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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 : Clinical and Experimental, Vol. 32 (3):e2575, May 2017.

DOI: https://doi.org/10.1002/hup.2575

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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, 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, derivatives, novel psychoactive Keyword: substances, , online fora

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1 2 3 TITLE PAGE 4 5 6 Title: 4,4’dimethylaminorex (‘4,4’DMAR’; ‘Serotoni’) 7 8 misuse; a webbased 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 & Postgraduate 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 201416; contract no. 52 53 JUST/ 2013/DPIP/AG/4823; EUMADNESS 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//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 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 evidencebased literature on this topic. 37 38 39 Methods: Different website drug fora were identified. A critical 40 41 review of the existing evidencebased 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 transporter: DAT 35 36 37 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://drugsforum.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: 4methyl5(4 11 12 13 methylphenyl)4,5dihydrooxazol2amine), is a synthetic 14 15 substituted 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 ‘paraMethyl4methylaminorex’, ‘4methyleuphoria’, ‘4 29 30 methylU4Eu’, ‘4M4MAR’, ‘4,4dimethylaminorex’ 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, longterm 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 headshops 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. white, pink, green and blue) and shapes 23 24 (EMCDDA and Europol, 2014). 25 26 27 Both the tablets’ and powder composition can be considerably 28 29 different from a product to a product as they may contain 4,4’ 30 31 DMAR alone or in combination with other psychoactive 32 33 substances, including: synthetic , synthetic 34 35 36 cannabinoids, benzofurans and . To date, the 37 38 purity of the 4,4′DMAR available on the drug market has 39 40 not been reported (EMCDDA, 2015). 41 42 43 As described by the EMCDDA (2015), seizures of products 44 45 containing 4,4′DMAR were reported in seven Member States 46 47 48 (Denmark, Finland, Hungary, the Netherlands, Romania, 49 50 Sweden and the United Kingdom), with a preferential 51 52 availability of this substance in the Hungarian drug market. 53 54 55 56 57 58 59 60 6 http://mc.manuscriptcentral.com/hup Page 7 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 In some cases, 4,4′DMAR is offered on the illicit market as 4 5 ‘ecstasy’ and ‘’, therefore users may not always 6 7 be aware of the associated health risks (EMCDDA, 2015). 8 9 10 Because of serious adverse effects reported, including fatal 11 12 13 intoxications entirely caused by (±)cis4,4’DMAR, this 14 15 drug was banned in the UK, being placed in schedule 1 16 17 (ACMD, 2014) of the Misuse of Drugs Act 1971 . 18 For Peer Review 19 20 4,4'DMAR is also under drug control legislation in Bulgaria; 21 22 Croatia; Cyprus; Czech Republic; Denmark; Estonia; Finland; 23 24 25 Germany; Hungary; Ireland; Lithuania; Luxembourg; 26 27 Netherland; Norway; Poland; Slovenia; Spain; Sweden, 28 29 Turkey, Japan (EMCDDA 2015, ELDD 2016). Additionally, 30 31 in March 2016, the commission on Narcotic drugs decided 32 33 34 to internationally control 4,4’DMAR adding it into 35 36 schedule 2 of the Convention on Psychotropic Substances of 37 38 1971. The decision became effective in November 2016 39 40 (UNODC, 2016). 41 42 43 Pharmacology 44 45 (±)Cis4,4′DMAR is a monoaminereleasing agent that 46 47 48 displays high potency at all three monoamine transporters. 49 50 According to some pharmacodynamics studies, this compound 51 52 was found to show equivalent potency at the dopamine and 53 54 norepinephrine transporters (DAT and NET, respectively) and 55 56 57 greater potency at the serotonin transporter (SERT), in 58 59 60 7 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 8 of 37

1 2 3 comparison with damphetamine and aminorex (Brandt et al., 4 5 2014a). 6 7 In another study performed on rat brain synaptosomes, the 8 9 10 monoamine releasing activity of (±)cis4,4’DMAR and 11 12 (±)trans4,4’DMAR isomers was compared to that of MDMA. 13 14 Both cis4,4’DMAR and trans4,4’DMAR were found to be 15 16 stronger than MDMA as releasing agents at the DAT and NET. 17 18 For Peer Review 19 Concerning the activity at SERT, (±)cis4,4’DMAR acted as a 20 21 fully effective releasing agent, whereas (±)trans4,4’DMAR 22 23 acted as a fully efficacious uptake blocker (McLaughlin et al., 24 25 2014). 26 27 28 Additionally, our unpublished data obtained using PreADMET 29 30 online server (https://preadmet.bmdrc.kr/) indicate that 4,4’ 31 32 33 DMAR has similar predicted blood brain barrier (BBB) 34 35 permeability as MDMA. 36 37 38 To date, no published data are available on the 39 40 of 4,4′DMAR in animals or humans and 41 42 no metabolites of this substance have been detected up to 43 44 45 now (EMCDDA, 2015). 46 47 48 Fatalities and adverse effects 49 50 In December 2012, 4,4′DMAR was first detected in fatalities 51 52 reported from Sweden, followed by Denmark, Finland, 53 54 Hungary, Romania, Sweden, France and the United Kingdom 55 56 57 (EMCDDA, 2015). 58 59 60 8 http://mc.manuscriptcentral.com/hup Page 9 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 Since October 2013, 38 4,4’DMARrelated deaths have been 4 5 identified in the United Kingdom (e.g. 36 in Northern Ireland 1 6 7 in Scoltand and 1 in England); 8 in Hungary; and 1 in Poland in 8 9 10 July 2013 (ACMD, 2014, Cosbey et al., 2014; EMCDDA, 11 12 2015; Shropshire Star, 2016) 13 14 15 In all 47 cases, the 4,4’DMAR presence, either alone or in 16 17 combination with remaining recreational drugs (e.g. , 18 For Peer Review 19 , cannabis, , , 20 21 22 secondgeneration antipsychotics, opioids and synthetic 23 24 cathinones), was confirmed at postmortem (ACMD, 2014, 25 26 EMCDDA, 2015). 27 28 29 Conversely, nonfatal 4,4’DMAR acute toxicity events are 30 31 characterized by features such as: hyperthermia, pupil dilation, 32 33 muscular spasm, seizures, increased perspiration, cardiac and 34 35 36 respiratory arrest, agitation, confusion, convulsions, 37 38 unconsciousness and paranoid features. The presence of and/or 39 40 interaction with other substances may account for some of the 41 42 reported effects (EMCDDA and Europol, 2014; EMCDDA, 43 44 45 2015). 46 47 48 The 4,4′DMAR activity on catecholamine transporters may be 49 50 relevant in this respect, especially if the molecule is associated 51 52 with recreational drugs altering dopamine and norepinephrine 53 54 levels. 55 56 57 58 59 60 9 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 10 of 37

1 2 3 Indeed, psychotic episodes can occur if 4,4’DMAR is ingested 4 5 in combination with other catecholaminereleasing agents (e.g. 6 7 amphetaminetype stimulants, cocaine) and cardiovascular 8 9 10 issues may result from the excessive systemic levels of 11 12 norepinephrine released. 13 14 15 Additionally, the risk of experiencing a serotonergic syndrome 16 17 may be increased by the association of 4,4’DMAR with 18 For Peer Review 19 compounds affecting either the serotonin release (e.g. 20 21 22 MDMA/ecstasy) or its reuptake, such as the selective serotonin 23 24 reuptake inhibitors (SSRIs) (McLaughlin et al., 2014). 25 26 27 We aimed here at reviewing the literature relating to 4,4’ 28 29 DMAR intake. Furthermore, we aimed at describing, through 30 31 an assessment of related anecdotal online reports, a range of 32 33 clinical pharmacological issues to its misusing issues potential. 34 35 36 37 Methods 38 39 To identify peerreviewed papers and online reports 40 41 commenting on 4,4’DMAR misuse issues, a comprehensive 42 43 search on the Embase, Scopus; Google Scholar and 44 45 Pubmed/Medline databases was performed using the following 46 47 48 key words: (4,4’DMAR) AND (abuse OR misuse OR 49 50 poisoning OR dependence OR addiction ). No language or time 51 52 restrictions were placed on the electronic search; focus was on 53 54 both preclinical and clinical data and covered the period up to 55 56 57 November 15th, 2016. 58 59 60 10 http://mc.manuscriptcentral.com/hup Page 11 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 To identify information on 4,4’DMAR misusers’ firsthand 4 5 experiences, a qualitative/observational, i.e. netnographic, 6 7 approach on selected websites was carried out. In doing so, 8 9 10 between March and October 2016, a range of qualitative 11 12 Google searches was carried out, in English, using key words 13 14 such as ‘4,4’DMAR and abuse’, ‘4,4’DMAR and misuse’; 15 16 ‘4,4’DMAR and experience’; ‘Serotoni and forum’; ‘Speckled 17 18 For Peer Review 19 Cherry forum’; ‘Speckled Cross forum’; ‘ParaMethyl4 20 21 Methylaminorex forum’; ‘4methyleuphoria forum’; ‘4 22 23 methylU4Eu forum’; ‘4,4dimethylaminorex forum’. 24 25 26 The first 2 pages/20 hits per keyword (e.g. 60 per language; 27 28 120 links) were considered. A number of websites were 29 30 subsequently excluded, because: not relevant; being duplicates; 31 32 33 or requiring a registration/payment procedure. 34 35 36 A total of six sites hosting forum activity around 4,4’DMAR 37 38 use were identified: 39 40 41 1. https://www.chemsrus.com; 42 43 44 2. https://www.reddit.com; 45 46 47 3. https://www.ukchemicalresearch.org; 48 49 50 4. http://www.bluelight.org; 51 52 53 5. http://www.psychonaut.com/forum.php; 54 55 56 6. https://drugsforum.com. 57 58 59 60 11 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 12 of 37

1 2 3 Overall, twenty detailed posts (19 in English, and 1 in French) 4 5 focusing on 4,4’DMAR use were found and individually 6 7 analysed by identifying the common topics and patterns of 8 9 10 discussion. Conversely, a range of fora posts/threads relating to 11 12 a few 4,4’DMAR themes, including: 13 14 15 1. routes of administration and doses 16 17 18 2.For desired effectsPeer Review 19 20 21 3. adverse effects 22 23 24 4. comparisons with other substances 25 26 27 5. concurrent intake with other drugs 28 29 30 6. medication use to counteract 4,4’DMAR action 31 32 33 7. overall impression 34 35 36 8. availability of harm reduction messages; warning other 37 38 people regarding possible drugrelated health risks 39 40 41 were specifically analysed. No posts/other contributions to fora 42 43 44 discussions were made, and no information or clarification of 45 46 content was sought by the researchers. 47 48 49 Ethical consideration 50 51 Our research involved the collection and characterization of 52 53 already existing reports published on public Internet fora. A 54 55 56 discrete approach was undertaken, and no interactions with fora 57 58 members were made. In order to preserve the anonymity of the 59 60 12 http://mc.manuscriptcentral.com/hup Page 13 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 fora members, users’ nicknames were not mentioned and the 4 5 quotes were not integrally reported. Ethics’ approval for the 6 7 study was granted by the University of Hertfordshire School of 8 9 10 Pharmacy Ethics Committee, on December 15th, 2010 11 12 (reference code PHAEC/1042), with a further 5year extension 13 14 of the approval having been granted in November 2013. 15 16 Results 17 18 For Peer Review 19 Literature identification and analysis 20 21 The comprehensive literature search led to the identification of 22 23 13 peerreviewed papers and 3 reports (EMCDDA and 24 25 Europol, 2014; ACMD, 2014; EMCDDA, 2015) focusing on 26 27 4,4’DMAR use, which were critically analysed. 28 29 30 Published information on routes of administration (ROA), 31 32 suggest that nasal insufflation and oral consumption practices 33 34 are the most widely used followed by inhalation and injection 35 36 (ACMD, 2014; EMCDDA and Europol, 2014; EMCDDA, 37 38 39 2015; Cosbey et al., 2014; Coppola et al., 2015; Glanville et al., 40 41 2015; Hentig, 2016). 42 43 Oral doses were described ranging from 10 to 200 mg, while 44 45 the insufflated ones vary from 10 to 65 mg (ACMD, 2014; 46 47 EMCDDA and Europol, 2014; EMCDDA, 2015; Coppola et 48 49 50 al., 2015; Glanville et al., 2015; Nizar et al., 2015; Hentig, 51 52 2016). 53 54 Oral consumption was reported to be commonly practiced by 55 56 directly ingesting tablets/powder or by swallowing powder 57 58 59 60 13 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 14 of 37

1 2 3 previously wrapped in cigarette papers (‘bombing’) (ACMD, 4 5 2014; EMCDDA and Europol, 2014; EMCDDA, 2015; Cosbey 6 7 et al., 2014; Coppola et al., 2015; Glanville et al., 2015). 8 9 10 Commonly reported desired effects include: euphoria, 11 12 increased sociability and energy, alertness, and increased 13 14 confidence; while untoward effects vary from increased heart 15 16 rate, hyperthermia, sweating, agitation, jaw clenching 17 18 For Peer Review 19 (bruxism), facial spasms, stimulation, nausea, dysphoria, 20 21 dilated pupils, to psychosis and hallucinations (ACMD, 2014; 22 23 EMCDDA and Europol, 2014; EMCDDA, 2015; Cosbey et al., 24 25 2014; Coppola et al., 2015; Glanville et al., 2015). 26 27 The use of a range of sedatives and was reported as 28 29 30 a common practice to reverse 4,4’DMAR longlasting 31 32 stimulants’ effects (1216 hours) (Glanville et al., 2015; 33 34 Schifano et al., 2016). 35 36 Desired and untoward effects were described to be comparable 37 38 39 to those observed with other stimulanttype drugs (e.g. MDMA, 40 41 ) characterized by similar pharmacology and 42 43 pharmacokinetic properties (Brandt et al., 2014a; McLaughlin 44 45 et al., 2014; Schifano et al., 2015, 2016; Nils et al., 2016; 46 47 Hentig, 2016; Lucchetti et al., 2016). 48 49 50 Combination with other drugs (e.g. synthetic cathinones, 51 52 amphetamines, cocaine) has been widely reported and 53 54 accounted for several toxicity events (e.g. cardiovascular 55 56 effects, psychotic symptoms, agitation hyperthermia) and 57 58 59 60 14 http://mc.manuscriptcentral.com/hup Page 15 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 fatalities (Brandt et al., 2014b; ACMD, 2014; EMCDDA and 4 5 Europol, 2014; EMCDDA, 2015; Cosbey et al., 2014; Coppola 6 7 et al., 2015; Glanville et al., 2015; Berg, 2016; Hentig, 2016). 8 9 10 Social cohesion, support, and harm reduction advice have been 11 12 also widely described among a range of NPS users (Soussan & 13 14 Kjellgren, 2014). 15 16 17 Selfreported routes of administration and dosages 18 For Peer Review 19 20 Dosages and routes of administration were found to be a 21 22 widelydebated topic of discussion. Overall users tended to 23 24 specify doses, frequency of redosing and the combination of 25 26 different ROA to achieve the optimal ‘high level’. The 27 28 indication of dosages and ROAs was reported by 85% (17/20) 29 30 31 of users. Among them, 76% (13/17) described oral use, 12% 32 33 (2/17) reported the intranasal ROA or vaping, 12% (2/17) 34 35 reported a multiple redosing practice describing an oral 36 37 ingestion followed by the intranasal route, or by snorting and 38 39 40 vaping. The formulations described were powder and pellets. 41 42 The oral doses ranged from 10 to 120 mg; the intranasal ones 43 44 varied from 25 to 30 mg and the vaporised doses were in the 45 46 1060 mg range (Figure 2). A quarter of users (5/20) described 47 48 a slow onset of the drug’s psychoactive effects (Figure 2). 49 50 51 Selfreported desired and untoward effects 52 53 Intensity and duration of the ‘positive’ effects were widely 54 55 56 reported; 70% (14/20) of users described a range of positive 57 58 effects including: stimulation, energy increase, euphoria, 59 60 15 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 16 of 37

1 2 3 relaxation, increased sociability, empathy, disinhibition, arousal 4 5 (Figure 2). 6 7 By contrast, a range of adverse effects was described by 55% of 8 9 10 users (11/20) and included: hallucinations, altered perceptions, 11 12 insomnia, queasiness, jaw clenching/tension/bruxism, blurry 13 14 vision, , psychosis, confusion, nausea, sweatiness, 15 16 increased heart rate, and hyperthermia (Figure 3). 17 18 For Peer Review 19 The effects of 4,4’DMAR were compared with those 20 21 22 associated with other stimulant (e.g. 4FA, MDMA, 6APB, 23 24 APB, 3MMC, 4MMC, MDPV aPVP, 4MMA, MDMA) 25 26 intake by 50% of the users (10/20). Comments included: “Way 27 28 better than cathinones!…it was also way way better than 4-FA 29 30 which never really felt serotonergic to me”;…“It definitely felt 31 32 33 stronger than any of my experiences on 6-APB though”;…“I 34 35 found it to be a very nice experience, somewhat comparable to 36 37 3-MMC but a lot longer lasting and thus with a lot less 38 39 craving”) (Figure 3). 40 41 42 Association with other recreational drugs 43 44 45 Some 30% (6/20) of users used 4,4’DMAR with other drugs, 46 47 especially alcohol (66%; 4/6); 6APB (17%; 1/6); and 48 49 phenylpiracetam (17%, 1/6) (Figure 3). 50 51 Some users described a potentiation of 4,4’DMAR effects 52 53 54 whilst on alcohol (“definitely potentiated with alcohol” ); and a 55 56 feeling of “head clearness” (“ Normally I would become sloppy 57 58 and hazy with alcohol, but this was clear and fresh” ). Finally, 59 60 16 http://mc.manuscriptcentral.com/hup Page 17 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 to cope with social anxiety issues, 4,4’DMAR was associated 4 5 with either alcohol or 6APB. 6 7 8 Medication(s) selfadministered to revert 4,4’DMAR action 9 10 Since 4,4’DMAR stimulant effects seemed to be quite long 11 12 13 lasting, some 20% of users (4/20) stated they had used 14 15 sedatives/anxiolytics (e.g. , zolpidem, trazodone, 16 17 baclofen, flubromazepam, and etizolam) (Figure 3). 18 For Peer Review 19 20 Overall impression 21 22 Some 50% (10/20) of fora users provided their peers with either 23 24 a positive or a negative summary of their 4,4’DMAR personal 25 26 27 experiences, hence to promote or denigrate the use of this drug 28 29 (Figure 4). Indeed, most of them described their experience as 30 31 “awesome”, “enjoyable”, “nice”, “clean”, “comfortable” 32 33 while others considered it “disappointing”. Other users 34 35 described their experience using technical language which 36 37 38 involved a reference to the molecule’s pharmacodynamics (“I 39 40 really liked the dopamine-serotonin activation ration” ); 41 42 pharmacokinetics (“…a biphasic effect with a stimulation 43 44 predominant on the side end…residual stimulation the day 45 46 47 after” ); or addictive liability levels (“ significative addictive 48 49 potential” ). 50 51 Overall, some users appeared enthusiastic (“I think it’s the most 52 53 beautiful, awesome stimulant I’ve ever tried” …“to me this feels 54 55 like a product the market has been seriously lacking for a long 56 57 58 time” ). 59 60 17 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 18 of 37

1 2 3 Harm reduction advice 4 5 Some fora discussions identified here were characterized by a 6 7 general concern for safety, with some 30% (6/20) of users 8 9 10 providing a range of advice, including: avoiding concurrent 11 12 ingestion of other drugs both on the intake day and for a few 13 14 days after 4,4’DMAR use ; being careful about both the dosage 15 16 selfadministered and tendency to redosing, whilst considering 17 18 For Peer Review 19 the 4,4’DMAR intensity of the psychoactive effects (“this is 20 21 not a functional/ stimulant, this is a more potent 22 23 version of MDMA/APB”) (Figure 4 ). 24 25 Discussion 26 27 4,4’DMAR popularity in a range of different countries may 28 29 30 well be related to both its significant psychoactive effects and 31 32 the current intense webbased marketing activities (EMCDDA 33 34 and EUROPOL, 2014). 35 36 This drug belongs to the category of NPS which includes 37 38 39 numerous harmful substances like: “Synthetic 40 41 Cannabinoids” (the largest group of new drugs monitored 42 43 by the EMCDDA and found to be highly toxic according to 44 45 the high affinity and efficacy at the level of the neural CB1 46 47 receptors) (EMCDDA, 2016; Santacroce et al., 2015; De 48 49 50 Luca et al., 2015); “Synthetic Cathinones” (the second 51 52 widest group monitored by the EMCDDA, implicated in a 53 54 number of overdose deaths and serious 55 56 sympathomimetic adverse effects) (EMCDDA, 2016); 57 58 59 60 18 http://mc.manuscriptcentral.com/hup Page 19 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 “hallucinogens” (including compounds like 25I and 25C 4 5 NBoMe, responsible for acute and chronic toxicities, 6 7 according to their ability to act at the level of the 8 9 10 serotoninergic system) (Bersani et al., 2014 ). 11 12 The public health risks related to 4,4′DMAR use may be 13 14 associated with a range of factors, including: drug availability; 15 16 quality and purity; levels of risk awareness amongst users; and 17 18 For Peer Review 19 potential combination of this drug with other substances (e.g. 20 21 entactogens, stimulants and/or including alcohol) 22 23 (EMCDDA, 2015; EMCDDA and Europol, 2014). 24 25 Much of our knowledge about 4,4’DMAR comes from 26 27 retrospective selfreports from recreational users (e.g. the ‘e 28 29 30 psychonauts’, Orsolini et al., 2015) who use the fora as a 31 32 widely available platforms to disseminate a range of drug 33 34 related personal experiences. 35 36 37 According to previous reports (ACMD, 2014; EMCDDA and 38 39 Europol, 2014), the main 4,4’DMAR routes of administration 40 41 42 include oral ingestion, at a dosage of 10200 mg per occasion, 43 44 and nasal insufflation (1065 mg dosage), with injection having 45 46 been only rarely reported. 47 48 49 In the present study, fora users have been widely sharing their 50 51 4,4’DMAR intake experiences and knowledge, with most 52 53 54 (80%) messages having been posted in 2013, e.g. in parallel 55 56 with first seizures of the drug in the EU. Starting from 2015, 57 58 the online discussions focusing on this drug, rapidly 59 60 19 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 20 of 37

1 2 3 disappeared from the surface web, in parallel with 4,4' 4 5 DMAR being banned in different countries. 6 7 8 This tendency was already observed with other substances, 9 10 such as 2CT7, a stimulant drug which rapidly 11 12 13 disappeared from the cyber market after control legislation 14 15 (Schifano et al., 2005). However, this does not excluded the 16 17 possibility of a move of 4,4’DMARrelated illegal activities 18 For Peer Review 19 into the ‘deep web’, as already observed with other 20 21 22 controlled substances (Orsolini et al., 2015). Moreover, the 23 24 fall noted in deaths involving this molecule in 2015 25 26 (Corkery, 2016) may be due, in part, to the control of this 27 28 substance. Equally, the fall may be due to fewer individuals 29 30 using it following the bad reputation it received because of 31 32 33 the sudden outbreaks of these severe adverse effects. 34 35 Overall, fora users mostly ingested 4,4’DMAR powder and 36 37 pellets, at dosages (e.g. 10120 mg) consistent with previous 38 39 reports (ACMD, 2014; EMCDDA and Europol, 2014), 40 41 42 although vaping and snorting ROAs were at times preferred, 43 44 with multiple redosing practice being described as quite a 45 46 popular approach. 47 48 49 Most of the 4,4’DMAR fora enthusiasts described here seemed 50 51 to present with a previous history of drug misuse, whilst 52 53 54 possessing large levels of technical/pharmacological 55 56 knowledge regarding NPS and 4,4’DMAR in particular, hence 57 58 59 60 20 http://mc.manuscriptcentral.com/hup Page 21 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 well resembling the classical/standard ‘epsychonauts’ 4 5 description. 6 7 8 The present report seems to confirm that 4,4’DMAR is a 9 10 popular recreational drug which, similarly to remaining 11 12 13 stimulants, is associated with feelings of stimulation, euphoria, 14 15 energy, alertness, increasing confidence. The powerful ‘pro 16 17 social’ effects (e.g. increased empathy, feelings of friendliness, 18 For Peer Review 19 interpersonal closeness, openness) were here particularly 20 21 22 emphasized (EMCDDA and Europol, 2014). Related stimulant 23 24 effects seemed to be characterized by a significant lag time, 25 26 peaking in 25 hours, but were longlasting (e.g. 1216 hours) 27 28 as well (Glanville et al., 2015). 29 30 31 Consistent with previous studies (Glanville et al., 2015), 32 33 untoward effects were here described in some 55% of users, 34 35 36 starting from the minimal (e.g. 5mg) dosage, and included: 37 38 nausea, dysphoria, agitation, confusion, aggression, sweating, 39 40 increased heart rate, hyperthermia, dilated pupils, psychosis, 41 42 hallucinations, insomnia, jaw clench/jaw tension/bruxism, 43 44 45 blurry vision, nystagmus. 46 47 48 Both the psychoactive (including the entactogenic and 49 50 nootropic properties) and the adverse effects being here 51 52 described are consistent with 4,4’DMAR being a 53 54 phenethylamine/MDMA like compound (Bershad et al., 2016; 55 56 57 Schifano et al., 2016; Iversen, 2013; Miliano et al., 2016). 58 59 60 21 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 22 of 37

1 2 3 The 4,4’DMAR pharmacodynamics profile may be broadly 4 5 similar to that of other stimulants. However, because of both 6 7 the intensity and the longduration of its effects, the 4,4’ 8 9 10 DMAR intake may be a reason of particular concern, and 11 12 especially so if the molecule, as here described by 30% of 13 14 users, is ingested in combination with remaining 15 16 serotonergic/dopaminergic compounds (Coppola et al., 2014). 17 18 For Peer Review 19 These peculiar clinical pharmacological characteristics may 20 21 22 help explaining the disturbingly high rate of 4,4’DMAR 23 24 fatalities observed over a relatively short period of time in the 25 26 EU and especially in Northern Ireland (EMCDDA and Europol, 27 28 2014). 29 30 31 To counteract the longlasting stimulant effects, it is of interest 32 33 to note that some 20% of users here allegedly selfadministered 34 35 36 with a range of sedatives, including designer/’exotic’ 37 38 benzodiazepines (Schifano et al., 2016). In this way, users were 39 40 arguably adding further health risks to the already risky 41 42 practice of ingesting a powerful, but virtually unknown to the 43 44 45 medical literature, stimulant such as 4,4’DMAR. 46 47 48 Limitations 49 50 There are a number of possible limitations of the present study; 51 52 a multilingual analysis of a larger sample of websites could 53 54 have provided better levels of information. Furthermore, only 55 56 57 publicly available web sites/fora were monitored here, and 58 59 60 22 http://mc.manuscriptcentral.com/hup Page 23 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 further data of interest could possibly have been identified by 4 5 the analysis of the ‘deep web’ and ’dark net’ material (Orsolini 6 7 et al., 2015). We made no 4,4’DMAR purchase attempts, 8 9 10 hence one could argue about the product content/dosage being 11 12 delivered. Overall, anecdotal reports are only partially reliable 13 14 and it may be inappropriate to trust information obtained from 15 16 the internet without independent verification. Additionally, 17 18 For Peer Review 19 there is no certainty that multiple threads or posts were 20 21 generated by different individuals, as it is not unusual that 22 23 people can access the fora multiple times with different 24 25 pseudonyms. 26 27 Since very few peerreviewed papers relating to 4,4’DMAR 28 29 30 misuse issues were identified, the present conclusions mainly 31 32 relied on sources (e.g. web sites) are characterized by levels of 33 34 unreliability. Only largescale, adequately controlled, clinical 35 36 studies can give a clear indication of a drug characteristics and 37 38 39 adverse effects. However, in line with present observations, 40 41 previous studies (Corkery et al., in press) Schifano et al., 2010; 42 43 Soussan & Kjellgren, 2014; 44 45 https://www.drugabuse.gov/publications/drugfacts/nationwide 46 47 trends) have clearly suggested that the increase in online 48 49 50 trafficking/debate about a specific typically 51 52 precedes the occurrence of clinical incidents at the population 53 54 level. 55 56 57 Conclusions 58 59 60 23 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 24 of 37

1 2 3 This study suggests that fora members cooperate in 4 5 exchanging an extensive body of knowledge about NPS, 6 7 including 4,4’DMAR. The combination of sensation seeking, 8 9 10 harmreduction, and social networks’ pressure may arguably 11 12 have detrimental effects on many aspects of fora members’ 13 14 drug intake behaviour. The issue of 4,4’DMAR misuse may be 15 16 a reason for concern; consumers may not be fully aware of the 17 18 For Peer Review 19 pharmacological activity, and possible medical consequences, 20 21 of the compound(s) they are ingesting. Indeed, 4,4’DMAR 22 23 misuse may often occur in the context of polydrug intake, and 24 25 the pharmacodynamics/pharmacokinetics’ interactions of 4,4’ 26 27 DMAR with other substances are not known. 28 29 30 Further analyses should be undertaken to better draft a risk 31 32 profile for this drug. As with any centrally active drug, 33 34 physicians should carefully evaluate patients for history of drug 35 36 abuse and observe them for signs of any products’, including 37 38 39 4,4’DMAR, misuse. Additionally, prevention strategies should 40 41 be developed and better public awareness levels should be 42 43 promoted. 44 45 46 Acknowledgements 47 48 BL gratefully acknowledges the PhD studentship support from 49 50 the University of Hertfordshire. This paper was supported in 51 52 53 part by grants of the European Commission (Drug Prevention 54 55 and Information Programme 201416; contract no. JUST/ 56 57 2013/DPIP/AG/4823; EUMADNESS project). Further 58 59 60 24 http://mc.manuscriptcentral.com/hup Page 25 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 financial support was provided by the EU Commissiontargeted 4 5 call on cross border law enforcement cooperation in the field of 6 7 drug trafficking DG Justice/DG Migrations and Home Affairs 8 9 10 (JUST/2013/ISEC/DRUGS/AG/6429) Project 11 12 EPS/NPS (Enhancing Police Skills concerning Novel 13 14 Psychoactive Substances; NPS). F. Schifano is a full member 15 16 of the UK Advisory Council on the Misuse of Drugs (ACMD) 17 18 For Peer Review 19 and a member of its NPS Committee; EMA Advisory board 20 21 member. J. Corkery is a coopted member of the ACMD’s 22 23 Technical and NPS Committees and its DrugRelated Deaths 24 25 Working Group. The authors have no other relevant affiliations 26 27 or financial involvement with any organization or entity with a 28 29 30 financial interest in or financial conflict with the subject matter 31 32 or materials discussed in the manuscript apart from those 33 34 disclosed. 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 25 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 26 of 37

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1 2 3 Kozinets, R.V. (2002). The field behind the screen: Using 4 5 netnography for marketing research in online communities. 6 7 Journal of Marketing Research, 39(1), 61–72 8 9 10 Loi, B., Corkery, J.M., Claridge, H., Goodair, C., Chiappini, 11 12 S., Gimeno Clemente, C., Schifano F. 2015. Deaths of 13 14 individuals aged 1624 years in the UK after 15 16 using mephedrone. Hum Psychopharmacol. 30(4):22532. 17 18 For Peer Review 19 DOI: 10.1002/hup.2423 20 21 Lucchetti, J., Marzo, C.M., Di Clemente, A., Cervo, L., Gobbi, 22 23 M. (2016). A validated, sensitive HPLCMS/MS method for 24 25 quantification of cisparamethyl4methylaminorex (cis4,4' 26 27 DMAR) in rat and human plasma: application to 28 29 30 pharmacokinetic studies in rats. Drug Test Anal . DOI: 31 32 10.1002/dta.2052. [Epub ahead of print] 33 34 Martinotti, G., Lupi, M., Acciavatti, T., Cinosi, E., Santacroce, 35 36 R., Signorelli, M.S., … Giannantonio, M. (2014). Novel 37 38 39 psychoactive substances in young adults with and without 40 41 psychiatric comorbidities. Biomed Res Int. 2014:815424. DOI: 42 43 10.1155/2014/815424 44 45 McLaughlin, G., Morris, N., Kavanagh, P.V., Power, J.D., 46 47 Twamley, B., O’Brien, J. Talbot, B., Dowling, G., Mahony, O., 48 49 50 Brandt S.D., Patrick, J., Archer R.P., Partilla, J.S., Baumann 51 52 M.H. (2014). Synthesis, characterization, and monoamine 53 54 transporter activity of the new psychoactive substance 30,40 55 56 57 58 59 60 30 http://mc.manuscriptcentral.com/hup Page 31 of 37 Human Psychopharmacology: Clinical and Experimental

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1 2 3 Shropshire Star. (2016). Retrieved from: 4 5 http://www.shropshirestar.com/news/crime/2016/12/31/legal 6 7 highstoblameforprisontroublesayssisteroftelforddrug 8 9 10 deathman/ 11 12 Soussan, C., & Kjellgren, A. (2014). Harm reduction and 13 14 knowledge exchangeA qualitative analysis of drugrelated 15 16 Internet discussion forums . Harm Reduction Journal, 11(1), 25. 17 18 For Peer Review 19 DOI: 10.1186/147775171125 20 21 Ukchemicalresearch (2013). Retrieved from: 22 23 https://www.ukchemicalresearch.org 24 25 UNODC (2016). Commission on Narcotic Drugs decision on 26 27 international control of PMMA, αPVP, 4,4’DMAR, MXE and 28 29 30 Phenazepam enters into force. Retrieved from: 31 32 https://www.unodc.org/LSS/Announcement/Details/6dd8eae4 33 34 7b304ae1889ef8a03d62df18 35 36 Wax, P. M. (2002). Just a click away: Recreational drug web 37 38 39 sites on the Internet. Pediatrics , 109(6), e96. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 33 http://mc.manuscriptcentral.com/hup Human Psychopharmacology: Clinical and Experimental Page 34 of 37

1 2 3 Figure 1: 4,4’DMAR chemical structure 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 34 http://mc.manuscriptcentral.com/hup Page 35 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 Figure 2: 4,4’DMAR selfreported routes of administration and 4 dosages; long onset awareness; selfreported desired effects 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53

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1 2 3 Figure 3: 4,4’DMAR selfreported untoward effects; selfreported 4 comparisons with other substances; selfreported association with 5 6 other drugs; selfreported medications use to revert 4,4’DMAR 7 action. 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 36 http://mc.manuscriptcentral.com/hup Page 37 of 37 Human Psychopharmacology: Clinical and Experimental

1 2 3 4 5 Figure 4: Selfreported overall impression; harm reduction advice 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 37 http://mc.manuscriptcentral.com/hup