Pharmacokinetics, systemic toxicity, thermoregulation and acute behavioural effects of 25CN‐NBOMe

Abstract

N‐(2‐methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5‐HT2A agonists containing substances emerging on the illicit drug market as a replacement for N,N‐diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group‐housed animals, and acute behavioural effects after subcutaneous administration of 2,5‐dimethoxy‐4‐(2‐((2‐methoxybenzyl)amino)ethyl)benzonitrile (25CN‐NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half‐life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co‐operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN‐NBOMe readily passes the blood–brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes.

Acute pharmacological profile of 2C-B-Fly-NBOMe in male Wistar rats—pharmacokinetics, effects on behaviour and thermoregulation

“…Other examinations imply that NBOMe substances, namely 25B-NBOMe, 25C-NBOMe and 25I-NBOMe, when administered i. p., cause a dose-dependent decrease in locomotor activity ( Gatch et al, 2017 ; Wojtas et al, 2021 ), which is in correlation to our observation. 25CN-NBOMe manifested a similar, yet less pronounced decrease in locomotion ( Šíchová et al, 2022 ). It is of note that the inhibitory effect of 2C-B-Fly-NBOMe was so prominent that the animals were unable to exhibit typical thigmotactic behaviour, especially in higher doses.…”

“…Indeed, self-reports of recreational users declare peak effects of various NBOMes within 45–90 min and duration for up to 8 h ( Lawn et al, 2014 ). Our recent study of closely related substance 25CN-NBOMe determined half-life values of 1.88 h for the blood serum and 2.28 h for the brain tissue, however, in a five-fold higher applied dose of 5 mg/kg ( Šíchová et al, 2022 ). A higher half-life value of 2C-B-Fly-NBOMe in the brain might indicate its slower turnover and possibly a longer mechanism of action of the drug.…”

“…Similarly, 25CN-NBOH also showed tendencies to disrupt PPI in rats ( Halberstadt and Geyer, 2017 ). 25CN-NBOMe affected PPI only in the highest dose of 5 mg/kg in the 15 min onset ( Šíchová et al, 2022 ). According to our data, 2C-B-Fly-NBOMe strongly attenuates ASR even in the lowest dose of 0.2 mg/kg, which is fully in line with our previous observations with 2C-B.…”

“…200–250 g at the time of testing. Each experimental group consisted of 10 rats based on our previous studies with a standardized protocol for comparable data ( Rohanová et al, 2008 ; Páleníček et al, 2013 ; Šíchová et al, 2022 ), and each subject was tested only once according to the principle of acute behavioural testing, except for the pharmacokinetic studies–to minimize the number of sacrificed animals, rats from behavioural experiments treated with saline and 1 mg/kg of 2C-B-Fly-NBOMe were used for the determination of drug concentrations in brain and serum. Experiments were conducted during the light phase of the cycle; animals were brought to the testing rooms with a controlled temperature (22°C ± 2°C) 1 h before the start of each experiment for acclimatization.…”

“…Based on previously published behavioural studies with 25B-NBOMe, 25C-NBOMe and 25I-NBOMe ( Halberstadt and Geyer, 2014 ; Elmore et al, 2018 ; Nakamura et al, 2018 ; Miliano et al, 2019 ) our experience with related compound 25CN-NBOMe ( Šíchová et al, 2022 ), and reports on selectivity and potency of 2C-B-Fly-NBOMe on 5-HT 2A receptors, a range of three concentrations was estimated for the experiments: 0.2, 1 and 5 mg/kg s. c. dissolved and administered in a total volume of 2 ml/kg. An equivalent volume (2 ml/kg) of deionized water and 20 μl of Tween 20 was used as negative control (ctrl).…”