Abstract

Current research is exploring the potential of serotonergic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) as treatments for major depression (MDD). The recent clinical trial NCT03866252 investigated LSD’s antidepressant effects in 61 MDD patients, randomly assigned to one of two groups receiving two low (LD-LSD; 2 x 25μg) or two moderate-to-high doses (HD-LSD; 2 x 100μg or 200μg in the second session), with positive outcomes. The mechanism underlying psychedelics’ antidepressant effects is unclear, but increased neuroplasticity seems a viable candidate. The current study investigated whether LSD induces alterations in white matter (WM) integrity, reflected by fractional anisotropy (FA), and microstructure, reflected by mean diffusivity (MD), and examined potential links between any changes observed and improvements in symptoms, evaluated by changes from baseline in the Inventory of Depressive Symptomatology (ΔIDS-C, clinician-rated) and Beck’s depression inventory (ΔBDI) at 2, 6, and 12 weeks post-intervention.

Data were obtained from NCT03866252 and included DTI scans from 35 MDD patients (17 HD-LSD), consisting of a pre- and a post-intervention scan. DTI data analyzed with FSL included distortion, eddy current, and motion correction as preprocessing steps. A tensor model was applied to calculate FA and MD and tract-based spatial statistics (TBSS) was used to determine changes in these measures. Two-way mixed effect ANOVAs followed by two-sample t-tests were used to evaluate group X time interactions and group differences in FA and MD.

While no group differences were observed for MD, the HD-LSD group had significantly higher FA-values post-intervention in the internal and external capsule, sagittal stratum, and fornix/stria-terminalis. Post-intervention FA-values extracted from the regions that reflected group differences were significantly correlated with ΔIDS-C at 2 (r=-.51, p=.03), 6 (r=-.53, p=.03), and 12 weeks post-intervention (r=-.71, p=.002) in the HD-LSD but not in the LD-LSD group. Notably, the post-intervention FA-values were similarly associated with ΔBDI at 2 (r=-.67, p=.003), 6 (r=-.43, p=.09), and 12 weeks (r=-.63, p=.009) after intervention only in the HD-LSD group.

Data suggest that at moderate-to-high doses LSD may bring about structural modifications in the WM of MDD patients that are associated with symptom improvement, potentially via enhanced neuroplasticity.