01 — Introduction

What this page covers

For each ingredient we give the study design, the number of participants, the measured effect with its confidence interval and p-value, and the route of administration that was studied. Every figure on this page is traceable to a numbered source with a DOI or PubMed link.

Any transdermal formulation begins with the same question: can the molecule cross the stratum corneum? The reference point is the 500 Dalton rule (Bos and Meinardi, Experimental Dermatology 2000): compounds below roughly 500 g/mol can pass the horny layer, larger ones generally cannot. All four actives here sit well under that line - glycine at 75.07 g/mol, magnesium as an ion at 24.31 g/mol, melatonin at 232.28 g/mol, valerenic acid at 234.33 g/mol.

Below: what the literature establishes, ingredient by ingredient, and a numbered bibliography of 24 sources with DOI or PubMed links.

02 — Actives

The actives in detail

Melatonin

0.4 mg per patchEstablished

Melatonin is the one active in this formula with a randomised, double-blind, crossover trial of a transdermal patch behind it. Aeschbach and colleagues (2009, Clinical Pharmacology and Therapeutics) applied a 2.1 mg melatonin patch to eight healthy adults sleeping during the daytime. Plasma melatonin peaked at 690 pmol/L (SD 139) after 8.6 hours. Wake after sleep onset fell from 119.6 to 64.0 minutes (p = 0.047) and REM sleep rose by 20.7 minutes (p = 0.016). Plasma levels differed strongly by sex (women 1018.7 pmol/L, men 362.0 pmol/L, p = 0.002). That trial is the closest published analogue to a melatonin patch worn overnight.

Melatonin is also by a wide margin the best-studied of the four actives, and the pooled evidence is consistent in direction. Ferracioli-Oda and colleagues (2013, PLOS ONE) meta-analysed 19 randomised placebo-controlled trials covering 1,683 participants with primary sleep disorders. Melatonin shortened sleep onset latency by a weighted mean of 7.06 minutes (95% CI 4.37 to 9.75; Z = 5.15; p < 0.001) and increased total sleep time by 8.25 minutes (95% CI 1.74 to 14.75; Z = 2.48; p = 0.013). Oral route.

Cruz-Sanabria and colleagues (2024, Journal of Pineal Research) ran a dose-response meta-analysis across 26 randomised controlled trials and 1,689 observations. The effect on sleep onset latency and total sleep time grew with dose up to roughly 4 mg per day and flattened above that, and was largest when melatonin was taken about three hours before bedtime. Timing matters at least as much as amount.

The effect is measurable at very low doses, which is the finding most relevant to a low-dose patch. Zhdanova and colleagues (1996, Sleep) gave 0.3 to 1.0 mg orally two to four hours before habitual bedtime and found a significant shortening of polysomnographic sleep onset latency. Pires and colleagues (2001, Journal of Pineal Research) repeated the low-dose design in six healthy young men at 0.3 and 1.0 mg and again measured significantly reduced sleep latencies. Brzezinski and colleagues (2005) pooled 17 studies with 284 subjects: reduced latency, longer total sleep time, sleep efficiency up by about 2 percentage points. Auld and colleagues (2017) found the most convincing signal for sleep onset latency in primary insomnia (p = 0.002) and in delayed sleep phase syndrome (p < 0.0001).

Form studied: Melatonin, C13H16N2O2, molecular weight 232.28 g/mol - well below the 500 Dalton threshold of Bos and Meinardi (2000), and lipophilic, which is the favourable combination for crossing the lipid bilayers of the stratum corneum. Human skin absorption is documented (TRANSDERMAL: Lee 1994, Benes 1997, Aeschbach 2009, Zetner 2021 - mean transdermal bioavailability about 10 percent, tmax around 20 hours). Efficacy data above are from the ORAL route except where marked transdermal.
Study design: Meta-analysis of 19 randomised placebo-controlled trials (oral route), supported by a dose-response meta-analysis of 26 RCTs; plus one randomised double-blind crossover trial of a 2.1 mg transdermal patch (n=8)
Source: Ferracioli-Oda E, Qawasmi A, Bloch MH (2013). PLOS ONE 8(5):e63773. 19 RCTs, n=1683, oral route. | Aeschbach D, Lockyer BJ, Dijk DJ, et al. (2009). Clin Pharmacol Ther 86(4):378-382. Transdermal 2.1 mg patch, randomised double-blind crossover, n=8.
View study

Glycine

30.0 mg per patchEmerging

Glycine shortens the time it takes to fall asleep, and that has been measured with full polysomnography rather than by questionnaire alone.

Yamadera and colleagues (2007, Sleep and Biological Rhythms) gave 3 g of glycine orally before bedtime to volunteers who reported unsatisfactory sleep. Glycine improved subjective sleep quality and sleep efficiency (sleep time divided by time in bed) and shortened the polysomnographically measured latency both to sleep onset and to slow-wave sleep, while leaving sleep architecture intact. It also reduced daytime sleepiness and improved performance on a memory recognition task the following day. Sleep architecture staying intact is the striking part: benzodiazepine hypnotics typically suppress slow-wave and REM sleep, and glycine did not.

Inagawa and colleagues (2006, Sleep and Biological Rhythms) ran a randomised double-blind crossover trial in volunteers dissatisfied with their sleep, again 3 g orally before bed, assessed with the St Mary's Hospital Sleep Questionnaire and a fatigue checklist. Glycine significantly improved the morning-after ratings for fatigue, for liveliness and peppiness, and for clear-headedness.

Glycine acts both as an inhibitory neurotransmitter at strychnine-sensitive glycine receptors and as an obligatory co-agonist at the NMDA receptor. Bannai and Kawai (2012, Journal of Pharmacological Sciences) summarised this line of work and proposed the mechanism: glycine lowers core body temperature. Core temperature falls physiologically at sleep onset, and accelerating that fall plausibly shortens latency.

Kawai and colleagues (2015, Neuropsychopharmacology) tested the mechanism directly in animals. Glycine induced c-Fos expression in the shell of the suprachiasmatic nucleus; bilateral microinjection of glycine into the suprachiasmatic nucleus raised cutaneous blood flow dose-dependently; and ablation of the nucleus abolished both the sleep-promoting and the hypothermic effects. The mechanism is therefore central and NMDA-receptor mediated, with peripheral vasodilatation as the effector step.

Form studied: Glycine, C2H5NO2, molecular weight 75.07 g/mol - the smallest of the twenty proteinogenic amino acids and the lightest active in this formula, far below the 500 Dalton threshold of Bos and Meinardi (2000). The sleep trials cited used the ORAL route at 3 g.
Study design: Randomised, double-blind, placebo-controlled crossover trials with polysomnography (oral route, 3 g); mechanism confirmed in a controlled animal lesion and microinjection study
Source: Yamadera W, Inagawa K, Chiba S, et al. (2007). Sleep and Biological Rhythms 5(2):126-131. Polysomnography, 3 g oral. | Inagawa K, Hiraoka T, Kohda T, et al. (2006). Sleep and Biological Rhythms 4(1):75-77. Randomised double-blind crossover, 3 g oral.
View study

Magnesium

40.0 mg per patchEmerging

Magnesium shortens sleep onset latency by 17.36 minutes against placebo. That figure comes from Mah and Pitre (2021, BMC Complementary Medicine and Therapies), who pooled three randomised controlled trials with 151 adults aged 55 and over who had insomnia, taking 320 to 729 mg of elemental magnesium daily by mouth, split across two or three doses, for 20 days to 8 weeks (95% CI -27.27 to -7.44; p = 0.0006).

Schuster and colleagues (2025, Nature and Science of Sleep) ran a larger and cleaner trial: 155 adults aged 18 to 65 reporting poor sleep quality, randomised double-blind to 250 mg elemental magnesium as magnesium bisglycinate or to placebo, taken orally. The Insomnia Severity Index fell further on magnesium than on placebo from baseline to week 4 (-3.9, 95% CI -5.8 to -2.0, versus -2.3, 95% CI -4.1 to -0.4; p = 0.049).

Abbasi and colleagues (2012, Journal of Research in Medical Sciences) randomised 46 older adults to 500 mg magnesium or placebo for 8 weeks and reported improvements in Insomnia Severity Index, sleep efficiency and sleep onset latency.

The mechanism is well characterised. Magnesium is a cofactor in more than 300 enzymatic reactions and acts as a physiological NMDA receptor antagonist and GABA-A agonist - the same inhibitory axis that the other actives in this formula engage.

Form studied: Magnesium is delivered as the Mg2+ ion (atomic mass 24.31 g/mol); in the bisglycinate salt the complex is 172.42 g/mol. Both sit far under the 500 Dalton threshold of Bos and Meinardi (2000). The efficacy trials cited used the ORAL route.
Study design: Systematic review and meta-analysis of 3 randomised controlled trials (oral route), plus a 4-week randomised double-blind placebo-controlled trial (n=155, oral route)
Source: Mah J, Pitre T (2021). BMC Complement Med Ther 21:125. Meta-analysis of 3 RCTs, n=151, oral, 320-729 mg elemental Mg/day. | Schuster J, Cycelskij I, Lopresti A, et al. (2025). Nat Sci Sleep 17:2027-2040. RCT, n=155, oral magnesium bisglycinate 250 mg elemental.
View study

Valerian Root Extract

10.0 mg per patchEmerging

Valerian improves the Pittsburgh Sleep Quality Index with a standardised mean difference of -1.21 (95% CI -1.92 to -0.51). That is the headline result from Shinjyo, Waddell and Green (2020, Journal of Evidence-Based Integrative Medicine), who screened 60 studies covering 6,894 participants and meta-analysed the subset with usable sleep-quality data (10 studies, 1,065 participants). The same analysis found improved self-reported sleep quality with a risk ratio of 1.37 (95% CI 1.13 to 1.68) and improved self-reported sleep duration with a risk ratio of 1.27 (95% CI 1.02 to 1.57). On polysomnography, valerian significantly increased the length of NREM stage 3. Trials used oral extract.

Bent and colleagues (2006, American Journal of Medicine) reviewed 16 randomised placebo-controlled trials with 1,093 patients and found significant improvement in sleep quality alongside a favourable adverse-effect profile.

Mechanistically the picture is well resolved. Benke and colleagues (2009, Neuropharmacology) showed that valerenic acid, the marker sesquiterpenoid of valerian root, selectively modulates GABA-A receptors containing beta-2 or beta-3 subunits, with negligible effect on receptors containing beta-1. The modulation is insensitive to flumazenil and does not require the gamma-2 subunit, so it is pharmacologically distinct from benzodiazepines, and valerenic acid did not markedly reduce locomotor activity even at high doses.

Valeriana officinalis is among the most-studied herbal sleep aids, and the variation between trials tracks variation in plant material and extraction method - which is why the extract used matters.

Form studied: The marker constituent is valerenic acid, C15H22O2, molecular weight 234.33 g/mol - under the 500 Dalton threshold of Bos and Meinardi (2000) and markedly lipophilic as a sesquiterpene carboxylic acid, which favours partition into the stratum corneum. Valerian root extract is a multi-component botanical, so the 500 Dalton figure applies to valerenic acid specifically. The clinical trials cited used ORAL extract, typically 300-600 mg.
Study design: Systematic reviews and meta-analyses of randomised placebo-controlled trials (oral route); mechanism from in vitro receptor electrophysiology and in vivo behavioural pharmacology
Source: Shinjyo N, Waddell G, Green J (2020). J Evid Based Integr Med 25:2515690X20967323. 60 studies screened, n=6894; meta-analysis of 10 studies, n=1065, oral. | Fernandez-San-Martin MI, Masa-Font R, Palacios-Soler L, et al. (2010). Sleep Medicine 11(6):505-511. 18 RCTs, n=1317, oral.
View study

03 — Transdermal evidence

Why through the skin

A SHORT HISTORY OF THE ROUTE

Delivering a drug through intact skin into the bloodstream is regulated pharmaceutical practice with a documented starting date: in December 1979 the US Food and Drug Administration approved Transderm Scop, a scopolamine patch for motion sickness, as the first transdermal delivery system. Nicotine, estradiol, testosterone, nitroglycerin, clonidine, fentanyl, rivastigmine, rotigotine and buprenorphine patches followed. More than four decades of regulated clinical use stand behind the route.

THE 500 DALTON RULE

The standard screening heuristic comes from Jan Bos and Marcus Meinardi, writing in Experimental Dermatology in 2000. Their conclusion: for a compound to be absorbed through the skin its molecular weight should be below approximately 500 Dalton.

They built the rule on three independent observations, and it is worth naming them precisely, because the rule is usually cited without them.

First: virtually all common contact allergens are under 500 Dalton. Larger molecules are not known as contact sensitizers - which follows if they never reach the immune cells of the epidermis in the first place.

Second: the most commonly used pharmacological agents in topical dermatotherapy are all under 500 Dalton.

Third: every known drug used in a transdermal drug-delivery system is under 500 Dalton.

Bos and Meinardi added a fourth supporting line from clinical experience with large topical immunomodulators: ciclosporin, at about 1202 Dalton, fails when applied topically, while the smaller ascomycin macrolactams work - exactly what the rule predicts.

Alongside mass, lipophilicity favours permeation, because the intercellular route through the stratum corneum runs through lipid bilayers.

THE FOUR ACTIVES BY MOLECULAR WEIGHT

Magnesium, delivered as the Mg2+ ion: atomic mass 24.31 g/mol. As magnesium bisglycinate, the complex is 172.42 g/mol.
Glycine, C2H5NO2: 75.07 g/mol.
Melatonin, C13H16N2O2: 232.28 g/mol.
Valerenic acid, C15H22O2, the marker constituent of valerian root: 234.33 g/mol.

All four sit comfortably below 500 Dalton. Melatonin and valerenic acid are also lipophilic, which is the favourable combination for partition into the stratum corneum.

HUMAN EVIDENCE FOR TRANSDERMAL MELATONIN

Melatonin has published human data on skin absorption. Four studies are relevant.

Lee and colleagues (1994) applied a 3.80 cm2 transdermal device to the forearm of four subjects. Plasma melatonin rose above baseline within two to four hours, and cumulative urinary excretion of the metabolite 6-sulfatoxymelatonin over six hours was about three times that of controls. Absorption through human skin: demonstrated.

Benes and colleagues (1997, Journal of Pharmaceutical Sciences) ran a crossover study in twelve adult male volunteers comparing oral controlled-release, oral transmucosal and transdermal melatonin, with melatonin and 6-sulfatoxymelatonin measured in plasma by radioimmunoassay. The transdermal system produced slower systemic levels, consistent with the skin acting as a reservoir.

Zetner and colleagues quantified it. Their 2016 systematic review covered ten studies of alternative melatonin administration routes. Their 2021 crossover study in ten healthy female volunteers - comparing intravenous, rectal, intravesical, vaginal and transdermal melatonin at 25 mg - measured a mean transdermal bioavailability of 10.0 percent (SD 5.7), a mean tmax of 20.5 hours and a terminal half-life of 14.6 hours. Slow and sustained.

The study that connects transdermal melatonin to an actual sleep outcome is Aeschbach and colleagues (2009, Clinical Pharmacology and Therapeutics): a randomised, double-blind, crossover trial in eight healthy adults attempting to sleep during the daytime, using a 2.1 mg patch. Plasma melatonin peaked at 690.4 pmol/L (SD 138.8) at 8.58 hours. Wake after sleep onset dropped from 119.6 to 64.0 minutes (p = 0.047) and REM sleep increased by 20.7 minutes (p = 0.016). Plasma levels differed sharply by sex - 1018.7 pmol/L in women versus 362.0 pmol/L in men (p = 0.002) - a reminder that skin permeability varies between people.

Flo and colleagues (2017, European Journal of Pharmaceutical Sciences) showed in hairless rats that transdermal melatonin pharmacokinetics shift with the time of day.

FIRST-PASS METABOLISM, AND WHY A PATCH IS NOT A CAPSULE

An oral dose is not a systemic dose. Anything swallowed is absorbed across the gut wall and carried by the portal vein to the liver, where a portion is metabolised before it ever reaches the general circulation. For melatonin this first-pass effect is severe: a large share of an oral dose is metabolised on the first hepatic pass, principally by the cytochrome P450 enzyme CYP1A2, and reported oral bioavailability is both low and highly variable between individuals, driven largely by differences in CYP1A2 activity. Most of the dose ends up excreted in urine as the inactive metabolite 6-sulfatoxymelatonin.

A transdermal system bypasses the portal circulation entirely. The systemically available fraction is governed by skin flux instead, which for melatonin was measured at about 10 percent of the applied dose with a tmax near 20 hours.

What a patch offers is a slow, continuous input across roughly eight hours of wear rather than a single peak that has largely cleared by the middle of the night - which is precisely the pharmacokinetic profile the transdermal melatonin studies describe.

04 — Product evidence

What exists for this product itself

Sleep Please rests on three established foundations.

The ingredient science is peer-reviewed and, for melatonin, extends to randomised placebo-controlled trials and meta-analyses covering thousands of participants. Sleep onset latency, total sleep time and sleep efficiency have all been measured against placebo and reported with confidence intervals and p-values, and every one of those figures is cited below.

The delivery route is regulated pharmaceutical practice. Transdermal systems have been approved and in continuous clinical use since the FDA cleared the first one in December 1979 - more than 45 years of nicotine, estradiol, testosterone, nitroglycerin, fentanyl, rivastigmine, rotigotine and buprenorphine patches. For melatonin specifically, human skin absorption is documented, with a measured transdermal bioavailability of 10.0 percent (SD 5.7) and a mean tmax of 20.5 hours.

The formulation is built around what that route provides: a slow, continuous input across a night of wear rather than a single peak that has largely cleared by the middle of the night.

Alongside the published literature we run our own customer research, reported in full below with its method. We are investing in product-specific testing of the finished patch, and results will be published on this page as they arrive.

05 — User data

What our users report

In an internal customer survey, users reported the following after using Sleep Please:

91 percent fell asleep faster
85 percent slept through the night
89 percent woke up feeling refreshed

These are self-reported figures from our own customers. They are not clinical trial endpoints and should be read together with the method note below, which is part of the claim and not a footnote to it.

Internal customer survey, n greater than 500 users, after 30 or more days of consistent use, self-reported questionnaire. This is NOT a randomised clinical trial: there was no placebo control, no blinding, no randomisation and no objective sleep measurement, and respondents were existing customers, which introduces selection and response bias. These numbers describe what our customers told us, not a measured treatment effect.

06 — Safety

Safety and side effects

For external use only. Do not reuse a patch. Wear for up to 8 hours and change the application site with every use. Do not apply to broken, damaged, irritated or sensitive skin. Discontinue use and seek medical advice if irritation or an allergic reaction occurs.

Do not use during pregnancy or while breastfeeding, and do not use alongside prescription medication - in particular sedatives, hypnotics, anticoagulants, antihypertensives, immunosuppressants or antidepressants - without consulting a doctor first. Melatonin is metabolised by the liver enzyme CYP1A2, and inhibitors of that enzyme such as fluvoxamine can substantially raise melatonin plasma levels. Valerian may add to the effect of alcohol and of other central nervous system depressants. Do not drive or operate machinery if you feel drowsy.

Not for use by anyone under 18 years of age. Keep out of the reach of children. Consult a doctor before use if you have a diagnosed sleep disorder, an autoimmune condition, epilepsy or liver disease, or if your symptoms persist beyond two weeks.

These statements have not been evaluated by the Food and Drug Administration, or by the equivalent regulatory authority in the country of sale. This product is not intended to diagnose, treat, cure or prevent any disease.

07 — References

References

MELATONIN - CLINICAL EFFICACY

[1] Ferracioli-Oda E, Qawasmi A, Bloch MH (2013). Meta-analysis: melatonin for the treatment of primary sleep disorders. PLOS ONE 8(5):e63773. 19 randomised placebo-controlled trials, n = 1,683. Sleep onset latency reduced by 7.06 min (95% CI 4.37 to 9.75; Z = 5.15; p < 0.001); total sleep time increased by 8.25 min (95% CI 1.74 to 14.75; Z = 2.48; p = 0.013). Oral route.
https://doi.org/10.1371/journal.pone.0063773
[2] Cruz-Sanabria F, Bruno S, Crippa A, et al. (2024). Optimizing the time and dose of melatonin as a sleep-promoting drug: a systematic review of randomized controlled trials and dose-response meta-analysis. Journal of Pineal Research 76(5):e12985. 26 RCTs, 1,689 observations. Effect on sleep onset latency and total sleep time increases with dose up to about 4 mg/day; largest effect when taken about 3 hours before bedtime. Oral route.
https://doi.org/10.1111/jpi.12985
[3] Brzezinski A, Vangel MG, Wurtman RJ, et al. (2005). Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Medicine Reviews 9(1):41-50. 17 studies, n = 284. Decreased sleep onset latency, increased sleep efficiency by about 2 percentage points, increased total sleep duration. Oral route.
https://doi.org/10.1016/j.smrv.2004.06.004
[4] Auld F, Maschauer EL, Morrison I, et al. (2017). Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Medicine Reviews 34:10-22. Strongest evidence for reduced sleep onset latency in primary insomnia (p = 0.002) and in delayed sleep phase syndrome (p < 0.0001). Oral route.
https://doi.org/10.1016/j.smrv.2016.06.005
[5] Zhdanova IV, Wurtman RJ, Morabito C, et al. (1996). Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep 19(5):423-431. 0.3 to 1.0 mg oral; significant shortening of polysomnographic sleep onset latency.
https://doi.org/10.1093/sleep/19.5.423
[6] Pires ML, Benedito-Silva AA, Pinto L, et al. (2001). Acute effects of low doses of melatonin on the sleep of young healthy subjects. Journal of Pineal Research 31(4):326-332. n = 6 healthy men, double-blind, 0.3 and 1.0 mg oral at three fixed evening times; significant decrease in sleep latencies.
https://doi.org/10.1034/j.1600-079X.2001.310407.x

MELATONIN - TRANSDERMAL ROUTE

[7] Lee BJ, Parrott KA, Ayres JW, Sack RL (1994). Preliminary evaluation of transdermal delivery of melatonin in human subjects. Research Communications in Molecular Pathology and Pharmacology 85(3):337-346. n = 4, 3.80 cm2 device on the forearm. Plasma melatonin above baseline within 2 to 4 hours; cumulative urinary 6-sulfatoxymelatonin over 6 hours about 3 times control. Transdermal, human.
https://pubmed.ncbi.nlm.nih.gov/7827808/
[8] Benes L, Claustrat B, Horriere F, et al. (1997). Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: a crossover study with melatonin. Journal of Pharmaceutical Sciences 86(10):1115-1119. n = 12 adult male volunteers, three routes, radioimmunoassay of melatonin and 6-sulfatoxymelatonin. Transmucosal delivery best reproduced the physiological profile with least variability; transdermal delivery gave slower and more variable systemic levels.
https://doi.org/10.1021/js970011z
[9] Aeschbach D, Lockyer BJ, Dijk DJ, Lockley SW, et al. (2009). Use of transdermal melatonin delivery to improve sleep maintenance during daytime. Clinical Pharmacology and Therapeutics 86(4):378-382. Randomised, double-blind, crossover, n = 8, 2.1 mg patch. Cmax 690.4 pmol/L (SD 138.8) at 8.58 hours. Wake after sleep onset 64.0 vs 119.6 min (p = 0.047); REM sleep +20.7 min (p = 0.016); sleep efficiency 85.2 vs 74.3 percent (p = 0.063). Sex difference in plasma levels: 1018.7 vs 362.0 pmol/L (p = 0.002). Transdermal, human.
https://doi.org/10.1038/clpt.2009.109
[10] Zetner D, Andersen LPH, Rosenberg J, et al. (2021). Pharmacokinetics and safety of intravenous, intravesical, rectal, transdermal, and vaginal melatonin in healthy female volunteers: a cross-over study. Pharmacology 106(3-4):169-176. n = 10, 25 mg. Transdermal bioavailability 10.0 percent (SD 5.7); mean tmax 20.5 hours; elimination half-life 14.6 hours.
https://doi.org/10.1159/000510252
[11] Zetner D, Andersen LP, Rosenberg J (2016). Pharmacokinetics of alternative administration routes of melatonin: a systematic review. Drug Research 66(4):169-173. 10 studies. Transdermal administration shows a variable absorption rate and probable deposition of melatonin in the skin.
https://doi.org/10.1055/s-0035-1565083
[12] Flo A, Cambras T, Diez-Noguera A, Calpena A (2017). Melatonin pharmacokinetics after transdermal administration changes according to the time of the day. European Journal of Pharmaceutical Sciences 96:164-170. ANIMAL STUDY (hairless rat), not human: transdermal bioavailability, tmax and absorption rate differed between Zeitgeber Time 4 and Zeitgeber Time 16.
https://doi.org/10.1016/j.ejps.2016.09.020

MAGNESIUM

[13] Mah J, Pitre T (2021). Oral magnesium supplementation for insomnia in older adults: a systematic review and meta-analysis. BMC Complementary Medicine and Therapies 21:125. 3 RCTs, n = 151, adults aged 55 and over, 320 to 729 mg elemental magnesium per day for 20 days to 8 weeks. Sleep onset latency 17.36 min shorter than placebo (95% CI -27.27 to -7.44; p = 0.0006); total sleep time +16.06 min, not significant. Oral route.
https://doi.org/10.1186/s12906-021-03297-z
[14] Schuster J, Cycelskij I, Lopresti A, et al. (2025). Magnesium bisglycinate supplementation in healthy adults reporting poor sleep: a randomized, placebo-controlled trial. Nature and Science of Sleep 17:2027-2040. n = 155, 250 mg elemental magnesium daily. Insomnia Severity Index, baseline to week 4: -3.9 (95% CI -5.8 to -2.0) versus placebo -2.3 (95% CI -4.1 to -0.4); p = 0.049; Cohen d = 0.2. Oral route.
https://doi.org/10.2147/NSS.S524348
[15] Abbasi B, Kimiagar M, Sadeghniiat K, et al. (2012). The effect of magnesium supplementation on primary insomnia in elderly: a double-blind placebo-controlled clinical trial. Journal of Research in Medical Sciences 17(12):1161-1169. n = 46, 500 mg per day for 8 weeks; improvements in Insomnia Severity Index, sleep efficiency and sleep onset latency. Oral route.
https://pubmed.ncbi.nlm.nih.gov/23853635/

GLYCINE

[16] Yamadera W, Inagawa K, Chiba S, et al. (2007). Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes. Sleep and Biological Rhythms 5(2):126-131. 3 g glycine before bedtime, polysomnography. Improved subjective sleep quality and sleep efficiency; shortened latency both to sleep onset and to slow-wave sleep; no change in sleep architecture; less daytime sleepiness and better memory recognition performance. Oral route.
https://doi.org/10.1111/j.1479-8425.2007.00262.x
[17] Inagawa K, Hiraoka T, Kohda T, et al. (2006). Subjective effects of glycine ingestion before bedtime on sleep quality. Sleep and Biological Rhythms 4(1):75-77. Randomised double-blind crossover, 3 g glycine. Significant improvement in morning ratings for fatigue, for liveliness and peppiness, and for clear-headedness. Oral route.
https://doi.org/10.1111/j.1479-8425.2006.00193.x
[18] Bannai M, Kawai N (2012). New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep. Journal of Pharmacological Sciences 118(2):145-148. Review; proposes reduction of core body temperature as the mechanism.
https://doi.org/10.1254/jphs.11R04FM
[19] Kawai N, Sakai N, Okuro M, et al. (2015). The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus. Neuropsychopharmacology 40(6):1405-1416. ANIMAL STUDY. Glycine induced c-Fos expression in the suprachiasmatic nucleus shell; microinjection raised cutaneous blood flow dose-dependently; ablation of the nucleus abolished both the sleep-promoting and the hypothermic effects.
https://doi.org/10.1038/npp.2014.326

VALERIAN

[20] Shinjyo N, Waddell G, Green J (2020). Valerian root in treating sleep problems and associated disorders - a systematic review and meta-analysis. Journal of Evidence-Based Integrative Medicine 25:2515690X20967323. 60 studies screened, n = 6,894; subjective sleep quality meta-analysis on 10 studies, n = 1,065. PSQI standardised mean difference -1.21 (95% CI -1.92 to -0.51); dichotomous sleep quality RR 1.37 (95% CI 1.13 to 1.68); self-reported sleep duration RR 1.27 (95% CI 1.02 to 1.57). Among objective parameters, significant for the length of NREM stage 3. Oral route.
https://doi.org/10.1177/2515690X20967323
[21] Fernandez-San-Martin MI, Masa-Font R, Palacios-Soler L, et al. (2010). Effectiveness of valerian on insomnia: a meta-analysis of randomized placebo-controlled trials. Sleep Medicine 11(6):505-511. 18 RCTs, n = 1,317. Dichotomous self-reported sleep quality RR 1.37 (95% CI 1.05 to 1.78) across 6 trials; sleep onset latency weighted mean difference 0.70 min (95% CI -3.44 to 4.83) across 10 trials. Oral route.
https://doi.org/10.1016/j.sleep.2009.12.009
[22] Bent S, Padula A, Moore D, et al. (2006). Valerian for sleep: a systematic review and meta-analysis. American Journal of Medicine 119(12):1005-1012. 16 randomised placebo-controlled trials, n = 1,093. Significant improvement in subjective sleep quality with a favourable adverse-effect profile. Oral route.
https://doi.org/10.1016/j.amjmed.2006.02.026
[23] Benke D, Barberis A, Kopp S, et al. (2009). GABA-A receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts. Neuropharmacology 56(1):174-181. Valerenic acid selectively modulates GABA-A receptors containing beta-2 or beta-3 subunits, with negligible effect on beta-1-containing receptors; the modulation is insensitive to flumazenil and does not require the gamma-2 subunit, and so is pharmacologically distinct from benzodiazepines.
https://doi.org/10.1016/j.neuropharm.2008.06.013

TRANSDERMAL DELIVERY - FUNDAMENTALS

[24] Bos JD, Meinardi MMHM (2000). The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Experimental Dermatology 9(3):165-169. The rule rests on three observations: virtually all common contact allergens are under 500 Dalton; the most commonly used topical dermatotherapeutic agents are all under 500 Dalton; and all known drugs used in transdermal delivery systems are under 500 Dalton. Supported by clinical experience with ciclosporin (about 1202 Dalton, ineffective topically) versus the smaller ascomycin macrolactams.
https://doi.org/10.1034/j.1600-0625.2000.009003165.x

View Bonne Nuit

Last reviewed: 19.08.2026 · 24 References