DSIP Research

DSIP, or delta sleep-inducing peptide, is a synthetic nonapeptide described in the 1970s as a candidate sleep factor. DSIP research is unusual in that the compound was named for an effect that later work largely failed to confirm.

What DSIP is

DSIP is a linear nonapeptide, sequence Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu or WAGGDASGE. PubChem records CID 68816, CAS 62568-57-4, formula C35H48N10O15 and molecular weight 848.8 for the free base. Research material is commonly supplied as an acetate salt, a chemically distinct substance of higher molecular weight. Its WHO International Nonproprietary Name, emideltide, is a naming assignment and confers no regulatory approval of its own.

The origin is widely misreported. In the founding animal study, the peptide was purified from the extracorporeal dialysate of cerebral venous blood in rabbits undergoing hypnogenic electrical stimulation of the thalamus ^[1]. It was not isolated from cerebrospinal fluid, nor from a naturally sleeping animal.

Whether DSIP occurs naturally in the body

In an in silico sequence study, Mikhaleva and colleagues reported in 2011 that nothing is known of DSIP's protein precursors or their encoding genes ^[2]. They proposed a JMJD1B-type histone demethylase as a possible precursor. That remains a hypothesis, not a demonstration.

A review by Kovalzon and Strekalova states that the link between DSIP and sleep was never characterized, partly because no DSIP gene, protein or receptor was isolated ^[3]. That review calls the sleep-factor hypothesis poorly documented and weak, and suggests another unidentified peptide accounts for the tissue signal. Most human reports of DSIP in plasma, brain, gut or milk measure DSIP-like immunoreactivity, which is antibody binding rather than identification of the peptide.

NCBI Gene 1831 is aliased DSIPI, but its official symbol is TSC22D3, and a structural study shows its product does not contain the DSIP sequence ^[4]. Evidence about that protein is not evidence about DSIP. No DSIP receptor has been identified ^[3]. Writing in 1987, DSIP researchers stated that several mechanisms of action had been proposed but that no convincing evidence had been obtained for any of them ^[5].

Animal and in vitro research

In a controlled rat EEG study, Tobler and Borbély concluded that neither DSIP nor arginine vasotocin qualified as a specific sleep-promoting substance ^[6]. In a second controlled rat study, Obál and colleagues found DSIP did not increase sleep while two D-amino-acid analogues did ^[7]. A controlled rabbit study of fourteen compounds found DSIP and most analogues had no statistically significant effect on sleep against saline ^[8].

In animal sleep assays, protease-resistant analogues repeatedly promoted sleep where the parent nonapeptide did not. Those analogues were engineered because DSIP itself failed in such assays. Analogue results are not DSIP results. In the same animal work, one analogue suppressed sleep ^[8] and one fragment was frankly arousing ^[7].

One in vitro result bears on non-injected routes: in cultured human intestinal epithelial monolayers, roughly 8 percent of apically applied DSIP survived two hours, with free tryptophan as the major metabolite ^[9].

What DSIP research shows in humans

The controlled human record is small, old and unregistered. Total exposure across all published controlled human sleep studies is roughly sixty to seventy subjects. No trial with DSIP as an intervention is registered on ClinicalTrials.gov under any of its names, and PubMed holds no systematic review, meta-analysis or Cochrane review of it. FDA states that the American Academy of Sleep Medicine and American College of Physicians chronic-insomnia guidelines do not discuss emideltide, and that the same holds for narcolepsy and opioid withdrawal ^[10]. Fourteen drugs are FDA-approved for insomnia in adults ^[10].

The founding human trial reported that DSIP did not change sleep onset latency or final waking time against placebo ^[10][11]. Its authors described only tendencies toward fewer awakenings and higher sleep efficiency, plus a slight arousing effect in the first hour. FDA's review also identifies a carryover problem in that crossover design. The same authors reported elsewhere that DSIP has delayed effects 13 to 22 hours later, so the placebo nights may have been contaminated by the preceding DSIP night ^[10].

The most quoted positive human study reported sleep onset latency falling from 58.4 to 27.6 minutes in fourteen chronic insomniacs ^[12]. FDA's 2026 review found this human study had no placebo arm despite being described as placebo-controlled, and reclassified it as externally matched controlled ^[10]. Those figures therefore describe change from baseline and comparison with an external matched control group, not a placebo comparison.

Monti and colleagues, the first independent group to test the claim in humans, ran a randomized, double-blind, placebo-controlled crossover in six severe chronic insomniacs ^[13]. A shorter sleep latency and roughly twenty extra minutes of total sleep did not reach significance against baseline or placebo. Where DSIP and placebo did differ significantly, for NREM sleep time and stage 2 sleep, the same differences were already present in the baseline values. The authors called the improvement of little clinical significance.

Bes and colleagues, independently, ran the only chronic-insomnia trial with a parallel placebo group, in sixteen chronic insomniacs ^[14]. They judged the effects weak and possibly an artifact of a change in the placebo group. Whether any objective measure reached significance there is disputed, because the abstract and FDA's reading of that paper differ ^[10][14].

The only modern controlled human EEG data point the other way. In a randomized human trial, Pomfrett and colleagues assigned twenty-four female surgical patients to DSIP or saline, awake and under isoflurane ^[15]. DSIP significantly reduced delta rhythm, lightened anesthetic depth and increased heart rate. Enrollment was single-sex, which limits how far the finding generalizes.

Four human studies of the endogenous signal also ran against the hypothesis. In twelve volunteers, plasma DSIP-like immunoreactivity peaked in mid-afternoon and bottomed after midnight, tracking body temperature rather than sleep ^[16]. In human patients with Cushing syndrome, delta sleep was markedly reduced while its correlation with morning DSIP-like immunoreactivity was negative ^[17]. In seven healthy men, DSIP-like immunoreactivity decreased at the initiation of sleep and showed no sleep-stage specificity ^[18]. Across a 34-hour manipulation of activity and bed rest in five men, DSIP and its phosphorylated form showed no or minimal change while TSH, cortisol, melatonin and LH moved ^[19].

Human endocrine findings conflict with each other. One controlled human trial found no effect of DSIP on CRH-induced or meal-induced ACTH and cortisol ^[20]. Two other human studies point the other way on ACTH. A randomized crossover in eleven men reported reduced plasma ACTH-like immunoreactivity for at least three hours after intravenous DSIP ^[21]. An independent group in Parma also reported a significant decrease in ACTH ^[22]. This literature is not settled in either direction. A separate controlled human trial in healthy women found no effect on growth hormone or prolactin, at an intravenous exposure the authors noted was enough to alter ECG patterns ^[23].

No systematic human safety dataset exists. FDA's account of adverse effects, drawn from small uncontrolled human studies, lists transient headache, nausea and vertigo, plus progressive hypotension in opioid-withdrawal patients ^[10].

Who produced the evidence

The early positive human sleep trials came from the Basel group that isolated the peptide, with its discoverer a co-author on the founding trial ^[1][11]. Independent groups in Montevideo, Amsterdam and Manchester reported null, weak or paradoxical human findings ^[13][14][15]. Independent animal laboratories had already failed to find the effect, in Zurich, in Moscow and elsewhere ^[6][7][8]. The split is not perfect, since the independent Parma group reported a positive endocrine effect ^[22]. None of the positive trials from that era carries a conflict-of-interest statement. Disclosure was not routinely required then, so the absence means little.

The clearest concession came from the positive side. Graf and Kastin reviewed the field in 1986 and treated the therapeutic work as still unestablished ^[24]. Graf had co-published DSIP work with the peptide's discoverer ^[5]. FDA reads that 1986 review as finding the results preliminary, with insufficient evidence that the peptide reliably induced or maintained sleep ^[10].

A publication-type search of the DSIP corpus returns no retractions, expressions of concern or errata. The problem is small samples, weak design by present standards and failed replication, not misconduct.

Regulatory status

Emideltide is not approved as a drug in the United States. FDA states there is no USP or NF monograph for its free base or acetate, and that neither is a component of an FDA-approved drug ^[10]. FDA reviewers proposed, in a briefing document dated May 2026, not adding either substance to the 503A Bulks List ^[10]. Their grounds included poor physicochemical characterization, insufficient evidence of effectiveness, immunogenicity concern for an injected nonapeptide, and uncharacterized addiction liability. FDA linked the reported sleep and analgesic effects to opioid-dependent mechanisms and noted that no nonclinical study characterizes that addiction risk ^[10]. FDA also found no human effectiveness or safety data for the subcutaneous route specified in the nominations.

The two compounding businesses that nominated the substance withdrew their nominations, and FDA continued the evaluation on its own initiative. No marketing application was ever filed with FDA, so no application was refused. News coverage of the July 2026 advisory committee meeting reported a vote against listing, with emideltide the only one of seven peptides not advanced. Health Affairs Forefront reported that every supporting vote for peptides at that meeting came from committee members with ties to peptide businesses or clinics.

A DSIP-containing Russian product, Deltaran, is described in the FDA document as marketed. It mixes the peptide with glycine, and FDA cautioned that its toxicology results cannot be attributed to DSIP. A current Russian registration has not been confirmed from a primary regulatory record.

Conclusion

DSIP's name records what its discoverers sought in the 1970s, not a replicated finding. Whether the nonapeptide occurs as such in the human body is unresolved, with no gene, precursor or receptor identified. Where independent groups tested the sleep claim in humans and in animals, the effect was weak, absent or reversed. That makes DSIP a failed replication problem rather than simply old evidence.

Frequently Asked Questions

Is there controlled human evidence that DSIP improves sleep? There is controlled human evidence, and it is mostly negative or weak. The founding human trial found no change in sleep onset latency or final waking time against placebo ^[10][11]. The two independent replications in chronic insomnia reported effects that were not significant, or weak and possibly a placebo-group artifact ^[13][14]. The most quoted positive human study had no placebo arm according to FDA's 2026 review ^[10][12].

Is DSIP approved or permitted for compounding in the United States? It is not approved in the United States. FDA states there is no USP or NF monograph for emideltide or its acetate, and that neither is a component of an FDA-approved drug ^[10]. FDA reviewers proposed in May 2026 not adding either to the 503A Bulks List ^[10].

References

1. 1

   Schoenenberger GA, Maier PF, Tobler HJ, Wilson K, Monnier M. The delta EEG (sleep)-inducing peptide (DSIP). XI. Amino-acid analysis, sequence, synthesis and activity of the nonapeptide. Pflugers Arch. 1978;376(2):119-29. PMID: 568769
2. 2

   Mikhaleva II, Prudchenko IA, Ivanov VT, Voitenkov VB. JmjC-domain-containing histone demethylases of the JMJD1B type as putative precursors of endogenous DSIP. Peptides. 2011;32(4):826-31. PMID 21262293.
3. 3

   Kovalzon VM, Strekalova TV. Delta sleep-inducing peptide (DSIP): a still unresolved riddle. J Neurochem. 2006;97(2):303-9. PMID 16539679.
4. 4

   Seidel G, Adermann K, Schindler T, Ejchart A, Jaenicke R, Forssmann WG, Rösch P. Solution structure of porcine delta sleep-inducing peptide immunoreactive peptide A homolog of the shortsighted gene product. J Biol Chem. 1997;272(49):30918-27. PMID 9388238.
5. 5

   Graf MV, Schoenenberger GA. Delta sleep-inducing peptide modulates the stimulation of rat pineal N-acetyltransferase activity by involving the alpha 1-adrenergic receptor. J Neurochem. 1987;48(4):1252-7. PMID 3029331.
6. 6

   Tobler I, Borbély AA. Effect of delta sleep inducing peptide (DSIP) and arginine vasotocin (AVT) on sleep and motor activity in the rat. Waking Sleeping. 1980;4(2):139-53. PMID 7405185.
7. 7

   Obál F Jr, Kovalzon VM, Kalikhevich VN, Török A, Alföldi P, Sáry G, Hajós M, Penke B. Structure-activity relationship in the effects of delta-sleep-inducing peptide (DSIP) on rat sleep. Pharmacol Biochem Behav. 1986;24(4):889-94. PMID 3754970.
8. 8

   Koval'zon VM. [Hypnogenic properties of DSIP peptide analogs: structural-functional relationship]. Izv Akad Nauk Ser Biol. 2001;(4):467-74. PMID 11525128.
9. 9

   Augustijns PF, Borchardt RT. Transport and metabolism of delta sleep-inducing peptide in cultured human intestinal epithelial cell monolayers. Drug Metab Dispos. 1995;23(12):1372-8. PMID 8689946.
10. 10

    US Food and Drug Administration. Pharmacy Compounding Advisory Committee briefing document: emideltide (free base) and emideltide acetate. Dated 11 May 2026; meeting 24 July 2026. https://www.fda.gov/media/193344
11. 11

    Schneider-Helmert D, Schoenenberger GA. The influence of synthetic DSIP (delta-sleep-inducing-peptide) on disturbed human sleep. Experientia. 1981;37(9):913-7. PMID 7028502.
12. 12

    Schneider-Helmert D. Effects of delta-sleep-inducing peptide on 24-hour sleep-wake behaviour in severe chronic insomnia. Eur Neurol. 1987;27(2):120-9. PMID 3622582.
13. 13

    Monti JM, Debellis J, Alterwain P, Pellejero T, Monti D. Study of delta sleep-inducing peptide efficacy in improving sleep on short-term administration to chronic insomniacs. Int J Clin Pharmacol Res. 1987;7(2):105-10. PMID 3583493.
14. 14

    Bes F, Hofman W, Schuur J, Van Boxtel C. Effects of delta sleep-inducing peptide on sleep of chronic insomniac patients. A double-blind study. Neuropsychobiology. 1992;26(4):193-7. PMID 1299794.
15. 15

    Pomfrett CJ, Dolling S, Anders NR, Glover DG, Bryan A, Pollard BJ. Delta sleep-inducing peptide alters bispectral index, the electroencephalogram and heart rate variability when used as an adjunct to isoflurane anaesthesia. Eur J Anaesthesiol. 2009;26(2):128-34. PMID 19142086.
16. 16

    Friedman TC, Garcia-Borreguero D, Hardwick D, Akuete CN, Stambuk MK, Dorn LD, Starkman MN, Loh YP, Chrousos GP. Diurnal rhythm of plasma delta-sleep-inducing peptide in humans. J Clin Endocrinol Metab. 1994;78(5):1085-9. PMID 8175965.
17. 17

    Friedman TC, García-Borreguero D, Hardwick D, Akuete CN, Doppman JL, Dorn LD, Barker CN, Yanovski JA, Chrousos GP. Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome. Neuroendocrinology. 1994;60(6):626-34. PMID 7700506.
18. 18

    Seifritz E, Müller MJ, Schönenberger GA, Trachsel L, Hemmeter U, Hatzinger M, Ernst A, Moore P, Holsboer-Trachsler E. Human plasma DSIP decreases at the initiation of sleep at different circadian times. Peptides. 1995;16(8):1475-81. PMID 8745061.
19. 19

    Schulz P, Lustenberger S, Degli Agosti R, Rivest RW. Plasma concentration of nine hormones and neurotransmitters during usual activities or constant bed rest for 34 H. Chronobiol Int. 1994;11(6):367-80. PMID 7895296.
20. 20

    Späth-Schwalbe E, Schäfer A, Uthgenannt D, Born J, Fehm HL. Delta-sleep-inducing peptide does not affect CRH and meal-induced ACTH and cortisol secretion. Psychoneuroendocrinology. 1995;20(3):231-7. PMID 7777652.
21. 21

    Bjartell A, Ekman R, Bergquist S, Widerlöv E. Reduction of immunoreactive ACTH in plasma following intravenous injection of delta sleep-inducing peptide in man. Psychoneuroendocrinology. 1989;14(5):347-55. PMID 2554357.
22. 22

    Chiodera P, Volpi R, Capretti L, Giacalone G, Caffarri G, Davoli C, Nigro E, Coiro V. Different effects of delta-sleep-inducing peptide on arginine-vasopressin and ACTH secretion in normal men. Horm Res. 1994;42(6):267-72. PMID 7698722.
23. 23

    Giusti M, Carraro A, Porcella E, Valenti S, Nicora D, Sessarego P, Giordano G. Delta sleep-inducing peptide administration does not influence growth hormone and prolactin secretion in normal women. Psychoneuroendocrinology. 1993;18(1):79-84. PMID 8475226.
24. 24

    Graf MV, Kastin AJ. Delta-sleep-inducing peptide (DSIP): an update. Peptides. 1986;7(6):1165-87. PMID 3550726.