This presentation is structured for the non-scientist and while some of the technical information seems complicated, the issue of neurotoxicity or the effects of MDMA on serotonin brain cells is really quite straight forward. This information is highly relevant for people who experiment with MDMA. For non-chemists, MDMA can be viewed as a chemical hybrid of amphetamine (a stimulant) and mescaline (a prototypic hallucinogen). Some people refer to MDMA as a "hallucinogenic amphetamine" although users of MDMA do not think that is a very good characterisation since they believe MDMA has unique effects of its own. When Shulgin and Nichols first wrote about MDMA in 1978 and described some of its pharmacology in humans, they drew attention to the fact that this was a drug that had unique psychedelic effects. Indeed, they were the first to propose that maybe it would even have a place in psychiatry as a psychotherapeutic adjunct.

Numbers of people involved in MDMA use

Over the last ten or fifteen years MDMA has become very popular in the club scene and in large parties known as ‘raves’. Prior to that it was popular on college campuses in the United States and in universities in Europe. Trying to get a firm hand on exactly how many people use MDMA or have used MDMA is somewhat difficult. It is only in the 1990s that MDMA has been included in formal drug use epidemiological surveys. In 1985, Segal estimated that 30,000 dosage units were being sold per month. In 1992, it was reported that the use of MDMA and related amphetamines was second only to cannabis in the UK. In 1994, the National Institute on Drug Abuse first published annual results on MDMA in the US. By 1995, use increased by about four or five fold. There seems to be reasonable agreement amongst the various formal surveys that the percentages of people who say that they have used MDMA at some time during the last year or at some time during their lifetime are somewhere in the range of 3-7%. It varies a little by country and the age of the individual but these figures generally hold for the United States and the UK. There are some surveys that say 10, 12, 14 % of individuals in these age groups have used MDMA but some of these estimates may be a bit high and perhaps be a function of the group under study. Nonetheless, these figures do give us some indication of how many people have actually experimented with MDMA.

Serotonin Neurotoxicity

Data from neuroscience laboratories suggests that that MDMA is a potent serotonin neurotoxin. This simply means that this is a drug that can damage or harm brain cells, specifically the cells that produce serotonin in the brain. Serotonin neurones are nerve cells that originate or have their nerve cell bodies in the base of the brain. There are axon projections or fibres that go down to the spinal cord and those are thought to be important in pain perception and in some other sensory modalities. There are also ascending projections that go to both the cortex and subcortical regions. Indeed, there is almost no area of the brain that is not innovated by serotonin nerve cells.

Neuroscientists are interested in studying the effects of MDMA on serotonin cells because their function is not really fully understood. Serotonin neurones have been implicated in a number of very important functions such as mood regulation, memory and cognition, impulse control, aggression, sleep, sexual function and appetite. However, we still do not really know what brain serotonin does. The hope, at least amongst neuroscientists, is that by studying animals and people who may have selective lesions of these cells, we can learn more about their functional role in the central nervous system.

The toxic effect of MDMA is on serotonin nerve fibres. If you give MDMA to animals and you measure any one of a number of serotonin nerve ending markers, you find they are markedly reduced. For example, MDMA-treated animals have lasting decreases in brain serotonin, 5HIAA (the major metabolite of serotonin), and the 5HT transporter etc. No matter what component of the nerve ending is measured, it is decreased on a long-term basis. The most plausible explanation for this is that MDMA has destroyed the serotonin nerve endings.

Studies in monkeys

Monkeys given MDMA show a marked reduction in the number and density of serotonin containing nerve fibres, not only in the cortical, but also in the subcortical regions. The MDMA treated animal has much fewer serotonin containing axons. A series of studies were recently completed where monkeys were examined seven years after MDMA treatment. These animals still showed evidence of serotonin axon loss.This suggests that in monkeys the toxic effect of MDMA may be permanent.

Key issues in animal data

A number of factors must be considered to see if the animal data is relevant to people who take MDMA, including dose, frequency of administration, route of administration and possible species differences. Clearly, if you are given enough of any drug it is going to be toxic, and one of the major points is that this is not the case for MDMA. Many people in neuroscience are interested in and concerned about MDMA because the dose or amount that produces the toxic effect is very low. Specifically, it is not true that species such as rats are uniquely sensitive to MDMA. Every animal species that has been tested, be it a mouse, rat, baboon or monkey, is sensitive to MDMA neurotoxicity. In fact, we have yet to find any animal species that is insensitive to MDMA neurotoxicity.

A series of studies on the monkey shows that the lowest neurotoxic dose given orally is 5 milligrams per kilogram. When you compare that with the dose that humans usually take (depending on the weight) it is going to be anywhere from 1.5 to 1.7 milligrams per kilogram. Thus, the toxic dose in monkeys appears to be 3 to 5 times higher than the dose typically taken by humans. However, when comparing across animal species, you have to use established principles of ‘inter species dose scaling’ to calculate the equivalent human dose. When ‘inter species scaling’ is performed for MDMA, the 5 milligrams per kilogram dose in the monkey is equivalent to a 1.2 milligram per kilogram dose in a human. This analysis suggests that the single dose in a monkey that produces a toxic effect is identical to the dose of MDMA that humans generally take in order to experience the desired pharmacological effect. So the safety margin for MDMA in humans, based on the animal study, is virtually non existent. That is one of the most important points that comes out of the studies on animals.

One of the major findings in the field in the late 1990s has been that the toxic effect of MDMA, certainly in rodent species, is highly dependent on room temperature. The warmer the room, the greater the toxicity. The converse is also true. If room temperature is lowered from 22ºC down to 18ºC, toxicity is virtually eliminated. Thus, temperature is a major factor that influences the neurotoxic effect of MDMA in animals. This may have implications for people using MDMA in a club setting.

Studies in the human brain

It is very difficult to assess the status of brain serotonin neurones in the living human brain. To my knowledge, there are only two validated methods for measuring the status of brain serotonin cells in the living brain. One is the ‘CSF’ method and the other is the ‘PET’ method. The’ CSF’ method entails obtaining a sample of spinal fluid which is the fluid that bathes the brain and the spinal cord and measuring the amount of serotonin breakdown product, 5HIAA. It is known from animal studies that if an animal has sustained toxic injury from MDMA, the amount of 5HIAA, the breakdown product of serotonin, is reduced in the spinal fluid of the animal. Several studies in humans who have taken MDMA have been completed and what we see is the exact same thing as we see in monkeys. That is, that there is a 30 to 35% reduction or decrease in ‘CSF’ 5HIAA. This is the marker for brain serotonin cells. It is reduced significantly in the humans previously exposed to MDMA.

‘PET’ stands for positron emission tomography. It is an elegant imaging technique that can be used to see brain serotonin cells in the living human brain. This is done by labelling the serotonin transporter. This molecule is a structural component of the nerve ending. It is tagged with a radioactive probe, then its distribution is measured with ‘PET’.

To validate the ‘PET’ method, a baboon was given MDMA and studied two weeks later. At this time, a reduction in the labelling of the serotonin transporter was seen. Thus, the ‘PET’ method is capable of detecting MDMA neurotoxicity in living primates. With this knowledge, a study in human subjects was undertaken. The inclusionary and exclusionary criteria had to be that people could not have used drugs for at least two to three weeks prior to the study, and they had to be free of any psychiatric disorders in which serotonin has been implicated. Furthermore they had to have used MDMA on at least 25 occasions. Control subjects were matched with regards to age, education and gender distribution. Notably, the MDMA cohort, on average, had used MDMA for about five years on over 200 or more occasions, and they used it about 6 times per month. For the entire group, the average length of time that they reported not having used MDMA was 19 weeks. What we found was that there was a reduction in serotonin transporter labelling, and that the reduction was proportional to the number of occasions that individuals reported having used MDMA.

We recognise that there are some limitations to the human studies. This is probably why the animal studies are so important, since they help to address the various potential limitations of human studies.

Conclusions

In conclusion, it is clear that MDMA produces toxic effects on brain serotonin neurones in animals. Further, it is important to recognise that the toxic effect of MDMA in animals occurs with doses that approach closely those used by humans. Recent ‘PET’ studies indicate MDMA-induced serotonin neurotoxicity also occurs in humans. As yet, functional consequences of brain serotonin neurotoxicity remain largely unknown. However, a number of studies do point to problems with memory. Clearly, much more research is needed to more fully charcterise the long-effects of MDMA in humans. In the meantime, however, users should be mindful of MDMA’s serotonin neurotoxic potential.