Alprazolam

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Alprazolam, sold under the brand name Xanax among others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines.<ref>Template:Cite book</ref> Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD).<ref name="Xanax FDA label" /> Other uses include the treatment of chemotherapy-induced nausea, together with other treatments.<ref name="AHFS2018" /> GAD improvement occurs generally within a week.<ref name="Verster2004">Template:Cite journal</ref><ref>Template:Cite book</ref> Alprazolam is generally taken orally.<ref name="AHFS2018">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include sleepiness, depression, suppressed emotions, mild to severe decreases in motor skills, hiccups, dulling or declining of cognition, decreased alertness, dry mouth (mildly), decreased heart rate, suppression of central nervous system activity, impairment of judgment (usually in higher than therapeutic doses), marginal to severe decreases in memory formation, decreased ability to process new information, as well as partial to complete anterograde amnesia,<ref>Template:Cite journal</ref> depending on dosage.<ref name=AHFS2018/> Some of the sedation and drowsiness may improve within a few days.<ref name=Pav10>Template:Cite book</ref>

Benzodiazepine withdrawal symptoms may occur if use is suddenly decreased.<ref name=AHFS2018 /><ref name="Verster2004" />

Alprazolam was invented by Jackson Hester Jr. at the Upjohn Company<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and patented in 1971 and approved for medical use in the United States in 1981.<ref name=AHFS2018/><ref name=Fis2006>Template:Cite book</ref> Alprazolam is a Schedule IV controlled substance and is a common drug of abuse.<ref name=Ait2018>Template:Cite journal</ref><ref>Template:Cite book</ref> It is available as a generic medication.<ref name="Xanax FDA label" /> In 2022, it was the 41st most commonly prescribed medication in the United States, with more than 14Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical uses

File:Boites d'alprazolam444.jpg

Alprazolam pills in boxes, as sold in France; both the original Pfizer brand product Xanax and various generic forms of alprazolam are depicted here.

File:Xanax 2 mg.jpg

A prescription bottle of Xanax

Alprazolam is used in the management of anxiety disorders and nausea due to chemotherapy.<ref name="AHFS2018" /> Alprazolam is indicated for the treatment of generalized anxiety disorder (GAD) and panic disorder with or without agoraphobia in adults.<ref name="Xanax FDA label" />

Panic disorder

Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks.<ref name="Xanax FDA label" /> In Australia, alprazolam is not recommended for the treatment of panic disorder because of concerns regarding tolerance, dependence, and abuse.<ref name= Moy2012>Template:Cite journal</ref> Most evidence shows that the benefits of alprazolam in treating panic disorder last only four to ten weeks. However, people with panic disorder have been treated on an open basis for up to eight months without apparent loss of benefit.<ref name="Xanax FDA label" />

Alprazolam is recommended by the World Federation of Societies of Biological Psychiatry (WFSBP) for treatment-resistant cases of panic disorder where there is no history of tolerance or dependence.<ref>Template:Cite journal</ref>

A 2023 meta-analysis of published and unpublished FDA-submitted regulatory trials of alprazolam extended-release for panic disorder found that only one of five clinical trials showed a positive efficacy outcome (20%), while the rest were negative and did not demonstrate effectiveness.<ref name="pmid37853797">Template:Cite journal</ref> In the published literature, three trials were published conveying a positive outcome (100%), but of these, only one was positive and the other two were considered to have been inappropriately spun as positive.<ref name="pmid37853797" /> The effect size (Hedges's g) of alprazolam for the treatment of panic disorder based on the five clinical trials was 0.33 (a small effect) and based on the published trials was 0.47 (a moderate effect), equating to an increase of 0.14 or 42%.<ref name="pmid37853797" /> The authors concluded that publication bias substantially inflated the effectiveness of alprazolam for panic disorder.<ref name="pmid37853797" />

Anxiety disorders

Anxiety associated with depression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to four months for anxiety disorders.<ref name="Xanax FDA label" /> However, the research into antidepressant properties of alprazolam is poor and has only assessed its short-term effects against depression.<ref name="van Marwijk-2012">Template:Cite journal</ref> In one study, some long term, high-dosage users of alprazolam developed reversible depression.<ref>Template:Cite journal</ref>

In the US, alprazolam is indicated for the treatment of generalized anxiety disorder and panic disorder with or without agoraphobia.<ref name="Xanax FDA label" /><ref name="Xanax XR FDA label" />

In the UK, alprazolam is indicated for short-term symptomatic treatment of anxiety in adults.<ref name="Xanax UK SmPC" />

Chemotherapy-induced nausea and vomiting

Alprazolam may be used in combination with other medications for chemotherapy-induced nausea and vomiting.<ref name=AHFS2018/>

Contraindications

Benzodiazepines require special precaution if used in children and in alcohol- or other drug-dependent individuals. Particular care should be taken in pregnant or elderly people, people with substance use disorder history, particularly alcohol dependence, and people with comorbid psychiatric disorders.<ref>Template:Cite journal</ref>

Alprazolam should be avoided or carefully monitored by medical professionals in individuals with myasthenia gravis, acute narrow-angle glaucoma, severe liver deficiencies such as cirrhosis, severe sleep apnea, pre-existing respiratory depression, marked neuromuscular respiratory, acute pulmonary insufficiency, chronic psychosis, hypersensitivity, allergy to alprazolam or other benzodiazepines, and borderline personality disorder, where it may induce suicidality and dyscontrol.<ref name=bnf>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=hori>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Like all central nervous system depressants, alprazolam in larger-than-normal doses can cause significant deterioration in alertness and increase drowsiness, especially in those unaccustomed to the drug's effects.<ref>Template:Cite journal</ref>

Side effects

File:Side effects of alprazolam.svg

Side effects from alprazolam

Sedative drugs, including alprazolam, have been associated with an increased risk of death.<ref>Template:Cite journal</ref>

Possible side effects include:

• Anterograde amnesia<ref name=Barbee95/>
• Concentration problems
• Ataxia
• Dysarthria<ref>Template:Cite journal</ref>
• Disinhibition<ref name="Michel L, Lang JP 2003 479–85">Template:Cite journal</ref>
• Drowsiness, dizziness, lightheadedness, fatigue, ataxia, and vertigo<ref name=drftb>Template:Cite journal</ref><ref name="acmirttoadom">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Dry mouth (infrequent)<ref>Template:Cite journal</ref>
• Hallucinations (rare)<ref name=ase/>
• Jaundice (very rare)<ref>Template:Cite journal</ref>
• Seizure (less common)<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Skin rash
• Respiratory depression
• Constipation<ref name="drftb" /><ref name="acmirttoadom" />
• Suicidal ideation or suicide<ref name=Dobb2017>Template:Cite journal</ref>
• Urinary retention (infrequent)<ref name=ase>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Muscle weaknessTemplate:Medical citation needed

In September 2020, the US Food and Drug Administration (FDA) required that boxed warnings for all benzodiazepine medications be updated to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref>

Paradoxical reactions

Although unusual, the following paradoxical reactions have been shown to occur:

• Aggression<ref>Template:Cite journal</ref>
• Mania, agitation, hyperactivity, and restlessness<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Rage and hostility<ref name="Michel L, Lang JP 2003 479–85"/>
• Twitches and tremor<ref>Template:Cite journal</ref>

Pregnancy and breastfeeding

Benzodiazepines cross the placenta, enter the fetus, and are also excreted in breast milk.<ref name="Xanax FDA label" />

The use of alprazolam during pregnancy is associated with congenital abnormalities,<ref name="Xanax FDA label" /><ref>Template:Cite journal</ref> and use in the last trimester may cause fetal drug dependence and withdrawal symptoms in the post-natal period as well as neonatal flaccidity and respiratory problems.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> However, in long-term users of benzodiazepines, abrupt discontinuation due to concerns of teratogenesis has a high risk of causing extreme withdrawal symptoms and a severe rebound effect of the underlying mental health disorder. Spontaneous abortions may also result from abrupt withdrawal of psychotropic medications, including benzodiazepines.<ref>Template:Cite journal</ref>

Overdose

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File:Xanax 0.25, 0.5 & 1 mg.jpg

Xanax 0.25 mg. (top row), 0.5 mg. (middle row), and 1 mg. (bottom row) tablets

The maximum recommended daily dose is 10 milligrams per day.<ref name="Xanax FDA label" />

Overdoses of alprazolam can be mild to severe depending on the quantity ingested and if other drugs are taken in combination.<ref>Template:Cite journal</ref>

Alprazolam overdoses cause excess central nervous system (CNS) depression.<ref name=ase/>

Dependence and withdrawal

Template:See also The potential for misuse among those taking it for medical reasons is controversial, with some expert reviews stating that the risk is low and similar to that of other benzodiazepine drugs.<ref name= "APAguide">Template:Cite book</ref> Others state that there is a substantial risk of misuse and dependence in both patients and non-medical users and that the short half-life and rapid onset of action may increase the risk of misuse.<ref name=AHFS2018/><ref name=Moy2012/> Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.<ref name= DEAbrief>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Alprazolam, like other benzodiazepines, binds to specific sites on the GABA_A (gamma-aminobutyric acid) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABA_A receptors and, thus, of GABAergic neurons.<ref name=":0" />Template:Unreliable medical source Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.<ref name=":1">Template:Cite book</ref>

Withdrawal and rebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.<ref name=Verster2004/>

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 person may be experiencing a rebound effect due to the removal of the drug. Either of these can occur without the person actually being drug dependent.<ref name=":1" />

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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> There is a higher chance of withdrawal reactions if the drug is administered in a higher dosage than recommended, or if a person stops taking the medication altogether without slowly allowing the body to adjust to a lower-dosage regimen.<ref name="Ashton manual">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

Some common symptoms of alprazolam discontinuation include malaise, weakness, insomnia, tachycardia, lightheadedness, and dizziness.<ref>Template:Cite journal</ref>

Those taking more 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, as well as marked delirium similar to that produced by the anticholinergic tropane alkaloids of Datura (scopolamine and atropine).<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The discontinuation of this medication may also cause rebound anxiety.Template:Medical citation needed

In a 1983 study, only 5% of patients who abruptly ceased taking long-acting benzodiazepines after less than eight months demonstrated withdrawal symptoms, but 43% who had been taking them for more than eight months did. With alprazolam, a short-acting benzodiazepine, taken for eight weeks, 65% of patients experienced significant rebound anxiety. To some degree, these older benzodiazepines are self-tapering.<ref name="Schatzberg">Template:Cite book</ref>

The benzodiazepines diazepam and oxazepam have been found to produce fewer withdrawal reactions than alprazolam, temazepam, or lorazepam. Factors that determine the risk of psychological dependence or physical dependence and the severity of the benzodiazepine withdrawal symptoms 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/-tolerant drugs, use of other short-acting, high-potency benzodiazepines,<ref name="wolf1991">Template:Cite journal</ref><ref>Template:Cite journal</ref> and method of discontinuation.<ref name="Ashton manual"/>

Interactions

Alprazolam is primarily metabolized via CYP3A4.<ref name="Otani-2003">Template:Cite journal</ref> Combining CYP3A4 inhibitors such as cimetidine, erythromycin, norfluoxetine, fluvoxamine, itraconazole, ketoconazole, nefazodone, propoxyphene, and ritonavir delay the hepatic clearance of alprazolam, which may result in its accumulation<ref>Template:Cite journal</ref> and increased severity of its side effects.<ref name="cpoati">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Imipramine and desipramine have been reported to increase an average of 31% and 20% respectively by the concomitant administration of alprazolam tablets.<ref name="Xanax FDA label" /> Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.<ref>Template:Cite journal</ref>

Alcohol is one of the most common interactions; alcohol and 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.<ref name="Michel L, Lang JP 2003 479–85" /> Combination of alprazolam with the herb kava can result in the development of a semi-comatose state.<ref>Template:Cite journal</ref> Plants in the genus Hypericum, including St. John's wort, conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pharmacology

File:6huo GABAA-Rezeptorstruktur.png

Alprazolam binds at the α1β3γ2 GABAA receptor. Alprazolam with red space-filling carbon atoms. γ2 receptor subunit in mint green. The α1' subunit is hidden.<ref name="Masiulis_2019">Template:Cite journal</ref>

Alprazolam is a GABA_A receptor positive allosteric modulator.<ref name=":0">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>Template:Unreliable medical source When it binds to the receptor, effects of GABA are enhanced, leading to inhibition of neurons in the brain. This results in effects including reduced anxiety, muscle relaxant, and anticonvulsant activity.<ref>Template:Cite journal</ref> The activity of alprazolam in the central nervous system is dose-dependent.<ref name="Xanax FDA label" />

Mechanism of action

Alprazolam is classed as a high-potency triazolobenzodiazepine:<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> a benzodiazepine with a triazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to the GABA_A benzodiazepine receptor site and modulating its function; GABA receptors are the most prolific inhibitory receptor within the brain. The GABA chemical and receptor system mediates the inhibitory or calming effects of alprazolam on the nervous system. The binding of alprazolam to the GABA_A receptor, a chloride ion channel, enhances the effects of GABA, a neurotransmitter. When GABA binds the GABA_A receptor the channel opens and chloride enters the cell which makes it more resistant to depolarisation. Therefore, alprazolam has a depressant effect on synaptic transmission to reduce anxiety.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

The GABA_A receptor is made up of 5 subunits out of a possible 19, and GABA_A receptors made up of different combinations of subunits have different properties, different locations within the brain, and, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such as triazolam that have a triazole ring fused to their diazepine ring appear to have antidepressant properties.<ref name="Barbee95">Template:Cite journal</ref><ref>Template:Cite journal</ref> This is perhaps due to the similarities shared with tricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of the hypothalamic–pituitary–adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and include anxiolytic, anticonvulsant, muscle relaxant, hypnotic,<ref>Template:Cite journal</ref> and amnesic; however, it is used mainly as an anxiolytic.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Giving alprazolam, as compared to lorazepam, has been demonstrated to elicit a statistically significant increase in extracellular dopamine D₁ and D₂ concentrations in the striatum.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Pharmacokinetics

File:Alprazolam metabolism.svg

Alprazolam metabolized into 4-hydroxyalprazolam (top) and α-hydroxyalprazolam (bottom)

Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds to proteins in the serum (the majority binding to albumin). The concentration of alprazolam peaks after one to two hours.<ref name="Xanax FDA label" />

Alprazolam is metabolized in the liver, mostly by the cytochrome enzyme CYP3A4. Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactive benzophenone. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they have little to no contribution to the effects of alprazolam.<ref name="Xanax FDA label" />

The metabolites and some unmetabolized alprazolam are filtered out by the kidneys and are excreted in the urine.<ref name="Xanax FDA label" />

Chemistry

Physical properties

Alprazolam is a triazole and benzodiazepine derivative substituted with a phenyl group at position 6, with a chlorine atom at position 8, and with a methyl group at position 1. It is an analogue of triazolam, the difference between them being the absence of a chlorine atom in the ortho position of the phenyl ring.<ref name=SED>Template:Cite book</ref> It is slightly soluble in chloroform, soluble in alcohol, slightly soluble in acetone and insoluble in water.<ref name=merck>Template:Cite book</ref> It has a melting point of Template:Convert.<ref name=merck/><ref name="Patent3">Template:Cite patent Template:Webarchive </ref>

Synthesis

For the synthesis of alprazolam the same method can be used as for triazolam, excepting that it starts from 2-amino-5-chlorobenzophenone.<ref name="Patent">Template:Cite patent Template:Webarchive </ref> However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts with hydrazine giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture with triethyl orthoacetate results in cyclization with the formation of the triazole ring. The product undergoes oxidative degradation in the presence of periodate and ruthenium dioxide in acetone solution, giving 2-[4-(3'-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxy-methylation with formaldehyde results in a product that is treated with phosphorus tribromide when 2-[4-(3'-methyl-5'-bromomethyl-1,2,4-triazolo)]-5-chlorobenzophenone is obtained. By substituting the bromine atom with an amino group conferred by ammonia, it forms alprazolam triazolobenzophenone, following which an intramolecular heterocyclization takes place to obtain alprazolam.<ref name=SED/><ref name=Synthesis>Template:Cite journal</ref><ref name="Patent3"/>

Detection

Quantification of alprazolam in blood and plasma samples may be necessary to confirm a diagnosis of intoxication in hospitalized patients, or to provide evidence in the case of crimes e.g., impaired driving arrest, or to assist in a thorough forensic investigation, e.g., 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 300–2,000 μg/L in victims of acute overdosage. Most of the commercial immunoassays used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done by chromatographic techniques.<ref>Template:Cite book</ref>

Dosage forms

Alprazolam regular release and orally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets.<ref name="Xanax FDA label" /> Extended-release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg tablets.<ref name="Xanax XR FDA label" /> Liquid alprazolam is available in a 1 mg/mL oral concentrate.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Legal status

Alprazolam has varied legal status depending on jurisdiction:

• 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 (DEA).<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Under the UK drug misuse classification system, alprazolam is a Class C drug.<ref name="misuse of drugs legislation" /><ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> In the UK, alprazolam is not available on the National Health Service (NHS) and can only be obtained on a private prescription.<ref name=BNF60>Template:Cite book</ref>

• In Ireland, alprazolam is a Schedule 4 medicine.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• In the Netherlands, alprazolam is a List 2 substance of the Opium Law and is available for prescription.Template:Cn
• In Germany, alprazolam can be prescribed normally in doses up to 1 mg. Higher doses are scheduled as Anlage III drugs and require a special prescription form.Template:Cn
• In Australia, alprazolam, as of February 2014, is a Schedule 8 medication.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

• In the Philippines, alprazolam is legally classified as a "dangerous drug" under the Comprehensive Dangerous Drugs Act of 2002, along with other schedule drugs listed in the 1971 Convention on Psychotropic Substances.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> The importation of dangerous drugs including alprazolam, requires authorization from the Philippine Drug Enforcement Agency.<ref>Template:Cite news</ref>

Internationally, alprazolam is included under the United Nations Convention on Psychotropic Substances as Schedule IV.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Availability

In December 2013, in anticipation of the rescheduling of alprazolam to Schedule 8 in Australia, Pfizer Australia announced they would be discontinuing the Xanax brand in Australia as it was no longer commercially viable.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Recreational use

Template:Further There is a risk of misuse and dependence in both patients and non-medical users of alprazolam; alprazolam's high affinity binding, high potency, and rapid onset increase its abuse potential. The physical dependence and withdrawal syndrome of alprazolam also add to its addictive nature. In the small subgroup of individuals who escalate their doses, there is usually a history of alcohol or other substance use disorders.<ref name=Moy2012/>

Despite this, most prescribed alprazolam users do not use their medication recreationally, and the long-term use of benzodiazepines does not generally correlate with the need for dose escalation.<ref>Template:Cite journal</ref> However, based on US findings from the Treatment Episode Data Set (TEDS), an annual compilation of patient characteristics in substance abuse treatment facilities in the United States, admissions due to "primary tranquilizer" (including, but not limited to, benzodiazepine-type) drug use increased 79% from 1992 to 2002, suggesting that misuse of benzodiazepines may be on the rise.<ref>Template:Cite journal</ref>

The Centers for Disease Control and Prevention (CDC) reported an 89 percent increase in emergency room visits nationwide related to nonmedical benzodiazepine use between 2004 and 2008.<ref>Template:Cite journal</ref><ref>Template:Cite news</ref>

Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States.<ref name=APPT>Template:Cite book</ref><ref name= dawn2neodredv>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A large-scale nationwide U.S. government study conducted by the Substance Abuse and Mental Health Services Administration concluded that, in the US, benzodiazepines are recreationally the most frequently used pharmaceuticals due to their widespread availability, accounting for 35% of all drug-related visits to hospital emergency and urgent care facilities. Men and women are equally likely to use benzodiazepines recreationally. The report found that alprazolam is the most common benzodiazepine for recreational use, followed by clonazepam, lorazepam, and diazepam. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.<ref name="dawn2neodredv"/> Template:Cquote

Those at particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and people with borderline personality disorder.<ref>Template:Cite journal</ref>

The poly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing an overdose, which may cause fatal respiratory depression.<ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A 1990 study found that diazepam has a higher misuse potential relative to many other benzodiazepines and that some data suggest that alprazolam and lorazepam resemble diazepam in this respect.<ref name="griffiths1990">Template:Cite journal</ref>

Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization), and decay of muscle tissue (rhabdomyolysis).<ref>Template:Cite journal</ref> Alprazolam is not very soluble in water; when crushed in water, it does not fully dissolve (40 μg/ml of H₂O at pH 7).<ref name="DB00404 Alprazolam">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> There are also reports of alprazolam being snorted.<ref>Template:Cite journal</ref> Due to the low weight of a dose, alprazolam, in one case, was distributed on blotter paper in a manner similar to LSD.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Misuse of alprazolam and other benzodiazepines has been shown to cause cognitive impairment.<ref name="The Effect of Chronic Alprazolam In">Template:Cite journal</ref> Alprazolam has typically caused anterograde amnesia effects (inability to recall new events), but a study conducted on mice by the Department of Pharmaceutical Sciences and Drug Research at Punjabi University has also determined that alprazolam can produce retrograde amnesic effects (inability to remember events occurring before amnesia). One 2016 study found that "chronic administration of alprazolam affects memory but attentive and psychomotor performance remained unaffected".<ref>Template:Cite journal</ref>

A 2016 randomized controlled trial stated that "overall, long-term benzodiazepine users may not be in their full cognitive state upon withdrawal".<ref name="The Effect of Chronic Alprazolam In"/> Similarly, a 2017 meta-analysis concluded that "a range of neuropsychological functions are impaired as a result of long-term benzodiazepine use, and that these are likely to persist even following withdrawal".<ref>Template:Cite journal</ref>

Slang terms

Slang terms for alprazolam vary by geographic location. Some of the more common terms are modified versions of the trade name "Xanax", such as Xannies (or Xanies) and the phonetic equivalent of Zannies;<ref>Template:Cite book</ref><ref>Template:Cite book</ref> references to their drug classes, such as benzos or downers; or remark upon their shape or color (most commonly a straight, perforated tablet or an oval-shaped pill): bars, ladders, Xanbars, Xans, Z-bars, handlebars, beans, footballs, planks, poles, sticks, blues, or blue footballs.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="MPR Xanax Slang">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In popular culture

• Take Your Pills: Xanax, a 2022 Netflix documentary, provides an overview of the drug's history and usage.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

External links

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