Mephedrone (4-Methylmethcathinone) appearing in "Ecstasy" in the Netherlands

I have in the past discussed the fact that a substantial amount of recreational drug being sold as “Ecstasy” on the street contains psychoactive constituents other than 3,4-methylenedioxymethamphetamine (MDMA). This is old news and you can play around with one source of data for yourself at ecstasydata.org*. In addition, I have mentioned the UK explosion in use of 4-methylmethcathinone (4-MMC, aka mephedrone) over the past year (here, here, here, here).
Brunt and colleagues have provided an update from the Netherlands Drug Information and Monitoring System which obtains drug samples, described in their prior paper, from recreational users at clubs and somehow turned over to police. For this paper they have included analysis from 12,331 tablets collected from 2008-2009. The first major observation is that the proportion of tablets containing zero MDMA increased sharply in late 2008 which is a big change from the ~90% MDMA-containing samples in prior years. Something on the order of 50-60% of the Ecstasy obtained in the Netherlands in 2009 didn’t have any MDMA in it. Bummer, dude.
The other fascinating thing is that even though the usual suspect non-MDMA components were found (23-54% mCPP, methamphetamine/amphetamine, caffeine are common) the substituted cathinone 4-MMC/mephedrone is a new player.

A total of 995 (11.5% of the total ) tablets sourced from the DIMS system in 2009 contained only mephedrone. The authors note that this compound was also found in samples derived from over 100 police seizures. Although it is unclear how the proportions match up, at least the sample biases represented from the voluntary (?) user submissions and the police actions are grossly comparable in the sense that mephedrone tablets are appearing in the Dutch market. The paper goes on to note that 4-MMC is not yet “under the Scheduled Substances Act” so presumably it is a situation much like the UK up until April of 2010.

A final note of interest is the downturn in the proportion of non-MDMA tablets in late 2009- it will be interesting to see if this MDMA-drought was a shortlived blip or if actions such as Cambodia, Vietnam and Thailand finally getting serious about controlling the production of the safrole oil used as a precursor in MDMA manufacture is having a lasting effect on world markets.

One thing that I would personally like a little more clarity on is the degree to which the authors assert that the tablets they are analyzing were “sold as ecstasy”. Given the popularity of the drug under its own name in the UK, one wonders if it is merely being marketed as mephedrone/4-MMC instead of deceptively as “Ecstasy” which I think is commonly understood to mean MDMA. There is also the usual problem with samples sourced from users in this paper- there could always be a substantial bias to submit or turn over tablets (which are likely batch-identifiable by stampings/color) of unexpected or suspicious subjective character. Likewise, it is hard to determine marketshare for a particular batch or appearance of tablet. This makes it hard to infer what the constituents are in the population of pills actually being consumed by users with high accuracy. Nevertheless these data are very welcome since across time and geographical region we can get some confidence on relative MDMA content, the appearance of new drugs, etc.

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*Since I mentioned the pill testing outfit ecstasydata.org at the top, I should note that a search for mephedrone pulls up 5 different tablets, all sourced from Zurich (it is possible that the other source laboratories are not testing for 4-MMC yet). All 5 contain caffeine and two contain MDMA in addition to the 4-MMC.

Brunt TM, Poortman A, Niesink RJ, & van den Brink W (2010). Instability of the ecstasy market and a new kid on the block: mephedrone. Journal of psychopharmacology (Oxford, England) PMID: 20826554

And the troll shouted "Who's that trip-tropping across MY BRIDGE!??"

Namnezia is sorely provoking YHN.

I do the best imitation of myself

So why is it plagiarism? Because you are copying text of something that already has been published. And since most journals own the copyright to your manuscripts, re-using your own text verbatim is likely a copyright violation. It’s a bit silly, but apparently that’s the way it is and according to the article in The Scientist, papers have been retracted by journals because of this. My approach that I tell people in my lab is that it’s OK to take the old methods and change them around a bit, but that the introduction should be written from scratch. They can read an old introduction and then replicate it by memory, and this is usually enough to make the two texts sufficiently different, but they should never cut and paste text form their old papers.

No, no, NO! This is NOT plagiarism. There is no intent to deceive and academic papers are not supposed to contain lyrical text of overwhelming genius and originality. NOT. The text is there to service understanding the data, how it was collected and to advance the scientific interpretations. Which might be repeated over and over again.

“…which all supports Darwin’s conception of the Origin of Species”. This is science. We all create unique studies to address issues of common interest. We use common techniques. For common reasons. There are only so may ways to say “dopamine overflow in the nucleus accumbens” for chrissakes! Or to say “the rat presses the lever to get an intravenous infusion of drug”.

On Expanding Diversity

For the most part, in these programs the definition of enhancing diversity in sciences and other academic fields means increasing participation of minorities (and women) within the sciences. However, I’ve started to think that this is a somewhat narrow view of what diversity should mean. In my view, the current rationale for providing programs to help minority students is that these students traditionally don’t have access to the same type of educational resources as non-minorities do. This is due in part to the fact that many come from socioeconomically disadvantaged areas which simply do not have the same resources and academic support networks. Yet, there are several other people who also do not have access to these resources because they also come from socioeconomically disadvantaged areas, but just not happen to be from an underrepresented racial or ethnic minority group.

Straw-man. I’m sorry but if your University has not clued into the need to include first-generation college students and other indicators of impoverished background into the diversity effort, it has been living under a policy rock for at least 5-8 years, maybe more.

Take the wording of the NIH program traditionally shorthanded as “Minority Supplements”.

Individuals from disadvantaged backgrounds which are defined as:

1. Individuals who come from a family with an annual income below established low-income thresholds. These thresholds are based on family size; published by the U.S. Bureau of the Census; adjusted annually for changes in the Consumer Price Index; and adjusted by the Secretary for use in all health professions programs. The Secretary periodically publishes these income levels at http://aspe.hhs.gov/poverty/index.shtml . For individuals from low income backgrounds, the institution must be able to demonstrate that such candidates have qualified for Federal disadvantaged assistance or they have received any of the following student loans: Health Professions Student Loans (HPSL), Loans for Disadvantaged Student Program, or they have received scholarships from the U.S. Department of Health and Human Services under the Scholarship for Individuals with Exceptional Financial Need.

2. Come from a social, cultural, or educational environment such as that found in certain rural or inner-city environments that have demonstrably and recently directly inhibited the individual from obtaining the knowledge, skills, and abilities necessary to develop and participate in a research career. Eligibility related to a disadvantaged background is most applicable to high school and perhaps to undergraduate candidates, but would be more difficult to justify for individuals beyond that level of academic achievement.

That’s the 2005 Notice which replaced the older 2001 Notice which did not contain this sort of language and was apparently exclusive to ethnic minorities. So ever since 2005 even the NIH has been on board with this. I am aware of University level revisions of diversity language that date to at least five years before that. The times have changed so people who keep banging on about how this is needed are a bit out of step. If your local University hasn’t adapted, it needs to get with the program pronto.

Given my understanding of this change in the reality of diversity efforts in modern academia, it rings quite jarringly in my ears to bang on with the “what about the poor white folks” line. That, my friend, is falling right into anti-diversity talking points. Are you sure you want to align yourself with those folks?
Grrr, Namnezia-Goat Gruff. Grr.

NIDA / NIAAA Merger Advances to NIH Director Collins' Desk

The CPDDblog alerts us to the fact that the Scientific Management Review Board [roster] voted 12/3 in favor of dissolving NIDA and NIAAA and create a new Substance Abuse/Addictions Institute to replace the two. In this action the SMRB was selecting from options that were developed by the Substance Use, Abuse, and Addiction (SUAA) Workgroup Charge.

Brief notes from me on this topic are here, here here and here.

My thoughts on the wisdom of creating a new Institute from the ashes of NIDA and NIAAA are pretty simple.

1-If any Institutes of the NIH are to be merged these two are at the very top of the list. Really, if these two aren’t merged, there is no argument for merging Institutes.

2-From a scientific communication standpoint I really like the optics of making it very clear that alcohol is an addictive drug, just like all the others.

3-I’m not buying the “NIAAA’s non-brain related portfolio (think cirrhosis) will be lost” argument one bit. Nicotine research is scattered all over the place- the NCI has a huge amount, probably even to rival NIDA’s nicotine portfolio. I see no reason alcoholic cirrhosis and whatever else is of concern can’t land in other ICs if not the new, yet to be named National Institute On Addictive Drugs.

4-As far as securing research funding goes, I’m not one that is frightened of this. There will be approximately the same sorts of Divisions and Branches and a whole boatload of the same POs retained. My life won’t change that much.

5-It will be a big loss that Nora Volkow, current NIDA Director, cannot possibly be selected to head a new Institute. This would be too much like NIDA “winning”. They have to find someone new, inevitably someone with impeccable alcohol and non-alcohol substance abuse research credentials.

What are you thinking on this folks? A no-brainer that has been frustratingly stalled by whiners from the NIAAA side? A horrible idea? The end of life as we know it?
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As always DearReader, you should be aware that I have may have previously held, currently hold and/or be actively seeking to hold research funds through NIDA and/or NIAAA. I am an interested party and you should read my remarks with that in mind.

The NIGMS Director Jeremy Berg is da CandyMan!

He just keeps that data crack flowing for the grant geeks in the audience. Today’s analysis breaks down the NIGMS funded and unfunded applications by Investigator status. Early Stage Investigator and New Investigator (collectively never had a major R01 award before, distinguished by ESI’s having to be no more than 10 yrs out from terminal degree) applications are identified as are Type 1 (new submissions) and Type 2 (competing continuation applications for established investigators.

A plot of the overall impact score versus the percentile for 655 NIGMS R01 applications reviewed during the January 2010 Council round. Solid symbols show applications for which awards have been made and open symbols show applications for which awards have not been made. Red circles indicate early stage investigators, blue squares indicate new investigators who are not early stage investigators and black diamonds indicate established investigators.

Yowsa, data galore!

Go over to his post, he has a cumulative percentile breakdown that is pretty fascinating too.

Director Berg is once again to be congratulated for really leading the way at the NIH. Transparency of this type cannot help but accrue to the benefit of Institutes that are making funding decisions in a reasonable way. Sure, there are going to be cases to explain such as the poor sucker with the fantastic score that didn’t get funded. But these data point to the relative consistency with which their apparent exceptional funding decisions (aka “pickups”) are made. These types of plots (especially the cumulative one he included but I’ve not poached here) also help us to assess the degree to which study sections are disadvantaging ESI or NI apps in their scoring and how so. Are the truly excellent top 10% getting their due but then things break down in the grey zone? Are study sections assigning good ESI/PI apps to the scored but decidedly not-good ranges of 25-35th%ile land? Do these relationships change over time as the NIH commitment to ESI/NI investigators takes hold?

Wired Science Blog Network Launches!

Wow. Wired Science has launched a blog network of six writers that looks fashioned in the mold of the Discovery Magazine blog stable. Look who’s joined up.

Wired Science Blog Network

Pretty good lineup, mostly ex-Scienceblogs.com authors, looks like- Brian Romans of Clastic Detritus is the only one of the six to not previously have blogged at the Sb, as far as I know.

There’s a couple of things that jump out, in addition to the WOW! factor of such interesting writers being pulled together. @KateClancy observed:

Wow, only one woman in the new Wired Science Blog network… it’s like we just don’t do science or write about it…

@myrmecos noted:

@KateClancy another trend in new science blog networks is that there aren’t any scientists in them, just journalists.

And naturally, your most humble narrator noticed that the lineup is kinda….pale.

Perhaps these are issues they might care to address with any subsequent recruiting they might do….

Changing effort on your NIH award

Per usual, writedit’s epic thread on NIH Paylines & Resources provides a question that launches today’s discussion. DK asked:

What if a proposal is past council and pending administrative review and funding that proposal would take the PI’s total effort beyond 100%?

Is the proposal dead at that time?

Or can effort be reduced somehow? how?

Any efforts to deconvolute this would be appreciated.

writedit wisely advises DK to consult the local (University) office of sponsored programs/award but I have a simple answer.

Yes….and Good God, no!

Wired Science Blog Network Launches!

crossposting from DM on Scientopia:
Wow. Wired Science has launched a blog network of six writers that looks fashioned in the mold of the Discovery Magazine blog stable. Look who’s joined up.

Wired Science Blog Network

Pretty good lineup, mostly ex-Scienceblogs.com authors, looks like- Brian Romans of Clastic Detritus is the only one of the six to not previously have blogged at the Sb, as far as I know.
There’s a couple of things that jump out, in addition to the WOW! factor of such interesting writers being pulled together. @KateClancy observed:

Wow, only one woman in the new Wired Science Blog network… it’s like we just don’t do science or write about it…

@myrmecos noted:

@KateClancy another trend in new science blog networks is that there aren’t any scientists in them, just journalists.

And naturally, your most humble narrator noticed that the lineup is kinda….pale.
Perhaps these are issues they might care to address with any subsequent recruiting they might do….

Repost: The Women of MDMA Research

There is a #womeninscience meme bouncing around the Twitts today. Click the link and you’ll see some of the conversation, even if you are not a habitual Twitter user. Please consider joining in with an observation about, well, anything related to the life of women in science. On the Twitts, on your blog, Facebook or in the comments here or elsewhere.

I have an older post that I wrote some time ago to introduce some of the women who have contributed to the science that I talk about on the blog. This post originally appeared 24 Jul 2008.

---

A comment left by a reader some time ago took exception to one of my posts highlighting another blogger.

wow, that is some excellent PR for a grad student to get for free. perhaps you could spotlight a female grad student as well…?

The ensuing discussion planted the idea for this post.

Science Enemies

Dr. Becca has a hilarious story up over at LabSpaces.

My history with Science Enemy goes back around 10 years, when I was presenting my first ever conference poster. She was very interested in my work, and, wanting to be sociable, I casually asked her whose lab she was in. My friendly query was met with an indignant “MINE,” and it’s there I believe the rivalry began. I of course tried to remedy this faux pas with “Oh, it’s just because you look so YOUNG!!” (and truly she did), but my conciliatory words fell on deaf ears; it was on.

Go read because there is one part you will have in your mind forevermore.
But it makes me think. A very long time ago I was interested in memory, from the long-term / short-term and other nomenclature debates, to interesting cases from H.M. forward to the experimental literature. And one part of that interest that was always good for entertainment was the TemporalLobeMemoryWarz. This was a war played out most hilariously every year at the Society for Neuroscience in the late eighties/early nineties or thereabouts. Zola-Morgan, Squire, Mishkin, Murray, Gaffan, Moss and assorted other players would bring their latest arguments for how they had proved how many angels could dance on the head of a pin exactly what behavioral task in monkeys or humans (or rats, a bit of spillover into rats let us not forget) revealed which amazing new fact about the temporal lobe memory system (hippocampal formation and overlying cortical regions such as PeriRhinal! ParaHippocampal! whoo-whoo!). And they would take shots at each other.
Then they would go back to their labs and publish some papers and create new experiments to prove their hated rivals wrong. Next fall, the cycle would repeat. More data, more potshots and more hot air about memory.
It was AWESOME!
Quite obviously there were big egos involved. Some of the key players are, by near universal acclaim, grade A egotists. And even if they are not, boy, they sure came across that way.
However, I got the firm impression that science, and our understanding of all the functions of the temporal lobe memory structures, was advanced by this process. I’d estimate more so than if it was some boring epiphenomenon that only one lab was interested in pursuing or if everyone stood around doing independent work and politely golf-clapping each other.
Science Enemies are not always a bad thing, even if Dr. Becca’s is a wackaloon.

Ed Yong and the Gonadomorphic Chicken: A Blogging Success Story

Seriously. You need to read
In which I set up a collaboration between a biologist, a farmer and a chimeric chicken
Everyone will be wetting themselves over the blogging angle but this is just a cool story no matter how it happened.

Seriously? They think this three month study is worth a publication?

A question has arisen, my friends, yes it has.

When you are reviewing a paper do you ever think to yourself that the authors just haven’t done enough work to justify a paper? Is it a criterion for you, implicit or explicit, that a paper must require at least a certain minimum amount of time spent doing the experiments?

Or does it never even cross your mind to think about how long it took to come up with the results? Is your standard based on what is being shown and how cool and important (timely? novel?) it is?

The NIH Biosketch section on Research Support

A little reminder and clarification since this seems to be confusing to some at first introduction to the NIH system.
First, from the Biosketch sample (doc):

List both selected ongoing and completed research projects for the past three years (Federal or non-Federally-supported). Begin with the projects that are most relevant to the research proposed in the application. Briefly indicate the overall goals of the projects and responsibilities of the key person identified on the Biographical Sketch. Do not include number of person months or direct costs.

Note that use of the term “selected”?
The 424 Guide makes it even clearer:

An Opiate Antagonist Precipitates Withdrawal…From Exercise.

In my prior post, I overviewed a pair of papers which suggested the possibility that rats provided with running wheels might be used to model exercise addiction. The application hinged on a finding that when rats are provided with longer term 4 or 24 hr access to a wheel they gradually escalate their running over the course of about three weeks; this effect is greater than any increases seen when rats have wheel access for only an hour or two. As I alluded to, however, confidence in wheel running as a model of human exercise addiction akin to substance dependence is going to require a lot more converging evidence.

Kanarek and colleagues have provided some of this converging evidence. The authors examined the effects of challenge with the opiate antagonist naloxone in groups of male and female rats which had been permitted to run on an activity wheel.

This study relies on an effect* which has been known for quite some time, namely that the acute administration of low doses of drugs which block mu opiate receptors can rapidly precipitate withdrawal signs in rats or mice which have been treated chronically with morphine, heroin or other mu opiate agonists. Withdrawal signs that are similar in appearance to those that emerge with spontaneous withdrawal of the animal from chronic exposure to opiates. As Marshall and Weinstock observed in 1969, withdrawal symptoms could be quantified as an index of opiate dependence.

The purpose was to determine whether the number of jumps elicited by nalorphine in groups of mice could be used as a method of measuring the intensity of the withdrawal syndrome…The number of jumps was a monotonic increasing function of both the number of injections and the total dose [of morphine-DM] injected…In conclusion it is suggested that the number of jumps elicited by an antagonist in chronically narcotized mice can be used as a quantitative measure of the withdrawal syndrome.

Kanarek and colleagues were thus not just hypothesizing that they could precipitate withdrawal differentially in exercised animals, but also that the neuropharmacological change associated with exercise involved endogenous opioids. To wit, the endorphins which have been speculated in common use to underlie the so-called runner’s high.

The study is a bit complicated because it includes a manipulation termed Activity-Based Anorexia. Apparently if you give rats access to food for only an hour a day, they can survive with approximately normal maintenance of weight but if you also provide them with an activity wheel, they stop eating and drop weight-even to the point of death. This is a mere distraction for the present purpose, however, since the effect of challenge with the opiate antagonist was not qualitatively changed by the feeding condition. Nevertheless, the designs were between groups with factors of wheel access and feeding condition (24 hr food vs 1 hr food). There was also an additional yoked-pair feeding group which was inactive but fed the same amount of food consumed by the 1-hr / wheel access animals. This is by way of explaining the graphs, but the key effect for today’s discussion lies in the main effect of exercise condition.

The first experiment was conducted in female rats permitted wheel access for 7 days (plus sedentary groups) and then initiated on the 1 hr / 24 hr / yoked feeding conditions. The naloxone challenge (1 mg/kg) was initiated after 3-6 days when the 1 hr / activity group had dropped to 80% of their initial bodyweight. Since individuals took different numbers of days to reach this criterion, matched numbers of animals from the other groups were challenged with naloxone on the days over which the critical group reached criterion. Traditional withdrawal symptoms were scored.

As you can see in the Figure, withdrawal was precipitated more robustly in the group which had been permitted to exercise on the wheel and received 1 hr access to food, relative to the remaining groups. The authors also reported a correlation between total withdrawal signs exhibited by an individual and the wheel activity on the day before naloxone challenge in all activity rats but this was attributable to the food restricted subgroup. Similar results were found when they assessed the number of rats expressing a given withdrawal symptom, instead of the overall withdrawal score, as shown in the Table.

The second experiment was conducted in males with similar wheel access and feeding groups. In this case, however, the males in the exercise groups were permitted 25 days of wheel access (instead of the 7 used for the females) prior to initiation of the feeding conditions. Again, naloxone challenges were conducted when the 1-hr feeding / Wheel access group dropped to 80% of their prior weight.

Effects of naloxone challenge were most pronounced in exercised rats however in this case the effect did not depend on feeding condition. The graph of the mean total withdrawal scores shows that naloxone precipitated more signs of withdrawal in the 24-hr feeding / Wheel access group than in the sedentary groups.

So why the difference in the 24-hr feeding / wheel access condition between the experiments? I think the most likely issue is the difference in wheel access duration prior to the food conditions. The males, although they ran less than the females, escalated their running through about 16 days of access and had plateaued by the start of the food-access manipulation at day 25. The females were still increasing their running at the end of 7 days and into the food manipulation condition, but very likely had not completely expressed the commonly observed increase in daily running associated with 24 hr access over ~3-4 weeks duration.

In some senses these two experiments are not discordant but rather complement each other. Together they point out that the amount of activity on a wheel is not sufficient to increase liability for precipitated withdrawal. The females in the 24-hr feeding condition peaked at about 21,000 revolutions per day whereas the males in the 1-hr feeding condition peaked at about 8,500 revolutions per day. Only the latter exhibited increased withdrawal signs after naloxone when compared with their inactive control group. This suggests that it is the relative increase from baseline activity levels that is most important, rather than the spontaneous difference in baseline running.

And that interpretation, DearReader, is consistent with the idea that repeatedly engaging in physical activity can disrupt the neuronal mechanisms that subserve the rewarding aspects of that exercise. This disruption can then be observed as withdrawal signs, given acute administration of an opiate antagonist. This further suggests that endogenous opioids may be critically involved in the rewarding, and therefore addictive, aspects of repetitive exercise.

As with the behavioral escalation papers I previously discussed, this is not in and of itself proof that rats are addicted to, or become dependent on, wheel running.
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A PubMed search for naloxone precipitated withdrawal finds 1135 references.

Kanarek RB, D’Anci KE, Jurdak N, & Mathes WF (2009). Running and addiction: precipitated withdrawal in a rat model of activity-based anorexia. Behavioral neuroscience, 123 (4), 905-12 PMID: 19634951

Marshall I, & Weinstock M (1969). A quantitative method for the assessment of physical dependence on narcotic analgesics in mice. British journal of pharmacology, 37 (2) PMID: 5388579

w000t! CPDD joins the blogosphere!!!!!1111!!!!

I am delighted to report that the College on Problems of Drug Dependence has joined the science blogosphere. The CPDD Community Website is a new effort of the Media Relations Committee and intends to be:

a moderated Blog open to comment by CPDD members and invited contributors.

The email notification I received indicates that the comments and the blog will be open to the public so no worries, they are just planning to moderate* the content.
The initial offerings include:
A comment from the new editor of the College’s journal, Drug and Alcohol Dependence on changes to the journal.
A link-heavy update on the proposed NIDA-NIAAA merger.
A response to the McCain-Coburn attack on drug abuse research included in their mid-summer sneer at ARRA projects.
A general post on the politics of substance abuse research.
And what’s this? Little old us in the blogroll? Awwwww.
Well done, CPDD, well done.
[my CPDD related posts are here]
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*I’ll work on ’em DearReader, don’t worry.
CPDD.org
CPDD Facebook
Drug and Alcohol Dependence

Your verbal citation practices: A silly poll

Do you have a particular style by which you cite literature in your common scientific parlance?

This poll was motivated by a comment from a trainee who observed that one style was common in the prior training stop and a distinctly different style was common in the current training stop. I found that odd.