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Alprazolam, sold under the brand name Xanax and others, is a fast-acting, potent tranquilizer of moderate duration within the triazolobenzodiazepine group of chemicals called benzodiazepines.[15] Alprazolam is most commonly prescribed in the management of anxiety disorders, especially panic disorder and generalized anxiety disorder (GAD).[9] Other uses include the treatment of chemotherapy-induced nausea, together with other treatments.[14] GAD improvement occurs generally within a week.[16][17] Alprazolam is generally taken orally (by mouth).[14]
Common side effects include sleepiness, depression or suppressed emotions, mild to severe decreases in motor skills, hiccups, dulling or declining of cognition as well as alertness or general awareness of one's surroundings or even behavior, dry mouth (mildly), decreased heart rate, suppression (physiological inhibition) of general central nervous system activity (opposite of physiological excitation), 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 amnesia (anterograde amnesia[18]) depending on dosage.[14] Some of the sedation and tiredness may improve within a few days.[19]
Alprazolam was invented by Jackson Hester Jr. at the Upjohn Company[20] and patented in 1971 and approved for medical use in the United States in 1981.[14][21] Alprazolam is a Schedule IV controlled substance and is a common drug of abuse.[3][22] It is available as a generic medication.[9] In 2021, it was the 42nd most commonly prescribed medication in the United States, with more than 15 million prescriptions.[23]
Alprazolam is used in the management of anxiety disorders, panic disorders, and nausea due to chemotherapy.[14] Alprazolam is indicated for the treatment of generalized anxiety disorder and panic disorder with or without agoraphobia in adults.[9]
Alprazolam is effective in the relief of moderate to severe anxiety and panic attacks.[9] In Australia, alprazolam is not recommended for the treatment of panic disorder because of concerns regarding tolerance, dependence, and abuse.[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.[9]
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 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.[26] In the published literature, three trials were published conveying a positive outcome (100%), but of these, only one was actually positive and the other two were considered to have been inappropriately spun as positive.[26] The effect size (Hedges's g) of alprazolam for 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 that publication bias substantially inflated the effectiveness of alprazolam for panic disorder.[26]
Anxiety associated with depression is responsive to alprazolam. Clinical studies have shown that the effectiveness is limited to four months for anxiety disorders.[9] However, the research into antidepressant 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 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.[29]
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.[30][31][32]
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.[33]
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.[45]
Alprazolam is primarily metabolized via CYP3A4.[51] 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[52] and increased severity of its side effects.[53][54]
Imipramine and desipramine have been reported to increase an average of 31% and 20% respectively by the concomitant administration of alprazolam tablets.[9] Combined oral contraceptive pills reduce the clearance of alprazolam, which may lead to increased plasma levels of alprazolam and accumulation.[55]
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.[37] Combination of alprazolam with the herb kava can result in the development of a semi-comatose state.[56] Plants in the genus Hypericum, including St. John's wort, conversely can lower the plasma levels of alprazolam and reduce its therapeutic effect.[57][58][59]
The use of alprazolam during pregnancy is associated with congenital abnormalities,[9][60] 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.[61][62] 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.[63]
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.[65] 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.[14][24] Compared to the large number of prescriptions, relatively few individuals increase their dose on their own initiative or engage in drug-seeking behavior.[66]
Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA (gamma-aminobutyric acid) receptor. When bound to these sites, which are referred to as benzodiazepine receptors, it modulates the effect of GABAA receptors and, thus, of GABAergic neurons.[67][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.[68]
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.[68]
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.[69][70] 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.[71][72]
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.[73]
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).[75][76][77] 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.[78]
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