NutriStack
Diphenhydramine and Melatonin, a caution.
Melatonin can add to diphenhydramine's sleepiness and next-day grogginess when both are used as sleep aids. Melatonin has documented short-term effects on sleepiness and flight-relevant performance in some dosing contexts, while diphenhydramine can impair driving and attention. Risk is higher with higher melatonin doses, nighttime redosing, older age, or early-morning driving.
One pair, every claim cited. The two substances, the type, the mechanism, the recommendation, and the primary literature.
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From the interaction database
What the row says.
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At a glance
- Substances
- Diphenhydramine and Melatonin
- Pair type
- Caution
- Evidence (highest tier)
- Emerging
- Source citations
- 2 sources
- Stack Score effect
- −5 to your Stack Score (per scored caution row).
- Scope
- Supplement × Prescription
- Last verified
- May 30, 2026
Caution · Emerging evidence
Caution
What is happening. Melatonin can add to diphenhydramine's sleepiness and next-day grogginess when both are used as sleep aids. Melatonin has documented short-term effects on sleepiness and flight-relevant performance in some dosing contexts, while diphenhydramine can impair driving and attention. Risk is higher with higher melatonin doses, nighttime redosing, older age, or early-morning driving.
Mechanism. Diphenhydramine blocks central H1 and muscarinic receptors, producing sedation and anticholinergic cognitive slowing. Melatonin activates MT1/MT2 receptors to shift circadian timing and promote sleepiness, which can add to diphenhydramine-related impairment.
Recommendation. Avoid stacking melatonin with diphenhydramine unless your clinician specifically recommends it. If you use them together, use the lowest effective doses and leave a full night's sleep window before driving. Stop the combination if you wake confused, unsteady, or excessively drowsy.
Sources (2)
- Nave R, Iani C, Herer P, Gopher D, Lavie P. Residual effects of daytime administration of melatonin on performance relevant to flight. Behav Brain Res. 2002;131(1-2):87-95. PMID 11844575
- Weiler JM, Bloomfield JR, Woodworth GG, et al. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance: a randomized, placebo-controlled trial in the Iowa driving simulator. Ann Intern Med. 2000;132(5):354-363. PMID 10691585
Stack Score
How this pair moves the number.
Effect on the composite score
If both Diphenhydramine and Melatonin are in the same stack, this pair applies −5 to your Stack Score (per scored caution row).
The full algorithm, the clamping rules, and four worked stacks are documented at /methodology/stack-score.
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