Interoceptive effects of N1-substituted lysergamides in rats: Role of agonist affinity at 5-hydroxytryptamine receptors and in vivo metabolism to lysergic acid diethylamide

22/08/2026

AI Summary

N1-substituted lysergamides exhibited reduced affinity or efficacy at 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C yet fully substituted for LSD in rats.
Following dosing, N1-substituted drugs yielded high blood LSD levels, implying metabolic conversion; LSZ remained unmetabolised and retained LSD-like receptor activity.
Pharmacokinetics and analytical chemistry reconcile in vitro-in-vivo discrepancies, and inter-individual metabolic variability may produce markedly different human pharmacologic effects.

AI Summary

Despite their impaired receptor affinities and efficacies, the N1-substituted compounds all fully substituted for LSD in the rat, as did the diethylamide-substituted LSZ.

SIGNIFICANCE STATEMENT: Four N1-substituted lysergamides (1A-lysergic acid diethylamide [LSD], 1P-LSD, 1B-LSD, and 1CP-LSD) and 1 diethylamide-substituted drug were screened for serotonin receptor binding, LSD-like discriminative stimulus effects, and disposition in rat blood.

In contrast, the diethylamide-substituted drug exhibited LSD-like affinities and efficacy at 5-hydroxytryptamine receptors, was not metabolically converted to LSD, and elicited potent LSD-like interoceptive effects.

Basic summary

J Pharmacol Exp Ther. 2026 Jul 17:104988. doi: 10.1016/j.jpet.2026.104988. Online ahead of print.

ABSTRACT

Novel analogs of the psychedelic lysergic acid diethylamide (LSD) have emerged on the gray market in recent years, typically containing substitutions to the ergoline scaffold on the indole (N₁) nitrogen or at the diethylamide moiety. In these studies, we screened 4 N₁-substituted drugs (1A-LSD, 1P-LSD, 1B-LSD, and 1CP-LSD) and 1 diethylamide-substituted drug (LSZ) in assays of serotonin receptor binding, LSD-like discriminative stimulus effects, and disposition in rat blood after systemic injection. As compared with LSD, we found that all of the N₁-substituted drugs exhibited worse affinity for and/or weaker efficacy at 5-hydroxytryptamine (5-HT)_1A, 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors, while LSZ displayed an LSD-like binding profile at these sites. Despite their impaired receptor affinities and efficacies, the N₁-substituted compounds all fully substituted for LSD in the rat, as did the diethylamide-substituted LSZ. Following systemic injection of the N₁-substituted drugs at doses producing full substitution for LSD, we detected similar high blood levels of LSD at time points relevant to the behavioral assay, suggesting that these compounds are converted to LSD in vivo. In contrast, LSZ was the only species detected after its administration, which, combined with its high-affinity binding and intrinsic efficacy at psychedelic-relevant receptors, implies that it is biologically active on its own. These studies highlighted the role of pharmacokinetics and analytical chemistry in connecting seemingly disparate in vitro and in vivo drug profiles and strongly implied that variability in human metabolism of these compounds may result in dramatically different pharmacologic effects across individuals. SIGNIFICANCE STATEMENT: Four N₁-substituted lysergamides (1A-lysergic acid diethylamide [LSD], 1P-LSD, 1B-LSD, and 1CP-LSD) and 1 diethylamide-substituted drug were screened for serotonin receptor binding, LSD-like discriminative stimulus effects, and disposition in rat blood. Despite their generally impaired receptor binding profiles compared with LSD, all the N₁-substituted lysergamides were LSD-like in vivo, most likely through metabolic conversion to LSD. In contrast, the diethylamide-substituted drug exhibited LSD-like affinities and efficacy at 5-hydroxytryptamine receptors, was not metabolically converted to LSD, and elicited potent LSD-like interoceptive effects.