Neuropharmacology
May 1, 2020
Adam L Halberstadt, Muhammad Chatha, Adam K Klein et al.
274 citations
Serotonergic hallucinogens like LSD cause head twitches in rodents through 5-HT2A receptor activation. This study tested whether the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm correlates with their potencies in rats and humans. Dose-response experiments with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice expanded HTR potency data to 41 compounds. For 36 agents with human data, a strong positive correlation (r = 0.9448) was found between mouse HTR potencies and human hallucinogenic potencies. HTR potencies also correlated with drug discrimination ED50 values in rats trained with LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). These three behavioral effects show consistent potencies linked to 5-HT2A receptor activation, supporting the HTR assay as a predictive preclinical model for hallucinogen potency in humans.
ACS chemical neuroscience
July 15, 2015
David E Nichols, M Flori Sassano, Adam L Halberstadt et al.
81 citations
A series of N-benzylated-5-methoxytryptamine analogues and a parallel series of N-benzylated 2C-I analogues were synthesized and tested. Most compounds showed highest affinity for 5-HT2 family receptors. Para substitution on the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional testing at human and rat 5-HT2A, 5-HT2B, and 5-HT2C receptors revealed no general correlation between affinity and function. Several tryptamine congeners were potent functional agonists (EC50 values from 7.6 to 63 nM) but mostly partial agonists. In the mouse head twitch assay, many compounds induced head twitches, and this behavior correlated significantly with functional potency at the rat 5-HT2A receptor.
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.
Neuropharmacology
November 1, 2018
Landon M Klein, Nicholas V Cozzi, Paul F Daley et al.
43 citations
Most DALT derivatives bind to several serotonin receptors, sigma sites, and other targets. In mice, several compounds triggered the head-twitch response, a behavioral proxy for hallucinogen effects, with 4-acetoxy-DALT being most potent, followed by 5-fluoro-DALT, 5-methoxy-DALT, 4-hydroxy-DALT, DALT, and 5-bromo-DALT; four derivatives did not induce the response. Head-twitch potency was not linked to binding affinity at either 5-HT1A or 5-HT2A receptors alone, but a regression analysis showed that 5-HT2A receptors contribute positively and 5-HT1A receptors contribute negatively to potency, explaining 87% of the variance. These results support the role of 5-HT2A receptors in the head-twitch response and suggest that 5-HT1A activation by tryptamine hallucinogens dampens this effect.
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.
Journal of forensic sciences
May 1, 2020
Simon P Elliott, Tanith Holdbrook, Simon D Brandt
32 citations
The concept of a prodrug—a substance that metabolizes into an active drug—is well established in medicine but has recently extended to new psychoactive substances (NPS), posing forensic challenges. Prodrugs of NPS, such as 1-propanoyl-LSD, 1-butanoyl-LSD, 1-acetyl-LSD, and 2C-B-AN, have been developed and discussed in user forums and sold online. These substances complicate toxicological analysis of biological fluids and chemical analysis due to their instability or metabolism. While current monitoring data suggest prodrugs are not yet widespread or problematic, awareness of their potential impact and forensic implications is important for both chemical and toxicological considerations.
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.
Neuropharmacology
January 1, 2019
Adam L Halberstadt, Muhammad Chatha, Alexander Stratford et al.
25 citations
Rigid analogs of phenylalkylamine hallucinogens, such as 2C-B-FLY and Bromo-DragonFLY (DOB-DFLY), have emerged as recreational drugs. In mice, the head twitch response—a behavior mediated by the 5-HT2A receptor—was used to compare potencies. DOB (ED50 = 0.75 μmol/kg) and 2C-B (ED50 = 2.43 μmol/kg) induced the response. Benzodifurans DOB-DFLY (ED50 = 0.20 μmol/kg) and 2C-B-DFLY (ED50 = 1.07 μmol/kg) showed significantly higher potency than their non-rigid counterparts. Tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 μmol/kg) and 2C-B-FLY (ED50 = 1.79 μmol/kg) were approximately equipotent. Three novel tetrahydrobenzodifurans were active but had relatively low potency.
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.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
March 1, 2022
Deborah Rudin, John D McCorvy, Grant C Glatfelter et al.
18 citations
Derivatives of (2-aminopropyl)indole and (2-aminopropyl)benzofuran are new psychoactive substances with stimulant effects. This study characterized six isomers of the sulfur-based analog (2-aminopropyl)benzo[β]thiophene (APBT) in vitro and three isomers in vivo. APBTs inhibited monoamine reuptake and induced transporter-mediated substrate release, similar to MDMA, but did not stimulate locomotion in mice. Instead, they acted as full agonists at 5-HT2 receptor subtypes and induced head-twitch responses, indicating psychedelic-like activity. Replacing oxygen with sulfur enhanced serotonin transporter release potency and 5-HT2 receptor activity, shifting the profile toward psychedelic and entactogenic effects with minimal psychomotor stimulation, suggesting potential for drug-assisted psychotherapy.
International journal of molecular sciences
November 30, 2021
Thomas J F Angenoorth, Stevan Stankovic, Marco Niello et al.
18 citations
Many psychoactive compounds primarily interact with high-affinity monoamine transporters, but their interactions with low-affinity, high-capacity transporters like human organic cation transporters (hOCTs) and the plasma membrane monoamine transporter (hPMAT) are understudied. Using radiotracer-based uptake inhibition assays in HEK293 cells, 17 psychoactive substances were tested. Most compounds inhibited hOCT1 and hOCT2 in the low micromolar range, while few affected hOCT3 or hPMAT. Methylphenidate and ketamine selectively inhibited hOCT1 or hOCT2, respectively, and MDMA potently inhibited hOCT1, hOCT2, and hPMAT. Enantiospecific differences were observed for R- and S-α-PVP and R- and S-citalopram. These findings highlight the importance of studying drug interactions with hOCTs and hPMAT for regulating monoamine concentrations and xenobiotic clearance.
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.
Drug testing and analysis
February 1, 2018
Tristan Colestock, Jason Wallach, Matt Mansi et al.
14 citations
A new dissociative anesthetic, 3-MeO-PCMo, a morpholine analogue of 3-MeO-PCP, was synthesized and characterized along with five related compounds. All six arylcyclohexylmorpholines were analyzed using chromatographic, mass spectrometric, and spectroscopic techniques, allowing differentiation of positional isomers. In vitro binding studies in rat forebrain preparations showed moderate affinity for the N-methyl-D-aspartate receptor (NMDAR), with 3-Me-PCMo having the highest affinity, followed by 3-MeO-PCMo. 3-MeO-PCMo had affinity comparable to ketamine and approximately 12-fold lower than PCP. These findings support anecdotal reports of dissociative effects from 3-MeO-PCMo in humans.
Drug testing and analysis
June 1, 2015
John D Power, Pierce Kavanagh, John O'Brien et al.
12 citations
A substance called bk-2C-B, a cathinone analogue of the psychoactive phenethylamine 2C-B, has become available from online retailers. Its identity was confirmed through multiple analytical methods, including nuclear magnetic resonance spectroscopy, gas and liquid chromatography, and high-resolution mass spectrometry. The compound was also synthesized using the Delépine reaction. Gas chromatography-mass spectrometry showed potential for artificial formation of byproducts, but these were not seen with liquid chromatography. Analysis revealed the purchased material was a mixture of hydrochloride and hydrobromide salts, suggesting a specific synthetic route, and X-ray crystallography showed it exists as polymorphs.
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.
Forensic science international
July 4, 2008
Simon D Brandt, Cláudia P B Martins, Sally Freeman et al.
10 citations
DMT, a psychoactive compound, reacts with common laboratory solvents like dichloromethane (DCM) to form a quaternary ammonium salt, which can rearrange during analysis into products including 3-(2-chloroethyl)indole and 2-methyltetrahydro-beta-carboline. This study extends these findings to other halogenated solvents—dibromomethane and 1,2-dichloroethane—characterizing the resulting derivatives. The DCE derivative produced at least six rearrangement products. Using deuterated compounds helped clarify the rearrangement mechanisms. These solvent-derived marker molecules could help identify which solvents were used in the manufacture of controlled substances, a factor often overlooked because solvents are assumed inert.
Drug testing and analysis
January 1, 2018
Kelly B Texter, Rachel Waymach, Pierce V Kavanagh et al.
9 citations
When the new psychoactive substance bk-2C-B is heated in a simulated meth pipe, it breaks down into at least twelve different products, some of which could be inhaled. A closely related compound, bk-2C-I, produced similar breakdown products, plus two additional ones. The toxicity of these pyrolysis products is unknown, raising concerns about potential harm from smoking or inhaling these substances.
Drug testing and analysis
January 1, 2025
Pierce V Kavanagh, Folker Westphal, Benedikt Pulver et al.
8 citations
A novel LSD derivative, 1-dodecanoyl-LSD (1DD-LSD), was synthesized and tested in mice to see if it produces LSD-like effects. The compound induced a head-twitch response in C57BL/6J mice with a median effective dose of 2.17 mg/kg (3.60 μmol/kg). LSD was 27-fold more potent than 1DD-LSD under similar conditions. Other homologues, such as ALD-52 and 1-propanoyl-LSD, also showed considerably higher potency, suggesting that hydrolysis of the 1-dodecanoyl moiety may be less efficient in vivo. The increased lipophilicity of 1DD-LSD might cause it to be sequestered in fat, reducing enzymatic hydrolysis. Further studies are needed to assess its activity in humans and its potential as a long-acting prodrug for LSD.
Drug testing and analysis
March 1, 2023
Pierce V Kavanagh, Folker Westphal, Benedikt Pulver et al.
7 citations
A new lysergamide, 1cP-AL-LAD, was analyzed using chromatographic, mass spectrometric, and spectroscopic methods. A powdered sample from an online vendor contained 17 impurities, including AL-LAD and 1P-AL-LAD (confirmed by reference standards) and tentatively identified compounds such as 1-acetyl-AL-LAD and oxidation products of the N6-allyl group and ergoline ring. The substance was also found in blotter paper samples sold online for recreational use. These findings provide analytical data for researchers interested in lysergamide chemistry.
Drug testing and analysis
September 1, 2024
Verena Angerer, Yasmin Schmid, Florian Franz et al.
6 citations
In six healthy volunteers, the new psychoactive substance MDAI at 3.0 mg/kg produced subjective effects comparable to 125 mg of MDMA, including increased blood pressure, but did not raise heart rate or body temperature. MDAI increased cortisol and prolactin levels, appeared in serum about 20 minutes after ingestion, and remained detectable for at least 4 days in serum and 6 days in urine. The drug was well tolerated. Further research is needed to evaluate whether MDAI might have medicinal applications.
Drug testing and analysis
December 3, 2024
Simon D Brandt, Pierce V Kavanagh, Sarah Gare et al.
5 citations
1-(2-furoyl)-lysergic acid diethylamide (1F-LSD, SYN-L-005) is a novel analog of the recently detected recreational drug 1-(thiophene-2-carbonyl)-LSD (1T-LSD). Both substances are N1-acylated LSD derivatives that bind to the 5-HT2A receptor, the primary site of action for psychedelic drugs. In C57BL/6J mice, 1F-LSD and 1T-LSD induced the head-twitch response, a 5-HT2A-mediated behavior, and were hydrolyzed to LSD after administration. These findings indicate that both compounds exhibit LSD-like properties and likely act as prodrugs for LSD, releasing the active drug in the body.
Drug testing and analysis
February 1, 2024
Simon D Brandt, Pierce V Kavanagh, Folker Westphal et al.
5 citations
N-ethyl-N-isopropyllysergamide (EIPLA), an isomer of the psychedelic lysergamide ETH-LAD, shows LSD-like properties in preclinical tests. Mass spectrometry, chromatography, and NMR spectroscopy distinguished EIPLA from ETH-LAD by their structural features. Blotter extracts contained 96.9 ± 0.5 μg and 85.8 ± 2.8 μg of EIPLA base. In mice, EIPLA induced head-twitch responses (ED50 = 234.6 nmol/kg), about half the potency of LSD (ED50 = 132.8 nmol/kg), consistent with serotonergic psychedelic effects. Analytical data are provided to aid forensic and clinical identification.
Drug testing and analysis
April 1, 2025
Simon D Brandt, Pierce V Kavanagh, Sarah Gare et al.
4 citations
A newly developed LSD derivative, 1-hexanoyl-LSD (1H-LSD), was characterized analytically and tested in mice using the head-twitch response assay, a behavioral proxy for psychedelic activity. 1H-LSD induced head-twitch responses with a median effective dose of 192.4 μg/kg, making it roughly as potent as the known analog 1A-LSD (ALD-52) under similar conditions. Like other N1-acylated LSD derivatives, 1H-LSD is expected to be hydrolyzed to LSD in the body, acting as a prodrug. It is not yet known whether this compound has appeared on the recreational drug market or in research chemical supplies.