Psychedelic LSD activates neurotrophic signal but fails to stimulate neural stem cells

Abstract

Accumulating evidence has shown that some hallucinogens, such as LSD, have fast and persistent effects on anxiety and depression. According to a proposed mechanism, LSD activates the TrkB and HTR2A signaling pathways, which enhance the density of neuronal dendritic spines and synaptic function, and thus promote brain function. Moreover, TrkB signaling is also known to be crucial for neural stem cell (NSC)-mediated neuroregeneration to repair dysfunctional neurons. However, the impact of LSD on neural stem cells remains to be elucidated. In this study, we observed that LSD and BDNF activated the TrkB pathway in human NSCs similarly to neurons. However, unlike BDNF, LSD did not promote NSC proliferation. These results suggest that LSD may activate an alternative mechanism to counteract the effects of BDNF-TrkB signaling on NSCs. Our findings shed light on the previously unrecognized cell type-specificity of LSD. This could be crucial for deepening our understanding of the mechanisms underlying the effects of LSD.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13287-024-03909-8.

To the Editor

Accumulating evidence has demonstrated that some hallucinogens, such as Lysergic acid diethylamide (LSD), have fast and persistent effects on anxiety and depression (particularly for patients with life-threatening illnesses) [1, 2]. According to a proposed mechanism, LSD activates the TrkB and HTR2A signaling pathways, which enhance the density of neuronal dendritic spines and synaptic function, and thus promote brain function [3, 4]. Meanwhile, TrkB signaling is also important for neural stem cell (NSC)-mediated neuroregeneration to restore impaired neuronal functions [5–8]. However, the impact of LSD on neural stem cells remains to be elucidated.

Given its TrkB-activating effect, we hypothesize that LSD may promote neural stem cell function since TrkB activation by brain-derived neurotrophic factor (BDNF) can stimulate NSC proliferation and thus contribute to neuroregeneration. However, our results demonstrated that LSD treatment had no significant impact on NSC proliferation, whereas BDNF steadily boosted NSC proliferation in a dose-dependent manner. (Fig. 1A, B). These findings were further confirmed by EdU incorporation (Fig. 1C, D). To further investigate whether the low LSD responsiveness was associated with the absence of TrkB receptor in NSCs, we measured the expression levels of TRK receptors on NSCs. We found that NSCs expressed high levels of TrkB receptor, while the expression of TrkA was relatively low (Fig. 1E). Furthermore, we also investigated the impact of LSD on the downstream signaling of TrkB in NSCs. In contrast to its effect on NSC proliferation, LSD significantly enhanced the phosphorylation of TrkB receptor and downstream ERK and AKT in NSCs (Fig. 1F–M). Together, our findings indicated that unlike BDNF, which activated the TrkB signaling pathway to modulate both neuronal and NSC function, LSD only affected the former. It was possible that LSD activated an inhibitory mechanism that counteracted its effects on NSC function. We wanted to know if HTR2A, another important target of LSD, had any role in this inhibitory process. However, we found that HTR2A expression was very low in NSCs, which suggested that HTR2A was not likely to be the inhibitor of LSD’s effects on NSC function. (Fig. 1N).

Fig. 1.

Effects of LSD on NSC. The proliferation level of 3L NSC (A) and 13A NSC (B) after 48 h LSD and BDNF treatments determined by Cell Counting-Lite 2.0 Luminescent cell viability assay. N = 4 independent experiments. Data are mean ± SEM. **P < 0.01, *P < 0.05, one-way ANOVA, followed by Dunnett’s multiple comparisons test. (C) Representive images of EdU positive cells. (D) The percentage of EdU-positive cells after 48 h treatment with LSD (100 nM) and BDNF (50 ng/mL). N = 4 independent experiments. Scale bars = 50 μm. Data are mean ± SEM. *P < 0.05, one-way ANOVA, followed by Dunnett’s multiple comparisons test. (E) Quantitative real‐time PCR analysis of TrkA and TrkB on 3L and 13A NSCs. N = 3 independent experiments. Data are mean ± SEM. Two-way ANOVA, followed by Dunnett’s multiple comparisons test. (F–M) Activation of TrkB and its downstream ERK and AKT in LSD- and BDNF-treated NSCs were analyzed and quantified by western blotting. 3L and 13A NSCs were treated with LSD (100 nM), BDNF (50 ng/mL) for 10 min before harvesting cells. N = 3 independent experiments. Data are mean ± SEM. ***P < 0.001, **P < 0.01, *P < 0.05, one-way ANOVA, followed by Dunnett’s multiple comparisons test. (N) Quantitative real‐time PCR analysis of HTR2A on 3L and 13A NSCs and SK-N-SH cell line. N = 3 independent experiments. ***P < 0.001. Data are mean ± SEM. One-way ANOVA, followed by Dunnett’s multiple comparisons test

Our study indicates that LSD activates the same neurotropic BDNF-TrkB pathway in NSCs as it does in neurons, but this does not affect NSC proliferation significantly. This is a distinct contrast to the effects of BDNF on NSCs. These results suggest that LSD may activate an alternative mechanism to counteract the effects of BDNF-TrkB signaling on NSCs. This is significant as it allows LSD to have cell type-specific effects on neurons, rather than on NSCs. This helps to prevent potential side effects, such as the exhaustion of NSCs due to inappropriate activation of these cells. Moreover, researchers have been recently developing nonhallucinogenic analogs from psychedelic drugs including LSD [9, 10]. Based on our findings, it might be necessary to examine whether the new analogs maintain the cell type-specificity of LSD. Overall, our findings are important for deepening our understanding of the mechanisms underlying the effects of LSD, which may help us in developing novel LSD-derived therapeutic agents with better efficiency and less side effects.

Abbreviations

LSD

Lysergic acid diethylamide

TrkB

Tropomyosin related kinase B

HTR2A

5-HT(2A) serotonin receptor

NSC

Neural stem cell

TrkA

Tropomyosin related kinase B

BDNF

Brain-derived neurotrophic factor

ERK

Extracellular signal-regulated kinase

AKT

Serine/Threonine Kinase 1

Author contributions

X.D.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. H.L.: administrative supports. Y.L.: conception and administrative. G.P.: conception and design, financial support, manuscript writing, final approval of manuscript. S.H.: manuscript writing, final approval of manuscript.

Funding

This research was funded by the National Key Research and Development Program of China (2018YFA0108003), the National Science Foundation for Young Scientists of China (81901094).

Availability of data and materials

All data generated during this study are included in the published article.

Declarations

Ethics approval and consent to participate

Human iPSC/iPSC-derived NSCs were purchased from IxCell Biotechnology, Ltd. The study entitled “Peripheral Blood Mononuclear Cells-Derived Neural Stem Cells” was approved on 11/10/2016 by Tongji University School of Medicine Review Board (reference number EC.D(BG)0.016.01.1). All patients gave written informed consent.

Consent for publication

No applicable.

Competing interests

All authors reported no biomedical financial interests or potential conflicts of interest.