AH-7921: the list of new psychoactive opioids is expanded

Forensic Toxicol (2015) 33:195–201 DOI 10.1007/s11419-015-0271-z REVIEW ARTICLE AH-7921: the list of new psychoactive opioids is expanded Maria Katselou • Ioannis Papoutsis • Panagiota Nikolaou • Chara Spiliopoulou • Sotiris Athanaselis Received: 15 December 2014 / Accepted: 8 February 2015 / Published online: 21 February 2015 Ó Japanese Association of Forensic Toxicology and Springer Japan 2015 Abstract AH-7921 is a structurally unique synthetic opioid analgesic that has recently entered the drug arena in Europe, the USA, and Japan. Although it was synthesized and patented in the mid-1970s, it was first identified in a seized sample purchased via the Internet in July 2012 and formally brought to the attention of the European Union early warning system in August 2012 by the United Kingdom. Several in vitro experiments and animal model studies established the morphine-like analgesic action of AH-7921 as a l-opioid receptor agonist that has been found to be several times more potent than codeine and at least as potent as morphine. This novel psychoactive substance has already led to eight non-fatal intoxications and 16 deaths in Sweden, the United Kingdom, Norway, and the USA. Thus, AH-7921 is a current public health risk, and better international collaboration, effective legislation and continuous community alertness are needed to tackle this current growing problem. The aim of this review is to summarize the current knowledge about this drug concerning its chemistry, pharmacology, and toxicology, as well as its international legal status. The limited existing analytical methodologies for the determination of AH-7921 in biological samples are also presented. Published or reported AH-7921-related cases, fatalities, or intoxications, and self reports from drug users are reviewed. M. Katselou
I. Papoutsis
P. Nikolaou (&)
C. Spiliopoulou
S. Athanaselis Department of Forensic Medicine and Toxicology, Faculty of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias, 115 27 Athens, Greece e-mail: Keywords AH-7921
Doxylam
New psychoactive substance
l-Opioid receptor agonist
Pharmacology and toxicology Introduction New psychoactive substances (NPSs) are continuously emerging on the recreational and illicit drug market. They are often referred to as ‘‘legal highs’’, ‘‘designer drugs’’, or ‘‘bath salts’’ [1–3]. They are mainly synthetic derivatives and analogues of existing controlled drugs, analogues of pharmaceutical products, herbs, fungi, and their extracts that show psychoactive actions. Some NPSs are controlled, while others are legally sourced and can either be sold directly on the drug market or be used as precursors for the synthesis of other designer drugs that mimic the psychoactive effects of controlled substances [4, 5]; thus, due to the chemical alterations of the parent compounds, NPS derivatives can avoid drug legislation. Furthermore, for most NPSs, pharmacological and analytical data are limited or unavailable, which makes detection, monitoring, and control more difficult. AH-7921 is a new, structurally atypical synthetic opioid analgesic that appears to be sold as a ‘‘research chemical’’ or ‘‘legal opioid’’ on the Internet since 2012. It was synthesized in the 1970s by Allen and Hanburys Ltd. as a potential analgesic medicine; however, its development was abandoned due to its addictive properties. It has never been marketed as a medicine, nor used as pharmaceutical or medicinal product; it has also no industrial use [6]. There are very few references available on this compound [7]. In vivo studies in animals indicated its l-opioid receptor agonistic activities, although no studies have evaluated its pharmacological and toxicological properties 123 196 in humans. Its activities are similar to those of morphine and include analgesia, hypothermia, respiratory depression, and addictive behavior [7–9]. The abuse of AH-7921 has been reported in eight member states of the European Union as well as in Norway, leading to severe toxicity (non-fatal) cases and 16 reported deaths within a limited period of time (December 2012–September 2013). Thus, AH-7921 is controlled in six European countries (Sweden, Poland, Romania, Finland, Netherlands, and Norway) since 2013 [6]. The aim of this review is to summarize the current knowledge about AH-7921 concerning its chemistry, pharmacology, and toxicology, as well as its legal status. The limited existing analytical methodologies for determination of AH-7921 in biological samples are also presented. Published or reported AH-7921-related cases, fatalities, intoxications, and self reports from drug users are reviewed. Chemistry AH-7921 is an N-substituted cyclohexylmethylbenzamide, where the benzamide moiety is dichlorinated at positions 3 and 4 of the benzyl ring, and the aminocyclohexane moiety is N,N-dimethylated. ‘‘AH’’ refers to ‘‘Allen and Hanburys’’, the company that patented the drug. Its systematic (International Union of Pure and Applied Chemistry) name is 3,4-dichloro-N-{[1-(dimethylamino)cyclohexyl]methyl} benzamide, but it can also be found as 1-(3,4-dichlorobenzamidomethyl)cyclohexyldimethylamine [6, 10]. Common names like doxylam, doxylan, and CN 2924 29 98 (CAS Number) are also used [6]. The chemical structure of AH-7921 is shown in Fig. 1. AH-7921 is an off-white solid with the molecular formula C16H22Cl2N2O. Its molecular weight is 329.26 g/mol, and the melting point of its hydrochloride salt is 215–216 °C. It is soluble in ethanol (11 mg/ml), dimethylsulfoxide (3 mg/ml) and dimethylformamide (10 mg/ ml). The drug absorbs at 205 and 237 nm spectrophotometrically [10]. Prevalence and use AH-7921 appeared on the European drug market in 2012. However, in July 2012 it was formally brought to the attention of the European Union early warning system for the first time by Norway and Sweden, and later, in August 2012, by the United Kingdom. In 2013, it was identified as a co-ingredient in synthetic cannabinoid- and cathinone-derivative products sold in Japan [11]. AH-7921 is sold via the Internet on various websites where it is 123 Forensic Toxicol (2015) 33:195–201 sometimes referred to as ‘‘doxylam’’, which is its alternative street name, and is also used in Internet drug forums, ‘‘legal high’’ websites, and head shops. This name may be confused with ‘‘doxylamine’’, the International Nonproprietary Name of a widely used (non-prescription) antihistaminic medicine with sedative-hypnotic properties that is chemically completely different from AH-7921 (Fig. 1). Thus, intake of AH-7921 mislabeled as ‘‘doxylamine’’ could lead to unintentional toxicity or overdoses with the drug. AH-7921 has no established or acknowledged industrial, agrochemical, cosmetic, human, or veterinary medical value or use, and thus there is neither marketing authorization for this NPS in the European Union nor in the 28 member states, Norway, and Iceland. AH-7921 is legitimately used as an analytica (...truncated)