Single oral dose MDMA neurotoxicity revisited

I have been awaiting this paper since I saw the poster a few meetings back, Dear Reader. It contributes to an ongoing theme of posts on MDMA (Ecstasy) that I have neglected for some time. Some of you may recall the topic of my third blog post which noted the current attempts to get MDMA approved as adjunctive treatment during PTSD psychotherapy. I have been somewhat critical of their approach, mostly because of my understanding of the MDMA-associated neurotoxicity literature in animal species.

To overview, very briefly, if you administer MDMA twice per day at approximately 6-12 hr intervals for four days to rats, monkeys and a few other species, you produce lasting decrements in many markers for serotonin neurons / serotonin function in the brain. Lasting as in, as long as 7 years in a monkey (Hatzidimitriou, 1999). There is a parallel literature identifying lasting affective and cognitive alterations in human consumers of MDMA / Ecstasy and some imaging evidence of similar serotonergic changes.

It is tempting to associate at least the affective disruptions with the lasting serotonergic alterations. (Three monkey studies failed to connect these serotonergic patterns to substantial changes in cognitive behavior so that one is a little more tenuous…you can find some hints in the rat literature and some mother’s eye stuff in the monkey studies but the gun ain’t smoking very much.) However, as you are aware DearReader, the human studies of drug users are fraught with complications. One doesn’t know anything about pre-existing differences (depressives more likely to use MDMA?), the precise dose and pattern folks exposed themselves to, the environmental conditions, co-administered psychoactive substances and even the identity of the drugs being consumed as “Ecstasy”.

This cycles the discussion back to the controlled animal models. The MDMA enthusiast is frequently found to contest the relevance of the animal models, primarily on the grounds of the dose. The typical animal model features 10-20 mg/kg of MDMA per injection in rats and 5-10 mg/kg in monkeys. Again, these are repeated twice daily for four days. In addition, the route of administration is typically intraperitoneal (rat) and either intramuscular or subcutaneous in monkeys. Naturally, the majority of human use is oral which Pharm101 tells us should reduce the peak brain exposure as well as the rapidity with which peak levels are attained compared with the injected routes. So there has been vigorous debate, including between animal-research and human-research scientists, as to whether the animal data should be taken as relevant to the human condition.

As I blogged before, there is another concept from Pharm101 that relates to this discussion, i.e., that of species-scaling of drug doses. The short version is that you need higher per-kilogram-of-bodyweight doses in smaller species to produce similar outcome on parameters such as peak plasma levels, Area Under the Curve as well as toxic outcomes for various body systems including the brain. That prior post lays out data which show that a 1.6 mg/kg oral MDMA dose in a human produces peak plasma levels similar to 2.8 mg/kg in a squirrel monkey but an AUC similar to 5.7 mg/kg in a squirrel monkey (with a higher peak, obviously).

All well and good but the evidence of lasting serotonin changes on the low-end of the dosing spectrum has not been all that good. There was an old Ricaurte paper from the early days that found serotonergic changes in a handful of brain regions after a single oral dose of 5 mg/kg MDMA in squirrel monkeys. The trouble is, it was never replicated by any other papers and it was only in 3 subjects. So…not quite as convincing as the data on the higher-dose, injected, repeated models which come from multiple labs, in several species of laboratory animals and in many (total) animals per species.

A new paper from the Ricaurte group,

Mueller M, Yuan J, McCann UD, Hatzidimitriou G, Ricaurte GA. Single oral doses of (±) 3,4-methylenedioxymethamphetamine (‘Ecstasy’) produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations. Int J Neuropsychopharmacol. 2012 Jul 24:1-11. [Epub ahead of print] [PubMed]

provides a long-past-due update on their prior report (Ricaurte et al, 1988; PubMed).

The study tested single oral doses of 5.7 (N=8), 10.0 (N=6) and 14.3 (N=4) mg/kg MDMA and the brains were collected one week later for analysis. As with prior studies, significant reductions in brain content of serotonin and its major metabolite 5-HIAA were observed in multiple brain regions including frontal, temporal, parietal and occipital cortex, the hippocampus, caudate nucleus, putamen and thalamus. Importantly, these reductions were dose-dependent in magnitude with some differences from the vehicle control group (N=8) failing to reach statistical significance. The lowest dose, however, did produce significant reductions of serotonin in frontal and temporal cortex, hippocampus and caudate.

This last is the most critical contribution because it replicates the prior study in a larger sample.

The one oddest thing about the design was the collection of brains at one week instead of two. For the vast majority of studies in this area, two weeks seems to be the modal time for brain harvest. I think the choice of one week here is going to muddy the waters because there will be those that claim this is reflective of acute depletion of serotonin stores rather than the classic neurotoxicity profile. Concerns are partially alleviated by some serotonin transporter binding data provided suggesting reduced expression, but only a single brain slice per treatment group was shown. It would have been nicer if this had been a completed study with quantification from all animals. They authors have left some daylight for their critics and it is not really clear why they would have done this.

In the discussion, the authors continue their thesis that 5.7 mg/kg is equivalent to 1.6 mg/kg for a human. Therefore, they conclude that they have shown that lasting serotonergic deficits can be produced at doses that are unarguable “typical human doses” of MDMA. I have previously argued that this is a dose range that is being used in the clinical protocols even if you leave off notions of species scaling. So overall, yes I would say I agree with their basic contention that they have shown the expected serotonergic effects with MDMA exposure that is 1) oral, 2) single-dose and 3) within the range of expected human single-use episodes.

This study should further convince those who have previously argued that the animal data has no relevance because of dosing issues. This shows that there is no magic threshold of protection that happens to coincide with notions of “typical human use”.

Self-Citation will not make you go blind

From this post at Scientific American:

Fowler and Aksnes (2007) did another research on the Norwegian database, but this time it was author rather than publication oriented. The percentage of author self-citation was rather low – 11% – but every self-citation yield, on average, 3.65 citations from others in 10 years. Fowler and Aksnes concluded that “self-citation advertises not only the article in question, but the authors in question.”

So yeah. Cite your own papers. Liberally.
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Fowler, J. H., & Aksnes, D. W. (2007). Does self-citation pay? Scientometrics, 72 (3), 427-437 DOI: 10.1007/s11192-007-1777-2

The 2nd Amendment and Idiotic Leftie Rhetoric

This picture is circulating the Facebooks, I snagged it from “The Pragmatic Progressive Page”.

It is absolutely, one hundred percent wooly headed leftie-libby insanity.

The 2nd Amendment to the US Constitution reads:

A well regulated Militia, being necessary to the security of a free State, the right of the people to keep and bear Arms, shall not be infringed.

There is absolutely no doubt that the people that wrote and approved this sucker were absolutely steeped in recent historical events. Historical events that were made up of an effort to free, by armed conflict, one part of a nation State from the rest of it. To take up arms against, they felt, a tyrannical controlling central governmental authority. To throw off the chains that bound them to that authority and to form a new Nation State.

During that conflict, the military might of the controlling central authority was deployed against citizens, including by trying to control their access to the very “arms” that might be used to resist said controlling central authority.

It is inexplicable to me how anyone with even a modicum of sense can view the 2nd Amendment as anything other than guaranteeing the ability of a local, semi-organized subset of a nation State to fight, with equivalent arms, against the military power of said national authority.

Consequently, the 2nd Amendment guarantees the right not just to muskets but to all of the arms available to the nation State itself.

Thus, Stinger missiles, F16s and M1 tanks are covered just as cedrtainly as your thirtyoughtsix deer rifle. The 100 round drum clip for an AR-15 style “rifle” as assuredly as hand-polished birdshot for Cheney’s lovingly waxed Italian sparrow murderer.

Walking that narrow line

The key to being a science rockstar, if you like that sort of thing*, is to become legendary in the minds of others while never believing it for a second yourself.

If you fail on the second part, you are just kind of a jerk.
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*I don’t, obv.

Moderates

My observation of today is that the large scale, society based horrible things that happen are not the fault of the fringe extreme. Yes, the wackanuts are the ones coming up with the bad stuff and driving it forward. But these are usually a minority. The problem comes about when the so called moderates let the nutters advance. Either by tepid opposition or by tacit approval, either way, the vaster middle is the gatekeeper.

I don’t much care for the unthinking moderate.

Kudos to Senator McCain

From the WaPo:

“Ultimately, what is at stake in this matter is larger even than the reputation of one person. This is about who we are as a nation, and who we still aspire to be. What makes America exceptional among the countries of the world is that we are bound together as citizens not by blood or class, not by sect or ethnicity, but by a set of enduring, universal, and equal rights that are the foundation of our constitution, our laws, our citizenry, and our identity. When anyone, not least a member of Congress, launches specious and degrading attacks against fellow Americans on the basis of nothing more than fear of who they are and ignorance of what they stand for, it defames the spirit of our nation, and we all grow poorer because of it.”

There is no secret information that your NIH Program Officer is withholding from you

Chill.

Really, my friends, you are going to drive yourselves completely insane if you don’t step back and wait.

The examples can be found over on writedit’s mondo thread on paylines, scores and whatnot for NIH grants. Start here and page up.

I find it alternately saddening, maddening and hilarious to read these comments. In the end, I do sympathize. After all, I’m in the same boat as all of the rest of you seekers of NIH largesse.

It boils down to this. Nobody knows with any precision if your grant will get funded, unless it is well within any conceivable payline. Right now, I’d say you can have confidence with 3%ile. The POs don’t know how the funds will be spent around the margins. If it is for the Dec 1 funding date, well, we’ve talked before about how this depends on what Congress does and the relative conservativeness of a given IC in the face of a continuing resolution budget.

So believe your POs. When they give you a space of probability to work with, they are not lying to you or hiding some sekrit information just to mess with little old you. You are NOT this important. More critically, some random Internet yahoo like YHN or writedit cannot improve on your PO’s information. We deal in generalities and those ICs of our closest experience. With random Internet anecdata. These sources of information are far less specific than your PO.

So do yourself a favor and stop trying to game out your chances. Just get back to writing your next application. It will serve you better in the long run.

Is an NIH intramural postdoc worth it?

In your field, does it come with any particular value? Good or bad?

Is there something about the “NIH name on the CV” that advantages a trainee?

Are there critical connections of lasting worth? Or perhaps critical career opportunities- the K22 or the chance to stay intramural for ever?

Are there other Universities or research institutes that are more valuable?

Or are you best off just going lab by lab, with no particular concern for the host institution?

A letter to the blog wanted to know and I can’t offer more than anecdotes and a dose of “it depends”, both of which are not helpful. Any thoughts, Dear Reader?

Open Thread: PIs v Postdocs and other assorted yelling at each other

In case you absolutely must continue the 300 comment thread which developed under

Alternate careers” is just the next exploitation strategy?

you can have at it here.

It's just the place you live

One of the categories of people that crack me up, just like they did Vonnegut, are those that have an unhealthy obsession with the coincidence of where they live. Or were born.

You know the type….they are endlessly fascinated with being from New York, Chi-town, LA or The Bay Area. I imagine you non-USians have your London, Sydney, Toronto, Stockholm and whatnot snobbery. Don’t even get me started about Paris. You wouldn’t think so, the weather being so shitty and all, but people in the US cities of Seattle and Portland are some of the worst.

They really seem to think it makes them better, smarter, hipper, cooler and just plain more important than other folks. Like we’d be just endlessly fascinated by those daredevils who *wash their windows*! Amazing!

Dudea, get real.

Their reaction to Mitt Romney is worth 2,000 words, easy.

The captions practically write themselves, don’t they?

(AFP PHOTO/Nicholas KAMM) from here.

Wait. Full stop. Ann Romney's HORSE nets them a $77,000 tax CREDIT???

How any person in the US who makes under a MILLION DOLLARS PER YEAR can even remotely contemplate voting for this clown is a mystery to me. Complete and utter mystery.

Rafalca, the Romney’s Olympics-bound dressage horse, nets the family a $77,000 tax credit, $2,000 of which, according to Current’s calculations, is for what they spent on health care for the horse. The average American family only spends $1,557 a year on health care.

It is really a credit to our citizenry that we have not broken out the guillotine for the 1 percenters yet.

More Rafalca v. Regular Americans.

UPDATE: Phew, appears to be a standard business thing where the $77K is a “loss”, not a tax credit. At least, by reading a bit of the commentary around the webs. They can subtract this loss from any future earnings they may get from this money-sink, fun-toy but they aren’t getting a tax credit. That makes me a little less grumpy about it. But still. They can sink a cool $77K into this and not even blink….the comparison to the yearly expenditures of a family of four at the median in the US is still apt.

Estimating the Purchasing Power of the NIH Grant

You are probably aware, DearReader, of the concept of inflation. This means that the amount of money that you pay today for a good or service is higher than the amount of money that you paid yesterday.

On average.

So for example, this US inflation calculator tells me that the purchasing power of $12,000 in 1972 has the purchasing power of $65,975.60 in 2012. This is a convenient set of figures if, for example, you are shooting the breeze with a senior faculty member* who started his or her Assistant Professor appointment in the early 70s. You may want to grapple with pay on even terms. Naturally, not every good or service has the same inflation rate and this is just one model/estimator. Jeans may cost less and houses may cost more. etc.

Moving along, we come to the discussion of NIH Grants. In the past I’ve posted the analysis that shows that the doubling of the NIH budget was rapidly un-doubled and fell back on the historical trend line. That analysis depended on the Biomedical Research and Development Price Index or BRDPI. This brings us to an interest in the purchasing power of the full modular R01. “Modular” refers to the specification of the budget for most NIH grant types in units of $25,000 in direct costs. These are the “modules”.

There has been a cap of $250,000 per year in direct costs since the 6/1/1999 initiation of this structure, if I have that right. You can ask for more money per year but then you revert to a line-item type budget (called “traditional budgeting”). The modular cap has not changed and, I assert, this limit affects the vast majority of NIH R01 proposals since there is high motivation (or has been, I may have touched on reasons for future changes before) to adhere to the modular grant structure. Overall, I do like the notion of the modular budgeting procedures because it keeps reviewers from ticky-tacking a bunch of irrelevancies about grants when they should focus on the science.

However, the use of a limit like this brings up the unpleasant inevitability of inflation.

Comrade PhysioProf has been noting that the real purchasing power of the R01 has been dropping due to inflation in the context of postdoctoral fellow demands for ever increasing salaries. He’s not alone in noticing. I offer today, a graphical depiction pulled from data provided by the NIH Office of Budget on the BRDPI.
I”ve taken their table of yearly adjustments and used those to calculate the increase necessary to keep pace with inflation (black bars) and the decrement in purchasing power (red bars). The starting point was the 2001 fiscal year (and the BRDPI spreadsheet is older so the 2011 BRDPI adjustment is predicted, rather than actual). As you can see, a full modular $250,000 year in 2011 has 69% of the purchasing power of that same award in 2001.

For those looking at the increasing numbers of applications being submitted presented in the prior post, you must include some understanding of this inflationary pressure in your thinking.

The second thing we’ve found here is the target number to restore spending parity.

In simple terms, we should now be advocating for an increase to $350,000 as the new modular cap.

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*Particularly handy when said senior (or emeritized, retired) faculty members are members of one’s own family. just sayin.

Are you a better scientist than your mentors?

Wow.

I am addicted to comment threads for just this reason. Someone comes up with an offhand remark…and I’ve never thought about this before now.

Have you surpassed any of your mentors as a scientist?

I think my answers are hell yes, apples-to-oranges, yes (in some ways), yes (in many ways), not yet and meh. Then there are the variety of quasi-mentors….not sure these are fair to discuss.

More data on historical success rates for NIH grants

Thanks to a query from a reader off the blog and a resulting request from me, our blog-friend microfool pointed us to some data. Since I don’t like Tables, and the figure on the excel file stinks, here is a different graphical depiction:

The red trace depicts success rates from 1962 to 2008 for R01 equivalents (R01, R23, R29, R37). Note that they are not broken down by experienced/new investigators status, nor are new applications distinguished from competing continuation applications. The blue line shows total number of applications reviewed…which may or may not be of interest to you. [update 7/12/12: I forgot to mention that the data in the 60s are listed as “estimated” success rates.]

The bottom line here is that looking at the actual numbers can be handy when playing the latest round of “We had it tougher than you did” at the w(h)ine and cheese hour after departmental seminar. Success rates end at an unusually low point…and these numbers stop in 2008. We’re seeing 15% for R01s (only) in FY2011.

Things are worse than they’ve ever been and these dismal patterns have bee sustained for much longer. If we look at the ~30% success rates that ruled the day from 1980-2003, the divergence from the trend from about 1989 to 1996 was interrupted in the middle and, of course, saw steady improvement in the latter half. The badness that started in FY2004 has been 8 unrelieved Fiscal Years and shows no sign of abatement. Plus, the nadir (to date) is much lower.

Anyone who tries to tell you they had it as hard or harder at any time in the past versus now is high as a kite. Period.

Now, of course, it IS true that someone may have had it more difficult in the past than they do now, simply because it has always been harder for the inexperienced PIs to win their funding.

sourceAs we know from prior posts, career-stage differences matter a LOT. In the 80s when the overall success rate was 30%, you can see that newcomers were at about 20% and established investigators were enjoying at least a 17%age point advantage (I think these data also conflate competing continuation with new applications so there’s another important factor buried in the “Experienced” trace.) Nevertheless, since the Experienced/New gap was similar from 1980 to 2006, we can probably assume it held true prior to that interval as well.