Melatonin is a small indoleamine produced primarily by the pineal gland that circulates in the bloodstream in a characteristic nocturnal pattern. While its role as a chronobiotic is well‑known, the pharmacokinetic (PK) profile of exogenously administered melatonin determines how effectively it can advance sleep onset, especially when used as an over‑the‑counter supplement. Understanding the absorption, distribution, metabolism, and elimination (ADME) of melatonin—and how these processes are influenced by formulation, dose, age, and genetic factors—provides clinicians and informed consumers with a rational basis for selecting the right product and timing it appropriately.
Absorption: From the Gut to the Systemic Circulation
Oral Bioavailability
Oral melatonin exhibits a highly variable bioavailability, reported in the literature as ranging from 10 % to 56 %. The primary determinants of this variability are first‑pass hepatic metabolism and the physicochemical properties of the formulation:
| Formulation | Approx. Cmax (ng/mL) | Tmax (h) | Relative Bioavailability |
|---|---|---|---|
| Immediate‑release (IR) tablets, 1 mg | 30–45 | 0.5–1.0 | Baseline |
| IR tablets, 5 mg | 120–180 | 0.5–1.0 | Similar to 1 mg (dose‑proportional) |
| Sublingual spray, 0.5 mg | 40–55 | 0.2–0.4 | ↑ 1.5–2× IR |
| Lipid‑based softgel, 3 mg | 80–110 | 0.8–1.2 | ↑ 1.2–1.4× IR |
| Controlled‑release (CR) capsules, 5 mg | 70–90 (peak) | 2–4 | Sustained plateau |
The rapid rise in plasma concentration after IR dosing (Tmax ≈ 30–60 min) aligns with the physiological surge of endogenous melatonin that precedes sleep onset. In contrast, CR preparations produce a flatter curve, extending exposure over 6–8 h and potentially supporting sleep maintenance rather than initiation.
Food Effects
A high‑fat meal can increase the area under the curve (AUC) of IR melatonin by up to 30 % and delay Tmax by 30–45 min, likely due to delayed gastric emptying and enhanced solubilization of the lipophilic molecule. For patients seeking a prompt sleep‑inducing effect, it is advisable to ingest melatonin on an empty stomach or at least 30 min before a meal.
Distribution: Crossing the Blood–Brain Barrier
Melatonin is a small (MW = 232 Da), amphiphilic molecule that readily diffuses across biological membranes. After oral absorption, plasma protein binding is modest (≈ 15 % to albumin), leaving a large free fraction available for tissue distribution. The volume of distribution (Vd) ranges from 0.5 to 1.0 L/kg, indicating extensive distribution beyond the vascular compartment.
Central Nervous System Penetration
The blood–brain barrier (BBB) expresses organic anion transporting polypeptides (OATPs) that facilitate melatonin entry. Cerebrospinal fluid (CSF) concentrations typically reach 30–50 % of plasma levels within 30 min of an IR dose, sufficient to activate high‑affinity MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN) and other sleep‑regulating nuclei. The rapid CNS penetration of sublingual and buccal formulations further shortens the latency to receptor engagement.
Metabolism: The Role of Hepatic Enzymes
Primary Pathways
Melatonin undergoes extensive first‑pass metabolism in the liver, primarily via cytochrome P450 isoforms CYP1A2 and CYP2C19. The major metabolic route is 6‑hydroxylation, producing 6‑hydroxymelatonin, which is subsequently conjugated with sulfate or glucuronic acid and excreted in urine.
| Enzyme | Contribution to Clearance | Inter‑individual Variability |
|---|---|---|
| CYP1A2 | ~ 70 % of hepatic metabolism | High (induced by smoking, cruciferous vegetables; inhibited by fluvoxamine) |
| CYP2C19 | ~ 20 % | Moderate (genetic polymorphisms: *2/*2 poor metabolizers) |
| Others (CYP2D6, UGTs) | < 10 % | Minor |
Because CYP1A2 activity can be modulated by lifestyle and co‑administered drugs, the metabolic clearance of melatonin may vary up to threefold among healthy adults. This variability directly influences the duration of elevated plasma melatonin and, consequently, the window of sleep‑promoting activity.
Metabolite Activity
6‑Hydroxymelatonin retains modest affinity for MT receptors but is rapidly sulfated, rendering it largely inactive. Therefore, the pharmacodynamic (PD) effect of melatonin is tightly coupled to the parent compound’s plasma concentration rather than to its metabolites.
Elimination: Half‑Life and Clearance
The apparent elimination half‑life (t½) of melatonin after a single IR dose ranges from 30 to 60 minutes in young adults, extending to 80–120 minutes in the elderly due to reduced hepatic blood flow and lower CYP1A2 activity. Renal excretion accounts for ~ 15 % of the administered dose, primarily as conjugated metabolites.
| Population | Mean t½ (min) | Clearance (L/h) |
|---|---|---|
| Young adults (20–35 y) | 35–45 | 12–15 |
| Middle‑aged (36–55 y) | 45–55 | 10–12 |
| Elderly (≥ 65 y) | 80–120 | 6–8 |
| CYP1A2 poor metabolizers | 90–130 | ↓ 30 % |
The relatively short half‑life underscores why a single low dose (0.3–1 mg) can be sufficient to advance sleep onset when timed correctly, while higher doses may produce a prolonged exposure that could interfere with the natural decline of melatonin in the early morning.
Pharmacokinetic Variability: Factors Influencing Sleep‑Onset Efficacy
- Age – Declining CYP1A2 activity and reduced renal clearance in older adults lengthen melatonin exposure, often allowing lower doses to achieve the same PD effect as higher doses in younger individuals.
- Genetic Polymorphisms – CYP1A2*1F (inducible) carriers metabolize melatonin faster, potentially requiring a modest dose increase or earlier administration. Conversely, CYP2C19 poor metabolizers may experience prolonged exposure.
- Smoking and Diet – Polycyclic aromatic hydrocarbons in tobacco induce CYP1A2, shortening melatonin half‑life. Conversely, cruciferous vegetables and certain flavonoids can inhibit CYP1A2, extending exposure.
- Drug Interactions – Strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) can double melatonin AUC, raising the risk of next‑day grogginess. Inducers (e.g., carbamazepine, rifampin) may halve exposure, diminishing efficacy.
- Formulation Choice – Immediate‑release products deliver a sharp, transient peak that aligns with the physiological “melatonin surge” needed for sleep initiation. Controlled‑release formulations flatten the curve, which may be less effective for pure sleep‑onset problems but useful for fragmented sleep.
Translating PK Data into Practical Recommendations for Sleep Onset
| Goal | Recommended Formulation | Typical Dose | Timing Relative to Bedtime | Rationale |
|---|---|---|---|---|
| Rapid sleep onset (≤ 15 min) | Sublingual spray or IR tablet | 0.3–1 mg (low dose) | 30 min before intended sleep | Fast Tmax, minimal residual morning levels |
| Moderate latency (≈ 30 min) | IR tablet or softgel | 1–3 mg | 45–60 min before bedtime | Adequate Cmax, still short t½ |
| Prolonged latency (≥ 45 min) or mild insomnia | IR tablet | 3–5 mg | 60–90 min before bedtime | Higher Cmax compensates for delayed absorption (e.g., after a light snack) |
| Elderly or CYP1A2 poor metabolizers | IR tablet, low dose | 0.5–1 mg | 30 min before bedtime | Longer t½ reduces need for higher dose; avoids morning hangover |
| Patients on CYP1A2 inhibitors | IR tablet, reduced dose | 0.3–0.5 mg | 30 min before bedtime | Prevents excessive plasma levels |
Key Timing Principle: The plasma melatonin concentration should rise ≈ 30 min before the desired sleep onset and begin to decline ≈ 2 h after lights‑off. This mirrors the natural nocturnal profile and minimizes interference with the circadian “melatonin trough” that occurs in the early morning.
Special Populations and Clinical Considerations
Pediatric Use
Children metabolize melatonin faster than adults (t½ ≈ 20–30 min). Consequently, higher per‑kilogram doses (0.5–1 mg/kg) are often required to achieve comparable plasma peaks. However, the short half‑life still supports a rapid decline, reducing the risk of daytime sedation.
Pregnancy and Lactation
Placental transfer of melatonin is limited, and the fetal pineal gland is immature. While PK data are sparse, the short half‑life and low oral bioavailability suggest minimal systemic accumulation. Nonetheless, clinicians typically recommend the lowest effective dose (≤ 1 mg) and avoid use in the first trimester unless clearly indicated.
Renal Impairment
Since only a minor fraction of melatonin is renally excreted unchanged, moderate renal dysfunction does not markedly affect PK. Severe impairment (eGFR < 15 mL/min) may modestly increase plasma levels of conjugated metabolites, but clinical relevance for sleep onset remains low.
Future Directions in Melatonin Pharmacokinetics Research
- Population PK Modeling – Integrating age, genotype, and lifestyle covariates into a unified model could enable personalized dosing algorithms embedded in mobile health apps.
- Nanoparticle and Liposomal Delivery – Early-phase studies suggest that encapsulating melatonin in lipid nanocarriers can increase oral bioavailability up to 2‑fold and shorten Tmax, potentially improving sleep‑onset efficacy at lower doses.
- Chronopharmacology of Metabolism – Emerging evidence indicates that CYP1A2 activity itself follows a circadian rhythm, peaking during the day. Administering melatonin at night may therefore encounter reduced metabolic clearance, a factor that could be leveraged to fine‑tune dosing schedules.
- Real‑World Pharmacovigilance – Large‑scale databases (e.g., FDA’s FAERS) are being mined to quantify the incidence of next‑day somnolence in relation to dose, formulation, and concomitant CYP1A2 inhibitors, providing a pragmatic safety net for clinicians.
Bottom Line
The pharmacokinetic profile of melatonin—characterized by rapid absorption, extensive distribution, swift hepatic metabolism (predominantly via CYP1A2), and a short elimination half‑life—directly shapes its ability to advance sleep onset. By selecting the appropriate formulation, adjusting the dose for age and metabolic status, and timing administration to coincide with the natural rise of endogenous melatonin, clinicians and users can harness the drug’s PK properties to achieve a prompt, reliable transition to sleep while minimizing residual morning effects. Understanding these PK nuances transforms melatonin from a generic over‑the‑counter supplement into a precision chronobiotic tailored to individual physiological and lifestyle variables.
