Sunday, April 01, 2001

Our Dangerous Love Affair with Ecstasy

By: Cynthia M. Kuhn Ph.D. and Wilkie A. Wilson Ph.D.

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.

Peace, relaxation, and intimacy: Who would object to more of them in our lives? Advocates of Ecstasy praise the drug as all those qualities wrapped in a pill, along with the cure for everything from the distress of terminal illness to post-traumatic stress disorder and depression. Drug-abuse experts counter that Ecstasy is dangerous, warning of overdoses and, more important, a subtle but long-lasting nervous system toxicity that produces sleep disorders, depression, anxiety, impulsiveness, hostility, and memory failure. 

Who is right? Is Ecstasy a safe fun drug of choice for high-school Ravers and in-touch twentysomethings? Could it be an invaluable aid in psychotherapy? Are the government and its scientists just trying to spoil the fun? The controversy over Ecstasy typifies all that is confusing and contradictory about our use of psychoactive drugs and society’s reaction to them.

FROM ENLIGHTENMENT TO RAVING

The Merck drug company originally patented Ecstasy (methylenedioxymethamphetamine, abbreviated as MDMA) in 1913 in Germany. It languished, mainly unstudied, for many years. The U.S. Army did some research on it in the 1950s, but even those results were not published until the 1970s. In the few studies, scientists found that its neurochemical effects resembled a group of drugs that released brain transmitters such as catecholamines and serotonin. It did not seem unique, but was similar to a chemical cousin, fenfluramine.

During the late 1970s, a group of neuroscientists and psychologists became fascinated with the possibilities of enlightenment that might be obtained from using psychoactive drugs. Timothy Leary led the bandwagon in proselytizing for the use of LSD, but he was not alone. A neuropharmacologist named Andrew Shulgin, as well as others, examined an array of chemical substances known as phenethylamines and indolalklyamines in trying to understand the chemistry of the plant-based hallucinogens like mescaline and psilocybin. These scientists themselves used many of the drugs and catalogued their effects. Shulgin’s book  Phenylethylamines I Have Known and Loved is posted on the Internet, and his followers continue the search today.

One result of their work was discovery of a sense of warmth and empathy engendered by MDMA and its close relative MDA (methylendioxyamphetamine). They coined the term “entactogens” to describe the unique psychological profile of these drugs. Not hallucinogens, not stimulants, they put you in touch with your own emotional state and made you feel self-assured and calm, more loving and empathic to all around you.

MDMA entered the mainstream when these scientists, in collaboration with a group of psychotherapists, decided that the empathic state produced by Ecstasy could be useful in therapy for both increased self-esteem and personal insight, as well as in couples therapy for producing a temporary state of interpersonal empathy during the therapy session. From there, it seemed but a short hop in time into the Rave dance scene, in which party goers took MDMA and danced all night. As MDMA moved out of a controlled research and therapeutic environment, a few deaths occurred, and the controversy was born when the Drug Enforcement Administration in 1985 designated MDMA a Schedule I drug—one with no potential clinical use and significant risk of abuse.

Now, MDMA is rapidly becoming the most popular illegal drug in America. Everyone from teens to boomers seems to be taking it, and it is the only drug whose use is increasing among teenagers. But it is also one of the most scientifically reviled, with worldwide research reports appearing regularly about the dangers of its use—both acute overdose and long-term neurotoxicity. Now, even in the face of this research, a small group of scientists and clinicians is urging that we carefully test the potential therapeutic benefit of Ecstasy, a position strongly opposed by the government.

BIASES AND CONSENSUS

Who is right? We think each group has its biases that keep it from seeing the truth. Let us look first at the purely recreational users. These people simply like the drug and argue that it makes people treat each other well, not badly, as alcohol can. They know that many people take it without immediate adverse consequences, and they absolutely believe that scientists exaggerate the dangers because they disapprove of drug use in general. They remember that scientists were wrong to say that LSD breaks your chromosomes and that saccharin causes cancer, and now they consider current warnings about MDMA more scientific mistakes.

Then there are the scientists who conduct research on MDMA. As scientists, seeking the truth is our profession, but the truth can come in many different forms. Today, research is expensive. The notion that scientists sit in an ivory tower studying problems from which they draw no benefit is long gone. Scientists have to keep their labs funded, and most have to raise their own salaries. So the part of the truth that they discover may be, to some extent, determined by how a question is examined, which in turn is in part controlled by who pays for the research. For example, a scientist can focus on the toxic effects of a drug or can choose a different approach and study its clinical value. Almost all scientists studying MDMA can obtain funding only from agencies that either aim to eliminate drug use (like the National Institute for Drug Abuse) or endorse psychoactive drug use (like MAPS, the Multidisciplinary Association for Psychedelic Studies). Despite scientists’ best efforts, this funding bias can have an effect.

In the current climate, the government, which provides the vast majority of funding, is not likely to fund a study based on the proposition that MDMA could have wonderful clinical utility, because it believes the drug is toxic. Conversely, MAPS is unlikely to fund research on the potential toxicity of MDMA and its analogs, because it believes it can be of value. The many excellent and committed scientists who are studying MDMA walk a tightrope between these interest groups, and although they all seek the truth, they may find only part of it.

The final interest group is made up of the scientists and therapists who are MDMA activists. They believe that MDMA, or some drug like it, could be a powerful agent for personal change. Like the Ravers, their agenda is to prove that the drug is safe and effective. They are vocal, articulate, and committed.

Despite the biases of the various interest groups, there is general consensus about the acute effects of MDMA. It is an amphetamine-like drug, and its physiologic effects are easily explained by what it does in the brain. We have known for decades that serotonin regulates body temperature and that chemicals that quickly release a lot of serotonin can cause lethal hyperthermia. So, when Ravers began to die from MDMA overdoses, scientists were not surprised. The Ravers rationalized that they could avoid toxicity by drinking lots of water or ensuring that their MDMA was not contaminated with the more toxic PMA (paramethoxyamphetamine), which is not entirely true. In fact, the apologists try to rationalize away every such death—ignoring the fact that it is possible to die from an overdose of MDMA, as scientists have shown in the lab with experimental animals.

It is, however, also true that you can decrease your risk by staying in a cool environment and staying hydrated. Furthermore, you can probably take a modest, clinically effective dose and almost entirely avoid potentially lethal effects. In fact, current research studies cannot tell us whether one use of a single, small, and clinically relevant dose of MDMA is any more dangerous than a number of legal drugs.

Most of the effects you see with a small dose are also perfectly predictable. All drugs that release serotonin and catecholamines reduce our appetite, increase our heart rate and blood pressure, and dilate our pupils. MDMA, whether in a therapeutic setting or at a Rave, does all this and causes some nausea, teeth clenching, and a few days of feeling down.1 In return, people describe being in a nearly blissful state—more calm, self-assured, and empathic, with heightened sensory awareness.

DO WE KNOW THE REAL DANGERS?

The long-term consequences of MDMA use present the really contentious issue. Although both advocates and critics mostly agree about what a single dose of MDMA does, they part company when it comes to interpreting the effects of repeated dosing. There is a strange disconnect in our information. We have lots of data from animal studies and an emerging literature in humans suggesting that MDMA damages serotonin neurons, but we do not yet know the consequences of this damage.

Studies in rats and monkeys show unequivocally that a few large doses (at the upper range that humans would take) cause a loss of serotonin nerve endings that lasts from at least one year (in rats) to at least seven years (in monkeys). In some studies, there was recovery in some brain areas, but others showed no recovery. There are a few brain imaging studies in humans using neurochemical markers of serotonin nerve endings showing that heavy users (between 50 and 200 times) have the same type of loss. Levels of the main serotonin metabolite in cerebrospinal fluid also decrease in studies of small populations of heavy MDMA users. As with the acute effects, this long-term neurotoxicity was not a surprise to scientists. Drugs with similar structure and action have displayed the same effect. 

The best science, although not perfect, leads us to the conclusion that a high dose of MDMA is definitely neurotoxic. We have no idea whether small doses produce small amounts of neurotoxicity.

Critics of the human studies take issue with the choice of MDMA users studied and the makeup of the control groups, but the predictability of producing this damage in animals and the parallels between experimental studies and findings in recreational users are compelling. A few studies show that lower doses do not cause measurable damage, at least in rodents. But we just do not know what repeated low doses do to nonhuman primates or humans. The best science, although not perfect, leads us to the conclusion that a high dose of MDMA is definitely neurotoxic. We have no idea whether small doses produce small amounts of neurotoxicity.

Although most likely some damage to serotonin neurons results from MDMA use, we do not know what the behavioral consequences are. Case reports of a single person or small groups indicate that some people experience transient disturbances of mood (anxiety disorders, depression, and the like) between doses of MDMA. Even when they stop using the drug completely, they can experience these problems for months. Recently, several larger-scale studies reported sleep disturbances, anxiety, impulsiveness, sensation seeking, and depression as persistent aftereffects.2 The frequency of these problems varies according to the dose taken, with little evidence that occasional use causes problems, but more frequent reports that heavy use does (50 to 200 times).

Many of these studies could be challenged on their methodology. It is difficult to match subjects for use of other drugs and there is no control over or validation of the doses of MDMA subjects had taken. MDMA users as a group might be more anxious, impulsive, hostile, and depressed than the average population, so the problems found in the MDMA studies may be reflecting their personalities before ever taking the drug. Nevertheless, since these effects are those that would be predicted for serotonin deficiency, it is at least possible that taking MDMA contributed to them.

There is somewhat more consistent evidence that heavy MDMA use is associated with specific memory deficits; at least 15 human studies suggest that repeated MDMA use leads to cognitive impairment, especially substantial memory loss. Again, MDMA advocates criticize these studies on the basis of subject selection and control population. In this case, they argue, correctly, that many of the MDMA users also smoked marijuana, which itself impairs memory. All of the studies report the same problems, however, despite different subject and control populations. Given the consistency among the studies, we should at least consider the possibility that MDMA, not Raves or marijuana, could be the cause.

MDMA IN THERAPY

These toxicity studies focus on possible adverse outcomes of recreational use, but there is another whole side to MDMA: its potential use as a psychotherapeutic agent.

Advocates present evidence on the Internet, in self-published books, and in a scattering of papers in the peer-reviewed scientific literature that MDMA can be useful for everything from troubled marriages to the pain of terminal illness. 

Advocates present evidence on the Internet, in self-published books, and in a scattering of papers in the peer-reviewed scientific literature that MDMA can be useful for everything from troubled marriages to the pain of terminal illness, post-traumatic stress disorder, depression, and anxiety disorders. The data from these reports are as subject to criticism as the neurotoxicity studies in humans. Most reports of clinical efficacy are of individual cases, not placebo-controlled, double-blind studies comparing the therapeutic utility of MDMA to other therapeutic strategies. There are only a few studies in the mainstream peer-reviewed scientific literature, and these, like studies of MDMA toxicity, are based on a carefully selected patient population, who usually have taken MDMA before and so expect to benefit from taking it during the study. Despite decades of privately funded research, the results have not been published in legitimate journals, so the larger scientific community cannot benefit from this information to assess the clinical utility of MDMA.

One likely reason there is little information about potential clinical uses of MDMA is that few physicians advocate using this type of drug for psychotherapy. In addition, most previous research has studied experienced hallucinogen users who are supportive of altered mental states.

Good mainstream science is funded; bad science rarely gets funded. But what about unpopular science that is well-conceived?

Is the small community of interested researchers the only reason there has been little progress? Advocates say that research has been actively suppressed, but scientists argue that credible research always gains support. Both points of view have been heard at scientific meetings. The “establishment” proclaims its support for a diversity of novel strategies, but unpopular ideas probably do not get equal consideration. Good mainstream science is funded; bad science rarely gets funded. But what about unpopular science that is well-conceived? That can be a tough sell that is successful only when the arguments in favor of it are strong.

A broader question here applies to any potential novel therapy: When is the potential benefit great enough to outweigh the risks of trying the therapy? Since we have so little information now, MDMA would start through the traditional pipeline at Phase I trials, in which safety testing and dosing are performed. Only if safety is ensured are later trials conducted to see if the potential treatment is actually effective.

Even to begin testing in humans, it is usually desirable to be in a state of “clinical equipoise,” in which the scientific community is divided over whether the potential new therapy will be safe and effective.3 Does MDMA meet that challenge of balance? What about potential harm? The immediate risks of small clinical doses are small, except for the potential for post-drug letdown and some degree of neurotoxicity, and MDMA has at least some potential benefit through enhancing empathetic feelings.

Making a decision to proceed with research and clinical trials should also be based on consideration of the existing therapies for a given condition. If there are numerous alternative therapies, none of them presenting any physiologic risk to patients, why start with one that presents any risk? This is the territory where MDMA runs into trouble, because most other treatments for the conditions proposed do not have any risk of long term toxicity, although some (like narcotic analgesic treatment for the pain of terminal illness) offer similar risks from overdose. We do not know if MDMA has unique benefits, but we urge that all involved in the argument carefully consider the issue of balance before they proceed.

The question we are really asking is whether we can use the state of heightened awareness and perception that these drugs bring to treat psychological conditions. Right now, this is not accepted medical practice. 

JUDGING ANY DRUG

Now let us do something daring. Assume just for the moment that MDMA is like any other psychoactive drug that we use to treat disease, and hold it up to the same lens that we do all other drugs on and off the market.

  • Do we use addictive or abused drugs to treat disease? We do it all the time. Cocaine, morphine, amphetamines, and barbiturates are all used in proper medical practice, and all are abused by drug users. When we use these drugs clinically, doctors control the dose, the government supervises the prescribing practice, and companies formulate the drugs in special ways. There are a host of basic principles of good medical practice that ensure safe use of dangerous or addictive drugs that we could apply to MDMA. Furthermore, we do not have compelling evidence that MDMA is, in fact, addictive—the jury is still out.
  • Do we use drugs that can kill in overdose to treat disease? Again, we do this all the time. We use morphine to treat pain, and amphetamine to treat Attention Deficit Hyperactivity Disorder, although both can kill in overdose. We even allow ethanol, a highly toxic compound, to be sold over the counter at every liquor store. With all these drugs, as with MDMA, small and clinically relevant doses are fairly safe.
  • Do we use psychedelic drugs to treat disease? We do use drugs that cause dissociative states or hallucinations as side effects— the anesthetic ketamine provides a good example. The medical community, however, views them as undesirable. We are also rapidly embracing the medical use of marijuana, despite its psychological effects. The question we are really asking is whether we can use the state of heightened awareness and perception that these drugs bring to treat psychological conditions. Right now, this is not accepted medical practice, in part because years of attempts with LSD (which are reported in the medical literature) proved unsuccessful. While case reports show that some people given LSD can achieve life-changing states of increased personal insight, the drug-induced state proved too unpredictable to be clinically useful. We are unaware of any substantial data published in the peer-reviewed literature that demonstrate the therapeutic value of awareness-increasing drugs. This does not necessarily mean that these drugs do not have this effect, only that the data are not available in the medical literature for review by scientists.
  • Would it be acceptable to give somebody a hallucinogen for therapeutic purposes if you could control the experience and prove it effective? Some people have said that this is no different than getting a patient drunk, but in fact there are accepted forms of medical therapy in which we seek to lower patients’ inhibitions for psychiatric treatment using hypnosis or barbiturate drugs. Nonetheless, MDMA can cause a rebound “down” phase for a couple of days, even when it is used in clinical doses, and it would be difficult to feel comfortable giving such a drug to a depressed patient, for example. Psychiatric patients also deserve heightened protection because they can be especially vulnerable.
  • Could we use MDMA clinically? We just do not yet have the information that would come from formal and credible research in the peer-reviewed psychiatric literature.
  • Do we use drugs that are neurotoxic? We try not to, but it happens. Remember fenfluramine, which resembles MDMA chemically? One of its forms, dexfenfluramine, is the appetite suppressant Redux, which was withdrawn from the U.S. market when heart valve abnormalities showed up in a number of users. Most people do not know that fenfluramine, like MDMA, damages serotonin neurons. In fact, controversy erupted during FDA hearings about whether dexfenfluramine should have ever been approved in the U.S. Studies in Europe showed a ninefold increased risk in users of a rare condition called primary pulmonary hypertension. Also, scientists wrote to the FDA expressing concern about its neurotoxicity. They argued (and we agree) that this drug never should have been approved, because no one could demonstrate a safe minimal dose that could guarantee no permanent harm to serotonin neurons.

On the other hand, another form of fenfluramine had been on the market as an appetite suppressant for many years, and scientists had not heard reports of anxiety disorders, depression, hostility, or sensation seeking in those who have used it. So the drug was approved, but the unexpected appearance of heart valve damage in patients who used it for longer than the indicated three months resulted in its withdrawal from the market. This controversy still rages, even among scientists.

SAFETY AND EFFICACY

Pro- and anti-drug rhetoric aside, in order to adopt any new drug for treatment of psychiatric disease, the criteria we use now are that it must be proven safe and effective. Let us follow this logic for MDMA.

self-published treatises and Is it effective? As we mentioned, our current knowledge of MDMA’s clinical efficacy comes only from a few articles reporting positive effects, primarily in experienced users who, having had a good experience before, expected to benefit from taking it again. What it takes to prove efficacy is placebo-controlled, double blind studies that can bear up under critical peer review in the medical literature. Normally, no drug would be approved by the FDA without such studies, and they have not been carried out for MDMA.

The next question is tougher: Is it safe? The high-dose toxicities of MDMA could easily be avoided with rational lower dosing for therapeutic use. Neurotoxicity raises a sticking point, however, where we get to the present limits of science. We know clearly that high doses are neurotoxic in rodents, primates, and humans. While there are a couple of studies of low-dose regimens in rats that show no damage, it is difficult to figure out the situation in people. Because all biologic measures have some variance, we can identify and quantify only damage that exceeds that variance. We probably cannot detect 10 percent changes in many biologic variables in the brain, but we can conduct research that shows us statistically significant damage.

We probably would not accept 30  percent damage to our serotonin terminals in exchange for, say, a possibly happier marriage.

Are we willing to accept 10 percent, 5 percent, or even 1 percent damage each time we take a dose? If we are going to take MDMA once, and the damage is 1 percent, we might accept that risk if there were a great benefit. If, on the other hand, we were to need a series of MDMA sessions, and the risk is 10 percent for each session, we probably would not accept 30 percent damage to our serotonin terminals in exchange for, say, a possibly happier marriage.

DO NO HARM

When we consider whether we should work hard to develop clinical uses of drugs that are already widely used for recreational purposes, we run into the same firestorm that rages over the proposed medical use of marijuana. As we pointed out, the simple fact that drugs might be abused does not mean they cannot and should not be used clinically. If you eliminated all drugs that could be abused, there would be no narcotic analgesics to treat pain or stimulants to treat ADHD. The key difference between MDMA and this latter group is that we have proof that the latter actually work.

Another important consideration in developing new drugs is the available alternatives. If a patient is in the final stages of a cancer that has metastasized, then we accept the risk of treating him with a toxic drug with significant side effects because all other treatments have failed. Furthermore, we accept significant adverse side effects if the payoff is big. Antipsychotic drugs can cause terrible side effects, but these are deemed a fair exchange for the marked improvement in symptoms that they can achieve.

We reach a dilemma when we try to judge whether the effects of MDMA are uniquely beneficial, and whether the conditions it can treat are so dire, as to be worth running the risk of potentially damaging neurons in the brain. An important rule of medicine is “do no harm,” but doctors cannot at this time assure patients that they are doing no harm when they give them small doses of MDMA. Another important rule of medicine is to do good, to maximize benefits and minimize risks. Medical ethicists say that the balance between the good you can do by treating with a drug and the potential harm you do because of its side effects should dictate your choices. Can we say that the benefit that MDMA brings to the treatment of psychological disorders outweighs the potential but unknowable risks of neurotoxicity?

BACK TO THE DRAWING BOARD

If we had to decide today what to do with MDMA, advocates and critics would come to opposite conclusions. Probably no amount of information will reconcile these points of view. Part of the difference has to do with how we evaluate risk. Scientists and physicians can take a nearly mathematical risk/benefit approach, weighing the possible benefits of the interesting and unique psychological effects of modest doses of this drug against the probability of neurotoxicity and long-term psychiatric trouble. To us, a “no” vote is dictated by science and ethics.

Not everyone sees the risks as scientists see them. An MDMA advocacy Web site includes a discourse about the potential cognitive impairment caused by MDMA, recommending that people who are worried may consider modulating their dose of the drug. It would never occur to scientists that someone would not view cognitive impairment as an unacceptable risk, so the two are clearly worlds apart.

From the vantage point of scientists somewhat above the fray (we are not active MDMA researchers, although we have done similar work), we conclude that MDMA is a drug with a unique spectrum of action. No other drug is known to create the sense of warmth and empathy that people attribute to MDMA, so we cannot dismiss its potential utility. It can kill at high doses, however, and people use it for recreation in often harmful ways. There may be doses that are not overtly dangerous; also very likely, MDMA causes dose-related permanent damage to serotonin neurons. We cannot predict the consequences of small amounts of damage, but recreational users are conducting that experiment for us right now.  

The authors would like to thank Dr. Jeremy Sugarman for providing a medical ethicist’s view and Nicholas Donoghoe for his research assistance.

 

References

  1. Greer, G. and Tolbert, R. Subjective reports of the effects of MDMA in a clinical setting. Journal of Psychoactive Drugs 18:319-327. 1986
  2. Morgan, M.J. Ecstasy (MDMA): a review of its possible persistent psychological effects. Psychopharmacology 152:230-248. 2000
  3. Sugarman, Jeremy. Ethical considerations in leaping from bench to bedside. Science 285: 2071. 1999.



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Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

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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