Mephedrone is also more reinforcing than MDMA or Methylone in male rats

Methylone has now surpassed MDMA in Forensic Laboratory samples in the US. Mephedrone is less popular in the US but maintains a high degree of popularity in the UK. We recently published a paper [Creehan et al, 2015; PubMed; blogpost] showing that the drug mephedrone was a more effective reinforcer than either MDMA or methylone in female rats.

Our followup study which compared the self-administration of these three drugs in male rats has been accepted for publication.

Vandewater, S.A., Creehan, K.M. and Taffe, M.A. Intravenous self-administration of entactogen-class stimulants in male rats. Neuropharmacology, 2015, 99:538-545. [ PubMed ][ Publisher Site ]

We are interested in the reinforcing potential of mephedrone and methylone due in large part to their neuropharmacological similarity to MDMA. Specifically, these three drugs have a relatively greater enhancement of serotonin in the nucleus accumbens of the rat brain compared with the enhancement of dopamine. The latter effect is associated with pleasurable/rewarding effects of traditional stimulant drugs like methamphetamine whereas the preferential serotonin release/accumulation is associated with reduced reward potential. In short, rats have shown much less intravenous self-administration of MDMA versus methamphetamine.

The fact that Mephedrone and Methylone share the MDMA-like neurochemical profile groups them all together as atypical or entactogen-class stimulant drugs and predicts less compulsive use compared with traditional stimulants like methamphetamine. Yet several self-administration studies with mephedrone have already shown a greater abuse potential compared with MDMA. The one available study with methylone (Watterson et al, 2012; blogpost) prior to our work implied the same. Our study in female rats was the first to directly compare these three drugs and we confirmed that mephedrone is a much more effective reinforcer, thus predicting higher liability for compulsive use. MDMA and methylone, however, appeared to be quite similar.

Our new study in the male rats used essentially the same procedures as the study in females and had the same conclusion. In this figure we show mean (±SEM) daily infusions of drug (upper panel) and the proportion of responses on the drug-associated lever versus the inactive lever (lower panel) obtained for groups of male rats trained to self-administer MDMA (N=17), Methylone (N=14) or Mephedrone (N=15) in 2 hour sessions. [Significant differences from the first session within group are indicated by *, differences between mephedrone and both other groups by #, differences from methylone by ‡ and differences from MDMA by †.] The MDMA and mephedrone groups differed from each other and the methylone-trained group was intermediate.

The results from the female animals in the previous study differed slightly in that the methylone and MDMA intakes were nearly identical and were both significantly different from the mephedrone self-administration.

We did some follow up comparisons between males and females for the new paper and those ended up in the Supplemental Materials file. The only significant sex-difference was for the MDMA-trained groups where there was a significant main effect of rat sex confirmed in the analysis. The methylone intakes appeared to be nearly identical between males and females, as is depicted and the mephedrone intakes did not differ either (not shown).We did some further sub-groups analysis and found that this difference in MDMA self-administration was mostly in the less-preferring half of the male group.

At this point we have a direct confirmation of the enhanced liability of mephedrone for compulsive use over that of MDMA. This is a clear rejection of the suggestion based on intra-cranial self-stimulation reward data that it has reduced liability- clearly something is off about the way the results were interpreted by Bonano et al (2014). Methylone appears to be much more similar to MDMA although it might be a slightly more effective reinforcer in male rats. Nevertheless we still cannot reconcile our results with methylone self-administration with the apparently robust self-administration reported by Watterson et al (2012). As there are only now three published studies of the self-administration of methylone, we must await further studies to better understand the reasons for these different outcomes.