Mephedrone, methylone, ethylone, butylone and naphyrone exhibited relative DAT versus SERT inhibition potencies in the range of 1–5, similar to cocaine. Uptake inhibition studies using rat synaptosomes found that mephedrone was equally potent at the DAT and SERT (Hadlock et al., 2011). Methylone and butylone were slightly more potent DAT than SERT inhibitors at the human transporter as previously shown for methylone (Cozzi et al., 1999). Equal uptake inhibition potencies for the DAT and SERT were shown for methylone and butylone using rat brain synaptosomes (Nagai et al., 2007; Lopez-Arnau et al., 2012). Ethylone was an equipotent inhibitor of all three transporters, and we are not aware of other published data. Compared with methylone, ethylone and butylone, the respective non-β-keto analogue entactogens MDMA, MDEA and MBDB were 10-fold more selective for the SERT versus DAT, consistent with previous data on methylone and MDMA (Cozzi et al., 1999; Nagai et al., 2007). Together the data indicate that the cocaine–MDMA–mixed cathinones are more dopaminergic with regard to monoamine transporter inhibition than their entactogen analogs.
In terms of monoamine release, the cocaine–MDMA–mixed cathinones were comparable with MDMA. Ethylone and butylone released 5-HT, comparable with their non-β-keto entactogen analogues MBDB and MDEA, but with lower potency. Previous studies found that the monoamine release profiles of mephedrone and methylone resembled those of MDMA, with DAT/SERT and NET/DAT ratios close to unity (Nagai et al., 2007; Baumann et al., 2012). However, mephedrone was a more potent releaser of DA than MDMA in the present study and from striatal suspensions preloaded with DA (Hadlock et al., 2011). An in vivo microdialysis study in rats showed that mephedrone also produced a rapid and pronounced increase in nucleus accumbens DA levels, comparable with amphetamine and unlike MDMA, which only moderately elevates DA levels (Kehr et al., 2011). Both mephedrone and MDMA also produced strong increases in extracellular 5-HT, whereas amphetamine had only a moderate effect on 5-HT levels (Kehr et al., 2011). Other microdialysis studies showed that mephedrone and methylone elevated extracellular DA and 5-HT levels in the rat nucleus accumbens, with relatively higher effects on 5-HT levels (Aarde et al., 2011; Baumann et al., 2012), similar to MDMA and unlike methamphetamine, which preferentially increases DA (Baumann et al., 2012). Thus, mephedrone shares some of the DA-releasing properties of amphetamine and methamphetamine and 5-HT-releasing property of MDMA. Mephedrone also produced relatively weak motor stimulation similar to MDMA, unlike amphetamine that strongly increases locomotor activity in rats (Kehr et al., 2011), and a preference to move along the walls of the test box (Motbey et al., 2012) as previously described for MDMA. Like MDMA, mephedrone also reduced voluntary wheel running in rats, while running was increased by methamphetamine or MDPV (Huang et al., 2012). Similar to mephedrone, methylone was also reported to be a weak motor stimulant compared with methamphetamine (Baumann et al., 2012). Drug discrimination studies in rats also showed that methylone generalized well to MDMA and at lower potency also to amphetamine (Dal Cason et al., 1997). Mephedrone is self-administered by rats (Aarde et al., 2011; Hadlock et al., 2011), has been reported to produce strong craving in humans (Brunt et al., 2011) and when administered intranasally is rated by users to be more addictive than cocaine (Winstock et al., 2011). Furthermore, mephedrone showed very high BBB permeability in our in vitro model, confirming that mephedrone readily enters the brain (Hadlock et al., 2011). Overall, the pharmacological effects of mephedrone and methylone appear to be relatively similar to those of MDMA but share more of the DA system-stimulating properties of amphetamine and methamphetamine and the DAT versus SERT inhibition profile of cocaine. The subjective effects of mephedrone have been reported to be similar to those of cocaine (Winstock et al., 2011) but also MDMA (Carhart-Harris et al., 2011). Importantly, MDMA is mostly used orally, whereas intranasal administration is the most common route of use for mephedrone (Winstock et al., 2011) and cocaine. Users noted that the high obtained with the intranasal use of mephedrone was similar to or better than the high produced by cocaine (Winstock et al., 2011). These observations indicate that the oral use of mephedrone produces overall similar effects to MDMA, whereas intranasal use results in more cocaine-like psychotropic effects. Similar to mephedrone and methylone, ethylone and butylone may be associated with an increased risk of addiction compared to their non-β-keto analogues because of the stronger relative activation of the DA system.
The pyrovalerone derivative naphyrone exhibited a monoamine uptake transporter inhibition profile that was very close to that of cocaine, with equal relative potency at all three transporters. Similar to cocaine, naphyrone was not a monoamine releaser. Naphyrone is distinct from pyrovalerone and its derivative MDPV because of its higher absolute and relative SERT-inhibiting potency. Although the structure would suggest similar pharmacological effects to the other pyrovalerone derivatives, the additional SERT inhibition may indicate more similar effects to cocaine in humans (Derungs et al., 2011).