'Ecstasy: a Human Neurotoxin?' A Novartis Foundation Meeting. Transcript of Press Conference

Key

AP: Professor Andy Parrott

GR: Professor George Ricaurte

UM: Professor Una McCann

FS: Dr Fabrizio Schifano

Full name of discussants is given. Questioners names are not given.

[...] represents a word not clear enough on tape to transcribe.

Questions are in bold.

Can you discuss the problems in telling us what heavy use represents - I have no idea at all what it might represent - perhaps you could give us the boundaries?

AP: We set artificial boundaries - for instance we say if someone has taken it less than twenty times they are a light user and someone who has taken it more than twenty times is a heavy user, simply to generate groups of people that we can then compare. What you find with that sort of comparison is that the people who have taken it twenty times or more, you've got measurable problems. You've got reduced memory function, you've got impairment on various tasks, you've got questionnaire scores indicating greater impulsivity, compared with the light users who tend to be closer to the non-users.

Does frequency come into this at all? Is a heavy user someone who is likely to use it once a week over a period of youth?

AP: the patterns of use tend to vary a lot. Five years ago patterns of use were quite different to what they were today. The drug was taken far more infrequently, typically one tablet every three or four weeks. These days people are taking more tablets, they are taking heavier doses more frequently and there are also more questions about the purity of the tablets, particularly in Britain.

GR: I think it goes to the issue of this misconception that you need heroically high or repeated dosages to produce this toxic effect in animals. The animal data is very clear on that point - even single doses can produce long term effects. This has been seen in rats as well as in non-human primates. If there is one important notion to dispel it is this: you do not need repeated high doses to produce neurotoxic changes in animals. Ofentimes dosages that you can calculate the equivalent dosages for humans, those are the doses that produce long term changes in the animals.

How much new data are you looking at today?

UM: I presented some data today that are in press - cognitive data from our own laboratory. I also presented some neuroendochrine data using pharmacological challenge to a drug that's known to act on the pre-synaptic serotonin receptors. I also presented some new data that is similar to data found by other laboratories but regarding personality [...] and MDMA users and I also presented some new data regarding sleep changes in MDMA users.

Could you summarise the bottom lines or conclusions from your new data?

UM: Without getting into details because I might get into difficulties with publication of this data later, I can tell you that in all of these areas MDMA users were different from the control group who had never used MDMA but who may have used other recreational drugs.

It would be helpful if you could give us some clue as to what might happen once serotonin is damaged...

UM: I would be happy to entertain that. The precise role of serotonin [...] in the human brain is not known but serotonin has been implicated in a variety of normal human behaviours including sleep. You'll find that many of the mechanisms that have been looked at are those which scientists believe may be affected by serotonin neurotoxicity. So these include mood regulation, anxiety, sleep, aggression, impulsivity, sexual behaviour, neuroendochrine regulation, some very fundamental, basic, physiological roles in the brain.

And is the alteration within heavy or regular ecstasy users one that makes them groupable from the outside, could the rest of recognise that they had been taking.. is there some trauma visible to the rest of the human race?

UM: The studies that we have done, because serotonin has been implicated in all of these behaviours, we did not include individuals who had [...] psychiatric diagnoses related to serotonin because that would then represent a confound to the interpretation of our data. However, there are individuals who do run into psychiatric problems following MDMA usage and Dr Schifano this afternoon will be looking at some of that data.

FS: My name is Fabrizio Schifano and I come from Padua in the north eastern part of Italy. We have studied a group of one hundred and fifty patients and we found out that those people who took a large number of tablets...and now I am going to answer to your question about how many tablets is a large number... we found out that the people taking more than fifty tablets in their lifetime, if you compare them with those people taking less than fifty tablets, the risk was seventy five times higher, which is a very high risk, really a high risk indeed. So, which were the most frequent psychiatric behaviours or psychopathological disturbances? First of all we found depression, mild depressive episodes. Second, psychotic episodes. Third, cognitive discrepancies, cognitive troubles. Fourth, we found eating disorders, and especially a high craving for carbohydrates and chocolate which is quite interesting and curious because when you binge on carbohydrates and chocolate you binge on tryptophan which is the precursor of serotonin. So this is a sort of an overview of the psychopathological disorders.

UM: I would like to make one other point related to this. We don't know what will happen to MDMA users as they age. We know that as we age certain populations of neurons, for example dopamine neurons, drop out. Serotonin not only has function of its own but it is known to modulate other neurotransmitters in the brain system. So it's quite possible that as people advance in age that MDMA users are going to be at a much greater risk of developing some of the neuro-psychiatric syndromes that Dr Schifano has alluded to.

Is there any evidence that there is any synergy between ecstasy and either the other amphetamine like things usually found in the tablets like MDA, MDEA, or with other recreational drugs because in most of the users there is polydrug use, so is there any evidence of a synergy which might cause extra neurotoxicity?

GR: With the particular compounds you mentioned - is there a synergy with MDMA and MDA or another chemical cousin, MDEA - if you look at MDA and MDEA in animal studies, it is clear that MDEA and MDMA have the same potential to damage brain serotonin as MDMA has. I don't know if anybody has put the two together in animal studies to see if you get a greater effect, but from everything that I know I would anticipate that you would see a synergy. With other drugs such as alcohol and some of the recreational drugs, that has been studied much less systematically but the potential might exist in both directions - some of these drugs might provide a neuroprotective effect, particularly if they lower body temperature. On the other hand if it is a drug that increases body temperature, which turns out to be a very important environmental factor, that can markedly influence the toxicity of MDMA in animals. Agents that increase temperature increase the neurotoxicity of MDMA.

There's a real debate about the reversabilty of these effects in animals. Is there any evidence for reversibility?

GR: Very important question - is there evidence for reversibility of the effects in animals? Very reasonable question because neurons or nerve cell tissue consist of a cell body which sends a projection or an axon and terminates on the adjoining nerve cell. What MDMA does is prune the axon terminal, or the nerve ending, leaving the cell body intact. So there's the potential for regrowth. In rodents, given a year to recover, you do indeed see recovery. In most rodents you see recovery of the serotonin nerve cell. Interestingly, in the non-human primates the effect is very long-lasting. We're about to publish a series of studies that show effects as long as seven years after MDMA exposure in the non-human primates.

We have not, as yet, carried out longitudinal studies with PET in humans. In non-human primates we've actually followed them out to about a year, year and a half and you can see the effect over the time although there are important changes.

You seem to be saying that just taking it once is enough to cause damage, or could do in humans aswell as animals, and no-one else seems to be going quite that far. Am I reading you correctly or are some people just very susceptible?

GR: There is no question that in animals a single dose, a single exposure of MDMA can be sufficient to produce long-term changes in brain serotonin neurons.

But do we have any evidence that that could happen in humans?

GR: No, we don't.

UM: I think this also speaks to your question. We know that, for example, in another neuro-transmitter system, dopamine, one does not see overt clinical manifestations of a problem with dopamine, i.e. Parkinsonism, until we have an eighty percent depletion of the dopamine. So it is quite possible that the reason individuals can use fifty or twenty five or twenty doses of MDMA and start developing functional consequences is because they are getting to that point. I think that one has to rely on the animal data to guide us and the animal data suggests that yes indeed a single dose of oral MDMA is likely to produce damage. Whether that damage has long term potential functional consequences is a second question.

Dr Schifano has bravely guessed the number of uses in Italy, do we have any conjectural figures for Britain and the US - the number of people using it?

AP: There's a paper from a couple of years ago which found that 13 percent of university students in Britain had taken it. It was similar across all the universities studied, red-brick and new. There were some differences across faculties - engineers tended to use it a bit less, medical students used it quite a lot.

Do you test on MDMA or street pills?

AP: We do the tests on people that have taken a drug which they say is ecstasy, recreationally. We simply take what people say they have taken - we're studying people that have said they have taken ecstasy. We test what recreational ecstasy users say is ecstasy.

When you give it to a rat or a monkey you're giving them pure MDMA?

UM: Correct.

But when you test on humans it's using ecstasy pills which may not be pure MDMA...

GR: When we test human subjects these are human subjects who have come to us with a history of having used ecstasy in the past. For a number of reasons more recently we haven't been analysing samples of what these people have been taking, partly because we have subjects from the UK coming to Baltimore to participate in the study at Johns Hopkins. At one point I was asking subjects to provide us with a sample of the drug they believed to be MDMA but then I was called on by the institutional review board for having subjects bring illegal substances overseas...

More recently we haven't been carrying out tests of what people take. However, in the studies we performed about six years ago we asked the twenty two subjects to provide a sample of the drug that they had been using that believed to be MDMA. We got twenty three samples (one subject provided two samples - he said this one I think is MDMA, the other one I think is similar but I don't think it is the same). So we had twenty three samples from twenty two subjects. In twenty two of the samples we found pure MDMA. The twenty third sample, interestingly was MDA.

UM: Many of the subjects in the study would tell us now that they believe that some of the samples of the MDMA that they are taking are not as good as they used to be, that a few years ago they were much purer, now they believe that they are being cut with other things as well. Either for cost or other reasons. So your point is a good one that some of these people are quite likely to be exposed to other drugs as well.

AP: This is similar in London. A couple of years ago testing recreational ecstasy users we didn't have any complaints about the purity of the tablets. These days they say that a lot of it is pretty poor.

In your recent Lancet article you highlighted fourteen cases. I was wondering how you selected those fourteen cases out of the hundreds of subjects you studied?

UM: In the Lancet paper every PET scan we did on an MDMA subject was in that paper. The PET procedure has been very recently developed, it's taken years in collaboration with our colleagues at Hopkins to get a radioligand that selectively and effectively labels the 5-HT transporter. As soon as we had ascertained that, yes, this was a valid measure of brain serotonin neurotoxicity in our animal model of the baboon we went on to evaluate human MDMA users and every person, every MDMA user, was represented in that paper.

GR: Just to follow up on that, the selection criteria pre-determined subjects had to be in general good health, between the ages of 18 and 65, be free of any neuro-psychiatric disorder which could be linked to serotonin. There's a number of pre-determined inclusionary and exclusionary criteria. Any subject that met such criteria and was appropriate for the study was included.

Are there any other drugs or disease processes that mimic the effects that we saw on the PET?

GR: That's a very important question. There's a misconception amongst the lay community, but also many neuro-scientists, that many recreational drugs can produce this type of serotonin neurotoxicity. In point of fact the number of drugs that can produce brain serotonin toxicity of the type observed and described after ecstasy is very limited. If you tinker with the structure of MDMA just a little bit you can completely eliminate the toxicity of MDMA. When you get out of the ring-substituted amphetamine class of drugs - marijuana, alcohol and so on - none of those drugs produce the same effects. So it is a fairly unique effect that ecstasy produces from the neurotoxicological standpoint.

It's not been seen in any pathological condition?

GR: That's a good question: do other neuropsychiatric diseases produce destruction of serotonin nerve endings? To my knowledge, no, but since we don't know, since our knowledge is limited in that area, that's why we specifically excluded any neuropsychiatric disease where that was a possibility.

Dr Eric Fromberg: But Fenfluramine is known to create the same changes in experimental animals...

UM: Fenfluramine belongs to this same class of ring-substituted amphetamines

Dr Eric Fromberg: yes, but that at least is another substance that has been used for a long time by many, many people, on a daily basis - Fenfluramine is an anti-appetite pill which people take three times a day for months. It giving exactly the same structural damage in the animal experiments and here we observe the same problem: what are the functional effects? We don't know.

GR: Can I just add to that - in the Fenfluramine exposed human cohort we don't as yet have comparable PET imaging evidence of neurotoxicity of the type that we have collected in the MDMA cohort, but that's a line of evidence that we are currently pursuing.

I don't have a medical background but from what I can understand this has been a test group of about twenty two subjects who have been coming to you and saying what they have been taking over the past few years. So that is going very much on their word and it seems that their word is fairly good in distinguishing between MDMA and MDEA, but I'm unsure whether that is enough to produce medical conclusions. That's my first point - it seems to me that this is all fairly inexact and what we need to be doing is giving people measured doses of something we know exactly what it is...

GR: That's why the animal studies are so important because that's precisely what we can do with animals. Obviously to conduct a similar study of MDMA's neurotoxic potential in human beings would be unethical.

Well, it's happening and has been happening for the past ten years on the dance floor and as somebody who has been vaguely involved in that I can see that in some cases that, yes, people are going over the top and I can see that in a whole range of drugs and to my mind, at least, MDMA is not the most dangerous one by any means, and I'm talking about legal or illegal drugs. So I guess my question is: what you're saying seems to filter down to the general population as 'is ecstasy safe'... what I'm asking is have you compared it with other drugs? Can you say 'is ecstasy safer than, say, ketamine, alcohol, amphetamine, other drugs that are being used'?

UM: I think George alluded to the fact earlier that only drugs in this ring-substituted amphetamine class produce this particular type of neurotoxic imagery. Ketamine actually happens to be a drug that produces a very different problem, but I would put that in the class of dangerous drugs as well. Cocaine, heroin, marijuana do not produce selective serotonin damage. I'm not saying that these drugs are safe - they could cause death for other reasons, obviously they are dangerous for totally distinct reasons, but perhaps one of the most dangerous things about MDMA is the possibility of [...] such that in a few years as people age, or when stressed later in life that the vulnerability of this person is going to greatly increased for the development of severe and chronic neuropsychiatric problems.

Dr Charles Grob: This is speculative. This has not been established.

UM: It is totally speculative. But, Dr Schifano, I think, just told us that it is not totally speculative because the people...

Dr Charles Grob: ...he's got a cohort of heavy, heavy users, polydrug users, likely with significant pre-morbid psychopathology. I think that what this question pertains to is people without underlying vulnerability who are taking modest dosages, maybe even only one time.

UM: As George said earlier, one dose is sufficient to produce a neurotoxic lesion. Perhaps a neurotoxic lesion is not such as bad thing, and we can't really say if it is or not but certainly given what we think the importance of serotonin is in the brain, I wouldn't cavalierly toss the possibility of a neurotoxic injury away.

FS: The study that we did in Italy was retrospective. So it was subject to several biases. But all of the psychopathological disturbances that we have found in the people, according to the people, they developed after the beginning of the MDMA use. Also, all of the people that came to me had already stopped MDMA administration. Most of them had stopped MDMA many months before. They came to me because, as you know, most MDMA users they don't come easily to the drug addiction units because they don't see themselves as drug addicts. So they just come to you if they perceive that they have some trouble. So my guess is that MDMA, especially if you take larger doses, or small doses over a long time, can be really dangerous. I am not working with animals, I am working with humans and it is quite frequent with the humans to take large dosages on only one night in their life, or small dosages, let's say one tablet for eight months each weekend and you can find out psychiatric troubles. I understand that it is easier to make up studies in a prospective way. You take two groups of people. To the left people I administer placebo, to the other group I administer MDMA at a fixed dosage for a long time. And then I sacrifice all of the people and then I can see easily the damage. But it is impossible, for ethical reasons. It is very difficult. We do have a lot of biases in these kinds of studies pertaining to humans, but the animals studies plus the evidence from the retrospective studies in humans for me they are quite dangerous, quite worrying.

Coming back to my earlier question, I get the drift that there is the possibility that serotonin levels are being affected and therefore there is a possibility, unproven at the moment, that there may be longer term effects. My question is how does this compare to the same amount of amphetamine use, the same amount of alcohol use... because ultimately this is the question that people who are going out to enjoy themselves are going to be asking.

GR: I take your point. I would make several points in response. We're not talking about a drug that is [...] affecting serotonin levels. When we talk about ecstasy we're talking about a drug that destroys serotonin axons permanently. That is the reading of the animal literature and that's the reading of the available, validated studies in human subjects. Now, I think the question you are asking is to rate ecstasy relative to other drugs of abuse, in terms of danger. I don't think that's an easy thing to do, depending on what you perceive as risky or not risky. I would say that I know of no other recreational drug outside the drugs in this small class of ring-substituted amphetamines such as MDMA, MDA, that prune serotonin nerve cells in the brain and do so without producing an immediate and obvious change in the user to alert him or her that brain injury has occurred. That's the reading of the available clinical experience to date. To me the fact that we have a potent and selective neurotoxin to braincells, that it can produce these changes without giving an immediate warning that something is amiss, to me that is one of the most insidious aspects about MDMA because it allows the user to continue using the drug for prolonged periods of time, potentially sustaining greater and greater serotonin nerve cell injury and the concern, I think, on many neuroscientists part is does the loss of brain serotonin nerve endings over time put an individual at higher risk for developing the wide array of neuropsychiatric disturbances in which brain serotonin neurons have been implicated. Such as mood disturbance, impulse control, aggressive tendencies, sleep disturbances, anxiety disorders. I think that's the experiment in nature that's currently on-going.

Dr Madhu Kalia: I just want to come back to the question that Dr Ricaurte has raised, and that is relating the animal data to the human data. The validated measures that Dr McCann has used are actually measures of depletion of the 5-HT transporter and metabolite. They are not measures of brain lesions. There is no evidence that there are real lesions in the brain. There is no evidence that there are changes of gliosis, that there is any scarring, that any neurons are lost. What we have seen here in this meeting is that we have gone from depletion measures to some specific measures in animals, very few, and brought it back to the validation studies which only reflect the very non-specific depletors which are the pharmacological effects of the drug. So please remember that we are not seeing brain lesions in animals.

UM: Dr Kalia, I'd like to respond to that. These non-human primates which have "chemical markers", one of which is a structural and one of which is a brain serotonin transporter. Seven years after a four day course of drugs...

Dr Madhu Kalia: How many such animals do you have?

UM: Every single monkey that has been tested to date in many labs across the world.

Dr Madhu Kalia: Seven years later?

UM: The seven years were very recent but...

Dr Madhu Kalia: ...but you see these lesions are the pharmacological, the way the drug acts, by depleting serotonin - there are no brain lesions.

GR: I think that's mis-spoken. We're not talking about a serotonin depletion, we're talking about a loss of every chemical marker of the serotonin nerve cell [...] and that's not only true at seven years, it's also true at a year and a half and it's true two weeks later. Perhaps you missed the earlier portion of the presentation - in the animal data if you look at the entire battery of changes that is observed in animals previously exposed to MDMA, I would challenge anyone in this room to come up with another plausible explanation for the basis of the loss of all of those serotonin neuronal markers over such a long period of time after MDMA exposure. Maybe you don't want to call it serotonin neurotoxicity...

Dr Madhu Kalia: No. I don't, it's a misonomer

Dr Gregory Bock: Excuse me, I think this is a matter we should deal with in the scientific part of our meeting, this is not press conference material, this is part of our scientific discussion.

It clarifies the point, though. I found it quite useful. I don't think there is any doubt, from your research, that there is a problem with serotonin transporters but what you keep saying is that we don't know what the functional consequences are of this. I wonder, having come to the conclusion that there is a cutting down of the end of the axons there, what does that mean? Shouldn't we really focus on that? Is what you have done so far not an interesting conclusion but where does that leave us in understanding what the consequences are? And, if I may, I would like to add to that because you said earlier it is unethical to do research on humans, and I wonder if, given the data you have come up with, it is not unethical not to do it on humans because isn't this what we need... and there are plenty of humans who would volunteer for pure MDMA research...

GR: I think your point is an excellent one because ideally we'd have a prospective, controlled study. The problem with doing such a study with ecstasy is two-fold in my mind. One, I personally would not feel comfortable enrolling subjects, or at least I can perceive considerable difficulties, not only on my part but on the prospective subjects part. Would you, sir or madam, wish to participate in a study the purpose of which is to see whether or not we can destroy serotonin nerve terminals in your brain. That's a problem.

Comment from the floor: People do it every weekend!

GR: The second problem is that despite many claims I don't know of any well-documented study showing that there is a clear medical indication for MDMA. However, as has been mentioned, Fenfluramine is another toxic amphetamine which was used for weight management. In that case I ended up reaching the exact same conclusions you did. About a year or two ago Fenfluramine was being widely prescribed in the United States aswell as abroad for weight loss purposes. And there were so many people using it that I ended up changing my mind

[tape break]

But for Fenfluramine there was a clear indication - people were coming to our university and other centres saying "I want this drug to achieve weight loss" and there was a medical indication. There I felt more comfortable approaching people, "okay, you want this medication, you can have it as part of this trial but be aware that you are running the risk of toxic injury". And if people signed informed consent under those conditions, with a clear medical indication, I think that's one thing. I don't think we have such a clear medical indication for MDMA.

How about supporting people who feel that they do have that, like MDMA within psychotherapy. There are psychiatrists who are happy to conduct research within that field, definitely being convinced that it has got a medical use.

GR: I personally have made at least two efforts to join forces with physicians to carry out exactly those types of test and those attempts have not been fruitful. Despite the many claims about its potential therapeutic efficacy for a plethora of psychiatric conditions, and despite ten, fifteen years of such claims, there is still no documented evidence that MDMA has any medical utility. That complicates research in this field.

Dr Charles Grob: There's no documented evidence because putative medical application has not been put to rigorous testing. There have been no authorised, sound, methodological investigations, in large part because of concerns which you are raising about neurotoxic potential. It's a catch 22 - there's no medical evidence but it's not possible to conduct these studies because of the concerns that you're raising. You also said earlier about this narrow window for putative medical efficacy.I might point out that many established pharmaceutical applications do indeed have a narrow window of safety and if you exceed that window you are putting patients health and life at risk.

We talked a lot about the problems and the possible problems - how can you or do you medically measure the reason why people take ecstasy - can you measure happiness, love, empathy, these sort of things which, let us remember, are the reason that probably half a million people take it each week.

AP: We did a study of London clubbers. These people were planning to take ecstasy so we measured them before they went to the dance club, at the dance club, two days later and then four days later. We had a group of regular users who had taken the drug more than twenty times, light users who had taken it less than twenty times and also non-users who weren't taking ecstasy and weren't planning to. We asked them to rate their moods and what we found was that mood improvement of the ecstasy users compared with the control group was very slight at the club so what was happening was everyone on the Saturday night was having a good time. So ecstasy users were rating high elation, euphoria, all the rest of it as you'd expect, but the thing was, the controls were almost as happy as the ecstasy users - they were having a good time on their Saturday night so the actual benefit of the drug was very slight but what we did find was two days later the ecstasy users had significant levels of depression, sadness, bad temper, irritability, you name it, they were suffering from it because of the neurochemical problems of having taken the drug. So the ecstasy users then had changeable moods during the week, but the controls who had taken alcohol, some of them taking cannabis, a few taking amphetamine, their moods were almost flat during the week. Their mood changes that week were slight. The ecstasy users mood changes were really quite remarkable. So we think that you can have a good time on a Saturday night, at least this is what the ecstasy users were telling us, but the controls drinking alcohol, whatever, going out dancing, were also having a good time, not taking the drug. That's on self-rated mood questions.

I'll take chairman's prerogative and close the meeting now.

4 December 1998

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