FACT SHEET Acrylfentanyl May 2017 For more information, please contact: Dr. P. Blanckaert Coordinator Belgian Early Warning System Drugs Scientific Institute of Public Health National Focal Point on Drugs Jyliette Wytsmanstraat 14 B-1050 Brussels, Belgium Tel : 02/642 5408 [email protected] Science at the service of Public health, Food chain safety and Environment. The information in this message is exclusively meant for the EWS-network, and was sent to you, as a member of this network, in a confidential way. Therefore the information in this message may not be copied, transferred or made public without the prior permission of the WIV-ISP. The WIV-ISP takes responsibility for the editing of a press release, if considered as necessary in the framework of its mission. The information contained in this document is also available on the BEWSD-website (with corresponding pdf-files and analytical data). This part of the website is not accessible for the general public. A login can be requested by contacting [email protected]. © Scientific Institute of Public Health, Brussels 2011 This report may not be reproduced, published or distributed without the consent of the ISP | WIV. A. General information Recent sample in Belgium In the first half of May 2017, a death was reported in Belgium after the use of acrylfentanyl. The victim, male, presumably consumed a powder containing acrylfentanyl by sniffing, and was found dead at the scene, in the region of Ghent. It remains unclear whether the victim knowingly consumed acrylfentanyl. Several other powders and tablets were found at the scene, one of which was identified as N- ethylhexedrone, a cathinone of the stimulant category. Created July 2016 Updated May 2017 Type Narcotic drugs Group Opioids Name Acryloylfentanyl/acrylfentanyl Nature of substance Acryloylfentanyl is a piperidinamine, which is structurally related to internationally controlled opiod fentanyl (Schedule I of the 1961 United Nations Single Convention On Narcotic Drugs). They differ in the double bond present in the 2- position of the propane attached to the N-phenyl moiety. Acryloylfentanyl is also structurally related to acetylfentanyl, which has been recently subjected to international control (Schedule I, 1961 UN Convention). Because of the structural similarity of acryloylfentanyl and fentanyl, their GC-MS may be similar, with a mass difference of M-2 for the base peak (m/z 243 for acryloylfentanyl). Systematic chemical name N-(1-phenethylpiperidin-4-yl)-N-phenylacrylamide Other names Chemical names: 1-phenethyl-4-N-acryloylanilinopiperidine Other names: acrylfentanyl, ACF B. Alerts Alerts 23 deaths associated with acrylfentanyl in Sweden – April – August 2016 The EMCDDA has received reports of 23 deaths associated with acryloyl fentanyl. The deaths occurred between April and August 2016 in Sweden. The presence of acryloyl fentanyl was analytically confirmed in all the cases from biological samples taken from the deceased. The decedents were aged 22 to 54 years old (mean 33, median 29); 4 were female, 19 were male. The cause of death is known for 8 cases: acryloyl fentanyl was the cause of death or a contributing factor in all of them; the remaining 15 cases are still under investigation. Acryloyl fentanyl was the only substance consumed in 2 out of 23 deaths. No details are known regarding the source of the substance or the route of administration except for one case where the death occurred after the person consumed acryloyl fentanyl with friends using a nasal spray. In at least 2 cases the deaths were said to have occurred “suddenly”. Reports to EMCDDA Denmark: On 16 May 2017 the Danish FP reported a post-mortem blood and urine sample analysed on 21.01.2017 by the Department of Forensic Medicine, Aarhus University. The concentration of acryloylfentanyl in blood was 0,0072 mg/kg. Estonia: On 17 November 2016 the Estonian FP informed the death cases of 2016: - 1 pure case of acrylfentanyl death; - 2 cases of combination of acrylfentanyl and regular fentanyl deaths. Latvia: On 10 October 2016 the Latvian FP reported a seizure of 0,3699 g beige powder seized on 24/07/2016 by the Police at Riga. Estonia: On 13 September 2016 the Estonian FP reported 6 seizures of powder during Summer 2016 at Tallin. Finland: On 1 September 2016 the Finnish FP reported a seizure of 99 tablets seized on 8.8.2016. The police seized tablets in the Åland island between Sweden and Finland. Sweden: On 31 August 2016 the Swedish FP reported a seizure of 10ml of liquid seized on 19.04.2016 by the Police at Eskilstuna. Sweden: On 22 August 2016 the Swedish FP reported 23 deaths associated with acryloylfentanyl. The substance has been reported as the cause of death in 5 cases. Slovenia: On 1 August 2016 the Slovenian FP reported a sample of 5g light green powder collected on 10.05.2016 by the National Forensic Laboratory. Sample was shipped from China. C. Pictures Tablet seized in Finland Capsule seized in Denmark D. Clinical information Usage This compound has no known uses, and is currently only found as a (legal) fentanyl derivative sold online as a new psychoactive substance. Health risks Acryloylfentanyl is a potent opioid; overdose risks are higher compared to e.g. heroin or morphine. A study by Zhu measured the analgesic activity of derivatives of fentanyl (mouse, intravenous, hot plate test). This study shows that acryloylfentanyl (ED50= 0.082 mg/kg) and fentanyl (ED50=0.062 mg/kg) have high activity as compared to morphine (ED50=13.9 mg/kg). A study by Essawi reports that, at similar doses, acrylfentanyl had longer-lasting antinociceptive effects than fentanyl (mouse, intraperitoneal, hot plate test). Maryanoff et al. measured the inhibitory concentration in vitro (rat brain opioid receptor, naloxone binding) for acryloylfentanyl (IC50= 1.4 nM), fentanyl (IC50= 1.6 nM) and morphine (IC50= 4.2 nM), indicating that acryloylfentanyl has higher affinity to the opioid receptor. Other uses None known. E. Legal status Currently legal in Belgium. Controlled in Austria, Cyprus, Denmark, Estonia, Finland, Ireland, Latvia, Lithuania, Norway, Poland, Sweden, Turkey, United Kingdom, China. F. Chemistry Other chemical names and variants 1-phenethyl-4-N-acryloylanilinopiperidine Chemical Abstracts Service (CAS) registry number 79279-03-1 (HCl) Molecular information Molecular structure: Molecular formula: C22H26N2O Molecular weight: 334.20 g/mol Identification and analytical profile: It has to be noted that the GC-MS EI-spectra of acryloylfentanyl and fentanyl are similar, but with a mass difference of M-2 for the base peak (m/z 243 for acryloylfentanyl). Analytical spectra can be found at the end of this fact sheet, and were provided by the EDND-website of the EMCDDA. These spectra should be considered confidential, and should not be shared without permission. G. Recent references Davide Guerrieri, Emma Rapp, Markus Roman, Gunilla Thelander, Robert Kronstrand, Acrylfentanyl: Another new psychoactive drug with fatal consequences, Forensic Science International http://dx.doi.org/10.1016/j.forsciint.2017.05.010 Ujváry I, et al. Acryloylfentanyl, a recently emerged new psychoactive substance: a comprehensive review. Forensic Tox. 2017. doi: http://dx.doi.org/10.1007/s11419- 017-0367-8 Watanabe S, et al. In vitro and in vivo metabolite identification studies for the new synthetic opioids acetylfentanyl, acrylfentanyl, furanylfentanyl, and 4-fluoro- isobutyrylfentanyl. AAPS J. 2017. doi: https://dx.doi.org/10.1208/s12248-017-0070-z Helander A, et al. Intoxications involving acrylfentanyl and other novel designer fentanyls – results from the Swedish STRIDA project. Clin Tox. 2017. doi: http://dx.doi.org/10.1080/15563650.2017.1303141 J. Suzuki, S. El-Haddad, A review: Fentanyl and non-pharmaceutical fentanyls, Drug and Alcohol Dependence 171 (2017) 107–116, http://dx.doi.org/10.1016/j.drugalcdep.2016.11.033 Anders Helander & Matilda Bäckberg (2016): New Psychoactive Substances (NPS) – the Hydra monster of recreational drugs, Clinical Toxicology. Figure 6: Mass spectrum for precursor (+MS) (top) and product ions (+bbCID) (bottom) for fentanyl, (C22H28N2O). The product ion at m/z 188.1437 corresponds to C13H18N, which is a well known fragmentation pathway for fentanyl. Figure 7: Mass spectrum for precursor (+MS) (top) and product ions (+bbCID) (bottom) for acrylfentanyl, (C22H28N2O). The product ion at m/z 188.1437 corresponds to C13H18N, which is a well known fragmentation pathway for fentanyl. Supporting information for: Identification of a new psychoactive substance in seized material: The synthetic opioid N-phenyl-N-[1-(2-phenethyl)piperidin-4-yl]prop-2-enamide (Acrylfentanyl) Table of contents Characterisation of acrylfentanyl (seized sample) 2 1 Acrylfentanyl (seized sample), H NMR, 400 MHz (CD3OD) 2 Acrylfentanyl (seized sample), COSY, 400 MHz(CD3OD) 3 Acrylfentanyl (seized sample), MALDI-TOF HRMS 3 Characterisation of fentanyl (standard) 4 1 Fentanyl (standard), H NMR, 400 MHz (CD3OD) 4 Fentanyl (standard), MALDI-TOF HRMS 5 Acrylfentanyl (seized sample) compared to acrylfentanyl (standard), 1 H NMR, 600 MHz (CDCl3) 5 Enlargements: Acrylfentanyl (seized sample) compared to acrylfentanyl 1 (standard), H NMR, 600 MHz (CDCl3) 6 Acrylfentanyl (seized sample) compared to acrylfentanyl (standard), DEPT, 600 MHz (CDCl3) 7 1 Acrylfentanyl (seized sample), H NMR, 600 MHz (DMSO-d6) 7 Acrylfentanyl (seized sample) compared to triethylamine hydrochloride, DEPT, 600 MHz (DMSO-d6) 8 Acrylfentanyl (seized sample) spiked with triethylamine hydrochloride, 1 H NMR,