Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the neurotoxic properties of synthetic cathinones, encompassing their capacity to induce neuroinflammation, dysregulate neurotransmitter systems, and alter monoamine transporters and receptors. Additionally, it discusses the rewarding and abuse potential of synthetic cathinones drawing from findings obtained through various preclinical animal models, contextualized with other classical psychostimulants. The review also offers an overview of current abuse trends of synthetic cathinones on the illicit drug market, specifying the aspects covered, and underscores the risks they pose to public health. Finally, the review discusses public health initiatives and efforts to reduce the hazards of synthetic cathinones, including harm reduction methods, education, and current clinical management strategies.

Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second-largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the neurotoxic properties of synthetic cathinones, encompassing their capacity to induce neuroinflammation, dysregulate neurotransmitter systems, and alter in monoamine transporters and receptors. Additionally, it discusses the rewarding and abuse potential of synthetic cathinones drawing from findings obtained through various preclinical animal models, contextualized with other classical psychostimulants. The review also offers an overview of current abuse trends of synthetic cathinones on the illicit drug market, specifying the aspects covered, and underscores the risks they pose to public health.

4F‐ABUTINACA, a fourth‐generation synthetic cannabinoid, has been identified in branded herbal smoking mixtures and e‐cigarettes seized in China. However, its potential for abuse and its corresponding neurotoxic effects remain poorly understood. In the present study, we evaluated the abuse potential of 4F‐ABUTINACA using the intravenous self‐administration (IVSA) model and assessed anxiety‐like behaviour using the open‐field test (OFT) and the elevated plus maze test (EPM). Additionally, neuronal injury, apoptosis, alterations in glia expression and the BDNF‐TrkB‐AKT signalling pathway in multiple brain regions were assessed simultaneously. Rats acquired stable nose‐poke operant response for self‐administering 4F‐ABUTINACA (0.00625 mg·kg ⁻¹ ·infusion ⁻¹ ) and showed significant drug‐seeking behaviour induced by conditioned cues. Persistent anxiety‐like behaviours were observed both immediately after drug‐taking (SA group) and cue‐induced reinstatement testing after a 14‐day extinction period (CIR group). Histochemical analysis revealed more pronounced neuronal injury and apoptosis in the hippocampus, prefrontal cortex (PFC) and nucleus accumbens (NAc) in the SA group than in the CIR group. Reactive astrogliosis and microgliosis were observed in the hippocampus and the PFC in the SA group, whereas the numbers of microglia and astrocytes decreased in the NAc of the CIR group. We also found the distinct region‐specific alterations in the BDNF‐TrkB‐AKT signalling pathway expression profile between the SA and CIR groups. The present results demonstrate that 4F‐ABUTINACA exhibits significant potential for abuse and produces anxiety‐like behaviour during both the active drug‐taking and cue‐induced relapse stages, which are associated with the neuropathological alterations in specific brain regions.

To elucidate the Δ⁹-tetrahydrocannabinol (THC)-like discriminative stimulus effects of 4F-ABUTINACA and to investigate the potential mechanisms underlying anxiety-like behaviors induced by chronic 4F-ABUTINACA administration. A THC drug discrimination procedure was used in adult male rats to evaluate the THC-like discriminative stimulus effects of 4F-ABUTINACA and the effects of the cannabinoid receptor type 1 (CB1) antagonist rimonabant on these effects. In a separate cohort, rats received intraperitoneal injections of 4F-ABUTINACA at a high dose (2 mg/kg) or a low dose (0.3 mg/kg) for 15 consecutive days. Anxiety-like behaviors were assessed using the open field test and elevated plus maze at 1 day (short-term withdrawal) and 20 days (long-term withdrawal) after the final administration. Immunofluorescence staining was used to examine glial cell activation and changes in inhibitory synaptic markers in the hippocampus. Western blotting was performed to detect the expression of synaptic plasticity-related proteins in the rat hippocampus. After stable THC (2 mg/kg) discrimination was established, 4F-ABUTINACA (2 mg/kg) produced full substitution for THC, and this discriminative stimulus effect was partially inhibited by rimonabant. In the low-dose 4F-ABUTINACA group, rats exhibited anxiety-like behavior in the open field test at short-term withdrawal, accompanied by increased hippocampal glial marker expression (P<0.05), decreased expression of N-methyl-D-aspartate receptor subunits 2A (NR2A) and 2B (NR2B) and synaptosome-associated protein 25 kDa (SNAP25) (all P<0.05), and increased expression of glutamate receptor, ionotropic, AMPA 1 (GluA1) (P<0.05). Decreased gephyrin expression was observed at both short-term and long-term withdrawal (all P<0.05), whereas decreased vesicular GABA transporter (VGAT) expression and increased GluA2 expression were observed at long-term withdrawal (P<0.05). In the high-dose 4F-ABUTINACA group, rats exhibited anxiety-like behaviors and increased hippocampal glial marker expression at both short-term and long-term withdrawal (P<0.05), along with decreased NR2A, NR2B, and gephyrin expression (all P<0.05). Additionally, GluA1 expression increased at short-term withdrawal (P<0.05), while VGAT expression in the DG and CA3 subregions and SNAP25 expression were decreased at long-term withdrawal (all P<0.05). 4F-ABUTINACA produces THC-like discriminative stimulus effects via CB1 receptor activation, suggesting that it has abuse liability. Chronic 4F-ABUTINACA administration induces anxiety-like behaviors in rats, and the underlying mechanism may involve sustained hippocampal glial activation and impaired synaptic plasticity.