Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents

Abstract

There has been increasing use of novel synthetic hallucinogenic compounds, 25B-NBOMe, 25C-NBOMe, 25I-NBOMe, and 5-MeO-DALT, which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (−)-2,5-dimethoxy-4-methylamphetamine (DOM) and to the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time course information. 25B-NBOMe, 25C-NBOMe and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose-dependently increased locomotor activity with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM- and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM- and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74 to 78% drug-appropriate responding in DOM- and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced little few or no MDMA-like effects. All of the compounds but except 25I-NBOMe produced fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely due to its substantial rate rate-depressant effects than to weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but likely probably much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

Neurochemical and Behavioral Profiling in Male and Female Rats of the Psychedelic Agent 25I-NBOMe

“…The serotonergic psychedelic effects of this compound have been confirmed by behavioral responses such as head twitch in C57BL/6J mice (NBOMe 0.1-1 mg/kg, s.c.) (Halberstadt and Geyer, 2014), wet dog shakes, and back muscle contraction (0.01-3 mg/kg, s.c.) in rats (Elmore et al, 2018), and all these effects were prevented by the administration of the selective 5-HT2A antagonist M100907 (Halberstadt and Geyer, 2014;Elmore et al, 2018). Indeed, 25I-NBOMe timedependently and dose-dependently decreased locomotor activity in mice (Eshleman et al, 2014;Gatch et al, 2017) and showed full substitution of LSD in rats drug discrimination and more than 50% of appropriate responding in MDMA-trained rats (Eshleman et al, 2014). The MDMA-like action of 25I-NBOMe has been also confirmed in vitro since it acts inhibiting the monoamine reuptake transporters with different IC 50 (hSERT, IC 50 = 4.3 µM; hDAT, IC 50 = 75 µM; hNET, IC 50 = 19 µM) in HEK 293 cells (Zwartsen et al, 2017).…”

Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors

“…There are several case reports of abuse of 25BNBOMe, 25C-NBOMe, and 25I-NBOMe and their harmful effects include prolonged agitation, hallucinations, seizures, rhabdomyolysis, acute kidney injury and death [6–10]. In animal studies, these three NBOMe compounds substituted for the discriminative stimulus effects of the hallucinogen DOM [11] and were recently categorized as Schedule 1 compounds [12]. There is much less information available regarding other NBOMe compounds although anectodal evidence indicates that many are psychoactive and hallucinogenic.…”

NBOMes–Highly Potent and Toxic Alternatives of LSD

“…Thus, ketanserin, a 5-HT 2A antagonist, blocked the 25B-NBOMe-evoked HTR and normalized 5-HT 2A mRNA levels in the mouse prefrontal cortex upregulated by a prolonged administration of the drug (Custodio et al, 2019). Gatch et al (2017) tested 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe for discriminative stimulus effects similar to a prototypical psychedelic/hallucinogen DOM and to an empathogen, 3,4-methylenedioxymethamphetamine (MDMA). In DOM-trained rats 25B-NBOMe and 25C-NBOMe, but not 25I-NBOMe, fully substituted for this drug.…”

“…In both tests, the dose-effect curves for 25B-NBOMe had an inverted U-shape. It is suggested that 25B-NBOMe and 25C-NBOMe are most likely used as recreational psychedelics, although 25B-NBOMe may also be used as an empathogenic compound (Gatch et al, 2017). However, the latter assumption should be taken with caution, as some compounds (e.g., fenfluramine) that substitute for MDMA in rats do not produce MDMA-like empathogenic effects in humans (Schechter, 1988).…”