Current Drug Metabolism
June 1, 2010
Markus R Meyer, Hans H Maurer
112 citations
This review updates a 2005 paper on how the body metabolizes new designer drugs that have appeared on the black market. It covers 2C compounds (phenethylamines like 2C-B, 2C-I, 2C-D, 2C-E, 2C-T-2, and 2C-T-7), beta-keto drugs (butylone, ethylone, methylone, mephedrone), pyrrolidinophenones (MPBP and PVP), phencyclidine-derived drugs (PCPr, PCEEA, PCMPA, PCMEA), tryptamines (5-MeO-DIPT), and fentanyl analogs (alpha-MF and 3-MF). The review focuses on studies that identified human or animal metabolites formed in vivo or in vitro and the roles of cytochrome P450 and monoamine oxidase enzymes in their metabolism.
Pharmacogenomics
February 1, 2011
Markus R Meyer, Hans H Maurer
107 citations
The effects of drugs of abuse and other foreign substances depend on an individual's genetic makeup and the specific enzymes that break down those substances. This article summarizes current knowledge about the enzymes—such as cytochrome P450, glucuronyltransferases, esterases, and reductases—involved in metabolizing frequently abused opioids (oxycodone, hydrocodone, methadone, fentanyl, buprenorphine, tramadol, heroin, morphine, codeine), anesthetics (GHB, propofol, ketamine, phencyclidine), cognitive enhancers (methylphenidate, modafinil), plant-derived hallucinogens (LSD, salvinorin A, psilocybin, psilocin), and nicotine. Understanding these metabolic pathways helps predict drug interactions, explain individual differences in drug response, assess toxicity, and improve drug testing interpretation.
Analytical and Bioanalytical Chemistry
June 24, 2015
Achim T. Caspar, Andreas G. Helfer, Julian A Michely et al.
69 citations
25I-NBOMe, a potent hallucinogenic drug that activates 5-HT2A receptors, is extensively metabolized in rats. After administration to male Wistar rats, 68 metabolites were identified in urine using liquid chromatography-high-resolution tandem mass spectrometry. The main metabolic pathways include O-demethylation, O,O-bis-demethylation, hydroxylation, and combinations, followed by glucuronidation and sulfation. Detection of intake is possible through metabolites using LC-MS methods but not by GC-MS standard urine screening. Initial tests indicate that CYP1A2 and CYP3A4 are involved in hydroxylation, while CYP2C9 and CYP2C19 mediate O-demethylation, suggesting potential drug-drug interactions.
Analytical and Bioanalytical Chemistry
October 1, 2015
Julian A Michely, Andreas G. Helfer, Simon D. Brandt et al.
49 citations
N,N-Diallyltryptamine (DALT) and 5-methoxy-DALT (5-MeO-DALT) are synthetic tryptamines with psychoactive effects. In rats, after high-dose administration, their metabolism involves aromatic and aliphatic hydroxylations, N-dealkylation, N-oxidation, and combinations; 5-MeO-DALT also undergoes O-demethylation, followed by extensive glucuronidation or sulfation. The main cytochrome P450 enzymes for DALT are CYP2C19, CYP2D6, and CYP3A4; for 5-MeO-DALT, CYP1A2, CYP2C19, CYP2D6, and CYP3A4. For detecting low-dose consumption in rat urine, LC-MS(n) and LC-HR-MS-MS are suitable; the most abundant markers are a ring hydroxy metabolite of DALT, the N,O-bis-dealkyl metabolite of 5-MeO-DALT, and their glucuronides. GC-MS can screen DALT only via its main metabolites.
Journal of Pharmaceutical and Biomedical Analysis
November 27, 2016
Achim T. Caspar, Simon D. Brandt, Andreas E. Stoever et al.
43 citations
25B-NBOMe and 25C-NBOMe, potent 5-HT2A receptor agonists linked to hallucinogenic effects and severe intoxications, are extensively metabolized in rats and humans. Using LC-HR-MS/MS, 66 metabolites were identified for 25B-NBOMe and 69 for 25C-NBOMe, primarily through O-demethylation, O,O-bis-demethylation, hydroxylation, and subsequent glucuronidation and sulfation. After low-dose administration to rats, both substances were detectable mainly via their metabolites using LC-based screening approaches. In an authentic human urine sample from an acute intoxication, 25B-NBOMe and its metabolites were detected by GC-MS as well. Initial screening showed CYP1A2 and CYP3A4 involvement in hydroxylation, and CYP2C9 and CYP2C19 in O-demethylation.
Analytical and Bioanalytical Chemistry
January 1, 2014
Markus R Meyer, Achim T. Caspar, Simon D. Brandt et al.
39 citations
A new laboratory method using liquid chromatography and linear ion trap mass spectrometry can detect 37 synthetic tryptamines plus five β-carbolines, ibogaine, and yohimbine in human urine and plasma. The method is selective for all tested substances, with detection limits in urine between 10 and 100 ng/mL and in plasma between 1 and 100 ng/mL. Validated quantification in plasma was achieved for 33 of the 44 analytes. This addresses the previous scarcity of analytical data on detecting these emerging designer drugs in human biosamples.
Chemical Research in Toxicology
May 22, 2009
Markus R Meyer, Hans H Maurer
39 citations
The designer drugs MDMA, MDEA, and MBDB are chiral compounds whose metabolism is enantioselective, favoring the S-enantiomer. This study investigated whether the elimination of their catecholamine metabolites via O-methylation by catechol-O-methyltransferase (COMT) is also enantioselective. Using human liver cytosol and microsomes, the S-enantiomers of all three catecholamines were preferentially O-methylated by both soluble and membrane-bound COMT. The membrane-bound COMT had 10-fold higher affinity for substrates, while the soluble form had 10-fold higher turnover rate. All tested catechols uncompetitively inhibited dopamine methylation. Enantioselective elimination may contribute to different pharmacokinetic properties of the enantiomers.
Neuropharmacology
November 19, 2019
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein et al.
37 citations
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52) and other 1-acyl-substituted LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs assumed to act as prodrugs for LSD. Competitive binding studies and calcium mobilization assays showed 1-acyl-substitution reduced affinity for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude, and these derivatives had weak efficacy or acted as antagonists in Ca2+-mobilization assays. Despite this, they induced head twitches in mice with relatively high potency. High levels of LSD were detected in rat plasma after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating rapid and efficient deacylation in vivo, consistent with the prediction that these compounds serve as prodrugs for LSD.
Drug Testing and Analysis
January 1, 2018
Achim T. Caspar, Jonas B Gaab, Julian A Michely et al.
33 citations
Three new psychoactive tryptamines—5-MeO-2-Me-DALT, 5-MeO-2-Me-ALCHT, and 5-MeO-2-Me-DIPT—are mainly broken down in the body through O-demethylation, hydroxylation, and N-dealkylation, followed by glucuronidation or sulfation. In rats given 20 mg/kg doses, 5-MeO-2-Me-DALT produced 24 phase I and 12 phase II metabolites, 5-MeO-2-Me-ALCHT produced 24 phase I and 14 phase II metabolites, and 5-MeO-2-Me-DIPT produced 20 phase I and 11 phase II metabolites. Human liver enzyme incubations suggest the same major metabolic pathways occur in humans. CYP1A2, CYP2C19, CYP2D6, and CYP3A4 catalyze hydroxylation; CYP2C19 and CYP2D6 catalyze O-demethylation; and CYP2C19, CYP2D6, and CYP3A4 catalyze N-dealkylation. Liquid chromatography-based urine screening detected intake of all three compounds after low doses (0.1–1 mg/kg), whereas gas chromatography-based screening did not.
Clinical Chemistry
October 7, 2011
Andrea E. Schwaninger, Markus R Meyer, Allan J. Barnes et al.
33 citations
After oral MDMA (ecstasy) intake, human urine contains mostly sulfate and glucuronide conjugates of MDMA metabolites, with sulfates present at higher concentrations than glucuronides. More than 90% of the metabolites DHMA and HMMA were excreted as conjugates. HMMA sulfate had the longest detection window in urine. The ratio of HMMA sulfate to glucuronide was 2.0, and the ratio of DHMA 3-sulfate to 4-sulfate was 5.3 during the first 24 hours, matching predictions from earlier lab experiments. These findings can improve direct urine analysis for MDMA and its metabolites in clinical and forensic toxicology.
Drug Testing and Analysis
February 17, 2016
Marie Mardal, Juliet Kinyua, Pedram Ramin et al.
31 citations
Wastewater-based epidemiology can track community drug use, but biomarkers are often diluted. Pooled urine and urinated soil from festivals were screened for illicit drug excretion products. Cocaine and ecstasy-like compounds were most frequent. A method was developed to quantify their excretion products. Hydroxymethoxymethamphetamine (HMMA), MDMA, MDA, HMMA sulfate, benzoylecgonine, and cocaethylene retained 85–102% of initial concentration after 8 hours, while cocaine and ecgonine methyl ester dropped to 74% and 67%, respectively. HMMA increased over 24 hours, likely from conjugate cleavage and MDMA biotransformation. HMMA is suggested as a stable analytical target for MDMA consumption in wastewater.
Drug Testing and Analysis
February 1, 2019
Lea Wagmann, Simon D. Brandt, Alexander Stratford et al.
26 citations
Thirteen of 17 phenethylamine-derived designer drugs (12 from the 2C-series and five FLY analogs) inhibited monoamine oxidase A (MAO-A), and 11 inhibited monoamine oxidase B (MAO-B) in an in vitro assay using heterologously expressed enzymes and hydrophilic interaction liquid chromatography-high resolution tandem mass spectrometry. For the seven drugs where MAO-A IC50 values were determined, values ranged from 10 to 125 μM; for the nine drugs with MAO-B IC50 values, the range was 1.7 to 180 μM. Because clinical information on most test drugs is lacking, a pharmacological contribution of MAO inhibition cannot be excluded, and further studies are warranted.
Analytical and Bioanalytical Chemistry
February 1, 2017
Julian A Michely, Simon D. Brandt, Markus R Meyer et al.
23 citations
Derivatives of N,N-diallyltryptamine (DALT) are new psychoactive substances. Their metabolism and detectability were studied in rat urine and human liver microsomes using liquid chromatography-high resolution-tandem mass spectrometry. Main metabolic pathways include aromatic and aliphatic hydroxylations, N-dealkylation, N-oxidation, and combinations; carboxylation was detected for 7-Me-DALT and O-demethylenation for 5,6-MD-DALT. Phase I metabolites were extensively glucuronidated or sulfated, catalyzed by several CYP isoenzymes. GC-MS could not reliably monitor consumption, but LC-MSn and LC-HR-MS/MS approaches were suitable, especially for detecting 5-F-DALT and 7-Me-DALT at low doses. The most abundant targets for each compound are specified.
Biochemical Pharmacology
September 29, 2011
Andrea E. Schwaninger, Markus R Meyer, Allan J. Barnes et al.
23 citations
The R- and S-enantiomers of MDMA are eliminated differently in human urine. After controlled oral doses of 1.0 and 1.6 mg/kg, urine from ten participants was analyzed. Over five days, a median of 21% of the measured compounds were excreted as R-stereoisomers and 17% as S-stereoisomers. Significantly more R-enantiomers of MDMA, DHMA, and HMMA sulfate were excreted, while more S-stereoisomers of HMMA and HMMA glucuronide were excreted. No significant differences appeared for MDA and DHMA sulfate. The ratio of R- to S-stereoisomers changed steadily over the first 48 hours, suggesting it could help estimate time of MDMA ingestion in clinical and forensic toxicology.
Drug Testing and Analysis
October 1, 2019
Lea Wagmann, Nora Hempel, Lilian H. J. Richter et al.
20 citations
Three new psychoactive substances of the 2C-FLY series—2C-E-FLY, 2C-EF-FLY, and 2C-T-7-FLY—were studied to determine how the body metabolizes them and how they can be detected in toxicological tests. Using rat urine and human liver S9 fractions analyzed by LC-HRMS/MS, 32 metabolites were identified. Main metabolic steps were hydroxylation and N-acetylation, catalyzed by CYP2D6, CYP3A4, FMO3, NAT1, and NAT2. Deamination by MAO-A and B was also observed. Polymorphisms or drug interactions may cause interindividual differences. Standard urine screening approaches using GC-MS, LC-MSn, and LC-HRMS/MS were suitable for detecting intake, but common metabolites of 2C-E-FLY and 2C-EF-FLY must be considered when interpreting results.
Talanta
October 1, 2018
Achim T. Caspar, Markus R Meyer, Folker Westphal et al.
17 citations
Two new hallucinogens, 3,4-DMA-NBOMe and 4-MMA-NBOMe, are extensively metabolized in rats and human liver preparations. Using nano liquid chromatography with high-resolution mass spectrometry, 38 metabolites of 3,4-DMA-NBOMe and 33 metabolites of 4-MMA-NBOMe were identified. The main metabolic pathways are O-demethylation and glucuronic acid conjugation for 3,4-DMA-NBOMe, and oxidation of the tolyl group to carboxylic acid for 4-MMA-NBOMe. The nanoLC approach performed comparably to conventional UHPLC. Standard urine screening methods could detect an estimated low user dose only through metabolites. Suggested screening targets include O-demethyl- and O,O-bis-demethyl-3,4-DMA-NBOMe and their glucuronides, and carboxy-4-MMA-NBOMe and its glucuronide and N-demethyl-carboxy-4-MMA-NBOMe.
Drug Testing and Analysis
January 1, 2017
Simon D. Brandt, Pierce V. Kavanagh, Geraldine Dowling et al.
16 citations
Many N,N-dialkylated tryptamines have psychoactive properties in humans, and the number of derivatives has grown across research areas. Some are used in medicinal products, others as recreational drugs, and sometimes these uses overlap. 5-Methoxy-N,N-diallyltryptamine (5-MeO-DALT) recently emerged as a new psychoactive substance, while 4-acetoxy-DALT and unsubstituted DALT have been detected only recently. This report describes the analytical characterization of 17 N,N-diallyltryptamines (DALTs), including 15 prepared via microwave-accelerated synthesis. The compounds were characterized using NMR, GC-MS, mass spectrometry, photodiode array detection, and GC solid-state infrared analysis. The resulting spectral data are provided to help researchers identify newly emerging substances and explore clinical and non-clinical uses.
Analytical and Bioanalytical Chemistry
January 1, 2015
Carina S. D. Wink, Markus R Meyer, Tina Braun et al.
13 citations
2C-P is a hallucinogenic designer drug from the phenethylamine class. This work identified its phase I and II metabolites and tested detectability in urine. Proposed metabolic pathways include N-acetylation, deamination with reduction to alcohol or oxidation to carbonic acid, mono- and bis-hydroxylation, mono- and bis-O-demethylation followed by glucuronidation or sulfation, and combinations. A common user's dose of 2C-P was reliably detectable in urine using standard GC-MS and LC-MS(n) screening methods, supporting its identification in clinical and forensic cases.
Journal of Pharmaceutical and Biomedical Analysis
August 1, 2024
Tanja M Gampfer, Victoria Schütz, Philip Schippers et al.
11 citations
Two new hallucinogenic drugs, 1cP-LSD and 4-AcO-DET, were metabolized in human liver S9 fraction and in zebrafish larvae, with several phase I and phase II metabolites identified. Some metabolites were unique to zebrafish larvae. Neither compound showed toxic effects on human liver cells, though 4-AcO-DET combined with a CYP inhibitor altered two cellular parameters at concentrations far above expected in vivo levels. The authors suggest further testing with other liver cell lines that express more CYP enzymes.
Journal of Analytical Toxicology
June 3, 2021
Lea Wagmann, Sascha K. Manier, Markus R Meyer
11 citations
A non-fatal clinical case involving the synthetic tryptamine 4-HO-MET (metocin or methylcybin) was analyzed using blood plasma. Liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS-MS) detected the parent compound and four metabolites—N-demethyl-, oxo-, hydroxy-4-HO-MET, and the N-oxide—while gas chromatography-mass spectrometry did not detect it. The plasma concentration of 4-HO-MET was 193 ng/mL. These findings provide data for clinical and forensic toxicologists interpreting future cases involving synthetic tryptamines, particularly when only blood samples are available.
Journal of Neurochemistry
September 1, 2024
Ana Sofia Alberto-Silva, Selina Hemmer, Hailey A. Bock et al.
10 citations
Three new chemical variants of MDMA—ODMA, TDMA, and SeDMA—show similar activity at serotonin, dopamine, and norepinephrine transporters but reduced activity at 5-HT2A/2B/2C receptors compared to MDMA. They also differ in liver metabolism, with N-demethylation as the only shared route and no phase II metabolites formed. TDMA showed faster clearance. The analogs interacted more weakly with organic cation transporters and plasma membrane monoamine transporter. These bioisosteres may offer therapeutic alternatives to MDMA with a reduced off-target profile, but further studies are needed to determine if they pose lower risks.
Metabolites
May 8, 2024
Fabian Frankenfeld, Lea Wagmann, Anush Abelian et al.
3 citations
Five deschloroketamine derivatives—deschloro-N-cyclopropyl-ketamine, deschloro-N-ethyl-ketamine, deschloro-N-isopropyl-ketamine, deschloro-N-propyl-ketamine, and deschloroketamine—are primarily metabolized through N-dealkylation, hydroxylation, multiple oxidations, and combinations, plus glucuronidation and N-acetylation. In total, 29 phase I and 10 phase II metabolites were detected in rat urine after a 2 mg/kg body weight dose, using liquid chromatography high-resolution tandem mass spectrometry and gas chromatography-mass spectrometry. For the LC-HRMS/MS standard urine screening approach, compound-specific metabolites were identified and confirmed in pooled human liver microsomes for all derivatives except deschloro-N-cyclopropyl-ketamine. The GC-MS approach detected only non-specific acetylated N-dealkylation metabolites.
Drug Testing and Analysis
August 1, 2025
Fabian Frankenfeld, Lea Wagmann, Markus R Meyer
2 citations
Five deschloroketamine derivatives and most of their metabolites remain sufficiently stable in raw wastewater to serve as analytical targets for wastewater-based epidemiology. After incubating the parent compounds, rat urine, or rat feces in untreated influent wastewater for 24 hours, all parent compounds, seven Phase I metabolites, and one Phase II metabolite were detected in rat feces. Peak areas of Phase II N- and O-glucuronides decreased markedly, consistent with earlier findings that Phase II conjugates are unstable in wastewater and unsuitable as biomarkers. The results indicate that the parent drugs and their Phase I metabolites can be used for wastewater surveillance of these new psychoactive substances.
British Journal of Clinical Pharmacology
June 16, 2025
Wellenberg K Simon, Tanja M Gampfer, Wagmann Lea et al.
1 citation
A workflow using zebrafish embryos (ZEs) followed by human microdosing (HMD) can identify human urine biomarkers for drugs of abuse and new psychoactive substances. Metabolites of amphetamine, cocaine, LSD, MDMA, methamphetamine, THC, MDMB-CHMICA, and MDPPP were first identified in ZEs exposed via immersion or injection, then compared with known human metabolites and confirmed by HMD. Both methods identified main human urine metabolites, except for LSD (due to low dose) and cannabinoids (due to low oral bioavailability). ZEs produced more metabolites, including conjugates, than HMD. The approach provides quick, reliable data for urinary drug screening, though challenges remain with HMD, including different administration routes and low-dose detectability.
ACS Chem Neurosci
March 4, 2026
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.
correction
A correction notice clarifies that two errors in the original paper do not affect the accuracy of the results, interpretations, or conclusions. The first correction addresses a presentation issue in Table 1, confirming the data are correct. The second correction clarifies that thigmotaxis, a measure of anxiety-like behavior, was evaluated in rats given SDA or SDMA compounds. Compared to saline, only the 10 mg/kg dose of SDA significantly increased thigmotaxis, meaning the rats spent less time in the center of the arena.