Alprazolam

Alprazolam
Systematic (IUPAC) name
8-chloro-1-methyl-6-phenyl-4H-
[1,2,4]triazolo[4,3-a][1,4]benzodiazepine
Identifiers
CAS number 28981-97-7
ATC code N05BA12
PubChem CID 2118
DrugBank APRD00280
ChemSpider 2034
Chemical data
Formula C17H13ClN4 
Mol. mass 308.765
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 80–90%
Metabolism Hepatic, via Cytochrome P450 3A4
Half-life Immediate release: 11.2 hours;[1] Extended release: 10.7–15.8 hours[2]
Excretion Renal
Therapeutic considerations
Pregnancy cat. D(US)
Legal status POM (UK) Schedule IV (US)
Routes Oral
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Alprazolam (trade name Xanax, among others) is a potent short-acting drug of the benzodiazepine class. It is primarily used to treat moderate to severe anxiety disorders (e.g., social anxiety disorder) and panic attacks, and is used as an adjunctive treatment for anxiety associated with moderate depression. It is available in an instant release and an extended-release (Xanax XR) preparation, both of which are available under several generic names. Alprazolam possesses anxiolytic, sedative, hypnotic, anticonvulsant, and muscle relaxant properties.[3]

Alprazolam has a fast onset of symptom relief (within the first week). It is the most commonly misused benzodiazepine; however, the majority of prescribed users do not develop a substance use disorder.[4][5] Tolerance to the therapeutic effects of alprazolam is controversial with one view being that alprazolam is ineffective with long term use[6] and the other view being that tolerance to the therapeutic effects does not occur.[7] A physical dependence commonly occurs as a result of alprazolam treatment, typified by a withdrawal and rebound symptoms necessitating a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[4] Withdrawal symptoms similar in character to those noted with sedative-hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include anxiety, abdominal pain, muscle cramps, vomiting, depression, sweating, tremors and in very rare cases suicidal ideation or suicide itself.[8]

Contents

History

Alprazolam was first released by Upjohn (now a part of Pfizer). It is covered under U.S. Patent 3,987,052, which was filed on October 29, 1969, granted on October 19, 1976 and expired in September 1993. Alprazolam was released in 1981.[9][10] The first approved indication was panic disorder. Upjohn took this direction at the behest of a young psychiatrist David Sheehan. Sheehan's suggestion was to use the new distinction the DSM-III created in the classification of anxiety disorders between generalized anxiety disorder (GAD) and panic disorder in order to market alprazolam specifically for the latter. Panic disorder was, at that point, perceived to be rare and treatable only with tricyclic antidepressants; benzodiazepines were thought to be ineffective.

However, from his clinical experience, Sheehan knew panic disorder to be both widespread among the populace and responsive to benzodiazepines. He suggested to Upjohn that marketing alprazolam for panic disorder would both cover new diagnostic territory and emphasize the unique potency of this drug. Sheehan describes that the first group of patients treated by alprazolam was so impressed by its action that the company knew outright that the drug was going to be a hit. A few of those patients actually pooled their money and purchased stock in Upjohn. Several months later, when alprazolam was approved by the United States Food and Drug Administration, they sold out and made a profit.[11]

Alprazolam has an exceptional history insofar as soon after its introduction a number of case reports were published in the medical literature of severe withdrawal symptom-related case reports of psychoses, seizures, and intense rebound anxiety upon discontinuation of alprazolam.[12] Several studies found that initial treatment of panic disorder with alprazolam was significantly superior but after 8 weeks of use alprazolam lost its effectiveness and was no more effective than placebo. It was found that behavioural therapy and the drug imipramine however, proved superior to both placebo and alprazolam. It has been argued that placebo is superior than alprazolam after 8 weeks of use due to lack of rebound withdrawal effects and side effects. Controversy exists in that there are allegations that the drug manufacturer suppressed these negative findings regarding lack of sustained efficacy.[13][14]

Indications

The main medical uses for alprazolam include:

Panic disorder

Alprazolam is FDA-approved for the short-term treatment (up to 8 weeks) of panic disorder, with or without agoraphobia. Alprazolam is very effective in the short-term symptomatic relief of moderate to severe anxiety, essential tremor, and panic attacks. Physicians that elect to prescribe alprazolam for longer than 8 weeks should be aware that continued efficacy has not been systematically demonstrated beyond 8 weeks' use, as tolerance to alprazolam's effects may occur after 8 weeks and necessitate discontinuation or physician-directed dose escalation.[15] The physician should periodically reassess the usefulness of the drug for the individual patient.[16] Alprazolam is recommended for treatment resistant cases of panic disorder where there is no history of tolerance or dependence.[17]

Anxiety disorders

Alprazolam is indicated for the management of anxiety disorders (a condition corresponding most closely to the APA Diagnostic and Statistical Manual DSM-III-R diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety.[16] Alprazolam is recommended for the short-term treatment (2–4 weeks) of severe acute anxiety.[18][19]

Alprazolam is sometimes prescribed for anxiety with associated depression. There is some evidence that it has antidepressant effects in treating clinical depression in outpatient settings; evidence for inpatients is lacking.[20] The antidepressant effects of alprazolam may be due to its effects on beta-adrenergic receptors.[21] Other benzodiazepines are not known to have antidepressant activity.[22][23] Studies show that any antidepressant action of alprazolam is questionable and generally weak in comparison to those of antidepressant medications.[24][25][26][27] In contrast, while alprazolam in acute or short-term treatment may have some antidepressant properties, there is evidence that up to a third of long-term users of alprazolam may develop depression.[28]

Side effects

Although the side-effect profile of alprazolam is, in general, benign, side-effects may occur in some patients and are more likely the higher the dosage taken. Some side-effects may disappear with continued treatment. If signs of an allergic reaction occur - such as hives; difficulty breathing; swelling of face, lips, tongue, or throat - medical attention should be sought immediately. Medical attention should also be sought immediately if signs of jaundice appear: yellowing of the skin or eyes. Other side-effects that may occur are as follows:

Paradoxical reactions

Although unusual, if the following paradoxical reactions occur, the prescribing physician or other healthcare professional should be alerted and the medication gradually discontinued:

Physical dependence and withdrawal

Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA A receptors and, thus, GABAnergic neurons. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and less powerful in their effects.[49]

Not all withdrawal effects are evidence of true dependence or withdrawal. Recurrence of symptoms such as anxiety may simply indicate that the drug was having its expected anti-anxiety effect and that, in the absence of the drug, the symptom has returned to pretreatment levels. If the symptoms are more severe or frequent, the patient may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the patient's actually being drug-dependent.[49]

Alprazolam and other benzodiazepines may also cause the development of physical dependence, tolerance, and benzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment.[50][51] There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a patient stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.[52][53][54]

In 1992, Romach and colleagues reported that dose escalation is not a characteristic of long-term alprazolam users, and that the majority of long-term alprazolam users change their initial pattern of regular use to one of symptom control only when required.[55]

If a patient feels the need to end treatment with alprazolam, he/she should consult his/her physician before discontinuing the medication. Some common symptoms of alprazolam discontinuation include tachycardia, dysphoria, dry mouth, loss of appetite, insomnia, anxiety, dizziness, tremors, nausea, cramps, vomiting, diarrhea, panic attacks, mood swings, heart palpitations, memory loss. Less common and more severe reactions can occur, including hallucinations, seizures or fever[56]

Patients taking a dosing regimen larger than 4 mg per day have an increased potential for dependence. This medication may cause withdrawal symptoms upon abrupt withdrawal or rapid tapering, which in some cases have been known to cause seizures. The discontinuation of this medication may also cause a reaction called rebound anxiety. Other withdrawal effects reported from discontinuing alprazolam therapy include homicidal ideation (very rare), rage reactions, hyperalertness, vivid dreams, and intrusive thoughts.[57] Grand mal seizures have occurred after abrupt withdrawal after only short-term use. Therefore, even short-term users of alprazolam should taper off of their medication slowly to avoid serious withdrawal reactions including seizures.[58][59]

Alprazolam should never be abruptly stopped if taken regularly for any length of time because severe withdrawal symptoms may occur. Severe psychosis and seizures have been reported in the medical literature from abrupt alprazolam discontinuation,[60][61] and one death occurred from withdrawal-related seizures after gradual dose reduction.[61]

In a 1983 study of patients that had taken long-acting benzodiazepines, e.g., clorazepate, for extended periods, the medications were stopped abruptly under double-blind conditions (that is, patients were receiving either placebo or the same drug they had been taking). Only 5% of patients that had been taking the drug for less than 8 months demonstrated withdrawal symptoms, but 43% of those that had been taking them for more than 8 months did, whereas, with alprazolam - a short-acting benzodiazepine - taken for 8 weeks, 35% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.[62]

The benzodiazepines diazepam (Valium) and oxazepam (Serepax) have been found to produce fewer withdrawal reactions than alprazolam (Xanax) or lorazepam (Temesta/Ativan). Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms experienced during dose reduction of alprazolam include: dosage used, length of use, frequency of dosing, personality characteristics of the individual, previous use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), current use of cross-dependent/cross-tolerant drugs (alcohol or other sedative-hypnotic drugs), use of other short-acting, high-potency benzodiazepines[12][63] and method of discontinuation.[64]

Contraindications

Benzodiazepines require special precaution if used in children and in alcohol- or drug-dependent individuals.[65] Use of alprazolam should be avoided or carefully monitored by medical professionals in individuals with the following conditions: Myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies (e.g., cirrhosis), severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory weakness including unstable myasthenia gravis, acute pulmonary insufficiency, chronic psychosis, hypersensitivity or allergy to alprazolam or other drugs in the benzodiazepine class, borderline personality disorder (may induce suicidality and dyscontrol).[66][67][68][69]

Women who are pregnant or are planning on becoming pregnant should avoid starting alprazolam.[70] It should be considered that the child born of a mother receiving benzodiazepines may be at risk of developing withdrawal reactions during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers that have been receiving benzodiazepines.[71]

Benzodiazepines, including alprazolam, are known to be excreted in human milk.[72] Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight.[73][74] As a general rule, nursing should not be undertaken by mothers who use alprazolam.

Elderly individuals should be cautious in the use of alprazolam due to the possibility of increased susceptibility to side-effects, especially loss of coordination and drowsiness.[74]

Like all central nervous system depressants, including alcohol, alprazolam in larger-than-normal doses can cause significant deterioration in alertness, combined with increased feelings of drowsiness, especially in those unaccustomed to the drug's effects.[75] People driving or conducting activities that require vigilance should exercise caution in using alprazolam or any other depressant.

Pregnancy and lactation

Benzodiazepines cross the placenta and enter into the fetus and also penetrate into breast milk. The use of benzodiazepines during pregnancy or lactation should be weighed against the potential risks. Alprazolam should not be used during pregnancy and lactation as it is believed to be associated with congenital abnormalities. In general benzodiazepines should not be used during pregnancy. If a benzodiazepine is needed during pregnancy diazepam or chlordiazepoxide are recommended as these benzodiazepines have a better safety profile than alprazolam. Possible adverse effects to the fetus include abortion, malformation, intrauterine growth retardation, functional deficits, carcinogenesis, and mutagenesis. Use in the last trimester may cause fetal drug dependence and withdrawal symptoms.[76] However, in long-term users of benzodiazepines or antidepressants abrupt discontinuation due to concerns of teratogenic effects of the medications is more likely to do harm than good. Abrupt withdrawal has a high risk of causing extreme withdrawal symptoms including suicidal ideation and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications including benzodiazepines. In general physicians are not aware of the severe consequences of abrupt withdrawal of psychotropic medications such as benzodiazepines or antidepressants.[77]

Pharmacology

Alprazolam is classed as a high-potency benzodiazepine and is a triazolobenzodiazepine,[78][79] that is, a benzodiazepine with a triazole ring attached to its structure. Benzodiazepines produce a variety of therapeutic and adverse effects by binding to the benzodiazepine site on the GABAA receptor and modulating the function of the GABA receptor, the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates inhibitory or calming effects of alprazolam on the nervous system. The GABAA receptor is made up from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and, what is significant, different activities with regard to benzodiazepines.[38][80] Benzodiazepines and in particular alprazolam causes a marked suppression of the hypothalamicpituitary-adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic[81] and amnesics.[82]

Pharmacokinetics

Alprazolam is readily absorbed from the gastrointestinal tract with a bioavailability of 80–100%. The peak plasma concentration is achieved in 1–2 hours. Most of the drug is bound to plasma protein, mainly serum albumin. Alprazolam is hydroxylated in the liver to α-hydroxyalprazolam, which is also pharmacologically active but much less so than the parent compound. This and other metabolites are later excreted in urine as glucuronides. Some of the drug is also excreted in unchanged form. The elderly clear alprazolam more slowly than younger adults.[83]

Food and drug interactions

Alprazolam is primarily metabolised via CYP3A4.[84] Combining CYP3A4 inhibitors with alprazolam can lead to profound sedating effects.[85] Cimetidine, erythromycin, fluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir all interact with alprazolam leading to a delayed clearance of alprazolam, which may result in excessive accumulation of alprazolam. This may result in excessive sedation and other adverse effects associated with excessive intake of alprazolam.[83][86]

Imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam tablets in doses up to 4 mg/day.[87] Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[88]

Alcohol is one of the most important and common interactions. Alcohol and benzodiazepines such as alprazolam taken in combination have a synergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken the worse the interaction.[31] Combination of alprazolam with the herb kava can result in the development of a semi-comatose state.[89] Hypericum conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.[90][91][92]

Recreational use

Sandoz generic 2 mg alprazolam tablets

Alprazolam has a relatively high potential for recreational use[93] and is the most commonly misused benzodiazepine.[5] Injection of alprazolam, though extremely rare, is considered especially dangerous by medical professionals[94] because, when crushed in water it will not fully dissolve (40 µg/ml of H2O at pH 7, and 12 mg/mL at pH 1.2[95]), potentially causing severe damage to arteries if not filtered properly. While it is somewhat soluble in alcohol, the combination of the two, particularly when injected, has the potential to cause a serious, and potentially fatal, overdose. Alprazolam may also be insufflated.[96] Snorting alprazolam is highly inefficient, as it is insoluble in water and does not readily cross the nasal membranes, resulting in reduced bioavailability. However, long-term use of benzodiazepines does not usually result in notable dose escalation, and most prescribed alprazolam users do not use their medication recreationally.[97]

Alprazolam is sometimes used with other recreational drugs to relieve the panic or distress of dysphoric reactions to psychedelics such as LSD, and also to promote sleep in the "come-down" period following use of recreational drugs with stimulant or insomniac properties (such as LSD, cocaine, amphetamine and other related amphetamines, DXM, and MDMA). It is also often used in conjunction with marijuana or heroin to potentiate the relaxing effect.[98][99][100][101][102] Due to the low weight of a dose, alprazolam in one case was found to be distributed on blotter paper in a manner similar to LSD.[103]

A large-scale nationwide USA government study conducted by SAMHSA found that, in the USA, benzodiazepines are recreationally the most frequently-used pharmaceutical due to their widespread availability, with 35% of drug-related visits to the Emergency Department involving them. Benzodiazepines are more commonly used recreationally than opioid pharmaceuticals, which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly used recreationally than benzodiazepines; however, benzodiazepines remain in Schedule IV of the Controlled Substances Act, whereas opioids are much more strictly controlled due to their higher abuse potential. Men use benzodiazepines recreationally as commonly as women. The report found that alprazolam is the most common benzodiazepine for recreational use followed by clonazepam, lorazepam, and diazepam.[8]

Patients at a high risk for misuse and addiction

At a particularly high risk for misuse and dependence are patients with a history of alcoholism (including a family history of alcoholism) or drug abuse and/or dependence[104][105][106][107][108] and patients with borderline personality disorder.[109]

Overdose

Overdoses of alprazolam can be mild to severe depending on how much of the drug is taken and if any other depressants have been taken. Alprazolam is significantly more toxic in overdose having higher rates of fatalities compared to other benzodiazepines. A study in New Zealand found that alprazolam is almost 8 times more likely to result in death in overdose than other sedative hypnotics as a group, with higher rates of intensive-care unit admissions and mechanical ventilation. Combined overdose with tricyclic antidepressants, alcohol, or opiates, or overdoses of alprazolam in the elderly, significantly increases the likelihood for severe toxicity and possible fatality.[110] Alprazolam (Xanax) overdose reflect the central nervous system depression of the brain and may include one or more of the following symptoms:[34]

About 50% of the cases of death involving alprazolam were attributed to combined drug toxicity of alprazolam and another drug, most often cocaine and methadone. Only 1% of such deaths were attributed to alprazolam alone.[111][112]

Detection in body fluids

Alprazolam 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 alprazolam concentrations are usually in a range of 10-100 μg/L in persons receiving the drug therapeutically, 100-300 μg/L in those arrested for impaired driving and 300-2000 μg/L in victims of acute overdosage. Most commercial immunoassays for the benzodiazepine class of drugs will cross-react with alprazolam, but confirmation and quantitation is usually performed using chromatographic techniques.[113][114][115]

Availability

Alprazolam instant release (IR) is available in 0.25 mg, 0.5 mg, 1 mg and 2 mg strength regular and orally disintegrating tablets.[116] Alprazolam Extended Release (XR) is available in 0.5 mg, 1 mg and 2 mg 3 mg strength oral.

Alprazolam is available in English-speaking countries under the following brand names:[117]

Legal status

In the United States, alprazolam is a prescription drug and is assigned to Schedule IV of the Controlled Substances Act by the Drug Enforcement Administration.[118] Under the UK drug misuse classification system benzodiazepines are class C drugs;[119] alprazolam itself is not available on the NHS and can only be obtained on private prescription.[120] Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.[121] In Ireland, alprazolam is a Schedule 4 medicine.[122] In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).[123] In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.

See also

References

  1. ↑ First DataBank (July 2008). "Xanax (Alprazolam) clinical pharmacology - prescription drugs and medications at RxList". RxList. http://www.rxlist.com/xanax-drug.htm#cp. 
  2. ↑ First DataBank (July 2008). "Xanax XR (Alprazolam) clinical pharmacology - prescription drugs and medications at RxList". RxList. http://www.rxlist.com/xanax-xr-drug.htm#cp. 
  3. ↑ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. http://www.benthamdirect.org/pages/content.php?CDM/2008/00000009/00000008/0009F.SGM. 
  4. ↑ 4.0 4.1 Verster JC, Volkerts ER. (2004). "Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature". CNS Drug Rev. 10 (1): 45–76. PMID 14978513. 
  5. ↑ 5.0 5.1 Galanter, Marc (1 July 2008). The American Psychiatric Publishing Textbook of Sustance Abuse Treatment (American Psychiatric Press Textbook of Substance Abuse Treatment) (American Psychiatric ... Press Textbook of Substance Abuse Treatment) (4 ed.). American Psychiatric Publishing, Inc.. p. 222. ISBN 978-1-58562-276-4. http://books.google.com/?id=6wdJgejlQzYC. 
  6. ↑ McIntosh A, Cohen A, Turnbull N et al. (2004). "Clinical guidelines and evidence review for panic disorder and generalised anxiety disorder" (PDF). National Collaborating Centre for Primary Care. http://www.nice.org.uk/nicemedia/pdf/cg022fullguideline.pdf. Retrieved 2009-06-16. 
  7. ↑ Work Group on Panic Disorder (January 2009). "APA Practice Guideline for the Treatment of Patients With Panic Disorder, Second Edition" (PDF). http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=PanicDisorder_2e_PracticeGuideline. Retrieved 07/12/09. 
  8. ↑ 8.0 8.1 United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2006). "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. http://dawninfo.samhsa.gov/files/ed2006/DAWN2k6ED.htm. Retrieved 9 February 2009. 
  9. ↑ Cynthia Cotts (November 19, 2007). "Xanax junkies". Boston, USA: The Phoenix. http://thephoenix.com/article_ektid51411.aspx. 
  10. ↑ Walker, Sydney (3 December 1996). A dose of sanity: mind, medicine, and misdiagnosis. New York: John Wiley & Sons. pp. 64–65. ISBN 978-0-471-19262-6. http://books.google.com/?id=1H_jx9XO4dcC&pg=PA65. 
  11. ↑ Healy, David (2000). The Psychopharmacologists, Vol. III: Interviews. London: Arnold. pp. 479–504. ISBN 0-340-761105. 
  12. ↑ 12.0 12.1 Wolf B, Griffiths RR (December 1991). "Physical dependence on benzodiazepines: differences within the class". Drug Alcohol Depend 29 (2): 153–6. doi:10.1016/0376-8716(91)90044-Y. PMID 1686752. http://linkinghub.elsevier.com/retrieve/pii/0376-8716(91)90044-Y. 
  13. ↑ Walker, Sydney (3 December 1997). A dose of sanity: mind, medicine, and misdiagnosis. New York: Wiley Sons. pp. 65–74. ISBN 978-0-471-19262-6. http://books.google.com/?id=1H_jx9XO4dcC. 
  14. ↑ J. McNally, Richard (1994). Panic disorder: a critical analysis. New York: Guilford Press. pp. 93–99. ISBN 978-0-89862-263-8. http://books.google.com/?id=SlUl5oTQIHoC. 
  15. ↑ FDA (23rd). "FDA APPROVED LABELING FOR XANAX XR" (pdf). Federal Drug Administration. pp. 4. http://www.fda.gov/cder/foi/label/2003/21434_xanax_lbl.pdf. Retrieved 2 August 2007. "The longer-term efficacy of XANAX XR has not been systematically evaluated. Thus, the physician that elects to use this drug for periods longer than 8 weeks should periodically reassess the usefulness of the drug for the individual patient." 
  16. ↑ 16.0 16.1 First DataBank (July 2008). "Xanax (Alprazolam) clinical pharmacology - prescription drugs and medications at RxList". RxList. http://www.rxlist.com/xanax-drug.htm. 
  17. ↑ Bandelow, B.; Zohar, J.; Hollander, E.; Kasper, S.; Möller, HJ.; World Federation of Societies of Biological Psychiatry Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders (Oct 2002). "World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders.". World J Biol Psychiatry 3 (4): 171–99. doi:10.3109/15622970209150621. PMID 12516310. 
  18. ↑ NetDoctor (October 1, 2006). "Xanax". netdoctor.co.uk. http://www.netdoctor.co.uk/medicines/100002807.html. Retrieved 2 August 2007. 
  19. ↑ The British National Formulary (2007). "Alprazolam". BNF. http://www.bnf.org/bnf/bnf/53/3173.htm. Retrieved 2 August 2007. 
  20. ↑ Warner MD; Peabody CA, Whiteford HA, Hollister LE (April 1988). "Alprazolam as an antidepressant". J Clin Psychiatry 49 (4): 148–50. PMID 3281931. 
  21. ↑ Sethy, Vh; Hodges, Dh, Jr (May 1982). "Role of beta-adrenergic receptors in the antidepressant activity of alprazolam.". Research communications in chemical pathology and pharmacology 36 (2): 329–32. PMID 6285432. 
  22. ↑ Lader, Mh (9 December 1985). "Treatment of affective disorders." (Free full text). British journal of clinical pharmacology 19 (Suppl 1): 29S–30S. PMID 2859875. 
  23. ↑ Johnson, Da (9 December 1985). "The use of benzodiazepines in depression." (Free full text). British journal of clinical pharmacology 19 (Suppl 1): 31S–35S. PMID 2859876. 
  24. ↑ Kostowski W, Malatyńska E, Płaźnik A, Dyr W, Danysz W (1986). "Comparative studies on antidepressant action of alprazolam in different animal models". Pol J Pharmacol Pharm 38 (5-6): 471–81. PMID 2883637. 
  25. ↑ Srisurapanont, M; Boonyanaruthee, V (March 1997). "Alprazolam and standard antidepressants in the treatment of depression: a meta-analysis of the antidepressant effect.". Journal of the Medical Association of Thailand = Chotmaihet thangphaet 80 (3): 183–8. PMID 9175386. 
  26. ↑ Brasfield, Kh (September 1991). "Practical psychopharmacologic considerations in depression.". The Nursing clinics of North America 26 (3): 651–63. PMID 1891399. 
  27. ↑ Hubain, Pp; Castro, P; Mesters, P; De, Maertelaer, V; Mendlewicz, J (January 1990). "Alprazolam and amitriptyline in the treatment of major depressive disorder: a double-blind clinical and sleep EEG study.". Journal of affective disorders 18 (1): 67–73. doi:10.1016/0165-0327(90)90118-R. PMID 2136871. 
  28. ↑ Lydiard, Rb; Laraia, Mt; Ballenger, Jc; Howell, Ef (May 1987). "Emergence of depressive symptoms in patients receiving alprazolam for panic disorder.". The American journal of psychiatry 144 (5): 664–5. PMID 3578580. 
  29. ↑ 29.0 29.1 Rawson NS, Rawson MJ (1999). "Acute adverse event signalling scheme using the Saskatchewan Administrative health care utilization datafiles: results for two benzodiazepines". Can J Clin Pharmacol 6 (3): 159–66. PMID 10495368. 
  30. ↑ 30.0 30.1 "Alprazolam – Complete medical information regarding this treatment of anxiety disorders on MedicineNet.com". medicinenet.com. http://www.medicinenet.com/alprazolam/article.htm. Retrieved 2 August 2007. 
  31. ↑ 31.0 31.1 31.2 Michel L, Lang JP (2003). "[Benzodiazepines and forensic aspects"] (in French). Encephale 29 (6): 479–85. PMID 15029082. http://www.masson.fr/masson/MDOI-ENC-12-2003-29-6-0013-7006-101019-ART2. 
  32. ↑ Kravitz HM, Fawcett J, Newman AJ (October 1993). "Alprazolam and depression: a review of risks and benefits". J Clin Psychiatry 54 (Suppl): 78–84; discussion 85. PMID 8262892. 
  33. ↑ Hori A (February 1998). "Pharmacotherapy for personality disorders". Psychiatry Clin. Neurosci. 52 (1): 13–9. doi:10.1111/j.1440-1819.1998.tb00967.x. PMID 9682928. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1323-1316&date=1998&volume=52&issue=1&spage=13. 
  34. ↑ 34.0 34.1 "alprazolam Side Effects, Interactions and Information - Drugs.com". drugs.com. http://www.drugs.com/alprazolam.html. Retrieved 2 August 2007. 
  35. ↑ "Complete Alprazolam information from Drugs.com". drugs.com. http://alprazolam.drugs.com/. Retrieved 2 August 2007. 
  36. ↑ Cassano GB, Toni C, Petracca A, et al. (March 1994). "Adverse effects associated with the short-term treatment of panic disorder with imipramine, alprazolam or placebo". Eur Neuropsychopharmacol 4 (1): 47–53. doi:10.1016/0924-977X(94)90314-X. PMID 8204996. 
  37. ↑ Münte TF, Gehde E, Johannes S, Seewald M, Heinze HJ (1996). "Effects of alprazolam and bromazepam on visual search and verbal recognition memory in humans: a study with event-related brain potentials". Neuropsychobiology 34 (1): 49–56. doi:10.1159/000119291. PMID 8884760. 
  38. ↑ 38.0 38.1 Barbee, Jg (October 1993). "Memory, benzodiazepines, and anxiety: integration of theoretical and clinical perspectives.". The Journal of clinical psychiatry 54 (Suppl): 86–97; discussion 98–101. PMID 8262893. 
  39. ↑ "ALPRAZOLAM - ORAL (Xanax) side effects, medical uses, and drug interactions.". medicinenet.com. http://www.medicinenet.com/alprazolam-oral/article.htm. Retrieved 2 August 2007. 
  40. ↑ Elie R, Lamontagne Y (June 1984). "Alprazolam and diazepam in the treatment of generalized anxiety". J Clin Psychopharmacol 4 (3): 125–9. doi:10.1097/00004714-198406000-00002. PMID 6145726. 
  41. ↑ http://doublecheckmd.com/EffectsDetail.do?dname=Xanax&sid=1327&eid=2974
  42. ↑ Evans SM, Foltin RW, Fischman MW (June 1999). "Food "cravings" and the acute effects of alprazolam on food intake in women with premenstrual dysphoric disorder". Appetite 32 (3): 331–49. doi:10.1006/appe.1998.0222. PMID 10336792. http://linkinghub.elsevier.com/retrieve/pii/S0195-6663(98)90222-7. 
  43. ↑ Noyes R, DuPont RL, Pecknold JC, et al. (May 1988). "Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety". Arch. Gen. Psychiatry 45 (5): 423–8. PMID 3358644. 
  44. ↑ Béchir M, Schwegler K, Chenevard R, et al. (July 2007). "Anxiolytic therapy with alprazolam increases muscle sympathetic activity in patients with panic disorders". Auton Neurosci 134 (1-2): 69–73. doi:10.1016/j.autneu.2007.01.007. PMID 17363337. http://linkinghub.elsevier.com/retrieve/pii/S1566-0702(07)00008-2. 
  45. ↑ Rapaport, M; Braff, Dl (January 1985). "Alprazolam and hostility.". The American journal of psychiatry 142 (1): 146. PMID 2857070. 
  46. ↑ Arana, Gw; Pearlman, C; Shader, Ri (March 1985). "Alprazolam-induced mania: two clinical cases.". The American journal of psychiatry 142 (3): 368–9. PMID 2857534. 
  47. ↑ Strahan A, Rosenthal J, Kaswan M, Winston A (July 1985). "Three case reports of acute paroxysmal excitement associated with alprazolam treatment". Am J Psychiatry 142 (7): 859–61. PMID 2861755. http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=2861755. 
  48. ↑ Reddy J, Khanna S, Anand U, Banerjee A (August 1996). "Alprazolam-induced hypomania". Aust N Z J Psychiatry 30 (4): 550–2. doi:10.3109/00048679609065031. PMID 8887708. 
  49. ↑ 49.0 49.1 Stahl, Stephen (1996). Essential Pharmacology: Neuroscientific Basis and Practical Applications. Cambridge: Cambridge University Press. ISBN 0-521-42620-0. 
  50. ↑ Juergens, Sm; Morse, Rm (May 1988). "Alprazolam dependence in seven patients.". The American journal of psychiatry 145 (5): 625–7. PMID 3258735. 
  51. ↑ Klein, E (2002). "The role of extended-release benzodiazepines in the treatment of anxiety: a risk-benefit evaluation with a focus on extended-release alprazolam.". The Journal of clinical psychiatry 63 (Suppl 14): 27–33. PMID 12562116. 
  52. ↑ Professor Heather Ashton (2002). "The Ashton Manual – Benzodiazepines: How They Work and How to Withdraw". benzo.org.uk. http://www.benzo.org.uk/manual/. Retrieved 2008-10-31. 
  53. ↑ Dr JG McConnell (May 2007). "The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam". bcnc. http://www.bcnc.org.uk/whyvalium.html. Retrieved 2008-10-31. 
  54. ↑ Closser, Mh; Brower, Kj (July 1994). "Treatment of alprazolam withdrawal with chlordiazepoxide substitution and taper.". Journal of substance abuse treatment 11 (4): 319–23. doi:10.1016/0740-5472(94)90042-6. PMID 7966502. 
  55. ↑ Romach MK, Somer GR, Sobell LC, Sobell MB, Kaplan HL, Sellers EM (October 1992). "Characteristics of long-term alprazolam users in the community". J Clin Psychopharmacol 12 (5): 316–21. doi:10.1097/00004714-199210000-00004. PMID 1479048. 
  56. ↑ Fyer AJ; Liebowitz MR, Gorman JM, Campeas R, Levin A, Davies SO, Goetz D, Klein DF (March 1987). "Discontinuation of Alprazolam Treatment in Panic Patients". Am J Psychiatry (benzo.org.uk) 144 (3): 303–8. PMID 3826428. http://www.benzo.org.uk/alprazolam.htm. Retrieved 10 December 2008. 
  57. ↑ Risse SC; Whitters A, Burke J, Chen S, Scurfield RM, Raskind MA. (1990). "Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder". The Journal of clinical psychiatry. 51 (5): 206–9. PMID 2335496. 
  58. ↑ Breier, A; Charney, Ds; Nelson, Jc (December 1984). "Seizures induced by abrupt discontinuation of alprazolam.". The American journal of psychiatry 141 (12): 1606–7. PMID 6150649. 
  59. ↑ Noyes R, Perry PJ, Crowe RR, et al. (January 1986). "Seizures following the withdrawal of alprazolam". J. Nerv. Ment. Dis. 174 (1): 50–2. doi:10.1097/00005053-198601000-00009. PMID 2867122. 
  60. ↑ Levy AB (1984). "Delirium and seizures due to abrupt alprazolam withdrawal: case report". J Clin Psychiatry 45 (1): 38–9. PMID 6141159. 
  61. ↑ 61.0 61.1 Haque W, Watson DJ, Bryant SG (1990). "Death following suspected alprazolam withdrawal seizures: a case report". Tex Med 86 (1): 44–7. PMID 2300914. 
  62. ↑ Schatzberg, Alan; DeBattista, Charles (2003). Manual of Clinical Psychopharmacology. Washington, DC: American Psychiatric Pub.. pp. 328–331. ISBN 1-58562-209-5. 
  63. ↑ Higgitt, A; Fonagy, P; Lader, M (1988). "The natural history of tolerance to the benzodiazepines.". Psychological medicine. Monograph supplement 13: 1–55. doi:10.1017/S0264180100000412. PMID 2908516. 
  64. ↑ Professor Heather Ashton (August 2002). "The Ashton Manual - Benzodiazepines: How They Work and How to Withdraw". http://www.benzo.org.uk/manual/. 
  65. ↑ Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM. et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome.". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  66. ↑ Hori A. (February 1998). "Pharmacotherapy for personality disorders". Psychiatry and clinical neurosciences. 52 (1): 13–9. doi:10.1111/j.1440-1819.1998.tb00967.x. PMID 9682928. 
  67. ↑ Gardner DL, Cowdry RW (January 1985). "Alprazolam-induced dyscontrol in borderline personality disorder". Am J Psychiatry 142 (1): 98–100. PMID 2857071. 
  68. ↑ "Alprazolam". British National Formulary. 2007. http://www.bnf.org/bnf/bnf/53/3173.htm. Retrieved 3 August 2007. 
  69. ↑ mentalhealth.com (2007). "Alprazolam". http://www.mentalhealth.com/drug/p30-x01.html. Retrieved 3 August 2007. 
  70. ↑ "Xanax (Alprazolam) Drug Information: Uses, Side Effects, Drug Interactions and Warnings at RxList". USA: RxList.com. July 2008. pp. 4. http://www.rxlist.com/xanax-drug.htm#wcp. 
  71. ↑ García-Algar O; López-Vílchez MA, Martín I, Mur A, Pellegrini M, Pacifici R, Rossi S, Pichini S. (2007). "Confirmation of gestational exposure to alprazolam by analysis of biological matrices in a newborn with neonatal sepsis". Clinical toxicology (Philadelphia, Pa.). 45 (3): 295–8. doi:10.1080/15563650601072191. PMID 17453885. 
  72. ↑ Oo CY; Kuhn RJ, Desai N, Wright CE, McNamara PJ. (September 1995). "Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk". British journal of clinical pharmacology. 40 (3): 231–6. PMID 8527284. 
  73. ↑ DataBank, Inc (July 2008). "Xanax (Alprazolam) Drug Information: Uses, Side Effects, Drug Interactions and Warnings at RxList". RxList. pp. 8. http://www.rxlist.com/cgi/generic/alpraz_wcp.htm. Retrieved 7 December 2008. 
  74. ↑ 74.0 74.1 "ALPRAZOLAM - ORAL (Xanax) side effects, medical uses, and drug interactions". MedicineNet. July 2005. http://www.medicinenet.com/alprazolam-oral/article.htm. Retrieved 7 December 2008. 
  75. ↑ Kozená L; Frantik E, Horváth M. (May 1995). "Vigilance impairment after a single dose of benzodiazepines". Psychopharmacology (Berl). 119 (1): 39–45. doi:10.1007/BF02246052. PMID 7675948. 
  76. ↑ Iqbal, MM.; Sobhan, T.; Ryals, T. (Jan 2002). "Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant.". Psychiatr Serv 53 (1): 39–49. doi:10.1176/appi.ps.53.1.39. PMID 11773648. http://ps.psychiatryonline.org/cgi/content/full/53/1/39. 
  77. ↑ Einarson A, Selby P, Koren G (January 2001). "Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling" (PDF). J Psychiatry Neurosci 26 (1): 44–8. PMID 11212593. PMC 1408034. http://www.cma.ca/multimedia/staticContent/HTML/N0/l2/jpn/vol-26/issue-1/pdf/pg44.pdf. 
  78. ↑ Skelton KH; Nemeroff CB, Owens MJ (October 20, 2004). "Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression". J Neurosci 24 (42): 9303–12. doi:10.1523/JNEUROSCI.1737-04.2004. PMID 15496666. 
  79. ↑ Chouinard G (2004). "Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound". J Clin Psychiatry 65 (Suppl 5): 7–12. PMID 15078112. http://article.psychiatrist.com/?ContentType=START&ID=10000770. 
  80. ↑ White, G; Gurley, Da (February 1995). "Alpha subunits influence Zn block of gamma 2 containing GABAA receptor currents.". Neuroreport 6 (3): 461–4. doi:10.1097/00001756-199502000-00014. PMID 7766843. 
  81. ↑ Arvat, E.; Giordano, R.; Grottoli, S.; Ghigo, E. (Sep 2002). "Benzodiazepines and anterior pituitary function.". J Endocrinol Invest 25 (8): 735–47. PMID 12240908. 
  82. ↑ Mandrioli, R.; Mercolini, L.; Raggi, MA. (Oct 2008). "Benzodiazepine metabolism: an analytical perspective.". Curr Drug Metab 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. 
  83. ↑ 83.0 83.1 Greenblatt, Dj; Wright, Ce (June 1993). "Clinical pharmacokinetics of alprazolam. Therapeutic implications.". Clinical pharmacokinetics 24 (6): 453–71. doi:10.2165/00003088-199324060-00003. PMID 8513649. 
  84. ↑ Otani, K. (2003). "[Cytochrome P450 3A4 and Benzodiazepines]". Seishin Shinkeigaku Zasshi 105 (5): 631–42. PMID 12875231. 
  85. ↑ Dresser, GK.; Spence, JD.; Bailey, DG. (Jan 2000). "Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.". Clin Pharmacokinet 38 (1): 41–57. doi:10.2165/00003088-200038010-00003. PMID 10668858. 
  86. ↑ Wang JS, DeVane CL (2003). "Pharmacokinetics and drug interactions of the sedative hypnotics" (PDF). Psychopharmacol Bull 37 (1): 10–29. PMID 14561946. http://www.medworksmedia.com/psychopharmbulletin/pdf/12/010-029_PB%20W03_Wang_final.pdf. 
  87. ↑ "FDA SPL Approved Application Filing for NDC Code 0228-3083 (Alprazolam by Actavis Elizabeth LLC)". AD535DF9-6361-460D-9648-450A0A6F61CD.xml. 
  88. ↑ Back DJ; Orme ML. (June 1990). "Pharmacokinetic drug interactions with oral contraceptives". Clin Pharmacokinet. 18 (6): 472–84. doi:10.2165/00003088-199018060-00004. PMID 2191822. 
  89. ↑ Izzo, AA.; Ernst, E. (2001). "Interactions between herbal medicines and prescribed drugs: a systematic review.". Drugs 61 (15): 2163–75. doi:10.2165/00003495-200161150-00002. PMID 11772128. 
  90. ↑ Izzo, AA. (Mar 2004). "Drug interactions with St. John's Wort (Hypericum perforatum): a review of the clinical evidence.". Int J Clin Pharmacol Ther 42 (3): 139–48. PMID 15049433. 
  91. ↑ Madabushi, R.; Frank, B.; Drewelow, B.; Derendorf, H.; Butterweck, V. (Mar 2006). "Hyperforin in St. John's wort drug interactions.". Eur J Clin Pharmacol 62 (3): 225–33. doi:10.1007/s00228-006-0096-0. PMID 16477470. 
  92. ↑ Izzo, AA.; Ernst, E. (2009). "Interactions between herbal medicines and prescribed drugs: an updated systematic review.". Drugs 69 (13): 1777–98. doi:10.2165/11317010-000000000-00000. PMID 19719333. 
  93. ↑ Griffiths RR, Wolf B (August 1990). "Relative abuse liability of different benzodiazepines in drug abusers". J Clin Psychopharmacol 10 (4): 237–43. doi:10.1097/00004714-199008000-00002. PMID 1981067. 
  94. ↑ Eric C; Wang, Felix S, Chew. (2006). "MR Findings of Alprazolam Injection into the Femoral Artery with Microembolization and Rhabdomyolysis" (pdf). Radiology Case Reports 1 (3). http://www.radiologycasereports.net/index.php/rcr/article/viewPDFInterstitial/33/187. 
  95. ↑ "DB00404 (Alprazolam)". Canada: DrugBank. August 26, 2008. http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD00280. 
  96. ↑ Sheehan MF, Sheehan DV, Torres A, Coppola A, Francis E (1991). "Snorting benzodiazepines". Am J Drug Alcohol Abuse 17 (4): 457–68. doi:10.3109/00952999109001605. PMID 1684083. 
  97. ↑ Soumerai SB, Simoni-Wastila L, Singer C, et al. (July 2003). "Lack of relationship between long-term use of benzodiazepines and escalation to high dosages". Psychiatr Serv 54 (7): 1006–11. doi:10.1176/appi.ps.54.7.1006. PMID 12851438. http://ps.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=12851438. 
  98. ↑ Walker, Bm; Ettenberg, A (April 2003). "The effects of alprazolam on conditioned place preferences produced by intravenous heroin.". Pharmacology, biochemistry, and behavior 75 (1): 75–80. doi:10.1016/S0091-3057(03)00043-1. PMID 12759115. 
  99. ↑ MARCIA LANE (29 September 2006). "Xanax, alcohol mix kills 2". USA: St. Augustine Record. http://staugustine.com/stories/092906/news_4113407.shtml. Retrieved 10 December 2008. 
  100. ↑ Wright State University and the University of Akron (January 2008). "OSAM - O- GRAM Highlights of Statewide Drug Use Trends" (PDF). USA: Ohio Government. http://www.odadas.state.oh.us/WebManager/UltimateEditorInclude/UserFiles/WebDocuments/Planning/Jan05ExecSummry.pdf. Retrieved 10 December 2008. 
  101. ↑ Detective Eladio M. Paez (15 June 2008). "STATEMENT ON RAVES AND CLUB DRUGS TO THE SUBCOMMITTEE ON CRIME, CONGRESS OF THE UNITED STATES, HOUSE OF REPRESENTATIVES". USA: GOV House Judiciary. http://judiciary.house.gov/Legacy/paez0615.htm. Retrieved 10 December 2008. 
  102. ↑ "SURVEILLANCE OF DRUG ABUSE TRENDS IN THE STATE OF OHIO - A Report Prepared for the Ohio Department of Alcohol and Drug Addiction Services". USA: The Ohio Substance Abuse Monitoring Network. 31 July 2001. http://www.odadas.ohio.gov/GD/DocumentManagement/DocumentDownload.aspx?DocumentID=225. Retrieved 10 December 2008. 
  103. ↑ "Microgram bulletin". US DEA. http://www.justice.gov/dea/programs/forensicsci/microgram/mg0508/mg0508.html. 
  104. ↑ Ballenger, Jc (December 1984). "Psychopharmacology of the anxiety disorders.". The Psychiatric clinics of North America 7 (4): 757–71. PMID 6151647. 
  105. ↑ Evans, Sm; Levin, Fr; Fischman, Mw (June 2000). "Increased sensitivity to alprazolam in females with a paternal history of alcoholism.". Psychopharmacology 150 (2): 150–62. doi:10.1007/s002130000421. PMID 10907668. 
  106. ↑ Streeter, Cc; Ciraulo, Da; Harris, Gj; Kaufman, Mj; Lewis, Rf; Knapp, Cm; Ciraulo, Am; Maas, Lc; Ungeheuer, M; Szulewski, S; Renshaw, Pf (May 1998). "Functional magnetic resonance imaging of alprazolam-induced changes in humans with familial alcoholism.". Psychiatry research 82 (2): 69–82. doi:10.1016/S0925-4927(98)00009-2. PMID 9754450. 
  107. ↑ Ciraulo, Da; Sarid-Segal, O; Knapp, C; Ciraulo, Am; Greenblatt, Dj; Shader, Ri (July 1996). "Liability to alprazolam abuse in daughters of alcoholics.". The American journal of psychiatry 153 (7): 956–8. PMID 8659624. 
  108. ↑ Ciraulo, Da; Barnhill, Jg; Greenblatt, Dj; Shader, Ri; Ciraulo, Am; Tarmey, Mf; Molloy, Ma; Foti, Me (September 1988). "Abuse liability and clinical pharmacokinetics of alprazolam in alcoholic men.". The Journal of clinical psychiatry 49 (9): 333–7. PMID 3417618. 
  109. ↑ Vorma, H; Naukkarinen, Hh; Sarna, Sj; Kuoppasalmi, Ki (2005). "Predictors of benzodiazepine discontinuation in subjects manifesting complicated dependence.". Substance use & misuse 40 (4): 499–510. doi:10.1081/JA-200052433. PMID 15830732. 
  110. ↑ Isbister GK, O'Regan L, Sibbritt D, Whyte IM (July 2004). "Alprazolam is relatively more toxic than other benzodiazepines in overdose". Br J Clin Pharmacol 58 (1): 88–95. doi:10.1111/j.1365-2125.2004.02089.x. PMID 15206998. 
  111. ↑ Wolf BC, Lavezzi WA, Sullivan LM, Middleberg RA, Flannagan LM (2005). "Alprazolam-related deaths in Palm Beach County". Am J Forensic Med Pathol 26 (1): 24–7. doi:10.1097/01.paf.0000153994.95642.c1. PMID 15725773. 
  112. ↑ Rogers, Wo; Hall, Ma; Brissie, Rm; Robinson, Ca (January 1997). "Detection of alprazolam in three cases of methadone/benzodiazepine overdose.". Journal of forensic sciences 42 (1): 155–6. PMID 8988593. 
  113. ↑ Jones AW, Holmgren A, Kugelberg FC. Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results. Ther. Drug Monit. 29: 248-260, 2007.
  114. ↑ Fraser AD, Bryan W. Evaluation of the Abbott ADx and TDx serum benzodiazepine immunoassays for analysis of alprazolam. J. Anal. Toxicol. 15: 63-65, 1991.
  115. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 45-48.
  116. ↑ Merck Manual; Davis-Drug-Guide (5 February 2009). "alprazolam". Unbound Medicine. http://www.unboundmedicine.com/merckmanual/ub/view/Davis-Drug-Guide/51030/8/alprazolam. Retrieved 10 March 2009. 
  117. ↑ "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. Retrieved 2008-10-31. 
  118. ↑ "DEA, Drug Scheduling". DEA. http://www.usdoj.gov/dea/pubs/scheduling.html. Retrieved 2008-10-31. 
  119. ↑ UK Gov (1991). "Misuse of Drugs Act 1971 (c. 38)". The UK Statute Law database. http://www.statutelaw.gov.uk/content.aspx?LegType=All+Primary&PageNumber=56&NavFrom=2&parentActiveTextDocId=1367412&activetextdocid=1367464. 
  120. ↑ British Medical Association, Royal Pharmaceutical Society of Great Britain (March 2009). "4.1.2: Anxiolytics". British National Formulary (BNF 57). United Kingdom: BMJ Group and RPS Publishing. p. 190. ISBN 9780853698456. 
  121. ↑ International Narcotics Control Board (August 2003). "List of psychotropic substances under international control" (PDF). incb.org. http://www.incb.org/pdf/e/list/green.pdf. Retrieved 7 December 2008. 
  122. ↑ "Misuse Of Drugs (Amendment) Regulations". Irish Statute Book. Office of the Attorney General. 1993. http://www.irishstatutebook.ie/1993/en/si/0342.html. 
  123. ↑ ____284.aspx Narkotikaklassade läkemedel, Läkemedelsverket
Benzodiazepine derivatives
1,4-Benzodiazepines

Bromazepam · Camazepam · Carburazepam · Chlordiazepoxide · Cinolazepam · Clonazepam · Clorazepate · Cyprazepam · Delorazepam · Demoxepam · Devazepide * · Diazepam · Doxefazepam · Elfazepam · Ethyl carfluzepate · Ethyl dirazepate · Ethyl loflazepate · Fletazepam · Fludiazepam · Flunitrazepam · Flurazepam · Flutemazepam · Flutoprazepam · Fosazepam · Gidazepam · Halazepam · Iclazepam · Ketazolam · Lorazepam · Lormetazepam · Meclonazepam · Medazepam · Menitrazepam · Metaclazepam · Motrazepam · Nimetazepam · Nitrazepam · Nitrazepate · Nordazepam · Nortetrazepam · Oxazepam · Phenazepam · Pinazepam · Pivoxazepam · Prazepam · Proflazepam · Quazepam · QH-II-66 · Reclazepam · Ro5-2904 · Ro5-4864 * · Sulazepam · Temazepam · Tetrazepam · Tifluadom * · Tolufazepam · Tuclazepam · Uldazepam
1,5-Benzodiazepines

Arfendazam · Clobazam · CP-1414S · Lofendazam · Triflubazam
2,3-Benzodiazepines *

Girisopam · GYKI-52466 · GYKI-52895 · Nerisopam · Talampanel · Tofisopam
Triazolobenzodiazepines

Adinazolam · Alprazolam · Estazolam · Flubromazolam · Triazolam
Imidazobenzodiazepines

Bretazenil · Climazolam · Flumazenil · Imidazenil · L-655,708 · Loprazolam · Midazolam · PWZ-029 · Ro15-4513 · Ro48-6791 · Ro48-8684 · Sarmazenil · SH-053-R-CH3-2′F
Oxazolobenzodiazepines

Cloxazolam · Flutazolam · Haloxazolam · Mexazolam · Oxazolam
Thienodiazepines

Bentazepam · Brotizolam · Ciclotizolam · Clotiazepam · Etizolam · Olanzapine
Pyridodiazepines

Lopirazepam · Zapizolam
Pyrazolodiazepines

Razobazam * · Ripazepam · Zolazepam · Zomebazam
Pyrrolodiazepines

Premazepam
Tetrahydroisoquinobenzodiazepines

Clazolam
Benzodiazepine prodrugs

Avizafone · Rilmazafone
 * atypical activity profile (not GABAA receptor ligands)
Anxiolytics (N05B)
GABAA PAMs
Adinazolam • Alprazolam • Bretazenil • Bromazepam • Camazepam • Chlordiazepoxide • Clobazam • Clonazepam • Clorazepate • Clotiazepam • Cloxazolam • Diazepam • Ethyl Loflazepate • Etizolam • Fludiazepam • Halazepam • Imidazenil • Ketazolam • Lorazepam • Medazepam • Nordazepam • Oxazepam • Pinazepam • Prazepam
Carbamates
Emylcamate • Mebutamate • Meprobamate (Carisoprodol, Tybamate) • Phenprobamate • Procymate
Nonbenzodiazepines
Abecarnil • Adipiplon • Alpidem • CGS-9896 • CGS-20625 • Divaplon • ELB-139 • Fasiplon • GBLD-345 • Gedocarnil • L-838,417 • NS-2664 • NS-2710 • Ocinaplon • Pagoclone • Panadiplon • Pipequaline • RWJ-51204 • SB-205,384 • SL-651,498 • Taniplon • TP-003 • TP-13 • TPA-023 • Y-23684 • ZK-93423
Pyrazolopyridines
Cartazolate • Etazolate • ICI-190,622 • Tracazolate
Others
Chlormezanone • Ethanol (Alcohol) • Etifoxine • Kavalactones (Kava Kava) • Skullcap • Valerenic Acid (Valerian)
α2δ VDCC Blockers
Gabapentin • Pregabalin
5-HT1A Agonists
Azapirones: Buspirone • Gepirone • Tandospirone; Others: Flesinoxan • Oxaflozane
H1 Antagonists
Diphenylmethanes: Captodiame • Hydroxyzine; Others: Brompheniramine • Chlorpheniramine • Pheniramine
CRH1 Antagonists
Antalarmin • CP-154,526 • Pexacerfont • Pivagabine
NK2 Antagonists
GR-159,897 • Saredutant
MCH1 antagonists
ATC-0175 • SNAP-94847
mGluR2/3 Agonists
Eglumegad
mGluR5 NAMs
Fenobam
TSPO agonists
DAA-1097 • DAA-1106 • Emapunil • FGIN-127 • FGIN-143
σ1 agonists
Afobazole • Opipramol
Others
Benzoctamine • Carbetocin • Demoxytocin • Mephenoxalone • Mepiprazole • Oxanamide • Oxytocin • Promoxolane • Tofisopam • Trimetozine • WAY-267,464
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

: PSO/PSI

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dsrd (o, p, m, p, a, d, s), sysi/, spvo

, drug(N5A/5B/5C/6A/6B/)

External links