False-Positive Amphetamines in Urine Drug Screens: A 6-Year Review

Abstract

Immunoassays are routinely used to provide rapid urine drug screening results in the clinical setting. These screening tests are prone to false positive results and ideally require confirmation by mass spectrometry. In this study, we have examined a large number of urine specimens where drugs other than the amphetamines may have caused a false positive amphetamine immunoassay screening result. 12,250 urine drug screens in a clinical laboratory that used the CEDIA amphetamine/ecstasy method were reviewed for false positive results over a six-year period (2015-2020). An additional 3,486 referred samples, where confirmatory mass spectrometry was requested were also reviewed. 86 in-house samples and 175 referral samples that were CEDIA false positives screens were further analyzed by an LC–QTOF general unknown screen. Potential cross-reacting drugs were identified and their molecular similarities to the CEDIA targets were determined. Commercial standards were also analyzed for cross-reactivity in the amphetamine/ecstasy CEDIA screen. Positive amphetamine results in 3.9% of in-house samples and 9.9% of referred tests for confirmatory analysis were false positive for amphetamines. Of these false positive specimens, on average, 6.8 drugs were detected by the LC–QTOF screen. Several drugs were identified as possible cross-reacting drugs to the CEDIA amphetamine/ecstasy assay. Maximum common substructure scores for 70 potential cross-reacting compounds were calculated. This was not helpful in identifying cross reacting drugs. False positive amphetamine screens make up to 3.9 – 9.9% of positive amphetamine screens in the clinical laboratory. Knowledge of cross-reacting drugs may be helpful when mass spectrometry testing is unavailable.

Guilty or not guilty? — False positive results of common medicines in drug tests: review and practical guide

“…-False positive results of common medicines in drug tests.... example, metoprolol was the sixth most frequently sold drug in the United States in 2020, with over 15 million patients. This underscores the need for further investigation into the potential cross-reactivity of other beta antagonists with drug tests [5,10,13,32].…”

“…Additionally, atenolol and bisoprolol have been found to produce F/P results in amphetamine CEDIA tests [10]. This indicates that individuals undergoing antihypertensive therapy with beta-antagonists, particularly pregnant women taking labetalol, are at a higher risk of experiencing false positive amphetamine results.…”

Residents’ Knowledge regarding Recreational Drug Screening Immunoassays at a Swiss Hospital Group

“…Knowledge about cross-reactivities in drug tests was not widespread based on the results of the survey, even though false-positive results due to interacting substances are well described, mainly for the amphetamine component of drug screening immunoassays [ 23 ]. The antidepressants trazodone and bupropion, the H2-antihistamine ranitidine, and stimulants such as ephedrine or methylphenidate are among the substances that can cross-react with amphetamines in immunoassays [ 24 ].…”

The ASAM/AAAP Clinical Practice Guideline on the Management of Stimulant Use Disorder

“…A recent review found that amphetamine immunoassays are subject to a roughly 4% to 10% false positive rate. 255 Confirmatory testing for amphetamines can rule out false positive from other drugs (eg, bupropion, MPH, pseudoephedrine). 256 Clinicians should refer to the test manufacturer and/or consult with their laboratory to determine the capabilities and cross-reactivity of specific assays.…”

“…As discussed in ASAM’s Appropriate Use of Drug Testing in Clinical Addiction Medicine consensus statement, there are known limitations to urine immunoassays for amphetamines, and providers should be cautious when interpreting their results. A recent review found that amphetamine immunoassays are subject to a roughly 4% to 10% false positive rate 255 . Confirmatory testing for amphetamines can rule out false positive from other drugs (eg, bupropion, MPH, pseudoephedrine) 256 .…”