January 2023
Repova K, Baka T, Krajcirovicova K, et al. Melatonin as a Potential Approach to Anxiety Treatment. Int J Mol Sci. 2022;23(24):16187. Published 2022 Dec 19. doi:10.3390/ijms232416187
Overview
Melatonin has been shown in animal and human studies to have an anxiolytic action. This review explores the mechanisms of how anxiety develops and how melatonin may be an additional or alternative treatment option for the management of anxiety and anxiety-like symptoms due to its impact on one or more of these mechanisms. Melatonin’s effects may “reside in its sympatholytic action, inhibition of the renin-angiotensin and glucocorticoid system, modulation of GABA-serotonergic signaling and its extraordinary antioxidant and scavenging nature.”
Our comments/takeaway from the article
We understand that the manifestation of anxiety is complex and therefore the clinical treatment can be equally complex. It is of no surprise that due to its mechanisms of action and its unique properties to be produced in several systems and organs of the body, as well as the utilization of endogenous sources (diet and supplements) melatonin would have an impact on reducing anxiety in one or more potential ways.
This article provides a comprehensive summary of the possible mechanisms for action, each of which could be explored in greater detail in future human studies. While specific dosing of melatonin is not described in this review article, the clinical usefulness of understanding the possible mechanisms of action allows clinicians to implement this knowledge to consider melatonin as an option for the management of anxiety disorders.
Article summary
Due to the prevalence of anxiety disorders and the impact they can impose on daily living, along with the limited effectiveness and significant side effects that may present using pharmaceutical therapies, the authors explored the beneficial role melatonin could have on anxiety disorders and anxiety-related symptoms.
To begin, the authors describe the proposed mechanisms for anxiety development including a stress reaction that activates the sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and the hypothalamus-pituitary-adrenal (HPA) axis. Additionally, free radical formation is enhanced during the stress reaction. Figure 1 displays the interconnection between these mechanisms, neurotransmitter production, and the physical manifestations that may occur.
Figure 1: Proposed mechanisms of anxiety development. During the stress reaction, neurohumoral systems including the sympathetic nervous system (SNS), renin–angiotensin–aldosterone system (RAAS) and hypothalamus–pituitary–adrenal (HPA) axis are activated, and free radical formation is enhanced. As a result, aside from adaptive hemodynamic and metabolic changes, inflammatory and degenerative alterations and the disbalance of the vegetative nervous system (NS) occur. The result is the development of anxiety, which, in turn, potentiates or modifies the stress reaction. Established anxiety results in pathological behavior, mood and sleep disturbances and potentially in cardiovascular (CVS) and other systems’ disorders, while each of them or together may further promote anxiety. GABA, γ-aminobutyric acid; ROS, reactive oxygen species; RNS, reactive nitrogen species.
Image and Description Credit: Repova K, Baka T, Krajcirovicova K, et al. Melatonin as a Potential Approach to Anxiety Treatment. Int J Mol Sci. 2022;23(24):16187. Published 2022 Dec 19. doi:10.3390/ijms232416187. PMID: 36555831. PMCID: PMC9788115. CC-BY 4.0.
“Melatonin is an unusually multitasking molecule that participates in anuncountable number of physiological and pathological actions.”
Many of melatonin’s effects are receptor-independent actions, such as its antioxidant and anti-inflammatory actions and mitochondrial protection. Melatonin is well-known for its receptor-dependent actions, which coordinate the circadian rhythm. Both, receptor-dependent and receptor-independent actions can have an impact on anxiolytic effects, as well as a host of other benefits to the cardiovascular system, metabolism, and nervous system. (Figure 2)
Figure 2: Receptor-dependent and receptor-independent effects of melatonin.(Original work-Figure 3)Image Credit: Repova K, Baka T, Krajcirovicova K, et al. Melatonin as a Potential Approach to Anxiety Treatment. Int J Mol Sci. 2022;23(24):16187. Published 2022 Dec 19. doi:10.3390/ijms232416187. PMID: 36555831. PMCID: PMC9788115. CC-BY 4.0.
Melatonin’s anxiolytic effects
Multiple animal and human studies have demonstrated melatonin’s effect on reducing anxiety. Of interest, multiple human studies have demonstrated melatonin’s effectiveness for reducing pre- and post-surgery anxiety in both adults and children. It also has been reported to help reduce post-surgery pain and reduce the request for morphine to manage pain. Further, melatonin has been shown to work as effectively as benzodiazepines to reduce anxiety before and after surgery.
These anxiolytic effects by melatonin (Figure 3) are not fully understood and are thought to be:
Direct-- melatonin receptors, MT1 and MT2, in the brain mediate anxiety-like behaviors
Indirect--modulating SNS, RAAS, glucocorticoids, and neurotransmitters, thereby reducing the stress response, lowering inflammation and reducing oxidative stress
Figure 3: The proposed mechanisms contributing to the anxiolytic effects of melatonin. (Original work- Figure 6)
Image Credit: Repova K, Baka T, Krajcirovicova K, et al. Melatonin as a Potential Approach to Anxiety Treatment. Int J Mol Sci. 2022;23(24):16187. Published 2022 Dec 19. doi:10.3390/ijms232416187. PMID: 36555831. PMCID: PMC9788115. CC-BY 4.0.
Since melatonin has been well-documented for a favorable safety profile and is easily accessible, the authors concluded this review by stating, “...it may be considered as additional or alternative treatment for different conditions associated with anxiety.”
Limitations noted in this review
This study was only exploring the potential actions of melatonin to reduce anxiety, it did not report on possible doses or timing of doses to be used clinically.
Article review completed by Kim Ross, DCN
Content reviewed by Deanna Minich, PhD
December 29, 2022