Valium without dependence? Individual GABAA receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects
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Abstract: Benzodiazepines are one of the most prescribed medications as first-line treatment of anxiety, insomnia, and epilepsy around the world. Over the past two decades, advances in the neuropharmacological understanding of gamma aminobutyric acid (GABA) A receptors revealed distinct contributions from each subtype and produced effects. Recent findings have highlighted the importance of α1 containing GABA A receptors in the mechanisms of addiction and tolerance in benzodiazepine treatments. This has shown promise in the development of tranquilizers with minimal side effects such as cognitive impairment, dependence, and tolerance. A valium-like drug without its side effects, as repeatedly demonstrated in animals, is achievable. Keywords: benzodiazepines, subtype, tolerance, dependence, anxiolytic, GABA A receptor
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Benzodiazepines and z-drugs are positive allosteric modulators of the GABA-A receptor and produce their clinical effects by enhancing the effect of GABA at the GABA-A receptor.
“Benzodiazepines and z-drugs are positive allosteric modulators of the GABA-A receptor, producing their clinical effects by enhancing the effect of the neurotransmitter GABA at the GABA-A receptor (Cheng, Wallace, Ponteri, & Tuli, 2018; Gunja, 2013).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng, Wallace, Ponteri, & Tuli, 2018
The “Pharmacological targets of benzodiazepine” section describes benzodiazepines as GABA-A receptor positive allosteric modulators and says they increase inhibitory signaling through chloride-channel activity. The paper discusses zolpidem’s GABA-A receptor effects, but the passages do not establish the same mechanism for z-drugs as a class. Its statement that benzodiazepines do not enhance GABA’s binding does not contradict the claim that they enhance GABA’s effect. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPreclinical models suggest uncoupling-loss of allosteric modulation at the benzodiazepine site-as a likely mechanism of benzodiazepine tolerance.
“Preclinical models suggest uncoupling – loss of allosteric modulation at the benzodiazepine site – as a likely mechanism (Cheng et al., 2018).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018
The potency of BDZ may play a role in tolerance development, as full agonists produce more tolerance than partial agonists.
“It has been shown that the potency of BDZ may play a role in tolerance development, as full agonists produce more tolerance than partial agonists (Cheng et al., 2018).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Cheng et al., 2018
The physiological mechanisms of benzodiazepine tolerance and adaptation remain uncertain, with mixed findings on reduced number or sensitivity of GABA-A receptors.
“The physiological mechanisms of benzodiazepine tolerance and adaptation remain uncertain, with mixed findings on reduced number or sensitivity of GABA-A receptors (Cheng et al., 2018).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018
Chronic benzodiazepine use down-regulates adenosine receptors and up-regulates glutamatergic NMDA and AMPA receptors, likely compensating for enhanced GABA activity.
“Chronic benzodiazepine use also down-regulates adenosine receptors and up-regulates glutamatergic NMDA and AMPA receptors, likely compensating for enhanced GABA activity (Cheng et al., 2018).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018
GABA is a universal inhibitor of neural activity and decreases the release of many excitatory neurotransmitters, including acetylcholine, noradrenaline, dopamine, serotonin, and glutamate.
“GABA is a universal inhibitor of neural activity and decreases the release of many neurotransmitters with excitatory properties (acetylcholine, noradrenaline, dopamine, serotonin, and glutamate), thought to produce the subjective experience of anxiolysis and sedation (Cheng et al., 2018; Turton & Lingford-Hughes, 2016).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Cheng et al., 2018
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CURSOS, L. C. E. &., Silva, B. D. M., Trajano, A. L., dos Santos, A. C. C., de Oliveira, L. C., LOPO, N. C. F., de Araújo, D. S., da Silva, J. J., & Lima, N. M. F. V. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/06
REPERCUSSÕES ORIUNDAS DE FAKE NEWS SOBRE VITAMINA D NO INSTAGRAM EM TEMPOS DE CORONAVÍRUS
CURSOS, L. C. E. &., Nascimento, M. O., & Monteiro, R. A. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/11 · Cited by 2 · see citing works
PERFIL DE INTOXICAÇÕES PELA UTILIZAÇÃO DE BENZODIAZEPÍNICOS E BARBITÚRICOS NA PARAÍBA NO ANO DE 2020
CURSOS, L. C. E. &., Farias, B. K. D. S., Monteiro, M. M. D. O., Oliveira, N. D. R., & Brandão, D. O. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/05
SEXUALIDADE E ABORDAGEM DE GÊNERO NA SAÚDE: UMA REVISÃO NARRATIVA
CURSOS, L. C. E. &., de Oliveira, K. D. L., Oliveira, B. D. S., Flor, M. A., Leyva, D. C. F., da Silva, L. G., Costa, J. W. T., Batista, B. R., Pereira, R. C., Teixeira, A. G. B. D. Q., et al. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/14
A CIDADANIA COMO DISCURSO E PRÁTICA NAS POLÍTICAS PÚBLICAS DE SAÚDE MENTAL
CURSOS, L. C. E. &., Araújo, D. D. S., Paiva, M. N., Andrade, M. D. J. B. G., & Melo, C. S. L. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/01
CURSOS, L. C. E. &., SILVA, J. J. C. D., Perrelli, M. R. S. M., do Nascimento, R. C., Pereira, L. H. D. S., do Nascimento, M. D. C., SALES, A. D. S., & da Costa, L. A. G. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/08
CURSOS, L. C. E. &., dos Santos, J. P. C., Almeida, C. G., Nepomuceno, A. F. S. F., & Figueiredo, M. S. (2023) · Literacia Cientifica Editora & Cursos eBooks · doi:10.53524/lit.edt.978-65-84528-22-2/02
Ma, M., xu, H., Liang, Y., Li, C., Zhu, H., Jiang, W., Wang, W., Yang, H., Yang, Y., Wang, Y., et al. (2024) · SSRN Electronic Journal · doi:10.2139/ssrn.4821743
Safe Deprescribing of Benzodiazepines and Z‐drugs
(2024) · Wiley eBooks · doi:10.1002/9781394291052.mdg003
Zopiclone-associated hallucinations: a case report and database pharmacovigilance study
Zhang, P., Zhang, R., Gao, Y., Wei, C., Zhao, Q., Yang, Q., & Diao, J. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1925410
Aranda, B. B., Aznar‐Lou, I., Peñarrubia‐María, M. T., Chilet‐Rosell, E., Puig‐García, M., Lumbreras, B., López-Pintor, E., Beltrán-Pérez, A., & Parker, L. A. (2026) · BMJ Public Health · doi:10.1136/bmjph-2025-004639
BindingDB Entry 50009300: Subtype Selective γ-Aminobutyric Acid Type A Receptor (GABA
BindingDB (2021) · UC San Diego · doi:10.7270/q2vd72wn
- Authors
- Cheng, T., Wallace, D. M., Ponteri, B. B., & Tuli, M.
- Affiliations
- Pitzer College (US)
- Portland State University (US)
- University of British Columbia (CA)
- Corresponding author
- Cheng, Tianze
- ORCID
- Cheng, Tianze
- Venue
- Neuropsychiatric Disease and Treatment
- Publisher
- Informa UK Limited
- Published
- 2018-05
- Volume
- Volume 14
- Pages
- 1351-1361
- ISSN
- 1176-6328 (ISSN-L)
- 1178-2021
- PMC
- PMC5973310
- OpenAlex
- W2804391210
- Cited by
- 66
- References
- 133
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 10 · 2023: 23 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 5
- FWCI
- 0.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neuropsychiatric Disease and Treatment (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- benzodiazepines, GABAA receptor subtypes, alpha1 subunit, benzodiazepine dependence, tolerance (pharmacology and immunology), anxiolytic effects, tranquilizers, cognitive impairment
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