Preliminary Results; Newest MDMA (human) study yet to be released (2012), clarify??

[somedud]

Functional Consequnces/Serotonin release in MDMA users/Ex-users vs. Non -using controls

Ok, so I was googling and came across this study, which was only approved/updated in Feb 2011, because they needed to have evidence that dexfenfluramine-induced release of serotonin, and PET-radiotracer [18F]altanserin were valid methods of determining serotogenic function in the living human brain; which they did. Here: http://www.sciencedirect.com/science/article/pii/S1053811911011025

The full document (on dexfenfluramine-mediated 5 HT release after MDMA exposure, and prolonged abstinence) has yet to be released, even though the study has already been completed. Here: http://clinicaltrials.gov/show/NCT01296802

So I decieded to google a few things, and came across this link, which was the professor "Boris B. Quednow" university class notes, and mind you he was the main researcher involved in the study. His notes showed graphs of his study, which he states is still under revision/yet to be released (full document).

Here's the link with graphs of the dexfenfluramine-mediated 5-HT relasein: controls vs Ex-users vs current, as well as
5HT2A bindings in current, former and control subjects.

GRAPHS of results: http://www.neuroscience.ethz.ch/education/handouts/ZNZ_Lecture_FS_2011_Boris_Quednow.pdf

The graphs are at the bottom.

"Brain serotonin function in MDMA (ecstasy) users
Boris B. Quednow
Univ. Hospital of Psychiatry, Experimental Psychopathology, Zurich, Switzerland
Felix Hasler, Valerie Treyer, Matthias Wyss, Simon Ametamey, Alfred Buck,
Franz Vollenweider

Objectives: Chronic administration of the MDMA (“Ecstasy”) is associated
with long-term depletion of serotonin and loss of serotonin axons
in the brains of rodents and non-human primates. Moreover, it has been
consistently shown that MDMA users display dose-related neurocognitive
deficits suggesting that MDMA also affect the human serotonin system.
However, because of a multitude of methodological problems and a limited
number of studies, no firm conclusions can be established whether
chronic MDMA exposure in fact produces a long lasting serotonin deficiency
in humans. Therefore, we developed a novel method to assess
serotonin release capacity in the human brain employing [18F]altanserin
positron emission tomography (PET) after dexfenfluramine and placebo
challenge. This approach enables measuring altered serotonin-2A receptor
occupation after forced serotonin release.
Methods: We investigated serotonin release capacity in 15 current and
12 former male MDMA users, as well as in 15 matched male drug-naïve
controls. Subjects received placebo or oral doses of 60 mg of the potent
serotonin releaser dexfenfluramine on two days separated by an interval
of 14 days. Two hours after dexfenfluramine intake, 250 MBq of the
serotonin-2A receptor selective PET-radiotracer [18F]altanserin were administered
intravenously as a 30 sec bolus. Dynamic PET data were subsequently
acquired over 90 min. Moreover, in arterial blood samples drawn
for measurement of total activity, dexfenfluramine levels as well as prolactin
plasma concentration-time profiles were quantitatively determined.
Results: Current MDMA users a displayed blunted prolactin response,
and decreased serotonin-2A receptor densities and diminished serotonin
release capacity overall investigated brain regions when compared to
drug-naïve controls. Former MDMA users still showed a blunted prolactin
response and decreased serotonin-2A receptor densities, but they did not
significantly differ in their serotonin release capacity from controls.
Conclusions: These first functional data suggest that MDMA use leads
to long-lasting alterations in the serotonin system that might be reversible
only in part."

^^ This study here, I copied a few markers he posted in his slide, and came across a new verison of "THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY" on google, which had the Abstract to the yet to be released study in its preliminary findings.

http://www.wfsbp.org/fileadmin/user_upload/WJBP_10Supp01.pdf

page 11 for anoter interested, I keyword searched MDMA in the open file, seeing how its quite large.




Now heres my question, would you mind looking at the graphs, and telling me what the ratio meaning mean in simple terms of percentages, I don't quite get how they are calculated or are relevant.

(Change in [18F]altanserin binding after 60mg dexfenfluramine (serotonin release capacity; % reduction in tracer DV) was 13% controls vs. 10.5 % in Ex-Users vs. 5% in current) <-- This is the total overall average of ALL brain regions. (I eyed out results from graph posted in link above)

Distribution volume [Vtot] of serotonin‐2A receptor density
in current,former MDMA users and controls was 1.9 Control, 1.25 current users, and 1.4 in Ex-users. <-- This was also the total overall average of all 11 brain regions studied. (eye out results from graph post in link above)


So can someone please translate this to english for me, that would be fantastic. By which I mean the DV ratios and graph interpretations, as i'm well aware most studies use the 'framing effect' to exagerate the results. I'm well versed in the concept and through understanding of the study, just not the graphs.

Thanks in advance. Discussion on the consequences based on results of this study would be good to.

P.S.

Hypothesis:If MDMA users suffer from a loss of serotonin axon terminals they should release
less serotonin after dexfenfluramine challenge and more postsynaptic receptors
should be available for the [18F]altanserin in comparison to drug‐naive controls.

 

[ebola?]

I don't think that the hypothesis about axon density is particularly well supported by their dependent measure. In fact, I'm skeptical that their dependent measure is a valid indicator of long term changes in neural function under normal conditions. It could easily be that reduced serotonin release reflects long-lasting tolerance to SSRA class compounds (via epigenetic changes or otherwise), this tolerance leaving function of serotonergic circuits under sober conditions relatively unscathed. Nonetheless, the recovery of former MDMA users is pretty promising.

One take-away message, I guess, is that one should not use MDMA frequently, or one runs the risk of skewing neural function in the medium term. Duh...

ebola

 

[somedud]

I don't think that the hypothesis about axon density is particularly well supported by their dependent measure. In fact, I'm skeptical that their dependent measure is a valid indicator of long term changes in neural function under normal conditions. It could easily be that reduced serotonin release reflects long-lasting tolerance to SSRA class compounds (via epigenetic changes or otherwise), this tolerance leaving function of serotonergic circuits under sober conditions relatively unscathed. Nonetheless, the recovery of former MDMA users is pretty promising.

One take-away message, I guess, is that one should not use MDMA frequently, or one runs the risk of skewing neural function in the medium term. Duh...

ebola

Indeed their method is of a different class, but taken into consideration the limitations in technology we have to visually access and interpret how a distinguishable system works; it's the closest they've come so far (in terms of MDMA atleast). It could easily be adressed that MDMA users, which are almost indeinfately (not to discriminate) poly drug users aswell, have a sustained tolerance to SSRA's, be it from previous MDMA use or the higher deviations in poly-drug use when compared to controls. But I do agree with the idea of adressing functional consequences of the SERT, as opposed to just simple SERT bindings measured in previous studies; as some could be rendered useless from the recovery/adaption process or other unknown biochemical process indolved in the breakdown of MDXX's metabolites.

Would you mind giving me a quick synopisis of the graph interpretations in laymens terms? (i.e. percentages or any other simple analogy)

 

[Epsilon Alpha]

Great post man, though this link almost exploded my iphone
http://www.wfsbp.org/fileadmin/user_upload/WJBP_10Supp01.pdf

What I'm reading here is that very sparing and responsible MDMA use in absence of everything else is probably reasonably safe. However the E-tard lifestyle is toxic.

 

[skillet]

because they needed to have evidence that dexfenfluramine-induced release of serotonin, and PET-radiotracer [18F]altanserin were valid methods of determining serotogenic function in the living human brain; which they did.

Weird, I thought fenfluramine and citalopram were well known to cause a several fold increase in serotonin concentrations, and [18F]altanserin is widely used for imaging 5-HT2A, and challenges with SSRA's have surely been done already.

Now heres my question, would you mind looking at the graphs, and telling me what the ratio meaning mean in simple terms of percentages, I don't quite get how they are calculated or are relevant.

(Change in [18F]altanserin binding after 60mg dexfenfluramine (serotonin release capacity; % reduction in tracer DV) was 13% controls vs. 10.5 % in Ex-Users vs. 5% in current) <-- This is the total overall average of ALL brain regions. (I eyed out results from graph posted in link above)

Dexfenfluramine administration increases serotonin levels, serotonin competes with the radiotracer for binding to 5-HT2A, so you see a reduction in radiotracer binding after dexfenfluramine. The ability of fenfluramine to reduce radiotracer binding in MDMA users is probably due to its reduced capacity to cause serotonin release, though the release capacity is mostly recovered on abstinence.

Distribution volume [Vtot] of serotonin‐2A receptor density
in current,former MDMA users and controls was 1.9 Control, 1.25 current users, and 1.4 in Ex-users. <-- This was also the total overall average of all 11 brain regions studied. (eye out results from graph post in link above)

This shows the amount of radiotracer bound to specific brain regions, presumably reflecting functional 5-HT2A receptor density in those regions. The graph suggests MDMA use reduces 5-HT2A receptor density in all regions measured, with slight recovery on abstinence.

Hypothesis:If MDMA users suffer from a loss of serotonin axon terminals they should release
less serotonin after dexfenfluramine challenge and more postsynaptic receptors
should be available for the [18F]altanserin in comparison to drug‐naive controls.

Exactly, though I'd guess the reduced ability of fenfluramine to cause serotonin release probably has more to do with depletion of serotonin stores, maybe some loss of axon terminals could account for the incomplete recovery, I don't know how long it takes, or if they recover.

The long-term reduction in 5-HT2A receptor density is interesting, though I doubt the implications are very severe - MDL 100,907 was in trials for treating insomia, but it doesn't really seem to have any pronounced effect.

Hope that's what you were looking for, I'm not sure?

 

[somedud]

Weird, I thought fenfluramine and citalopram were well known to cause a several fold increase in serotonin concentrations, and [18F]altanserin is widely used for imaging 5-HT2A, and challenges with SSRA's have surely been done already.


Dexfenfluramine administration increases serotonin levels, serotonin competes with the radiotracer for binding to 5-HT2A, so you see a reduction in radiotracer binding after dexfenfluramine. The ability of fenfluramine to reduce radiotracer binding in MDMA users is probably due to its reduced capacity to cause serotonin release, though the release capacity is mostly recovered on abstinence.


This shows the amount of radiotracer bound to specific brain regions, presumably reflecting functional 5-HT2A receptor density in those regions. The graph suggests MDMA use reduces 5-HT2A receptor density in all regions measured, with slight recovery on abstinence.



Exactly, though I'd guess the reduced ability of fenfluramine to cause serotonin release probably has more to do with depletion of serotonin stores, maybe some loss of axon terminals could account for the incomplete recovery, I don't know how long it takes, or if they recover.

The long-term reduction in 5-HT2A receptor density is interesting, though I doubt the implications are very severe - MDL 100,907 was in trials for treating insomia, but it doesn't really seem to have any pronounced effect.

Hope that's what you were looking for, I'm not sure?

Not exactly. I understand the intrepretation of the graphs but can't seem to grasp how severe the differences are. I was hoping to get someone to translate the DVR's and relase capicity in simple terms. (i.e. vaugely speaking, presume that controls 5-HT systems are at 100%, vaguely, after abstinence whats the ex-MDMA users 5-HT percentage, I know this is a very vague interpretation but its god enough for me). Because simply dividing the ratios, comes out to be a DRAMATIC loss, which it says in this case isn't "significantly" different.

What I find strange is their method, theortically if MDMA does cause axonal degeneration, wouldn't there be less tracer bindings either way, due to less transmission from axonal loss, and from less receptors being present, therefore resulting is less tracer binding, which in this study is a "positive" result, meaning better transmission (lower trace bindings). So couldn't they easily be skewed? Not to mention the fact that the Controls only had 13% change in relase capacity after denfenfluramine serotogenic relase, which would entail a very low standard/level to go by?

 

[somedud]

Not to mention high 5HT2A densitys have been linked to depression, but this could negatively affect psychedelic's affect, and maybe why theres pleantly anecdotal reports of people not enjoying weed after MDxx use/abuse.

 

[skillet]

The ratios don't seem that large to me, excluding the current users. And the error bars are fairly large, and not marked as statistically significant.

theortically if MDMA does cause axonal degeneration, wouldn't there be less tracer bindings either way, due to less transmission from axonal loss, and from less receptors being present, therefore resulting is less tracer binding

Yes it would lower binding, but they would have done 2 scans per subject, one baseline, and one after fenfluramine, to compare the relative change in binding. You need a baseline scan for reference, otherwise it would be worthless.

Controls only had 13% change in relase capacity after denfenfluramine serotogenic relase, which would entail a very low standard/level to go by?

No, controls had a 13% reduction in radiotracer binding after fenfluramine, but fenfluramine causes a several fold increase in synaptic 5-HT concentrations (I've seen 700% somewhere, but can't remember if it was for fenfluramine or citalopram, and obviously it depends on the dose). A fairly massive increase in serotonin concentrations only results in a small decrease in tracer binding, because antagonist tracers (altanserin) aren't that sensitive to competition by the agonist 5-HT.

 

[somedud]

Ohhh, seems somewhat promising

I'm assuming this is suggesting that (severe) axonal loss isn't actually happening in humans, just some compensatory down-regulation and de-sensitization to serotonin agents?

I'd like to see the results from those who used <100 pills, as the average pill count was 350