Cocaine adulteration with the anthelminthic tetramisole (levamisole/dexamisole): Long‐term monitoring of its intake by chiral LC–MS/MS analysis of cocaine‐positive hair samples

Abstract

Recent studies indicate that not only the anthelminthic levamisole but also the racemate tetramisole (R-/S-phenyltetraimidazothiazole, PTHIT) was found as an adulterant for cocaine. We herein report on the investigation of the prevalence of PTHIT among cocaine-positive hair samples and the discrimination of the presence of its stereoisomers levamisole and dexamisole. Cocaine-positive hair samples were collected in a forensic context in 2015 and mainly 2017 (n = 724). Cocaine and PTHIT concentrations have been determined by achiral liquid chromatography-tandem mass spectrometry (LC-MS/MS). For distinction of levamisole/dexamisole chiral LC-MS/MS was performed. Cocaine hair concentrations ranged from 500 (cut-off) to approximately 800 000 pg/mg. The study demonstrates a strong prevalence of PTHIT in cocaine users' hair (87%, n = 627). PTHIT hair concentrations ranged from below LLOQ 3.5 to approximately 61 000 pg/mg (median: 260 pg/mg). Surprisingly, enantiomeric ratios of levamisole/dexamisole ranged from 0.17 to 1.34 (median: 0.63). Therefore, PTHIT-adulterated street cocaine samples (n = 24) seized between 2013 and 2016 were tested. Samples mainly contained racemic tetramisole (87.5%), only one sample contained levamisole only and two samples contained non-racemic PTHIT.Our experiments suggest that the presence of tetramisole in biological samples may have hitherto been underestimated. Most probably higher dexamisole than levamisole concentrations in hair specimens arise from stereoselective metabolism and/or elimination. This is particularly important in light of the different pharmacological activities of the two enantiomers and potentially different adverse effects. Toxicological interpretations in intoxication cases with adulterated cocaine should not only consider levamisole but also tetramisole and terminology in scientific contributions should be used accordingly.

Levamisole—a Toxic Adulterant in Illicit Drug Preparations: a Review

“…Liquid chromatography-tandem mass spectrometry has been successfully used to detect and quantify levamisole in a variety of biological specimens, including urine, plasma, whole blood, and hair. 30,32,[64][65][66] Similarly, high-pressure liquid chromatography-time-of-flight-mass spectrometry (LC/TOF-MS) has been used to detect levamisole in blood and lung tissue. 33,34 Levamisole Exposure through Illicit Use Concentrations of levamisole in cocaine steadily increased from around 2002, when it was first reported as an adulterant by the United States Drug Enforcement Agency, until the end of 2012.…”

“…31 In the hair, recent chirality experiments have shown higher concentrations of dexamisole than levamisole (typically from consumption of racemic tetramisole), suggesting that stereoselective differences in metabolism and elimination of the drugs may occur. 32 Postmortem cases involving levamisole typically find the drug in combination with other illicit drugs, particularly cocaine. Although studies are limited, lung tissue and blood have been identified as suitable matrices for levamisole testing in postmortem cases, with lung tissue affording higher concentrations than heart blood or femoral blood.…”

Chiral pharmacokinetics of tetramisole stereoisomers—Enantioselective quantification of levamisole and dexamisole in serum samples from users of adulterated cocaine

“…While levamisole as well as the racemic mixture tetramisole are used for veterinary purposes, dexamisole represents the less potent distomer and is neither commercially available in isolated form nor has it ever been used medicinally 4,8 . Because most publications on these substances do not have a particular focus on stereochemistry, the terms levamisole and tetramisole are unfortunately often used as synonyms 9 …”

“…Existing chiral studies on PTHIT in hair 9 and urine 4 already suggested stereoselective pharmacokinetics. The interpretation of (R)/(S)‐ratios has already been proposed for several other drugs to facilitate an assessment of the effect at the time of the offense 16–18 .…”

“…Therefore, it seems pertinent to examine the suitability of levamsiole and dexamisole to serve as surrogate markers for the forensic toxicological interpretation of cocaine intoxications. A few studies examining the PTHIT content of seized cocaine samples are available in the literature, but those that investigated the chiral composition of PTHIT yielded quite diverse results 4,9,19 . Furthermore, in the existing pharmacokinetic studies in human blood, enantiomerically pure levamisole was administered in each case but never tetramisole 20–22 .…”