The synthetic cathinone mephedrone (MEPH) has two mirror-image forms (enantiomers), R-MEPH and S-MEPH, which produce different effects in rats. Both enantiomers similarly release dopamine, but R-MEPH is much weaker than S-MEPH at releasing serotonin. R-MEPH caused more repetitive movements, produced sensitization to those movements after repeated doses, and was rewarding in a conditioned place preference test, whereas S-MEPH was not. In a brain-stimulation reward test, both enantiomers showed biphasic effects, but R-MEPH produced greater facilitation. These findings indicate that R-MEPH's stronger dopamine actions and weaker serotonin actions make it more stimulant-like than S-MEPH.
The classic hallucinogens LSD, mescaline, and psilocybin, classified as Schedule 1 drugs, were tested in rats using intracranial self-stimulation (ICSS), a procedure that detects abuse-related effects of other drugs. In acute tests, all three drugs predominantly depressed ICSS, with weak and inconsistent evidence of abuse-related facilitation. Repeated LSD treatment did not alter its own depressant effects or the abuse-related effects of methamphetamine, but it did attenuate ICSS depression caused by the kappa opioid receptor agonist U69,593. These findings suggest that 5-HT2A agonist hallucinogens have weak abuse potential and provide evidence that repeated LSD may reduce depressant-like effects mediated by kappa opioid receptors.