In the early 2000s Wyeth pharmaceuticals modified the drug package insert for pantoprazole (ProtonixTM) to state there had been reports of false-positive urine screens for THC in patients taking pantoprazole and other proton pump inhibitors (PPIs). Unfortunately, no data were provided and no specific manufacturer or cut-off was mentioned. This package insert continues to get referenced in literature without specific manufacturer or cut-off values being mentioned (1, 2). To our knowledge, no manufacturer’s package insert lists any cross-reactivity with PPIs. The ThermoFisher CEDIA DAU THC assay insert specifically states that 1,000,000 ng/mL omeprazole tested negative at a 50 ng/mL cutoff. Various publications through the years have reported a higher percentage of false positive THC urine screens in infants compared to adults; however, the source of the false positives has been attributed to baby wash products (2) or unique infant metabolites (3) rather than PPI administration to the infant.

Our laboratory investigated PPI cross-reactivity for THC using the EMIT II Plus Cannabinoid Assay (Beckman Coulter) run on a Beckman AU5810. This assay detects the 11-nor-Δ9-carboxy-THC metabolite (THC-COOH) with a 20 ng/mL cutoff. Spiking 10,000 ng/mL pantoprazole into THC-negative patient urine did not result in a positive screen indicating the parent drug does not cross-react to an appreciable degree. But what about metabolites? We then recruited patients currently taking one of five proton pump inhibitors, including pantoprazole, to determine if PPI metabolite cross-reactivity was an issue. Of the 32 patient urine samples analyzed, none of them had an optical density that met our cutoff value for a positive THC result. One patient slightly below the positive cutoff was noted. Quantitation using our laboratory’s LC-MS/MS confirmation showed this to be a true positive with THC-COOH present at 7.3 ng/mL.

A subsequent approach was to identify 50 urine samples that screened positive for THC and either failed to confirm by LC-MS/MS (cutoff of 5 ng/mL) or confirmed at low concentrations (6 – 25 ng/mL). We then used liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS) to investigate the presence of eight common PPIs or histamine H2 antagonists in these urine samples. Results were compared to a vendor-supplied library using mass match, isotope ratios, and chromatographic retention time as criteria for a positive result. None of these samples showed evidence of a PPI.

We also used a molecular modeling approach to compare the main pantoprazole metabolite with THC-COOH. The most populated and lowest energy tautomer, which also has the same overall negative charge as THC-COOH, was used for comparisons. The global electrostatic surface map of each was found to be quite different indicating a lack of evidence to support the major pantoprazole metabolite as a likely target in the EMIT II Plus Cannabinoid Assay.

What about your laboratory’s THC immunoassay? Have you seen evidence of this reported false-positive from PPI use? Or was this something that existed only with previous generations of THC screens? Was there ever concrete evidence or only a defense made famous to reduce suspicion for unexpected THC drug screen results?

(1) Standridge JB, et al. Urine Drug Screening: A Valuable Office Procedure. Am Fam Physician 2010; 81:635-640.
(2) Felton D, et al. 13-Year-Old Girl with Recurrent, Episodic, Persistent Vomiting: Out of the Pot and into the Fire. Pediatrics 2015; 135:4-7.
(3) Cotton SW, et al. Unexpected Interference of Baby Wash Products with a Cannabinoid (THC) Immunoassay. Clin Biochem. 2012; 45:605-609.
(4) Barakauskas, VE et al. Unresolved Discrepancies between Cannabinoid Test Results for Infant Urine. Clin Chem. 2012; 58:1364-1367.

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