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Neuropharmacology. 2014 Feb;77:200-7. doi: 10.1016/j.neuropharm.2013.08.025. Epub 2013 Sep 4.

Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response.

Author information

1
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. Electronic address: ahalberstadt@ucsd.edu.
2
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA; Research Service, VA San Diego Healthcare System, San Diego, CA, USA.

Abstract

N-benzyl substitution markedly enhances the affinity of phenethylamine hallucinogens at the 5-HT(2A) receptor. N-benzyl substituted derivatives of 2,5-dimethoxy-4-iodophenethylamine (2C-I), such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) and N-(2,3-methylenedioxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBMD), have appeared recently as designer drugs, but have not been characterized behaviorally. The head twitch response (HTR) is induced by 5-HT(2A) receptor activation in rats and mice, and is widely used as a behavioral proxy for hallucinogen effects in humans. Nevertheless, it is not clear whether phenethylamine hallucinogens reliably provoke this behavior. Hence, we investigated whether 2C-I, 25I-NBOMe and 25I-NBMD induce head twitches in C57BL/6J mice. The HTR was assessed using a head-mounted magnet and a magnetometer coil. 2C-I (1-10 mg/kg SC), 25I-NBOMe (0.1-1 mg/kg SC), and 25I-NBMD (1-10 mg/kg SC) induced the HTR. 25I-NBOMe displayed 14-fold higher potency than 2C-I, and the selective 5-HT(2A) antagonist M100,907 completely blocked the HTR induced by all three compounds. These findings show that phenethylamine hallucinogens induce the HTR by activating 5-HT(2A) receptors. Our results demonstrate that 25I-NBOMe is a highly potent derivative of 2C-I, confirming previous in vitro findings that N-benzyl substitution increases 5-HT(2A) affinity. Given the high potency and ease of synthesis of N-benzylphenethylamines, it is likely that the recreational use of these hallucinogens will become more widespread in the future.

KEYWORDS:

5-HT2A; Head twitch; LSD; Psychedelic

PMID:
24012658
PMCID:
PMC3866097
DOI:
10.1016/j.neuropharm.2013.08.025
[Indexed for MEDLINE]
Free PMC Article

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