THE PEOPLE'S PROZAC

Dissident Scientists Question the Ban on Ecstasy

Consider the two dosing lines for America's young people--the one outside
the club and the one in the school nurse's office. At the door to raves,
kids stand with Ecstasy pills on their tongues, waiting for the weekly surge
of empathy and good feeling that comes from the combination of hallucinogen
and amphetamine. For this rush, which was legal before 1985, they risk jail
terms and the loss of student aid.

But every day outside the nurse's office, roughly 2 million kids line up for
their daily dose of stimulant, very likely Adderall, a prescription
amphetamine that is quickly replacing Ritalin as the drug of choice for
attention deficit hyperactivity disorder. For this high, which is said to
help learning, teachers and parents lend encouragement.

The double standard, says neurotoxicologist Dr. James O'Callaghan, points to
the nation's blind spot when it comes to Ecstasy, also known as MDMA.
O'Callaghan says that chemical cousins Adderall and Ecstasy carry similar
risks, but while one is considered safe for America's youth, the other is
its scourge. Maybe the government's line--that MDMA causes brain
damage--isn't so clear-cut after all. ''You can buy d-amphetamine on the
street, and that's bad, but you can give the same compound to a kid
chronically--twice a day, every day for the rest of their lives,'' says
O'Callaghan. ''If you truly believe MDMA is bad, then why would you give
Adderall to your kids?''

In an America that has declared war on Ecstasy, O'Callaghan's is a lonely
voice of dissent. This summer, Florida senator Bob Graham introduced the
''Ecstasy Prevention Act of 2001,'' which would provide more than $22
million for stepped-up law enforcement, a ''national youth antidrug media
campaign,'' and the creation of a new test to suss out MDMA users. New York
senators Hillary Clinton and Chuck Schumer are co-sponsors of the bill,
which came on the heels of a two-day conference at the National Institutes
of Health in Bethesda, Maryland, that presented some of the latest research
findings.

So why all the fuss about a little pill? Ecstasy, like a host of legal drugs
on the market, affects the chemical serotonin, which regulates critical
brain functions like mood, aggression, sexual desire, sleep, and sensitivity
to pain. By decreasing serotonin, scientists can send you spiraling into
despair; alternately, by increasing it, they can lift you out. Yet for all
their tinkering, surprisingly little is known about the brain chemical--we
still don't know, for instance, why serotonin affects mood; it just does.

As part of its campaign against club drugs, the National Institute on Drug
Abuse is running ads that picture ''your brain on Ecstasy'' as a lump with
dark blotches and holes. And the pitch goes, ''Chronic use of MDMA can
produce long-lasting, perhaps permanent, damage to the neurons that release
serotonin.''

Not necessarily true, says O'Callaghan, who works for the federal Centers
for Disease Control and Prevention. He says these ads are misleading because
they leap beyond what we already know--that administering the popular club
drug, also known as MDMA, carries the aftereffect of temporarily decreasing
serotonin. ''It looks like a blank slate, but it comes back,'' says
O'Callaghan. ''I'm not saying that MDMA isn't bad. I'm just saying that
there's no evidence that it destroys serotonin neurons.''

While clinical trials treating mental disorders with MDMA have never been
conducted, proponents say anecdotal evidence from before 1985, when the drug
was still legal, looked promising. It appeared to help people open up during
psychotherapy, and some doctors suggested it could aid trauma victims or
people suffering from terminal illness.
Now researchers are gearing up to try again. In late September, scientists
at the Medical University of South Carolina will submit a draft protocol to
the FDA for a study examining Ecstasy-assisted psychotherapy for the
treatment of post-traumatic stress disorder.

Some even foresee a future where a few doses of Ecstasy, taken in a
therapist's office, replace a lifetime of couch sessions and serotonin
manipulators like Prozac. Those supporters include Rick Doblin, president of
the Multidisciplinary Association for Psychedelic Studies. Despite its
flaky-sounding name, the group has actually funded much of the current
research--pro and con--on Ecstasy. Presently, it's backing a study in Spain
that uses the drug to help rape victims recover.

''MDMA could be a tool to get you past drugs,'' says Doblin. ''Prozac is a
tool to get the pharmaceutical industry rich.''

Ecstasy, like Prozac, primarily targets serotonin-producing nerve cells. It
is inside the axons--the part of the cell that sends out signals--that the
chemical is stored. Under normal conditions, the brain works on electrical
signals that cause the axon to release some of its serotonin into the
synapse, or the gap between neurons. Any excess is then either broken down
or reabsorbed in a recycling process called re-uptake.

MDMA, however, can cause a neuron to dump its entire store of serotonin into
the synapse, flooding the adjacent neuron's receptors. This time, excess
serotonin is not recycled: MDMA causes the transporters responsible for
re-uptake to flow out instead of in. It is this massive serotonin overload,
combined with secondary effects on the brain's dopamine system, that
produces Ecstasy's loved-up sensations.

What happens next is less clear. According to Dr. George Ricaurte, a
neurotoxicologist at Johns Hopkins University School of Medicine, monkeys
dosed with MDMA show evidence of ''pruning''--a rewiring of the brain's
serotonin system in which longer axons are lost, replaced by a dense growth
of shorter ones. This pruning phenomenon remained evident eight years later,
and although there's no proof of permanent changes, that's also, says
Ricaurte, ''a pretty long time, given monkeys live 25 years.''

Since these changes are associated with decreased serotonin levels and lower
numbers of serotonin transporters, Ricaurte believes they indicate damage
from Ecstasy. ''It's a harmful drug, and it's harmful in doses used by
humans,'' he says.

O'Callaghan thinks this view is too simplistic. He says that just because
the drug affects serotonin doesn't mean the damage takes place in those
neurons. The rewiring, he argues, stems from something other than injury.
''The pruning phenomenon is not necessarily reflective of damage,'' he says,
''just profound and long-lasting changes.''

He contends that if MDMA caused nerve-cell degeneration, star-shaped cells
would form, leading to an increase of the glial fibrillary acidic protein,
or GFAP. ''Any chemical known to damage the brain has caused an increase in
GFAP,'' explains O'Callaghan. ''We don't see that response with MDMA.''

While detractors agree that GFAP is a valid indicator of brain damage, they
still take issue with O'Callaghan's measurements. ''MDMA is a potent brain
neurotoxin. The entire field reads the literature as such,'' says Ricaurte.
''Are all 100 nails in to shut the coffin? No. But are there 70, 85, 90? At
what point do you look at the data and say it's met a certain criteria? That
criteria's been met long ago.''

O'Callaghan doesn't get invited to speak at many conferences anymore--even
though he has been publishing extensively in this area for years. So
politicians end up listening less to dissidents like him than to
mainstreamers like Ricaurte and Dr. Alan Leshner, director of the National
Institute on Drug Abuse. In a hearing before the Senate Subcommittee on
Governmental Affairs this past July, Leshner stated, ''There is substantial
evidence to show that MDMA damages brain cells. Within the scientific
community we cannot say with absolute certainty how and to what extent...but
there is across-the-board agreement that brain damage does occur.''

But O'Callaghan believes the whole idea of neurotoxicity--of brain
damage--has been tossed around too freely. A single dose of reserpine, a
prescription drug used to treat hypertension, markedly lowers serotonin
levels for extended periods. ''It's just as neurotoxic as MDMA, if you
equate neurotoxicity with serotonin decrease,'' he says. ''But if you look
at damage as defined by loss of structure, you don't see it with MDMA , even
in whopping doses.''

The long-term consequences of MDMA use are similarly ill-defined. ''The
evidence up to date has been pretty crummy,'' Dr. H. Valerie Curran, a
psychopharmacology professor at University College London, told the NIDA
conference in July, noting that the most consistent findings relate to
learning and memory. ''The effects are subtle, but have real implications.''

If MDMA does indeed cause brain damage by pruning the neuronal pathways,
then a whole host of serotonin agents, including Prozac and Adderall, could
be rewiring, and thus damaging, our brains. The latter--often given to
hyperactive children--is particularly worrisome, say critics, because it
also affects dopamine, which helps the immature brain develop normally.

A paper co-authored by O'Callaghan in Brain Research last year concluded
that all compounds acting on the brain's serotonin system can cause changes
in serotonin neurons. O'Callaghan says the creation of these abnormalities,
including corkscrew-shaped neurons, could be part of Prozac's desired
therapeutic effect.

While scientists like Ricaurte say Ecstasy is a much different drug from
Prozac, it's not that different from the amphetamine Adderall. They admit
that the research on such pharmaceuticals is still lacking. ''I think we
need more experimental studies addressing that question,'' says Ricaurte.
''We know amphetamines can damage dopamine cells. What is not known is
whether the amount of amphetamine used in kids is the amount required for
toxicity.''

This scares O'Callaghan. ''You can market a compound,'' he says, ''unless it
puts holes in your head.''

What separates a good drug from a bad drug? Why is it OK to prescribe
amphetamines to children but bad when they ingest them for fun? Drug-company
ads pitch chemical remedies for everything from social anxiety to severe
PMS. Since 1970, their profits have more than quadrupled; roughly a quarter
are from drugs that affect the central nervous system and sensory organs.
More people are taking more pills--whether Ecstasy or Prozac--to feel
better. Yet the war on drugs drags on.

For Ecstasy, it began in the early '80s, when rising use and a ''designer
drug'' media scare forced the Drug Enforcement Agency to take notice.
Although a judge ruled during 1985 hearings that MDMA had therapeutic value
and could be safely administered under medical supervision, the opinion was
struck down by the DEA's director. The drug became illegal, and the black
market boomed. Next came Ecstasy of questionable quality and potency.
DanceSafe, a nonprofit that tests the purity of pills at raves, reports that
dangerous adulterants like the cough suppressant DXM and the hallucinogen
PMA are on the increase, and says these compounds are the prime culprits for
Ecstasy-related visits to emergency rooms.

For now, Ecstasy's medical potential is all anecdote and no hard fact.
Little data exists on its therapeutic value.

But that's not for lack of trying, say supporters of MDMA-assisted therapy.
Dr. Charles Grob, director of Child and Adolescent Psychiatry at the Los
Angeles Department of Mental Health, was the first researcher to gain Food
and Drug Administration approval for a study of MDMA, submitting a proposal
in the early '90s to treat people with end-stage cancer. The agency
initially turned him down, saying a trial was first needed to determine the
drug's dosage and safety. After that was completed, Grob went back to the
FDA with what he thought were promising results. Again, the government
turned down his bid to test Ecstasy among cancer patients. ''The bottom line
was political, I felt,'' says Grob. ''This would have been the first
treatment protocol. This kind of schedule-one drug, with abuse liability,
would have been very controversial.''

Doblin is more optimistic. ''I think the FDA is the most immune of all
agencies to outside pressure. They're sympathetic to patients.'' He also
believes the FDA may take issue with the South Carolina study of Ecstasy and
post-traumatic stress disorder on the grounds that it's too risky to
decrease the serotonin levels of depressed subjects.

It may be this psychoactive element that most hinders the progress of
Ecstasy as therapy. With medical marijuana--which has gained acceptance and
been doled out for decades to a handful of patients in a federal
program--the high is almost a side effect, since the real good comes from
increased appetite, decreased nausea, and a lessening of spasms and pain.
With Ecstasy, the benefit is the high.

In this way, Ecstasy is more like the roster of mood elevators prescribed
every day. Without the media scare, a company application to market this
drug now, says O'Callaghan, would pass government muster. ''MDMA would have
slipped through as an approved drug,'' says O'Callaghan. "No one would think
a priori that it was causing damage.''