This post is partly in response to a comment by Ecstatic1 in the "Safer Drugs and Combinations" thread, and partly as a clarification to others who are just as misguided and ignorant of the facts. Ecstatic1, you claim I am only presenting opinion and haven't read much at all about neurotoxicity. That's bullshit, and anyone who's been around long enough would know that. Ecstatic1 says that "One should not present their own opinions as professional ones which are backed up by scientific knowledge and animal studies." He also says "At best, you are paraphrasing -and- interpreting Ricaurte's findings without citing his study." Which is obviously crap and shows how little you know about me. "At worst, you haven't even read dissenting studies like O'Callaghan and are spreading misinformation not unlike the media." Oh please. Now you just sound like like an ignoramus. I'm sorry I have to pick on you, but by insulting not only my intelligence and reading but those of most of Bluelight as well as the medical community warrants this.
The first step is to clarify the situation. Ecstatic1 pointed to a series of interviews on a rabidly pro-ecstasy site from 1995, 5 years and thousands of hours of research ago. (The interviews can be read here: http://www.ecstasy.org/info/interviews.html ) Much has changed and much has been discovered about MDMA and neurotoxicity since then; yet the crux of the argument remains the same, as it has for the last twenty years: MDMA is a human neurotoxin that destroys serotonin axons. The extent and the consequences of the damage are not fully known, and may differ much between individuals. However, what we are concerned with here is the neurotoxicity itself, not it's long-term effects, which, based on the well-established connection between serotonin concentration and depression, do not bode well for heavy abusers of MDMA. Those like Ecstatic1, who have been Bluelighters for less than a month, and are obtusely unaware of the body of evidence on MDMA neurotoxicity, are in dire need of the proper information and clarification, which I will do below.
I will start with the interview itself, which Ecstatic1 holds as his lone piece of evidence against the many scientific studies I will present. Simply put, in 1995, Dr. O'Callaghan, while conceding that MDMA does reduce striatal serotonin levels on a longer than short-term basis, denies that MDMA is specifically neurotoxic to serotogenic axons. What Ecstatic1 is ignorant of is that not only does the literature before O'Callaghan's statements belie this, but O'Callaghan's own recent research contradicts his statment as well. After 1995, O'Callaghan did not publish any MDMA neurotoxicity articles, until his groundbreaking study in 2000.
In the interview in 1995, O'Callaghan states that the reason neurotoxicity damage can't be assessed properly is because "the gold standard for determining whether something damages thenervous system is based on morphology...However, in the brain that doesn't work so well...The problem is that there are so many myriads of cell types that compose the brain with different structural DNA/RNA make ups that you can't tell one from another...Unfortunately, classical staining procedures (i.e. ones that will tell you if a brain cell is lost) will not allow you to determine if there has been damage to nerve terminals, nerve axons, or damage to a small population of cells. You can't see it even with a systematic survey of the entire brain using classical techniques."
He was absolutely right; you CAN'T determine it with classical techniques. So what did he do? He developed a new immunohistochemistry staining method! This method enables you to see on the cellular level specific axon morphology, the gold standard itself! In fact, he used this method in his 2000 study ("Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry" in Brain Res. 2000 Mar 6;858(1):92-105 by Kalia M, O'Callaghan JP, Miller DB, Kramer M) to show (now quoting from the study) that "MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network." These changes are specifically, (again I quote) "curved, corkscrew-like swellings and thickened short axons randomly distributed in several brain regions." So what O'Callaghan did is not only provide the method but actually proved himself that MDMA is neurotoxic to serotonin axons by his own "gold standard"! Ta-Da!
I could stop there, but I would hate for another person as equally as ignorant as Ecstatic1 to throw up another MDMA propaganda piece and claim it to be the gospel truth in the face of an Titanic-worthy iceberg of evidence to the contrary. So I know present the tip of that iceberg, and specifically articles that not only butress neurotoxicity findings but that also directly counter incorrect beliefs from the time period of the O'Callaghan interview.
I will give Ecstatic1 the benefit of the doubt here, and pretend that he came in a time machine from 1995 and didn't believe any of the evidence of neurotoxicity up until then. So we begin after October 1995, the time of the interview, using some choice articles to demonstrate the fact of MDMA neurotoxicity on serotonin axon terminals.
But first, we investigate why O'Callaghan made his claims in the first place. The root is in this article ("The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine" in Molecular Neurobiology 1995 Aug-Dec;11(1-3):177-92 by Miller DB, O'Callaghan JP) in which he concludes from a study on mouse body temperature and MDMA-linked neurotoxicity that "the neurotoxic effects of d-MDMA, and most likely other AMPs (amphetamines), are linked to an effect on body temperature." At the time, this was thought to a valid hypothesis. However, since Ecstatic1 came in a time machine from 1995, he missed a very recent article ("Effect of GBR 12909 and fluoxetine on the acte and long term changes induced by MDMA ('ecstasy') on the 5-HT and dopamine concentrations in mouse brain" in Neuropharmacology 200 Oct 1;40(1):65-74 by O'Shea E, Esteban B, Camarero J, Green AR, Colado MI) in which the conclusions "rule out any direct relationship between the neurotoxic effects of MDMA and its acute effects on body temperature in mice." This proves O'Callaghan's previous work to be incorrect.
Now on to the rest of the studies that Ecstatic1 missed in the last five years.
(From "In vivo detection of short- and long-term MDMA neurotoxicity--a positron emission tomorgraphy study in the living baboon brain" in Synapse 1998 Jun;29(2):183-92 by Scheffel U et al.):
In this study, they used a (surprise!) new application of the technique of positron emission tomogrophy (PET) that shows "PET imaging of the living nonhuman primate brain...can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity." These changes varied from 44% to 89% decreases in radioactivity concentrations, a significant indicator of neurotoxicity.
(From "An integrated hypothesis for the sertonergic axonal loss induced by 2,4-methylenedioxymethamphetamine" in Neurotoxicology 1998 Jun;19(3):427-41 by Sprague JE et al.):
This is an integrated hypothesis that is supported by the current literature of MDMA neurotoxicity (the deamination by MAO-B of DA in the 5-HT terminal). A great summary of neurotoxicity.
(From "Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA users" in British Journal of Psychiatry 1999 July;175:63-9 by Semple DM et al.):
Using the (surprise again!) relatively new application of single photon emission computed tomography (SPECT), they found reduced SERT but not DA transporter binding in vivo that provides "suggestive evidence for specific, at least temporary, serotonergic neurotoxicity of MDMA in humans."
(From "Toxicodynamics and long-term toxicity of the recreational drug, 3,4-methylenedioxymethamphetamine" in Toxicology Letters 2000 Mar 15;112-113;143-6 by Ricaurte GA et al.):
Using PET, they found "lasting decrements in global brain...binding...results that suggest human MDMA use results in brain 5-HT neurotoxicity."
I think this pretty much wraps it up for now. So please, Ecstatic1, think you before you post. Thank you.
The first step is to clarify the situation. Ecstatic1 pointed to a series of interviews on a rabidly pro-ecstasy site from 1995, 5 years and thousands of hours of research ago. (The interviews can be read here: http://www.ecstasy.org/info/interviews.html ) Much has changed and much has been discovered about MDMA and neurotoxicity since then; yet the crux of the argument remains the same, as it has for the last twenty years: MDMA is a human neurotoxin that destroys serotonin axons. The extent and the consequences of the damage are not fully known, and may differ much between individuals. However, what we are concerned with here is the neurotoxicity itself, not it's long-term effects, which, based on the well-established connection between serotonin concentration and depression, do not bode well for heavy abusers of MDMA. Those like Ecstatic1, who have been Bluelighters for less than a month, and are obtusely unaware of the body of evidence on MDMA neurotoxicity, are in dire need of the proper information and clarification, which I will do below.
I will start with the interview itself, which Ecstatic1 holds as his lone piece of evidence against the many scientific studies I will present. Simply put, in 1995, Dr. O'Callaghan, while conceding that MDMA does reduce striatal serotonin levels on a longer than short-term basis, denies that MDMA is specifically neurotoxic to serotogenic axons. What Ecstatic1 is ignorant of is that not only does the literature before O'Callaghan's statements belie this, but O'Callaghan's own recent research contradicts his statment as well. After 1995, O'Callaghan did not publish any MDMA neurotoxicity articles, until his groundbreaking study in 2000.
In the interview in 1995, O'Callaghan states that the reason neurotoxicity damage can't be assessed properly is because "the gold standard for determining whether something damages thenervous system is based on morphology...However, in the brain that doesn't work so well...The problem is that there are so many myriads of cell types that compose the brain with different structural DNA/RNA make ups that you can't tell one from another...Unfortunately, classical staining procedures (i.e. ones that will tell you if a brain cell is lost) will not allow you to determine if there has been damage to nerve terminals, nerve axons, or damage to a small population of cells. You can't see it even with a systematic survey of the entire brain using classical techniques."
He was absolutely right; you CAN'T determine it with classical techniques. So what did he do? He developed a new immunohistochemistry staining method! This method enables you to see on the cellular level specific axon morphology, the gold standard itself! In fact, he used this method in his 2000 study ("Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry" in Brain Res. 2000 Mar 6;858(1):92-105 by Kalia M, O'Callaghan JP, Miller DB, Kramer M) to show (now quoting from the study) that "MDMA depleted brain serotonin and produced morphological changes in the serotonin nerve network." These changes are specifically, (again I quote) "curved, corkscrew-like swellings and thickened short axons randomly distributed in several brain regions." So what O'Callaghan did is not only provide the method but actually proved himself that MDMA is neurotoxic to serotonin axons by his own "gold standard"! Ta-Da!
I could stop there, but I would hate for another person as equally as ignorant as Ecstatic1 to throw up another MDMA propaganda piece and claim it to be the gospel truth in the face of an Titanic-worthy iceberg of evidence to the contrary. So I know present the tip of that iceberg, and specifically articles that not only butress neurotoxicity findings but that also directly counter incorrect beliefs from the time period of the O'Callaghan interview.
I will give Ecstatic1 the benefit of the doubt here, and pretend that he came in a time machine from 1995 and didn't believe any of the evidence of neurotoxicity up until then. So we begin after October 1995, the time of the interview, using some choice articles to demonstrate the fact of MDMA neurotoxicity on serotonin axon terminals.
But first, we investigate why O'Callaghan made his claims in the first place. The root is in this article ("The role of temperature, stress, and other factors in the neurotoxicity of the substituted amphetamines 3,4-methylenedioxymethamphetamine and fenfluramine" in Molecular Neurobiology 1995 Aug-Dec;11(1-3):177-92 by Miller DB, O'Callaghan JP) in which he concludes from a study on mouse body temperature and MDMA-linked neurotoxicity that "the neurotoxic effects of d-MDMA, and most likely other AMPs (amphetamines), are linked to an effect on body temperature." At the time, this was thought to a valid hypothesis. However, since Ecstatic1 came in a time machine from 1995, he missed a very recent article ("Effect of GBR 12909 and fluoxetine on the acte and long term changes induced by MDMA ('ecstasy') on the 5-HT and dopamine concentrations in mouse brain" in Neuropharmacology 200 Oct 1;40(1):65-74 by O'Shea E, Esteban B, Camarero J, Green AR, Colado MI) in which the conclusions "rule out any direct relationship between the neurotoxic effects of MDMA and its acute effects on body temperature in mice." This proves O'Callaghan's previous work to be incorrect.
Now on to the rest of the studies that Ecstatic1 missed in the last five years.
(From "In vivo detection of short- and long-term MDMA neurotoxicity--a positron emission tomorgraphy study in the living baboon brain" in Synapse 1998 Jun;29(2):183-92 by Scheffel U et al.):
In this study, they used a (surprise!) new application of the technique of positron emission tomogrophy (PET) that shows "PET imaging of the living nonhuman primate brain...can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity." These changes varied from 44% to 89% decreases in radioactivity concentrations, a significant indicator of neurotoxicity.
(From "An integrated hypothesis for the sertonergic axonal loss induced by 2,4-methylenedioxymethamphetamine" in Neurotoxicology 1998 Jun;19(3):427-41 by Sprague JE et al.):
This is an integrated hypothesis that is supported by the current literature of MDMA neurotoxicity (the deamination by MAO-B of DA in the 5-HT terminal). A great summary of neurotoxicity.
(From "Reduced in vivo binding to the serotonin transporter in the cerebral cortex of MDMA users" in British Journal of Psychiatry 1999 July;175:63-9 by Semple DM et al.):
Using the (surprise again!) relatively new application of single photon emission computed tomography (SPECT), they found reduced SERT but not DA transporter binding in vivo that provides "suggestive evidence for specific, at least temporary, serotonergic neurotoxicity of MDMA in humans."
(From "Toxicodynamics and long-term toxicity of the recreational drug, 3,4-methylenedioxymethamphetamine" in Toxicology Letters 2000 Mar 15;112-113;143-6 by Ricaurte GA et al.):
Using PET, they found "lasting decrements in global brain...binding...results that suggest human MDMA use results in brain 5-HT neurotoxicity."
I think this pretty much wraps it up for now. So please, Ecstatic1, think you before you post. Thank you.
