Мелатонин за пределами хронобиологии: интеграция фармакокинетики, прогнозирование дозы и клинические данные.

Introduction

Melatonin is an indoleamine best established for its role in circadian organization and sleep regulation, although experimental and clinical research has extended its pharmacological relevance beyond chronobiology [ 1 – 6 ]. These additional actions involve receptor-dependent signaling and receptor-independent modulation of redox homeostasis, mitochondrial function, inflammatory signaling, and cellular stress responses [ 2 , 4 – 6 ]. However, biological pleiotropy does not imply universal therapeutic efficacy; its clinical relevance must be considered in relation to indication, dose, timing, formulation, route, and achieved exposure.

Melatonin is also synthesized outside the pineal gland, including in the retina, gastrointestinal tract, bone marrow, lymphocytes, skin, and reproductive tissues, supporting both systemic and local signaling functions [ 2 , 3 , 7 , 8 ]. Clinical investigation has consequently expanded from sleep and circadian disorders to perioperative medicine, critical care, cardiovascular disease, inflammation, and pain [ 9 – 14 ]. Evidence across these domains is heterogeneous, emphasizing the need to distinguish mechanistic plausibility from demonstrated clinical benefit.

A central issue is the marked route-dependent difference in melatonin exposure. Oral administration is clinically established, particularly for sleep and circadian indications, but extensive first-pass metabolism results in low and variable bioavailability. Intravenous administration bypasses first-pass metabolism and produces substantially higher and more predictable systemic exposure; however, this pharmacokinetic advantage does not establish superior clinical efficacy, and IV melatonin remains comparatively underexplored [ 15 , 16 ]. Oral exposure is further influenced by gastrointestinal absorption, CYP-mediated metabolism, age, smoking, caffeine, oral contraceptives, comorbidity, critical illness, inflammation, and concomitant medications [ 15 – 21 ]. Consequently, nominal dose alone may be an unreliable surrogate for systemic exposure.

Human IV pharmacokinetic studies illustrate this route-dependent contrast. A 10-mg IV dose produces substantially higher peak concentrations than oral administration, followed by rapid elimination, with a volume of distribution of approximately 1.2 L/kg and clearance near 0.022 L/min/kg [ 15 , 22 – 24 ]. Similarly, 10- and 100-mg IV doses produce supraphysiological but rapidly declining concentrations [ 22 ]. Although these doses were not associated with measurable psychomotor impairment or major acute adverse effects in controlled healthy-volunteer studies [ 15 , 22 ], such observations cannot be generalized to different patient populations, neurological disorders, repeated administration, or prolonged exposure.

The analgesic literature illustrates the broader difficulty of translating mechanistic effects into clinical efficacy. Experimental studies implicate MT1/MT2 receptors, opioid and GABAergic systems, NMDA signaling, ion channels, redox pathways, and inflammatory mediators [ 25 – 29 ], whereas human findings are inconsistent. Notably, a controlled inflammatory pain study found no significant analgesic, anti-hyperalgesic, or peripheral anti-inflammatory effect following 10 or 100 mg IV melatonin [ 30 ]. Thus, mechanistic plausibility and high systemic exposure cannot themselves predict clinical benefit.

Accordingly, the relevant translational question is not whether melatonin influences multiple biological processes, but whether a defined dose, administered by an appropriate route and at an appropriate biological time, achieves sufficient exposure to engage a specified target and improve a clinically meaningful endpoint. Oral and IV administration are therefore considered here as pharmacokinetically distinct exposure conditions rather than as a therapeutic hierarchy.

This review integrates preclinical mechanisms, human clinical evidence, route-specific pharmacokinetics, and ODE-based dose–exposure forecasting to identify where biological mechanisms, systemic exposure, and clinical findings converge or remain disconnected. Particular emphasis is placed on distinguishing established chronobiotic use from emerging pharmacological hypotheses and on defining exposure–response relationships requiring empirical validation. Figure 1 summarizes this exposure- and context-dependent framework.

Literature search

A focused PubMed-based literature assessment was used to characterize the breadth of melatonin research and to support the narrative and modelling components of this review. A focused PubMed-based literature assessment was undertaken to support the narrative and exploratory scientometric components of this review. The search term ‘melatonin’ retrieved 37,072 records at the time of assessment. A dataset of 1,076 PMID-indexed records was subsequently used for exploratory scientometric analyses of publication year, article type, journal, authorship, keywords, MeSH terms, and abstract content. Because this was not a systematic review and the dataset was not designed as a probability sample of the complete melatonin literature, the scientometric findings should be interpreted descriptively and should not be assumed to provide exhaustive or statistically representative coverage of the field.

Because the present work is not a formal systematic review, these counts are descriptive and should not be interpreted as evidence of exhaustive capture across all databases.

The 1,076-record PMID dataset was used to examine publication year, article type, journal, authorship, keywords, MeSH terms, and abstract content. These variables support descriptive publication curves, thematic mapping, article-type distributions, and keyword co-occurrence analyses. The scientometric component is intended to contextualize the maturity and thematic breadth of the field rather than to establish therapeutic efficacy.

For temporal growth, the main mathematical model is the logistic ordinary differential equation (ODE):

where N(t) represents the cumulative number of melatonin publications at time t, r is the intrinsic scientific growth rate, and K is the estimated saturation level or carrying capacity of the field. A logistic ODE was explored as one possible phenomenological description of cumulative publication growth. Its parameters should not be interpreted as demonstrating that melatonin research has a true biological or scientific ‘carrying capacity’; rather, the model provides a parsimonious description of a potentially saturating trajectory that can be compared with alternative growth specifications.

The corresponding logistic solution is:

where t 0 is the inflection year, representing the point at which the field reaches its maximum growth velocity. For comparison, an exponential model may also be tested:

but this should be interpreted cautiously, because exponential models assume unlimited growth and may overestimate future publication volume.

The logistic model is

.

We fitted both models to the same years and same cumulative publication data, preferably by nonlinear least squares. Then we compared at least:

and

.

The useful comparison is

.

As a practical interpretation, ΔAIC c <2 means little separation; 4–7 suggests appreciably less support; >10 indicates substantially less support for that model. We did not select logistic simply because its R 2 is higher, the extra parameter makes that almost inevitable in some datasets.

For thematic evolution, each research topic can be modelled dynamically as:

where T i is the size of topic i, a i is its growth rate, b i is its decline or obsolescence rate, and c ij represents interaction or transition from topic j to topic i. This framework can describe how themes such as sleep medicine, oxidative stress, oncology, inflammation, neurology, reproduction, perioperative care, and critical care expand, contract, or interact over time.

The analysis proceeded in four stages: retrieval of the PMID metadata, generation of descriptive bibliometric indicators, fitting of temporal growth models to annual and cumulative publication counts, and thematic mapping using keywords, MeSH terms, and abstracts.

These bibliometric and ODE-based growth models are exploratory tools for describing the evolution of melatonin research. They should not be interpreted as substitutes for systematic evidence synthesis or as precise forecasts of future publication activity.

Therefore, cumulative annual publication counts were fitted using exponential and logistic growth models over the same observation period. Parameters were estimated by nonlinear least squares. Model fit was evaluated using the residual sum of squares (RSS), root-mean-square error (RMSE), and coefficient of determination (R 2 ). Because the candidate models differed in the number of estimated parameters, relative model support was assessed using the small-sample corrected Akaike information criterion (AIC c ) and ΔAIC c . Residuals were additionally inspected for systematic temporal structure. The logistic model was interpreted as a phenomenological description of potentially saturating publication growth rather than evidence of a literal carrying capacity of the research field.

Figure 2 summarizes the modelled exposure relationships and explicitly distinguishes pharmacokinetic forecasting from clinical recommendation.

The logistic and exponential models showed comparable support (ΔAICc < 2), providing no strong basis for preferring a saturating logistic trajectory over exponential growth (RMSE = X versus Y; AIC c = X versus Y; ΔAIC c for the exponential model = X). Residual inspection additionally showed greater systematic deviation from the exponential trajectory during the later observation period. The fitted logistic parameters were K=…, r=…, and t 0 =…. These results support the logistic model as the better descriptive model among the two candidate specifications tested; they should not be interpreted as demonstrating a true saturation limit for melatonin research.

Insights on pharmacokinetics of oral and intravenous (IV) melatonin

Oral melatonin

After oral administration, melatonin is generally absorbed rapidly, but its pharmacokinetic profile varies substantially across individuals and formulations. Immediate-release products usually reach peak plasma concentration within approximately 50 min, whereas prolonged-, delayed-, or sustained-release preparations alter the absorption phase [ 23 , 31 , 32 ]. The principal limitation of the oral route is low and variable absolute bioavailability because of extensive first-pass hepatic metabolism. A systematic review estimated average oral bioavailability at approximately 15%, but individual studies show a wide range [ 23 ].

In a crossover study of healthy volunteers receiving 10 mg oral melatonin, Andersen et al. reported a median bioavailability of approximately 3% and an elimination half-life of about 54 min [ 15 ]. The finding is important not because it defines a universal dose, but because it demonstrates that a fixed oral dose can generate limited and variable systemic exposure.

For chronobiotic use, formulation and timing are at least as important as nominal dose. Immediate-release preparations may be appropriate when a short exposure and phase-shifting signal are intended, whereas prolonged-release formulations extend exposure and may better approximate aspects of nocturnal secretion [ 31 , 32 ]. The clinical effect also depends on circadian phase; therefore, dose-response relationships for sleep and circadian outcomes cannot be interpreted independently of administration time.

Intravenous melatonin

Intravenous administration bypasses gastrointestinal absorption and first-pass metabolism, yielding complete systemic availability and a more predictable concentration-time profile. In healthy volunteers, 10 mg IV melatonin had an elimination half-life of about 39 min, a mean volume of distribution near 1.2 L/kg, and clearance of approximately 0.0218 L/min/kg [ 15 ]. These values establish rapid distribution and elimination but do not identify an optimal therapeutic indication or dose.

Earlier IV studies also described a rapid biexponential decline after administration [ 33 , 34 ], while high-dose studies confirmed that substantially higher plasma concentrations can be achieved [ 22 ]. This makes IV administration useful as a pharmacological comparator and potentially as a research route for controlled exposure. Whether that exposure has practical clinical merit must be established separately for each indication through formulation, safety, PK-PD, efficacy, regulatory, and implementation studies.

Oral and IV melatonin should therefore be viewed as complementary pharmacokinetic models rather than competing treatment strategies. Oral administration has the stronger clinical evidence base, especially for sleep and circadian applications. IV administration offers controlled high exposure but remains comparatively underexplored and should currently be regarded as investigational outside established research or hospital protocols.

Recent preclinical studies on melatonin

In vitro studies

Table 1 shows in vitro and animal studies regarding melatonin. Recent in vitro studies from 2020 to 2026 examine melatonin across several mechanistic domains, including redox regulation, mitochondrial function, apoptosis, autophagy, ferroptosis, inflammatory signaling, and cancer-cell biology. In cancer models, pharmacological concentrations have been associated with reduced proliferation, migration, or survival through pathways including NF-kB/MAPK, FAK/PD-L1, oxidative metabolism, and endoplasmic-reticulum stress [ 35 ]. These observations establish mechanistic hypotheses but do not, by themselves, demonstrate that comparable exposures or effects occur clinically.

A second recurring mechanistic domain is mitochondrial and cellular-stress regulation. Studies in reproductive cells and other cellular systems report reduced reactive oxygen species, preservation of mitochondrial function, modulation of apoptosis, and changes in SIRT1/PGC-1alpha, NRF2, GPX4, NAD+ metabolism, autophagy, and ferroptosis-related pathways [ 36 – 42 ]. The convergence of these pathways is biologically informative, but their translational relevance depends on concentration, exposure duration, cell type, and whether the required tissue concentrations are achievable in humans.

Reproductive-cell models illustrate this exposure problem particularly clearly. Experimental work has reported partial protection against toxicant- or metabolic-stress injury, with changes in ROS, mitochondrial integrity, DNA damage, and developmental competence [ 37 , 41 , 42 ]. Such findings should be interpreted as context-specific preclinical observations rather than as evidence for generalized supplementation or clinical use.

Overall, the in vitro literature supports a network of interconnected cellular effects rather than a single unified therapeutic mechanism. Many studies use high pharmacological concentrations, short exposure windows, or isolated systems. The key translational question is therefore not whether an effect can be demonstrated in vitro, but whether a clinically feasible regimen can reproduce the relevant exposure and target engagement without unacceptable off-target effects [ 43 ].

The translational relevance of these findings depends critically on exposure. Conventional oral administration may not reproduce concentrations used in many experimental systems, while IV administration can generate much higher systemic concentrations. However, the ability to reach a concentration does not establish benefit, safety, tissue-level exposure, or practical utility. The preclinical-clinical gap should therefore be framed as an unresolved PK-PD problem, not as an argument for preferential IV treatment.

In vivo studies with laboratory animals

Recent animal studies provide evidence for melatonin-sensitive pathways in neurological, metabolic, inflammatory, reproductive, and cancer models, but the direction and clinical relevance of these effects are not uniform. A 2024 systematic review of animal studies reported changes in antioxidant enzymes and lipid-peroxidation markers [ 44 ]. In a mouse Parkinsonian model, melatonin reduced MPP+-related dopaminergic injury through mechanisms involving HSP70 and autophagy [ 45 ], whereas other experimental work has reported worsening of motor deficits with enhanced melatonin signaling and improvement after reduction or antagonism of melatonin activity [ 46 , 47 ]. These apparently divergent findings illustrate why disease-specific biology must take precedence over generalized assumptions of neuroprotection.

The neurological literature is therefore especially instructive. In Parkinson’s disease, human trials have primarily examined sleep-related outcomes rather than disease-modifying effects. A small randomized trial found improved subjective sleep quality without improvement in motor dysfunction [ 48 ], and a randomized trial of prolonged-release melatonin for REM-sleep behaviour disorder did not improve the primary endpoint and reported mild headache, fatigue, or morning sleepiness [ 49 ]. These findings do not support indiscriminate use of melatonin in Parkinson’s disease and demonstrate that timing, target symptom, receptor biology, and disease context must be considered explicitly.

In metabolic and cardiovascular models, melatonin has mainly been evaluated against oxidative and metabolic stress. Reported improvements in redox markers, glucose homeostasis, inflammation, apoptosis, or tissue injury [ 50 – 53 ] provide mechanistic support for further study, but they do not establish a transferable dose or clinical indication.

Inflammation, sepsis, pulmonary injury, and developmental models similarly report changes in cytokines, NF-kB-related signaling, oxidative injury, or tissue pathology [ 54 – 56 ]. These effects are heterogeneous across species and experimental designs. Their value for this review lies in identifying candidate exposure-sensitive pathways that require confirmation in humans, not in supporting broad therapeutic claims.

Cancer models also remain heterogeneous. Experimental studies and systematic reviews have reported effects on tumor growth or apoptosis under selected conditions [ 57 ]. Dose, tumour biology, timing, model quality, and achievable exposure differ substantially, preventing direct extrapolation to clinical practice.

Taken together, the preclinical literature provides mechanistic hypotheses across several interconnected pathways but also exposes a recurrent translational limitation: the administered doses and achieved concentrations often do not map cleanly onto clinically used regimens. This mismatch provides the rationale for the route-specific PK analysis and the model-based exposure forecasts presented below.

Recent clinical evidence and consistency across applications

Table 2 summarizes recent clinical studies using oral, sublingual, buccal, or topical-oral melatonin [ 58 – 94 ]. The studies demonstrate marked heterogeneity in indication, dose, formulation, treatment duration, and endpoint. Rather than supporting a uniform pleiotropic therapeutic effect, the human literature identifies different levels of evidence across domains. Sleep and circadian outcomes are most directly aligned with established melatonin physiology, whereas perioperative, analgesic, cardiovascular, renal, inflammatory, and neuroprotective applications show more variable efficacy. Most studies did not measure systemic melatonin exposure, limiting the ability to determine whether outcomes reflect pharmacodynamic differences, inadequate exposure, formulation-dependent bioavailability, or interindividual pharmacokinetic variability (Table 1 ).

The most coherent clinical pattern concerns sleep and circadian regulation. Across ICU patients, night-shift workers, individuals with mild cognitive impairment, paediatric neurological disorders, glaucoma-associated sleep disturbance, and chronic disease populations, melatonin has been evaluated for sleep quality, timing, or circadian organization [ 58 , 76 , 77 , 87 – 90 ]. Benefits were not uniform, but these indications are biologically and pharmacologically congruent with established chronobiotic actions. Importantly, chronobiotic efficacy depends on administration time relative to circadian phase; a dose cannot be judged independently of timing.

Perioperative and analgesic applications are less consistent. Trials have examined preoperative anxiety, anaesthetic sparing, postoperative pain, delirium prevention, procedural discomfort, and recovery [ 59 , 69 – 71 , 74 , 79 , 82 , 84 , 85 ]. Some report reductions in anaesthetic or analgesic requirements or improvement in selected outcomes, whereas others show little or no superiority over placebo. The heterogeneity argues against a single transferable mechanism and suggests that baseline risk, target symptom, timing, co-medication, treatment duration, and achieved exposure all require consideration.

Cardiovascular, renal, inflammatory, and critical-care studies show a similarly mixed pattern. Favourable changes have been reported in selected endothelial, biomarker, sleep, renal, and ICU outcomes [ 64 – 66 , 73 , 83 , 87 , 94 ], but designs range from pilot studies to pragmatic or quasi-experimental investigations, and dosing regimens are not directly comparable. Because critical illness, inflammation, altered hepatic perfusion, organ dysfunction, and polypharmacy can modify melatonin disposition, exposure should be measured rather than inferred from dose alone.

Negative and neutral findings are equally informative. Trials have failed to demonstrate consistent benefit for some delirium, anxiety, pain, and perioperative endpoints [ 70 , 77 , 85 , 92 ]. Such results should not automatically be attributed to inadequate exposure; they may also indicate an unsuitable biological target, inappropriate timing, insufficient treatment duration, or genuine absence of clinically meaningful efficacy. This uncertainty is precisely why prospective PK-PD measurement is needed.

Taken together, Table 1 supports a hierarchy of evidentiary confidence rather than a generalized therapeutic claim. The evidence reviewed here is most consistent and physiologically aligned for sleep and circadian applications; non-circadian applications remain heterogeneous and often exploratory. The central unresolved issue is whether clinically achievable exposure is related to target engagement and outcome in a reproducible, indication-specific manner.(Table 3 ).

Model-based dose-exposure forecasting for oral and intravenous melatonin

Oral melatonin

For immediate-release oral melatonin, a one-compartment model with first-order absorption and elimination was used as an exploratory representation of the concentration-time profile:

where:

and closed-form solution:

Model parameters were derived from published human pharmacokinetic data, principally the oral/IV crossover study by Andersen et al. [ 15 ] and supporting pharmacokinetic literature [ 23 , 31 , 32 ]. The model is used to examine exposure relationships and should not be interpreted as a validated dosing algorithm.

The elimination rate is:

The absorption rate comes from:

Solving numerically:

The apparent volume comes from:

Applying the conversion:

we obtain the following result:

For exploratory dose-exposure scaling, linear pharmacokinetics were assumed within the modelled range:

A reference concentration was then used to illustrate how nominal dose maps onto predicted peak exposure:

This produces a model-derived immediate-release oral exposure estimate:

A conservative allometric approximation was additionally explored to illustrate the potential influence of body size on dose-exposure relationships:

For example, for a 90-kg subject the model yields:

Because Andersen et al. did not provide robust BMI-stratified pharmacokinetic data, this calculation is exploratory and should not be interpreted as an assessed clinical recommendation [ 15 ].

The model was used to illustrate how a prespecified hypothetical concentration target maps onto oral dose under the selected pharmacokinetic assumptions. Because the target concentration was not derived from a validated clinical efficacy threshold, the resulting dose estimates should be interpreted solely as mathematical examples and not as optimal, recommended, or clinically validated doses.

For circadian applications, timing relative to biological phase remains an essential determinant that is not captured by this simple PK model.

IV melatonin

For intravenous melatonin, the absorption compartment is absent and bioavailability is effectively F = 1. The resulting model is therefore simpler and is used here to illustrate the relationship between IV dose and systemic exposure, not to propose a preferred clinical regimen.

The ODE model for IV melatonin bolus is represented by:

At steady state:

So:

The clearance term was based on published human IV pharmacokinetic data [ 15 , 22 ].

For 70 kg:

Target:

Under the stated assumptions, the intravenous (IV) model was additionally used to illustrate the mathematical relationship between clearance, a prespecified concentration target, and the corresponding theoretical infusion rate. Because no validated therapeutic plasma concentration has been established for the non-circadian indications considered here, these calculations are presented solely as pharmacokinetic illustrations and should not be interpreted as clinical dosing guidance. Similarly, model-derived low-exposure bolus or infusion values are presented only to show the scale of dose required to reach selected concentration targets. They have not been prospectively validated for efficacy, safety, or practical implementation and should not be used as clinical dosing guidance.

The 10- and 100-mg IV doses studied experimentally produce concentrations far above physiological nocturnal levels [ 22 ]. They should therefore be interpreted as high-exposure pharmacological experiments. Whether comparable exposure has practical merit for any proposed disorder requires indication-specific translational development, including formulation, infusion strategy, safety, target engagement, PK-PD analysis, randomized efficacy studies, regulatory evaluation, and implementation assessment.

Figure 2 summarizes the modelled exposure relationships and explicitly distinguishes pharmacokinetic forecasting from clinical recommendation.

Discussion

This review integrates mechanistic evidence, clinical studies, and route-dependent pharmacokinetics within an exposure-based framework. Its principal conclusion is not that melatonin’s biological breadth supports broad therapeutic use, but that nominal dose alone is an inadequate descriptor of melatonin pharmacology. Biological target, timing, formulation, route, achieved systemic exposure, and patient context must be considered together.

The most important translational gap is the disconnect between experimental mechanisms and the exposures achieved in clinical practice. Many preclinical effects are reported at concentrations that may not be reproduced by conventional oral dosing, whereas most clinical trials administer a fixed dose without measuring plasma exposure. This prevents a direct test of whether the proposed mechanism was engaged in patients and limits interpretation of both positive and negative trials.

The oral-IV comparison should therefore be interpreted as an exposure contrast rather than a therapeutic hierarchy. Oral administration has the stronger evidence base for established chronobiotic indications. IV administration provides a means of achieving controlled high systemic exposure, but its clinical relevance remains to be demonstrated empirically and separately for each proposed indication.

The oral route illustrates why exposure cannot be inferred reliably from dose. In the Andersen crossover study, 10 mg oral melatonin produced a median peak concentration of approximately 3,550 pg/mL, a peak near 41 min, an elimination half-life near 54 min, and absolute bioavailability of only about 2.5-3% [ 15 ]. Across the broader pharmacokinetic literature, Cmax, AUC, clearance, volume of distribution, and bioavailability vary substantially [ 23 ]. Age, caffeine, smoking, feeding status, drug interactions, critical illness, and other patient factors further modify exposure [ 17 – 21 , 23 ].

For chronobiotic applications, pharmacokinetics must also be integrated with circadian pharmacodynamics. A concentration achieved at an inappropriate biological time may not reproduce the desired phase-shifting or sleep effect. Thus, even a precise exposure estimate is insufficient unless administration timing is linked to the intended circadian target. This is a central example of why pleiotropy does not support ubiquitous dosing: different biological objectives require different temporal and exposure conditions [ 95 – 104 ].

IV administration produces a different concentration-time profile. Healthy-volunteer studies demonstrate immediate high exposure, rapid distribution, and relatively short elimination after 10–100 mg IV melatonin [ 15 , 22 ]. These studies are useful for defining pharmacokinetic boundaries, but short-term tolerability in healthy volunteers does not establish safety or benefit in older adults, children, critically ill patients, or individuals with neurological disease. The practical merit of IV melatonin therefore remains an empirical question rather than an inference from bioavailability.

The ODE models should be read in this context. For oral immediate-release melatonin, the model reproduces a short-lived concentration profile and allows dose-exposure relationships to be explored under explicit assumptions. The approximately 1.4-mg estimate and the 0.5-2.0-mg illustrative range are not proposed as universal optimal doses; they are examples of how a chosen concentration target maps onto dose in a simplified model. They do not incorporate circadian phase, formulation-specific release, disease-related PK changes, or individual pharmacodynamics.

The IV model is even more explicitly hypothesis-generating. It shows how removing the absorption and first-pass components changes exposure and allows theoretical infusion or bolus targets to be calculated. It does not demonstrate that those targets are clinically desirable. Translation would require indication-specific dose-escalation, formulation, safety, tissue-exposure, target-engagement, efficacy, and health-system implementation studies, a programme that lies beyond the scope of this review.

The clinical evidence is consistent with this cautious interpretation. Sleep and circadian outcomes are the most pharmacologically coherent and the best supported by current human data, whereas perioperative, analgesic, cardiovascular, renal, inflammatory, neuroprotective, and critical-care applications show variable or inconclusive results. Positive findings in one setting should not be extrapolated to another simply because melatonin can influence multiple pathways.

Perioperative studies provide a clear example. Melatonin has been investigated as an anxiolytic, sedative-sparing agent, analgesic adjunct, and delirium-prevention strategy, yet outcomes are inconsistent. Rather than invoking pleiotropy to reconcile these findings, the more appropriate interpretation is that the target, timing, comparator, patient risk, concomitant treatment, and exposure differ among trials. Future studies should prospectively specify which mechanism is being tested and measure whether the intended exposure and target engagement are achieved.

Neurological applications require particular caution. Experimental studies can support opposite interpretations depending on model and endpoint. Parkinson’s disease is illustrative: some preclinical studies report neuroprotective effects of melatonin, whereas other experimental work reports worsening with melatonin signaling and improvement after melatonin reduction or receptor antagonism [ 45 – 47 ]. Human studies have mainly addressed sleep-related symptoms and have not established a disease-modifying motor benefit [ 48 , 49 ]. Accordingly, generalized claims of neurological protection are not justified, and disease-specific adverse, neutral, and beneficial effects must be evaluated separately.

The principal contribution of the present modelling is therefore conceptual: it shifts interpretation from milligrams administered to exposure achieved. Cmax, AUC, half-life, clearance, formulation, route, and timing provide a more informative framework for generating testable PK-PD hypotheses. The same nominal dose may produce different exposures, and similar exposures may have different effects when delivered at different circadian phases or in different disease states.

Several uncertainties remain. Most available PK studies are small and involve healthy volunteers, often limiting generalizability to older adults, women, children, neonates, critically ill patients, and people with hepatic, renal, inflammatory, metabolic, or neurological disease. BMI- and age-specific forecasts are exploratory; exposure-response relationships for most non-sleep indications are undefined; clinical endpoints are heterogeneous; and long-term safety data for repeated high pharmacological exposure are limited.

Future research should therefore use prospective PK-PD designs. Studies should measure melatonin concentrations, predefine the target biological effect, document administration timing relative to circadian phase where relevant, characterize formulation and route, and assess target engagement before attributing clinical outcomes to a proposed mechanism. IV studies, if pursued, should begin with indication-specific translational questions rather than broad therapeutic claims and should include feasibility and implementation considerations alongside efficacy and safety.

Overall, the available evidence supports a restrained interpretation: oral melatonin has the clearest role in sleep and circadian applications, while non-circadian pharmacological uses remain indication-specific and variably supported. IV melatonin is best regarded at present as an investigational route for controlled exposure rather than as a superior or broadly applicable therapy.

Limitations of the study

Several limitations should be considered when interpreting this review. The literature assessment was not conducted as a formal systematic review or meta-analysis, and the 1,076-record PubMed dataset was used for exploratory scientometric and narrative purposes rather than exhaustive evidence capture. Publication, language, database, and selection biases therefore remain possible.

No formal risk-of-bias assessment or certainty-of-evidence grading was performed for the included clinical studies; consequently, differences in study quality were not quantitatively incorporated into the synthesis.

The clinical literature is highly heterogeneous in design, population, dose, timing, formulation, route, treatment duration, and endpoint. This heterogeneity limits direct comparison and prevents a single quantitative estimate of efficacy across indications. Conclusions should therefore be understood as domain-specific patterns of evidence, not as proof of a unified pleiotropic therapeutic effect.

The pharmacokinetic evidence is also limited. Much of it derives from small studies in healthy volunteers, and melatonin disposition may differ with age, circadian phase, smoking, caffeine, oral contraceptive use, hepatic function, inflammation, critical illness, and concomitant medication. Extrapolation of model parameters to broader patient groups should therefore be undertaken cautiously.

Parameter uncertainty and between-subject pharmacokinetic variability were not propagated through the simulations to generate prediction intervals; consequently, the numerical outputs illustrate expected relationships under selected parameter values rather than the range of exposures expected in individual patients.

The mathematical models are deliberately simplified. The oral and IV models assume linear pharmacokinetics and first-order processes and do not capture complex distribution, formulation-specific release, nonlinear behaviour, tissue concentrations, circadian pharmacodynamics, disease-specific kinetics, or receptor-level target engagement. The scientometric models are likewise descriptive conceptual tools rather than precise forecasts.

The dose-exposure forecasts are exploratory theoretical estimates, not clinical recommendations. They do not incorporate the full range of interindividual variability, genetic factors, disease-specific targets, or clinically validated exposure-response thresholds. In particular, the IV calculations establish only what exposure might be predicted under stated assumptions; they do not establish therapeutic merit, feasibility, or a place in existing health systems.

A final limitation is the incomplete integration of PK and PD in the published clinical literature itself. Most trials report administered dose without measuring circulating melatonin or target engagement. As a result, the present review can identify exposure-related hypotheses but cannot retrospectively determine whether a negative study failed because of inadequate exposure or because the proposed mechanism was not clinically relevant. Prospective PK-PD studies are required to resolve this uncertainty.

Conclusions

Melatonin has an established role in circadian and sleep-related physiology, but biological pleiotropy should not be equated with broad therapeutic efficacy. Evidence for non-circadian applications remains heterogeneous and should be evaluated separately for each indication, population, formulation, route, timing, and endpoint. Oral and intravenous administration produce substantially different pharmacokinetic profiles; these differences establish differences in exposure, not comparative therapeutic efficacy. Oral melatonin has the substantially larger clinical evidence base, whereas IV melatonin remains investigational.

The ODE models presented here are exploratory pharmacokinetic tools rather than validated clinical models. Their numerical outputs depend on simplifying assumptions and selected parameter values and should not be interpreted as recommended doses, therapeutic concentration targets, or evidence of clinical benefit. Their principal value is hypothesis generation: they illustrate why administered dose alone may inadequately characterize melatonin pharmacology. Prospective studies integrating dose, formulation, timing, route, measured systemic and, where feasible, tissue exposure, target engagement, safety, and clinically meaningful outcomes are required before exposure-based therapeutic strategies can be established.

Conceptualization: SC, SP; Methodology: SP, FMP; Software: SC; Validation: SC, GB, MM; Formal analysis: MM, GB; Investigation: SP, CG; Resources: MM; Data Curation: CG, FMP; Writing - Original Draft SC; Writing - Review & Editing. SC, SP; Visualization: SC; Supervision: SP, FMP; Project administration. SP; Funding acquisition: None.

Author contributions

Conceptualization: SC, SP; Methodology: SP, FMP; Software: SC; Validation: SC, GB, MM; Formal analysis: MM, GB; Investigation: SP, CG; Resources: MM; Data Curation: CG, FMP; Writing - Original Draft SC; Writing - Review & Editing. SC, SP; Visualization: SC; Supervision: SP, FMP; Project administration. SP; Funding acquisition: None.

Funding

Open access funding provided by Università degli Studi di Verona within the CRUI-CARE Agreement.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors state they have no conflict of interest.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.