I have occasionally mentioned that I really like the way that Nature Publishing Group (NPG) have promoted the online discussion of scientific research articles. After all, the publication of an article is merely the starting point and the authors’ interpretations of their data are only part of a larger set. Science proceeds best when we collaborate with our data, our ideas, our interpretations and our conclusions. Internet technologies can assist with this process. Indeed, these technologies already are assisting and have been doing so for some time. How many times in the last month have you used email to discuss a figure or a paper with a colleague? A ubiquitous phenomenon, is it not? Yeah, well when I started graduate school there was no email*.
I have also, I confess, waxed slightly critical of the execution of online paper discussion. Although I mostly bash NPG because they leave so much tasty chum lying in the water, I am generally critical; PLoS hasn’t really managed to do much better than the NPG titles when it comes to consistent online discussion.
Science blogs are slightly better at generating robust discussion of an article which in some cases feels a little more like journal club. This latter is a touchstone target for this behavior, IMNSHO. Science blogs suffer, however, from a lack of focus and a lack of comprehensive coverage. Researchblogging.org is a focal portal to select the journal article discussions out from the cacophony of a typical blog but again, it tends to suffer from coverage issues. The audience is presumed to be a general audience by most science bloggers and therefore they tend to select topics of general interest.
This brings me to a new internet creation: The Third Reviewer

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As you know, DearReader, I enjoy talking about science with the Boss, aka the US taxpayer, aka my friends, neighbors and acquaintances. In fact I not only enjoy it but I think of it as responsibility both to them, the people who fund the NIH, and to my fellow scientists.
You are also likely aware that I have school-aged children and therefore this circle of interactions with the taxpayer includes chatting with the parents of children that my own kids interact with.
One of the conversations that arises fairly frequently has to do with medications prescribed for Attention Deficit Disorder / Attention Deficit Hyperactivity Disorder (ADD, ADHD). This is, of course, a big can of worms to be opening on the blogosphere and let me make it clear I’m not planning on discussing ADHD science per se.
In brief outline of the issues let us reflect on the following.
-as with most of the mental/behavioral disorders there exists a distribution or spectrum of traits, symptoms or behaviors. Depending on how you want to view them. At some point of extremity, we (meaning the clinical psychiatry/psychology communities) define or diagnose conditions as pathological and in need of intervention
-diagnosis is imperfect, we do not have alternate biomarker validation in most cases and there will always be those on the threshold
-specific traits or behaviors can be either trivial or maladaptive depending on circumstances.
-therapeutic intervention, even in the clearly pathological cases, is less than 100% successful.
-interventions which involve repeated or chronic administration of drugs which affect brain and other body systems have risks.
These end up being complicated situations for parents to navigate. Parents are subject to the usual stigmas about mental health, and are reluctant to consider that their child might actually benefit from therapeutic drugs. They are worried about the lasting consequences. They have, perhaps, run across the criticisms (some valid, many not) of ADHD diagnosis and medication that are available on the internet.
And their doctors are failing them.

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As you know, DearReader, I enjoy talking about science with the Boss, aka the US taxpayer, aka my friends, neighbors and acquaintances. In fact I not only enjoy it but I think of it as responsibility both to them, the people who fund the NIH, and to my fellow scientists.
You are also likely aware that I have school-aged children and therefore this circle of interactions with the taxpayer includes chatting with the parents of children that my own kids interact with.
One of the conversations that arises fairly frequently has to do with medications prescribed for Attention Deficit Disorder / Attention Deficit Hyperactivity Disorder (ADD, ADHD). This is, of course, a big can of worms to be opening on the blogosphere and let me make it clear I’m not planning on discussing ADHD science per se.
In brief outline of the issues let us reflect on the following.
-as with most of the mental/behavioral disorders there exists a distribution or spectrum of traits, symptoms or behaviors. Depending on how you want to view them. At some point of extremity, we (meaning the clinical psychiatry/psychology communities) define or diagnose conditions as pathological and in need of intervention
-diagnosis is imperfect, we do not have alternate biomarker validation in most cases and there will always be those on the threshold
-specific traits or behaviors can be either trivial or maladaptive depending on circumstances.
-therapeutic intervention, even in the clearly pathological cases, is less than 100% successful.
-interventions which involve repeated or chronic administration of drugs which affect brain and other body systems have risks.
These end up being complicated situations for parents to navigate. Parents are subject to the usual stigmas about mental health, and are reluctant to consider that their child might actually benefit from therapeutic drugs. They are worried about the lasting consequences. They have, perhaps, run across the criticisms (some valid, many not) of ADHD diagnosis and medication that are available on the internet.
And their doctors are failing them.

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doin it right

March 20, 2010

[ Please welcome our guest blogger, who identifies as robin, just your average everyday neuropharmacologist. -DM ]
One of the most important yet overlooked tasks of the average pharmacologist is dissolving drugs into solution. Those of you who work with things that don’t have to cross the blood-brain barrier probably have a generally easier time dissolving shit than those of us who prefer to study CNS-active compounds. For those of us who play with compounds that are hydrophobic enough to cross the blood-brain barrier, I can testify that those range from fairly easy to major suck to put into an aqueous solution.

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4-MMC.jpg
source
My Google news alert for MDMA, Ecstasy and the like has been turning up references to a cathinone analog called variously 4-methylmethcathinone (4-MMC), mephedrone (2-methylamino-1-p-tolylpropan-1-one), Meow-Meow, MMCAT and a few other things. There has been one fatality attributed* to 4-MMC that I can find and a few bits of seized-drug analysis confirming that the stuff is indeed being used. A quick scan over at PubMed finds little reported on the effects of this compound in animal models or in humans. I did, however, run across an article on other cathinone analog drugs that caught my attention.
ResearchBlogging.orgThe newpaper reports on 4-MMC coming out of the UK, for the most part, are experiencing the usual difficulty in characterizing the subjective properties of an analog of a stimulant class of drugs. This not dissimilar to the case of MDMA and relatives such as MDA, MDEA/MDE which are structurally similar to amphetamine and methamphetamine but convey subtly different subjective properties. This also gives me an opportunity to talk about an animal model used quite a bit in drug abuse studies: The drug-discrimination assay. The paper of interest is the following one.
Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs. Dal Cason TA, Young R, Glennon RA. Pharmacol Biochem Behav. 1997 Dec;58(4):1109-16. (DOI)

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HAHAHAHAHAHHAHHA! Okay dope fans….go beat up on the new doc in town for awhile….

CB1 receptors affect the function of the presynaptic terminal. When CB1 receptors are activated, they signal through G proteins to close calcium channels, preventing entry of calcium into the terminal. Calcium is needed for vesicles to fuse with the membrane and release inhibitory neurotransmitters into the synapse. So CB1 signaling stops inhibitory neurotransmitters from being released to the postsynaptic neuron. CB1 receptor activation also results in opening of potassium channels. In a resting neuron, these channels are closed. Outflow of positively charged potassium ions leads to increases in the net negative charge across the membrane. This is called hyperpolarization, the opposite of depolarization. As you might imagine, since depolarization causes neurons to fire, hyperpolarization keeps a neuron from firing. This further decreases the chances that neurotransmitter will be released from the presynaptic terminal. There are some other effects too, which I won’t detail here.

Now let us see, do you think this closing bit is a tad optimistic?

I hope that this helps to make the effects of marijuana make more sense. For the record, I am not interested in discussing policy or the legal status of the drug. I am just here writing about how it works.

Sorry, just a linky-lurve but you have to see this. Stephanie Z and a minion or two over at Almost Diamonds are giving hell to operatives of some homeopath supply house over the Zicam/Zinc/anosmia debacle.
An example of the antiFDA, antiBigPharmaAieee!! silliness is here:

How can you possibly fully support the FDA? Look at all of the terrible antipsychotics, SSRIs, and other drugs that are being fully approved to be prescribed for 20-30 years of use, when they have only been studied for on average 2 weeks. The FDA approves brain altering drugs, and they are prescribed to children, often 3-5 years old. People need to quit relying on the FDA to tell them what is safe, because they aren’t doing a great job. They do a good job, but not a great one. Vaccines, Antidepressants, and on and on, are dangerous, but fully approved because they make big money.

Go Play.

One of the fondest arguments of the MDMA/Ecstasy fan is that the doses used in animal studies are so large as to invalidate predictions or inferences about human health concerns. This most usually comes up in the long standing literature demonstrating lasting reductions in markers for serotonergic neuron function associated with MDMA. In such studies, doses of 5-10 mg/kg (monkeys) or 10-20 mg/kg (rats) are reasonably common; the regimen is often twice per day for 4 days in a row. The chronicity is debatable and indeed shorter regimens can produce significant effects, but that is a topic for another day because the complaints focus on the individual dose levels as well.
But this argument also arises when trying to figure out why three teens have died after consuming Ecstasy tablets, particularly when a medical doctor issues an opinion that it is unlikely to be 3,4-methylenedioxymethamphetamine which is at fault.
It breaks down to “Oh, c’mon! Nobody takes 5 or 10 mg/kg of Ecstasy”. The defense is based on a Pharmacology 101 concept that mg of drug per kg of bodyweight is very rough in estimating realistic drug exposure across species. Better to use a complex scaling equation, based on empirical data, that takes into account species-typical differences in drug distribution and metabolism. I overviewed the initial foofraw over the dose-scaling argument that has been subsequently used repeatedly by Ricaurte in defense of his dose selection. Although I also buy the notion that dose-scaling based on species size (mass to surface area, more or less) is important and meaningful… there are caveats to keep in mind.

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AbelsBeard.jpgThere’s a post up over at Terra Sigillata that just makes you go hmmmm… Abel had previously noted a case in which a Palm Beach acupunterist (sic; see Figure) was busted for forging medical credentials to obtain controlled substances.

If this was the result of personal issues of substance dependence, I wish Ms Hoyt my best in seeking rehabilitative care.
But if the compounds obtained were to be used in some herbal preparation with purported anti-anxiety or analgesic activity doled out to clients, my sympathy is hereby revoked.

Developing evidence suggests some merit to his prior supposition. As Abel notes the current allegations include obtaining controlled medicines “for patients” and list several approved sedatives and muscle relaxers.
Which takes this out of the realm of (merely) a drug diversion issue and straight into the consideration of woo-based alternative pharmacy and therapy. What a total and complete scam. To use so called “conventional” medications that have actual function, while claiming it is acupuncture or some other woo that is having the effect? What hubris. What chutzpah.


BikeMonkey GuestPost
I had comments in the past on the topic of cognitive performance doping. You know, taking drugs to artificially improve how smart you are so as to gain a competitive advantage over your non-drug-taking peers. Doping. Just like sports doping. My prior comments on the WP blog were in these two posts.
Doping is A-Okay According to Nature.
November 14, 2007

Ha. Of course this is a considerable misrepresentation and minimization. Caffeine (prescribed by BM for “falling asleep in 4pm seminars”) and nicotine (ditto by a colleague) are also good for focusing of attention, improving memory and other GoodThings for complex brain function. Considerably more than 15% of students and “anecdotes” of “postdocs and academics” use these cognitive enhancers I can tell you. Sucks that they are addictive drugs, but them’s the breaks. I mean, we gotta function in our jobs, right?
But let’s get right down to the point in the Nature editorial, eh? Wouldn’t you become addicted to crack if it would cure “tumor development”? I mean surely if Nature believes a little chronic Ritalin (methylphenidate) is called for just for “memoriz(ing) a postulated signalling pathway” relevant to cancer they can get behind addiction for a cure, right?

Performance Doping in Academia, Take 2
December 19, 2007

The original commentary then asks, in essence if it is “cheating” for otherwise normal people to use cognitive enhancers. The central consideration is that we’ve already crossed that Rubicon. Caffeine and nicotine being the primary examples. It is completely acceptable, particularly in the case of caffeine, to brag on use of this stimulant to confer unnatural and unfair advantage over the competition in academic performance. From undergrad, to grad to professordom. Any argument that tries to overlook or minimize this reality is completely bogus. “I wrote my last grant on Modafinil”, “I wrote my last grant at the local coffeeshop” and “I wrote my last grant on Adderall” should have precisely the same ethical implications. The legal status, common acceptance, route of administration of the compound, specificity of the compound, etc have nothing to do with the ethical question of “cheating” by taking a cognitive enhancing compound.

This story just won’t go away. Today’s offering is from a PBS broadcast on smart drugs on a program called These Days.

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…what in the heck are you talking about DM?
Here’s the fantastic thing about being a lazy blogger. You wait long enough and someone will come along and write the post you really should have written ages ago. Not only that, but someone will write one that is about eleventy-million times better than what you would have done in your lassitude and preferred, um, bloggy style.
Well, as I’ve referred to now and again, one of the consequences of the drug 3,4-methylenedioxymethamphetamine (MDMA) which is the molecule people generally mean by “Ecstasy” is a lasting, possibly permanent, decrement in the function of neurons in the brain which use serotonin as a neurotransmitter. Well so what? Why should we care about serotonin function? What are those neurons up to, anyway?
Go read scicurious’ excellent overview of serotonin neuropharmacology.

250px-Percy_Lavon_Julian.jpg
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Percy Lavon Julian, Ph.D. (1899-1975) was a scientist who rose from humble beginnings, was trained and educated in an adverse cultural era and became a highly accomplished synthetic chemist and entrepreneur (Wikipedia; PubMed; ACS bio). From the American Chemical Society biography:

He was born in Montgomery, Alabama, on April 11, 1899, the son of a railway clerk and the grandson of slaves. From the beginning, he did well in school, but there was no public high school for African-Americans in Montgomery. Julian graduated from an all-black normal school inadequately prepared for college. Even so, in the fall of 1916, at the age of 17, he was accepted as a subfreshman at DePauw University in Greencastle, Indiana. This meant that in addition to his regular college courses he took remedial classes at a nearby high school. He also had to work in order to pay his college expenses. Nevertheless, he excelled. Julian was elected to Phi Beta Kappa and graduated with a B.A. degree in 1920 as valedictorian of his class.

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NIMH has issued an RFA on Clinical Pharmacotherapy for PTSD: Single and Collaborative Studies (R34). From the summary:

Purpose. The sponsoring agencies jointly issue this Funding Opportunity Announcement (FOA) to stimulate research grant applications focused on pharmacological treatments for Post-Traumatic Stress Disorder (PTSD). Medications along a continuum of development and testing (i.e., exploratory compounds ready for human testing, medications used in other areas of medicine and thought to be useful for a new indication (PTSD), and psychiatric medications currently used off-label to treat PTSD) are appropriate as the focus of a research grant application in response to this FOA. The sponsoring agencies seek to advance PTSD pharmacotherapy research by providing resources to better understand feasibility, tolerability, acceptance, safety, possible efficacy and risk/benefit ratios pertaining to symptoms and symptom severity, side effects, and treatment gains in functioning associated with available and novel medications. The sponsoring agencies anticipate the results of such studies will help identify potential medications suitable for larger scale efficacy, effectiveness and services research studies.

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A story I recently heard from an correspondent who works as a medical professional in a general surgery practice reminds me of the distance we have yet to travel in understanding even the seemingly obvious implications of drug abuse. My correspondent’s practice sees a breadth of cases, including a diversity of acute trauma cases which are severe enough to require a surgery consult. Some cases will require immediate surgery and a lengthy hospitalization for recovery; several weeks may be required when someone has suffered severe trauma. Other cases might involve a little wait-and-see to determine if surgical intervention is going to be required; a several day observation window would not be uncommon. One of these latter cases resulted in an interesting story.
Agent: “We had a guy check himself out against medical advice while we were waiting to see if he was going to get better or require surgery. The patient was apparently really ticked off that they wouldn’t let him out to smoke. He was found a couple of hours later lying in the street.”
YHN: “So what happened, you mean he bled out or something?”
Agent: “Oh, no. In the Emergency Department they hit him with [the opiate antagonist] Narcan and he woke right up”

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RIP: Billy Ray Martin

June 9, 2008

An absolute lion, perhaps even the dean, of exogenous cannabinoid pharmacology has passed away.
The obituary from the Richmond (VA) Times-Dispatch is here.

MARTIN, Dr. Billy Ray, 65, of Richmond, died Sunday, June 8, 2008. He was Chairman of the Department of Pharmacology and Toxicology at VCU.

Billy Martin’s scientific output was prodigious, with a majority of it focused on the pharmacological properties of the cannabinoids. His interest dated at least back to 1975 with the publication of this paper:

Martin BR, Dewey WL, Harris LS, Beckner J. Marihuana-like activity of new synthetic tetrahydrocannabinols. Pharmacol Biochem Behav. 1975 Sep-Oct;3(5):849-53.

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