Did I mention I enjoy learning more about the neurobiological and behavioral effects of recreational drugs as well as the development and treatment of addictions?

The College on Problems of Drug Dependence will be holding their annual meeting in Hollywood Florida this upcoming week. I’ve been going through the Itinerary Planner and Program Book to get a preview. There are a few presentations that touch on topics that we’ve blogged about here at the DrugMonkey blog, including

-treating the hyponatremia associated with MDMA-induced medical emergency

vaccination against drug abuse

exercise as a potential therapy for, or antidote against, stimulant drug addiction

-JWH-018 and other synthetic cannabinoid constituents of Spice/K2 and similar “incense” products

-some preclinical studies on mephedrone / 4-methylmethcathinone

-presentations from the DEA on scheduling actions that are in progress

I’m certainly looking forward to seeing a lot of interesting new data over the next week.

I kid you not.

A simple Twitt story, really. Some Tweep involved in an exchange with some folks about MDMA says

@ayiasophia Are you reading @drugmonkeyblog on MDMA research? Great source. @girlinterruptin @beckyfh

So I looked at what the participants were chatting about and chimed in. As is my wont.

One of these discussions got a little involved since it started getting off into the science. Unsurprisingly, as is typical for Twitter and the 140 char limit, it can be hard to advance very quickly. Mostly because one has little knowledge of the other person’s pre-existing knowledge base and has to operate on the basis of what they actually Tweet. So, you know, when someone starts down the road of “MDMA is totes self-limiting because you can never regain the original high”, yeah, I’m going to check and make sure the person understands that this drug is structurally an amphetamine and has some shared pharmacological effects with all the other amphetamines. I kind of have an interest.

At any rate after a whole string of exchanges (I count 11 replies to me) this person says:

Am I missing something, do you just barge into other ppl’s convos, pick fights and patronise them for any particular reason?

AHAHAHHAHAHAHAHAHAHAAAAHAHAAHA!!!!!!!

This is hilarious. Of course, I DO barge into other people conversations and pick fights with them. Yes, I have been known to patronize now and again. Whether I do it for “any particular reason” is, of course, up to the observer to judge.

But all independent of me….

WTMFFRUBBQ?

You got your social media that is private…cell phone, Skype, email, direct messaging on Twitter…heck you can even lock your Twitter account to keep it semi-limited.

And then you got your social media that is public. That would be “public” to the entire Internet-using population of the planet. Open Twitter messaging is public.

What the stones are you doing engaging on one of the public Internet-enabled media types if you don’t expect the Internet using public to read?

Christ. Sometimes I think the entire Internet was constructed just to give PhysioProf and I constant LOLs…

Professor David E. Nichols is a legend for scientists who are interested in the behavioral pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, aka, ‘Ecstasy’). If you look carefully at many of the earlier papers (and some not-so-early) you will see that people obtained their research supply of this drug from him. As well as much of their background knowledge from publications he has co-authored. He has also worked on a number of other compounds which manipulate dopaminergic and/or serotonergic neurotransmission, some of which are of great interest to those in the recreational user community who seek (ever and anon) new highs, particularly ones that might be similar to their favorite illicit drugs but that may not currently be controlled. Those who are interested in making money supplying the recreational consumer population are particularly interested in the latter, of course.

Professor Nichols has published a recent viewpoint in Nature in which he muses on the uses to which some of his work has been put:

A few weeks ago, a colleague sent me a link to an article in the Wall Street Journal. It described a “laboratory-adept European entrepreneur” and his chief chemist, who were mining the scientific literature to find ideas for new designer drugs — dubbed legal highs. I was particularly disturbed to see my name in the article, and that I had “been especially valuable” to their cause. I subsequently received e-mails saying I should stop my research, and that I was an embarrassment to my university.

I have never considered my research to be dangerous, and in fact hoped one day to develop medicines to help people.

As with most scientists, I have little doubt. And ultimately, I agree with his observation that

There really is no way to change the way we publish things, although in one case we did decide not to study or publish on a molecule we knew to be very toxic. I guess you could call that self-censure. Although some of my results have been, shall we say, abused, one cannot know where research ultimately will lead. I strive to find positive things, and when my research is used for negative ends it upsets me.

It is unfortunate that Professor Nichols has been put in this position. Undoubtedly John Huffman of JWH-018 fame (one of the more popular synthetic full-agonist cannabinoids sprayed on herbal incense products) feels much the same about his own work. But I suppose this is the risk that is run with many lines of basic and pre-clinical work. Not just recreational drug use but even therapeutic use- after all off-label prescribing has to start somewhere. And individual health (or do I mean “health”) practices such as high-dosing on blueberries or cranberries, various so-called “nutritional supplements”, avoiding certain foods, exercise regimes, diets, etc may be based on no more than a single scientific paper, right?

So we should all feel some bit of Professor Nichols’ pain, even if our own work hasn’t been mis-used or over-interpreted…yet.

UPDATE: Thoughts from David Kroll over at the cenblog home of Terra Sigillata.

This is Drug Facts Week, an effort of NIDA to promote understanding of the effects of recreational drugs. Although I’m slightly busy with other matters, I wanted to participate, partially, with a series of re-posts. This post originally appeared July 7, 2009.


I’ve taken the liberty of providing a title for a new case report on a fatality associated with consumption of Ecstasy which more accurately captures the tone of the article. In this case the authors go to some length to beat home a message that I have been known to blog now and again. The report is in the pre-print stage in the Journal of Emergency Medicine.
RHABDOMYOLYSIS IN MDMA INTOXICATION: A RAPID AND UNDERESTIMATED KILLER. “CLEAN” ECSTASY: A SAFE PARTY DRUG?
Herve Vanden Eede, MD, Leon J. Montenij, MD, Daan J. Touw, and Elizabeth M. Norris, MB, CHB. J Emerg Med. 2009 Jun 3. [Epub ahead of print], doi: 10.1016/j.jemermed.2009.04.057

Read the rest of this entry »

Mephedrone, or 4-methylmethcathinone, is a recreational drug that got very popular in the UK in recent years, no doubt due to it being legal to sell and possess up until April of this year. There is not a tremendous amount known about the pharmacology of this drug at present, however we can deduce quite a bit about where we should start looking from user experiences. I am currently intrigued by the fact that if you look at online user forums you can get Ecstasy fans describing mephedrone as being sortof like Ecstasy…only not as good, or not quite the same. In addition, a recent paper which surveyed a certain subset of users found that many of them report intranasal mephedrone to be as good or better than intranasal cocaine. You will recall, of course, that I have a great deal of blog interest in discussing MDMA-related fatalities.
ResearchBlogging.orgA Case Report that recently appeared in the Lancet helps us to connect up some dots. Sammler and colleagues report on the case of a 15 year old girl who presented to their emergency department one afternoon with “altered mental status, vomiting and nausea”. She had been out drinking the night before and had also consumed a “white powdery substance”. The clinical workup contained a few interesting clues:

-the cerebrospinal fluid (CSF) opening pressure during lumbar puncture in the lateral decubitus position was raised at 350 mm of water.
-Blood tests showed profound hyponatraemia at 118 mmol/L.
-Serum osmolality was low at 256 mmol/kg, whereas urine osmolality was high at 742 mmol/kg.

Well, well, well. Hyponatraemia is frequently reported in cases of MDMA-related medical emergency and death. This is very likely related to an effect on vasopressin / antidiuretic hormone release that would cause the kidneys to retain water, perhaps in combination with induced polydipsia (urge to drink) or intentional (albeit misguided) prophylactic strategies. This is likely driven by the serotonin transporter inhibition properties of MDMA, this indirect agonist effect perhaps working through the serotonin 3, 2C, 4 and/or 7 receptor subtypes to induce vasopressin release.

I have no good stats but there is a distinct impression from reading MDMA case reports that young women may be particularly liable to hyponatremia following MDMA. This is something I need to take up at some point- is there evidence for increased sensitivity of adolescent women to fluid balance dysregulation?

Returning to the topic at hand, is this just a case of MDMA-induced hyponatraemia?

Fortunately, the doctors ran the tox panels:

We suspected drug intoxication and did gas chromatography-mass spectroscopy of the patient’s urine; this was unequivocally positive for mephedrone metabolites, but was negative for opioids, methadone, barbiturates, cocaine, cannabinoids, alcohol, benzodiazepines, and amphetamines including ecstasy. Analysis of the white powder was consistent with mephedrone.

Interesting. This suggests to me, as it did to the authors, that there is a MDMA-like component to this mephedrone stuff. It may be a dopamine transporter inhibitor and/or dopamine releaser like cocaine, amphetamine, methamphetamine but the hyponatraemia suggests an additional (significant) serotonergic component of the pharmacological response to mephedrone. This would be consistent with those users who report it as being at least somewhat like Ecstasy.

As I discussed before, one prior paper reported on the subjective effects of several cathinone analog compounds using the drug-discrimination assay. The cathinone structure if very similar to amphetamine and supports parallel modifications. The question becomes whether the same modifications of the cathinone and amphetamine core structures convey similar changes in the pharmacology.

In very brief overview of the drug-discrimination procedure, you train rats to tell you if the drug you have just given it is similar to a reference drug such as amphetamine or MDMA. The prior paper found that methylenedioxycathinone (MDC) and methylenedioxymethcathinone (MDMC) fully substituted for MDMA at reasonably similar doses. MDMC also fully substituted for amphetamine whereas MDC did not; in both cases the potency was much lower-higher doses had to be employed for comparable effect to the reference amphetamine.

This is complicated, because if anything MDA is closer in subjective and behavioral effect to amphetamine than is MDMA. And if there are any data on the 4-Methylmeth modification of amphetamine, I am unaware of them. Nevertheless it provides some clue that we are not totally out of line to suspect that the 4-Methylmeth modification to cathinone adds on a serotonergic agonist component, very likely mediated by blockade of the serotonin transporter (with perhaps some releasing effect)…just like one sees with the methylenedioxymeth modification of amphetamine in the case of MDMA.

Final note: The 15 year old girl in this Case Report made a full recovery. That’s a very good thing.
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Sammler EM, Foley PL, Lauder GD, Wilson SJ, Goudie AR, & O’Riordan JI (2010). A harmless high? Lancet, 376 (9742) PMID: 20801405

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).
ResearchBlogging.orgBrunt 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

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. Read the rest of this entry »