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Stem Cell Res Ther
Stem Cell Res Ther
Stem Cell Research & Therapy
1757-6512
BioMed Central London

39256856
3909
10.1186/s13287-024-03909-8
Letter
Psychedelic LSD activates neurotrophic signal but fails to stimulate neural stem cells
Dong Xiaoxu 12
Lin He 3
Li Yuting 4
Pei Gang 256
http://orcid.org/0000-0002-2287-2016
Huang Shichao huangshichao@sibcb.ac.cn

2
1 grid.440637.2 0000 0004 4657 8879 School of Life Science and Technology, Shanghai Tech University, Shanghai, China
2 grid.9227.e 0000000119573309 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031 China
3 https://ror.org/01dkhme60 grid.495908.9 The Drug Reference Materials Laboratory, The Third Research Institute of Ministry of Public Security, Beijing, China
4 https://ror.org/03dnytd23 grid.412561.5 0000 0000 8645 4345 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016 China
5 https://ror.org/03rc6as71 grid.24516.34 0000 0001 2370 4535 Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-Based Biomedicine, The Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, 200070 China
6 https://ror.org/034t30j35 grid.9227.e 0000 0001 1957 3309 Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, 100045 China
11 9 2024
11 9 2024
2024
15 28529 3 2024
28 8 2024
© The Author(s) 2024
2024
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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.

Keywords

LSD
TrkB signaling
Neural stem cell
BDNF
National Key Research and Development Program of China2018YFA0108003 Huang Shichao National Science Foundation for Young Scientists of China81901094 Huang Shichao issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
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pmcTo 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.

Supplementary Information

Additional file1 (PDF 1628 KB)

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

Acknowledgements

We thank Sheng Wang for helpful advice; we thank all members of our laboratory for their technical assistance, sharing reagents and advice. The authors declare that they have not use AI-generated work in this manuscript.

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.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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