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.

11 responses so far

  • [...] Gaining clarity on the pharmacology of the bath salt MDPV … Posts related to Gaining clarity on the pharmacology of the bath salt MDPV ...Bath Salts Drug: Dangers of MDPV, Mephedrone, Pyrovalerone ...Top Shelf Marijuana Strains ,Research chemical ,Bath salts for sale ...Miramichi Police Force has their first confirmed case of MDPVCheap MDMA, MDPV, AM-2201, Heroin, Mephedrone, Dmt, Morphine No Comments. Tags: actions, browser, cocaine, goldberg, hoffman, problem, schindler, sitte, tella, thorndike   « Subject: Which is better: 5apb...Subject: propylhexedrine &#821... » [...]

  • Beaker says:

    It would be interesting if experienced stimulant users posted their MDPV experiences here--and compared them to cocaine, meth, etc. Erowid is nice, but I'd like to hear first-hand comparisons of "classic" stimulants versus this new "legal" stuff. Does the psychotropic experience match the molecular mechanism?

  • physioprof says:

    If you gave people access to pure safe accurate doses of MDMA, they wouldn't fucke themselves up with this kind of shitte.

  • DrugMonkey says:

    Blue light doesn't give you enough to work with Beaker?

    And CPP, no, as usual.

  • physioprof says:

    Prove I'm wrong or GTFO.

  • Beaker says:

    DM, wow I was clueless about Bluelight. The intertoobz rock.

  • science is my life says:

    x i agree with physioprof

  • Spiny Norman says:

    "If you gave people access to pure safe accurate doses of MDMA, they wouldn't fucke themselves up with this kind of shitte."

    Dumbass: people inhale glue, paint remover, and tobacco smoke. Self-destructiveness knows no boundaries.

    That said, harm reduction is a Good Idea.

  • drugmonkey says:

    Bluelight.ru tells you people will never be satisfied with one drug.

  • I just could not leave your web site before suggesting that I really loved the usual information an individual supply for your guests?

    Is gonna be back often in order to investigate cross-check new posts

  • Wow, incredible blog structure! How long have you been blogging for?
    you make running a blog look easy. The entire look of your website is
    excellent, let alone the content!

Leave a Reply