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

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

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

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

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

Fortunately, the doctors ran the tox panels:

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

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

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

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

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

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

I have in the past discussed the fact that a substantial amount of recreational drug being sold as “Ecstasy” on the street contains psychoactive constituents other than 3,4-methylenedioxymethamphetamine (MDMA). This is old news and you can play around with one source of data for yourself at*. In addition, I have mentioned the UK explosion in use of 4-methylmethcathinone (4-MMC, aka mephedrone) over the past year (here, here, here, here).
ResearchBlogging.orgBrunt and colleagues have provided an update from the Netherlands Drug Information and Monitoring System which obtains drug samples, described in their prior paper, from recreational users at clubs and somehow turned over to police. For this paper they have included analysis from 12,331 tablets collected from 2008-2009. The first major observation is that the proportion of tablets containing zero MDMA increased sharply in late 2008 which is a big change from the ~90% MDMA-containing samples in prior years. Something on the order of 50-60% of the Ecstasy obtained in the Netherlands in 2009 didn’t have any MDMA in it. Bummer, dude.
The other fascinating thing is that even though the usual suspect non-MDMA components were found (23-54% mCPP, methamphetamine/amphetamine, caffeine are common) the substituted cathinone 4-MMC/mephedrone is a new player.

A total of 995 (11.5% of the total ) tablets sourced from the DIMS system in 2009 contained only mephedrone. The authors note that this compound was also found in samples derived from over 100 police seizures. Although it is unclear how the proportions match up, at least the sample biases represented from the voluntary (?) user submissions and the police actions are grossly comparable in the sense that mephedrone tablets are appearing in the Dutch market. The paper goes on to note that 4-MMC is not yet “under the Scheduled Substances Act” so presumably it is a situation much like the UK up until April of 2010.

A final note of interest is the downturn in the proportion of non-MDMA tablets in late 2009- it will be interesting to see if this MDMA-drought was a shortlived blip or if actions such as Cambodia, Vietnam and Thailand finally getting serious about controlling the production of the safrole oil used as a precursor in MDMA manufacture is having a lasting effect on world markets.

One thing that I would personally like a little more clarity on is the degree to which the authors assert that the tablets they are analyzing were “sold as ecstasy”. Given the popularity of the drug under its own name in the UK, one wonders if it is merely being marketed as mephedrone/4-MMC instead of deceptively as “Ecstasy” which I think is commonly understood to mean MDMA. There is also the usual problem with samples sourced from users in this paper- there could always be a substantial bias to submit or turn over tablets (which are likely batch-identifiable by stampings/color) of unexpected or suspicious subjective character. Likewise, it is hard to determine marketshare for a particular batch or appearance of tablet. This makes it hard to infer what the constituents are in the population of pills actually being consumed by users with high accuracy. Nevertheless these data are very welcome since across time and geographical region we can get some confidence on relative MDMA content, the appearance of new drugs, etc.

*Since I mentioned the pill testing outfit 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

The recreational drug 4-methylmethcathinone (4-MMC; aka mephedrone, MMCAT) was legal in the UK up until mid April of this year. I had previously covered the only work in a behaving animal model that I could find, a paper using drug-discrimination techniques to evaluate the discriminative stimulus (aka, subjective) properties of several cathinone derivative compounds (but not 4-MMC) in comparison with amphetamine and MDMA. In a subsequent post I mentioned what appears to be the first well characterized death of someone due to 4-MMC, the relative dearth of scientific evidence about this compound and speculated on what I’d like to see happen if I were a Program Officer in NIDA.

I was very interested to see news accounts that investigators at John Moores University in Liverpool were going to start some laboratory studies in human volunteers. It really is unfortunate that we know very little about cathinones at all and essentially zero about 4-MMC, particularly when you compare it to research on the amphetamine class derivative compounds that are in recreational use. By the news account the JMU study was approved by the local IRB and it appeared to be heading into standard territory for looking at the subjective/affective, cognitive and physiological reactions to a drug in human subjects.

The public health department at JMU has won “ethical approval” to begin researching the drug with the help of students determined to get their weekend thrills.

While getting “high”, they will be questioned by university academics throughout the night about their different states of consciousness. Tests will study their thoughts and ability to think coherently, as they are asked to describe how they feel on an “adjective bar”, with “sad” or “depressed” at the bottom and “euphoric” or “very happy’ at the top. Further tests include matching objects to numbers and being asked to recall logical sequences.

Well, plans have changed. A piece in click Liverpool reports

A study testing the effects of the controversial deadly drug mephedrone has been scrapped by a Liverpool university.

Liverpool John Moores University (JMU) were given the green light to research the one-time legal high after the project initially raised eyebrows in March.

Scientists planned to monitor the effects of the white powder also known as “Mcat” or “Miaow Miaow”, which became popular among party-goers.

But now after months of deliberation, the university has cancelled its research following several casualties since the plant food hit shelves across the country.

A spokeswoman said: “This particular research project at the School of Natural Sciences and Psychology was discontinued following the change in the legal status of mephedrone.

Bummer. Far be it from me to question the actions of an IRB but given that the Swedish fatality occurred in late 2008 and the link to 4-MMC was clear by fall of 2009, well, I’m not certain I see where the risk/benefit has changed. Lots more people were taking it by early 2010 so the identification of a few more fatalities that were linked to 4-MMC shouldn’t really change the odds. Oh well, perhaps the JMU IRB simply overlooked the Swedish death or something.

There is one minor bit of hope for those of us that want to see some research data become available.
“However, a team at the School of Pharmacy and Bimolecular Sciences is continuing its own area of research into the damaging effects of this drug.”

They don’t specify but I’m thinking that perhaps this means animal studies are ongoing. So we should see at least something out of this University over the next year, hopefully.

If, and admittedly this is an assumption, the JMU IRB got cold feet over reports of fatalities in the popular press, this turns our attention back to the tox reports. In the case of MDMA (see prior link) we often resort to the Case Report literature for additional clues as to the likely causal role of the recreational drug in medical emergency and fatality. I have on offer one such report for 4-MMC that has just popped up in pre-publication form.

ResearchBlogging.orgA Letter to the Editor published in Forensic Science International by Torrance and Cooper presents an analysis of blood levels of 4-methylmethcathinone in four fatalities. This is not a full Case Report so the details are a bit sketchy. The main point seems to be identifying the presence of 4-MMC and the levels observed (22, 3.3, 5.1 and 1.2 mg/L). The authors do make clear that in only two of the four cases was 4-MMC identifed by the medical examiner as being causal in the death of the decedent. The first two cases involved suspicion of 4-MMC/mephedrone from presentation. It doesn’t specify but presumably friends or acquaintances of the victims identified drug taking in the interval immediately prior to the death. In the two other cases 4-MMC was not suspected or causal (one case involved an abdominal stabbing, the other is unspecified) but rather was identified in the victim via tox screening.

So the main result from this paper is the identification of a range of blood levels of 4-MMC that might be associated with fatality (3.3-22 mg/L) and the mention of the presence of other drugs

Case1 had less than 0.1mg/L of diazepam and nordiazepam and 0.34mg/L of amphetamine. In case 2,mephedrone was the only drug detected in blood with low concentrations of benzoylecgonine [cocaine metabolite-DM] and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid detected in urine only.

We’d prefer more of a full Case Report workup, of course. Including more details about the subjects, their use timeline and the clinical picture prior to death. But as always in science you have to build the case, brick by brick, so every little bit can be informative. We’ll just have to stay tuned.
Torrance H, & Cooper G (2010). The detection of mephedrone (4-methylmethcathinone) in 4 fatalities in Scotland. Forensic science international PMID: 20685050

The UK has now made the 4-MMC (Meow-Meow, mephedrone) compound illegal to possess as of April 16, 2010. It will be interesting to see what pops up next as the latest waiting-to-be-criminalized recreational drug.
Apparently MDAI (5,6-Methylenedioxy-2-aminoindane; Wikipedia) is a hot prospect in the UK drug user stakes. I dunno, the go-to user forum thread on MDAI doesn’t make it look all that promising but who knows. It will be interesting to see how this plays out.
Legal sourcing has a way of trumping the actual quality of the high, as we’ve seen with mephedrone in the UK in the past year. My read on the user descriptions (such as they are) sure doesn’t make it seem as if mephedrone is as fun as MDMA. The primary draw seems to be that it was a reasonably good high but more importantly it was legal and available. Hmm, now where are those cannabis fans who claim that legality and ready availability of cannabis has nothing to do with use patterns?

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

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