Proceedings of a Workshop
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This activity was supported by contracts between the National Academy of Sciences and American Academy of Neurology; American Brain Coalition; American College of Neuropsychopharmacology; American Neurological Association; Alzheimer’s Association; Boehringer Ingelheim; BrightFocus Foundation; California Institute for Regenerative Medicine; Cohen Veterans Bioscience; Dana Foundation; Department of Health and Human Services’ Food and Drug Administration (R13FD005362); Department of Veterans Affairs (36C24E20C0009); and National Institutes of Health (75N98024F00001 [Under Master Base HHSN263201800029I]) through the National Center for Complementary and Integrative Health, National Eye Institute, National Institute of Environmental Health Sciences, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute on Aging, National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, and NIH BRAIN Initiative; Eisai Inc.; Eli Lilly and Company; Foundation for the National Institutes of Health; Gatsby Charitable Foundation; Harmony Biosciences, Huo Family Foundation; Janssen Research & Development, LLC; Lundbeck Research USA; National Multiple Sclerosis Society; National Science Foundation (DBI-1839674); One Mind; Paul G. Allen Frontiers Group; Simons Foundation Autism Research Initiative; The Michael J. Fox Foundation for Parkinson’s Research. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-73505-6
International Standard Book Number-10: 0-309-73505-X
Digital Object Identifier: https://doi.org/10.17226/29061
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2025. Examining glucagon-like peptide-1 receptor (GLP-1R) agonists for central nervous system disorders: Proceedings of a workshop. Washington, DC: National Academies Press. https://doi.org/10.17226/29061.
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EXAMINING GLUCAGON-LIKE PEPTIDE-1 RECEPTOR (GLP-1R) AGONISTS FOR CENTRAL NERVOUS SYSTEM DISORDERS PLANNING COMMITTEE1
MATTHEW HAYES (Co-chair), University of Pennsylvania
BRIAN FISKE (Co-chair), Michael J. Fox Foundation for Parkinson’s Research
LAWRENCE CHARNAS, Pfizer, Inc.
MATTHEW COGHLAN, Eli Lilly and Company
JON DAVIS, Novo Nordisk
EVA FELDMAN, University of Michigan
EDWIN (TED) GEORGE, Food and Drug Administration
SERENA JINGCHUAN GUO, University of Florida
ELISABET JERLHAG, University of Gothenburg
LORENZO LEGGIO, National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism
IVÁN MONTOYA, National Institute on Drug Abuse
KIMBERLEI RICHARDSON, Howard University
LINDA RINAMAN, Florida State University
Health and Medicine Division Staff
SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders
EVA CHILDERS, Program Officer
KIMBERLY OGUN, Senior Program Assistant
CHRISTIE BELL, Senior Finance Business Partner
CLARE STROUD, Senior Director, Board on Health Sciences Policy
Consultant
ROBERT POOL, Science Writer
___________________
1 The planning committee’s role was limited to planning the workshop, and the Proceedings of a Workshop was prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants; have not been endorsed or verified by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine; and should not be construed as reflecting any group consensus.
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FORUM ON NEUROSCIENCE AND NERVOUS SYSTEM DISORDERS1
DEANNA BARCH (Co-chair starting September 2024), Washington University in St. Louis
FRANCES JENSEN (Co-chair), University of Pennsylvania
JOHN KRYSTAL (Co-chair until September 2024), Yale University
SHELLI AVENEVOLI, National Institute of Mental Health (starting September 2024)
RITA BALICE-GORDON, Muna Therapeutics (until December 2024)
BRUCE BEBO, National Multiple Sclerosis Society (starting September 2024)
DIANE BOVENKAMP, BrightFocus Foundation
KATJA BROSE, The Chan Zuckerberg Initiative
TERESA BURACCHIO, Food and Drug Administration
SARAH CADDICK, The Gatsby Charitable Foundation
ROSA CANET-AVILÉS, California Institute for Regenerative Medicine
MARIA CARRILLO, Alzheimer’s Association (until September 2024)
MICHAEL CHIANG, National Eye Institute
TIMOTHY COETZEE, National Multiple Sclerosis Society (until August 2024)
BEVERLY DAVIDSON, University of Pennsylvania
M. DENISE DEARING, National Science Foundation (starting September 2024)
NITA FARAHANY, Duke University
EVA FELDMAN, University of Michigan
BRIAN FISKE, Michael J. Fox Foundation for Parkinson’s Research
JOSHUA A. GORDON, National Institute of Mental Health (until August 2024)
DANIELLE GRAHAM, American College of Neuropsychopharmacology (starting September 2024)
MORTEN GRUNNET, Lundbeck
MAGALI HAAS, Cohen Veterans Bioscience
RICHARD J. HODES, National Institute on Aging
STUART W. HOFFMAN, Department of Veterans Affairs
YASMIN HURD, Icahn School of Medicine at Mount Sinai
STEVEN E. HYMAN, The Broad Institute of MIT and Harvard
MICHAEL IRIZARRY, Eisai Inc.
GEORGE KOOB, National Institute on Alcohol Abuse and Alcoholism
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
WALTER KOROSHETZ, National Institute of Neurological Disorders and Stroke
ROBERT MALENKA, Stanford University
HUSSEINI MANJI, Oxford University; Yale University; UK Government Mental Health
HUGH MARSTON, Boehringer Ingelheim
BILL MARTIN, The Janssen Pharmaceutical Companies of Johnson & Johnson
DAVID MCMULLEN, Food and Drug Administration
CAROLINE MONTOJO, Dana Foundation
JOHN NGAI, BRAIN Initiative
GENTRY PATRICK, University of California, San Diego
KATHRYN RICHMOND, Allen Institute
MARSIE ROSS, Harmony Biosciences
M. ELIZABETH ROSS, American Neurological Association
NATALIA S. ROST, American Academy of Neurology (starting October 2024)
KATIE SALE, American Brain Coalition
RAYMOND SANCHEZ, Bain Capital Life Sciences
TERRENCE SEJNOWSKI, Salk Institute for Biological Studies
JOAN SERENO, National Science Foundation (starting September 2024)
VIKAS MOHAN SHARMA, Neuraxpharm (starting February 2025)
SARA SHNIDER, One Mind
DAVID SHURTLEFF, National Center for Complementary and Integrative Health
JOHN SPIRO, Simons Foundation
ALESSIO TRAVAGLIA, Foundation for the National Institutes of Health
NORA VOLKOW, National Institute on Drug Abuse
CHRISTOPHER WEBER, Alzheimer’s Association (starting September 2024)
GARY WILSON, Huo Family Foundation
RICHARD WOYCHIK, National Institute of Environmental Health Sciences
STEVIN ZORN, MindImmune Therapeutics, Inc.
Health and Medicine Division Staff
SHEENA M. POSEY NORRIS, Director, Forum on Neuroscience and Nervous System Disorders
EVA CHILDERS, Program Officer
KIMBERLY OGUN, Senior Program Assistant
CHRISTIE BELL, Senior Finance Business Partner
CLARE STROUD, Senior Director, Board on Health Sciences Policy
Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.
We thank the following individuals for their review of this proceedings:
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by ELI Y. ADASHI, Brown University. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
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Acknowledgments
The National Academies staff would like to express gratitude to the sponsors of the Forum on Neuroscience and Nervous Systems Disorders for supporting this workshop and other work of the National Academies; to the speakers whose presentations and remarks informed workshop discussions on the use of glucagon-like peptide-1 receptor agonists to treat central nervous system disorders; to the planning committee members for their time and effort in the development of the workshop scope and agenda; to Stephanie Eldridge (Spark Street Digital), Tunde Ogunfolaju (Spark Street Digital), and Caset Associates for their support in the broadcasting and transcription of the workshop; to Robert Pool and Billie Smith-Haffener for their writing and copyediting expertise and contributions, respectively, on this proceedings; and to the additional National Academies staff who provided critical support to the workshop and this proceedings: Christie Bell, Lori Brenig, Samantha Chao, Amber McLaughlin, Alexandra Molina, Marguerite Romatelli, and Taryn Young.
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Contents
History of GLP-1 Receptors and Current Therapeutic Applications
Organization of the Proceedings
2 GLP-1 MECHANISMS IN THE BRAIN
Overview of GLP-1R Circuitry in the Central Nervous System
Mechanisms of CNS Penetrance for GLP-1R Agonists
3 LEARNING FROM THOSE WITH LIVED EXPERIENCES
An Experience with Binge Eating Disorder and Obesity
A Success Story of Using a GLP-1R Agonist To Lose Weight
4 INGESTIVE BEHAVIOR DISORDERS
GLP-1R Agonists and Eating Disorders
The Response of the Brain’s Reward Regions to GLP-1R Agonists
Binge Eating and the Endogenous GLP-1R System
5 SUBSTANCE USE DISORDER AND ALCOHOL USE DISORDER
Preclinical Studies Examining the Effects of GLP-1R Agonists on Alcohol Consumption
DPP-4 Inhibitors and Alcohol Consumption in Rats
Preclinical Studies on the Use of GLP-1R Agonists to Decrease Cocaine Use
Clinical Trials of GLP-1R Agonists for Treating Opioid Use Disorder
Using Real-World Evidence to Study the Use of Semaglutide in Treating Substance Use Disorders
6 NEURODEGENERATIVE DISORDERS AND OTHER EMERGING AREAS
GLP-1 Receptor Activity in Neurodegenerative Disorders
GLP-1R Agonists in Treating Parkinson’s Disease
Penetration of the Blood–Brain Barrier by GLP-1R Class Drugs and Neuroprotectionm
Treating Idiopathic Intracranial Hypertension and Other Pressure-Related Disorders
Biomarkers in Drug Development
7 REAL-WORLD EVIDENCE, ACCESSIBILITY, AND HEALTH EQUITY
Using Real-World Data for Trial Emulation
Potential Barriers and Solutions to Widening Access to GLP-1R Agonists for the Treatment of Obesity
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Boxes and Figures
BOXES
FIGURES
2-1 The central glucagon-like peptide-1 (GLP-1) projection system
3-1 Personal weight loss on Wegovy
4-1 The CNS mesolimbic dopamine system
5-1 GLP-1R agonist reduces alcohol intake in rodents
6-1 Effect of exenatide on Parkinson’s disease
6-2 Effects of GLP-1R agonists on the central nervous system
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Acronyms and Abbreviations
| AUD | alcohol use disorder |
| AUDIT-C | Alcohol Use Disorders Identification Test-Consumption |
| BMI | body mass index |
| CNS | central nervous system |
| CUD | cannabis use disorder |
| DPP-4 | dipeptidyl peptidase-4 |
| FDA | U.S. Food and Drug Administration |
| GIP | glucose-dependent insulinotropic polypeptide |
| GLP-1 | glucagon-like peptide-1 |
| GLP-1R | glucagon-like peptide-1 receptor |
| MOUD | medications for opioid use disorder |
| MPTP | 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine |
| NIAAA | National Institute on Alcohol Abuse and Alcohol |
| NIDA | National Institute on Drug Abuse |
| NIH | National Institutes of Health |
| NST | nucleus of the solitary tract |
| PEG | polyethylene glycol |
| RCT | randomized controlled trial |
| TBI | traumatic brain injury |
| TUD | tobacco use disorder |
| VTA | ventral tegmental area |
