Bootlegger
Bluelighter
- Joined
- Dec 9, 2000
- Messages
- 222
Interview with Dr. Una McCann
Q. How long have you been involved in MDMA research?
A. Seven years. I've been involved in two major clinical studies. One is ongoing and the other one's completed.
Q. Tell me about the first study.
A. The first study was really the first prospective controlled study which looked at whether there was evidence for serotonin neurotoxicity in humans who were exposed to MDMA. The second study is a follow-up study intended to both confirm these findings and extend them.
Q. What do the findings from the first study indicate?
A. In essence, what we found was that in those individuals who were taking substantial amounts of MDMA - on average, these individuals had used it at least 100 times - there was evidence of serotonin injury. In particular, they had significantly decreased levels of the major metabolite of serotonin (5-hydroxy indole acetic acid, 5-HIAA) in their cerebro spinal fluid (CSF). Since we can't directly measure serotonin in the brains of living humans, we have to rely on indirect measures like levels of neurotransmitter metabolites in cerebro spinal fluid. This is probably the most direct biological evidence that we obtained in that study.
In addition to our CSF findings, we also found that those affected individuals had altered sleep patterns. Specifically, they had decreased stage two sleep. In addition, they had altered impulsivity. Since serotonin is thought to be involved in sleep regulation as well as impulsivity and control, these findings may suggest that MDMA does damage serotonin neurones in the brains of humans.
Q. What behavioural effects is that likely to have on people?
A. When someone says serotonin, one of the first things we psychiatrists think about is mood. Serotonin is also implicated in anxiety disorders, particularly one called obsessive compulsive disorder. It's involved in the modulation of pain, sexual function, sleep, implusivity and a host of other behaviours as well, including cognition, memory and attention. Theoretically, all these behaviours could be altered in individuals with damaged serotonin function. Basically, what we're attempting to do in the present study is one, confirm the cerebro spinal fluid findings from the first study and two, further probe for evidence of alterations in neuro endocrine function which is regulated by serotonin sleep cognition and mood and psychiatric illnesses.
Q. At this stage, what's the actual process of testing?
A. This is a joint research project with Doctor George Ricaurte at Johns Hopkins Medical Center. Individuals who participate in this study are asked to give up five days of their time.
On the morning of the first day, volunteers are admitted to the Johns Hopkins Medical Center's clinical research unit where they undergo a physical and neurological examination, and complete interviews and questionnaires regarding their drug histories. They also complete questionnaires designed to screen for possible alterations in impulsivity, mood and other behaviours in which serotonin has been implicated. On the second day in the hospital, they undergo the first of two pain studies, and that night undergo a "mock" sleep study (so they become adapted to the polysomnographic equipment used to test sleep). The third morning of the study, they have a lumber puncture which is the procedure utilised for collecting cerebro spinal fluid. Later that day (in the afternoon), participants are transported to the NIH clinical centre where they undergo structured psychiatric interviews both for personality and formal psychiatric disorders. That night, they have sleep studies, involving EEG recordings of sleep stages. The fourth day of the study, they undergo a pharmacological challenge with m-CPP, which is a metabolite of an antidepressant known as Trazadone in the United States. m-CPP is known to act at serotonin receptors, and may be useful for unmasking subtle changes in MDMA users, since its main behavioural and neuro endocrine effects are thought to be mediated at serotonin receptors. It is hoped that if there are changes in the serotonin neurones of MDMA users, we might be able to detect them by doing a challenge study with a drug that actually acts on the serotonin system. The night after the m-CPP challenge, participants have another sleep study, and the next morning they are transferred back to Johns Hopkins University where they have a second pain test. Some participants go on to have PET scans using a type of scan aimed at detecting changes in serotonin nerve terminals.
Q. What are you looking for in the M-CPP challenge?
A. We're looking for several things. For example, do individuals who take MDMA report different behavioural sensations following administration with m-CPP? We're also looking at various physiological measures such as blood pressure, pulse, temperature and pupil size, all of which can be affected by activity at serotonin receptors. We're also collecting blood samples to look for m-CPP induced changes in proactin and cortisol which are known to typically increase in individuals who receive intravenous m-CPP. The bottom line is we're hoping to find differences in the two populations should damage exist.
Q. Is this an important area of study?
A. I think it's important from two standpoints. First, there's the issue of public health. Apparently, MDMA use is on the rise in the US, Europe and, as you've mentioned, in Australia. Surely then, if individuals are incurring damage, they should know about it and its consequences. It's quite possible that damage does occur but the manifestations of that damage may not appear until later in life with aging. We hope to be able to perform a certain public health service by alerting individuals to what the consequences of their actions are.
Secondly, although serotonin has been implicated in a wide array of normal human behaviours, its precise role is not yet known. We're hoping that should it be determined that indeed damage does occur, we'll be able to learn more about how exactly serotonin is affecting these various behaviours.
Q. Do you think MDMA is as harmless as a lot of people say?
A. Certainly when you consider that thousands of people have used MDMA and only a few have got into medical difficulties, it's not so surprising that the drug is regarded by many as relatively safe. However serotonin damage may be occurring. The problem is the types of behaviours that serotonin is implicated in are quite subtle and difficult to detect. An individual who has a mild disturbance in cognition, sleep or mood might attribute it to other things and not think it severe enough to warrant a visit to their physician. It really remains to be determined just how significant the adverse effects associated with MDMA use are.
Q. I guess we won't know this until the users get older.
A. Not necessarily. When we were looking for volunteers for our two studies, a number of individuals approached us who had got into trouble after using MDMA. But because we're rather conservative about who we use in our studies, we didn't allow these people to participate. However, their histories have been reported in the medical literature. Some developed anxiety and panic disorders, even with minimal use. One individual used it just the once and developed a full-blown panic disorder. Others who used quite heavy doses of MDMA developed problems such as psychosis and cognitive and sleep disturbances. All of these things have been reported. Sometimes they occur acutely, shortly after the drug is taken. It is also possible that with time other things will appear.
Q. Do we know much about how MDMA is actually working in the brain or is that what you're trying to figure out?
A. MDMA is a ring substituted amphetamine analogue. Like other amphetamines, MDMA releases dopamine (another neurotransmitter). Some of MDMA's acute effects are likely due to dopamine release. Other actions of MDMA are said to be unique (e.g., its effect on interpersonal relations) and may be due to actions at serotonin receptors or at some unique, as yet unknown brain site.
The mechanisms for MDMA induced neurotoxicity are not known. However, there are several hypotheses and a number of laboratories are researching that question.
Q. Is it politically a difficult area of research?
A. It's surprising how open-minded the powers-that-be in this government are. This project is actually being funded by the National Institute On Drug Abuse. I think if a study is well thought out and the risks to the subjects are clearly delineated, people are pretty open-minded about it.
Q. How do you find the subjects for your studies?
A. It has been remarkably easy to find subjects for this study. There is a network of MDMA users who subscribe to the same newsletters and chat on the same internet sites. Most are well informed and health conscious. If MDMA does damage the brain, most want to know. I've found that many don't hesitate to volunteer. We've had individuals approach us from not just the US, but Europe as well. Most heard about our study via word of mouth, although we did put an ad on the internet, which we got a big response to.
Q. Were the sort of people who volunteered to participate in your second study different from those who volunteered to participate in your first?
A. Yes. In our first study which we basically started in California, we tended to attract people who were older. They tended to have one or two academic degrees, and a significant number gave as their reason for taking MDMA a desire to more deeply understand themselves. In fact, many claimed MDMA has improved their life. Thanks to the drug, they were able to critically question their actions with much greater ease. These people tended to be quite scholarly about their MDMA use. I'd say half of our subjects in the first study came under this category.
In our current study - I don't know if it's because we're now on the east coast - our subjects are younger and less interested in using MDMA as a tool for self-exploration. Instead they prefer to use it at raves and dance parties because of its effects in that environment.
Q. Is MDMA a drug you can use over and over again?
A. From our studies, we found that those individuals who took MDMA to learn more about themselves, probably used no more than twice a month. If they took it more frequently than that, the positive effects were dissipated. They weren't as strong. In fact, sometmes the effects were even unpleasant.
Q. What adivce would you give someone who was thinking of using MDMA for the first time?
A. As scientists, we tend to err on the side of caution with regard to making global recommendations about a topic until our science has been reviewed by scientific peers. What I will say though is that in every animal species evaluated to date, including non human primates (monkeys), MDMA induced long-term serotonin deficits. Because of that, I would think twice about taking it. Not only that, it appears that in primates, the neurotoxic effects of MDMA last longer.
Q. Is it scientifically accurate to compare monkeys with humans?
A. Certain groups do tend to discount the primate findings. They say that humans are different to monkeys and that the doses used are totally different. In fact, there are individuals in our current study who have taken doses that would be neurotoxic in monkeys. Further more, if you use the method of inter species scaling where you adjust the dose for body surface area relative to body mass, the doses are quite close. Even if there was only a one to two ratio difference, I would be cautious. Clearly though, the doses overlap so I do think that the animal data should be taken quiet seriously until it can be shown that humans are, for whatever reason, resistant to the neurotoxic effects of MDMA.
Q. What immediate effects does MDMA have?
A. We aren't administering MDMA to subjects. We're studying people who have used lots of MDMA. However, what people tell us is that initially there is sort of a rush. Although I can't say this for sure, I would imagine that that rush might be related to the release that dopamine that amphetamines tend to do as a class. The "rush" tends to occur fairly early on in the drug experience. According to experienced users, around 30 minutes or so after taking MDMA, a second group of sensations occurs. People often report feeling suddenly at peace and more able to love and understand the people around them in a way that they've never been able to before.
Other effects that might be related to MDMA's amphetamine-like quality include jaw clenching and nausea. Sometimes people who've used MDMA report having trouble sleeping straight after the experience.
Q. How does MDMA compare with those drugs that are presently being used in a therapeutic context? The latter's side effects are just as bad, surely?
A. Antidepressants are not known to lead to brain damage. All drugs have potential side effects some of which are quite unpleasant. Certainly, I would be delighted if somebody did a controlled perspective study that evaluated the therapeutic effects of MDMA to treat a particular disorder. Unfortunately, there just aren't those studies at present.
Q. What other research into MDMA does your group hope to do?
A. We'd like to look at other pharmacological challenge agents. We've already talked about the m-CPP challenge. It's possible that other drugs that are aimed at other serotonin receptors or even other neurotransmitter systems might be useful in uncovering deficits if they exist. In addition to those types of challenge paradigms, there is an increasing effort to develop neuro ligands for PET studies that could be used to take pictures of serotonin neurons. These could be used to evaluate individuals who've been exposed to MDMA as well as other potential neuro toxic drugs. As I mentioned earlier, we are evaluating some of our study participants at Johns Hopkins using one potential ligand. Hopefully, this will detect the absence or presence of serotonin terminals. Hopefully there will also be other ligands that might be directed at serotonin itself or at elements of the neuron.
Q. Can you explain again how you're challenging the volunteers in your current study?
A. On day two, first thing in the morning, two intravenous catheters are inserted into the subjects' arms. One catheter is used to draw repeated blood samples. The other is used to administer a drug called m-CPP which is a metabolite of an antidepressant called Trazadone. Each subject also receives during the morning an infusion of placebo or salt water after each of the two infusions. The nurse and the technician take repeated measures of blood pressure, pulse, pupil size and cognition. At various times, they also draw blood samples. In addition, each individual is asked throughout the procedure to report any changes in mood and any physical symptoms.
Dr Una McCann is Chief of the Unit on Anxiety Disorders, Biological Psychiatry Branch, National Institutes of Mental Health. In addition to research regarding the effects of neurotoxic amphetamine analogs (i.e., MDMA and fenfluramine), Dr McCann does clinical research in patients with anxiety disorders, including post traumatic stress disorder, panic disorder and social phobia.
------------------
And the Mission is the Mouse...
[This message has been edited by Bootlegger (edited 10 December 2000).]
Q. How long have you been involved in MDMA research?
A. Seven years. I've been involved in two major clinical studies. One is ongoing and the other one's completed.
Q. Tell me about the first study.
A. The first study was really the first prospective controlled study which looked at whether there was evidence for serotonin neurotoxicity in humans who were exposed to MDMA. The second study is a follow-up study intended to both confirm these findings and extend them.
Q. What do the findings from the first study indicate?
A. In essence, what we found was that in those individuals who were taking substantial amounts of MDMA - on average, these individuals had used it at least 100 times - there was evidence of serotonin injury. In particular, they had significantly decreased levels of the major metabolite of serotonin (5-hydroxy indole acetic acid, 5-HIAA) in their cerebro spinal fluid (CSF). Since we can't directly measure serotonin in the brains of living humans, we have to rely on indirect measures like levels of neurotransmitter metabolites in cerebro spinal fluid. This is probably the most direct biological evidence that we obtained in that study.
In addition to our CSF findings, we also found that those affected individuals had altered sleep patterns. Specifically, they had decreased stage two sleep. In addition, they had altered impulsivity. Since serotonin is thought to be involved in sleep regulation as well as impulsivity and control, these findings may suggest that MDMA does damage serotonin neurones in the brains of humans.
Q. What behavioural effects is that likely to have on people?
A. When someone says serotonin, one of the first things we psychiatrists think about is mood. Serotonin is also implicated in anxiety disorders, particularly one called obsessive compulsive disorder. It's involved in the modulation of pain, sexual function, sleep, implusivity and a host of other behaviours as well, including cognition, memory and attention. Theoretically, all these behaviours could be altered in individuals with damaged serotonin function. Basically, what we're attempting to do in the present study is one, confirm the cerebro spinal fluid findings from the first study and two, further probe for evidence of alterations in neuro endocrine function which is regulated by serotonin sleep cognition and mood and psychiatric illnesses.
Q. At this stage, what's the actual process of testing?
A. This is a joint research project with Doctor George Ricaurte at Johns Hopkins Medical Center. Individuals who participate in this study are asked to give up five days of their time.
On the morning of the first day, volunteers are admitted to the Johns Hopkins Medical Center's clinical research unit where they undergo a physical and neurological examination, and complete interviews and questionnaires regarding their drug histories. They also complete questionnaires designed to screen for possible alterations in impulsivity, mood and other behaviours in which serotonin has been implicated. On the second day in the hospital, they undergo the first of two pain studies, and that night undergo a "mock" sleep study (so they become adapted to the polysomnographic equipment used to test sleep). The third morning of the study, they have a lumber puncture which is the procedure utilised for collecting cerebro spinal fluid. Later that day (in the afternoon), participants are transported to the NIH clinical centre where they undergo structured psychiatric interviews both for personality and formal psychiatric disorders. That night, they have sleep studies, involving EEG recordings of sleep stages. The fourth day of the study, they undergo a pharmacological challenge with m-CPP, which is a metabolite of an antidepressant known as Trazadone in the United States. m-CPP is known to act at serotonin receptors, and may be useful for unmasking subtle changes in MDMA users, since its main behavioural and neuro endocrine effects are thought to be mediated at serotonin receptors. It is hoped that if there are changes in the serotonin neurones of MDMA users, we might be able to detect them by doing a challenge study with a drug that actually acts on the serotonin system. The night after the m-CPP challenge, participants have another sleep study, and the next morning they are transferred back to Johns Hopkins University where they have a second pain test. Some participants go on to have PET scans using a type of scan aimed at detecting changes in serotonin nerve terminals.
Q. What are you looking for in the M-CPP challenge?
A. We're looking for several things. For example, do individuals who take MDMA report different behavioural sensations following administration with m-CPP? We're also looking at various physiological measures such as blood pressure, pulse, temperature and pupil size, all of which can be affected by activity at serotonin receptors. We're also collecting blood samples to look for m-CPP induced changes in proactin and cortisol which are known to typically increase in individuals who receive intravenous m-CPP. The bottom line is we're hoping to find differences in the two populations should damage exist.
Q. Is this an important area of study?
A. I think it's important from two standpoints. First, there's the issue of public health. Apparently, MDMA use is on the rise in the US, Europe and, as you've mentioned, in Australia. Surely then, if individuals are incurring damage, they should know about it and its consequences. It's quite possible that damage does occur but the manifestations of that damage may not appear until later in life with aging. We hope to be able to perform a certain public health service by alerting individuals to what the consequences of their actions are.
Secondly, although serotonin has been implicated in a wide array of normal human behaviours, its precise role is not yet known. We're hoping that should it be determined that indeed damage does occur, we'll be able to learn more about how exactly serotonin is affecting these various behaviours.
Q. Do you think MDMA is as harmless as a lot of people say?
A. Certainly when you consider that thousands of people have used MDMA and only a few have got into medical difficulties, it's not so surprising that the drug is regarded by many as relatively safe. However serotonin damage may be occurring. The problem is the types of behaviours that serotonin is implicated in are quite subtle and difficult to detect. An individual who has a mild disturbance in cognition, sleep or mood might attribute it to other things and not think it severe enough to warrant a visit to their physician. It really remains to be determined just how significant the adverse effects associated with MDMA use are.
Q. I guess we won't know this until the users get older.
A. Not necessarily. When we were looking for volunteers for our two studies, a number of individuals approached us who had got into trouble after using MDMA. But because we're rather conservative about who we use in our studies, we didn't allow these people to participate. However, their histories have been reported in the medical literature. Some developed anxiety and panic disorders, even with minimal use. One individual used it just the once and developed a full-blown panic disorder. Others who used quite heavy doses of MDMA developed problems such as psychosis and cognitive and sleep disturbances. All of these things have been reported. Sometimes they occur acutely, shortly after the drug is taken. It is also possible that with time other things will appear.
Q. Do we know much about how MDMA is actually working in the brain or is that what you're trying to figure out?
A. MDMA is a ring substituted amphetamine analogue. Like other amphetamines, MDMA releases dopamine (another neurotransmitter). Some of MDMA's acute effects are likely due to dopamine release. Other actions of MDMA are said to be unique (e.g., its effect on interpersonal relations) and may be due to actions at serotonin receptors or at some unique, as yet unknown brain site.
The mechanisms for MDMA induced neurotoxicity are not known. However, there are several hypotheses and a number of laboratories are researching that question.
Q. Is it politically a difficult area of research?
A. It's surprising how open-minded the powers-that-be in this government are. This project is actually being funded by the National Institute On Drug Abuse. I think if a study is well thought out and the risks to the subjects are clearly delineated, people are pretty open-minded about it.
Q. How do you find the subjects for your studies?
A. It has been remarkably easy to find subjects for this study. There is a network of MDMA users who subscribe to the same newsletters and chat on the same internet sites. Most are well informed and health conscious. If MDMA does damage the brain, most want to know. I've found that many don't hesitate to volunteer. We've had individuals approach us from not just the US, but Europe as well. Most heard about our study via word of mouth, although we did put an ad on the internet, which we got a big response to.
Q. Were the sort of people who volunteered to participate in your second study different from those who volunteered to participate in your first?
A. Yes. In our first study which we basically started in California, we tended to attract people who were older. They tended to have one or two academic degrees, and a significant number gave as their reason for taking MDMA a desire to more deeply understand themselves. In fact, many claimed MDMA has improved their life. Thanks to the drug, they were able to critically question their actions with much greater ease. These people tended to be quite scholarly about their MDMA use. I'd say half of our subjects in the first study came under this category.
In our current study - I don't know if it's because we're now on the east coast - our subjects are younger and less interested in using MDMA as a tool for self-exploration. Instead they prefer to use it at raves and dance parties because of its effects in that environment.
Q. Is MDMA a drug you can use over and over again?
A. From our studies, we found that those individuals who took MDMA to learn more about themselves, probably used no more than twice a month. If they took it more frequently than that, the positive effects were dissipated. They weren't as strong. In fact, sometmes the effects were even unpleasant.
Q. What adivce would you give someone who was thinking of using MDMA for the first time?
A. As scientists, we tend to err on the side of caution with regard to making global recommendations about a topic until our science has been reviewed by scientific peers. What I will say though is that in every animal species evaluated to date, including non human primates (monkeys), MDMA induced long-term serotonin deficits. Because of that, I would think twice about taking it. Not only that, it appears that in primates, the neurotoxic effects of MDMA last longer.
Q. Is it scientifically accurate to compare monkeys with humans?
A. Certain groups do tend to discount the primate findings. They say that humans are different to monkeys and that the doses used are totally different. In fact, there are individuals in our current study who have taken doses that would be neurotoxic in monkeys. Further more, if you use the method of inter species scaling where you adjust the dose for body surface area relative to body mass, the doses are quite close. Even if there was only a one to two ratio difference, I would be cautious. Clearly though, the doses overlap so I do think that the animal data should be taken quiet seriously until it can be shown that humans are, for whatever reason, resistant to the neurotoxic effects of MDMA.
Q. What immediate effects does MDMA have?
A. We aren't administering MDMA to subjects. We're studying people who have used lots of MDMA. However, what people tell us is that initially there is sort of a rush. Although I can't say this for sure, I would imagine that that rush might be related to the release that dopamine that amphetamines tend to do as a class. The "rush" tends to occur fairly early on in the drug experience. According to experienced users, around 30 minutes or so after taking MDMA, a second group of sensations occurs. People often report feeling suddenly at peace and more able to love and understand the people around them in a way that they've never been able to before.
Other effects that might be related to MDMA's amphetamine-like quality include jaw clenching and nausea. Sometimes people who've used MDMA report having trouble sleeping straight after the experience.
Q. How does MDMA compare with those drugs that are presently being used in a therapeutic context? The latter's side effects are just as bad, surely?
A. Antidepressants are not known to lead to brain damage. All drugs have potential side effects some of which are quite unpleasant. Certainly, I would be delighted if somebody did a controlled perspective study that evaluated the therapeutic effects of MDMA to treat a particular disorder. Unfortunately, there just aren't those studies at present.
Q. What other research into MDMA does your group hope to do?
A. We'd like to look at other pharmacological challenge agents. We've already talked about the m-CPP challenge. It's possible that other drugs that are aimed at other serotonin receptors or even other neurotransmitter systems might be useful in uncovering deficits if they exist. In addition to those types of challenge paradigms, there is an increasing effort to develop neuro ligands for PET studies that could be used to take pictures of serotonin neurons. These could be used to evaluate individuals who've been exposed to MDMA as well as other potential neuro toxic drugs. As I mentioned earlier, we are evaluating some of our study participants at Johns Hopkins using one potential ligand. Hopefully, this will detect the absence or presence of serotonin terminals. Hopefully there will also be other ligands that might be directed at serotonin itself or at elements of the neuron.
Q. Can you explain again how you're challenging the volunteers in your current study?
A. On day two, first thing in the morning, two intravenous catheters are inserted into the subjects' arms. One catheter is used to draw repeated blood samples. The other is used to administer a drug called m-CPP which is a metabolite of an antidepressant called Trazadone. Each subject also receives during the morning an infusion of placebo or salt water after each of the two infusions. The nurse and the technician take repeated measures of blood pressure, pulse, pupil size and cognition. At various times, they also draw blood samples. In addition, each individual is asked throughout the procedure to report any changes in mood and any physical symptoms.
Dr Una McCann is Chief of the Unit on Anxiety Disorders, Biological Psychiatry Branch, National Institutes of Mental Health. In addition to research regarding the effects of neurotoxic amphetamine analogs (i.e., MDMA and fenfluramine), Dr McCann does clinical research in patients with anxiety disorders, including post traumatic stress disorder, panic disorder and social phobia.
------------------
And the Mission is the Mouse...
[This message has been edited by Bootlegger (edited 10 December 2000).]