Pharmacology and toxicology of new psychoactive substances

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

Substantial progress was made on this project, with the publication of five research articles reporting on the pharmacology and toxicology of opioid, cannabinoid, and stimulant NPS. In particular, there has been an increased availability of potent synthetic cathinones, like N,N-dimethylpentylone (DMP), in non-medical drug markets. DMP is a stimulant NPS that has caused significant intoxications and deaths, especially in Florida. Our team at NIDA IRP partnered with the Center for Forensic Science Research and Education (CFSRE) and the University of Florida College of Medicine (UFCM) to characterize the forensic detection, clinical symptomatology, and molecular mechanism of action for DMP (Fogarty et al., 2025). Identification of DMP in counterfeit “Ecstasy” and “Molly” tablets may pose risks to public health. However, little information is available about the pharmacological activity or relevant blood or tissue concentrations of DMP, and even less is known about other structurally related beta-keto methylenedioxyamphetamine analogs. We reported a novel toxicological assay utilizing liquid chromatography-tandem quadrupole mass spectrometry for the quantitation of DMP and five related synthetic cathinones (eutylone, pentylone, N-ethyl pentylone (NEP), N-propyl butylone, and N-cyclohexyl butylone), with chromatographic resolution of isomeric variants. A forensic series of 125 human cases was evaluated for the presence of DMP and related analogs, along with pharmacological activity assessments using in vitro monoamine transporter and in vivo mouse behavioral assays. The blood concentration range for DMP in postmortem forensic cases was 3.3-4,600 ng/mL (mean±SD: 320±570 ng/mL, median: 150 ng/mL), whereas pentylone, the primary N-demethylated metabolite of DMP, was identified in 98% of cases with a concentration range 1.3-710 ng/mL (mean±SD: 105±120 ng/mL, median: 71 ng/mL). Most DMP cases involved polydrug exposures, but there were two dozen cases where DMP was the only drug detected. DMP displayed potent uptake inhibition at the dopamine transporter (IC50=49 nM ), with 100-fold weaker potency at the serotonin transporter (IC50=4990 nM). DMP was a locomotor stimulant in mice (ED50=3.5 mg/kg) exhibiting potency similar to eutylone, NEP, and pentylone. Our results show that DMP is a psychomotor stimulant associated with adverse clinical outcomes leading to death. DMP has much higher potency for inhibiting the dopamine transporter, when compared to its effects on the serotonin transporter, portending high risk for addiction and repeated misuse. Forensic laboratories must continue to update testing methods to capture emerging drugs, with specific emphasis on resolution and identification of isomeric species. Following the scheduling of DMP in early 2024, there could be an anticipated market shift towards a new unregulated synthetic stimulant to replace DMP.