Dr. George Ricaurte of The John S. Hopkins Medical Institution in Baltimore Is A Big Fat Liar A Sloppy Researcher

Update 2:38pm -- it has been brought to my attention that Ricaurte's screw up was a "mistake," rather than an intentional, precalculated deception. As you may well know by now, intent matters to me, so incompetence is sort of a defense in this case, I suppose, but it still sounds pretty shaky at best.

Here's a great synopsis about it by Derek Lowe. (Note that Derek also agrees with me -- that the original results should not have been published at all without first being repeated!)

It's still irresponsible to publish information that could have such a profound impact on the population without qualifying it first at least twice in one's own lab. Sloppy research at best. But the stuff I say below was said when I thought there was a deliberate misconception going on. Here's the original retraction article. Nuff said. There's more important stuff going on.

So the bozo that scared the world into thinking that one Ecstasy trip could scar your brain for life has admitted that he lied about his test results. (He has officially "retracted" them -- and admitted to using other substances on the subjects involved than the substances that were supposed to be the focus of the study. That's lying!)

Yeah I'll say it's "a major flaw in his research" that the research was absent of the the drug he's supposedly testing.

This guy shouldn't even be allowed to do research anymore. We don't need big fat liars like you in Academia buddy. Away with you!

Leave your beaker at the door!

Here's ABC World News on the subject.

Here's the report containing some of the lies.

I hope it goes without saying that anything else this guy's done should be considered suspect as well.

Here's a clip from the summary I quote above:

But all that said, I have to then turn around and wonder why the original paper was published at all. I was surprised to learn that their results hadn't been repeated beforehand. You'd think that this would be necessary, given the public health implications of the work and its variance with the results of others in the field. I can't help but think that the researchers got their original data, thought they had a hot result that would make everyone sit up straight, and got it into publication as fast as they could.

I'm really taken aback to learn that they hadn't looked at the original monkeys for MDMA levels before. Getting blood samples from monkeys is no easy task, but why wait until there's a problem to do the post-mortem brain levels? Those numbers really would have helped to shore up the original results - and would have immediately shown that there was a problem, long before the paper was even published. I don't like to sound this way, but it's true: in the drug industry, we consider pharmacokinetic data like this to be essential when interpreting an animal study.

http://www.corante.com/pipeline/20030901.shtml#51811

Backing Down, in Public

There's been a very public retraction of a controversial paper from last year, one which linked MDMA (Ecstasy) to dopamine-linked neuronal damage (and thus possible Parkinson's disease.) The researchers (at Johns Hopkins) injected monkeys with what they thought was a sample of MDMA and saw clear signs of neurotoxicity.

But the next study, this time via oral dosing with another sample of MDMA, failed to show the effect. So they went back and tried the injection route again, and this time it showed no dopamine-neuron toxicity, either. The discrepancy in the oral versus i.v. dosing would be unexpected, but you could find ways to explain it, if it were a real and reproducible effect. But when the i.v. experiment failed that second time, the authors must have known that they had a real problem.

The vial that the MDMA came from in the first experiment had long since been discarded, but they had a sample of methamphetamine that had been received from the same source at the same time - and it proved, on examination, to contain MDMA instead. That led to suspicions of a label-swapping mistake, and sure enough, examination of the brain samples from the original monkey experiment showed the presence of methamphetamine, but not MDMA. It all fits, and it's all wrong.

Doubts were expressed, very loud doubts, about the results of the study when it first came out. Other research groups in the field were sceptical, pointing out that there should be a lot more cases of Parkinson's showing up in the ecstasy-using population, especially considering the doses that some of these folks were exposing themselves to. Those sceptics have been vindicated more thoroughly than they ever could have hoped.

I have several comments on all this. The first thing I need to do is commend the Johns Hopkins people for doing the right thing and retracting their paper. It must have been mighty quiet around the lab for a while after they got the results from that repeat i.v. study. The thought of something like this happening can really keep you up at night.

I'm sure that some people are going to point the finger at this group for not checking the samples of MDMA and methamphetamine. But I can't fault them so much on that point. In vivo pharmacologists are not chemists, and aren't expected to assay the samples that they're dosing. In every drug research project I've been on, the animal folks make it clear that they depend on compounds being what the label says they are. They have no way to confirm it themselves. (In this case, Research Triangle Institute, the source of the samples, says that things were fine on their end, as you'd figure they would. Depends on where the label came from on that remaining methamphetamine sample, doesn't it?)

But all that said, I have to then turn around and wonder why the original paper was published at all. I was surprised to learn that their results hadn't been repeated beforehand. You'd think that this would be necessary, given the public health implications of the work and its variance with the results of others in the field. I can't help but think that the researchers got their original data, thought they had a hot result that would make everyone sit up straight, and got it into publication as fast as they could.

I'm really taken aback to learn that they hadn't looked at the original monkeys for MDMA levels before. Getting blood samples from monkeys is no easy task, but why wait until there's a problem to do the post-mortem brain levels? Those numbers really would have helped to shore up the original results - and would have immediately shown that there was a problem, long before the paper was even published. I don't like to sound this way, but it's true: in the drug industry, we consider pharmacokinetic data like this to be essential when interpreting an animal study.

It's even more vital when you're trying to figure out brain effects, since the levels of compounds in the CNS can only be determined by specifically checking there. So, you see brain damage? The next question is "How much compound was there in the brain?" And you don't go on until you've answered it. Perhaps the authors decided to rely on known brain exposures when they ran the study. But those known exposures would have been from studies that didn't show the neuronal damage. I just can't find a good excuse here.

The further experiments that disproved the original results are the sort of thing that should have been done before the first paper was published, frankly. Like anyone else in the drug industry, I understand that monkey studies are slow, costly, and hard to get started. But this was an extraordinary claim, and should have been held to a higher standard of evidence. If you live by making a big splash in Science, you may die by the same route.

posted at 9:17 pm

http://www.erowid.org/chemicals/mdma/references/journal/2002_ricaurte_science_1/2002_ricaurte_science_1_retraction1.shtml

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Retraction of Research Findings
Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (“Ecstasy”)
by Ricuarte G, Yuan J, Hatzidiitriou G, Cord BJ, McCann UD
September 5, 2003
Review of Article
Article Index Page

We write to retract our report "Severe dopaminergic neurotoxicity in primates after a common recreational dose regimen of methylenedioxymethamphetamine (MDMA)" (1) following our recent discovery that the drug used to treat all but one animal in that report came from a bottle that contained d-methamphetamine instead of the intended drug, racemic MDMA. Notably, d-methamphetamine would be expected to produce the same pattern of combined dopaminergic/serotonergic neurotoxicity (2) as that seen in the animals reported in our paper (1).

The originally published report (1) presented results from multiple studies performed in our laboratory over a span of approximately two years demonstrating that a novel systemic dose regimen of what we believed was MDMA produced severe dopamine neurotoxicity in two species of nonhuman primates, in addition to the previously reported serotonin neurotoxicity (3-6). Subsequent to the publication of those findings, we were unable to extend the dopamine neurotoxicity to orally administered doses. Multiple subsequent attempts to reproduce the original findings with systemically administered doses of MDMA identical to those used in the original study were also unsuccessful, under a variety of laboratory conditions.

We then noted that our studies aimed at extending and replicating the finding of MDMA-induced dopamine neurotoxicity were performed using a new batch of MDMA. This new batch of MDMA was determined to be authentic by several methods, including gas chromatography/mass spectrometry (GC/MS). Upon investigation of our laboratory records, we determined that the studies detailed in our paper (1) utilized a batch of MDMA that had been requested on the same date as a batch of d-methamphetamine, and that both drug requests were for the same amount (10 g), and were processed by the supplier on the same day. Both drugs were delivered to our laboratory on the same day, in the same package. At delivery, the two bottles had different affixed labels, the same delivery reference number, but different batch numbers, as specified in their respective chemical data sheets. Following receipt, both drugs were stored in our laboratory in their original containers, in a locked safe.

When we began to suspect that the two bottles of drug might have borne incorrect labels (i.e., that the putative MDMA was actually d-methamphetamine, and vice versa), we requested that a sample of the drug in the bottle bearing the original and intact label of "d-methamphetamine" be analyzed by various analytical techniques, including GC/MS. Three independent laboratories found the sample to consist of MDMA, with no evidence of even trace amounts of methamphetamine.

Although the drug sample used in our original studies (1) was depleted and the empty bottle labeled MDMA had been discarded, we did have frozen brains from two animals that died shortly after drug treatment during the course ofthe original experiments (1). When these brains were analyzed by GC/MS by three independent laboratories, they were found to contain methamphetamine and its metabolite, amphetamine, neither of which is a metabolite of MDMA(7). Not even trace amounts of MDMA nor its metabolite, MDA, were found inthese brains. Detailed review of our laboratory records revealed that allbut one animal in our study (1) had been treated with the drug in the bottle labeled "(±)methylenedioxymethamphetamine" (MDMA) processed at the same time as the bottle labeled "d-methamphetamine".

This labeling error does not call into question the results of multiple previous studies demonstrating the serotonin neurotoxic potential of MDMA invarious animal species, including several nonhuman primate species (3-6,8). Regarding the dopamine neurotoxic potential of MDMA in nonhumanprimates, it remains possible that dose regimens in the range of those used by some humans, but different from those thus far tested, produce dopamine neurotoxicity in primates, as they do in rodents (9, 10). Moreover, lasting effects of MDMA on dopaminergic function in humans have recently been reported (11), and some humans with a history of MDMA abuse have developed Parkinsonism (12-14). However, until the dopamine neurotoxic potential ofMDMA in primates can be examined more fully, this possibility remains uncertain.

George A. Ricaurte1, Jie Yuan1, George Hatzidimitriou1, Branden J. Cord2, Una D. McCann3

Department of Neurology, 2 - Department of Neurosciences, 3 - Department of Psychiatry
Johns Hopkins Bayview Medical Center
Johns Hopkins University
School of Medicine, Baltimore, MD 21224, USA.

References

1. G. Ricaurte, J. Yuan, G. Hatzidimitriou, B. Cord, U. McCann, Science 297, 2260 (2002).
2. V. Villemagne et al., J Neurosci 18, 419 (1998).
3. G. A. Ricaurte, L. E. Delanney, I. Irwin, J. W. Langston, Brain Res. 446, 165 (1988).
4. T. R. Insel, G. Battaglia, J. N. Johannessen, S. Marra, E. B. DeSouza, J. Pharmacol. Exp. Ther. 249, 713 (1989).
5. M. S. Kleven, W. L. Woolverton, L. S. Seiden, Brain Res. 488, 121 (1989).
6. D. L. Frederick et al., Neurotoxicol. Teratol. 17, 531 (1995).
7. A. Cho, Y. Kumagai, in Amphetamine and its Analogs: Neuropsychopharmacology, Toxicology and Abuse, A. Cho, D. Segal, Eds. (Academic Press, New York, 1994), pp. 43-77.
8. W. Slikker Jr. et al., Toxicol. Appl. Pharmacol. 94, 448 (1988).
9. D.L. Commins et al., J. Pharmacol. Exp. Ther. 241, 338(1987).
10. E. O'Shea, B. Esteban, J. Camarero, A. R. Green, M. I. Colado, Neuropharmacology. 40, 65 (2001).
11. G. Gerra et al. Behav. Brain Res. 134, 403 (2002).
12.
13. S. Mintzer, S. Hickenbottom, S. Gilman, N. Engl. J. Med. 340, 1443 (1999).
14. S.M. Kuniyoshi and J. Jankovic N Engl J Med. 349, 96 (2003).
15. G. Ricaurte, unpublished data.
16. We gratefully acknowledge helpful discussions with Dr. Jonathan Katz of the NIDA Intramural Research Program, Baltimore, MD, Dr. W. Lee Hearn, Laboratory Director of the Miami-Dade County Medical Examiner Department, Miami, FL and Dr. Nancy Ator, Johns Hopkins University School of Medicine, Baltimore, MD. We are also grateful for the expert chemical analytical assistance of Ms. Rebecca Fernandez, Toxicologist I, Miami-Dade County Medical Examiner Department, Miami, FL, Terry L. DalCason of the DEA North Central Laboratory, Chicago, IL., Dr. Max Courtney, Forensic Consultant Services, Fort Worth, TX., Dr. Michael Daggett, Quest Diagnostics-Nichols Institute, Chantilly, VA, Dr. Ivy Carroll and associates at RTI International, Research Triangle Park, NC, and Dr. Roger Foltz at the University of Utah, Salt Lake City, UT.

Last Modified - Tue, Sep 9, 2003 By Erowid

http://www.pcdpap.org/files/ecstacy.htm

Ecstacy

"ECSTASY" DAMAGES THE BRAIN AND IMPAIRS MEMORY IN HUMANS

By Robert Mathias

NIDA NOTES Staff Writer

ANIDA-supported study has provided the first direct evidence

that chronic use of MDMA, popularly known as "ecstasy,"

causes brain damage in people. Using advanced brain

imaging techniques, the study found that MDMA harms

neurons that release serotonin, a brain chemical thought to

play an important role in regulating memory and other

functions. In a related study, researchers found that heavy

MDMA users have memory problems that persist for at least

two weeks after they have stopped using the drug. Both

studies suggest that the extent of damage is directly

correlated with the amount of MDMA use.

"The message from these studies is that MDMA does change

the brain and it looks like there are functional consequences

to these changes," says Dr. Joseph Frascella of NIDA's

Division of Treatment Research and Development. That

message is particularly significant for young people who

participate in large, all-night dance parties known as "raves,"

which are popular in many cities around the Nation. NIDA's

epidemiologic studies indicate that MDMA

(3,4-methylenedioxymethamphetamine) use has escalated in

recent years among college students and young adults who

attend these social gatherings.

In the brain imaging study, researchers used positron

emission tomography (PET) to take brain scans of 14 MDMA

users who had not used any psychoactive drug, including

MDMA, for at least three weeks. Brain images also were

taken of 15 people who had never used MDMA. Both groups

were similar in age and level of education and had

comparable numbers of men and women.

In people who had used MDMA, the PET images showed

significant reductions in the number of serotonin

transporters, the sites on neuron surfaces that reabsorb

serotonin from the space between cells after it has

completed its work. The lasting reduction of serotonin

transporters occurred throughout the brain, and people who

had used MDMA more often lost more serotonin transporters

than those who had used the drug less.

Previous PET studies with baboons also produced images

indicating MDMA had induced long-term reductions in the

number of serotonin transporters. Examinations of brain

tissue from the animals provided further confirmation that the

decrease in serotonin transporters seen in the PET images

corresponded to actual loss of serotonin nerve endings

containing transporters in the baboons' brains. "Based on

what we found with our animal studies, we maintain that the

changes revealed by PET imaging are probably related to

damage of serotonin nerve endings in humans who had

used MDMA," says Dr. George Ricaurte of The Johns

Hopkins Medical Institutions in Baltimore. Dr. Ricaurte is the

principal investigator for both studies, which are part of a

clinical research project that is assessing the long-term

effects of MDMA.

"The real question in all imaging studies is what these

changes mean when it comes to functional consequences,"

says NIDA's Dr. Frascella. To help answer that question, a

team of researchers, which included scientists from Johns

Hopkins and the National Institute of Mental Health who had

worked on the imaging study, attempted to assess the

effects of chronic MDMA use on memory. In this study,

researchers administered several standardized memory tests

to 24 MDMA users who had not used the drug for at least

two weeks and 24 people who had never used the drug.

Both groups were matched for age, gender, education, and

vocabulary scores.

The study found that, compared to the nonusers, heavy

MDMA users had significant impairments in visual and verbal

memory. As had been found in the brain imaging study,

MDMA's harmful effects were dose related, the more MDMA

people used, the greater difficulty they had in recalling what

they had seen and heard during testing.

The memory impairments found in MDMA users are among

the first functional consequences of MDMA-induced damage

of serotonin neurons to emerge. Recent studies conducted

in the United Kingdom also have reported memory problems

in MDMA users assessed within a few days of their last drug

use. "Our study extends the MDMA-induced memory

impairment to at least two weeks since last drug use and

thus shows that MDMA's effects on memory cannot be

attributed to withdrawal or residual drug effects," says Dr.

Karen Bolla of Johns Hopkins, who helped conduct the

study.

The Johns Hopkins/NIMH researchers also were able to link

poorer memory performance by MDMA users to loss of brain

serotonin function by measuring the levels of a serotonin

metabolite in study participants' spinal fluid. These

measurements showed that MDMA users had lower levels of

the metabolite than people who had not used the drug; that

the more MDMA they reported using, the lower the level of

the metabolite; and, that the people with the lowest levels of

the metabolite had the poorest memory performance. Taken

together, these findings support the conclusion that MDMA

induced brain serotonin neurotoxicity may account for the

persistent memory impairment found in MDMA users,

according to Dr Bolla.

Research on the functional consequences of MDMA-induced

damage of serotonin-producing neurons in humans is at an

early stage, and the scientists who conducted the studies

cannot say definitively that the harm to brain serotonin

neurons shown in the imaging study accounts for the

memory impairments found among chronic users of the

drug. However, "that's the concern, and it's certainly the

most obvious basis for the memory problems that some

MDMA users have developed," Dr. Ricaurte says.

Findings from another Johns Hopkins/NIMH study now

suggest that MDMA use may lead to impairments in other

cognitive functions besides memory, such as the ability to

reason verbally or sustain attention. Researchers are

continuing to examine the effects of chronic MDMA use on

memory and other functions in which serotonin has been

implicated, such as mood, impulse control, and sleep cycles.

How long MDMA-induced brain damage persists and the

long-term consequences of that damage are other questions

researchers are trying to answer. Animal studies, which first

documented the neurotoxic effects of the drug, suggest that

the loss of serotonin neurons in humans may last for many

years and possibly be permanent. "We now know that brain

damage is still present in monkeys seven years after

discontinuing the drug," Dr. Ricaurte says. "We don't know

just yet if we're dealing with such a long-lasting effect in

people."

Sources Bolla, KI; McCann, U.D.; and Ricaurte, G.A.

Memory impairment in abstinent MDMA ("ecstasy") users.

Neurology 51:1532-1537,1998. Hatzidimitriou, G.; McCann,

U.D.; and Ricuarte, G.A. Altered serotonin innervation

patterns in the forebrain of monkeys treated with MDMA

seven years previously: Factors influencing abnormal

recovery journal of Neuroscience 191(12):5096-5107,1999.

McCann, U.D.; Mertl, M.; Eligulashvili, V; and Ricaurte, G.A.

Cognitive performance in W

3,4-methylenedioxymethainphetamine (MDMA, "ecstasy")

users: a controlled study. Psychopharmacology

143:417-425,1999. McCann, U.D.; Szabo, Z.; Scheffel, U.;

Dannals, R.F; and Ricaurte, G.A. Positron emission

tomographic evidence of toxic effect of MDMA ("ecstasy") on

brain serotonin neurons in human beings. Lancet 352

(9138):1433-37,1998.

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