Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context
Summary: Background: Alcohol use disorder (AUD) is associated with an enormous burden of disease and cost to society. The dopamine deficiency hypothesis posits that negative reinforcement generated by a low brain dopamine state drives ethanol intake. Here, we evaluated the efficacy and safety of co...
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Elsevier
2025-07-01
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| Series: | The Lancet Regional Health. Europe |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666776225001024 |
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| author | Bo Söderpalm Helga Lidö Johan Franck Anders Håkansson Daniel Lindqvist Markus Heilig Joar Guterstam Markus Samuelson Barbro Askerup Cecilia Wallmark-Nilsson Andrea de Bejczy |
| author_facet | Bo Söderpalm Helga Lidö Johan Franck Anders Håkansson Daniel Lindqvist Markus Heilig Joar Guterstam Markus Samuelson Barbro Askerup Cecilia Wallmark-Nilsson Andrea de Bejczy |
| author_sort | Bo Söderpalm |
| collection | DOAJ |
| description | Summary: Background: Alcohol use disorder (AUD) is associated with an enormous burden of disease and cost to society. The dopamine deficiency hypothesis posits that negative reinforcement generated by a low brain dopamine state drives ethanol intake. Here, we evaluated the efficacy and safety of combined administration of two dopamine-enhancing drugs, varenicline (a partial nicotinic acetylcholine receptor agonist) and bupropion (a weak dopamine-reuptake inhibitor) on alcohol intake in AUD. Methods: Participants aged 25–70 years with moderate-to-severe AUD (defined as ≥4/11 Diagnostic and Statistical Manual of Mental Disorders [DSM]-5 criteria) were enrolled in this randomized, double-blind, placebo-controlled trial, done at four outpatient clinics in Sweden. Participants were randomly assigned (block size 8) 1:1:1:1 to Placebo + Placebo, Varenicline + Bupropion, Varenicline + Placebo, or Placebo + Bupropion. After a 1-week titration period, Varenicline was taken as 1 mg orally twice per day and bupropion as 150 mg orally twice per day for 12 weeks. Participants, investigators, and all study personnel were unaware of treatment allocation. The two primary outcomes were phosphatidylethanol in blood (B-PEth) and self-reported percentage heavy drinking days (%HDD), assessed over a steady state 10-week-period (from start of week 2 to end of week 11). Modified intention-to-treat (mITT) and per protocol analyses (PP) were performed using a sequential hierarchical statistical method. This registered study (EudraCT 2018–000048-24; clinicaltrials.gov NCT04167306) is completed. Findings: Between March 4, 2019, and December 14, 2022, 384 participants were randomly assigned: Placebo + Placebo = 97, Varenicline + Bupropion = 100, Varenicline + Placebo = 96, Placebo + Bupropion = 91. 72% participants were male (277/384) and 28% female (107/384), median age 57 (13) years. In the mITT analyses, Varenicline + Bupropion reduced B-PEth (Cohen's d [d] = 0·39, p = 0·004) and %HDD (d = 0·31, p = 0·008) vs Placebo + Placebo. Varenicline + Placebo also reduced B-PEth (d = 0·30, p = 0·005) and %HDD (d = 0·36, p = 0·023) vs Placebo + Placebo. For both primary endpoints, differences between the Varenicline + Bupropion and Varenicline + Placebo groups were not statistically significant (B-PEth: d = 0·022, p = 0·97, %HDD: d = 0·027, p = 0·76), precluding further comparisons according to the statistical hierarchy. In PP analyses, both primary outcomes were reduced with Varenicline + Bupropion (d = 0·43 [B-PEth]; d = 0·41 [%HDD]) and Varenicline + Placebo (d = 0·29 [B-PEth]; d = 0·34 [%HDD]) compared with Placebo + Placebo. Nausea, the only safety concern, was more common in the Varenicline + Placebo group than in the Placebo + Placebo group (49/96 vs 11/97, p < 0·0001) and of longer median duration (45 (70) vs 10 (14·5) days, p = 0·001). Nausea incidence was lower in the Varenicline + Bupropion group vs Varenicline + Placebo (36/100 vs 49/96, p = 0·048) and of shorter median duration (16·5 (39·3) vs 45 (70) days, p = 0·010). Interpretation: Two brain dopamine elevating treatments (Varenicline + Bupropion; Varenicline + Placebo) reduce alcohol consumption compared with placebo alone. Effect sizes were largest when Varenicline and Bupropion were combined and compliance was high (PP-population). Bupropion reduced Varenicline-induced nausea. Varenicline + Bupropion or other mild dopamine enhancers should be further explored for treatment of AUD. Funding: This study was funded primarily by the Swedish Research Council. |
| format | Article |
| id | doaj-art-48c0f0505b734ca6a0e4f86c611c3bb7 |
| institution | Kabale University |
| issn | 2666-7762 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | The Lancet Regional Health. Europe |
| spelling | doaj-art-48c0f0505b734ca6a0e4f86c611c3bb72025-08-20T03:49:33ZengElsevierThe Lancet Regional Health. Europe2666-77622025-07-015410131010.1016/j.lanepe.2025.101310Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in contextBo Söderpalm0Helga Lidö1Johan Franck2Anders Håkansson3Daniel Lindqvist4Markus Heilig5Joar Guterstam6Markus Samuelson7Barbro Askerup8Cecilia Wallmark-Nilsson9Andrea de Bejczy10Addiction Biology Unit, Psychiatry and Neurochemistry Section, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden & Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, Sweden; Corresponding author. Addiction Biology Unit, Psychiatry and Neurochemistry Section, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.Addiction Biology Unit, Psychiatry and Neurochemistry Section, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden & Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, SwedenDepartment of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institute & Stockholm Health Care Services, Stockholm County Council, Stockholm, SwedenLund University, Faculty of Medicine, Department of Clinical Sciences Lund, Psychiatry, Lund, Sweden & Office for Psychiatry and Habilitation, Malmö Addiction Centre, Region Skåne, Malmö, SwedenUnit for Biological and Precision Psychiatry, Department of Clinical Sciences Lund, Lund University, Sweden and Office for Psychiatry and Habilitation, Psychiatry Research Skåne, Region Skåne, Lund, SwedenCentre for Social and Affective Neuroscience, BKV, Linköping University, SwedenDepartment of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institute & Stockholm Health Care Services, Stockholm County Council, Stockholm, SwedenMalmö Addiction Centre, Bokgatan 16, Malmö, SwedenAddiction Biology Unit, Psychiatry and Neurochemistry Section, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden & Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, SwedenAddiction Biology Unit, Psychiatry and Neurochemistry Section, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden & Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, SwedenAddiction Biology Unit, Psychiatry and Neurochemistry Section, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden & Department of Addiction and Dependency, Sahlgrenska University Hospital, Gothenburg, SwedenSummary: Background: Alcohol use disorder (AUD) is associated with an enormous burden of disease and cost to society. The dopamine deficiency hypothesis posits that negative reinforcement generated by a low brain dopamine state drives ethanol intake. Here, we evaluated the efficacy and safety of combined administration of two dopamine-enhancing drugs, varenicline (a partial nicotinic acetylcholine receptor agonist) and bupropion (a weak dopamine-reuptake inhibitor) on alcohol intake in AUD. Methods: Participants aged 25–70 years with moderate-to-severe AUD (defined as ≥4/11 Diagnostic and Statistical Manual of Mental Disorders [DSM]-5 criteria) were enrolled in this randomized, double-blind, placebo-controlled trial, done at four outpatient clinics in Sweden. Participants were randomly assigned (block size 8) 1:1:1:1 to Placebo + Placebo, Varenicline + Bupropion, Varenicline + Placebo, or Placebo + Bupropion. After a 1-week titration period, Varenicline was taken as 1 mg orally twice per day and bupropion as 150 mg orally twice per day for 12 weeks. Participants, investigators, and all study personnel were unaware of treatment allocation. The two primary outcomes were phosphatidylethanol in blood (B-PEth) and self-reported percentage heavy drinking days (%HDD), assessed over a steady state 10-week-period (from start of week 2 to end of week 11). Modified intention-to-treat (mITT) and per protocol analyses (PP) were performed using a sequential hierarchical statistical method. This registered study (EudraCT 2018–000048-24; clinicaltrials.gov NCT04167306) is completed. Findings: Between March 4, 2019, and December 14, 2022, 384 participants were randomly assigned: Placebo + Placebo = 97, Varenicline + Bupropion = 100, Varenicline + Placebo = 96, Placebo + Bupropion = 91. 72% participants were male (277/384) and 28% female (107/384), median age 57 (13) years. In the mITT analyses, Varenicline + Bupropion reduced B-PEth (Cohen's d [d] = 0·39, p = 0·004) and %HDD (d = 0·31, p = 0·008) vs Placebo + Placebo. Varenicline + Placebo also reduced B-PEth (d = 0·30, p = 0·005) and %HDD (d = 0·36, p = 0·023) vs Placebo + Placebo. For both primary endpoints, differences between the Varenicline + Bupropion and Varenicline + Placebo groups were not statistically significant (B-PEth: d = 0·022, p = 0·97, %HDD: d = 0·027, p = 0·76), precluding further comparisons according to the statistical hierarchy. In PP analyses, both primary outcomes were reduced with Varenicline + Bupropion (d = 0·43 [B-PEth]; d = 0·41 [%HDD]) and Varenicline + Placebo (d = 0·29 [B-PEth]; d = 0·34 [%HDD]) compared with Placebo + Placebo. Nausea, the only safety concern, was more common in the Varenicline + Placebo group than in the Placebo + Placebo group (49/96 vs 11/97, p < 0·0001) and of longer median duration (45 (70) vs 10 (14·5) days, p = 0·001). Nausea incidence was lower in the Varenicline + Bupropion group vs Varenicline + Placebo (36/100 vs 49/96, p = 0·048) and of shorter median duration (16·5 (39·3) vs 45 (70) days, p = 0·010). Interpretation: Two brain dopamine elevating treatments (Varenicline + Bupropion; Varenicline + Placebo) reduce alcohol consumption compared with placebo alone. Effect sizes were largest when Varenicline and Bupropion were combined and compliance was high (PP-population). Bupropion reduced Varenicline-induced nausea. Varenicline + Bupropion or other mild dopamine enhancers should be further explored for treatment of AUD. Funding: This study was funded primarily by the Swedish Research Council.http://www.sciencedirect.com/science/article/pii/S2666776225001024AUDBupropionCombination treatmentRCTVarenicline |
| spellingShingle | Bo Söderpalm Helga Lidö Johan Franck Anders Håkansson Daniel Lindqvist Markus Heilig Joar Guterstam Markus Samuelson Barbro Askerup Cecilia Wallmark-Nilsson Andrea de Bejczy Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context The Lancet Regional Health. Europe AUD Bupropion Combination treatment RCT Varenicline |
| title | Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context |
| title_full | Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context |
| title_fullStr | Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context |
| title_full_unstemmed | Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context |
| title_short | Efficacy and safety of varenicline and bupropion, in combination and alone, for alcohol use disorder: a randomized, double-blind, placebo-controlled multicentre trialResearch in context |
| title_sort | efficacy and safety of varenicline and bupropion in combination and alone for alcohol use disorder a randomized double blind placebo controlled multicentre trialresearch in context |
| topic | AUD Bupropion Combination treatment RCT Varenicline |
| url | http://www.sciencedirect.com/science/article/pii/S2666776225001024 |
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