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Paramethoxyamphetamine (PMA) and paramethoxymethamphetamine (PMMA) are methoxylated phenylethylamine derivatives that have been banned in Taiwan since December 2005. The case history and pathological and toxicological findings of eight recent PMMA fatalities were investigated. All specimens from these cases were initially identified by an AxSYM fluorescence polarization immunoassay screening test for amphetamines with a 300 ng/mL cutoff. Specimens screened positive were confirmed and quantitated by gas chromatography-mass spectrometry. The mean age of these PMMA-related fatalities was 18.9 +/- 4.4 years in the range of 14-25. Seven (87.5%) of these eight cases were men. The mean, standard deviation, and range of PMA found in the heart blood collected from these 8 cases were 0.213, 0.144, and 0.079-0.489 microg/mL, respectively. The corresponding data for PMMA were 4.312, 4.806, and 1.208-15.824 microg/mL, respectively. Other drugs, such as MDA, MDMA, ketamine, norketamine, hydroxymidazolam, methamphetamine, and pentobarbital, were also found in these cases.

Interpretation of drug testing results requires detailed scientific information, particularly in those cases where the question of legitimate use versus illicit use arises. Amphetamine remains a widely abused drug throughout the world, although it is also used therapeutically for weight loss, narcolepsy, and attention-deficit disorder with hyperactivity (ADHD). Treatment of ADHD using stimulant drugs is much more common now than it was in even the recent past. Increasingly, older individuals are diagnosed and treated for ADHD, and treatment often continues into adulthood. Amphetamine is commonly used for the treatment of ADHD and is available by prescription as either the d-enantiomer or a mixture of enantiomers. Although used for many years, there are no data available to describe the excretion profile of amphetamine and its enantiomers following repeated use of the drug. As a result, medical review officers (MROs) and forensic toxicologists have no direct evidence to base their decisions on when it comes to evaluation of use of these drugs. The current study was designed to determine the concentration and enantiomer excretion profile following repeated daily administration of mixed enantiomers of amphetamine. Twenty milligrams of Adderall was administered daily to five healthy subjects with all subsequent ad lib urine samples collected for at least five days following administration of the five-dose regimen. Adderall is a 3:1 mixture of d- and l-enantiomers of amphetamine salts and represents the mixed enantiomer proportion of amphetamine available in the United States through pharmaceutical channels. Peak amphetamine concentrations ranged from 5739 to 19,172 ng/mL. Samples containing > or = 500 ng/mL amphetamine (the administrative cutoff for a positive result by gas chromatography-mass spectrometry) were seen up to 60:15 (h:min) following administration of the last dose. Enantiomer analysis showed the d-enantiomer to be in excess of the l-enantiomer for as long as the drug was administered. After administration of the last dose of drug, the proportion of l-enantiomer increased over time. Not all samples that contained > or = 500 ng/mL total amphetamine were positive when tested by immunoassay because of the differing cross-reactivity of the enantiomers. This study provides the first description of the excretion of amphetamine following repeated administration of Adderall. The presence of the l-enantiomer separates this drug from other formulations composed of only the d-enantiomer (i.e., Dexedrine and much illicit amphetamine), thus readily differentiating them from Adderall use. Some illicit and medicinal amphetamine is, however, a mixture of amphetamine enantiomers. Because the enantiomers are metabolized at different rates, their proportion offers the opportunity to describe excretion versus time. Coupling this data with drug concentration makes it possible for forensic toxicologists and MROs to come to an informed decision regarding the involvement of this drug in a positive drug test result.

The case history and toxicological findings of an overdose fatality involving 4-methylthioamphetamine (4-MTA) and 3,4-methylenedioxymethamphetamine (MDMA) are reported along with a description of the analytical method. Detection and quantitation of 4-MTA and MDMA were performed by liquid chromatography-tandem mass spectrometry using phentermine as internal standard. Application of this technique to a variety of matrices allowed an insight in the distribution of 4-MTA. Several blood samples including femoral vein blood (5.23 mg/L), urine (95.5 mg/L), vitreous humor (1.31 mg/L), bile (36.4 mg/L), and numerous tissue samples such as liver (30.8 mg/kg), spleen (4.10 mg/kg), and frontal lobe (31.7 mg/kg) were assayed. These values indicated that 4-MTA could be identified as the cause of this fatality, whereas the concentrations of MDMA, also described, are less important because the concentrations found are lower. This case reports, for the first time, an extensive toxicological analysis of 4-MTA, by which the data presented may shed some light on the distribution of 4-MTA.

Fenproporex is a sympathomimetic agent with a pharmacological profile similar to that of amphetamine. It is available in many countries throughout the world, but it is currently not available in the United States. Because of its stimulant effects, it has a great potential for abuse. To the best of our knowledge, there have been no literature reports of blood or serum concentrations found in therapeutic, toxic, or fatal cases. We report a case where fenproporex was a finding in the death of a young adult. Blood, urine, and gastric contents were analyzed. The following drug concentrations were found: 0.90 mg/L (inferior vena cava blood), 1.2 mg/L (urine), and 120 mg total (gastric) for fenproporex and 0.084 mg/L (inferior vena cava blood), 0.94 mg/L (urine), and 0.14 mg total (gastric) for amphetamine. In addition to the fenproporex, other medications detected and their blood concentrations found in this case were H diazepam (0.54 mg/L), nordiazepam (0.46 mg/L), diphenhydramine (0.12 mg/L), and gamma hydroxybutyric acid (GHB) (1100 mg/L).

Clobenzorex (Asenlix) is an anorectic drug used as part of a weight-management program. The drug is metabolized by the body to amphetamine, which is then excreted in the urine, thus causing difficulty in interpretation of amphetamine-positive drug tests. Previous studies have shown that the parent drug and several metabolites are excreted in urine. Clobenzorex itself has been detected for as long as 29 h following administration of a single dose. However, the parent drug was not always detected in samples that contained amphetamine at > or =500 ng/mL, the administrative cutoff for a positive result. Consequently, the parent compound clobenzorex is not ideal for ascertaining whether the drug was the origin of the amphetamine. Several metabolites of clobenzorex have been shown to be detected for a longer period of time than the parent. One of these, a hydroxy metabolite, was shown to be detected for an extended period of time. In a study of urine samples provided following administration of a single 30-mg dose of this drug, 4-hydroxyclobenzorex could be detected for up to 91.5 h. More significantly, that study showed all samples that were positive for amphetamine also contained detectable amounts of 4-hydroxyclobenzorex. This metabolite proved to be easily detected and was typically found at higher levels than amphetamine in urine samples positive for amphetamine long after clobenzorex itself could no longer be detected. The present study analyzed samples from a controlled multidose administration (30 mg of clobenzorex daily for seven days) for the presence of 4-hydroxyclobenzorex. The analytical procedure used acid hydrolysis followed by liquid-liquid extraction and gas chromatographic-mass spectrometric analysis with monitoring of ions at m/z 125, 330, and 364 for 4-hydroxyclobenzorex and its 3-Cl regioisomer, which was used as an internal standard. Peak concentrations of 4-hydroxyclobenzorex ranged from 17,786 to 99,044 ng/mL. Most importantly, this study also found that all samples that contained amphetamine at > or =500 ng/mL also contained detectable amounts of this hydroxy metabolite (LOD 10 ng/mL), making it a valuable tool in differentiating use of clobenzorex from illicit amphetamine use.

Clobenzorex (Asenlix) is an anorectic drug metabolized by the body to amphetamine, thus causing difficulty in the interpretation of amphetamine-positive drug tests. Previous studies have shown the parent drug and several metabolites are excreted in urine. Clobenzorex itself has been detected for as long as 29 h postdose using a detection limit of 1 ng/mL. Despite this fact, several amphetamine-positive samples (> or = 500 ng/mL) contained no detectable clobenzorex. Thus, the absence of clobenzorex in the urine does not exclude the possibility of its use. To more definitively assess the possibility of clobenzorex use, evaluation of another metabolite was considered. One study reported the presence of unidentified hydroxy metabolites of clobenzorex for as long as amphetamine was detected in some subjects. To assess the viability of using a hydroxy metabolite to confirm the use of clobenzorex in samples containing amphetamine, 4-hydroxyclobenzorex was synthesized for this study. This metabolite proved to be easily detected and was typically found at levels higher than amphetamine in amphetamine-positive urines, long after clobenzorex itself was no longer detected. Samples obtained from a controlled single-dose study involving the administration of clobenzorex (30 mg) were analyzed for the presence of the 4-hydroxy metabolite. The analytical procedure used acid hydrolysis followed by liquid-liquid extraction and analysis with gas chromatography-mass spectrometry by monitoring ions at m/z 125, 330, and 364. 4-Hydroxyclobenzorex and its 3-Cl regioisomer were used in the identification and quantitation of the metabolite. Peak concentrations of 4-hydroxyclobenzorex were found at approximately 1:30-5:00 h postdose and ranged from approximately 5705 to 88,410 ng/mL. Most importantly, however, all samples that contained amphetamine at > or = 500 ng/mL also contained detectable amounts of this hydroxy metabolite (LOD 10 ng/mL), making it a valuable tool in differentiating use of clobenzorex from illicit amphetamine use.

The analysis of time-lapse changes of d- and l-enantiomers after administration of racemic dl-ethylamphetamine (EAMP) to rats was performed by a high-performance liquid chromatograph equipped with a chiral activity column. After oral administration of dl-EAMP to five rats (dose, 15 mg/kg), the rat urine specimens were collected at four time intervals, 0-4, 4-12, 12-20, and 20-24 h. The two enantiomers of nonmetabolized EAMP and the two enantiomers of metabolized amphetamine (AMP) in urine were simultaneously detected within 20 min. The rate of urinary excretion during 24 h was 3.67% for d-EAMP, 1.03% for l-EAMP, 2.14% for d-AMP, and 1.92% for l-AMP. The total percent of the excreted doses of EAMP and AMP was approximately 8.8% of the administered dosage of dl-EAMP (5.81% for the d-enantiomers and 2.95% for the l-enantiomers). The l/d ratio was 0.51, which was significantly smaller than that (1.01) of the original dl-EAMP powder used (p < .01). The percentages of the doses of l-EAMP in each collection time were significantly less than those of d-EAMP (p < .01), and the l/d ratios of nonmetabolized EAMP decreased to 0.17 within 24 h. For the AMP metabolites, there was a somewhat greater percentage of l-AMP in urine collected up to 4 h than d-AMP (p < .05). Thereafter, it decreased more slowly than d-AMP with time. The l/d ratios of AMP changed from 1.57 to 0.76 within 24 h. The greater decrease of l-EAMP as compared with d-EAMP suggested the stereoselective metabolism of dl-EAMP in rats.