Novel Psychoactive Substances

had been reported to the United Nations Office on Drug and Crime Early Warning Advisory on NPS As of December 2020. Why has the emergence of NPS challenged traditional approaches to drug monitoring?  The vast number of NPS and the speed at which they enter and exit the drug market makes them difficult to track.  The diversity of NPS means that potency, adverse effects and risk profiles are often unknown or difficult to determine.  NPS are found in many forms making the purification step that is required to enable further testing challenging.  NPS can remain undetected since they are not part of standard drug panels that are routinely screened in laboratories.  NPS are typically found in extremely low concentrations in biofluids. NPS can be analyzed from several different biological matrices including: Urine is the preferred matrix in various areas of analytical toxicology because collection is noninvasive and a large sample volume can be obtained easily. 36% 29% 15% 9% 3% 3% 5% Blood Urine Oral Fluid Hair Tissue To better understand how NPS are metabolized and to assess toxicology, in vitro and in vivo studies can be performed using model systems. Due to the varied nature of NPS and an inadequate understanding of their potential harmful effects, controlled studies and/or clinical trials are scarce. EMCDDA = European Monitoring Centre for Drugs and Drug Addiction; UNODC = United Nations Office on Drugs and Crime; ECDD = Expert Committee on Drug Dependence ; CND = Commission on Narcotic Drugs First reports of mephedrone availability and use in Europe Novel psychoactive substances (NPS) are compounds that are designed to mimic the effects of established illicit drugs. Many NPS emerged during the early- to mid-2000s and the number of new substances being reported continues to rise. Their use and misuse have swiftly increased, posing a significant risk to public health. Potential side effects include agitation, aggression, paranoia, psychosis and seizures, as well as possible NPS dependence. In this infographic, we will explore various NPS, highlight ways to analyze them and consider challenges associated with their detection. ! The emergence of NPS and pivotal timepoints 2004 Reports of benzylpiperazine (BZP) use and harms emerge in New Zealand 2006 2007 2008 Detection of synthetic cannabinoid JWH-018 in Spice mix in Europe Online darknet marketplace Silk Road opens — major platform for selling drugs US passes Synthetic Drug Abuse Prevention Act CND places 10 NPS (eg, BZP, JWH-018) under international control UNODC launches Early Warning Advisory on NPS Russia mass intoxication from synthetic cannabinoids New York mass intoxication from synthetic cannabinoid AMB-FUBINACA Increasing in opioid deaths involving NPS opioids in North America Chief Coroner in New Zealand issues warning after cluster of synthetic cannabinoids deaths New Zealand passes Psychoactive Substances Act ECDD first major review of various NPS UK passes New Psychoactive Substances Act Cryptomarket Dream Market bans sale of fentanyl and analogs 2009 2010 2011 2012 2015 2013 2014 2016 2018 2017 2005 Ireland passes first blanket ban of NPS via Criminal Justice Act UK and then EU controls mephedrone 7 substances notified to EMCDDA 15 substances notified to EMCDDA 13 substances notified to EMCDDA 24 substances notified to EMCDDA (117 to UNODC) 41 substances notified to EMCDDA (42 to UNODC) 48 substances notified to EMCDDA (41 to UNODC) 74 substances notified to EMCDDA (56 to UNODC) 98 substances notified to EMCDDA (137 to UNODC) 81 substances notified to EMCDDA (202 to UNODC) 101 substances notified to EMCDDA (69 to UNODC) 66 substances notified to EMCDDA (72 to UNODC) 55 substances notified to EMCDDA 51 substances notified to EMCDDA (78 to UNODC) New Zealand makes BZP restricted access 13 substances notified to EMCDDA NPS can be broadly categorized into six “effect groups” based on their similarity to existing drugs and pharmacological mechanisms Detection methods An immunoassay is a biochemical test used to detect a specific target molecule (in this case an NPS) using antibody–antigen reactions. While several different immunoassay types exist, they are all based on the selective binding between an antibody and its antigen. These systems rely on cell systems that express receptors known to be activated by specific NPS groups. The receptors are connected to a reporter (e.g., luciferase), allowing for the detection and measurement of activation. Mass spectrometry (MS) is a powerful analytical technique used to assess the mass-to-charge ratio of ions in a sample. Many toxicological analyses approaches exploit the combined power of chromatography (e.g., gas or liquid chromatography) and mass spectrometry. Fourier transform infrared spectroscopy (FTIR) is used to assess the infrared spectrum of absorption or emission of a sample. Combining high-resolution gas chromatography with FTIR enables quick identification of functional groups in unknown substances. Immunoassays Structure-independent assay systems Mass spectrometry Fourier transform infrared spectroscopy KEY CONSIDERATIONS: KEY CONSIDERATIONS: KEY CONSIDERATIONS: KEY CONSIDERATIONS:  Easy to use and cheap to produce  Can provide an initial indication of the presence of drugs of abuse  Antibodies required for the assay can take a long time to produce  Cross reactivity, low specificity and risk of false positives/negatives  Sample destructive  NPS compound structure isn’t required to run the assay  Assay requires a sufficient concentration of active substance in the biosample  Unable to distinguish between traditional drugs vs NPS, meaning additional confirmation steps are required (e.g., mass spectrometry)  Fast, sensitive and high specificity  Complex sample matrices can be assessed  High-resolution MS circumvents the need to match MS library spectra or compare against known standards  While searchable mass spectral libraries exist, data may be in different formats  NPS identification by MS can be dependent on spectral data which may not be available for new substances  Sample destructive  Fast analysis and non-destructive  Easy to perform, allowing non-expert users to adopt  Able to identity pure compounds but has limited value if used for mixtures Stimulants Others Synthetic Opioids Dissociatives Classic Hallucinogens Sedatives/ Hypnotics Synthetic Cannabinoid Receptor Agonists This group of NPS mimics drugs such as cocaine and MDMA. As the name suggests, stimulants work by stimulating the central nervous system by increasing synaptic levels of dopamine, norepinephrine and serotonin via various mechanisms. Stimulants produce a sense of euphoria. They are typically white/offwhite in color and can be in pill, capsule or loose powder form. EXAMPLES INCLUDE: This group includes a range of substances that are not necessarily chemically similar, but all elicit their effect via endogenous cannabinoid receptors (CB1 and CB2 ). This group of NPS produce a relaxed state. They are typically composed of inert plant material treated with an active synthetic ingredient and are either smoked or inhaled. EXAMPLES INCLUDE: Classic hallucinogens are also sometimes referred to as NPS psychedelics as they cause psychedelic effects including perceptual alterations. They work as agonists or partial agonists of the 5-HT2A receptor and can be further divided into three categories: phenethylamines; tryptamines; lysergamines. Classic hallucinogens come in paper, liquid or capsule form. EXAMPLES INCLUDE: Synthetic opioids include analogs of fentanyl and structurally distinct non-fentanyl compounds. Like natural opioids (e.g., morphine and codeine), they elicit their effects via presynaptic μ-opioid receptors. Synthetic opioids can be administered via various routes (oral, intravenous, rectal, inhalation, insufflation, smoked, vaporized). EXAMPLES INCLUDE: Compounds in this group are classed as depressants of the central nervous system. They have an inhibitory effect on the brain and produce hypnotic and anxiolytic effects. Synthetic benzodiazepines, a type of sedative, interact with gamma-aminobutyric acid-A (GABAA) receptors and have also been shown to mediate effects via the mitochondrial translocator protein and the AMPA glutamate receptor. Sedatives are usually administered orally or intravenously. EXAMPLES INCLUDE: Dissociatives create a distinctive euphoric “dissociated” state. They typically illicit their effects by disrupting the action of glutamate – an abundant chemical messenger involved in many brain functions (e.g., cognition, emotion, pain) – via N-methyl-D-aspartate (NMDA) receptors. They can either be swallowed, injected or inhaled. EXAMPLES INCLUDE: Stimulants Synthetic Cannabinoid Receptor Agonists Classic Hallucinogens Synthetic Opioids Sedatives/Hypnotics Dissociatives O H N O O O N CH2 N NH OH OH O OH OH H O H N N 0 Cl N N N O O Cl N H N N N O Br F S N N N N Cl N H N N Br N N O O Cl NH O H N Mephedrone (M-cat) ethylenedioxypyrovalerone (MPDV) 1-benzylpiperazine (BZP) CP 47497 (non-classical cannabinoid) JWH-018 (aminoalkylindoles) HU-210 (classical cannabinoid) alpha-methyltryptamine (AMT) AH-7921 Mescaline Furanylfentanyl 5-MeO-DALT MT-45 Pyrazolam phencyclidine (PCP or angel dust) Flubromazepam Methoxetamine (Mexxy) Etizolam Ketamine