Psychostimulants Modafinil, Atomoxetine and Guanfacine Impair Bone Cell Differentiation and MSC Migration

Abstract

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.

The D1 receptor agonist SKF38393 improves waiting impulsivity in a baseline dependent manner

“…Non-stimulants (such as atomoxetine and guanfacine) are the second-line treatment for ADHD; however, these are less effective than stimulants and have a delayed onset of action. It has also been shown that atomoxetine and guanfacine negatively influence mesenchymal stem cell migration during bone formation (Wagener et al, 2022). Therefore, there is a pressing need for new therapeutic agents that act without these side effects (e.g., reduced physical growth) and dependence potential (Sharma et al, 2014).…”

Chondral/Desmal Osteogenesis in 3D Spheroids Sensitized by Psychostimulants

“…Wagener and colleagues were recently able to show that modafinil, atomoxetine, and guanfacine inhibited hMSC osteogenic differentiation and migration without inducing apoptosis or necrosis. The migration inhibitory effect of these psychostimulants could be abolished by the administration of the selective beta-2 blocker ICI-118551 [ 14 ]. For the first time, this research will investigate the effects of the three psychostimulants on chondrogenic and osteogenic differentiation of three-dimensional hMSC and MG63 cell spheroids.…”