sourceI 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?
[ Before we start, let me remind you that my usual disclaimers apply. I may or may not have a variety of dogs in this hunt but I would suggest that if issues of potential conflict of interest concern you, you simply assume that I am conflicted up the wazzoo and read my thoughts accordingly. ]
In this exercise, feel free to inhabit any of a number of players so long as you keep focused on the science. Perhaps you want to approach this as a Principal Investigator or maybe a funding agency's Program Official. Perhaps as a member of a policy advisory panel or governmental advisory division (such as the US DEA which contains people whose job it is to make reports on whether a drug should be scheduled or not). Even as a member of tax paying public or recreational user groups- if you are in this latter I would appreciate you keeping it as brief and on-topic (e.g., you might make an argument for why existing information on cathinone class drugs is enough knowledge).
The answers I am looking for are varied. We start with a pretty low baseline of scientific knowledge about this specific compound, but some decent knowledge of related cathinones and slightly-more-distantly related amphetamine class drugs. Do we need to know more? What? What should we throw money into and in what order?
I'd like to first play Program Official (and probably IC Director because she's the one that gets to really make things happen by fiat).
The scope of the problem: First off, I'd like to lean on my drug epidemiology folks and those running clinical research programs to start asking where mephedrone is being used, how popularity is growing and how many people are calling Poison Hotlines to ask about toxicity. I'd think I can pull this off first by making a request of existing grantees, maybe bring a few to Bethesda (or wherever your local apparatus may meet) for a one-day brainstormer. If pressed, maybe we could cut loose a few supplements, maybe 10 or so, to the tune of about $50K to do some additional surveying.
Pharmacology: Yes, we have a general idea of what cathinone derivatives do but I'd want to see some pharm workup in bench models right away. This would have the benefit of helping to guide any animal work we'd want to do later. What are the affinities for dopamine, serotonin and norepinephrine signalling components such as pre- and post-synaptic receptors and transporter mechanisms? How effective is mephedrone at activating, inhibiting of being a substrate for these? How does it compare to the various amphetamine analog drugs? I can probably task someone in the Intramural Research Program of the NIH for this, if not I expect to have to cough up at least $100K in directs to an extramural laboratory. Definitely worth it.
Animal studies: Even on the strength of the UK popular reports, I think we have enough to justify some initial work in animals. Rodent lab stuff, done to the tune, again, of R03 money. I'd want to immediately generate the standard LD50 estimates. This a research design in which groups of animal subjects are dosed with a range of doses until you can get an estimate of at which dose half of them die. (You can start thinking about the ethical implications now a little bit but I'm planning to have another virtual-Animal Care and Use Committee post tied into this later.) I'd also want to see some self-administration data, here I think mephedrone substitution in amphetamine and cocaine trained rats would probably do for starters. Then I'd want some drug-discrimination data, preferably in animals trained to discriminate amphetamine and MDMA. Maybe some data from one of the hyperlocomotion / stereotypy laboratories as well. So maybe four $50K awards to run off some quick and dirty data.
A question for me (again, as a Program Official) is whether to issue an RFA on this topic. It is tempting. Why? Because rumoring and then putting out an RFA on mephedrone has a damn good chance of getting the bigger laboratories with the major models to whip out some quick studies as Preliminary Data within their existing funding. I.e., I can get all of the above data generated, and into the NIH system where I can see it, at no additional cost (save the opportunity cost of a bunch of PIs diverting their ongoing work for this purpose). Trouble is, we may not be at the point where we're ready to actually justify funding bigger / longer term projects yet. (Hmm, I suppose we could just troll the investigators and then not actually fund anything out of the RFA but that seems kind of mean.)
So, DearReader, what would you do? As a scientist do you have some studies to put the grad student on? Are you taking a pass for affirmative reasons? Do we need to know anything more about mephedrone or not? If we do, where do we start?