Sunday, April 01, 2001

Seeking Insight by Prescription

By: Stephen Braun

The high that they call “Ecstasy” has been illegal since 1985, banished into Schedule I, the government’s category for criminal drugs. Now, two things are happening. People (mostly young) are risking the penalties and the sometimes fatal danger of overdose to make MDMA (methylenedioxymethamphetamine) the fastest growing illegal drug on the street. And a resolute band of scientists and advocates, who remember when MDMA was used in psychotherapy and still believe it uncaps personal insights available in no other way, are pressuring to have it reclassified as a prescription drug.

In the late summer of 1984, a college student walked up the steps of the Drug Enforcement Administration headquarters in Washington, DC, to do battle. He did not expect to win.

At the time, the War on Drugs was urging Americans to “Just Say No” to illegal drugs. Texas Senator Lloyd Bentsen, who would later run for vice president with Michael Dukakis, had been informed earlier that year about an amphetamine-like drug being sold openly to enthusiastic users in Texas bars. It was a seemingly new drug, cooked up in the sophisticated labs of modern drugmakers. Called “Ecstasy” on the street, its chemical name was methylenedioxymethamphetamine, or MDMA for short. Because MDMA’s molecular structure was novel, it was as legal and easily available as aspirin. Sellers in Texas put up fliers advertising the drug and accepted credit cards as payment.1 Even though the drug was said to be mild compared to LSD or heroin, and at that time no deaths had been associated with it, Bentsen asked the Drug Enforcement Administration (DEA) to ban MDMA by putting it in Schedule I, the most restrictive of five such schedules governing drug use. Schedule I drugs are deemed to have high potential for abuse and no medical or therapeutic uses, hence they are illegal except for the small group of scientists who have research licenses to study them.

On July 27, 1984, the DEA announced its intention to schedule MDMA. Believing that MDMA was just the latest in a long line of “designer drugs,” the DEA did not expect any challenges to the scheduling.

So it came as a complete shock when Rick Doblin, then a student at New College in Sarasota, Florida, walked into DEA headquarters to present a formal legal challenge by a group of respected physicians and scholars to the proposed scheduling.

Doblin and two fellow students, Alise Agar and Debby Harlow, had recruited these experts and spearheaded the legal challenge because they knew what the DEA did not: that MDMA was not new (it had been patented in 1912 by the German drug company Merck), that it had been used by some psychotherapists, and that some of these therapists claimed it was a useful adjunct to psychotherapy with a low potential for abuse.

In the months to come, three public hearings entertained arguments for and against scheduling MDMA. The hearings were organized and presided over by DEA Administrative Law Judge Francis Young. Many therapists, psychiatrists, and patients came forward in the hearings to plead for a less restrictive scheduling—one that would allow for continued use of MDMA on a prescription basis and for research unshackled by the heavy restrictions placed on Schedule I drugs. The resulting testimony filled 10 volumes of transcripts. The MDMA advocates were stunned when Judge Young announced his recommendation on May 22, 1986.

“The record now assembled contains much more material about MDMA than the Agency was aware of when it initiated this proceeding,” Young wrote. “The evidence of record does not establish that MDMA has a high potential for abuse. It cannot be placed in Schedule I because it does have a currently accepted medical use in treatment and it does have accepted safety for use under medical supervision. Based on this record it is the recommended decision of the administrative law judge that MDMA should be placed in Schedule III.”

“I was really surprised,” says Doblin, who now heads the nonprofit Multidisciplinary Association for Psychedelic Studies. “My first reaction was, ‘My God, the system works at some level.’ ”

“We felt good,”recalls Lester Grinspoon, M.D., now emeritus associate professor of psychiatry at Harvard. “That was exactly what we wanted and we thought we had won the day.”

The victory, however, was short-lived. John Lawn, administrator of the DEA, immediately announced that he would place MDMA permanently in Schedule I. Advocates for the therapeutic use of MDMA sued his decision in federal district court—and again won, though this time the arguments turned on technicalities of law rather than the weight of scientific or clinical evidence in favor of MDMA’s safety or clinical efficacy. Following the court decision, the DEA corrected the procedural problems and inconsistencies identified by the court and again put MDMA in Schedule I, where it has remained to this day.

THE RISE OF RECREATIONAL USE

Except by a handful of maverick therapists willing to risk fines and imprisonment,
there has been virtually no therapeutic use of MDMA since the 1986 scheduling. Research into the potential therapeutic utility of MDMA has been very limited. Meanwhile, recreational use of MDMA has soared.

“It’s a misnomer to call MDMA a controlled substance because it is so obviously out of control.”

 “It’s a misnomer to call MDMA a controlled substance because it is so obviously out of control,” says Charles Grob, M.D., professor of psychiatry at UCLA School of Medicine and one of the scientists urging more research into psychedelics. “It has certainly controlled the use of these drugs by reputable investigators; however, it has allowed for the uncontrolled proliferation of use out there in society, particularly by the more vulnerable, self-destructive members of society.” 

The spring 2000 survey of teen drug use by the Partnership for a Drug Free America found that teenagers’ use of Ecstasy has doubled since 1995, from 5 percent to 10 percent. The National Institute on Drug Abuse reports MDMA-related deaths in major cities around the country and frequent calls to poison-control centers and emergency rooms in conjunction with MDMA problems. At first glance, 2001 seems like an even less opportune time than 1985 for advocates to press their fight for looser restrictions on MDMA.

But that is exactly what they are doing. They argue that its placement into Schedule I was an ideological, not a scientific, decision that has “locked up” a medicine with the potential to facilitate psychotherapy and treat such conditions as alcohol and drug addiction, post-traumatic stress disorder, and refractory depression. Advocates also assert that the illegal status of drugs such as MDMA makes it difficult to confirm and extend the substantial, but methodologically weak, literature on this therapeutic potential. Some advocates look forward to the day when MDMA, LSD, and other currently illegal drugs are approved as prescription medicines with proven uses and widely accepted methods of administration and use. As unlikely—even dangerous—as that goal might sound to some people, it may not be far off.

SHIFTING STRATEGIES

Like the youth of the 1960s and 70s themselves, advocates for therapeutic use of currently illegal drugs have honed their strategies and become more sophisticated. The weapons in this fight are not the ballot box or the courts—the favored weapons of the past—but are more clever, expensive, difficult, and risky.

“I think there’s a realization that the only way to be heard is to do it above board in a sanctioned context and make the scientific case,” says Professor Grob. “The goal is to develop research protocols using state-of-the-art scientific methodologies and working with reputable groups within university medical school settings to implement these investigations.”

“We should be true to the data rather than waging a media war.” 

With a reference to Harvard’s psychedelic guru of the 1960s, Doblin says: “I see one of my missions as helping to bury the ghost of Tim Leary so we can move forward with a new generation of research that is more contained within the scientific context. We should be true to the data rather than waging a media war.”

To this end, Doblin has raised hundreds of thousands of dollars for research programs on MDMA and other illegal drugs—research that he says is conducted by scientists following rigorous, FDA-approved protocols. Doblin has supported scientists and reported research results even when they have not turned out as he hoped.

For example, in 1986, as the hearings on MDMA’s legal status were under way, Doblin volunteered as a subject in a study he helped to fund. The study was conducted by George Ricuarte, the most frequently cited scientist on the topic of MDMA’s effects on the brain.2 “I was basically daring George to find any brain damage,” Doblin recalls.

Ricuarte had done some preliminary studies using high doses of MDMA in rodents. Results suggested the drug might damage serotonin-releasing neurons in the brain. “I felt that the people with the deepest vested interest in knowing what was happening were the users,” Doblin says. “We don’t want to be poisoning ourselves. If there’s a problem, we want to know.”

Doblin recruited 20 other MDMA users for the unpleasant study. Since it is impossible to measure neurotransmitter levels in a human brain directly, Ricuarte performed spinal taps on the volunteers in order to measure the levels of a primary serotonin metabolite in the spinal fluid. It was a relatively crude way to assess damage to brain serotonin neurons, but it was all he had. Doblin was confident that Ricuarte would find nothing.

“Subjectively we all felt fine,” he says. “I thought this study would end the discussion about neurotoxicity and we could move on to studies of therapeutic usefulness.”

But Ricuarte did find something. Volunteers had, on average, 25 percent less serotonin metabolite than a comparison group of people who had never used MDMA.3 “I was surprised,” Doblin says. “We found a difference. That’s not to say we found a problem. We still haven’t found a problem—but the difference was there. And that meant we needed more studies to figure out if this difference meant something. I never thought that 15 years later we would still be struggling with the neurotoxicity issue.”

SHIFTING PARADIGMS

Reference to the scientific method by Doblin, Grob, Grinspoon, and many other physicians and therapists puts them, intentionally or not, on the same side of the methodological fence as the leaders of the government’s major antidrug efforts.

“Look, I’m a public health guy,” says Alan Leshner, Ph.D., head of The National Institute for Drug Abuse (NIDA). “You need to separate whether a substance is abusable from whether a substance is also a medicine. When it’s a medicine, I’m for it. Morphine is an example. Morphine is an incredibly abusable substance; however, when used for pain it’s a terrific medicine. Ritalin is another example. Amphetamine is an example. When they’re used as medicines, I’m for it. When they’re being abused, I’m against it. With MDMA and other illegal drugs, when they’re shown to be a medicine, we’ll conduct a scientific analysis and recommend that they be moved out of Schedule I. I think anything’s movable, but my bottom line is that I want to know the answers before we do something.”

Millions of people have taken their doctors’ recommended medications to help them cope with fear, anxiety, depression, and even mild disturbances in mood that in an earlier era were considered nomal.

Another significant cultural change is the pharmacological revolution in psychiatry. In the past 20 years, millions of people have taken their doctors’ recommended medications to help them cope with fear, anxiety, depression, and even mild disturbances in mood that in an earlier era were considered normal. The result is a much broader interest in the interplay between brain chemistry and well-being.

“I think the widespread use of drugs like Prozac is going to help,” Doblin says. “The use of antidepressants is getting people more and more comfortable with the idea of substances that don’t feel false. That was a big issue: that drugs induced a false sense of this or that. But now you have a lot of people saying that using these drugs makes them feel more like themselves. So the lines between licit and illicit are getting harder to draw.”

INSIDE MDMA

From a strictly neuroscientific view, MDMA is an interesting molecule. Although, as its name implies, it is closely related structurally to amphetamine, it is just different enough to have profoundly different actions in the brain. Like a weak amphetamine, MDMA appears to cause the release of dopamine, and research has shown that the effects of many drugs, including cocaine, crack, amphetamine, and alcohol, are due to the ability of these molecules to release dopamine in the brain.

But unlike amphetamine, MDMA’s major effect appears to be on neurons containing the neurotransmitter serotonin. MDMA seems to cause a direct release of presynaptic stores of serotonin into the synaptic cleft, the microscopic gap between neurons. It also appears to block reuptake, or reabsorbing, of serotonin by brain cells, thus prolonging and amplifying the effects of serotonin release. It is the release of serotonin and the stimulation of a subset of serotonin receptors (the 5HT2 family) that is alleged to be responsible for the qualities of MDMA that may make it useful in psycho-therapeutic settings. The subjective effects claimed for a typical 125-milligram oral dose include reduced anxiety and defensiveness, enhanced ability to confront trauma or emotional discomfort, greater insight into oneself and one’s behavior patterns, enhancement of empathy, and a sensation of openness and connection with others.4

The physiological effects of MDMA include pupil dilation, modest increases in pulse and blood pressure, a tense or chattering jaw, reduced appetite, and feelings of heat and/or chills. Although the sensation of touch is often enhanced and users feel unusually close to those around them, MDMA is not reported to have significant sexual effects. It does not stimulate the libido and often retards orgasm. The alterations of consciousness induced by a standard dose typically last three to four hours, with the peak sensations lasting between half an hour and one hour. Sleep can be disrupted if MDMA is taken in the evening.

These experiences are set in a context of an overall mental stimulation said to be largely devoid of perceptual changes and without hallucinations (in contrast to a major effect of another illegal serotonin-releasing agent, LSD). Users often talk freely and copiously during an MDMA therapy session and can easily respond to questions or guidance from a therapist.

“You can liken using MDMA in therapy to using anesthesia during surgery,” says Julie Holland, M.D., assistant professor of psychiatry at New York University School of Medicine and a practicing psychiatrist in New York City. “It allows the doctor to go much deeper with much less pain. You can get to the malignant thing that needs to be examined and removed. It can make therapy much more efficient.”

The validity and longevity of personal insights attained through use of MDMA (or other drugs) have long been viewed with much skepticism.

SUSPICIOUS INSIGHTS

The validity and longevity of personal insights attained through use of MDMA (or other drugs) have long been viewed with much skepticism, and scientific doubters far outnumber believers.

“The problem is that no one has ever shown in a methodologically reasonable way that the ‘insights’ gained while intoxicated are either accurate or useful in one’s normal state,” warns Steven Hyman, M.D., director of the National Institute of Mental Health. “The apparent ‘insights’ experienced during acute intoxication with hallucinogens may be no more than drug-induced illusions that disappear in the light of day.”

While agreeing with Hyman in principle, advocates say the sheer number of reports in the literature or their own personal experience suggests that such insight can be lasting. “I don’t think that insights gained under the influence of a drug fade more quickly than insights gained through more traditional means,” Grinspoon says. “I think these insights can stick to the ribs, so to speak, and become integrated into one’s way of thinking about the world and one’s self.”

THE PLURAL OF ANECDOTE

Obviously, personal opinions cannot satisfy the demands of science or of government agencies charged with protecting the public from ineffective or dangerous drugs. Claims of drug efficacy must today be proven with placebo-controlled, double-blind clinical trials and large numbers of experimental subjects. Studies based on anecdotal evidence are dismissed. As NIDA’s Alan Leshner likes to say, “The plural of ‘anecdote’ is not ‘data.’”

Advocates agree with the need for careful studies, but they take issue with the constant dismissive characterization of anecdotal evidence. Scientific inquiry does not begin with double-blind studies, they argue. It begins with ideas, findings, and hypotheses that are based on personal observations, case studies, hunches, intuition, and other forms of “anecdote.”

“Anecdote is a different kind of data,” says Grinspoon. “It’s data you have to be much more cautious of. But many medicines, including aspirin, insulin, and penicillin, were developed and approved for use prior to the invention of the double-blind study. It’s also important to remember that double-blind placebo-controlled studies are not perfect either. Look at all the drugs that have been recalled by the FDA that had passed through the double-blind process.”

Still, MDMA advocates have embarked on the long, expensive, and risk-filled road of acquiring nonanecdotal data—data obtained using the current gold-standard methodologies for drug evaluation. Doblin, one of the main organizers of the effort, estimates the task will consume five years and at least four million dollars.

An equally challenging task will be to explain, refute, and overcome a veritable mountain of data collected in the past 20 years linking MDMA to long-term damage of the brain’s serotonin system. 

Nor is that the only difficulty advocates face in their effort to turn MDMA into a medicine. An equally challenging task will be to explain, refute, and overcome a veritable mountain of data collected in the past 20 years linking MDMA to long-term damage of the brain’s serotonin system.

THE NEUROTOXIC DEBATE

Advocates and skeptics agree on some major issues concerning the data on MDMA neurotoxicity. They agree that giving rats, dogs, and monkeys high doses of MDMA changes the axons of serotonergic neurons and that these changes can last many years. There is also little disagreement that people who report having used MDMA extensively (and who often use many other drugs besides MDMA) do not score as well on tests of mental functioning as do control subjects (who are often graduate students). Most MDMA advocates agree with Leshner that the drug should not be used regularly or at high doses by anybody, but particularly not by young people.

“We’re not trying to say that MDMA is harmless,” Doblin insists. Instead, Doblin and others argue that the data from high-dose experiments, while potentially relevant to Rave dancers who use MDMA several times each weekend, are not relevant to therapeutic use.

“The bottom line is that even with those animals given mega doses to the point where they could identify the so-called neurotoxic findings, they’ve had a hell of a time trying to demonstrate behavioral abnormalities,” says Grob. “I’m not at all an advocate for the frequent administration of MDMA, or a high-dose administration of MDMA. For a variety of reasons that can be problematic, and I have a lot of concerns about recreational use. But a moderate dose used once or a handful of times in the context of ongoing psychotherapy? I believe that thorough, objective investigations may show that the benefits outweigh any risks. And ultimately, it’s a matter of risks versus benefits. There is no substance without risk.”

Advocates argue that in all the data thus far collected, nobody has found evidence of harm at the levels being suggested for therapeutic use: 100 to 150 milligrams once or, at most, three times a year. For instance, Ricuarte and his team found no effects in squirrel monkeys after giving them oral doses of 2.5 milligrams per kilogram of body weight every two weeks for four months (equivalent to giving a 150-pound human 168 milligrams of MDMA with the same frequency).5 In another study, 1.25 milligrams per kilogram of MDMA given orally twice daily for four consecutive days produced no detectable long-term serotonergic changes in rhesus monkeys.6

Moreover, the meaning of the neuronal changes seen in some of the high-dose animal studies is hotly debated. Those who argue that the changes are not relevant to therapeutic use of MDMA were bolstered this year by a study that found nearly identical types of serotonin neuron damage with high doses of some popular antidepressants. In a recent issue of Brain Research, Madhu Kalia of Jefferson Medical College and her colleagues report clear evidence of morphological changes in serotonin-containing rat neurons following administration of fluoxetine (Prozac), sertraline (Zoloft), sibutramine (the weight-loss drug Meridia), and dexfenfluramine (one of the drugs in the infamous Fen-Phen weight-loss regimen).7 As is typical in toxicology studies, all doses used, including the doses used for MDMA, which served as a control, were far higher than are typically used: 10 times and 100 times the normal therapeutic dose for each drug.

Kalia’s study showed that two FDA-approved and widely used antidepressants have a similar capacity to induce serotonergic damage as MDMA. Advocates say the point of the research is not that Prozac is harmful and should be banned, but rather that many drugs can be shown to be neurotoxic if given in sufficient quantities.

These are the kinds of data on which the case for FDA approval of MDMA in therapeutic settings will rest. The arguments will be technical; details of methodology will be challenged, supported, and refuted. The weapons will be sophisticated and highly technical concepts and facts. This is a novel strategy indeed for MDMA advocates.

Their goal is to follow FDA guidelines and modern methodologies to demonstrate MDMA’s effectiveness in the treatment of a single, specific psychiatric condition: post-traumatic stress disorder. PTSD is a debilitating condition of fear, anxiety, depression, and a host of physical symptoms arising from the experience of war, abuse, disaster, or other severe trauma. If controlled clinical trials ever demonstrate that MDMA is significantly better than a placebo or as effective as Zoloft (which has already been approved for PTSD), then the FDA may have little choice but to approve MDMA for use. But that would not end the battle.

FDA approval does not mean that MDMA will be automatically rescheduled. That is a separate process governed by the DEA. In this struggle, advocates will not be seeking a blanket shift to Schedule III (commonly used for prescription drugs). Instead, the goal is to place MDMA in a so-called bifurcated schedule—meaning it could be manufactured, distributed, and prescribed as a Schedule III drug when used by specially certified physicians for therapeutic goals, but it would remain a Schedule I drug for everyone else, that is, illegal as a recreational drug.

This is exactly the type of scheduling given to GHB, or gamma-hydroxybutyrate, a date-rape drug that has legitimate medical uses. The pharmaceutical company Orphan Medical is now developing GHB under the trade name Xyrem for the treatment of narcolepsy. Following lengthy clinical trials, the drug was recommended for approval this June by an FDA advisory panel charged with evaluating its scientific merits. If it gets FDA approval, that would be good news for advocates of MDMA. It would model a system that bases a drug’s legal status on how it is used rather than simply on the nature of the drug itself.

Whether MDMA, or any of the hundreds of other drugs now in Schedule I ever become prescription drugs remains to be seen, but the terms of engagement have changed significantly from those of 30 years ago. Science, data, and reason now exist in a dramatic tension with the hopes, fears, and dreams of players on both sides of the debate.

References

  1. Cohen, Richard S. 1998. The Love Drug: Marching to the Beat of Ecstasy, Haworth Medical Press, Binghamton, NY. p. 24.
  2. I made repeated attempts via phone and e-mail over the course of two months to interview Ricuarte and one of his chief collaborators, Uma McCann. Neither of them responded.
  3. Some controversy exists about this study because Ricuarte could not ethically expose “normal” volunteers to spinal taps. He thus used samples of spinal fluid obtained from people who had had the taps as part of a diagnostic work up for chronic pain. The difficulty is that some, but not all, studies show that chronic pain raises serotonin levels. Hence Ricuarte's control group may not have been a valid comparison.
  4. For fuller descriptions of the range of MDMA experiences, see “Pursuit of Ecstasy: the MDMA Experience” by Jerome Beck and Marsha Rosenbaum, 1994, State University of New York Press.
  5. Cited in Vollenweider FX, Gamma A, Liechti M, Huter T (1999). Is a single dose of MDMA harmless? [letter]. Neuropsychopharmacology 21: 598-600.
  6. Baggott, BA and Mendelson, J in Ecstasy: The Complete Guide, J. Holland Ed. In Press.
  7. Kalia M, O'Callaghan JP, Miller DB, Kramer M (2000). Comparative study of fluoxetine, sibutramine, sertraline and defenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry. Brain Research 858: 92-105.



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Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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