Stability-Guided Formulation of a Light-Sensitive D-LSD Capsule for Clinical Investigation.
Pharmaceutics – June 11, 2025
Source: PubMed
Summary
A key challenge for D-LSD's therapeutic potential is its extreme light sensitivity. Researchers successfully developed a protective capsule, using advanced DFT and LC-IM-MS for orthogonal analysis of D-LSD degradation products. This robust formulation development significantly boosted the compound's photostability, preventing rapid degradation seen in solutions. This offers a stable platform for D-LSD's clinical investigation for alcohol use disorder.
Abstract
Background/Objectives: D-lysergic acid diethylamide (D-LSD) is under investigation as a potential therapeutic strategy for alcohol use disorder (AUD). However, the extreme light sensitivity of D-LSD presents a significant challenge in developing suitable pharmaceutical forms, particularly for clinical trial settings. This study proposes a liquid-filled capsule formulation designed to provide accurate dosing while protecting D-LSD from photodegradation. Methods: To support formulation development and ensure its suitability as an investigational medicinal product, a multi-tiered analytical strategy was employed. This included liquid chromatography coupled with ion mobility spectrometry and mass spectrometry (LC-IM-MS), along with quantum chemical calculations (density functional theory (DFT) and time dependent-DFT (TD-DFT)), to ensure robust and orthogonal structural characterization of degradation products. Results: Photostress studies demonstrated that while D-LSD in solution rapidly degrades into photoisomers and photooxidative byproducts, the capsule formulation markedly mitigates these transformations under ICH-compliant conditions. Conclusions: These findings highlight the essential role of orthogonal stability profiling in guiding formulation development and demonstrate that this approach may offer a viable, photostable platform for future clinical investigation of D-LSD in the treatment of AUD.