Alprazolam
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Overview
Overview
Drug Name:
DRE Category:
FDA Pharmacological Class:
DEA Schedule:
Common Routes of Administration
Authorized Trade Names in U.S.
Pharmacology
Pharmacology
Mechanism of Action
Nervous system function requires transmission of excitatory and inhibitory signals. One of the primary neurotransmitters responsible for inhibitory signaling is γ-aminobutyric acid (GABA), which exerts significant effects on the central nervous systems (CNS) at a receptor known as GABA-A (among others). The primary effects of benzodiazepines are thought to result from attaching to a peripheral site on the GABA-A complex, potentiating (increasing) the action of GABA. Primary therapeutic benefits from this mechanism include reduction in anxiety (anxiolysis), sedation, and easier induction of sleep (hypnosis).
Pharmacokinetic Parameters
Parameter
Value
Half-Life
Bioavailability (oral unless otherwise stated)
Volume of Distribution
Blood to Plasma Ratio
May be found as a metabolite of
Metabolites
Metabolism Pathways
Primarily oxidation (via CYP3A4) and conjugation
Metabolites
Primary metabolites include alpha-hydroxyalprazolam (~17% of dose), 4-hydroxyalprazolam (~0.3%), and alpha,4-dihydroxyalprazolam (~0.2%). Alpha-hydroxyalprazolam and 4-hydroxyalprazolam retain ~66% and ~19% of the parent drug’s potency, respectively, but occur in plasma at less than 10% of alprazolam levels, even with chronic use.
Notable Drug Interactions
⚠ FDA Boxed Warning:
FDA boxed warning: “Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation.” Additive CNS depressant effects may occur when combined with other CNS depressing drugs, such as alcohol, barbiturates, anxiolytics, antidepressants, antipsychotics, sedative-hypnotics, sedating antihistamines, anticonvulsants, and anesthetics. Combining with drugs that inhibit Cytochrome 3A enzymes may increase the concentration of alprazolam (and its effects on the patient).
Manufacturer & FDA Warnings
The drug manufacturer warns of potential to impair driving. See FDA Label link on left for further details. Other adverse effects mostly include typical CNS depressant findings (sedation, confusion, etc.) and can be reviewed in detail on FDA labels or in the Prescriber’s Digital Reference (both linked on left).
Effects
Effects
Therapeutic Effects
Alprazolam is a short-acting anxiolytic agent used in the short-term treatment of generalized anxiety disorders, moderate to severe anxiety during ethanol withdrawal in alcoholics, panic attacks with or without agoraphobia, panic disorders, and depression. Off-label uses include the treatment of insomnia and depression.
General Side Effects
Headache
Nausea
Dry Mouth
Hypotension
Sedation
Eye Effects
Blurred vision
Double vision
Visual disturbances
Impairment of vision
Sensitivity to light (photophobia)
Reduced ability to visually track moving objects (impaired smooth pursuit)
Horizontal gaze nystagmus (HGN)
Vertical gaze nystagmus (at high doses)
Lack of convergence
Slowed pupil reaction to light
Glassy or bloodshot appearance of the eyes
Droopy eyelids
Dry eyes
Cognitive Effects
Euphoria
Reduced alertness
Anterograde amnesia
Reduced inhibitions
Reduced concentration
Psychomotor Effects
Slurred Speech
Unsteadiness
Ataxia
Drowsiness
Driving Effects
Impaired psychomotor performance
Slowed reaction time
Reduced vigilance and alertness
Increased sedation and drowsiness
Impaired coordination and tracking ability
Poor lane control / lane drifting (increased SDLP)
Reduced ability to respond to sudden changes while driving
Increased risk of driving impairment comparable to ethanol intoxication
Observable signs consistent with CNS depressant impairment during roadside testing
Residual impairment after dosing in some individuals
Tolerance
Chronic alprazolam use leads to tolerance to its behavioral effects, including sedation and anxiolysis. Long-term use results in physical dependence, with withdrawal symptoms emerging upon cessation or antagonist administration.
Withdrawal Effects
Withdrawal symptoms are more likely with high doses, long-term use, or abrupt cessation. Symptoms include palpitations, tremors, restlessness, insomnia, fatigue, dysphoria, panic attacks, reduced cognitive performance, and depression. Severe effects may include seizures, mania, and suicidal ideation.
DRE Observations
DRE Major Indicators
Major Indicator
Finding Typical for Category
HGN (Horizontal Gaze Nystagmus)
VGN (Vertical Gaze Nystagmus)
LOC (Lack of Convergence)
Pupil Size
Reaction to Light (RTL)
Pulse
Blood Pressure (BP)
Body Temperature
Muscle Tone
DRE General Indicators
Disorientation
Droopy eyelids
Drowsiness
Drunk-like behavior
Slow, sluggish reactions
Thick, slurred speech
Uncoordinated
Unsteady walk
Footnotes
These indicators are generally consistent with the drug’s category. There may be variations due to individual reaction, dose taken and drug interactions. Not all drugs are typical of their category, and considerable variations may be observed.
(1) Soma, Quaaludes, and some antidepressants usually dilate.
(2) Quaaludes, ETOH, and some antidepressants may elevate.
(3) Certain psychedelic amphetamines may cause slowing.
(4) Possibly dilated.
(5) Down with anesthetic gases, up with volatile solvents and aerosols.
(6) Possibly normal.
Analytical Information
Analytical Data
Analytical Considerations
Alprazolam has been determined in biological specimens by GC with ECD, NPD, MS, or MSMS detection. LC with UV, MS, MSMS, or QTOF detection has also been employed. LCMSMS is the ideal technique for determine the concentration of low dose benzodiazepines in biological samples. Immunoassays that detect benzodiazepines, alprazolam and/or its metabolites are commercially available.
Analyte Stability Considerations
4-Hydroxyalprazolam is unstable in aqueous solution at room temperature or acidic pH. Alprazolam and 4-hydroxyalprazolam are stable in plasma for 24 hours at room temperature, 3 months at -20°C, and 7 months at -70°C. Alprazolam is stable in fluoridated blood for 1 week at room temperature and 1 year at -20°C. It is stable in urine for 12 hours at room temperature, 1 month at 5°C, and 3 months at -20°C.
Postmortem Redistribution
Postmortem redistribution may occur; heart/femoral ratios ranged from 0.5–2.8 across several studies, with median or average ratios generally near 0.9–1.5.
Detection Times in Biological Matrices
The values provided below are general guidelines and can be substantially influenced by analytical sensitivity, use patterns, inter-individual variability, and other factors. These values are provided for information only; expert interpretation of individual case factors is necessary to form defensible opinions on these matters.
| Matrix | Detection Time (Approximate) | Notes |
|---|---|---|
| Urine | 1-3 days | Indicates prior exposure; not a measure of impairment |
| Blood | 1-2 days | Correlates more closely with impairment |
| Oral Fluid | Median 26 hrs (Range: 4-37 hrs) | Reflects recent use for some drugs |
| Hair | 4-6 months | Indicates exposure or ingestion over an extended window of detection (months) |
NSC ADID & ANSI/ASB Recommended Cutoffs
Blood- Screen
Blood – Confirm
Urine – Screen
Urine – Confirm
Oral Fluid – Screen
Oral Fluid – Confirm
Matrix / Test Type
Alprazolam Cutoff
α-Hydoxyalprazolam: Cutoff
NSC ADID Recommended Tier
NSC ADID Recommended Blood Screen Cutoff
NSC ADID Recommended Blood Confirm Cutoff
NSC ADID Recommended Urine Screen Cutoff
NSC ADID Recommended Urine Confirm Cutoff
NSC ADID Recommended Oral Fluid Screen Cutoff
NSC ADID Recommended Oral Fluid Confirm Cutoff
ANSI / ASB Std. 120 Required Minimum Sensitivity Blood Screen Cutoff
ANSI / ASB Std. 120 Required Minimum Sensitivity Blood Confirm Cutoff
Therapeutic Concentrations
Therapeutic Blood Concentrations
| Reference | Micrograms per liter (μg/L) or Nanograms per milliliter (ng/mL) | Milligrams per liter (mg/L) or Micrograms per milliliter (μg/mL) |
|---|---|---|
| Baselt (2020) | 25 - 102 | 0.025 - 0.102 |
| Schulz, et al. (2020) | 5 - 50 | 0.005 - 0.050 |
| Winek, et al. (2001) | 25 - 102 | 0.025 - 0.102 |
References for Therapeutic Ranges
R.C. Baselt. Disposition of Toxic Drugs and Chemicals in Man, 12th edition, Biomedical Publications, Seal Beach, CA, 2020, ISBN 978-0-578-57749-4
Schulz M, Schmoldt A, Andresen-Streichert H, Iwersen-Bergmann S. Revisited: Therapeutic and toxic blood concentrations of more than 1100 drugs and other xenobiotics. Crit Care. 2020 May 6;24(1):195. doi: 10.1186/s13054-020-02915-5. PMID: 32375836; PMCID: PMC7201985.
Winek CL, Wahba WW, Winek CL Jr, Balzer TW. Drug and chemical blood-level data 2001. Forensic Sci Int. 2001 Nov 1;122(2-3):107-23. doi: 10.1016/s0379-0738(01)00483-2. PMID: 11672964.
Note Regarding Schulz, et al. values: When a value is expressed in brackets or parentheses, it typically indicates an extension of the corresponding lower or upper parameter based upon unique or unusual conditions (e.g., very old or very young patients, high or low body mass, adapted tolerance to the drug, etc.) See page 84 of the attachment to Shulz et al. for a more complete description.
Caution: Refer to source text for further details of values provided. Be cognizant of sample matrix (e.g., serum vs. whole blood) and dosing regimen that resulted in stated values, when such information is available and disclosed. See ANSI / ASB Best Practice Recommendation 037: Guidelines for Opinions and Testimony in Forensic Toxicology for further guidance on appropriate application of such information.
Bibliography
Bibliography
Driving Studies
- Bramness, J.G. et al. Testing for benzodiazepine inebriation-relationship between benzodiazepine concentration and simple clinical tests for impairment in a sample of drugged drivers.Eur J Clin Pharmacol 59:593-601 (2003)
- Dubois S, Bédard M, Weaver B. The impact of benzodiazepines on safe driving. Traffic Inj Prev. 2008 Oct;9(5):404-13. doi: 10.1080/15389580802161943. PMID: 18836950.
- Leufkens, T.R., et al. Cognitive, psychomotor and actual driving performance in healthy volunteers after immediate and extended release formulations of alprazolam 1 mg.Psychopharmacology 191:951-959 (2007)
- Stone, B.T., et al. Behavioral and neurophysiological signatures of benzodiazepine-related driving impairments.Front Psychol 6:1799 (2015)
- van der Sluiszen, N.J.J.M. et al.Driving performance and neurocognitive skills of long-term users of benzodiazepine anxiolytics and hypnotics. Hum Psychopharmacol 34:e2715 (2019)
- Verster, J. C., Volkerts, E. R., & Verbaten, M. N. (2002). Effects of alprazolam on driving ability, memory functioning and psychomotor performance: a randomized, placebo-controlled study. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 27(2), 260–269. https://doi.org/10.1016/S0893-133X(02)00310-X
- Verster, J.C. et al. Blood drug concentrations of benzodiazepines correlate poorly with actual driving impairment.Sleep Med Rev 17:153-159 (2013)
- Vinckenbosch FRJ, Vermeeren A, Vuurman EFPM, van der Sluiszen NNJJM, Verster JC, van de Loo AJAE, van Dijken JH, Veldstra JL, Brookhuis KA, De Waard D, Ramaekers JG. An explorative approach to understanding individual differences in driving performance and neurocognition in long-term benzodiazepine users.Hum Psychopharmacol. 2021 Jul;36(4):e2778. doi: 10.1002/hup.2778. Epub 2021 Feb 6. PMID: 33547849; PMCID: PMC8365705.
Pharmacology
- Drummer, O.H. Benzodiazepines – effects on human performance and behavior. Forensic Sci Rev 14:1-14 (2002)
- Greenblatt, D. J., & Wright, C. E. (1993). Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clinical pharmacokinetics, 24(6), 453–471. https://doi.org/10.2165/00003088-199324060-00003
- Griffin CE 3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013 Summer;13(2):214-23. PMID: 23789008; PMCID: PMC3684331.
- Jones, A.W. et al. Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results. Ther Drug Monitor 29:248-260 (2007)
- Verster, J.C. and Volkerts, E.R. Clinical pharmacology, clinical efficacy, and behavioral toxicity of alprazolam: a review of the literature. CNS Drugs Rev 10:45-76 (2004)
Drug Interactions
- Høiseth, G. Impairment due to alcohol, tetrahydrocannabinol, and benzodiazepines in impaired drivers compared to experimental studies. Traffic Inj Prev 18:244-250 (2019)
- Høiseth, G. Impairment due to amphetamines and benzodiazepines, alone and in combination. Drug Alcohol Depend 145:174-9 (2014)
Simulator Studies
- Brown, T. L., Milavetz, G., Gaffney, G., & Spurgin, A. (2018). Evaluating drugged driving: Effects of exemplar pain and anxiety medications. Traffic injury prevention, 19(sup1), S97–S103. https://doi.org/10.1080/15389588.2017.1378814
- Su, S., Kay, G., Hochadel, T., Rojo, J., Christopher Stein, J., Boinpally, R., & Periclou, A. (2022). A randomized, multicenter trial assessing the effects of rapastinel compared to ketamine, alprazolam, and placebo on simulated driving performance. Clinical and translational science, 15(1), 255–266. https://doi.org/10.1111/cts.13145
- Willumeit, H. P., Ott, H., & Neubert, W. (1984). Simulated car driving as a useful technique for the determination of residual effects and alcohol interaction after short- and long-acting benzodiazepines. Psychopharmacology. Supplementum, 1, 182–192. https://doi.org/10.1007/978-3-642-69659-6_16
Epidemiological Studies and Other References
- Couper, F., Huestis, M., Fulford, J., Perkinson, N., Miller, S., Raymond, P., Katz, A., Symoun, J., Smither, D. D., & Berning, A. (2024). Benzodiazepines. In Drugs and human performance fact sheets: 2024 (pp. 35–39). National Highway Traffic Safety Administration.
- Couper, F., Huestis, M., Fulford, J., Perkinson, N., Miller, S., Raymond, P., Katz, A., Symoun, J., Smither, D. D., & Berning, A. (2024). Alprazolam. In Drugs and human performance fact sheets: 2024 (pp. 41–47). National Highway Traffic Safety Administration.
- Couper, F., Huestis, M., Fulford, J., Perkinson, N., Miller, S., Raymond, P., Katz, A., Symoun, J., Smither, D. D., & Berning, A. (2024). Drug combination 3: Opioid and Depressant. In Drugs and human performance fact sheets: 2024 (pp. 291–292). National Highway Traffic Safety Administration.
- Dassanayake, T. et al. Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. Drug Saf 34:125-156 (2011)
- Kelly, E., Darke, S., & Ross, J. (2004). A review of drug use and driving: epidemiology, impairment, risk factors and risk perceptions. Drug and alcohol review, 23(3), 319–344. https://doi.org/10.1080/09595230412331289482
- Leung, S.Y. Benzodiazepines, opioids and driving: an overview of the experimental research. Drug Alcohol Rev 30:281-286 (2011)
- MacDonald T. M. (1998). Association of road-traffic accidents with benzodiazepine use. Lancet (London, England), 352(9145), 2019–2020. https://doi.org/10.1016/s0140-6736(05)61365-7
- Murphy AL, Sawires K, Peltekian SM, Helwig M, Macdonald M, Martin-Misener R, Saini B, Neyedli H, Giacomantonio C, Gardner DM. A scoping review of motor vehicle operator performance assessments for benzodiazepine receptor agonists. Explor Res Clin Soc Pharm. 2024 Nov 9;16:100538. doi: 10.1016/j.rcsop.2024.100538. PMID: 39634377; PMCID: PMC11615539.
- Neutel, I. (1998). Benzodiazepine-related traffic accidents in young and elderly drivers. Hum. Psychopharmacol. Clin. Exp., 13: S115-S123. https://doi.org/10.1002/(SICI)1099-1077(1998110)13:2+<S115::AID-HUP56>3.0.CO;2-O
- Skurtveit, S., Abotnes, B., & Christophersen, A. S. (2002). Drugged drivers in Norway with benzodiazepine detections. Forensic science international, 125(1), 75–82. https://doi.org/10.1016/s0379-0738(01)00623-5
- van Laar, M.W., Volkerts, E.R. & van Laar, M. Driving and Benzodiazepine Use. Mol Diag Ther 10, 383–396 (1998). https://doi.org/10.2165/00023210-199810050-00007