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.
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.
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.
European journal of pharmacology
August 15, 2019
Jason Wallach, Tristan Colestock, Julià Agramunt et al.
Fluorolintane, a 1,2-diarylethylamine sold as a 'research chemical' for dissociative effects, was studied pharmacologically for the first time alongside five related isomers. In vitro binding showed fluorolintane has high affinity for NMDA receptors (Ki = 87.92 nM) and even higher affinities for dopamine transporters (DAT) in most cases. Functional experiments in rat hippocampal slices demonstrated that fluorolintane inhibits NMDA receptor-induced field excitatory postsynaptic potentials and blocks long-term potentiation, consistent with NMDA receptor antagonism. In rats, fluorolintane disrupted prepulse inhibition (a measure of sensorimotor gating) with a median effective dose of 13.3 mg/kg, supporting anecdotal reports of dissociative effects in humans.
Handbook of experimental pharmacology
January 1, 2018
Jason Wallach, Simon D Brandt
Phencyclidine (PCP), discovered in 1956, became the model dissociative drug and later a street drug, with about 14 analogs identified as such between the 1960s and 1990s. In the 2000s, the Internet enabled communities to explore new PCP analogs, some previously unknown in scientific literature. This chapter provides an introductory overview of recent PCP-derived new psychoactive substances (NPS) and their pharmacology. Because N-methyl-D-aspartate receptor (NMDAR) antagonism underlies the subjective effects of many dissociatives, data from other analogs not currently identified as NPS are also included.
Handbook of experimental pharmacology
January 1, 2018
Torsten Passie, Simon D Brandt
Scientists and therapists have a long tradition of self-experimenting with psychoactive substances, dating back to the mid-eighteenth century. Substances producing complex effects—such as altered space/time experience, ego dissolution, and heightened insights (e.g., hallucinogens, entactogens)—have been the focus of the vast majority of these self-experiments, while those producing simple effects like euphoria or emotional blunting (e.g., cocaine, opioids) are much rarer. Self-experimenters fall into two types: exploratory, seeking expanded awareness and insight, and compensatory, aiming to cope with psychiatric symptoms or personality deficits. Scientific limitations are clear compared to double-blind, randomized, placebo-controlled trials, and adverse effects include loss of objectivity, increased risk of addiction, isolation, and problematic group dynamics.
Handbook of experimental pharmacology
January 1, 2018
Jason Wallach, Simon D Brandt
Beyond the well-studied dissociative drugs phencyclidine (PCP) and ketamine, hundreds of related compounds have been developed since the late 1950s, some through legitimate research and others originating from clandestine chemists. The internet in the 1990s enabled global collaboration on designing novel dissociative compounds with goals like improved duration, analgesia, and reduced toxicity. These creations, marketed as "research chemicals" or "legal highs," have entered wider distribution and sometimes reached academic labs for potential clinical applications. Two structurally distinct classes of dissociative new psychoactive substances (NPS) are the 1,2-diarylethylamines (e.g., diphenidine, fluorolintane) and β-keto-arylcyclohexylamines (e.g., methoxetamine, deschloroketamine). This chapter introduces these emerging NPS and their known pharmacology.
Toxicology letters
April 15, 2017
Lea Wagmann, Simon D Brandt, Pierce V Kavanagh et al.
Thirteen analogs of the psychoactive substance alpha-methyltryptamine (AMT) were tested for their ability to inhibit monoamine oxidase (MAO), an enzyme that breaks down neurotransmitters. All analogs inhibited MAO-A, with IC50 values ranging from 0.049 to 166 μM, and four also inhibited MAO-B (IC50 82–376 μM). 7-Me-AMT was the most potent MAO-A inhibitor, comparable to the known inhibitors harmine and harmaline, and acted competitively. Most analogs also inhibited MAO in human liver S9 fractions. These findings suggest that MAO inhibition by these compounds could contribute to dangerous serotonin- and adrenaline-related effects, especially when combined with other drugs that block monoamine reuptake.