Clinical MedicineClinical trials Open Access | 10.1172/jci.insight.182331

Monica L. Faulkner,1 Mehdi Farokhnia,1,2 Mary R. Lee,1 Lisa Farinelli,1 Brittney D. Browning,1 Kelly Abshire,1 Allison M. Daurio,1 Vikas Munjal,1 Sara L. Deschaine,1 Selim R. Boukabara,1 Christopher Fortney,3 Garrick Sherman,4 Melanie Schwandt,5 Fatemeh Akhlaghi,6 Reza Momenan,7 Thomas J. Ross,8 Susan Persky,3 and Lorenzo Leggio1,9,10,11

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Faulkner, M. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Farokhnia, M. in: JCI | PubMed | Google Scholar |

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

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1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

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1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

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1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Abshire, K. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Daurio, A. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Munjal, V. in: JCI | PubMed | Google Scholar |

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Deschaine, S. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Boukabara, S. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Fortney, C. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Sherman, G. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Schwandt, M. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Akhlaghi, F. in: JCI | PubMed | Google Scholar |

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Momenan, R. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Ross, T. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

Find articles by Persky, S. in: JCI | PubMed | Google Scholar

1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse (NIDA) Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA) Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA.

2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

3Immersive Simulation Program, Social and Behavioral Research Branch, National Human Genome Research Institute (NHGRI), NIH, Bethesda, Maryland, USA.

4Office of the Clinical Director, NIDA, Intramural Research Program, NIH, Baltimore, Maryland, USA.

5Office of the Clinical Director, NIAAA Division of Intramural Clinical and Biological Research, NIH, Bethesda, Maryland, USA.

6Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA.

7Clinical NeuroImaging Research Core, NIAAA, NIH, Bethesda, Maryland, USA.

8Neuroimaging Core, NIDA Intramural Research Program, NIH, Baltimore, Maryland, USA.

9Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, Rhode Island, USA.

10Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

11Department of Neuroscience, Georgetown University Medical Center, Washington DC, USA.

Address correspondence to: Lorenzo Leggio, NIDA/NIAAA, NIH, 251 Bayview Boulevard, BRC Suite 200, Room 04A515, Baltimore, Maryland, 21224, USA. Phone: 443.740.2801; Email: lorenzo.leggio@nih.gov.

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Published December 20, 2024 - More info

Published in Volume 9, Issue 24 on December 20, 2024
JCI Insight. 2024;9(24):e182331. https://doi.org/10.1172/jci.insight.182331.
© 2024 Faulkner et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published December 20, 2024 - Version history
Received: April 23, 2024; Accepted: October 30, 2024 View PDF Abstract

BACKGROUND. Studies have demonstrated the role of ghrelin in alcohol-related behaviors and consumption. Blockade of the growth hormone secretagogue receptor (GHSR), which is the ghrelin receptor, has been shown to decrease alcohol drinking and reward-related behaviors across several animal models. We previously conducted a human study testing a GHSR inverse agonist/competitive antagonist, PF-5190457, in individuals who are heavy drinkers and showed its safety when coadministered with alcohol. Here, we conducted a phase IIa experimental medicine study in patients with alcohol use disorder (AUD) to investigate the effects of PF-5190457 on alcohol- and food-related outcomes.

METHODS. Forty-two individuals with AUD (n = 29 completers) participated in a randomized, double-blind, placebo-controlled study where they received PF-5190457 100mg b.i.d. (or placebo) in 2 counterbalanced, within-subject stages. Participants completed an alcohol cue-reactivity (CR) experiment in a bar-like laboratory and a virtual food choice experiment in a cafeteria-like virtual reality (VR) environment. A subset of participants (n = 12) performed a CR task during a brain functional MRI (fMRI) experiment.

RESULTS. PF-5190457 did not reduce cue-elicited alcohol craving. PF-5190457 reduced virtual calories selected (P = 0.04) in the VR environment. PF-5190457 did not influence neural activation during CR task in the fMRI experiment.

CONCLUSION. This study provides human evidence of the role of GHSR blockade in behaviors related to food selection and highlights the need for future investigations into targeting the ghrelin system in AUD.

TRIAL REGISTRATION. ClinicalTrials.gov (accession no. NCT02707055).

FUNDING. NIDA and NIAAA ZIA-DA000635; National Center for Advancing Translational Sciences UH2/UH3-TR000963.

Introduction

Alcohol use disorder (AUD) and excessive alcohol drinking is a leading cause of preventable morbidity and mortality worldwide (1, 2). Treatment for AUD often includes a combination of psychological, social, and pharmacologic interventions, and effectiveness is highly variable across individuals (3, 4). There are currently only 3 Food and Drug Administration–approved (FDA-approved) medications for AUD, disulfiram, naltrexone, and acamprosate; hence, there is a critical need to develop additional novel effective treatments for AUD (3, 4).

The ghrelin system has recently gained attention as a potential pharmacotherapeutic target for AUD. The 28–amino acid peptide acyl-ghrelin (here referred to as ghrelin) (5) is an endogenous agonist for the growth hormone secretagogue receptor (GHSR), a G-protein coupled receptor which when activated induces growth hormone (GH) release from the pituitary (6) and stimulates appetite via changes in the activity of both orexigenic and anorexigenic neurons (7), among several other functions (8–10).Preclinical studies have demonstrated ghrelin’s role in the modulation of reward processing and alcohol use (11, 12). For example, ghrelin administration into the laterodorsal tegmental (LDTg) and ventral tegmental areas (VTA) increased extracellular concentrations of accumbal dopamine in mice (13), and these effects, as well as alcohol intake and alcohol-induced conditioned place preference, were attenuated in GHSR-KO mice (14). Similarly, alcohol binge-like drinking was reduced in GHSR-KO rats, compared with WT controls (15). Importantly, ghrelin administered into the lateral hypothalamus or paraventricular nucleus did not reduce alcohol drinking, suggesting that the neural regions regulating the effects of ghrelin on alcohol intake do not overlap completely with those that regulate the effects of ghrelin on appetite and food intake (14). Ghrelin has also been shown to modulate the central amygdala function, a brain region involved in stress regulation and alcohol consumption (16). Furthermore, ghrelin has been implicated in the modulation of negative emotional processing and stress-related neural pathways via the hypothalamic/pituitary/adrenal (HPA) axis and amygdala (17). Systemic and central administration of GHSR antagonists has been repeatedly shown to decrease alcohol intake and alcohol-seeking behaviors in different rodent models and across several independent laboratories (11–18).

Clinical studies have also demonstrated a relationship between alcohol use and ghrelin. Acute alcohol administration reduces circulating endogenous ghrelin levels (19–26), while chronic alcohol consumption appears to increase ghrelin levels (27, 28). Baseline ghrelin levels are positively correlated with alcohol craving (29–32) and may predict relapse to alcohol drinking (29). In 2 double-blind, placebo-controlled, experimental medicine studies, our team showed that i.v. ghrelin administration increased cue-elicited alcohol craving (33) and i.v. alcohol self-administration (34) in heavy-drinking individuals with AUD. The latter study also found that, during an alcohol/food incentive delay task, i.v. ghrelin administration increased alcohol-related neural activation in the amygdala, increased food-related neural activation in the nucleus accumbens, and decreased food-related neural activation in the medial orbitofrontal cortex (mOFC) (