Alprazolam was developed by Jackson Hester Jr. at theUpjohn Company[19] and patented in 1971 and approved for medical use in the United States in 1981.[13][20] Alprazolam is aSchedule IV controlled substance and is a common drug of abuse.[3][21] It is available as ageneric medication.[8] In 2023, it was the 37th most commonly prescribed medication in the United States, with more than 15million prescriptions.[22][23]
Alprazolam pills in boxes, as sold inFrance; both the originalPfizer brand product Xanax and variousgeneric forms of alprazolam are depicted here.A prescription bottle of XanaxAlprazolam tablets sold in China
Alprazolam is effective in the relief of moderate to severeanxiety andpanic attacks.[8] InAustralia, alprazolam is not recommended for the treatment ofpanic disorder because of concerns regardingtolerance,dependence, andabuse.[24] 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.[8]
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.[25]
A 2023meta-analysis of published and unpublished FDA-submitted regulatory trials of alprazolam extended-release for panic disorder found that only one of five clinical trials showed a positive efficacy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.[26] 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.[26] Theeffect 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%.[26] The authors concluded thatpublication bias substantially inflated the effectiveness of alprazolam for panic disorder.[26]
Anxiety associated withdepression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to four months foranxiety disorders.[8] However, the research intoantidepressant properties of alprazolam is poor and has only assessed its short-term effects against depression.[27] In one study, some long term, high-dosage users of alprazolam developed reversible depression.[28]
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 withsubstance use disorder history, particularlyalcohol dependence, and people withcomorbidpsychiatric disorders.[29]
In September 2020, the USFood and Drug Administration (FDA) required thatboxed 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.[45]
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.[56] 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.[13][24] Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage indrug-seeking behavior.[57]
Alprazolam, like other benzodiazepines, binds specifically on an allosteric site on theGABAA receptor. Long-term use causes adaptive changes in the benzodiazepine receptors, making them less sensitive to stimulation and thus making the drugs less potent.[58]
Withdrawal andrebound symptoms commonly occur and necessitate a gradual reduction in dosage to minimize withdrawal effects when discontinuing.[15]
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 arebound effect due to the removal of the drug. Either of these can occur without the person actually being drug dependent.[58]
Alprazolam and other benzodiazepines may also cause the development ofphysical dependence,tolerance, andbenzodiazepine withdrawal symptoms during rapid dose reduction or cessation of therapy after long-term treatment.[59][60] 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.[61][62]
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.[63]
Some common symptoms of alprazolam discontinuation includemalaise, weakness,insomnia,tachycardia, lightheadedness, and dizziness.[64]
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 markeddelirium similar to that produced by theanticholinergic tropane alkaloids of Datura (scopolamine andatropine).[65][66][67] The discontinuation of this medication may also cause rebound anxiety.[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.[68]
The benzodiazepinesdiazepam andoxazepam have been found to produce fewer withdrawal reactions than alprazolam,temazepam, orlorazepam. Factors that determine the risk ofpsychological dependence orphysical dependence and the severity of thebenzodiazepine 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,[69][70] and method of discontinuation.[61]
Imipramine anddesipramine have been reported to increase an average of 31% and 20% respectively by theconcomitant administration of alprazolam tablets.[8]Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[75]
Alcohol is one of the most common interactions; alcohol and alprazolam taken in combination have asynergistic effect on one another, which can cause severe sedation, behavioral changes, and intoxication. The more alcohol and alprazolam taken, the worse the interaction.[37] Combination of alprazolam with the herbkava can result in the development of a semi-comatose state.[76] Plants in the genusHypericum, includingSt. John's wort, conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.[77][78][79]
Alprazolam binds at the α1β3γ2GABAA receptor. Alprazolam with red space-fillingcarbon atoms. γ2 receptor subunit in mint green. The α1' subunit is hidden.[80]
Alprazolam is aGABAA receptor positive allosteric modulator.[81] When it binds to the receptor, effects ofGABA are enhanced, leading to inhibition of neurons in the brain. This results in effects including reduced anxiety, muscle relaxant, and anticonvulsant activity.[82] The activity of alprazolam in the central nervous system is dose-dependent.[8]
Alprazolam is classed as a high-potencytriazolobenzodiazepine:[83][84] a benzodiazepine with atriazole ring attached to its structure. As a benzodiazepine, alprazolam produces a variety of therapeutic and adverse effects by binding to theGABAA 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 GABAA receptor, a chloride ion channel, enhances the effects of GABA, aneurotransmitter. When GABA binds the GABAA 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.[85][86]
The GABAA receptor is made up of 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, importantly, different activities with regard to benzodiazepines. Alprazolam and other triazolobenzodiazepines such astriazolam that have a triazole ring fused to their diazepine ring appear to haveantidepressant properties.[35][87] This is perhaps due to the similarities shared withtricyclic antidepressants, as they have two benzene rings fused to a diazepine ring. Alprazolam causes a marked suppression of thehypothalamic–pituitary–adrenal axis. The therapeutic properties of alprazolam are similar to other benzodiazepines and includeanxiolytic,anticonvulsant,muscle relaxant,hypnotic,[88] andamnesic; however, it is used mainly as an anxiolytic.[89]
Giving alprazolam, as compared tolorazepam, has been demonstrated to elicit a statistically significant increase in extracellulardopamineD1 andD2 concentrations in thestriatum.[90][91]
Alprazolam metabolized into 4-hydroxyalprazolam (top) and α-hydroxyalprazolam (bottom)
Alprazolam is taken orally, and is absorbed well – 80% of alprazolam binds toproteins in the serum (the majority binding toalbumin). The concentration of alprazolam peaks after one to two hours.[8]
Alprazolam is metabolized in the liver, mostly by thecytochrome enzymeCYP3A4. Two major metabolites are produced: 4-hydroxyalprazolam and α-hydroxyalprazolam, as well as an inactivebenzophenone. 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.[8]
The metabolites and some unmetabolized alprazolam are filtered out by the kidneys and are excreted in the urine.[8]
Alprazolam is atriazole andbenzodiazepine derivative substituted with aphenyl group at position 6, with achlorine atom at position 8, and with amethyl group at position 1. It is an analogue oftriazolam, the difference between them being the absence of a chlorine atom in the ortho position of the phenyl ring.[92] It is slightly soluble inchloroform, soluble inalcohol, slightly soluble inacetone and insoluble in water.[93] It has amelting point of 228–229.5 °C (442.4–445.1 °F; 501.1–502.6 K).[93][94]
For the synthesis of alprazolam the same method can be used as fortriazolam, except that it starts from 2-amino-5-chlorobenzophenone.[95] However, an alternative easier synthesis starting with 2,6-dichloro-4-phenylquinoline has been suggested, in which it reacts withhydrazine giving 6-chloro-2-hydrazino-4-phenylquinoline. Boiling the mixture withtriethyl orthoacetate results in cyclization with the formation of thetriazole ring. The product undergoes oxidative degradation in the presence ofperiodate andruthenium dioxide inacetone solution, giving 2-[4-(3'-methyl-1,2,4-triazolo)]-5-chlorobenzophenone. Oxy-methylation withformaldehyde 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 thebromine atom with an amino group conferred by ammonia, it formsalprazolam triazolobenzophenone, following which an intramolecular heterocyclization takes place to obtain alprazolam.[92][96][94]
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 amedicolegal 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 commercialimmunoassays used for the benzodiazepine class of drugs cross-react with alprazolam, but confirmation and quantitative determination are usually done bychromatographic techniques.[97]
Alprazolam regular release andorally disintegrating tablets are available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg tablets.[8] Extended-release tablets are available as 0.5 mg, 1 mg, 2 mg, and 3 mg tablets.[9] Liquid alprazolam is available in a 1 mg/mL oral concentrate.[98]
Under the UK drug misuse classification system, alprazolam is aClass C drug.[7][100] In the UK, alprazolam is not available on theNational Health Service (NHS) and can only be obtained on a private prescription.[101]
In Ireland, alprazolam is a Schedule 4 medicine.[102]
In Sweden, alprazolam is a prescription drug in List IV (Schedule 4) under the Narcotics Drugs Act (1968).[103]
In the Netherlands, alprazolam is a List 2 substance of theOpium Law and is available for prescription.[citation needed]
In Germany, alprazolam can be prescribed normally in doses up to 1 mg. Higher doses are scheduled asAnlage III narcotic drugs and require aspecial prescription form.[104]
In Australia, alprazolam, as of February 2014, is a Schedule 8 medication.[105][106][107]
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.[111]
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.[112] 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.[113]
Alprazolam is one of the most commonly prescribed and misused benzodiazepines in the United States.[116][117] A large-scale nationwideU.S. government study conducted by theSubstance 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 hospitalemergency andurgent 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 byclonazepam,lorazepam, anddiazepam. The number of emergency department visits due to benzodiazepines increased by 36% between 2004 and 2006.[117]
Regarding the significant increases detected, it is worthwhile to consider that the number of pharmaceuticals dispensed for legitimate therapeutic uses may be increasing over time, and DAWN estimates are not adjusted to take such increases into account. Nor do DAWN estimates take into account the increases in the population or ED use between 2004 and 2006.[117]
Those at particularly high risk for misuse and dependence are people with a history of alcoholism or drug abuse and/or dependence[118][119] and people withborderline personality disorder.[120]
Thepoly-drug use of powerful depressant drugs poses the highest level of health concerns due to a significant increase in the likelihood of experiencing anoverdose, which may cause fatalrespiratory depression.[121][122]
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.[123]
Anecdotally, injection of alprazolam has been reported, causing dangerous damage to blood vessels, closure of blood vessels (embolization), and decay of muscle tissue (rhabdomyolysis).[124] Alprazolam is not very soluble in water; when crushed in water, it does not fullydissolve (40 μg/ml ofH2O at pH 7).[125] There are also reports of alprazolam beingsnorted.[126] Due to the low weight of a dose, alprazolam, in one case, was distributed onblotter paper in a manner similar to LSD.[127]
Misuse of alprazolam and other benzodiazepines has been shown to causecognitive impairment.[128] Alprazolam has typically causedanterograde amnesia effects (inability to recall new events), but a study conducted on mice by the Department of Pharmaceutical Sciences and Drug Research atPunjabi 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".[17]
A 2016 randomized controlled trial stated that "overall, long-term benzodiazepine users may not be in their full cognitive state upon withdrawal".[128] 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".[129]
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;[130][131] 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.[132][133][134][135]
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^Mesibov G (2004).Outer Strength, Inner Strength. Xulon Press. p. 213.ISBN978-1-59467-504-1.Archived from the original on 26 April 2021. Retrieved18 July 2017.Some people sell Xanax on the street for ten or fifteen dollars a pill. They call them Xannies.
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