Drug Testing and Analysis
October 12, 2015
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
79 citations
1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD), a non-controlled derivative of LSD, was characterized and tested for LSD-like effects. Using chromatographic, mass spectrometric, infrared, and nuclear magnetic resonance methods, the compound was compared to LSD. In male C57BL/6J mice, 1P-LSD produced a dose-dependent increase in head-twitch response (HTR) counts, a behavioral marker of 5-HT2A receptor activation. 1P-LSD had about 38% of the potency of LSD (ED50 = 349.6 nmol/kg vs. 132.8 nmol/kg for LSD). Pretreatment with the selective 5-HT2A receptor antagonist M100907 abolished the HTR, confirming that the response was mediated by 5-HT2A receptor activation. These results indicate 1P-LSD produces LSD-like effects in mice, consistent with classification as a serotonergic hallucinogen, though human psychoactive effects remain unknown.
Drug Testing and Analysis
May 13, 2019
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
72 citations
1-Butanoyl-LSD (1B-LSD), a new analog of lysergic acid diethylamide (LSD), was fully characterized using multiple analytical techniques including NMR, mass spectrometry, and infrared spectroscopy, allowing clear differentiation from a similar compound, 1P-ETH-LAD. In behavioral tests with C57BL/6J mice, 1B-LSD produced a dose-dependent increase in head-twitch response, a marker of serotonergic hallucinogen activity, though with only about 14% of LSD's potency (ED50 = 976.7 nmol/kg vs. 132.8 nmol/kg for LSD). This suggests 1B-LSD has LSD-like behavioral effects and may act as a pro-drug for LSD, but further research is needed to confirm psychoactive effects in humans.
Drug Testing and Analysis
June 5, 2017
Simon D. Brandt, Pierce V. Kavanagh, Brendan Twamley et al.
56 citations
Lysergic acid morpholide (LSM-775), a structural relative of LSD, appeared on the market for new psychoactive substances in 2013, but its potency and psychoactive effects in humans have been disputed. This investigation characterized a powdered sample using multiple analytical techniques and tested its receptor activity. LSM-775 acted as a nonselective agonist at 5-HT1A and 5-HT2A receptors. In head twitch studies with C57BL/6J mice, LSM-775 did not induce the head twitch response unless 5-HT1A receptors were blocked by the antagonist WAY-100,635 (1 mg/kg, subcutaneous). The findings suggest that activation of 5-HT1A receptors by LSM-775 masks its hallucinogen-like effects, consistent with reports that it produces only weak LSD-like effects in humans.
Journal of Analytical Toxicology
February 19, 2015
Simon Elliott, Simon D. Brandt, Jason Wallach et al.
54 citations
2-Methoxydiphenidine (2-MXP), a dissociative research chemical sold as an alternative to methoxetamine and ketamine, was detected in post-mortem blood and urine from three fatalities. Femoral blood concentrations were 24.0, 2.0, and 1.36 mg/L; the lowest case had an alternative cause of death. Therapeutic levels of prescription drugs were also present. Metabolites included hydroxy-2-MXP (with hydroxylation on the piperidine ring), O-desmethyl-2-MXP, and hydroxylated O-desmethyl-2-MXP. Diphenidine and hydroxy-diphenidine were detected, but it was unclear if they came from 2-MXP or separate diphenidine use. These are the first published fatalities involving 2-MXP, providing analytical data for forensic toxicologists.
Drug Testing and Analysis
March 16, 2020
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
38 citations
1-Cylopropanoyl-LSD (1CP-LSD), a new lysergamide-based designer drug, was analyzed using multiple chemical and spectroscopic methods. Incubation with human serum converted 1CP-LSD into LSD, suggesting it may act as a prodrug for LSD in the body. In mice, 1CP-LSD induced a head-twitch response (HTR) with an ED50 of 430.0 nmol/kg, comparable to 1P-LSD (ED50 = 349.6 nmol/kg), indicating an LSD-like behavioral profile. The study includes analysis of blotters and pellets, and detected artificially induced degradation products during GC-MS analysis. Clinical studies are needed to determine its potency and effects in humans.
Drug Testing and Analysis
May 19, 2014
Simon D. Brandt, Michael H. Baumann, John S. Partilla et al.
37 citations
A new designer drug, para-methyl-4-methylaminorex (4,4'-DMAR), was linked to 26 deaths in Europe in 2013. Laboratory analysis of samples from online vendors identified the (±)-cis isomer in at least 18 cases. The drug acts as a potent releaser at dopamine, norepinephrine, and serotonin transporters, with EC50 values of 8.6 nM, 26.9 nM, and 18.5 nM respectively. Its potency at dopamine and norepinephrine transporters rivaled that of d-amphetamine and aminorex, but it was far more potent at the serotonin transporter. This broad activity predicts serious side effects including psychosis, agitation, hyperthermia, and cardiovascular stimulation, especially at high doses or with other stimulants.
Drug Testing and Analysis
April 15, 2015
Gavin McLaughlin, Noreen Morris, Pierce V. Kavanagh et al.
32 citations
Three powdered samples sold online as the 'research chemical' 2-methoxydiphenidine (2-MXP) were analytically characterized and compared with synthesized isomers. Gas chromatography, high-performance liquid chromatography, mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy, and thin layer chromatography all confirmed the samples were 2-MXP. The three positional isomers (2-, 3-, and 4-MXP) could be differentiated, notably by distinct stability differences observed during in-source collision-induced dissociation of the protonated molecule under HPLC selected-ion monitoring. Additionally, matrix assisted inlet ionization Orbitrap mass spectrometry detected the protonated molecule of 2-MXP directly from a tablet surface after adding 3-nitrobenzonitrile as matrix.
Neuropharmacology
October 12, 2017
Felix P. Mayer, Nadine V. Burchardt, Ann M. Decker et al.
30 citations
Three isomers of the new psychoactive substance 3-fluorophenmetrazine (2-FPM, 3-FPM, and 4-FPM) inhibit dopamine and norepinephrine transporters with potencies comparable to cocaine (IC50 values below 2.5 μM) but show much weaker effects at the serotonin transporter (IC50 values above 80 μM). They also induce efflux of monoamines via all three transporters, an effect enhanced by the ionophore monensin. These compounds act as monoamine releasers with marked potency at catecholamine transporters implicated in abuse and addiction.
Drug Testing and Analysis
July 15, 2014
Jason Wallach, Pierce V. Kavanagh, Gavin McLaughlin et al.
26 citations
Diphenidine, a dissociative agent sold as a 'research chemical,' and its isomer 2,2-DEP can be distinguished using gas chromatography-mass spectrometry by their unique iminium ions. The study synthesized and characterized both compounds and their pyrrolidine analogues. Two vendor samples confirmed diphenidine. In rat hippocampal slices, diphenidine (30 μM) reduced NMDA-mediated electrical signals to a similar extent as ketamine (30 μM), indicating it acts on the same receptor. This suggests 1,2-diphenylethylamines are emerging alternatives to arylcyclohexylamine-type dissociatives like PCP and methoxetamine.
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
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.
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
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.
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 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.