Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of consumption and relapse that acute treatment with a combination of these medications was more efficacious than either alone. To determine whether the mechanism for its beneficial effects is through modulation of ethanol's reinforcing effects, we measured the effect of this combination in male alcohol preferring (P) rats (N = 22) responding for ethanol under a progressive-ratio (PR) schedule. Low doses, which either do not affect (ondansetron; 0.001 mg/kg) or only modestly affect (topiramate; 10 mg/kg) alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side effects. In addition to acute treatment (1 day), the effects of chronic administration (10 days) were examined in an attempt to model human treatment approaches. The effects of the combination were compared with the low dose of topiramate alone hypothesizing that the combination would be more efficacious than topiramate alone. Although both topiramate and the combination similarly reduced PR responding for ethanol following acute treatment and during the initial phase of chronic treatment (Days 1-5), after repeated administration (Days 6-10), only the combination produced a sustained reduction in ethanol-maintained responding. These results suggest an advantage of the combination over topiramate alone at producing a sustained reduction in ethanol's reinforcing effects following prolonged treatment, and lend further support for its use as a potential treatment for AUDs.

Ondansetron

Self-administration

Alcohol Dependence

10.1037/a0035215

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Citations (18)

Ondansetron for Reduction of Drinking Among Biologically Predisposed Alcoholic Patients

JAMA (2000)

Bankole A. Johnson John D. Roache Martin A. Javors Carlo C. DiClemente C. Robert Cloninger

ContextEarly-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent.ObjectiveTo test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT3 (serotonin) antagonist ondansetron.DesignDouble-blind, randomized, placebo-controlled clinical trial.SettingsUniversity of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999).ParticipantsA total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization.InterventionsAfter 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 µg/kg (n = 67), 4 µg/kg (n = 77), or 16 µg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy.Main Outcome MeasuresSelf-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption.ResultsPatients with early-onset alcoholism who received ondansetron (1, 4, and 16 µg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P = .03, P = .01, and P = .02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P = .03, P = .004, and P = .03, respectively). Ondansetron, 4 µg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P = .02) and total days abstinent per study week (6.74 vs 5.92; P = .03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 µg/kg twice per day) compared with those who received the placebo (−0.17 and −0.19 vs 0.12; P = .03 and P = .01, respectively).ConclusionOur results suggest that ondansetron (particularly the 4 µg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality.

Ondansetron

Alcohol Dependence

10.1001/jama.284.8.963

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Citations (425)

Abstinence

Springer eBooks (2010)

Jean‐Michel Scherrmann Kim Wolff Christine A. Franco Marc N. Potenza Tayfun Uzbay

10.1007/978-3-540-68706-1_786

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Allosteric Potentiating Ligand

Springer eBooks (2010)

Jean‐Michel Scherrmann Kim Wolff Christine A. Franco Marc N. Potenza Tayfun Uzbay

Allosteric enzyme

10.1007/978-3-540-68706-1_1174

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Activities of Living Scales

Springer eBooks (2010)

Jean‐Michel Scherrmann Kim Wolff Christine A. Franco Marc N. Potenza Tayfun Uzbay

10.1007/978-3-540-68706-1_3014

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Alexithymia

Springer eBooks (2010)

Jean‐Michel Scherrmann Kim Wolff Christine A. Franco Marc N. Potenza Tayfun Uzbay

10.1007/978-3-540-68706-1_1289

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Augmentation

Springer eBooks (2010)

Jean‐Michel Scherrmann Kim Wolff Christine A. Franco Marc N. Potenza Tayfun Uzbay

10.1007/978-3-540-68706-1_1189

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Current status of carbohydrate deficient transferrin, total serum sialic acid, sialic acid index of apolipoprotein J and serum β‐hexosaminidase as markers for alcohol consumption

Addiction (2003)

Martin A. Javors Bankole A. Johnson

The purpose of this paper is to present a brief review of the literature and to summarize the current status of four biochemical markers for alcohol consumption, carbohydrate deficient transferrin (CDT), total serum sialic acid (TSA), sialic acid index of apolipoprotein J (SIJ) and serum beta-hexosaminidase (beta-HEX).Of these markers, CDT has been the most widely studied, is currently thought to be the most accurate predictor of alcohol consumption, is most readily available and is the only test approved by the FDA for the identification of heavy alcohol use. TSA and SIJ have the potential to be useful markers, but have only recently been discovered, are not readily available and have not yet been studied comprehensively. Finally, the relationship between serum beta-HEX and heavy alcohol consumption has been studied for about 20 years, but the test is not readily available and has not been widely accepted or used as a marker for heavy alcohol consumption.These markers have the potential to be included in a combination of measurements to provide an accurate, more exact assessment of alcohol consumption in a variety of clinical and research settings.

Carbohydrate deficient transferrin

10.1046/j.1359-6357.2003.00582.x

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Citations (56)

Acute Tolerance

Springer eBooks (2010)

Jean‐Michel Scherrmann Kim Wolff Christine A. Franco Marc N. Potenza Tayfun Uzbay

10.1007/978-3-540-68706-1_1084

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Citations (0)