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

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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”.

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

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.

ResearchBlogging.orgA 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

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.


CarlHart.jpgAssociate 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.

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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.

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.

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