Ecstasy and the Brain: Club Drug Rants and Raves

To see someone over 30 at a rave is unusual. Nicholas Saunders was one of the few who fit in, although he could have been a grandfather to the pierced, candy-sucking kids who flock to the orgiastic besotment of the London rave.

“Before I got into this whole rave thing I would tell [rave kids] to just try taking MDMA [the chemical name for Ecstasy] quietly in the country with friends, or try taking it with a blindfold … and none of them would listen,” Saunders told me in 1996. Saunders -- with mismatched socks, slender fingers, and piercing eyes – exuded a quiet intensity. He was the laymen’s expert of Ecstasy. Before he died in a car accident two years ago at the age of 60, he had published several books that acted as “Let’s Go” guides to the Ecstasy scene.

When we met, he had traveled to Baltimore, MD from his home in London to participate in a Johns Hopkins University study on the effects of Ecstasy. As the research coordinator, I interviewed more than two dozen Ecstasy users, ranging in age from 18 to 65. (Footnote: The conversations with Saunders mentioned here were not part of the study. He consented to be interviewed for an article.)

I liked them all. The study participants were an introspective, intelligent lot, and they asked sophisticated questions about the research we were conducting. I came to think of them as Peter Pan like psychological cosmonauts: they showed a child-like curiosity for understanding the mind and for pharmacologically enhanced insight.

But I noticed a generational divide. The study participants fell into two broad camps: The more prevalent under-30 crowd tended to use Ecstasy much more frequently and in higher doses—as high as 10 tablets a night, once a week for the past ten years. The older generation of Ecstasy users took Ecstasy in more moderate doses in quiet environments that fostered reflection, away from the pulsing techno trance.

There’s more than a cultural divide between the different generations of Ecstasy users. The experiences of these two groups were different, and scientists say there’s a chemical reason. The chemical reactions that go on in your brain on Ecstasy at a rave is different than at the psychiatrist’s office.

Generation X
The older generation first started taking Ecstasy in the late 1970s and early 1980s before it became illegal. Back then, a growing circle of psychiatrists exploited the “empathic” affects of MDMA, using it as a tool to enhance communication in psychoanalysis. Psychiatrists say their patients felt less defensive and were more open to explore their fears.

Now, a small community of psychiatrists from around the world is trying to bring MDMA back to its roots in psychiatric treatment. Many drugs, like opiates and marijuana, have a potential for abuse but can also have legitimate medical purposes, Rick Doblin points out. Doblin, president of the Multidisciplinary Association for Psychedelic Studies, has been lobbying for 15 years to make MDMA legal for medical treatment. Last month, he scored a victory: A research team in Spain received approval to start administering MDMA to 29 rape victims as part of a treatment for trauma. “I should frame this letter,” Doblin says, referring to the approval letter from the government of Spain. Trials begin next month. Other groups may not be far behind. Charles Grob at the Harbor UCLA Medical Center in Los Angeles is looking to use MDMA in treatment for terminally ill cancer patients.

But many scientists think MDMA is just too dangerous a drug to have any legitimate use. “There is no safe way to use any of these drugs,” said National Institutes of Drug Abuse Director Alan Leshner recently, referring to Ecstasy and other club drugs used at raves. Many scientists believe MDMA can cause long-term brain damage. And every year, over 1000 Ecstasy users show up in the emergency room with Ecstasy-related problems, according to statistics from the Department of Human Health Services. A few die, although the death rate is a tiny fraction of the rate associated with other drugs such as methamphetamine, cocaine, or heroin. Most of the complications are related to heat stroke or dehydration after taking Ecstasy at a club, experts say.

Is Ecstasy a dangerous club drug abused by kids or a therapeutic medical aid? Bringing MDMA back into clinical practice is a scientific and political fight that will require its proponents to sell the idea that dangers associated with Ecstasy are specific to raves.

Rave on
Raves have morphed from underground, roaming, often illegal parties that last through dawn to regular held events in huge clubs. No longer just the province of metropolitan centers, raves are cropping up in college town, U.S.A. Customs officials have seized almost 3.5 million pills in January and February of this year alone, more than 10 times the amount sold in all of 1993. In a 1999 survey, 8.0 % of high school seniors reported they had tried Ecstasy, up from 5.8% the previous year. As raves become ubiquitous, so has Ecstasy.

Ecstasy provides “a heady cocktail of hedonism and altruism which deepens one’s sense of self-identity while liberating an extraordinary sense of love, compassion, and empathy..." says an Internet rave fan. On Ecstasy, music can feel like an extension of your self, and aggression melts away.

“After I experienced this dance rave situation – which was really extraordinary the first time – I went around telling my generation, ‘you’ve really got to experience this rave setting,’” Saunders said. “Each experience is so good, it’s hard to believe that it could be even better taken another way.”

But it turns out that a hot, crowded environment is the most dangerous environment to take the drug, says neuropharmacologist Lewis Seiden of the University of Chicago. Whether it's broiling or freezing outside, one's internal temperature usually stay put at around 98.7 degrees Fahrenheit - unless you've popped a tablet of Ecstasy.

Seiden has been conducting studies on Ecstasy's effects on the brain since the mid-1980s. While studying the effects of various doses of Ecstasy on rats, he noticed that on some days, regardless of the amount of MDMA given, all the rats died.

He suspected the cause was related to high room temperatures, and Seiden and his graduate student Jessica Malberg decided to investigate. They carefully regulated the temperature of the lab and measured the core temperature of the rats using implanted thermometers as the rats were given various doses of MDMA. Slight increases in the environmental temperature caused larger changes in the rats’ internal temperature. When the rats' body temperature topped 106 degrees F, the rodents started to die. With Ecstasy surging through our veins, our bodies become more susceptible to small fluctuations in the temperature of the environment, Seiden and Malberg concluded. [J Neurosci, 1998 Jul 1 18:13, 5086-94]

Amphetamines, Ecstasy included, already tend to give our bodies a temperature-boosting buzz. Add a weakened ability to regulate temperature, vigorous dancing, and the synergistic blast of hundreds of other warm bodies, and heat stroke can be the-lack-of-a-glass-of-water away.

Malberg points out that their findings make sense considering the historical patterns of Ecstasy-related deaths. "You only began to see Ecstasy users showing up in emergency rooms after Ecstasy became associated with raves," she says. The advice: Stay cool and drink water (but not too much water. At least one death has been attributed to over-ingestion of water). “We know that at the very least, drinking water or going outside if you feel sick can prevent hyperthermia,” Malberg says.

Serotonin side-effects
But Seiden's rats suffered more than just heat stroke. When the temperature was cranked up, the rats on Ecstasy were also more likely to have damage to the brain cells that release serotonin—a chemical molecule in the brain that sends signals between nerves. Research by neurologist George Ricaurte of Johns Hopkins University in Baltimore (my former boss) backs up this claim. He has concluded in several animal studies and two human studies that MDMA can cause long-term damage to the ends of the long branch-like projections of serotonin-releasing nerve cells.

MDMA causes nerve cells (neurons) to release serotonin while also preventing the serotonin from becoming reabsorbed back into the cell. This means there's more serotonin in the junction between cells activating neighboring cells. This increase in serotonin is probably related to the rush users feel for the 3 to 6 hours after taking the drug.

Individual affects vary, but it tends to start with a prickly, tingly feeling in the scalp. Ecstasy heightens tactile sensation, yet seems to decrease sexual aggression. Saunders suggested that one of the main social features about raves is this lack of aggressive sexuality. “Ecstasy has this open feeling without all the sizing up business,” he said. Saunders added that the rush seemed to come on stronger and faster at a rave, and the amphetamine-like qualities of Ecstasy are enhanced.

If Ecstasy can cause damage to the nerve terminals, how does this happen? "No one knows exactly how the mechanism works," says Seiden. A popular hypothesis going around, Seiden says, has to do with the reaction of MDMA with super oxide radicals and hydroxy radicals that naturally float around our brain. In the presence of MDMA, these molecules could combine with the excess serotonin. When this new molecule is taken back up into the cell, it's in a form that may be neurotoxic to the cell. And in the presence of heat, and chemical reactions tend to speed up, Seiden notes.

Previously, Seiden and Malberg had found that serotonin cells could be protected against neurotoxicity when the researchers kept the rats body temperatures down. [J Pharmacol Exp Ther 1996 Jul; 278(1):258-67]. Can keeping cool protect humans against neurotoxicity as well? "I wouldn't make any claims about humans," Seiden says. "We just don't know." Researchers first have to show that keeping body temperatures down in primates protects against neurotoxicity, he says. But the research has yet to be done. "I would advise anyone not to take the drug until we know more about it, unless they want to take risks. But there are risks," Seiden adds.

Researchers suspect that a low level of serotonin might affect a host of behaviors regulated by serotonin, including mood (Prozac also affects serotonin), sleep, and appetite. Neurotoxicity--damage to brain cells that release neurotransmitters like serotonin -- may not kill but may lead to memory loss, sleeping problems, or depression.

Ricaurte's wife and colleague, psychiatrist Una McCann, has been looking for signs of behavioral changes in Ecstasy users. While she and others have found some evidence of mild memory impairments, what others find so striking is the lack of obvious deficits in people who use Ecstasy regularly over extended periods of time. Last month, Ricaurte told Time magazine that his work has never shown that the damage has any visible effect on “the vast majority of people who have experimented with MDMA.” While we may not see obvious signs of impairment now, McCann worries problems may begin to surface with old age.

Scientists disagree as to whether the amount taken during recreational use is enough to cause problems. The animal evidence clearly suggests MDMA may cause long term damage to neurons, but many researchers question the relevance of the data to regular recreational use in humans. The amount of MDMA given to both Ricaurte's monkeys and Seiden's rats were up to 40 times (as scaled for body weight), the amount of Ecstasy in one pure tablet.

And some call the finding in humans into question because researchers have no way of knowing exactly what the users were taking. What’s sold as Ecstasy in clubs usually isn’t pure. A 1996 study done on Ecstasy tablets sold in various U.S. cities by the Multidisciplinary Association for Psychedelic Studies (www.maps.org) found that only 14% of the samples contained pure MDMA. MDMA powder is often combined into tablets of various colors and sizes with MDA and MDEA (two related substances that are a halfway point in manufacturing MDMA) and / or ephedrine, a stimulant often used in asthma treatments.

Psychiatrist Charles Grob at the Harbor UCLA Medical Center in Los Angeles suspects the media place too much emphasis on the neurotoxicity findings and not enough attention on the increased dangers associated with overheating. Indeed, Seiden and Malberg’s work “is the most important research to come out” in the field. Sighing heavily, he realizes the implications: “It looks as if these [rave] kids have found the most dangerous model” for Ecstasy use.