Comments by Lamont Granquist
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
It seems on a preliminary examination of Ricaurte's study (in other words i skimmed it pretty fast) that Figure 3 and Figure 4 are where the "meat" of this study is, and they're not terribly impressive. It has already been reported that subchronic (less than a month) administration of 5-HT transporter ligands like antidepressants (SSRIs, TCAs and tianeptine) reduce 5-HT transporter mRNA and radioligand binding to 5-HT transporter[1,2,3]. These results call into question the interpretation of reduced [11C]McN-5652 binding in human brain as "neurotoxicity." To reach this conclusion Ricaurte would really need to show decreases in binding to the 5-HT transporter in excess of a 25% reduction -- I would accept that as valid evidence since there is no known non-neurotoxic 5-HTT ligand which "down-regulates" the 5-HTT by this amount, while the neurotoxic doses of MDMA (5 mg/kg x 2/day x 4 days in non-human primates, 20 mg/kg x 2 x 4 in rats) do produce more substantial reductions. However, eyeballing Figure 3, I don't see such a clear and substantial reduction. Furthermore in Ricaurte's Figure 4 barring one outlying point in a user of appx 150 MDMA doses, none of the MDMA users range lower than the low end of the control subjects, and the reduction (if i understand this plot correctly) is of the order of 25% and therefore not significant.
The line they drew through this plot also tends to make me cringe -- it just smells bad -- the phrase "how to lie with statistics" leaps to mind.
And, of course, there are other issues with the study -- such as the possible exposure to other neurotoxins like methamphetamine, and possible selection effects (perhaps MDMA users with low initial 5-HTT counts tend to be the ones that wind up using it 300 times). Ultimately, I think these matched retrospective studies are probably worthless in general unless there are very strong correlations, which I just don't see. The more I look at this study the more I think there's even less to worry about here than there was in the CSF 5-HIAA studies of human users...
[1] Watanabe, Y, Sakai, RR, McEwen, BS, Mendelson, S. Stress and
Antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2
receptors and transport sites for serotonin. Brain Research. Vol 615. P 87-94. 1993.
[2] Kuroda, Y, Watanabe, Y, McEwen, BS. Tianeptine Decreases Both
Serotonin Transporter mRNA and Binding Sites in Rat Brain. European
Journal of Pharmacology. Vol 268. P R3-R5. 1994.
[3] Lesch, PK, Aulakh, CS, Wolozin, BL, Tolliver, TJ, Hill, JL, Murphy,
DL. "Regional Brain Expression of Serotonin Transporter mRNA and its
Regulation by Reuptake Inhibiting Antidepressants." Molecular Brain
Research. Vol 17. P 31-35. 1993.
It seems on a preliminary examination of Ricaurte's study (in other words i skimmed it pretty fast) that Figure 3 and Figure 4 are where the "meat" of this study is, and they're not terribly impressive. It has already been reported that subchronic (less than a month) administration of 5-HT transporter ligands like antidepressants (SSRIs, TCAs and tianeptine) reduce 5-HT transporter mRNA and radioligand binding to 5-HT transporter[1,2,3]. These results call into question the interpretation of reduced [11C]McN-5652 binding in human brain as "neurotoxicity." To reach this conclusion Ricaurte would really need to show decreases in binding to the 5-HT transporter in excess of a 25% reduction -- I would accept that as valid evidence since there is no known non-neurotoxic 5-HTT ligand which "down-regulates" the 5-HTT by this amount, while the neurotoxic doses of MDMA (5 mg/kg x 2/day x 4 days in non-human primates, 20 mg/kg x 2 x 4 in rats) do produce more substantial reductions. However, eyeballing Figure 3, I don't see such a clear and substantial reduction. Furthermore in Ricaurte's Figure 4 barring one outlying point in a user of appx 150 MDMA doses, none of the MDMA users range lower than the low end of the control subjects, and the reduction (if i understand this plot correctly) is of the order of 25% and therefore not significant.
The line they drew through this plot also tends to make me cringe -- it just smells bad -- the phrase "how to lie with statistics" leaps to mind.
And, of course, there are other issues with the study -- such as the possible exposure to other neurotoxins like methamphetamine, and possible selection effects (perhaps MDMA users with low initial 5-HTT counts tend to be the ones that wind up using it 300 times). Ultimately, I think these matched retrospective studies are probably worthless in general unless there are very strong correlations, which I just don't see. The more I look at this study the more I think there's even less to worry about here than there was in the CSF 5-HIAA studies of human users...
[1] Watanabe, Y, Sakai, RR, McEwen, BS, Mendelson, S. Stress and
Antidepressant effects on hippocampal and cortical 5-HT1A and 5-HT2
receptors and transport sites for serotonin. Brain Research. Vol 615. P 87-94. 1993.
[2] Kuroda, Y, Watanabe, Y, McEwen, BS. Tianeptine Decreases Both
Serotonin Transporter mRNA and Binding Sites in Rat Brain. European
Journal of Pharmacology. Vol 268. P R3-R5. 1994.
[3] Lesch, PK, Aulakh, CS, Wolozin, BL, Tolliver, TJ, Hill, JL, Murphy,
DL. "Regional Brain Expression of Serotonin Transporter mRNA and its
Regulation by Reuptake Inhibiting Antidepressants." Molecular Brain
Research. Vol 17. P 31-35. 1993.