by Earth Erowid
Originally published in The Resonance Project
December 11, 1998
Positron emission tomographic evidence of toxic effect of MDMA ('Ecstasy') on brain serotonin neurons in human beings,
by U. D. McCann; Z Szabo; U Scheffel; R.F. Dannals; G. A. Ricaurte
The Lancet Vol 352, Oct 31, 1998, 1437
"The drug Ecstasy causes brain damage in people who take it frequently, scientists have proved. ... The capacity for thought, memory and emotion is impaired."[a] or so The Times of London reported the results of a new study into the long term effects of MDMA on the structure and chemistry of the brain.
While the study develops some exciting new techniques for studying neurons in living brains, the reported results, the study's press release, and the media reports surrounding it do not stop at reporting the measured data…
The study, published in The Lancet medical journal at the end of October, was conducted by Dr. U.D. McCann, George Ricaurte, and colleagues, and is another in a series of studies indicating that MDMA may cause semi-permanent changes in the functioning of serotonin neurons. It involved some of the most sensitive brain imaging techniques to date, using PET (Positron Emissions Tomography) scans to study the brains of 15 control individuals and 14 men and women who had ingested MDMA between 70 and 400 times, from 1 to 16 times per month, at dosages estimated by the researchers to be between 150 and 1250 mg.
As part of the study, each subject was injected with a radioactive marker that selectively binds to 5-HT transporters (serotonin re-uptake sites) on the axons of 5-HT neurons. Transporters are protein structures embedded in the membranes of nerve endings that are part of the inter-neuron communication system. The test showed that the marked chemical bound to an average of 22% fewer 5-HT transporter sites in measured areas of the brains of MDMA users than non-users. The researchers believe that this reduced binding indicates that the transporters have been destroyed and the serotonin neurons are damaged. Some dispute this interpretation and point out that reduced binding could also indicate neuroregulation similar to that produced by Prozac or other SSRIs.[b] While this study shows the most direct evidence so far that heavy MDMA users may have lower serotonin levels than non users, it does not demonstrate that MDMA causes reductions in serotonin transporters.
Unfortunately, the study, its press release, and the media reports surrounding it do not stop at reporting the measured data. They assert that not only is there a measurable difference in the amount of binding to 5-HT transporter sites, but they conclude that this difference is caused by the use of MDMA, that increased use causes further decreases in serotonin levels, that reduced 5-HT binding constitutes "brain damage", and that this 'damage' may have negative consequences including "depression, anxiety, memory disturbance, and other neuropsychiatric disorders".[c]
Critics of the study point out several possible weaknesses in the assumption that MDMA is the cause of the differences in 5-HT transporter binding. First, with only 14 MDMA-using participants in the study, the sample is extremely small. Second, McCann-Ricaurte assume that other drugs played no role in whatever changes occurred, yet they did not attempt to control for exposure to drugs other than MDMA, MDA, and MDE.[d] The MDMA-using subjects may have taken large amounts of many other drugs and it is very likely that they unwittingly took MDMA mixed with an unknown assortment of adulterants.[e] Third, the researchers mistakenly assume they can know that the differences between study subjects did not predate their ingestion of MDMA. From this type of study, there is no way of knowing that the MDMA using subjects did not have naturally lower 5-HT transporter binding levels before their MDMA use. McCann et al. argue that "since none of the MDMA users had a neuropsychiatric disorder in which 5-HT has been implicated, [the possibility that the lower levels preexisted] is unlikely." But this logic is flawed. Neither the MDMA nor control subjects were found to have any disorders, their binding levels were different, so lack of disorder cannot be used as an indicator of 5-HT levels. Also, since even the heaviest users had levels within the range of levels found in non-users, the differences between the two groups could be accounted for by improperly matched subject groups. Some researchers point out that the criteria for selecting subjects from the pool of available MDMA users is not included in the published study [f]. It is quite possible that these heavy MDMA users belong to a group with naturally lower 5-HT binding levels and that lower levels may even correspond to an increased likelihood to use MDMA.
McCann-Ricaurte also assert that they demonstrate a "strong" correlation between increased MDMA use and increasingly lower levels of the 5-HT transporter. "Scans tended to [show lower levels] in those who had taken the drug more often."[g] This correlation has been questioned by several critics of the paper because it is based on controversial readings of the data. Specifically, the calculation of the "strong correlation" includes both the controls and the MDMA users which improperly weights the analysis by exaggerating the influence of the control group. The removal of the controls and a single MDMA user from the equation causes the apparent correlation to disappear.[h,i] Both groups of subjects showed substantial variation between individual 5-HT transporter binding levels and all but one of the MDMA users fell within the same overall range as the non-users. The most that can be said is that the MDMA users tended to cluster near the lower end of the overall range. Even Ricaurte reportedly does not consider the correlation between increased use and further decreased levels to be a primary finding of the paper because the small size of the study may make extrapolations from the data inaccurate or misleading.
The published study and its press release refer to the differences in 5-HT transporter levels as "brain damage". Whether one calls these differences in neurochemistry "brain damage" or not appears to be mostly a question of perspective. Opponents of MDMA's therapeutic and recreational use argue that any reduction in available serotonin (or in this case transporters) should be considered "neural injury" and that "potential functional consequences of MDMA-induced brain 5-HT neurotoxic lesions are not yet clear, but may include depression, anxiety, memory disturbance, and other neuropsychiatric disorders in which brain 5-HT has been implicated."[c] All too frequently, negative speculations by researchers are misread as scientific "proof" when it comes to recreationally used psychoactives.[j]
Proponents of MDMA therapy and critics of the designation "brain damage" point out that there is little to no evidence that heavy MDMA users experience any functional problems. Optimists suggest that it is even possible that MDMA precipitated neurochemical changes are positive. Administration of SSRI antidepressants such as Prozac cause similar reductions in 5-HT transporters[b] and one study found that MDMA users were "less impulsive, more harm-avoidant, and had decreased hostility,"[k] a finding which is at odds with what researchers expect to see in people with abnormally low serotonin levels. As mentioned earlier, the subjects in the study were tested for "axis I psychiatric disorders". Only subjects who were both heavy MDMA users and free of psychiatric problems were chosen for the study. If the researchers are right that the lower levels of 5-HT transporters can lead to "neuropsychiatric disorders", why do none of the heavy MDMA users studied have any of these problems?
One explanation given by reporters is the "Time Bomb' theory, which suggests that as users age, their past use will come back to haunt them: "Users of the drug would be likely to have a higher incidence of depression in later life."[l] But there is no evidence to support this theory. While other neurotransmitter systems have been shown to decline with age (dopamine, for example), serotonin has not been shown to decline over time. While caution is prudent, this speculation is refuted by current knowledge about serotonin.
An additional criticism is that the study's findings do not point out that the level of MDMA use exhibited by the subjects is extremely high, well above the levels used in therapeutic contexts or by most recreational users. The reported average dose is 386 milligrams with maximum doses estimated at 1250 mg where the normal dose of MDMA is between 100 and 200 mgs. Animal studies suggest that even a single very high dose of MDMA can cause long term changes (and damage) to the 5-HT system, while Ricaurte himself showed that in non-human primates lower doses (2.5 mg per kg) administered every two weeks for four months had no measurable effect. By failing to point this out where the study mentions potential long term health consequences, the non-expert reader is left to incorrectly assume that even carefully controlled therapeutic use of MDMA causes "brain damage".
Considering that there are few long time users of MDMA who report permanent negative health consequences, that preliminary research has failed to detect serious clinical problems[c,m,n], and that MDMA has been used therapeutically and recreationally for over 15 years, the practical negative health consequences of moderate MDMA use are likely to be subtle and may even be non-existent. For most users, the dangers associated with ingesting 'street E' of unknown quality are far more concrete.
But neither should the research be ignored. Prospective users of MDMA should weigh carefully the collected data before swallowing their next dose. Individuals who choose to take the risk of long term changes to their neurophysiology make themselves research subjects in an uncontrolled investigation of the long term effects of their chosen psychoactives. Will we live to regret our decisions? Will those users who choose to use more heavily be prone to problems later in life?
In choosing how to live, we assume known and unknown risks every day. We weigh benefits against risks and choose a path based on our own unique situation. Learning a sense of appropriate risk is part of maturing into ourselves as fragile living creatures. Yet in most of the world, political and social organizations have tried to take the freedom to decide whether to ingest a psychoactive away from the individual, under the auspices of protecting citizens from psychological and physical harm. Any risk is considered too great a risk. 'Any non-medical use is abuse.'[o] This extreme position fails to minimize physical and mental harms because it offers no practical knowledge of how to make intelligent choices in real situations. Instead, our communities and governments should encourage people to become aware of the risks and help them relate to psychoactives more responsibly.
For millions of MDMA users there is little trust in the dire 'scientific' claims of brain decay. Unless verified individual dysfunctions surface, or at least reliable anecdotal reports of problems, users will remain jaded and unconvinced, hardened by warning after hyperbolic warning of immanent "Murder! Insanity! Death!".[p] Despite claims by popular news media and medical 'experts' that we now have "direct evidence" that MDMA is harmful to man[q], the question of how much risk is still far from answered.
Comments, criticisms, and corrections welcomed: corrections@erowid.org
More information on this study can be found at: www.erowid.org/mdma/ricaurte/
Notes:
"The drug Ecstasy causes brain damage in people who take it frequently, scientists have proved. ... The capacity for thought, memory and emotion is impaired."[a] or so The Times of London reported the results of a new study into the long term effects of MDMA on the structure and chemistry of the brain.
While the study develops some exciting new techniques for studying neurons in living brains, the reported results, the study's press release, and the media reports surrounding it do not stop at reporting the measured data…
The study, published in The Lancet medical journal at the end of October, was conducted by Dr. U.D. McCann, George Ricaurte, and colleagues, and is another in a series of studies indicating that MDMA may cause semi-permanent changes in the functioning of serotonin neurons. It involved some of the most sensitive brain imaging techniques to date, using PET (Positron Emissions Tomography) scans to study the brains of 15 control individuals and 14 men and women who had ingested MDMA between 70 and 400 times, from 1 to 16 times per month, at dosages estimated by the researchers to be between 150 and 1250 mg.
As part of the study, each subject was injected with a radioactive marker that selectively binds to 5-HT transporters (serotonin re-uptake sites) on the axons of 5-HT neurons. Transporters are protein structures embedded in the membranes of nerve endings that are part of the inter-neuron communication system. The test showed that the marked chemical bound to an average of 22% fewer 5-HT transporter sites in measured areas of the brains of MDMA users than non-users. The researchers believe that this reduced binding indicates that the transporters have been destroyed and the serotonin neurons are damaged. Some dispute this interpretation and point out that reduced binding could also indicate neuroregulation similar to that produced by Prozac or other SSRIs.[b] While this study shows the most direct evidence so far that heavy MDMA users may have lower serotonin levels than non users, it does not demonstrate that MDMA causes reductions in serotonin transporters.
Unfortunately, the study, its press release, and the media reports surrounding it do not stop at reporting the measured data. They assert that not only is there a measurable difference in the amount of binding to 5-HT transporter sites, but they conclude that this difference is caused by the use of MDMA, that increased use causes further decreases in serotonin levels, that reduced 5-HT binding constitutes "brain damage", and that this 'damage' may have negative consequences including "depression, anxiety, memory disturbance, and other neuropsychiatric disorders".[c]
Critics of the study point out several possible weaknesses in the assumption that MDMA is the cause of the differences in 5-HT transporter binding. First, with only 14 MDMA-using participants in the study, the sample is extremely small. Second, McCann-Ricaurte assume that other drugs played no role in whatever changes occurred, yet they did not attempt to control for exposure to drugs other than MDMA, MDA, and MDE.[d] The MDMA-using subjects may have taken large amounts of many other drugs and it is very likely that they unwittingly took MDMA mixed with an unknown assortment of adulterants.[e] Third, the researchers mistakenly assume they can know that the differences between study subjects did not predate their ingestion of MDMA. From this type of study, there is no way of knowing that the MDMA using subjects did not have naturally lower 5-HT transporter binding levels before their MDMA use. McCann et al. argue that "since none of the MDMA users had a neuropsychiatric disorder in which 5-HT has been implicated, [the possibility that the lower levels preexisted] is unlikely." But this logic is flawed. Neither the MDMA nor control subjects were found to have any disorders, their binding levels were different, so lack of disorder cannot be used as an indicator of 5-HT levels. Also, since even the heaviest users had levels within the range of levels found in non-users, the differences between the two groups could be accounted for by improperly matched subject groups. Some researchers point out that the criteria for selecting subjects from the pool of available MDMA users is not included in the published study [f]. It is quite possible that these heavy MDMA users belong to a group with naturally lower 5-HT binding levels and that lower levels may even correspond to an increased likelihood to use MDMA.
McCann-Ricaurte also assert that they demonstrate a "strong" correlation between increased MDMA use and increasingly lower levels of the 5-HT transporter. "Scans tended to [show lower levels] in those who had taken the drug more often."[g] This correlation has been questioned by several critics of the paper because it is based on controversial readings of the data. Specifically, the calculation of the "strong correlation" includes both the controls and the MDMA users which improperly weights the analysis by exaggerating the influence of the control group. The removal of the controls and a single MDMA user from the equation causes the apparent correlation to disappear.[h,i] Both groups of subjects showed substantial variation between individual 5-HT transporter binding levels and all but one of the MDMA users fell within the same overall range as the non-users. The most that can be said is that the MDMA users tended to cluster near the lower end of the overall range. Even Ricaurte reportedly does not consider the correlation between increased use and further decreased levels to be a primary finding of the paper because the small size of the study may make extrapolations from the data inaccurate or misleading.
The published study and its press release refer to the differences in 5-HT transporter levels as "brain damage". Whether one calls these differences in neurochemistry "brain damage" or not appears to be mostly a question of perspective. Opponents of MDMA's therapeutic and recreational use argue that any reduction in available serotonin (or in this case transporters) should be considered "neural injury" and that "potential functional consequences of MDMA-induced brain 5-HT neurotoxic lesions are not yet clear, but may include depression, anxiety, memory disturbance, and other neuropsychiatric disorders in which brain 5-HT has been implicated."[c] All too frequently, negative speculations by researchers are misread as scientific "proof" when it comes to recreationally used psychoactives.[j]
Proponents of MDMA therapy and critics of the designation "brain damage" point out that there is little to no evidence that heavy MDMA users experience any functional problems. Optimists suggest that it is even possible that MDMA precipitated neurochemical changes are positive. Administration of SSRI antidepressants such as Prozac cause similar reductions in 5-HT transporters[b] and one study found that MDMA users were "less impulsive, more harm-avoidant, and had decreased hostility,"[k] a finding which is at odds with what researchers expect to see in people with abnormally low serotonin levels. As mentioned earlier, the subjects in the study were tested for "axis I psychiatric disorders". Only subjects who were both heavy MDMA users and free of psychiatric problems were chosen for the study. If the researchers are right that the lower levels of 5-HT transporters can lead to "neuropsychiatric disorders", why do none of the heavy MDMA users studied have any of these problems?
One explanation given by reporters is the "Time Bomb' theory, which suggests that as users age, their past use will come back to haunt them: "Users of the drug would be likely to have a higher incidence of depression in later life."[l] But there is no evidence to support this theory. While other neurotransmitter systems have been shown to decline with age (dopamine, for example), serotonin has not been shown to decline over time. While caution is prudent, this speculation is refuted by current knowledge about serotonin.
An additional criticism is that the study's findings do not point out that the level of MDMA use exhibited by the subjects is extremely high, well above the levels used in therapeutic contexts or by most recreational users. The reported average dose is 386 milligrams with maximum doses estimated at 1250 mg where the normal dose of MDMA is between 100 and 200 mgs. Animal studies suggest that even a single very high dose of MDMA can cause long term changes (and damage) to the 5-HT system, while Ricaurte himself showed that in non-human primates lower doses (2.5 mg per kg) administered every two weeks for four months had no measurable effect. By failing to point this out where the study mentions potential long term health consequences, the non-expert reader is left to incorrectly assume that even carefully controlled therapeutic use of MDMA causes "brain damage".
Considering that there are few long time users of MDMA who report permanent negative health consequences, that preliminary research has failed to detect serious clinical problems[c,m,n], and that MDMA has been used therapeutically and recreationally for over 15 years, the practical negative health consequences of moderate MDMA use are likely to be subtle and may even be non-existent. For most users, the dangers associated with ingesting 'street E' of unknown quality are far more concrete.
But neither should the research be ignored. Prospective users of MDMA should weigh carefully the collected data before swallowing their next dose. Individuals who choose to take the risk of long term changes to their neurophysiology make themselves research subjects in an uncontrolled investigation of the long term effects of their chosen psychoactives. Will we live to regret our decisions? Will those users who choose to use more heavily be prone to problems later in life?
In choosing how to live, we assume known and unknown risks every day. We weigh benefits against risks and choose a path based on our own unique situation. Learning a sense of appropriate risk is part of maturing into ourselves as fragile living creatures. Yet in most of the world, political and social organizations have tried to take the freedom to decide whether to ingest a psychoactive away from the individual, under the auspices of protecting citizens from psychological and physical harm. Any risk is considered too great a risk. 'Any non-medical use is abuse.'[o] This extreme position fails to minimize physical and mental harms because it offers no practical knowledge of how to make intelligent choices in real situations. Instead, our communities and governments should encourage people to become aware of the risks and help them relate to psychoactives more responsibly.
For millions of MDMA users there is little trust in the dire 'scientific' claims of brain decay. Unless verified individual dysfunctions surface, or at least reliable anecdotal reports of problems, users will remain jaded and unconvinced, hardened by warning after hyperbolic warning of immanent "Murder! Insanity! Death!".[p] Despite claims by popular news media and medical 'experts' that we now have "direct evidence" that MDMA is harmful to man[q], the question of how much risk is still far from answered.
Comments, criticisms, and corrections welcomed: corrections@erowid.org
More information on this study can be found at: www.erowid.org/mdma/ricaurte/
Notes:
- "The End of Ecstasy," The Times (of London) 31 October 1998. Internet edition: http://www.the-times.co.uk/
- Granquist, Lamont. - www.erowid.org/entheogens/x/ricaurte/ricaurte_comment5.shtml Referring to: Hoffman BJ, Hansson SR, Mezey E, Palkovits M. "Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system." Front Neuroendocrinol 1998; 19: 187-231 and Lesch KP, Aulakh CS, Wolozin BL, Tolliver TJ, Hill JL, Murphey, DL. "Regional brain expression of serotonin transporter mRNA and its regulation by reuptake inhibiting antidepressants." Brain Res Mol Brain Res 1993; 17:31-35.
- McCann, U.D., et al. "Positron emission tomographic evidence of toxic effect of MDMA ('Ecstasy') on brain serotonin neurons in human beings" the lancet, Volume 352, Number 9138 31 October 1998. Internet edition: www.thelancet.com
- H (anonymous contributor). "A Prospective Guinea Pig." The Vaults of Erowid, 1998. Erowid.org/mdma/ricaurte/ricaurte_comment3.shtml.
- Numerous studies of 'street E' have found that they are unreliable sources of MDMA and often contain other substances. See http://www.ecstasy.org/testingTOC.
- Erowid, earth. "A Summary of Karl Jansen's Comments." The Vaults of Erowid. Erowid.org/mdma/ricaurte/ricaurte_comment6.shtml
- Press Release for McCann study. Erowid.org/mdma/ricaurte/ricaurte_press_release.shtml
- Erowid, earth . "Questioning the Correlation between Increased MDMA Use and Decreased Binding - an Analysis of Figure 4 of the McCann-Ricaurte MDMA Study Results." The Vaults of Erowid, 1998. Erowid.org/mdma/ricaurte/ricaurte_statistics.shtml
- Doblin, Rick. "More Comments on the Ricaurte Data." 11 November 1998, email to the MAPS list.
- Murray, Ian (Medical Correspondent). "Proof that Ecstasy damages brain," The Times (of London) 30 October 1998. Internet ed. Available at: www.erowid.org/mdma/ricaurte/ricaurte_article3.shtml
- Saunders, Nicholas. Ecstasy- Dance, Trance & Transformation. Quick American Archives, 1996. He is missed :\
- Henry, Dr. John. Professor at St. Mary's Hospital in London, as quoted in San Jose Mercury, 29 October 1998. His 'Time Bomb' theory makes it into "Study Says Ecstasy Causes Brain Damage" in The Houston Chronicle, October 30 1998.
- Granquist, Lamont. "Yet Another MDMA FAQ." 1998. Erowid.org/chemicals/mdma/mdma_faq3.shtml. The Neurotoxicity section of Lamont's newest FAQ is the best, most up to date overview of the MDMA neurotoxicity issue that I know of.
- McCann, UD, Ridenour, A, Shaham, Y, Ricaurte, GA. "Serotonin neurotoxicity after (+/-) 3,4-methylenedioxy-methamphetamine (MDMA, Ecstasy): a controlled study in humans," Neuropsychopharmacology, Vol 10(2), P 129-138, 1994.
- 1997 Annual Report of the International Narcotics Control Board, the policy writing wing of the United Nation's Drug Control Program and other INCB publications.
- Text from an anti-marijuana leaflet from the 1940's, produced under Harry Anslinger, Commissioner of the newly formed U.S. Narcotics Bureau.
- "Study Says Ecstasy Causes Brain Damage," The Houston Chronicle, 30 October, 1998. Internet edition: http://www.chron.com/.