The therapeutic properties of the synthetic compound MDMA, which would soon become known on the street as Ecstasy, were discovered by Alexander “Sasha” Shulgin, a leading researcher for Dow Chemical in the late 1950s and early 1960s who had been so awed by the psychoactive effects of mescaline that he decided to devote his life to experimenting with similar compounds, which he concocted in a backyard lab at his home in Lafayette, California. When he cooked up MDMA and “taste-tested” the drug in the 1970s, he thought he’d discovered a pleasant “no-calorie martini.” Then he increased the dose. The world cracked open.

“I am afraid to turn around and face the mountains,” he wrote in his lab notes, “for fear they will overpower me. But I did look, and I am astounded. Everyone must get to experience a profound state like this. I feel totally peaceful. I have lived all my life to get here, and I feel I have come home. I am complete. I feel absolutely clean inside, and there is nothing but pure euphoria. I have never felt so great, or believed this to be possible.”

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Shulgin urgently contacted his friend, the psychiatrist Leo Zeff, who following the lead of pioneering researchers in the 1950s and early 1960s, had been using psychedelic drugs like LSD, mescaline and psilocybin to assist in therapy with private patients. In 15 years of psychedelic practice, he hadn’t done any formal studies of his results, but his patients often said they felt they accomplished more in one session with Zeff than they had in years of traditional therapy. By the time Shulgin contacted him, Zeff was ready to retire — until he tried the MDMA.

The online Urban Dictionary lists Zeff as “the Johnny Appleseed of MDMA.” Estimates of the number of therapists he persuaded to use MDMA in their practice range up to 4,000, and the number of clients they treated to 200,000.

This gray market in MDMA-assisted psychotherapy was shut down in 1985 when the Drug Enforcement Administration declared MDMA a Schedule I drug — a drug with a high potential for abuse and no medical use. A Schedule I designation made MDMA use criminal and research into its therapeutic potential virtually impossible.

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Some therapists took their practice underground, continuing to conduct illegal sessions in the shadows. But a handful of highly credentialed doctors and researchers — under the unlikely leadership of Rick Doblin, a perpetual college student and former housing contractor turned founder of a non-profit advocacy group called the Multidisciplinary Association for Psychedelic Studies (MAPS) — labored for 15 years to persuade the FDA that MDMA-assisted therapy was safe enough to study under clinical conditions. In 2001, Doblin, who by then was pursuing a PhD at Harvard’s Kennedy School of Public Policy, teamed up with a former Charleston, S.C. emergency room doctor turned psychiatrist named Michael Mithoefer to submit a protocol for a study using MDMA-assisted therapy to treat subjects suffering from long-term, treatment-resistant Post Traumatic Stress Disorder that had been triggered by sexual abuse or rape. The theory was that MDMA’s apparent ability to enhance memory, diminish fear and promote patient therapist bonding would match up perfectly with the pathology of PTSD, a condition that made patients repress traumatic memories and distrust those who tried to help them. In traditional therapy, attempts to approach the root causes — a necessary step in defusing the PTSD cycle — often set off a cascade of negative reactions that only made things worse. Mithoefer wanted to test MDMA’s ability to open a door through the patients’ wall of fear.

In some ways, the timing for attempting to launch the study couldn’t have been worse. Just two weeks after the nearly complete protocol was sent out to colleagues for comment, Alan Leshner, the director of the National Institute on Drug Abuse, spoke before the Senate Governmental Affairs Committee to warn that MDMA use was spreading beyond nightlife into high schools (and middle schools — in 2000, 4.3% of eighth graders said they had tried Ecstasy). Scientists, Leshner declared, had reached “across-the-board” agreement that MDMA caused brain damage.

NIDA launched a public service campaign to persuade potential users that MDMA was dangerous, highlighted by PET scan images of blood flow in the brains of a “healthy baseline brain” compared to that brain two weeks after MDMA use. The colors indicated drastically reduced blood flow, which Leshner suggested indicated permanent brain damage.

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Ironically, what Leshner didn’t know was that the “perfectly healthy baseline” image came from a formerly heavy Ecstasy user who had been abstinent for some time, ironically demonstrating the opposite of what he said it demonstrated: that even a heavy user of Ecstasy returned to apparently normal levels in the long run.

The previous year, an even scarier image popped up on MTV and the Oprah show: a scan of the brain of a heavy Ecstasy user that appeared to show numerous holes where brain tissue should be. These images “tell the story,” Oprah said. But in fact, they didn’t. The “holes” were mapping artifacts. They weren’t holes at all, but artifacts created by coding the computer to represent areas of the brain with a slight decrease in blood flow, which may have been caused by any number of things, as null spaces. But the idea that Ecstasy ate holes in people’s brains seized the public imagination.

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This was the playing field when Mithoefer submitted the protocol to FDA on October 1, 2001, “a major milestone in the history of MAPS, and hopefully in the history of MDMA research,” Doblin wrote on his website. Though literally true, Doblin’s optimism seemed premature, given the black cloud still hanging over MDMA. So it seemed something of a miracle when just one month and one day later, he posted this: “It’s my pleasure to report some excellent news. About 10 AM, Friday, November 2, FDA contacted me to say that MAPS’ MDMA/PTSD protocol was approved.”

But before they could begin recruiting subjects for the trials, they would need to obtain the approval of the Institutional Review Board of the Medical University of South Carolina, where the trial would take place. All human medical research needed not only FDA approval, but the approval of an “IRB” as they were called, which served as a ethical and scientific backstop to protect the subjects’ rights and welfare.

But after several months, Michael got word from a source at the university that the members of the IRB were getting “cold feet about allowing a controversial study.”

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The source was on target: After six months of stalling, it became clear the university had no intention of housing the clinical trials.

Rick and Michael huddled tensely until they came up with a plan B. They would move the trials to Michael’s private office, a 1950s-vintage cottage on the beach road between downtown Charleston and Sullivan’s Island, tastefully remodeled to create a sky-lit, high-ceilinged sanctuary.

Of course the new plan had to go back to the FDA regulators, who didn’t care about the atmosphere. What concerned them was prompt access to emergency care if the experiment went bad. They put a “clinical hold” on the project until the issue could be resolved.

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Michael and Rick ultimately proposed hiring an emergency room doctor and nurse to sit in a spare room in the cottage with a crash cart during all MDMA sessions, just in case. The FDA agreed, and removed the hold.

Seven months had passed.

They found a new IRB — the for-profit Western Institutional Review Board, which claimed to conduct the majority of reviews for new drug submissions to the FDA. The application was submitted on June 19, 2002. Less than a month later, it was approved.

Once again, they were cooking. “We can now definitely say that the US study will take place,” Doblin crowed in a web post. As he went into high gear trying to raise the remaining $90,000 they would need to complete the study, Mithoefer busily began his effort to obtain a DEA license to handle Schedule I drugs. The regulations required that Schedule I compounds be stored in a “securely locked, substantially constructed cabinet.” But an agent in the local field office advised him that “given what you’re dealing with” it would be better to have a safe bolted to the floor and an alarm system. Expensive, and time-consuming, but do-able. The agent told him he should have the license in three to five weeks.

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Mithoefer formally submitted his application to the DEA on July 3.

After a month he had heard nothing back. He called to check on the application’s progress. There had been no progress. Whoever answered the phone told him, “it’s not in the system yet,” and gave him another person to call, who told him the application was on her desk and she was “getting ready to take it to the reviewer.”

Ten days later he called again, but couldn’t get a live human. He left a voice mail message saying he “hoped to avoid further delays.”

He called again in five days and left another message.

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Two weeks later, when nobody had responded to any of his messages, he called once more.

This time he got lucky and the woman answered. She told him that the application was no longer on her desk, but it still wasn’t in the system. She didn’t know why.

When Mithoefer asked if it usually took so long for an application to get “in the system” she said, “this isn’t a priority.”

He still hadn’t heard anything back from the DEA some weeks later when he got a faxed letter from the Western IRB, which, without notification, had reconvened in a special meeting to reconsider their approval of the study protocol. Doblin would report the letter under the headline “Terrible News!” But there really was no easy way to say just how devastating it was. The letter began badly and got worse until it arrived here:

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“The Board concluded that MAPS appears to have submitted information about MDMA in a manner that omits significant facts and that uses information in ways that are overly reassuring regarding the risk/benefit analysis. The Board concluded that both the sponsor and yourself appear to lack the scientific objectivity and rigor required to carry out this research and the research presents unacceptable risks to subjects. … You are directed to immediately terminate all research activities.”

The unexpectedly personal attack almost knocked Mithoefer down. As best as he and Doblin could piece it together in a frantic few days of phone calls, an IRB staff member who had taken exception to the initial approval had assembled a brief against it and persuaded the board to reconvene. He attacked Mithoefer’s credentials and Doblin’s motives. But the ultimate ammunition in the dissenter’s arsenal turned out to be a phone conversation with some researchers who claimed to have as-yet-unpublished data showing that MDMA was far more dangerous than anyone had previously understood.

It wasn’t unpublished for long. Three weeks later, on September 27, an article by a government-funded researcher named George Ricaurte appeared in Science, titled, “Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (‘Ecstasy’).”

The headline is ominous enough even if you don’t speak neurosience. But the translation is worse. The $1.3 million, federally funded study claimed that MDMA was not only damaging the serotonin neurotransmitter system in the brain, but the dopamine system as well, and severely. Attributing specific negative consequences to changes in the serotonin system had proven difficult. But dopamine depletion, over time, led to a well known, and disastrous result: Parkinson’s, a scary, progressively debilitating disease that can ultimately lead to near-paralysis and dementia.

Ricaurte, who had been awarded millions of federal dollars over the years for his MDMA toxicity studies, reported that he had injected squirrel monkeys with MDMA in a regimen he said was “modeled closely” on the way heavy Ecstasy users would attempt to “boost” their high at all-night dance parties by taking another pill (rather than an injection) as soon as the effects of the first began to wane, and so on for hours at a time.

Of the five monkeys, “three tolerated drug treatment without any apparent difficulty. One monkey became less mobile and had an unstable, tentative gait after the second dose, and therefore it was not given the third planned dose. The fifth monkey developed malignant hyperthermia and died within hours of receiving the last dose of MDMA.”

When the surviving primates were killed and autopsied, Ricaurte found something shocking. Previously, many toxicity studies showed that MDMA left the dopamine system unaffected. But this time was different. The dopamine systems of the test animals had been severely damaged.

Alan Leshner, the former NIDA director who had launched the “brain after Ecstasy” campaign with the misleading PET scan images, was now chief executive officer of the American Association for the Advancement of Science, publisher of the journal that printed Ricaurte’s study. His statement on the subject played in newspapers around the world: “Using ecstasy is like playing Russian roulette with your brain function.”

As soon as Doblin saw Ricaurte’s results, he felt certain something was very wrong with them. If these were doses, as Ricaurte claimed, “lower than those typically used by humans,” then the 20% death rate should have been a blinking neon question mark on the study’s validity: Millions upon millions of doses of MDMA had been consumed by humans in uncontrolled circumstances with a multitude of aggravating factors, and yet the death rate was nowhere near 20% -- it was a tiny fraction of one percent. Plus recent human studies, including autopsies of heavy Ecstasy users, not only didn’t show massive dopamine neural damage, it showed none at all.

Doblin wasn’t the only one suspicious.

Dr. Glen Hanson, who was interim director of NIDA at the time of the study, so more or less Ricaurte’s boss, questioned the extreme results as soon as he saw them. As Hanson recalled to journalist Thomas Bartlett for a story in the Chronicle of Higher Education, when he saw Ricaurte he said, “George, we never see this. Where is this coming from?” Ricurte responded, “Well, the dosing paradigm is different and there are some subtle differences and maybe there is just this little window that you don't see unless you do it exactly right.”

"I really need to see this in more animals,” Hanson said he responded. “And you always like to see it done in another lab."

But the study was published as it was, generating world-wide headlines. Hope that Mithoefer’s study would ever get full approval was fading fast. A month later, he got a terse letter: The Western Institutional Review Board, Inc. has made the decision not to provide institutional review board services for the Multidisciplinary Association for Psychedelic Studies

Meanwhile he was getting nowhere with the DEA. Finally, the second week of 2003, Mithoefer managed to reach someone senior at the FDA who told him, “I have no reason to drag this out … but we have some serious concerns and we have given it to somebody else outside the agency to look at.”

As Mithoefer told Doblin in an email, “When I asked him if he could tell me anything about what the concerns were, he would say only that they had to do with ‘safety.’”

Which was odd, and disturbing. It was the job of the FDA and the IRB to determine if the study was safe, not the DEA. The role of the DEA in approving a Schedule I license was solely to ascertain that the drug could be secured from theft and distributed in accordance with the research protocol.

A new IRB – the third they had pursed -- notified Doblin it was tabling their application. A month later, a fourth IRB that had agreed to review the protocol informed them it had changed its mind. By the end of summer, more than a year after the Western IRB had originally approved the protocol, they were applying to a fifth IRB, responding to yet another long list of questions and concerns.

In early September, Rick got a call from a source at Johns Hopkins: Something big was about to be published concerning Ricaurte’s MDMA-dopamine study.

Rick had no idea how big. On September 5, Science published Ricaurte’s full retraction:

“We write to retract our report ‘Severe dopaminergic neurotoxicity in primates … following our recent discovery that the drug used to treat all but one animal in that report came from a bottle that contained d-methamphetamine instead of the intended drug, racemic MDMA.”

Methamphetamine?

The irony wasn’t lost on Rick and Michael:

The drug that had been “mislabeled” as MDMA and proven so horribly toxic that it had stopped Michael’s study cold; the drug that was far more toxic than actual MDMA, methamphetamine, already was a prescription medicine.

Excerpted from “Acid Test: LSD, Ecstasy, and the Power to Heal” by Tom Shroder. Copyright © 2014 by Tom Shroder. Reprinted by arrangement with Blue Rider Press. All rights reserved.