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Effect of -NBOMe Compounds on Sensorimotor, Motor, and Prepulse Inhibition Responses in Mice in Comparison With the 2C Analogs and Lysergic Acid Diethylamide: From Preclinical Evidence to Forensic Implication in Driving Under the Influence of Drugs - PubMed

️Sat Jan 01 2022

doi: 10.3389/fpsyt.2022.875722. eCollection 2022.

Sabrine Bilel¹, Raffaella Arfè¹, Giorgia Corli¹, Beatrice Marchetti¹, Tatiana Bernardi², Federica Boccuto², Giovanni Serpelloni³, Francesco Botrè⁴, Fabio De-Giorgio^{5

6}, Krystyna Golembiowska⁷, Matteo Marti^{1

8}

Affiliations

PMID: 35530025
PMCID: PMC9069068
DOI: 10.3389/fpsyt.2022.875722

Effect of -NBOMe Compounds on Sensorimotor, Motor, and Prepulse Inhibition Responses in Mice in Comparison With the 2C Analogs and Lysergic Acid Diethylamide: From Preclinical Evidence to Forensic Implication in Driving Under the Influence of Drugs

Micaela Tirri et al. Front Psychiatry. 2022.

Abstract

In the last decade, the market for new psychoactive substances has been enriched by numerous psychedelic phenethylamines, which mimic the psychoactive effect of lysergic acid diethylamide (LSD). In particular, the -NBOMe series, which are more potent than their 2C compounds analogs, are considered worthy substitutes for LSD by users. The purpose of this study was to assess the effects of 25H-NBOMe and its halogenated derivatives (25I-NBOMe and 25B-NBOMe) in comparison to their 2C compounds analogs and LSD on the sensorimotor (visual, acoustic, and overall tactile), reaction time, spontaneous (total distance traveled) and stimulated (drag, accelerod test) motor activity, grip strength test, and prepulse inhibition (PPI) responses in mice. Systemic administration of -NBOMe, 2C compounds analogs, and LSD (0.001-10 mg/kg) differently impaired the sensorimotor, reaction time, motor, and PPI responses in mice. In particular, halogenated (25I and 25B)-NBOMe derivatives appear to be more effective than the entire class of 2C compounds analogs in altering visual and acoustic responses, affecting reaction time, and motor and sensory gating in PPI test. In fact, the specific rank order of compounds potency for nearly all of the experiments showed that (25I and 25B)-NBOMe were more potent than 2C compounds analogs and LSD. -NBOMe and 2C compounds analogs impaired not only the reception of incoming sensory stimuli (visual and acoustic), but their correct brain processing (PPI) in an equal and sometimes stronger way than LSD. This sensory impairment directly affected the spontaneous motor response and reaction time of mice, with no change in performance in stimulated motor activity tests. These aspects should be carefully considered to better understand the potential danger that psychedelic phenethylamines, in particular -NBOMe, may pose to public health, with particular reference to decreased performance in driving and hazardous works that require special sensorimotor skills.

Keywords: -NBOMe; 2C compounds; DUID (driving under the influence of drugs); LSD; novel psychoactive substances (NPS); phenethylamine; pre-pulse inhibition; sensorimotor.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

**FIGURE 1**
Chemical structures of 2,5-dimethoxyphenethylamine (2C-H), 2,5-Dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2,5-dimethoxy-N-[(2-methoxyphenyl) methyl]-benzeneethanamine (25H-NBOMe), 4-iodio-2,5-dimethoxy-N-[(2-methoxyphenyl) methyl]-benzeneethanamine (25I-NBOMe), 4-bromo-2,5-dimethoxy-N-[(2-methoxyphenyl) methyl]-benzeneethanamine (25B-NBOMe), and Lysergic acid diethylamide (LSD).

**FIGURE 2**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)** 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)** 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)** 2C-H (0.001–10 mg/kg i.p.) **(D)** 2C-I (0.001–10 mg/kg i.p.) **(E)** 2C-B (0.001–10 mg/kg i.p.) **(F),** and LSD (0.001–10 mg/kg i.p.) **(G)** on the visual object tests in mice, and comparison of the maximum **(H)** and average **(I)** effects observed in 5 h. Data are expressed as mean ± SEM (n = 8/group). Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test **(A–G)** for multiple comparisons for the dose–response curve of each compound at different time points. The comparison of maximum effect observed in 5 h was also presented **(H,I)**. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 vs. LSD.

**FIGURE 3**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)** 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)** 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)** 2C-H (0.001–10 mg/kg i.p.) **(D)** 2C-I (0.001–10 mg/kg i.p.) **(E)** 2C-B (0.001–10 mg/kg i.p.) **(F)** and LSD (0.001–10 mg/kg i.p.) **(G)** on the visual placing tests in the mice and comparison of the maximum **(H)** and average **(I)** effect observed in 5 h. Data are expressed as mean ± SEM (n = 8/group). Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test **(A–G)** for multiple comparisons for the dose–response curve of each compound at different time points. The comparison of maximum effect observed in 5 h was also presented **(H,I)**. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle; ^#p < 0.05 vs. LSD.

**FIGURE 4**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)** 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)** 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)** 2C-H (0.001–10 mg/kg i.p.) **(D)** 2C-I (0.001–10 mg/kg i.p.) **(E)** 2C-B (0.001–10 mg/kg i.p.) **(F)**, and LSD (0.001–10 mg/kg i.p.) **(G)** on the acoustic tests in mice and comparison of the maximum **(H)** and average **(I)** effects observed in 5 h. Data are expressed as mean ± SEM (n = 8/group). Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test **(A–G)** for multiple comparisons for the dose–response curve of each compound at different time points. The comparison of maximum effect observed in 5 h was also presented **(H,I)**. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle; ^#p < 0.05, ^##p < 0.01, ^###p < 0.001 vs. LSD.

**FIGURE 5**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)** 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)** 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)** 2C-H (0.001–10 mg/kg i.p.) **(D)** 2C-I (0.001–10 mg/kg i.p.) **(E)** 2C-B (0.001–10 mg/kg i.p.) **(F)**, and LSD (0.001–10 mg/kg i.p.) **(G)** on reaction time test in the mice and comparison of the maximum **(H)** and average **(I)** effect observed in 5 h. Data are expressed as mean ± SEM (n = 8/group). Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test **(A–G)** for multiple comparisons for the dose–response curve of each compound at different time points. The comparison of maximum effect observed in 5 h was also presented **(H,I)**. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle; ^##p < 0.01, ^###p < 0.001 vs. LSD.

**FIGURE 6**
Correlation between sensory dysperception and reaction time of mice following administration of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)**, 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)**, 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)**, 2C-H. (0001–10 mg/kg i.p.) **(D)**, 2C-I (0.001–10 mg/kg i.p.) **(E)**, 2C-B (0.001–10 mg/kg i.p.) **(F)**, and LSD (0.001–10 mg/kg i.p.) **(G)** observed in 1 h. Data are expressed as mean ± SEM (n = 8/group). Statistical analysis was performed by XY correlation, which revealed a correlation between the two different effects of treatment. p < 0.0001.

**FIGURE 7**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)**, 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)**, 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)**, 2C-H (0.001–10 mg/kg i.p.) **(D)**, 2C-I (0.001–10 mg/kg i.p.) **(E)**, 2C-B (0.001–10 mg/kg i.p.) **(F)**, and LSD (0.001–10 mg/kg i.p.) **(G)** on the total distance traveled of mice over a 4-h observation period. Data are expressed as meters traveled and represent the mean ± SEM of eight determinations for each treatment. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons for the dose–response curve of each compound at different times. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle.

**FIGURE 8**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.), 25I-NBOMe (0.001–10 mg/kg i.p.), and 25B-NBOMe (0.001–10 mg/kg i.p.) **(A)**; 2C-H (0.001–10 mg/kg i.p.), 2C-I (0.001–10 mg/kg i.p.) and 2C-B (0.001–10 mg/kg i.p.) **(B)**; and LSD (0.001–10 mg/kg i.p.) **(C)** on the time spent in the C1 zone of mice during the 4-h observation period. Data are expressed as seconds and represent the mean ± SEM of 8 determinations for each treatment. Statistical analysis was performed by one-way ANOVA followed by Bonferroni’s test for multiple comparisons for the dose–response curve of each compound at different times. *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle.

**FIGURE 9**
Correlation between sensory dysperception and total distance traveled by mice following administration of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)**, 25I-NBOMe (0.001–10 mg/kg i.p.) **(B)**, 25B-NBOMe (0.001–10 mg/kg i.p.) **(C)**, 2C-H. (0001–10 mg/kg i.p.) **(D)**, 2C-I (0.001–10 mg/kg i.p.) **(E)**, 2C-B (0.001–10 mg/kg i.p.) **(F)**, and LSD (0.001–10 mg/kg i.p.) **(G)** observed after 1 h. Data are expressed as mean ± SEM (n = 8/group). Statistical analysis was performed by XY correlation, which revealed a correlation between the two different effects of treatment for p < 0.0001 (2C-H, 2C-I, 2C-B, 25H-NBOMe, 25I-NBOMe and 25B-NBOMe) and p = 0.5572 (LSD).

**FIGURE 10**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)**, 25B-NBOMe (0.001–10 mg/kg i.p.) **(B)**, 25I-NBOMe (0.001–10 mg/kg i.p.) **(C)**, 2C-H (0.1–10 mg/kg i.p.) **(D)**, 2C-I (0.1–10 mg/kg i.p.) **(E)**, 2C-B (0.1–10 mg/kg i.p.) **(F)**, and LSD (0.1–10 mg/kg i.p.) **(G)** on startle amplitude in mice. Startle amplitude was expressed in absolute values (in dB) and the values represent the mean ± SEM of 10 animals for each treatment. The statistical analysis was performed with a one-way ANOVA followed by Bonferroni’s test for multiple comparisons. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. vehicle.

**FIGURE 11**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)**, 25B-NBOMe (0.001–10 mg/kg i.p.) **(B)**, 25I-NBOMe (0.001–10 mg/kg i.p.) **(C)**, 2C-H (0.1–10 mg/kg i.p.) **(D)**, 2C-I (0.1–10 mg/kg i.p.) **(E)**, 2C-B (0.1–10 mg/kg i.p.) **(F)**, and LSD (0.1–10 mg/kg i.p.) **(G)** on prepulse inhibition (PPI) in mice. Effects on PPI are shown for the three prepulse intensities (68, 75, and 85 dB) at 15 min after treatment. PPI was expressed as the percentage decrease in the amplitude of the startle reactivity caused by presentation of the prepulse (% PPI; see section “Material and Methods”) and values represent mean ± SEM of 10 animals for each treatment. The statistical analysis was performed with a one-way ANOVA followed by Bonferroni’s test for multiple comparisons. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. vehicle.

**FIGURE 12**
Effect of 25H-NBOMe (0.001–10 mg/kg i.p.) **(A)**, 25B-NBOMe (0.001–10 mg/kg i.p.) **(B)**, 25I-NBOMe (0.001–10 mg/kg i.p.) **(C)**, 2C-H (0.1–10 mg/kg i.p.) **(D)**, 2C-I (0.1–10 mg/kg i.p.) **(E)**, 2C-B (0.1–10 mg/kg i.p.) **(F)**, and LSD (0.1–10 mg/kg i.p.) **(G)** on prepulse inhibition (PPI) in mice. Effects on PPI are shown for the three prepulse intensities (68, 75, and 85 dB) 120 min after treatment. PPI was expressed as the percentage decrease in the amplitude of the startle reactivity caused by presentation of the prepulse (% PPI; see section “Material and Methods”) and values represent mean ± SEM of 10 animals for each treatment. The statistical analysis was performed with a one-way ANOVA followed by Bonferroni’s test for multiple comparisons. *p < 0.05, **p < 0.01 and ***p < 0.001 vs. vehicle.

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