Journal of Psychopharmacology
February 21, 2019
Adam L. Halberstadt, Muhammad Chatha, Stephen J. Chapman et al.
25 citations
In mice, the hallucinogenic compound mescaline and several of its chemical analogs produce a distinctive head-twitch response that depends on activation of the 5-HT2A receptor. Adding a methyl group to mescaline (making TMA) doubled its potency, and replacing the 4-methoxy group with larger ethoxy or propoxy groups also increased potency for both mescaline and TMA. However, for a different set of isomers (TMA-2 and its analogs), changing the 4-alkoxy group did not alter potency, even though TMA-2 itself was twice as potent as mescaline. These potency patterns in mice closely match known human hallucinogenic data and show that different substitution patterns on the phenyl ring produce distinct structure-activity relationships.
Psychopharmacology
February 14, 2019
Adam L. Halberstadt, Landon M. Klein, Muhammad Chatha et al.
25 citations
The lysergamide ECPLA, a close structural analog of LSD, binds with high affinity to serotonin, adrenergic, and dopamine receptors, and acts as a potent agonist at the 5-HT₂A receptor, which mediates psychedelic effects. In mice, ECPLA induced head twitches with an ED₅₀ of 317.2 nmol/kg, about 40% as potent as LSD. Two other analogs, LAMPA (ED₅₀ = 358.3 nmol/kg) and MIPLA (ED₅₀ = 421.7 nmol/kg), showed similar or slightly lower potency. These findings indicate that ECPLA, MIPLA, and LAMPA share pharmacological properties with LSD and other lysergamide hallucinogens.
Drug Testing and Analysis
September 20, 2013
Tomás Herraiz, Simon D. Brandt
25 citations
5-(2-Aminopropyl)indole (5-IT), a psychoactive compound linked to fatal and non-fatal intoxications in Europe, was tested for its effect on human monoamine oxidase (MAO) enzymes. Using kynuramine as a substrate, 5-IT selectively, competitively, and reversibly inhibited MAO-A with an IC50 of 1.6 μM and a Ki of 0.25 μM, while showing no inhibition of MAO-B up to 500 μM. Compared to established inhibitors, 5-IT was less potent than clorgyline (IC50 16 nM) and harmaline (20 nM) but more potent than toloxatone (6.7 μM) and moclobemide (>500 μM). This MAO-A inhibition suggests 5-IT may contribute to serotonergic toxicity, though further research is needed.
Neuropharmacology
June 23, 2018
Julian Maier, Felix P. Mayer, Dino Luethi et al.
24 citations
4,4′-DMAR, a new psychoactive substance linked to 31 deaths in Europe between June 2013 and February 2014, acts as a potent non-selective monoamine releasing agent. It inhibits dopamine, norepinephrine, and serotonin transporters at low micromolar concentrations (IC50 values below 2 μM) and induces reverse transport via these transporters. It also inhibits the vesicular monoamine transporter 2 in both rat and human cells with potency similar to MDMA. Unlike aminorex and 4-methylaminorex, 4,4′-DMAR strongly affects the serotonin transporter, suggesting fatalities may involve monoaminergic toxicity including serotonin syndrome. Its activity at VMAT2 indicates potential long-term neurotoxicity with chronic abuse.
Drug Testing and Analysis
May 16, 2020
Christina Grumann, Kerstin Henkel, Simon D. Brandt et al.
23 citations
1P-LSD, a non-controlled alternative to LSD, acts as a prodrug that converts almost entirely into LSD in the human body. In two volunteers, oral and intravenous doses of 100 μg 1P-LSD were administered. After oral intake, only LSD was detected in serum and urine, with a terminal elimination half-life of about 6.4 hours. Intravenous 1P-LSD was detectable for only a few hours, while LSD persisted much longer. The bioavailability of LSD from oral 1P-LSD was nearly 100%. Subjective drug effects and altered states of consciousness scores were comparable to those from LSD, supporting the prodrug hypothesis. Oral administration produced higher 5D-ASC scores than intravenous.
Drug Testing and Analysis
August 15, 2016
Gavin McLaughlin, Noreen Morris, Pierce V. Kavanagh et al.
23 citations
Mexedrone, a derivative of mephedrone that appeared in 2015, was synthesized and analytically characterized. It was a weak non-selective uptake blocker at dopamine, norepinephrine, and serotonin transporters with IC50 values in the low micromolar range, and lacked releasing activity at dopamine and norepinephrine transporters but showed weak releasing activity at serotonin transporters (EC50 = 2.5 μM). Its isomer, N-methoxymephedrone, acted as a weak uptake blocker and a fully efficacious substrate-type releasing agent across all three transporters with EC50 values in the low micromolar range. A synthesis by-product, α-chloromethylmephedrone, was inactive in all assays.
Drug Testing and Analysis
April 2, 2013
Jason Wallach, Giorgia de Paoli, Adeboye Adejare et al.
21 citations
Six new psychoactive substances related to PCP and ketamine were synthesized and analyzed: three substituted 1-(1-phenylcyclohexyl)piperidines (3-MeO-, 4-MeO-, and 3-Me-PCP) and three substituted 1-(1-phenylcyclohexyl)pyrrolidine analogues (3-MeO-, 4-MeO-, and 3-Me-PCPy). Mass spectrometry, chromatography, infrared, and NMR spectroscopy characterized all six compounds and their intermediates. Solvent and protonation effects on NMR spectra were examined. Isomeric 3-MeO- and 4-MeO-PCP and PCPy analogues could be distinguished by mass spectrometry. Gas chromatography caused notable degradation of 4-MeO-substituted analytes, especially hydrochloride salts, producing a 1-phenylcyclohex-1-ene nucleus; this degradation was less pronounced with 3-MeO isomers, likely due to para-methoxy group resonance facilitating amine elimination.
Drug Testing and Analysis
November 27, 2021
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
19 citations
A new LSD derivative called 1-valeroyl-LSD (1V-LSD, or "Valerie") has appeared on the online market. It is a higher homolog of earlier derivatives like ALD-52, 1P-LSD, and 1B-LSD. The study analytically characterized 1V-LSD using mass spectrometry, chromatography, NMR, and Raman spectroscopy. In mice, 1V-LSD induced a head-twitch response, a behavioral proxy for human hallucinogenic effects, in a dose-dependent manner. Its median effective dose was 373 nmol/kg, about a third the potency of LSD (ED50 = 132.8 nmol/kg). 1V-LSD likely acts as a prodrug that is hydrolyzed to LSD, but further studies on its biotransformation and receptor pharmacology are needed.
Drug Testing and Analysis
October 20, 2014
Gavin McLaughlin, Noreen Morris, Pierce V. Kavanagh et al.
18 citations
A newly emerged psychoactive substance, 3,4-methylenedioxy-4-methylaminorex (MDMAR), was synthesized and characterized. Analysis of vendor-sourced MDMAR found it to be predominantly the cis-isomer (90%), which could artificially convert to the trans-isomer under certain liquid chromatography conditions. Both MDMAR isomers, along with cis- and trans-4,4'-DMAR, were more potent than MDMA in releasing dopamine and norepinephrine in rat brain tissue. While cis-4,4'-DMAR, cis-MDMAR, and trans-MDMAR fully released serotonin, trans-4,4'-DMAR acted as a serotonin uptake blocker. The high potency of these analogues at monoamine transporters may indicate potential for serious side-effects at high doses.
ACS Chemical Neuroscience
September 30, 2018
Julian Maier, Felix P. Mayer, Simon D. Brandt et al.
15 citations
Aminorex and its analogues are psychostimulants that interact with monoamine transporters, sharing pharmacological similarities with amphetamines and cocaine. Some of these substances, originally failed pharmaceuticals, have reemerged as new psychoactive substances (NPS) for recreational use. Consumption of certain analogues, such as 4-methylaminorex and 4,4'-dimethylaminorex, has been linked to adverse events including death. This review covers the historical background, pharmacodynamic and pharmacokinetic properties, and misuse of these drugs as adulterants. It highlights the dangers of the NPS market, where users often lack knowledge of the pharmacology, potency, or identity of active ingredients.
Drug Testing and Analysis
May 7, 2022
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
14 citations
The lysergamide 1P-AL-LAD is characterized and tested in vitro and in mice. In pooled human liver microsomes, 1P-AL-LAD converts to AL-LAD as the most abundant metabolite, supporting the idea that it acts as a prodrug. Fourteen metabolites are detected, including hydroxylation and deacylation products. In mice, 1P-AL-LAD produces a dose-dependent increase in head twitch response, a behavioral proxy for human hallucinogenic effects, with an inverted U-shaped dose-response curve. Its median effective dose is 491 nmol/kg, almost three times less potent than AL-LAD (174.9 nmol/kg). The prodrug mechanism likely explains its activity despite N1-substitution disrupting 5-HT2A receptor activation.
Drug Testing and Analysis
July 1, 2010
Simon D. Brandt, Sharon A. Moore, Sally Freeman et al.
14 citations
An impurity profile was established for a synthetic route to the hallucinogen N,N-dimethyltryptamine (DMT) using reductive amination of tryptamine with formaldehyde and reduction by sodium cyanoborohydride. Seven compounds were detected and quantified, including DMT and several byproducts. Replacing sodium cyanoborohydride with sodium borohydride almost exclusively produced tetrahydro-β-carboline instead of DMT. Detection limits ranged from 21.5 to 87.7 ng mL⁻¹, and quantification limits from 24.6 to 88.3 µg mL⁻¹, with linearity from 20.8 to 980 µg mL⁻¹. The method is useful for forensic and pharmaceutical analysis of DMT.
Drug Testing and Analysis
September 11, 2015
Jason Wallach, Tristan Colestock, Brian Cicali et al.
13 citations
Fifteen N-alkyl-arylcyclohexylamines, including compounds related to the dissociative substances 3-MeO-PCP, 3-MeO-PCE, and 3-MeO-PCPr, were synthesized and characterized. Analytical methods such as gas chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy were used. Positional isomers of methoxy-substituted arylcyclohexylamines were readily distinguishable under various analytical conditions. The work provides previously unreported analytical data to aid in identifying newly emerging research chemicals.
Drug Testing and Analysis
May 22, 2021
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
12 citations
Lysergic acid diethylamide (LSD) is a potent psychoactive substance of clinical interest, and its analogs, including N-methyl-N-isopropyl isomer (MIPLA), have appeared on the street market. This report describes analytical methods to differentiate MIPLA from LSD and the N-methyl-N-propyl isomer (LAMPA) under routine conditions. Gas chromatography-solid phase infrared spectroscopy was particularly helpful. GC-electron ionization-tandem mass spectrometry of the m/z 72 iminium ion distinguished the three isomers on mass spectral grounds alone. Derivatization with BSTFA improved GC separation. LC-Q-MS and in-source collision-induced dissociation differentiated MIPLA and LAMPA based on distinct m/z 239 ion ratios. An alternative LC-MS/MS method improved separation but LSD co-eluted with iso-LSD; comparing ion ratios at m/z 324.2 > 223.2 and 324.2 > 208.2 facilitated differentiation. Two blotters contained 180 and 186 μg MIPLA per blotter.
Journal of chromatography. A
August 14, 2009
Cláudia P.B. Martins, Sally Freeman, John F. Alder et al.
11 citations
A purported two-step internet recipe for making the psychoactive compound DMT was tested and found to produce almost none. The second step, methylation of tryptamine, was analyzed with advanced mass spectrometry. Instead of DMT, the reaction yielded 47.4% 1-N-methyl-TMT, 21.0% TMT, 11.1% unreacted tryptamine, and a 0.5% trace of N-methyltryptamine. The work demonstrates that synthetic methods circulated online can be unreliable and produce largely unintended, non-psychoactive products.
Microchemical Journal
March 20, 2013
Alain Gaujac, James L. Ford, Nicola M. Dempster et al.
10 citations
N,N-dimethyltryptamine (DMT) may exist in at least two polymorphic forms, explaining the wide variation in reported melting points (38–40 °C to 73–74 °C). Using X-ray powder diffraction and differential scanning calorimetry, including fast scan DSC, on DMT extracted from Mimosa tenuiflora bark or synthesized in the lab, two polymorphs were identified: Form I melts at 57–58 °C and Form II at 45–46 °C, with respective enthalpies of 91.9 ± 2.4 J g⁻¹ and 98.3 ± 2.8 J g⁻¹. Form II converts to Form I during standard DSC, but conversion is prevented at fast scanning rates (100 °C min⁻¹).
Drug Testing and Analysis
January 1, 2012
Simon D. Brandt, Ruchanok Tearavarich, Nicola M. Dempster et al.
10 citations
Thirteen new tryptamine derivatives were synthesized and analyzed to provide reference data for forensic and clinical identification. Using NMR and mass spectrometry, the compounds were characterized and distinguished from each other and from related substances. Key mass spectral fragments were identified, including an iminium ion and indole-related ions at specific mass-to-charge ratios. The work extends earlier research on similar compounds and supplies analytical standards that can help professionals identify these substances before they cause adverse health effects.
Drug Testing and Analysis
December 29, 2010
Ruchanok Tearavarich, Viwat Hahnvajanawong, Nicola M. Dempster et al.
10 citations
Twelve novel 5-ethoxy-N,N-dialkyl-tryptamines and their deuterated counterparts were synthesized using a microwave-accelerated reduction step that took 5 minutes in tetrahydrofuran at 150 °C. The resulting 24 tryptamines were characterized by nuclear magnetic resonance spectroscopy and gas chromatography ion trap mass spectrometry, revealing differential fragmentation of side-chain-related iminium ions. These compounds are intended as internal standards for bioanalytical and pharmacological assays, aiding identification of novel tryptamines from non-traditional sources, and are of immediate value in forensic, research, and public health contexts.
The Analyst
January 1, 2005
Simon D. Brandt, Sally Freeman, Ian A. Fleet et al.
10 citations
Twelve symmetrically and 13 asymmetrically N,N-disubstituted glyoxalylamide precursors and their corresponding tryptamine derivatives were characterized using gas chromatography low-pressure chemical ionization ion trap tandem mass spectrometry with methanol as the chemical ionization reagent. In tryptamines, formation of [CH2=N+R2R3] iminium ions after beta-cleavage dominates, while dissociation into [3-vinylindole]+ is a minor pathway compared to electrospray triple quadrupole tandem mass spectrometry, where that transition is distinctively important. This method also enables differentiation between most isomeric derivatives studied.
Drug Testing and Analysis
April 30, 2019
Michael Dybek, Jason Wallach, Pierce V. Kavanagh et al.
9 citations
Six possible racemic isomers of the research chemical fluorolintane (2-F-DPPy) were synthesized and characterized. The isomers differ by the position of a fluorine substituent on the phenyl or benzyl ring of the 1,2-diarylethylamine structure. Using mass spectrometry, chromatography, nuclear magnetic resonance spectroscopy, and infrared spectroscopy, each isomer was distinguishable. A tandem mass spectrometry method analyzing the [M + H – HF]+ species produced distinct product ions for all six substances, aiding identification of positional isomers that pose challenges for stakeholders confronting new psychoactive substances.
Drug Testing and Analysis
April 19, 2018
Gavin McLaughlin, Michael H. Baumann, Pierce V. Kavanagh et al.
8 citations
Two new psychoactive substances, 4-methylphenmetrazine (4-MPM) and 3-methylphenmetrazine (3-MPM), have appeared on the recreational drug market following the earlier emergence of 3-fluorophenmetrazine. Analytical characterization of vendor samples confirmed the presence of 4-MPM in two samples and 3-MPM in one sample. In vitro transporter assays using rat brain synaptosomes tested the isomers' ability to inhibit uptake or stimulate release of dopamine, norepinephrine, and serotonin. The findings suggest that 2-MPM and 3-MPM will exhibit stimulant properties similar to phenmetrazine, whereas 4-MPM may display entactogen properties more similar to MDMA. Combining test purchases, analytical characterization, targeted synthesis, and pharmacological evaluation provides an effective approach for generating data on emerging substances.
Drug Testing and Analysis
August 15, 2013
Leslie A. King, István Ujváry, Simon D. Brandt
8 citations
The term 'derivative' has a precise but context-dependent meaning in chemistry, yet it appears widely in drug legislation without clear definition. Many assume only first-order derivatives—substances made in one reaction step—are covered, but this excludes substances like 2-carbomethoxytropinone, convertible to cocaine in multiple steps, which courts have ruled as controlled. The US Drug Enforcement Administration successfully argued in 1986 that buprenorphine, requiring six or more steps from thebaine, is a derivative. This ambiguity leaves the legal status of substances like 2-bromo-LSD uncertain. The authors suggest that unless qualified, the term should be avoided in future legislation.
Psychopharmacology
December 7, 2022
Adam L. Halberstadt, Dino Luethi, Marius C. Hoener et al.
7 citations
A series of 4-thio-substituted phenylalkylamines, including the psychedelic drugs 2C-T-2 and 2C-T-7, were tested in mice using the head twitch response (HTR), a behavioral proxy for human psychedelic effects. Adding an α-methyl group to the parent compound 2C-T increased potency fivefold, and extending the 4-methylthio group by one to three methylene units also increased potency. Fluorination of the 4-position alkylthio chain or a 4-allylthio substituent reduced activity, and bulky 4-benzylthio groups showed little or no effect. Binding studies confirmed nanomolar affinity for 5-HT2 receptor subtypes and partial agonism at 5-HT2A, supporting classification of these compounds as psychedelic drugs.
Drug Testing and Analysis
August 24, 2020
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
5 citations
N-ethyl-N-cyclopropyl lysergamide (ECPLA) produces LSD-like behavioral effects in mice and may act as a hallucinogen in humans. ECPLA is an isomer of the recreational drug LSZ. Several analytical methods—mass spectrometry, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, and GC condensed-phase infrared spectroscopy—can differentiate ECPLA from LSZ. Key mass spectral differences include ion abundances at m/z 196, 207/208, 98, and 41. Electrospray ionization spectra show lysergamide-related ions, and LSZ (but not ECPLA) produces product ions at m/z 267 and 98 under the conditions used. These data support forensic and clinical detection of ECPLA.
Drug Testing and Analysis
September 1, 2011
Simon D. Brandt
5 citations
This special issue presents a variety of techniques and topics in illicit drug research, ranging from classic drugs like cocaine to internet drugs and new psychoactive substances. Raman spectroscopy is reviewed for non-destructive analysis of street drugs, including detection on fibers, fingerprints, banknotes, and in body fluids, as well as for detecting cocaine concealed in rum bottles down to 6% w/v solutions. Proton magnetic resonance spectroscopy at 3 Tesla can detect cocaine in wine bottles at 5 mM levels. Synthetic cathinones and other online-accessible drugs like GHB are reviewed for clinical effects and harm reduction. Internet products often have misleading labels; six out of seven products analyzed showed incorrect labeling.