Search Results for "mephedrone"

Nov 13 2012

Mephedrone Brief 11/13/2012: Yes, it was the 4-methylmethcathinone that killed him

There's a new Case Report in the Journal of Analytical Toxicology

Adamowicz P, Tokarczyk B, Stanaszek R, Slopianka M. Fatal Mephedrone Intoxication--A Case Report. J Anal Toxicol. 2012 Nov 7. [Epub ahead of print] [PubMed][DOI]

The victim was a 30 year old male, found in a stairwell in a "critical state". Emergency response was ineffectual and the individual died at the scene. The toxicology testing found his blood and vitreous humour positive for mephedrone (5.5 and 7.1 ug/mL, respectively). There was no alcohol in the individual, no positives on "routine screening analysis" nor any sign of amphetamine, methamphetamine or MDMA. The 2C-B compound initially suspected by police (based on some field assay, looks like) was not confirmed in the powder in his possession nor in tissue samples.

That's it, short and sweet. The mephedrone (aka 4-methylmethcathinone) killed him.

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Additional reading on the substituted cathinone designer drugs of abuse can be found in my archive.

Related reading on MDMA-induced fatality can be found in the MDMA Archive.

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Dec 08 2011

Congress moves to control synthetic cannabimimetic (K2/Spice) and designer cathinone (mephedrone/MDPV) drugs

HR 1254 (pdf) has passed the House.

This Act would criminalize possession of a range of compounds which activate the endogenous cannabinoid CB1 receptor. The language covers several structural classes as well as an extended list of, e.g. the JWH-xxx compounds. In essence this is another attempt on the analog front in which the DEA is not able to move quickly enough on specific new drugs that emerge within a general neuropharmacological class.

The bill also doubles the amount of time the DEA has to generate the support for a final rule, once an emergency action has been invoked.

The House Resolution next addresses 17 compounds in the likely stimulant/empathogen class, with most of them being cathinone derivatives. Readers of this blog will be familiar with the well known 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV) on this list.

One assumes that Chuck Schumer will be leading the charge on this in the Senate and that it will pass in short order...opposition to this sort of legislation is not usually robust among elected politicians.

8 responses so far

Sep 30 2010

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.
ResearchBlogging.orgA Case Report that recently appeared in the Lancet helps us to connect up some dots. Sammler and colleagues report on the case of a 15 year old girl who presented to their emergency department one afternoon with "altered mental status, vomiting and nausea". She had been out drinking the night before and had also consumed a "white powdery substance". The clinical workup contained a few interesting clues:

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

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

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

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

Fortunately, the doctors ran the tox panels:

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

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

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

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

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

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

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Sep 19 2010

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).
ResearchBlogging.orgBrunt and colleagues have provided an update from the Netherlands Drug Information and Monitoring System which obtains drug samples, described in their prior paper, from recreational users at clubs and somehow turned over to police. For this paper they have included analysis from 12,331 tablets collected from 2008-2009. The first major observation is that the proportion of tablets containing zero MDMA increased sharply in late 2008 which is a big change from the ~90% MDMA-containing samples in prior years. Something on the order of 50-60% of the Ecstasy obtained in the Netherlands in 2009 didn't have any MDMA in it. Bummer, dude.
The other fascinating thing is that even though the usual suspect non-MDMA components were found (23-54% mCPP, methamphetamine/amphetamine, caffeine are common) the substituted cathinone 4-MMC/mephedrone is a new player.

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

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

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

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*Since I mentioned the pill testing outfit ecstasydata.org at the top, I should note that a search for mephedrone pulls up 5 different tablets, all sourced from Zurich (it is possible that the other source laboratories are not testing for 4-MMC yet). All 5 contain caffeine and two contain MDMA in addition to the 4-MMC.

Brunt TM, Poortman A, Niesink RJ, & van den Brink W (2010). Instability of the ecstasy market and a new kid on the block: mephedrone. Journal of psychopharmacology (Oxford, England) PMID: 20826554

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Aug 18 2010

Recreational Mephedrone Brief (8/18/10)

4-MMC.jpg
source
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.
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Torrance H, & Cooper G (2010). The detection of mephedrone (4-methylmethcathinone) in 4 fatalities in Scotland. Forensic science international PMID: 20685050

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Apr 08 2010

UK bans Mephedrone

The UK House of Lords has followed the riff-raff MPs in voting for a ban of the previously uncontrolled recreational drug 4-methymethcathinone (4-MMC, mephedrone, meow-meow, plant-food, etc). Prior observations from me are here and here.
This is a good opportunity to point to the report on the cathinones [ pdf ] that was created by the Advisory Council on the Misuse of Drugs. This more or less echos my points in my prior posts that while we may know a bit about cathinones the available scientific knowledge is pretty pathetic compared to the amphetamine-class drugs. And essentially nothing has been published on 4-MMC/mephedrone.

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Mar 19 2010

Scientific Research 101: Meow-Meow, "plant food", 4-MMC, mephedrone...

Published by under Science 101

4-MMC.jpg
source
I recently introduced a paper on the discriminative stimulus properties of cathinone analog drugs with reference to the recent emergence in the popular media of an analog called 4-methylmethcathinone (4-MMC), mephedrone (2-methylamino-1-p-tolylpropan-1-one), Meow-Meow, MMCAT. The name "plant food" is what 4-MMC is apparently being marketed under in the UK, given that the compound itself is not controlled but it is illegal (I surmise) to sell things as "legal ecstasy" or "legal methamphetamine" or similar. 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.
An early report of a fatality associated with consumption of the drug in Sweden resulted in placement of mephedrone on the controlled list. The followup in the Swedish press shows that the woman was reported to have consumed mephedrone (confirmed post-mortem) and smoked cannabis (no apparent confirmation; alcohol and other narcotics excluded postmortem) and then collapsed. Emergency services were unable to revive her and she died a day and a half later; symptoms of brain swelling, stroke, hyponatremia and hypokalemia were mentioned, as well as a low body temperature of 33 degrees C.
The story has heated up recently in the UK press after the death of two individuals who are, at present, suspected of taking 4-MMC/mephedrone, reportedly in combination with methadone (an opiate) and alcohol. As I mentioned before, a quick scan of PubMed finds little reported on the effects of this compound in animal models or in humans.
So the question is, scientists, what next?
Let's play virtual science, shall we?

Continue Reading »

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Sep 13 2013

It was the methylone that killed him

The Daily Mail is reporting followup toxicity findings in the June 17 death of one Matthew Rybarczyk the after attending a rave party.

The Daily Mail:

There are fears that a string of fatal overdoses this summer have been caused by the toxic substance bath salts after it was pushed to young festival-goers as the party drug 'Molly', officials said today.

The substance had been sold to at least one young person as 'molly' - a potent form of ecstasy - but was in fact the meth-like street drug bath salts.

Officially known as methylone, it can have similar effects to ecstasy or MDMA on the user.

It has been confirmed as cause of death of a 20-year-old man and is suspected in the deaths of others.

StructureFig-mdma-vs-cathinones450As you can see in this structural diagram, methylone is the cathinone cousin of 3,4-methylenedioxy-methamphetamine (MDMA) which is the canonical psychoactive of both Ecstasy and Molly.I am delighted to see some actual toxicity data followup reporting. Perhaps other sources will have more specifics with regard to the medical examiner's findings and the various drugs found in the decedent's blood. For now, however, at least we have something to go on.

And I covered one prior Case Report containing three methylone-related deaths. And as I noted there, we know perfectly well that MDMA itself is capable of killing people.

As we've also discussed, MDMA can result in significant medical emergency and death. Yes, really, it is the MDMA.

It would not be at all surprising if methylone deaths were via the same neuropharmacological triggers, see Baumann et al 2012 and Simmler et al, 2013. Certainly what one can glean from the symptoms is very familiar.

I take issue, however, with the Louise Boyle piece in the Daily Mail. We can start from the headline:

Did all these festival-goers die from taking BATH SALTS? One death confirmed as fears others were duped into buying toxic street drug while believing it was 'molly'

See that? Nice trick. Methylone is a "toxic street drug" while apparently 'molly' is no such thing. Bzzzt, wrong. Methylone and MDMA are the same category of thing. Recreational drugs obtained from sources of dubious quality. Trying to distinguish one as a "toxic street drug" as different from the other is silly and nonsensical.

next we have this whopper:

but was in fact the meth-like street drug bath salts

Another report from the NY Post goes down the same path of underinformed sensationalism:

New York club kids who use the party drug Molly ... are often being peddled deadly “bath salts” by ruthless dealers,...The dangerous narcotic — which causes a violent, meth-like high — has killed at least one reveler this year and is being eyed in the deaths of two partiers at the Electric Zoo festival on Randall’s Island two weeks ago...Known to drug regulators as methylone

The term "bath salts" is just a nickname. It is no different than Ecstasy, molly, crack, crystal, weed, smack. It has meaning in so far as there is a consensus use of it, but in the absence of consensus it is near meaningless. I would say that at this point in time "bath salts" in the US can mean any of the substituted cathinone drugs. There was a time when I might have said it was semi-uniquely referring to 3,4-methylenedioxypyrovalerone (MDPV) but given the diversity in the market this is no longer correct.

The above referenced papers from Baumann and Simmler, and this additional one from Baumann, should tell the tale about the "meth-like" charge as well. While some of the substituted cathinones could be argued to be "meth-like", methylone sure isn't one of them. In fact the neuropharmacology suggests "MDMA-like" if anything. And really, given the most popular cathinones being used to date, it is silly to say that bath salts are meth-like. Mephedrone and methylone are MDMA-like in many ways and MDPV is turning out to be more like cocaine in activity. That's neuropharmacology, for the most part. When we look at compulsive use and propensity for addiction it in fact looks like methylone (Watterson et al, 2012) and mephedrone (Hadlock et al, 2011; Aarde et al, 2013a; Motbey et al, 2013) might have more reinforcing effect in rodent models than would be expected for a MDMA-like drug (see Schenk 2009; de la Garza et al, 2007 for review). In some of these studies the authors show data suggesting* the "MDMA-like" cathinones might actually be more effective in self-administration than methamphetamine. MDPV appears to generate more compulsive use than does methamphetamine (Watterson et al, 2012; Aarde et al 2013b). So, I suppose if the journalists mean the compulsive-use or reinforcing value as indexed by rat self-administration studies then they might have some defense for the "meth-like" charge. Somehow I doubt they are so informed.

Nevertheless.

When we are talking the acute overdose profile, the symptoms sure sound like MDMA and the relative reinforcing properties are most likely not directly related.

Oh boy. As I was writing this, some tox reporting from the New York Electric Zoo overdoses (it also repeated the methylone finding for Mr. Rybarczyk). James C. McKinley Jr reports at an Arts Beat blog at the NYT:

Toxicology results showed Ms. Rotondo died from acute intoxication after taking pure MDMA, the euphoria-producing drug sold on the street in pill form as ecstasy and in powdered form as molly, said Ellen Borakove, a spokeswoman for the medical examiner’s office.

Mr. Russ had taken a fatal mix of MDMA and methylone, a closely related stimulant that is also often sold under the name molly.

Nice to see some confirmation since there are definitely other drugs to suspect, like PMA and PMMA, when it comes to rave-drug overdoses.

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*there are some methodological questions to be answered. I'd like to see a few more comparisons, myself.

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Oct 18 2012

Gaining clarity on the pharmacology of the bath salt MDPV

There are two new pharmacological investigations on the substituted cathinone drugs that have been discussed here on occasion.

Each of

Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW.Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive 'Bath Salts' Products. Neuropsychopharmacology. 2012 Oct 17. doi: 10.1038/npp.2012.204.

and

Simmler LD, Buser TA, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME.Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol. 2012 Aug 17. doi: 10.1111/j.1476-5381.2012.02145.x.

report very similar findings for MDPV, the cathinone that appears most frequently in US newspaper reports.

As a very general rule, the amphetamine class stimulants do a couple of things to enhance the neuron-to-neuron chemical communication that occurs in the brain. The most common and significant effects tend to involve the transporter mechanisms that remove dopamine, norepinephrine and / or serotonin from the synapse, the gap between two neurons. These transporter molecules are an integral part of terminating a signalling event which has been caused by the release of one of these three monoamines from one of the neurons in question. Interfere with the operation of these transporters and a drug can potentiate the magnitude or duration of a given signalling event (i.e., release of one of the dopamine (DA), norepinephrine (NE) or serotonin neurotransmitters).

The amphetamine class stimulants have these properties. As does cocaine. As do therapeutic drugs such as methylphenidate (Ritalin) and Prozac. The term selective serotonin re-uptake inhibitor, SSRI, for Prozac-class antidepressant drugs refers to the transporter, obviously, and also indicates a key thing with the term "selective". Drugs which have the ability to interact with one of the monoamine transporters tend to interact with the other ones as well. Substantial differences in effect can be associated with differences in the relative ability a specific molecule has to attach to the DAT versus the NET versus the SERotonin transporter (SERT). As one clear example, methamphetamine and MDMA differ in their relative ability to inhibit the SERT....this property of MDMA is associated with many of it's stimulant-atypical properties relative to other amphetamine-class drugs.

The new studies both show that MDPV blocks all three transporters with much more potent effects at the DAT and NET relative to SERT. As Baumann and colleagues note, MDPV is 50 and 10 times more potent than cocaine (not an amphetamine, we'll come to this) at DAT and NET respectively. Simmler and colleagues similarly indicate that MDPV is much more potent at DAT than cocaine or methamphetamine which did not qualitatively differ from each other.

So to this point, MDPV looks like a high-potency traditional stimulant. Most effective at the DAT, fairly effective at the NET and with less ability to block the SERT.

Cocaine and the amphetamines diverge at this point because the amphetamines act as a substrate at the transporters. Instead of only interfering and blocking them from doing anything, the amphetamines actually substitute for the neurotransmitter in question and are taken up into the cell. In so doing, they also cause an exchange to happen whereby the transporter moves some neurotransmitter from inside the cell back into the synapse. This transporter mediated efflux contributes to any "regular" release of neurotransmitter mediated through the merging of intracellular sacs (called vesicles) with the cell membrane.

The two papers agree in finding that MDPV has no ability to cause transporter-mediated efflux of dopamine and is therefore best categorized neuropharmacologically as a "pure" blocker (like cocaine) rather than an amphetamine-like transporter substrate.

The Simmler paper adds an in vitro model of blood/brain barrier penetration...in very simple terms the degree to which a molecule is fat-liking versus water-liking can alter the speed at which it can cross cell membranes and get into the brain. This paper used an in vitro preparation of human capillary endothelial cells (that form the blood-brain barrier) to show that MDPV is likely to cross the blood-brain barrier very rapidly, consistent with high lipophilicity predicted from its structure.

The upshot of the two papers is that MDPV shows pharmacological properties consistent with classical stimulants. It shows relatively high selectivity for DAT over SERT and high potency relative to drugs such as methamphetamine or cocaine. In vivo neurochemistry in the Baumann paper confirm that MDPV has potent effects on dopamine levels in the nucleus accumbens, a hallmark of drugs (beyond the stimulants even) which have substantial risk for compulsive use. The only somewhat discordant note for the structure-activity nerds is that MDPV looks so much like the rest of the amphetamines and cathinones that it will be interesting to discover why it doesn't act as a transporter substrate (Simmler et al included a number of other cathinones and showed that many of them do act as transporter substrates.)

Together these papers suggest that MDPV has high abuse liability with a use pattern characterized by frequent re-dosing much like one sees with cocaine. This is consistent with many self-reports that are emerging from people who use MDPV and therefore, despite the relatively brief time on the "market", we can predict a cocaine-like dependence problem to emerge for MDPV in the near future.

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Jun 26 2012

An interesting twist in Congressional efforts to ban cathinone derivative drugs

Last week the US House of Representatives voted to approve a ban on several recreational drugs in the two classes we've been discussing of late. Namely the synthetic cannabinoids and the cathinones. They slipped the ban into a bill first called the "Food and Drug Administration Safety and Innovation Act" (Senate version; S.3187) and then, apparently the "FDA User Fee Agreement" (House version maybe) so you can tell they were on the hurry-up about it. As noted in this account from the Bangor Daily News:

The measure combines three bills previously introduced by Sens. Chuck Grassley, R-Iowa, Chuck Schumer, D-N.Y., and Amy Klobuchar, D-Minn. Among the chemicals it would outlaw are mephedrone and methylenedioxypyrovalerone, known as MDPV, which can be used to make bath salts. The bill carries a penalty of up to 30 years for those caught selling the drug.

The lone dissenter in the Senate vote was Sen. Bernie Sanders, an independent from Vermont.

The U.S. Drug Enforcement Administration took emergency action in September 2011 to federally ban mephedrone, Methylone and MDPV and designated the hallucinogenic stimulants a Schedule 1 drug, the same class as heroin and LSD.

I'm having trouble finding anything that specifies exactly what was passed by the House last week but this page S.3190 lists 4-MMC/mephedrone and 3,4-methylenedioxypyrovalerone (MDPV) and then some phenethylamines in the 2C family. These lack the beta-ketone signature of a cathinone so calling them "bath salts" even further confuses the identity issue, I will note. Curiously, methylone (or 3,4-methylenedioxymethcathinone, the MDMA cousin) is not on this list. If anything, the available data tend to suggest this is the one most likely to be a breakout hit in this country...it is already pretty popular in the UK.

Anyway, the news of the day is that Sen Patrick Leahy of VT has blocked the inclusion of the 2C compounds and the resulting bill has passed the Senate with only mephedrone and MDPV included from that class of compounds (apparently all the cannabinoids were included). According to this reporting, a member of his staff said:

"Sen. Leahy has been clear that scheduling controlled substances is not something to be taken lightly."

"It is not without implication to put a whole lot of chemicals on the federal drug schedule," he said. "It means putting more people in jail and makes it harder to seek legitimate uses for these drugs. Leahy is most comfortable sticking with what has been carefully considered."

Here's how I read this from my perspective as one that has been interested in the effects of the cathinones and has followed the developing scientific literature and, to lesser extent the street seizures and policy initiatives, via published work and discussions with researchers, DEA representatives, NIDA Program Officials and even FDA folks.

I bet they presented actual data on mephedrone and MDPV. Published data and as-yet-unpublished data from laboratories in addition to the public health and law enforcement data. Data that are probably limited but still reasonably convincing. To a CongressCritter. This is the "carefully considered" part.

What I also would predict is that there was comparatively less information about the 2C drugs, if any at all. And the DEA hoped that by calling it all "bath salts" they could criminalize the lot. I would surmise that at best the pro-ban folks based their demands on finding some 2C family compounds in products being sold as bath salts along with, or in a context similar to, substituted cathinone drugs like mephedrone and MDPV.

And I bet Sen Leahy called bullshit on an information disparity.

If this is what happened, I have to issue a pat on the back to him for standing up for the rule of information in making policy decisions.

UPDATE: ok, this appears to be a House bill version that includes a full list. Several cathinones were included in addition to the 2C-? phenethylamines. Interesting. There's a link which compares it to S.31690 and you can see where the Senate version had just the 4-MMC and MDPV with the 2C-? phenethylamines.

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