Diazepam

Diazepam
Systematic (IUPAC) name
7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one
Clinical data
Pronunciation /daɪˈæzᵻpæm/
Trade names Valium and many others
AHFS/Drugs.com monograph
MedlinePlus a682047
Pregnancy
category
  • AU: C
  • US: D (Evidence of risk)
Dependence
liability		 Moderate
Addiction
liability		 Moderate[1][2]
Routes of
administration		 Oral, IM, IV, suppository
Legal status
Legal status
Pharmacokinetic data
Bioavailability 93–100%
Metabolism Hepatic—CYP2B6 (minor route) to desmethyldiazepam, CYP2C19 (major route) to inactive metabolites, CYP3A4 (major route) to desmethyldiazepam
Biological half-life 20–100 hours (36–200 hours for main active metabolite desmethyldiazepam)
Excretion Renal
Identifiers
CAS Number 439-14-5 YesY
ATC code N05BA01 (WHO)
PubChem CID 3016
IUPHAR/BPS 3364
DrugBank DB00829 N
ChemSpider 2908 YesY
UNII Q3JTX2Q7TU YesY
KEGG D00293 YesY
ChEBI CHEBI:49575 YesY
ChEMBL CHEMBL12 YesY
Chemical data
Formula C16H13ClN2O
Molar mass 284.7 g/mol
 NYesY (what is this?)  (verify)

Diazepam, first marketed as Valium, is a medication of the benzodiazepine family that typically produces a calming effect. It is commonly used to treat a range of conditions including anxiety, alcohol withdrawal syndrome, benzodiazepine withdrawal syndrome, muscle spasms, seizures, trouble sleeping, and restless legs syndrome.[3] It may also be used to cause memory loss during certain medical procedures.[4][5] It can be taken by mouth, inserted into the rectum, injected into muscle, or injected into a vein.[5] When given into a vein, effects begin in one to five minutes and last up to an hour.[5] By mouth, effects may take 40 minutes to begin.[6]

Common side effects include sleepiness and trouble with coordination.[5] Serious side effects are rare.[3] They include suicide, decreased breathing, and an increased risk of seizures if used too frequently in those with epilepsy.[3][5] Occasionally excitement or agitation may occur.[7][8] Long term use can result in tolerance, dependence, and withdrawal symptoms on dose reduction. Abrupt stopping after long term use can be potentially dangerous.[3] After stopping, cognitive problems may persist for six months or longer.[7] They are not recommended during pregnancy or breastfeeding.[5] Its mechanism of action is by increasing the effect of the neurotransmitter gamma-Aminobutyric acid (GABA).[7]

Diazepam was first synthesized by Leo Sternbach, and was first manufactured by Hoffmann-La Roche. It has been one of the most frequently prescribed medications in the world since its launch in 1963. In the United States it was the highest selling medication between 1968 and 1982, selling more than two billion tablets in 1978 alone. In 1985 the patent ended, and there are now more than 500 brands available on the market.[3] Diazepam is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[9] The wholesale cost is about 0.01 USD per dose as of 2014.[10] In the United States it is about 0.40 USD per dose.[5]

Medical uses

Diazepam tablets (2, 5, and 10 mg)

Diazepam is mainly used to treat anxiety, insomnia, panic attacks and symptoms of acute alcohol withdrawal. It is also used as a premedication for inducing sedation, anxiolysis, or amnesia before certain medical procedures (e.g., endoscopy).[11][12] Diazepam is the drug of choice for treating benzodiazepine dependence with its long duration of action allowing easier dose reduction. Benzodiazepines have a relatively low toxicity in overdose.[7]

Diazepam has a number of uses including:

Dosages should be determined on an individual basis, depending on the condition being treated, severity of symptoms, patient body weight, and any other conditions the person may have.[18]

Seizures

Intravenous diazepam or lorazepam are first-line treatments for status epilepticus.[7][20] However, lorazepam has advantages over diazepam, including a higher rate of terminating seizures and a more prolonged anticonvulsant effect.[21] Diazepam is rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects usually develops within six to 12 months of treatment, effectively rendering it useless for that purpose.[18][22]

The anticonvulsant effects of diazepam can help in the treatment of seizures due to a drug overdose or chemical toxicity as a result of exposure to sarin, VX, or soman (or other organophosphate poisons), lindane, chloroquine, physostigmine, or pyrethroids.[18][23]

It is sometimes used intermittently for the prevention of febrile seizures that may occur in children under five years of age.[7] This use; however, is not typically recommended as the benefits are small and side effects are common.[24] Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup of individuals with treatment-resistant epilepsy benefit from long-term benzodiazepines, and for such individuals, clorazepate has been recommended due to its slower onset of tolerance to the anticonvulsant effects.[7]

Other

Diazepam is used for the emergency treatment of eclampsia, when IV magnesium sulfate and blood-pressure control measures have failed.[25][26] Benzodiazepines do not have any pain-relieving properties themselves, and are generally recommended to avoid in individuals with pain.[27] However, benzodiazepines such as diazepam can be used for their muscle-relaxant properties to alleviate pain caused by muscle spasms and various dystonias, including blepharospasm.[28][29] Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.[30] Baclofen[31] or tizanidine is sometimes used as an alternative to diazepam.

Availability

Diazepam is marketed in over 500 brands throughout the world.[32] It is supplied in oral, injectable, inhalation, and rectal forms.[18][33][34]

The United States military employs a specialized diazepam preparation known as Convulsive Antidote, Nerve Agent (CANA), which contains diazepam. One CANA kit is typically issued to service members, along with three Mark I NAAK kits, when operating in circumstances where chemical weapons in the form of nerve agents are considered a potential hazard. Both of these kits deliver drugs using autoinjectors. They are intended for use in "buddy aid" or "self aid" administration of the drugs in the field prior to decontamination and delivery of the patient to definitive medical care.[35]

Contraindications

Use of diazepam should be avoided, when possible, in individuals with:[36]

Caution

Adverse effects

Adverse effects of benzodiazepines such as diazepam include anterograde amnesia and confusion (especially pronounced in higher doses) and sedation. The elderly are more prone to adverse effects of diazepam, such as confusion, amnesia, ataxia, and hangover effects, as well as falls. Long-term use of benzodiazepines such as diazepam is associated with drug tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome.[7] Like other benzodiazepines, diazepam can impair short-term memory and learning of new information. While benzodiazepine drugs such as diazepam can cause anterograde amnesia, they do not cause retrograde amnesia; information learned before using benzodiazepines is not impaired. Tolerance to the cognitive-impairing effects of benzodiazepines does not tend to develop with long-term use, and the elderly are more sensitive to them.[43] Additionally, after cessation of benzodiazepines, cognitive deficits may persist for at least six months; it is unclear whether these impairments take longer than six months to abate or if they are permanent. Benzodiazepines may also cause or worsen depression.[7] Infusions or repeated intravenous injections of diazepam when managing seizures, for example, may lead to drug toxicity, including respiratory depression, sedation and hypotension. Drug tolerance may also develop to infusions of diazepam if it is given for longer than 24 hours.[7] Adverse effects such as sedation, benzodiazepine dependence, and abuse potential limit the use of benzodiazepines.[44]

Diazepam has a range of side effects common to most benzodiazepines, including:

Less commonly, paradoxical side effects can occur, including nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in libido, and in some cases, rage and violence. These adverse reactions are more likely to occur in children, the elderly, and individuals with a history of drug or alcohol abuse and or aggression.[7][47][48][49] Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.[50] Very rarely dystonia can occur.[51]

Diazepam may impair the ability to drive vehicles or operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants.[17]

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.[52]

Patients with severe attacks of apnea during sleep may suffer respiratory depression (hypoventilation), leading to respiratory arrest and death.

Diazepam in doses of 5 mg or more causes significant deterioration in alertness performance combined with increased feelings of sleepiness.[53]

Tolerance and dependence

Diazepam, as with other benzodiazepine drugs, can cause tolerance, physical dependence, substance use disorder, and benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms similar to those seen during barbiturate or alcohol withdrawal. The higher the dose and the longer the drug is taken, the greater the risk of experiencing unpleasant withdrawal symptoms.

Withdrawal symptoms can occur from standard dosages and also after short-term use, and can range from insomnia and anxiety to more serious symptoms, including seizures and psychosis. Withdrawal symptoms can sometimes resemble pre-existing conditions and be misdiagnosed. Diazepam may produce less intense withdrawal symptoms due to its long elimination half-life.

Benzodiazepine treatment should be discontinued as soon as possible by a slow and gradual dose reduction regimen.[7][54] Tolerance develops to the therapeutic effects of benzodiazepines; for example tolerance occurs to the anticonvulsant effects and as a result benzodiazepines are not generally recommended for the long-term management of epilepsy. Dose increases may overcome the effects of tolerance, but tolerance may then develop to the higher dose and adverse effects may increase. The mechanism of tolerance to benzodiazepines includes uncoupling of receptor sites, alterations in gene expression, down-regulation of receptor sites, and desensitisation of receptor sites to the effect of GABA. About one-third of individuals who take benzodiazepines for longer than four weeks become dependent and experience withdrawal syndrome on cessation.[7]

Differences in rates of withdrawal (50–100%) vary depending on the patient sample. For example, a random sample of long-term benzodiazepine users typically finds around 50% experience few or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups show a higher rate of notable withdrawal symptoms, up to 100%.[55]

Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.[56] Diazepam is therefore only recommended for short-term therapy at the lowest possible dose owing to risks of severe withdrawal problems from low doses even after gradual reduction.[57] The risk of pharmacological dependence on diazepam is significant, and patients experience symptoms of benzodiazepine withdrawal syndrome if it is taken for six weeks or longer.[58] In humans, tolerance to the anticonvulsant effects of diazepam occurs frequently.[59]

Dependence

Improper or excessive use of diazepam can lead to dependence.[60] At a particularly high risk for diazepam misuse, abuse or dependence are:

Patients from the aforementioned groups should be monitored very closely during therapy for signs of abuse and development of dependence. Therapy should be discontinued if any of these signs are noted, although if dependence has developed, therapy must still be discontinued gradually to avoid severe withdrawal symptoms. Long-term therapy in these people is not recommended.[17][61]

People suspected of being dependent on benzodiazepine drugs should be very gradually tapered off the drug. Withdrawals can be life-threatening, particularly when excessive doses have been taken for extended periods of time. Equal prudence should be used whether dependence has occurred in therapeutic or recreational contexts.

Overdose

An individual who has consumed too much diazepam typically displays one or more of these symptoms in a period of approximately four hours immediately following a suspected overdose:[17][64]

Although not usually fatal when taken alone, a diazepam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. The antidote for an overdose of diazepam (or any other benzodiazepine) is flumazenil (Anexate). This drug is only used in cases with severe respiratory depression or cardiovascular complications. Because flumazenil is a short-acting drug, and the effects of diazepam can last for days, several doses of flumazenil may be necessary. Artificial respiration and stabilization of cardiovascular functions may also be necessary. Though not routinely indicated, activated charcoal can be used for decontamination of the stomach following a diazepam overdose. Emesis is contraindicated. Dialysis is minimally effective. Hypotension may be treated with levarterenol or metaraminol.[17][18][64][65]

The oral LD50 (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.[17] D. J. Greenblatt and colleagues reported in 1978 on two patients who had taken 500 and 2000 mg of diazepam, respectively, went into moderately deep comas, and were discharged within 48 hours without having experienced any important complications, in spite of having high concentrations of diazepam and its metabolites desmethyldiazepam, oxazepam, and temazepam, according to samples taken in the hospital and as follow-up.[66]

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.[65][67]

Interactions

If diazepam is administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that potentiate the effects of diazepam, such as barbiturates, phenothiazines, opioids, and antidepressants.[17]

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. No evidence would suggest diazepam alters its own metabolism with chronic administration.[18]

Agents with an effect on hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. These interactions would be expected to be most significant with long-term diazepam therapy, and their clinical significance is variable.[18]

Pharmacology

10 mg Valium.

Diazepam is a long-acting "classical" benzodiazepine. Other classical benzodiazepines include chlordiazepoxide, clonazepam, lorazepam, oxazepam, nitrazepam, temazepam, flurazepam, bromazepam, and clorazepate.[75] Diazepam has anticonvulsant properties.[76] Diazepam has no effect on GABA levels and no effect on glutamate decarboxylase activity, but has a slight effect on gamma-aminobutyric acid transaminase activity. It differs from some other anticonvulsive drugs with which it was compared.[77] Benzodiazepines act via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.[78]

Diazepam inhibits acetylcholine release in mouse hippocampal synaptosomes. This has been found by measuring sodium-dependent high-affinity choline uptake in mouse brain cells in vitro, after pretreatment of the mice with diazepam in vivo. This may play a role in explaining diazepam's anticonvulsant properties.[79]

Diazepam binds with high affinity to glial cells in animal cell cultures.[80] Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.[81] Diazepam also decreases prolactin release in rats.[82]

Mechanism of action

See also: Benzodiazepine

Benzodiazepines are positive allosteric modulators of the GABA type A receptors (GABAA). The GABAA receptors are ligand-gated chloride-selective ion channels that are activated by GABA, the major inhibitory neurotransmitter in the brain. Binding of benzodiazepines to this receptor complex promotes binding of GABA, which in turn increases the total conduction of chloride ions across the neuronal cell membrane. This increased chloride ion influx hyperpolarizes the neuron's membrane potential. As a result, the difference between resting potential and threshold potential is increased and firing is less likely.

The GABAA receptor is a heteromer composed of five subunits, the most common ones being two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). GABAA receptors containing the α1 subunit mediate the sedative, the anterograde amnesic, and partly the anticonvulsive effects of diazepam. GABAA receptors containing α2 mediate the anxiolytic actions and to a large degree the myorelaxant effects. GABAA receptors containing α3 and α5 also contribute to benzodiazepines myorelaxant actions, whereas GABAA receptors comprising the α5 subunit were shown to modulate the temporal and spatial memory effects of benzodiazepines.[83]

Diazepam appears to act on areas of the limbic system, thalamus, and hypothalamus, inducing anxiolytic effects. Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.[84]

The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.[85]

The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.[86]

Pharmacokinetics

Diazepam can be administered orally, intravenously (must be diluted, as it is painful and damaging to veins), intramuscularly (IM), or as a suppository.[18]

When administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is one to five minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to one hour for both routes of administration.[46] The bioavailability after oral administration is 100%, and 90% after rectal administration. Peak plasma levels occur between 30 and 90 minutes after oral administration and between 30 and 60 minutes after intramuscular administration; after rectal administration, peak plasma levels occur after 10 to 45 minutes. Diazepam is highly protein-bound, with 96 to 99% of the absorbed drug being protein-bound. The distribution half-life of diazepam is two to 13 minutes.[7]

When diazepam is administered IM, absorption is slow, erratic, and incomplete.[11]

Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood–brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam quickly build to a high concentration in the body (mainly in adipose tissue), far in excess of the actual dose for any given day.[7][18]

Diazepam is stored preferentially in some organs, including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the neonate, and withdrawal of diazepam during pregnancy and breast feeding is clinically justified.[87]

Diazepam undergoes oxidative metabolism by demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) and glucuronidation in the liver as part of the cytochrome P450 enzyme system. It has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Its other active metabolites include the minor active metabolites temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug. Diazepam has a biphasic half-life of about one to three days, and two to seven days for the active metabolite desmethyldiazepam.[7] Most of the drug is metabolised; very little diazepam is excreted unchanged.[18] The elimination half-life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly, which may result in prolonged action, as well as accumulation of the drug during repeated administration.[88]

Physical and chemical properties

Diazepam occurs as solid white or yellow crystals with a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists it as being very slightly soluble in water, soluble in alcohol, and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 ethyl alcohol, 1 in 2 of chloroform, 1 in 39 ether, and practically insoluble in water. The pH of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf life of five years for oral tablets and three years for IV/IM solutions.[18] Diazepam should be stored at room temperature (15–30 °C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.[33]

Diazepam can absorb into plastics, so liquid preparations should not be kept in plastic bottles or syringes, etc. As such, it can leach into the plastic bags and tubing used for intravenous infusions. Absorption appears to depend on several factors, such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and does not dissolve.[33]

Detection in body fluids

Diazepam may be quantified in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or to assist in a medicolegal death investigation. Blood or plasma diazepam concentrations are usually in a range of 0.1–1.0 mg/l in persons receiving the drug therapeutically, 1–5 mg/l in those arrested for impaired driving, and 2–20 mg/l in victims of acute overdose. Most commercial immunoassays for the benzodiazepine class of drugs cross-react with diazepam, but confirmation and quantitation are usually performed using chromatographic techniques.[89][90][91]

History

Diazepam was the second benzodiazepine invented by Dr. Leo Sternbach of Hoffmann-La Roche at the company's Nutley, New Jersey, facility[92] following chlordiazepoxide (Librium), which was approved for use in 1960. Released in 1963 as an improved version of Librium, diazepam became incredibly popular, helping Roche to become a pharmaceutical industry giant. It is 2.5 times more potent than its predecessor, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.[93]

The benzodiazepines gained popularity among medical professionals as an improvement over barbiturates, which have a comparatively narrow therapeutic index, and are far more sedative at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or opioids).[65] Benzodiazepine drugs such as diazepam initially had widespread public support, but with time the view changed to one of growing criticism and calls for restrictions on their prescription.[94]

Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.[93] Diazepam, along with oxazepam, nitrazepam and temazepam, represents 82% of the benzodiazepine market in Australia.[95] While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, for example, forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.[16]

Society and culture

Recreational use

Diazepam is a drug of potential abuse and can cause drug dependence. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam.[96][97] A single dose of diazepam modulates the dopamine system in similar ways to how morphine and alcohol modulate the dopaminergic pathways.[98] Between 50 and 64% of rats will self-administer diazepam.[99] Diazepam has been shown to be able to substitute for the behavioural effects of barbiturates in a primate study.[100] Diazepam has been found as an adulterant in heroin.[101]

Diazepam drug misuse can occur either through recreational misuse where the drug is taken to achieve a high or when the drug is continued long term against medical advice.[102]

Sometimes, it is used by stimulant users to "come down" and sleep and to help control the urge to binge.[103]

A large-scale study in the US, conducted by SAMHSA, using data from 2011, determined benzodiazepines were present in 28.7% of emergency department visits involving nonmedical use of pharmaceuticals. In this regard, benzodiazepines are second only to opiates, the study found in 39.2% of visits. About 29.3% of drug-related suicide attempts involve benzodiazepines, making them the most frequently represented class in drug-related suicide attempts. Males abuse benzodiazepines as commonly as females.[104]

Benzodiazepines, including diazepam, nitrazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.[105]

Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden, and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range, suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone.[89] In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found in 87% of cases. Diazepam was the most commonly detected benzodiazepine.[106]

Legal status

Diazepam is regulated in most countries as a prescription drug:

Judicial executions

The states of California and Florida offer diazepam to condemned inmates as a pre-execution sedative as part of their lethal injection program, although the state of California has not executed a prisoner since 2006.[111][112]

Veterinary uses

Diazepam is used as a short-term sedative and anxiolytic for cats and dogs,[113] sometimes used as an appetite stimulant.[113][114] It can also be used to stop seizures in dogs and cats.[115][116]

References

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  2. ↑ Ries, Richard K. (2009). Principles of addiction medicine. (4 ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 106. ISBN 9780781774772.
  3. 1 2 3 4 5 Calcaterra, NE; Barrow, JC (16 April 2014). "Classics in chemical neuroscience: diazepam (valium).". ACS Chemical Neuroscience 5 (4): 253–60. doi:10.1021/cn5000056. PMID 24552479.
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