Neuroplastic white matter changes in patients with major depression following lysergic acid diethylamide treatment
Mihai Avram, Aurore Menegaux, Felix Müller, Hannes Zaczek, Alexandra Korda, Helena Rogg, Anna M. Becker, Laura Ley, Matthias E. Liechti, Stefan Borgwardt
Cell Reports Medicine May 7, 2026 Peer reviewed DOI: 10.1016/j.xcrm.2026.102791 via OpenAlex
Summary
Lysergic acid diethylamide (LSD) was tested for its antidepressant effects in 61 patients with major depressive disorder. The study found that patients receiving a high dose of LSD showed increased fractional anisotropy in specific brain regions, indicating changes in white matter microstructure. These changes were correlated with improvements in depressive symptoms measured at 2, 6, and 12 weeks. The results suggest a link between LSD-induced white matter alterations and its antidepressant effects.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 61 |
| Population | patients with major depressive disorder |
| Key finding | Increased fractional anisotropy in the high-dose LSD group correlated with improvements in depressive symptoms. |
Abstract
The clinical trial NCT03866252 investigates the antidepressant effects of lysergic acid diethylamide (LSD) in 61 patients with major depressive disorder (MDD) randomized to low-dose LSD (LD-LSD; 2 × 25 μg) or moderate-to-high-dose LSD (HD-LSD; 100 μg followed by 200 μg) 4 weeks apart. Although the trial reports positive clinical outcomes, underlying mechanisms remain unclear. Here, we test whether LSD alters white matter (WM) microstructure, potentially reflecting enhanced neuroplasticity. Diffusion tensor imaging data from 35 patients (17 HD-LSD) include pre- and post-intervention scans. Voxel-wise permutation tests reveal group-by-time interactions, with increased fractional anisotropy (FA) in the internal and external capsule, sagittal stratum, and fornix/stria terminalis in the HD-LSD group. In this group, post-intervention FA values correlate with improvements in depressive symptoms at 2, 6, and 12 weeks, measured using the Inventory of Depressive Symptomatology (IDS-clinician rated [C] and IDS- self report [SR]). These findings suggest that LSD-induced WM microstructural changes are associated with antidepressant effects in MDD.