(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
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.

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
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.

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’.

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.