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.