Technical report on 1-phenyl-2- (pyrrolidin-1-yl)pentan-1-one (α-pyrrolidinovalerophenone, α-PVP)

This publication presents the data and findings of the risk assessment on α-PVP (1-phenyl- 2-(1-pyrrolidinyl)-1-pentanone), carried out by the extended Scientific Committee of the EMCDDA on 18 November 2015. α-PVP is the eleventh new psychoactive substance to be risk assessed under the terms of Council Decision 2005/387/JHA. On the basis of the Risk Assessment Report — and on the initiative of the European Commission — on 27 June 2016, the Council decided that α-PVP should be subject to control measures across the Member States

Technical report on 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25I-NBOMe). Annex 2 to the “Risk Assessment Report of a new psychoactive substance: 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25I-NBOMe)”.

This report forms the basis for a risk assessment, which is convened by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) under auspices of its Scientific Committee and other externally invited experts. Furthermore, the Commission, Europol and the EMA are invited to participate in the risk assessment meetings. The risk assessment takes into account all factors that, according to the 1961 United Nations Single Convention on Narcotic Drugs or the 1971 United Nations Convention on Psychotropic Substances, would warrant the placing of a substance under international control (see http://www.emcdda.europa.eu/html.cfm/index16776EN.html)

First Reported Fatalities Associated with the 'Research Chemical' 2-Methoxydiphenidine

2-Methoxydiphenidine, i.e. 1-[1-(2-methoxyphenyl)-2-phenylethyl]piperidine, also known as 'MXP' or '2-MeO-diphenidine' (or 2-MXP), has been available as a 'research chemical' since 2013 as a purported alternative to the 'dissociative anesthetics' methoxetamine and ketamine. Three deaths which involved the detection of 2-MXP in post-mortem blood and urine were encountered in forensic casework. The 2-, 3- and 4-methoxyphenyl positional isomers were synthesized to confirm the identity and concentration of 2-MXP. The 2-MXP femoral blood concentrations in the cases were found to be 24.0, 2.0 and 1.36 mg/L (the latter with an alternative cause of death). Some additional prescription drugs were encountered at therapeutic concentrations in all three cases. Analysis of the biofluids allowed the detection and characterization of various metabolites, including the suggested presence of hydroxy-2-MXP as the main metabolite with the hydroxyl group located on the piperidine rather than the phenyl or benzyl moiety. Additional metabolites included O-desmethyl-2-MXP and hydroxylated O-desmethyl-2-MXP. Diphenidine and hydroxy-diphenidine, also showing the presence of the hydroxyl group on the piperidine ring, were also detected. It was not possible to identify whether these arose from 2-MXP biotransformation or whether they represented the presence of diphenidine as a separate substance. These are the first published fatalities involving 2-MXP and presents analytical data to assist analytical toxicologists with future casework

Exposure of benthic invertebrates to sediment vibration: From laboratory experiments to outdoor simulated pile-driving

This is the final version of the article. Available from Acoustical Society of America via the DOI in this record.Fourth International Conference on the Effects of Noise on Aquatic Life, Dublin, Ireland, 10-16 July 2016Activities directly interacting with the seabed, such as pile-driving, can produce vibrations that have the potential to impact benthic invertebrates within their vicinity. This stimuli may interfere with crucial behaviors such as foraging and predator avoidance, and the sensitivity to vibration is largely unknown. Here, the responsiveness of benthic invertebrates to sediment vibration is discussed in relation to laboratory and semi-field trials with two marine species: the mussel (Mytilus edulis) and hermit crab (Pagurus bernhardus). Sensory threshold curves were produced for both species in controlled laboratory conditions, followed by small-scale pile-driving exposures in the field. The merits of behavioral indicators are discussed, in addition to using physiological measures, as a method of determining reception and measuring responses. The measurement and sensors required for sediment vibration quantification are also discussed. Response and threshold data were related to measurements taken in the vicinity of anthropogenic sources, allowing a link between responsiveness and actual operations. The impact of pile-driving on sediment-dwelling invertebrates has received relatively little research, yet the data here suggest that such activities are likely to impact key coastal species which play important roles within the marine environment.LR would like to thank the organizers and sponsors of the 2016 conference for supporting her attendance for which she is extremely grateful. This study was partially funded by a research award from the Malacological Society of London to LR. The authors would also like to acknowledge Defra and NERC who funded the laboratory and field work aspects respectively, and the staff at the OREC field site, Blyth

Analytical characterization of bioactive N-benzyl-substituted phenethylamines and 5-methoxytryptamines

RationaleSubstances based on the N-(2-methoxybenzyl)phenethylamine template ('NBOMe' derivatives) play an important role in medicinal research but some of these derivatives have also appeared as 'research chemicals' for recreational use which has attracted attention worldwide. A major challenge associated with newly emerging substances includes the lack of analytical data and the ability to correctly identify positional isomers.Methods Six N-benzylphenethylamines based on the 2,5-dimethoxy-4-iodophenethylamine structure ('25I') and twelve substituted N-benzyl-5-methoxytryptamines ('5MT') have been prepared and extensively characterized. Techniques used for characterization were gas chromatography/ion trap mass spectrometry in electron and chemical ionization mode, liquid chromatography/diode array detection (DAD), infrared spectroscopy, electrospray high mass accuracy quadrupole time-of-flight tandem mass spectrometry, and triple quadrupole tandem mass spectrometry.ResultsThe characterization of 18 'NBOMe' compounds provided a comprehensive collection of chromatographic and spectral data. Four groups of three positional isomers, i.e. 25I-NB2OMe, 25I-NB3OMe, 25I-NB4OMe, 25I-NB2B, 25I-NB3B, 25I-NB4B and their 5-methoxytryptamine counterparts, were included and assessed for ability to obtain differentiation. Six meta-substituted N-benzyl derivatives of 5-methoxytryptamine (CF3, F, CH3, Cl, I, SCH3) were also studied.Conclusions The implementation of mass spectral techniques was helpful for the differentiation between isomers, for example, when considering the difference in a number of ion ratios. This was considered beneficial in cases where chromatographic separation was only partially achieved under liquid chromatography (LC) conditions. The use of LC/DAD analysis was also found to be valuable for this particular purpose, which confirmed the integrative value of complementary techniques used in areas related to forensic toxicology

N-Benzyl-5-methoxytryptamines as Potent Serotonin 5-HT2 Receptor Family Agonists and Comparison with a Series of Phenethylarnine Analogues

A series of N-benzylated-5-methoxytryptamine analogues was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogues of 2,5- dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had the highest affinity at the 5-HT2 family receptors. Substitution at the para position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or the meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head

The first reported fatality associated with the synthetic opioid 3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and implications for forensic analysis

The search for synthetic opioids as alternatives to opium-based derivatives has provided an important impulse to drug development around the globe. An important goal in the systematic evaluation of new drug candidates is the identification of compounds that provide a more favorable side-effect profile, which includes reduced dependence-producing properties and abuse liability. A rich source of information about these research efforts can be found in the scientific literature. However, the exploration of these important discoveries has also been increasingly mined by largescale producers of these materials, which are then offered for sale. These so-called ‘research chemicals’ or new psychoactive substances (NPS)[1] have created challenges to policy makers, clinicians, and law enforcement around the world.[2] Recent examples of synthetic opioids that emerged as NPS on the market, and which were associated with severe cases of adverse effects, include 3,4-dichloro-N- {[1-(dimethylamino)cyclohexyl]methyl}benzamide (AH-7921), 1-cyclohexyl-4-(1,2- diphenylethyl)piperazines (MT-45) and N-phenyl-N-[1-(2-phenylethyl)piperidin-4- yl]acetamide (acetylfentanyl), respectively (Figure 1). Following the recommendation provided by the World Health Organization’s Expert Committee on Drug Dependence (ECDD),[3] AH-7921 was placed in Schedule I of the 1961 Single Convention, as amended by the 1972 Protocol in 2015.[4] Furthermore, ECDD’s recommendation to place MT-45 into Schedule I and acetylfentanyl in Schedules I and IV of the same Convention[5] have been recently confirmed by the Commission on Narcotic Drugs.[6] -Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) (Figure 1) has recently emerged on the market and can be purchased from various Internet retailers and is a structural isomer of AH-7921 (Figure 1). The preparation of U- 47700 and other derivatives was disclosed by the Upjohn Company in the 1970s[7] followed by the recognition that U-47700 showed increased analgesic properties and morphine-like behavioural features in mice compared to morphine itself.[8,9] The presence of two chiral centres gives rise to a cis- and trans- racemic mixture with the trans-form being advertised for sale. Binding studies also revealed that U-47700 displayed an appreciable selectivity for the μ-opioid receptor over the −opioid receptor.[10,11] A variety of cyclohexyl trans-1,2-diamines have been found to be potent analgesics and the vicinal 1,2-diamine pattern has provided access to a large range of substances with diverse biological activities.[12-14] Since U-47700 did not progress to clinical trials, there is no direct clinical information pertaining to its effects. Keeping in mind the various limitations that may be associated with descriptions obtained from self-reporting users, its effects have been described with various positive and negative symptoms but appeared to be essentially comparable to other opioids. Specifically, euphoria was reported in individuals, sometimes being short-lived, as well as general lift in mood with these desired effects being experienced in waves. The negative effects were also opioid based, including nausea with some users describing respiratory depression. For some users, U-47700 had a shorter duration of action and the urge to keep re-dosing was stated as being very high

Return of the lysergamides. Part I: Analytical and behavioural characterization of 1-propionyl-d-lysergic acid diethylamide (1P-LSD).

1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD) has become available as a 'research chemical' in the form of blotters and powdered material. This non-controlled derivative of d-lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1-acetyl-LSD (ALD-52), which was developed in the 1950s. This study describes the characterization of 1P-LSD in comparison with LSD using various chromatographic and mass spectrometric methods, infrared and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic hallucinogens is that they produce 5-HT2A -receptor activation and induce the head-twitch response (HTR) in rats and mice. In order to assess whether 1P-LSD displays LSD-like properties and activates the 5-HT2A receptor, male C57BL/6 J mice were injected with vehicle (saline) or 1P-LSD (0.025-0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P-LSD produced a dose-dependent increase in HTR counts, and that it had ~38% (ED50  = 349.6 nmol/kg) of the potency of LSD (ED50  = 132.8 nmol/kg). Furthermore, HTR was abolished when 1P-LSD administration followed pretreatment with the selective 5-HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which was consistent with the concept that the behavioural response was mediated by activation of the 5-HT2A receptor. These results indicate that 1P-LSD produces LSD-like effects in mice, consistent with its classification as a serotonergic hallucinogen. Nevertheless, the extent to which 1P-LSD might show psychoactive effects in humans similar to LSD remains to be investigated. Copyright © 2015 John Wiley & Sons, Ltd

Return of the lysergamides. Part V: Analytical and behavioural characterization of 1-butanoyl-d-lysergic acid diethylamide (1B-LSD)

The psychedelic properties of lysergic acid diethylamide (LSD) have captured the imagination of researchers for many years and its rediscovery as an important research tool is evidenced by its clinical use within neuroscientific and therapeutic settings. At the same time, a number of novel LSD analogs have recently emerged as recreational drugs, which makes it necessary to study their analytical and pharmacological properties. One of the most recent additions to this series of LSD analogs is 1-butanoyl-LSD (1B-LSD), a constitutional isomer of 1-propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), another LSD analog that was described previously. This study presents a comprehensive analytical characterization of 1B-LSD employing nuclear magnetic resonance spectroscopy (NMR), low- and high-resolution mass spectrometry platforms, gas- and liquid chromatography (GC and LC), and GC-condensed phase and attenuated total reflection infrared spectroscopy analyses. Analytical differentiation of 1B-LSD from 1P-ETH-LAD was straightforward. LSD and other serotonergic hallucinogens induce the head-twitch response (HTR) in rats and mice, which is mediated by 5-HT2A receptor activation. HTR studies were conducted in C57BL/6J mice to assess whether 1B-LSD has LSD-like behavioral effects. 1B-LSD produced a dose-dependent increase in HTR counts, acting with ~14% (ED50 = 976.7 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). This finding suggests that the behavioral effects of 1B-LSD are reminiscent of LSD and other serotonergic hallucinogens. The possibility exists that 1B-LSD serves as a pro-drug for LSD. Further investigations are warranted to confirm whether 1B-LSD produces LSD-like psychoactive effects in humans