Diphenhydramine (Benadryl) and False-Positive Benzodiazepine Results
Diphenhydramine does NOT cause false-positive results for benzodiazepines on standard urine drug screens. The available evidence shows no cross-reactivity between diphenhydramine and benzodiazepine immunoassays 1.
Evidence for Lack of Cross-Reactivity
A comprehensive 2014 review of false-positive interferences in urine drug screen immunoassays covering literature from 2000 to present did not identify diphenhydramine as causing false-positive benzodiazepine results 1.
Research specifically examining benzodiazepine immunoassay cross-reactivity focused on other benzodiazepines and their metabolites, but did not identify antihistamines like diphenhydramine as interfering substances 2.
Standard benzodiazepine immunoassay panels primarily detect oxazepam (a common benzodiazepine metabolite) and may miss certain benzodiazepines like clonazepam and lorazepam, but this is due to metabolic pathways rather than cross-reactivity with other drug classes 3.
What Diphenhydramine DOES Cause
Diphenhydramine can cause false-positive methadone results on certain rapid urine drug screens, specifically documented with the One Step Multi-Drug, Multi-Line Screen Test Device 4.
This methadone cross-reactivity occurs with diphenhydramine itself but not with its metabolites (nordiphenhydramine or dinordiphenhydramine) 4.
Critical Clinical Implications
If a patient taking diphenhydramine has a positive benzodiazepine screen, the positive result is NOT attributable to the antihistamine and requires investigation of other causes 5, 6.
Always obtain a complete medication history including all prescription medications, over-the-counter drugs, and supplements before interpreting any positive drug test 5, 6.
Request confirmatory testing using gas chromatography-mass spectrometry (GC-MS) before making consequential clinical decisions based on immunoassay results, as this definitively distinguishes true positives from false positives 7, 5, 6.
Common Pitfall to Avoid
- Product information for urine drug screens may not include all cross-reacting agents, so clinicians should not assume the absence of a substance from package inserts means no cross-reactivity exists 4. However, in this specific case, diphenhydramine has been extensively studied and does not interfere with benzodiazepine testing 1.