Why PMA if dealers don’t want to kill their clients?

There’s an interesting piece on Ecstasy in Mixmag that addresses something that is a side issue of the MDMA overdose issue that I’ve talked about on the blog. These issues bubble up to our conscious consideration every time there is a mysterious Ecstasy-related cluster of adverse events such as at Wesleyan University. Until there is confirmation of the drug(s) involved from toxicological testing we can only speculate as to the cause of the events.

Even though we know that MDMA itself is always a top suspect, PMA, (para-Methoxyamphetamine), is a fine Usual Suspect of a non-MDMA substance sold to users as “Ecstasy” but resulting in adverse consequences.

The Mixmag piece reminds us of the MDMA drought in the UK that launched mephedrone into the recreational pharmacopeia.

One of the easiest ways to make MDMA is to use an essential oil called safrole, which occurs naturally in the roots and bark of the yellow camphor tree, found in Cambodian rainforests and elsewhere. The UN has targeted the trade repeatedly in the last decade, with the noble aims of protecting the rainforest, which is being chopped down by the gangs that steam-distil the oil out of the bark in giant, bubbling cauldrons in jungle labs. The UN burned 33 tonnes of it in 2008, which caused a worldwide drought of MDMA and the emergence of mephedrone as both gangsters and clubbers looked for alternatives. In September 2010, 50 tonnes were burned in Thailand.

Yep, we recall.

However, this previous preferred-method for synthesizing MDMA leads on to the reason why PMA is sometimes pushed out on the market for consumers to use, unsuspectingly in many cases. Mixmag proposes this hypothesis:

PMA is made from an oil called anethole, which is legal, cheap, and easy to get hold of.

Professor David Nutt agrees that the likely scenario is that clandestine chemists use anethole in a trial run, to test new lab set-ups, and then sell the resulting PMA to unscrupulous pill pressers. Making PMA involves an identical set of chemical reactions to making MDMA – only the precursor is different. Think about it: if you had a limited amount of very expensive safrole or PMK, and you had a new lab, or a new chemist, you’d want to test your kit out. A trial run making PMA from anethole would help you practice the technique and avoid losing valuable precursors – and you’d make some money back.

They then ask any chemists reading to confirm so one must take this as speculation rather than journalistically confirmed with clandestine labs.

Molly, Ecstasy and the alleged profession of journalism

Look people, this is really very exceptionally easy to understand. It is not rocket science.

New drug “Molly” produces lasting side effects

Recent social media posts have focused on the side effects of Molly, an MDMA (3,4-methylenedioxy-methamphetamine) drug similar to ecstasy that has become increasingly popular among college students over the past year.

No, it is not “an” MDMA drug and it is not “similar” to ecstasy.

Recreational drugs have all kinds of nicknames. Names that vary across time, place and subpopulation. A given user, however, means something specific.

“Ecstasy” was and is the drug 3,4-methylenedioxymethamphetamine, known as MDMA for short. You can read my musings in the archives.

It is also the case that illicit drug sellers, at times, provide the customers with a drug product which is something other than what the person intends to purchase. In the case of cocaine and heroin, most casual readers will be intimately familiar with teevee and movie plot lines which involve “cutting” pure cocaine or heroin with other substances. The goal, in fiction and in reality, is to make more money from a limited commodity.

“Ecstasy” supplies are notoriously variable in both active drug quantity per dose (i.e. traditional concepts of “cutting”) and in the psychoactive ingredients contained therein. In the case of the latter, there is reason to believe that the non-MDMA, psychoactive drugs might serve as a partial substitute. These alternatives include meth/amphetamine, MDA, MDE, mCPP and caffeine here, here, here, here and here. (Lots of caffeine, actually.) Head over to ecstasydata.org and you can search for pill constituents yourself.

Now, given this diversity and given that these are psychoactive drugs that have their own fan bases, it would not be surprising in the least to find people actually seeking out or preferring “Ecstasy” that was in fact not MDMA. There is a set of focus group comments here that I find illuminating. You can imagine for yourself why an Ecstasy consumer would prefer to think of methamphetamine as “speedy”-MDMA rather than good old methamphetamine. Also, people are very bad at blind identification of, say, methamphetamine vs MDMA. So there’s that. It is not impossible that some individual might have consistently been sold “Ecstasy” that is actually something else, like mCPP and caffeine, and prefer it and think that this is “Ecstasy”. But I doubt it. Hard to get clear estimates and it varies across time but something on the order of at least half of “Ecstasy” contains only MDMA.

Now, against this history of things marketed as “Ecstasy” that might or might not be pure MDMA, there arose a marketing trend (and user bragging right boast) for pure, genuine Ecstasy/MDMA. Reflecting, of course, that this particular compound/molecule is what substantial parts of the “Ecstasy” market were intending to purchase.

This marketed-as-pure MDMA became termed “Molly” in recent parlance.

Get it journalists? Molly = MDMA = Ecstasy.

And juuuuuusssst as with the prior episode, illicit drug suppliers are motivated to cut and substitute the product they move to people who are seeking to purchase MDMA. Once again, there is undoubtedly drug being sold as “Molly” that in fact contains other psychoactive substances and/or is cut with inert substances.

None of this makes “Molly” some new drug of uncertain identity, however.

Additional Reading:
Music Festival in Washington Leads to Dozens of Drug Overdoses, One Death
Molly: Pure, but Not So Simple
There’s something (potentially dangerous) about molly
Club drug ‘Molly’ on major upswing as Ultra Music Fest Miami approaches
These Rappers Hate Ecstasy

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”.

Go read the guest blogge!

This one has posted a topic that you will recognize Dear Reader. Go Read!

Methylone, or beta-keto-MDMA, also causes fatality

If you’ve been following along my posts on the substituted cathinones you will recall that cathinone is beta-keto-amphetamine. And much like amphetamine, chemists can hang little bits off the core structure to create new and interesting drugs which may offer different subjective experiences. For people who are into that sort of thing. The compound termed “Methylone” is the cathinone cousin of 3,4-methylenedioxymethamphetamine or MDMA. Which we’ve discussed a time or two on this blog. As we’ve also discussed, MDMA can result in significant medical emergency and death. Yes, really, it is the MDMA.

A Case Report has just popped up on the preprint queue of the Journal of Analytical Toxicology. In it, Pearson and colleagues detail three cases of fatality involving the methylone compound. For me the interest is the way this slots neatly into the Case Reports on MDMA fatalities, especially given the drug-discrimination paper that was our first introduction to the cathinones on this blog. Although there is great diversity, MDMA cases frequently involve an individual who was “found collapsed” by friends. Emergency medical services are invoked, whereupon the individuals are frequently found with high body temperature, rhabdomyolysis, hyponatremia (dilute blood) and may have seizure-like symptoms. Cardiac arrest is not uncommon during the course of care, as is cascading organ failure. Diversity rules the day. Some individuals have been rave dancing, some have not. Some were exposed to a broad array of other psychoactives. Alcohol, nicotine and cannabis are very common but you also see methamphetamine, caffeine and a list of other stimulant/entactogen/hallucinogen class drugs. The denialists like to point to the other factors as causal, insisting that “pure MDMA” is as safe as sea salt. My position is that the great similarity of clinical courses across the diversity of “other factors” makes it even more convincing that the single shared factor, i.e., MDMA, is the causal factor. ….plus there’s this little thing called the preclinical literature.

As always with Case Reports, the work by Pearson et al. will be less than satisfying. It is only through the gradual building of the Case Reports and the addition of preclinical investigations that we will really know what is going on. But every journey starts with a single step….

The second case is the most canonical, to my eye. A 19 year old woman at a rave was observed to collapse, briefly recover, claim to “not feel well” and then exhibit seizure-like symptoms. She went into asystole en route to the Emergency Department and had a body temperature of 103.9 F. She was found negative for cocaine metabolite, cannabinoids,
opiates, benzodiazepines, phencyclidine, amphetamines, barbiturates, methadone and propoxyphene on immunoassay and positive for methylone and lamotrigine. Wait, what? This anticonvulsant sodium channel blocker is a most interesting finding. Was it being used intentionally (by the user or the tablet manufacturer) to modulate the methylone effect on monoamines? Perhaps. Or was she an epileptic prescribed an anticonvulsant? That would be interesting given this prior MDMA-related Case and the Giorgi et al. 2005 preclinical study.

Case 1 is a little more unusual, if we’re assuming methylone acts much like MDMA. In this case a 23 year old male was acting erratically in public and was detained by the police and transported to the ED. This one sounds a bit more like a classical amphetamine case, with reports of forced restraint, combativeness and, sigh, the strength-of-five*-men thing. Initial symptoms included rhabdomyolysis, a body temperature of 105.9F, seizure and renal failure. After about 3.5 hrs of care a series of cardiac arrest/recovery events culminated in a fatal arrest about 24 hrs after admission. The blood workup detected detected methylone, dextromethorphan, cotinine, caffeine and lidocaine and the Medical Examiner ruled it due to methylone. As we’ve occasionally seen from the outside of the deaths of the rich and famous, the MEs are seemingly going on an assessment of drug levels to reach their decision. One might assume that the levels of the other drugs were considered to be below the threshold for causing a death. Naturally, we are in the purest speculation territory to start dreaming up drug interaction stories. For me, the strength will eventually lie in matching up the constellation of clinical symptoms with all the cases of fatality and medical emergency that involve methylone. I’d like to know a bit more about the dextromethorphan, however, given that it is degraded by the same CYP2D6 hepatic enzyme which degrades MDMA and, presumably, methylone. Dextromethorphan is also capable of causing serotonin syndrome, thus might have the same direction of effect as methylone in this context, i.e., this may support a relatively simple additive-effects conclusion.

The final case is just plain disturbing. A 23 year old male was acting erratically in an after-hours club when management had him secured to a chair in a van outside with plastic wrap. He was left there for 3-4 hours before being discovered. Paramedics found low blood pressure, weak (but rapid) heart rate and convulsions. Upon arrival at the ED, he had body temperature of 107 F and died after about 45 minutes of attempted life support. He had 0.03 g/dL blood alcohol concentration and methylone, in addition to several therapeutics administered in the ER (but might possibly have obscured recreational use of benzodiazepines and synthetic opiates). A positive immunoassay for cannabinoids was not confirmed on followup analysis.

I think you can see that being wrapped in a chair with plastic wrap for 3-4 hours in a van might have possible had effects. I’m most concerned about the physical exertion that might have been going on, much like in Case 1 in which the guy was struggling against police. The body heat has to come from somewhere and muscular exertion (due to intentional activity) could be that somewhere. Note that in Malignant Hyperthermia, seizure-like muscular contraction can provide that same input to the system. This would be relevant to all three cases.

As I mentioned above, this is the beginning of the story. By no means can three Cases nail down a connection with high confidence. But this is all strikingly familiar and dovetails with the aforementioned drug-discrimination finding and a recent report of neuropharmacological similarity of methylone and MDMA. So I’m betting we’ll see more of these Case Reports of medical emergency and death that involve methylone.

And the profiles are going to look just like the ones involving MDMA.
__
*well, at least it was five, not ten.

Julia M. Pearson, Tiffanie L. Hargraves, Laura S. Hair, Charles J. Massucci, C. Clinton Frazee III, Uttam Garg, & B. Robert Pietak (2012). Case Report: Three Fatal Intoxications Due to Methylone Journal of Analytical Toxicology

Repost- Faces of Drug Abuse Research: Carl L. Hart, Ph.D.

As I noted on the repost for Percy L. Julian, Ph.D., earlier this week, I’m swamped this month. So for Black History Month I’m offering up reposts. Today’s installment features a scientist who authored a paper I had occasion to blog a few weeks ago and my email box reports has just been elected to the Board of Directors for the academic society College on Problems of Drug Dependence. This post originally appeared on the Sb blog Feb 2, 2009.

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Associate Professor Carl L. Hart, Ph.D. (PubMed; Department Website; ResearchCrossroads Profile) of the Psychology and Psychiatry Departments of Columbia University conducts research on several drugs of abuse with concentrations on cannabis and methamphetamine. In his studies he uses human subjects to determine many critical aspects of the effects of recreational and abused drugs including acute and lasting toxicities as well as dependence. Dr. Hart is also a contributing member of the New York State Psychiatric Institute Division on Substance Abuse.
In his academic research role, Professor Hart works within the highly respected and very well known Substance Use Research Center of Columbia University where he directs both the Methamphetamine Research Laboratory (Meth R01 Abstract) and the Residential Laboratory. The blurb for this latter will give you a good flavor for the workaday of Dr. Hart’s work:

The residential laboratory, designed for continuous observation of human behavior over extended periods of time, provides a controlled environment with the flexibility to establish a range of behaviors, and the ability to monitor simultaneously many individual and social behavior patterns. This laboratory is equipped with a closed circuit television and audio system encompassing each individual chamber for surveillance and measurement purposes, and to provide continuous monitoring for the participant’s protection. We believe that this relatively naturalistic environment can best meet the challenge of modeling the workplace to predict the interaction between drug use and workplace variables. Because our participants live in our laboratory with minimal outside contact, we are able to evaluate multiple aspects of the effects of drugs on workplace productivity in the same individuals.

Double blind lab testing for the win!

It’s been awhile since I last talked about MDMA, aka 3,4-methylenedioxymethamphetamine, the canonical ingredient in Ecstasy. I phrase it this way because street drug sold as Ecstasy is notoriously promiscuous in terms of psychoactive drug content. Stroll on over to www.ecstasydata.org if you are new to this topic.

Not that there haven’t been more emergencies and deaths, including ones that didn’t involve MDMA but something else, like PMMA. And yes, the MAPS folks are marching on with great dispatch, dosing more and more people with MDMA in the context of trying to prove it an effective adjunct to psychotherapy for PTSD. So, you know, I keep up with my interests as expressed in earlier days on the blog, I just don’t necessarily bore you with it.

There’s a human laboratory paper I’ve been looking at that makes a point semi-related to some of the above issues. It’s from the laboratory of Carl Hart (who I profiled a few years ago as part of D.N. Lee’s Diversity in Science Blog Carnival.)

Kirkpatrick MG, Gunderson EW, Perez AY, Haney M, Foltin RW, Hart CL. A direct comparison of the behavioral and physiological effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl). 2012 Jan;219(1):109-22. Epub 2011 Jun 30. [PubMed]

The essence of the design is that it was a human laboratory study with a repeated measures design. They orally dosed the subjects with inactive placebo, 100 mg of MDMA and both 20 and 40 mg of methamphetamine with these treatment conditions separated by 3 days. A series of cognitive, physiological and self-report assessments were conducted- I’m not going to overview the findings here, you can go read the paper for yourself.

The interesting part about this paper for today’s discussion is that the subjects were really bad at identifying the drug that they’d been given. Keep in mind that the subjects had to have prior experience with both methamphetamine and MDMA. I imagine there are few people in the audience that are not aware that at least the mean, reported subjective effects of MDMA and methamphetamine differ considerably. Although it does have a prototypical psychomotor stimulant character to it, MDMA’s subjective properties have people reaching for new terms like “entactogen”. Likening it to a hybrid of a classical hallucinogen and a stimulant. Insisting vociferously that it is different.

This ties into the question of the pharmacological diversity of the recreational “Ecstasy” market, people’s ability to know what they have just taken, etc. Which may influence their decision to take more drug later on, to take more tablets in the original dose, etc. It also plays into the blinding that might otherwise be assumed to be impossible in the clinical trials and their occasional selection of something else like methylphenidate as their control drug.

Kirkpatrick and colleagues report:

On the questionnaire probing what drug the participants thought they had received, 72.7% of participants (i.e., eight out of 11) correctly identified placebo (18.2% reported MDMA and 9.1% reported sedative; confidence rating= 72.7±9.5), 45.5% correctly identified 20 mg methamphetamine (45.5% reported MDMA and 9.1% reported placebo; confidence rating=76.7±13.3), 72.7% correctly identified 40 mg methamphetamine (27.3% reported MDMA; confidence rating=80.1±5.6), and 45.5% correctly identified 100 mg MDMA (27.3% reported methamphetamine and 27.3% reported sedative; confidence rating=87.6±5.2).

Now, just for reference, the 100 mg MDMA and 40 mg methamphetamine conditions resulted in approximately the same effects on heart rate, blood pressure and self-report measures of “good drug effect” and “feeling stimulated”. So no need to go looking there for reasons. This isn’t some sort of meta assessment of physiological responses or a good/bad drug binary decision. These compounds must produce subjective effects that are pretty indistinguishable. They did differ in group terms on several of the outcome measures so this really does focus on the subject’s awareness and not on the actual effects, so to speak.

And do recall this was a controlled laboratory study in which the environment was relatively invariant compared with potential differences in environments in which Ecstasy is consumed in the natural setting. There is every reason to expect that situational variables and expectations would hugely influence the subjective response.

My consideration for the blog topics is this. When someone starts going on confidently about knowing the purity and/or nature of other non-MDMA constituents of street Ecstasy they have consumed, this is unlikely to be a credible assertion. In either direction. I.e., it is as dubious if they claim to have the pure stuff as if they claim it “must” have been contaminated with methamphetamine.

Unfortunately the study did not manipulate MDMA dose so we’re unable to extend our interpretation in another obvious direction which would be whether or not individuals were very good at identifying how much MDMA they had consumed. I’m betting not very good at this either but we’ll have to wait on another study for that evidence.

News on substituted cathinone stimulants, aka “bath salts”

The New York Times had a piece up Sunday that was entitled “An Alarming New Stimulant, Legal in Many States“. I was alerted to this by David Kroll who reposted some prior comments at his Take as Directed blog. I’ve been getting some traffic from a BoingBoing linker from Maggie Koerth-Baker to an older post from me so I thought I’d better address a couple of points that jump out at me.
First and foremost, the reader should be extremely cautious whenever there is conflation of two different drugs under one purported street name. Even if they are structurally quite similar and some human reports have overlapping properties. In the case of “bath salts”, there is quite a bit of confusion over whether a news account is referring to 4-methylmethcathinone (4-MMC), methylenedioxypyrovalerone (MDPV), sees no difference between them* or doesn’t know if there is any difference.

CPDD Annual Meeting 2011!!!!!111111!!!!!

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.

The most hilarious thing I have experienced on Twitter to date

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…

David Nichols on the impact of his scientific work with recreational drug users

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.

DrugFacts 2010 Repost: Yes, it really is the MDMA that killed him

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.

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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

Recreational Mephedrone Brief (09/30/10)

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.
A 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

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

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.

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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.