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Review
. 2022 Dec 19;23(24):16187.
doi: 10.3390/ijms232416187.

Melatonin as a Potential Approach to Anxiety Treatment

Kristina Repova  1 , Tomas Baka  1 , Kristina Krajcirovicova  1 , Peter Stanko  1 , Silvia Aziriova  1 , Russel J Reiter  2 , Fedor Simko  1   3   4
Affiliations
Review

Melatonin as a Potential Approach to Anxiety Treatment

Kristina Repova et al. Int J Mol Sci. .

Abstract

Anxiety disorders are the most common mental diseases. Anxiety and the associated physical symptoms may disturb social and occupational life and increase the risk of somatic diseases. The pathophysiology of anxiety development is complex and involves alterations in stress hormone production, neurosignaling pathways or free radical production. The various manifestations of anxiety, its complex pathophysiological background and the side effects of available treatments underlie the quest for constantly seeking therapies for these conditions. Melatonin, an indolamine produced in the pineal gland and released into the blood on a nightly basis, has been demonstrated to exert anxiolytic action in animal experiments and different clinical conditions. This hormone influences a number of physiological actions either via specific melatonin receptors or by receptor-independent pleiotropic effects. The underlying pathomechanism of melatonin's benefit in anxiety may reside in its sympatholytic action, interaction with the renin-angiotensin and glucocorticoid systems, modulation of interneuronal signaling and its extraordinary antioxidant and radical scavenging nature. Of importance, the concentration of this indolamine is significantly higher in cerebrospinal fluid than in the blood. Thus, ensuring sufficient melatonin production by reducing light pollution, which suppresses melatonin levels, may represent an endogenous neuroprotective and anxiolytic treatment. Since melatonin is freely available, economically undemanding and has limited side effects, it may be considered an additional or alternative treatment for various conditions associated with anxiety.

Keywords: anxiety; depression; melatonin; neurohumoral activation; oxidative stress; sympathetic nervous system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
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.
Figure 2
Figure 2
Biochemical structure of melatonin (N-acetyl-5-methoxytryptamine).
Figure 3
Figure 3
Receptor-dependent and receptor-independent effects of melatonin. MTR, melatonin receptor; CV system, cardiovascular system; BP, blood pressure; BW, body weight.
Figure 4
Figure 4
Mechanisms of melatonin’s antioxidant actions. 6-OHM, 6-hydroxymelatonin; AFMK, N1-acetyl-N2-formyl-5-methoxykynuramine; AMK, N1-acetyl-5-metoxykynuramine; RNS, reactive nitrogen species; ROS, reactive oxygen species.
Figure 5
Figure 5
Interaction of the sympathetic nervous system (SNS) with melatonin. Darkness (the absence of light impulses) is the driver of melatonin synthesis and release. The retinohypothalamic tract leads from melanopsin-containing retinal neurons to the suprachiasmatic nucleus (SCN), which generates rhythmic oscillations. These impulses pass via the neurons of the paraventricular nucleus (PVN) of the hypothalamus and via the rostral ventrolateral medulla (RVLM) and nucleus of the solitary tract (NTS) to the upper thoracic intermediolateral cell column, which innervates the superior sympathetic ganglion, generating a sympathetic tone. The sympathetic impulses enhance the peripheral vascular tone and cardiac contractility with a blood pressure (BP) increase, and they activate additional humoral systems and induce behavioral changes. At the same time, the sympathetic impulses from the intermediolateral nucleus project to the superior cervical ganglia from where postganglionic fibers enter the pineal gland to stimulate melatonin production via beta and alpha-1 adrenoceptor activation by norepinephrine. Furthermore, melatonin released from the pineal gland can presumably exert a negative feedback effect on the central sympathetic system via enhancing γ-aminobutyric acid (GABA)ergic signaling, which is involved in the inhibition of PVN, RVLM and NTS. Melatonin also enhances nitric oxide (NO) availability, which potentiates the GABAergic inhibitory effects in the PVN and RVLM. Red arrows represent the sympathetic impulses and blue arrows represent the sympatholytic impulses.
Figure 6
Figure 6
The proposed mechanisms contributing to anxiolytic effect of melatonin. AT1 receptors, angiotensin II type 1 receptors; GABA, γ-aminobutyric acid; GC, glucocorticoids; RNS, reactive nitrogen species; ROS, reactive oxygen species.
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