A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects.

Patrick C Dolder,Stefan J Borgwardt,Felix Müller,Edna Grünblatt,Matthias E Liechti

doi:10.3389/fphar.2017.00423

Abstract

Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes.Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study.Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo.Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.

Highlights

Lysergic acid diethylamide (LSD) is a well-known psychoactive substance that transiently alters mind and perception
The administration of LSD in healthy subjects was authorized by the Swiss Federal Office for Public Health, Bern, Switzerland
The lack of an acute effect of LSD on HTR2A gene expression in humans is consistent with a study in rats that reported no changes in HTR2A gene expression in different brain areas (Nichols and Sanders-Bush, 2002)

Summary

Introduction

Lysergic acid diethylamide (LSD) is a well-known psychoactive substance that transiently alters mind and perception. Consistent with a role for 5-HT2A receptors in the development of tolerance, daily LSD administration for 3 days decreased 5HT2A receptor binding in the rat frontal cortex (Buckholtz et al, 1985, 1990; Gresch et al, 2005). Another study reported only a non-significant trend toward a reduction of frontocortical 5-HT2A receptor binding in rats during the development of tolerance to LSD (Buchborn et al, 2015). No effects of acute LSD on 5-HT2A receptor mRNA expression were found in the rat prefrontal cortex, hippocampus, or midbrain (Nichols and Sanders-Bush, 2002), the effects of repeated LSD administration were not studied. LSD was shown to produce a characteristic transcriptome signaling pattern in normal but not HTR2A−/− mice (Gonzalez-Maeso et al, 2007)

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Results

Discussion

Conclusion