News on substituted cathinone stimulants, aka “bath salts”

The New York Times had a piece up Sunday that was entitled “An Alarming New Stimulant, Legal in Many States“. I was alerted to this by David Kroll who reposted some prior comments at his Take as Directed blog. I’ve been getting some traffic from a BoingBoing linker from Maggie Koerth-Baker to an older post from me so I thought I’d better address a couple of points that jump out at me.
First and foremost, the reader should be extremely cautious whenever there is conflation of two different drugs under one purported street name. Even if they are structurally quite similar and some human reports have overlapping properties. In the case of “bath salts”, there is quite a bit of confusion over whether a news account is referring to 4-methylmethcathinone (4-MMC), methylenedioxypyrovalerone (MDPV), sees no difference between them* or doesn’t know if there is any difference.

By “know” I mean that when you see a typical news account of some horrific case of criminal activity, police resistance, violence, traffic accident or self-contained medical emergency and it is attributed to “bath salts”, it is very likely that nobody really knows exactly what was ingested. Until the medical toxicology reports emerge…. but of course then most of the attention has moved onward. And the copious amount of drug seized in a bust, well again, until there is some analysis conducted it is not certain which drug is under discussion.

So, back to the NYT piece and the general impression that these drugs are more or less the same thing, due to their failure to distinguish. 4-MMC and MDPV are similar in the sense that they contain the core structure of cathinone. They also have shared stimulant-like properties if you go by the user accounts. Such as the Erowid (MDPV, 4-MMC) experience vaults or the bluelight (MDPV, 4-MMC site currently down) user forums. You will see reports of stimulant typical (cocaine, methamphetamine) effects. For 4-MMC this impression is buttressed by a couple of user surveys by Winstock (Web based, interview based) which find that users see this as a stimulant.
Of course, there is also a subpopulation revealed, particularly in the online user accounts, that thinks of 4-MMC subjective effects as being like Ecstasy or 3,4-methylenedioxymethamphetamine (MDMA), albeit an inferior version.
And this gets us back to expectations based only on structure. The easiest way to convey it is to point out that methamphetamine and MDMA are structurally similar to each other and yet they convey very different subjective phenomena. Going by user accounts of MDMA and methamphetamine, at any rate. These compounds are also pretty well studied in the laboratory and they have meaningful differences in pharmacological effect. They both interact with pre-synaptic elements of monoaminergic terminals of neurons. This leads to an enhanced release of dopamine and blockade of the dopamine transporter, probably the greatest source of stimulant-typical effects. They also interact with elements of serotonergic and noradrenergic terminals….but in different affinities. Such that the simplest description is that methamphetamine has negligible effect other than dopamine whereas MDMA has a very pronounced serotonergic character to the effect. They differ in some other pharmacological aspects but you take the point for this discussion…seemingly modest modifications of cathinone structures may have similarly dramatic effects on the subjective and physiological effects of these novel drugs.
Unfortunately, we know very little about these specific compounds from the perspective of laboratory studies (see here for a drug discrimination study). A recent paper by Kehr and colleagues provides a hint, at least so far as 4-MMC is concerned. The upshot is that based on microdialysis evidence of dopamine and serotonin release / uptake blockade in the nucleus accumbens of rats, 4-MMC looks more like MDMA than it does like methamphetamine. There was a big serotonin effect. On the other hand, the dopamine response was potentially greater than what would be obtained with MDMA (caveat that they would need to have run more doses for high level of confidence on this). I have not seen any data on MDPV yet but the users hint at even more cocaine-like, compulsive use, binging type of effects of this drug. If I were a betting man, I’d bet that MDPV turns out to have pharmacology that lacks the serotonin signal of 4-MMC. Sure, we’re going to see differences in affinities for different receptors that affect neurotransmission mediated by dopamine, serotonin, norepinephrine and other minor players. Sure, we’re going to see potency differences. But overall our thinking can clearly be shaped by the understanding of different amphetamine drugs of abuse.
However. We do not know. Not until the studies have been done will we know more about how 4-MMC and MDPV are the same and how they are dissimilar. Human reports can only take us so far, for example check out this paper from the Hart laboratory. Experienced human users have difficulty determining whether they were given MDMA or methamphetamine under controlled, blinded, lab conditions. Humans are not always the best judges of pharmacological effects. If they can’t do it under controlled lab conditions, well, the varied contexts, doses and routes of administration in which they take recreational drugs in the field (so to speak) does not give us particularly high confidence in subjective report. Now me, I’m a believer in the crowd-source thing and try to get an overall impression from online user forums. But I always have a healthy suspicion.
Then, reading along I noticed something: the NYT seems to have lost its mind.

They are similar to so-called synthetic marijuana, which has also caused a surge in medical emergencies and been banned in a number of states.

Come on now. These stimulants are not “similar” to cannabimimetic incense in any recognizable way. Unless they were referring to the quasi-legality of them and the mad profits being made by head shops and the like. In the context presented however, it seems they are making comparisons of the drug effects. That really doesn’t make any sense.
Many of my readers will also be howling at the “alarming” headline inclusion and the generally breathless tone of the NYT article. I can’t say that I disagree. There is nothing so far that indicates these compounds are going to be any more or less dangerous than the amphetamine drugs that are being used by many more people. I really object to the “strength of ten men” type of hysteria*** familiar to a not atypical media line on PCP. I suspect we will eventually find that different cathinones can have different risks for compulsive use, generating dependence, behavioral disruption, mood alterations and lasting neurotoxicity. Just as is the case with substituted amphetamine drugs.
We are not going to know, however, until we see some science.
UPDATE 7/20/11: Finally found a way to link to what was one of my favorite cartoons during my formative years, Doonesbury. In August of 1985 Trudeau took up the phenomenon of designer amphetamines (this is one of my favorites). We are, I suspect, in a similar era of designer cathinones, with different compounds emerging both for their different experiential effects and to stay one step ahead of the legal controls.
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*I am limiting my discussion to the two best well known compounds. The DEA’s April Microgram publication is seeking information on additional cathinone derivative compounds including methylone (3,4-methylenedioxymethcathinone**), 4-fluoromethcathinone and 4-methoxymethcathinone.
**aka bk-MDMA for “beta-ketoMDMA”; a ketone in the beta position being what distinguishes a cathinone from an amphetamine if I have that correctly.
***insensitivity to pain, maybe? impulsivity and energetic stimulation, yes. but strength of ten men crap is just that. crap. and unfortunately I think it may get police in the mindset of ludicrously excessive uses of force where it is not needed at times.