Drug Testing and Analysis
July 1, 2014
Simon D. Brandt, Leslie A. King, Michael Evans‐brown
164 citations
The new drug phenomenon over the past decade has been driven by the commodification of a wide range of psychoactive substances not controlled under drug laws, sold openly as 'legal highs', 'bath salts', or 'research chemicals' by entrepreneurs and criminal groups, especially via the Internet. In Europe, the rate of appearance of new psychoactive substances (NPS) averaged one new substance every 5–6 days, with 81 detected in 2013, 74 in 2012, 49 in 2011, and 41 in 2010. The number of Internet shops selling these substances rose from 170 in 2010 to 693 in 2012 and 651 in 2013. Many substances were originally synthesized years ago, some as failed pharmaceuticals, and their re-discovery has fueled the market.
Drug Testing and Analysis
June 26, 2012
Torsten Passie, H. M. Emrich, Matthias Karst et al.
114 citations
A 19-year-old male with severe PTSD symptoms, including flashbacks, panic attacks, and self-mutilation, experienced dramatic symptom reduction after smoking cannabis resin. This review examines clinical and preclinical neurobiological evidence for cannabis's effects on PTSD. Cannabis may reduce the strength and emotional impact of traumatic memories through synergistic mechanisms, potentially aiding sleep, reducing anxiety, and lessening flashback involvement. Endocannabinoid signaling systems in stress-sensitive brain regions like the hypothalamus and amygdala suggest their role in regulating stress responses. Evidence increasingly indicates cannabinoids may play a role in fear extinction and have antidepressive effects. Further studies are needed to evaluate cannabinoids' therapeutic potential in PTSD.
ACS Pharmacology & Translational Science
December 14, 2020
Adam K. Klein, Muhammad Chatha, Lauren J. Laskowski et al.
103 citations
The 5-HT2A receptor is the primary target for psilocybin and other serotonergic hallucinogens. Seventeen tryptamines with 4-hydroxy or 4-acetoxy groups and various N,N-dialkyl substituents were tested. All acted as full or partial agonists at 5-HT2 subtypes, with similar potencies at 5-HT2A and 5-HT2B receptors, though bulkier N-alkyl groups reduced potency at 5-HT2C receptors and increased 5-HT2B efficacy. O-acetylation reduced in vitro 5-HT2A potency by 10- to 20-fold without altering efficacy. All compounds induced head twitches in mice, consistent with LSD-like effects. Acetylation had little effect on head-twitch potency, suggesting O-acetylated tryptamines may act as prodrugs deacetylated in vivo. These derivatives have psilocybin-like properties, supporting their classification as psychedelic drugs.
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
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.
BMJ
July 6, 2010
Simon D. Brandt, Harry Sumnall, Fiona Measham et al.
57 citations
After mephedrone was banned, internet vendors began selling substitute products. One widely promoted second-generation compound is Energy 1 (NRG-1), also called naphyrone (naphthylpyrovalerone, O-2482). This substance comes from a group of compounds originally documented in medicinal chemistry research.
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.
The Analyst
January 1, 2005
Simon D. Brandt, Sally Freeman, Ian A. Fleet et al.
46 citations
The degree of alkylation of the side chain nitrogen in tryptamines influences psychoactivity. The Speeter and Anthony method, which reduces a substituted indole-3-yl-glyoxalylamide to the desired tryptamine with metal hydride, was used to synthesize 12 symmetrically and 13 asymmetrically N,N-disubstituted glyoxalylamides and their corresponding tryptamine derivatives. These compounds were characterized by gas chromatography EI-ion trap mass spectrometry, electrospray-triple quadrupole-tandem mass spectrometry, and NMR spectroscopy. A solvent dependency in NMR chemical shifts must be considered for unambiguous assignment. The 1H-NMR study allowed evaluation of rotamer populations of asymmetrical glyoxalylamides. For forensic or clinical monitoring, appropriate ion transitions focus on beta-cleavage and alpha-cleavage fragmentations. The analytical data aid in spectral identification of psychoactive tryptamines.
Clinical Chemistry
June 30, 2017
Marilyn A. Huestis, Simon D. Brandt, Suman Rana et al.
42 citations
Novel psychoactive substances (NPS) have been present in clinical and forensic toxicology for over a century, with early examples including heroin, LSD, MDMA, and GHB. After synthetic cannabinoids emerged in the early 2000s, hundreds of synthetic cathinones, benzodiazepines, and opioids rapidly appeared. Toxicology laboratories, once focused on a narrow range of compounds, now face potent fentanyl derivatives mixed with or substituted for heroin, causing rising fatalities. Labs struggle to detect short-lived drug analogs, unknown urinary metabolites, and lack reference standards. Four international experts discuss what drove the global NPS market, how toxicology laboratories can address these challenges, and how public health and law enforcement can reduce NPS-related morbidity and mortality.
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.
Neuropharmacology
November 19, 2019
Adam L. Halberstadt, Muhammad Chatha, Adam K. Klein et al.
37 citations
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52) and other 1-acyl-substituted LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs assumed to act as prodrugs for LSD. Competitive binding studies and calcium mobilization assays showed 1-acyl-substitution reduced affinity for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude, and these derivatives had weak efficacy or acted as antagonists in Ca2+-mobilization assays. Despite this, they induced head twitches in mice with relatively high potency. High levels of LSD were detected in rat plasma after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating rapid and efficient deacylation in vivo, consistent with the prediction that these compounds serve as prodrugs for LSD.
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.
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
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.
Drug Testing and Analysis
May 11, 2012
Alain Gaujac, Sandro Navickiene, Mark I. Collins et al.
33 citations
Ayahuasca, a hallucinogenic beverage traditionally used by Amazonian indigenous communities, is gaining global popularity through syncretic religions like Santo Daime and União do Vegetal. Similarly, jurema wine, originating from indigenous cultures in northeastern Brazil, is now used in urban neo-shamanic rituals and religions such as Catimbó and Umbanda. Both drinks contain N,N-dimethyltryptamine, which requires co-administration of naturally occurring monoamine oxidase inhibitors, such as β-carboline derivatives, to induce psychoactive effects in humans. This review examines the cultural use of tryptamines and β-carbolines and describes recent analytical techniques for detecting these compounds in ayahuasca, its analogues, and the plants used in preparing these beverages.
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.
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.
Talanta
February 1, 2013
Alain Gaujac, Nicola M. Dempster, Sandro Navickiene et al.
29 citations
A method using solid-phase microextraction (SPME) combined with gas chromatography ion trap mass spectrometry (GC-IT-MS) reliably detects and measures N,N-dimethyltryptamine (DMT) in ayahuasca and vinho da jurema, plant-based beverages used in South American religious ceremonies. The technique, optimized with a PDMS/DVB fiber at 60°C for 70 minutes, achieves good precision (relative standard deviation below 8.6%), accuracy (71–109%), and a detection limit of 0.78 mg/L. Analysis of twelve real samples from Brazilian religious groups found DMT concentrations ranging from 0.10 to 1.81 g/L. The method minimizes sample handling and is robust for quantifying DMT in these increasingly globally available beverages.
Journal of Pharmaceutical and Biomedical Analysis
May 28, 2019
Christina Grumann, Kerstin Henkel, Alexander Stratford et al.
27 citations
1-propionyl-LSD (1P-LSD), an uncontrolled derivative of LSD, requires sensitive detection methods due to its high potency. A validated LC-MS/MS method quantified 1P-LSD and LSD in urine and serum with a calibration range of 0.015-0.4 ng mL⁻¹ and limits of detection and quantification at 0.005 and 0.015 ng mL⁻¹, respectively. Stability tests showed 1P-LSD remained stable in samples stored at -20 °C, 5 °C, or room temperature for up to five days, but LSD formed at room temperature (up to 21% in serum), likely from enzymatic hydrolysis. Sodium fluoride prevented this conversion. In an intoxication case, only LSD was detected: 0.51 ng mL⁻¹ in urine and 3.4 ng mL⁻¹ in serum, suggesting rapid in-vivo hydrolysis of 1P-LSD to LSD.
The Analyst
January 1, 2004
Simon D. Brandt, Sally Freeman, Ian A. Fleet et al.
27 citations
5-MeO-DIPT, a new psychoactive tryptamine derivative, was synthesized using the Speeter and Anthony procedure. The synthetic route was characterized by ESI-MS-MS, ESI-TOF-MS, and NMR. Side products were identified as 3-(2-N,N-diisopropylamino-ethyl)-1H-indol-5-ol, 2-N,N-diisopropylamino-1-(5-methoxy-1H-indol-3-yl)-ethanol, 2-(5-methoxy-1H-indol-3-yl)-ethanol, and 2-N,N-diisopropylamino-1-(5-methoxy-1H-indol-3-yl)-ethanone.
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.