Drug Abuse

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, was held on 29 October 2001. This meeting sought to assess the health and social risks of PMMA, especially in association with PMA, as well as to assess the possible consequences of prohibition. This meeting was subsequent to the formal notification of the Swedish Presidency of the Council of the EU requesting a risk assessment of PMMA under Article 4 of the joint action on new synthetic drugs of 16 June 1997.

The meeting considered the following documents:

i.    Technical Annexes A and B: the pharmacotoxicological report on PMMA; report to the EMCDDA
ii. Technical Annex D: public health risks: epidemiological evidence; EMCDDA
iii. Technical Annex C: sociological/criminological evidence; EMCDDA
iv. Europol contribution to the risk assessment on PMMA
In conjunction with further information and comments provided by the expert participants, these documents formed the basis of the risk assessment which is reported below.

Chemical description

PMMA is para-methoxymethylamphetamine or N-methyl-1-4-(methoxyphenyl)-2- aminopropane. Other chemical names are 4-methoxy-N-methyl-amphetamine (4-MMA) and 2-methylamino-1-(p-methoxyphenyl)-propane. It is a structural hybrid of two phenylisopropylamine stimulants: PMA and methamphetamine. Precursors and reagents include 4-methoxyphenylacetone (4-methoxyphenyl-2-propanone), methylamine hydrochloride, sodium cyanoborohydride, ethyl chloroformate and formic acid.

PMA is para-methoxyamphetamine or 4-methoxyamphetamine (4-MA). Another chemical name is 1-(4-methoxyphenyl)-2-aminopropane. PMA is a methoxylated amphetamine derivative. Precursors and reagents include 4-methoxybenzaldehyde, nitro-ethane, benzene, methanol and cyclohexane.

Precursors for PMA and PMMA are widely available commercially. PMMA and PMA themselves have no therapeutic value.

In general, colour tests for PMMA and PMA are presumptive and need confirmation. Limited data have indicated that, with regard to the reaction of PMA and PMMA to colour change tests, two samples analysed by gas chromatography–mass spectometry (GC–MS) which identified PMA and PMMA, produced no reaction in the Marquis colour test. They gave a positive result for the nitroprusside colour test and a colour change of purple to brown for the Liebermann colour test. PMMA produces the positive blue colour of a secondary amine, while PMA does not elicit a colour. Additional complications arise with colour tests performed on tablets that contain mixtures of different amphetamine analogues.

Pharmaceutical description

PMMA/PMA have been sold as tablets for oral consumption. They are sold in the guise of MDMA with ‘ecstasy’ type logos such as ‘Mitsubishi’, ‘Jumbo’ or ‘E’.

Health risks

Individual health risks

Acute effects
A recent animal study indicated that PMMA induces awakening and stimulant effects. In discrimination studies, in MDMA-trained rats, PMMA is considered to be identical to MDMA. In PMMA-trained rats, MDMA is considered to be identical to PMMA, but this is not the case for amphetamine or the hallucinogen 4-methyl-2,5-dimethoxyamphetamine (DOM). Lacking hallucinogenic properties, PMMA may have mostly ‘entactogenic’
effects, meaning that it enhances introspective states, while PMA has some amphetamine-like characteristics.

Pharmacokinetic experiments with five amphetamine-like stimulants revealed a poor penetration of PMA into the brain. Comparisons of the brain levels of these amphetamines suggested that PMMA crosses the brain barrier to a lesser extent even than PMA.

Neurochemical effects of PMMA have not been investigated in in vitro studies. Structure-activity investigations on the neurotoxic effects of amphetamine derivatives suggested that PMMA is a serotonin (5-hydroxytryptamine, 5-HT) releaser, yielding potent and selective effects on serotonergic neurones. Repeated administration of PMMA (or PMA) in rats for four days produced a brain depletion of serotonergic markers. The results of recent animal experiments in rats and mice have confirmed previous studies which found some symptoms indicative of ‘serotonergic syndrome’, although some symptoms (e.g. short-term respiratory depression) were not found.

The neuronal basis for the hyperactivity and sympathomimetic stimulation observed with PMMA is still unclear. Unlike MDMA, PMA and PMMA do not seem to release dopamine. From its chemical structure, it is likely that PMMA plays a dominant role in the inhibition of monoamineoxidase (MAO)-A. In vitro experiments demonstrated that PMA is a potent inhibitor of MAO. As is the case for PMA, the phenylisopropylamine PMMA is probably also metabolised by the cytochrome isoenzyme P450 2D6. It can be concluded from these findings that the acute effects of PMA (and probably PMMA) are more likely to be associated with alterations in serotonergic rather than in dopaminergic neurotransmission.

With PMMA administration in rats, hypertension and long-lasting tachycardia are observed; these cardiovascular effects are dose dependent. MAO inhibition may contribute to the long-lasting cardiovascular effects.

The main acute toxicity effect of PMMA in rats is hyperthermia. This effect occurs soon after PMMA administration and before the onset of hyperactivity. Hyperthermic responses are dose dependent.

From experiments in animals, it may be assumed that PMMA is an effective psychoactive substance with toxic effects. The median subcutaneous lethal dose value (LD50) of PMMA was found to be 80–100 mg/kg in rats. This value suggests a narrow margin between the behaviourally active dose and the lethal dose and therefore there is a high risk for acute toxicity. PMA has a similar toxicity (LD50) to PMMA in mice.

Standard toxicity data on the teratogenic, mutagenic and carcinogenic potential of PMMA are lacking. In general, arrangements should be made for the provision of standard reference materials and associated analytical data to forensic and toxicology laboratories in the EU.

Clinical effects

Tablets containing PMMA alone, marketed as ‘ecstasy’, were associated with one death which took place in Spain in 1993. Due to the presence of significant concentrations of 3,4-methylenedioxy-N-ethylamphetamine (MDEA) and ethanol in the blood sample, forensic experts considered that the role of PMMA in this death was problematic.

During a recent episode of seizures of PMMA in combination with PMA in the EU, there appeared to be some tablets in which PMMA was the principal substance (e.g. 97 mg PMMA combined with 4 mg PMA in one tablet). In most cases, PMMA was found in combination with PMA and other drugs such as methylenedioxyamphetamine (MDA), MDMA, amphetamine, methamphetamine and ephedrine.

PMMA/PMA have been involved in four deaths in the EU between July and September 2000 — one took place in Austria (4) and three in Denmark.

PMA alone has been implicated in six deaths in the Member States since June 2000: two in Germany in 2000 and four in Belgium in 2001. Hyperthermia (ranging between 41.5 and 46.1 °C) was a recurrent symptom in a number of documented cases of PMA-related fatalities.

Repeated intake of PMA or PMMA may cause inhibition of the isoenzyme responsible for its metabolism in the liver and could consequently enhance the hyperthermic response. High ambient temperatures and water deprivation also augmented the hyperthermia. The acute toxicity of PMA and PMMA may be due to increased extraneuronal serotonin levels.

In the human cases of fatalities, blood concentrations of PMMA were within the same range as the blood concentrations of PMA or MDMA in the case of deaths.

Monitoring the area under the plasma concentration–time curve (AUC), the findings in rats were that the maximum effects of PMMA and MDMA occurred 15 minutes after their administration. This may be relevant when analysing causes of overdose leading to human fatalities. The risk of overdose could be linked to the fact that, after receiving only a weak stimulant effect, the lack of the expected MDMA-like properties may lead users to take more tablets in the belief that this initial dose was too low.

The combination of PMA and PMMA, as well as the combination of PMMA with other amphetamines, increases toxicity and may present an additional risk factor in the case of overdose.

As with MDMA, there is some concern that PMMA and PMA could induce degeneration of serotonergic neurones.

Dependence

Drug discrimination learning for PMMA has only been studied in animals. Low doses of PMMA (1.25 mg/kg) have a discriminative stimulus similar to that induced by ‘entactogen’ substances such as MDMA. There have been no systematic studies of the potential for PMMA dependence in animals or in humans. The lack of dopamine effects would tend to indicate a low dependence potential because of the central reinforcing role of dopamine release. In contrast with MDMA effects, reports from users indicate reduced motivation to talk and to get involved with others, and undesired physical effects. It is unlikely that, in the long term, fake ‘ecstasy’ tablets combining PMMA and PMA could replace MDMA on the retail market.

Psychological effects

There are few data on the neuropsychological effects of PMMA in humans. Limited animal data suggest effects similar to the ‘entactogen’ class, which are different to amphetamine-type stimulants and to hallucinogenic (LSD) effects. Anecdotal reports from ‘ecstasy’ users, although not entirely consistent, indicate that it frequently produces more unpleasant effects than ‘ecstasy’.

Public health risks

Availability and quality

There appears to be no explicit consumer market in the EU for either PMA or PMMA. PMMA is sold on the illicit market as a substitute for ‘ecstasy’. The combination of PMMA with PMA in tablets sold with an ‘ecstasy’-type logo does not seem to be accidental but more probably is a deliberate association of the two compounds, whose behavioural effects have been described in the existing literature, in order to imitate the expected effects of MDMA as closely as possible for users. The widespread availability of the precursors implicated in the synthesis of both PMMA and PMA may have enhanced this process.

Since June 2000, four Member States (Denmark, Germany, Austria and Sweden) have reported a total of nine large seizures of PMMA/PMA tablets sold as ‘ecstasy’. The Netherlands reported three large seizures of tablets containing PMA together with MDMA or MDA, and two seizures of tablets containing PMA alone. A significant number of small seizures of ‘ecstasy’ tablets containing PMA and/or PMMA have been
reported in eight Member States (Sweden, France, Germany, the Netherlands, Belgium, Austria, the United Kingdom and Spain) as well as in Norway and Poland. Large PMA and/or PMMA seizures have also been reported in Hungary and Canada.

The most common logos found on tablets containing PMMA/PMA are ‘Mitsubishi’, ‘Jumbo’ or ‘E’. In one seizure, a tablet with a four-leafed clover logo was found. Other tablets containing PMA (but no PMMA) have carried ‘Mitsubishi’, ‘Elephant’, ‘Nike’, ‘Superman’, and ‘xTc’ logos.

PMMA has always been found in combination with PMA in tablets sold as ‘ecstasy’ (5). Most PMMA/PMA tablets also contain a mixture of amphetamine, methamphetamine or ephedrine. On the basis of the available information, tablets contain between 20 and 97 mg PMMA.

Knowledge, perceptions and availability of information

There is considerably more scientific information about PMA than about PMMA. Specific information about the dangers of PMA is available in a variety of forms including peer education, outreach work, leaflets, youth media, television, newspapers and the Internet. Furthermore, the availability of ‘ecstasy’ testing kits sold commercially on the Internet indicates a demand for better knowledge about the contents of tablets, although this demand may be largely from dealers.

There is no information about the knowledge or the perceptions of users of PMMA, used alone or when combined with PMA, as there is no market for PMMA/PMA as such.

Prevalence and patterns of use

The prevalence of the (inadvertent) use of PMMA depends on the extent to which, as is currently the case, it is sold as ‘ecstasy’. However, PMMA is believed to form only a very small proportion of the ‘ecstasy’ market. Patterns of use are the same as for ‘ecstasy’, a situation which could be a matter of serious concern as users may seek similar effects to MDMA. In that regard, the combination of PMA with PMMA represents a major risk.

Characteristics and behaviours of users

Evidence suggests that age and where people live have more influence than gender on ‘ecstasy’ use, and therefore on inadvertent PMMA/PMA use. However, there is anecdotal evidence that males are more likely to use ‘ecstasy’ excessively and to be less concerned about the harmful effects than female users.

Special concerns are the lack of knowledge both about drug contents and about the specific harmful effects of PMA and PMMA. The greatest risk behaviour associated with use is taking large doses of PMMA/PMA as if it were MDMA. People who take more than one tablet over a short time period are at the greatest risk of both acute and long-term health risks. One group of young people who are particularly vulnerable are heavy, excessive users who belong to groups that are at high risk for a range of problems.

Indicators of health consequences

In Spain, there was a death associated with the use of PMMA alone, in 1993, and another fatality with PMA in 1995. Since 1995, PMA has been implicated in at least eight deaths in Australia and in 10 in the United States (USA).

Since July 2000, four deaths have been recorded as being linked to PMMA/PMA: one in Austria and three in Denmark. A further six deaths have been linked to PMA alone in two other Member States: two in Germany and four in Belgium. In at least five out of the nine deaths, more than one tablet had been taken. In one case, at least six other drugs had also been taken. PMA was also suspected to be involved in the recent death of a young man in the Netherlands.

Four non-fatal hospital admissions associated with PMA have been reported in Belgium since April 2001.

It should be noted that increased investigations for PMA may have been prompted by a heightened awareness of the potential role of PMA in ‘ecstasy’ intoxication.

Context of use

PMMA is taken in the context of an ‘ecstasy’ culture in which prior expectations exist with regard to the quality and the timing of effects. Consequently, the poor MDMA-like effects of PMMA, even when combined with PMA, 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.

Social risks

Sociological aspects

Sociological evidence for PMMA and PMA is limited by the fact that there is no evident consumer market for these drugs in Europe. In the cases where PMMA has appeared on the European market, it has always been consumed with PMA in a tablet which was taken as ‘ecstasy’ and where the user expected to experience MDMA effects accordingly.

Social consequences

There is no specific evidence on PMMA. 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.

The recent deaths that have occurred from PMMA/PMA or from PMA alone contribute to growing concerns about dangerous products on the ‘ecstasy’ market. These concerns are reflected in some Internet discussions where an interest in health issues and avoiding harm from new synthetic drugs is evident.

Consequences for the social behaviour of the user

There is no evidence to specifically link the effects of PMMA use with disorderly conduct, acquisitive crime or violence. Its effect on driving is unknown, but the narrow safety margin between the behavioural and the lethal doses may be a matter of concern.

Other social consequences

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

Criminological aspects

Distribution of PMA is known to have taken place in six Member States: Belgium, France, Germany, the Netherlands, Sweden and the United Kingdom. This relates to the seizure of some 5 480 tablets in 19 incidents. Trafficking and distribution of PMMA is known to have taken place in four Member States: Denmark, Germany, Austria and Sweden.

In those cases where PMMA was seized — 18 870 tablets in 29 incidents — all tablets also contained PMA and had either the ‘Mitsubishi’ logo or the ‘E’ logo, with the exception of 337 tablets with the ‘Jumbo’ logo. The total number of PMA and PMMA/PMA tablets seized in the Member States in 2000 is relatively small when compared to the overall seizures of ‘ecstasy’ in the EU (17 426 531 tablets in 2000). Large-scale production of PMA or PMMA is not thought to occur in any Member State.

Three Member States — Denmark, Austria and Sweden — have information on the role of organised crime in the trafficking of PMMA/PMA. This relates to criminal groups from Poland. Combined with links established by the Bundeskriminalamt (BKA), and the fact that the Polish authorities have discovered two illicit laboratories used for the production of PMA and PMMA, this indicates that PMMA/PMA tablets seized in the Member States, Canada and the USA, are likely to have originated in Poland. According to the Polish authorities, production of PMA and/or PMMA continues to take place in other laboratories in the country and in the Ukraine.

Seizures of PMMA/PMA tablets in 2001 in the Member States probably relate to importation from Poland in 2000.

Prohibition

Legal status

An analysis of the legal status of PMMA in the 15 Member States shows that the drug is controlled under the national drugs legislation in four of them: Germany, Ireland, Sweden and the UK. PMMA is also controlled in Norway. Steps are being taken in France to schedule PMMA control under its national drugs legislation. In addition, an assessment on PMMA/PMA has recently been conducted by the Coordination Centre for Assessment and Monitoring of New Drugs of Misuse (CAM) in the Netherlands.

PMA has been listed as a controlled drug in Schedule I of the 1971 UN Convention on Psychotropic Substances since 1986.

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 PMMA, and in view of the fact that the acute hazards of PMMA were generally not considered to be any less serious, there was strong support at the meeting that prohibition is the most appropriate measure of control. Another point of view expressed at the meeting was that PMMA cannot be regarded as a major public health problem for the time being.

In accepting prohibition of PMMA as the most applicable model of control, there was a strong consensus that prohibition should not impede any kind of non-repressive preventive or harm-reducing actions. Most importantly, an urgent need for educating and informing potential user groups of the hazards of the substance was expressed by the meeting to prevent them from inadvertently taking overdoses.

The meeting noted that, since PMMA is part of the larger ‘ecstasy’ market, prohibition is unlikely to have a significant impact on the availability and usage of ‘ecstasy’ in
general. Nevertheless, prohibition in all Member States will facilitate international law enforcement and judicial cooperation against producers and traffickers of PMMA.

Conclusions

The Scientific Committee of the EMCDDA, extended with experts from the Member States and representatives of the Commission, Europol and the EMEA, has considered the health and social risks as well as the possible consequences of prohibition of PMMA alone and also when associated in ‘ecstasy’-like tablets in combination with the controlled drug PMA. In accordance with Article 4 of the joint action, it submits the following conclusions:

•    PMMA has no therapeutic value.
•    The scientific evidence submitted to the meeting shows that PMMA is a psychoactive agent which seems to release serotonin and may inhibit MAO-A activity. In combination with PMA, it has been associated with four deaths within the EU. The reported adverse events are noteworthy in that they occur within a short period of time and in an apparently small population exposed to the drug. The simultaneity of a weak, MDMA-like, stimulant effect and a lack of other anticipated effects apparently increases the risk of overdose. Combination with alcohol, MDMA, amphetamines or ephedrine may increase the risks of neurotoxicity.

The expert participants noted that PMMA had been identified in four Member
States and also in Norway, Poland, Canada and the USA. Three of these Member States have identified a role for organised crime in the trafficking of PMMA. PMMA is almost exclusively sold in combination with PMA and is consumed as ‘ecstasy’. Anecdotal reports suggest that PMMA/PMA tablets may be less attractive than MDMA to users because of their unpleasant effects.

Compared to MDMA, PMMA, especially when associated with PMA in ‘ecstasy’-like tablets, appears to be associated with a higher risk of acute effects including adverse   
reactions and overdose. The meeting also recognised gaps in knowledge. Further studies should be conducted to establish the exact role of PMMA in these toxic effects.   
•    As a consequence of the previous two points, because PMMA is an amphetamine analogue that is very similar to PMA, and also because both MDMA and PMA are subject to control in all Member States, the opinion which received strong support at the meeting was that this compound should be placed under control.   
This opinion also recommended that a decision to place PMMA under control   
should not inhibit the gathering of information about drugs on the market or the dissemination of accurate information about PMMA and PMMA/PMA to users and   
relevant professionals. The risk of overdosing should be highlighted, as should the risks of consuming it with alcohol, MDMA, amphetamines and ephedrine products.   
•    The major chemical precursors of PMMA are available commercially. The meeting recommends that the Drug Precursors Committee, which was set up under Article 10 of Regulation (EEC) No 3677/90 and Directive 92/109/EEC, should be invited to closely examine the specific precursor chemicals which have been found to be used in the manufacture of PMMA and which are not yet subject to any measure of surveillance.   
•    The meeting reiterates its previous risk assessment recommendations that, when a new synthetic drug is notified for risk assessment, arrangements be made for the provision of standard reference material and associated analytical data to forensic and toxicology laboratories within the EU. The meeting further recommends that PMMA be included in the UN Drug Control Programme (UNDCP) proficiency testing programme.   


Lisbon, 29 October 2001

(4) It has been confirmed that the cause of the fatality which occurred in Austria, which was allegedly associated only with PMA, was in fact due to PMA and PMMA.

(5) With the exception of Spain where, between August and October 2000, three seizures took place of a small number of tablets which contained PMMA but no other identifiable drug contents.

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