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

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.

Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders

“…As of today, investigations on psychedelic-induced (epi)genetic modifications in humans are scarce. One clinical study with 15 subjects did not find any alterations in expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration of 100 μg LSD compared with placebo [102]. Rodent studies, however, consistently show a widespread upregulation of different genes and their translation into proteins, primarily those involved in synaptic plasticity, neural signaling, and memory, in various brain regions (including the cortex, amygdala, nucleus accumbens, and striatum) after LSD and DOI exposure [101,103,104].…”

“…Considering the described neural regional specificity of changes in gene expression observed in animal studies, it is questionable how meaningful the respective results from human studies might be. This methodological weakness of clinical epigenetic studies could also be the reason for the null result reported by Dolder et al [102].…”

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…It was recently reported that microdoses of LSD increase circulating BDNF levels in healthy volunteers, suggesting that LSD might have neurotrophic effects in humans . Another study investigated whether LSD produces acute gene expression changes in peripheral blood mononuclear cells 1.5 and 24 hours after administration, with no detected changes in 5-HT2A receptor or EGR-1, -2, and -3 transcript levels (Dolder et al, 2017a). In rodents, LSD upregulates CCAAT/enhancer-binding protein-b in the prefrontal cortex (Nichols and Sanders-Bush, 2004).…”

Neuroendocrine Associations Underlying the Persistent Therapeutic Effects of Classic Serotonergic Psychedelics

“…For example, egr-2 expression was increased in rat cortical tissue cultures after LSD (10 μM), but not lisuride (10 μM), treatment ( González-Maeso et al, 2007 ), though in a human study, LSD (100 μg p.o.) failed to alter expression of egr-1, -2, or -3 in peripheral blood at 1.5 or 24 h after ingestion ( Dolder et al, 2017 ). Thus, while gene activation studies offer a valuable means to identifying long-term effects, results should be interpreted with careful consideration.…”