In vitro monoamine reuptake inhibition and forensic case series in Sweden of the synthetic cathinones 2-, 3-, and 4-Me-alpha-PiHP.

Synthetic cathinones are the second largest class of new psychoactive substances (NPS) and are sold as replacements of traditional stimulant drugs. Pyrovalerone-type synthetic cathinones have been present on the recreational drug market for over a decade, including their detection in intoxication cases and drug-related fatalities. This work investigated the in vitro pharmacological profiles at the dopamine, norepinephrine, and serotonin re-uptake transporters (DAT, NET, and SERT) of the recently emerged pyrovalerone-type synthetic cathinones 2-, 3-, and 4-Me-alpha-PiHP. This study is complemented with nation-wide casework data on drug seizures and forensic toxicological investigations from forensic institutions in Sweden. 2-, 3-, and 4-Me-alpha-PiHP showed strong selectivity to target DAT, over NET and SERT with half-maximal inhibitory concentrations (IC50s) at DAT of 7.6 nM, 1.7 nM, and 0.5 nM, respectively. For all three compounds the DAT/SERT ratio, an indicator for reinforcing effects, surpassed cocaine's ratio by > 40-fold. 4-Me-alpha-PiHP was the first isomer to emerge in 2020, followed by 2-Me-alpha-PiHP in 2022, and 3-Me-alpha-PiHP in 2023, with a total of 113 seizures. The compounds were detected in forensic toxicological casework 37 times during this period, including 5 autopsy cases. A high rate of co-detections (e.g. amphetamines, benzodiazepines, and opioids) was observed. This work demonstrates the dynamics of the synthetic cathinone market. Whilst the overall use of 2-, 3-, and 4-Me-alpha-PiHP appears to be regional and relatively limited, their dopaminergic action and harm potentials render their characterization, close monitoring, and reporting important.