From Tolerance to Toxicity: Evaluation of the Biological Effects of Lisdexamfetamine Dimesylate in C. elegans

Abstract

Background: Lisdexamfetamine dimesylate (LDX) is a prodrug of d-amphetamine used in the treatment of attention-deficit/hyperactivity disorder (ADHD) [1]. Despite its clinical use, several gaps remain regarding its toxicity profile. To address these gaps, this study used Caenorhabditis elegans, an animal model with a short life cycle, transparent body, and well-characterized development, making it suitable for preliminary toxicological assessment [2]. Objective: To evaluate the effects of LDX on the survival, development, and longevity of C. elegans. Methods: Synchronized L1-stage DC19 [bus-5(br19)] animals (~200 worms) were exposed in liquid medium to increasing concentrations of LDX (10 µM–10 mM for the survival assay; 0.5 and 1 mM for the development and longevity assays). After 72 hours of incubation in M9 buffer containing OP50 bacteria as a food source, nematodes were analyzed using a stereomicroscope. Survival was assessed by counting the number of live and dead animals. Development was evaluated by measuring body length using Fiji software. For the longevity assay, animals were monitored every two days and mortality was recorded over time. Results: Exposure to LDX did not significantly reduce animal survival at concentrations up to 2 mM. In contrast, exposure to 3, 4, 5, or 10 mM LDX significantly decreased survival in a concentration-dependent manner [survival percentage: 0 mM = 96.98 ± 4.1% (p > 0.9999); 3 mM = 47.71 ± 26.2% (p = 0.0157); 4 mM = 42.87 ± 29.1% (p = 0.0138); 5 mM = 40.37 ± 27.2% (p = 0.0003); and 10 mM = 1.663 ± 3.426% (p < 0.0001)]. No significant changes were detected in the development of animals directly exposed to 0.5 or 1 mM LDX over time, nor in their progeny, nor were significant alterations observed in longevity. Conclusions: These results suggest that LDX is relatively well tolerated at low doses in this experimental model.