25C-NBOMe: preliminary data on pharmacology, psychoactive effects and toxicity of a new potent hallucinogenic drug

Copyright © 2014 Francesco Saverio Bersani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly citedIntroduction. The use of novel psychoactive substances (NPSs) has rapidly increased as well as their online availability. The aim of this paper is to provide a comprehensive review of the nature and the risks associated with 25C-NBOMe, which has recently appeared in the drug market. Methods. A systematic analysis of the scientific literature and a qualitative assessment of online and media resources (e.g., e-newsgroups, chat-rooms, and e-newsletters) in 10 languages were carried out. Results. 25C-NBOMe is sold online as legal LSD or as research chemical with different designations such as “Boom,” “Pandora,” “Holland film,” or “N-bomb.” It is a partial agonist of 5-HT2A receptors. It is usually ingested orally/sublingually and, less commonly, nasally, through injection, vaginally, rectally, and smoked. Its effects include sublingual numbing, stimulation, “body high,” hallucinations, dissociation, and anxiety. 25C-NBOMe presents high risk of overdoses; acute toxicity and fatalities have been reported. Conclusions. 25C-NBOMe consumption represents an emerging phenomenon with potential harmful effects. Its use is increased by its online availability at low costs. Health and other professionals should be informed about this new trend of substance usePeer reviewedFinal Published versio

Pharmacology of novel psychoactive substances

This PhD work consists of an in vitro and in vivo part. In the in vivo part, we investigated the role of dopamine in the acute clinical effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) in healthy human subjects. The role of dopamine in the addictive effects of drug of abuse is well established, but whether it contributes to the acute psychotropic effects of MDMA is unclear. In this pharmacological interaction study, we used the dopamine and weak norepinephrine transporter inhibitor bupropion (Stahl et al. 2004) as a pharmacological tool to block the MDMA-induced dopamine release and to study the role of dopamine in the effects of MDMA. We hypothesized that bupropion would decrease the subjective effects of MDMA to the extent that they depend on MDMA-induced release of dopamine. We included 16 healthy human subjects in this double-blind, placebo-controlled, crossover study. Bupropion pretreatment slightly increased MDMA plasma concentration and prolonged but not reduced the subjective effects contrary to our hypothesis. Additionally, bupropion reduced the MDMA-induced elevations in plasma norepinephrine concentrations and the heart rate response to MDMA. These findings support a role for norepinephrine in the MDMA-induced cardiostimulant effects but no role for MDMA-induced transporter-mediated dopamine release in the elevated mood effects after MDMA administration. Possibly, most of the acute psychotropic effects of MDMA are mediated via transporter-mediated release of serotonin and norepinephrine as previously shown (Hysek et al. 2011, Hysek et al. 2012). In the second and main part of this work we characterized the pharmacological profiles of novel psychoactive substances (NPS). Specifically, we studied whether and how potently NPS interacted with the human transporters for norepinephrine, dopamine, and serotonin, stably expressed in human embryonic kidney (HEK293) cells. Additionally, we assessed binding affinity to the serotonin 5-HT1A, 5-HT2A, 5-HT2C-receptors and the activation potency and activation efficacy at 5-HT2A and 5-HT2B receptors. Furthermore, binding to alpha1A/2A-adrenergic, dopamine D1-3, histamine H1 receptors, as well as trace amine-associated receptor 1 (TAAR1) was also assessed. The NPS studied in this project included para-4-halogenated amphetamine derivatives, which were shown to be relatively more serotonergic than their non-4-halogenated counterparts and pyrovaleronering-substituted cathinones, which were highly potent dopamine transporter inhibitors with a high risk for abuse. Para-halogenated drugs (4-fluoroephedrine, 4-fluoroamphetamine, 4-fluoromethamphetamine, 4-fluoromethcathinone, and 4-bromomethcathinone) also released monoamines, similar to MDMA, whereas pyrovalerones were found to be pure uptake inhibitors. Most benzofurans were similar to MDMA but slightly more serotoninergic than MDMA and additionally activated the serotonin 5-HT2B receptor. The last big group of NPS studied in this project, were novel hallucinogens, which predominantly interacted with the 5-HT2A receptor. This serotonin receptor subtype mediates the hallucinogenic and hallucinogenic-like visual effects of classic serotonergic hallucinogens (Vollenweider et al. 1998, Nichols 2004, Halberstadt et al. 2013, Halberstadt et al. 2014, Halberstadt 2015). Compounds tested in this project included the benzodifuran 8-Bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine (2C-B-FLY), 2C-drugs with their highly potent N-(2-methoxy)benzyl (NBOMe)-derivatives, and lysergic acid diethylamide (LSD). Interestingly, NBOMe derivatives displayed higher affinities at the 5-HT2A receptor than LSD, together with a high selectivity for 5-HT2A over the 5-HT1A receptor, contrary to LSD. NBOMes were partial 5-HT2A receptor agonists, similar to LSD. These novel drugs likely carry a high hallucinogenic potential when used recreationally by humans and the high binding to α1A-receptor (Ki < 1µM) may result in additional vasocontrictive and cardiovascular stimulant effects. Taken together, this PhD contributed to the understanding of the role of dopamine in the effects of MDMA, an important recreational substances. Additionally, we characterized the in vitro pharmacology of many novel designer drugs, which will be helpful in the prediction of the clinical toxicological effects of these newly used recreational drugs

Market Analysis of Synthetic Drugs: Amphetamine-type Stimulants, New Psychoactive Substances

An estimated quarter of a billion people, or around 5 per cent of the global adult population, used drugs at least once in 2015. Even more worrisome is the fact that about 29.5 million of those drug users, or 0.6 per cent of the global adult population, suffer from drug use disorders. This means that their drug use is harmful to the point that they may experience drug dependence and require treatment.The magnitude of the harm caused by drug use is underlined by the estimated 28 million years of "healthy" life (disability-adjusted life years (DALYs)) lost worldwide in 2015 as a result of premature death and disability caused by drug use.Of those years lost, 17 million were attributable solely to drug use disorders across all drug types. DALYs attributable to morbidity and mortality resulting from all causes of drug use have increased overall in the past decade.Yet, with fewer than one in six persons with drug use disorders provided with treatment each year, the availability of and access to science-based services for the treatment of drug use disorders and related conditions remain limited

Recent trends in analytical methods to determine new psychoactive substances in hair

New Psychoactive Substances (NPS) belong to several chemical classes, including phenethylamines, piperazines, synthetic cathinones and synthetic cannabinoids. Development and validation of analytical methods for the determination of NPS both in traditional and alternative matrices is of crucial importance to study drug metabolism and to associate consumption to clinical outcomes and eventual intoxication symptoms. Among different biological matrices, hair is the one with the widest time window to investigate drug-related history and demonstrate past intake. The aim of this paper was to overview the trends of the rapidly evolving analytical methods for the determination of NPS in hair and the usefulness of these methods when applied to real cases. A number of rapid and sensitive methods for the determination of NPS in hair matrix has been recently published, most of them using liquid chromatography coupled to mass spectrometry. Hair digestion and subsequent solid phase extraction or liquid-liquid extraction were described as well as extraction in organic solvents. For most of the methods limits of quantification at picogram per milligram hair were obtained. The measured concentrations for most of the NPS in real samples were in the range of picograms of drug per milligram of hair. Interpretation of the results and lack of cut-off values for the discrimination between chronic consumption and occasional use or external contamination are still challenging. Methods for the determination of NPS in hair are continually emerging to include as many NPS as possible due to the great demand for their detection

An index of fatal toxicity for new psychoactive substances

The final, definitive version of this paper has been published in Journal of Psychopharmacology, February 2018, published by SAGE Publishing, All rights reserved.An index of fatal toxicity for new psychoactive substances has been developed based solely on information provided on death certificates. An updated index of fatal toxicity (T f), as first described in 2010, was calculated based on the ratio of deaths to prevalence and seizures for the original five substances (amphetamine, cannabis, cocaine/crack, heroin and 3,4-methylenedioxymethylamphetamine) *. These correlated well with the 2010 index. Deaths were then examined for cases both where the substance was and was not found in association with other substances. This ratio (sole to all mentions; S/A) was then calculated for deaths in the period 1993 to 2016. This new measure of fatal toxicity, expressed by S/A, was well-correlated with the index L n (T f) of the original reference compounds. The calculation of S/A was then extended to a group of new psychoactive substances where insufficient prevalence or seizure data were available to directly determine a value of T f by interpolation of a graph of T f versus S/A. Benzodiazepine analogues had particularly low values of S/A and hence T f. By contrast, γ-hydroxybutyrate/γ-butyrolactone, α-methyltryptamine, synthetic cannabinoid receptor agonists and benzofurans had a higher fatal toxicity.Peer reviewedFinal Accepted Versio

NBOMe Toxicity and Fatalities: A Review of the Literature

In the decade since the introduction of the novel synthetic hallucinogen NBOMe into the consumer market, this drug has become an increasingly prevalent, yet poorly understood cause of altered mental status (AMS) resulting in hospitalization. In this literature review, we conducted a PubMed query for mentions of NBOMe ingestion since Suzuki et al.’s publication of their 2015 review. Among English language publications published between October 2014 and June 8, 2021, were sixteen case reports and six case series detailing a total of 42 cases of NBOMe toxicity. Notably, 26 (62%) patients experienced tachycardia, 22 (52%) had hypertension, 34 (81%) experienced hallucinations. Nine of 42 cases ended in fatality, including six cases of apparent direct NBOMe toxicity, one death by suicide, and two cases of fatalities from trauma after “excited delirium.” At least seven individuals believed that they had purchased and consumed LSD. This updated review of the literature underlines the high prevalence of fatality associated with NBOMe ingestion, as well as the need for increased knowledge among law enforcement and emergency medical providers of the toxidrome of NBOMe when responding to cases of AMS

Development of a method for the screening of sports doping compounds using multidimensional liquid chromatography and time of flight mass spectrometry

Athletes have often resorted to a variety of methods to gain an edge in sporting competitions. One such method is through doping, the use of compounds or methods to produce a theoretically enhancing biological effect. In order to combat doping, many governing sports bodies have prohibited specific compounds or methods and installed programs to test for these compounds in athletes. However, due to the large number of banned substances and the varying chemistries of those compounds, it can be challenging and time consuming to determine the presence of those compounds in an athlete’s sample. Therefore, there is a necessity to develop a quick and sensitive method that can precisely and accurately screen for banned substances. This research was an attempt to develop such a method. This was accomplished using multidimensional liquid chromatography with time of flight mass spectrometry. While none of the methods tested here were useful for screening all 79 compounds tested in a single injection, a multi-method approach was evaluated in lieu of a multi-residues single method process The analytical run time was less than 10 minutes for each method. Further studies were performed to determine the limit of detection, linearity, lifetime, robustness and the optimal solid phase extraction method

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro.; We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human receptors or transporters were used (with the exception of trace amine-associated receptor-1 [TAAR1], in which rat/mouse receptors were used).; All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C receptors and rat TAAR1 (most Ki and EC50: &lt;1 μM). The N-2-methoxybenzyl substitution of 2C drugs increased the binding affinity at serotonergic 5-HT2A, 5-HT2C, adrenergic α1, dopaminergic D1-3, and histaminergic H1 receptors and monoamine transporters but reduced binding to 5-HT1A receptors and TAAR1. As a result, NBOMe drugs were very potent 5-HT2A receptor agonists (EC50: 0.04-0.5 μM) with high 5-HT2A/5-HT1A selectivity and affinity for adrenergic α1 receptors (Ki: 0.3-0.9 μM) and TAAR1 (Ki: 0.06-2.2 μM), similar to LSD, but not dopaminergic D1-3 receptors (most Ki:&gt;1 μM), unlike LSD.; The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of α1 receptor interactions

A data-independent acquisition workflow for qualitative screening of new psychoactive substances in biological samples

Identification of new psychoactive substances (NPS) is challenging. Developing targeted methods for their analysis can be difficult and costly due to their impermanence on the drug scene. Accurate-mass mass spectrometry (AMMS) using a quadrupole time-of-flight (QTOF) analyzer can be useful for wide-scope screening since it provides sensitive, full-spectrum MS data. Our article presents a qualitative screening workflow based on data-independent acquisition mode (all-ions MS/MS) on liquid chromatography (LC) coupled to QTOFMS for the detection and identification of NPS in biological matrices. The workflow combines and structures fundamentals of target and suspect screening data processing techniques in a structured algorithm. This allows the detection and tentative identification of NPS and their metabolites. We have applied the workflow to two actual case studies involving drug intoxications where we detected and confirmed the parent compounds ketamine, 25B-NBOMe, 25C-NBOMe, and several predicted phase I and II metabolites not previously reported in urine and serum samples. The screening workflow demonstrates the added value for the detection and identification of NPS in biological matrices