d) Discussion
Erik Fromberg, Trimbos Instituut, Netherlands; Karl Jansen, South London and Maudsley NHS Trust, UK; George Ricaurte, John Hopkins Bayview Medical Centre, USA; Emanuel Sferios, Harm Reduction, Hawai`i, USA.
Question 1: In a neuroscientific context, would the long-term effects on health of taking ecstasy occasionally be greater or less than the long-term effects on health from going to prison for being in possession of ecstasy?
George Ricaurte
When I use the term ‘toxicity’ or ‘neuro-toxicity’ it is really within the description of a neuro-scientist. I am specifically referring to ‘a persistent alteration in the serotonin system’. As a neurologist I see the delicacy of brain cells that do not tend to grow back with any great ease and that is why I talk about toxicity. I do not pass a value judgement saying, "If you have damaged or destroyed or altered the serotonin system in the long term it is going to be good or bad". I do not mean to imply one or the other.
Eric Fromberg
I agree with findings of animal data although the more specific question of interest is "What is the lowest safest dose of MDMA?" This question cannot be answered definitely based on the data and it shows the significant differences of opinion between different researchers. For example it has been clearly proven that a dose of 1.7mil per kilogram gives no indication of a lasting serotonergic disfunction. How do we translate all the data from neuroscientists into something that we can tell people? People ask whether neuro-toxicity means they will be ‘vegetables’ within 30 or 40 years because of the dying off of serotonergic neurones. There are two points that suggest the effects on some people may not be as serious as it is presented.
Fenfluramine gives exactly the same type of changes in the serotonergic system when applied to non human primates and to humans. Fenfluramine or "Pondlmin" is a very common, extensively used appetite suppressant, taken by millions of men and women three times a day. In these people there are no clear signs of an important change in their serotonin functioning over the years, while the frequency of use is much higher than the highest frequency of use for MDMA as far as we can estimate. This might be an indication that although these changes appear there are no lasting consequences on the functional, clinical levels of everyday life.
What is seen from long-term ecstasy users who still do not show any negative effects is anecdotal evidence. For the moment we know that Alexander Shulgin and a couple of others have taken enormous amounts of MDMA, but the implications of use in the long term are completely unknown. They do not show any evidence for any real important changes.
George Ricaurte
Ecstasy is a drug that can produce a long-term harmful effect on your cells and the animal data would suggest that the single dose you take may be sufficient to produce a partial toxic effect. I would call it a toxic effect because scientifically it looks like it is pruning the serotonin neurone. The animal data shows a toxic effect on brain cells but it is not known how this translates into function and whether it will become a major public health problem of the millenium. That should not be taken to mean that everything will be okay.
Taking the dopamine nerve cells as a precedent, they are important in movement and if you destroy over 80 or 90% of them you become ‘parkinsoniam’ and you develop what looks like Parkinson’s disease. You can destroy 30% or 40% of the dopamine cells and look normal. Heroin addicts who got into a toxic drug called MTPT that was harmful to dopamine cells ended up destroying over 90% of their cells and they were obviously parkinsoniam. Thus, whether people who take MDMA appear normal or not, we do not know if there has been partial injury that is not clinically evident, and further more we do not know what the long term effect is. Regarding the fenfluramine example, while I agree in many respects, it is important to recognise that it was withdrawn from the Swedish market because of neuro-psychiatric problems and it was withdrawn from the Danish market. We do not know in the case of fenfluramine if there are long-term effects. The kind of studies that are needed to make sure that there are no long term effects have not been carried out either for MDMA or fenfluramine.
Karl Jansen
MTPT is a completely different drug to MDMA and the example is reassuring rather than worrying with respect to MDMA. The young men who took the MTPT developed parkinsoniam symptoms almost immediately and the fact that we have so many people taking MDMA for so long who have not developed very much is quite reassuring.
George Ricaurte
Research has to be done with a clear understanding not only for the researcher but also the research subject, of potential risks and potential benefits. For example when you give a subject (be it an experienced user or a naive user) a dose of 1.5-2 milligrams per kilogram, that individual is being put at risk of incurring some of the serotonin changes. If a local review board perceives that the risks are to be counter balanced by potential benefits that would come from the study then that is a decision for the researchers to make. Given the risks I do not think it is the kind of research that can simply proceed without any careful consideration of the subjects.
Karl Jansen
It is important to remember that in the American Constitution the pursuit of happiness is enshrined. So if ecstasy, which a lot of people do want to take, was shown to be neuro-toxic, would the government have a moral obligation to invest some money in developing ecstasy-like drugs which are not toxic?
Question 2: Most people are willing to take risks, while there are some people who avoid harm and will never take MDMA because of this data. As a harm reduction or policy maker how do we assess the risks involved compared to the perceived and real benefits of recreation?
Emmanuel Sferios
Many laboratories around the world have been doing work on the toxicity of MDMA. By contrast you can count on one hand the number of laboratories that have been looking at the pharmacological effects (the usual drug effects) and how it is that MDMA produces this apparently unique constellation of effects in humans. There is a great imbalance. This has to do partly with the fact that over the last twenty years, people in the toxicity area have done a very good job documenting what they mean by toxicity or long term effect, but there has not been enough work on the part of the people who say that MDMA has some therapeutic potential. It is disappointing that to this day there has yet to appear a study that documents some useful potential of MDMA. Without that evidence it is very hard to go to a review board and give reasons for the study, saying what the benefits and the risks are.
Karl Jansen
It is difficult to assess the outcome of psychotherapy and the question raised is one that has been asked about psychoanalysis and psychotherapy as well. It has taken about one hundred years to develop any sort of method for assessing those sorts of outcomes. It really is a subjective issue - people just say "I am less aggressive now", "I feel better now and wiser" or "my interpersonal relations are better" but it is very difficult to document that.
Some types of research are hard, but not impossible to do. Maybe ten, twenty, thirty years ago that line of research was much less mature. Nowadays people can establish the efficacy of antidepressant and anti-anxiety drugs. The effect of a drug that is said to make your life better may be much harder to measure precisely and this is certainly a challenge.
Question 3: People who take MDMA can significantly decrease the risk and protect themselves by taking Prozac. From the point of view of secondary, not primary prevention, what is the actual dose level of Prozac needed to protect against the neuro-toxicity of MDMA?
Erik Fromberg
Data from many laboratories shows that if you take Prozac or any serotonin re-uptaker (the classic drugs that Prozac belongs to) with MDMA, you completely protect against the serotonin toxic effect. All the research has been on rodents, none of it has been on primates. College students who said they had taken Prozac and then taken MDMA reported that they still experienced the desired subjective effect of MDMA. (These reports were anecdotal, not hard science). I do not know if a human could be different from a rat. There are secondary effects of Prozac - one would want to do the studies in primates to make sure that no unexpected effects were occurring.
A study has just been completed which concludes that people who take Prozac do not experience the usual subjective effect of MDMA. So at least on a theoretical level one of the potential problems of saying to a user of MDMA to use Prozac as a secondary safety measure would be that they would not experience the usual MDMA effect. There is no hard data so far to indicate that Prozac will not interfere with the desired subjective effect, and thousands of reports from users who take Prozac and experience a significantly reduced effect from MDMA.
In the animal studies the neuro-protective effect of Prozac existed even if the Prozac was administered up to six hours after the MDMA. This would mean that in the case of the neuro-toxic effect, after the "come down", after the serotonin has depleted, is the time when the Prozac offers the protection. Therefore users could enjoy the subjective effects as well as prevent adverse effects.
Karl Jansen
There are many confounding factors when researching people who use a lot of different drugs such as trying to fish out one effect from another. People who take a lot of ecstasy do lots of everything else as well and are daily cannabis smokers. People who take Prozac everyday have to be asked why they take it - it is usually prescribed for depression. Perhaps when they did not get the usual effect of the ecstasy, they were taking Prozac everyday for depression or had a neuro-chemical problem.
It is very difficult to do research at the human end, considering the many different effects of poly-drug use. Some of the research is almost impossible to do unless you admit people to a ward for months, and that takes tremendous resources. Ricaurte has probably come closer than anybody to doing things in the way in which they are supposed to be done but it is very difficult for people with fewer resources.
Question 4: What are the differences in the pre-existing conditions between people who may become heavy ecstasy users or users and people who don’t?
George Ricaurte
Briefly, I can answer that by really going back to a point that was made previously. The human studies are very difficult to do. One of the reasons could be pre-existing differences. Another as Karl points out, are that people take lots of other drugs besides MDMA. I think that is where the animal data is very helpful - you know in animals how much we give, what we give, when we give it. It is the animal data that makes the human data a bit easier to interpret.
Erik Fromberg
The only thing the animal data does not tell us is what will happen to us. That is a big problem.
George Ricaurte
We do not do that. It is not our line of expertise. That is not to say that people have not studied animals functionally. At least in terms of the vast majority of the study this would lead to them thinking the animals look normal.
Karl Jansen
My understanding of the animal studies is that you cannot differentiate an animal with these persistent changes from an animal that does not have the persistent changes on the basis of the animal’s behaviour. I have done a reasonable amount of neuro-science, mostly in the human brain, and having watched the Alzheimers story unfolding year after year since the mid 80s. What I remember from that period was that there were papers in Nature on how some serotonin receptors were down and other indicators were down and everything you could look at was changed. That was in a respected journal. When we look back at that now at the end of 1999 most of it is completely irrelevant. I mean there are some important changes involving glutamate and acetyletoline but a lot of these other things just did not turn out to be very relevant.
What this makes me think is that important questions are raised by George’s work about what the role of serotonin actually is and whether that role can be easily taken over by other neuro-chemicals in the brain. The conclusion I draw is that the role of serotonin can be fairly easily taken over by other neuro-chemicals in the brain because animals with persistent changes in serotonin, post ecstasy, are not more depressed or anxious than control animals. Serotonin is a very old neuro-chemical. We can trace serotonin a long, long way back in the evolutionary tree. It is not the most important neuro-transmitter in the brain by any means. The most important neuro-transmitter, by an enormous distance, is glutamate.
In statistical terms just about every cell in the part of your brain that makes you human, your neo-cortex, uses glutamate as its messenger. It is glutamate that gives you language and thought, and it is vastly more important in memory than serotonin. Glutamate is the main messenger in the hippocampus and in the frontal lobe. If you block it you do not remember anything. It is not a subtle effect. That is what PCP does- blocks glutamate. That is what you lose in Alzheimers disease; you lose these glutamate pathways. It is a vastly more important neuro-transmitter.
Dopamine is also a much more important neuro-transmitter than serotonin. If you block dopamine you do not get subtle effects, you get Parkinson’s Disease. The appendix has been removed for years and whether it is important or not has been re-examined recently. I think we have to wonder whether or not the role of serotonin can be taken over by other neuro-chemicals. I think that is a very important question. The lack of clinical effect of having persistent changes after ecstasy suggests that other chemicals do take over.
Question 5: What do you recommend that we do to protect ourselves against MDMA toxicity?
George Ricaurte
I certainly would not take it in a room where the ambient temperature is hot, as a practical matter. Ten years ago when we first began these studies it was very unusual to find subjects who would take three, four, five, six pills over a twelve hour period. That has come in with this dance situation. The norm used to be one tablet and maybe three, four hours later another half tablet. That is what the subjects all told me. Then they might go without using MDMA for four, six, eight weeks, months sometimes. From what we know in the animal studies this is a much less risky pattern than someone who would take three, four, five doses over a ten, twelve hour period. That is just a formula for producing the effect on animals.
Just because we do not know does not mean that serotonin might not be important- remember serotonin is implicated in things that are hard to measure in animals. How in the world do you measure impulse control in an animal? How do you measure mood in an animal? Those are very difficult things. Finally, I should emphasis that even though we know little about long term effects in humans it is not that we do not know anything. There are at least three or four studies pointing to possible effects on memory functioning in human beings. Certainly there is no scarcity of individual case reports of people who have got into trouble with MDMA so it is not a totally innocuous drug when used in its usual setting.
Karl Jansen
Every time you read a paper about the effects of drugs on memory you should always look for urine analysis result. If you do not see urine analysis results for cannabis and other drugs then I think you really have to treat that study and its results much more carefully. You really need to see some positive proof that no other drugs and their breakdown products are involved. I think that failure to do so is a major failing in a lot of the work that has been done.
I will give you my personal opinion. I do not think we know the mechanism of the persistent post-ecstasy changes yet. It is a very important question. I know a lot of people talk about certain different theories but the bottom line right now is that we do not know how MDMA prunes these terminals. We do know Prozac and other transporter blockers are protective and if we understood more about how they protect we would understand more about the mechanism. We would love to know what the mechanism is, to see if what we have learnt teaches us something about Parkinson’s disease, Alzeimer’s disease or mechanisms of cell degeneration but we do not know yet.
Emmanuel Sferios
I have done a lot consulting with researchers around the country and we have a neuro-chemistry slide show on our web site ‘ harm reduction.net’ which has a visual presentation of some of the current theories on MDMA toxicity taking you through the data that Dr Ricaurte showed us. We have got a lot of positive feedback, that those have been very helpful in allowing people to understand the mechanism or at least the current theories.
Question 6: How do you feel that your research and your conclusions may be unfortunately contributing to some of the alarmism in the press around the drug?
George Ricaurte
I hope the data that we are generating is not contributing to any of the alarmism. It is remarkable to me. The messages are very simple when we do the studies- not only us but lots of laboratories in Europe, in the States, everywhere. The message is that MDMA can produce these long-term effects at doses which are right in the order of those taken by humans. We do not have to give the animals very high doses to produce the long-term effects. The most candid calculations we can make based on the animal data leads us to conclude that doses of the types taken by humans may be producing these effects. These effects are observable anatomic or chemical changes and not subjective effects in the user or behavioural effects. I hope you do not walk out of this room thinking that crazy researchers have to give heroically high doses of MDMA to animals, monkeys and baboons to produce this effect. There could not be anything further from the truth. When you talk about harm reduction one of the things that has to be conveyed honestly and directly to people who are going to use MDMA is that the animal data suggests that the dose that you are going to take may be enough to produce long-term effects in the highly articulate intelligent, well-meaning individuals who come to our study. They walk into my office and they are so confused about these long-term toxic effects of MDMA that they do not know whether they are coming or going. It is not their fault. I think the fault is in the dissemination of information that lacks clarity and lacks care for the individuals who are going to experiment with the drug.
Question 7: Are there other categories of compounds that have blocked the neuro toxicity?
George Ricaurte
Now there are a very broad range of drugs and lots of different categories that block but they do not do this in a specific way. In rats the way that they protect or block against the effects of MDMA is by lowering the body temperature. That is the common thread. There are two important points. It is not only the room temperature. The hotter it is the more likely the toxicity is to occur in an animal core temperature but the temperature inside the animal’s body is equally important. So anything that lowers the temperature, for example ketamine and PCP as well as a whole range of drugs, alters the effect. It is important to remember that temperature regulation in a rat may be very different than it is in a human being. So do not walk out of here thinking "If I take a little alcohol with MDMA I am protected". We do not know that. To answer the question, a broad category of drugs can protect against MDMA but they all do so by lowering the body temperature.
Emanuel Sferios
I would just like to say ketamine definitely raises the body temperature.
We have got this question a lot from users particularly users who cannot get Prozac. I have asked a number of researchers about St Johns Wort and other substances and basically their answer has been theoretically, yes, but it has not been studied. Also Prozac is a very long lasting acting accessory; it has a thirty-hour half-life. The neuro-toxic effect with the Prozac studies has been shown to take place beginning six hours after the administration of MDMA in rats and then taking place for about twenty-four hours after that period
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