PCP or phencyclidine was discovered in 1956 and soon became a popular street drug. Dissociatives including PCP, ketamine, and dextromethorphan have been used non-medically for their mind-altering effects for over 60 years. Many of these compounds have also been used clinically and in legitimate research. At least 14 derivatives of PCP were sold for non-medical and illict use from the late 1960s until the 1990s. With the advent of the Internet, the drug market underwent a dramatic evolution. While initially gray-market chemical vendors offering dextromethorphan and ketamine thrived, most recently the market has shifted to legal high and online-based research chemical vendors. Starting with the first dissociative research chemical, 4-MeO-PCP in 2008, the dissociative research chemical market has rapidly evolved and currently comprises at least 12 dissociatives, almost half of which were unknown in the scientific literature prior to their introduction. Several of these, including methoxetamine, have reached widespread use internationally. A historical account of non-medical use of over 30 dissociative compounds was compiled from a diverse collection of sources. The first complete portrait of this underground market is presented along with the relevant legal, technological, and scientific developments which have driven its evolution.

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine.

Physician, institutional and patient factors all contribute to self-discharge. Improving cultural safety may be the key to lowering self-discharge rates. WHAT IS KNOWN ABOUT THE TOPIC? Rates of self-discharge by Aboriginal adults in Central Australia are the highest reported worldwide. Previous studies have been retrospective and focussed on patient demographics without addressing the environmental and cultural contexts in which self-discharge occurs. WHAT DOES THIS PAPER ADD? In this acute care setting, we found a pervasive failure to communicate effectively with Aboriginal patients. Consequently, most patients were unaware of their diagnosis or length of stay. Self-discharge was a common practice; nearly half of all previously admitted patients had self-discharged in the past. We demonstrate that physician, hospital and patient factors all contribute to this practice. Prospectively determined risk factors included the treating medical team, the need for transfer outside Central Australia, and patient factors such as male gender and alcohol dependence. Self-discharge rates fell significantly with Aboriginal Liaison involvement. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Cross-cultural communication skills must be markedly improved among medical staff caring for this marginalised population. Critical to reducing rates of self-discharge are improvements in institutional cultural safety by involving Aboriginal Liaison Officers and family members. However, persistently high self-discharge rates suggest a need to redirect medical services to a more culturally appropriate community-based model of care.

The structurally diverse nature of the 1,2‐diphenylethylamine template provides access to a range of substances for drug discovery work but some have attracted attention as ‘research chemicals’. The most recent examples include diphenidine, i.e. 1‐(1,2‐diphenylethyl)piperidine and 2‐methoxydiphenidine, i.e. 1‐[1‐(2‐methoxyphenyl)‐2‐phenylethyl]piperidine (MXP, methoxyphenidine, 2‐MXP) that have been associated with uncompetitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist activity. Analytical challenges encountered during chemical analysis include the presence of positional isomers. Three powdered samples suspected to contain 2‐MXP were obtained from three Internet retailers in the United Kingdom and subjected to analytical characterization by gas chromatography (GC) and high performance liquid chromatography (HPLC) coupled to various forms of mass spectrometry (MS). Nuclear magnetic resonance spectroscopy, infrared spectroscopy and thin layer chromatography were also employed. This was supported by the synthesis of all three isomers (2‐, 3‐ and 4‐MXP) by two different synthetic routes. The analytical data obtained for the three purchased samples were consistent with the synthesized 2‐MXP standard and the differentiation between the isomers was possible. Distinct stability differences were observed for all three isomers during in‐source collision‐induced dissociation of the protonated molecule when employing detection under HPLC selected‐ion monitoring detection, which added to the ability to differentiate between them. Furthermore, the analysis of a 2‐MXP tablet by matrix assisted inlet ionization Orbitrap mass spectrometry confirmed that it was possible to detect the protonated molecule of 2‐MXP directly from the tablet surface following addition of 3‐nitrobenzonitrile as the matrix. Copyright © 2015 John Wiley & Sons, Ltd.

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.