Progress in neuro-psychopharmacology & biological psychiatry
December 3, 2012
John Corkery, Emma Durkin, Simon Elliott et al.
105 citations
5-MeO-DALT is a psychoactive tryptamine sold online as a 'research chemical' with little scientific study. A review of available knowledge and a first reported death involving the substance is described: a man in his mid-20s died in mid-2010 after being hit by a lorry while under the influence of 5-MeO-DALT, as concluded by the coroner. The authors call for documentation of other cases to build an evidence base.
Drug Testing and Analysis
November 4, 2013
Yan Ni Annie Soh, Simon Elliott
97 citations
Thirteen new psychoactive substances (NPS) were tested for stability in human blood and plasma stored at room temperature. Most remained stable for at least 21 days, but 4-MEC became undetectable in blood within 14 days and lost 54% in plasma, with a breakdown product (dihydro-4-MEC) also found in a real case sample. AMT produced several breakdown products that also appeared in vivo. The findings indicate that additional compounds observed in forensic casework are likely metabolites rather than instability products. This is the first published stability data for these emerging substances, and presumptive metabolites for 25C-NBOMe and AH-7921 are reported.
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.
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
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.
Human Psychopharmacology Clinical and Experimental
July 1, 2013
John Corkery, Simon Elliott, Fabrizio Schifano et al.
52 citations
MDAI (5,6-methylenedioxy-2-aminoindane), a psychoactive substance sold as a 'legal high', is structurally similar to MDMA and shares its behavioral properties. Recreational use began around 2007 in Europe, increasing after 2009 in the UK. Calls to poisons services started in 2010, with few emergency department presentations. A review of recent literature, including grey literature, presents information on MDAI's toxicity, including the first three UK deaths involving MDAI use in 2011 and 2012. 'Serotonin syndrome' appears to be a possible factor in these fatalities. Documentation of further cases, including non-fatal overdoses, is vital to establish a scientific evidence base.
Journal of Analytical Toxicology
July 1, 2005
Simon Elliott
52 citations
MDMA and its metabolite MDA show postmortem redistribution, meaning concentrations measured after death are often higher than those taken just before death. In five hospital fatalities with both antemortem and postmortem blood samples, postmortem MDMA concentrations ranged from 0.47 to 28.39 mg/L compared to antemortem levels of 0.55 to 4.33 mg/L. Postmortem-to-antemortem ratios ranged from 1.1 to 6.6 for MDMA and 1.5 to 13.3 for MDA. Central sites like the heart had much higher concentrations than peripheral sites like the femoral vein. Thus, postmortem blood levels, even from peripheral sites, are not directly comparable to antemortem findings near death.
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
October 5, 2012
Simon Elliott, Simon D. Brandt, Sally Freeman et al.
36 citations
5-(2-Aminopropyl)indole (5-IT) and 3-(2-aminopropyl)indole (α-methyltryptamine, AMT) are isomeric substances that are difficult to differentiate under routine analytical conditions, especially without reference material. Subtle differences in mass spectral and UV conditions can facilitate their differentiation. Analyses included 1H and 13C NMR, GC-EI/CI ion trap MS, and several U/HPLC-DAD and HPLC-MS methods. AMT was detected in a number of fatal intoxications, and there is a potential risk of misidentification when dealing with both substances.
Journal of Forensic Sciences
May 1, 2020
Simon 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
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.
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
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
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
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
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
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
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.
UNC Libraries
October 29, 2020
Simon D. Brandt, Maria F. Sassano, David E. Nichols et al.
4 citations
A series of N-benzylated-5-methoxytryptamine analogues and N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) were synthesized and tested. Most compounds showed highest affinity for the 5-HT2 family of serotonin receptors. Substitution at the para position of the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional potency was measured at human 5-HT2A, 5-HT2B, and 5-HT2C receptors and rat 5-HT2A and 5-HT2C receptors using intracellular calcium mobilization. Several tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM) but were mostly partial agonists. In mouse head twitch tests, many compounds induced the behavior, which correlated significantly with functional potency at the rat 5-HT2A receptor.