Report on the risk assessment of 4-MTA in the framework of the joint action on new synthetic drugs : EMCDDA Risk assessments.
Date: 1999-10-22
Institutions: European Monitoring Centre for Drugs and Drug Addiction
Subjects: data collection, exchange of information, health risk, psychotropic substance

EUROPEAN MONITORING CENTRE FOR DRUGS AND DRUG ADDICTION 

Report on the Risk Assessment of 4-MTA  

in the Framework of the  

Joint Action on New Synthetic Drugs 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report on the Risk Assessment of 4-MTA in the Framework of the Joint 

Action on New Synthetic Drugs 

On  3  February  1999,  the  German  Presidency  formally  notified  4-MTA  for  risk  assessment  under 
Article 4 of the Joint Action on new synthetic drugs of 16 June 1997. 

A  meeting  of  the  Scientific  Committee  of  the  EMCDDA  extended  with  experts  nominated  by  the 
Member  States  and  representatives  of  the  European  Commission,  Europol  and  the  EMEA  to 
assess the health and social risks as well as the possible consequences of prohibition of 4-MTA, 
was held on 18-19 May 1999. 

The meeting considered the following documents: 

I. 

II. 
III. 
IV. 

Technical  Annexes  A  and  B:  The  Pharmacotoxicological  Report  on  4-MTA,  Report  to  the 
EMCDDA. Doc. N° ST/SCO/12/99  
Technical Annex D: public health risks: epidemiological evidence, EMCDDA 
Technical Annex C: sociological/criminological evidence, EMCDDA 
Europol contribution to the risk assessment on 4-MTA 

These documents in conjunction with further information and comments from the expert participants 
formed the basis of the Risk Assessment which is reported below.  

1.  CHEMICAL DESCRIPTION 

4-MTA  is  p-methylthioamphetamine  also  known  as  4-methylthioamphetamine.  4-MTA  may  be 
synthesised by chemical reactions similar to those used to produce MDA. Recognised precursors 
include  4-methythiophenylacetic  acid  and  4-methylthiobenzaldehyde.  Other  reagents  include 
nitroethane and n-butylamine. 4-MTA was originally synthesised as a potential antidepressant but 
at present it has no therapeutic use. 

2.  PHARMACEUTICAL DESCRIPTION 

4-MTA is sold as tablets for oral consumption. Their street name is ‘flatliners’, ‘S-5’ or ‘MK’. They 
are usually sold as a form of ‘ecstasy’.  

3.  HEALTH RISKS 

(Documents I and II) 

3.1  Individual Health Risks 

(a) Acute Effects 

The  major  acute  neuropharmacological  effect  of  4-MTA  in  the  rat  is  an  increased  release  of 
serotonin, an inhibition of serotonin uptake and of monoamine oxidase A. This combination of 
effects  results  in  a  pharmacological  profile  which  gives  rise  to  concern.  The  limited 
experimental  data  (from  only  4  studies)  indicates  a  weak  effect  on  dopamine  and 
noradrenaline which is consistent with the results of a study with a single dose of 4-MTA in the 
rat  which  showed  no  evidence  of  neurotoxicity  after  one  week.  No  study  of  the  effects  of 
multiple  dosing  with  4-MTA  exists  either  in  rodents  or  in  non-human  primates  recognised  as 
being  a  more  appropriate  model  of  potential  neurotoxicity  in  humans.  Studies  in  animals 

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indicate a rapid onset of action which is in contrast to the observations from users and clinical 
cases.  Animal  studies  have  shown  convulsive  effects  which  might  lead  to  respiratory 
depression.  Co-administration  of  ketamine  increased  the  toxicity  of  4-MTA  in  mice.  Standard 
toxicity  data  on  4-MTA  eg  single  dose,  repeated  dose  toxicities,  reproductive  toxicity, 
teratogenicity,  and  on  mutagenic  and  carcinogenic  potential  are  all  lacking.  Nitro-derivatives 
which might be produced during the synthesis of 4-MTA, may also contribute to toxicity. 

(b) Clinical Effects 

4-MTA has been associated with 5 deaths: 4 in the UK and 1 in the Netherlands. 4-MTA was 
the only drug detected in one death, in the others it was found in combination with other drugs 
(MDMA,  amphetamine,  alcohol,  methadone).  Preliminary  evaluation  of  the  deaths  suggests 
that  some  of  the  symptomatology  described  could  be  related  to  the  ‘serotonin  syndrome1’ 
leading  to  respiratory  depression,  which  appears  to  be  the  main  cause  of  death.  One 
explanation  could  be  that  the  combination  of  drugs  is  important.  Alcohol  would  also  be 
expected  to  contribute  to  respiratory  depression.  Ten  non-fatal  overdoses,  nine  requiring 
hospitalisation,  have  been  reported:  five  from  the  UK  and  five  from  Belgium.  Respiratory 
collapse seems to be a feature common to some of these cases also. In three UK cases, other 
amphetamines  were  detected  in  body  fluids.  The  risk  of  overdose  may  be  linked  to  the  slow 
onset of effects, compared to MDMA, and the possibility that users take more ‘pills’ in the belief 
that that initial dose was too low.  

(c) Dependence 

There  have  been  no  systematic  studies  of  dependence  potential  in  animals  or  in  humans. In 
drug  discrimination  studies  in  rats,  4-MTA  has  shown  similar  properties  to  MDMA.  The  weak 
dopamine  effect  would  tend  to  indicate  a  low  dependence  potential  because  of  the  central 
reinforcing role of dopamine release. 

(d) Psychological Effects 

There is no systematic data on the neuropsychological effects in humans. Limited animal data 
suggest  effects  similar  to  the  ‘entactogen2’  class  which  are  different  to  amphetamine-type 
stimulant  and  to  hallucinogenic  (LSD)  effects.  Anecdotal  reports  from  experienced  ‘ecstasy’ 
users  (who  may  not  be  representative  for  all  such  users),  although  not  entirely  consistent, 
indicate that it has stronger and longer lasting effects than ‘ecstasy’, and that it has frequently 
more  unpleasant  effects  than  ‘ecstasy’.  The  effects  reported  in  the  Netherlands  by  a  small 
number of users are the combination of a peaceful and calm feeling and a stimulating effect, 
which is neither energizing nor psychedelic, but it strongly hampers sleep. The negative effects 
reported  by  users  and  healthcare  professionals  in  a  number  of  countries  include:  nausea, 
nystagmus,  hyperthermia,  pressure  on  the  eyeball,  thirst,  shivering,  confusion,  memory  loss, 
coma, and heart attack. Amnesic effects lasting several hours have been reported. This long 
duration of action linked to the half-life of the drug may have implications for the ability to drive 
and use machinery.  

1 The ‘serotonin syndrome’ is a hyperserotonergic state which is a very dangerous and a potentially fatal side effect of 
serotonergic enhancing drugs. If such drugs are not discontinued, the condition can progress rapidly to a more serious 
state  and  become  fatal.  The  symptoms  of  the  serotonin  syndrome  are:  euphoria,  drowsiness,  sustained  rapid  eye 
movement,  overreaction  of  the  reflexes,  rapid  muscle  contraction  and  relaxation  in  the  ankle  causing  abnormal 
movements of the foot, clumsiness, restlessness, feeling drunk and dizzy, muscle contraction and relaxation in the jaw, 
sweating, intoxication,  muscle  twitching,  rigidity,  high body  temperature,  mental status changes  are  frequent  (including 
confusion and hypomania – a ‘happy drunk’ state), shivering. 

2 Dr David Nichols coined the term ‘entactogen’ for drugs such as MDMA. The entactogenic effect of the drug is that it 
acts  as  an  emotional  brace  reflected  in  the  drug's  ability  to  facilitate  the  retrieval  of  inner  material  and  enhance 
introspective  states.  It  means  essentially  ‘to  produce  a  touching  within’  (Nichols).  In  the  words  of  a  user  of  MDMA,  it 
provides a sense that the world is sort of ‘an okay place to be’. 

2 

 
 
 
 
 
 
 
 
                                                 
 
3.2  Public Health Risks 

(a)  Availability and Quality 

4-MTA  has  been  identified  in  six  Member  States,  and  in  Australia,  although  seizures  and 
clinical cases have been found mainly in three States (Belgium, UK and The Netherlands). In 
two States, it appears to have been available in sporadic batches, rather than on the consistent 
basis  reported  by  the  third.  In  some  cases,  4-MTA  is  the  only  ingredient  (‘flatliners’)  while  in 
others  caffeine  is  encountered  (‘S-5’s’).  On  the  basis  of  limited  information,  tablets  typically 
contain 100-130 milligrammes of 4-MTA.  

(b)  Knowledge and Perception of 4-MTA Among Users 

Knowledge of 4-MTA is low among users and tablets containing it are generally believed to be 
a type of ‘ecstasy’. These ‘pills’ have been perceived as a particularly strong, and long-lasting, 
type  of  ‘ecstasy’  by  atypical  ‘innovators3’,  who  have  a  particular  interest  in  experimenting. 
Among more general ‘ecstasy’ users, there is anecdotal evidence of an increasingly negative 
image associated with ‘flatliners’ and ‘S5s’. Paradoxically, media coverage that reports 4-MTA 
as an ‘extra strong, ‘ecstasy’-type’ drug may inadvertently generate awareness that stimulates 
use amongst ‘ecstasy’ users.  

(c) Prevalence and Patterns of Use 

Prevalence of (inadvertent) use of 4-MTA depends on the extent to which it is sold as a special 
type  of  ‘ecstasy’.  It  is  believed  to  form  only  a  very  small  proportion  of  the  ‘ecstasy’  market. 
Patterns of use are the same as for ‘ecstasy’, which appears to be experimental or occasional 
rather than heavy. There appears to be a small proportion of heavy users of 4-MTA. 

(d) Characteristics and Behaviours of Users 

Information on users of ‘ecstasy’ indicate that they are primarily  young people aged between 
16 and 30 with a more equal gender ratio than observed with other illicit drugs. Use is likely to 
be  in  combination  with  other  party  drugs  such  as  amphetamines,  cannabis  and  alcohol.  The 
limited  information  available  suggests  that  the  people  who  are  most  likely  to  use  4-MTA 
knowingly,  are  ‘innovators’  who  are  often  perceived  as  ‘deviant’.  Other  people  who  may  try 
‘flatliners’ are regular ‘ecstasy’ users who are more integrated into the social system and are 
less deviant than ‘innovators’. 

(e) Indicators of Health Consequences 

Information on the health consequences in the population are limited to those stated in 3.1.b. It is 
noteworthy that these adverse effects have been reported within a nine-months period and with an 
apparently  small  population  of  users.  No  information  on  the  long-term  consequences  of  4-MTA 
use is available. 

(f) Context of Use  

4-MTA  is  taken  in  the  context  of  an  ‘ecstasy’  culture  in  which  prior  expectations  exist  with 
regard to the timing of effects. Consequently, the delayed effects of 4-MTA may be perceived 

3 ‘Innovators’ are a category of drug users who are often perceived as deviant, have cosmopolitan social relationship and 
may communicate regularly with a clique of other geographically dispersed innovators. They fulfil a gatekeeping role for 
information about new drugs. 

3 

 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
 
 
as a weakness, or failure, of the pill taken in the belief that it is ‘ecstasy’. This may lead to the 
consumption of more ‘pills’ and subsequent overdose. 

4.  SOCIAL RISKS: Sociological/criminological aspects 

(Documents III and IV) 

4.1  Sociological aspects 

Some experienced ‘ecstasy’ users are a channel for the dissemination of information on 4-MTA. For 
young people outside of the ‘ecstasy’-using population there seems to be a  very  low probability  of 
coming into contact with 4-MTA under present conditions. 

There is no indication that 4-MTA is widely sought after, or likely to grow in popularity. The contrary 
appears to be the case. The negative effects that have been described and attributed to ‘flatliners’ 
(such as: nausea, headaches and delayed effects) indicate a low likelihood that ‘flatliners’ will grow 
in popularity, or become widely used. ‘Grapevine news’ of deaths and intoxications associated with 
‘flatliners’ contribute to its negative image.  

A proportion of more’ innovative’ drug users appear to be motivated to use ‘flatliners’ by a desire to 
experience the full diversity of sensations. The number of ‘ innovators’ is not known but they are 
not an insignificant group.  
Increased  testing  services,  informed  Internet  advice,  and  peer  education  may  produce  more 
discrimination in the ‘ecstasy’ market. 

Little is known of the use of 4-MTA in other settings. It has been suggested that a small minority of 
drug users, who seek specific effects, might be using 4-MTA in their homes. 

4.1.1  Social Consequences 

There is no evidence specifically on 4-MTA. The available evidence on MDMA does not show any 
major harmful social consequences for users arising directly from its use, in terms of family or other 
social relations, problems concerning education, employment, or marginalisation. On the basis of 
comparison with MDMA, and given that 4-MTA constitutes a small proportion of the much broader 
‘ecstasy’  market,  it  is  very  unlikely  that there  are  any  significant  harmful social  consequences for 
the user that could be attributed specifically to the use of 4-MTA.  

4.1.2  Consequences for the Social Behaviour of the User  

There  is  no  evidence  specifically  on  4-MTA  and  consequences  linked  to  disorderly  conduct, 
acquisitive crime or violence. However, it might be considered even more unlikely than with MDMA 
that there is any important link between the use of 4-MTA and such consequences. The effect on 
driving is unknown but the long duration of action of 4-MTA is a matter of concern. 

4 

 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.3  Other Social Consequences  

There is no indication that 4-MTA in particular is associated with any major value conflicts or has 
any important implications for social institutions beyond those described for MDMA. 

4.2  Criminological Aspects 

Manufacture, trafficking and distribution of 4-MTA is unknown to the law enforcement authorities of 
eleven  Member  States.  Trafficking  and  distribution  of  4-MTA  is  known  in  four  Member  States: 
Belgium, Germany, the Netherlands and the United Kingdom. One Member State has information 
on the role of organised crime in the production, trafficking and distribution of 4-MTA. 

Three  Member  States,  Belgium,  the  United  Kingdom  and  the  Netherlands,  seized  considerable 
amounts  of  4-MTA  tablets,  although  these  amounts  were  limited  to  single  seizures  only  and  one 
Member State, Germany, seized small quantities. In two Member States, trafficking of 4-MTA was 
found  in  combination  with  other  illegal  substances.  According  to  some  reports,  this  is  a  growing 
tendency. 

The  seizures  of  considerable  amounts  in  Belgium,  the  United  Kingdom  and  the  Netherlands 
suggest an involvement of organised crime in the production of, and trafficking in, these amounts, 
although there is no further information for the time being to confirm this. 

5. POSSIBLE CONSEQUENCES OF PROHIBITION 

5.1  Legal Status 

An analysis of the legal status of 4-MTA in the 15 Member States shows that only in Sweden is the 
drug  controlled  permanently.  In  the  Netherlands,  following  the  assessment  of  the  Coordination 
Center for Assessment and Monitoring of New Drugs of Misuse (CAM), options being considered 
include the placing of 4-MTA within the Opium Act for a period of one year, or the use of medicines 
legislation as a means of control. In Germany, 4-MTA has been provisionally controlled under the 
Narcotics  Act,  for  a  one-year  period.  Recently,  the  Bundeskriminalamt  (BKA)  has  carried  out  an 
risk assessment. In January 1999, the German Expert Board endorsed the permanent control of 4-
MTA. The amendment of the narcotics regulation is scheduled to come into operation during 1999. 
In France, 4-MTA is under immediate review. Steps are being taken in the UK to schedule 4-MTA 
under the Misuse of Drugs Act. 

5.2 Possible Consequences of Prohibition 

The meeting acknowledged the well established and broadly accepted fact of prohibition of MDMA. 
As this substance served as a point of reference for the risk assessment of 4-MTA and in view of 
the fact that  the  acute  hazards  of  4-MTA  were generally  not  considered as  less  serious,  there  is 
little scope for an alternative to prohibition as a measure of control. The possibility of bringing the 
substance under the regulations for the control of medicines was the only alternative considered. 
Doubts were expressed as to whether this approach was the most appropriate method of control. 
Exempting  4-MTA  from  legal  control  would  send  an  inaccurate  message  about  the  comparative 
safety of the substance.  

In  accepting  prohibition  of  4-MTA  as  the  most  viable  model  of  control  there  was  a  strong 
consensus  that  prohibition  should  not  impede  any  kind  of  non-repressive  preventive  or  harm 
reduction  actions.  Most  importantly  an  urgent  need  for  educating  and  informing  (potential)  user 
groups  of  the  realistic  hazards  of  the  substance  was  expressed  by  the  meeting.  Such  an  effort 

5 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
should  specifically  be  directed  at  informing  users  of  4-MTA  of  the  long  latency  period  to  prevent 
them from inadvertently taking overdoses. 

The opinion was also expressed that the application of criminal law should specifically be directed 
at  the  supply  level  (producers  and  distributors)  of  4-MTA.  Marginalisation  of  users  should  be 
avoided as much as possible. 

The meeting noted that since 4-MTA is part of the larger ‘ecstasy’ market, prohibition is unlikely to 
have  a  significant  impact  on  the  availability  and  usage  of  ‘ecstasy’  in  general.  It  was  also 
suggested  that  one  consequence  of  prohibition  might  be  to  stimulate  the  search  for  newer 
synthetic drugs. 

6.  CONCLUSIONS 

The  Scientific  Committee  of  the  EMCDDA  extended  with  experts  from  the  Member  States  and 
representatives  of  the  Commission,  Europol  and  EMEA  have  considered  the  health  and  social 
risks  as  well  as  the  possible  consequences  of  prohibition  of  4-methylthioamphetamine  and  in 
accordance with Article 4 of the Joint Action submit the following conclusions: 

6.1    The scientific evidence submitted to the meeting shows that 4-methylthio-amphetamine (4-
MTA)  is  a  potent  psychoactive  agent  which  rapidly  releases  serotonin  and  inhibits 
monoamine oxidase A activity. It has been associated with five deaths within the EU. Ten 
non-fatal  cases,  nine  requiring  hospitalisation  and  resuscitation,  have  been  reported  from 
the  UK  and  Belgium.  The  reported  adverse  events  are  noteworthy  in  that  they  have 
occurred within a short period of time and in an apparently small population exposed to the 
drug.  Respiratory  collapse  has  been  reported  in  some  cases.  A  delayed  onset  of  action 
apparently  increases  the  risk  of  overdose  and  combination  with  alcohol,  MDMA, 
amphetamines  or  ephedrine  also  appears  to  increase  the  risks.  Since  the  drug  inhibits 
monoamine  oxidase  A,  a  serious  interaction  with  certain  foods  could  occur.  Toxicity  data 
normally used to assess the health effects of a new chemical are not available for 4-MTA. 

The expert participants noted that 4-MTA had been identified in 6 Member States and also 
in  Australia.  Reports  suggest  that  4-MTA  is  sold  and  consumed  as  ‘ecstasy’.  Anecdotal 
reports  suggest  that  this  drug  may  be  less  attractive  than  MDMA  to  users  because  of  its 
unpleasant effects. 

Compared to MDMA, and also to MBDB, 4-MTA appears to be associated with a higher risk 
of  acute  effects  including  adverse  reactions  and  overdosage.  The  long-term  risk  of 
neurotoxicity  of  4-MTA  on  its  own  is,  like  MBDB,  possibly  lower  than  for MDMA  but  as  in 
the case of MBDB no data is available. 

6.2    Arising from 6.1 and because 4-MTA is the sulphur analogue of amphetamines already  

subject to control in Member States, the opinion which received strong support at the  

  meeting was that this compound should be placed under control. 

This  opinion  also  recommends  that  a  decision  to  place  4-MTA  under  control  should  not 
inhibit  the  gathering  of  information  about  drugs  on  the  market  and  the  dissemination  of 
accurate  information  on  4-MTA  to  users  and  to  relevant  professionals.  The  risk  of 
overdosing due to the delayed onset of action should be highlighted, as should the risks of 
mixing it with alcohol, MDMA, amphetamines, ephedrine products and certain tyramine rich 
foods (MAOI effects). 

6.3   

 The  major  chemical  precursors  of  4-MTA,  namely  methylthiobenzaldehyde  and 
methylthiophenylacetic acid are commercially available. The meeting recommends that the 
Drug  Precursors  Committee  set  up  under  Article  10  of  Regulation  3677/90  and  Directive 

6 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
92/109/EEC  closely  examine  the  situation  of  those  precursor  chemicals  which  have  been 
found  in  the  manufacture  of  4-MTA  and  which  are  not  yet  subject  to  any  measure  of 
surveillance. 

6.4   

 The meeting recommends that, when a new synthetic drug is notified for risk assessment, 
arrangements  be  made  for  the  provision  of  reference  standard  material  and  associated 
analytical  data  to  forensic  and  toxicology  laboratories  within  the  European  Union.  The 
meeting further recommends that 4-MTA be included within the UNDCP proficiency testing 
programme. One opinion was, that as part of the Early Warning System specific testing of 
‘pills’  available  on  the  market  should  be  possible,  in  order to  inform  potential  users  of the 
actual composition of those ‘pills’. 

Lisbon, 19 May 1999 

Annex 1:  
Annex 2:  

List of participants 
Agenda 

7