Acute Pharmacological Effects of Two Synthetic Cathinones in Humans: An Observational Study of N-Ethylhexedrone and N-Ethyl-nor-pentedrone

<b>Background:</b> Synthetic cathinones (SCs) are the second most representative class of New Psychoactive Substances, with more than 100 analogues identified in the illicit drug market up to 2024. According to the United Nations Office on Drugs and Crimes, <i>N</i>-ethylhexedrone (NEH) and <i>N</i>-ethyl-nor-pentedrone (NEP) were identified among the most frequently seized SCs worldwide. However, still, little is known with regard to their pharmacological effects in humans. <b>Methods</b>: For the first time, we conducted a naturalistic, prospective observational study in 16 participants (7 women and 9 men) with a previous history of psychostimulant recreational use. They intranasally self-administered a single dose of NEP (<i>n</i> = 8, 20-40 mg) or NEH (<i>n</i> = 8, 20-40 mg). The physiological effects (systolic and diastolic blood pressure, heart rate, and temperature) and subjective effects (visual analogue scales, Addiction Research Center Inventory questionnaire and Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire) were assessed up to 4 h after the self-administration at different time points (0, 20 and 40 min and 1, 1.5, 2, 3 and 4 h). <b>Results</b>: Despite several differences, both NEP and NEH produced significant effects within 20 min, with a return to baseline 3-4 h after self-administration. In general, NEP showed a faster onset and a more rapid disappearance of subjective effects than NEH. Moreover, intranasal self-administration of NEH and NEP in experienced recreational drug users, within a non-controlled setting, induces a constellation of psychostimulant-like effects. <b>Conclusion</b>: NEH and NEP showed similar pharmacological properties after insufflation, with typical effects of SCs.