Tabernanthalog, a Non-Hallucinogenic Psychedelic, Alleviates Cancer-Induced Cognitive Deficits via Serotonergic Pathways

Cancer-related cognitive impairment (CRCI), which includes anxiety, depression, and memory deficits, reduces quality of life but is often underrecognized. In a mouse model of Lewis lung carcinoma, tabernanthalog (TBG), a non-hallucinogenic psychedelic analog, reversed anxiety-like behavior and memory impairment. Tumor-bearing mice had reduced tryptophan levels in blood and hippocampus, downregulated serotonergic receptor genes, and upregulated pro-inflammatory cytokine genes, along with increased microglial density and activation. TBG treatment normalized microglial density and morphology and restored serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in microglial cells exposed to tumor-conditioned medium. These findings suggest TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation.

Study at a glance

Abstract

Cancer-related cognitive impairment (CRCI)-encompassing anxiety, depression, and memory deficits-significantly diminishes the quality of life in patients with cancer, yet remains underrecognized in clinical practice. In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer.