Ecstasy and neurodegeneration

Ecstasy's long term effects are potentially more damaging than its acute toxicity

Publicity in the popular press and medical journals1 on the dangers of using ecstasy (3,4-methylenedioxymethamphetamine) has concentrated almost exclusively on the problems of acute toxicity. While the unnecessary death of any young person is rightly deplored, it is strange that so little attention is being paid to the long term effects of this recreational drug. This lack of attention is particularly surprising because evidence has been available for several years that ecstasy induces neurodegeneration in the brains of experimental animals.2 If young people continue to use the drug socially they should at least be fully informed of the risks.

Administration of ecstasy to various animals has been shown to cause long term destruction of serotoninergic axons and axon terminals in the brain. This damage occurs in rodents' brains and in several species of primate.2 Some reinnervation may occur after several months, but in squirrel monkeys several brain regions showed no recovery even after a year, while in areas where it did occur the innervation was often highly abnormal.3 This long term damage to serotoninergic neurones can occur in rats and primates after a single high dose of ecstasy (20 mg/kg) or several lower doses (4 x 5 mg/kg). A recent study in rats, however, found considerable degeneration after a single dose of 10 mg/kg, which produced plasma concentrations in the same range as those seen in patients admitted with an acute toxic response to the drug.4 Only 5 mg/kg of the major metabolite of ecstasy, 3,4-methylenedioxyamphetamine, was needed to produce similar damage.4

Many of the acute toxic effects of ecstasy are probably due to the parent compound and its effect of releasing serotonin from nerve terminals. Neurodegeneration, however, seems to result from metabolites of ecstasy; these oxidise to products that give rise to free radicals, which in turn induce oxidative stress and membrane damage.5 Tucker et al used a yeast microsomal preparation expressing the human enzyme to provide evidence that the rate of metabolism of ecstasy is probably linked to whether a person taking the drug is an extensive or poor metaboliser of debrisoquine (via the CYP2D6 enzyme).6 They proposed that extensive metabolisers may be at less risk of an acute toxic reaction to ecstasy but in more danger of long term neurodegeneration.

The prime example of a recreational drug producing long term neurotoxic degeneration occurred in a group of subjects who ingested a meperidine analogue, which was contaminated with MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridone). After ingestion this was metabolised to MPP⁺ (1-methyl-4-phenylpyridinium), a compound that produces free radicals.7 The accidental ingestion of MPTP by these individuals resulted in the appearance of a severe and irreversible form of Parkinsonism, caused by neurotoxic degeneration of dopaminergic neurones in the nigrostriatal pathway.8 The neurotoxic damage produced by MPTP is not only demonstrable in rodents and primates but also occurs at much lower doses in humans.2 In humans ingestion of large amounts of MPTP rapidly produces overt signs of neurological damage, but there is now evidence that low doses or transient exposure produce occult effects revealed only by brain imaging.9

No unequivocal evidence yet exists that regular users of ecstasy have brain damage, but the studies that have been performed give no grounds for reassurance. McCann et al reported that 30 regular users of ecstasy had lowered concentrations of the serotonin metabolite 5-hydroxyindole acetic acid in their cerebrospinal fluid,10 a change also reported in primates with brain damage induced by ecstasy.11 Since serotonin plays a major part in the control of mood, regular use of ecstasy might be expected to lead to psychiatric abnormalities. There are case reports to support this expectation,2 12 but the interpretation of such data is difficult.2 What is of great concern is the possibility that the neurotoxicity in humans might be slow and insidious and that problems such as major depression will appear only in several years' time.

A recent editorial argued against legalising ecstasy because of the problems of acute toxicity. To this we add that no one should seriously consider legalising a compound that can be shown to cause long term neurodegeneration in rodents and primates at doses that differ little from those used recreationally by humans.