NutriStack
Melatonin and Promethazine, a caution.
Melatonin can add to promethazine-related drowsiness, slowed reaction time, and next-day grogginess. Promethazine significantly impairs psychomotor function in healthy-volunteer studies, and melatonin can affect sleepiness and performance depending on timing and dose. The combination is more concerning when promethazine is used as a nighttime sedative or alongside cough products containing opioids.
One pair, every claim cited. The two substances, the type, the mechanism, the recommendation, and the primary literature.
Same shape as the other 1,729 pairs in the public database.
From the interaction database
What the row says.
Every entry follows the same shape: what is happening, the mechanism, the recommendation, and the primary literature.
At a glance
- Substances
- Melatonin and Promethazine
- 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 promethazine-related drowsiness, slowed reaction time, and next-day grogginess. Promethazine significantly impairs psychomotor function in healthy-volunteer studies, and melatonin can affect sleepiness and performance depending on timing and dose. The combination is more concerning when promethazine is used as a nighttime sedative or alongside cough products containing opioids.
Mechanism. Promethazine causes CNS depression through central H1 blockade with antimuscarinic and antidopaminergic effects. Melatonin promotes sleepiness through MT1/MT2 receptor signaling, which can add to promethazine's psychomotor and vigilance impairment.
Recommendation. Do not use melatonin to intensify promethazine's sedating effect. If your prescriber approves both, use the lowest effective doses and avoid driving until you know how you respond. Avoid adding alcohol, cannabis, opioids, or other sleep medicines.
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
- Kamei H, Isaji A, Noda Y, et al. Effects of single therapeutic doses of promethazine, fexofenadine and olopatadine on psychomotor function and histamine-induced wheal- and flare-responses: a randomized double-blind, placebo-controlled study in healthy volunteers. Arch Dermatol Res. 2012;304(4):263-272. PMID 22130869
Stack Score
How this pair moves the number.
Effect on the composite score
If both Melatonin and Promethazine 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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