Can I Take Melatonin with Tretinoin?

Is there an interaction between melatonin and topical tretinoin?

Topical tretinoin is a prescription retinoid sold as several products, each with its own label. Retin-A and Retin-A Micro are labeled for acne; Renova 0.02% cream is labeled only as an adjunct to a comprehensive skin care and sunlight avoidance program for mitigation (palliation) of fine facial wrinkles, and its label states that it does not eliminate wrinkles, repair sun-damaged skin, reverse photoaging or restore a more youthful skin structure [1]. The findings below come from the Renova label and should not be assumed to apply to every tretinoin product.

The Renova drug interactions section names other topical medications, medicated or abrasive soaps, shampoos, cleansers, cosmetics with a strong drying effect, products with high concentrations of alcohol, astringents, spices or lime, permanent wave solutions, electrolysis, hair depilatories or waxes, and other products that may irritate the skin, because they may increase irritation with Renova [1]. The same section says Renova should not be used by patients also taking drugs known to be photosensitizers, such as thiazides, tetracyclines, fluoroquinolones, phenothiazines or sulfonamides, because of possible augmented phototoxicity [1]. Melatonin is not named in that section [1].

How much tretinoin gets into the body?

The Renova label states that no percutaneous absorption study was conducted with Renova 0.02% in human volunteers [1]. For a different, 0.05% cream, absorption in healthy men was less than 2% after a single application and after 28 days of daily use, and bioavailability was less after repeated application [1]. The label also reports that transdermal absorption of tretinoin from various topical formulations ranged from 1% to 31% of the applied dose, depending on whether it was applied to healthy skin or dermatitic skin [1].

Melatonin's documented interactions

The best documented melatonin interaction involves fluvoxamine, a strong CYP1A2 inhibitor. In a small study of five healthy men, 50 mg of fluvoxamine taken with 5 mg of oral melatonin raised melatonin exposure about 17-fold and peak concentration about 12-fold, and the authors concluded that fluvoxamine inhibits melatonin elimination [7]. The Rozerem label, for ramelteon (a different, prescription melatonin-receptor drug), states that fluvoxamine raised ramelteon exposure roughly 190-fold and that the two should not be used together [5].

NCCIH says people with epilepsy and people taking blood thinner medications need to be under medical supervision if they use melatonin [8].

What melatonin can and cannot do for sleep

A 2013 meta-analysis of 19 randomized placebo-controlled trials in 1,683 adults and children with primary sleep disorders found melatonin shortened sleep latency by 7.06 minutes and increased total sleep time by 8.25 minutes compared with placebo [3]. A 2022 meta-analysis of 24 trials found melatonin was not significantly effective for sleep onset latency, total sleep time or sleep efficiency in adults with non-comorbid chronic insomnia, though it was effective in children and adolescents [9]. The American Academy of Sleep Medicine's 2017 guideline suggests clinicians not use melatonin for sleep-onset or sleep-maintenance insomnia in adults [10].

NCCIH says short-term use appears safe for most people, with headache, dizziness, nausea and sleepiness reported, and that long-term safety information is lacking [8]. A systematic review of adult trials using 10 mg or more found no detectable increase in serious adverse events across four low-risk-of-bias studies, but more drowsiness, headache and dizziness (rate ratio 1.40, 95% CI 1.15 to 1.69) [6].

The bigger problem: what is in the bottle

Melatonin is regulated as a dietary supplement, not an FDA-approved drug [4]. In a 2023 analysis, 25 melatonin gummy products bought online were tested, one sample per brand: 22 were inaccurately labeled, and among the 24 that contained melatonin the measured amount ranged from 74% to 347% of the labeled quantity, or 1.3 mg to 13.1 mg per serving [2]. One product labeled as containing 5 mg melatonin and 30 mg CBD had no detectable melatonin [2]. An earlier analysis of 31 supplements found melatonin content ranging from 83% below to 478% above the label, more than 71% outside a 10% margin, and serotonin in 8 products at 1 to 75 micrograms [11].

Poison control centers received 260,435 reports of pediatric melatonin ingestion from 2012 to 2021, a 530% rise in annual reports, including two deaths [4].

Using both: what the Renova label says

The Renova label directs once-daily evening use: gently wash the face with a mild soap, pat dry, wait 20 to 30 minutes, then apply a small pearl-sized amount (about a quarter inch or 5 mm across) in a light layer over the affected area, avoiding the eyes, ears, nostrils and mouth [1].

The label calls Renova a dermal irritant. In double-blind vehicle-controlled studies of 339 patients, almost all reported one or more local reactions such as peeling, dry skin, burning, stinging, erythema and pruritus; 32% had irritation that was severe, led to temporary discontinuation or led to use of a mild topical corticosteroid, and about 4% discontinued because of adverse reactions [1]. The label also says not to use Renova if the patient is pregnant, attempting to become pregnant or at high risk of pregnancy, or is sunburned or has eczema or other chronic facial skin conditions, and it advises minimizing exposure to sunlight and sunlamps and using sunscreen with an SPF of at least 15 plus protective clothing [1].