The People's Prozac
Consider the two dosing lines for America's young peoplethe 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 linethat MDMA causes brain damageisn'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 chronicallytwice 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 chemicalwe 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 knowthat 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 researchpro and conon 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 axonsthe part of the cell that sends out signalsthat 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 anymoreeven 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 neurotoxicityof brain damagehas 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 latteroften given to hyperactive childrenis 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 pillswhether Ecstasy or Prozacto 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 Harbor-UCLA Medical Center, 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 marijuanawhich has gained acceptance and been doled out for decades to a handful of patients in a federal programthe 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."
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