Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder

Abstract

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Keywords: analytical variability; autism; autism spectrum disorder (ASD); autistic behavioral impairments; circadian rhythm; concentration-effect relationship; dose-response effect; melatonin; pharmacokinetics; tolerability.

Figure 1

Melatonin synthetic pathway. Tryptophan is converted to 5-OH tryptophan by tryptophan 5-hydroxylase (TPH) and to serotonin by aromatic amino acid decarboxylase (AAD). Then, serotonin is converted to melatonin by the action of arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIMT) (based on Tordjman et al. [4]).

Figure 2

The two main melatonin physiological pathways in humans. The receptor-dependent and receptor-independent pathways are shown with their relevant families of receptors and their associated pleiotropic physiological effects (based on Reiter et al. [1]).

Figure 3

Melatonin chronobiological properties: exogenous melatonin administration modifies melatonin secretion by modulating suprachiasmatic (SCN) neuronal activity. A phase advance (solid gray line) is observed when melatonin is administered at the beginning of the night and a phase delay (dashed line) is seen when melatonin is administered in the morning (based on Grivas et al. [2]).