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The Oxford English dictionary defines it as a ‘rapturous feeling, state
of frenzy or stupor’. But to thousands of young people it comes in the shape
of an innocuous-looking white tablet. More prosaically known as 3,4-methylenedioxymetham-phetamine,
or MDMA, ecstasy is now believed to be the third most popular illicit drug
in Britain after cannabis and amphetamine (‘speed’). This weekend alone
an estimated half a million Britons will go in search of its renowned bacchic
pleasures: an intense feeling of emotional closeness to other people, a
heightened sense of touch, a rush of energy.

Reports of deaths and repeated official condemnations of ecstasy have
so far done little to quell demand. In one sense this is only to be expected:
young people have always been society’s great risk takers, as research
on smoking habits testifies. Yet with ecstasy another factor may come into
play. While much is now known about the effects of MDMA on rats – in particular,
which neurotransmitter pathways it interferes with in the animal’s brain
– information about the drug’s effects on humans is patchy. It is hard to
build up a convincing case against a drug when you can’t say exactly how
dangerous it is or what the consequences of long-term use are.

Britain has no long-term research programme aimed at unravelling the
physiological and neurological effects of ecstasy. And in the past few years
no major pharmacological papers have been published describing how the drug
acts in humans. During the same period police seizures of ecstasy – a good
index of overall consumption – have increased more than a thousand times,
and a handful of deaths have provided glimpses of the drug’s more sinister
effects.

Marcus Rattray, of Guy’s Hospital in London, is one of the few biochemists
in Britain to have won funding for ecstasy research. As part of a two-year
project sponsored by the UK’s Medical Research Council, he is tackling
what is perhaps the most troubling question of all: does MDMA cause permanent
brain damage, and if so how? ‘Ecstasy causes big changes in the brains of
animals,’ says Rattray, ‘but there is still no firm evidence that the drug
is neurotoxic in humans.’

The dearth of information is not surprising. The biological effects
of illicit drugs have always been notoriously difficult to study. It is
unlawful for researchers to give drugs like ecstasy to volunteers, so the
only way they can study their long-term physical and psychological effects
is to enroll people who use the drug recreationally. Most drugs users, however,
are wary of participating in such studies. And even when they are willing
to take part, acquiring interpretable data is tricky. People tend to take
ecstasy intermittently, and these days the drug is rarely bought and consumed
in a pure state.

Research into drugs such as heroin and cocaine has suffered for similar
reasons. But with these substances neuroscientists have persevered, lured
by the prize of understanding what makes them so addictive. Heroin acts
on opiate receptors which are involved in processing pain signals; cocaine
amplifies strongly the effects in the brain of a neurotransmitter called
dopamine, which plays a fundamental part in addiction. Ecstasy does neither
and is not physiologically addictive. While the neural basis of addiction
is considered a fundamental problem in biology, mood alteration of the kind
induced by ecstasy is not.

MEDICAL SPIN-OFFS

Medically speaking, MDMA is also deemed much less interesting than cannabis.
Research into cannabis hit the doldrums after the drug was banned in the
US and Britain earlier this century. But recent years have witnessed a revival
– partly because of the discovery of the receptor that binds cannabinoid
compounds in the brain, and partly because of renewed interest among pharmaceuticals
companies in developing cannabis-like drugs for controlling pain.

By contrast, any medical spin-offs from ecstasy are likely to be indirect.
Some doctors have allegedly prescribed the drug as an antidepressant; and
in the 1970s marriage guidance therapists in the US used it to foster empathy
between warring partners. But the consensus today is that ecstasy’s hallucinogenic
properties render it wholly unsuitable as a medical drug.

What little information there is about the biological effects of ecstasy
suggests that the drug acts like a mixture of LSD and ordinary amphetamine.
The most detailed survey was completed in 1988 by Stephen Peroutka, a
physician and biochemist then working at Stanford University in California.

Peroutka found that nearly 40 per cent of a random sample of students
at Stanford University had tried the drug at least once. Ninety per cent
of the 143 users reported a feeling of closeness to other people, and nearly
70 per cent reported symptoms similar to the natural fight-or-flight reaction
we experience when faced with danger – racing heart, dry mouth, tremors,
palpitations, sweating. One in five users said they had mild hallucinations,
and more than a third complained of insomnia.

Most of the students in Peroutka’s survey used ecstasy in the same way
that people tend to use cannabis – sitting quietly with friends. And nobody
reported any serious ill effects. But in Britain things are different. Here
ecstasy is inextricably linked with the rave dance scene, the youth culture
that began out in fields and warehouses in the late 1980s but quickly moved
onto the dance floors of mainstream clubs as proprietors and drug dealers
realised the potential for exploitation. Doctors in Britain have rapidly
come to the conclusion that high levels of physical activity hold the greatest
short-term threat for ecstasy users.

According to figures released this month by the National Poisons Unit
at Guy’s Hospital, London, the drug has killed seven people in Britain since
1990. At first the deaths were a mystery, but now pathologists are sure
of the cause: heat stroke. Unlike quiet campus rooms, hot, sweaty clubs
can combine fatally with some of the drug’s effects.

Ravers enjoy the ‘hug factor’. But they get very hot. Not only is the
fight-or-flight response exaggerated by dancing all night, but research
on rats suggests that ecstasy automatically increases body temperature.
Typically users develop a great thirst for water, but soft drinks at the
bar are often beyond the budgets of ravers who may already have spent their
free cash on hefty entrance fees. Some clubs have been found guilty of turning
off water supplies in the toilets to force ravers back to the bars. Under
such conditions, the body cannot fight the overheating and dehydrating effects
of the drug – and this is when deaths tend to occur. Now clubs are starting
to clean up their act, and some even offer air-conditioned ‘chill out’ rooms.

John Henry, a consultant physician at the National Poisons Unit was
the first person to suggest that the deaths from ecstasy were due to hyperthermia
worsened by the conditions in clubs. Everyone who takes ecstasy is a potential
victim, he says: there are no predisposing factors such as a weak heart.
Convulsions and widespread blood clotting accompany the sudden rise in body
temperature and victims go into a terminal coma. Nor is hyperthermia the
only threat. Henry and his colleagues report 12 cases of severe toxicity
from ecstasy, including seven patients with liver damage. Most of these
patients partially recovered, but one died and another needed a liver transplant.

Another problem is that as demand grows, supplies are increasingly contaminated.
According to Russell Newcombe of the University of Manchester, who spent
the past eight years studying drug abuse in northwest England, ecstasy has
become the most adulterated drug ever used in Britain. ‘When demand outstripped
supply, gangsters moved in to fill the gap,’ he says. ‘Less than half of
the drugs bought at clubs as ecstasy contain pure MDMA. Police have found
capsules containing anything from MDA, LSD and amphetamine to fish-tank
oxygenating tablets and cold cure powders.’

More worrying, he believes, is the contamination with heroin and ketamine,
an anaesthetic used by vets. Little research has been done on the dangers
of mixing drugs. While the effects of any two drugs may be purely additive,
unpredictable pharmacological interactions are always possible.

BIZARRE EFFECTS

How does ecstasy produce its bizarre range of effects? From research
on rats, scientists have known for several years that it boosts the circulation
in the brain of a neurotransmitter called 5-hydroxytryptamine (5-HT), which
is known as serotonin in the US. Like the scores of other neurotransmitters
in the brain’s natural pharmacopoeia, 5-HT acts as a messenger molecule.
It is released at the points – or synapses – where neurons connect and communicate
with each other (see Figure 2).

The biochemical role of 5-HT in the brain is subtle and complex, but
its main task is to modify the responses of neurons to a range of other
neurotran-smitters. This probably explains why it influences that most
subtle of human attributes – mood.

In normal circumstances the brain exercises strict control over the
amount of 5-HT circulating among its neurons. Only a subset of neurons –
those that make up the so-called serotonergic pathway in the brain – have
the ability to release or respond to 5-HT. And even these exercise restraint:
they have special transporter proteins which pump 5-HT out of a synapse
and back into the neuron where it originated soon after it is released.
This means that the 5-HT ‘signal’ is brief and that 5-HT stores inside neurons
are continually replenished.

The main effect of ecstasy in rats is to block the return of 5-HT to
neurons by occupying its binding sites on the transporter protein. Once
inside a neuron, ecstasy – unlike 5-HT – cannot be stored, so it leaks out
again. As a result, levels of 5-HT in synapses rise sharply in the short
term, and 5-HT signalling between neurons is amplified. The ‘high’ this
causes eventually fades when neurons become drained of their stored 5-HT.
Some speculate that this depletion of 5-HT may cause the psychological
‘crash’ experienced by some ecstasy users the morning after.

Antidepressants such as fluoxetine are thought to work by boosting levels
of 5-HT. Moreover, they do this in the same way as ecstasy, by blocking
the transporter protein.

Ecstasy’s influence in the brain is unlikely to be restricted to 5-HT.
Research on rats suggests that the drug has similar, but less potent, effects
on the transporter proteins that control the neuro-transmitters noradrenaline
and dopamine. A close relative of adrenaline, noradrenaline is the main
neurotransmitter affected by amphetamine. Amphetamine prevents noradrenaline
from being mopped up by neurons, and in so doing boosts the amount of noradrenaline
circulating in synapses in certain parts of the brain. Most of ecstasy’s
amphetamine-like effects, including the fight-or-flight response, are probably
caused by increased levels of noradrenaline.

Although the picture is far from complete, the pharmacology of ecstasy
in animals offers some clues to the darker side of the drug. For example,
scientists think that the rise in body temperature observed so clearly in
rats in hot environments may be caused by increased levels of 5-HT in the
part of the brain that regulates temperature, the hypothalamus. In humans,
too much circulating 5-HT may render the hypothalamus unable to respond
appropriately to overheating caused by dancing.

INSIDIOUS SIDE EFFECT

Experiments on animals also hint at a more insidious side effect: brain
damage. American research on rats has shown that a dose of ecstasy equivalent
to about 10 milligrams per kilogram of body weight, which corresponds to
about four injections given over two days, is sufficient to damage the neurons
that release 5-HT in a rat’s brain. The drug causes the fibres, or axons,
through which 5-HT neurons comunicate with the rest of the brain to break
and swell. On top of that, ecstasy appears to block the activity of an enzyme
called tryptophan hydroxylase, which neurons need to synthesise 5-HT.

Perhaps the bleakest message of all for ravers is that primates appear
to be even more sensitive than rats to the neurotoxic effects of ecstasy.
George Ricaurte and his colleagues at Johns Hopkins University, Maryland,
in the US have discovered that a dose of only 2.5 milligrams per kilogram
of body weight is enough to damage 5-HT neurons in the brains of New World
and Old World monkeys. An equivalent dose for humans would be little more
than two 100-milligram tablets – a less than excessive intake for many
regular users of ecstasy.

On the face of it, gloomy news. Yet many researchers remain cautious
about extrapolating such results to humans. Most ravers take ecstasy intermittently,
which may reduce its impact on their 5-HT neurons. Moreover, it is still
not clear whether the brain damage seen in animals is permanent. According
to Rattray, ecstasy damages the fibres of 5-HT neurons but has little effect
on their cell bodies. And that, he believes, could mean the neurons retain
the ability to repair themselves. ‘It’s too simplistic to say that ecstasy
kills neurons,’ Rattray argues.

But what if ecstasy does damage human 5-HT neurons permanently? The
consequences are far from obvious. Destruction of dopamine-producing neurons
causes Parkinson’s disease, and it has long been known that many of the
symptoms of Alzheimer’s disease reflect the gradual loss of a class of neuron
that releases a neurotransmitter called acetylcholine. By contrast, there
is no common disease process which selectively attacks 5-HT neurons. Based
on the normal function of 5-HT neurons, some researchers speculate that
ecstasy abuse could lead to depression, sleep abnormalities and chronic
psychosis. But, as everyone admits, such predictions are no more than guesswork.

Another intriguing question is how ecstasy inflicts its damage on neurons.
Once again, the picture is distinctly hazy. Rattray and his colleague John
Priestly are hoping to glean clues from ecstasy’s effects on genes. Does
the drug interfere indirectly with the activities of genes stowed in the
nuclei of 5-HT neurons? If so, which genes? Elsewhere, researchers are
focusing on ecstasy’s effects on dopamine. According to David Nichols, a
pharmacologist at Purdue University in Indiana in the US, the reason ecstasy
poisons neurons lies in the trickle of extra dopamine that is released when
the drug reaches the brain. In some as yet unknown way, says Nichols, this
dopamine acts to damage neurons that have been depleted of 5-HT.

Nichols bases his theory on experiments in which he synthesised a series
of chemicals with structures similar to MDMA and tested their toxic effects
on neurons isolated from rat brains. Substances that triggered the release
of 5-HT but not dopamine failed to kill any cells, while those that triggered
the release of both neurotransmitters proved toxic. Unfortunately, none
of these substances can be safely given to humans, so it is impossible to
say if they retain the psychoactive properties of ecstasy, or whether mood
enhancement also depends on the release of extra dopamine.

Weighing up the pros and cons, then, how does ecstasy fare in the league
table of recreational drugs? In 1990, the Home Office Statistical Unit recorded
five deaths from ecstasy in Britain. In the same year cocaine caused four
deaths, heroin and morphine, 153 and ordinary amphetamines, two. Cannabis
and LSD caused no deaths.

The death tolls from alcohol and tobacco in 1990 stood at 30 000 and
110 000 respectively. A sobering perspective. Yet these figures may be deceptive.
Tobacco and alcohol have always been readily available and so much of the
annual death toll reflects long-term abuse. It could be years before the
health risks of chronic abuse of ecstasy – in particular, any adverse neurological
effects – show up in the statistics.

Alison Abbott is European Correspondent for Nature.

* * *

A chequered history

Ecstasy’s roots go back to 1914, when a German pharmaceuticals company,
E. Merck, synthesised it from a similar substance called MDA. Both drugs
were forgotten for decades.

In the 1940s, MDA was investigated, and then rejected, first as a drug
to treat Parkinson’s disease and then as an appetite suppressant for the
clinically obese. In the 1950s, both MDA and MDMA turned up on a list of
test agents in the US Army’s chemical warfare programme. Exactly what their
military potential was imagined to be has never been disclosed.

The scientific community became aware of the psychoactive properties
of MDA and MDMA only in 1957, when an American scientist called Gordon Alles
reported his personal experience with MDA at a conference. A relatively
low dose of MDA had caused Alles to experience heightened per-ception and
mild hallucinations.

A decade later, thousands of Californian hippies were experiencing the
same. But the party was short-lived: the ‘love drug’, as MDA became known
, was banned in the US in 1970. Its chemical sibling, MDMA, remained legal
in the US for a further 15 years, but it too was eventually banned because
of its popularity on American college campuses. The British government banned
MDMA in 1977.

Ecstasy’s effects vary from person to person and depend on the environment
in which the drug is taken. The drug induces hallucinations at high doses,
yet its effects are not the same as those of LSD. Nor are they quite the
same as those of ordinary amphetamine.

Most people start with a dose of 75 to 100 milligrams. But regular users
quickly become ‘tolerant’ and often take five times the dose to get the
kick they felt first time round. It usually takes a break of six or more
weeks before a regular user becomes sensitive once again to a normal dose.
Users also report that they cannot intensify the effects of ecstasy simply
by increasing the dose. At high doses, the special hallucinatory-like state
they seek becomes drowned out by ever stronger amphetamine-like effects.