Peptides Studied for Sleep: DSIP and the Thin Evidence Base

Several peptides are marketed for sleep, and one of them has "sleep" in its name. The research behind them is thin. Most of the human studies are small laboratory experiments from the 1980s and 1990s, often in a dozen or so volunteers, measuring brain-wave sleep stages for a few nights. None has been tested as a sleep treatment in the kind of large, long trial used for approved sleep medicines.

This guide covers what each compound is, the strongest level of evidence we could find, and one or two findings sourced to PubMed. We order them by strength of evidence, not by how well they might work. Two non-peptides are included because they are sold alongside sleep peptides and give useful context.

A quick note on sleep terms

Sleep studies usually measure sleep stages with polysomnography (overnight recording of brain waves, eye movement and muscle tone). Slow-wave sleep (also called stage 4 or deep sleep) is the deepest non-REM stage. REM sleep is the stage linked to dreaming. Sleep latency is how long it takes to fall asleep. A change in these stages does not automatically mean people feel better rested.

Summary table

Melatonin (context, not a peptide)

What it is. A hormone made by the pineal gland at night. Chemically it is an indoleamine, not a peptide. See the melatonin page.

Strongest evidence: meta-analyses. A meta-analysis of 19 placebo-controlled studies (1,683 participants) found melatonin reduced the time to fall asleep by about 7 minutes and increased total sleep by about 8 minutes, with modest improvement in sleep quality (Ferracioli-Oda 2013). An earlier meta-analysis concluded melatonin was not effective for most primary sleep disorders with short-term use, with some evidence of benefit in delayed sleep phase syndrome (Buscemi 2005).

This is the best-studied compound in this guide, and its measured effects are small. Keep that in mind when reading claims about the peptides below.

MK-677 (context, not a peptide)

What it is. An oral, non-peptide growth hormone secretagogue (a compound that prompts the body to release growth hormone). See the MK-677 page.

Strongest evidence: one small controlled study. In 8 young adults, the higher of two bedtime doses (25 mg, the dose used in the study) increased stage 4 sleep by about 50% and REM sleep by more than 20% versus placebo over 7-day periods. In 6 older adults, REM sleep rose by nearly 50% (Copinschi 1997). The older-adult arm had no placebo period, and we found no larger follow-up trial.

DSIP (delta sleep-inducing peptide)

What it is. A nine-amino-acid peptide isolated from rabbit cerebral venous blood in 1977 and first regarded as a possible natural sleep-promoting factor (Kovalzon 2006). See the DSIP page. Products sold as emideltide are described as DSIP-related; we found no separate sleep studies for them.

Strongest evidence: small, conflicting human trials. In 14 people with chronic insomnia, DSIP given under placebo-controlled, double-blind conditions for 7 nights improved night sleep and daytime alertness (Schneider-Helmert 1987). A later double-blind study in 16 insomnia patients found higher sleep efficiency and shorter sleep latency, but the authors judged the effects weak, possibly due partly to a chance change in the placebo group, and concluded DSIP was "not likely to be of major therapeutic benefit" (Bes 1992).

The gap. That 2006 review called the link between DSIP and sleep "extremely poorly documented and still weak," noting that no DSIP gene, precursor protein or receptor had been identified (Kovalzon 2006).

GHRH (growth hormone-releasing hormone)

What it is. The brain hormone that signals the pituitary to release growth hormone. See the GHRH (1-29) page. The studies below tested GHRH, not sermorelin or other commercial analogues.

Strongest evidence: small randomized studies, with mixed results. In 12 young and 11 older healthy men, intranasal GHRH at bedtime increased REM and slow-wave sleep, mainly in the second half of the night (Perras 1999). In healthy young women, however, systemic GHRH reduced REM sleep at one dose and stage 4 sleep at another, and the authors concluded that GHRH "impairs sleep in women" (Mathias 2007).

Ghrelin

What it is. A hormone best known for signalling hunger, which also activates growth hormone release. See the ghrelin acetate page.

Strongest evidence: one small randomized study. In 10 healthy young men, ghrelin given at night, alone or with GHRH or CRH (a stress hormone), increased non-REM sleep and decreased REM sleep compared with placebo (Kluge 2008). The study was single-blind.

GHRP-6

What it is. A synthetic six-amino-acid peptide that stimulates growth hormone release. See the GHRP-6 page.

Strongest evidence: one small randomized study. In healthy men, repeated IV doses of GHRP-6 increased light (stage 2) sleep but did not change slow-wave sleep, while raising the stress hormones ACTH and cortisol (Frieboes 1995).

Orexin-A

What it is. A brain peptide (also called hypocretin-1) involved in regulating sleep and wakefulness. A deficiency of it can cause narcolepsy with cataplexy. See the orexin-A page.

Strongest evidence: small crossover trials in narcolepsy. In 8 patients, intranasal orexin-A before bed did not significantly change night-time wakefulness but reduced and stabilized REM sleep (Baier 2011). In 14 patients given it in the morning, REM sleep fell and attention errors decreased (Weinhold 2014). This is research into a wakefulness disorder, not a sleep aid.

Epitalon

What it is. A synthetic four-amino-acid peptide related to pineal gland peptide preparations. See the epitalon page.

Strongest evidence: animal and human reports of unclear design. A Russian-language paper reported that pineal peptide preparations, including epitalon, restored night-time melatonin release in old monkeys and raised night melatonin levels in elderly people with reduced pineal function (Korkushko 2007). The English abstract gives no participant numbers or control design, and no sleep outcomes were reported.

The bottom line

The sleep-peptide literature is small, old and inconsistent. The best-controlled work measures sleep stages over a few nights in healthy volunteers, and effects sometimes differ by sex or by time of dosing. DSIP, the compound most associated with sleep, produced mixed results in two small insomnia trials four decades ago and has no confirmed receptor. Melatonin, the comparison point here, has far more data and still shows only modest effects.

Sources

• Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One, 2013. PMID 23691095
• The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med, 2005. PMID 16423108
• Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology, 1997. PMID 9349662
• Delta sleep-inducing peptide (DSIP): a still unresolved riddle. J Neurochem, 2006. PMID 16539679
• Effects of delta-sleep-inducing peptide on 24-hour sleep-wake behaviour in severe chronic insomnia. Eur Neurol, 1987. PMID 3622582
• Effects of delta sleep-inducing peptide on sleep of chronic insomniac patients. A double-blind study. Neuropsychobiology, 1992. PMID 1299794
• Sleep and endocrine changes after intranasal administration of growth hormone-releasing hormone in young and aged humans. Psychoneuroendocrinology, 1999. PMID 10451909
• Systemic growth hormone-releasing hormone (GHRH) impairs sleep in healthy young women. Psychoneuroendocrinology, 2007. PMID 17850984
• Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males. Psychoneuroendocrinology, 2008. PMID 18329818
• Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology, 1995. PMID 7617137
• Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy. Sleep Med, 2011. PMID 22036605
• The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res, 2014. PMID 24406723
• [Normalizing effect of the pineal gland peptides on the daily melatonin rhythm in old monkeys and elderly people]. Adv Gerontol, 2007. PMID 17969590

This article is for educational and research purposes only and is not medical advice.