Topiramate; High-dose topiramate (250 mg) with brief behavioral enhancement therapy	Drug: High-Dose Topiramate; High-dose topiramate (up to 250 mg/day) with brief behavioral enhancement therapy; Other Names: Topamax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Continuous Smoking Abstinence in the Last 4 Weeks of Treatment Continuous Smoking Abstinence in the Last 4 Weeks of Treatment	No smoking in the last 4 weeks of the 18-week treatment with an expired carbon monoxide level of <10 ppm as the biochemical verification. We used the intent-to-treat assumption, where missing smoking data were considered as smoking.	Week 15 - 18 of the 18-week medication treatment
Percentage of Heavy Drinking Days (PHDD) in the Last 4 Weeks of Treatment	A heavy drinking day is defined as >= 5 standard drinking units for men and >= 4 standard drinking units for women. We calculated the PHDD used the intent-to-treat assumption, where missing drinking data were considered as heavy drinking.	Week 15 - 18 of the 18-week medication treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life in the Last 4 Weeks of Treatment	We used the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) to measure quality of life in the last 4 weeks of treatment. Scoring involves summing the individual item scores on a 5-point scale, with higher scores indicating greater life satisfaction and enjoyment (better outcome). We report here a percent score of subscales contained within the Q-LES-Q, with higher scores indicating a better outcome. The subscales within the questionnaire have different numbers of items, resulting in different ranges of raw scores, so using a percent score, which used the following formula: (raw_score - scale_min_possible_score) / (scale_max_possible_score - scale_min_possible_score), helped normalize such differences, improving interpretation using the same range (i.e., 0 - 100) between subscales.	Week 15 - 18 of the 18-week medication treatment
Craving for Alcohol and Cigarettes in the Last 4 Weeks of Treatment	We used the Visual Analog Scales (VAS) to assess the craving levels for alcohol and cigarettes, respectively. VAS uses a 100 millimeter line, where 0 mm = no craving (minimum value) and 100 mm = strongest craving ever (maximum value). Participants are asked to make a mark on the line that best represents their current level of craving. Research staff then measure the distance in millimeters from the "No Craving" anchor (0 mm) to the participant's mark, which is their score. A higher score is equal to higher craving (worse outcome). Mean scores of the last 4 weeks of treatment are reported.	Week 15 - 18 of the 18-week medication treatment

Collaborators and Investigators

• Sponsor: University of Virginia
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA); M.D. Anderson Cancer Center; University of California, San Diego
• Investigators: Principal Investigator: Nassima Ait-Daoud Tiouririne, MD, University of Virginia; Principal Investigator: Robert M Anthenelli, MD, University of California, San Diego; Principal Investigator: Paul M Cinciripini, PHD, M.D. Anderson Cancer Center; Principal Investigator: Bankole A Johnson, MD, University of Virginia

Publications and helpful links

Helpful Links

• (UVA CARE Website)

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2011
• Primary Completion (Actual): October 6, 2017
• Study Completion (Actual): October 6, 2017

Study Registration Dates

• First Submitted: August 10, 2010
• First Submitted That Met QC Criteria: August 16, 2010
• First Posted (Estimated): August 17, 2010

Study Record Updates

• Last Update Posted (Estimated): October 31, 2025
• Last Update Submitted That Met QC Criteria: October 3, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: alcohol; nicotine; cigarette; alcoholism
• Additional Relevant MeSH Terms: Mental Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Alcoholism; Tobacco Use Disorder; Carbohydrates; Hexoses; Monosaccharides; Fructose; Ketoses; Topiramate; Sugars
• Other Study ID Numbers: 15597; 5R01AA019720-02 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No