What are the common causes of a false‑positive blood screening result for alprazolam (Xanax) and how should it be confirmed?

False-Positive Blood Test for Alprazolam

Understanding the Test Result

A positive blood screening result for alprazolam (or benzodiazepines) without actual use requires immediate confirmatory testing with gas chromatography-mass spectrometry (GC-MS) before making any clinical decisions, as immunoassay screening tests have significant limitations in specificity and are prone to false-positives. 1

Primary Causes of False-Positive Benzodiazepine Results

Sertraline (Most Common Medication Cause)

• Sertraline is a well-documented cause of false-positive benzodiazepine screening results on immunoassay testing. In a two-year retrospective analysis, 26.5% of false-positive benzodiazepine screens (26 out of 98 cases without actual benzodiazepine prescriptions) were associated with concurrent sertraline use. 2
• These false-positives are resolved when confirmatory GC-MS testing is performed, which definitively distinguishes sertraline from actual benzodiazepines. 2

Other Medications Known to Cause False-Positives

• Carbamazepine can cause false-positive results on certain immunoassay panels, though this is more commonly reported for tricyclic antidepressant screens. 3
• Various antipsychotic medications, antihistamines, and cyclobenzaprine (muscle relaxant) have been documented to cause cross-reactivity on drug screening immunoassays. 3

Test-Specific Limitations

• Different immunoassay screening devices have vastly different sensitivities for detecting specific benzodiazepines and their metabolites. For example, etizolam (a thienodiazepine) can be detected by AccuSign BZO at 1,000 ng/mL but requires concentrations exceeding 25,000 ng/mL to be detected by other common screening kits like Triage DOA. 4
• The specific immunoassay platform used determines which substances will cross-react and cause false-positives. 4

Critical Diagnostic Approach

Immediate Steps

• Obtain a complete medication history including all prescription medications (especially antidepressants like sertraline), over-the-counter drugs, and supplements before interpreting any positive benzodiazepine result. 1
• Order confirmatory GC-MS testing immediately before making any consequential clinical decisions, as this is the gold standard that definitively distinguishes true positives from false-positives. 1, 2

Interpretation Framework

• Immunoassay screening tests are presumptive only and should never be considered definitive due to known cross-reactivity with structurally similar compounds. 1, 5
• False-positive laboratory results are 8 times more frequent than true positives (1.8%) in patients undergoing routine testing. 6
• A positive screening test in the absence of clinical findings suggesting benzodiazepine use has lower positive predictive value. 1

Clinical Decision-Making

What NOT to Do

• Never dismiss patients, make punitive decisions, or take legal action based solely on immunoassay screening results without confirmatory testing. This may constitute patient abandonment and can have severe legal consequences. 1, 6
• Do not assume all positive benzodiazepine screens represent illicit drug use, as many prescribed medications cause false-positives. 6

Recommended Actions

• Discuss unexpected positive results promptly with the patient in a non-judgmental manner before taking any action, keeping in mind the high likelihood of false-positives. 6
• Contact the toxicology department of the testing laboratory to review the specific immunoassay methodology used and request GC-MS confirmation. 1
• Establish a working relationship with a local toxicologist for consultation on complex results. 1, 6

Additional Considerations

Counterfeit Substances

• If the patient reports taking alprazolam obtained from unregulated sources, be aware that counterfeit Xanax tablets frequently do not contain alprazolam. In one study, only 23.7% of expected alprazolam tablets from the unregulated market actually contained alprazolam when analyzed by FTIR, and many contained novel psychoactive substances instead. 7

Clinical Context Assessment

• Evaluate for behavioral or mental health symptoms consistent with benzodiazepine use (sedation, ataxia, slurred speech, memory impairment). 1
• Multiple positive tests over time increase the likelihood of true use versus a single false-positive result. 1
• Timing of specimen collection relative to any reported benzodiazepine use affects detection. 1