SUMMARY

• For information on the possibility of SPRAVATO causing a false-positive on a urine screening test for drugs of abuse, clinicians should contact the manufacturer of the test in question.
• A search of the published literature did not yield information related to false-positive urine drug screen results for SPRAVATO. However, since they are chemically related, summaries are provided for literature found on ketamine. Ketamine is typically not included as part of a standard drug screen panel, however, drug testing kits are available for expanded point of care toxicology and confirmatory urine drug screens.¹
• Two case reports of false-positive urine drug screen results for ketamine are described below.^2,3 See Potential for Ketamine-Associated False-Positive Results.
• During SPRAVATO nasal spray clinical trials, patients that had a positive urine drug screen for barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine were excluded from study participation.⁴
  • In the long-term, phase 3 safety study⁵, urine drug screens for barbiturates, methadone, cocaine, cannabinoids (day 1 only), phencyclidine, and amphetamine/methamphetamine tests were conducted at screening, days 1, 15, and 28 of the induction phase, and every 8 weeks during the optimization/maintenance phases. Drug screening was not done during the follow-up phase.⁶
• The mean terminal half-life (t_1/2) of esketamine is 7 to 12 hours.⁷
• Esketamine hydrochloride, the (S)-enantiomer of ketamine, is a Schedule III controlled substance under the Controlled Substances Act.⁸

BACKGROUND

Screening Tests for Drugs of Abuse and Prescription Drugs

False-positive drug tests can be associated with prescription medications, over-the-counter drugs, or certain foods. FDA regulations regarding a positive drug screen (e.g. via immunoassay) commonly require confirmatory analysis with different methods, such as mass spectrum/chromatography, which is most reliable if performed on the same specimen as that used for the initial test. The underlying mechanisms related to cross-reactivity in urine drug screening have not been completely elucidated. Though similarities in chemistry and molecular structure are sometimes identified/hypothesized as a possible explanation, many reported false-positive cases involved structurally unrelated or chemically diverse substances.^9-14

Techniques used in identifying and/or quantifying drugs include spot tests, spectrochemical tests, immunoassays, chromatographic techniques, and mass spectrometry. There is significant variability in sensitivity, specificity, quantitation, analyte range, speed, and cost among the available toxicology tests.¹⁵

The 5 most commonly tested drugs of abuse, referred to as the NIDA 5 and recommended by the National Institute on Drug Abuse for screening federal employees, are amphetamines, cannabinoids, cocaine, opiates, and phencyclidine (PCP).¹⁰ In addition to the NIDA 5, immunoassays are also available for screening barbiturates, benzodiazepines, methadone, propoxyphene, tricyclic antidepressants, lysergic acid diethylamide (LSD), methaqualone, methylenedioxymethamphetamine (“ecstasy”), and oxycodone.¹⁵

Potential for Ketamine-Associated False-Positive Results

Case Reports

Liu et al (2017)² reported positive urine drug screen results for ketamine in 2 patients in Taiwan on the Formoso One Sure KET/MDMA 2 in 1 Rapid Test Kit, Formosa Biomedical Inc., Taiwan and the ketamine enzyme immunoassay test (DRI^® Ketamine Assay, Thermo Fisher Scientific Inc., Fremont, CA, USA).

A 22-year-old male patient with a history of multiple substance misuse (amphetamine, MDMA, and ketamine) reported positive for ketamine on the Formoso One Sure KET/MDMA 2 in 1 Rapid Test Kit. The patient denied any illicit drug exposure within the past 7 months and at the time of the positive result, the patient was on a regimen amounting to quetiapine 300 mg daily, bupropion 300 mg daily, and alprazolam 1 mg daily.

A 33-year-old male patient with a history of amphetamine use admitted to the acute psychiatric ward due to manic-like symptoms tested positive for ketamine using the same test described in the previous case report. This patient had stopped using amphetamine for the last 2 years and tested negative for amphetamine and ketamine while on a regimen of fludiazepam 0.5 mg/day, diazepam 4 mg/day, and atomoxetine 75 mg/day. On day 12, the diazepam was discontinued, and quetiapine 25 mg was added with subsequent dose titration to 50 mg on day 15. On day 21, a routine urine drug screen was positive for ketamine. During this time period, his other drug regimens included atomoxetine 50 mg daily, lorazepam 1mg at bedtime as needed, and fludiazepam 0.25 mg as needed.

The urine samples from both patients were sent to a different lab and again tested positive for ketamine using the ketamine enzyme immunoassay test (DRI^® Ketamine Assay). Both samples, however, were confirmed negative by gas chromatography-mass spectrometry (GC/MS).

Fitzsimons et al (2013)³ reported a false-positive urine drug screen in an individual credentialed to provide anesthesia services at Massachusetts General Hospital. An initial urine sample was split into 2 urine containers closed, secured, and initialed by a clinician. One sample was used for testing and the other sample was stored at the facility. The sample tested positive for ketamine using the enzyme-linked immunosorbent assay (ELISA) and confirmatory GC/MS was interpreted as “Invalid result – GC/MS Interference”. None of the other prescription medications that the individual was on (medications not disclosed in the case report) were known to cause a false-positive result. Results of the second sample sent to a different lab came back “none detected” for ketamine and ketamine metabolites.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 07 March 2024.