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New MDMA PET results from Ricuarte et al (for anyone who cares)

VelocideX

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http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15841106

Neuropsychopharmacology. 2005 Apr 20; [Epub ahead of print] Related Articles,Links

Quantitative PET Studies of the Serotonin Transporter in MDMA Users and Controls Using [(11)C]McN5652 and [(11)C]DASB.

1Department of Psychiatry, The Johns Hopkins School of Medicine, Baltimore, MD, USA.

(+/-)3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') is a widely used illicit drug that produces toxic effects on brain serotonin axons and axon terminals in animals. The results of clinical studies addressing MDMA's serotonin neurotoxic potential in humans have been inconclusive. In the present study, 23 abstinent MDMA users and 19 non-MDMA controls underwent quantitative positron emission tomography (PET) studies using [(11)C]McN5652 and [(11)C]DASB, first- and second-generation serotonin transporter (SERT) ligands previously validated in baboons for detecting MDMA-induced brain serotonin neurotoxicity. Global and regional distribution volumes (DVs) and two additional SERT-binding parameters (DV(spec) and DVR) were compared in the two subject populations using parametric statistical analyses. Data from PET studies revealed excellent correlations between the various binding parameters of [(11)C] McN5652 and [(11)C]DASB, both in individual brain regions and individual subjects. Global SERT reductions were found in MDMA users with both PET ligands, using all three of the above-mentioned SERT-binding parameters. Preplanned comparisons in 15 regions of interest demonstrated reductions in selected cortical and subcortical structures. Exploratory correlational analyses suggested that SERT measures recover with time, and that loss of the SERT is directly associated with MDMA use intensity. These quantitative PET data, obtained using validated first- and second-generation SERT PET ligands, provide strong evidence of reduced SERT density in some recreational MDMA users.Neuropsychopharmacology advance online publication, 20 April 2005; doi:10.1038/sj.npp.1300736.

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I'd be interested in seeing how much they recovered, and how long the abstinant users had been abstaining for....
 
Download .pdf of this journal article.

Exploratory correlational analyses suggested that SERT measures recover with time

Well I'll be darned. Not that the results are surprising at this point; just the source.

I'm still disappointed that he hasn't published his cognitive/movement studies 'demonstrating' dopaminergic toxicity; the work was riddled with serious problems and could have been the last nail in the credibility of the 'holes in your brain' camp.
 
so this is the dude that came out with the hole in the brain research?
 
Politicians came out with that, he was one of several groups that showed data of that nature.
 
Ricuarte was the dude who gave meth to baboons and told everyone it was MDMA. It was the defining pro-neurotoxicity study for MDMA until the cock-up was discovered.
 
The bottom-line question is: did he just plain fuck up methodology of the prior non-human primate MDMA studies, or did he purposefully "fuck up" in order to skew the data? The former is certainly forgivable--everyone fucks up now and again--the later, however, is not as easily forgiven. Perhaps I am simply paranoid, but I still suspect Ricuarte is guilty of later transgression--made to order science. Similarly to the data of a number of big pharma-sponsored studies, I believe his data are fitted to a hypothesis supported by a competing financial interest (in this case, the government propaganda machine, which incidentally happens to be the same organization writing out grant checks).

That still leaves us with an even larger unanswered question: does MDMA cause significant neurotoxicity? Doubtless we can agree that chronic, high-dose MDMA administration causes measurable damage to 5-HTergic nerve terminals. However, humans do not administer MDMA chronically (at least, smart ones don't). Thus, the question becomes: does a one-off high-dose exposure to MDMA cause significant, lingering neurotoxicity? I sincerely doubt that this is the case. Perhaps MDMA alters the trafficking of the SERT protein--for example, instead of internalization into the recycled synaptic receptor "pool," perhaps MDMA-affected SERT is trafficked to the endosome for degradation. Thus, the cell now has to synthesize a full-complement of nascent SERT proteins, explaining the slow restoration of synaptic SERT levels. I wonder if this is an MDMA-specific effect? That is, is the "neurotoxicity" seen in one-off high-dose (d)-methamphetamine exposure really due to DAT & SERT trafficking problems.

More importantly, for all of ADD people out there, does chronic low- to moderate-dose (d)-amphetamine exposure cause neurotoxicity? Are any putative neurotoxic effects dose-specific, time-course specific or subject-specific?
 
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A review, courtesy of MAPS, has emerged:

http://www.maps.org/sys/w3pb.pl?mode=show&type=review&r_id=49
Five years after their first imaging study of ecstasy users (McCann et al. 1998), McCann and colleagues have published another imaging study comparing ecstasy users and non-ecstasy user controls (McCann et al. 2005). The new study employs better imaging methods than the first study, but it still failed to match ecstasy users and controls on substance use. In this study, the researchers performed two brain scans using two different radioactively labeled drugs, or "ligands," one of which they had used in the previous study. They found that both ligands produced similar scans, and that ecstasy users had lower estimated levels of serotonin transporter sites in a number of brain areas, such as the occipital cortex, dorsolateral pre-frontal cortex, and parietal cortex. People who had refrained from ecstasy use for a longer period of time had less reduction in estimated serotonin transporters, and people who used ecstasy more frequently or at higher doses had greater reductions. The difference between estimated serotonin transporter binding in ecstasy users and controls was generally greater than seen in the most recent study using one of the same ligands. Study results suggest that repeated ecstasy use is associated with reduced estimated serotonin transporter binding, but the findings do not suggest that people receiving MDMA in clinical trials face similar risks. Even the authors state that their study findings may not be applicable for people who have used ecstasy on fewer than 25 occasions.

McCann and colleagues measured estimated levels of serotonin transporter by performing positron emission tomography (PET) scans using ligands that latch onto (or bind with) the serotonin transporter. One ligand is referred to as McN5652, and the other is DASB. The first drug has already been employed in previous reports, including the first study these researchers performed, and more recent reports by Buchert and colleagues (Buchert et al. 2003; Buchert et al. 2004), and the other drug is a newer compound with a better ratio of specific to non-specific binding (meaning it is more likely to bind to serotonin transporter than to other proteins or receptors).

The researchers performed two brain scans, one with McN5652 and one with DASB on 23 ecstasy users and 19 non-ecstasy user controls, with both scans performed on the same day. Ecstasy users were 10 women and 13 men, average age of 22, and non-ecstasy users were 11 women and 8 men, average age of 26. The study enrolled only ecstasy users who reported using ecstasy on 25 or more occasions. Ecstasy users' average lifetime ecstasy use was approximately 97 occasions, with lifetime use ranging from 28 to 324 occasions), an average dose per use of 1.8 tablets per occasion, and an average duration of nearly three years (34.8 months). Self-reported time since last use was 4.7 months (between 141 and 146 days). Ecstasy users reported having used a greater number of substances than controls. For example, 22 ecstasy users had used cannabis at least once, 11 had used stimulants, and 13 had used ketamine, while only 7 controls had used cannabis, one had used stimulants, and none had used ketamine. All participants had to report no drug use for two weeks prior to the study day.

McCann and colleagues first performed the PET scan with McN5652, followed by a scan using DASB, with average time between scans of 135 minutes, and with scans normalized through measuring ligand metabolites in blood taken 5, 15, 30, 60 and 90 minutes after each scan. The researchers used two different means of examining scans, including assessment in 15 regions of interest by a person blind to participant condition, and a model that compared areas with the cerebellum, a brain area with few serotonin transporter sites. McCann et al. also correlated regional McN5652 or DASB binding with time since last use and "intensity" of ecstasy use (undefined, but appears to be frequency of use, possibly along with average dose per use.) McCann et al. found that McN5652 and DASB produced similar scans, though scans with McN5652 detected a few more significant differences in regional binding between ecstasy users and controls. The researchers found that ecstasy users had lower global, or overall, levels of specific binding, implying that ecstasy users had lover serotonin transporter levels than non-user controls. Both McN5652 and DASB scans detected lower binding in ecstasy users in regions such as the occipital, parietal and temporal cortex, dorsolateral prefrontal cortex, and hippocampus. While ecstasy users had lower estimated serotonin transporter levels in subcortical regions, such as thalamus, caudate and putamen, the degree of difference was comparably small. Percentage of difference ranged from 9% (for ventral pons, after McN5652) to 68% (in occipital cortex, with DASB), most percentages ranged from 20% to 40%. Finally, correlational analyses found a positive association between global McN5652 binding and length of abstinence from ecstasy, implying less reduction in estimated serotonin transporter binding with continued abstinence from ecstasy, and an inverse (negative) association between global McN5652 binding and "typical monthly use". Correlational analyses using DASB scan data produced similar results. McCann and colleagues interpret these findings to mean that continued ecstasy use is associated with changes in serotonin transporter binding, and that greater use of ecstasy in a month is associated with reductions in serotonin transporter sites.

This is the first imaging study in ecstasy users to employ a new ligand, DASB, and the first to examine estimated serotonin transporter binding in cortical as well as sub-cortical areas. This study is also the first to "normalize" scan data through assessing blood levels of ligand metabolite over time. This study found considerably larger reductions in estimated serotonin transporter sites than those reported by Buchert and colleagues (Buchert et al. 2003; Buchert et al. 2004). However, unlike the previous study, this study did not compare current ecstasy users with former users. Buchert and colleagues found lower estimated serotonin transporter sites in current ecstasy users, but failed to find reductions in former users, who reported no ecstasy use for at least six months. The findings from the Buchert team suggest that ecstasy-related reductions in brain serotonin transporter sites are transient. A more significant methodological flaw is that the present study failed to match ecstasy users with non-users on degree and type of substance use. This means that ecstasy users were more likely to take a number of other substances than non-users. Buchert and colleagues solved the problem of matching for drug use by having three control groups; former ecstasy users, polydrug users, and non-drug users. Other researchers who studied planning and memory in ecstasy users and controls dealt with this difficulty by recruiting both groups from a sample reporting minimal drug use (Halpern et al. 2004). The failure to match groups on drug use means that while the imaging techniques used in this study are superior to those used by Buchert and colleagues, the study design suffers from a grater number of methodological flaws. Because of these problems, it is possible that some of the differences in estimated brain serotonin transporter sites are related to use of other substances, such as stimulants, or in some pre-existing condition that leads people to use ecstasy and other drugs. As is true of most studies in ecstasy users, interpretation of study results is limited by small sample size and retrospective study design (meaning the researchers imaged brains after people had chosen to use ecstasy rather than imaging brains before and after ecstasy use). It is also possible that adulterated or fake pills sold as MDMA but containing other substances, such as methamphetamine or MDA, might also incur some of the effects attributed to "ecstasy."

PET scans do not measure serotonin transporter levels directly, instead measuring radiation given off by drugs that can bind with serotonin transporter. Furthermore, there may be several reasons for differences in serotonin transporter site levels, so having lower transporter levels does not necessarily imply damage to serotonin axons, even if studies in non-human animals have found more direct signs of damage after MDMA administration (e.g. Callahan et al. 2001). Nevertheless, this most recent study may represent a better view of the brain serotonin system in ecstasy users than previous imaging studies, finding that ecstasy use is associated with reductions in presumed numbers of serotonin transporter sites.

McCann and colleagues acknowledge that they did not find any behavioral differences in the ecstasy users they studied despite detecting lower levels of estimated transporter binding, and they also state that their results may not be applicable to people with lower lifetime ecstasy use. They noted that the relationship between changes in the brain serotonin system and other changes, such as subtle impairments in verbal memory, are not clear. In fact, when imaging and cognitive testing has been performed in the same samples, changes in one area do not seem to be related to changes in the other (compare Buchert et al. 2004 with Thomasius et al. 2003). This study does not change our estimation of risk involved in clinical trials of MDMA, and aside from a potentially better picture of brain serotonin transporter sites, the information offered in this paper is not in itself novel.
 
Why are studies still done on the short-medium term of MDMA use?

It's like doing a PET scan of a cocaine or alcohol user a few days after a binge - OF COURSE there are going to be temporary brain changes.

With serotogenic system being a more "delicate" system with a naturally longer replenishment time... wouldn't only long-term results indicate anything truly sinister about the drug? (on the order of 6 months post-use?)
 
fastandbulbous said:
Now is he sure that he's been using people from a population of MDMA users for the scans, and not meth addicts?

Well he's done that before...

They were monkeys. Ssh. That's only a technicality. They're both primates, right?
 
lifeisforliving said:
Why are studies still done on the short-medium term of MDMA use?

It's like doing a PET scan of a cocaine or alcohol user a few days after a binge - OF COURSE there are going to be temporary brain changes.

With serotogenic system being a more "delicate" system with a naturally longer replenishment time... wouldn't only long-term results indicate anything truly sinister about the drug? (on the order of 6 months post-use?)

Why do this? It's much more profitable (in terms of research grants from NIDA) to do study after study demonstrating changes of questionable significance soon after use than it is to produce equivocal studies of users with a long abstention time....

I'm surprised Ricuarte et al can still get funding for something like this after their last screwup. I would have thought that they'd become a liability rather than an asset.
 
Now is he sure that he's been using individuals from a population of MDMA users for the scans, and not meth addicts?

Now it's accurate!


I'll not have anyone calling me a 'Ricuarte' ! :)


Lets try and make that a term of abuse for someone who's an incompetent, sycophantic tool for someone else's crusade.

as in 'you total Ricuarte' (hey if it worked for non-cooperation with a landlord's agent named Boycott!)
 
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I think "you Dubya" would serve equally well, aisde from the bit about being a sycophantic tool for someone else's crusade. He's just a tool ;)
 
^ Yes, but incompetent sort of implies that you were once competent, but have lost the ability - Dubya was never competent at anything in the first place (except drinking and lying - then not that good. He should take lessons in lying from Tony Blair...)

Now the Labour cabinet is full of potential recipients of the 'Ricuarte' title
 
The bottom-line question is: did he just plain fuck up methodology of the prior non-human primate MDMA studies, or did he purposefully "fuck up" in order to skew the data? The former is certainly forgivable--everyone fucks up now and again--the later, however, is not as easily forgiven. Perhaps I am simply paranoid, but I still suspect Ricuarte is guilty of later transgression--made to order science. Similarly to the data of a number of big pharma-sponsored studies, I believe his data are fitted to a hypothesis supported by a competing financial interest (in this case, the government propaganda machine, which incidentally happens to be the same organization writing out grant checks).

I like you Riemann, but I've got to say, I think that is a load of fucking toss. While Ricuarte was obviously not paying very good attention to the data, neither were J. Yuan Hatzidimitriou, Cord and McCann. Now I don't know who the fuck Hatzidimitriou or cord are, but Yuan and McCann write good stuff... I just find it a completely bizzare idea that all of them sat around and said "you know what would be a good idea? Completely fucking up a study to make the government happy, so they can put through an anti-rave act"... Why the fuck would they care? They were allready on the gravy train, they didn't need anything more... They HURT themselves by doing this. Drugs get mixed up... I've found a whole box of unlabled, and misslabled mGluR ligands a lab I've been in... I've mislabeled things, people give animals the wrong doses, the forget to give them doses... stuff like this happens...

And the idea that independent researchers, funded by drug companies, completely alter their results to keep the company happy doesn't make any sense either. For one, scientists do have morals and ethics, secondly, people get payed on contract, they get payed before they do the research.
 
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