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”.

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

Wikipedia meme: MDMA

June 10, 2011

via Pascale

1. MDMA
2. Entactogen
3. Psychoactive drug
4. Chemical substance
5. Chemistry
6. Science
7. Knowledge
8. Description
9. Rhetorical modes
10. Exposition (which goes to Expository writing)
11. Writing
12. Language
13. Human
14. Living
15. Biology
16. Natural science
17. Naturalistic (goes to Naturalism (philosophy))
18. Philosophical (goes to Philosophy)

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

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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 »

The following is a more casual description of a stream of thought I had about these posts I’ve been writing on the MDMA/PTSD paper.


ok, so there’s this paper that has finally come out. I’ve been bashing away at the project itself on the blog since, oh, forever. I finally had a chance to get around to blogging the paper. no biggie.
takehome message, MDMA is good for treating PTSD if given in the therapy session.
one of the features of such a study is that it is going to get media attention. I was ignoring that all week so that I could blog the paper unmolested.
Trolling around the media coverage I started on a slow burn.
Going through Google hits, there was a great deal of emphasis on PTSD caused by combat stress. Angles on the story which suggested we have a big ol’ problem looming (true dat) and won’t it be great to have some new hope (true dat) and then doing a less than complete cockup of the facts of the paper.
Problem is that it is a small study as it is, 12 MDMA-treated, 8 placebo controls, but only ONE had combat trauma as the index trauma. ONE. The rest were mostly sexual assault, crime (not further specified) and childhood trauma (sexual assault and physical neglect). Me, I was happily bashing away at the overselling of the single combat PTSD case in my draft.
On the way home it hit me.

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I am disappointed in the mainstream, and not so mainstream, media coverage of the Mithoefer et al, 2010 paper on MDMA-assisted therapy for Post-Traumatic Stress Disorder. I had been holding off reading any of it because I suspected it might distract me from actually discussing the paper.
After writing up my thoughts on the paper, I went strolling around the Google News hits for MDMA to see what had been written about this paper. There was a whole lot of of really bad journalism. Sure, for the most part they got the basic facts right, but I noticed a consistent issue having to do (I assume) with journalism’s penchant for selling a story they’d like to tell over the story that exists.
Let us start with the more venerable news organizations.
ABC News Ecstasy may help traumatised veterans
See the title? Pretty common to see something abut veterans or combat PTSD in the title as well as in the article body.

found that the drug seems to improve the effects of therapy in military veterans

No, there was one combat stress case. I noted that this stuck out as odd in my post on the paper. Well, now you can see why the authors might have been so keen to include this single warfighter subject. They enjoyed much wider press and nobody called them out for this scientific distraction
(This part of the ABC report caused me to laugh though:

The researchers, led by Dr Rick Doblin of the Multidisciplinary Association for Psychedelic Studies

Of course this is true, the driving force behind getting these studies rolling is the recreational legalization Trojan outfit MAPS. It looks better though, if you ask me, when they credit the therapist Mithoefer as being the leader of the project and MAPS as only providing support and assistance. )

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ecstasypills.jpgMy readers will recall that I have blogged now and again about ongoing efforts to get 3,4-methylenedioxymethamphetamine (MDMA), the psychoactive compound preferentially sought as Ecstasy in recreational users, approved as a medication to be used in psychotherapy. The initial attempts have focused on the treatment of Post-Traumatic Stress Disorder. PTSD is a seriously debilitating condition and we may not have sufficient resources and knowledge to deal with, e.g., an anticipated uptick due to the current wars that the US is prosecuting.
I introduced the MDMA/PTSD Phase I clinical trials here, noting

The short version of the theory is that the subjective properties of MDMA (empathic, inhibition lowering, etc) are consistent with helping people in difficult psychotherapeutic situations (such as for post-traumatic stress disorder (PTSD) and, supposedly, end stage cancer anxiety) make therapeutic breakthroughs during a limited number of treatment sessions of talk therapy. This is not proposed as a chronic medication like a selective serotonin reuptake inhibitor (SSRI). The funny thing is, I approve of the concept of moving forward with clinical trials based on the available evidence.
Why not? I mean PTSD can be a very devastating psychological issue and if there are treatment-resistant cases that can benefit from a limited number of MDMA exposures, great.

I concluded that particular post with this observation.

As is general practice in medicine, sometimes there are going to be risks associated with therapy. Sometimes quite substantial risks can be acceptable if the alternative is bad. However we get ourselves into a world of trouble, sometimes even losing a perfectly helpful medication, if we are not as honest as possible, up front, over the actual risks.

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From the LA Times we learn that the Los Angeles edition of the Electric Daisy Carnival held this past weekend resulted in about 120 emergency room visits. An estimated 185,000 persons attended the event.
As one might predict, at least one person died from taking Ecstasy. LA Times:

At 15, Sasha Rodriguez did not meet the minimum age requirement of 16 to enter the event without a legal guardian. Family and friends said that she attended the party with a 16-year-old friend and that doctors told them she had the hallucinogenic drug Ecstasy in her system when she was taken by ambulance to the emergency room.
Rodriguez … died at California Hospital Medical Center downtown before 5:30 p.m. Tuesday after her family decided to remove the comatose teen from life support.

Yes it is the MDMA.
Are teenage girls at particular risk? I don’t know the answer to this.

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The CDC has an interesting report out in their Morbidity and Mortality Weekly Report (MMWR).

Ecstasy Overdoses at a New Year’s Eve Rave — Los Angeles, California, 2010

This bit overviews a report from the Los Angeles County Department of Public Health which sought information on Emergency Department visits and other fatalities involving people who attended a New Year’s event Dec 31, 2009-Jan 1, 2010. The investigation determined that

18 patients visited EDs in LAC for MDMA-related illness within 12 hours of the rave. All were aged 16–34 years, and nine were female. In addition to using MDMA, 10 of the 18 had used alcohol, and five had used other drugs. Three patients were admitted to the hospital, including one to intensive care. A tablet obtained from one of the patients contained MDMA and caffeine, without known toxic contaminants.

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My readers are no doubt becoming a little bored with this but I assure you I do not bother to blog every one that pops up. Yes, another tragedy. A life cut short at 19 years of age because of the recreational drug MDMA, aka Ecstasy.

Friend Darren Anscombe said: ‘Me and him took some.
‘We were having a laugh at that time. I went into the kitchen and heard Danny’s girlfriend scream.
‘I went into the front room and he was lying on the floor, lifeless.’
Mr Anscombe dialled 999 and under instruction from the operator, carried out chest compressions until paramedics arrived.
Mr Anscombe said Daryl had been ‘happy’ that night but starting ‘acting strangely’.

Here is what I like about the reporting on this. They head off much speculation this way:

Dr Barbara Borek, forensic pathologist, said: ‘Toxicological analysis has detected the presence of a potentially fatal concentration of MDMA, commonly known as ecstasy.’
Tests showed there was 4,491mg of the drug per litre in his blood.

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1805_lg_obama.jpgSome random news report popping up in my Google Alert seemed kind of interesting, seeing as how it was referring to an “Obama pill” and Ecstasy and whatnot. There was also a reference to a DEA agent being interviewed.

the discovery of about 200 Ecstasy pills Monday during a traffic stop in Palmview is something of an anomaly, given how infrequently investigators in the region come across MDMA, as the drug is also known.
“We know that it is here, but it’s not here in large quantities in the way that it is in some other metro cities in the country,” said Special Agent Will Glaspy, who heads the U.S. Drug Enforcement Administration’s McAllen office.

The DEA should know some stuff, right? They collate a great deal of drug seizure info, do they not?

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A recent bit in the Vancouver Courier touts another clinical trial for MDMA as adjunctive therapy for Post-Traumatic Stress Disorder. If you haven’t been following along some of my prior observations are here, here, here. If you want everything I’ve opined on this drug, click the MDMA link under the archive.
I was just talking about main stream media accounts and how they generate an inaccurate impression by making comments that are, in isolation, more or less true but add up to an incorrect impression. In this case it was two quotes from the psychiatrist in charge of the Vancouver clinical trial.

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I am grateful to occasional reader and commenter Klem for putting me on the track of an older story. Klem was trying to argue that the authorities in Canada have long been issuing warning about non-MDMA content of “Ecstasy” and about the methamphetamine in particular. This is not news to me, of course. I am not unaware of the problem of non-MDMA psychoactive content of putative “Ecstasy” obtained on the illicit market. What I attempt to address, of course, is the seeming default assumption in the news reporting and subsequent reader comments that every case of Ecstasy fatality must have been caused by something (anything) other than 3,4-methylenedioxymethamphetamine.
Klem cites some 2005 reporting out of Vancouver and I was struck by this comment in the story.

A 13-year-old girl died in September when she took what she and friends believed was ecstasy they bought from a street dealer in Victoria.
Richard Stanwick, chief medical health officer for Vancouver Island, said an amphetamine overdose was suspected in Mercedes-Rae Clarke’s death.

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Hey, here’s another one! The University of Cincinnati school paper has a bit entitled “Ecstasy might be linked to mental deficits” by one Gin A. Ando.

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