Long-term neurological consequences following benzodiazepine exposure: A scoping review

Abstract

Benzodiazepine acute withdrawal syndrome is well known, but the long-term neurological consequences of benzodiazepine exposure are much less familiar. A scoping review was conducted of electronic databases for studies that reported on patient outcomes four or more weeks after complete cessation of benzodiazepine use. Forty-six results were retrieved in total, some of which provided signals for protracted symptoms, often reported as incidental findings, and others that showed benzodiazepine discontinuation was beneficial. Some overlap occurred in the outcomes, but these two groups of studies suggest that the benefits of benzodiazepine discontinuation for many patients tended to obscure the more prolonged, severe, and sometimes debilitating symptoms that persisted for months and years in a subpopulation of patients. The prevalence or trajectory of these enduring symptoms could not be determined from these studies. Further elucidation of the potential neurotoxicity of benzodiazepines is needed to better understand protracted symptoms and their treatment. Clinicians, patients, and the healthcare system must be cognizant of the risks of benzodiazepine exposure beyond two to four weeks.

Background

In the 1950s, to overcome the drawbacks of barbiturates, pharmaceutical companies sought to develop safer but similarly effective anxiolytic agents and sleep-promoting drugs. Meprobamate (Miltown) was released to market in 1954 by Wallace Laboratories for the same purposes as barbiturates but with lesser risk of use, and despite commercial success, it became evident that physical dependence made it difficult to withdraw from this drug without a tapering protocol, just as for barbiturates and the risks of use were not appreciably better [1]. In 1960, the first benzodiazepine, chlordiazepoxide (Librium), was released to market and became the most-prescribed drug in the United States until it was eclipsed by another benzodiazepine, diazepam (Valium) [2]. In a clinical study, dependence and withdrawal problems were associated with benzodiazepines within one year after their introduction [3]. Initial reports of dependence and sometimes severe withdrawal symptoms were overlooked because of the substantially reduced risk of overdose death [4,5].

In 1979, Senator Ted Kennedy led a Senate subcommittee hearing on the reported dangers of benzodiazepines [6]. Growing concerns with benzodiazepines led to use of antidepressants for some of the same indications for which benzodiazepines were used. An important benefit of newer antidepressants, including such selective serotonin-reuptake inhibitors (SSRIs) as fluoxetine (Prozac), was that, unlike benzodiazepines, they were thought to have no dependence liability. A confounding between anxiety and depression treatments emerged. Medications sometimes termed second-generation benzodiazepines, e.g., alprazolam (Xanax), were developed and primarily marketed as antidepressants. By 1986, alprazolam was the best-selling drug to date in the United States and was predominantly employed as an anxiolytic [7]. Alprazolam and clonazepam (Klonopin) were newer agents and more potent than diazepam [4,5]. As exposure to these drugs increased, so did reports of adverse events, especially the risks of serious acute withdrawal reactions [8]. When tolerance and a potentially severe withdrawal syndrome became recognized, benzodiazepines were recommended for short-term use only. Despite this caution, they continued to be prescribed to many patients for prolonged periods of months or years [9]. Abrupt cessation of benzodiazepines resulted in acute withdrawal symptoms of variable severity for most patients. Initially, withdrawal protocols were developed, but many patients resumed benzodiazepine use after detoxification [10]. Tapers were eventually recommended when it was recognized that short-term detoxification may not be effective for all, and protracted neurological symptoms sometimes occurred even after tapered drug discontinuation [11]. Reports emerged of prolonged problematic clinical symptoms that could persist after completion of the acute withdrawal syndrome, enduring for months or even years after benzodiazepine cessation [12].

Benzodiazepine-induced neurological dysfunction (BIND) is a relatively recent term to describe neurological consequences and symptoms persisting past the period of acute benzodiazepine withdrawal following chronic benzodiazepine use [13]. Enduring benzodiazepine withdrawal symptoms were sometimes conflated with the acute withdrawal syndrome and/or a return of the symptoms for which the benzodiazepines were prescribed. However, earlier literature had described a separate and distinct condition of “prolonged neurological dysfunction [14,15].” To the best of our knowledge, the first report of enduring neurological dysfunction associated with benzodiazepine use was published in 1984 by Heather Ashton [16]. This detailed case series reported that all 12 patients developed new symptoms after benzodiazepine cessation that lasted at least six months after drug discontinuation [16]. These symptoms included perceptual distortion, depersonalization, and paresthesia. Ashton later reported on a cohort of 50 patients [14]. At 10 months to 3.5 years after discontinuation of benzodiazepine treatment, approximately 30% were still experiencing these symptoms. Based on a review of the literature as well as clinical experience with 60 patients, it was suggested that only about one third of patients emerge symptom free following the acute benzodiazepine withdrawal syndrome [17]. Meta-analyses of cognitive effects following withdrawal reported problems with recent memory, processing speed, visuo-construction, divided attention, working memory, and sustained attention [17,18].

This area of research was neglected for decades, because symptoms after discontinuation were considered to be a return of the problems for which the medication was initially prescribed. Nevertheless, reports of prolonged symptoms continued to confront physicians in clinical practice. In the largest survey to date of individuals who reported taking benzodiazepines long term, approximately two-thirds of 1,200 active and former benzodiazepine users reported de novo symptoms that commenced early in the course of benzodiazepine therapy or upon its cessation [13]. More than half of respondents’ reported symptoms began early in the treatment and lasted for more than one year after discontinuation. Among the most frequently reported symptoms were: low energy, difficulty focusing, memory loss, nervousness or anxiety, and sleep disturbances. Many respondents stated they had multiple symptoms, with over 40% reporting more than 17 symptoms lasting for over a year. The majority of respondents also reported adverse life consequences, such as the loss of home or business or failed relationships [13]. There is little overlap between these de novo symptoms and the symptoms of acute withdrawal, and their persistence and manifestations suggest that they must be considered distinct from pharmacologic withdrawal.

The acute withdrawal syndrome following cessation of chronic benzodiazepine exposure has been well described [19–21]. The incidence of acute withdrawal is dose- and duration-dependent, ranging from approximately 30% to 100% [22]. A more prolonged condition had been observed decades ago, which typically can be identified after the acute withdrawal syndrome had abated, although nomenclature was inconsistent [23]. This survey included “life consequences,” which are not symptoms in the medical sense but include issues, such as marital and family problems, financial loss, and loss of home or business.

The aim of this scoping review is to examine existing evidence in the clinical and scientific literature regarding the de novo neurological consequences and symptoms persisting beyond the period of acute benzodiazepine withdrawal, a condition for which the term BIND was recently coined. Four research questions emerged to help understand the limitations of current evidence surrounding neurological changes following chronic benzodiazepine use. The scoping review sought to better define the acute withdrawal period, differentiate it from a prolonged withdrawal, identify signals of neurologic symptoms persisting four or more weeks after complete drug discontinuation, and identify and potentially quantify of incidence and prevalence.

There are strengths and limitations to this work. To the best of the authors’ knowledge, this is the first such scoping review ever undertaken and a great deal of literature was considered with few delimiters. No randomized clinical trials were specifically designed to look for enduring symptoms following complete benzodiazepine cessation, but many studies reported prolonged symptoms. The fact that these were signals rather than primary outcomes and were often reported incidentally rather than as specific study endpoints is a weakness.

Methods

A scoping review that allows for a broad range of studies of variable quality is most appropriate, since the search is severely confounded due to inconsistent terminology used in the existing literature. Given that symptoms rely heavily on patient reports as well as limited available data, a scoping review was also an ideal choice for investigation.

A preliminary literature search was conducted on August 9, 2023 to determine if scoping or systematic reviews had previously been conducted. Most reviews on this topic pertain to general use, dependence, treatment of alcohol withdrawal, and acute benzodiazepine withdrawal syndrome rather than enduring symptoms. Addiction-related terminology has been modified with respect to benzodiazepines and the term “physical dependence” has been replaced by the more precise term of “physiologic dependence.” However, the older literature often contains such words. The last review on the topic of enduring symptoms was conducted by Ashton in 1991, but she did not use a systematic methodology [15]. A gap in literature was observed, with initial work done in the 1980s and 1990s with very little done around the turn of the millennium.

A protocol was developed, which included experimental studies, observational studies, case studies and case series, and clinical trials, while clinical trial registrations, commentaries, editorials, correspondence, reviews, conference abstracts, and animal studies were excluded [24]. Clinical trial registrations were excluded due to a current lull in research. Grey literature was excluded due to an already low-quality body of evidence. The complete protocol is attached as Appendix 1.

The growing understanding of benzodiazepine use, withdrawal, and prolonged symptoms has resulted in changes in terminology about this condition. Keywords in wide use today, such as “protracted withdrawal,” “neuroadaptation,” and even “neurocognitive symptoms” were rare in the literature. The complete list of search terms appears in Appendix 2. Since the goal was to find symptoms or adverse effects that were present four or more weeks after benzodiazepine cessation, a new search strategy had to be developed. This would include articles on pathophysiology, signs and symptoms, clinical management, nomenclature, and diagnostic criteria.

Inclusion criteria allowed for literature of any geographic origin of the article or income level of the nation. Articles not published in a peer-reviewed journal or platform or not in English were excluded. All care settings were included, such as rural, outpatients, in-hospital, and so on.

Patients were ≥ 18 years of age and may have taken benzodiazepines chronically, long term, or consistently for a period of > 2 weeks and who had discontinued benzodiazepines for a period of > 4 weeks. The three terms: “chronically,” “long term,” and “consistently” were used as key words and their definitions have considerable overlap. Studies could include patients prescribed benzodiazepines for any number of diagnoses with the exclusion of a primary psychotic illness, including schizophrenia, or bipolar disorder. There were no specific inclusion or exclusion criteria related to type or dose of benzodiazepine. Since protracted withdrawal identifies symptoms not present prior to benzodiazepine use, all comorbidities and coexisting conditions were considered when information was available.

The scoping review was conducted following JBI evidence synthesis methodology and the PRISMA ScR guidelines [25,26]. A comprehensive literature search was designed and performed by a medical librarian (CP) for the concepts of: benzodiazepines, specifically Alprazolam, Diazepam, Lorazepam, Clonazepam, and Nordazepam; and adverse effects of drug tolerance or dependency, or substance withdrawal. The search was initially run in August 2023 and updated in December 2024.

Relevant publications were identified by searching the following databases with a combination of standardized index terms and keywords: Ovid MEDLINE(R) ALL (1946 to December 6, 2024), Embase (via Elsevier, Embase.com, 1947 to present), and APA PsycInfo (via Ovid, 1806 to December 2024 Week 1). Searches excluded the concepts of seizures, epilepsy, and alcohol withdrawal. Searches were limited to human studies and English language articles. When possible, clinical trials, conference abstracts, and editorials/comments were excluded in the search. All results were exported to EndNote 21 for removal of duplicates. See Supplementary Materials for complete search strategies. Unique results were imported into Covidence Systematic Review software (Veritas Health Innovation, Melbourne, Australia) for screening and selection against inclusion criteria.

Prior to initiation of title and abstract screening a calibrating exercise was conducted with the first 50 publications randomly pulled from the search to increase internal validity of the review process. Disagreements were resolved via discussion and any needed clarification or updates to the inclusion criteria were made at that time. All reviewers participated in the original training or completed an independent asynchronous review of the material with the original recorded session for reference prior to beginning title and abstract screening. Conflicts during screening of the titles and abstracts were resolved by group discussion amongst several available reviewers in groups of at least three people. Reviewers independently and sequentially evaluated titles and abstracts in pairs. Following completion of the abstract screening, full text screening took place. Conflict resolution was performed by reviewers KS or AR.

Prior to initiation of data extraction, a second calibration exercise was conducted to increase internal validity and update the data extraction template as necessary. The calibrating exercise was performed with an initial set of 4 different publications chosen from the included lists of publications following full text review. A group of four reviewers; DF, AR, BS, and RF piloted the data extraction template with any relevant changes made at that time. Following completion of data extraction while reconciling data categories, another data extraction category was added (significant outcomes after more than 4 weeks post-discontinuation), and extraction re-performed for this category. The extracted variables were the following: author, year published, publication source, study identifiers, title, intended audience (geographic practice community), country in which the study was conducted, study objective, study design, study intervention duration, post intervention follow up time, study funding sources, possible conflicts of interest for study authors, age, gender, ethnicity, method recruitment of participants, total number of participants, type of benzodiazepine, duration of treatment with benzodiazepine, tapering approach/protocol, time after discontinuation, significant outcomes after > 4 weeks post discontinuation, new onset symptoms, life consequences, other medications or interventions, reported instruments. A descriptive analysis of extracted data was performed, which identified article type and summarized relevant data as it relates to our research question to look for signals of BIND. All conflicts following data extraction were resolved by AR or KS. The PRISMA checklist is attached as Appendix 3.

Results

A total of 14,097 publications were retrieved, of which 46 were included after eligibility assessment. No additional references were added after performing a back search by screening the references of included papers. See Fig 1.

[Figure omitted. See PDF.]

[27] At the end of the screening, 46 articles were considered.

Of the studies retrieved in the search, 41% reported on randomized clinical trials. The bulk of the literature was published prior to 1996 and there were comparatively few results after 2006. See Fig 2.

[Figure omitted. See PDF.]

There is a considerable dearth of results in the period from 2006 to present.

Four main themes emerged from the 46 studies. Nearly all of the studies described the acute withdrawal phase and many recognized that even after benzodiazepine cessation, some patients resumed the use of benzodiazepines. Second, there was some evidence that many new and varied symptoms indicative of neurologic dysfunction emerged during the taper or discontinuation that persisted four or more weeks after benzodiazepine cessation. Third, several studies showed beneficial effects attributable to stopping benzodiazepine use four or more weeks post-discontinuation. Finally, protracted withdrawal did not affect all persons, but there was no clear evidence of potential risk or protective factors for protracted symptoms following benzodiazepine discontinuation. The number and types of studies that supported the second and third observations are shown in Fig 3.

[Figure omitted. See PDF.]

The literature is summarized in Tables 1–3. Since studies did not specifically evaluate protracted symptoms following benzodiazepine withdrawal, those findings relevant to our research question were suggestive signals rather than specific study endpoints. Studies reporting the strongest signals for symptoms after four or more weeks after benzodiazepine discontinuation appear in Table 1, while studies that demonstrate notable improvement upon benzodiazepine discontinuation appear in Table 2. There is some overlap between these two groups, but each study is assigned to only one table. Table 3 covers studies which demonstrated no notable results or which were disqualified due to lack of significant findings, study design, or other reasons.

[Figure omitted. See PDF.]

[Figure omitted. See PDF.]

[Figure omitted. See PDF.]

The studies retrieved addressed our four research questions regarding acute withdrawal, the protracted withdrawal phase, the possibility of neurologic dysfunction, and possible methods to quantify the phenomenon of protracted withdrawal or find risk factors or protective features for it.

The acute withdrawal phase

The population of benzodiazepine patients has been described as a “diagnostically heterogenous group,” which aligns with these results [30,36,40,55,59,65,67]. The most common indications for benzodiazepine use in these studies were insomnia [30,36,40,55,59,67], generalized anxiety disorder [32,34,45,50,54,65,68], and anxiety with or without panic attacks [30,36,48,54,59,65], although studies noted the inclusion of other patients with indications such as bereavement [40] and major depressive disorder [40,65]. Enrollment criteria in these studies did not always specify indications.

Benzodiazepine acute withdrawal syndrome has been well described in the literature and is familiar to clinicians [72]. The proportion of patients who experienced acute withdrawal in our findings ranged from approximately 44% [52] to 100% [61,62]. Muscular fasciculations, mood swings, depression [53], perceptual abnormalities, dysphoria [52], trembling, nausea, vomiting, palpitations [40], headache, sweating, sensory disturbances, fear, fatigue [30], enuresis, disinhibition, aggression, impaired memory, weight loss, and ataxia [46] were reported along with the more common acute withdrawal symptoms of insomnia, anxiety, and nervousness [40]. There are established treatment protocols for benzodiazepine acute withdrawal syndrome [10,72,73].

A protracted withdrawal phase

Following the acute withdrawal period, the emergence of de novo symptoms, including akathisia, pelvic pain, tinnitus, suicidal ideation, reduced appetite, weight loss, perceptual disturbances, paresthesia, depersonalization, derealization, numbness, and involuntary movements have been reported [30,31,50,52,61]. Twenty-eight of the 46 studies retrieved in the scoping review (61%) provide signals that suggest a protracted withdrawal phase. Months or years after benzodiazepine discontinuation, a subset of patients experienced mild to severe, even debilitating, symptoms unrelated to their prior condition, such as tinnitus, gastrointestinal symptoms, fatigue, and anxiety that do not meet criteria for another diagnosis [47,50,52,54.]

In a study of 50 patients, some patients reported symptoms ≥ 1 year after benzodiazepine discontinuation, and, paradoxically, some underlying symptoms, such as irritable bowel syndrome, resolved after benzodiazepine discontinuation [14]. A randomized clinical trial of 40 long-term benzodiazepine users tapering to discontinuation experienced symptoms of panic, anxiety, and depression to the point that 28% required antidepressant therapy at 12 weeks after benzodiazepine discontinuation, which investigators speculated may reflect de novo symptoms.[49] Higgitt and colleagues matched nine protracted withdrawal syndrome (PWS) patients to nine anxiety patients not taking any drugs, 13 conversion hysteria patients, and nine healthy controls. Based on psychophysiologic metrics, the PWS group was most similar to healthy controls, suggesting that protracted withdrawal is not an affective disorder, but rather an iatrogenic disorder related to benzodiazepine exposure [17].

Evidence of neurologic dysfunction

While the majority of studies showed a range of long-term symptoms that may emerge after benzodiazepine discontinuation, neurologic symptoms are of particular concern because of their impact on daily living and the uncertain trajectory of neurological injury [13]. In one study of prolonged symptoms in 20 benzodiazepine users matched to controls, 100% of the benzodiazepine patients had neurologic symptoms at six months after complete drug cessation [51]. In a study that compared benzodiazepine patients who had ceased using benzodiazepines to benzodiazepine-free patients using control groups of anxiety patients and healthy controls, participants underwent a series of cognitive tests at three weeks post-discontinuation and again at 10 months. At both time points, the benzodiazepine patients had significantly worse scores than the controls [38]. In another study, electroencephalography testing showed that PWS patients had abnormal results when compared to healthy controls who had not used benzodiazepines [17].

Twenty participants undergoing a taper to discontinue benzodiazepines were divided into two study arms: one group was tested before the taper, the other after the taper started. Benzodiazepine patients were matched to healthy controls who took no drugs. These groups were tested again one year later. In the initial round of testing, benzodiazepine patients had test scores that showed impaired intelligence and impaired nonverbal memory versus controls but at one year, scores were similar to controls, suggesting that neurologic deficits may be at least partly, albeit slowly, reversible [66].

Incidence and prevalence/risk stratification

Not all benzodiazepine users develop protracted symptoms after benzodiazepine discontinuation, but at present, there are no reliable metrics to quantify individual risk. This scoping review was unable to find studies describing incidence and prevalence data, and few studies offer information that might prove useful in identifying risk factors.

Acute withdrawal symptoms occurred in up to 100% of participants from studies found in this scoping review [52,61,62], but prolonged symptoms were less frequently reported, occurring in approximately 30% of benzodiazepine patients [17,54,69]. Many studies showed that benzodiazepine cessation conferred benefits on patients, and this beneficial effect may have obscured the emergence of prolonged symptoms.

Discussion

The proportion of patients who experience prolonged symptoms and their characteristics has not been well described in the literature, likely because few benzodiazepine studies looked for prolonged symptoms. Persistent symptoms after benzodiazepine discontinuation had been observed decades earlier, but since these symptoms emerged unpredictably and only in a subpopulation of patients, they were never systematically studied. Bibliometric findings confirm an initial scientific interest in this enduring syndrome followed by a lull in research. Even nomenclature was confusing, since it was unclear whether these protracted symptoms were a continuation of acute withdrawal, the unmasking of original symptoms, or an entirely new condition [17,52,69].

This scoping review found 46 studies of benzodiazepine cessation, of which 27 provided signals that certain symptoms persisted or emerged more than four weeks after complete benzodiazepine withdrawal. Some of these symptoms were severe, persisted for a year or more, and had life-altering ramifications for the affected patients.

Many studies in this scoping review found relatively high numbers of patients who dropped out of the study, could or would not discontinue benzodiazepines, or who discontinued benzodiazepines but resumed them a short time later. This suggests that for certain patients, benzodiazepine cessation can be far more challenging than generally appreciated. This difficulty in complete discontinuation of benzodiazepines may in itself suggest BIND.

These prolonged symptoms are many and varied. The most frequently used list of anxiolytic-associated symptoms is the Physician Withdrawal Checklist (PWC-20), but anecdotal reports of benzodiazepine-associated symptoms have appeared in the literature as well [22,74]. Neurologic, gastrointestinal, cutaneous, psychological, and other symptoms have been reported [15]. A persistent difficulty in studying protracted symptoms is differentiating them from unmasked symptoms that recurred once benzodiazepines were stopped.

Consistent with other published studies and clinical observations, this scoping review showed that some people can discontinue benzodiazepines even after prolonged exposure with relatively little problem [12,13,23]. In fact, the main finding of 14 studies retrieved (30.4%) was that, overall, benzodiazepine discontinuation was unproblematic and beneficial. However, when studies had mixed results, such that many patients discontinued without problem while others had persistent symptoms, the persistent symptoms were reported incidentally and not systematically studied. It may be that such enduring symptoms are under-reported.

The signals that emerged in the majority of the studies in this scoping review suggest that an iatrogenic condition of prolonged symptoms impacts a subpopulation of patients who have been prescribed benzodiazepines. The two primary results of the scoping review regarding what happens four or more weeks after benzodiazepines are discontinued may appear to conflict with each other. These results may be better contextualized as a continuum, and findings may depend on what investigators were seeking and where those things occurred on the continuum. Most studies that looked for enduring neurological dysfunction found it. Likewise, most studies that looked for evidence of eventual improvement following benzodiazepine discontinuation found it. This suggests that benzodiazepine cessation may reveal induced neurological dysfunction in a subset of patients, but overall confer long-term benefits to most patients.

While BIND may represent a major new challenge to the healthcare system, this is not to trivialize the importance of benzodiazepines for their specific indications: long-term treatment of acute movement disorders such as catatonia, stiff-person syndrome, status dystonicus and, more rarely, seizure disorders and burning mouth syndrome (clonazepam only) [75–80]. Nevertheless, benzodiazepines are not indicated for the long-term treatment of anxiety, insomnia, or stress, for which they are most often prescribed [81–83]. While benzodiazepines may be taken for a brief period of days or possibly a few weeks to manage stress or anxiety in a crisis or other short-term situation, they are not intended as nightly sleep aids or daily calming agents. While the chronic use of benzodiazepines is often contraindicated, benzodiazepines are sometimes prescribed for years. Good prescribing practice for benzodiazepines is to use the lowest effective dose for the shortest period of time, limiting prescription duration to no more than four to six weeks in most cases. Benzodiazepine therapy should never be initiated without patient education about the drug’s proper use and the risk of possible long-term complications and an exit plan clearly defined by the prescriber. Even short-term use of benzodiazepines may be problematic, because physiologic dependence on benzodiazepines can occur after two to four weeks of use [84–89].

The acute withdrawal syndrome, with which clinicians are acquainted, is associated with the removal of the central nervous system depressant drugs from brain GABA receptors they occupied during benzodiazepine treatment and the associated autonomic hyperactivity that ensues. Acute withdrawal follows a short and relatively predictable trajectory; the literature provides guidelines to manage this syndrome, including tapering protocols [72,90]. Protracted symptoms, formerly called post-acute withdrawal syndrome but likely better described as BIND, occur long after benzodiazepines are eliminated from the body. This suggests another mechanism, one other than withdrawal, is in play; this mechanism is likely the lasting neurotoxic consequences of benzodiazepines. Neurotoxicity is a complex condition which may or may not be reversible and which can manifest differently in different patients [91–93]. For those individuals who experience debilitating symptoms long after complete benzodiazepine cessation, the concept of BIND not only explains these symptoms, but may help such patients find support in the healthcare system. However, the neurobiological underpinnings of these phenomena need to be established before they can be fully accepted by the scientific community. Further study is needed. A limitation of this work was that no randomized clinical trials made as an endpoint enduring symptoms following complete benzodiazepine cessation, so the protracted symptoms that were observed must be considered signals.

Benzodiazepines are powerful agents, the use of which may lead to long-term neurologic dysfunction in some patients. The patient’s susceptibility, the extent, and reversibility of these neurologic changes is not known. There is an urgent need to answer those questions and limit long-term benzodiazepine use in accordance with the Hippocratic oath: first, do no harm.

While BIND is a newly evolving concept and lacks diagnostic criteria, broad medical acceptance, and treatment protocols, this scoping review provides evidence that these prolonged symptoms are not outliers, but valid scientific observations that merit greater study.

Acknowledgments

The authors of this paper must posthumously acknowledge a great debt they owe to Christy Huff, MD, who passed away in March 2024 before this scoping review could be completed. Huff was a core member of a group of collaborators who worked on three benzodiazepine papers based on an online survey that she herself helped to compose and administer. She was zealous in educational efforts for the benzodiazepine community, and she was among the first authors to conceive and help formulate the protocol for this scoping review. Her work on behalf of benzodiazepine safety is well known, deserves praise, and will benefit many patients in years to come. She was an uncompromising patient advocate, but, to us, she was also a dear friend and beloved colleague. The authors regret that she cannot be recognized as an author on this paper, as she has left us before it could be completed, but all of the authors gratefully acknowledge her work, her support, her intelligence, and the fact that none of this would have been possible without her. The authors would like to acknowledge and thank the following contributors. Jaden Brandt (BSc.Pharm, MSc., DipPH) contributed to protocol development, drafting of abstract, and initial screening of articles. Jaden is a clinical instructor at University of Manitoba. Anthony Cao assisted in the abstract draft process as well as initial screening process. He is a student at St. Joseph’s University in his final year of studies. The authors also acknowledge the contribution of Jo Ann LeQuang of Angleton, Texas, a medical writer, whose services were covered by the Alliance for Benzodiazepine Best Practices.

References

1. 1. Foster D. Benzo Free: The World of Anti-Anxiety Drugs and the Reality of Withdrawal. Erie, Colorado: Denim Mountain Press; 2018. 309 p.

2. 2. Lopez-Munoz F, Alamo C, Garcia-Garcia P. The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. J Anxiety Disord. 2011;25(4):554–62.

* View Article

* Google Scholar

3. 3. Hollister L, Motzenbecker FP, Degan RO. Withdrawal reactions from chlordiazepoxide (“Librium”). Psychopharmacologia. 1961;2:63–8. pmid:13715373

* View Article

* PubMed/NCBI

* Google Scholar

4. 4. Greenblatt DJ, Shader RI. Drug therapy. Benzodiazepines (first of two parts). N Engl J Med. 1974;291(19):1011–5. pmid:4153318

* View Article

* PubMed/NCBI

* Google Scholar

5. 5. Greenblatt DJ, Shader RI. Drug therapy. Benzodiazepines (second of two parts). N Engl J Med. 1974;291(23):1239–43. pmid:4153568

* View Article

* PubMed/NCBI

* Google Scholar

6. 6. Use and misuse of benzodiazepines: Examination on the use and misuse of Valium, Librium, and other minor tranquilizers: Hearing before the Subcommittee on Health and Science Research of the Committee on Labor and Human Resources United States Senate, U.S. Senate, 96th Congress Sess. 1979.

7. 7. Wong DT, Perry KW, Bymaster FP. The discovery of fluoxetine hydrochloride (Prozac). Nature Reviews Drug Discovery. 2005;4(9):764–74.

* View Article

* Google Scholar

8. 8. Brandt J, Leong C. Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research. Drugs R D. 2017;17(4):493–507. pmid:28865038

* View Article

* PubMed/NCBI

* Google Scholar

9. 9. Rosenberg HC, Chiu TH. Time course for development of benzodiazepine tolerance and physical dependence. Neurosci Biobehav Rev. 1985;9(1):123–31. pmid:2858077

* View Article

* PubMed/NCBI

* Google Scholar

10. 10. Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256–64. pmid:455894

* View Article

* PubMed/NCBI

* Google Scholar

11. 11. Robertson S, Peacock EE, Scott R. Benzodiazepine Use Disorder: Common Questions and Answers. Am Fam Physician. 2023;108(3):260–6. pmid:37725458

* View Article

* PubMed/NCBI

* Google Scholar

12. 12. Finlayson A, Macoubrie J, Huff C, Foster D, Martin P. Experiences with benzodiazepine use, tapering, and discontinuation: an Internet survey. Ther Adv Psychopharmacol. 2022;2:1–10.

* View Article

* Google Scholar

13. 13. Ritvo AD, Foster DE, Huff C, Finlayson AJR, Silvernail B, Martin PR. Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey. PLoS One. 2023;18(6):e0285584. pmid:37384788

* View Article

* PubMed/NCBI

* Google Scholar

14. 14. Ashton H. Benzodiazepine withdrawal: outcome in 50 patients. Br J Addict. 1987;82(6):665–71. pmid:2886145

* View Article

* PubMed/NCBI

* Google Scholar

15. 15. Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat. 1991;8(1–2):19–28. pmid:1675688

* View Article

* PubMed/NCBI

* Google Scholar

16. 16. Ashton H. Benzodiazepine withdrawal: an unfinished story. Br Med J (Clin Res Ed). 1984;288(6424):1135–40. pmid:6143582

* View Article

* PubMed/NCBI

* Google Scholar

17. 17. Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria?. Acta Psychiatr Scand. 1990;82(2):165–8. pmid:1978465

* View Article

* PubMed/NCBI

* Google Scholar

18. 18. Barker MJ, Greenwood KM, Jackson M, Crowe SF. Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs. 2004;18(1):37–48. pmid:14731058

* View Article

* PubMed/NCBI

* Google Scholar

19. 19. Lader M. Benzodiazepines revisited--will we ever learn?. Addiction. 2011;106(12):2086–109.

* View Article

* Google Scholar

20. 20. Hood SD, Norman A, Hince DA, Melichar JK, Hulse GK. Benzodiazepine dependence and its treatment with low dose flumazenil. Br J Clin Pharmacol. 2014;77(2):285–94. pmid:23126253

* View Article

* PubMed/NCBI

* Google Scholar

21. 21. Quaglio G, Pattaro C, Gerra G, Mathewson S, Verbanck P, Des Jarlais DC, et al. High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam. Psychiatry Res. 2012;198(3):457–62.

* View Article

* Google Scholar

22. 22. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249–55.

* View Article

* Google Scholar

23. 23. Huff C, Finlayson A, Foster D, Martin P. Enduring neurological sequelae of benzodiazepine use: an Internet survey. Ther Adv Psychopharmacol. 2022;12:1–9.

* View Article

* Google Scholar

24. 24. Shade K, Ritvo A, Silvernail B, Martin P, Foster D, Huff C, et al. Benzodiazepine induced neurological dysfunction: an overview of adverse long-term neurological consequences following chronic use of benzodiazepines: a scoping review protocol. 2023.

25. 25. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169(7):467–73. pmid:30178033

* View Article

* PubMed/NCBI

* Google Scholar

26. 26. Peters MDJ, Godfrey C, McInerney P, Khalil H, Larsen P, Marnie C. Best practice guidance and reporting items for the development of scoping review protocols. JBI Evid Synth. 2022;20(4):953–68.

* View Article

* Google Scholar

27. 27. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. pmid:33782057

* View Article

* PubMed/NCBI

* Google Scholar

28. 28. Amirzadeh-Shams A. Psychophysiological aspects of anxiety and depression. Ovid. 2018.

29. 29. Barker MJ, Greenwood KM, Jackson M, Crowe SF. An evaluation of persisting cognitive effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol Soc. 2005;11(3):281–9. pmid:15892904

* View Article

* PubMed/NCBI

* Google Scholar

30. 30. Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N Engl J Med. 1986;315(14):854–9. pmid:3092053

* View Article

* PubMed/NCBI

* Google Scholar

31. 31. Busto U, Fornazzari L, Naranjo CA. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. J Clin Psychopharmacol. 1988;8(5):359–62. pmid:2903182

* View Article

* PubMed/NCBI

* Google Scholar

32. 32. Cassano G, Petracca A, Borghi C, Chiroli S, Didoni G, Garreau M. A randomized, double-blind study of alpidem vs placebo in the prevention and treatment of benzodiazepine withdrawal syndrome. Eur Psychiatry. 1996;11(2):93–9.

* View Article

* Google Scholar

33. 33. Curran HV, Bond A, O’Sullivan G, Bruce M, Marks I, Lelliot P, et al. Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. Psychol Med. 1994;24(4):969–76. pmid:7892364

* View Article

* PubMed/NCBI

* Google Scholar

34. 34. Delle Chiaie R, Pancheri P, Casacchia M, Stratta P, Kotzalidis GD, Zibellini M. Assessment of the efficacy of buspirone in patients affected by generalized anxiety disorder, shifting to buspirone from prior treatment with lorazepam: a placebo-controlled, double-blind study. J Clin Psychopharmacol. 1995;15(1):12–9. pmid:7714222

* View Article

* PubMed/NCBI

* Google Scholar

35. 35. Golombok S, Higgitt A, Fonagy P, Dodds S, Saper J, Lader M. A follow-up study of patients treated for benzodiazepine dependence. Br J Med Psychol. 1987;60(2):141–9. pmid:2887197

* View Article

* PubMed/NCBI

* Google Scholar

36. 36. Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psychological medicine. 1988;18(2):365–74.

* View Article

* Google Scholar

37. 37. Gorenstein C, Bernik MA, Pompéia S. Differential acute psychomotor and cognitive effects of diazepam on long-term benzodiazepine users. International Clinical Psychopharmacology. 1994;9(3):145–53.

* View Article

* Google Scholar

38. 38. Gorenstein C, Bernik MA, Pompéia S, Marcourakis T. Impairment of performance associated with long-term use of benzodiazepines. J Psychopharmacol. 1995;9(4):313–8. pmid:22298395

* View Article

* PubMed/NCBI

* Google Scholar

39. 39. Higgitt A, Fonagy P, Lader M. The natural history of tolerance to the benzodiazepines. Psychol Med Monogr Suppl. 1988;13:1–55. pmid:2908516

* View Article

* PubMed/NCBI

* Google Scholar

40. 40. Hopkins DR, Sethi KB, Mucklow JC. Benzodiazepine withdrawal in general practice. J R Coll Gen Pract. 1982;32(245):758–62. pmid:6130150

* View Article

* PubMed/NCBI

* Google Scholar

41. 41. Keshavan MS, Moodley P, Eales M, Joyce E, Yeragani VK. Delusional depression following benzodiazepine withdrawal. Can J Psychiatry. 1988;33(7):626–7. pmid:3197017

* View Article

* PubMed/NCBI

* Google Scholar

42. 42. Kiliç C, Curran HV, Noshirvani H, Marks IM, Başoğlu M. Long-term effects of alprazolam on memory: a 3.5 year follow-up of agoraphobia/panic patients. Psychol Med. 1999;29(1):225–31. pmid:10077311

* View Article

* PubMed/NCBI

* Google Scholar

43. 43. Modell JG. Protracted benzodiazepine withdrawal syndrome mimicking psychotic depression. Psychosomatics. 1997;38(2):160–1. pmid:9063050

* View Article

* PubMed/NCBI

* Google Scholar

44. 44. Morton S, Lader M. Buspirone treatment as an aid to benzodiazepine withdrawal. J Psychopharmacol. 1995;9(4):331–5. pmid:22298398

* View Article

* PubMed/NCBI

* Google Scholar

45. 45. Murphy SM, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks’ treatment with diazepam or buspirone. Br J Psychiatry. 1989;154:529–34. pmid:2686797

* View Article

* PubMed/NCBI

* Google Scholar

46. 46. O’Sullivan GH, Swinson R, Kuch K, Marks IM, Basoglu M, Noshirvani H. Alprazolam withdrawal symptoms in agoraphobia with panic disorder: observations from a controlled Anglo-Canadian study. J Psychopharmacol. 1996;10(2):101–9. pmid:22302886

* View Article

* PubMed/NCBI

* Google Scholar

47. 47. Olajide D, Lader M. Depression following withdrawal from long-term benzodiazepine use: a report of four cases. Psychol Med. 1984;14(4):937–40. pmid:6152745

* View Article

* PubMed/NCBI

* Google Scholar

48. 48. Petursson H, Gudjonsson GH, Lader MH. Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology (Berl). 1983;81(4):345–9. pmid:6140702

* View Article

* PubMed/NCBI

* Google Scholar

49. 49. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry. 1991;48(5):448–52. pmid:2021297

* View Article

* PubMed/NCBI

* Google Scholar

50. 50. Silvernail CM, Wright SL. Surviving Benzodiazepines: A Patient’s and Clinician’s Perspectives. Adv Ther. 2022;39(5):1871–80. pmid:35239167

* View Article

* PubMed/NCBI

* Google Scholar

51. 51. Tata PR, Rollings J, Collins M, Pickering A, Jacobson RR. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. 1994;24(1):203–13. pmid:8208885

* View Article

* PubMed/NCBI

* Google Scholar

52. 52. Tyrer P, Owen R, Dawling S. Gradual withdrawal of diazepam after long-term therapy. Lancet. 1983;1(8339):1402–6. pmid:6134180

* View Article

* PubMed/NCBI

* Google Scholar

53. 53. Wilbur R, Kulik AV. Abstinence syndrome from therapeutic doses of oxazepam. Can J Psychiatry. 1983;28(4):298–300. pmid:6871816

* View Article

* PubMed/NCBI

* Google Scholar

54. 54. Ashton CH, Rawlins MD, Tyrer SP. A double-blind placebo-controlled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry. 1990;157:232–8. pmid:2224374

* View Article

* PubMed/NCBI

* Google Scholar

55. 55. Belleville G, Morin CM. Hypnotic discontinuation in chronic insomnia: impact of psychological distress, readiness to change, and self-efficacy. Health Psychol. 2008;27(2):239–48. pmid:18377143

* View Article

* PubMed/NCBI

* Google Scholar

56. 56. Bourgeois J, Elseviers MM, Van Bortel L, Petrovic M, Vander Stichele RH. Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study. Eur J Clin Pharmacol. 2014;70(10):1251–60.

* View Article

* Google Scholar

57. 57. Cantopher T, Olivieri S, Cleave N, Edwards JG. Chronic benzodiazepine dependence. A comparative study of abrupt withdrawal under propranolol cover versus gradual withdrawal. Br J Psychiatry. 1990;156:406–11. pmid:1971767

* View Article

* PubMed/NCBI

* Google Scholar

58. 58. Curran HV, Collins R, Fletcher S, Kee SCY, Woods B, Iliffe S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med. 2003;33(7):1223–37. pmid:14580077

* View Article

* PubMed/NCBI

* Google Scholar

59. 59. O’Connor KP, Marchand A, Bélanger L, Mainguy N, Landry P, Savard P, et al. Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication. Addict Behav. 2004;29(3):583–93. pmid:15050676

* View Article

* PubMed/NCBI

* Google Scholar

60. 60. Peperkamp P, Goodman L. The discontinuation of lorazepam and diazepam following sub-chronic therapy in anxious outpatients. J Drug Dev. 1993;6(4):171–82.

* View Article

* Google Scholar

61. 61. Petursson H, Lader MH. Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed). 1981;283(6292):643–5. pmid:6114776

* View Article

* PubMed/NCBI

* Google Scholar

62. 62. Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry. 1990;47(10):899–907. pmid:2222129

* View Article

* PubMed/NCBI

* Google Scholar

63. 63. Rickels K, Case WG, Schweizer E, Garcia-Espana F, Fridman R. Long-term benzodiazepine users 3 years after participation in a discontinuation program. Am J Psychiatry. 1991;148(6):757–61.

* View Article

* Google Scholar

64. 64. Rickels K, Lucki I, Schweizer E, García-España F, Case WG. Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation. J Clin Psychopharmacol. 1999;19(2):107–13. pmid:10211911

* View Article

* PubMed/NCBI

* Google Scholar

65. 65. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Arch Gen Psychiatry. 1990;47(10):908–15. pmid:2222130

* View Article

* PubMed/NCBI

* Google Scholar

66. 66. Tönne U, Hiltunen AJ, Vikander B, Engelbrektsson K, Bergman H, Bergman I, et al. Neuropsychological changes during steady-state drug use, withdrawal and abstinence in primary benzodiazepine-dependent patients. Acta Psychiatr Scand. 1995;91(5):299–304. pmid:7639085

* View Article

* PubMed/NCBI

* Google Scholar

67. 67. Vikander B, Koechling UM, Borg S, Tönne U, Hiltunen AJ. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010;64(4):273–82. pmid:20629611

* View Article

* PubMed/NCBI

* Google Scholar

68. 68. Hadley SJ, Mandel FS, Schweizer E. Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. J Psychopharmacol. 2012;26(4):461–70. pmid:21693549

* View Article

* PubMed/NCBI

* Google Scholar

69. 69. Lader MH, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol. 1992;6(3):357–63. pmid:22291380

* View Article

* PubMed/NCBI

* Google Scholar

70. 70. Romach MK, Kaplan HL, Busto UE, Somer G, Sellers EM. A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine discontinuation. J Clin Psychopharmacol. 1998;18(2):121–31. pmid:9555597

* View Article

* PubMed/NCBI

* Google Scholar

71. 71. Voshaar RCO, Gorgels WJMJ, Mol AJJ, van Balkom AJLM, van de Lisdonk EH, Breteler MHM, et al. Tapering off long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial. Br J Psychiatry. 2003;182:498–504. pmid:12777340

* View Article

* PubMed/NCBI

* Google Scholar

72. 72. Martin P, Patel S. Pharmacology of drugs of abuse. In: Golan D, Armstrong E, Armstrong A, editors. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia, Pennsylvania: Wolters Kluwer Health. 2017. p. 308–34.

73. 73. Greenblatt DJ, Allen MD, Noel BJ, Shader RI. Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther. 1977;21(4):497–514.

* View Article

* Google Scholar

74. 74. Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). J Clin Psychopharmacol. 2008;28(4):447–51.

* View Article

* Google Scholar

75. 75. Ślebioda Z, Lukaszewska-Kuska M, Dorocka-Bobkowska B. Evaluation of the efficacy of treatment modalities in burning mouth syndrome-A systematic review. J Oral Rehabil. 2020;47(11):1435–47. pmid:32979878

* View Article

* PubMed/NCBI

* Google Scholar

76. 76. Cui Y, Xu H, Chen FM, Liu JL, Jiang L, Zhou Y, et al. Efficacy evaluation of clonazepam for symptom remission in burning mouth syndrome: a meta-analysis. Oral Dis. 2016;22(6):503–11. pmid:26680638

* View Article

* PubMed/NCBI

* Google Scholar

77. 77. Zdziarski P. A Case of Stiff Person Syndrome: Immunomodulatory Effect of Benzodiazepines: Successful Rituximab and Tizanidine Therapy. Medicine (Baltimore). 2015;94(23):e954. pmid:26061327

* View Article

* PubMed/NCBI

* Google Scholar

78. 78. Hansbauer M, Wagner E, Strube W, Röh A, Padberg F, Keeser D, et al. rTMS and tDCS for the treatment of catatonia: A systematic review. Schizophr Res. 2020;222:73–8. pmid:32600779

* View Article

* PubMed/NCBI

* Google Scholar

79. 79. Pelzer AC, van der Heijden FM, den Boer E. Systematic review of catatonia treatment. Neuropsychiatr Dis Treat. 2018;14:317–26. pmid:29398916

* View Article

* PubMed/NCBI

* Google Scholar

80. 80. Bhatti AB, Gazali ZA. Recent advances and review on treatment of stiff person syndrome in adults and pediatric patients. Cureus. 2015;7(12):e427.

* View Article

* Google Scholar

81. 81. Lie JD, Tu KN, Shen DD, Wong BM. Pharmacological treatment of insomnia. P T. 2015;40(11):759–71.

* View Article

* Google Scholar

82. 82. Offidani E, Guidi J, Tomba E, Fava GA. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom. 2013;82(6):355–62. pmid:24061211

* View Article

* PubMed/NCBI

* Google Scholar

83. 83. Bateson AN. Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des. 2002;8(1):5–21. pmid:11812247

* View Article

* PubMed/NCBI

* Google Scholar

84. 84. Ashton H. Guidelines for the rational use of benzodiazepines. When and what to use. Drugs. 1994;48(1):25–40. pmid:7525193

* View Article

* PubMed/NCBI

* Google Scholar

85. 85. Rosenberg HC, Chiu TH. Time course for development of benzodiazepine tolerance and physical dependence. Neurosci Biobehav Rev. 1985;9(1):123–31. pmid:2858077

* View Article

* PubMed/NCBI

* Google Scholar

86. 86. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455–9. pmid:7841856

* View Article

* PubMed/NCBI

* Google Scholar

87. 87. Eagles L. Guidance for prescribing and withdrawal of benzodiazepines & hypnotics in general practice. NHS Grampian. 2008. https://benzo.org.uk/amisc/bzgrampian.pdf

88. 88. Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015;38(5):152–5. pmid:26648651

* View Article

* PubMed/NCBI

* Google Scholar

89. 89. Brunner E, Chen CYA, Klein T. Joint Clinical Practice Guideline on Benzodiazepine Tapering: Considerations When Benzodiazepine Risks Outweigh Benefits. https://downloads.asam.org/sitefinity-production-blobs/docs/default-source/guidelines/benzodiazepine-tapering-2025/bzd-tapering-document---final-approved-version-for-distribution-02-28-25.pdf?sfvrsn=5bdf9c81_3

90. 90. The Maudsley desprescribing guidelines: Antidepressants, benzodiazepines, gabapentindoids and Z-drugs. Wiley-Blackwell. 2024.

91. 91. Jung ME, Metzger DB, Hall J. The long-term but not short-term use of benzodiazepine impairs motoric function and upregulates amyloid β in part through the suppression of translocator protein. Pharmacol Biochem Behav. 2020;191:172873. pmid:32105662

* View Article

* PubMed/NCBI

* Google Scholar

92. 92. Furukawa T, Nikaido Y, Shimoyama S, Masuyama N, Notoya A, Ueno S. Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice. Front Aging Neurosci. 2021;13:777404. pmid:34899279

* View Article

* PubMed/NCBI

* Google Scholar

93. 93. Furukawa T, Shimoyama S, Miki Y, Nikaido Y, Koga K, Nakamura K, et al. Chronic diazepam administration increases the expression of Lcn2 in the CNS. Pharmacol Res Perspect. 2017;5(1):e00283.

* View Article

* Google Scholar

Citation: Shade KN, Ritvo AD, Silvernail B, Finlayson AJR, Bressi JE, Foster DE, et al. (2025) Long-term neurological consequences following benzodiazepine exposure: A scoping review. PLoS One 20(8): e0330277. https://doi.org/10.1371/journal.pone.0330277

About the Authors:

Kyla N. Shade

Roles: Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

Affiliation: University of Colorado School of Medicine, Aurora, Colorado, United States of America

Alexis D. Ritvo

Roles: Conceptualization, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

E-mail: [email protected]

Affiliation: Department of Psychiatry, University of Colorado School of Medicine, Aurora, Colorado, United States of America

ORICD: https://orcid.org/0000-0002-0440-1894

Bernard Silvernail

Roles: Conceptualization, Investigation, Project administration, Supervision, Writing – original draft, Writing – review & editing

Affiliation: Alliance for Benzodiazepine Best Practices, Portland, Oregon, United States of America

ORICD: https://orcid.org/0000-0003-1710-0668

A. J. Reid Finlayson

Roles: Investigation, Writing – original draft, Writing – review & editing

Affiliation: Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America

Jolene E. Bressi

Roles: Investigation, Writing – original draft, Writing – review & editing

Affiliation: School of Public Health, Yale University, New Haven, Connecticut, United States of America

ORICD: https://orcid.org/0009-0007-3256-5689

D. E. Foster

Roles: Investigation, Writing – original draft, Writing – review & editing

Affiliation: Easing Anxiety, Erie, Colorado, United States of America

ORICD: https://orcid.org/0000-0002-6478-1024

Ian J. Martin

Roles: Investigation, Writing – original draft, Writing – review & editing

Affiliations: School of Public Health, Yale University, New Haven, Connecticut, United States of America, Together We Can, Drug & Alcohol Recovery and Education Society, Vancouver, British Columbia, Canada

ORICD: https://orcid.org/0009-0001-1865-0533

Christi Piper

Roles: Data curation, Methodology

Affiliation: Strauss Health Sciences Library, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America

Peter R. Martin

Roles: Investigation, Writing – original draft, Writing – review & editing

Affiliations: Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America

ORICD: https://orcid.org/0000-0003-2292-4741

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References

1. Foster D. Benzo Free: The World of Anti-Anxiety Drugs and the Reality of Withdrawal. Erie, Colorado: Denim Mountain Press; 2018. 309 p.

2. Lopez-Munoz F, Alamo C, Garcia-Garcia P. The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. J Anxiety Disord. 2011;25(4):554–62.

3. Hollister L, Motzenbecker FP, Degan RO. Withdrawal reactions from chlordiazepoxide (“Librium”). Psychopharmacologia. 1961;2:63–8. pmid:13715373

4. Greenblatt DJ, Shader RI. Drug therapy. Benzodiazepines (first of two parts). N Engl J Med. 1974;291(19):1011–5. pmid:4153318

5. Greenblatt DJ, Shader RI. Drug therapy. Benzodiazepines (second of two parts). N Engl J Med. 1974;291(23):1239–43. pmid:4153568

6. Use and misuse of benzodiazepines: Examination on the use and misuse of Valium, Librium, and other minor tranquilizers: Hearing before the Subcommittee on Health and Science Research of the Committee on Labor and Human Resources United States Senate, U.S. Senate, 96th Congress Sess. 1979.

7. Wong DT, Perry KW, Bymaster FP. The discovery of fluoxetine hydrochloride (Prozac). Nature Reviews Drug Discovery. 2005;4(9):764–74.

8. Brandt J, Leong C. Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research. Drugs R D. 2017;17(4):493–507. pmid:28865038

9. Rosenberg HC, Chiu TH. Time course for development of benzodiazepine tolerance and physical dependence. Neurosci Biobehav Rev. 1985;9(1):123–31. pmid:2858077

10. Martin PR, Bhushan CM, Kapur BM, Whiteside EA, Sellers EM. Intravenous phenobarbital therapy in barbiturate and other hypnosedative withdrawal reactions: a kinetic approach. Clin Pharmacol Ther. 1979;26(2):256–64. pmid:455894

11. Robertson S, Peacock EE, Scott R. Benzodiazepine Use Disorder: Common Questions and Answers. Am Fam Physician. 2023;108(3):260–6. pmid:37725458

12. Finlayson A, Macoubrie J, Huff C, Foster D, Martin P. Experiences with benzodiazepine use, tapering, and discontinuation: an Internet survey. Ther Adv Psychopharmacol. 2022;2:1–10.

13. Ritvo AD, Foster DE, Huff C, Finlayson AJR, Silvernail B, Martin PR. Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey. PLoS One. 2023;18(6):e0285584. pmid:37384788

14. Ashton H. Benzodiazepine withdrawal: outcome in 50 patients. Br J Addict. 1987;82(6):665–71. pmid:2886145

15. Ashton H. Protracted withdrawal syndromes from benzodiazepines. J Subst Abuse Treat. 1991;8(1–2):19–28. pmid:1675688

16. Ashton H. Benzodiazepine withdrawal: an unfinished story. Br Med J (Clin Res Ed). 1984;288(6424):1135–40. pmid:6143582

17. Higgitt A, Fonagy P, Toone B, Shine P. The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria?. Acta Psychiatr Scand. 1990;82(2):165–8. pmid:1978465

18. Barker MJ, Greenwood KM, Jackson M, Crowe SF. Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs. 2004;18(1):37–48. pmid:14731058

19. Lader M. Benzodiazepines revisited--will we ever learn?. Addiction. 2011;106(12):2086–109.

20. Hood SD, Norman A, Hince DA, Melichar JK, Hulse GK. Benzodiazepine dependence and its treatment with low dose flumazenil. Br J Clin Pharmacol. 2014;77(2):285–94. pmid:23126253

21. Quaglio G, Pattaro C, Gerra G, Mathewson S, Verbanck P, Des Jarlais DC, et al. High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam. Psychiatry Res. 2012;198(3):457–62.

22. Ashton H. The diagnosis and management of benzodiazepine dependence. Curr Opin Psychiatry. 2005;18(3):249–55.

23. Huff C, Finlayson A, Foster D, Martin P. Enduring neurological sequelae of benzodiazepine use: an Internet survey. Ther Adv Psychopharmacol. 2022;12:1–9.

24. Shade K, Ritvo A, Silvernail B, Martin P, Foster D, Huff C, et al. Benzodiazepine induced neurological dysfunction: an overview of adverse long-term neurological consequences following chronic use of benzodiazepines: a scoping review protocol. 2023.

25. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169(7):467–73. pmid:30178033

26. Peters MDJ, Godfrey C, McInerney P, Khalil H, Larsen P, Marnie C. Best practice guidance and reporting items for the development of scoping review protocols. JBI Evid Synth. 2022;20(4):953–68.

27. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. pmid:33782057

28. Amirzadeh-Shams A. Psychophysiological aspects of anxiety and depression. Ovid. 2018.

29. Barker MJ, Greenwood KM, Jackson M, Crowe SF. An evaluation of persisting cognitive effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol Soc. 2005;11(3):281–9. pmid:15892904

30. Busto U, Sellers EM, Naranjo CA, Cappell H, Sanchez-Craig M, Sykora K. Withdrawal reaction after long-term therapeutic use of benzodiazepines. N Engl J Med. 1986;315(14):854–9. pmid:3092053

31. Busto U, Fornazzari L, Naranjo CA. Protracted tinnitus after discontinuation of long-term therapeutic use of benzodiazepines. J Clin Psychopharmacol. 1988;8(5):359–62. pmid:2903182

32. Cassano G, Petracca A, Borghi C, Chiroli S, Didoni G, Garreau M. A randomized, double-blind study of alpidem vs placebo in the prevention and treatment of benzodiazepine withdrawal syndrome. Eur Psychiatry. 1996;11(2):93–9.

33. Curran HV, Bond A, O’Sullivan G, Bruce M, Marks I, Lelliot P, et al. Memory functions, alprazolam and exposure therapy: a controlled longitudinal study of agoraphobia with panic disorder. Psychol Med. 1994;24(4):969–76. pmid:7892364

34. Delle Chiaie R, Pancheri P, Casacchia M, Stratta P, Kotzalidis GD, Zibellini M. Assessment of the efficacy of buspirone in patients affected by generalized anxiety disorder, shifting to buspirone from prior treatment with lorazepam: a placebo-controlled, double-blind study. J Clin Psychopharmacol. 1995;15(1):12–9. pmid:7714222

35. Golombok S, Higgitt A, Fonagy P, Dodds S, Saper J, Lader M. A follow-up study of patients treated for benzodiazepine dependence. Br J Med Psychol. 1987;60(2):141–9. pmid:2887197

36. Golombok S, Moodley P, Lader M. Cognitive impairment in long-term benzodiazepine users. Psychological medicine. 1988;18(2):365–74.

37. Gorenstein C, Bernik MA, Pompéia S. Differential acute psychomotor and cognitive effects of diazepam on long-term benzodiazepine users. International Clinical Psychopharmacology. 1994;9(3):145–53.

38. Gorenstein C, Bernik MA, Pompéia S, Marcourakis T. Impairment of performance associated with long-term use of benzodiazepines. J Psychopharmacol. 1995;9(4):313–8. pmid:22298395

39. Higgitt A, Fonagy P, Lader M. The natural history of tolerance to the benzodiazepines. Psychol Med Monogr Suppl. 1988;13:1–55. pmid:2908516

40. Hopkins DR, Sethi KB, Mucklow JC. Benzodiazepine withdrawal in general practice. J R Coll Gen Pract. 1982;32(245):758–62. pmid:6130150

41. Keshavan MS, Moodley P, Eales M, Joyce E, Yeragani VK. Delusional depression following benzodiazepine withdrawal. Can J Psychiatry. 1988;33(7):626–7. pmid:3197017

42. Kiliç C, Curran HV, Noshirvani H, Marks IM, Başoğlu M. Long-term effects of alprazolam on memory: a 3.5 year follow-up of agoraphobia/panic patients. Psychol Med. 1999;29(1):225–31. pmid:10077311

43. Modell JG. Protracted benzodiazepine withdrawal syndrome mimicking psychotic depression. Psychosomatics. 1997;38(2):160–1. pmid:9063050

44. Morton S, Lader M. Buspirone treatment as an aid to benzodiazepine withdrawal. J Psychopharmacol. 1995;9(4):331–5. pmid:22298398

45. Murphy SM, Owen R, Tyrer P. Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks’ treatment with diazepam or buspirone. Br J Psychiatry. 1989;154:529–34. pmid:2686797

46. O’Sullivan GH, Swinson R, Kuch K, Marks IM, Basoglu M, Noshirvani H. Alprazolam withdrawal symptoms in agoraphobia with panic disorder: observations from a controlled Anglo-Canadian study. J Psychopharmacol. 1996;10(2):101–9. pmid:22302886

47. Olajide D, Lader M. Depression following withdrawal from long-term benzodiazepine use: a report of four cases. Psychol Med. 1984;14(4):937–40. pmid:6152745

48. Petursson H, Gudjonsson GH, Lader MH. Psychometric performance during withdrawal from long-term benzodiazepine treatment. Psychopharmacology (Berl). 1983;81(4):345–9. pmid:6140702

49. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome. Arch Gen Psychiatry. 1991;48(5):448–52. pmid:2021297

50. Silvernail CM, Wright SL. Surviving Benzodiazepines: A Patient’s and Clinician’s Perspectives. Adv Ther. 2022;39(5):1871–80. pmid:35239167

51. Tata PR, Rollings J, Collins M, Pickering A, Jacobson RR. Lack of cognitive recovery following withdrawal from long-term benzodiazepine use. Psychol Med. 1994;24(1):203–13. pmid:8208885

52. Tyrer P, Owen R, Dawling S. Gradual withdrawal of diazepam after long-term therapy. Lancet. 1983;1(8339):1402–6. pmid:6134180

53. Wilbur R, Kulik AV. Abstinence syndrome from therapeutic doses of oxazepam. Can J Psychiatry. 1983;28(4):298–300. pmid:6871816

54. Ashton CH, Rawlins MD, Tyrer SP. A double-blind placebo-controlled study of buspirone in diazepam withdrawal in chronic benzodiazepine users. Br J Psychiatry. 1990;157:232–8. pmid:2224374

55. Belleville G, Morin CM. Hypnotic discontinuation in chronic insomnia: impact of psychological distress, readiness to change, and self-efficacy. Health Psychol. 2008;27(2):239–48. pmid:18377143

56. Bourgeois J, Elseviers MM, Van Bortel L, Petrovic M, Vander Stichele RH. Feasibility of discontinuing chronic benzodiazepine use in nursing home residents: a pilot study. Eur J Clin Pharmacol. 2014;70(10):1251–60.

57. Cantopher T, Olivieri S, Cleave N, Edwards JG. Chronic benzodiazepine dependence. A comparative study of abrupt withdrawal under propranolol cover versus gradual withdrawal. Br J Psychiatry. 1990;156:406–11. pmid:1971767

58. Curran HV, Collins R, Fletcher S, Kee SCY, Woods B, Iliffe S. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med. 2003;33(7):1223–37. pmid:14580077

59. O’Connor KP, Marchand A, Bélanger L, Mainguy N, Landry P, Savard P, et al. Psychological distress and adaptational problems associated with benzodiazepine withdrawal and outcome: a replication. Addict Behav. 2004;29(3):583–93. pmid:15050676

60. Peperkamp P, Goodman L. The discontinuation of lorazepam and diazepam following sub-chronic therapy in anxious outpatients. J Drug Dev. 1993;6(4):171–82.

61. Petursson H, Lader MH. Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed). 1981;283(6292):643–5. pmid:6114776

62. Rickels K, Schweizer E, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation. Arch Gen Psychiatry. 1990;47(10):899–907. pmid:2222129

63. Rickels K, Case WG, Schweizer E, Garcia-Espana F, Fridman R. Long-term benzodiazepine users 3 years after participation in a discontinuation program. Am J Psychiatry. 1991;148(6):757–61.

64. Rickels K, Lucki I, Schweizer E, García-España F, Case WG. Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation. J Clin Psychopharmacol. 1999;19(2):107–13. pmid:10211911

65. Schweizer E, Rickels K, Case WG, Greenblatt DJ. Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper. Arch Gen Psychiatry. 1990;47(10):908–15. pmid:2222130

66. Tönne U, Hiltunen AJ, Vikander B, Engelbrektsson K, Bergman H, Bergman I, et al. Neuropsychological changes during steady-state drug use, withdrawal and abstinence in primary benzodiazepine-dependent patients. Acta Psychiatr Scand. 1995;91(5):299–304. pmid:7639085

67. Vikander B, Koechling UM, Borg S, Tönne U, Hiltunen AJ. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010;64(4):273–82. pmid:20629611

68. Hadley SJ, Mandel FS, Schweizer E. Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a double-blind, placebo-controlled trial. J Psychopharmacol. 2012;26(4):461–70. pmid:21693549

69. Lader MH, Morton SV. A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal. J Psychopharmacol. 1992;6(3):357–63. pmid:22291380

70. Romach MK, Kaplan HL, Busto UE, Somer G, Sellers EM. A controlled trial of ondansetron, a 5-HT3 antagonist, in benzodiazepine discontinuation. J Clin Psychopharmacol. 1998;18(2):121–31. pmid:9555597

71. Voshaar RCO, Gorgels WJMJ, Mol AJJ, van Balkom AJLM, van de Lisdonk EH, Breteler MHM, et al. Tapering off long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial. Br J Psychiatry. 2003;182:498–504. pmid:12777340

72. Martin P, Patel S. Pharmacology of drugs of abuse. In: Golan D, Armstrong E, Armstrong A, editors. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia, Pennsylvania: Wolters Kluwer Health. 2017. p. 308–34.

73. Greenblatt DJ, Allen MD, Noel BJ, Shader RI. Acute overdosage with benzodiazepine derivatives. Clin Pharmacol Ther. 1977;21(4):497–514.

74. Rickels K, Garcia-Espana F, Mandos LA, Case GW. Physician Withdrawal Checklist (PWC-20). J Clin Psychopharmacol. 2008;28(4):447–51.

75. Ślebioda Z, Lukaszewska-Kuska M, Dorocka-Bobkowska B. Evaluation of the efficacy of treatment modalities in burning mouth syndrome-A systematic review. J Oral Rehabil. 2020;47(11):1435–47. pmid:32979878

76. Cui Y, Xu H, Chen FM, Liu JL, Jiang L, Zhou Y, et al. Efficacy evaluation of clonazepam for symptom remission in burning mouth syndrome: a meta-analysis. Oral Dis. 2016;22(6):503–11. pmid:26680638

77. Zdziarski P. A Case of Stiff Person Syndrome: Immunomodulatory Effect of Benzodiazepines: Successful Rituximab and Tizanidine Therapy. Medicine (Baltimore). 2015;94(23):e954. pmid:26061327

78. Hansbauer M, Wagner E, Strube W, Röh A, Padberg F, Keeser D, et al. rTMS and tDCS for the treatment of catatonia: A systematic review. Schizophr Res. 2020;222:73–8. pmid:32600779

79. Pelzer AC, van der Heijden FM, den Boer E. Systematic review of catatonia treatment. Neuropsychiatr Dis Treat. 2018;14:317–26. pmid:29398916

80. Bhatti AB, Gazali ZA. Recent advances and review on treatment of stiff person syndrome in adults and pediatric patients. Cureus. 2015;7(12):e427.

81. Lie JD, Tu KN, Shen DD, Wong BM. Pharmacological treatment of insomnia. P T. 2015;40(11):759–71.

82. Offidani E, Guidi J, Tomba E, Fava GA. Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom. 2013;82(6):355–62. pmid:24061211

83. Bateson AN. Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal. Curr Pharm Des. 2002;8(1):5–21. pmid:11812247

84. Ashton H. Guidelines for the rational use of benzodiazepines. When and what to use. Drugs. 1994;48(1):25–40. pmid:7525193

85. Rosenberg HC, Chiu TH. Time course for development of benzodiazepine tolerance and physical dependence. Neurosci Biobehav Rev. 1985;9(1):123–31. pmid:2858077

86. Pétursson H. The benzodiazepine withdrawal syndrome. Addiction. 1994;89(11):1455–9. pmid:7841856

87. Eagles L. Guidance for prescribing and withdrawal of benzodiazepines & hypnotics in general practice. NHS Grampian. 2008. https://benzo.org.uk/amisc/bzgrampian.pdf

88. Brett J, Murnion B. Management of benzodiazepine misuse and dependence. Aust Prescr. 2015;38(5):152–5. pmid:26648651

89. Brunner E, Chen CYA, Klein T. Joint Clinical Practice Guideline on Benzodiazepine Tapering: Considerations When Benzodiazepine Risks Outweigh Benefits. https://downloads.asam.org/sitefinity-production-blobs/docs/default-source/guidelines/benzodiazepine-tapering-2025/bzd-tapering-document---final-approved-version-for-distribution-02-28-25.pdf?sfvrsn=5bdf9c81_3

90. The Maudsley desprescribing guidelines: Antidepressants, benzodiazepines, gabapentindoids and Z-drugs. Wiley-Blackwell. 2024.

91. Jung ME, Metzger DB, Hall J. The long-term but not short-term use of benzodiazepine impairs motoric function and upregulates amyloid β in part through the suppression of translocator protein. Pharmacol Biochem Behav. 2020;191:172873. pmid:32105662

92. Furukawa T, Nikaido Y, Shimoyama S, Masuyama N, Notoya A, Ueno S. Impaired Cognitive Function and Hippocampal Changes Following Chronic Diazepam Treatment in Middle-Aged Mice. Front Aging Neurosci. 2021;13:777404. pmid:34899279

93. Furukawa T, Shimoyama S, Miki Y, Nikaido Y, Koga K, Nakamura K, et al. Chronic diazepam administration increases the expression of Lcn2 in the CNS. Pharmacol Res Perspect. 2017;5(1):e00283.