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A historical perspective on clonidine as an alpha-2A receptor agonist in the treatment of addictive behaviors: Focus on opioid dependence

Mark S. Gold1 ,  Kenneth Blum2,3,4,5,6,7,8,9,10,11* ,  Abdalla Bowirrat5 ,  Albert Pinhasov5 ,  Debasis Bagchi12,13 ,  Catherine A. Dennen14 ,  Panayotis K. Thanos5,15,16 ,  Colin Hanna15,16 ,  Kai-Uwe Lewandrowski17,18,19 ,  Alireza Sharafshah20 ,  Igor Elman5,21 ,  Rajendra D. Badgaiyan22,23
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1 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
2 Division of Addiction Research and Education, Center for Sports, Exercise and Global Mental Health, Western University Health Sciences, Pomona, California, United States of America
3 The Kenneth Blum Behavioral and Neurogenetic Institute LLC, Austin, Texas, United States of America
4 Department of Psychology, Faculty of Education and Psychology, Institute of Psychology, Eötvös Loránd University Budapest, Budapest, Hungary
5 Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, Israel
6 Division of Personalized Medicine, Cross-Cultural Research and Educational Institute, San Clemente, California, United States of America
7 Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, West Bengal, India
8 Department of Clinical Psychology and Addiction, Institute of Psychology, Faculty of Education and Psychology, Eötvös Loránd University, Budapest, Hungary
9 Department of Psychiatry, University of Vermont, Burlington, Vermont, United States of America
10 Department of Psychiatry, Wright University, Boonshoft School of Medicine, Dayton, Ohio, United States of America
11 Division of Personalized Medicine, Ketamine Infusion Clinic of South Florida, Pompano, Florida, United States of America
12 Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, Florida, United States of America
13 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, United States of America
14 Department of Family Medicine, Jefferson Health Northeast, Philadelphia, Pennsylvania, United States of America
15 Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, New York, United States of America
16 Department of Psychology, State University of New York at Buffalo, Buffalo, New York, United States of America
17 Division of Personalized Pain Therapy Research, Center for Advanced Spine Care of Southern Arizona, Tucson, Arizona, United States of America
18 Department of Orthopaedics, Fundación Universitaria Sanitas, Bogotá, Colombia
19 Department of Orthopedics, Hospital Universitário Gaffree Guinle Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
20 Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Gilan, Iran
21 Department of Psychiatry, School of Medicine, Harvard University, Cambridge, Massachusetts, United States of America
22 Department of Psychiatry, Mt. Sinai School of Medicine, New York City, New York, United States of America
23 Department of Psychiatry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America
INNOSC Theranostics and Pharmacological Sciences 2024, 7(3), 1918 https://doi.org/10.36922/itps.1918
Submitted: 26 September 2023 | Accepted: 27 March 2024 | Published: 29 July 2024
(This article belongs to the Special Issue Behavioral Addictions: From Bench to Bedside)
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
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Abstract

Clonidine operates through agonism at the alpha-2A receptor, a specific subtype of the alpha-2-adrenergic receptor located predominantly in the prefrontal cortex. By inhibiting the release of norepinephrine, which is responsible for withdrawal symptoms, clonidine effectively addresses withdrawal-related conditions such as anxiety, hypertension, and tachycardia. The groundbreaking work by Gold et al. demonstrated clonidine’s ability to counteract the effects of locus coeruleus stimulation, reshaping the understanding of opioid withdrawal within the field. In the 1980s, the efficacy of clonidine in facilitating the transition to long-acting injectable naltrexone was confirmed for individuals motivated to overcome opioid use disorders (OUDs), including physicians and executives. Despite challenges with compliance, naltrexone offers sustained blockade of opioid receptors, reducing the risk of overdose, intoxication, and relapse in motivated patients in recovery. The development of clonidine and naltrexone as treatment modalities for OUDs, and potentially other addictions, including behavioral ones, underscores the potential for translating neurobiological advancements from preclinical models (bench) to clinical practice (bedside), ushering in innovative approaches to addiction treatment.

Keywords
Behavioral addictions
Clonidine
Opioid use disorder
Substance use disorder
Naltrexone
Locus coeruleus
Funding
The study is supported by The Pharmacotherapies for Alcohol and Substance Abuse (PASA) Consortium (grant no.: AS170014-A6).
Conflict of interest
Dr. Blum is the inventor of GARS® and Pro-dopamine Regulation (KB220Z™). There are no other conflicts of interest.
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INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823 Print ISSN: 2705-0734, Published by AccScience Publishing
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