4,4′-DMAR : report on the risk assessment of 4,4′-DMAR in the framework of the Council Decision on new psychoactive substances.
Date: 2015-10-21
Institutions: European Monitoring Centre for Drugs and Drug Addiction
Subjects: drug addiction, health control, health policy, health risk, psychotropic substance, public health, scientific report, stimulant

RISK ASSESSMENTS 16

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4,4′-DMAR

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.

 
 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

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.

EMCDDA risk assessment team: Andrew Cunningham, Michael Evans-Brown, 
Ana Gallegos and Roumen Sedefov

2 / 46

 
 
 
 
 
 
 
 
 
I  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

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RISK ASSESSMENTS I 4,4′-DMARI  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 information exchange, 
risk-assessment and control of new psychoactive substances

I. Information exchange
Early-warning system (EWS)

EMCDDA–Europol Joint Reports

II. Risk assessment

EMCDDA Risk Assessments

III. Decision-making

Council Decisions on control

4 / 46

RISK ASSESSMENTS I 4,4′-DMARI   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 

5 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment Report of a new 
psychoactive substance:  
4-methyl-5-(4-methylphenyl)- 
4,5-dihydrooxazol-2-amine 
(4,4′-dimethylaminorex, 4,4′-DMAR)

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′-dimethylaminorex (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.

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.

6 / 46

five 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

NH2

2

3
N

*

4

O

1

*

5

1’

2’

5’

4’

6’

3’

NH2

N

*

4

O

*

5

NH2

N

O

*

5

4,4′-DMAR

4-MAR

Aminorex

Molecular formula: C11H14N2O
Molecular weight: 190.25

Molecular formula: C10H12N2O
Molecular weight: 176.22

Molecular formula: C9H10N2O
Molecular weight: 162.19

Monoisotopic mass: 190.1106

Monoisotopic mass: 176.0950

Monoisotopic mass: 162.0793

Note: Structures of 4-MAR and aminorex are provided for comparison. Asterisk indicates chiral carbon.

7 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment Report 
but 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 

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. 

FIGURE 2
Molecular structures of the four possible 4,4′-DMAR enantiomers

O

NH2

N

O

NH2

N

O

NH2

N

O

NH2

N

(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

(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.

(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.).

8 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment ReportFurther 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 

9 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment ReportStates 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. 

10 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment ReportI  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 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.

organised crime, seizures and/or 
detections by the authorities, and the 
manufacture of 4,4′-DMAR 

I   Information on the level of involvement of 

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   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 

11 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment Reportby ‘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 

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.
 A health consequence that might result from this control 
option is the benefit brought about by the presumed 
reduction in availability and use. 

n 

n 

n 

n 

n 

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.
 This control option would imply additional costs for the 
criminal justice system, including forensic services, law 
enforcement and the courts.
 This control option could lead to replacement with other 
(established or new) psychoactive substances that may 
also have public health consequences.
 It is difficult to predict the impact of this control option on 
current or future research by the pharmaceutical or 
chemical industries. 
 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.
 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. 

12 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment ReportData 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.

13 / 46

RISK ASSESSMENTS I 4,4′-DMARRisk Assessment ReportANNEX 1
Technical report on 4-methyl-5-(4-
methylphenyl)-4,5-dihydrooxazol-2-amine 
(4,4′-dimethylaminorex, 4,4′-DMAR)

Dr Simon Brandt

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.).

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. 

14 / 46

Compared 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.

pharmaceutical and pharmacological 
information

I   Section A. Physical, chemical, 
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.

FIGURE 1
The molecular structure, formula, relative molecular weight and monoisotopic mass of 4,4′-DMAR

NH2

2

3
N

*

4

O

1

*

5

1’

2’

5’

4’

6’

3’

NH2

N

*

4

O

*

5

NH2

N

O

*

5

4,4′-DMAR

4-MAR

Aminorex

Molecular formula: C11H14N2O
Molecular weight: 190.25

Molecular formula: C10H12N2O
Molecular weight: 176.22

Molecular formula: C9H10N2O
Molecular weight: 162.19

Monoisotopic mass: 190.1106

Monoisotopic mass: 176.0950

Monoisotopic mass: 162.0793

Note: Structures of 4-MAR and aminorex are provided for comparison. Asterisk indicates chiral carbon.

(3)   4-MAR is listed in Schedule I and aminorex is listed in Schedule IV of the 1971 

United Nations Convention on Psychotropic Substances.

15 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportTABLE 1
Alternative names, codenames, street names, and 
abbreviations that may be encountered for 4,4′-DMAR

TABLE 2
Chemical Abstract Service (CAS) Registry Numbers for 
4,4′-DMAR

4-Methyl-5-(p-tolyl)-4,5-dihydrooxazol-2-amine

CAS Registry Numbers

Variant

1445569-01-6

364064-08-4

Form not specified

(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.

4,5-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.

FIGURE 2
Molecular structures of the four possible 4,4′-DMAR enantiomers

O

NH2

N

O

NH2

N

O

NH2

N

O

NH2

N

(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

(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.

16 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportIdentification 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).

17 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportsalt 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.

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).

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 

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), 

FIGURE 3
Synthesis of cis- and trans-4,4′-DMAR, as reported by Brandt et al., 2014

O

Br2

4,4’-DMAR
(±)-cis

4,4’-DMAR
(±)-trans

BrCN

KOCN

O

O

O

O

Br

N

Na

NH2

NaBH4

O

O

O

N

O

EtOH1 HCI

NH2

(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-one

18 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportPVP (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.

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).

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).

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).

19 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical report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)

d-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).

TABLE 3
Stimulation of release in rat brain synaptosomes (a)

Drug

d-Amphetamine

Aminorex

cis-4-MAR (c)

cis-4,4′-DMAR

Release at DAT
EC50 (nM) 

Release at NET
EC50 (nM) 

5.5 ± 0.5

9.1 ± 0.9

1.7 ± 0.2

8.6 ± 1.1

8.2 ± 1.6

15.1 ± 3.5

4.8 ± 0.9

26.9 ± 5.9

Release at SERT
EC50 (nM) 

2602 ± 494

414 ± 78

53.2 ± 6.8

18.5 ± 2.8

DAT/SERT ratio (b)

473

45

31

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.

20 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical report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)

A 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.

TABLE 4
Stimulation of release in rat brain synaptosomes (a)

Drug

(S)-(+)-MDMA (b)

cis-4,4′-DMAR

trans-4,4′-DMAR 

Release at  
DAT EC50 (nM) 

143 ± 16

10.9 ± 0.7

24.4 ± 2.7

Release at  
NET EC50 (nM)

98.3 ± 15.0

11.8 ± 2.0

31.6 ± 4.6

Release at  
SERT EC50 (nM)

85.0 ± 13.3

17.7 ± 2.3

59.9 ± 17.2 (d)

DAT/SERT ratio (c)

0.6

1.6

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).

21 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportPharmacokinetics

I  A3. Psychological and behavioural effects

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).

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 (4S,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: (4R)-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.

22 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportStates 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 

23 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical report4,4′-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.

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. 

Finland reported a seizure by customs of two red tablets in 
May 2013, and Hungary reported a total of 78 seizures.

Collected samples

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.

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’.

24 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportAvailability 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).

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 

(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. 

(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).

(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).

25 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportwebsites 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.

26 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical report;

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30 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I  D2. Chronic health effects

D2.1. Animal data

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.

There are no published studies investigating the chronic 
health effects of 4,4′-DMAR in animals.

D3.3. Characteristics and behaviour of users 

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.

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.

32 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportI  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.

33 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportI  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.

34 / 46

RISK ASSESSMENTS I 4,4′-DMARAnnex 1: Technical reportReferences

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

 Ashby, C. R., Jr., Pan, H., Minabe, Y., et al. (1995), ‘Comparison of the action of the stereoisomers of 

the psychostimulant 4-methylaminorex (4-MAX) on midbrain dopamine cells in the rat: an 

extracellular single unit study’, Synapse 20(4), pp. 351–361.

 Batsche, K., Ashby, C. R., Jr., Lee, C., Schwartz, J. and Wang, R. Y. (1994), ‘The behavioral effects of 

the stereoisomers of 4-methylaminorex, a psychostimulant, in the rat’, Journal of Pharmacology and 

Experimental Therapeutics 269(3), pp. 1029–1039.

 Baumann, M. H., Ayestas, M. A., Jr., Partilla, J. S., et al. (2012), ‘The designer methcathinone analogs, 

mephedrone and methylone, are substrates for monoamine transporters in brain tissue’, 

Neuropsychopharmacology 37(5), pp. 1192–1203.

 Baumann, M. H., Wang, X. and Rothman, R. B. (2007), ‘3,4-Methylenedioxymethamph-etamine 

(MDMA) neurotoxicity in rats: a reappraisal of past and present findings’, Psychopharmacology 

189(4), pp. 407–424.

 Boyer, E. W. and Shannon, M. (2005), ‘The serotonin syndrome’, New England Journal of Medicine 

352(11), pp. 1112–1120.

 Brandt, S. D., Baumann, M. H., Partilla, J. S., Kavanagh, P. V., Power, J. D., Talbot, B., Twamley, B., 

O’Brien, J., Mahony, O., Elliott, S. P., Archer, R. P., Patrick, J., Singh, K., Dempster, N. M. and Cosbey, S. 
H. (2014), ‘Characterization of a novel and potentially lethal designer drug, (±)-cis-para-methyl-4-

methylaminorex (4,4′-DMAR, or ‘Serotoni’)’, Drug Testing and Analysis, 6(7-8), pp. 684–695.

 Bunker, C. F., Johnson, M., Gibb, J. W., Bush, L. G. and Hanson, G. R. (1990), ‘Neurochemical effects of 

an acute treatment with 4-methylaminorex: a new stimulant of abuse’, European Journal of 

Pharmacology 180(1), pp. 103–111.

 By, A. W., Dawson, B. A., Lodge, B. A. and Sy, W. W. (1989), ‘Spectral distinction between cis- and 

trans-4-methylaminorex’, Forensic Science International 43(1), pp. 83–91.

 Cooper, D. A. (1988). ‘Future synthetic drugs of abuse’, in Castonguay, R.T. (ed.), Proceedings of the 

international symposium on the forensic aspects of controlled substances: March 28–April 1, 1988, 

Laboratory Division, Federal Bureau of Investigation, U.S. Dept. of Justice, Washington, D.C., pp. 

79–103.

 Cosbey, S., Kirk, S., McNaul, M., Peters, L., Prentice, B., Quinn, A., Elliott, S. P., Brandt, S. D. and Archer, 

R. P. (2014), ‘Multiple fatalities involving a new designer drug: para-methyl-4-methylaminorex’, 

Journal of Analytical Toxicology 38(6), pp. 383–384.

 Davis, F. T. and Brewster, M. E. (1988), ‘A fatality involving U4Euh, a cyclic derivative of 

phenylpropanolamine’, Journal of Forensic Sciences 33(2), pp. 549–553.

 Decoret, G., Galley, G., Groebke Zbinden, K. and Norcross, R. (2010), ‘2-Aminooxazolines as TAAR1 

ligands’, F. Hoffmann-La Roche AG, Patent, WO2010/139707A1.

 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), Joint Reports, Publications 

Office of the European Union, Luxembourg (www.emcdda.europa.eu/attachements.cfm/

att_229825_EN_TDAS14006ENN.pdf).

 Europol and EMCDDA (2014), Early-warning notification: link suspected between deaths and new 

psychoactive substance: 4-methylaminorex, para-methyl derivative, Europol, The Hague (www.

europol.europa.eu/sites/default/files/publications/ewn_4-methylaminorex__para-methyl-

derivative_feb_2014_-_public_.pdf)

 Fodor, G. and Koczka, K. (1952), ‘155. The stereochemical course of the conversion of 

2-ureidoalcohols into oxazolidines: part I’, Journal of the Chemical Society pp. 850–854.

 Galley, G., Groebke Zbinden, K., Norcross, R. and Stalder, H. (2008), ‘Novel 2-aminooxazolines as 

TAAR1 ligands for CNS disorders’, Hoffmann-La Roche, Patent, WO2008/092785A1.

 Glennon, R. A. and Misenheimer, B. (1990), ‘Stimulus properties of a new designer drug: 

4-methylaminorex (“U4Euh”)’, Pharmacology Biochemistry and Behavior 35(3), pp. 517–521.

35 / 46

RISK ASSESSMENTS I 4,4′-DMARReferences

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

I 

 Goodman, R.M. (1990), ‘Methods of decongesting the nose without adverse stimulant effects’, 

Patent, US4980364A, 25 December.

 Gurtner, H. P. (1979), ‘Pulmonary hypertension, “plexogenic pulmonary arteriopathy” and the appetite 

depressant drug aminorex: post or propter?’, Bulletin Européen de Physiopathologie Respiratoire 

15(5), pp. 897–923.

 Gurtner, H. P. (1985), ‘Aminorex and pulmonary hypertension: a review’, Cor Vasa, 27(2–3), pp. 

160–171.

 Hanson, G. R., Bunker, C. F., Johnson, M., Bush, L. and Gibb, J. W. (1992), ‘Response of 

monoaminergic and neuropeptide systems to 4-methylaminorex: a new stimulant of abuse’, 

European Journal of Pharmacology 218(2–3), pp. 287–293.

 Hanson, G. R., Jensen, M., Johnson, M. and White, H. S. (1999), ‘Distinct features of seizures induced 

by cocaine and amphetamine analogs’, European Journal of Pharmacology 377(2–3), pp. 167–173.

 Henderson, G. L., Harkey, M. R. and Chueh, Y. T. (1995), ‘Metabolism of 4-methylaminorex (“EU4EA”) 

in the rat’, Journal of Analytical Toxicology 19(7), pp. 563–570.

 ICH (1994), ICH harmonised tripartite guideline: clinical safety data management: definitions and 

standards for expedited reporting E2A, International Conference of Harmonisation of Technical 

Requirements for Registration of Pharmaceuticals for Human Use (www.ich.org/products/

guidelines/efficacy/article/efficacy-guidelines.html).

 Isbister, G. K., Buckley, N. A. and Whyte, I. M. (2007), ‘Serotonin toxicity: a practical approach to 

diagnosis and treatment’, Medical Journal of Australia 187(6), pp. 361–365.

 Kankaanpää, A., Ellermaa, S., Meririnne, E., Hirsjärvi, P. and Seppälä, T. (2002), ‘Acute neurochemical 

and behavioral effects of stereoisomers of 4-methylaminorex in relation to brain drug concentrations’, 

Journal of Pharmacology and Experimental Therapeutics 300(2), pp. 450–459.

 Klein, R. F. X., Sperling, A. R., Cooper, D. A. and Kram, T. C. (1989), ‘The stereoisomers of 

4-methylaminorex’, Journal of Forensic Sciences 34(4), pp. 962–979.

 Mansbach, R. S., Sannerud, C. A., Griffiths, R. R., Balster, R. L. and Harris, L. S. (1990), ‘Intravenous 

self-administration of 4-methylaminorex in primates’, Drug and Alcohol Dependence 26(2), pp. 

137–144.

 McLaughlin, G., Morris, N., Kavanagh, P. V., Power, J. D., Twamley, B., O’Brien, J., Talbot, B., Dowling, 

G., Mahony, O., Brandt, S. D., Patrick, J., Archer, R. P., Partilla, J. S. and Baumann, M. H. (2014), 

‘Synthesis, characterization and monoamine transporter activity of the new psychoactive substance 

3′,4′-methylenedioxy-4-methylaminorex (MDMAR)’, Drug Testing and Analysis, in press, doi:10.1002/

dta.1732.

 Meririnne, E., Ellermaa, S., Kankaanpaeae, A., Bardy, A. and Seppaelae, T. (2004), ‘Pharmacokinetics 

and tissue distribution of the stereoisomers of 4-methylaminorex in the rat’, Journal of Pharmacology 

and Experimental Therapeutics 309(3), pp. 1198–1205.

 Meririnne, E., Kajos, M., Kankaanpaeae, A., Koistinen, M., Kiianmaa, K. and Seppaelae, T. (2005), 

‘Rewarding properties of the stereoisomers of 4-methylaminorex: involvement of the dopamine 

system’, Pharmacology Biochemistry and Behavior 81(4), pp. 715–724.

 Meyer, M. R., Wilhelm, J., Peters, F. T. and Maurer, H. H. (2010), ‘Beta-keto amphetamines: studies on 

the metabolism of the designer drug mephedrone and toxicological detection of mephedrone, 

butylone, and methylone in urine using gas chromatography–mass spectrometry’, Analytical and 

Bioanalytical Chemistry 397(3), pp. 1225–1233.

 Nizar, H., Dargan P. I. and Wood D. M. (2014), ‘Using Internet snapshot surveys to enhance our 

understanding of the availability of the novel psychoactive substance 4-methylaminorex and 

4,4’-dimethylaminorex’, Journal of Medical Toxicology, DOI 10.1007/s13181-014-04250.

 Noggle, F. T., Jr., Clark, C. R. and DeRuiter, J. (1992), ‘Liquid chromatographic and spectral analysis of 

the stereoisomers of dimethylaminorex’, Journal of AOAC (Association of Official Analytical 

Chemists) International 75(3), pp. 423–427.

36 / 46

RISK ASSESSMENTS I 4,4′-DMARReferences

I 

I 

I 

I 

I 

I 
I 

I 

I 

I 

 Poos, G. I., Carson, J. R., Rosenau, J. D., Roszkowski, A. P., Kelley, N. M. and McGowin, J. (1963), 

‘2-Amino-5-aryl-2-oxazolines: potent new anorectic agents’, Journal of Medicinal Chemistry, 6(3), 

pp.266–272.

 Rodriguez, W. R. and Allred, R. A. (2005), ‘Synthesis of trans-4-methylaminorex from norephedrine 

and potassium cyanate’, Microgram Journal 3(3–4), pp. 154–165.

 Roszkowski, A. P. and Kelley, N. M. (1963), ‘A rapid method for assessing drug inhibition of feeding 

behavior’, Journal of Pharmacology and Experimental Therapeutics 140(3), pp. 367–374.

 Rothman, R. B., Vu, N., Partilla, J. S., Roth, B. L., Hufeisen, S. J., Compton-Toth, B. A., Birkes, J., Young, 

R. and Glennon, R. A. (2003), ‘In vitro characterization of ephedrine-related stereoisomers at biogenic 

amine transporters and the receptorome reveals selective actions as norepinephrine transporter 

substrates’, Journal of Pharmacology and Experimental Therapeutics 307(1), pp. 138–145.

 Russell, B. R., Beresford, R. A., Schmierer, D. M., McNaughton, N. and Clark, C. R. (1995), ‘Stimulus 

properties of some analogues of 4-methylaminorex’, Pharmacology Biochemistry and Behavior 

51(2–3), pp. 375–378.

 Sternbach, H. (1991), ‘The serotonin syndrome’, American Journal of Psychiatry 148(6), pp. 705–713.

 Takagi, M., Ishimitsu, K. and Nishibe, T. (2003), ‘Oxa(thia)zolidine derivative and anti-inflammatory 

drug’, Patent, US 2003/0199479 A1.

 Yelnosky, J. and Katz, R. (1963), ‘Sympathomimetic action of cis-2-amino-4-methyl-5-phenyl-2-
oxazoline’, Journal of Pharmacology and Experimental Therapeutics 141(2), pp. 180–184.

 Young, R. and Glennon, R. A. (1993), ‘Cocaine-stimulus generalization to two new designer drugs: 

methcathinone and 4-methylaminorex’, Pharmacology Biochemistry and Behavior 45(1), pp. 

229–231.

 Young, R. and Glennon, R. A. (1998), ‘Discriminative stimulus effects of S(-)-methcathinone (CAT): a 

potent stimulant drug of abuse’, Psychopharmacology 140(3), pp. 250–256.

37 / 46

RISK ASSESSMENTS I 4,4′-DMARI  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.

38 / 46

RISK ASSESSMENTS I 4,4′-DMAR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.

Council Decision

39 / 46

RISK ASSESSMENTS I 4,4′-DMAR(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.

Council Decision

40 / 46

RISK ASSESSMENTS I 4,4′-DMAR(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

Council Decision

41 / 46

RISK ASSESSMENTS I 4,4′-DMARAbbreviations

Abbreviations

(R)

(S)

Levorotatory (rectus)

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-MEC

4-MMC

5-APB

5-APDB

5-HT

API 

BAC

4-Methylaminorex

4-Methylethcathinone

4-Methylmethcathinone

5-(2-aminopropyl)benzofuran

5-(2-aminopropyl)-2,3-dihydrobenzofuran

Serotonin

Active pharmaceutical ingredient

Blood alcohol content

bk-MDMA

bk-Methylenedioxymethamphetamine 
(Methylone)

bk-MPA

bk-Methylthienylpropamine

Bloodf

Bloodu

BrCN

CAS

CPR

DA

DAT 

Decision

EC50

ECHA

EI/CI

EI-MS

ELISA

EMA

ESI 

Femoral blood

Unspecified site of blood sample

Cyanogen bromide

Chemical Abstracts Service registry number

Cardiopulmonary resuscitation

Dopamine

Dopamine transporter 

Council Decision 2005/387/JHA of 10 May 2005 
on the information exchange, risk assessment and 
control of new psychoactive substances

Half maximal effective concentration

European Chemicals Agency

Electron- and chemical ionisation

Electron ionisation–mass spectroscopy

Enzyme linked immunosorbent assay

European Medicines Agency 

Electrospray ionisation

ESI-MS/MS

Electrospray ionisation tandem mass 
spectroscopy

ESPAD

European School Survey Project on Alcohol and 
other Drugs

Eth-Cat

Ethcathinone

Ethanol

European Union

Euro

EtOH

EU

EUR

EWS 

FMC

FTIR

GBP

GC

GC-MS

HCl

HPLC

IUPAC

KOCN

LC 

LC-MS

Fourier transform infrared spectroscopy

British Pound

Gas chromatography 

Gas chromatography–mass spectrometry

Hydrochloric acid

High performance liquid chromatography 

International Union of Pure and Applied Chemistry

Potassium cyanate

Liquid chromatography

Liquid chromatography–mass spectrometry

LC-MS/MS 

Liquid chromatography–tandem mass 
spectrometry 

LD50

MCAT

MDA

MDAI

MDEC

MDMA 

MPP

MPPP

MS

MS

MXE

NaBH4

NE

NEB

NET

NMR

Median lethal dose

4-Methylmethcathinone (Mephedrone)

3,4-Methylenedioxyamphetamine

Methylenedioxyaminoindane

3,4-Methylenedioxyethcathinone (Ethylone)

3,4-Methylenedioxymethamphetamine

1-Methyl-4-phenylpyridinium 

4’-Methyl-alpha-pyrrolidinopropiophenone

Mass spectrometry

Member State

Methoxetamine

Sodium borohydride

Norepinephrine

N-Ethylbuphedrone

Norepinephrine transporter

Nuclear magnetic resonance spectroscopy

p4-DMAR

4,4′-Dimethylaminorex

PMA

PMK

PMMA

REACH

RH-34

SD

SERT

SSRIs

ST

ST60

TAAR

para-Methoxyamphetamine

Piperonyl methyl ketone

para-Methoxymethamphetamine

Regulation on registration, evaluation, 
authorisation and restriction of chemicals, 
database hosted by European Chemicals Agency

3-[2-(2-Methoxybenzylamino)ethyl]-1H-
quinazoline-2,4-dione

Standard deviation

Serotonin transporter

Selective serotonin reuptake inhibitors

4,4′-Dimethylaminorex

4,4′-Dimethylaminorex

Trace amine associated receptor

Early Warning System (EMCDDA–Europol)

Fluoromethcathinone

THC-COOH

Tetrahydrocannabinol-carboxylic acid

42 / 46

RISK ASSESSMENTS I 4,4′-DMARAbbreviations

TOXBASE

UAC

UN

UR-144

WHO 

α-PVP

Clinical toxicology database of the National 
Poisons Information Service (United Kingdom)

Urine alcohol content

United Nations

(1-Pentyl-1H-indol-3-yl)-(2, 2, 3, 3-tetramethyl-
cyclopropyl)methanone

World Health Organization

α-Pyrrolidinovalerophenone

Abbreviations

43 / 46

RISK ASSESSMENTS I 4,4′-DMARParticipants of the risk assessment meeting, 16 September 2014

Scientific Committee members

I 

I 

I 

I 

I 
I 
I 
I 
I 
I 

I 

 Dr Henri Bergeron, Centre National de la Recherche Scientifique (CNRS), Institut d’Études Politiques 
de Paris (IEP), Paris

 Dr Anne-Line Bretteville Jensen, Norwegian Institute for Alcohol and Drug Research, Oslo, Vice-
Chair of the Scientific Committee

 Prof. Dr Gerhard Bühringer, Addiction Research Unit, Dep. of Clinical Psychology and Psychotherapy, 
Technische Universität Dresden, Institut für Therapieforschung (IFT), Munich, Chair of the Scientific 

Committee

 Dr Paul Dargan, Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation 
Trust, London

 Prof. Dr Matthew Hickman, Social Medicine, Bristol

 Prof. Dr Dirk J. Korf, Universiteit of Amsterdam, Law Faculty, Amsterdam

 Prof. Dr Krzysztof Krajewski, Department of Criminology, Jagiellonian University, Kraków

 Prof. Letizia Paoli, LINC, Leuven Institute of Criminology, University of Leuven Faculty of Law, Leuven

 Dr Fernando Rodriguez de Fonseca, Fundación IMABIS, Hospital Carlos Haya, Málaga

 Prof. Dr Brice De Ruyver, Department of Criminal Law and Criminology, Faculty of Law, Universiteit 
Gent

 Prof. Dr Rainer Spanagel, Institute of Psychopharmacology, Central Institute of Mental Health, 
Mannheim

Advisers to the Scientific Committee

I 

I 

I 
I 

 Dr Wim Best, Utrecht University, Faculty of Science, Department of Pharmaceutical Sciences, 
Utrecht

 Dr Simon Brandt, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, 
Liverpool

 Prof. Gaetano Di Chiara, Cagliari University, Biomedical Sciences Department, Cagliari

 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 
I 

 Elsa Maia, Anti-Drugs Policy Unit, European Commission, Brussels

 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

44 / 46

RISK ASSESSMENTS I 4,4′-DMARParticipants of the risk assessment meeting

Europol

I 

 Daniel Dudek, Project SYNERGY, Europol, The Hague

EMCDDA

I 
I 

 Paul Griffiths, Scientific Director, EMCDDA, Lisbon

 Roumen Sedefov, Head of unit, Supply reduction and new trends unit, EMCDDA, Lisbon

Invited external experts

I 
I 
I 

 Dr Simon Elliott, (ROAR) Forensics Ltd, Worcestershire 

 Dr István Ujváry, Budapest University of Technology and Economics, Budapest 

 Dr David Wood, Clinical Toxicology, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation 
Trust, London

EMCDDA staff present

I 
I 
I 
I 
I 
I 

 Anabela Almeida, Project assistant, Action on new drugs, Supply reduction and new trends unit

 Rachel Christie, Scientific analyst, Action on new drugs, Supply reduction and new drugs unit 

 Andrew Cunningham, Scientific analyst, Action on new drugs, Supply reduction and new trends unit

 Michael Evans-Brown, Scientific analyst, Action on new drugs, Supply reduction and new trends unit

 Ana Gallegos, Head of Sector, Action on new drugs, Supply reduction and new trends unit

 Brendan Hughes, Senior scientific analyst: national legislation ELDD, Supply reduction and new 
drugs unit

45 / 46

RISK ASSESSMENTS I 4,4′-DMARTD-AK-14-005-EN-N

Recommended citation:

European Monitoring Centre for Drugs and Drug Addiction (2014), Report on the risk 
assessment of 4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine 
(4,4′-dimethylaminorex, 4,4′-DMAR) in the framework of the Council Decision on new 
psychoactive substances, Risk Assessments, Publications Office of the European Union, 
Luxembourg.

About the EMCDDA

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 collecting, analysing and disseminating scientifically sound information on 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 including: policymakers and their advisors; professionals 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 publications and websites

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