What Medications Can Cause False Positive for Benzodiazepines?

A positive benzodiazepine urine screen does not always mean benzodiazepine use. Many common prescriptions and some over-the-counter drugs can cross-react with immunoassay drug tests, so unexpected results should be treated as presumptive until confirmed by a more specific test.[3]

Some medications can trigger a false positive benzodiazepine screen, especially sertraline, oxaprozin, efavirenz, and several NSAIDs or antihistamines. Because standard urine immunoassays can cross-react with similar compounds, unexpected positives should be confirmed with GC-MS or LC-MS before any clinical decision is made.[1][3][4]

What medications can cause a false positive for benzodiazepines?

The best-documented medications linked to false positive benzodiazepine screens include sertraline and oxaprozin.[1][2][4] UIC also lists efavirenz as a known interferent in benzodiazepine immunoassays.[3]

Other medications reported to produce false positives or unexpected positives include:

• Tolmetin
• Naproxen
• Etodolac
• Fenoprofen
• Chlorpromazine
• Diphenhydramine
• Hydroxyzine
• Promethazine
• Fluoxetine
• Warfarin[1][4]

MedCentral’s review also reports a broader list of medications associated with benzodiazepine false positives in some assays, including aspirin, clonidine, desipramine, dicyclomine, furosemide, hydroxyzine, indomethacin, imipramine, phenytoin, propranolol, and triprolidine.[1]

Why do false positives happen?

Most office-based urine drug screens use immunoassays, which rely on antibodies to detect a drug or its metabolites.[3] These tests are fast, but the antibodies can sometimes react with a different drug that has a similar structure.[3]

That matters because:

• The result is screening, not confirmation.[3]
• A medication may trigger the assay even if no benzodiazepine was taken.[1][3]
• The risk varies by test brand, lab method, and patient medication list.[1][2]

A published study in Primary Care Companion to the Journal of Clinical Psychiatry found that sertraline was associated with a meaningful number of false-positive benzodiazepine screens in one widely used assay, supporting the idea that this is a real and clinically relevant issue.[2]

Which drugs are most important to know about?

If you are reviewing an unexpected benzodiazepine screen, these are the medications most worth checking first:

• Sertraline: repeatedly reported in the literature and in package-insert warnings.[1][2][4]
• Oxaprozin: a well-known NSAID cause of false positives.[1][4]
• Efavirenz: listed by UIC as a benzodiazepine screen interferent.[3]
• Naproxen and related NSAIDs: reported in some testing systems.[3][4]
• Sedating antihistamines such as diphenhydramine, hydroxyzine, and promethazine: reported in some assays.[1]

If the result came from a point-of-care test rather than a definitive lab method, the chance of cross-reactivity is generally higher.[5]

What should you do if your test is unexpectedly positive?

The most important next step is confirmation testing. UIC notes that presumptive immunoassay positives should be confirmed with GC-MS to rule out false positives, and MedCentral similarly advises confirmation with GC-MS or LC-MS when sertraline or oxaprozin is present.[1][3]

That means:

• Review the full medication list, including OTC drugs and supplements.[3][4]
• Tell the clinician about recent prescriptions such as sertraline, naproxen, or hydroxyzine.[1][4]
• Ask whether the sample will be sent for confirmatory testing.[1][3]
• Do not assume the screening result is definitive until confirmation returns.[3]

Practical Tips

• Bring a complete list of all medications, including OTC pain relievers, sleep aids, and antihistamines.[3][4]
• Mention sertraline and oxaprozin specifically if either is on your list.[1][2][4]
• Ask whether the result was from a screening immunoassay or a confirmatory test.[3]
• If the result is unexpected, request GC-MS or LC-MS confirmation.[1][3]
• Keep in mind that different laboratories may use different assays, so one test can be positive while another is negative.[1][3]
• If you are taking a medication known to interfere, do not stop it on your own; discuss the result with the prescribing clinician.[4]

FAQ

Can sertraline cause a false positive for benzodiazepines?

Yes. Sertraline is one of the best-documented medications associated with false-positive benzodiazepine urine screens in some immunoassays.[1][2][4]

Can ibuprofen or naproxen make a benzodiazepine test positive?

Naproxen has been reported to cause false positives in some benzodiazepine tests; ibuprofen is more commonly associated with other drug classes, but interference depends on the assay.[3][4]

How is a false positive confirmed?

A positive screening result is usually confirmed with GC-MS or LC-MS, which are much more specific than immunoassay screening tests.[1][3]

Do over-the-counter medications cause false positives?

Yes. Some OTC drugs, especially certain antihistamines and sleep aids, have been reported to interfere with some benzodiazepine screens.[1][6]

Conclusion

False-positive benzodiazepine screens are a known limitation of urine immunoassays, and the medications most often implicated include sertraline, oxaprozin, efavirenz, and some NSAIDs and antihistamines.[1][3][4] If the result is unexpected, the safest approach is to review all medications and confirm the result with a more specific test before drawing conclusions.[1][3]