Ecstasy’s Odyssey

What does science tell us about MDMA? It is currently telling us a great deal, and the news is overwhelmingly positive. Over the past decade psychedelic research has made a spectacular ascent from a network of marginalized enthusiasts to the highest peaks of the academy. The path was opened by Johns Hopkins’s Psychedelic Research Unit, which in 2019 was succeeded by the Center for Psychedelic and Consciousness Research and has been followed by dedicated centers and programs for psychedelic studies at Imperial College London, the University of California at Berkeley, the University of Toronto, NYU, Harvard Medical School, and the University of Texas at Austin. Dozens more universities around the globe are conducting studies on psychedelics in their departments of medicine, cognitive research, and psychiatry, driven by voracious student demand: Charles Raison, a professor of psychiatry at the University of Wisconsin–Madison, estimates that 15 percent of students planning to specialize in mental health are specifically interested in psychedelic medicine.

In the race to achieve medical licensing for psychedelics, the compound in pole position is MDMA, or 3,4-methylenedioxymethamphetamine, also known by the street names “ecstasy” and “molly.” It is not by standard definitions a typical psychedelic: as its chemical name implies, it is strictly classified as an amphetamine—a stimulant, though one with unusual mind-expanding and mood-altering properties. Its leading place in the field is in large part the result of determined advocacy by the Multidisciplinary Association for Psychedelic Studies (MAPS), which in 2017 persuaded the US Food and Drug Administration to award MDMA a Breakthrough Therapy designation, fast-tracking clinical trials on its therapeutic use in PTSD treatment. MAPS, which began in the 1980s as an independent nonprofit far from the academic mainstream, is now advancing MDMA through Phase 3 trials, the final phase before FDA approval. At MAPS’s gathering in Denver last June, likely the largest psychedelic conference in history, its founder, Rick Doblin, predicted to a crowd of over 10,000 that MDMA would be officially approved for psychotherapy in 2024.

The recent surge in MDMA research has demonstrated applications that range far beyond psychiatry, from treating Parkinson’s disease and cancer to promoting trust and emotional bonding. The consistency of successful outcomes is striking, especially given the consensus that dominated the field when MAPS was founded. In 1985 MDMA was first criminalized amid a deluge of studies, many of them funded by the National Institute on Drug Abuse (NIDA), that suggested it was dangerously neurotoxic, burning out serotonin and dopamine receptors and causing irreversible brain damage. Public perception of these dangers was cemented by a 2001 episode of The Oprah Winfrey Show that featured scans of MDMA users’ brains, dotted with holes like Swiss cheese, with the claim that they showed where the dopamine system had been drastically depleted. In 2002 researchers at Johns Hopkins predicted a “time bomb” of MDMA toxicity that might leave tens of thousands of users with advanced and incurable Parkinson’s disease. Today’s research suggests that, among many other medical benefits, MDMA might extend the effectiveness of L-DOPA, the leading medication for treating Parkinson’s.

What can explain the 180-degree turn from the late-twentieth-century medical consensus to that of today? It cannot be presented as a simple narrative of scientific progress: there has been no paradigm shift in neuroscience that could account for it. A cynic might suggest that science simply follows the money, and it is true that the funding streams of the 1980s and 1990s overwhelmingly favored studies that elucidated the harms of illicit drugs, particularly their addictive potential, whereas the billions of research dollars now flowing into psychedelics and MDMA are aimed at making the case for their therapeutic and social benefits.

One might also observe that the science has shifted in emphasis, from brains to broader social studies. But perhaps another part of the explanation lies in the substance itself. A continuous thread through psychedelic research, from its origins in the 1950s to today, has been the finding that these drugs increase suggestibility: whatever the question asked, subjects on psychedelics are much more likely to reply in the affirmative. Psychedelic science displays a similarly obliging tendency to produce the results that researchers seek.

The interplay of science and shifting cultural meanings is illuminated by two excellent new histories of MDMA, I Feel Love by the science journalist Rachel Nuwer and The History of
MDMA by the pharmacologist Torsten Passie. Both tell essentially the same story; Passie’s account is underpinned by a deep knowledge of the scientific literature, Nuwer’s by diligent reportage and lively writing.

When MDMA came to the attention of psychedelic science in the 1970s, it was an obscure and little-studied compound. It had been synthesized by German chemists and patented by the Merck pharmaceutical company in the 1910s, long before the discovery of LSD or psilocybin, but apparently it was never tested on human subjects: the patents were issued for its use as an intermediate compound in new drug syntheses. Throughout the first psychedelic era of the 1950s and early 1960s, it was one of a series of synthetic mescaline derivatives, together with similar compounds such as MDA and MMDA, which were covertly investigated by military researchers and the CIA in animal experiments. Along with most psychoactive substances known at the time, some of these compounds had been briefly used as “truth drugs,” or pharmacological interrogation aids, both in Nazi Germany and by US military intelligence, but the classified material that has come to light includes no evidence that MDMA was ever given to human subjects.

The first confirmed personal experience of the drug, reported in detail for the first time in Nuwer’s book, was in 1975 by a Berkeley student named Carl Resnikoff, who had found references to MDMA in the work of the legendary psychedelic chemist Alexander Shulgin. Resnikoff was taking a forensic toxicology class taught by Shulgin, who operated an idiosyncratic private laboratory just outside Berkeley, and the pair synthesized a batch of the compound—legal at that time—in the university’s basement laboratory. One September morning Resnikoff and his partner, Judith, took doses of 120 milligrams, as recommended by Shulgin, on the ferry across San Francisco Bay to Sausalito.

Resnikoff’s description of the experience was oddly muted. He found MDMA benign and pleasant but was struck by the absence of classic psychedelic visual effects. It seemed similar to, though less intense than, its better-known cousin MDA, which had enjoyed a minor vogue in psychedelic circles since the late 1960s. This may explain why Shulgin, who had first synthesized MDMA in 1965 and has subsequently been credited with its rediscovery, had not gotten around to sampling it: he assumed that, as one among many amphetamines with mild psychedelic effects, it would be unspectacular. When he made his first self-experiments with it in 1976 and 1977, he felt a mellow sensation, a “pleasant lightness of spirit” that he compared to a “low-calorie martini.”

It struck Shulgin that MDMA might be useful in psychotherapy, and he passed some on to Leo Zeff, a therapist friend. Zeff, who had worked with LSD before California outlawed the drug in 1966, became one of MDMA’s first champions: he was, as Shulgin’s wife, Ann, described, “completely enraptured” by its ability to free the mind from negative and defensive feelings and to induce a state of openhearted and nonjudgmental honesty. He referred to it as “Adam,” a near-anagram that captured the sense of a return to Eden, and began using it in group therapy.

To nobody’s surprise, the boundaries between therapy and recreation proved highly permeable. Over the next dozen years Zeff administered MDMA to an estimated four thousand people; it was used in personal-growth workshops at the Esalen Institute and at parties that dissolved into group hugs. In the words of Ann Shulgin, it was “penicillin for the soul”: a panacea equally for those who needed healing and for those who simply wished to enjoy life to its fullest.

The first mentions of MDMA in the underground press characterized it as a “new love drug,” but its future was at that point hard to predict. When Timothy Leary tried it in 1978, he found that it generated empathy but pronounced confidently that it would not be a “party stimulant” or “recreational hit.” By the early 1980s, however, it was circulating in the upmarket nightclubs of New York and Dallas, where it was described variously as a new rival to cocaine and as “the yuppie psychedelic.”

MDMA’s ambiguous status—neither quite a stimulant nor a psychedelic, neither a recreational drug nor a psychotherapeutic—resolved into a distinctive identity on the dance floors of the 1980s. Rather than slotting into any existing niche, it created its own all-conquering cultural forms, public spaces, and musical styles. In the clubs of New York, the full moon parties of Ibiza, the Berlin Love Parades, and mass outdoor raves across Britain, it fueled an explosive succession of dance genres: house, garage, techno, Balearic. Its empathic mood elevation turned dance floors into arenas of pulsating joy, and its stimulant properties induced stereotypy—compulsion to repetitive and rhythmic movement—that united crowds under its influence in hours of communal trance and transcendence. The aggression and sexual assertiveness typically associated with alcohol vanished, and with it the need for licensed premises: the experience was similar to a nightclub, indeed better, in an industrial space or an open field with nothing to drink but water.

The scenes that emerged had endless local and musical variations, but their overarching spirit was, in Passie’s characterization, “like a huge, psychedelic children’s birthday party,” complete with balloons, whistles, pacifiers (like other amphetamines, MDMA can cause jaw tightness and tooth grinding), sparkling lights, confetti, and bright splashes of primary and fluorescent colors. Drug enforcement agents, used to dealing with heroin and meth, referred to it as “that kiddie drug.” Its early chemists and distributors attempted to brand it with various names—“empathy,” “therapy”—but the one that stuck was “ecstasy.”

From one angle, all this could be seen as a perfect expression of the Reagan and Thatcher years, an exuberant celebration of individual freedom and consumer choice, but MDMA’s ascent was, of course, in sharp conflict with the era’s hard authoritarian edge and the reenergized war on drugs. During the early 1980s MDMA was still legal, but its growing visibility in the nighttime economy, combined with rare but unexplained MDMA fatalities, later linked to heatstroke, made its prohibition inevitable.

In 1985 Charles Schuster, the head of the University of Chicago’s Drug Abuse Research Center, appeared on The Phil Donahue Show, where he told the audience that MDA caused brain damage in rats at large doses and that there was “a 99 percent chance” that the same was true of MDMA. Shortly thereafter the drug was given an emergency Schedule 1 designation by the Drug Enforcement Agency. During the scheduling hearings, a group of psychotherapy advocates (including Rick Doblin, at that point a young LSD researcher and an Esalen attendee) mounted a rearguard action, claiming that MDMA had valuable medical applications; their testimony led to a temporary reprieve, but they were overruled three weeks later on the grounds that their use of the drug had not been licensed by the FDA. There was still no solid evidence that MDMA at recreational doses was neurotoxic to humans, but it was nonetheless judged to be a drug of abuse and a danger to the public, and after another appeal it was permanently designated Schedule 1, alongside cocaine and heroin.

By the 1990s there were two polarized views of MDMA. In the mainstream media—particularly in the UK, where the rave scene had become a youth culture phenomenon—it was a deadly new drug craze, routinely branded “killer” and “evil” in the tabloids and on television; an unmissable British billboard campaign featured a teenager who had died after taking MDMA with the message that a single dose could be fatal. In 2002 then senator Joe Biden introduced the Reducing Americans’ Vulnerability to Ecstasy (RAVE) Act, which sought to increase the criminal penalties for MDMA and classified pacifiers and glow sticks as drug paraphernalia.

MDMA users, many of whom partied weekly among thousands of others and had never witnessed the negative consequences splashed across the media, inhabited an entirely different world. They believed they were participating in a love revolution that had dissolved the tribal aggression that blighted British youth culture and was transforming society for the better. The British underground activist Nicholas Saunders presented this perspective at an event in London in 1992 called “The Positive Properties of MDMA”—with hindsight a prescient intervention, but one that made no impact on the consensus of the day, which was endorsed by medical bodies and strictly enforced among government scientists. The most high-profile dissenter, the psychopharmacologist David Nutt, chair of the British government’s Advisory Council on the Misuse of Drugs, was fired from his post in 2009 for observing that the risk of fatality from consuming ecstasy was 1 in 5.2 million, compared with the equivalent risk from horse riding of 1 in 3.3 million.

MDMA’s neurotoxicity was accepted as proven fact by politicians, journalists, and medical bodies, but in reality the science remained unresolved. It had been based almost entirely on animal testing, since MDMA’s Schedule 1 listing made human trials illegal without FDA approval, which was virtually impossible to obtain. In the 1980s and early 1990s, the doses used on monkeys and rats to demonstrate damage to serotonin receptors were often orders of magnitude higher than the human recreational equivalent, and studies of more realistic doses that showed no toxic effect went unpublished. In 2000 the Johns Hopkins neurologist George Ricaurte, a protégé of Charles Schuster, was awarded funding by NIDA for a trial aiming to show “that MDMA neurotoxicity generalizes to humans.” Ricaurte injected ten squirrel monkeys and baboons three times a day with two milligrams of the drug per kilogram of body weight; four of the monkeys experienced dangerous increases in body temperature, and two died. When Ricaurte examined their brains postmortem, he found serious damage to the serotonin and dopamine systems. The trial was published in Science and picked up across the media, sparking the scare of a Parkinson’s “time bomb.”

Behind the scenes, questions mounted about a result so far out of kilter with any previous findings on MDMA’s neurotoxicity, and about a fatality rate that was plainly incommensurate with the estimated 10 million US citizens who had by then tried MDMA. After a letter to the editor prompted Science to dig deeper, it emerged that Ricaurte had accidentally given the monkeys not MDMA but methamphetamine, which at that dose was unsurprisingly deadly. Eventually, in September 2003, Ricaurte was obliged to publish a letter of retraction, but this had little impact: NIDA, which had already supported his research with $14.6 million in federal grants, continued to fund his work. (Neither Ricaurte nor any of his colleagues responded to Nuwer’s repeated interview requests for her book.)

With hindsight, this was a fatal moment of overreach for the first iteration of MDMA science, which had evolved against the background of antidrug programs such as DARE, government advertising campaigns (“Just Say No”), and NIDA’s stated mission to address the consequences of “drug use and addiction.” While the Ricaurte story was unfolding, MAPS finally received FDA sign-off on a protocol for human trials of MDMA as a treatment for PTSD, but only after it purchased a $1 million insurance policy to indemnify the review board.

Over the next decade the balance tipped toward activist organizations such as MAPS, buoyed by funders from outside institutional science: Silicon Valley venture capitalists, progressive-minded philanthropists, Bitcoin millionaires. Previously anathemized researchers such as David Nutt found themselves ideally positioned to attract funding for research that aimed to demonstrate the potential of MDMA and other psychedelics to enhance cognition by connecting different regions of the brain, increase neuroplasticity, and shift the ingrained patterns of thought that underpin mental illnesses such as depression. Nutt’s independent research initiative, Drug Science, now operates within the academy as the Centre for Psychedelic Research at Imperial College London.

The current iteration of MDMA science has diversified from the tight focus on brain studies and addiction pathways that characterized NIDA’s program. Clinical trials, led by MAPS’s studies of its effectiveness for treating PTSD, have confirmed Leo Zeff’s initial findings from the 1970s that MDMA can break down emotional defenses, enhancing patients’ ability to face their trauma and put their thoughts and feelings into words. Beyond its medical promise, there has been a growth of interest in its beneficial social effects: recent research has shown that it promotes emotional sharing and reduces negative thoughts, fear, and social anxiety. The most eye-catching animal experiment of recent years has been the neuroscientist Gül Dölen’s work, also at Johns Hopkins, on the behavior of octopuses under MDMA’s influence. Prior to the experiment the creatures were solitary, but as the drug took hold Dölen observed them unfurling their arms and embracing their fellows. Her conclusion that “at least one otherwise tightly wound octopus” appeared to be “really just having a good time” achieved the kind of breakthrough media coverage that Ricaurte’s deadly monkey trials had gotten sixteen years earlier.

In June of 2023 Oprah Winfrey welcomed onto her show Roland Griffiths, the founding director of Johns Hopkins’s Center for Psychedelics and Consciousness Research, to discuss how altered brain states can lead to new spiritual worldviews. The MDMA-fueled rave culture of the 1990s, routinely reported at the time as a “dance of death” or “Russian roulette,” has been reinterpreted in a recent study from the University of Kent as a powerfully positive phenomenon that promoted group bonding among ravers to the benefit of their mental health, satisfying the crucial “need to connect meaningfully with others.”

So, what does science tell us about MDMA? After twenty-five years of further research, the panic sparked in the late twentieth century appears to have been largely unfounded. There is still no clear evidence for any neurotoxic effects on humans at normal doses: MDMA depletes serotonin levels in the short term or in large doses, but long-term studies of former ravers show no cognitive damage separable from concomitant factors such as aging or polydrug use. Ricaurte’s trials inadvertently demonstrated that the drug does not damage dopaminergic neurons; overall, in Passie’s assessment, “it is astonishing how small the long-term effects are” on animals. The deaths with which it is associated in dance clubs appear to be caused by a conjunction of the drug, exhaustion, and the environment—overheating and dehydration leading to seizures and blood clotting—compounded by the unknown strength and purity of street drugs.

Perhaps it is worth turning the question around and asking what MDMA tells us about science. It follows the money, naturally, and so it also follows cultural trends, in particular the perception of whether the drug is an agent of pleasure or of medicine. This is reflected in the emergence of two parallel languages: psychotherapists are careful to speak of “psilocybin” rather than “shrooms,” “MDMA” rather than “ecstasy,” “medicine” rather than “drug.” A recent article in Frontiers in Psychiatry recommended careful use of language to destigmatize the medical use of psychedelics, for example by avoiding terms like “trip” or “journey” and instead referring to the experience as a “therapeutic state of altered consciousness.”

The same precepts are followed by former countercultural advocates such as MAPS, which made an early decision to medicalize its approach by changing the direction of its MDMA research from couples’ counseling to PTSD treatment in military veterans. “Marriage can’t be conceived of as a disease,” Rick Doblin explained to the journalist Lauren Slater, whereas treating members of the armed forces would turn MDMA into, as Slater notes, “a serious, even patriotic drug.”^* The strategy has paid dividends in transforming psychedelic therapy from a progressive to a bipartisan cause: Rick Perry, the former Republican governor of Texas, had a prominent speaking slot alongside Doblin at the recent MAPS conference, hailing the benefits of nonpartisan politics and the potential of MDMA for treating PTSD in veterans.

We might also ask what science will tell us about MDMA in twenty-five years, and how the effusive positivity of the current moment will have aged. Doblin’s keynote speech at the MAPS conference predicted not simply medically licensed MDMA but a wholesale transformation of society by the drug: from conflict resolution to a world of “spiritualized humanity” and “net-zero trauma by 2070.” Whatever the likelihood of its fulfillment—and however “net-zero trauma” might be measured—this expansive vision suggests that MDMA’s future applications are unlikely to be entirely medical.

Ann Shulgin’s description of it as “penicillin for the soul” captures its protean quality and the ease with which it crosses the boundaries between medical and social, body and spirit, hedonism and healing. Nuwer concludes by focusing on its ability to create warm human connection—a precious commodity in a society of increasingly lonely, anxious, and atomized individuals alienated by technology, work structures, and pervasive consumerism. Realizing this potential sounds more like a community or religious project than a medical intervention, but wherever MDMA finds a productive, culturally accepted, and profitable future niche, we can expect the science to follow.