Melatonin’s Role in Linking Sleep Loss to Immune System Changes

A comprehensive narrative review was conducted to investigate the potential causal relationship between sleep deprivation, melatonin synthesis, and immune system function. A total of 20 articles were excluded based on predefined inclusion criteria, resulting in a final selection of 50 studies. These studies formed the basis of the review and were analyzed in detail, with additional contextual discussion provided where relevant.

A narrative review was conducted to explore the potential causal relationship between sleep deprivation, melatonin synthesis, and immune system function. The initial literature search yielded a large number of articles. After screening the titles and abstracts, 70 potentially relevant studies were selected for a full-text review.

Twenty articles were subsequently excluded according to predefined inclusion and exclusion criteria that considered factors such as language, publication type, relevance to the review topic, and methodological quality. Although this review did not use a formal quality assessment tool, studies were excluded due to low perceived methodological rigor if they met one or more of the following general conditions: Insufficient clarity regarding the study population or sampling method; Absence of a control or comparison group; Lack of clearly defined outcomes; Very small sample size with no justification of power.

These exclusion criteria were applied to focus the review on studies with greater internal validity and scientific transparency. Ultimately, the final analysis included 50 studies, which were reviewed in depth with additional contextual commentary where appropriate.

The included studies exhibited considerable heterogeneity, encompassing case studies, clinical trials, meta-analyses, and observational research. The majority of the selected articles, consistent with the objective of this review, investigated melatonin as an immunomodulator in conditions associated with sleep deprivation. The findings from these studies indicated, among other outcomes, that melatonin mitigated inflammatory markers such as TNF-alpha and IL-6. A number of the reviewed studies utilized experimental models, applying sleep deprivation protocols to assess the impact of melatonin on immune responses.

Reduced melatonin production and increased cortisol levels in elderly individuals may contribute to impaired immune function [24]. Similarly, people suffering from insomnia exhibit lower melatonin levels and impaired immune responses [10]. Furthermore, people who work at night often have their melatonin levels suppressed due to constant exposure to light during that time of day [25]. This has been associated with higher rates of respiratory infections and cardiovascular issues [25]. Similarly, individuals with autism spectrum disorders tend to have lower melatonin levels, which correlate with immune irregularities, including reduced natural killer (NK) cell function and increased oxidative stress [5]. Additionally, preclinical studies, including animal models and in vitro experiments using immune cells, have demonstrated that melatonin plays a key role in supporting mitochondrial function [26]. It helps maintain ATP synthesis and prevents immune cell death during periods of immune stress [26]. These effects are essential for maintaining energy balance in activated immune cells, particularly under inflammatory or infectious conditions. It is also worth noting that in patients with gastrointestinal conditions, melatonin has demonstrated anti-inflammatory properties in gut tissues and the ability to improve mucosal immunity [27]. Furthermore, studies investigating melatonin’s role in gastrointestinal and metabolic health support its protective function in maintaining mucosal immunity. [27] Melatonin supplementation has been suggested to restore normal melatonin levels and support antioxidant and immunomodulatory functions, as demonstrated in various experimental models [28]. Likewise, dietary supplementation with melatonin or its precursor, tryptophan, has been shown to restore sleep quality and enhance immune cell functionality [29]. Nutritional studies also show that combining melatonin-rich foods with proper sleep hygiene contributes to restoring circadian hormonal rhythms and enhancing immunological resiliency [30]. Beyond these effects, melatonin has demonstrated immunomodulatory effects in clinical settings, including as an adjuvant during chemotherapy, where it enhances natural killer (NK) cell activity and reduces inflammation [31]. In addition, melatonin interacts with receptors found in various immune cells and organs, highlighting its key role in immune regulation [6]. Table 1 highlights the key clinical conditions and vulnerable populations in which melatonin has demonstrated significant immunomodulatory effects. These examples illustrate its broad therapeutic potential across diverse immunological contexts.

The synthesis of the findings across multiple studies reveals a strong and consistent association between sleep deprivation and reduced melatonin synthesis. These disruptions result in circadian misalignment and hormonal imbalances, including elevated cortisol levels [24,27]. Observational and clinical data indicate that irregular sleep schedules are linked to reduced melatonin production, which may impair immune function [23]. Clinical studies have shown that melatonin production, which is governed by the suprachiasmatic nucleus (SCN) and regulated by exposure to darkness, declines markedly when normal sleep patterns are disturbed [33].

A number of studies have reported that sleep deprivation increases circulating levels of cytokines linked to chronic inflammation and heightened susceptibility to infections [34]. These inflammatory markers, in turn, have been shown to impair sleep quality, thereby reinforcing a cycle of immune dysregulation [10]. The relationship between decreased melatonin levels and increased concentrations of proinflammatory cytokines, including IL-6, IL-1β, and TNF-α, has been demonstrated to be consistent [27]. This assertion is further substantiated by the experimental data, which demonstrates that melatonin exerts an upregulatory effect on protective cytokines such as IL-2 and IFN-γ [6,10]. Furthermore, the absence of adequate sleep has been shown to induce alterations in T-cell function, to diminish NK cell activity, and to trigger the hypothalamic–pituitary–adrenal (HPA) axis, thereby contributing to a state of immunosuppression [10]. Melatonin has been demonstrated to inhibit the activity of macrophages, resulting in diminished levels of IL-1β, TNF-α, and nitric oxide, as well as decreased oxidative stress [32]. The efficacy of these effects has been demonstrated in both in vivo and in vitro models [32]. Melatonin has also shown immunomodulatory effects in at-risk groups, such as children with Down syndrome [20]. The combined effects of melatonin deficiency and sleep deprivation on the key immune parameters in both animal and human models are summarized in Table 2.

To facilitate the interpretation of the immune changes associated with sleep deprivation and reduced melatonin levels, the immunological effects presented in Table 2 were recoded using a symbolic scoring system and visualized in Figure 1. This qualitative approach was chosen due to the absence of standardized numerical values in the referenced studies. The scores are not quantitative; they are purely illustrative. A value of 1 (red) indicates the increased expression or activity of a given immune marker, −1 (blue) indicates decreased expression or function, and 0 (gray) indicates a mixed effect, such as an immunological shift (e.g., decreased Th1/increased Th2). This simplified coding system provides a summary of the direction of immune modulation under conditions of sleep deprivation and melatonin deficiency in both animal and human models.

Overall, the evidence supports the conclusion that melatonin serves as a critical link between circadian regulation and immune function. Its suppression as a result of sleep loss represents a plausible mechanism underlying the increased vulnerability to inflammation and disease. These effects are consistently observed across different populations and biological systems, lending robust external validity to the proposed model. Melatonin, therefore, emerges as a central factor, acting both as a chronobiotic hormone and a key immunomodulator [29]. The relationships between sleep deprivation, melatonin levels, and immune function are illustrated in Figure 2.

Consequently, any disruption to circadian timing, such as that resulting from insufficient sleep, can significantly impair this process. It is noteworthy that melatonin not only functions as a regulator of the circadian clock but also as a potent immunomodulatory hormone [6,37]. In animal models and in vitro studies, melatonin has been shown to reduce oxidative stress by scavenging free radicals and upregulating antioxidant defense mechanisms [38].

A multitude of studies provide substantiation for the notion that sleep deprivation shifts the immune balance toward a more proinflammatory state [27]. Preclinical data suggest that lower melatonin levels may disinhibit the hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased cortisol secretion [21].

Elevated cortisol levels have been demonstrated to impair immune function by reducing lymphocyte activity and promoting systemic inflammation [4]. These effects appear to be particularly salient in aging populations. A decline in melatonin production with age has been demonstrated to coincide with an elevated risk of infection, as evidenced by numerous studies [12]. It has been demonstrated that individuals have exhibited improvements in immune markers following melatonin supplementation, highlighting its therapeutic potential [39]. Furthermore, research indicates that intestinal and metabolic disorders associated with circadian misalignment are exacerbated by melatonin deficiency [27,40], suggesting the presence of broader systemic consequences.

The findings of this review establish a significant relation between sleep deprivation and melatonin suppression, resulting in weakened immune system function. The conclusions drawn from the available studies also suggest a clear mechanism through which sleep deprivation affects immune function. However, certain inconsistencies in the data may marginally lower the confidence in the evidence in this context. Although a strong association has been demonstrated, uncertainty remains due to methodological differences in melatonin measurement, which may affect the reliability of findings in certain subgroups.

This review establishes a significant relationship between sleep deprivation, melatonin suppression, and dysregulated immune function. Multiple lines of evidence support a biologically plausible mechanism linking circadian misalignment, HPA axis activation, and proinflammatory cytokine release to reduced melatonin availability.

However, it is important to recognize that much of the data originates from preclinical studies, including animal models and in vitro experiments. For instance, animal studies have demonstrated that melatonin significantly reduces pro-inflammatory cytokine levels, modulates oxidative stress, and supports mitochondrial integrity. Similarly, preclinical data suggest that melatonin administration can enhance natural killer (NK) cell activity and restore T-cell balance under sleep-deprived conditions.

While these findings provide a strong mechanistic rationale, the clinical evidence is more limited and inconsistent in some cases. Clinical studies have shown the potential benefits of melatonin supplementation, particularly for elderly populations, individuals with sleep disorders, and patients undergoing chemotherapy. However, the results vary due to differences in study design, outcome measures, and sample sizes. Some of these trials lacked rigorous controls or used heterogeneous populations, which complicates generalizability.

Furthermore, certain associations reported in the literature, such as those linking melatonin to cytokine regulation, are based on indirect or correlative data, especially when extrapolated from different pathological or physiological contexts. While the reviewed studies collectively suggest a strong immunomodulatory role for melatonin, the degree to which these effects translate into clinical benefit is uncertain.

Most of the above findings are based on preclinical models, and their clinical relevance has yet to be fully confirmed. High-quality randomized controlled trials are needed to validate these mechanisms in humans and clarify melatonin’s therapeutic potential in immune-related conditions exacerbated by sleep deprivation.

At the same time, we acknowledge that some of the associations discussed, particularly those related to cytokine modulation, are supported by indirect or preclinical evidence, and certain mechanistic pathways have not yet been definitively proven in humans. Nonetheless, given the consistency of these findings across different models and their alignment with known biological pathways, we believe their inclusion is justified as a basis for further clinical investigation.

The lack of randomized clinical trials in humans prevents a conclusive assessment of the immunomodulatory efficacy of melatonin, as well as the determination of its optimal dosage and long-term safety [41]. Until these data are completed, melatonin remains a promising but not fully validated therapeutic tool. In the context of assessing stress responses, a promising direction may be the simultaneous measurement of IL-1β, cortisol, and melatonin. IL-1β may serve as an accurate physiological marker, particularly in situations perceived as aggressive, which may allow better monitoring of the immunological effects of stress in the future [42]. Chronic sleep restriction results in a persistent low-grade inflammatory state that increases the risk of developing chronic diseases such as atherosclerosis, type 2 diabetes, or autoimmune disorders [43]. Therefore, routine evaluation and treatment of sleep disorders should become an integral part of the prevention and treatment of inflammatory conditions.

As the main signal for the synchronization of peripheral clocks, melatonin plays a key role in maintaining the rhythmic activity of immune cells. Its deficiency due to sleep deprivation leads to desynchronization of molecular rhythms in leukocytes and disruption of their effector and regulatory functions. This can lead to chronic immune dysregulation and increased susceptibility to infection, implicating melatonin as a potential mechanistic link between sleep disturbance and immune dysregulation [44]. This demonstrates the need to implement sleep protection programs among shift workers.

For instance, melatonin also acts through the RORA and TLR4/TRIF pathways, making it a particularly interesting therapeutic target in the context of immune disorders associated with sleep deprivation [45]. Its supplementation may have future applications in the prevention and treatment of immune dysregulation associated with circadian rhythm disruption [45]. Preclinical data suggest that melatonin acts through the RORA and TLR4/TRIF pathways, making it a particularly interesting therapeutic target in the context of immune disorders associated with sleep deprivation [45]. These findings, observed primarily in animal models and cell-based studies, indicate that melatonin supplementation may have potential future applications in the prevention and treatment of immune dysregulation related to circadian rhythm disruption [45].

Furthermore, genetic links between sleep and the immune system, including the presence of genes such as IL-1β and TNF in sleep-regulating loci, provide strong evidence for a molecular coupling between these two systems. These findings pave the way for developing targeted therapies that account for the shared regulation of sleep and immunity [46]. Genetic studies in humans have revealed links between sleep and the immune system, including the localization of immune-related genes such as IL-1β and TNF within sleep-regulating loci. These clinical findings provide compelling evidence for a molecular coupling between sleep and immunity [46]. Such insights may help inform the development of targeted therapies that address the shared regulation of these two systems [46].

Sleep deprivation damages the intestinal barrier, disrupts the microbiota, and weakens cellular junctions. A significant decrease in melatonin levels suggests that its deficiency may be a key factor in these changes. Melatonin supplementation restores intestinal integrity, suggesting its potential role in the treatment of mucosal barrier dysfunction in individuals with chronic sleep deprivation [47]. In animal models, sleep deprivation damages the intestinal barrier, disrupts the microbiota, and weakens cellular junctions. A significant decrease in melatonin levels in sleep-deprived mice suggests that its deficiency may be a key factor in these changes. Melatonin supplementation restored intestinal integrity in mice, suggesting its potential therapeutic role in preventing mucosal barrier dysfunction under conditions of chronic sleep deprivation [47].

Supplementing with melatonin could be a potential therapeutic approach to restore intestinal integrity and treat mucosal barrier dysfunction in individuals with chronic sleep deprivation.

Viral infections alter sleep by reducing REM sleep and prolonging NREM sleep. This may represent an adaptive mechanism to support the immune response, suggesting that sleep structure is actively regulated during infection. [48]. Evidence from human studies suggests that viral infections reduce REM sleep and increase NREM sleep duration. This shift in sleep structure is hypothesized to be an adaptive response facilitating immune function during infection [48].

Understanding how viral infections affect sleep patterns could lead to strategies that optimize sleep during illness, enhancing immune function. Clinically, interventions aimed at improving sleep quality, particularly by restoring REM sleep, may support the body’s immune response and improve recovery during viral infections.

The postprandial increase in melatonin levels observed in birds suggests the existence of an alternative, food-dependent mechanism for synchronizing biological rhythms. If a similar mechanism operates in humans, gut-derived melatonin may become a new therapeutic target for the treatment of circadian, metabolic, and inflammatory disorders [49,50]. In the elderly, decreased melatonin and serotonin levels can lead to sleep disturbances and immune system aging. Clinically, tryptophan supplementation may offer a potential intervention to restore these neurotransmitters, improve sleep quality, and help mitigate age-related immunological decline [50].

These findings highlight the need for targeted therapeutic approaches, such as melatonin supplementation, to restore these systems, particularly in vulnerable populations such as shift workers and the elderly. While the lack of randomized clinical trials in humans prevents definitive conclusions, the promising effects of melatonin on immune function, sleep quality, and gut health open opportunities for further research. In addition, understanding the interplay between sleep and immunity may lead to the development of new, targeted therapies that address the joint regulation of these systems, ultimately improving overall health and reducing the risk of chronic disease and infection.

One of the main limitations which we encountered was the variability in research methodologies. The sleep deprivation protocols differed across the studies. These differences included the duration and intensity of sleep deprivation, as well as the characteristics of the participants. Another limitation was the significant predominance of studies examining short-term exposure to sleep deprivation. Long-term studies are scarce, which limits our understanding of chronic effects. While acute sleep deprivation provides valuable insights, it may not fully reflect the biological consequences of prolonged sleep disruption.

Additionally, many of the studies used animal models that do not fully replicate human physiology. Lastly, much of the existing evidence is correlational, which limits our ability to draw definitive causal inferences about the relationship between sleep deprivation, melatonin suppression, and immune function.

Despite the use of predefined inclusion and exclusion criteria, the review process had limitations. One significant concern was publication bias, whereby studies with statistically significant or positive results were more likely to be published and retrieved in searches, while studies with null or negative results may be underrepresented. This could affect the balance of evidence considered in the review. Furthermore, the review relied exclusively on secondary data; therefore, no direct experimental verification of the causal relationships between sleep deprivation, melatonin suppression, and immune dysfunction was performed. While many of the included studies suggest robust associations, a large proportion of this evidence is correlational, which limits the ability to draw firm causal conclusions. Another important limitation involves the subjective elements in the selection of the studies. Although the initial screening and eligibility process was based on predefined criteria (e.g., language, publication type, relevance, and methodological quality), the final selection of studies was also influenced by how well they aligned with the review’s central theme and objectives. Consequently, relevant studies that did not appear to fit the narrative focus may have been unintentionally excluded, introducing an element of selection bias. Additionally, although methodological quality was considered during the screening process, a formal quality assessment was not used. Studies were excluded due to low perceived methodological rigor if they met one or more of the following conditions: insufficient clarity regarding the study population or sampling method, absence of a control or comparison group, lack of clearly defined outcomes, or very small sample size without power justification.

These criteria were applied to ensure the internal validity and scientific transparency of the included studies. However, the lack of standardized scoring or independent validation introduces subjectivity into quality judgments. In summary, although the review aimed to synthesize the most relevant and credible available evidence, the narrative approach and reliance on potentially selective secondary data must be acknowledged as inherent limitations.

Taken together, this review demonstrates that melatonin suppression is a central mechanism through which sleep deprivation leads to immune dysfunction. The consistency of these effects across diverse populations and clinical contexts lends strong support to the proposed biological model. Despite the compelling evidence linking melatonin suppression to immune dysregulation, several knowledge gaps and potential sources of controversy remain. A major limitation of the current research is the heterogeneity of the methodologies used to measure melatonin levels. Differences include sampling times, biofluids analyzed (saliva, plasma, and urine), and assay sensitivity. This variability complicates direct comparisons across the studies and may introduce bias, particularly in subgroup analyses. Furthermore, the extent to which these findings will translate into clinical improvements, especially in complex conditions like those associated with SARS-CoV-2, remains to be seen and requires further validation in large-scale, randomized controlled trials.

Another unresolved issue is the optimal dosing and timing of melatonin supplementation, which may differ depending on chronotype, age, comorbidities, and baseline circadian disruption. Additionally, there has been a degree of controversy surrounding the potential consequences of exogenous melatonin administration for the desensitization of endogenous production over time or its interference with natural circadian adaptation mechanisms. Future studies should aim to standardize the melatonin measurement protocols, investigate the long-term safety and efficacy of supplementation, and explore personalized treatment strategies that account for interindividual variability. These efforts would clarify melatonin’s therapeutic potential and inform evidence-based clinical recommendations. The results of this review have significant implications for clinical practice and public health policy. Greater emphasis must be placed on promoting healthy sleep habits. Sleep should be regarded as a critical preventive strategy to reduce the incidence of diseases. It is crucial to emphasize the importance of sleep hygiene. Promoting adherence to a consistent sleep schedule and minimizing exposure to blue light should be widely encouraged. It is essential to develop guidelines for professionals at risk of sleep deprivation, ensuring appropriate rest periods to prevent the long-term consequences of insufficient sleep. In the early stages, sleep deprivation weakens the immune system, and in later stages, it can contribute to the development of serious diseases, such as cancers, which pose a direct threat to life. Further research should be conducted to identify a specific combination of immunological markers that could serve as a standard for assessing the role of sleep deprivation in impairing the body’s defense mechanisms. Additionally, further studies are needed to determine the optimal dosage of melatonin for treating immune dysfunction and to evaluate the long-term effects of this therapy.

Although this review discusses the promising effects of melatonin, it is important to recognize that long-term use, especially at pharmacological doses, raises several concerns. Chronic supplementation may desensitize melatonin receptors or downregulate endogenous production, which could impair the natural circadian rhythm over time. Furthermore, adverse effects, such as daytime drowsiness, hormonal disruption, and drug interactions, have been reported, particularly in vulnerable populations, such as the elderly or individuals with comorbidities.

Another critical consideration is the distinction between physiological doses (typically 0.1–0.5 mg, which mimic natural nocturnal peaks) and pharmacological doses (often ≥3 mg), as these doses may have different biological effects and safety profiles. While low doses may support circadian alignment, higher doses can act more like a drug, modulating immune responses and oxidative stress in ways that are not yet fully understood.

Future studies should address these concerns by investigating the long-term safety of melatonin, particularly with chronic administration, and by comparing physiological versus pharmacological dosing strategies. A more nuanced understanding of the dose–response relationship and how it interacts with age, chronotype, and baseline melatonin levels is essential for informing the safe and effective clinical use of melatonin.