New psychoactive substances (NPSs), also known as “designer drugs,” present a rapidly evolving challenge in the global drug landscape. They are designed to mimic traditional illicit drugs while evading existing regulations, encompassing synthetic cannabinoids, cathinones, hallucinogens, and stimulants. Their defining characteristic lies in the chemists’ ability to swiftly change their chemical structure, making regulation difficult (Guirguis, 2017). This adaptability poses significant public health concerns due to the unknown risks associated with NPS use. Factors such as online availability, global distribution networks, and the perception of legality contribute to the proliferation of NPSs, challenging traditional drug control methods and necessitating innovative strategies to monitor, assess, and respond to emerging trends (Guirguis, 2017).

Dissociative arylcyclohexylamine (ACX) anesthetics, including phencyclidine (PCP) and ketamine, have long been of interest due to their diverse neuropharmacological effects. Their mechanism of action involves their antagonistic effects on the N-methyl-D-aspartate (NMDA) receptor (Ellison, 1995). The emergence of analogs of PCP, ketamine, and eticyclidine (PCE) as drugs of abuse on the illicit market has raised concerns about their potential risks and toxicities, being associated with a range of adverse effects, including neurocognitive impairment, psychosis, and addiction. Very few studies analyzed their pharmacological effects concerning toxicity, abuse liability, and potential disruption of cognitive abilities.

The study by Shaw et al. (2024) published in The Journal of Pharmacology and Experimental Therapeutics sheds light on the abuse liability and neurocognitive effects of these drugs in rodents. In this study, the authors assessed locomotor effects in mice of a range of PCP, PCE, and ketamine analogs in comparison with psychostimulants (methamphetamine, MDMA, and two benzofuran analogs of MDMA), determined PCP-like interoceptive effects using a food-reinforced drug discrimination procedure in adult male rats, and profiled psychosis-like neurocognitive effects of PCP and 3-Cl-PCP in comparison with cocaine and morphine. For the latter experiment, they developed a novel operant assay of rule-governed behavior, which integrates elements of attentional set-shifting. The procedure used involves training rats in a series of behavioral sessions to assess their ability to shift attention and respond to changing rule sets. The rats were trained to respond for food reinforcement on the left and right nose-poke keys, with an orienting response consisting in a series of auditory and visual clues to signal the active nose-poke keys. Once the rats achieved >80% accuracy for five consecutive sessions, the rules were randomly changed by the controlling computer with different auditory and visual clues. Throughout the behavioral sessions, the rats had to attend to the auditory stimulus and respond appropriately to the changing rule sets, involving both intradimensional (left versus right lever) and extradimensional (lit versus unlit lever) shifts in their performance. The primary endpoint in this procedure was “trials to shift,” which represents the mean number of correct trials performed before a new rule set is selected. This procedure is designed to assess the rats' cognitive flexibility and ability to adapt to changing task demands, providing valuable insights into their attentional set-shifting abilities and rule-learning processes. The use of auditory stimuli and the requirement to respond to changing rule sets mimic aspects of cognitive flexibility and attentional shifting observed in humans, making this procedure relevant for studying cognitive processes. This methodology enables rapid animal training, displays a relatively high throughput, minimizes hands-on involvement for the experimenter, and exhibits selectivity in detecting the effects of PCP-like drugs as evidenced by their current findings. Interestingly, the robustness of this novel experimental procedure is confirmed by the lack of effects of cocaine or morphine, which do not disrupt cognitive abilities at the doses tested.

The study found that the novel ACX elicited varied locomotor stimulant and lethal effects in mice, exhibited PCP-like abuse liability in the drug discrimination assay, and induced psychosis-like neurocognitive effects in rats. These findings are consistent with previous studies reporting that administration of PCP or PCP derivatives increased locomotor and rotational activities in a dose-dependent manner (Fessler et al., 1979; French and Vantini, 1984; Abiero et al., 2020; Ryu et al., 2020) and display conditioned place preference in rodents (Botanas et al., 2015). Moreover, PCP and PCP derivatives were self-administered in rodent and primate animal models (Marquis et al., 1989; Campbell et al., 1998; Botanas et al., 2015; Abiero et al., 2020).

Shaw et al. (2024) showed that the locomotor stimulant effects of the ACX vary depending on the specific drug and the position of the substituent on the aromatic ring. Hence, ketamine and its analogs displayed limited motor activation effects when compared with PCP, PCE, and their analogs. All the ACXs tested induce psychosis-like neurocognitive deficits in the rule-governed behavior task not observed with cocaine or morphine. Of note, several of the drugs tested display lethal effects not observed with their parent drugs.

This paper significantly contributes to the field by expanding our knowledge of the behavioral effects of dissociative anesthetics and related compounds and fills a significant gap in our understanding of the risks of ACX NPS, providing important information regarding similarities and differences with the parent compounds. The main novel findings of the paper are that all ACXs display similar abuse potential to PCP, produce diverse stimulant effects on movement and lethal outcomes in mice, and trigger neurocognitive effects resembling psychosis in rats. In general, all analogs display pharmacological effects similar to those of the parent drug but with significant differences, specifically concerning potency and toxicity.

However, certain limitations warrant consideration. First, the use of male animals only may limit the generalizability of the findings to the broader population. Second, the abuse liability of ACX was assessed with indirect measures, such as locomotor stimulant effects and substitution for PCP (of which the abuse liability is well established). However, the magnitude of the locomotor stimulant effect does not seem to be a good predictor of abuse liability, whereas locomotor sensitization, which was not assessed in the study by Shaw et al. (2024), is believed to be a better predictor (Robinson and Berridge, 1993). A more thorough assessment would have required additional experimental procedures, such as conditioned place preference or intravenous drug self-administration, which should be a subject for future research.

A major challenge in NPS pharmacology, not addressed in this study but poorly addressed overall in the literature, is the possibility that active and/or toxic metabolites contribute to the effects of these drugs. In fact, metabolic pathways are thoroughly mapped only for a few compounds, and many are still to be studied.

The findings suggest that the emergence of novel ACX drugs of abuse on the illicit market poses risks for toxicities, including adverse neurocognitive effects.

The S(+) enantiomer of ketamine, esketamine, is an approved fast-acting antidepressant with efficacy in drug-resistant depression. Thus, findings of the potential abuse liability or psychotic-like side effects of its illegal derivatives are worrying (Lodge and Mercier, 2015; Bonaventura et al., 2021). Misuse of ketamine and similar dissociative agents for self-medication or recreational purposes raises considerable concerns regarding their potential for abuse and side effects when prescribed to treat depression (Le et al., 2022).

The insights gained from this research have implications for substance abuse research, neuropharmacology, and the development of potential therapeutic interventions.

Future research should consider addressing the identified limitations, such as exploring sex-specific differences in response to these compounds. Furthermore, investigations into the neurobiological mechanisms underlying the observed behavioral effects could provide a more comprehensive understanding of the pharmacology of these substances.

As substance use patterns evolve, understanding the motivations behind NPS consumption and their effects and associated risks becomes crucial for public health, clinical professionals, and policymakers, considering the raised interest in psychedelic substances as novel therapeutic agents in neuropsychiatric disorders.

The author has no actual or perceived conflict of interest with the contents of this article.

dx.doi.org/10.1124/jpet.124.002109.