Melatonin and cocaine: role of mitochondria, immunity, and gut microbiome.

I read with interest the recent article by Barbosa-Méndez & Salazar-Juárez on the role of melatonin in regulating the circadian effects of cocaine-induced locomotor activity in rodents.1 These authors also showed melatonin to decrease cocaine-induced locomotor activity at different times of the day and propose that it could be a readily available, safe and cheap treatment option in the management of cocaine addiction. Future research in a couple of areas should better clarify melatonin’s effects and treatment utility.

Many of the effects of cocaine are mediated by alterations in mitochondrial function. Recent work suggest that mitochondria are circadian-regulated, with the effects of pineal melatonin in optimizing mitochondrial function being mediated by the circadian gene, Bmal1.2 The interactions of melatonin and Bmal1 in the regulation of cocaine-driven changes in mitochondrial function will be important to determine.

Cocaine also significantly alters immune system responses, generally increasing the activity of most immune cell subsets.3 Immune cell activation is powerfully regulated by the shift in mitochondrial metabolism from oxidative phosphorylation to glycolysis, with the shift back to an anti-inflammatory phenotype being driven by the autocrine effects of melatonin, as first shown by Regina Markus and colleagues in Brazil.4 The effects of melatonin – including via Bmal1 – in the mitochondria of immune cells on the regulation of cocaine’s effects is an important avenue for future investigation.

Cocaine has significant effects on the gut microbiome, with the locomotor-inducing effects of cocaine being significantly modulated by the gut microbiome. This research suggests that increasing the levels of gut microbiome-derived short-chain fatty acids, especially butyrate, could have clinical utility. Butyrate effects include the induction of melatonin and the optimization of mitochondrial function, which may underpin its dampening effects on immune cell activity.5 Whether optimizing the gut microbiome with probiotics or with the nutraceutical sodium butyrate would afford additional clinical efficacy to melatonin in the management of cocaine addiction has yet to be clarified.

Such lines of research should considerably help to clarify the biological underpinnings to melatonin’s interaction with cocaine, as well as help optimize treatment.

Disclosure

The author reports no conflicts of interest.