ArticleAdvances in pharmacological sciences2012
Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA(A) Receptor Modulators?
Article in Advances in pharmacological sciences, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06446349 (Impact of Identification and Brief Motivational Intervention in Dispensing Pharmacies), which is not on this map. Cited by 104 papers, 8 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Impact of Identification and Brief Motivational Intervention in Dispensing Pharmacies (BMI) on the Deprescription of Benzodiazepines and Related Substances in Adult Chronic Drug Users
Who cites it
104 citing papers in PubMed, 8 syntheses or guidelines pooled it, 191 citations in OpenAlex.
- Pharmacological Influences on the R2 Blink Reflex Response in Healthy Participants: A Systematic Review.The European journal of neuroscience · 2026Pooled it
- Prescribed benzodiazepines and suicidal behaviors: a systematic review, meta-analysis, and clinical implications.BMC psychiatry · 2026Pooled it
- Joint Clinical Practice Guideline on Benzodiazepine Tapering: Considerations When Risks Outweigh Benefits.Journal of general internal medicine · 2025Guideline
- Chinese herbal medicine for the treatment of children with cerebral palsy: a meta-analysis of randomized controlled trials with core herbs exploration.Frontiers in pharmacology · 2025Pooled it
- Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline.Canadian family physician Medecin de famille canadien · 2018Guideline
- Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users.The Cochrane database of systematic reviews · 2018Pooled it
- Model-based meta-analysis of the effects of non-selective and α1-selective GABAA receptor agonists in healthy volunteers.European journal of clinical pharmacology · 2015Pooled it
- Pooled it
- A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAJournal of neurodevelopmental disorders · 2022Trial
- Safety, Tolerability, and Pharmacokinetics of Multiple Repeated Oral Doses of the α2/3/5-Subtype Selective GABAClinical pharmacology in drug development · 2021Trial
- The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome.Neurology · 2021Trial
- Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study.Neurology · 2016Trial
- Transcutaneous auricular vagus nerve stimulation for anxiety symptoms across fear, trauma, and disease contexts: a narrative review of clinical evidence and mechanisms.European archives of psychiatry and clinical neuroscience · 2026Review
- Synaptic Adaptations in the Amygdala During Alprazolam Withdrawal: Insights from a Female Rat Model of Benzodiazepine Withdrawal.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Chronic Chrysin, but Not Diazepam, Induces Anxiolytic-like Effects Without Behavioral Tolerance.Molecules (Basel, Switzerland) · 2026Article
- Tilia Tomentosa promotes sleep, preserving sleep structure.Npj biological timing and sleep · 2026Article
- Synaptic correlates of benzodiazepine tolerance.Molecular psychiatry · 2026Review
- Rational Use of Benzodiazepines in Modern Healthcare: Evidence-Based Strategies.Healthcare (Basel, Switzerland) · 2026Review
- Development of Sleep medications MYTH-understanding (SMYTH) and Sleep Medications Overexpectation of REsponses (SMORE) among the general population.Sleep & breathing = Schlaf & Atmung · 2026Article
- Impact of Preoperative Toxicological Screening on Perioperative Anesthetic Management and Short-Term Outcomes Following Metabolic and Bariatric Surgery: A Prospective Observational Study.Obesity surgery · 2026Observational
44 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite decades of basic and clinical research, our understanding of how benzodiazepines tend to lose their efficacy over time (tolerance) is at least incomplete. In appears that tolerance develops relatively quickly for the sedative and anticonvulsant actions of benzodiazepines, whereas tolerance to anxiolytic and amnesic effects probably does not develop at all. In light of this evidence, we review the current evidence for the neuroadaptive mechanisms underlying benzodiazepine tolerance, including changes of (i) the GABA(A) receptor (subunit expression and receptor coupling), (ii) intracellular changes stemming from transcriptional and neurotrophic factors, (iii) ionotropic glutamate receptors, (iv) other neurotransmitters (serotonin, dopamine, and acetylcholine systems), and (v) the neurosteroid system. From the large variance in the studies, it appears that either different (simultaneous) tolerance mechanisms occur depending on the benzodiazepine effect, or that the tolerance-inducing mechanism depends on the activated GABA(A) receptor subtypes. Importantly, there is no convincing evidence that tolerance occurs with α subunit subtype-selective compounds acting at the benzodiazepine site.
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.