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.