Research Archive Citation for published version: Barbara Loi, Mire Zloh, Maria Antonietta De Luca, Nicholas Pintori, John Corkery, and Fabrizio Schifano, ‘4,4′- Dimethylaminorex (“4,4′-DMAR”; “Serotoni”) misuse: A Web- based study, Human Psychopharmacology: Clinical and Experimental, Vol. 32 (3):e2575, May 2017. DOI: https://doi.org/10.1002/hup.2575 Document Version: This is the Accepted Manuscript version. The version in the University of Hertfordshire Research Archive may differ from the final published version. Users should always cite the published version of record. Copyright and Reuse: This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving. Enquiries If you believe this document infringes copyright, please contact the Research & Scholarly Communications Team at [email protected] Human Psychopharmacology: Clinical and Experimental 4,4’ -dimethylaminorex ('4,4’ -DMAR’; ‘Serotoni’) misuse; a web-based study Journal:For Human Peer Psychopharmacology: Review Clinical and Experimental Manuscript ID HUP-16-0111.R1 Wiley - Manuscript type: Special issue on novel psychoactive substances Date Submitted by the Author: 21-Jan-2017 Complete List of Authors: Loi, Barbara; University of Hertfordshire School of Life and Medical Sciences, Department of Pharmacy, Postgraduate Medicine and Pharmacology, University of Hertfordshire, UK Zloh, Mire; University of Hertfordshire School of Life and Medical Sciences, Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, Department of Pharmacy, Postgraduate Medicine and Pharmacology, University of Hertfordshire, UK De Luca, Maria Antonietta; University of Cagliari, Biomedical Sciences, Division of Neuropsychopharmacology Pintori, Nicholas; University of Cagliari, Biomedical Sciences, Division of Neuropsychopharmacology Corkery, John; University of Hertfordshire, Psychopharmaology, Drug Misuse & Novel Psychoactive Substances Research Unit Schifano, Fabrizio; University of Hertfordshire, School of Pharmacy drug abuse, 4,4’-DMAR, aminorex derivatives, novel psychoactive Keyword: substances, stimulants, online fora http://mc.manuscriptcentral.com/hup Page 1 of 37 Human Psychopharmacology: Clinical and Experimental 1 2 3 TITLE PAGE 4 5 6 Title: 4,4’-dimethylaminorex (‘4,4’-DMAR’; ‘Serotoni’) 7 8 misuse; a web-based study 9 10 11 Running head: 4,4’-DMAR on the web 12 13 Keywords : drug abuse; 4,4’-DMAR; aminorex derivatives; 14 15 novel psychoactive substances; psychonauts; online fora; 16 17 18 stimulantsFor Peer Review 19 1 1 2 20 Name of authors: Loi, B. , Zloh, M. , De Luca, M.A. , Pintori 21 22 N.2, Corkery J.M. 1, Schifano, F.1 23 24 1Psychopharmacology, Drug Misuse and Novel Psychoactive 25 26 27 Substances Research Unit, Department of Pharmacy, 28 29 Pharmacology & Post-graduate Medicine, University of 30 31 Hertfordshire, UK 32 33 2Department of Biomedical Sciences, Division of 34 35 Neuropsychopharmacology, University of Cagliari, Italy 36 37 38 Corresponding author: Barbara Loi, Address: College Lane 39 40 Campus, Hatfield AL10 9AB, UK, Tel: 00393495061720, E- 41 42 mail address: [email protected] 43 44 Conflict of interest : No conflict of interest has been declared. 45 46 47 Financial & competing interests disclosure : This paper was 48 49 supported in part by grants of the European Commission (Drug 50 51 Prevention and Information Programme 2014-16; contract no. 52 53 JUST/ 2013/DPIP/AG/4823; EU-MADNESS project) and by a 54 55 56 PhD studentship (bursary) from the University of Hertfordshire. 57 58 Further financial support was provided by the EU Commission- 59 60 1 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 2 of 37 1 2 3 targeted call on cross border law enforcement cooperation in 4 5 the field of drug trafficking - DG Justice/DG Migrations and 6 7 Home Affairs (JUST/2013/ISEC/DRUGS/AG/6429) Project 8 9 10 EPS/NPS (Enhancing Police Skills concerning Novel 11 12 Psychoactive Substances; NPS). 13 14 15 Abstract 16 17 Background: 4,4′-DMAR (4,4’-dimethylaminorex; ‘Serotoni’) 18 For Peer Review 19 is a potent stimulant drug which has recently been associated 20 21 22 with a number of fatalities in Europe. Over the last few years, 23 24 online communities have emerged as important resources for 25 26 disseminating levels of technical knowledge on novel 27 28 psychoactive substances/NPS. 29 30 31 Objective: Analysing the information provided by the fora 32 33 communities on 4,4’-DMAR use, additionally critical 34 35 36 reviewing the available evidence-based literature on this topic. 37 38 39 Methods: Different website drug fora were identified. A critical 40 41 review of the existing evidence-based literature was 42 43 undertaken. Individuation and analysis of qualitative data from 44 45 the identified website fora were performed. 46 47 48 Results: The combined search results identified six website fora 49 50 51 from which a range of qualitative data on recurring themes was 52 53 collected. These themes included: routes of administration and 54 55 doses; desired effects; adverse effects; comparison with other 56 57 drugs; association with other drugs; medications self- 58 59 60 2 http://mc.manuscriptcentral.com/hup Page 3 of 37 Human Psychopharmacology: Clinical and Experimental 1 2 3 administered to reverse 4,4’-DMAR action; overall impression; 4 5 provision of harm reduction advice. 6 7 8 Conclusions: Although being characterized by a number of 9 10 methodological limitations, the social networks’ web 11 12 13 monitoring approach (netnography) may be helpful to better 14 15 understand some of the clinical and psychopharmacological 16 17 issues pertaining to a range of NPS, including 4,4’-DMAR, for 18 For Peer Review 19 which only extremely little, if any, scientific knowledge is 20 21 22 available. 23 24 25 Abbreviations 26 27 28 Novel psychoactive substances: NPS 29 30 31 Blood brain barrier: BBB 32 33 34 Dopamine transporter: DAT 35 36 37 Norepinephrine transporter: NET 38 39 40 Serotonin transporter: SERT 41 42 43 Route of administration: ROA 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 4 of 37 1 2 3 Introduction 4 5 Internet use has become an unremarkable aspect of everyday 6 7 life, providing a revolutionary tool to facilitate rapid 8 9 10 interpersonal communication, exchange of ideas, opinions, and 11 12 information on a range of issues, including recreational drugs 13 14 (Wax, 2002). 15 16 Overall, the web represents the most popular source of 17 18 For Peer Review 19 information about NPS use (Nelson et al., 2014). In this 20 21 respect, web fora are being extensively used as discussion areas 22 23 (Orsolini et al., 2015). A forum moderator often oversees the 24 25 communication activities, whilst facilitating the debate, and 26 27 making decisions regarding the direction of threads. Apart from 28 29 30 drug enthusiasts, fora members may include researchers, harm- 31 32 reduction specialists, police officers, lawyers, physicians, 33 34 journalists and addiction specialists, all actively contributing to 35 36 the debate (https://drugs-forum.com/index.php). 37 38 39 Although fora communities are virtual, these social groups can 40 41 have consequential effects on many aspects of the member’s 42 43 44 behaviour (Kozinets, 2002) as the information being accessed 45 46 may be misleading, or even dangerous, and particularly so for 47 48 naïve users (Monahan & Colthurst, 2001). 49 50 51 With the increase in web marketing of drugs available for 52 53 purchase, online discussions have, however, become a reason 54 55 for concern as they could lead to an increase in drug using 56 57 58 59 60 4 http://mc.manuscriptcentral.com/hup Page 5 of 37 Human Psychopharmacology: Clinical and Experimental 1 2 3 levels (Soussan & Kjellgren, 2014) whilst playing a crucial part 4 5 in raising interest about drugs (Griffiths et al., 2010). 6 7 8 4,4’-DMAR 9 10 4,4’-DMAR (Figure 1) (IUPAC: 4-methyl-5-(4- 11 12 13 methylphenyl)-4,5-dihydrooxazol-2-amine), is a synthetic 14 15 substituted oxazoline derivative which contains two chiral 16 17 centres and two racemic mixtures (i.e. (±)-cis and (±) trans- 18 For Peer Review 19 racemates). Previous analytical characterizations confirmed 20 21 that the (±)-cis racemate is the most available isomer in the 22 23 24 market and the one involved in many deaths (Brandt et al., 25 26 2014). This stimulant drug is commonly advertised as 27 28 ‘para-Methyl-4-methylaminorex’, ‘4-methyl-euphoria’, ‘4- 29 30 methyl-U4Eu’, ‘4-M-4-MAR’, ‘4,4-dimethylaminorex’ and 31 32 33 ‘Serotoni’. 34 35 It belongs to the Novel Psychoactive Substance (NPS) 36 37 category, which encompasses a wide number of compounds 38 39 widely marketed in the ‘real’ and ‘virtual’ world as legal 40 41 substitutes for banned drugs (Miliano et al., 2016) and 42 43 44 being sometimes more harmful than their parental 45 46 compounds in terms of toxicity, adverse reactions, 47 48 dependence, long-term effects (Schifano et al., 2015), 49 50 fatalities (Chiappini et al., 2015; Loi et al., 2015) and 51 52 53 psychiatric consequences (Martinotti et al., 2014). 54 55 56 57 58 59 60 5 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 6 of 37 1 2 3 4,4’-DMAR was first detected in Europe in the Netherlands at 4 5 the end of 2012, and by the first half of 2013 it had emerged in 6 7 Denmark, Finland, Hungary, Poland, Romania, Sweden and the 8 9 10 United Kingdom (EMCDDA and Europol, 2014; EMCDDA, 11 12 2015). 13 14 15 It is a research chemical most commonly sold over the Internet 16 17 and head-shops in the form of powder and tablets, usually 18 For Peer Review 19 labelled ‘Speckled Cherry’ or ‘Speckled Cross’ with a variety 20 21 22 of logos, colours (e.g.