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Application of gabapentinoids and novel compounds for the treatment of benzodiazepine dependence: the glutamatergic model

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Abstract

Background

Current approaches for managing benzodiazepine (BZD) withdrawal symptoms are daunting for clinicians and patients, warranting novel treatment and management strategies. This review discusses the pharmacodynamic properties of BZDs, gabapentinoids (GBPs), endozepines, and novel GABAergic compounds associated with potential clinical benefits for BZD-dependent patients. The objective of this study was to review the complex neuromolecular changes occurring within the GABAergic and glutamatergic systems during the BZD tolerance and withdrawal periods while also examining the mechanism by which GBPs and alternative pharmacological therapies may attenuate withdrawal symptoms.

Methods and Results

An elaborative literature review was conducted using multiple platforms, including the National Center for Biotechnology (NCBI), AccessMedicine, ScienceDirect, pharmacology textbooks, clinical trial data, case reports, and PubChem. Our literature analysis revealed that many distinctive neuroadaptive mechanisms are involved in the GABAergic and glutamatergic systems during BZD tolerance and withdrawal. Based on this data, we hypothesize that GBPs may attenuate the overactive glutamatergic system during the withdrawal phase by an indirect presynaptic glutamatergic mechanism dependent on the α2δ1 subunit expression.

Conclusions

GBPs may benefit individuals undergoing BZD withdrawal, given that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor current significantly increases during abrupt BZD withdrawal in animal studies. This may be a conceivable explanation for the effectiveness of GBPs in treating both alcohol withdrawal symptoms and BZD withdrawal symptoms in some recent studies. Finally, natural and synthetic GABAergic compounds with unique pharmacodynamic properties were found to exert potential clinical benefits as BZD substitutes in animal studies, though human studies are lacking.

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Acknowledgements

We thank Editage (www.editage.com) for English language editing.

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  1. Dr. Kiran C. Patel College Of Osteopathic Medicine, Nova Southeastern University, Davie, FL, USA

    Halford Warlick IV, Lexie Leon, Rudresh Patel, Stefanie Filoramo, Ryan Knipe, Ernesto Joubran & Hoang Nguyen

  2. Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Davie, FL, USA

    Arkene Levy

  3. College of Pharmacy, Nova Southeastern University, Davie, FL, USA

    Jose Rey

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Contributions

HWIV developed the entire manuscript, formulated the hypotheses and figures, and performed the literature search/data analysis. LL helped revise the manuscript and assisted with rewriting the content relevant to the manuscript. RP assisted with writing the original manuscript and reference compilation with EndNote. SF and RK assisted with creating tables and incorporating content into the manuscript. EJ helped with manuscript editing. AL assisted with drafting the original version of the manuscript, as well as scheduling editing meetings. HN assisted with manuscript editing. JR assisted with revising the manuscript and critically analyzing several manuscript drafts.

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Warlick, H., Leon, L., Patel, R. et al. Application of gabapentinoids and novel compounds for the treatment of benzodiazepine dependence: the glutamatergic model. Mol Biol Rep 50, 1765–1784 (2023). https://doi.org/10.1007/s11033-022-08110-9

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