Report on the risk assessment of 4,4-DMAR [601069]

ISSN 1725-4493
Report on the risk assessment of 4,4′-DMAR
in the framework of the Council Decision on new
psychoactive substances
About this series
EMCDDA Risk Assessments are publications
examining the health and social risks of
individual new psychoactive substances.
The Risk Assessment Report consists of an
analysis of the scientific and law enforcement
information available on the new psychoactive
substance under scrutiny and the implications
of placing it under control. It is the outcome of
a meeting convened under the auspices of the
EMCDDA Scientific Committee.
This process is part of a three-step procedure
involving information exchange/early warning,
risk assessment and decision-making in the
framework of Council Decision 2005/387/JHA.RISK ASSESSMENTS 16
4,4′-DMAR

2 / 46
I Acknowledgements
The EMCDDA would like to thank the following for their contribution in producing this
publication:
I the members of the extended Scientific Committee of the EMCDDA; the advisers to the
Scientific Committee and the invited external experts who took part in the risk
assessment meeting;
I the Early Warning System (EWS) correspondents of the Reitox national focal points
(NFPs) and experts from their national EWS networks;
I the services within each Member State that collected the raw data for the risk
assessment;
I Europol, the European Medicines Agency (EMA) and the European Commission;
I Dr Simon Brandt for preparing the technical review on the pharmacological, toxicological,
sociological and criminological evidence and public health risks of 4,4’-DMAR;
I Dr Simon Elliott for contributing to specific sections of the technical review on 4,4’-DMAR;
I EMCDDA colleagues: Anabela Almeida, Rachel Christie, William Francis, Joanna Sekula
and Katarzyna Natoniewska, who managed the production of the publication. I Contents
3 I Foreword
4 I EMCDDA actions on monitoring and responding to new drugs
5 I EMCDDA–Europol Joint Report on 4,4′-DMAR: a summary
6 I Risk Assessment Report of a new psychoactive substance: 4,4′-DMAR
14 I Annex 1: Technical report on 4,4′-DMAR
38 I Council Decision on subjecting 4,4′-DMAR to control measures
42 I Abbreviations
44 I Participants of the risk assessment meeting
EMCDDA risk assessment team: Andrew Cunningham, Michael Evans-Brown,
Ana Gallegos and Roumen Sedefov

RISK ASSESSMENTS I 4,4′-DMAR3 / 46I Foreword
This publication presents the data and findings of the risk assessment on 4,4’-DMAR (4-methyl-5-
(4-methylphenyl)-4,5-dihydrooxazol-2-amine), carried out by the extended Scientific Committee of
the EMCDDA on 16 September 2014.
The Risk Assessment Report, which was submitted to the European Commission and the Council
of the European Union on 19 September 2014, examined the health and social risks of the drug,
information on international trafficking and the involvement of organised crime, and the potential
implications of subjecting the drug to control measures. 4,4’-DMAR is the ninth new psychoactive
substance to be risk assessed under the terms of Council Decision 2005/387/JHA.
On the basis of the Risk Assessment Report — and on the initiative of the European Commission —
on 8 October 2015, the Council decided that 4,4’-DMAR should be subject to control measures
across the Member States. This decision is the final stage of the three-step process — early
warning, risk assessment and control of new psychoactive substances — established by Council
Decision 2005/387/JHA. This legal framework allows the EU institutions and Member States to act
on all new and potentially threatening narcotic and psychotropic drugs that appear on the
European drug scene, with the EMCDDA and Europol, in collaboration with their respective
networks, playing a central role in the early detection of such substances and the harms caused by
their use — information that underpins risk assessment, and — ultimately, decision-making.
In this respect we would like to recognise the excellent work done by the networks of the EMCDDA,
Europol and the EMA — the Reitox national focal points, Europol national units and the national
competent authorities responsible for medicinal products — who played an essential role in
collecting and providing national data.
Finally, we would like to thank all the participants in the risk assessment process for the high
quality of work carried out. The resulting report is a valuable contribution at the European level,
which gives clear support to political decision-making.
Professor Dr Gerhard Bühringer
Chair , Scientific Committee of the EMCDDA
Wolfgang Götz
Director, EMCDDA

RISK ASSESSMENTS I 4,4′-DMAR4 / 46I EMCDDA actions on monitoring and responding to new drugs
The EMCDDA has been assigned a key role in the detection and assessment of new drugs
in the European Union under the terms of a Council Decision 2005/387/JHA on the
information exchange, risk-assessment and control of new psychoactive substances. It
establishes a mechanism for the rapid exchange of information on new psychoactive
substances and provides for an assessment of the risks associated with them in order to
permit the measures applicable in the Member States for the control of narcotic and
psychotropic substances to be applied also to new psychoactive substances.
The three-step process involves information exchange/early warning, risk assessment and
decision-making (see below). More detailed information can be found in the section ‘Action
on new drugs’ of the EMCDDA’s website:
www.emcdda.europa.eu/activities/action-on-new-drugs
Council Decision 2005/387/JHA of 10 May 2005 on the inf ormation exchange,
risk-assessment and contr ol of new psychoactive substances
I. Inf ormation exchange
Early-w arning system (EWS)EMCDDA–Eur opol Joint Reports
III. Decision-making Council Decisions on contr olII. Risk assessment EMCDDA Risk Assessments

RISK ASSESSMENTS I 4,4′-DMAR5 / 46I EMCDDA–Europol Joint Report on 4,4′-DMAR (4-methyl-5-
(4-methylphenyl)-4,5-dihydrooxazol-2-amine) — a summary
EMCDDA–Europol Joint Report on a new psychoactive substance: 4,4’-DMAR
(4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine) — in accordance with
Article 5 of Council Decision 2005/387/JHA on the information exchange, risk
assessment and control of new psychoactive substances
In February 2014, the EMCDDA and Europol examined the available information on a new
psychoactive substance 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine,
commonly known by the abbreviation `4,4′-DMAR’, through a joint assessment based upon
the following criteria: (1) the amount of the material seized; (2) evidence of organised crime
involvement; (3) evidence of international trafficking; (4) analogy with better-studied
compounds; (5) evidence of the potential for further (rapid) spread; and (6) evidence of
cases of serious intoxication or fatalities.
The EMCDDA and Europol agreed that the information available on 4,4′-DMAR satisfied
criteria 4, 5 and 6. The two organisations therefore concluded that sufficient information
has been accumulated to merit the production of a Joint Report on 4,4′-DMAR as
stipulated by Article 5.1 of the Decision. Accordingly, the NFPs, the Europol national units
(ENUs), the EMA and the World Health Organization (WHO) were formally asked to provide
the relevant information within six weeks from the date of the request, i.e. by 10 April 2014.
The resulting Joint Report on 4,4′-DMAR was submitted to the Council, the Commission
and the EMA on 8 May 2014. The report concluded that the health and social risks, caused
by the use of, the manufacture of, and traffic in 4,4′-DMAR, as well as the involvement of
organised crime and possible consequences of control measures, could be thoroughly
assessed through a risk assessment procedure as foreseen by Article 6 of Council
Decision 2005/387/JHA.
The full text of the Joint Report can be found at:
www.emcdda.europa.eu/publications/joint-reports/4-4-DMAR

6 / 46
act on all new narcotic and psychotropic substances (4) that
appear on the European Union drug market. The Council
Decision also provides for an assessment of the risks
associated with these new psychoactive substances so that, if
necessary, control measures can be applied in the Member
States (5).
4,4′-DMAR was first detected in a seizure by customs
authorities in the Netherlands in December 2012, and the
Early Warning System was formally notified in December
2012. Following an assessment of the available information on
4,4′-DMAR, and in accordance with Article 5 of the Council
Decision, on 8 May 2014 the EMCDDA and Europol submitted
a Joint Report on 4,4′-DMAR to the Council of the European
Union, the European Commission and the European
Medicines Agency (EMA) (6). Taking into account the
conclusion of the Joint Report, and in accordance with Article
6 of the Council Decision, on 20 June 2014 the Council
formally requested that ‘the risk assessment should be carried
out by the extended Scientific Committee of the EMCDDA and
be submitted to the Commission and the Council within
12 weeks from the date of this notification’.
In accordance with Article 6.2, the meeting to assess the risks
of 4,4′-DMAR was convened under the auspices of the
Scientific Committee of the EMCDDA with the participation of
(4) According to the definition provided by the Council Decision, ‘new
psychoactive substance’ means a new narcotic drug or a new psychotropic
drug in pure form or in a preparation; ‘new narcotic drug’ means a substance
in pure form or in a preparation that has not been scheduled under the 1961
United Nations Single Convention on Narcotic Drugs, and that may pose a
threat to public health comparable to the substances listed in Schedules I, II
or IV; ‘new psychotropic drug’ means a substance in pure form or in a
preparation that has not been scheduled under the 1971 United Nations
Convention on Psychotropic Substances, and that may pose a threat to public
health comparable to the substances listed in Schedules I, II, III or IV.
(5) In compliance with the provisions of the 1961 United Nations Single
Convention on Narcotic Drugs and the 1971 United Nations Convention on
Psychotropic Substances.
(6) EMCDDA and Europol (2014), EMCDDA–Europol Joint Report on a new
psychoactive substance: 4,4′-DMAR (4-methyl-5-(4-methylphenyl)-4,5-
dihydrooxazol-2-amine) , EMCDDA, Lisbon.I Introduction
This Risk Assessment Report presents the summary findings
and conclusions of the risk assessment carried out by the
extended Scientific Committee of the European Monitoring
Centre for Drugs and Drug Addiction (EMCDDA) on the new
psychoactive substance 4-methyl-5-(4-methylphenyl)-4,5-
dihydrooxazol-2-amine, commonly known as
4,4′-d imethyl amino rex (4,4′-DMAR) . The report has been
prepared and drafted in accordance with the conceptual
framework and the procedure set out in the risk assessment
operating guidelines (1). It is written as a stand-alone
document that presents a summary of the information
considered during the detailed analysis of the scientific and
law enforcement data available at this time. The conclusion of
the report summarises the main issues addressed and
reflects the opinions held by the members of the Scientific
Committee. A list of the information resources considered by
the Scientific Committee, including a detailed Technical report
on 4,4′-DMAR, is provided below.
The risk assessment has been undertaken in compliance with
Article 6 of Council Decision 2005/387/JHA of 10 May 2005
on the information exchange, risk assessment and control of
new psychoactive substances (2) (hereafter the ‘Council
Decision’). The Council Decision established a mechanism for
the rapid exchange of information on new psychoactive
substances (hereafter ‘Early Warning System’ (3)) that may
pose public health and social risks, including the involvement
of organised crime. The Council Decision therefore allows the
institutions of the European Union and the Member States to
(1) EMCDDA (2010), Risk assessment of new psychoactive substances:
operating guidelines , Publications Office of the European Union, Luxembourg.
(2) OJ L 127, 20.5.2005, p. 32.
(3) The information exchange mechanism laid down by the Council Decision is
operationalised as the European Union Early Warning System on New
Psychoactive Substances (‘Early Warning System’). It is operated by the
EMCDDA and Europol in partnership with the Reitox National Focal Points in
the Member States, the European Commission and the European Medicines
Agency.Risk Assessment Report of a new
psychoactive substance:
4-methyl-5-(4-methylphenyl)-
4,5-dihydrooxazol-2-amine
(4,4′-dimethylaminorex, 4,4′-DMAR)

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report7 / 46five additional experts designated by the Director of the
EMCDDA, acting on the advice of the Chairperson of the
Scientific Committee, chosen from a panel proposed by
Member States and approved by the Management Board of
the EMCDDA. The additional experts were from scientific
fields that were either not represented, or not sufficiently
represented on the Scientific Committee, and whose
contribution was necessary for a balanced and adequate
assessment of the possible risks of 4,4′-DMAR, including
health and social risks. Furthermore, two experts from the
Commission, one expert from Europol and one expert from
the European Medicines Agency (EMA) participated in the risk
assessment. The meeting took place on 16 September 2014 at
the EMCDDA in Lisbon. The risk assessment was carried out
on the basis of information provided to the Scientific
Committee by the Member States, the EMCDDA, Europol and
the EMA. A list of the extended Scientific Committee and the
other participants attending the risk assessment meeting is
included at the end of this publication.
The extended Scientific Committee considered the following
information resources during the risk assessment:
i. Technical report on 4-methyl-5-(4-methylphenyl)-4,5-
dihydrooxazol-2-amine (4,4′-dimethylaminorex, 4,4′-DMAR)
(Annex 1);
ii. EMCDDA–Europol Joint Report on a new psychoactive
substance: 4,4′-DMAR (4-methyl-5-(4-methylphenyl)-4,5-
dihydrooxazol-2-amine) ;
iii. scientific articles, official reports and grey literature, and
Internet drug discussion forums and related websites
(hereafter ‘user websites’);
iv. data from EMCDDA monitoring of Internet suppliers
(which typically appear to be manufacturers and/or
wholesalers) and retailers selling 4,4′-DMAR; v. Risk assessment of new psychoactive substances:
operating guidelines ; and
vi. Council Decision 2005/387/JHA of 10 May 2005 on the
information exchange, risk assessment and control of new
psychoactive substances.
Finally, it is important to note that this Risk Assessment
Report contains a discussion of the available information on
non-fatal intoxications and deaths associated with 4,4′-DMAR.
Such information is critical to the identification of emerging
toxicological problems associated with new psychoactive
substances within the European Union. In this context, it is
important to recognise that the capacity to detect, identify
and report these events differs both within and between
Member States. Some Member States have introduced
programmes in the past few years to strengthen these
capacities. As a result, more information is available; however,
it is likely that serious adverse events remain under-detected.
I Physical and chemical description of
4,4′-DMAR and its mechanisms of action,
including its medical value
4,4′-DMAR is a synthetic substituted oxazoline derivative
(Figure 1). 4,4′-DMAR may be considered a derivative of the
stimulants aminorex and 4-methylaminorex (4-MAR), which
are controlled under the 1971 United Nations Convention on
Psychotropic Substances. The systematic (International Union
of Pure and Applied Chemistry, IUPAC) name of 4,4′-DMAR is
4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine
FIGURE 1
The molecular structure, formula, relative molecular weight and monoisotopic mass of 4,4′-DMAR
5**
4NH2
4’NO
3’2’1’6’
5’12
3
5**
4NH2
NO
5*NH2
NO
4,4′-DMAR 4-MAR Aminorex
Molecular formula: C11H14N2O
Molecular weight: 190.25
Monoisotopic mass: 190.1106Molecular formula: C10H12N2O
Molecular weight: 176.22
Monoisotopic mass: 176.0950Molecular formula: C9H10N2O
Molecular weight: 162.19
Monoisotopic mass: 162.0793
Note: Structures of 4-MAR and aminorex are provided for comparison. Asterisk indicates chiral carbon.

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report8 / 46but other names and abbreviations are used, including
para -methyl-4-methylaminorex (Annex 1).
The presence of two chiral centres within the oxazoline ring
gives rise to four enantiomers or two (±)- cis and (±)- trans
racemates, which may have different biological properties
(Figure 2) (7). Due to additional complexities involved in the
preparation of these compounds, the enantiopure forms seem
less likely to appear on the drug market when compared to the
racemic cis and trans forms.
Detailed information on the analytical profile of 4,4′-DMAR is
provided in Annex 1. Briefly, analysis of the compound itself is
straightforward (e.g. as a powder or tablet) with suitable
equipment but the availability of analytical reference material
is important for the correct identification of the cis or trans
isomeric form. However, detection in biological fluids may
require the implementation of more sensitive techniques
coupled with appropriate chromatographic separation. A
range of positional isomers is possible, and implementation of
analytical separation techniques may be used to obtain
unambiguous differentiation. No information was provided
regarding the possible presence of the other isomers on the
drug market. There is no information on presumptive colour
tests with 4,4′-DMAR. No immunoassay field test for 4,4′-
DMAR is currently available. Analytical reference materials
facilitating the quantification of 4,4′-DMAR in biological
matrices are available.
The free base of the cis and trans isomers has been described
as colourless solids and the hydrochloride salt form is a white
(7) (±) denotes the presence of the racemic mixture and will be omitted for clarity
in the remaining text when reference is made to either cis- or trans 4,4′-DMAR
instead of (±)- cis- and (±)- trans -4,4’-DMAR, respectively.powder soluble in water. In cases where sufficient analytical
data were available from information provided about
detections (8), the presence of the cis form was indicated. It is
unknown if the trans isomers are also circulating on the drug
market.
4,4′-DMAR has typically been seized as white or coloured
powders and tablets.
Reported routes of administration for 4,4′-DMAR include nasal
insufflation, oral administration, inhalation (‘methpipe’) and, in
one of the death cases reported by Hungary, injection.
Information from user websites suggests that a range of
doses are used, depending on the route of administration;
single, typical oral ‘doses’ of between 10–60 mg were noted,
but doses up to 200 mg were also reported.
No data are available on the pharmacokinetics of 4,4′-DMAR,
and no metabolites of the substance have been identified.
Data on the pharmacology of 4,4′-DMAR is limited to recent in
vitro studies examining the monoamine transport/release
activity of cis- and trans -4,4′-DMAR (using rat brain
synaptosomes). cis-4,4′-DMAR was found to be a potent
releaser of dopamine (DA) (EC50 8.6 nM), norepinephrine (NE)
(EC50 26.9 nM) and serotonin (5-HT) (EC50 18.5 nM).
d-Amphetamine (DA: EC50 5.5 nM; NE: 8.2 nM; 5-HT: 2602
nM), aminorex (DA: EC50 9.1 nM; NE: 15.1 nM; 5-HT: 414 nM),
and cis-4-methylaminorex (DA: EC50 1.7 nM; NE: 4.8 nM; 5-HT:
53.2 nM) were used for comparison.
(8) ‘Detections’ is an all-encompassing term, which may include seizures and/or
collected and/or biological samples. Seizure means a substance available
(seized) through law enforcement activities (police, customs, border guards,
etc.). Collected samples are those that are actively collected by drug
monitoring systems (such as test purchases) for monitoring and research
purposes. Biological samples are those from human body fluids (urine, blood,
etc.) and/or specimens (tissues, hair, etc.).FIGURE 2
Molecular structures of the four possible 4,4′-DMAR enantiomers
NH2
NONH2
NONH2
NONH2
NO
(4S,5R)-4,4′-DMAR (4R,5S)-4,4′-DMAR (4S,5S)-4,4′-DMAR (4R,5R)-4,4′-DMAR
Racemic form: (±)- cis-4,4′-DMAR or (4/SR/,5/RS/)-4,4′-DMAR Racemic form: (±)- trans -4,4′-DMAR or (4/SR/,5/SR/)-4,4′-DMAR

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report9 / 46Further studies with ( S)-(+)-3,4-methylenedioxy –
methamphetamine as a comparator (DA: EC50 143 nM; NE:
98.3 nM; 5-HT: 85.0 nM) revealed that both cis-4,4′-DMAR
(DA: EC50 10.9 nM; NE: 11.8 nM; 5-HT: 17.7 nM) and trans -4,4′-
DMAR (DA: EC50 24.4 nM; NE: 31.6 nM; 5-HT: 59.9 nM) were
more potent catecholamine releasers. Of note, trans -4,4′-
DMAR appeared to act as an uptake inhibitor rather than a
substrate-type serotonin releasing agent.
Knowledge is emerging about the in vitro pharmacological
properties of 4,4′-DMAR but it is difficult to predict potential
drug interactions or contraindications. Briefly, as noted above,
the ability of both cis- and trans -4,4′-DMAR to display potent
monoamine transporter activity in vitro may be relevant when
considering potential interactions with other substances that
act on similar targets that affect dopamine, norepinephrine and
serotonin levels. For example, the use of substances including
medicinal products, known to increase 5-HT-release and/or
reuptake (such as selective serotonin reuptake inhibitors
(SSRIs), MDMA, mephedrone and cocaine) may increase the
risk of developing serotonergic toxicity (often also referred to as
serotonin syndrome). High dosage levels and/or combinations
of 4,4′-DMAR with other catecholamine releasing agents (e.g.
amphetamine-type stimulants) may lead to increasing risk of
developing psychotic symptoms and agitation, while potentially
dangerous cardiovascular effects could be produced by
excessive norepinephrine release in the periphery. However,
further studies are warranted to assess these effects in detail.
There are no animal or human study data related to the
toxicity, including median lethal dose (LD50), potential for
self-administration, nor investigations on psychological and/or
behavioural effects of 4,4′-DMAR. Self-reports available on
user websites suggest that the effects of 4,4′-DMAR include
euphoria, mental and physical stimulation, empathic effects
and changes in visual perception.
The synthesis and analytical characterisation of both cis- and
trans -4,4′-DMAR was first published in 2014 and adapted from
methods published in the scientific literature on related
aminorex derivatives. 4,4′-DMAR is available as an analytical
reference standard and for use in scientific research. The
(4S,5S)-trans -4,4′-DMAR enantiomer has been featured in
several patents related to the preparation of a range of
phospholipase A2 inhibitors. There are currently no other
indications that 4,4′-DMAR may be used for other legitimate
purposes, including as a component in industrial, cosmetic or
agricultural products.
4,4′-DMAR has no established or acknowledged medical value
or use (human or veterinary) in the European Union. There is
no marketing authorisation (existing, ongoing or suspended)
for 4,4′-DMAR in the European Union or in the Member States
that responded to the information request by the EMA that was launched under Article 5 of the Council Decision. In
addition, there is no information that 4,4′-DMAR is used for the
manufacture of a medicinal product or an active
pharmaceutical ingredient (API) of a medicinal product in the
European Union. It is important to note that the data collection
is incomplete and some countries indicated that this
information is not known. However, it should be noted that
there is no European Union database on the synthetic routes
of all registered medicinal products. Therefore, the use of
4,4′-DMAR cannot be ruled out with certainty.
I Chemical precursors that are used for the
manufacture of 4,4′-DMAR
There is currently no information regarding manufacturing
sites, the chemical precursors or the synthetic routes used for
4,4′-DMAR that has been detected on the drug market within
the European Union. The route(s) employed for the
preparation of the collected 4,4′-DMAR samples have not
been reported. The method published in the scientific
literature used 1-( p-tolyl)propan-1-one as the starting point.
This chemical is commercially available. Key intermediates
included the primary amine normephedrone, which
underwent a reduction to yield the 2-amino-1-( p-tolyl)
propan-1-ol precursor. The cyclisation carried on from that
gave the cis and trans isomers of 4,4′-DMAR. While it is
conceivable that these intermediates may be obtained from
alternative routes of synthesis, information about their
preparation associated with the seized products is not
available. It would be expected that any synthesis would
produce some impurities.
I Health risks associated with 4,4′-DMAR
I Individual health risks
The assessment of individual health risks includes
consideration of the acute and chronic toxicity of 4,4′-DMAR,
its dependence potential and its similarities to and differences
from other chemically or pharmacologically related
substances, such as 4-methylaminorex and aminorex, which
all share the ability to act as catecholamine releasers
(dopamine and noradrenaline).
It is important to note that when interpreting the information
on non-fatal intoxications and deaths reported by Member

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report10 / 46States and by user websites, individuals may have used other
pharmacologically active substances in addition to 4,4′-DMAR.
The presence of and/or interaction with other substances may
account for some of the reported effects.
The mode of use may involve the combined use (either
intentionally or unintentionally) of other drugs, especially when
encountered surreptitiously within ecstasy-type tablets or
powders offered and disguised in combination with other
substances that affect monoaminergic systems. Analysis of
various seized products has shown that the composition can
differ and the user is unlikely to be aware of the exact dose or
compound being ingested (by whatever route), which presents
an inherent risk to the individual.
One non-fatal analytically confirmed intoxication has been
reported from Poland.
A total of 31 deaths associated with 4,4′-DMAR were reported
by Hungary (eight deaths), Poland (one death) and the United
Kingdom (22 deaths). In all these cases 4,4′-DMAR was
analytically confirmed. In 23 deaths, 4,4′-DMAR was either the
cause of death (three cases) or is likely to have contributed to
death (20 cases) even in the presence of other substances; in
one of these deaths 4,4′-DMAR was the sole drug present. In
eight cases 4,4′-DMAR may have contributed to toxicity but
other substances were present that may have been more
toxicologically significant. In 27 cases other stimulants
(including cocaine, amphetamines and new psychoactive
substances such as synthetic cathinones) were also found.
Information provided by the Member States related to these
deaths noted a number of adverse effects, including: agitation,
hyperthermia, convulsions, breathing problems and cardiac
arrest.
There is no information on the psychosocial consequences of
(chronic) use of 4,4′-DMAR.
No studies have been published on the neurotoxicity,
reproductive toxicity, genotoxicity or carcinogenic potential of
single or repeated doses of 4,4′-DMAR. No studies have
examined the chronic toxicity of 4,4′-DMAR in animals or
humans.
I Public health risks
The public health risks associated with 4,4′-DMAR may be
categorised in terms of patterns of use (extent, frequency,
route of administration, etc.); availability and quality of the
drug; information, availability and levels of knowledge
amongst users; and negative health consequences. Detailed
information that would allow the public health risks associated with 4,4′-DMAR to be determined, including data on sporadic
versus chronic use, is unavailable.
In some cases, 4,4′-DMAR is being sold and consumed as a
substance in its own right, for example in the form of tablets
under the name ‘serotoni’. It has also been mis-sold on the
illicit market as ecstasy and amphetamines. Similar to other
stimulant drugs, users may combine 4,4′-DMAR with other
psychoactive substances (e.g. entactogens, stimulants and/or
depressants, including alcohol).
In September 2014 EMCDDA monitoring of Internet suppliers
and retailers identified one site offering 4,4′-DMAR for sale;
further details, including the quantities available and price,
were only available on application to the site. Based on data
available from EMCDDA monitoring, the number of Internet
shops offering this particular substance has declined. An earlier
study undertaken in April 2014 identified one Internet site
selling 4,4′-DMAR compared to 20 Internet sites selling 4-MAR.
No information has been reported on the purity of the
4,4′-DMAR that is available on the drug market. In most cases
4,4′-DMAR was reported as the only active substance, although
in about 20 % of detections it was found in combination with
other substances (predominantly stimulants). In these cases,
quantitative analyses were not available.
Since December 2012, when 4,4′-DMAR was first detected in
the Netherlands, eight additional Member States have
reported detections (Denmark, Finland, Hungary, Poland,
Romania, Sweden, France and the United Kingdom).
Where information was available about death cases, it
appears that the users did not intentionally purchase
4,4′-DMAR on the street market but had intended to buy
ecstasy tablets or powders associated with other stimulant
drugs (such as cocaine or mephedrone). The use of these
tablets and powders was associated with both home and
recreational settings.
Information obtained from user websites suggests that the
intentional purchase of 4,4′-DMAR from Internet retailers may
have been associated with ‘psychonauts’ who might have
explored this new substance in a home environment (whether
on their own or in the company of others).
As noted, the preferred route of administration appears to be
oral and nasal. Injection was also reported as the route of
administration in one of the deaths. In such instances, sharing
of needles and syringes carries the risk of transmission of
blood-borne viruses. There are no prevalence data on the use
of 4,4′-DMAR within the European Union or elsewhere, but
available information from user websites and seizures does
not suggest widespread use of the substance.

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report11 / 46I Social risks associated with 4,4′-DMAR
There is no information on the social risks associated with
4,4′-DMAR.
There is no information on whether the use of 4,4′-DMAR
affects education or career, family or other personal or social
relationships, including marginalisation.
There is a lack of data related to the social risk associated with
the distribution and trafficking of 4,4′-DMAR.
Due to a lack of data, it is not possible at this time to estimate
whether 4,4′-DMAR is associated with greater healthcare
costs than other stimulant drugs.
I Information on the level of involvement of
organised crime, seizures and/or
detections by the authorities, and the
manufacture of 4,4′-DMAR
Limited information has been provided by Member States in
relation to the involvement of organised crime in the
manufacture or trafficking of 4,4′-DMAR. Only one Member
State (Hungary) mentioned that organised crime groups are
involved in the trafficking and distribution of 4,4′-DMAR; no
other details were provided.
Seized tablets found to contain 4,4′-DMAR showed a range of
colours, markings and logos (9) consistent with ecstasy
tablets, raising the possibility that some of these were
designed to be sold as ecstasy on the illicit drug market.
The information about the small-scale production of the
related substance 4-MAR in the Netherlands in 2009
associated with a group producing other illicit substances
would suggest that the capability to manufacture 4,4′-DMAR
may exist within illicit drug-producing criminal groups in the
European Union.
The largest seizures of 4,4′-DMAR (22 kg and 70 kg) were
reported by the Netherlands. They were seized by customs
authorities and originated from outside the European Union.
(9) It is common to find markings on tablets sold as ecstasy, including popular
cultural and iconic brands often having an association with quality. I Information on any assessment of
4,4′-DMAR in the United Nations system
The World Health Organization is the specialised United
Nations agency designated for the evaluation of the medical,
scientific and public health aspects of psychoactive
substances under the 1961 Single Convention on Narcotic
Drugs and the 1971 Convention on Psychotropic Substances.
On 5 March 2014 the World Health Organization informed the
EMCDDA that 4,4′-DMAR is currently not under assessment
and has not been under assessment by the United Nations
system, and that no such assessment is planned.
I Description of the control measures that
are applicable to 4,4′-DMAR in the
Member States
4,4′-DMAR is not listed for control in the 1961 United Nations
Single Convention on Narcotic Drugs or in the 1971 United
Nations Convention on Psychotropic Substances (together
‘UN drug conventions’).
Three Member States (Denmark, Finland and Slovenia)
reported that 4,4′-DMAR is subject to control measures under
drug control legislation that is in accordance with the UN drug
conventions.
Denmark reported that on 27 May 2014 the Minister signed an
Executive Order amending the Executive Order on Euphoriant
Substances, which entered into force on 30 May 2014.
Subsequently, the substances mentioned in the Executive
Order may only be used for medical or scientific purposes.
Finland reported that 4,4′-DMAR was controlled by an
Amendment to Government Decree 543/2008, in effect from
4 August 2014.
Slovenia reported that 4,4′-DMAR was included in the Decree
on the scheduling of illicit drugs (Official Gazette RS, No.
45/2014) in July 2014.
The remaining 25 Member States, Turkey and Norway do not
control 4,4′-DMAR under drug control legislation that is in
accordance with the UN drug conventions. Of these, five
Member States (Hungary, Ireland, Poland, Romania and Spain)
and Norway reported that 4,4′-DMAR is controlled by other
legislative measures. In Hungary 4,4′-DMAR is specifically
named in Schedule C of Government Decree 66/2012 (added

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report12 / 46by ‘256/2013 (July 5) Government Regulation § 17, Annex 9’,
effective from 15 July 2013). Ireland, Poland and Romania have
legislation that prohibits the unauthorised supply of any
psychoactive substance that qualifies by conforming to certain
criteria. It was reported that national authorities may find that
4,4′-DMAR meets such criteria. Poland reported that 4,4′-DMAR
falls under the definition of a ‘substitution drug’ under the Act
amending the Act on Counteracting Drug Addiction and the Act
on State Sanitary Inspection, 2010; as such, its marketing and
production may be subject to an administrative fine.
Spain reported that ‘although there is no current specific
legislation, to our knowledge, controlling production,
commerce, imports, exports or use/consumption of this
substance and given that it may cause harmful effects to
those using it, the same way as illegal drugs do, there is
generic legislation (administrative and criminal) on health
protection which is fully applicable, if necessary’.
Norway reported that 4,4′-DMAR is subject to control
measures under medicines legislation.
Twenty Member States (Austria, Belgium, Bulgaria, Croatia,
Cyprus, the Czech Republic, Estonia, France, Germany,
Greece, Italy, Latvia, Lithuania, Luxembourg, Malta, the
Netherlands, Portugal, Slovakia, Sweden and the United
Kingdom) and Turkey reported that 4,4′-DMAR is not subject to
control measures at the national level.
I Options for control and the possible
consequences of the control measures
Under Article 9.1 of the Council Decision, the option for
control that is available at European Union level is for the
Member States to submit the new psychoactive substance
4,4′-DMAR to control measures and criminal penalties, as
provided for under their legislation, by virtue of their
obligations under the under the UN drug conventions. There
are no studies on the possible consequences of such control
measures on 4,4′-DMAR. If this option of control is pursued,
the Committee considers that the following consequences are
possible. Some of these may apply to any new psychoactive
substance.
n This control option could be expected to limit the
availability of 4,4′-DMAR and hence the further expansion
of the current open trade in this substance.
n A health consequence that might result from this control
option is the benefit brought about by the presumed
reduction in availability and use. n This control option could facilitate the detection, seizure
and monitoring of 4,4′-DMAR related to its unlawful
manufacture, trafficking and use. In so doing, it could
facilitate cooperation between the judicial authorities and
law enforcement agencies across the European Union.
n This control option would imply additional costs for the
criminal justice system, including forensic services, law
enforcement and the courts.
n This control option could lead to replacement with other
(established or new) psychoactive substances that may
also have public health consequences.
n It is difficult to predict the impact of this control option on
current or future research by the pharmaceutical or
chemical industries.
n This control option could create an illicit market in
4,4′-DMAR with the increased risk of associated criminal
activity, including organised crime. This could include
covert sales of 4,4′-DMAR on the Internet or in bricks and
mortar head shops.
n This control option could impact on both the quality/purity
and price of any 4,4′-DMAR still available on the illicit
market. The extent to which this will impact on public
health, criminality or levels of use is difficult to predict.
In order to examine the consequences of control, the
Committee wishes to note that it will be important to monitor
for the presence of 4,4′-DMAR on the market post-control,
should this control option be pursued.
Aside from the option for control under those stipulated in
Article 9.1 of the Council Decision, other options for control
may be available to Member States. These may include
restricting the importation and supply of the substance, as
some other Member States (and Norway) have already done.
I Conclusion
The new psychoactive substance 4-methyl-5-(4-
methylphenyl)-4,5-dihydrooxazol-2-amine (4,4′-DMAR)
appears to have psychostimulant properties. It has been
available on the drug market in the European Union since at
least December 2012. 4,4′-DMAR is structurally related to
4-methylaminorex (4-MAR) and aminorex, which are both
listed in the 1971 United Nations Convention on Psychotropic
Substances.
4,4′-DMAR can exist in the form of racemic cis- and trans -4,4′-
DMAR. Where isomeric differentiation has been reported, only
the cis- isomer has been detected. The potential presence of
the trans – form on the drug market cannot be excluded.

RISK ASSESSMENTS I 4,4′-DMAR Risk Assessment Report13 / 46Data on the pharmacology of 4,4′-DMAR is limited to in vitro
studies. cis-4,4′-DMAR is a potent efficacious substrate-type
releaser at DAT, NET and SERT in rat brain tissue with
comparable potency at DAT and NET to that of
d-amphetamine and aminorex. On the other hand, cis-4,4′-
DMAR exerted much more potent actions at SERT when
compared to d-amphetamine, aminorex and cis-4-MAR.
trans -4,4′-DMAR was also found to be a non-selective
catecholamine releaser but serotonin uptake inhibitor. Both
cis- and trans -4,4′-DMAR were more potent than ( S)-(+)-
MDMA) in their ability to evoke catecholamine release.
There are no data on the dependence potential and abuse
liability of 4,4′-DMAR. Although the information available does
not suggest it has been widely used, it has been associated
with 31 deaths over a period of approximately one year. This
raises the concern that if this substance were to become more
widely available and used, the implications for public health
could be significant.
The pharmacological and behavioural activities of 4,4′-DMAR
in humans have not been studied.
4,4′-DMAR has no established or acknowledged medical use
(human or veterinary) in the European Union. There are no
indications that 4,4′-DMAR may be used for any other purpose,
aside from as an analytical reference standard and in
scientific research.
4,4′-DMAR emerged on the new psychoactive substances
market where it was sold as a ‘research chemical’ by Internet
retailers, but recent data suggest this is no longer the case. In
addition, it has also been detected in tablets and powders
sold on the street market. In about 20 % of detections
4,4′-DMAR was found in combination with other psychoactive
substances (predominantly stimulants). It has been detected
in nine Member States.
One non-fatal intoxication and a total of 31 deaths associated
with 4,4′-DMAR have been reported, all of which were
analytically confirmed. In 23 deaths 4,4′-DMAR was either the
cause of death or is likely to have contributed to death (even in
presence of other substances); in one of these cases
4,4′-DMAR was the sole drug present. In eight cases
4,4′-DMAR may have contributed to toxicity but other
substances were present that may have been more
toxicologically significant. In 27 cases other stimulants
(including cocaine, amphetamines and new psychoactive
substances such as synthetic cathinones) were found.
Information provided by the Member States related to these
deaths noted a number of adverse effects, including: agitation,
hyperthermia, convulsions, breathing problems and cardiac
arrest.There are no prevalence data on the use of 4,4′-DMAR.
Information from the death cases suggests that users
unknowingly consumed 4,4′-DMAR as a result of seeking illicit
substances such as ecstasy, cathinones and cocaine. There is
no specific information on the social risks that may be related
to 4,4′-DMAR.
There is limited information to suggest the potential
involvement of organised crime in the manufacture,
distribution (trafficking) and supply of 4,4′-DMAR within the
European Union. The chemical precursors and the synthetic
routes used to manufacture the 4,4′-DMAR detected within
the European Union are unknown.
4,4′-DMAR is not listed for control in the 1961 United Nations
Single Convention on Narcotic Drugs or in the 1971 United
Nations Convention on Psychotropic Substances. It is not
undergoing assessment by the United Nations system. Three
Member States control 4,4′-DMAR under drug control
legislation, and five Member States control it under other
legislation.
Many of the questions posed by the lack of data on the risks of
4,4′-DMAR to individual health, and the absence of data on
public health and social risks, as for any new psychoactive
substance, could be answered through further research. Areas
where additional information would be important include:
prevalence and patterns of use (including targeted studies
that examine user groups and risk behaviours); market studies;
chemical profiling studies; receptor binding and functional
activity studies; metabolic pathway studies; behavioural
studies; clinical patterns of acute and chronic toxicity in
humans; the potential interaction between 4,4′-DMAR and
other substances (in particular those that affect the
monoaminergic system); the dependence and abuse potential;
and the social risks associated with its use.
The Committee notes that a decision to control 4,4′-DMAR has
the potential to bring with it both intended and unintended
consequences. Potential intended consequences include
reduced levels of availability and ultimately use. This may reduce
the health and social risks and consequences arising from the
use of 4,4′-DMAR. It is important to recognise that a potential
unintended consequence of control may be the manufacture
and availability of other substances. Although there is limited
information on the human (psycho)pharmacological effects, the
emergence of chemically analogous substances to replace
4,4′-DMAR is a possibility. The implementation of control
measures may also lead to the criminalisation of those who
continue to use this substance, with the possible attendant risks
of socio-economic stigmatisation and marginalisation. Finally,
control measures should not inhibit the gathering and
dissemination of accurate information on 4,4′-DMAR to users,
practitioners and decision-makers.

14 / 46
isomers are also available on the drug market is currently not
known.
4,4′-DMAR has been advertised under the name ‘Serotoni’ and
is available for purchase from online retailers as a ‘research
chemical’ in either powder or tablet/pellet form. It appears
that the number of Internet shops advertising this particular
substance may be declining. Information from the Member
States suggests that 4,4′-DMAR is sold as a drug in its own
right, and surreptitiously as ecstasy and other illicit drugs.
Seized tablets found to contain 4,4′-DMAR showed a range of
shapes, markings and logos (2), thus raising the likelihood that
these particular products were designed to be sold as
‘ecstasy’ tablets on the illicit drug market.
One analytically confirmed non-fatal intoxication has been
reported by Poland and 31 deaths associated with 4,4′-DMAR
have been reported by Hungary (eight deaths), Poland (one
death) and the United Kingdom (22 deaths). The deaths in
Hungary occurred between June and October 2013, the
Polish death occurred in July 2013 and those in the United
Kingdom occurred between June 2013 and June 2014. Data
on gender and age are currently available for 30 of the
decedents. Twenty-two were male (four from Hungary; one
from Poland; 17 from the United Kingdom); eight were female
(four from Hungary; four from the United Kingdom); they were
aged between 16 and 43 years. 4,4′-DMAR was detected in
post-mortem biological samples in all of the 31 deaths. With
the exception of one case, the presence of one or more
psychoactive substances (and/or their metabolites) in
post-mortem biological samples was noted.
There are no coordinated national or European population
surveys on the prevalence of 4,4′-DMAR use. There is no
information to suggest that 4,4′-DMAR has any industrial,
cosmetic or medicinal use.
(2) It is common to find markings on tablets sold as ‘ecstasy’, including those of
popular cultural and iconic brands often having an association with quality. I Summary
The substance 4-methyl-5-(4-methylphenyl)-4,5-
dihydrooxazol-2-amine (4,4′-dimethylaminorex, 4,4′-DMAR) is
a synthetic, substituted oxazoline derivative. 4,4′-DMAR is also
a derivative of 4-methylaminorex (4-MAR) and aminorex, both
of which are stimulants and controlled under the 1971 United
Nations Convention on Psychotropic Substances. Limited
information suggests that 4,4′-DMAR has stimulant-type
effects.
The detection of 4,4′-DMAR on the European drug market was
first officially notified to the European Monitoring Centre for
Drugs and Drug Addiction (EMCDDA) through the EU Early
Warning System by the Netherlands national focal point on
10 December 2012 and related to a seizure made by customs
authorities of 500 g of white powder that had arrived from
India in the previous month. Nine Member States (Denmark,
Finland, France, Hungary, the Netherlands, Poland, Romania,
Sweden and the United Kingdom) reported detections (1) of
4,4′-DMAR. This substance has typically been seized as
powders or tablets. In most cases, 4,4′-DMAR was reported as
the only active constituent, while in about 20 % of detections
it was found in combination with other substances. Most of
the Member States reported a small number of seizures;
however, in the case of the Netherlands these totalled more
than 90 kg of powder.
Chemically, 4,4′-DMAR can exist in the form of two different
racemic (±)- cis and (±)- trans mixtures or four distinct
enantiomers. In cases where sufficient analytical data were
available from collected and biological sample analyses, the
presence of the cis form was indicated. Whether the trans
(1) ‘Detections’ is an all-encompassing term and may include seizures and/or
collected and/or biological samples. Seizure means a substance available
(seized) through law enforcement activities (police, customs, border guards,
etc.). Collected samples are those that are actively collected by drug
monitoring systems (such as test purchases) for monitoring and research
purposes. Biological samples are those from human body fluids (urine, blood,
etc.) and/or specimens (tissues, hair, etc.).ANNEX 1
Technical report on 4-methyl-5-(4-
methylphenyl)-4,5-dihydrooxazol-2-amine
(4,4′-dimethylaminorex, 4,4′-DMAR)
Dr Simon Brandt

RISK ASSESSMENTS I 4,4′-DMAR15 / 46
Annex 1: Technical reportCompared to other types of new psychoactive substances
(such as the synthetic cathinones) there are limited self-
reported experiences with 4,4′-DMAR on user websites.
4,4′-DMAR appears to be generally recognised by users as a
stimulant, and is used in a range of ‘doses’. Single dosage
levels may range between 10 mg and 200 mg, depending on
the route of administration. Oral administration and nasal
insufflation are commonly reported; inhalation of the drug has
also been mentioned. In one of the deaths reported to the EU
Early Warning System the drug had been injected (the specific
route of injection was not reported). Warning messages have
been posted on user websites by users about comparatively
long-lasting effects and the potential for adverse reactions
(such as perceived serotonin toxicity), especially when taken
in combination with other substances including alcohol.
The first formal scientific investigations into the chemical,
analytical and pharmacological properties of cis- and trans –
4,4′-DMAR appeared in 2014. Monoamine transporter activity
studies in rat brain synaptosomes using d-amphetamine,
aminorex and 4-methylaminorex as control compounds,
showed that cis-4,4′-DMAR was a potent, non-selective and
fully efficacious substrate-type releaser at transporters for
dopamine (DAT), norepinephrine (NET), and serotonin (SERT).
The potency of cis-4,4′-DMAR at DAT and NET rivalled that of
other psychomotor stimulant drugs like d-amphetamine and
aminorex. However, cis-4,4′-DMAR had much more potent
actions at SERT. The trans -4,4′-DMAR isomer was also found
to be a potent releasing agent at DAT and NET while acting as an uptake blocker at SERT, thus showing a ’hybrid’ profile.
Both cis- and trans -4,4′-DMAR isomers were also more potent
than ( S)-(+)-3,4-methylenedioxymethamphetamine (( S)-(+)-
MDMA) as catecholamine releasers.
I Section A. Physical, chemical,
pharmaceutical and pharmacological
information
I A1. Physical, chemical and pharmaceutical
information
A1.1. Physical and chemical description
Chemical description and names
4-Methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine
(4,4′-DMAR) is a synthetic substituted oxazoline derivative. It
can also be classified as an analogue of 4-methylaminorex
(4-MAR) and aminorex, both of which are psychostimulants
and controlled under the 1971 United Nations Convention on
Psychotropic Substances (3). The structures of 4,4′-DMAR,
4-MAR and aminorex are provided in Figure 1.
(3) 4-MAR is listed in Schedule I and aminorex is listed in Schedule IV of the 1971
United Nations Convention on Psychotropic Substances.FIGURE 1
The molecular structure, formula, relative molecular weight and monoisotopic mass of 4,4′-DMAR
5**
4NH2
4’NO
3’2’1’6’
5’12
3
5**
4NH2
NO
5*NH2
NO
4,4′-DMAR 4-MAR Aminorex
Molecular formula: C11H14N2O
Molecular weight: 190.25
Monoisotopic mass: 190.1106Molecular formula: C10H12N2O
Molecular weight: 176.22
Monoisotopic mass: 176.0950Molecular formula: C9H10N2O
Molecular weight: 162.19
Monoisotopic mass: 162.0793
Note: Structures of 4-MAR and aminorex are provided for comparison. Asterisk indicates chiral carbon.

RISK ASSESSMENTS I 4,4′-DMAR16 / 46
Annex 1: Technical reportTABLE 1
Alternative names, codenames, street names, and
abbreviations that may be encountered for 4,4′-DMAR
4-Methyl-5-( p-tolyl)-4,5-dihydrooxazol-2-amine
4,5-Dihydro-4-methyl-5-(4-methylphenyl)-2-oxazolamine
[4-Methyl-5-( p-tolyl)-2-oxazolin-2-yl]amine
4-Methyl-5-( para -methylphenyl)-2-amino-oxazoline
para -Methyl-4-methylaminorex
p-Methyl-4-methylaminorex
4-Methylaminorex p-methyl derivative
4,4′-Dimethylaminorex
p4-DMAR
4-methyl-euphoria
4-methyl-U4Euh
4-M-4-MAR
Serotoni
ST
ST60
The systematic (International Union of Pure and Applied
Chemistry, IUPAC) name is 4-methyl-5-(4-methylphenyl)-4,5-
dihydro-1,3-oxazol-2-amine. Other commonly encountered
names, codenames, street names, and abbreviations are given
in Table 1. Chemical Abstract Service (CAS) registry numbers
are given in Table 2.TABLE 2
Chemical Abstract Service (CAS) Registry Numbers for
4,4′-DMAR
CAS Registry Numbers Variant
1445569-01-6 Form not specified
364064-08-4 (4S,5S) Free base
The words ‘euphoria’ and ‘U4Euh’, used in some of the street
names of 4,4′-DMAR (Table 1), are references to two of the
street names given to 4-methylaminorex (4-MAR) (4), a
psychostimulant encountered in the 1980s (By et al., 1989;
Cooper, 1988; Davis and Brewster, 1988; Klein et al., 1989).
Aminorex (5), i.e. the analogue without both methyl groups at
the para – and 4-position contained in 4,4′-DMAR, was briefly
available as an appetite suppressant in Europe during the late
1960s but was withdrawn from the market due to an
association with primary pulmonary hypertension (Gurtner,
1979, 1985).
The presence of two chiral centres within the oxazoline ring of
4,4′-DMAR gives rise to four enantiomers or two (±)- cis and
(±)-trans racemates, as shown in Figure 2 (6). However, it
seems unlikely that any of the enantiopure forms would
appear on the drug market, due to additional complexities
involved in their preparation.
(4) Other street names for 4-methylaminorex include: 4-MAX, McN-822 and ‘ICE’
(before this term was more frequently used for methamphetamine).
(5) 5-Phenyl-4,5-dihydro-1,3-oxazol-2-amine (aminoxafen; aminoxaphen; apiquel;
CPDD-0039; McN-742; NSC-66592; NSC-66952).
(6) (±) is used to denote the presence of the racemic mixture. For reasons of
clarity it will be omitted in the remaining text when reference is made to either
cis- or trans 4,4′-DMAR instead of (±)- cis- and (±)- trans -4,4′-DMAR,
respectively.FIGURE 2
Molecular structures of the four possible 4,4′-DMAR enantiomers
NH2
NONH2
NONH2
NONH2
NO
(4S,5R)-4,4′-DMAR (4R,5S)-4,4′-DMAR (4S,5S)-4,4′-DMAR (4R,5R)-4,4′-DMAR
Racemic form: (±)- cis-4,4′-DMAR or (4/SR/,5/RS/)-4,4′-DMAR Racemic form: (±)- trans -4,4′-DMAR or (4/SR/,5/SR/)-4,4′-DMAR

RISK ASSESSMENTS I 4,4′-DMAR17 / 46
Annex 1: Technical reportIdentification and analytical profile
An extensive analytical characterisation and preparation of
both cis- and trans -4,4′-DMAR racemates has recently been
reported (Brandt et al., 2014). These included 1H and 13C
nuclear magnetic resonance spectroscopy (NMR), electron-
and chemical ionisation (EI/CI), electrospray (ESI) triple
quadrupole and high-resolution mass spectrometry, Fourier
transform infrared spectroscopy (FTIR), ultraviolet-visible
spectroscopy, gas (GC)- and liquid chromatography (LC) and
X-ray crystallography. The differentiation of cis and trans
racemates may be facilitated by implementation of FTIR, NMR
or adequate separation techniques. Chiral resolution of all four
enantiomers may be obtained from derivatisation and
synthesis or separation using appropriate preparatory
stationary phases.
Analysis by EI-MS revealed the presence of key fragments at
m/z 190 (M•+), 175, 146, 119, 91, 70 (base peak) and m/z 43,
respectively. The EI spectra of both racemates are identical as
expected. Collision-induced dissociation of the protonated
molecule [M+H]+ at m/z 191 under ESI-MS/MS conditions
gave key product ions at m/z 148 (base peak, depending on
collision energy), 131, 116, 105, 91 and 56. Challenges (e.g.
peak broadening or artificially induced isomerisation) may be
encountered during characterisation by GC-MS.
Differentiation between cis- and trans -4,4′-DMAR may also be
obtained by NMR analysis:
cis-4,4′-DMAR free base: 1H NMR (CDCl3) δ 7.20 (d, J = 7.8 Hz,
2 H, Ar H), 7.12 (d, J = 7.8 Hz, 2 H, Ar H), 5.74 (d, J = 8.7 Hz,
H-5), 4.41 (dq, J = 8.7, 6.8 Hz, H-4), 2.38 (s, 3 H, Ar-CH3) and
0.84 (d, J = 6.8 Hz, 3 H, CH3); 13C NMR (CDCl3) δ 160.90 (C-2),
138.30 (Ar-C), 131.71 (Ar-C), 129.04 (Ar-CH), 125.85 (Ar-CH),
85.59 (C-5), 59.50 (C-4), 21.07 (Ar-CH3) and 17.59 (CH3).
trans -4,4′-DMAR free base: 1H NMR (CDCl3) δ 7.23 (m, 4 H, Ar
H), 5.08 (d, J = 7.7 Hz, 1 H, H-5), 4.05 (dq, J = 7.7, 6.2 Hz, 1 H,
H-4), 2.38 (s, 3 H, Ar-CH3) and 1.40 (d, J = 6.2 Hz, 3 H, CH3);
13C NMR (CDCl3) δ 160.49 (C-2), 139.34 (Ar-C), 133.84 (Ar-C),
129.76 (Ar-CH), 126.31 (Ar-CH), 90.25 (C-5), 63.71 (C-4),
21.03 (Ar-CH3) and 20.08 (CH3).
The direct analysis of 4,4′-DMAR (e.g. as a powder, tablet or in
liquid form) can be carried out using standard techniques.
Detection in biological fluids may require the implementation
of more sensitive technology including single or tandem mass-
spectrometry, in cases where low concentrations may be
encountered in the sample matrices. Detection methods such
as GC-MS, HPLC and/or LC-MS have been applied and
published as part of a recent case series relating to 18 deaths
associated with 4,4′-DMAR in the United Kingdom (Cosbey et al., 2014) (7) (Section D1.2.3). Data from these deaths and
others reported by the United Kingdom, and data from a
collected sample purchased from an Internet retailer (8),
indicate that it is the cis form of 4,4′-DMAR on the drug market
(Brandt et al., 2014). Information about the presence and
prevalence of its trans counterpart is unavailable but the
potential for its appearance cannot be excluded. The
implementation of analytical procedures applied to low
concentration sample matrices able to differentiate between
the cis and the trans forms requires access to suitable
reference material. It is worth noting that the preparation and
analytical characterisation of the 3,4-dimethylaminorex
isomers (both methyl groups present on the oxazoline ring)
has been described in the literature (Noggle et al., 1992) and
analytical differentiation from 4,4′-DMAR would not be
expected to cause difficulties (9). One of the trans enantiomers
appears to have been discussed on an online forum and called
‘4-DMAR’ and ‘Direx’ (10).
There is no information on presumptive colour tests with
4,4′-DMAR.
As of August 2014 there is no immunoassay field test for
4,4′-DMAR. Data on cross-reactivity with commercially
available urine immunoassay tests used for standard drugs
of abuse are currently unavailable. Information related to a
death reported by Poland (Section D1.2.3) noted that
preliminary screening with an ELISA test pointed towards the
presence of amphetamine, methamphetamine and
benzodiazepines. Blood analysis carried out by LC-MS/MS,
however, confirmed the presence of 4,4’-DMAR,
N-ethylbuphedrone (NEB), midazolam and α-hydroxy-
midazolam instead.
The REACH registered substances database hosted by the
European Chemicals Agency (ECHA) was searched using the
CAS Registry Numbers listed above and no information was
found.
Physical description
The free base of both cis and trans forms have been described
as colourless solids with melting points of 136–138°C
(cis-4,4′-DMAR) and 101–103°C ( trans -4,4′-DMAR). The
melting point of a recrystallised cis-4,4′-DMAR hydrochloride
(7) These 18 deaths are included in those that have been reported by the United
Kingdom.
(8) The term ‘Internet retailer’ is used in this report to describe Internet shops that
offer new psychoactive substances for sale, often advertising them as ‘legal
highs’ and ‘research chemicals’.
(9) Another isomer 3’,4-DMAR (‘Serotoni 2.0’), i.e. carrying the methyl group in
the meta- instead of the para-position, has been mentioned on the Internet
(serotoni.info, 2014), although data on this compound seem to be unavailable
at present.
(10) www.drugs-forum.com/forum/showthread.php?t=83865 (August 2014).

RISK ASSESSMENTS I 4,4′-DMAR18 / 46
Annex 1: Technical reportsalt sample obtained from an Internet retailer was given as
163–165°C (ethyl acetate/methanol) (Brandt et al., 2014)
(Section C). The cis-4,4′-DMAR HCl salt is a white crystalline
powder and soluble in water. Commercially available analytical
reference standards for all enantiomers and both racemic
forms are expected to be available in the near future. Section
A1.2 provides a description of the physical forms reported by
Member States.
Methods and chemical precursors used for the
manufacture of 4,4′-DMAR
Information is not available regarding manufacturing sites,
precursors or synthetic methods used for 4,4′-DMAR
detected on the drug market in Europe. A report on the
syntheses of cis- and trans -4,4′-DMAR was first published in
2014 and is outlined in Figure 3 (Brandt et al., 2014).
Important key intermediates in this reaction are the
cathinone (normephedrone) intermediate and the reduced
alcohol. Conversion to cis- and trans -4,4′-DMAR was
achieved with either cyanogen bromide (BrCN) or potassium cyanate (KOCN), respectively, based on a number of
variations published in the earlier literature related to the
chemistry of aminorex-type compounds (e.g. Fodor and
Koczka, 1952; Poos et al., 1963; Rodriguez and Allred, 2005).
Interestingly, the idea of synthesising 4,4′-DMAR following
established aminorex-type chemistry was discussed on an
online forum at least as early as 2003, although it is unclear
whether this was ever taken further to the preparatory
stage (11).
Typical impurities encountered in seized and collected
samples
Detailed information is not available with regard to route-
specific by-products produced during the synthesis of
4,4′-DMAR. In addition, there are no quantitative data currently
available on the impurities detected in seized and collected
samples. Analyses of seized powder and tablet materials
(Section C) have revealed mixtures with other new
psychoactive substances such as pentedrone (12),
methcathinone, MPPP (13), alpha-PVP (14), bk-MPA (15),
(11) For example, some of the files for ‘The Hive’ forum (defunct since 2004) have
been archived (‘Hive filez’). The contemplation on a potential 4,4′-DMAR synthesis
was posted on 05.04.2003 (post no. 424141). The Hive was an online discussion
forum for individuals interested in the practical synthesis of psychoactive
substances, their use, and the related social and policy issues.
(12) 2-(Methylamino)-1-phenylpentan-1-one
(13) 1-(4-Methylphenyl)-2-(pyrrolidin-1-yl)propan-1-one
(14) 1-Phenyl-2-(pyrrolidin-1-yl)pentan-1-one
(15) 2-(Methylamino)-1-(thiophen-2-yl)propan-1-oneFIGURE 3
Synthesis of cis- and trans -4,4′-DMAR, as reported by Brandt et al., 2014
O O O
NO
OBr
O O
NH2NH2Br2Na
NaBH4NOO
EtOH1 HCI
4,4’-DMAR
(±)-cis
4,4’-DMAR
(±)-tr ansBrCN
KOCN

RISK ASSESSMENTS I 4,4′-DMAR19 / 46
Annex 1: Technical reportPVP (16), mephedrone (17), UR-144 (18), RH-34 (19),
ethylphenidate and 5-APDB (20). In one case from Hungary,
the presence of creatine monohydrate was reported to be
present as a cutting agent. In the majority of cases 4,4′-DMAR
was the main constituent.
A1.2. Physical/pharmaceutical form
Reports of seizures and collected samples have noted that
4,4′-DMAR has typically been obtained in the form of powders
and tablets (EMCDDA and Europol, 2014). The majority of
powders are white, but other samples have also been
described as pale yellow, pink, green and blue coloured
powders. Tablets have been observed in various colours and
shapes, some of which bore logos such as ‘Playboy’, ‘Heart’,
‘Mitsubishi’, ‘Star’, ‘Transformers’, ‘Cherries’ and ‘Cross’. The
analysis of a collected sample of 5 g of 4,4′-DMAR in the form
of a white powder sample obtained from an Internet retailer
confirmed the presence of the cis form as a hydrochloride salt
(Brandt et al., 2014). Section C provides further details of the
seized and the collected sample of 4,4′-DMAR.
A1.3. Route of administration and dosage
Information provided by the Member States and from user
websites (21) suggests that common routes of administration
for 4,4′-DMAR are nasal insufflation and oral
administration (22). In the latter case, consumption of tablets
and ‘bombing’, i.e. the practice of wrapping powder in
cigarette paper (or similar) prior to swallowing, have been
noted. One self-reported experience from a user website
notes the inhalation of 20 mg 4,4′-DMAR, which appeared to
be based on the application of heat to what was described as
a ‘methpipe’. In this instance this was preceded by oral
administration of 40 mg (23). In one of the deaths reported by
Hungary to the EU Early Warning System the drug had been
injected (specific route of injection not reported). The physical
forms detected in seizures and the collected sample would
appear to be consistent with these routes of administration
(Section C).
Limited information on user websites suggests that a range of
‘doses’ are used. ‘Low doses’ were reported as 10–15 mg
insufflated or 10–25 mg oral, with a ‘high oral dose’ being
(16) Presumed to refer to alpha-PVP, i.e. 1-phenyl-2-(pyrrolidin-1-yl)pentan-1-one
(17) 2-(Methylamino)-1-(4-methylphenyl)propan-1-one
(18) (1-Pentyl-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl)methanone
(19) 3-{2-[(2-Methoxybenzyl)amino]ethyl}quinazoline-2,4(1H,3H)-dione
(20) 1-(2,3-Dihydro-1-benzofuran-5-yl)propan-2-amine
(21) The term ‘user website’ is used to describe Internet drug discussion forums
and related websites.
(22) www.chemsrus.com (2014); www.drugs-forum.com (2014); serotoni.info
(2014); www.bluelight.org (2014); www.ukchemicalresearch.org (2014).
(23) www.zoklet.net/bbs/showthread.php?t=289735 (15 August 2014).reported as 120 mg (24). Another site reported the ‘dosage’
(not further described) as 30–100 mg (25). Oral ‘doses’ of
between 60 and 200 mg and 65 mg insufflation have also
been mentioned, in addition to dosage levels of ‘around
360 mg over the course of around 4–5 hrs’ (26).
Information from Member States, particularly in relation to the
deaths associated with 4,4′DMAR, and from user websites (27)
suggests that 4,4′-DMAR may be used on its own or in
combination with other psychoactive substances.
I A2. Pharmacology, including pharmacodynamics and
pharmacokinetics
Pharmacodynamics
While a number of nonclinical studies have been published
on the psychostimulant-like properties of 4-methylminorex
(e.g. Ashby et al., 1995; Batsche et al., 1994; Bunker et al.,
1990; Glennon and Misenheimer, 1990; Goodman, 1990;
Hanson et al., 1992; Hanson et al., 1999; Kankaanpää et al.,
2002; Mansbach et al., 1990; Meririnne et al., 2005;
Roszkowski and Kelley, 1963; Russell et al., 1995; Yelnosky
and Katz, 1963; Young and Glennon, 1993, 1998), data on
4,4′-DMAR are more limited due to its recent emergence on
the drug market.
Recent in vitro investigations on the monoamine transporter
activity of cis-4,4′-DMAR using rat brain synaptosomes
(Baumann et al., 2012, Rothman et al., 2003) revealed a
robust ability to induce release of dopamine, noradrenaline
and serotonin at the dopamine transporter (DAT),
noradrenaline transporter (NET) and serotonin transporter
(SERT), respectively (Brandt et al., 2014). d-Amphetamine,
aminorex and cis-4-MAR (4-methylaminorex) were used as
control compounds. The determination of dose-response
curves (Figure 4) and potency values (expressed as half
maximal effective concentrations, EC50, Table 3) revealed
potent releasing activity of all compounds at DAT.
Considerable potency values were also obtained for NET while
activity at SERT varied more than 100-fold across the four
substances, with (±)- cis-4,4′-DMAR exhibiting the highest
potency at releasing serotonin (EC50 = 18.5 ± 2.8 nM). These
results suggested that cis-4,4′-DMAR is a potent efficacious
releaser at DAT, NET and SERT in rat brain tissue with
comparable potency at DAT and NET to that of
(24) www.drugs-forum.com/forum/showthread.php?t=216908 (April 2014).
(25) serotoni.info (April 2014).
(26) www.ukchemicalresearch.org/Thread-Serotoni-Powder-Serotonin-
Syndrome-and-Stimulant-Psychosis (April 2014) and www.chemsrus.com/
forum/6-stimulants/7358-serotoni?limit=10&start=40 (April 2014).
(27) www.drugs-forum.com/forum/showthread.php?t=216908 (April 2014).

RISK ASSESSMENTS I 4,4′-DMAR20 / 46
Annex 1: Technical reportd-amphetamine and aminorex. Table 3 also shows that the
potency of cis-4,4′-DMAR to release catecholamines was
lower than that observed for cis-4-MAR. On the other hand, cis-4,4′-DMAR exerted much more potent actions at SERT
when compared to d-amphetamine, aminorex and cis-4-MAR
(Brandt et al., 2014).FIGURE 4
Dose-response effects of d-amphetamine, aminorex, cis-4-MAR and cis-4,4′-DMAR in evoking release from DAT, NET and
SERT in rat brain synaptosomes (Brandt et al., 2014)
TABLE 3
Stimulation of release in rat brain synaptosomes (a)
DrugRelease at DAT
EC50 (nM) Release at NET
EC50 (nM) Release at SERT
EC50 (nM) DAT/SERT ratio (b)
d-Amphetamine 5.5 ± 0.5 8.2 ± 1.6 2602 ± 494 473
Aminorex 9.1 ± 0.9 15.1 ± 3.5 414 ± 78 45
cis-4-MAR (c) 1.7 ± 0.2 4.8 ± 0.9 53.2 ± 6.8 31
cis-4,4′-DMAR 8.6 ± 1.1 26.9 ± 5.9 18.5 ± 2.8 2
(a) Table modified from Brandt et al., 2014. DAT: dopamine transporter; NET: norepinephrine transporter; SERT: serotonin transporter; [3H]-1-methyl-4-phenylpyridinium
([3H]MPP+) used as radiolabeled substrate for DAT and NET and [3H]5-HT (serotonin) for SERT. Data expressed as mean ± SD for N = 3–4 experiments performed
in triplicate.
(b) DAT/SERT ratio calculated by (EC50 at DAT)-1/ (EC50 at SERT)-1; higher value = greater DAT selectivity.
(c) cis-4-Methylaminorex racemate.

RISK ASSESSMENTS I 4,4′-DMAR21 / 46
Annex 1: Technical reportA comparison between cis- and trans -4,4′-DMAR under
identical assay conditions, i.e. monoamine transporter release
using rat brain synaptosomes, showed that trans -4,4′-DMAR
was also a fully efficacious releasing agent at DAT and NET,
although slightly less potent than the cis isomer (Figure 5,
Table 4). The key difference between the cis and trans isomers
was observed at SERT where the trans isomer acted as an uptake blocker, which indicated that trans -4,4′-DMAR
displayed a ‘hybrid’ profile of a catecholamine releaser with
5-HT uptake blocking properties (McLaughlin et al., 2014). The
extent to which some pharmacological overlaps between
4,4-DMAR and MDMA might translate to
psychopharmacological overlap in humans has not been
investigated.FIGURE 5
Dose-response effects of cis- and trans -4,4′-DMAR compared to ( S)-(+)-3,4-methylenedioxymethamphetamine
((S)-(+)-MDMA)) in evoking release from DAT, NET and SERT in rat brain synaptosomes (McLaughlin et al., 2014)
TABLE 4
Stimulation of release in rat brain synaptosomes (a)
DrugRelease at
DAT EC50 (nM) Release at
NET EC50 (nM)Release at
SERT EC50 (nM)DAT/SERT ratio (c)
(S)-(+)-MDMA (b) 143 ± 16 98.3 ± 15.0 85.0 ± 13.3 0.6
cis-4,4′-DMAR 10.9 ± 0.7 11.8 ± 2.0 17.7 ± 2.3 1.6
trans -4,4′-DMAR 24.4 ± 2.7 31.6 ± 4.6 59.9 ± 17.2 (d) 2.5
(a) Table modified from McLaughlin et al. (2014). DAT: dopamine transporter; NET: norepinephrine transporter; SERT: serotonin transporter; [3H]-1-methyl-4-
phenylpyridinium ([3H]MPP+) used as radiolabeled substrate for DAT and NET and [3H]5-HT (serotonin) for SERT. Data expressed as mean ± SD for N = 3-4
experiments performed in triplicate.
(b) (S)-(+)-3,4-Methylenedioxymethamphetamine.
(c) DAT/SERT ratio calculated by (EC50 at DAT)-1/ (EC50 at SERT)-1; higher value = greater DAT selectivity.
(d) Fully efficacious as an uptake blocker at SERT and indication that it may not act as substrate-type releaser.
Note: In this follow-up study to Brandt et al., 2014, (S)-(+)-3,4-methylenedioxymethamphetamine ((S)-(+)-MDMA)) was employed as the control, which reflected the fact
that this substance is a well-characterised, non-selective substrate-type releaser (Baumann et al., 2007), which was consistent with the data reported in Figure 5 and
Table 4. All three test compounds were shown to be non-selective, with DAT/SERT ratios of 0.6 for MDMA, 1.6 for cis-4,4′-DMAR and 2.5 for trans-4,4′-DMAR (McLaugh –
lin et al., 2014).

RISK ASSESSMENTS I 4,4′-DMAR22 / 46
Annex 1: Technical reportPharmacokinetics
Published pharmacokinetic data for 4,4′-DMAR in animals or
humans are not available. A report published on the in vivo
metabolism of 4-methylaminorex (4-MAR) in Sprague-Dawley
rats following a single oral and intravenous administration
(10 mg/kg) revealed the identification of three metabolites in
urine. In addition to the parent molecule 4-MAR (major
constituent), the oxazolidinone derivative (oxidative
deamination), para -hydroxylated 4-MAR and norephedrine
were detected (Henderson et al., 1995). It is conceivable
therefore that in the case of 4,4′-DMAR detection of the
ring-opened, para -methylated norephedrine-type counterpart
may also be expected. It is worth noting that this latter analyte
has also been detected as a mephedrone metabolite (Meyer et
al., 2010). More recent work published on the conversion of all
stereoisomers of cis- and trans -4-MAR to their norephedrine/
norpseudoephedrine metabolites (adult male Han/Wistar rats;
intravenous, intraperitoneal, and oral routes of administration
at 2 mg/kg) confirmed differences in pharmacokinetic
parameters and tissue distribution. Interestingly, the trans –
(4R,5R)-isomer differed significantly from the remaining
isomers as it displayed high oral bioavailability and more than a
3-fold longer elimination half-life (Meririnne et al., 2004).
Details on the potential for stereospecific pharmacokinetics
related to 4,4′-DMAR have not been described.
Interactions with other substances
Given the current lack of data, it is difficult to predict with
accuracy any potential drug interactions or contraindications.
Briefly, as noted above, the ability of both cis-and trans -4,4′-
DMAR to display potent monoamine transporter activity in vitro
may be relevant when considering potential interactions with
other substances that act on similar targets that effect
dopamine, norepinephrine and serotonin levels. For example,
the use of substances including medicinal products, known to
increase 5-HT-release and/or reuptake (such as selective
serotonin reuptake inhibitors (SSRIs), MDMA and cocaine) may
increase the risk of developing serotonergic toxicity (often also
referred to as serotonin syndrome), the symptoms of which can
include tachycardia, hypertension, hyperthermia, muscle
rigidity and convulsions (Boyer and Shannon, 2005; Isbister et
al., 2007; Sternbach, 1991). High dosage levels and/or
combinations of 4,4′-DMAR with other amphetamine-type
substances, e.g. catecholamine releasing agents, may lead to
increasing risk of developing psychotic symptoms and agitation,
while potentially dangerous cardiovascular effects could be
produced by excessive norepinephrine release in the periphery.
The available information related to deaths reported to the EU
Early Warning System indicated that in 30 of the 31 deaths one
or more psychoactive substances (predominantly stimulants)
were present in the analysed biological samples (Section D).I A3. Psychological and behavioural effects
There are no published studies assessing the psychological
and/or behavioural effects of 4,4′-DMAR. Self-reported
experiences of 4,4′-DMAR use from user websites note a
range of effects that include: euphoria, change in visual
perception, mental and physical stimulation, empathic effects,
nausea, agitation and anxiety.
It is important to note that it is not possible to confirm the
specific substance(s) used, nor the purity, dose/amount, etc.,
in respect of self-reported cases. Analyses of new
psychoactive substances or products containing them that
are sold on the drug market have shown that the composition
can differ from that claimed by the retailer, and can vary over
geographical areas and time. Furthermore, the users’ physical
characteristics and health status are rarely reported. In
addition, the information on user websites should be regarded
as illustrative only and not taken as representative of users of
4,4′-DMAR in general. Consequently, these reports should be
interpreted with caution.
I A4. Legitimate uses of the product
4,4′-DMAR and the corresponding enantiomers are expected
to become available as an analytical reference standard for
use in scientific research and forensic applications. A range of
isomers and closely related derivatives/analogues (28) have
been featured in a number of patent applications filed by the
pharmaceutical company Hoffmann-La Roche, which describe
their uses as ligands for the trace amine associated receptor 1
(TAAR1) related to a range of potential applications to central
nervous system disorders (Decoret et al., 2010; Galley et al.,
2008). The (4 S,5S)-trans -4,4′-DMAR enantiomer has been
featured in several patents related to the preparation of a
range of phospholipase A2 inhibitors (e.g. Takagi et al., 2003),
thus giving rise to the associated CAS number shown in Table
2. The remaining three forms have not yet been encountered in
the existing scientific and patent literature.
There are currently no other indications that 4,4′-DMAR may
be used for other legitimate purposes. There are no known
uses of 4,4′-DMAR as a component in industrial, cosmetic or
agricultural products. There is no information that 4,4′-DMAR
is currently used in the manufacture of a medicinal product in
the European Union. However, in the absence of a European
Union database on the synthetic routes of all medicinal
products this information cannot be confirmed. There is no
marketing authorisation (existing, ongoing or suspended) for
4,4′-DMAR neither in the European Union nor in the Member
(28) Example: (4 R)-5,5-dimethyl-4-phenyl-4,5-dihydro-1,3-oxazol-2-amine or
4-ethyl-4-phenyl-4,5-dihydro-1,3-oxazol-2-amine.

RISK ASSESSMENTS I 4,4′-DMAR23 / 46
Annex 1: Technical reportStates that responded to the request for information from the
European Medicines Agency (EMCDDA and Europol, 2014).
I Section B. Dependence and abuse potential
I B1. Animal in vivo and in vitro data
There are no published animal studies that have examined the
dependence and abuse potential of 4,4′-DMAR.
I B2. Human data
There are no published studies investigating the dependence
and/or abuse potential of 4,4′-DMAR in humans. In addition,
there are no published case reports describing the potential
for dependence or abuse potential for 4,4′-DMAR. No
information is available from drug treatment agencies about
the dependence and abuse potential. It was not possible to
ascertain the dependence-producing properties or the abuse
potential associated with 4,4′-DMAR from user websites.
I Section C. Prevalence of use
I Information from seizures, collected and biological
samples
The first official notification of 4,4′-DMAR to the EU Early
Warning System was on 10 December 2012 by the
Netherlands national focal point. The Reporting Form details a
seizure of 500 g of white powder seized on 19 November 2012
by customs authorities at Amsterdam. The importation was
noted to have arrived from India.
Information provided to Europol
Europol received reports from four Member states with
regards to level of production, distribution and trafficking.
Finland reported a small seizure that took place on 23 May
2013. It was a confiscation of two tablets containing 4,4′-
DMAR (customs authorities in Helsinki), which arrived in a
parcel coming from the United Kingdom. This seizure was also
reported by the Finnish national focal point to the EMCDDA on
2 July 2013. Hungary reported that 4,4′-DMAR had been used to make
tablets, and that this tableting was presumably carried out in
Hungary, but further details were not available. A total of 78
seizures were reported by police between June and October
2013. 4,4′-DMAR was seized as tablets (41 seizures) and in
powder form (37 seizures). Quantities of tablets seized ranged
from a single tablet to 900 tablets, with three seizures above
100 tablets and a total of 1 852 tablets seized. Quantities of
seized powder ranged from 0.01 g to 193 g, with 27 seizures
below 1 g and a total weight of 337 g seized. In most cases,
4,4′-DMAR was reported as the only active substance; in
about 20 % of detections it was found in combination with
other substances (predominantly stimulants), including
pentedrone (eight cases, two of which also contained PVP or
alpha-PVP) and mephedrone (one case), RH-34 (two cases),
5-APDB (one case), bk-MPA (one case), ethylphenidate (one
case), the synthetic cannabinoid receptor agonist UR-144 (one
case) and the common cutting agent creatine monohydrate
(one case). In a separate case, 4,4′-DMAR was found in
combination with four cathinones (methcathinone, MPPP,
pentedrone and alpha-PVP) (see footnotes in Section A1.1).
The EMCDDA received the same information from the
Hungarian national focal point. In the majority of cases
powdered samples were white, but the presence of pink,
green and blue powder has also been reported. Tablets have
been observed to appear in different colours and in specific
shapes, or bearing specific logos such as ‘Playboy’, ‘Heart’,
‘Mitsubishi’, ‘Star’ and ‘Transformers’ (EMCDDA and Europol,
2014). According to Hungarian authorities, the number of
seizures related to 4,4′-DMAR significantly decreased after the
introduction of control measures.
As noted above, the Netherlands reported the first detection
of 4,4′-DMAR in December 2012. It was a shipment of a parcel
containing 500 g of pale yellow powder. The package was sent
from India and was destined for a well-known wholesaler of
new psychoactive substances in the Netherlands. On the
shipping documents, the substance was declared (and
misspelled) as: ‘4,5-DYHYDRO-4-METHYL -5(-4-
METHYLPHENYL)-2-OXAZOLAM’.
In Romania, 4,4′-DMAR was identified in 14 seizures. In 13
cases the substance was seized as a white powder, having a
total weight of 564.23 g. In the other case five tablets
containing 4,4′-DMAR were seized. It was also stated that in all
cases the substance was shipped from abroad and intended
for so-called ‘own consumption’. No further details were
provided. The Romanian national focal point also reported 13
of these seizures to the EMCDDA.
No reports were received that indicated licit or illicit production
of 4,4′-DMAR in any of the Member States, Turkey and Norway.
However, the Netherlands reported an incident from 2009
related to the production of 4-MAR, which is closely related to

RISK ASSESSMENTS I 4,4′-DMAR24 / 46
Annex 1: Technical report4,4′-DMAR. The case involved the discovery of an illicit
production site. The forensic examination of the site, conducted
by the Netherlands Forensic Institute, demonstrated that both
MDMA via the bromosafrole route and piperonyl methyl ketone
PMK (3,4-methylenedioxy phenylpropan-2-one) via the Wacker
method had been produced. Several different types of
substances, chemicals and recipes were also found. In addition,
two white plastic trays were found containing a few hundred
grams of white powder which was found to contain 4-MAR.
Moreover, according to the forensic examination, the 4-MAR
was produced at the site. While not related to 4,4′-DMAR, this
case would suggest that the capability to manufacture
4,4′-DMAR may exist within illicit drug-producing criminal
groups in the European Union.
Information provided to the EMCDDA
The EMCDDA has received reports of detections of
4,4′-DMAR (29) from nine Member States (Denmark, Finland,
France, Hungary, the Netherlands, Poland, Romania, Sweden
and the United Kingdom).
4,4′-DMAR has typically been seized as powders or tablets. In
most cases, 4,4′-DMAR was reported as the only active
substance; in about 20 % of detections it was found in
combination with other substances (Section A1.2).
Hungary reported the majority of seizures (78 cases). While
the remaining Member States reported a small number of
seizures, it is worth noting that in the case of the Netherlands
these totalled more than 90 kg of powder (30). Sweden and
Denmark reported that 4,4′DMAR was detected in seizures of
pink/red/purple octagonal tablets bearing the markings ‘ST’
on one side and ‘60’ on the other. According to user websites,
the ‘ST’ refers to ‘Serotoni’ and ‘60’ refers to a 60 mg dose.
Denmark reported a seizure by customs of two purple
octagonal tablets bearing the markings ‘ST/60’ in May 2013.
Finland reported a seizure by customs of two red tablets in
May 2013, and Hungary reported a total of 78 seizures.
France reported the identification of 4,4′-DMAR in a white
powder (604 mg), which appears to have been sold as MDMA;
the investigation is ongoing.
(29) ‘Detections’ is an all-encompassing term and may include seizures and/or
collected and/or biological samples. Seizure means a substance available
(seized) through law enforcement activities (police, customs, border guards,
etc.). Collected samples are those that are actively collected by drug
monitoring systems (such as test purchases) for monitoring and research
purposes. Biological samples are those from human body fluids (urine,
blood, etc.) and/or specimens (tissues, hair, etc.).
(30) This figure was given as ‘260 kilograms’ in the Joint Report (EMCDDA and
Europol, 2014); however, the Netherlands national focal point informed the
EMCDDA that the correct total quantity seized was around 90 kg.As noted, the Netherlands reported the first seizure of
4,4′-DMAR to the EMCDDA in December 2012. In addition,
during 2013 customs authorities in the Netherlands detected
a further 90 kg (30) of 4,4′-DMAR. No further details are
available regarding these cases.
Romania reported 13 seizures made by police in 2013. These
comprised one case of five tablets and 12 cases involving
powder (amounting to a total of 558.84 g).
Sweden reported two seizures made by customs between
June and December 2013 — a seizure of 10 g of white
powder, and a seizure of two (red or red/pink) octagonal
tablets bearing the markings ‘ST’ on one side and ‘60’ on the
other.
The United Kingdom reported a number of seizures by police
in Northern Ireland, amounting to 608 tablets. This included
three cases of 357 tablets that bore a ‘cherries’ logo and one
case of 91 tablets that bore a ‘cross’ logo (EMCDDA and
Europol, 2014). In addition, five plastic bags containing white
powder (a total amount of 1.81 g) were recovered by police in
Scotland in April 2014 during the investigation of a death
related to 4,4′-DMAR (Case 29, Table 5). It was reported that
the deceased had not intended to obtain 4,4′-DMAR, but
instead they had possibly wished to obtain mephedrone or
ketamine.
Biological samples
Three Member States (Hungary, Poland and the United
Kingdom) reported detections of 4,4′-DMAR in biological
samples from 31 deaths (eight in Hungary; one in Poland;
22 in the United Kingdom) and one non-fatal intoxication
(Poland) (Section D1.2.3). Hungary also reported the
detection of 4,4′-DMAR in biological samples taken in 18
criminal cases related to the suspected consumption of
narcotics.
Collected samples
The United Kingdom reported the detection of 4,4′-DMAR in a
collected sample. A 5 g sample was purchased for GBP 60
(EUR 73) from an Internet retailer (31) in March 2014. The
product was a white powder, labelled ‘5 g’ ‘4,4′-DMAR’
(EMCDDA and Europol, 2014). Analysis revealed the presence
of cis-4,4′-DMAR as the hydrochloride salt. No additional
constituents were detected (Brandt et al., 2014).
(31) www.chems-direct.org. It is noteworthy that the price of 4,4′-DMAR has
dropped on this website since purchase in late March 2014 (e.g. as of 19 April
2014: EUR 40 for 5  g). At the time of writing (21 August 2014), the website
was ‘unavailable due to maintenance’.

RISK ASSESSMENTS I 4,4′-DMAR25 / 46
Annex 1: Technical reportAvailability from Internet retailers
EMCDDA monitoring in May 2014 of Internet retailers selling
4,4′-DMAR identified two retailers that were selling the
substance. The first site marketed 4,4′-DMAR as a ‘research
chemical’. It was advertised in powder form only, with
quantities ranging from 500 mg (EUR 18.10) to 100 g
(EUR 220). All quantities above 500 mg appeared to be
offered with large price discounts ranging from 55–80 %
depending on the quantity purchased. This retailer was the
same site from which the collected sample of 4,4′-DMAR was
obtained (reported by the United Kingdom). The second site
offered 4,4′-DMAR in powder form; further details, including
on the quantities available and price, were only available on
application to the site. Four retailers were identified who
appear to have discontinued the sale of 4,4′-DMAR; the
reasons for the apparent discontinuation of the sale of this
substance were not provided. An earlier study undertaken in
April 2014 identified one Internet site selling 4,4′-DMAR with
similar reduction in price per gram with increasing purchase
quantities (Nizar et al., 2014). This study identified 20 Internet
sites selling 4-MAR. Based on this data it would appear that
the availability of 4,4′-DMAR from Internet retailers is limited.
Prevalence of use
There are currently no coordinated national or European
surveys on the prevalence of use of 4,4′-DMAR in the general
population or in targeted populations. Further, neither the
European School Survey Project on Alcohol and Other Drugs
(ESPAD) nor other school/college/university surveys have
investigated or reported on 4,4′-DMAR use. Information from
seizures and deaths (Section D1.2.3) reported by the Member
States suggests that in some cases 4,4′-DMAR is sold as
ecstasy and other illicit drugs, although the extent of this is
unknown.
Information from poison information services
The National Poisons Information Service in the United
Kingdom, which provides information on the number of
accesses to information held on its online poisons information
database TOXBASE® and details of telephone enquiries made
to the service by health professionals, reported eight accesses
to TOXBASE® between 12 February and the end of June 2014,
which indicates that the need for access to information with
regards to this particular substance has been limited (32).
(32) There have been two telephone enquiries involving the use of a product
termed ‘Euphoria’ and its involvement in adverse reactions (including
agitation and pyrexia). As noted in Section A1.1, the term ‘Euphoria’ was used
as a street name for 4-methylaminorex. Further information, for example
analytical confirmation or whether ‘euphoria’ was a branded product sold as
a new psychoactive substance, is unavailable. I Section D. Health risks
I D1. Acute health effects
D1.1. Animal data
No studies were identified that have investigated the adverse
events and acute toxicity of 4,4′-DMAR in animal models.
D1.2. Human data
No clinical studies were identified that have examined the
adverse events and acute toxicity of 4,4′-DMAR in humans.
D1.2.1. User reports
There are few self-reported user experiences on user
websites that discuss the subjective effects of 4,4′-DMAR (33),
including adverse effects. The number of posts that describe
detailed experiences with the substance is more limited, as
compared to more established psychostimulants and
‘research chemicals’. There is a need to interpret these user
reports with caution since there was no analytical
confirmation of the substances used (see caveat in Section
A3). In addition, some of the users describe taking other
drugs prior to or with 4,4′-DMAR.
The onset is described as being noticed within 10 to 60
minutes, although it appears to take longer in some
individuals, thus possibly leading to re-dosing while waiting
for the initial effects to be noticed (34). Effects appear to last
several hours (35,36) and increases in heart rate and body
temperature have been noted (37). One user who reported
having taken alcohol and an unspecified ‘triple re-uptake
inhibitor’ prior to using 4,4′-DMAR noted increased heart
rate, increased body temperature, jaw clenching, facial
spasms, sweating, stimulation, psychosis and
hallucinations (38).
The French national focal point provided information that
noted recommendations from users on French language user
(33) For example, ukchemicalresearch.org, 2014; drugs-forum.com, 2014;
chemsrus.com, 2014.
(34) www.chemsrus.com/forum/14-trip-reports/37810-serotoni-repeated-
dosing-familiar-feel (21 August 2014).
(35) www.drugs-forum.com/forum/showthread.php?t=216908 (August 2014).
(36) www.zoklet.net/bbs/showthread.php?t=289735 (August 2014).
(37) www.bluelight.org/vb/threads/676724-4-4-Dimethylaminorex-(4-5-dihydro-
4-methyl-5-(4-methylphenyl)-2-Oxazolamine) (15 August 2014).
(38) www.ukchemicalresearch.org/Thread-Serotoni-Powder-Serotonin-
Syndrome-and-Stimulant-Psychosis (August 2014).

RISK ASSESSMENTS I 4,4′-DMAR26 / 46
Annex 1: Technical reportwebsites to avoid ‘any other products and specifically
serotoninergic [ sic] products at least 4 days before and after
tacking [ sic] product’. It was also noted that users who may
have developed tolerance to stimulants may require longer
time periods before noticing the effects (> 1.5 hours). The
‘comedown’ period has been described to be long lasting, up
to 12 hours. Undesired after-effects were perceived to be less
demanding than those experienced with MDMA if appropriate
dosage regimes were followed.
D1.2.2. 4,4′-DMAR associated acute toxicity
Since October 2013 a total of 32 serious adverse events (39)
associated with 4,4′-DMAR have been reported to the EU Early
Warning System. Of the 32 cases, one was a non-fatal
intoxication and 31 were deaths. The presence of 4,4′-DMAR
was analytically confirmed in all 32 cases.
Poland reported the preliminary details of a non-fatal
intoxication, which occurred in September 2013. A 16-year-old
female was admitted to hospital with suspicion of intoxication
with ‘legal highs’. Based on information from witnesses, she
had been smoking an unknown herbal mixture after which she
felt ill, collapsed and vomited. On admission to hospital the
patient was in a generally fair condition, with verbal contact,
dilated pupils, blood pressure of 110/70 and heart rate of
89 bpm. The next day alarming symptoms were observed (not
further described). A blood sample (further details were not
reported) was collected 24 hours after admission and found
to contain 0.448 mg/L 4,4′-DMAR. The investigation is
currently ongoing.
Information provided by Member States related to 4,4′-DMAR
associated deaths (also involving other substances) note a
number of adverse effects, including: agitation, hyperthermia,
convulsions, breathing problems and cardiac arrest (Section
D1.2.3).
D1.2.3. 4,4′-DMAR associated deaths
A total of 31 deaths associated with 4,4′-DMAR were reported
by Hungary (eight deaths), Poland (one death) and the United
Kingdom (22 deaths) (40). The deaths in Hungary occurred
(39) Serious adverse event means any adverse event associated with the
consumption of a new psychoactive substance in a human that: results in
death; is life-threatening; requires hospitalisation; results in persistent or
significant disability or incapacity; consists of a congenital anomaly or birth
defect; or is an important medical event that may not be immediately
life-threatening or result in death or hospitalisation but may jeopardise the
patient or may require intervention to prevent one of the other outcomes
listed above should also be considered serious. Examples of such events are
intensive treatment in an emergency room; convulsions that do not result in
hospitalisation; or the development of substance dependency or substance
abuse. This definition was adapted from the guidelines of ICH (1994).
(40) Eighteen of the deaths from the United Kingdom have been formally
published as a case series to alert the scientific community about the
presence of 4,4′-DMAR on the illicit drug market (Cosbey, et al., 2014).between June and October 2013, the Polish death in July
2013 and those in the United Kingdom between June 2013
and June 2014. The cause of death has not yet been reported
for most of the cases. Table 5 provides the available details on
these cases.
Data on gender and age were available for 30 of the
decedents. Twenty-two were males aged between 18 and 41
(four from Hungary; the deceased from Poland; 17 from the
United Kingdom) and eight were females aged between 16
and 43 years (four from Hungary; four from the United
Kingdom).
4,4′-DMAR was detected in post-mortem biological samples
in all 31 deaths. 4,4′-DMAR was quantified in 26 of the
deaths, with concentrations ranging from less than
0.02 mg/L to 18.68 mg/L in blood, and from 5.93 mg/L to
43.49 mg/L in urine. In all apart from one case, other
stimulants (including cocaine, amphetamines and new
psychoactive substances such as synthetic cathinones) were
also found (Table 5).
In an attempt to evaluate the toxicological significance of
4,4′-DMAR in the deaths reported, an assessment of the
following evidence was considered in each case: presence
and concentration (and pharmacological nature) of 4,4′-DMAR;
presence and concentration (and pharmacological nature) of
other drugs present (including alcohol); circumstances of
death; pathological findings at post-mortem, and cited cause
of death. This allowed categorisation of the significance of
4,4′-DMAR in the deaths as being of low significance
(i.e. alternative cause of death), medium significance
(i.e. 4,4′-DMAR may have contributed to toxicity/death but
other drugs present may have been more toxicologically
significant) or high significance (i.e. 4,4′-DMAR was cited as
the cause of death or was assessed to have been likely to
contribute to toxicity/death even in the presence of other
drugs). In order to highlight potential interactions or
contributing toxicology, the other substances found in the
cases were characterised.
The results of this assessment concluded that in 23 deaths
4,4′-DMAR was either the cause of death (three cases) or is
likely to have contributed to death (20 cases) even in the
presence of other substances; in one of these deaths
4,4′-DMAR was the sole drug present. In eight deaths
4,4′-DMAR may have contributed to toxicity but other
substances were present that may have been more
toxicologically significant. In 27 cases other stimulants
(including cocaine, amphetamines and new psychoactive
substances such as synthetic cathinones) were found.

RISK ASSESSMENTS I 4,4′-DMAR27 / 46
Annex 1: Technical reportTABLE 5
Deaths associated with 4,4′-DMAR reported to the EU Early Warning System
Case MSDate of
deathAge Sex Matrix4,4′-DMAR
concentrationOther substances detected and
concentration (where available)Adverse events/autopsy findings Additional information reported
1 HU June
201325 M Bloodf
Urine1.158 mg/L
43.493 mg/L7-Amino-clonazepam 0.1405 mg/L
alpha-PVP 0.0056 mg/L
Pentedrone 0.0274 mg/L
7-Amino-clonazepam 0.0961 mg/L
alpha-PVP 0.0908 mg/L
Clonazepam 0.0137 mg/L
4-MEC 6.522 mg/L
Pentedrone 15.276 mg/LHigh body temperature, huge bleeding
in the muscles.No information on route of administration;
however, ‘there was no pin-prick’.
2 HU June
201325 F Bloodf 0.0427 mg/L Amphetamine 0.4918 mg/L
alpha-PVP 0.2357 mg/L
Midazolam 0.2374 mg/LHigh body temperature, huge bleeding
in the muscles, and organs.
Confusion, disorientation,
unconsciousness, perspiration.Injected, use about 3pm, 12 hours later died
in the hospital.
3 HU June
201318 M Bloodu + (no
quantitation)Mephedrone (no quantitation)
MDMA (no quantitation)
Pentedrone (no quantitation)Myoclonus, unconsciousness, body
temperature: 42.9°C, internal bleeding
(oral, intestinal), cardial and
respiratorical arrest. Autopsy: large
brain oedema, diffuse internal
bleeding, bleeding in lungs, dilatation
of the right ventricle and atrium. Went out, did not go home. His parents found
him on the street, in poor condition.
Ambulance took him to the hospital, he died
the next morning.
4 HU Aug 2013 43 F Bloodf
Urine2.055 mg/L
5.928 mg/LMephedrone 0.5723 mg/L
alpha-PVP 0.014 mg/L
Alprazolam 0.1124 mg/L
Mephedrone 0.3215 mg/L
alpha-PVP 0.0056 mg/L
Alprazolam 0.0534 mg/L
OH-Alprazolam 0.027 mg/L— She was found at home, had died 2–3 days
before. No information on route of
administration; however, ‘there was no
pin-prick’.
5 HU Sept
201320 F Bloodf
Urine3.565 mg/L
32.945 mg/LAlprazolam 0.0951 mg/L
alpha-PVP 0.0296 mg/L
Pentedrone 0.1730 mg/L
THC-COOH 0.0127 mg/L
Pentedrone 44.544 mg/L
Amphetamine 0.353 mg/L
alpha-PVP 0.0844 mg/L
Alprazolam 0.0167 mg/L— She died after a party. No information on
route of administration; however, ‘there was
no pin-prick’.
6 HU Oct 2013 18 F Bloodu + (no
quantitation)MDA 0.0251 mg/L
MDMA 0.1989 mg/LAgitation, sweat, pale. 41.2°C
temperature, glucose 1.7 mmol/L.
Autopsy: brain oedema, bleeding and
oedema in the lungs, ‘shock’ kidneys.She consumed drugs with her friend in the
afternoon. Parents took her to the hospital,
after one hour she died. (Arrived: 23:05, died:
00:04.)

RISK ASSESSMENTS I 4,4′-DMAR28 / 46
Annex 1: Technical reportCase MSDate of
deathAge Sex Matrix4,4′-DMAR
concentrationOther substances detected and
concentration (where available)Adverse events/autopsy findings Additional information reported
7 HU Oct 2013 27 M Bloodu
Urine+ (no
quantitation)
+ (no
quantitation)MDA 0.04 mg/L
MDMA 0.8863 mg/L
Mephedrone 0.0363 mg/L
MDA (no quantitation)
MDMA (no quantitation)
Mephedrone (no quantitation)Mild brain oedema, shock, in the heart
right atrial and ventricular dilatation,
intestinal bleeding.He consumed drugs with his friends at 18:30,
died the next morning.
8 HU Oct 2013 37 M Bloodu + (concentration
to be confirmed)MDA (concentration to be confirmed)
MDMA (concentration to be
confirmed)Autopsy: cardiomyopathy, brain
oedema, pulmonary oedema, tonsillar
herniation, emollient brain tissue—
9 PL July 2013 34 M Bloodu 0.679 mg/L N-Ethylbuphedrone 0.341 mg/L
Midazolam 0.052 mg/L
alpha-hydroxymidazolam 0.035 mg/LAdmitted to hospital deeply
unconscious, breathing on his own,
with no reaction to sensory
stimulation, fixed dilated pupils,
increased muscle tonus, muscle
tremor, spasm of the jaw muscles,
bruising around lips and ears, blood
pressure 70/30 and pulse 140. Patient
was intubated and gastric lavage was
performed. Patient died of cardiac
arrest. Resuscitation was ineffective.Male was found unconscious and with
seizures in his room at 3.00 p.m. He had
been seen the previous evening. In his room,
a number of empty packages were found
with the following labels: NEB (5 packages),
3,4 DMMC (2 packages), pentedrone (6
packages), MDAI (1 package), 5-APB (1
package), bufedrone (3 packages), Eth-Cat (4
packages) , MDEC (1 package), 3-MMC (1
package), IGNITE (10 packages), 4-FMA (1
package), MXE (1 package), ethylphenidate (2
packages), alpha-PVP (1 package) and 4,4
DMAR (1 package).
10 UK Jun 2013 36 M Bloodf 0.66 mg/L Benzoylecognine 0.97 mg/L
Cocaine <0.05 mg/L
Codeine <0.02 mg/L
Tetra/levamisole (unconfirmed)— —
11 UK Jun 2013 25 M Bloodf 0.9 mg/L 4-MEC 0.05 mg/L
MDMA 0.82 mg/L
MDA
PMMA 0.11 mg/L
PMA
THC-COOH— Drinking heavily, took ‘methadrone’,
continued drinking, took 2 ‘ecstasy’ tabs
immediately felt unwell, agitated.
Unresponsive 1 hour later.
12 UK Jun 2013 33 M Bloodf 0.28 mg/L Benzoylecognine 0.04 mg/L — Believed to have taken ‘cocaine and ecstasy’.
Deceased had taken ‘speckled cherries
tablets’ orally. Cerebral oedema at post
mortem, suspected to have taken drugs at
14:30, found unconscious the following day
at 07:30, died in hospital the day after at
10:30.
13 UK Jun 2013 27 M Bloodf 0.7 mg/L Benzoylecognine 0.36 mg/L
MDMA 0.19 mg/L
MDA
Mirtazapine (a low level)
Indications of low level of cocaine— 4,4′-DMAR detected with cocaine on nasal
swabs. Found dead on arrival of ambulance
service, tablets and powder found when
house searched.

RISK ASSESSMENTS I 4,4′-DMAR29 / 46
Annex 1: Technical reportCase MSDate of
deathAge Sex Matrix4,4′-DMAR
concentrationOther substances detected and
concentration (where available)Adverse events/autopsy findings Additional information reported
14 UK Jul 2013 29 M Bloodf <0.02 mg/L PMA 0.09 mg/L
Diazepam plus metabolite 0.14 mg/L
THC-COOH
Indications of lidocaineHe appeared ‘wiped out’, was agitated
and overheating, began foaming at
mouth.Friend purchased 10 x speckled cherries for
£50, two weeks prior from an unknown male
in a bar. Socialising with friends at his flat
drinking alcohol, taking ‘E’ ‘speckled cherry’,
witness describes him taking 3 x ‘speckled
cherry’ E tabs over the course of the evening.
15 UK Jul 2013 40 M Bloodf 1.25 mg/L MDMA 0.02 mg/L
Diazepam 0.05 mg/L
THC-COOH— Consumed alcohol, ecstasy and cannabis,
found dead the next day, nothing at post
mortem.
16 UK Aug 2013 41 M Bloodf 3.13 mg/L MDMA 0.3 mg/L
MDA
Citalopram 0.42 mg/L Epileptic type seizure prior to death. Deceased had taken ‘speckled cherries
tablets’. Alcoholic, heavy intake prior to death,
epileptic type seizure prior to death, tablets
at scene.
17 UK Aug 2013 18 F Bloodf 2.1 mg/L bk-MDMA 0.84 mg/L
4-MEC 0.72 mg/L
FMC
THC-COOH (low level)— Deceased had taken ‘speckled cherries
tablets’. Died at home following a house
party (same location) after consuming an
unknown quantity of ecstasy tablets and
‘meth’, tablets described as grey with cherry
logo, witnesses speculate she consumed
2–3 tablets.
18 UK Aug 2013 19 F Bloodf
Bloodu
(ante
mortem)~0.85 mg/L
1.8 mg/L4-MMC ~0.045 mg/L
4-MMC <0.01 mg/L
4-MEC <0.01 mg/L
bk-MDMA <0.01 mg/L— Collapsed at a party, suspected overdose,
taken to hospital unconscious and later died.
Witnesses described her ‘consuming ecstasy
and snorting “meth”’.
19 UK Aug 2013 20 M Bloodf 1.6 mg/L 4-MEC 1.68 mg/L
bk-MDMA 0.26 mg/L
4-MMC (low level)
Diazepam (low level)
THC-COOH
Indications FMCSuffered seizure. Deceased had taken ‘speckled cross tablet’.
Suffered seizure and died, unidentified
tablets and 9.36 g of powder was seized at
the scene. Powder contained 4-MEC,
bk-MDMA, fmc? (no quantification). Unclear if
this powder was linked to the deceased as
more than one person was present in the
house. 4,4′-DMAR and 4-MMC detected on
nasal swabs taken post-mortem.
20 UK Sep 2013 21 M Bloodf 0.21 mg/L 4-MMC 0.02 mg/L
4-MEC 0.1 mg/L
bk-MDMA 0.07 mg/L
Diazepam 0.03 mg/L
THC-COOH
AmiodaroneAgitated state, sweating profusely,
and had problems breathing.Alcohol, one or two ecstasy tablets, speckled
cherry possibly green, ‘methadrone’ had
been consumed. Taken to hospital (arrived
18:57), after taken ill at a house party.
Agitated state, sweating profusely, and had
problems breathing, deteriorated rapidly,
pronounced dead 23:10. Had been partying
for the previous two/three days.

RISK ASSESSMENTS I 4,4′-DMAR30 / 46
Annex 1: Technical reportCase MSDate of
deathAge Sex Matrix4,4′-DMAR
concentrationOther substances detected and
concentration (where available)Adverse events/autopsy findings Additional information reported
21 UK Sep 2013 31 M Bloodf 1.72 mg/L Benzoylecognine 0.55 mg/L
Indications of low levels of cocaine
and desmethyldiazepamCardiac arrest. Drinking and taking drugs (ecstasy and
cocaine, 4 x ‘blue’) in his home with two
friends in the morning, became unwell at
11:00, unresponsive when paramedics
attended, taken to hospital, suffered cardiac
arrest, and died at 12:24. Two witnesses also
admitted to hospital, one said they had all
taken drugs and deceased had taken 4
‘blues’ in one go.
22 UK Nov 2013 21 M Bloodf 1.75 mg/L bk-MDMA 0.14 mg/L
4-MEC 0.06 mg/L
4-MMC 0.04 mg/L
THC-COOH18:00: sweating, paranoid thoughts;
midnight: sweating profusely,
convulsion, cardiac arrest.No previous history of drug abuse. Thought to
have taken e tabs. Mirtazapine prescribed,
atropine and adrenaline administered.
23 UK Nov 2013 16 F Bloodf 1.1 mg/L Indications of diazepam (low level)
Lidocaine
Amiodarone
Methylprednisolone?Cardiac arrest. Cardiac arrest while out with friends. PMH
asthma.
24 UK Dec 2013 30 M Bloodf <0.02 mg/L Olanzapine 0.66 mg/L
Diazepam plus metabolite 0.41 mg/L
Codeine 0.13 mg/L
Paracetamol 11.1 mg/L
Indications pregabalin— History of drug misuse, overdoses and
mental illness.
25 UK Dec 2013 33 M Bloodf 1.01 mg/L 4-MEC (low level)
bk-MDMA 0.22 mg/L
Diazepam plus metabolite (low level)
THC-COOH— Thought to have taken ‘plant food’.
26 UK Dec 2013 — — Bloodf 1.72 mg/L THC-COOH
BAC 53 mg%
UAC 87 mg%— Found dead in bed, had been drinking
heavily, history of drug abuse including
ecstasy.
27 UK Dec 2013 41 M Bloodf 3.75 mg/L 4-MEC 0.53 mg/L
MDMA 0.72 mg/L
MDA
THC-COOH
Quetiapine (a low level)Shaking all over, sweating, having a fit,
hands stuck open with fingers
squeezing together like claws.Call to ambulance service reported a male
taking ecstasy and going into cardiac arrest.
At the time of his death he was hosting a
party, a large quantity of drugs were allegedly
available, ‘cocaine, speckled Rolex ecstasy
tablets, magic and cannabis’ and alcohol.
Severe heart disease at post mortem.
28 UK Feb 2014 35 M Bloodf 3.5 mg/L bk-MDMA 0.33 mg/L
4-MEC 0.16 mg/L
FMC 0.11 mg/L
Procyclidine 0.11 mg/L
Diazepam 0.06 mg/L
Desmethyldiazepam 0.09 mg/L
THC-COOHFitting, unconscious and breathing. Taking ecstasy tablets and legal highs, ‘taking
cocaine and ecstasy’, ‘fitting, unconscious
and breathing’ when ambulance called at
approx. 03:13, police and ambulance arrived
03:21, deceased. Other person present taken
to hospital described as critical.

RISK ASSESSMENTS I 4,4′-DMAR31 / 46
Annex 1: Technical reportCase MSDate of
deathAge Sex Matrix4,4′-DMAR
concentrationOther substances detected and
concentration (where available)Adverse events/autopsy findings Additional information reported
29 UK April 2014 19 F Blood ~1mg/L
(cis-isomer
confirmed) (no
certified
reference
material so not
reported
quantitatively)None detected Became agitated and collapsed, high
temperature (38.9oC)Deceased believed she had taken ‘MCAT’
(mephedrone). CPR performed by friends at
the scene until paramedics took over.
Witnesses uncooperative with police
regarding drug use.
cis-4,4′-DMAR was stated as the cause of
death.
30 UK June
201429 M Bloodf 1.68 mg/L MDMA 0.69 mg/L Ethylphenidate (low
conc.), cocaine (low conc.)Significant body stiffness was
observed.Collapsed in garden and
believed to have taken ‘Miaow’ (note: name
often associated with mephedrone).
Cause of death was reported as MDMA and
4,4′-DMAR toxicity.
31 UK June
201427 M Bloodf 18.68 mg/L Mephedrone 15.73 mg/L
Cocaine 0.46 mg/L
Benzoylecognine > 2mg/L Levamisole
(low conc.)
Hydroxyzine (low conc.)Reported to be twitchy and sweating.
Significant body rigidity was observed.Collapsed and believed to have taken
cocaine.
Cause of death reported as cocaine,
mephedrone and 4,4′-DMAR toxicity.
Key:
MS: Member State; HU: Hungary; PL: Poland; UK: United Kingdom; M: male; F: female; Bloodf: femoral blood sample; Bloodu: site of blood sample unspecified; –: not reported.

RISK ASSESSMENTS I 4,4′-DMAR32 / 46
Annex 1: Technical reportI D2. Chronic health effects
D2.1. Animal data
There are no published studies investigating the chronic
health effects of 4,4′-DMAR in animals.
D2.2. Human data
There are no published studies investigating the chronic
health effects of 4,4′-DMAR in humans.
I D3. Factors affecting public health risks
D3.1. Availability and quality of the new psychoactive
substance on the market
4,4′-DMAR is sold as a drug in its own right and offered for sale
by Internet retailers and in both retail and wholesale
quantities. It has been sold as a ‘research chemical’ and in
octagonal tablets with the markings ‘ST’ and ‘60’ called
‘Serotoni’. In comparison to many other more commonly
advertised new psychoactive substances or ‘research
chemicals’, it also appears that the number of Internet retailers
that offer this particular substance is limited (Section C).
Information from seizures and deaths associated with
4,4′-DMAR reported by Member States indicates that
4,4′-DMAR has also been sold as ecstasy and other illicit
drugs. Seized street tablets found to contain 4,4′-DMAR
showed a range of markings and logos (41), raising the
likelihood that these particular products were designed to be
sold as ‘ecstasy’ tablets on the illicit drug market.
D3.2. Availability of information, degree of knowledge
and perceptions amongst users concerning the
psychoactive substance and its effects
Relative to other more commonly advertised new
psychoactive substances or ‘research chemicals’, there
appears to be limited information on popular user websites
regarding the effects and potential health/adverse effects
related to the use of 4,4′-DMAR (Section D1.2.1). At the time of
writing (42), no entry in the ‘Erowid Experience Vaults’ (43)
(41) It is common to find markings on tablets sold as ‘ecstasy’ including those of
popular cultural and iconic brands often having an association with quality.
(42) 15 August 2014.
(43) Users have the opportunity to submit their experiences and ‘trip reports’ to this
drug information website: www.erowid.org/experiences/exp_front.shtml .could be identified. The users and forum discussion
participants appear to be generally aware of the stimulant-
type (wanted and unwanted) effects of this substance.
D3.3. Characteristics and behaviour of users
No studies were identified that have examined the
characteristics and behaviour of users of 4,4′-DMAR. There are
self-reported user experiences where individuals have posted
their experiences with the drug on user websites. In cases
where 4,4′-DMAR is sold surreptitiously as part of ‘ecstasy’-
type tablet formulations or other illicit drugs, it appears likely
that these may be taken within environments that may extend
beyond home use, such as clubbing situations, etc.
Information from the United Kingdom relating to deaths
associated with 4,4′-DMAR indicated a pattern of use to be
‘house party type environment, in combination with other
drugs, such as cocaine, “ecstasy” type drugs, substituted
cathinones, diazepam and cannabis’.
D3.4. Nature and extent of health consequence
The limited information on the acute health effects of
4,4′-DMAR was discussed in Section D1.2. There is insufficient
information in the reported deaths where 4,4′-DMAR has been
detected to discuss in detail the circumstances of these cases
and the potential impact on road traffic accidents or
psychological functioning.
D3.5. Long-term consequences of use
As noted in Sections D2.1 and D2.2, there are no animal or
human data on the chronic health effects of 4,4′-DMAR use.
D3.6. Conditions under which the new psychoactive
substance is obtained and used, including context-
related effects and risks
As noted, it appears that the sourcing and use of 4,4′-DMAR
can be related to either individuals attempting to source the
drug itself from online sources, for example as a ‘research
chemical’. In other cases it has been sold/provided
surreptitiously as ecstasy or other illicit drugs. It is likely that
4,4′-DMAR is used in the same environments as other
stimulant-type drugs. This would be typically (but not
restricted to) home environments (Section D3.3),
discotheques/nightclubs and outdoor music festivals.

RISK ASSESSMENTS I 4,4′-DMAR33 / 46
Annex 1: Technical reportI Section E. Social Risks
I E1. Individual social risks
No data are available to determine the impact of 4,4′-DMAR in
this area.
I E2. Possible effects on direct social environment
No data are available to determine the impact of 4,4′-DMAR in
this area.
I E3. Possible effects on society as a whole
No data are available to determine the impact of 4,4′-DMAR in
this area.
I E4. Economic costs
No data are available to determine the impact of 4,4′-DMAR in
this area.
I E5. Possible effects related to the cultural context, for
example marginalisation
No data are available to determine the impact of 4,4′-DMAR in
this area.
I E6. Possible appeal of the new psychoactive
substance to specific population groups within the
general population
No data are available to determine the possible appeal of
4,4′-DMAR to specific population groups within the general
population.
I Section F. Involvement of organised crime
I F1. Evidence that criminal groups are systematically
involved in production, trafficking and distribution for
financial gain
Limited information is available from the Member States in
relation to the involvement of organised crime in the
manufacture or trafficking of 4,4′-DMAR. According to the Hungarian authorities, organised crime
groups are involved in the trafficking and distribution of
4,4′-DMAR; no other details were provided.
The information about the small-scale production of the
related substance 4-MAR in the Netherlands in 2009 would
suggest that the capability to manufacture 4,4′-DMAR may
exist within illicit drug-producing criminal groups in the
European Union.
I F2. Impact on the production, trafficking and
distribution of other substances, including existing
psychoactive substances as well as new psychoactive
substances
Based on the information available it does not appear that the
production, trafficking and distribution of 4,4′-DMAR impacts
on other existing psychoactive substances or new
psychoactive substances.
I F3. Evidence of the same groups of people being
involved in different types of crime
No information has been received by Europol of evidence of
the same groups of people being involved in different types of
crime in connection with 4,4′-DMAR.
I F4. Impact of violence from criminal groups on society
as a whole or on social groups or local communities
(public order and safety)
No information has been received by Europol on incidents of
violence in connection with 4,4′-DMAR.
I F5. Evidence of money laundering practices, or
impact of organised crime on other socioeconomic
factors in society
No information has been received by Europol on incidents of
money laundering or the impact of organised crime on other
socioeconomic factors in society in connection with 4,4′-
DMAR.
I F6. Economic costs and consequences (evasion of
taxes or duties, costs to the judicial system)
No data are available to determine the impact of 4,4′-DMAR in
this area.

RISK ASSESSMENTS I 4,4′-DMAR34 / 46
Annex 1: Technical reportI F7. Use of violence between or within criminal groups
No information has been received by Europol on incidents of
violence in connection with 4,4′-DMAR.
I F8. Evidence of strategies to prevent prosecution, for
example through corruption or intimidation
No information has been received by Europol on strategies to
prevent prosecution in connection with 4,4′-DMAR.

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RISK ASSESSMENTS I 4,4′-DMAR38 / 46I Council Decision
COUNCIL IMPLEMENTING DECISION (EU) 2015/1873 of 8 October 2015 on subjecting
4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4′-DMAR) and 1-cyclohexyl-
4-(1,2-diphenylethyl)piperazine (MT-45) to control measures
THE COUNCIL OF THE EUROPEAN UNION,
Having regard to the Treaty on the Functioning of the European Union,
Having regard to Council Decision 2005/387/JHA of 10 May 2005 on the information
exchange, risk-assessment and control of new psychoactive substances (1), and in
particular Article 8(3) thereof,
Having regard to the proposal of the European Commission,
Having regard to the opinion of the European Parliament,
Whereas:
(1) A Risk Assessment Report on the new psychoactive substance 4-methyl-5-(4-
methylphenyl)-4,5-dihydrooxazol-2- amine (4,4′-DMAR) was drawn up in accordance with
Article 6 of Decision 2005/387/JHA by a special session of the extended Scientific
Committee of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA),
and was subsequently submitted to the Commission and to the Council on 19 September
2014.
(2) 4,4′-DMAR is a synthetic substituted oxazoline derivative. It is a derivative of aminorex
and 4-methylaminorex (4-MAR), two synthetic stimulants controlled under the 1971 United
Nations Convention on Psychotropic Substances.
(3) 4,4′-DMAR has been available on the drugs market in the Union since at least
December 2012 and was notified to the Early Warning System in December 2012. Nine
Member States have reported detections as a result of seizures of the substance, mainly in
the form of white or coloured powders and tablets, as well as biological and collected
samples.
(4) 4,4′-DMAR emerged on the new psychoactive substances market as a ‘research
chemical’ sold by internet retailers, and it is now available on the street market. 4,4′-DMAR
is being sold and consumed as a substance on its own, but it has also been mis-sold on
the illicit market as ecstasy and amphetamines.
(5) There have been 31 deaths associated with 4,4′-DMAR registered in three Member
States, between June 2013 and June 2014. In most cases, 4,4′-DMAR was either the
cause of death or, together with other substances, is likely to have contributed to death.
One Member State has reported a case of non-fatal intoxication.
(6) There are no studies on the toxicity of 4,4′-DMAR.
(7) There is no prevalence data on the use of 4,4′-DMAR. However, the information
available suggests that it has not been widely used. Information obtained from cases
(1) OJ L 127, 20.5.2005, p. 32.

RISK ASSESSMENTS I 4,4′-DMAR39 / 46Council Decision
involving death also suggests that users unknowingly consumed 4,4′-DMAR when seeking
other stimulants.
(8) There is limited involvement of organised crime in the manufacture, distribution,
trafficking and supply of 4,4′-DMAR within the Union. The chemical precursors and the
synthetic routes used to manufacture 4,4′-DMAR are unknown.
(9) 4,4′-DMAR is not listed for control under the 1961 United Nations Single Convention on
Narcotic Drugs or under the 1971 United Nations Convention on Psychotropic Substances.
It is not currently under assessment, and has not been under assessment, by the United
Nations’ system, and no such assessment is planned.
(10) 4,4′-DMAR has no established or acknowledged human or veterinary medical use in
the Union. Apart from its use in analytical reference materials, and in scientific research
investigating its chemistry, pharmacology and toxicology, there is no indication that it is
being used for other purposes.
(11) The Risk Assessment Report reveals that there is limited scientific evidence available
on 4,4′-DMAR and points out that further research would be needed to determine the
health and social risks that it poses. However, the evidence and information currently
available provides sufficient ground for subjecting 4,4′-DMAR to control measures across
the Union. As a result of the risks to health that the consumption of 4,4′-DMAR poses, as
documented by its detection in several fatalities, of the fact that users may unknowingly
consume it, and of the lack of medical value of this substance, 4,4′-DMAR should be
subjected to control measures.
(12) Given that three Member States control 4,4′-DMAR under national legislation
complying with the obligations of the 1971 United Nations Convention on Psychotropic
Substances and five Member States use other legislative measures to control it, subjecting
this substance to control measures across the Union would help avoid the emergence of
obstacles in cross-border law enforcement and judicial cooperation, and would protect
against the risks that its availability and use can pose.
(13) A Risk Assessment Report on the new psychoactive substance 1-cyclohexyl-4-(1,2-
diphenylethyl)piperazine (MT-45) was drawn up in accordance with Article 6(2), (3) and (4)
of Decision 2005/387/JHA by a special session of the extended Scientific Committee of
the EMCDDA, and was subsequently submitted to the Commission and to the Council on
6 October 2014.
(14) MT-45 is an N,N′ -disubstituted piperazine, having a cyclohexane ring attached to one
of the nitrogen atoms of the piperazine ring and a 1,2-diphenylethyl moiety attached to the
other nitrogen atom. MT-45 is one of a series of 1-(1,2-diphenylethyl)piperazine analgesics
invented in the early 1970s.
(15) MT-45 has been present on the drugs market in the Union since October 2013, where
it is sold as a ‘research chemical’, mostly on the internet. The EMCDDA has identified 12
sites of internet suppliers and retailers that have offered MT-45 for sale, including some
apparently based in the Union.
(16) A total of 28 fatalities occurring between November 2013 and July 2014 have been
reported by one Member State. In most cases, the presence of MT-45 in biological
samples was analytically confirmed. Some 18 non-fatal intoxications have also been
reported by the same Member State, the clinical features of which were similar to opioid
intoxication, responding in some cases to the opioid receptor antagonist naloxone.

RISK ASSESSMENTS I 4,4′-DMAR40 / 46Council Decision
(17) There are several studies in animals indicating that the acute toxicity of MT-45 is
several-fold higher than that of morphine.
(18) Currently available information suggests that MT-45 has not been widely used. The
substance appears to be mostly used in the home environment either by users willing to
try a new substance or by opioid dependent users with no access to heroin or any other
opioid. Users may combine MT-45 with other psychoactive substances. There is no
information on the social risks that may be related to MT-45.
(19) There is no evidence of involvement of organised crime in the manufacture,
distribution, trafficking and supply of MT-45 in the Union. The chemical precursors and the
synthetic routes used to manufacture the MT-45 detected in Member States are unknown.
(20) MT-45 is not listed for control under the 1961 United Nations Single Convention on
Narcotic Drugs or under the 1971 United Nations Convention on Psychotropic Substances.
It is not currently under assessment, and has not been under assessment, by the United
Nations’ system, and no such assessment is planned.
(21) MT-45 has no established or acknowledged human or veterinary medical use in the
Union. Apart from its use in analytical reference materials, and in scientific research
investigating its chemistry, pharmacology and toxicology, there is no indication that it is
being used for other purposes.
(22) The Risk Assessment Report reveals that there is limited scientific evidence available
on MT-45 and points out that further research would be needed to determine the health
and social risks that it poses. However, the evidence and information currently available
provides sufficient grounds for subjecting MT-45 to control measures across the Union. As
a result of the health risks that it poses, as documented by its detection in several
fatalities, and of the lack of medical value of this substance, MT-45 should be subjected to
control measures.
(23) Given that one Member State controls MT-45 under national legislation complying
with the obligations under the 1961 United Nations Single Convention on Narcotic Drugs
and under the 1971 United Nations Convention on Psychotropic Substances and seven
Member States use other legislative measures to control it, subjecting this substance to
control measures across the Union would help avoid the emergence of obstacles in
cross-border law enforcement and judicial cooperation, and would protect against the risks
that its availability and use can pose.
(24) Decision 2005/387/JHA confers upon the Council implementing powers with a view
to giving a quick and expertise-based response at Union level to the emergence of new
psychoactive substances detected and reported by the Member States, by subjecting
those substances to control measures across the Union. As the conditions and procedure
for triggering the exercise of such implementing powers have been met, an implementing
decision should be adopted in order to put 4,4′-DMAR and MT-45 under control across the
Union.
(25) Denmark is bound by Decision 2005/387/JHA and is therefore taking part in the
adoption and application of this Decision which implements Decision 2005/387/JHA.
(26) Ireland is bound by Decision 2005/387/JHA and is therefore taking part in the
adoption and application of this Decision which implements Decision 2005/387/JHA.

RISK ASSESSMENTS I 4,4′-DMAR41 / 46Council Decision
(27) The United Kingdom is not bound by Decision 2005/387/JHA and is therefore not
taking part in the adoption of this Decision which implements Decision 2005/387/JHA and
is not bound by it or subject to its application,
HAS ADOPTED THIS DECISION:
Article 1
The following new psychoactive substances shall be subjected to control measures across
the Union:
(a) 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4′-DMAR);
(b) 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45).
Article 2
By 21 October 2016, Member States shall take the necessary measures, in accordance
with their national law, to subject the new psychoactive substances referred to in Article 1
to control measures and criminal penalties, as provided for under their legislation
complying with their obligations under the 1961 United Nations Single Convention on
Narcotic Drugs and/or under the 1971 United Nations Convention on Psychotropic
Substances.
Article 3
This Decision shall enter into force on the day following that of its publication in the Official
Journal of the European Union .
This Decision shall apply in accordance with the Treaties.
Done at Luxembourg, 8 October 2015.
For the Council
The President
J. ASSELBORN

RISK ASSESSMENTS I 4,4′-DMAR42 / 46Abbreviations
(R) Levorotatory (rectus)
(S) Dextrorotatory (sinister)
3,4-DMMC 3,4-Dimethylmethcathinone
3-MMC 3-Methylmethcathinone
4,4’-DMAR 4,4′-dimethylaminorex
4-FMA 4-Fluoromethamphetamine
4-M-4-MAR 4,4′-Dimethylaminorex
4-MAR 4-Methylaminorex
4-MEC 4-Methylethcathinone
4-MMC 4-Methylmethcathinone
5-APB 5-(2-aminopropyl)benzofuran
5-APDB 5-(2-aminopropyl)-2,3-dihydrobenzofuran
5-HT Serotonin
API Active pharmaceutical ingredient
BAC Blood alcohol content
bk-MDMA bk-Methylenedioxymethamphetamine
(Methylone)
bk-MPA bk-Methylthienylpropamine
Bloodf Femoral blood
Bloodu Unspecified site of blood sample
BrCN Cyanogen bromide
CAS Chemical Abstracts Service registry number
CPR Cardiopulmonary resuscitation
DA Dopamine
DAT Dopamine transporter
Decision Council Decision 2005/387/JHA of 10 May 2005
on the information exchange, risk assessment and
control of new psychoactive substances
EC50Half maximal effective concentration
ECHA European Chemicals Agency
EI/CI Electron- and chemical ionisation
EI-MS Electron ionisation–mass spectroscopy
ELISA Enzyme linked immunosorbent assay
EMA European Medicines Agency
ESI Electrospray ionisation
ESI-MS/MS Electrospray ionisation tandem mass
spectroscopy
ESPAD European School Survey Project on Alcohol and
other Drugs
Eth-Cat Ethcathinone
EtOH Ethanol
EU European Union
EUR Euro
EWS Early Warning System (EMCDDA–Europol)
FMC FluoromethcathinoneAbbreviations
FTIR Fourier transform infrared spectroscopy
GBP British Pound
GC Gas chromatography
GC-MS Gas chromatography–mass spectrometry
HCl Hydrochloric acid
HPLC High performance liquid chromatography
IUPAC International Union of Pure and Applied Chemistry
KOCN Potassium cyanate
LC Liquid chromatography
LC-MS Liquid chromatography–mass spectrometry
LC-MS/MS Liquid chromatography–tandem mass
spectrometry
LD50Median lethal dose
MCAT 4-Methylmethcathinone (Mephedrone)
MDA 3,4-Methylenedioxyamphetamine
MDAI Methylenedioxyaminoindane
MDEC 3,4-Methylenedioxyethcathinone (Ethylone)
MDMA 3,4-Methylenedioxymethamphetamine
MPP 1-Methyl-4-phenylpyridinium
MPPP 4’-Methyl-alpha-pyrrolidinopropiophenone
MS Mass spectrometry
MS Member State
MXE Methoxetamine
NaBH4Sodium borohydride
NE Norepinephrine
NEB N-Ethylbuphedrone
NET Norepinephrine transporter
NMR Nuclear magnetic resonance spectroscopy
p4-DMAR 4,4′-Dimethylaminorex
PMA para- Methoxyamphetamine
PMK Piperonyl methyl ketone
PMMA para- Methoxymethamphetamine
REACH Regulation on registration, evaluation,
authorisation and restriction of chemicals,
database hosted by European Chemicals Agency
RH-34 3-[2-(2-Methoxybenzylamino)ethyl]-1H-
quinazoline-2,4-dione
SD Standard deviation
SERT Serotonin transporter
SSRIs Selective serotonin reuptake inhibitors
ST 4,4′-Dimethylaminorex
ST60 4,4′-Dimethylaminorex
TAAR Trace amine associated receptor
THC-COOH Tetrahydrocannabinol-carboxylic acid

RISK ASSESSMENTS I 4,4′-DMAR43 / 46Abbreviations
Abbreviations
TOXBASE Clinical toxicology database of the National
Poisons Information Service (United Kingdom)
UAC Urine alcohol content
UN United Nations
UR-144 (1-Pentyl-1H-indol-3-yl)-(2, 2, 3, 3-tetramethyl-
cyclopropyl)methanone
WHO World Health Organization
α-PVP α-Pyrrolidinovalerophenone

RISK ASSESSMENTS I 4,4′-DMAR44 / 46Participants of the risk assessment meeting, 16 September 2014
Scientific Committee members
I Dr Henri Bergeron, Centre National de la Recherche Scientifique (CNRS), Institut d’Études Politiques
de Paris (IEP), Paris
I Dr Anne-Line Bretteville Jensen, Norwegian Institute for Alcohol and Drug Research, Oslo, Vice-
Chair of the Scientific Committee
I Prof. Dr Gerhard B ühringer, Addiction Research Unit, Dep. of Clinical Psychology and Psychotherapy,
Technische Universität Dresden, Institut für Therapieforschung (IFT), Munich, Chair of the Scientific
Committee
I Dr Paul Dargan, Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation
Trust, London
I Prof. Dr Matthew Hickman, Social Medicine, Bristol
I Prof. Dr Dirk J. Korf, Universiteit of Amsterdam, Law Faculty, Amsterdam
I Prof. Dr Krzysztof Krajewski, Department of Criminology, Jagiellonian University, Kraków
I Prof. Letizia Paoli, LINC, Leuven Institute of Criminology, University of Leuven Faculty of Law, Leuven
I Dr Fernando Rodriguez de Fonseca, Fundación IMABIS, Hospital Carlos Haya, Málaga
I Prof. Dr Brice De Ruyver, Department of Criminal Law and Criminology, Faculty of Law, Universiteit
Gent
I Prof. Dr Rainer Spanagel, Institute of Psychopharmacology, Central Institute of Mental Health,
Mannheim
Advisers to the Scientific Committee
I Dr Wim Best, Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences,
Utrecht
I Dr Simon Brandt, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University,
Liverpool
I Prof. Gaetano Di Chiara, Cagliari University, Biomedical Sciences Department, Cagliari
I Dr Kalervo Kiianmaa, Addiction Prevention Unit, Department of Alcohol, Drugs and Addiction,
National Institute for Health and Welfare, Helsinki
Representatives of the institutions
European Commission
I Elsa Maia, Anti-Drugs Policy Unit, European Commission, Brussels
I Fabiano Reniero, Joint Research Centre, Institute for Health and Consumer Protection (IHCP),
Brussels
European Medicines Agency (EMA)
I Dr Leon Van Aerts, Section Pharmacology, Toxicology and Biotechnology (FTBB), College ter
Beoordeling van Geneesmiddelen, Medicines Evaluation Board, Utrecht

RISK ASSESSMENTS I 4,4′-DMAR45 / 46Participants of the risk assessment meeting
Europol
I Daniel Dudek, Project SYNERGY, Europol , The Hague
EMCDDA
I Paul Griffiths, Scientific Director, EMCDDA, Lisbon
I Roumen Sedefov, Head of unit, Supply reduction and new trends unit, EMCDDA, Lisbon
Invited external experts
I Dr Simon Elliott, (ROAR) Forensics Ltd, Worcestershire
I Dr István Ujváry, Budapest University of Technology and Economics, Budapest
I Dr David Wood, Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation
Trust, London
EMCDDA staff present
I Anabela Almeida, Project assistant, Action on new drugs, Supply reduction and new trends unit
I Rachel Christie, Scientific analyst, Action on new drugs, Supply reduction and new drugs unit
I Andrew Cunningham, Scientific analyst, Action on new drugs, Supply reduction and new trends unit
I Michael Evans-Brown, Scientific analyst, Action on new drugs, Supply reduction and new trends unit
I Ana Gallegos, Head of Sector, Action on new drugs, Supply reduction and new trends unit
I Brendan Hughes, Senior scientific analyst: national legislation ELDD, Supply reduction and new
drugs unit

TD-AK -14-005-EN-N
Recommended cita tion:
European Monitoring Centre for Drugs and Drug Addic tion (2015), Report on the ri sk
assessment o f 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-a mine
(4,4′-dimethylaminorex, 4 ,4′-DMAR) in t he framework o f the C ouncil D ecision on new
psychoactive substances , Risk Assessments, Publications Office of the European Union,
Luxembourg.
Abo ut the EMCDD A
The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the central
source and confirmed authority on drug-related issues in Europe. For over 20 years, it has
been c ollecting, anal ysing an d disseminating s cientifically s ound i nformation o n drugs and
drug addiction and their consequences, providing its audiences with an evidence-based
picture of the drug phenomenon at European level.
The EMCDDA’s publications are a prime source of information for a wide range of
audiences i ncluding: p olicymakers a nd t heir a dvisors; p rofessionals and researchers
working in the drugs field; and, more broadly, the media and general public. Based in
Lisbon, the EMCDDA is one of the decentralised agencies of the European Union.
Related p ublications a nd we bsites
EMCDDA
I Risk assessment of new psychoactive substances — operating guidelines, 2010
EMCDDA and Europol
I EMCDDA–Europol Joint Report on a new psychoactive substance: 4,4′-DMAR, 2014
I EMCDDA–Europol 2013 Annual Report on the implementation of Council Decision
2005/387/JHA, 2014
I EMCDDA–Europol Early-warning system on new psychoactive substances — operating
guidelines, 2007
These and all other EMCDDA publications are available from
emcdda.europa.eu/publications
I EMCDDA Action on new drugs website: www.emcdda.europa.eu/drug-situation/new-drugs
Legal notice: The contents of this publication do not necessarily reflect the official opinions of the
EMCDDA’s partners, the EU Member States or any institution or agency of the European Union. More
information on the European Union is available on the Internet (europa.eu).
Luxembourg: Publications Office of the European Union
doi:10.2810/58185 I ISBN 978-92-9168-751-0
© European Monitoring Centre for Drugs and Drug Addiction, 2015
Reproduction is authorised provided the source is acknowledged.
This publication is only available in electronic format.
EMCDDA, Praça Europa 1, Cais do Sodré, 1249-289 Lisbon, Portugal
Tel. (351) 211 21 02 00 I info@emcdda.europa.eu
emcdda.europa. eu I twitter .com/emcdda I facebook.com/emcdda