Melatonin as a support for stress: what science says

Introductory Note

This article was previously published and has been updated according to scientific and divulgative criteria. The purpose is informative: it does not replace medical advice. The information reported is based on peer-reviewed reviews and studies and is expressed clearly and cautiously.

IN BRIEF

• Melatonin is an endogenous hormone linked to circadian rhythms and sleep; it also has antioxidant and inflammation-modulating actions.
• Experimental and clinical evidence shows modest and contextual effects on sleep and, in some settings, a reduction in preoperative anxiety and certain aspects of psychophysiological stress.
• Proposed mechanisms include sleep-wake rhythm regulation, interaction with the serotonergic system, mitochondrial antioxidant effects, and modulation of the neuroendocrine response to stress.
• Studies vary in dose, duration, and populations; many conclusions are based on observational studies, experimental studies, and small-to-medium sized trials.

Abstract: what does science say?

Melatonin is an indole functionally central to signaling "night" to the body and promoting sleep. Clinical evidence indicates that exogenous melatonin use can reduce the time it takes to fall asleep and, in some cases, slightly increase sleep duration; effects are mediated by dose and timing. Beyond its action on sleep, melatonin possesses antioxidant and immunomodulatory actions that, in experimental models, attenuate certain parameters of biological stress. In the clinical setting, favorable results are observed in specific contexts (e.g., premedication for surgical procedures, some trials on mood disorders), but the evidence does not authorize general causal conclusions. Methodological limitations, heterogeneity of dosage, and study duration require cautious and contextual interpretation.

What it means in practice

For the general reader: melatonin is a natural modulator of biological rhythms that can support circumscribed sleep problems or acute anxiety situations related to events (for example, the preoperative period). The main effects observed in studies are modest — in practical terms, they often correspond to minutes gained in falling asleep or subjective improvements in sleep quality — and depend on when and how much is taken. There are also non-sleep-related cellular actions (antioxidant, modulation of inflammatory signals, receptor interaction) that explain the biological plausibility of its impact on adaptive stress reactions. However, decisions about melatonin use should be made with a doctor, considering concomitant medications, age, health status, and the overall clinical picture. Replacing or omitting therapies indicated by professionals is not recommended without specialized consultation.

Biological mechanisms: how melatonin can act in stress

Melatonin is synthesized from serotonin and secreted with a circadian rhythm, peaking at night. This temporal cycle makes it a key signal for synchronizing physiological activities, including sleep, metabolism, and some immune responses. At the cellular level, melatonin acts directly as a free radical scavenger and indirectly by promoting the expression of antioxidant enzymes and preserving mitochondrial function [3]. These molecular properties explain why, in experimental models, melatonin reduces indicators of oxidative damage and inflammatory activation after biological stress [5].

Furthermore, melatonin interacts with neurotransmitter systems: it is produced by a pathway starting from tryptophan and serotonin and can therefore indirectly influence the brain's serotonergic balance. This network of interactions provides plausibility for roles that go beyond simply inducing sleep, extending to mood modulation and behavioral adaptation to stress. Experimental evidence also shows that melatonin can directly or indirectly influence components of the stress axis (cortisol), although the complete mechanisms in humans remain partially described [3][9].

Melatonin, serotonin, and neurotransmitters

Melatonin is biochemically derived from serotonin through the enzymes AANAT and ASMT; this relationship provides a biological basis for the possibility that alterations in serotonin synthesis or availability are reflected in melatonin levels and vice versa [11]. In the brain, the modulation of serotonin, dopamine, and catecholamines is part of the complex adaptive response to stress: melatonin can help re-establish rhythms and modulate the emotional reactivity threshold, but the quantitative correspondence between hormonal variations and clinical symptoms is subject to many variables (age, medications, light exposure times) and is not in itself proof of causality [11].

Melatonin and the hypothalamic-pituitary-adrenal (HPA) axis

Experimental studies suggest that melatonin can modulate the glucocorticoid response to stress and influence the daily dynamics of cortisol. In animal models, melatonin administration reduces cortisol variations associated with acute or chronic stress; in humans, some chronobiological investigations show temporal interactions between melatonin and cortisol, especially in conditions of light-dark misalignment [3][9]. These data support the hypothesis that the synchronization of biological rhythms contributes to a more adaptive stress response, but it remains uncertain to what extent external melatonin administration can normalize complex HPA axis quotients in different clinical conditions.

Antioxidant action and immunomodulation

Melatonin is recognized as a molecule with the ability to neutralize free radicals and with actions that support the activity of antioxidant enzymes. In experimental and in vitro models, melatonin protects DNA from oxidative stress and limits the production of pro-inflammatory mediators; furthermore, mitochondrial actions contribute to maintaining energy homeostasis under cellular stress [5][4]. These properties provide biological plausibility for its use in conditions where oxidative stress and inflammation play a significant role, although they do not constitute proof that systemic treatment improves clinical outcomes in all contexts.

Clinical evidence: sleep, anxiety, and stress adaptation

The body of clinical trials and meta-analyses indicates that exogenously administered melatonin can reduce sleep onset latency and improve some subjective parameters of sleep quality. A meta-analysis on primary sleep disorders showed a modest effect on sleep onset latency and total sleep duration [1]. Broader systematic reviews confirm the effect, while highlighting heterogeneity among studies regarding dose and population [2].

In specific areas, such as premedication before surgical procedures, numerous randomized studies report a reduction in preoperative anxiety associated with melatonin compared to placebo or traditional therapies in some cases; a systematic review (Cochrane) concludes that melatonin probably reduces preoperative anxiety, with moderate quality evidence [7]. Furthermore, controlled clinical trials suggest possible benefits on depressive and anxious symptoms in selected contexts: for example, a randomized study in women with polycystic ovary syndrome found reductions in anxiety and depression scales after 12 weeks of melatonin supplementation [8]. These results indicate potential clinical applications, but generalization requires caution.

Key points to remember

• Melatonin is primarily a circadian signal that promotes sleep; its clinical effects are generally modest but significant in some contexts.
• It possesses antioxidant and immunomodulatory actions with a plausible impact on the biological response to stress, especially at the mitochondrial and molecular level.
• Some trials show reductions in anxiety in specific contexts (e.g., preoperative) and subjective improvements in sleep; however, the results do not support universal therapeutic claims.
• Dosage, timing (evening intake), formulation, and duration influence the effects; there is no "one-size-fits-all" dose.

Limitations of the evidence

It is important to distinguish between association, biological plausibility, observational data, and causal evidence. Many studies on melatonin are small, with heterogeneity in terms of dosage, formulation (e.g., immediate vs. prolonged release), and treatment duration; this complicates efficacy estimates. Meta-analyses identify average effects, but often with significant heterogeneity and risk of bias in primary studies [1][2].

Experimental and animal studies provide solid evidence of mechanistic plausibility (antioxidation, mitochondrial action, modulation of inflammatory signals), however, direct translation into clinical benefit depends on the pathological context, comorbidities, and drug interactions [3][4][5]. The presence of effects in some settings does not authorize generalized assumptions about the treatment of complex conditions such as major depression or chronic stress without robust specific data.

Editorial conclusion

Melatonin is a biologically plausible molecule as a support for sleep disorders and, in particular clinical conditions, can help reduce some aspects of anxiety and stress. Its antioxidant properties and ability to influence rhythms and neuroendocrine responses make it interesting from a pathophysiological point of view. However, the literature presents methodological limitations and variability that require caution. Its practical application should be evaluated individually and always in collaboration with a healthcare professional, avoiding absolute expectations or substitutions of established therapies.

Editorial Note

Article updated based on peer-reviewed literature. Informative purposes: does not constitute a therapeutic prescription. For diagnostic or therapeutic advice, consult a doctor.

SCIENTIFIC RESEARCH

1. Ferracioli‑Oda E, Qawasmi A, Bloch MH. Meta‑Analysis: Melatonin for the Treatment of Primary Sleep Disorders. PLoS One. 2013;8(5):e63773. https://doi.org/10.1371/journal.pone.0063773
2. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders: a meta‑analysis. J Gen Intern Med. 2005;20(12):1151–1158. https://doi.org/10.1111/j.1525-1497.2005.0243.x
3. Manchester LC, Tan DX, Reiter RJ, et al. Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res. 2015;59(4):403–419. https://doi.org/10.1111/jpi.12267
4. Reiter RJ. Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res. 2003;58(1):10–19. https://doi.org/10.1016/S0008-6363(02)00827-1
5. Galano A, Tan DX, Reiter RJ. Melatonin: A Versatile Protector against Oxidative DNA Damage. Molecules. 2018;23(3):530. https://doi.org/10.3390/molecules23030530
6. Arendt J, et al. Premedication with melatonin: a double‑blind, placebo‑controlled comparison with midazolam. Br J Anaesth. 1999;82(6):875–880. https://doi.org/10.1093/bja/82.6.875
7. Madsen BK, Zetner D, Møller AM, Rosenberg J. Melatonin for preoperative and postoperative anxiety in adults. Cochrane Database Syst Rev. 2020;12:CD009861. https://doi.org/10.1002/14651858.CD009861.pub3
8. Shabani A, Foroozanfard F, Kavossian E, et al. Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: A randomized, double‑blind, placebo‑controlled trial. J Affect Disord. 2019;250:51–56. https://doi.org/10.1016/j.jad.2019.02.066
9. Perreau‑Lenz S, et al. Characterizing the temporal dynamics of melatonin and cortisol changes in response to nocturnal light exposure. Sci Rep. 2019;9:19720. https://doi.org/10.1038/s41598-019-54806-7
10. Colunga Biancatelli RML, et al. Melatonin for the treatment of sepsis: the scientific rationale. J Thorac Dis. 2020;12(Suppl 1):S54–S65. https://doi.org/10.21037/jtd.2019.12.85