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.
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.
Analytical and bioanalytical chemistry
January 1, 2014
Markus R Meyer, Achim 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.
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.
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.
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 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.
Toxicology
March 1, 2026
Lea Wagmann, Simon D Brandt, Pierce V Kavanagh et al.
Three recently identified psychedelics and entactogens—3-APBT, 5-APBT, and 6-APBT—activate serotonin 2 receptor subtypes and cause head-twitch responses in mice. Their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition were characterized using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were identified in urine from male Wistar rats over 24 hours after oral administration (2 mg/kg) and in incubations with pooled human liver S9 fraction (25 µM). Hydroxylation, primarily catalyzed by CYP1A2, CYP2D6, CYP3A4, and CYP3A5, was the main phase I biotransformation; phase II reactions included N-acetylation, glucuronidation, and sulfation. All three isomers strongly inhibited MAO-A (IC50: 5-APBT 0.4 µM, 6-APBT 0.6 µM, 3-APBT 4 µM) but only weakly inhibited MAO-B (IC50 23-49 µM). Clinically relevant MAO-A inhibition and associated interaction risks cannot be excluded.
Metabolites
February 14, 2026
Prajwal Punnamraju, Sascha K Manier, Selina Hemmer et al.
A liquid chromatography–high-resolution mass spectrometry workflow was used to investigate the metabolism of two N1-sulfonated N,N-dimethyltryptamine derivatives, which have potential for both therapeutic use and recreational abuse. Zebrafish larvae and pooled human liver S9 fractions revealed key phase I and phase II biotransformations. Untargeted metabolomics showed significant downregulation of L-threonine associated with compound exposure. These findings advance the understanding of tryptamine metabolism and highlight the value of toxicometabolomics for evaluating novel psychoactive substances.
bioRxiv : the preprint server for biology
April 11, 2024
Ana Sofia Alberto-Silva, Selina Hemmer, Hailey A Bock et al.
preprint
Three new chemical variants of MDMA—ODMA, TDMA, and SeDMA—show similar activity at serotonin and dopamine transporters but reduced activity at serotonin 5-HT2A/2B/2C receptors, which may lower the risk of off-target side effects. They also differ from MDMA in how they are broken down by the liver, with fewer metabolic pathways and no phase II metabolites. The analogs interact more weakly with certain organic cation transporters. These findings suggest the new compounds could be promising therapeutic alternatives to MDMA for conditions like PTSD, though further research is needed to confirm whether they pose lower risks.