Discriminating Cathinone Analogs

sourceMy 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.
The 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)

In this case, for example, the rats were trained to discriminate 1.0 d-amphetamine (d-AMP) from saline. The drug (or saline vehicle) was administered by intraperitoneal injection and then the animal was placed in the operant chamber and allowed to respond on two levers to produce a delivery of sweetened powdered milk. When d-AMP was administered before the session one lever produced reward and this became the drug-associated lever for that animal (left/right was balanced across the group). Presses on the other lever were rewarded under saline conditions. In contrast to the self-administration paradigm, the drug is the cue but not the reinforcer of the lever pressing,
The critical step in this assay is that responses on the levers in the first 2.5 minutes of the session did not produce any consequences. Animals were considered trained when they made over 80% of their responses during this test interval on the drug-appropriate lever after receiving 1.0 d-AMP and less than 20% on the drug-appropriate lever after receiving saline. Once trained, animals are challenged with either different doses of the training drug or different drugs entirely. The procedure is interpreted as giving an indication of how similar the subjective properties of a drug is to the training drug and how potent that drug is relative to the training drug.
In this paper, the authors investigated the subjective properties of several cathinone analog compounds including N-Monoethylcathinone (N-Et CAT), N-mono-n-propylcathinone (N-Pr CAT), and N,N-dimethylcathinone (Di Me CAT), 3,4-Methylenedioxycathinone (MDC) and 3,4-Methylenedioxymethcathinone (MDMC). I have taken the liberty of graphing the data provided in tabular form in the paper.
As you can see in the graph, as you decrease the dose of the training drug, the rats are less and less likely to “report” that they have been given the active training drug. This is a classic feature of the assay. In terms of the cathinone analogs under investigation, four of them would substitute for the training drug if you pushed the dose high enough. Notice that in two cases the necessary dose was higher on a mg/kg basis than the training dose of d-AMP. In two other cases, the full-substitution dose was similar, but the dose to get approximately halfway there was higher. One compound (MDC) did not fully substitute for d-AMP; part of the reason for this is that beyond the graphed dose range, the animals were behaviorally disrupted- i.e., they didn’t make more than 5 total responses (on either lever) in the initial test interval.
So cathinone analogs are producing subjective properties similar to amphetamine in many cases, all well and good. At this point you are screaming that sure, this procedure just asks the animal to report if it is intoxicated on a drug or not. Unfortunately I don’t have the time or inclination to go through the arguments step by step so I’ll refer you back to the drug-discrimination database for the moment.
I did want to highlight two papers from Goodwin and Baker (here, here) that took the modestly unusual step of training rats to discriminate d-AMP and MDMA from saline using a three-lever setup. The take home here is that by using this procedure you can get the rats to report d-AMP classic stimulant-like effects differently from serotonin-mediated classic hallucinogen effects. The data confirm in a rat model that MDMA does indeed share stimulant and hallucinogen-like properties**. (Man, I wish more people would use this three-lever procedure.)
Returning the Dal Cason paper, we see that they also conducted another study in which the rats were initially trained to discriminate 1.5 mg/kg MDMA from saline and then tested on the methylenedioxycathinone and methylenedioxymethcathinone compounds. In this case 77% MDMA-like responding was produced at only 2 mg/kg of MDC and the 93% considered full substitution at 2.25 mg/kg. In contrast MDC did not substitute fully for d-AMP, producing the most d-AMP-like responding of 58% at 2.75 mg/kg. The MDMC compound produced full substitution for MDMA at 2 mg/kg (98% MDMA-appropriate) and nearly full substitution (77%) at 1.75 mg/kg. This drug produced full substitution for d-AMP at 3 mg/kg and 69% drug-appropriate responding at 2.75 mg/kg. Although this between-groups procedure is not as elegant as the three-lever paradigm, still we have some evidence here for how subjective properties of several cathinone analogs shake out in a behaving animal.
I’m hoping a lab or two is busily working on 4-MMC so we can start getting some data on the behavioral pharmacological properties of this drug which appears to be gaining popularity in the UK at the moment. Does it seem like a classic stimulant? Does it confer subjective effects more like MDMA? And then what are the modes of toxicity? The fatality I mentioned may have been associated with hyponatremia which is not uncommon in MDMA-related fatalities.
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*in combination with cannabis. Cue designer drug fans complaining how it can’t be the entactogen/stimulant, it must be the known danger of…um, uh-oh.
**I can’t help undercutting my attempt to get you to believe in drug-discrimination by pointing out this paper (also from the Glennon group) showing that MDMA-trained rats will report cocaine as MDMA-like but cocaine-trained rats do not fully generalize to MDMA. If it were easy it wouldn’t be interesting…
DALCASON, T., YOUNG, R., & GLENNON, R. (1997). Cathinone: An Investigation of Several N-Alkyl and Methylenedioxy-Substituted Analogs Pharmacology Biochemistry and Behavior, 58 (4), 1109-1116 DOI: 10.1016/S0091-3057(97)00323-7