Journal of Anxiety Disorders 25 (2011) 554562

Contents lists available at ScienceDirect

Journal of Anxiety Disorders

The discovery of chlordiazepoxide and the clinical introduction of

benzodiazepines: Half a century of anxiolytic drugs
a,b, , Cecilio lamo a , Pilar Garca-Garca a
Francisco Lpez-Munoz
a
b

Neuropsychopharmacology Unit, Department of Pharmacology, Faculty of Medicine, University of Alcal, Madrid, Spain
Health Sciences Faculty, Camilo Jos Cela University, Madrid, Spain

a r t i c l e

i n f o

Article history:
Received 28 September 2010
Received in revised form 14 January 2011
Accepted 14 January 2011
Keywords:
Chlordiazepoxide
Benzodiazepines
Anxiolytic drugs
History of psychiatry

a b s t r a c t
The clinical introduction of chlordiazepoxide half a century ago was one of the major breakthroughs in
the history of psychopharmacology, as it opened the door for the benzodiazepine saga, the pharmacological family par excellence in the treatment of anxiety disorders. This review analyses the discovery of
this drug, which was lled with chance events, and numerous chemical and clinical errors of approach.
Chlordiazepoxide, initially called methaminodiazepoxide, was patented in 1958 and introduced in clinical treatment in 1960 under the brand name Librium . The benzodiazepines became the most widely
prescribed drugs worldwide, provided truly effective treatment for minor forms (neuroses) of mental
disorders for the rst time, increased the quality of scientic methodology in clinical research, and enabled
the development of new etiopathogenic theories for anxiety disorders, especially after the discovery in
1977 of their high-afnity receptor complex.
2011 Elsevier Ltd. All rights reserved.

The 1950s saw the so-called psychopharmacology revolution,

with introduction in clinical treatment of the three major pharmacological groups used today in the treatment of mental disorders
(Ayd, 1991; Ban, 2001; Caldwell, 1970; Healy, 2002; Jacobsen,

1986; Lpez-Munoz,
lamo, & Cuenca, 2000, 2005). Of these, the
anxiolytic drugs were the last to be included in this pharma
cological arsenal, after the antipsychotic agents (Lpez-Munoz,

lamo, Rubio, & Cuenca, 2004; Lpez-Munoz,

lamo, Cuenca, Shen,
& lamo, 2009a) and the antidepressants
et al., 2005; Lpez-Munoz

(Fangmann, Assion, Juckel, lamo, & Lpez-Munoz,

2008; Lpez

Munoz
& lamo, 2009b; Lpez-Munoz,
lamo, Juckel, & Assion,
2007). As pointed out by Pichot (1990), this was at least partially
due to the prevailing doctrinal inuences within psychoanalytical thought at the time, which considered anxiety to be a clinical
manifestation of neuroses. According to this approach, these proles were even considered positive, as a means of externalising a
whole range of unconscious and traumatic internal conicts which
patients needed to work through. In this situation, a pharmacological approach to symptoms of anxiety was considered by the
psychiatric community, especially in North America, to be not only

Abbreviations: APA, American Psychiatric Association; BBC, British Broadcasting

Corporation; CNS, central nervous system; DBI, diazepam binding inhibitor; DSM,
Diagnostic and Statistical Manual of Mental Disorders; FDA, Food and Drug Administration; GABA, gamma-aminobutyric acid; WHO, World Health Organization.
Corresponding author at: C/ Gasmetro, 11, portal 3, 2 A, 28005 Madrid, Spain.

E-mail address: francisco.lopez.munoz@gmail.com (F. Lpez-Munoz).

0887-6185/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.janxdis.2011.01.002

a utopia, but even an error, as it would prevent the patient from

becoming aware of the roots of his or her internal conict. In
addition, the psychopharmacological agents available at that time,
which were mainly barbiturates, were sedative compounds, with
no specic effects on the symptoms of these psychiatric disorders

(lamo, Lpez-Munoz,
Echniz, & Cuenca, 1998).
However, a study published in 1952 by professor Hans Jurgen
Eysenck of the London Institute of Psychiatry began to call these
theories into question. In a retrospective analysis, Eysenck compiled data on the clinical response of neurotic patients treated using
psychoanalysis techniques and the rate of spontaneous remission,
and found that the condition of patients treated with psychoanalysis in fact worsened slightly (Eysenck, 1952). The clinical
introduction of chlorpromazine in 1952 and the conrmation of
its effectiveness as a major tranquilizer in the treatment of agi et al., 2004; Lpez-Munoz,

tated psychotic patients (Lpez-Munoz

lamo, Cuenca, Shen, et al., 2005) encouraged pharmacological
research to seek new compounds that could be useful alternatives
to psychoanalytical techniques. Publication, also in 1952, of the
rst edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-I) by the American Psychiatric Association (APA) also
increased clinical interest in dealing with anxiety disorders. For the
rst time in history, a distinction was made between psychiatric
and organic disorders, and two very different medical entities were
established; psychoses and neuroses. However, while drugs effective against various types of psychosis (chlorpromazine, reserpine)
began to appear, the chemical and psychological response to neuroses was quite unsatisfactory, until meprobamate was introduced

F. Lpez-Mu
noz et al. / Journal of Anxiety Disorders 25 (2011) 554562

into clinical treatment in 1955. Finally, the commercialization of the

rst benzodiazepine chlordiazepoxide in 1960 consolidated the
pharmacological treatment of anxiety disorders.
In this study, with the benet of half a centurys hindsight, we
will review the historic process that culminated in the discovery of
chlordiazepoxide and the subsequent clinical introduction of the
benzodiazepine saga, and the contribution of this pharmacological
family to anxiolytic therapy. We will also analyse the role played
by the benzodiazepines in establishing etiopathogenic theories on
anxiety disorders and therefore in the consolidation of biological
psychiatry as we know it today.

1. The forerunners of the benzodiazepine era: between

barbiturates and meprobamate
Therapeutic treatment of anxiety disorders before the 1950s
was restricted to very few drugs, which had very limited effectiveness. Among these were alcohol (in the form of wine, beer and
mead), alkaloids from opium and other narcotic plants (hyoscyamus, datura, belladonna, etc.), paraldehyde, chloral hydrate, the
bromides, and above all the barbiturates (lamo et al., 1998;

Lpez-Munoz,
lamo, & Cuenca, 2005). Among the alkaloids of the
Solanaceae family are hyoscyamine and hyoscine (called scopolamine in North America), which were included in numerous
cocktails administered in psychiatric institutions in the late 19th
century, mainly to very excited and aggressive manic patients
(Norton, 1979; Woodward, 1994). Meanwhile, the bromides,
despite initially being used as anticonvulsants, were also used
extensively in European asylums and mental hospitals in the second half of the 19th century, and were introduced in this indication
by the London internist and obstetrician Sir Charles Locock in 1857
(Locock, 1857). However, the main problem with the bromides was
their high level of toxicity (neurological and gastrointestinal disorders, irritability, hallucinations, delirium and lethargy) due to their
long average half-life (approximately 12 days), and their propensity
to tissues accumulation, all of which led to their gradual replacement when the barbiturates were introduced in the early 20th
century (Balme, 1976).
Between the 1920s and the mid-1950s, barbiturates were practically the only pharmacological tools used in the treatment of

anxiety (Lpez-Munoz,
Ucha-Udabe, & lamo, 2005). These closed
chain ureic compounds, the central core of which is malonylurea,
were synthesised in 1863 by Adolf von Baeyer, although the rst
agent in this family (diethyl-barbituric acid or barbital), synthesised by Emil Fisher and Jacob von Mering, was introduced into
clinical practice as a hypnotic in Germany in 1903 by the company
Bayer (Fisher & von Mering, 1903). This substance presented anticonvulsant, sedative and hypnotic properties. However, the most
frequently used agent in this family in subsequent years was phenobarbital, which was also commercialised by Bayer in 1912, with the
brand name of Luminal . Despite their extensive use in the rst half
of the 20th century, no barbiturate succeeded in eliminating the
main disadvantages of these drugs, which included dependence,
which was described in the medical literature as early as one year
after barbital was commercialized, and the frequent cases of death
due to overdose, a commonly used method in suicide attempts
(Johns, 1977).
The situation regarding therapy for anxiety disorders in the latter years of this pre-anxiolytic period is apparent in Paul Cossas
approach in his work Thrapeutiques neurologiques et psiquiatriques,
which was published in 1945. This author considers that there are
seven groups of drugs for the treatment of autonomous nervous
system imbalances, the equivalent at that time of todays anxiety disorders: opium, the bromides, phenobarbital, chloral hydrate,
calcium salts, phytotherapeutic remedies (such as Crataegus) and

555

other drugs which in low doses, act on the autonomous nervous

system. Of the seven groups, opium should be reserved for major
depressive disorders with associated anxiety, with the bromides
and phenobarbital being the anti-anxiety agents of choice, with the
latter administered at low doses, 710 times a day (Cossa, 1945).
Finally, clinical introduction of meprobamate was the rst
major breakthrough in the treatment of anxiety, as unlike the
barbiturates, this medication was less addictive and its anxiolytic effect was achieved with very little change in patients
physical performance and intellectual capacity (Ramchandani,

Lpez-Munoz,
& lamo, 2006). Meprobamate (2-methyl-2-npropyl-1,3-propanediol dicarbamate) was synthesised in May 1950
by Frank M. Berger, a Czech microbiologist and pharmacologist who
had emigrated to the USA, and was working as research director
at the pharmaceutical company Wallace Laboratories (Grambury,
New Jersey). The three pharmacological characteristics that dened
meprobamate were muscle relaxation, its anticonvulsant effect and
its calming action (Berger, 1952). Meprobamate was approved by
the Food and Drug Administration (FDA) in July 1955, and was
the rst medication specically marketed as an anxiolytic, on 22
November in the same year, under the brand name of Miltown .
However, it was subsequently found not to be an anxiolytic agent,
as it led to some degree of drowsiness, even at therapeutic doses.
In fact, despite high clinical expectations and enormous success of
meprobamate in terms of sales, it was relatively short-lived commercially, as it was withdrawn from the North American markets
in the mid-1960s, when problems of tolerance, abuse, lethal overdoses and dependence became apparent, which reminded many
clinicians of the problems previously observed with the barbi
turates (Greenblatt & Shader, 1971; Lpez-Munoz,
Ramchandani,
lamo, & Cuenca, 2005). Furthermore, its anxiolytic and sedative
effect was limited, and as such researchers continued to search
for a substance that would occupy the middle ground between
meprobamate and the recently introduced phenothiazines. This led
to the discovery of the benzodiazepines.

2. The discovery of chlordiazepoxide: chance as the

counterpoint between failure and success
As was the case with most of the psychotropic drugs discovered in the 1950s, scientic chance played a substantial role the
development of the benzodiazepines, the most important family
of anxiolytics in pharmacological and clinical terms. Indeed, this
research process involved a series of scientic errors and failures
that turned into unexpected successes by chance.
Discovery of the benzodiazepines is closely linked to the gure
of Leo Henryk Sternbach (Fig. 1), a Polish researcher, who was born
in the Austro-Hungarian Empire and died in 2005 (Bnninger et al.,
2004). Sternbach, who received his doctorate in organic chemistry in 1931 from the Jagiellonian University of Cracow, began
his research in the laboratories of Hoffmann-LaRoche Inc. in Basel
(Switzerland) in 1940 (Fig. 2). However, as a result of the Nazis
anti-Semitic persecution, he was forced to emigrate to the USA
during the Second World War, and found work as a chemist in
the Swiss companys North American headquarters (Nutley, New
Jersey). In 1954, he decided to continue his studies of some tricyclic
compounds (heptoxdiazines) that he had synthesised at the University of Crakow 20 years previously, during his postdoctoral studies
of colourings. The recent commercialization of chlorpromazine in
France in 1952, and its tricyclic chemical structure, made Sternbach
wonder whether some modications to the lateral chains of his old
compounds could endow them with properties similar to the new
neuroleptic agent (Sternbach, 1972, 1979). To that end, he focused
on a substance known as 4,5-benzo (hepto 1,2,6-oxdiazine) in the
German literature (Sternbach, 1979).

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F. Lpez-Mu
noz et al. / Journal of Anxiety Disorders 25 (2011) 554562

Fig. 1. Leo H. Sternbach (19082005), the man responsible for the synthesis and
introduction of the rst benzodiazepines, including the historically and clinically
important chlordiazepoxide and diazepam, in a photograph taken in his laboratory
in Nutley in 1962.

Using this substance, the Hoffmann-LaRoche researcher developed 40 new compounds from the reaction of his key product, a
haloalkane, with a number of secondary amines, selected to give
them some structural similarity to the recently marketed tricyclic
substances (Sternbach & Reeder, 1961a) However, when Lowell
O. Randall, director of Pharmacological Research at Roche, studied the sedative, anticonvulsants and relaxant properties of these
compounds, the results were negative (the rst failure). Further
chemical studies showed that the tricyclic system in the key intermediate product of synthesis was not benzoheptoxydiazine as
previously believed, but was instead 3-oxido-quinazoline, and this
appeared to be the reason for the lack of biological activity among
the derivatives synthesised from the intermediate synthesis (the
rst error). However, the last of the analogues (Ro 5-0690) synthesised by Sternbach had not yet been studied, and a year and a
half later (May, 1957), his colleague Earl Reeder (the rst twist of
chance) drew his attention to a few hundred milligrams of two
products, a nicely crystallized base and its hydrochloride. . . Pharmacological tests had not been run on these products at the time,
as we were busy with other problems. . . Instead of throwing them

away, we submitted the water-soluble salt for pharmacological

testing. We thought that the expected negative pharmacological
results would cap our work on this series of compounds. . . We
had no idea that this would be the start of a program that would
keep us occupied for years to come (Sternbach, 1972). Randall conrmed that this compound was superior to meprobamate in many
trials in terms of anxiolytic activity and as a central muscle relaxant,
and also had some sedative properties similar to chlorpromazine,
and lacked any signicant adverse effects (Randall, Schallek, Heise,
Keith, & Bagdon, 1960) (rst success). Of particular interest was its
calming effect, observed in a colony of wild monkeys whose level
of alertness was not affected (Randall, 1960). On 26th July 1957,
Randall wrote a few words that are today part of the history of
psychopharmacology: The substance has hypnotic, sedative, and
antistrychnine effects in mice similar to meprobamate. In cats it is
about twice as potent in causing muscle relaxation and ten times
as potent in blocking the exor reex (Cohen, 1984).
Sternbach quickly began to undertake the appropriate chemical analysis to nd out the reason why only this compound of
the 40 that had been synthesized had these characteristics. The
explanation appeared when he found that in the nal stage of the
synthesis, he had used methylamine, a primary amine, by mistake,
meaning that the reaction had taken a different form (transposition reaction with ring enlargement) from the one observed after
using secondary amines (Sternbach & Reeder, 1961a) (the second
twist of chance). This new tranquiliser, which was briey known
as methaminodiazepoxide, was patented by Sternbach on 15 May
1958, its name was then changed to chlordiazepoxide, and it was
the rst drug in a new family, known as the benzodiazepines (Fig. 3).

3. From the laboratory to the clinic: idem per idem

Before being tested in humans, chlordiazepoxide was assessed
in a preclinical study in leopards, lions, panthers, tigers, and pumas
at the San Diego and Boston zoos: the sedative effect was described
as taming these wild animals. This was followed in early 1958 by
the clinical phases of the study of Ro 5-0690, directed by Leonard R.
Hines (the Biological Research director at Roche). The rst clinical
trials were carried out on schizophrenic patients, and the drug was
found to have no real antipsychotic effect, although it did signicantly reduce anxiety in these patients, which was initially thought
to be a secondary effect of the drug (Nuss & Sanger, 2007). Very
high doses were also administered to a small number of elderly
patients, with completely negative results, because as well as an
intense sedative effect, it was found that at the doses adminis-

Fig. 2. The headquarters of Roche Pharmaceuticals in Basel, in the mid-twentieth century, when the development of the benzodiazepine agents began.

F. Lpez-Mu
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557

Fig. 3. The chemical structure of the rst two benzodiazepines introduced in clinical
treatment.

tered, the patients experienced severe ataxia and confused speech,

and as such the authors believe that the molecule lacked clinical
interest (lamo et al., 1998) (the second error). Irvin M. Cohen said
that these events are a clear example of what happens in clinical
research when a drug is tested at the wrong dose. . . in the wrong
type of patient (Cohen, 1984). Fig. 4 shows the handwritten notes
by Sternbach himself in these rst phases of study in humans, when
high doses of chlordiazepoxide were administered.
However, Hines continued to study Ro 5-0690 and designed a
new trial in a population consisting of patients found more regularly in clinical psychiatric outpatient treatment, and hospitalised
psychiatric patients. Three comparative clinical trials were therefore undertaken, and were directed by Irvin M. Cohen, of the Baylor
College of Medicine in Houston, Titus H. Harris, of the University
of Texas Medical Branch in Galveston, and James R. Sussex, of the
University of Alabama School of Medicine in Birmingham. Results
obtained by the three groups were very similar, and showed that
chlordiazepoxide was an effective anxiolytic drug, with very few
adverse effects, and with little effect on the state of awareness and
intellectual activity (the second success). Harris sent the results
of these studies, as a clinical history, to the Journal of the American
Medical Association. This article, which appeared on 12 March 1960,
was the rst publication on the therapeutic efciency of the new
family of benzodiazepines (Harris, 1960).
These data, together with the entire clinical experience obtained
in 1959, enabled Hines to organize a meeting at the University of
Texas Medical Branch (Galveston, 1315 November 1959), entitled Symposium on New Antidepressants and Other Psychotherapeutic
Drugs, which included communications on the pharmacological

Fig. 4. Hand-written notes by Leo M. Sternbach, January 1958, on his rst clinical
impressions of chlordiazepoxide.
Taken from Sternbach (1972).

Fig. 5. Advertisement for Librium (chlordiazepoxide) from the early 1960s. Note
the statement on this drugs ability to make patients with anxiety more accessible
and communicative.

and clinical properties of the new benzodiazepine, which had by

now been studied in over 16,000 patients. All these data were published in 1960 in a supplement to the journal Diseases of Nervous
System. By way of an example, Joseph M. Tobin, of the Northwest
Psychiatric Clinic in Eau Claire, gave details of his pilot experience
with this agent in 79 patients with primary symptoms of anxiety,
obtaining positive results in 81% of cases (Tobin, Bird, & Boyle,
1960), while H. Angus Bowes, of the Institute of Neurology and
Psychological Medicine in Grand Forks, reported on the effectiveness of chlordiazepoxide in patients with long evolution, in phobic
reactions and in obsessive states (Bowes, 1960). All these communications provided the foundations for the subsequent approval of
chlordiazepoxide by the FDA on 24 February 1960. Its trade name,
Librium , is now a key part of the history of pharmacology (Fig. 5).
4. The expansion of the benzodiazepine saga
Subsequent studies by the Swiss pharmaceutical company
showed that more powerful compounds were obtained when the
chemical structure of chlordiazepoxide was simplied (basically
by eliminating its basic lateral chain and the N-oxide radical). The
rst (a 1-methyl derivative with intense muscle relaxant properties) was synthesized by the Sternbach group in 1959, after they
had studied the activity of the main metabolite of chlordiazepoxide, demoxepam (Sternbach & Reeder, 1961b). This was diazepam
(Valium ) (Fig. 3), the prototype par excellence of the benzodiazepine agents, which was commercialized in December 1963.
Diazepam turned out to be a much more powerful compound
than chlordiazepoxide, with a shorter effect, and presented a disassociation between its anxiolytic and sedative effects. The rst
benzodiazepine not developed by Hoffmann-LaRoche, and the third
to be introduced to the North American market, was oxazepam. Its
chemical structure is similar to diazepam, but its pharmacological
action is closer to that of chlordiazepoxide, and it was synthesised
by Stanley C. Bell of Wyeth Laboratories (Philadelphia). The clinical trials with oxazepam, directed by Joseph M. Tobin and Sidney
Merlis, began in 1961, and it was marketed in June 1965 under
the brand name Serax . It was soon observed that as well as its
sedative and anxiolytic effects, the benzodiazepines also had hyp-

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F. Lpez-Mu
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notic, muscle relaxant and amnesic properties (lamo et al., 1998).

A third generation of benzodiazepines was introduced in the late
1970s, including alprazolam (Xanax ), which was basically used as
an anxiolytic, and triazolam (Halcion ), which was mainly used as
a hypnotic (Nuss & Sanger, 2007).
Thousands of benzodiazepines have been synthesized since
1960, by both HoffmanLaRoche and other pharmaceutical companies, and over 100 of these have been marketed in various countries
because of their anxiolytic and/or hypnotic properties.

5. The clinical introduction of the benzodiazepines: the

rise, fall and rationalisation
Usefulness of the benzodiazepines in dealing with symptoms
of anxiety was beyond doubt as soon as they were placed on the
market. During the second half of the 1960s the clinical studies
using this anxiolytic agents were multiplied, and the group led
by Karl Rickels, at Pennsylvania University, conrmed that drug
response in anxiety appears to be inuenced by many factors above
and beyond those associated with the medication: improvement
often occurs spontaneously; any effort at treatment, no matter
how small, may produce at least some placebo response; and any
doctorpatient contact may result in some change in clinical status (Rickels, Cattel, MacAfee, & Hesbacher, 1965; Rickels et al.,
1966; Uhlenhuth et al., 1966). Interestingly, they also conrmed
that some nonspecic factors predictors of good response to treatment with benzodiazepines as more realistic aspirations towards
mental health, high ego strength, low hostility, and better social
advantage eran also good predictors for psychotherapy outcome.
However, several years passed before thorough clinical studies
were undertaken in this area. One of the most comprehensive was
also undertaken by the group of Pennsylvania University, and the
results were published in 1970. These authors designed a randomized double-blind placebo-controlled clinical trial, which compared
the effectiveness and safety of diazepam (10 mg/day) and phenobarbital (150 mg/day) in a total sample of 472 patients. Duration
of the study was four weeks, with an intermediate control in
the second week after treatment began. The results showed that
both active substances were more effective than the placebo, but
there were no statistically signicant differences between them.
The major differences arose in the comparison of the medications
adverse effects; the incidence and intensity of the secondary effects
caused by the barbiturate were much greater than those of the benzodiazepine, which were in turn slightly more than those reported
in the placebo group. A further two factors analysed in the study
also conrmed the therapeutic superiority of diazepam compared
to phenobarbital. First, acceptance of the medication by the patients
(greater in the case of diazepam), and second, the discontinuation
of treatment, which was much higher in the group treated with the
barbiturate, perhaps as a result of the greater incidence of adverse
effects (Hesbacher et al., 1970).
The therapeutic impact of the benzodiazepines in the decade
between 1965 and 1975 was such that these drugs became the most
widely prescribed in the world (Rickels, 1978), and became known
in the non-scientic press as happy pills. According to Rickels
(1978), diazepam was the most prescribed medical treatment and
chlordiazepoxide was in third place. Meanwhile, the gures provided by Parish (1971) conrm that in the ve years between 1965
and 1970 alone, benzodiazepine prescriptions increased by 110%,
compared with just 9% for psychotropic drugs as a whole. The benzodiazepines obviously completely replaced the barbiturates and
meprobamate as a treatment for anxiety. According to Greenblatt
and Shader (1978a), in the mid-1970s, in the USA at least, there was
what can only be described as a passion for these anxiolytic agents,
which were consumed on a regular basis by 1020% of adults in the

Western countries. Balter, Levine, and Manheimer (1974) provide

specic data for various countries, which conrm the percentage
of individuals who had used anxiolytics-sedatives on one or more
occasions. These gures amounted to 10% in Spain, 11% in Italy, 13%
in the Netherlands, 14% in Germany and the United Kingdom, 15%
in the USA and in Denmark, 16% in Sweden, and 17% in France and
Belgium. Between 1973 and 1975, the annual number of benzodiazepine prescriptions exceeded 80 million (Shader, Greenblatt, &
Balter, 1991).
According to some analysts, the great success of the benzodiazepines was due to the rst major marketing campaigns
undertaken by the pharmaceutical companies, and by HoffmannLaRoche in particular. These new drugs were positioned as effective
anxiolytic and hypnotic agents which had a much more acceptable secondary effects prole compared to the classic tranquilisers,
and an insignicant risk of addiction providing that they were consumed at the prescribed doses, and a high level of safety, even
in cases of overdose in patients attempting suicide. The medical establishment was so rmly convinced of these ndings that
the rst communications on benzodiazepine dependence did not
receive the attention they deserved. The rst case, concerning
chlordiazepoxide, appeared in the scientic literature in 1963,
three years after its clinical introduction (Greenblatt & Shader,
1978b). However, the general opinion was that cases of dependence on these anxiolytics were due to their consumption in
combination with other substances, and alcohol in particular. This
idea changed after the publication of the cross-over double-blind
study with a single patient by Andrew Winokur, Rickels, Grenblatt,
Snyder, and Schatz (1980). These authors conrmed symptoms of
diazepam withdrawal developed in a young man who had been taking diazepam in dosages of 1525 mg/day during a six-year period
after abrupt discontinuation of benzodiazepine.
After this boom, the decline of the benzodiazepines began in
the United Kingdom in the mid-1970s, with the famous LaRoche
Affair (Gossop, 1993). In 1973, the National Health Service of
the United Kingdom took legal action against the pharmaceutical
company after a report from the Monopolies Commission, which
showed the high cost to the government of mass consumption
of diazepam and chlordiazepoxide. The British Government asked
HoffmanLaRoche to repay part of the costs generated by this
problem. Despite the legal action taken by the company against
the British Government, it had to pay almost four million pounds
to the National Health Service. Similar actions began in various
other European countries. In the following years, the idea gathered force, often supported by the mass media, of a medicalization
and tranquillization of everyday life and society (Tyrer, 1974).
Even renowned British clinicians, such as Malcolm Lader and Peter
Tyrer, echoed the opinion on this problem in mass circulation articles entitled respectively Benzodiazepines: the opium of the masses
(Lader, 1978) and The benzodiazepine bonanza (Tyrer, 1974), as well
as the famous rock group The Rolling Stones, who composed a
song about the widespread tranquiliser consumption, especially by
women, entitled Mothers Little Helper (1966). Likewise, the increase
in consumption of benzodiazepines in the USA was so marked in
the early 1970s that the North American media launched a campaign to discredit these drugs, which they contemptuously labeled
tranquillizing agents and addictive drugs. Medical and social
alarm heightened to the point that the FDA included the benzodiazepines on its list of controlled substances (Schedule IV). The
results of this measure were conclusive, as benzodiazepine prescriptions fell from 100 million units in 1975, when the measure
was introduced, to 70 million in 1979 (Rickels, 1980). Using the
same approach, in February 1984, the United Nations Commission
on Narcotic Drugs declared the benzodiazepines to be controlled
substances, at the request of the World Health Organization (WHO),
which after many years of deliberation had concluded that the ben-

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zodiazepines had the capacity to create a state of dependence and

depression of the central nervous system which leads to distortions
in motor function, behavior and personality.
These controls were tightened even further in some North
American states, such as New York, where on 1 January 1989 the
regulatory authority implemented the Triplicate Prescription Program (Rado, 1989), which restricted the prescription of these agents
even further, and made them subject to the same control measures
as other drugs, including opiates, barbiturates and amphetamines.
This triple prescription program involved one copy being sent to
the New York State Department of Health, another copy being kept
by the prescribing physician and another by the dispensing pharmacy. Furthermore, the program of treatment with the prescribed
medicine was limited to a maximum of 30 days. Obviously, all these
administrative obstacles led to a signicant reduction in benzodiazepine consumption (48% for anxiolytic benzodiazepines and
50% for hypnotic benzodiazepines compared to the previous year
or the measure coming into force) which was due not only to the
bureaucratic obstacles in themselves, but also to physicians reluctance to be classied as problem clinics by the authorities (with
the subsequent effect on their professional reputation), as well as
reluctance among patients, who were placed in an uncomfortable
situation as users of a medication subject to special supervision
(Shader et al., 1991).
However, the governments regulation of benzodiazepine prescriptions was subject to extensive response and discussion, not
only within the medical community, but also by ofcial institutions,
such as the USA National Institute of Drug Abuse, and scientic
societies including the American College of Neuropsychopharmacology. By way of an example, Shader et al. (1991) point out that
the implementation of the Triplicate Prescription Program in New
York state created more risks than benets, as while the prescription of benzodiazepines fell by half in 1989 compared to 1988, a
very signicant proportion of the prescriptions were transferred
to other less effective and much more dangerous pharmacological groups, such as intermediate-acting barbiturates, meprobamate
and other classic non-benzodiazepine hypnotics (chloral hydrate,
ethchlorvynol, glutethimide, etc.). Prescriptions of these drugs
increased by 27%, 129% and 87% respectively in the same timeframe. Data provided by the New York City Poison Control Center,
which received 2% fewer calls due to secondary problems arising
from benzodiazepine consumption between 1988 and 1989, but
30% more related to hypnotics and non-benzodiazepine sedatives
(Maddaloni, Hoffman, Wiper, & Weisman, 1990), are proof of this.
For Shader et al. (1991), implementation of control measures on
benzodiazepine prescriptions like the one mentioned above, as well
as leading to an obvious worsening of the quality of life of patients
complaining of anxiety disorders, was a deliberate forgetting of
more than three decades of clinical and scientic experience with
these substances.
Meanwhile, epidemiological studies that attempted to analyse
the real incidence of benzodiazepine dependence and the withdrawal syndrome increased rapidly from the early 1980s onwards.
Tyrer (1989) calculated that between 27% and 45% of British consumers of these drugs could be dependent, which would be over 1
million people who used these anxyolitics for at least one year in the
1980s. Some authors even talked about an epidemic of alarming
proportions (Lader, 1981). Simultaneously, and in society at large,
the term dependence was often replaced by the term addiction, which had much more dangerous connotations and to a large
extent contributed to creating the benzodiazepines bad reputation.
A classic example was the campaign promoted by the Public Citizen Health Group in the USA, which culminated in publication of
the book Stopping Valium (Bargmann, Wolfe, & Levin, 1982), which
stated that addiction to diazepam was a very serious problem
that could affect 1.5 million consumers, including patients that only

559

used it for less than a month. Another example was the campaign
promoted by some audiovisual media in the United Kingdom, such
as the BBC programme Panorama in 1991, which ended with the
suspension of the authorisation to market triazolam (The Halcion
case) (Bury, 1996).
Another problem which accentuated the disrepute of the benzodiazepines, and which was added to the mass consumption
of these drugs in banal nervous pathology, was their erroneous
use in numerous processes unrelated to their potential indications, and especially in combination, as well as the increase in
self-medication and deliberate overdoses. All these problems were
discussed at a very early stage in an editorial of the prestigious
journal Lancet, in 1973 (Editorial, 1973), and subsequently in a
report by the United Kingdoms Advisory Council on the Misuse of
Drugs, dated 1982. Numerous reports, articles, etc., followed in the
subsequent years, warning of the dangers of abuse and concomitant administration of benzodiazepines. In an interesting study,
Serfaty and Marteston (1993) analysed the cases of deaths directly
attributable to benzodiazepine consumption in Great Britain in the
1980s. During this period, there were 1576 deaths attributed to
benzodiazepines (56.5% associated to just one substance; 37.5%
to concomitant administration with alcohol; 6% attributed to a
combination of benzodiazepines with or without alcohol). 53.8%
of the deaths were suicides, 20.4% were fatal accidents, and the
cause of 25.8% of the deaths was not determined. As the number of prescriptions for benzodiazepines between 1980 and 1989
was 265.5 million, the number of deaths per million prescriptions
was 5.9. However, these gures were similar to those obtained
for other psychotropic agents, such as some tricyclic antidepressants (amitriptyline, dothiepin) and lower than those observed
with analgesics-antiinammatories, such as salicylates and paracetamol.
Fortunately, this group of anxiolytic drugs appears to have
entered a period of scientic and commercial stability since the
mid-1990s, with the gradual implementation of various guides
for the rational use of benzodiazepines. According to the British
National Institute for Health and Clinical Excellence, benzodiazepines are associated with fewer favorable outcomes than other
treatment options such as selective serotonin reuptake inhibitors
(SSRI), and, although the evidence for its efcacy is good in many
anxiety disorders, these agents are currently considered to be
second-line treatment because of their abuse potential. However,
some authors therefore point out that the rationale for the shift
from benzodiazepines to SSRIs is insufcient. Berney, Halperin,
Tango, Daeniker-Dayer, and Schulz (2008), in a systematic review
of controlled trials on anxiety disorders treatment, show that there
is no evidence of new antidepressants being superior to benzodiazepines, and they conclude that the major change of prescribing
pattern from benzodiazepines to newer antidepressants in anxiety
disorders has occurred in absence of comparative data of high level
of proof. Other authors have recently quoted this topic as one of
the best examples of a major change in patters of prescribing in
psychiatry without sufcient evidence (Fava, 2010).

6. Contributions of the benzodiazepines to the history of

biological psychiatry
Clinical breakthroughs in the elds of psychopharmacology for
anxiety in the last 50 years, beginning with meprobamate and
continuing with the benzodiazepines, have been highly important,
although not denitive. These pharmacological agents, mainly the
benzodiazepines, enabled truly effective treatment for the rst time
of the minor forms of mental disorders, improved the quality
of scientic methodology in clinical research, especially in terms
of objective measurement instruments, and showed the need for

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noz et al. / Journal of Anxiety Disorders 25 (2011) 554562

a new nosology. In this sense, must be mentioned that methodology in psychopharmacological research beneted greatly from
methodological advances introduced previously in the eld of psychotherapy research, thanks to the works of authors such as Michel
Hersen (Barlow & Hersen, 1973; Eisler, Hersen, Miller, & Wooten,
1973; Hersen, 1979, 1988). Similarly, with introduction of the psychotropic drugs and the randomised clinical trials in the 1950s,
was necessary to develop a suitable method for the evaluation of
the clinical effects of these agents. Thus were born the rating scales,
especially useful in the study of anxiety disorders (see the recent
review by Bech, 2009).
However, the greatest contribution of these drugs was enabling
the development, based on neurobiochemical approaches, of new
etiopathogenic theories on psychiatric pathologies, in general, and
anxiety disorders in particular (lamo et al., 1998).
Before the rst biochemistry-based theories on anxiety were
formulated, morphological hypotheses dating from the rst half of
the 20th century were used to explain the action mechanism of
tranquilising or ataraxic agents. According to these theories, these
drugs acted by blocking thalamic and hypothalamic regions of preference.
The rst observations on the presumable action mechanism
of benzodiazepines were made in 1967, when it was observed
that diazepam had an inhibitor action on the spinal column of
cats (Schmidt, Vogel, & Zimmermann, 1967), although at that
point it was impossible to identify the specic locus of action
of these agents. However, the benzodiazepines discovery process simultaneously made considerable progress in the eld of the
neurosciences in the intimate mechanisms transmitting nervous
information, and various possible substances were suggested as

neurotransmitters (Lpez-Munoz
& lamo, 2009c). One of these,
subsequently permanently linked to the benzodiazepines, was
gamma-aminobutyric acid (GABA). The presence of GABA in the
central nervous system was communicated simultaneously in 1950
by two research groups (Awapara, Landua, Fuerst, & Seale, 1950;
Roberts & Frankel, 1950), who used new chromatographic techniques to identify it. In subsequent years, Allan Elliott, Ernst

Florey, and Elizabeth Florey, at the Montreal Neurological Institute (Canada), described a cerebral factor in cow brain extracts,
which they called factor I, which was able to inhibit convulsions
induced by vitamin B6 deciency (Dupont, 1999). Finally, this group
identied factor I as GABA in 1956 (Bazemore, Elliott, & Florey,
1956), and its inhibitor actions at synaptic level were quickly conrmed (Kufer & Edwards, 1958). However, the incontrovertible
demonstration of the neurotransmission role of GABA in the central
nervous system of vertebrates did not occur until the 1970s, thanks
to the work of Leslie L. Iversen, of the Department of Pharmacology
at the University of Cambridge (Bloom & Iversen, 1971).
During the early 1970s, two research groups, led respectively
by Willy E. Haefely (director of the Preclinical Research Department at F. Hoffmann-La Roche Ltd. in Basel, Switzerland) and
Erminio Costa (Head of the Preclinical Pharmacology Laboratory
of the NIMH at St. Elizabeth Hospital, Washington, USA), independently came to the conclusion that the action mechanism of
the benzodiazepines was closely related to the effects of GABA,
the most important central inhibitory neurotransmitter, as these
anxiolytic agents improved neurotransmission in the GABAergic
synapses, thanks to the increased binding between GABA and its
post-synaptic receptors (Costa & Greengard, 1975; Polc, Mohler &
Haefely, 1974). A second historical milestone in the knowledge of
the action mechanisms of anxiolytic agents occurred in 1977. It was
possible to identify the loci of the neuronal membranes marked
with benzodiazepines in rats using radioligand techniques. A population of high afnity binding loci marked with [3 H]-diazepam
was located which had the pharmacological properties compatible with the denition of a receptor (Braestrud, Albreschtsen, &
Squires, 1977; Mhler & Okada, 1977). The presence of these receptors led to the assumption that natural substances able to bind to
them physiologically must exist, and these substances were called
endogenous ligands. Of particular importance in this respect was
the DBI (diazepam binding inhibitor), isolated by the Costa group
in 1978 (Guidotti, Toffano, & Costa, 1978).
Finally, the last major pharmacological breakthough in terms of
the action mechanism of the anxiolytics was the discovery that the

Fig. 6. GABA/benzodiazepinechlorine ionophore channel receptor complex, with its 5 subunits and the action loci of GABA and the benzodiazepines (A). Numerous substances
act on this receptor complex (B), modifying the conductance of chlorine towards the interior of the neuron. BZDs (benzodiazepines); DBI (diazepam binding inhibitor); -CB
(-carbolines).

F. Lpez-Mu
noz et al. / Journal of Anxiety Disorders 25 (2011) 554562

receptors for benzodiazepines and for GABA were closely linked,

forming a supramolecular complex from the functional point of
view, which has been called the GABA/benzodiazepine receptor
complex, a complex which also includes a channel (ionophore) for
the chlorine ions and other binding points for various substances:
picrotoxin-type molecules and barbiturate-type molecules (Fig. 6).
As a result, this GABAergic receptor consists of a genetic superfamily of ionic channels associated to receptors, arranged in the
neuronal membrane. Each of these elements is able to interact
alosterically with the others and thereby modify the afnity for
their binding sites of the substances concerned, and the inhibitor or
facilitator action of the opening of the chlorine channel (Richards,
Schoch, & Weise, 1991). The benzodiazepines act on the GABAA
receptor complex by increasing the afnity of GABA for its receptor, which leads to greater frequency of opening of the chlorine
channel and consequently a greater inhibitory effect of each GABA
molecule (Dubovsky, 1993). As a result, the benzodiazepines boost
the actions of GABA, leading to anxiolysis, muscle relaxation, anticonvulsant activity and sedation.
Histories of the benzodiazepines and GABA have therefore
always been interlinked since the late 1960s, and the discovery of
their saturable high afnity receptor complex in 1977 (Braestrud
et al., 1977; Mhler & Okada, 1977) opened the doors to todays
scientic knowledge on the biochemical foundations of anxiety
(Venault & Chapouthier, 2007).
7. Epilogue
Origins of the discovery of benzodiazepines were dened not
only by luck, but also by numerous errors in approach, as explicitly
recalled by Lowell Randall: the BZ molecule [i.e., chlordiazepoxide] had a difcult birth. The chemist made it by accident while
preparing an entirely different series of compounds. Discovery of
the pharmacological effects resulted from screening for central nervous activity by relatively crude methods which were designed to
test hundreds of compounds annually. . . Initial testing in human
subjects failed because of the selection of the wrong type of patient
and the wrong doses (Randall, 1983). In any event, the story of
Leo Sternbach and chlordiazepoxide, as Cohen says, contains all
the elements of drama that have characterized so many historical
medical discoveries (Cohen, 1984): exploration of the unknown,
disappointment and disillusionment, abandonment of the project,
optimism due to data from incipient clinical trials and conrmation
of properties superior to those of existing drugs.
However, it should be borne in mind that the history of science is part of the history of society in general, and that scientic
discoveries are made within a framework of very specic cultural
trends and beliefs (Nuss & Sanger, 2007). The advent of the benzodiazepines must therefore be analysed not only as a result of
scientic coincidence, but also from a broader cultural perspective,
in which the dominant concepts related to the cause and treatment
of states of anxiety were changing. Without this cultural change,
the important pharmacological discoveries that were made in the
1950s would probably never have been so quickly accepted by the
medical community.
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