Sleep disturbances affect millions of people worldwide, and many turn to over‑the‑counter (OTC) options before seeking prescription therapy. Two of the most commonly stocked products are melatonin, a hormone‑derived supplement, and first‑generation antihistamines such as diphenhydramine and doxylamine, which are marketed for “nighttime relief.” While both can improve sleep in certain circumstances, their effectiveness varies markedly depending on the underlying pattern of insomnia. This article examines the evidence for each agent across the major clinical subtypes of insomnia, highlighting where one may outperform the other and outlining a pragmatic approach for clinicians and consumers alike.
1. Classifying Insomnia: The Clinical Subtypes
A nuanced comparison requires first defining the insomnia phenotypes most frequently encountered in primary care and sleep‑medicine settings.
| Subtype | Core Feature | Typical Etiology |
|---|---|---|
| Sleep‑Onset Insomnia (SOI) | Difficulty falling asleep (latency > 30 min) | Anxiety, hyperarousal, delayed circadian phase |
| Sleep‑Maintenance Insomnia (SMI) | Frequent awakenings or inability to stay asleep (total wake time after sleep onset > 30 min) | Age‑related sleep fragmentation, obstructive sleep apnea, nocturnal pain |
| Early‑Morning Awakening (EMA) | Premature awakening with inability to return to sleep (wake time > 30 min before desired) | Depression, advanced sleep phase, hormonal shifts |
| Circadian Rhythm‑Related Insomnia (CR‑I) | Misalignment between internal clock and external schedule (e.g., shift work, jet lag) | Shift work, travel across time zones, delayed/advanced sleep phase syndrome |
| Comorbid Insomnia | Insomnia occurring alongside another medical or psychiatric condition | Chronic pain, PTSD, substance use, neurodegenerative disease |
These categories are not mutually exclusive; many patients present with mixed features. Nevertheless, they provide a useful framework for evaluating the relative efficacy of melatonin versus antihistamines.
2. Melatonin: A Chronobiotic Perspective
Melatonin is a naturally occurring indoleamine secreted by the pineal gland in response to darkness. Its primary pharmacologic action is to signal “night” to the suprachiasmatic nucleus, thereby facilitating the onset of the sleep‑waking cycle. In the OTC context, melatonin is typically delivered as an immediate‑release tablet or a prolonged‑release formulation that mimics the physiological secretion profile.
Key pharmacokinetic attributes relevant to efficacy:
| Property | Typical Value (OTC product) |
|---|---|
| Time to peak plasma concentration (Tmax) | 30–60 min (immediate‑release) |
| Half‑life | 30–50 min (rapidly cleared) |
| Duration of action | 4–6 h (immediate‑release) or up to 8 h (prolonged‑release) |
| Metabolism | Hepatic (CYP1A2) with renal excretion of metabolites |
Because melatonin directly influences circadian timing, its greatest therapeutic impact is observed when insomnia is rooted in a phase misalignment or when the sleep‑onset process is delayed by insufficient endogenous melatonin.
3. Antihistamines: Sedation via Histamine‑H1 Blockade
First‑generation antihistamines (e.g., diphenhydramine, doxylamine) cross the blood‑brain barrier and antagonize central H1 receptors, producing a generalized sedative effect. Their sleep‑promoting properties are largely non‑specific, stemming from reduced cortical arousal rather than any chronobiotic influence.
Relevant pharmacokinetic considerations:
| Property | Typical Value (OTC product) |
|---|---|
| Time to peak plasma concentration (Tmax) | 1–3 h |
| Half‑life | 8–12 h (diphenhydramine) to 12–18 h (doxylamine) |
| Duration of action | 6–10 h (sedative effect) |
| Metabolism | Hepatic (CYP2D6) with renal excretion of metabolites |
The relatively long half‑life can be advantageous for maintaining sleep throughout the night, but it also raises the potential for residual daytime sedation—an aspect that falls outside the scope of this efficacy‑focused review.
4. Evidence Synthesis: Sleep‑Onset Insomnia
Melatonin
Randomized controlled trials (RCTs) consistently demonstrate that melatonin shortens sleep latency in individuals with delayed sleep phase or anxiety‑related SOI. Meta‑analyses of ≥10 RCTs report a mean reduction in sleep onset latency (SOL) of 7–12 minutes compared with placebo, with the effect size increasing when administered 30–60 minutes before the intended bedtime.
Antihistamines
Antihistamines also reduce SOL, but the magnitude is modest and highly variable. In trials involving healthy volunteers, diphenhydramine shortened SOL by 3–5 minutes on average. The sedative effect appears more pronounced in older adults, likely due to age‑related pharmacodynamic changes, but this subgroup is beyond the present focus.
Comparative Insight
When the primary problem is delayed sleep onset without significant nighttime awakenings, melatonin’s chronobiotic action yields a more reliable and reproducible reduction in SOL than antihistamines. Antihistamines may still be useful for individuals who experience acute, situational difficulty falling asleep (e.g., after a stressful event) and who prefer a single‑dose “sleep aid” without the need for timing relative to circadian phase.
5. Evidence Synthesis: Sleep‑Maintenance Insomnia
Melatonin
Prolonged‑release melatonin formulations have been evaluated for SMI, particularly in older adults with fragmented sleep. Results show a modest increase in total sleep time (TST) of 15–30 minutes and a reduction in wake after sleep onset (WASO) of 10–20 minutes. The benefit is more evident when endogenous melatonin production is diminished (e.g., in the elderly).
Antihistamines
Because of their longer half‑life, antihistamines tend to sustain sedation throughout the night, leading to a more pronounced reduction in WASO. Clinical trials report an average 20–35 minute decrease in nighttime awakenings and a 30–45 minute increase in TST. However, the effect plateaus after the first few nights, suggesting a ceiling effect.
Comparative Insight
For pure SMI where the patient does not have a circadian misalignment, antihistamines often outperform melatonin in extending uninterrupted sleep. Nevertheless, the advantage must be weighed against the risk of next‑day residual effects, which, while not discussed in depth here, are a known consideration in clinical practice.
6. Evidence Synthesis: Early‑Morning Awakening
Melatonin
Studies targeting EMA, particularly in patients with depressive symptomatology, have shown that melatonin can shift the timing of the sleep episode later, thereby reducing the likelihood of premature awakening. A pooled analysis of 6 RCTs found a mean delay in wake time of 30–45 minutes relative to placebo.
Antihistamines
Antihistamines do not influence the timing of the circadian clock; they merely induce sedation. Consequently, they have limited impact on EMA and may even exacerbate early awakening if the sedative effect wanes before the desired wake time.
Comparative Insight
When early awakening is the dominant complaint, melatonin is the preferred OTC option because of its ability to modestly shift the sleep window later. Antihistamines are unlikely to provide meaningful benefit in this scenario.
7. Evidence Synthesis: Circadian Rhythm‑Related Insomnia
Melatonin
The chronobiotic property of melatonin makes it the cornerstone of OTC management for jet lag, shift‑work disorder, and delayed/advanced sleep phase syndrome. Controlled trials demonstrate that appropriately timed melatonin (0.5–5 mg taken 1–2 h before the target bedtime) can advance or delay the circadian phase by 1–2 hours per night, facilitating alignment with the new schedule.
Antihistamines
Because antihistamines lack phase‑shifting capability, they do not correct the underlying misalignment. Their sedative effect may help an individual fall asleep at an atypical time, but the benefit is transient and does not persist across successive days of schedule change.
Comparative Insight
For any insomnia driven primarily by circadian desynchrony, melatonin is unequivocally superior. Antihistamines may serve as an adjunct for occasional “catch‑up” sleep but cannot replace the phase‑adjusting action of melatonin.
8. Evidence Synthesis: Comorbid Insomnia (Non‑Psychiatric)
While the focus of this article is on primary insomnia phenotypes, a brief note on comorbid conditions is warranted for completeness.
- Pain‑Related Insomnia: Antihistamines, through their sedative effect, can modestly improve sleep continuity, but they do not address pain pathways. Melatonin’s anti‑inflammatory properties have been explored, yet evidence for a clinically significant analgesic benefit remains limited.
- Respiratory‑Related Insomnia (e.g., mild obstructive events): Antihistamines may worsen upper airway resistance due to anticholinergic activity, whereas melatonin is neutral in this regard.
Overall, when insomnia is secondary to another condition, the choice of OTC aid should be guided by the dominant sleep phenotype rather than the comorbidity itself.
9. Practical Decision‑Making Framework
| Predominant Insomnia Feature | Preferred OTC Agent | Rationale |
|---|---|---|
| Delayed sleep onset (phase delay) | Melatonin (immediate‑release) | Aligns circadian timing, modest SOL reduction |
| Frequent nocturnal awakenings with intact sleep drive | Antihistamine (diphenhydramine or doxylamine) | Longer sedative window sustains sleep |
| Early‑morning awakening | Melatonin (prolonged‑release) | Shifts sleep window later |
| Jet lag / shift‑work misalignment | Melatonin (timed dosing) | Phase‑shifting capability |
| Mixed SOI + SMI without circadian issue | Consider combination (melatonin for onset, antihistamine for maintenance) – use only short‑term and monitor for residual sedation | |
| Unclear phenotype | Trial of melatonin (low dose) first, assess response; if SOL improves but awakenings persist, add antihistamine on an as‑needed basis |
Key Points for Consumers
- Timing matters – melatonin must be taken 30–60 minutes before the desired bedtime; antihistamines are usually taken right before sleep.
- Duration of effect – melatonin’s effect wanes after ~4–6 hours (immediate‑release), whereas antihistamines can last 8 hours or more.
- Consistency – melatonin benefits are enhanced with nightly use for at least 5–7 days, reflecting its role in phase adjustment. Antihistamines tend to produce a similar effect each night without cumulative adaptation (though tolerance can develop over weeks).
10. Summary and Future Directions
- Melatonin excels in insomnia subtypes where circadian timing is the primary barrier—delayed sleep onset, early‑morning awakening, and any form of rhythm‑related misalignment. Its modest but reliable reduction in sleep latency and ability to shift the sleep window make it the first‑line OTC choice for these patterns.
- Antihistamines provide a broader sedative “blanket” that is most useful for maintaining sleep once it has begun, particularly in sleep‑maintenance insomnia. Their longer half‑life can bridge nocturnal awakenings, but they do not correct underlying timing issues.
- Evidence gaps remain regarding head‑to‑head trials that stratify participants by insomnia phenotype. Future research should focus on direct comparative RCTs, dose‑optimization for specific subtypes, and the impact of combined melatonin‑antihistamine regimens on sleep architecture.
In clinical practice, a phenotype‑driven approach—identifying whether the patient’s chief complaint is falling asleep, staying asleep, waking too early, or dealing with a shifted schedule—allows the practitioner or consumer to select the OTC agent most likely to deliver meaningful improvement. By aligning the pharmacologic profile of melatonin or antihistamines with the specific insomnia pattern, users can achieve better sleep outcomes while minimizing unnecessary exposure to less effective agents.
