Can trazodone cause a false positive for benzodiazepines on a urine drug toxicity panel? Are there any medications that could result in a false benzodiazepine positive?

Comment by InpharmD Researcher

A comprehensive literature search did not identify any reports of trazodone causing false-positive results for benzodiazepines on urine drug screens (UDS). Overall, evidence evaluating trazodone-related false positives for drugs of abuse is limited. Trazodone has been associated with false-positive results for amphetamines, methamphetamine, and MDMA, due to its metabolite meta-chlorophenylpiperazine (m-CPP), which can cross-react with certain immunoassays. There are also isolated reports of false positives with LSD. In contrast, cross-reactivity for benzodiazepines has been reported with agents such as sertraline, oxaprozin, and efavirenz, with sertraline being among the most frequently cited.

Background

Across several reviews, trazodone has been reported as a potential cause of false-positive results on urine drug screening (UDS) immunoassays, although the occurrence appears inconsistent and assay-dependent. False positives in immunoassays generally occur when medications or their metabolites share structural similarities with the target drug, leading to cross-reactivity; however, the specific cause of many false-positive results remains unknown. Multiple reviews have identified trazodone as a potential cross-reacting agent with amphetamine or methamphetamine assays, including reports of isolated false-positive amphetamine results. Additional reports describe cross-reactivity with 3,4-methylenedioxymethamphetamine (MDMA) assays, and trazodone has also been cited as a potential interferent in LSD immunoassays. Notably, documented cross-reactivity appears to occur specifically with amphetamine and MDMA immunoassays due to trazodone’s metabolite meta-chlorophenylpiperazine (m-CPP), which can cross-react with certain amphetamine screening platforms such as the EMIT II Ecstasy assay and the Thermo Scientific DRI Amphetamines immunoassay. Overall, the likelihood of these false-positive results varies depending on the specific immunoassay platform used and the characteristics of the tested agent. [1], [2], [3], [4], [5]

Additional reviews have also described false-positive benzodiazepine results associated with several commonly prescribed medications. Cross-reactivity with benzodiazepine immunoassays has been reported with sertraline, oxaprozin, and efavirenz, with sertraline being one of the most frequently cited agents. Retrospective studies have reported false-positive benzodiazepine screening rates of approximately 27% to 32% among patients receiving sertraline. In one retrospective chart analysis of 522 records with initial positive benzodiazepine immunoassay results that were later determined to be false positives by confirmatory gas chromatography–mass spectrometry, 26 of 98 non–benzodiazepine-associated cases occurred in patients receiving sertraline, suggesting a potential association with assay interference. Similar to other immunoassay cross-reactivity, the likelihood of these false-positive results appears to depend on the specific testing platform and assay characteristics. [5], [6], [7]

References: [1] Saitman A, Fitzgerald RL, Lund K, Suhandynata RT, Menlyadiev M. Review: False Positive Urine Drug Screens. J Anal Toxicol. Published online February 4, 2026. doi:10.1093/jat/bkag007
[2] Schwebach A, Ball J. Urine Drug Screening: Minimizing False-Positives and False-Negatives to Optimize Patient Care. US Pharm. 2016;41(8):26-30.
[3] Saitman A, Park HD, Fitzgerald RL. False-positive interferences of common urine drug screen immunoassays: a review. J Anal Toxicol. 2014;38(7):387-396. doi:10.1093/jat/bku075
[4] Brahm NC, Yeager LL, Fox MD, Farmer KC, Palmer TA. Commonly prescribed medications and potential false-positive urine drug screens. Am J Health Syst Pharm. 2010;67(16):1344-1350. doi:10.2146/ajhp090477
[5] Moeller KE, Kissack JC, Atayee RS, Lee KC. Clinical Interpretation of Urine Drug Tests: What Clinicians Need to Know About Urine Drug Screens. Mayo Clin Proc. 2017;92(5):774-796. doi:10.1016/j.mayocp.2016.12.007
[6] Kale N. Urine Drug Tests: Ordering and Interpreting Results. Am Fam Physician. 2019;99(1):33-39.
[7] Nasky KM, Cowan GL, Knittel DR. False-Positive Urine Screening for Benzodiazepines: An Association with Sertraline?: A Two-year Retrospective Chart Analysis. Psychiatry (Edgmont). 2009;6(7):36-39.