Diazepam: Difference between revisions

{{Drugbox

| verifiedrevid = 418699380

| IUPAC_name = 7-chloro-1,3-dihydro-<br />1-methyl-5-phenyl-<br />1,4-benzodiazepin-2(3''H'')-one

| image = Diazepam structure 2.svg

| width = 180

| image2 = Diazepam-from-xtal-3D-balls.png

| width2 = 180

| CASNo_Ref = {{cascite|correct|CAS}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = Q3JTX2Q7TU

| InChI = 1/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3

| smiles = CN1c2ccc(cc2C(=NCC1=O)c3ccccc3)Cl

| InChIKey = AAOVKJBEBIDNHE-UHFFFAOYAM

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 12

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C16H13ClN2O/c1-19-14-8-7-12(17)9-13(14)16(18-10-15(19)20)11-5-3-2-4-6-11/h2-9H,10H2,1H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = AAOVKJBEBIDNHE-UHFFFAOYSA-N

| CAS_number = 439-14-5

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2908

| ATC_prefix = N05

| ATC_suffix = BA01

| ATC_supplemental = {{ATC|N05|BA17}}

| ChEBI = 49575

| PubChem = 3016

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = APRD00642

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D00293

| C = 16 | H = 13 | Cl = 1 | N = 2 | O = 1

| molecular_weight = 284.7 g/mol

| molar_refractivity = 80.91 ± 0.5 cm³

| bioavailability = 93%

| metabolism = [[Liver|Hepatic]] - [[CYP2C19]]

| elimination_half-life = 20–100 hours (36-200 hours for main active metabolite [[desmethyldiazepam]])

| excretion = [[Kidney|Renal]]

| pregnancy_AU = C

| pregnancy_US = D

| legal_status = [[Schedule IV controlled substance|Schedule IV]] (International)

| legal_US = Schedule IV

| legal_AU = S4

| legal_CA = Schedule IV

| legal_UK = CD

| routes_of_administration = Oral, [[Intramuscular injection|IM]], [[Intravenous therapy|IV]], [[suppository]]

'''Diazepam''' ({{IPAc-en|icon|d|aɪ|ˈ|æ|z|ɨ|p|æ|m}}), first marketed as '''Valium''' ({{IPAc-en|icon|ˈ|v|æ|l|i|əm}}) by [[Hoffmann-La Roche]] is a [[benzodiazepine]] [[derivative (chemistry)|derivative]] [[drug]]. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating [[anxiety]], [[insomnia]], [[seizure]]s including [[status epilepticus]], [[muscle spasms]] (such as in cases of [[tetanus]]), [[restless legs syndrome]], [[alcohol withdrawal]], [[benzodiazepine withdrawal]] and [[Ménière's disease]]. It may also be used before certain medical procedures (such as [[endoscopy|endoscopies]]) to reduce tension and anxiety, and in some surgical procedures to induce [[amnesia]].<ref name="PubChem">{{cite web|author=|year= 2006|url=http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3016|title=Diazepam|work=[[PubChem]]| publisher=National Institute of Health: National Library of Medicine|accessdate= 2006-03-11}}</ref><ref name="NLM">{{cite web|author=|year=2006|url=http://www.nlm.nih.gov/cgi/mesh/2006/MB_cgi?mode=&term=Diazepam|title=Diazepam|work=Medical Subject Headings (MeSH)|publisher= National Library of Medicine|accessdate= 2006-03-10}}</ref> It possesses [[anxiolytic]], [[anticonvulsant]], [[hypnotic]], [[sedative]], [[skeletal muscle relaxant]], and [[amnestic]] properties.<ref>{{cite journal |author=Mandrioli, R., L. Mercolini, M.A. Raggi |title=Benzodiazepine metabolism: an analytical perspective |journal=Curr. Drug Metab. |volume=9 |issue=8 |pages=827–44 |year=2008 |month=October |pmid=18855614 |doi= 10.2174/138920008786049258|url=http://www.benthamdirect.org/pages/content.php?CDM/2008/00000009/00000008/0009F.SGM}}</ref> The pharmacological action of diazepam enhances the effect of the neurotransmitter [[GABA]] by binding to the benzodiazepine site on the [[GABAA receptor|GABA_A receptor]] leading to [[central nervous system]] depression.<ref name="Riss-2008"/>

Adverse effects of diazepam include [[anterograde amnesia]] (especially at higher doses) and [[sedation]] as well as [[paradoxical effects]] such as excitement, rage or worsening of seizures in epileptics. Benzodiazepines also can cause or worsen [[Major depression|depression]]. [[Long-term effects of benzodiazepines]] such as diazepam include [[drug tolerance|tolerance]], [[benzodiazepine dependence]] as well as a [[benzodiazepine withdrawal syndrome]] upon dose reduction; additionally after cessation of benzodiazepines [[cognitive]] deficits may persist for at least 6 months and may not fully return to normal, however it was suggested that longer than 6 months may be needed for recovery from some deficits.<ref name="Riss-2008"/> Diazepam also has abuse potential and can cause serious problems of addiction. Urgent action by National Governments to improve prescribing practices has been recommended.<ref name="Dièye-2006"/><ref name="Atack-2005"/>

Advantages of diazepam are a rapid onset of action and high efficacy rates which is important for managing acute seizures; benzodiazepines also have a relatively low toxicity in overdose.<ref name="Riss-2008"/> Diazepam is a core medicine in the [[World Health Organization]]'s "[[WHO Model List of Essential Medicines|Essential Drugs List]]", which is a list of minimum medical needs for a basic health care system.<ref name="essentialWHO">{{cite web | month = March | year = 2005 | url = http://whqlibdoc.who.int/hq/2005/a87017_eng.pdf | title = WHO Model List of Essential Medicines | format = PDF | publisher = World Health Organization | accessdate = 2006-03-12 }}</ref> Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past forty years. It was first synthesized by [[Leo Sternbach]].<ref>{{cite journal | author = L. H. Sternbach, E. Reeder, O. Keller, W. Metlesics | journal = [[J. Org. Chem.]] | year = 1961 | volume = 26 | issue = 11 | pages = 4488–4497 | doi = 10.1021/jo01069a069 | title = Quinazolines and 1,4-benzodiazepines III substituted 2-amino-5-phenyl-3H-1,4-benzodiazepine 4-oxides}}</ref>

==Medical uses==

[[Image:Diazepam(Valium) DOJ.jpg|thumb|Diazepam pills, (2mg, 5mg, and 10mg)]]

Diazepam is mainly used to treat [[anxiety]], [[insomnia]], 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]]).<ref name="DrugBank" /><ref name="Bråthen-2005">{{Cite journal | last1 = Bråthen | first1 = G. | last2 = Ben-Menachem | first2 = E. | last3 = Brodtkorb | first3 = E. | last4 = Galvin | first4 = R. | last5 = Garcia-Monco | first5 = JC. | last6 = Halasz | first6 = P. | last7 = Hillbom | first7 = M. | last8 = Leone | first8 = MA. | last9 = Young | first9 = AB. | title = EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force. | journal = Eur J Neurol | volume = 12 | issue = 8 | pages = 575–81 | month = Aug | year = 2005 | doi = 10.1111/j.1468-1331.2005.01247.x | pmid = 16053464 }}</ref>

Intravenous diazepam or [[lorazepam]] are first line treatments for [[status epilepticus]];<ref name="Riss-2008">{{Cite journal | last1 = Riss | first1 = J. | last2 = Cloyd | first2 = J. | last3 = Gates | first3 = J. | last4 = Collins | first4 = S. | title = Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. | url = http://www3.interscience.wiley.com/cgi-bin/fulltext/120119477/PDFSTART | format = PDF | journal = Acta Neurol Scand | volume = 118 | issue = 2 | pages = 69–86 | month = Aug | year = 2008 | doi = 10.1111/j.1600-0404.2008.01004.x | pmid = 18384456 }}</ref><ref>{{Cite journal | last1 = Walker | first1 = M. | title = Status epilepticus: an evidence based guide. | journal = BMJ | volume = 331 | issue = 7518 | pages = 673–7 | month = Sep | year = 2005 | doi = 10.1136/bmj.331.7518.673 | pmc = 1226249 | pmid = 16179702 }}</ref> However, [[lorazepam]] has advantages over diazepam including a higher rate of terminating seizures and a more prolonged anticonvulsant effect.<ref name="Prasad-2005">{{Cite journal | last1 = Prasad | first1 = K. | last2 = Al-Roomi | first2 = K. | last3 = Krishnan | first3 = PR. | last4 = Sequeira | first4 = R. | last5 = Prasad | first5 = Kameshwar | title = Anticonvulsant therapy for status epilepticus. | url = http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003723/pdf_fs.html | format = PDF | journal = Cochrane Database Syst Rev | issue = 4 | pages = CD003723 | month = October | year = 2005 | doi = 10.1002/14651858.CD003723.pub2 | pmid = 16235337 }}</ref> Diazepam is rarely used for the long-term treatment of [[epilepsy]] because tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for that purpose.<ref name="Inchem" /><ref>{{cite journal | last = Isojärvi | first = JI | coauthors = Tokola RA. | year = 1998 | month = December | title = Benzodiazepines in the treatment of epilepsy in people with intellectual disability | journal = J Intellect Disabil Res. | volume = 42 | issue = 1 | pages = 80–92 | pmid = 10030438 }}</ref> Diazepam is used for the emergency treatment of [[eclampsia]], when [[Intravenous therapy|IV]] [[magnesium sulfate]] and blood pressure control measures have failed.<ref>{{Cite journal | last1 = Kaplan | first1 = PW. | title = Neurologic aspects of eclampsia. | journal = Neurol Clin | volume = 22 | issue = 4 | pages = 841–61 | month = Nov | year = 2004 | doi = 10.1016/j.ncl.2004.07.005 | pmid = 15474770 }}</ref><ref>{{Cite journal | last1 = Duley | first1 = L. | title = Evidence and practice: the magnesium sulphate story. | journal = Best Pract Res Clin Obstet Gynaecol | volume = 19 | issue = 1 | pages = 57–74 | month = Feb | year = 2005 | doi = 10.1016/j.bpobgyn.2004.10.010 | pmid = 15749066 }}</ref> Benzodiazepines do not have any pain relieving properties of themselves and are generally recommended to be avoided in individuals with pain.<ref name="Zeilhofer-2009">{{Cite journal | last1 = Zeilhofer | first1 = HU. | last2 = Witschi | first2 = R. | last3 = Hösl | first3 = K. | title = Subtype-selective GABAA receptor mimetics--novel antihyperalgesic agents? | url = http://www.springerlink.com/content/u3555g26k736101p/fulltext.pdf | format = PDF | journal = J Mol Med | volume = 87 | issue = 5 | pages = 465–9 | month = May | year = 2009 | doi = 10.1007/s00109-009-0454-3 | pmid = 19259638 }}</ref> However, benzodiazepines such as diazepam can be used for their muscle relaxant properties to alleviate pain which is caused by [[muscle spasms]], caused by various dystonias, including [[blepharospasm]]<ref>{{cite journal |author=Mezaki T, Hayashi A, Nakase H, Hasegawa K |title=[Therapy of dystonia in Japan] |language=Japanese |journal=Rinsho Shinkeigaku |volume=45 |issue=9 |pages=634–42 |year=2005 |month=September |pmid=16248394 |doi= |url=}}</ref><ref>{{cite journal |author=Kachi T |title=[Medical treatment of dystonia] |language=Japanese |journal=Rinsho Shinkeigaku |volume=41 |issue=12 |pages=1181–2 |year=2001 |month=December |pmid=12235832 |doi= |url=}}</ref> Tolerance often develops to the muscle relaxant effects of benzodiazepines such as diazepam.<ref name=tdamobd2004>{{cite journal |author=Ashton H |title=The diagnosis and management of benzodiazepine dependence |journal=Curr Opin Psychiatry |volume=18 |issue=3 |pages=249–55 |year=2005 |pmid=16639148 |doi=10.1097/01.yco.0000165594.60434.84 |url=http://www.benzo.org.uk/amisc/ashdiag.pdf |format=PDF }}</ref> [[Baclofen]]<ref>{{cite journal |author=Mañon-Espaillat R, Mandel S |title=Diagnostic algorithms for neuromuscular diseases |journal=Clin Podiatr Med Surg |volume=16 |issue=1 |pages=67–79 |year=1999 |pmid=9929772 }}</ref> or [[tizanidine]] is sometimes used as an alternative to diazepam. Tizanidine has been found to be equally effective as other antispasmodic drugs and have superior tolerability than baclofen and diazepam.<ref name="Kamen-2008">{{Cite journal | last1 = Kamen | first1 = L. | last2 = Henney | first2 = HR. | last3 = Runyan | first3 = JD. | title = A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury. | journal = Curr Med Res Opin | volume = 24 | issue = 2 | pages = 425–39 | month = Feb | year = 2008 | doi = 10.1185/030079908X261113 | pmid = 18167175 }}</ref>

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 (nerve agent)|VX]], [[soman]] (or other [[organophosphate]] poisons; See [[#CANA]]), [[lindane]], [[chloroquine]], [[physostigmine]], or [[pyrethroid]]s<ref name="Inchem" /><ref>{{Cite journal | last1 = Bajgar | first1 = J. | title = Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. | journal = Adv Clin Chem | volume = 38 | issue = | pages = 151–216 | month = | year = 2004 | doi = 10.1016/S0065-2423(04)38006-6| pmid = 15521192 }}</ref> Diazepam is sometimes used intermittently for the prophylaxis of febrile seizures which occur as a result of a high fever in children and neonates under 5 years of age.<ref name="Riss-2008"/><ref>{{Cite journal | last1 = Karande | first1 = S. | title = Febrile seizures: a review for family physicians. | url = http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2007;volume=61;issue=3;spage=161;epage=172;aulast=Karande | journal = Indian J Med Sci | volume = 61 | issue = 3 | pages = 161–72 | month = Mar | year = 2007 | doi = 10.4103/0019-5359.30753| pmid = 17337819 }}</ref> Long-term use of diazepam for the management of epilepsy is not recommended; however, a subgroup individuals with treatment resistant epilepsy benefit from long-term benzodiazepines and for such individuals [[clorazepate]] has been recommended due to its slower onset of [[drug tolerance|tolerance]] to the anticonvulsant effects.<ref name="Riss-2008"/>

Diazepam has a broad spectrum of indications (most of which are off-label), including:

* Treatment of [[anxiety]], [[panic attacks]], and states of [[Psychomotor agitation|agitation]]<ref name="DrugBank" />

* Treatment of neurovegetative symptoms associated with [[Vertigo (medical)|vertigo]]<ref>{{cite journal |author=Cesarani A, Alpini D, Monti B, Raponi G |title=The treatment of acute vertigo |journal=Neurol. Sci. |volume=25 Suppl 1 |issue= |pages=S26–30 |year=2004 |month=March |pmid=15045617 |doi=10.1007/s10072-004-0213-8}}</ref>

* Treatment of the symptoms of alcohol, opiate and [[benzodiazepine withdrawal]]<ref name="DrugBank" /><ref>{{cite journal |author=Lader M, Tylee A, Donoghue J |title=Withdrawing benzodiazepines in primary care |journal=CNS Drugs |volume=23 |issue=1 |pages=19–34 |year=2009 |pmid=19062773 |doi= 10.2165/0023210-200923010-00002|url=}}</ref>

* Treatment of [[tetanus]], together with other measures of intensive-treatment<ref name=tetanus>{{cite journal | first = C. N. | last = Okoromah | coauthors = F. E. Lesi | year = 2004 | title = Diazepam for treating tetanus | journal = Cochrane database of systematic reviews (Online) | issue = 1 | pmid = 14974046 | doi = 10.1002/14651858.CD003954.pub2 | pages = CD003954}}</ref>

* Adjunctive treatment of spastic muscular [[paresis]] (para-/tetraplegia) caused by cerebral or [[spinal cord]] conditions such as [[stroke]], [[multiple sclerosis]], spinal cord injury (long-term treatment is coupled with other rehabilitative measures)<ref name="RXL.Indications" />

* Palliative treatment of [[stiff person syndrome]]<ref name="Drugs.com" />

* Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g., before [[endoscopic]] or surgical procedures)<ref name="RXL.Indications" />

* Treatment of complications with a [[hallucinogen]] crisis and [[stimulant]] overdoses and psychosis, such as [[LSD]], [[cocaine]], or [[methamphetamine]].<ref name="Inchem" />

* [[Prophylactic]] treatment of [[oxygen toxicity]] during [[hyperbaric oxygen therapy]]<ref name="Hyperbaric">{{cite book

| first= Kindwall

| last= <!--Incorrect/non-standard setup for names of authors-->

| year= 1999

| coauthors= Eric P. (Ed.), Whelan, Harry T. (Ed.)

| title= Hyperbaric Medicine Practice, Second Edition

| pages= <!--Unknown-->

| publisher= Best Publishing Company

| isbn= 0-941332-78-0

}}</ref>

Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any [[Comorbidity|comorbid]] conditions the patient may have.<ref name="Inchem" />

===Availability===

Diazepam is marketed in over 500 brands throughout the world.<ref>{{cite web| url= http://www.ilae.org/Visitors/Centre/AEDs/index.cfm| title=International AED Database| accessdate=2009-09-16| publisher=ILAE}}</ref> It is supplied in oral, injectable, inhalation and rectal forms.<ref name="Inchem" /><ref name="ElephantCare" /><ref>Pharmaceutical Patents. http://www.pharmcast.com/Patents100/Yr2004/Oct2004/101904/6805853_Diazepam101904.htm</ref>

The [[United States military]] employs a specialized diazepam preparation known as CANA {{Anchor|CANA}}(Convulsive Antidote, Nerve Agent), which contains a mixture of diazepam, [[atropine]] and [[pralidoxime]] (2-PAM). 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 [[auto-injector]]s. 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.<ref>[[United States Army Medical Research Institute of Chemical Defense|U.S. Army Medical Research Institute of Chemical Defense]], ''Medical Management of Chemical Casualties Handbook'', Third Edition (June 2000), [[Aberdeen Proving Ground]], MD, pp. 118–126.</ref>

==Contraindications==

Use of diazepam should be avoided, when possible, in individuals with the following conditions:<ref>{{cite web | url = https://online.epocrates.com/u/103193/diazepam/Contraindications+Cautions | title = Diazepam Contraindications and Cautions | accessdate = 16 December 2008 | author = Epocrates | publisher = Epocrates Online | location = USA }}</ref>

* [[Ataxia]].

* Severe [[hypoventilation]].

* Acute narrow-angle [[glaucoma]].

* Severe [[hepatic]] deficiencies ([[hepatitis]] and liver [[cirrhosis]] decrease elimination by a factor of 2).

* Severe [[renal]] deficiencies (for example, patients on [[dialysis]]).

* Liver disorders.

* Severe respiratory disorders.

* Severe [[sleep apnea]].

* Severe [[clinical depression|depression]], particularly when accompanied by suicidal tendencies.

* [[Psychosis]].

* [[Pregnancy]] or [[breast feeding]].

* Caution required in elderly or debilitated patients.

* [[Coma]] or shock.

* Abrupt discontinuation of therapy.

* Acute intoxication with [[ethanol|alcohol]], [[narcotics]], or other psychoactive substances (with the exception of some [[hallucinogens]], where it is occasionally used as a treatment for overdose).

* History of [[ethanol|alcohol]] or [[drug dependence]].

* [[Myasthenia gravis]], or MG, an [[autoimmune disorder]] causing marked fatiguability.

* [[Hypersensitivity]] or [[allergy]] to any drug in the [[benzodiazepine]] class.

===Special caution needed===

*Benzodiazepines require special precaution if used in the alcohol- or drug-dependent individuals and individuals with [[comorbid]] [[psychiatric disorders]].<ref>{{Cite journal | last1 = Authier | first1 = N. | last2 = Balayssac | first2 = D. | last3 = Sautereau | first3 = M. | last4 = Zangarelli | first4 = A. | last5 = Courty | first5 = P. | last6 = Somogyi | first6 = AA. | last7 = Vennat | first7 = B. | last8 = Llorca | first8 = PM. | last9 = Eschalier | first9 = A. | title = Benzodiazepine dependence: focus on withdrawal syndrome. | journal = Ann Pharm Fr | volume = 67 | issue = 6 | pages = 408–13 | month= November| year = 2009 | doi = 10.1016/j.pharma.2009.07.001 | pmid = 19900604 }}</ref>

* Pediatric patients

** Less than 18 years of age – Treatment usually not indicated, except treatment of epilepsy, and pre-/postoperative treatment. The smallest possible effective dose should be used for this group of patients.<ref name="PDRhealth" />

** Under 6 months of age – Safety and effectiveness have not been established; diazepam should not be given to individuals in this age group.<ref name="Drugs.com" /><ref name="PDRhealth" />

* Elderly and very ill patients – Possibility that apnea and/or cardiac arrest may occur. Concomitant use of other central nervous system depressants increases this risk. The smallest possible effective dose should be used for this group of patients.<ref name="Drugs.com" /><ref name="PDRhealth" /><ref name="RXL.Caution">{{cite web

| date= January 24, 2005

| url= http://www.rxlist.com/cgi/generic/diazepam_wcp.htm

| title= Diazepam: precautions

| work= Rxlist.com

| publisher= RxList Inc.

| accessdate= 2006-03-10

}}</ref> The elderly metabolise benzodiazepines much more slowly than younger adults and are also more sensitive to the effects of benzodiazepines even at similar blood plasma levels. Doses of diazepam are recommended to be about half of those given to younger individuals and treatment limited to a maximum of 2 weeks. Long-acting benzodiazepines such as diazepam are not recommended for the elderly.<ref name="Riss-2008"/> Diazepam may also be dangerous in geriatric patients owing to a significant increased risk of falls.<ref>{{cite journal | author = Shats V | coauthors = Kozacov S. | date = June 1, 1995 | title = [Falls in the geriatric department: responsibility of the care-giver and the hospital] | journal = Harefuah | volume = 128 | issue = 11 | pages = 690–3 | pmid = 7557666 }}</ref>

* I.V. or I.M. injections in hypotensive individuals or those in shock should be administered carefully and vital signs should be monitored.<ref name="RXL.Caution" />

* Benzodiazepines such as diazepam are lipophilic and rapidly penetrate membranes, and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including diazepam in late pregnancy, especially high doses, may result in [[floppy infant syndrome]].<ref>{{cite journal | author = Kanto JH. | coauthors = | year = 1982 | month = May | title = Use of benzodiazepines during pregnancy, labour and lactation, with particular reference to pharmacokinetic considerations | journal = Drugs. | volume = 23 | issue = 5 | pages = 354–80 | pmid = 6124415 | doi = 10.2165/00003495-198223050-00002}}</ref>

===Pregnancy===

Diazepam when taken late in pregnancy, during the [[third trimester]], causes a definite risk of a severe [[benzodiazepine withdrawal syndrome]] in the neonate with symptoms including [[hypotonia]], and reluctance to suck, to [[apnoeic]] spells, [[cyanosis]], and impaired [[metabolic]] responses to cold stress. Floppy infant syndrome and sedation in the newborn may also occur. Symptoms of [[floppy infant syndrome]] and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.<ref>{{cite journal | author = McElhatton PR. | coauthors = | year = 1994 | month = Nov–Dec | title = The effects of benzodiazepine use during pregnancy and lactation | journal = Reprod Toxicol. | volume = 8 | issue = 6 | pages = 461–75 | pmid = 7881198 | doi = 10.1016/0890-6238(94)90029-9}}</ref>

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|tolerance]], [[benzodiazepine dependence]] as well as a [[benzodiazepine withdrawal syndrome]].<ref name="Riss-2008"/> 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 benzodiazepines is not impaired. Tolerance to the cognitive impairing effects of benzodiazepines does not tend to develop with long-term use. The elderly are more sensitive to the cognitive impairing effects of benzodiazepines.<ref name="the_american_psychiatric_publishing_textbook_of_neuropsychia">{{Cite book | last1 = Yudofsky | first1 = Stuart C. | last2 = Hales | first2 = Robert E. | title = The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences, Fifth Edition (American Psychiatric Press Textbook of Neuropsychiatry) | url = http://books.google.co.uk/books?id=f5BEk-6yO_4C&pg=PA583 | date = 1 December 2007 | publisher = American Psychiatric Publishing, Inc. | location = USA | isbn = 978-1-58562-239-9 | pages = 583–584 }}</ref> 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 [[Major depression|depression]].<ref name="Riss-2008"/> Infusions or repeated intravenous injections of diazepam when managing seizures for example may lead to drug toxicity including respiratory depression, sedation as well as [[hypotension]]. [[Drug tolerance|Tolerance]] may also develop to infusions of diazepam if it is given for longer than 24 hours.<ref name="Riss-2008"/> Adverse effects such as sedation, [[benzodiazepine dependence]] and abuse potential limit the use of benzodiazepines.<ref name="Whiting-2006">{{Cite journal | last1 = Whiting | first1 = PJ. | title = GABA-A receptors: a viable target for novel anxiolytics? | journal = Curr Opin Pharmacol | volume = 6 | issue = 1 | pages = 24–9 | month = Feb | year = 2006 | doi = 10.1016/j.coph.2005.08.005 | pmid = 16359919 }}</ref>

Diazepam has a range of side-effects that are common to most benzodiazepines. Most common side-effects include:

* Suppression of [[REM sleep]]

** [[Dizziness]] and nausea

* [[depression (mood)|Depression]]<ref>{{cite journal |author=Kay DW, Fahy T, Garside RF |title=A seven-month double-blind trial of amitriptyline and diazepam in ECT-treated depressed patients |journal=Br J Psychiatry |volume=117 |issue=541 |pages=667–71 |year=1970 |month=December |pmid=4923720 |doi= 10.1192/bjp.117.541.667|url=http://bjp.rcpsych.org/cgi/content/abstract/117/541/667}}</ref>

* [[Tachycardia|Reflex tachycardia]]<!--This term appears numerous times throughout Wikipedia, and yet nowhere is it properly and clearly defined.--><ref name="Cuny.edu" />

Less commonly paradoxical side-effects can occur and include nervousness, irritability, excitement, worsening of seizures, insomnia, muscle cramps, changes in [[libido]] (increased or decreased libido<!-- This is mentioned in "Roche Pharmaceuticals (AUS) - Valium Product Information link" -->) and in some cases, rage, and violence. These adverse reactions are more likely to occur in children, the elderly, individuals with a history of drug or alcohol abuse and people with a history of aggression.<ref name="Riss-2008"/><ref name=rage>{{cite journal | last = Marrosu | first = F. | coauthors = G. Marrosu,

M. G. Rachel,

G. Biggio | month = July–September | year = 1987 | title = Paradoxical reactions elicited by diazepam in children with classic autism | journal = Functional Neurology | volume = 2 | issue = 3 | pages = 355–361 | pmid = 2826308 | accessdate = 2006-09-24}}</ref><ref name=next_three>{{cite web | url = http://www.rxlist.com/cgi/generic/diazepam_ad.htm | title = Diazepam: Side Effects | accessdate = September 26, 2006 | work = RxList.com}}</ref><ref name=violence>{{cite journal | last = Michel | first = L. | coauthors = J. P. Lang | month = November–December | year = 2003 | title = Benzodiazépines et passage à l'acte criminel / Benzodiazepines and forensic aspects | journal = L'Encéphale | volume = 29 | issue = 6 | pages = 479–85 | pmid = 15029082 | url = http://www.masson.fr/masson/portal/bookmark?Global=1&Page=18&MenuIdSelected=106&MenuItemSelected=0&MenuSupportSelected=0&CodeProduct4=539&CodeRevue4=ENC&Path=REVUE/ENC/2003/29/6/ARTICLE11106200473.xml&Locations=}}</ref> Diazepam may increase, in some people, the propensity toward self-harming behaviours and, in extreme cases, may provoke suicidal tendencies or acts.<ref>{{cite journal |author=Berman ME, Jones GD, McCloskey MS |title=The effects of diazepam on human self-aggressive behavior |journal=Psychopharmacology (Berl.) |volume=178 |issue=1 |pages=100–6 |year=2005 |month=February |pmid=15316710 |doi=10.1007/s00213-004-1966-8}}</ref> Very rarely [[dystonia]] can occur.<ref>{{cite journal |author=Pérez Trullen JM, Modrego Pardo PJ, Vázquez André M, López Lozano JJ |title=Bromazepam-induced dystonia |journal=Biomed. Pharmacother. |volume=46 |issue=8 |pages=375–6 |year=1992 |pmid=1292648 |doi= 10.1016/0753-3322(92)90306-R|url=}}</ref>

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.<ref name="Drugs.com" />

During the course of therapy, tolerance to the sedative effects usually develops, but not to the anxiolytic and myorelaxant effects.<ref name=sedative_effect_tolerance>{{cite journal | last = Hriscu | first = A. | coauthors = F. Gherase, V. Nastasa, and E. Hriscu | month = October–December | year = 2002 | title = [An experimental study of tolerance to benzodiazepines] | journal = Revista Medico-Chirurgicală̆ a Societă̆ţ̜ii de Medici ş̧i Naturaliş̧ti din Iaş̧i | volume = 106 | issue = 4 | pages = 806–811 | pmid = 14974234 }}</ref>

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.<ref>{{cite journal | author = Kozená L | coauthors = Frantik E, Horváth M. | year = 1995 | month = May | title = Vigilance impairment after a single dose of benzodiazepines | journal = Psychopharmacology (Berl). | volume = 119 | issue = 1 | pages = 39–45 | pmid = 7675948 | doi = 10.1007/BF02246052 }}</ref>

===Tolerance and dependence===

Diazepam as with other [[benzodiazepine]] drugs can cause [[drug tolerance|tolerance]], [[physical dependence]], [[Substance use disorder|addiction]] and what is known as the [[benzodiazepine withdrawal syndrome]]. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms that are 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 via a slow and gradual dose reduction regime.<ref name="Riss-2008"/><ref>{{cite journal | author = MacKinnon GL | coauthors = Parker WA. | year = 1982 | title = Benzodiazepine withdrawal syndrome: a literature review and evaluation | journal = The American journal of drug and alcohol abuse. | volume = 9 | issue = 1 | pages = 19–33 | pmid = 6133446 | doi = 10.3109/00952998209002608}}</ref>

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, however, 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. Approximately one third of individuals who take benzodiazepines for longer than 4 weeks become dependent and experience a withdrawal syndrome upon cessation.<ref name="Riss-2008"/> The difference in rates of withdrawal (50–100%) varies depending on the patient sample being investigated. For example, a random sample of long-term benzodiazepine users typically finds that around 50% will experience little or no withdrawal symptoms, with the other 50% experiencing notable withdrawal symptoms. Certain select patient groups will show a higher rate of notable withdrawal symptoms, up to 100%.<ref>{{cite journal |author=Onyett SR |title=The benzodiazepine withdrawal syndrome and its management |journal=The Journal of the Royal College of General Practitioners |volume=39 |issue=321 |pages=160–3 |year=1989 |month=April |pmid=2576073 |pmc=1711840}}</ref> Rebound anxiety, more severe than baseline anxiety, is also a common withdrawal symptom when discontinuing diazepam or other benzodiazepines.<ref>{{cite journal |author=Chouinard G |coauthors=Labonte A, Fontaine R, Annable L |year=1983 |title=New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines |volume=7 |issue=4–6 |pages=669–73 |pmid=6141609 |journal=Prog Neuropsychopharmacol Biol Psychiatry |doi=10.1016/0278-5846(83)90043-X}}</ref> 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.<ref>{{cite journal |author= Lader M. |coauthors= |title=Long-term anxiolytic therapy: the issue of drug withdrawal |journal=The Journal of clinical psychiatry. |volume=48 |issue= |pages=12–6 |month=December |year=1987 |pmid=2891684}}</ref> There is a significant risk of pharmacological dependence on diazepam and patients experiencing symptoms of [[benzodiazepine withdrawal syndrome]] if it is taken for 6 weeks or longer.<ref>{{cite journal |author=Murphy SM, Owen R, Tyrer P. |title=Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks' treatment with diazepam or buspirone |journal=The [[British Journal of Psychiatry]]: the journal of mental science. |volume=154 |issue= |pages=529–34 |year=1989 |pmid=2686797 |doi=10.1192/bjp.154.4.529}}</ref> In humans tolerance to the anticonvulsant effects of diazepam occurs frequently.<ref>{{cite journal |author=Loiseau P |year =1983 |title =[Benzodiazepines in the treatment of epilepsy] | journal =Encephale | volume =9 | issue =4 Suppl 2 | pages =287B–292B | pmid = 6373234 }}</ref>

Improper or excessive use of Diazepam can lead to [[psychological dependence]]/[[drug addiction]].<ref name="JohnHopkinsHealth.com">{{cite web | year= 2005| url= http://www.johnshopkinshealthalerts.com/reports/depression_anxiety/59-1.html?type=pf| title= Treating Anxiety -- Avoiding Dependence on Xanax, Klonopin, Valium, and Other Antianxiety Drugs| work= johnshopkinshealthalerts.com| publisher= Johnshopkinshealthalerts.com| accessdate= 2007-12-23}}</ref> At a particularly high risk for diazepam misuse, [[drug abuse|abuse]] or psychological dependence are:

* People with a history of alcohol or drug abuse or dependence<ref name="Drugs.com" /><ref name="RXL.Abuse">{{cite web| date= January 24, 2005| url= http://www.rxlist.com/cgi/generic/diazepam_ad.htm#DA| title= Diazepam: abuse and dependence| work= Rxlist.com| publisher= RxList Inc.| accessdate= 2006-03-10}}</ref> Diazepam increases craving for alcohol in problem alcohol consumers. Diazepam also increases the volume of alcohol consumed by problem drinkers.<ref>{{cite journal |author=Poulos CX, Zack M |title=Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers |journal=Behav Pharmacol |volume=15 |issue=7 |pages=503–12 |year=2004 |month=November |pmid=15472572 |doi= 10.1097/00008877-200411000-00006|url=}}</ref>

* People with severe personality disorders, such as [[Borderline Personality Disorder]]<ref name=not_in_BPD>{{cite journal | last = Vorma | first = Helena | coauthors = Hannu H. Naukkarinen, Seppo J. Sarna, and Kimmo I. Kuoppasalmi | year = 2005 | title = Predictors of Benzodiazepine Discontinuation in Subjects Manifesting Complicated Dependence | journal = Substance Use & Misuse | volume = 40 | issue = 4 | pages = 499–510 | pmid = 15830732 | format = PDF | accessdate = 2006-09-25 | doi = 10.1081/JA-200052433}}</ref>

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 [[physical dependence]] has developed therapy must still be discontinued gradually to avoid severe [[withdrawal symptoms]]. Long-term therapy in these people is not recommended.<ref name="Drugs.com" /><ref name="RXL.Abuse" />

People suspected of being physiologically dependent on benzodiazepine drugs should be very gradually tapered off the drug. Although rare, 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.

Diazepam in and of itself is not a recreational drug, but may be used to either enhance or "come down" from the effects of other recreational drugs. For example, diazepam increases the euphoriant effects of heroin (and other recreational opiates), yet decreases the undesirable side-effects of cocaine and/or methamphetamine come-down.

===Overdose===

An individual that has consumed too much diazepam will typically display one or more of the following symptoms in a period of approximately four hours immediately following a suspected overdose.:<ref name="Drugs.com" /><ref name="RXL.Overdose">{{cite web

| date= January 24, 2005

| url= http://www.rxlist.com/cgi/generic/diazepam_od.htm

| title= Diazepam: overdose

| work= Rxlist.com

| publisher= RxList Inc.

| accessdate= 2006-03-10

}}</ref>

* Impaired motor functions

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. Although 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]].<ref name="Inchem"/><ref name="Drugs.com"/><ref name="RXL.Overdose"/><ref name="Barondes1"/>

The oral {{LD50}} (lethal dose in 50% of the population) of diazepam is 720 mg/kg in mice and 1240 mg/kg in rats.<ref name="Drugs.com"/> 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, esmethyldiazepam, oxazepam, and temazepam; according to samples taken in the hospital and as follow-up.<ref name=Greenblatt_et_al_1978>{{cite journal | last = Greenblatt | first = D. J. | coauthors = E. Woo, M. D. Allen, P. J. Orsulak, and R. I. Shader | date = October 20, 1978 | title = Rapid recovery from massive diazepam overdose | journal = Journal of the American Medical Association | volume = 240 | issue = 17 | pages = 1872–4 | pmid = 357765 | doi = 10.1001/jama.240.17.1872 }}</ref>

Overdoses of diazepam with alcohol, opiates and/or other depressants may be fatal.<ref name="Barondes1"/><ref>{{cite journal | last = Lai | first = SH | coauthors = Yao YJ, Lo DS. | year = 2006 | month = October | title = A survey of buprenorphine related deaths in Singapore | journal = Forensic Sci Int. | volume = 162(1–3) | pages = 80–6 | pmid = 16879940 | doi = 10.1016/j.forsciint.2006.03.037 | issue = 1-3 }}</ref>

An Australian study has found people who take sleeping pills or anti-anxiety medications are more dangerous on the roads than drunk drivers.<ref>{{cite news|title=Valium users worse drivers than drunks|url=http://www.smh.com.au/lifestyle/wellbeing/valium-users-worse-drivers-than-drunks-20101019-16sl7.html |publisher=Sydney Morning Hearld |date=20 October 2010 |accessdate=20 October 2010}}</ref>

===Interactions===

If diazepam is to be administered concomitantly with other drugs, attention should be paid to the possible pharmacological interactions. Particular care should be taken with drugs that enhance the effects of diazepam, such as barbiturates, [[phenothiazines]], [[narcotics]] and [[antidepressants]].<ref name="Drugs.com" />

Diazepam does not increase or decrease hepatic enzyme activity, and does not alter the metabolism of other compounds. There is no evidence that would suggest diazepam alters its own metabolism with chronic administration.<ref name="Inchem" />

Agents that have 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.<ref name="Inchem" />

* Diazepam increases the central depressive effects of alcohol, other [[hypnotic]]s/sedatives (e.g., barbiturates), narcotics, other [[muscle relaxant]]s, certain antidepressants, sedative [[antihistamines]], [[opiates]], and [[antipsychotics]] as well as [[anticonvulsants]] such as [[phenobarbital]], [[phenytoin]] and [[carbamazepine]]. The euphoriant effects of opioids may be increased, leading to increased risk of psychological dependence.<ref name="Riss-2008"/><ref name="PDRhealth">{{cite web| author= | year= 2006| url= http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/val1473.shtml| title= Diazepam| work= PDRHealth.com| publisher= PDRHealth.com| accessdate= 2006-03-10 |archiveurl = http://web.archive.org/web/20060117065720/http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/val1473.shtml <!-- Bot retrieved archive --> |archivedate = 2006-01-17}}</ref><ref name="Holt">{{cite book| first= Gary A.| last= Holt| year= 1998| title= Food and Drug Interactions: A Guide for Consumers| pages= 90–91| location= Chicago | publisher=Precept Press| isbn= 0-944496-59-8 }}</ref>

* [[Cimetidine]], [[omeprazole]], [[oxcarbazepine]], [[ticlopidine]], [[topiramate]], [[ketoconazole]], [[itraconazole]], [[disulfiram]], [[fluvoxamine]], [[isoniazid]], [[erythromycin]], [[probenecid]], [[propranolol]], [[imipramine]], [[ciprofloxacin]], [[fluoxetine]] and [[valproic acid]] prolong the action of diazepam by inhibiting its elimination.<ref name="Inchem" /><ref name="ElephantCare" /><ref name="Riss-2008"/>

* Alcohol ([[ethanol]]) in combination with diazepam may cause a synergistic enhancement of the [[hypotensive]] properties of benzodiazepines and alcohol.<ref>{{cite journal | author = Zácková P | coauthors = Kvĕtina J, Nĕmec J, Nĕmcová J. | year = 1982 | month = December | title = Cardiovascular effects of diazepam and nitrazepam in combination with ethanol | journal = Pharmazie. | volume = 37 | issue = 12 | pages = 853–6 | pmid = 7163374 }}</ref>

* Oral contraceptives ("the pill") significantly decrease the elimination of desmethyldiazepam, a major metabolite of diazepam.<ref name="PDRhealth" /><ref>{{cite journal | author = Back DJ | coauthors = Orme ML. | year = 1990 | month = June | title = Pharmacokinetic drug interactions with oral contraceptives | journal = Clin Pharmacokinet. | volume = 18 | issue = 6 | pages = 472–84 | pmid = 2191822 | doi = 10.2165/00003088-199018060-00004 }}</ref>

* [[Rifampin]], [[phenytoin]], [[carbamazepine]] and [[phenobarbital]] increase the metabolism of diazepam, thus decreasing drug levels and effects.<ref name="Inchem" /> [[Dexamethasone]] and [[St John's wort]] also increase the metabolism of diazepam.<ref name="Riss-2008"/>

* Diazepam increases the serum levels of [[phenobarbital]].<ref>{{cite journal | author = Bendarzewska-Nawrocka B | coauthors = Pietruszewska E, Stepień L, Bidziński J, Bacia T. | year = 1980 | month = Jan-Feb | title = [Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy] | journal = Neurol Neurochir Pol. | volume = 14 | issue = 1 | pages = 39–45 | pmid = 7374896 }}</ref>

* [[Cisapride]] may enhance the absorption, and therefore the sedative activity, of diazepam.<ref name="Cisapride">{{cite journal | author= Bateman, D.N. | title= The action of cisapride on gastric emptying and the pharmacodynamics and pharmacokinetics of oral diazepam | journal= Eur J Clin Pharmacol. | year= 1986 | pages= 205–8 | volume= 30 | issue= 2 | pmid=3709647 | doi= 10.1007/BF00614304}}</ref>

* Small doses of [[theophylline]] may inhibit the action of diazepam.<ref name=theophylline>{{cite journal | last = Mattila | first = M. J. | coauthors = E. Nuotto | year = 1983 | title = Caffeine and theophylline counteract diazepam effects in man | journal = Medical Biology | volume = 61 | issue = 6 | pages = 337–343 | pmid = 6374311 }}</ref>

* Diazepam may block the action of [[levodopa]] (used in the treatment of [[Parkinson's Disease]]).<ref name="Holt" />

* Other drugs that may have interactions with diazepam include: [[Antipsychotic]]s (e.g. [[chlorpromazine]]), [[MAO inhibitors]], [[ranitidine]].<ref name="PDRhealth" />

* [[Caffeine]] may antagonise the effects of diazepam and vice versa.<ref>{{ cite journal |pmid=1351673 |url= |format= |year=1992 |month=Apr |author=Mattila, Me; Mattila, Mj; Nuotto, E |title=Caffeine moderately antagonizes the effects of triazolam and zopiclone on the psychomotor performance of healthy subjects. |volume=70 |issue=4 |pages=286–9 |issn=0901-9928 |journal=Pharmacology & toxicology |doi=10.1111/j.1600-0773.1992.tb00473.x }}</ref>

* Smoking [[tobacco]] can enhance the elimination of diazepam and decrease its action.<ref name="Holt" />

* Because it acts on the GABA receptor the herb [[Valerian (herb)|Valerian]] may produce an adverse effect.<ref>Possible Interactions with: Valerian, University of Maryland Medical Center, http://www.umm.edu/altmed/articles/valerian-000934.htm</ref>

* There are conflicting reports as to whether food in general has any effects on the absorption and activity of orally administered diazepam.<ref name="Holt" />

[[Image:2 10mg Valium pills.jpg|thumb|10mg Valium.]]

Diazepam is a long acting "classical" benzodiazepine. Other classical benzodiazepines include [[chlordiazepoxide]], [[clonazepam]], [[lorazepam]], [[oxazepam]], [[nitrazepam]], [[temazepam]], [[flurazepam]]{{Citation needed|date=July 2010}}, [[bromazepam]]{{Citation needed|date=July 2010}}, and [[clorazepate]]{{Citation needed|date=July 2010}}.<ref>{{cite journal | author = Braestrup C | coauthors = Squires RF. | date=1 April 1978| title = Pharmacological characterization of benzodiazepine receptors in the brain | journal = Eur J Pharmacol | volume = 48 | issue = 3 | pages = 263–70 | pmid = 639854 | doi = 10.1016/0014-2999(78)90085-7}}</ref> Diazepam has [[anticonvulsant]] properties.<ref>{{cite journal | journal = Life Sci | date = February 25, 1985 | volume = 36| issue = 8| pages = 737–44| title = Effect of GABA agonists on the neurotoxicity and anticonvulsant activity of benzodiazepines| author = Chweh AY| coauthors = Swinyard EA, Wolf HH, Kupferberg HJ| pmid = 2983169 | doi = 10.1016/0024-3205(85)90193-6}}</ref> 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 insofar from some other anticonvulsive drugs it was compared with.<ref>{{cite journal | journal = Neurochem Res | year = 1984 | month = February | volume = 9 | issue = 2 | pages = 225–31 | title = Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities | author = Battistin L | coauthors = Varotto M, Berlese G, Roman G | pmid = 6429560 | doi = 10.1007/BF00964170}}</ref> Benzodiazepines act via [[micromolar]] benzodiazepine binding sites as [[Ca2+]] channel blockers and significantly inhibit depolarization-sensitive Calcium uptake in rat nerve cell preparations.<ref>{{cite journal | journal = Proc Natl Acad Sci USA | year = 1984 | month = May | volume = 81 | issue = 10 | pages = 3118–22 | url = http://www.pnas.org/cgi/reprint/81/10/3118.pdf | type = PDF | title = Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations | author = Taft WC |coauthors = DeLorenzo RJ | pmid = 6328498 | doi = 10.1073/pnas.81.10.3118|format=PDF | pmc = 345232}}</ref>

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.<ref>{{cite journal |author=Miller JA, Richter JA |title=Effects of anticonvulsants in vivo on high affinity choline uptake in vitro in mouse hippocampal synaptosomes |journal=British Journal of Pharmacology |volume=84 |issue=1 |pages=19–25 |year=1985 |month=January |pmid=3978310 |pmc=1987204}}</ref>

Diazepam binds with high affinity to [[glial cells]] in animal cell cultures.<ref>{{cite journal |author=Gallager DW, Mallorga P, Oertel W, Henneberry R, Tallman J |title=[3H]Diazepam binding in mammalian central nervous system: a pharmacological characterization |journal=The Journal of Neuroscience |volume=1 |issue=2 |pages=218–25 |year=1981 |month=February |pmid=6267221 |url=http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=6267221}}</ref> Diazepam at high doses has been found to decrease histamine turnover in mouse brain via diazepam's action at the benzodiazepine-GABA receptor complex.<ref>{{cite journal | author = Oishi R | coauthors = Nishibori M, Itoh Y, Saeki K. | date = May 27, 1986 | title = Diazepam-induced decrease in histamine turnover in mouse brain | journal = Eur J Pharmacol. | volume = 124 | issue = 3 | pages = 337–42 | pmid = 3089825 | doi = 10.1016/0014-2999(86)90236-0}}</ref> Diazepam also decreases [[prolactin]] release in rats.<ref>{{cite journal |author=Grandison L |year=1982 |title=Suppression of prolactin secretion by benzodiazepines in vivo |journal=Neuroendocrinology |volume=34 |issue=5 |pages=369–73 |pmid=6979001 |doi=10.1159/000123330}}</ref>

Diazepam is a benzodiazepine that binds to a specific subunit on the [[GABA A receptor|GABA_A]] receptor at a site that is distinct from the binding site of the [[endogenous]] GABA molecule. The [[GABA A receptor|GABA_A]] receptor is an inhibitory channel which, when activated, decreases neuronal activity. Benzodiazepines do not supplement for the neurotransmitter GABA, rather benzodiazepines such as diazepam bind to a different location on the GABA_A receptor with the result that the effects of GABA are enhanced. Benzodiazepines cause an increased opening of the chloride ion channel when GABA binds to its site on the GABA_A receptor leading to more chloride ions entering the neuron which in turn leads to enhanced central nervous system depressant effects.<ref name="Riss-2008"/> Diazepam binds non-selectively to alpha1, alpha2, alpha3 and alpha5 subunit containing GABA_A receptors.<ref name="Atack-2005">{{Cite journal | last1 = Atack | first1 = JR. | title = The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics. | journal = Expert Opin Investig Drugs | volume = 14 | issue = 5 | pages = 601–18 | month = May | year = 2005 | doi = 10.1517/13543784.14.5.601 | pmid = 15926867 }}</ref>

Because of the role of diazepam as a positive [[Allosteric regulation|allosteric modulator]] of GABA, when it binds to benzodiazepine receptors it causes [[inhibitory]] effects. This arises from the [[hyperpolarization (biology)|hyperpolarization]] of the post-[[synapse|synaptic]] membrane, owing to the control exerted over negative [[chloride]] [[ion]]s by GABA_A receptors.<ref name="Drugs.com">{{cite web | author= Thomson Healthcare (Micromedex) | month= March | year= 2000 | url= http://www.drugs.com/pdr/diazepam.html | title= Diazepam | work= Prescription Drug Information | publisher= Drugs.com | accessdate= 2006-03-11 }}</ref><ref name="Barondes2" />

Diazepam appears to act on areas of the [[limbic system]], [[thalamus]], and [[hypothalamus]], inducing anxiolytic effects. Its actions are due to the enhancement of [[GABA]] activity.<ref name="PubChem" /><ref name="Barondes2">{{cite book | first= Samuel H. | last= Barondes | year= 1999 | month= MONTH | title= Molecules and Mental Illness | pages= 190–194 | location= New York | publisher=Scientific American Library | isbn= 0-7167-6033-9 }}</ref> Benzodiazepine drugs including diazepam increase the inhibitory processes in the cerebral cortex.<ref>{{cite journal | author = Zakusov VV | coauthors = Ostrovskaya RU, Kozhechkin SN, Markovich VV, Molodavkin GM, Voronina TA. | year = 1977 | month = October | title = Further evidence for GABA-ergic mechanisms in the action of benzodiazepines | volume = 229 | issue = 2 | pages = 313–26 | pmid = 23084 | journal = Archives internationales de pharmacodynamie et de therapie }}</ref>

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 to be limited by benzodiazepines' effect of slowing recovery of sodium channels from inactivation.<ref>{{cite journal | author = McLean MJ | coauthors = Macdonald RL. | year = 1988 | month = February | title = Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture | volume = 244 | issue = 2 | pages = 789–95 | pmid = 2450203 | journal = J Pharmacol Exp Ther. }}</ref>

The muscle relaxant properties of Diazepam are produced via inhibition of [[polysynaptic]] pathways in the spinal cord.<ref>{{cite journal | author = Date SK | coauthors = Hemavathi KG, Gulati OD. | year = 1984 | month = November | title = Investigation of the muscle relaxant activity of nitrazepam | volume = 272 | issue = 1 | pages = 129–39 | pmid = 6517646 | journal = Arch Int Pharmacodyn Ther. }}</ref>

[[File:Diazepam5mgPack.JPG|thumb|right|[[Generic drug|Generic]] pack of 5mg Diazepam.]]

Diazepam can be administered orally, [[intravenous therapy|intravenous]]ly (needs to be diluted, as it is painful and damaging to veins), [[intramuscular injection|intramuscular]]ly (see below), or as a [[suppository]].<ref name="Inchem">{{cite web | author= Pere Munne/M. Ruse, Ed. | year= 1990/1998 Ed. | url= http://www.inchem.org/documents/pims/pharm/pim181.htm | title= Diazepam | work= Inchem.org | publisher= Inchem.org | accessdate= 2006-03-11}}</ref>

When Diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1–5 minutes for IV administration and 15–30 minutes for IM administration. The duration of diazepam's peak pharmacological effects is 15 minutes to 1 hour for both routes of administration.<ref name="Cuny.edu">{{cite web | author= Langsam, Yedidyah | year= <!--Unknown--> | url= http://eilat.sci.brooklyn.cuny.edu/newnyc/DRUGS/Diazepam.htm | title= DIAZEPAM (VALIUM AND OTHERS) | work= | publisher= Brooklyn College (Eilat.sci.Brooklyn.CUNY.edu) | accessdate= 2006-03-23}}</ref> The bioavailability after oral administration is 100 percent, and 90 percent after rectal administration. Peak plasma levels occur between 30 minutes and 90 minutes after oral administration and between 30 minutes and 60 minutes after intramuscular administration; after rectal administration peak plasma levels occur after 10 minutes to 45 minutes. Diazepam is highly protein bound with 96 to 99 percent of the absorbed drug being protein bound. The distribution half-life of diazepam is 2 minutes to 13 minutes.<ref name="Riss-2008"/>

When Diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.<ref name="DrugBank">{{cite journal | title = Drug Bank - Diazepam | url = http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00642.txt }}</ref>

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 will quickly build up to a high concentration in the body (mainly in [[adipose tissue]]), which will be far in excess of the actual dose for any given day.<ref name="Riss-2008"/><ref name="Inchem" />

There is preferential storage of Diazepam in some organs including the heart. Absorption by any administered route and the risk of accumulation is significantly increased in the [[neonate]] and there is clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.<ref>{{cite journal | author = Olive G | coauthors = Dreux C. | year = 1977 | month = January | title = Pharmacologic bases of use of benzodiazepines in peréinatal medicine | volume = 34 | pages = 74–89 | pmid = 851373 | journal = Arch Fr Pediatr. | issue = 1 }}</ref>

Diazepam undergoes oxidative metabolism by Demethylation (CYP 2C9, 2C19, 2B6, 3A4, and 3A5), hydroxylation (CYP 3A4 and 2C19) as well as [[glucuronidation]] in the [[liver]] as part of the [[cytochrome P450]] enzyme system. Diazepam has several pharmacologically [[active metabolites]]. The main active metabolite of diazepam is [[nordiazepam|desmethyldiazepam]] (also known as ''nordazepam'' or ''nordiazepam''). Diazepam's 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 1–3 and 2–7 days for the active metabolite desmethyldiazepam.<ref name="Riss-2008"/>

Most of the drug is metabolised; very little diazepam is excreted unchanged.<ref name="Inchem" />

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.<ref>{{cite journal | author = Vozeh S. | coauthors = | date = November 21, 1981 | title = [Pharmacokinetic of benzodiazepines in old age] | journal = Schweiz Med Wochenschr. | volume = 111 | issue = 47 | pages = 1789–93 | pmid = 6118950 }}</ref>

Diazepam may be quantitated 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 overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with diazepam, but confirmation and quantitation is usually performed using chromatographic techniques.<ref>{{cite journal |last=Jones |first=A. W. |last2=Holmgren |first2=A. |last3=Kugelberg |first3=F. C. |title=Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results |journal=Ther. Drug Monit. |volume=29 |issue=2 |pages=248–260 |year=2007 |doi=10.1097/FTD.0b013e31803d3c04 |pmid=17417081}}</ref><ref>{{cite journal |last=Fraser |first=A. D. |last2=Bryan |first2=W. |title=Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays |journal=J. Anal. Toxicol. |volume=15 |issue=2 |pages=63–65 |year=1991 |doi= |pmid=1675703 }}</ref><ref>{{cite book |first=R. |last=Baselt |title=Disposition of Toxic Drugs and Chemicals in Man |edition=9th |publisher=Biomedical Publications |location=Seal Beach, CA |year=2011 |pages=471–473 |isbn=978-0-9626523-8-7}}</ref>

===Physical properties===

Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5 °C. It is odorless, and has a slightly bitter taste. The [[British Pharmacopoeia]] lists diazepam 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 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of [[ether]], and practically insoluble in water. The [[pH]] of diazepam is neutral (i.e., pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution.<ref name="Inchem">{{cite web|author=Pere Munne/M. Ruse, Ed.|year= 1990/1998 Ed.|url= http://www.inchem.org/documents/pims/pharm/pim181.htm|title=Diazepam|work=Inchem.org|publisher=Inchem.org|accessdate=2006-03-11}}</ref>

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.<ref name="ElephantCare">{{cite web|author=Mikota, Susan K. and Plumb, Donald C.|year=2005|url= http://www.elephantcare.org/Drugs/diazepam.htm|title=Diazepam|work=The Elephant Formulary|publisher= Elephant Care International|accessdate=}}</ref>

Diazepam can absorb into plastic, and, therefore, diazepam solution is not stored in plastic bottles or syringes, etc. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates, and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.<ref name="ElephantCare"/>

===Chemistry===

From a chemical point of view, diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, is the most simple of all of the examined derivatives of 1,4-benzodiazepin-2-ones. Various ways for the synthesis of diazepam from 2-amino-5-chlorobenzophenone have been proposed. The first two ways consist of the direct cyclocondensation of 2-amino-5-chlorobenzophenone or 2-methylamino-5-chlorobenzophenone with the ethyl ester of glycine hydrochloride. The amide nitrogen atom of the obtained 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, is methylated by dimethylsulfate, which leads to the formation of diazepam.

[[File:Diazepam synthesis.png|600px|center]]

The second way differs from the first in that the methylation of nitrogen is accomplished

before the cyclocondensation reaction. In order to do this, the initial 2-amino-5-chlorobenzophenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate

transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-N-tosyl-N-methyl-5-chlorobenzophenone is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone, which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam.<ref>{{Cite doi|10.1021/jo01070a038}}</ref><ref>K.B. Nutley, L.H. Sternbach, {{US Patent|3109843}} (1963).</ref><ref>E. Reeder, L.H. Sternbach, {{US Patent|3371085}} (1968).</ref><ref>{{Cite doi|10.1021/jo01297a030}}</ref><ref>{{Cite doi|10.1021/jo00133a042}}</ref>

[[File:Diazepam synthesis2.png|800px]]

Diazepam was the second benzodiazepine to be invented by Dr. [[Leo Sternbach]] of [[Hoffmann-La Roche]], 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 two and a half 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.<ref name="Obituary">{{cite news

| author= Sample, Ian

| title= Leo Sternbach's Obituary

| date= October 3, 2005

| publisher= The Guardian (Guardian Unlimited)

| url= http://www.guardian.co.uk/medicine/story/0,,1583671,00.html

| accessdate= 2006-03-10

}}</ref>

The benzodiazepines gained popularity among medical professionals as an improvement upon [[barbiturate]]s, which have a comparatively narrow [[therapeutic index]], and are far more sedating 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 other sedatives).<ref name="Barondes1">{{cite book | first= Samuel H. | last= Barondes | year= 2003 | month= | title= Better Than Prozac | pages= 47–59 | location= New York | publisher=Oxford University Press | isbn= 0-19-515130-5 }}</ref> 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.<ref name="Marshall-2009">{{Cite journal | last1 = Marshall | first1 = KP. | last2 = Georgievskava | first2 = Z. | last3 = Georgievsky | first3 = I. | title = Social reactions to Valium and Prozac: a cultural lag perspective of drug diffusion and adoption. | journal = Res Social Adm Pharm | volume = 5 | issue = 2 | pages = 94–107 | month = Jun | year = 2009 | doi = 10.1016/j.sapharm.2008.06.005 | pmid = 19524858 }}</ref>

Diazepam was the top-selling pharmaceutical in the [[United States]] from 1969 to 1982, with peak sales in 1978 of 2.3 billion tablets.<ref name="Obituary" /> Diazepam, along with [[oxazepam]], [[nitrazepam]] and [[temazepam]], represents 82% of the benzodiazepine market in Australia.<ref>{{cite journal | doi = 10.1111/j.1753-6405.1993.tb00167.x | author = Mant A | coauthors = Whicker SD, McManus P, Birkett DJ, Edmonds D, Dumbrell D. | title =Benzodiazepine utilisation in Australia: report from a new pharmacoepidemiological database | journal = Aust J Public Health. | volume =17 | issue =4 | pages=345–9 | month =December | year=1993 | pmid = 7911332 }}</ref> 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]].<ref name="RXL.Indications">{{cite web | date= January 24, 2005 | url= http://www.rxlist.com/cgi/generic/diazepam_ids.htm | title= Diazepam: indications | work= Rxlist.com | publisher= RxList Inc. | accessdate= 2006-03-11 }}</ref> In recent years, the public perception of benzodiazepines has become increasingly negative.<ref name="Atack-2005"/>

Diazepam is a drug of potential abuse and can cause serious problems of addiction and as a result is scheduled. Urgent action by national governments has been recommended to improve prescribing patterns of benzodiazepines such as diazepam.<ref name="Dièye-2006">{{Cite journal | last1 = Dièye | first1 = AM. | last2 = Sylla | first2 = M. | last3 = Ndiaye | first3 = A. | last4 = Ndiaye | first4 = M. | last5 = Sy | first5 = GY. | last6 = Faye | first6 = B. | title = Benzodiazepines prescription in Dakar: a study about prescribing habits and knowledge in general practitioners, neurologists and psychiatrists. | journal = Fundam Clin Pharmacol | volume = 20 | issue = 3 | pages = 235–8 | month = Jun | year = 2006 | doi = 10.1111/j.1472-8206.2006.00400.x | pmid = 16671957 }}</ref><ref name="Atack-2005"/> A single dose of diazepam modulates the [[dopamine]] system in similar ways to how morphine and [[ethanol|alcohol]] modulate the dopaminergic pathways.<ref>{{cite web | url = http://www.medicalnewstoday.com/articles/119284.php | title = New Evidence On Addiction To Medicines Diazepam Has Effect On Nerve Cells In The Brain Reward System | accessdate = September 25, 2008 | year = 2008 | month = August | publisher = Medical News Today}}</ref>

Between 50 and 64% of rats will self administer diazepam.<ref>{{cite journal | doi = 10.1254/fpj.83.39 | author = Yoshimura K | coauthors = Horiuchi M, Inoue Y, Yamamoto K. | year = 1984 | month = January | title = [Pharmacological studies on drug dependence. (III): Intravenous self-administration of some CNS-affecting drugs and a new sleep-inducer, 1H-1, 2, 4-triazolyl benzophenone derivative (450191-S), in rats] | volume = 83 | issue = 1 | pages = 39–67 | pmid = 6538866 | journal = Nippon Yakurigaku Zasshi.}}</ref>

Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity, which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines.<ref>{{cite journal | author = Thiébot MH | coauthors = Le Bihan C, Soubrié P, Simon P. | year = 1985 | title = Benzodiazepines reduce the tolerance to reward delay in rats | volume = 86 | issue = 1–2 | pages = 147–52 | pmid = 2862657 | journal = Psychopharmacology (Berl). | doi = 10.1007/BF00431700}}</ref> In addition diazepam has been shown to be able to substitute for the behavioural effects of [[barbiturates]] in a [[primate]] study.<ref>{{cite journal |author=Woolverton WL, Nader MA |title=Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline |journal=Psychopharmacology (Berl.) |volume=122 |issue=3 |pages=230–6 |year=1995 |month=December |pmid=8748392 |doi= 10.1007/BF02246544|url=}}</ref>

Diazepam has been found as an [[adulterant]] in [[heroin]].<ref name=heroin_adulterant>{{cite web | url = http://www.incb.org/incb/en/annual_report_1996_chapter2.html#IIB10 | title = CHAPTER II. OPERATION OF THE INTERNATIONAL DRUG CONTROL SYSTEM | accessdate = September 25, 2006 | author =International Narcotics Control Board | work = REPORT OF THE INTERNATIONAL NARCOTICS CONTROL BOARD FOR 1996 | year = 1996 }}</ref>

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.<ref>{{cite journal |author=Griffiths RR, Johnson MW |title=Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds |journal=J Clin Psychiatry |volume=66 Suppl 9 |issue= |pages=31–41 |year=2005 |pmid=16336040 |doi= |url=}}</ref>

Sometimes Diazepam is used by stimulant users to "come down" and sleep and to help control the urge to binge.<ref name=with_meth>{{cite web | url = http://de1.erowid.org/experiences/exp.phpquery=ID=9402.html | title = Methamphetamine and Benzodiazepines: Methamphetamine & Benzodiazepines | accessdate = September 26, 2006 | author = Overclocker | work = Erowid Experience Vaults }}</ref>

A large-scale nationwide USA government study conducted by [[SAMHSA]] found that benzodiazepines in the USA are the most frequently abused pharmaceutical with 35% of drug-related visits to the Emergency Department involved benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as females. Of drugs used in attempted suicide benzodiazepines are the most commonly used pharmaceutical drug, with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is, however, [[alprazolam]]. [[Clonazepam]] is the second-most-abused benzodiazepine. [[Lorazepam]] is the third-most-abused benzodiazepine, and diazepam the fourth-most-abused benzodiazepine in the [[USA]].<ref>{{cite web |url= http://dawninfo.samhsa.gov/files/DAWN2k4ED.htm|title= Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits|accessdate= 9 May 2008|author= United States Government|authorlink= samhsa|coauthors= U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES|year= 2004|publisher= Substance Abuse and Mental Health Services Administration |archiveurl = http://web.archive.org/web/20080331184508/http://dawninfo.samhsa.gov/files/DAWN2k4ED.htm <!-- Bot retrieved archive --> |archivedate = 31 March 2008}}</ref>

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.<ref>{{cite journal | author = Bergman U | coauthors = Dahl-Puustinen ML. | year = 1989 | title = Use of prescription forgeries in a drug abuse surveillance network | volume = 36 | issue = 6 | pages = 621–3 | pmid = 2776820 | journal = Eur J Clin Pharmacol. | doi = 10.1007/BF00637747}}</ref>

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]].<ref>{{cite journal | author = Jones AW | coauthors = Holmgren A, Kugelberg FC. | year = 2007 | month = April | title = Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results | volume = 29 | issue = 2 | pages = 248–60 | pmid = 17417081 | journal = Ther Drug Monit. | doi = 10.1097/FTD.0b013e31803d3c04}}</ref> In [[Northern Ireland]] in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.<ref>{{cite journal | author = Cosbey SH. | year = 1986 | month = December | title = Drugs and the impaired driver in Northern Ireland: an analytical survey | volume = 32 | issue = 4 | pages = 245–58 | pmid = 3804143 | journal = Forensic Sci Int. | doi = 10.1016/0379-0738(86)90201-X}}</ref>

Diazepam is regulated in most countries as a [[prescription drug]]:

* International: Diazepam is a [[Schedule IV]] controlled drug under the [[Convention on Psychotropic Substances]].<ref name="Legal">{{cite web| author=International Narcotics Control Board| year=2003| url= http://www.incb.org/pdf/elist/green.pdf| title= List of psychotropic substances under international control| work= Green list| accessdate=2006-03-11|format=PDF}} {{Dead link|date=September 2010|bot=H3llBot}}</ref>

* UK: classified as a controlled drug, listed under Schedule IV, Part I (CD Benz POM) of the Misuse of Drugs Regulations 2001, allowing possession with a valid prescription. The [[Misuse of Drugs Act 1971]] makes it illegal to possess the drug without a prescription, and for such purposes it is classified as a Class C drug. {{cite web| url= http://www.homeoffice.gov.uk/documents/cdlist2835.pdf?view=Binary | title = List of Controlled Drugs}}

* Germany: classified as a prescription drug, or in high dosage as a restricted drug (''Betäubungsmittelgesetz, Anhang III'').<ref>{{cite web| year=2001| url=http://bundesrecht.juris.de/btmg_1981/anlage_iii_61.html| title=Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel| work=Betäubungsmittelgesetz| accessdate=2010-01-05}}</ref>

===Judicial executions===

The State of [[California]] offers diazepam to [[Capital punishment|condemned]] inmates as a pre-execution sedative as part of their [[Lethal Injection]] program.<ref>San Quentin State Prison Operational Procedure 0-770, Execution By Lethal Injection (pp. 43 & 92). http://www.cdcr.ca.gov/News/docs/RevisedProtocol.pdf</ref>

Diazepam is used as a short-term sedative and [[anxiolytic]] for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. It can also be used as an appetite stimulant.<ref>http://www.merckvetmanual.com/mvm/index.jsp?cfile=htm/bc/190302.htm</ref><ref>{{cite journal |author=Rahminiwati M, Nishimura M |title=Effects of delta 9-tetrahydrocannabinol and diazepam on feeding behavior in mice |journal=The Journal of Veterinary Medical Science |volume=61 |issue=4 |pages=351–5 |year=1999 |month=April |pmid=10342284 |doi=10.1292/jvms.61.351}}</ref> For emergent treatment of seizures, the typical dose is 0.5cmg/kg intravenously, or 1–2c;mg/kg of the injectable solution administered in the rectum.<ref>{{cite web | last = Hines| first = Ron DVM PhD | date = 2006-01-14 | url = http://www.2ndchance.info/epilepsy.htm | title = Epilepsy In Your Dog Or Cat| publisher = 2nd Chance Sanctuary Pet Health Center | accessdate = May 18, 2006 }}</ref>

{{Reflist|2}}

* [http://www.roche-australia.com/downloads/valium-pi.cfm?action=get Roche Pharmaceuticals (AUS) - Valium Product Information]

* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Diazepam U.S. National Library of Medicine: Drug Information Portal - Diazepam]

* [http://www.pharmamotion.com.ar/animation-benzodiazepines-diazepam-lorazepam-alprazolam.html Flash animation about how bromazepam works (mechanism of action)]

* [http://www.amc.edu/patient/ems/ems_medication.htm Albany Medical Center] – "Medication of the month"

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