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Benzodiazepine Misuse: An Epidemic Within a Pandemic

Article in Cureus · June 2021

DOI: 10.7759/cureus.15816

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 Open Access Review
Article DOI: 10.7759/cureus.15816

Benzodiazepine Misuse: An Epidemic Within a

Pandemic
Ashish Sarangi 1 , Terry McMahon 1 , Jayasudha Gude 2

1. Psychiatry, Texas Tech University Health Sciences Center, Lubbock, USA 2. Psychiatry, Zuckerside Hillside Hospital,
New York, USA

Corresponding author: Ashish Sarangi, [email protected]

Abstract
Coronavirus disease 2019 (COVID-19) had deleterious effects on patients with mental health problems and
several studies have shown a spike in the rates of depression, insomnia, and post-traumatic stress disorder.
Anxiety and insomnia rates have also increased among both the general public and health care
professionals. Benzodiazepines are some of the most commonly used drugs in the treatment of anxiety and
insomnia. However, benzodiazepines are also misused, abused alone, or abused in combination with other
drugs. Lockdowns and social distancing have also had negative consequences on patients with mental health
problems. We assessed the extent of benzodiazepine use during the pandemic and interpreted its effects in
the future. We conducted a literature search using the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) protocol and eight articles reviewed specifically reported worrying fluctuations in
benzodiazepine use during the pandemic. We observed varied trends in the usage of benzodiazepines in
various parts of the world. Some studies showed an increase in the consumption of benzodiazepine while
others demonstrated a decrease in the prescription refills of benzodiazepine, which may be a result of gaps
in mental health care. At this time, we can conclude that the current trend with benzodiazepine use is
fluctuating and mental health professionals must continue to exercise caution before prescribing
benzodiazepines. Future research is also warranted to be aware of the changing patterns and to avoid misuse
and/or abuse at an epidemic level.

Categories: Psychiatry, Infectious Disease, Public Health

Keywords: benzodiazepine, covid-19, pandemic, coronavirus, psychiatry

Introduction And Background

It has been more than a year since the coronavirus disease 2019 (COVID-19) was first reported in December
of 2019 [1]. According to World Health Organization, there have been 170 million cases reported and almost
every country has been affected by the coronavirus pandemic [1,2]. The COVID-19 outbreak has led people
everywhere to implement drastic changes in lifestyle, including social distancing. Periods of social isolation
and loneliness have resulted in negative consequences on mental well-being. It was found that people were
three times more likely to have anxiety or depressive disorders in 2020 compared to the previous year [3],
Review began 05/28/2021 and more than one in three individuals presented one or both disorders. According to the CDC, from January
Review ended 06/21/2021 20, 2021, to February 1, 2021, more than two in five adults aged ≥18 years experienced symptoms of anxiety
Published 06/21/2021 or a depressive disorder during the past seven days [4]. It has also been reported that symptom rates of
© Copyright 2021 generalized anxiety, psychological distress, and COVID-19 related fear are 44.9%, 65.2%, and 59%
Sarangi et al. This is an open access respectively [5]. Since the pandemic onset, there has been also a 37% increase in the rate of clinical
article distributed under the terms of the insomnia (from 14.6% to 20%) [6]. Among health care workers caring for COVID-19 patients, there has been
Creative Commons Attribution License
an increase in the prevalence of anxiety to 25.8% (95% CI 20.5-31.9%) and stress to 45% (95% CI 24.3-
CC-BY 4.0., which permits unrestricted
use, distribution, and reproduction in any 67.5%) [7].
medium, provided the original author and
source are credited.
Benzodiazepines are a class of medications used to treat conditions such as anxiety and insomnia. In 1955,
the first benzodiazepine (BZD), chlordiazepoxide, was developed, followed by diazepam in 1963 [8-11]. In
1957, as an alternative to previous barbiturates, BZD use started to gradually replace the opiate derivates
[12]. Benzodiazepines became widely used drugs because of their potential benefits and were the most
abused drugs by the 1970s [13]. With growing concern about the abuse of BZDs, they were placed on Food
and Drug Administration drug list [14]. The risk of BZD dependence was officially recognized by the
American Psychiatric Association in 1990 [15,16]. BZDs act by binding to the gamma-aminobutyric acid A
(GABA-A) [17] receptors in the brain, inhibiting the brainstem arousal pathways. When BZDs interact with
GABA-A receptors, ion channels open more frequently, increasing the inflow of chloride ions which
increases membrane polarization and inhibits neuron firing resulting in central nervous system (CNS)
depression [15]. This mechanism results in anxiolytic, sedative, hypnotic, anticonvulsant and skeletal
muscle-relaxing effects.

Benzodiazepines are classified based on their elimination half-life. They include long-acting diazepam,
chlordiazepoxide, flurazepam, and clorazepate along with intermediate-acting alprazolam, clonazepam,
lorazepam, oxazepam, and temazepam with short-acting agents being midazolam and triazolam. BZDs are

How to cite this article

Sarangi A, Mcmahon T, Gude J (June 21, 2021) Benzodiazepine Misuse: An Epidemic Within a Pandemic. Cureus 13(6): e15816. DOI
10.7759/cureus.15816
 metabolized oxidatively in the liver by the cytochrome P450 enzymes (phase I), conjugated with glucuronide
(phase II), and excreted almost entirely in the urine [18]. They are prescribed for a wide range of conditions,
which include insomnia, agitation, anxiety and convulsions [19]. The dose-related side effects include
amnesia and central respiratory depression [18]. Benzodiazepines used in large quantities can also result in
a dopamine rush, which is responsible for creating a sense of pleasure and reward [20]. Benzodiazepines are
commonly consumed orally but some smoke, snort or inject. They are commonly referred to as “candy”,
“downers”, “sleeping pills”, or “tranks” [21]. Flunitrazepam is one of the commonly abused drugs and has
been referred to as date rape drug, roofies, or forget-me-pill [22].

Over the past several years there have been rising concerns about the misuse of benzodiazepines. A study
has estimated that 30.6 million adults (12.6%) reported benzodiazepine use in the year 2015-2016 [23].
Among them they report that 2.2% have misused a BZD prescription. Among adults and adolescents,
benzodiazepines are the third most commonly misused illicit or prescription drug in the USA [24,25]. Over
the past few decades, benzodiazepine use has increased tremendously. A study done by Bachhuber et al.
showed that the number of adults who filled a benzodiazepine prescription increased by 67%, from 8.1
million to 13.5 million between the years 1996 and 2013. The quantity obtained also increased from 1.1 kg to
3.6 kg lorazepam-equivalents per 100,000 adults [26].

According to the National Institute of Drug Abuse (NIDA), among 2017-2018 benzodiazepine misusers,
46.3% of respondents reported that the motivation for their most recent misuse was to relax or relieve
tension, followed by helping with sleep in 22.4%. About 5.7% reported “experimentation” as their main
motivation for misuse, and 11.8% reported using them to “get high” or because of being “hooked”. The data
also showed that most misusers obtained benzodiazepines from friends or relatives, with only about 20%
receiving them from their doctor [27]. Opioids have been largely involved in deaths related to overdose, and
NIDA reports that benzodiazepines have been involved in more than 30% of opioid-related overdose deaths
[27]. Benzodiazepines have also been implicated in causing addiction and long-term cognitive problems.
NIDA also reported that among benzodiazepine users, 17.1% misused them and fewer than 2% had
benzodiazepine use disorder [27]. Benzodiazepine derivatives are prescribed in large quantities globally and
are potentially new emerging environmental contaminants. Several studies have emerged showing the
presence of BZD derivatives in sewage water and hospital effluents [28-32]. Wastewater samples in
Mississippi, USA, have been found to contain alprazolam, α-OH-alprazolam, nordiazepam, oxazepam and
temazepam [32]. Scientists in Sweden found that fish living downstream from sewage treatment plants (STP)
had elevated benzodiazepine levels and found concentrations of a common benzodiazepine, oxazepam, of
0.73 mg/liter in treated wastewater effluent and 0.58 mg/liter in a midsized stream (River Fyris) receiving
input of treated wastewater. These studies indicate that wild fish populations may be affected, and we are
still unaware of how these trace levels affect humans [33]. These studies have not only provided information
on the prevalence of drug use on a community level, but also warn caution on the use of benzodiazepines.

We hypothesized an increase in benzodiazepine use during the COVID-19 pandemic and evaluated the
extent of benzodiazepine use during the COVID-19 pandemic in terms of benzodiazepine prescription and
other illicit use.

Table 1 below demonstrates half-life, onset of action and dose equivalency of commonly utilized
benzodiazepines.

2021 Sarangi et al. Cureus 13(6): e15816. DOI 10.7759/cureus.15816 2 of 9

 Benzodiazepine Half Life in hours Peak time of action in hrs Dose equivalent to 5mg Diazepam

Alprazolam 12 1-2 0.5-1

Chlordiazepoxide 100 1-4 10-25

Clonazepam 18-50 1-2 0.25-0.5

Clorazepate 100 0.5-2 7.5–15

Diazepam 100 1-2 5-10

Flurazepam 100 0.5-1 15–30

Lorazepam 15 1-4 1-2

Oxazepam 8 1-4 15-30

Quazepam 25-41 1.5 10-20

Temazepam 11 2-3 10-20

Triazolam 2 1-2 0.25-0.5

TABLE 1: Table demonstrating half life, onset of action and dose equivalency when compared to
5mg of diazepam [17,34-38]

Review
Methods
We conducted an extensive literature review using databases PubMed, CINAHL, Cochrane, and Google
Scholar (sorted by date and articles with abstracts only were included to review) using the keywords
“benzodiazepines” and “COVID-19 Pandemic” following the Preferred Reporting Items for Systematic
Review and Meta-Analysis (PRISMA) protocol [39]. Inclusion criteria included research conducted in all
countries after the beginning of the coronavirus pandemic, and both English and non-English articles were
included. Studies that reported the use of benzodiazepine since the beginning of the pandemic were
included. Excluded studies include non-peer-reviewed publications, case reports, case series, review articles,
and letters to editors. Studies involving substance abuse but not mentioning specifically benzodiazepine use
were also excluded. We included articles from January 1, 2020, to April 30, 2021.

Figure 1 below depicts the process of review and inclusion of articles for the purposes of this review.

2021 Sarangi et al. Cureus 13(6): e15816. DOI 10.7759/cureus.15816 3 of 9

 FIGURE 1: Preferred Reporting Items for Systematic Review and Meta-
Analysis (PRISMA) flow diagram depicting the process of identification
and selection of articles.

Results
Our search strategy resulted in 209 studies; 31 studies are excluded based on title screening. One hundred
seventy articles were excluded for various reasons. Reasons for exclusion included duplicates articles (35),
case reports (26), case series (seven), review articles (61), and editorial articles (10). Following this, 39
articles were retrieved out of which four were not accessible. Final full texts of 35 article are reviewed and
eight studies written in English which reported the use of benzodiazepines during COVID-19 pandemic are
included. The final eight articles were deemed suitable to be included for the conciseness of this review.

Discussion
Benzodiazepines, especially diazepam, have been the main course of treatment for anxiety and insomnia
[40]. Prescribing benzodiazepines has been controversial due to the recognized deleterious effects of long-
term treatment with these drugs. Benzodiazepine use in COVID-19 patients has been shown to exacerbate
delirium and suppress respiratory drive in patients with respiratory suppression [41]. Caution has been
exercised in the use of benzodiazepines, especially palliative care. Some drugs such as midazolam and
triazolam are contraindicated with the use of lopinavir/ritonavir because of the risk of increasing the level of
some benzodiazepines due to CYP450 inhibition [41]. With the emerging coronavirus pandemic, most
countries have updated their drug prescription policies [1]. In the USA, Prescription Drug Monitoring
Program (PDMP) is an electronic way to monitor the dispensing of controlled substances used in most states
[42].

The COVID-19 pandemic has caused a disruption of the availability of critical mental health services and as
a result many people may have faced an increase in the use of alcohol and drugs [1]. Benzodiazepines may
have a high potential for abuse and misuse during the pandemic [43], and they are typically co-abused in
patients with substance use disorders [44]. The most frequent primary abuse drugs are opioids and/or
alcohol; benzodiazepines are misused to enhance the other drug’s euphoric effects, reduce the unwanted

2021 Sarangi et al. Cureus 13(6): e15816. DOI 10.7759/cureus.15816 4 of 9

 effects of drugs, such as insomnia due to stimulant use, and alleviate withdrawal symptoms between
doses [45]. According to a recent study, among 196 participants, 47% reported an increase in substance use
since COVID-19 related to loss of employment, fear of catching the virus, social distancing and isolation.
Some people reported substance use as a coping mechanism to deal with the negative physical, mental and
social impacts of COVID-19 [46].

In Dublin, measures have been taken promptly after the declaration of the COVID-19 pandemic by the WHO.
There was a growing concern about the spread of coronavirus and mortality among people with drug
dependency and homelessness. Sixty-two percent of homeless people on opioid substitution therapy also
misused street benzodiazepines [47,48]. So, clients were placed in isolation units and shielding units.
Patients with benzodiazepine dependency were offered up to 30 mg of benzodiazepine daily to prevent
withdrawals for the period of isolation only. In the homeless sector, over 70 people were commenced on
benzodiazepine maintenance treatment [49]. In Ireland, it has been reported that 92% of overdoses where
methadone was implicated and 81% of deaths where heroin was implicated involved benzodiazepines
predominantly [47]. In France, because of social isolation or psychological troubles due to lockdown with the
potential increase of marital conflicts and domestic violence, there was a prediction for increased
consumption of benzodiazepines [50]. Further data collection by the French addictovigilance centers,
pharmacies, and addiction specialized centers revealed abuse or misuse with alcohol or other psychoactive
substances. Among benzodiazepines, clonazepam, alprazolam, and oxazepam were the most frequently
reported to be misused or abused [50].

Lockdown has also resulted in a lot of online browsing about potential drugs of abuse. Google trends in
health-related research showed a significant increase in online search interest for the keywords representing
benzodiazepines during the lockdown in India [51]. Ireland also reported an increase in the use of alcohol
and benzodiazepine use during lockdown periods which has continued after the lockdown as well [52]. The
use of illicit drugs has returned to pre-lockdown levels, leading to an elevated risk of developing comorbid
psychiatric disorders and other health conditions [52].

The United Nations reports that the non-medical use of benzodiazepines is a well-known phenomenon and
represents an increasingly widespread public health problem during the pandemic since its magnitude is
difficult to estimate, mainly due to the lack of monitoring and data collection in most countries [53]. This
misuse pattern is associated with an elevated risk of serious health consequences or fatal overdose,
especially among high-risk opioid users, who misuse benzodiazepines to increase the effects of opioids or to
self-medicate to treat symptoms of psychiatric disorders, negative emotional states, opioid withdrawal
symptoms, and the side effects of alcohol and cocaine use. The diversion of benzodiazepines most commonly
involves alprazolam, diazepam, and lorazepam which seem to have a wider diffusion than oxazepam,
clorazepate, and chlordiazepoxide because of their higher abuse potential [53]. In Europe, causes of deaths
among high-risk opioid users are more frequently related to the use of benzodiazepines with rapid onset of
action such as diazepam, clonazepam, and alprazolam rather than those with a slower onset such as
oxazepam and flunitrazepam [54].

In Texas, USA, a study was done to observe the trend in benzodiazepine prescription during the pandemic.
According to the Texas Prescription Monitoring Program, the average daily number of patients who filled
new benzodiazepine prescriptions was 17,548.56 (Standard Deviation (SD) = 1295.06). There was a
significant decrease in the benzodiazepine prescriptions between January 5, 2020, and May 12, 2020 (β =
−1982, 95%CI = −3712.43, −252.14) [55]. A similar trend was observed with benzodiazepine prescribers [55].
On March 22, 2020, the governor issued an executive order restricting elective medical procedures including
many routine outpatient visits. Before the executive order, there was an average of 9,087.24 (SD = 356.26)
unique daily prescribers of new benzodiazepine prescriptions. There was a significant decrease in
benzodiazepine prescribers associated with the executive order (β = −708.62, 95%CI = −1190.54, −226.71).
This result may be due to a large gap in the care for patients having benzodiazepine prescriptions that has
emerged during the pandemic [55]. A study was done by Niles et al. analyzing the deidentified urine
specimen samples from the Quest Diagnostics medMATCH® method. There was a significant decrease in
non-prescribed benzodiazepine use (4%, p<0.02) indicating a decrease in overall misuse during the
pandemic. However, among benzodiazepine users, positivity for non-prescribed fentanyl increased by
48% (P < 0.01) [56].

In the USA, a study was done comparing the unique dispense of medications from January 2019 to May 2020
[57]. The monthly number of unique patients dispensed as benzodiazepines (mean = 4,781,043 [SD =
166,850]; range = 4,478,448 to 5,011,279) was relatively stable until March 2020. Since March 2020 the
number of unique patients dispensed benzodiazepines (5,128,721) was statistically and significantly higher
than forecast estimates. In March 2020, an estimated additional 450,074 (95% CI:189,999 to 710,149) unique
patients were dispensed benzodiazepines, compared to forecast estimates [57]. Another study was done in
Italy by analyzing hair samples to see drug use patterns during the COVID-19 pandemic. It revealed the
percentage of samples positive for benzodiazepines ranged from 16.7% (5/30 cases) in the period before the
lockdown to 53.3% (16/30 cases, p<0.01) during the lockdown and remained high (43.3%, 13/30 cases,
p<0.01) even after the lockdown [58]. The benzodiazepines reported in this study were not prescribed and
their intake indicated illicit use. The study revealed changes in the overall trend of drug intake during the
considered study period; 11/30 (37%) patients switched from single-drug use in the two pre-lockdown period

2021 Sarangi et al. Cureus 13(6): e15816. DOI 10.7759/cureus.15816 5 of 9

 controls to poly-drug use in the post-lockdown period [58]. According to an Italian report during COVID-19,
there has been a concerning increase in the prescription of hypnotics/sedatives with the potential for abuse,
which has almost doubled and increased by about 17-19% [59,60]. In another study in Ontario, data from
January 1 to May 31, 2019, were compared with data from January 1 to May 31, 2020. There was a 43.7%
increase in benzodiazepine dispensing in the first five months of the year compared to the year prior [61].
The same study also reported that the number of benzodiazepine tablets dispensed monthly during the
COVID-19 pandemic was statistically higher compared to the previous year
(1037.4 ± 122.24, 721.6 ± 156.87, respectively, z=-2.402, p=0.016) [61].

In Spain, a telephone survey was conducted by the health professionals among the Drug Addiction
Assistance of Castile and Leon (DAACYL) units. The professionals in the DAACYL units expressed that the
clinical impact during the first six weeks of the pandemic was moderate; however, six centers reported that
patients increased or started consuming alcohol and benzodiazepines, especially alprazolam [62]. Among
people who were confirmed with coronavirus infection and discharged subsequently, there was a 3.3%
initiation of new benzodiazepine prescriptions [63]. The findings of all the studies discussed are summarized
in Table 2.

Site of Sample
Author Study Period Data Collection Findings
Study Size

Lapeyre-
March 17th, 2020 – May Data collected from French Addictovigilance Significant misuse and abuse of benzodiazepines reported (with alcohol or other psychoactive
Mestre et France n=231
31 st, 2020 Network substances).
al. [50] 2020

Downs et January 5 th, 2020, to May

USA Texas Prescription Monitoring Program. n=18000 Significant decrease associated with both benzodiazepine prescriptions and prescribers.
al. [55] 2020 12 th, 2020

Niles et January 1 st, 2019, through De-identified results from all medMATCH specimens
USA n= 44211 There was a 4% decrease in non-prescribed benzodiazepine use (p<0.02)
al. [56] 2020 May 16th, 2020 with clinician-provided prescribed drug information

Jones et The results of the study showed additional 450,074 (95 % CI:189,999 to 710,149) unique patients
USA January 2019-May 2020 Data from the IQVIA Total Patient Tracker database n=5,128,721
al. [57] 2020 were dispensed benzodiazepines compared to forecasted estimates

Hair Sample collected from 30 patients (aged 18–48 The percentage of samples positive for benzodiazepines increased from 16.7% (5 cases) in the
Gili et March 22nd, 2020 – May
Italy y; 17 males; 13 females) from urban areas of central n=30 period before the lockdown to 53.3% (16 cases, p < 0.01) during the lockdown and remained high
al. [58] 2020 18 th, 2020
Italy for analysis after the lockdown (43.3%, 13 cases, p < 0.01).

January 1 st to May 31 st
Yu et Prescription refill information from independent There was significantly more frequent dispensing of benzodiazepine tablets (z= 2.402, p=0.016) in
Canada 2019 Vs January 1 st to n=365
al. [61] 2020 community pharmacy the first five months of 2020 compared to those of 2019.

May 31st, 2020

McCarthy et March 7th, 2020 - March

USA Data collected from Confirmed coronavirus infection n=213 New benzodiazepine initiation was 3.3% among discharged patients.
al. [63] 2020 30 th, 2020.

TABLE 2: Summary of significant findings of major studies conducted evaluating benzodiazepine

use during the COVID-19 pandemic.

Five out of eight studies showed an increase in benzodiazepine use, whereas two have reported a decrease.
These data indicate there have been changing trends in benzodiazepine prescription and misuse during the
pandemic.

Limitations
We restricted our review to the search terms Benzodiazepines and COVID-19 pandemic, so we may have
missed relevant studies which did not have these keywords. We discussed in a broader sense the use of a
benzodiazepine during the pandemic including their prescriptions, rather than strictly focusing on
benzodiazepine misuse. Several studies which have reported other benzodiazepine use along with opioids
and other psychotropics are also included. The studies lacked clear details of benzodiazepine misuse and the
individuals might have been using benzodiazepines as prescribed, not representing misuse. We also included
studies done using urine and hair sample analysis rather than restricting to strict terms of benzodiazepine
misuse.

Conclusions

2021 Sarangi et al. Cureus 13(6): e15816. DOI 10.7759/cureus.15816 6 of 9

 We discussed the various trends observed regarding the benzodiazepines use during COVID-19 pandemic as
reported in different studies. We reviewed benzodiazepine misuse and predict how the trends of
benzodiazepine misuse may vary in the post-pandemic era. COVID-19 has been a global pandemic that has
spiked the rates of anxiety and insomnia. Mental health professionals need to be prepared for issues that
may arise due to COVID-19 such as anxiety, depression, fear, coronophobia, trauma and grief due to loss of a
loved one. The risk of developing benzodiazepine tolerance, abuse and addiction must be considered by
health care professionals before prescribing them. This review summarizes the trends observed during the
pandemic and emphasizes the importance of weighing risks versus benefits before the prescription of
benzodiazepines. The studies which showed an increase in benzodiazepine use represent the tip of an
iceberg. We hypothesize the trends in benzodiazepine usage may increase in the future and caution is
warranted. We hope mental health professionals prescribe benzodiazepines carefully and make changes in
practice according to the prescription drug monitoring program data to avoid a benzodiazepine crisis. Future
research is warranted for the periodic assessments of an evolving benzodiazepine crisis.

Additional Information
Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.

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