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.
Drug testing and analysis
January 1, 2014
Hamilton Morris, Jason Wallach
240 citations
More than 30 dissociative compounds have been used non-medically over the past 60 years, starting with PCP in the 1950s and later including ketamine and dextromethorphan. At least 14 PCP derivatives were sold illicitly from the 1960s to the 1990s. The Internet transformed the drug market, shifting from gray-market vendors to online research chemical suppliers. The first dissociative research chemical, 4-MeO-PCP, appeared in 2008, and the market now includes at least 12 dissociatives, nearly half previously unknown in scientific literature. Methoxetamine achieved widespread international use. This historical account presents the first complete portrait of the underground dissociative market, alongside legal, technological, and scientific developments driving its evolution.
Nat Commun
December 15, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
153 citations
Serotonergic psychedelics show therapeutic potential, but the specific roles of 5-HT2A receptor signaling pathways are unclear. Researchers developed selective ligands with varying Gq efficacies, including β-arrestin-biased ones. In male mice, 5-HT2A-Gq recruitment efficacy, not β-arrestin2 recruitment, predicted psychedelic potential measured by head-twitch response magnitude. Disrupting Gq-PLC signaling reduced this response, and a threshold Gq activation level was needed for psychedelic-like effects, explaining why partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists blocked psychedelic effects and caused receptor downregulation and tachyphylaxis. Fine-tuning 5-HT2A Gq-signaling enables development of non-psychedelic 5-HT2A agonists.
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.
PLoS ONE
June 17, 2016
Jason Wallach, Heather Kang, Tristan Colestock et al.
73 citations
1,2-Diarylethylamines such as diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP) are sold as 'legal highs' and have been linked to fatal and non-fatal overdoses. Binding studies at 46 central nervous system receptors show these compounds are relatively selective N-methyl-D-aspartate receptor (NMDAR) antagonists with weak off-target inhibition of dopamine and norepinephrine reuptake. In rats, DPH and 2-MXP significantly reduced prepulse inhibition of startle (PPI), an effect seen with dissociative drugs like phencyclidine (PCP) and ketamine. DPH acted with a median effective dose (ED50) of 9.5 mg/kg, less potent than PCP and ketamine.
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.
Current Neuropharmacology
November 3, 2016
Julian A. Michely, Sascha K. Manier, Achim T. Caspar et al.
36 citations
Two new psychoactive substances, 3-MeO-PCP and 3-MeOPCPy, are metabolized in rat and human liver microsomes through multiple pathways including hydroxylation, O-demethylation, and glucuronidation. Specific cytochrome P450 enzymes (CYP 2B6, 2C19, 2C9, 2D6) catalyze initial metabolic steps. Because only polymorphically expressed enzymes are involved, pharmacogenomic variations may affect metabolism, though clinical data are needed to confirm relevance. Standard urine screening approaches using GC-MS, LC-MSn, and LC-HR-MS/MS can detect intake of both drugs via identified metabolites.
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.
Journal of Analytical Toxicology
April 3, 2013
Giorgia de Paoli, Simon D. Brandt, Jason Wallach et al.
30 citations
Three psychoactive arylcyclohexylamines sold online as research chemicals were chemically identified: methoxetamine, N-ethyl-1-(3-methoxyphenyl)cyclohexanamine, and 1-[1-(3-methoxyphenyl)cyclohexyl]piperidine. A validated liquid chromatography method with ultraviolet detection reliably measured these compounds in blood, urine, and vitreous humor at concentrations from 0.16 to 5.0 mg/L, while mass spectrometry served as a confirmatory technique.
Neuropharmacology
August 10, 2016
Heather Kang, Pojeong Park, Zuner A. Bortolotto et al.
29 citations
Ephenidine, a new psychoactive substance, acts as a selective NMDA receptor antagonist by binding to the PCP site (Ki: 66 nM). It also shows modest activity at dopamine and noradrenaline transporters and at sigma 1 and sigma 2 binding sites. In rat hippocampal slices, ephenidine (1 and 10 μM) inhibited NMDA receptor-mediated field excitatory postsynaptic potentials by 25% and near maximally after 4 hours, without affecting AMPA receptor-mediated responses. It blocked NMDA receptor-mediated EPSCs in a voltage-dependent manner and prevented the induction of long-term potentiation. These properties resemble ketamine and help explain its dissociative, cognitive, and hallucinogenic effects in humans.
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.
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
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
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.
bioRxiv (Cold Spring Harbor Laboratory)
July 31, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
11 citations
preprint
Serotonergic psychedelics show therapeutic promise, but the specific signaling pathways responsible for their effects have been unclear. Researchers developed a series of 5-HT2A receptor ligands with varying Gq efficacies, including β-arrestin-biased ligands. They found that 5-HT2A-Gq efficacy, not β-arrestin2 efficacy, predicts psychedelic potential, measured by head-twitch response in male mice. Disrupting Gq-PLC signaling reduced this response, and a threshold of Gq activation is needed for psychedelic-like effects, explaining why some partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists caused receptor downregulation and tachyphylaxis, and showed an anti-psychotic-like profile. This fine-tuning of 5-HT2A signaling can generate ligands distinct from classical psychedelics.
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.
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.
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
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.
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.