In a double-blind, low-dose controlled trial, 61 patients with moderate-to-severe major depressive disorder received supportive psychotherapy and either two high doses (100 μg then 200 μg) or two low doses (25 μg each) of LSD. At the primary endpoint two weeks after the second session, the high-dose group showed a greater average reduction in self-rated depression scores (11.8 points) compared to the low-dose group (3.9 points), a difference that approached but did not reach statistical significance. Clinician-rated scores also favored the high dose, but significance was lost after adjusting for baseline depression severity. Improvements were numerically maintained through 12 weeks. Adverse events were similar between groups. The authors suggest these exploratory results warrant a larger phase 3 trial.
Lysergic acid diethylamide (LSD) may alleviate depression by altering white matter microstructure in the brain, potentially reflecting enhanced neuroplasticity. In a clinical trial of 61 patients with major depressive disorder, those receiving moderate-to-high doses (100 μg then 200 μg) showed increased fractional anisotropy in several white matter tracts, including the internal and external capsule, sagittal stratum, and fornix/stria terminalis. These microstructural changes correlated with improvements in depressive symptoms measured at 2, 6, and 12 weeks. The findings suggest that LSD-induced white matter changes are linked to antidepressant effects.