DSIP (delta sleep-inducing peptide) — identity, handling and published literature

DSIP is a synthetic linear nonapeptide, INN emideltide, supplied as a lyophilised solid for laboratory use; it is not sold by NovoVita and this entry is a literature record only.

Presentation and physical properties

DSIP is a nine-residue peptide with the sequence H-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-OH (single-letter WAGGDASGE), first characterised from rabbit cerebral venous blood and then synthesised and sequenced by the Basel group of Schoenenberger and Monnier [1, 2]. It is described in that work as an amphiphilic molecule; solution conformational studies have since examined its behaviour at membrane interfaces.

The peptide carries no basic side chains at all. Its only ionisable groups besides the N-terminal amine are the aspartate and glutamate carboxylates and the C-terminal carboxyl, so it is a strongly acidic peptide with a low isoelectric point. That single fact governs most of its practical behaviour: it is freely soluble in water and in mildly alkaline buffers, retains negative charge across the neutral range, binds anion-exchange media, and ionises more readily in negative-mode mass spectrometry than in positive mode.

Material is normally isolated as an acetate salt after preparative reversed-phase purification. The gross mass of a lyophilised solid therefore exceeds its net peptide content, typically by several per cent once counterion and residual water are accounted for. Where a certificate states net peptide content separately from purity, the two figures are not interchangeable and the arithmetic below assumes the labelled nominal mass rather than a measured net content.

Reconstitution arithmetic

Concentration is a division and nothing more. For a vial containing a nominal mass m milligrams reconstituted with a volume V millilitres of diluent, the resulting concentration is m ÷ V milligrams per millilitre. Multiplying by 1,000 converts to micrograms per millilitre. Because the lyophilised solid occupies negligible volume relative to the diluent, the final volume is taken as the diluent volume added.

The table below works this through for a nominal 5 mg vial, which is a commonly encountered research presentation. The rightmost columns restate the same concentration as the mass contained in fixed small volumes — 0.1 mL and 0.01 mL correspond to the 10-unit and 1-unit graduations of a 100-unit-per-millilitre graduated syringe. These are unit conversions, not recommendations of any kind.

For any other nominal mass the same division applies: a 2 mg vial reconstituted to 2 mL gives 1 mg/mL, a 10 mg vial reconstituted to 2 mL gives 5 mg/mL. The 3 mL row is recurring and has been rounded; carrying the unrounded value through any subsequent calculation avoids compounding the rounding error.

Storage and stability

As a lyophilised solid the peptide is handled like other small synthetic peptides: sealed, desiccated, protected from light, and held at −20 °C or below for long-term storage. Vials taken from cold storage should be equilibrated to ambient temperature before opening, because condensing atmospheric moisture onto a hygroscopic lyophilisate is the commonest avoidable cause of degradation before a vial has even been opened.

Three sequence features determine what degrades and how.

• The N-terminal tryptophan. Trp is the most photolabile of the proteinogenic residues and oxidises readily. Amber vials or foil overwrap, and minimising exposure to laboratory lighting, are ordinary precautions for any Trp-containing peptide. Loss of Trp also degrades the ultraviolet signal used for identity confirmation, so oxidation is doubly inconvenient here.
• The aspartate at position 5. Asp followed by a small residue — here Asp5-Ala6, with Gly4 preceding — is the classic motif for succinimide (aspartimide) formation and subsequent rearrangement to the β-aspartyl isomer. This is not a theoretical concern for DSIP. The 1978 sequencing paper reports explicitly that of the synthesised variants only the pure alpha-aspartyl peptide is highly active in the rabbit electroencephalographic assay [2]. Aspartyl isomerisation therefore produces a species of identical mass and near-identical retention behaviour that the original investigators found did not reproduce the reported activity. Mass spectrometry alone cannot distinguish the two.
• The serine and the free carboxyl termini. Ser can undergo β-elimination under alkaline conditions, and the two carboxylates make the peptide sensitive to pH extremes at either end. Neutral to mildly acidic aqueous buffers are the usual working compromise.

There is no disulfide bond, no methionine and no glutamine, so the peptide is spared the oxidative and deamidation pathways that dominate the stability profile of many other research peptides. In solution, aqueous preparations are refrigerated at 2–8 °C and treated as short-lived; freeze-thaw cycling is minimised by aliquoting. No published stability-indicating study specific to DSIP under defined storage conditions was located, so shelf-life statements for this peptide rest on general peptide-chemistry principles rather than on compound-specific data.

Analytical identity

The compound is registered under CAS 62568-57-4, UNII YN28Z5YZ73 and PubChem CID 68816, with molecular formula C₃₅H₄₈N₁₀O₁₅ and an average molecular weight of 848.8 g/mol. The recommended international non-proprietary name is emideltide.

Routine identity work uses the standard combination for a short synthetic peptide:

• Reversed-phase HPLC with ultraviolet detection. The single tryptophan gives absorbance near 280 nm; with one Trp, no tyrosine and no cystine, the expected molar extinction coefficient at 280 nm is that of a lone tryptophan residue, approximately 5,500 M⁻¹cm⁻¹. Peptide-bond detection at 214 nm is used in parallel because it does not depend on an intact Trp.
• Electrospray mass spectrometry. The singly protonated ion is expected near m/z 849.8 and the doubly protonated near 425.4. Given the peptide’s acidic character, negative-mode detection of [M−H]⁻ near m/z 847.8 is often the more sensitive route.
• Amino acid analysis after hydrolysis, which was how the sequence was originally established [2] and which remains the reference method for net peptide content.
• Sequence confirmation by tandem mass spectrometry or Edman degradation. Sequence confirmation matters more than usual for this peptide because the α- and β-aspartyl forms are isobaric and co-eluting isomers are a documented issue in this exact sequence [2].

A further analytical caution comes from the literature itself. Much of the published work measuring endogenous DSIP relied on radioimmunoassay and reported DSIP-like immunoreactivity rather than the peptide itself. Kovalzon and Strekalova argue in their 2006 review that this immunoreactivity may reflect one or more distinct DSIP-like peptides rather than DSIP [19]. Antibody-based quantification of this sequence should therefore not be treated as equivalent to a chromatographic or mass-spectrometric measurement.

What the published literature investigated

The DSIP literature is unusual in shape. It is concentrated almost entirely in the 1977–1995 period, published largely by a small number of groups, and it includes human administration studies from very early in the compound’s history — before the pharmacology had been characterised, and before the standards that would now govern such trials existed. What follows reports what those studies examined and what they concluded, not what the compound does.

Isolation and animal electroencephalography

The founding work is a 1977 report in the Proceedings of the National Academy of Sciences in which Schoenenberger and Monnier described isolating a nonapeptide from the cerebral venous blood of rabbits given low-frequency thalamic stimulation, synthesising it, and testing it alongside five metabolic variants, two substitution analogues and a related tripeptide by intraventricular infusion in 58 rabbits under double-blind conditions [1]. They reported that only the synthetic parent peptide produced significant enhancement of delta and spindle activity in fast-Fourier analysis of neocortical and archicortical recordings, and named it delta sleep-inducing peptide. The companion 1978 paper in Pflügers Archiv set out the amino acid analysis, sequence and synthesis, reported a mean increase in delta activity of approximately 35 per cent across 61 rabbits, and established the α-aspartyl requirement noted above [2].

Later rodent electroencephalographic work is sparse. Stanojlović and colleagues administered DSIP intraperitoneally to adult male Wistar rats in 2000 and reported significantly enhanced delta-range activity and power spectra against saline controls over a twelve-hour recording window [17].

Distribution and transport

Banks, Kastin and Coy examined blood-brain barrier passage in anaesthetised dogs in 1982, reporting that intact peptide reached cerebrospinal fluid after intravenous injection, that cerebrospinal-fluid-to-plasma ratios exceeded those for tritiated insulin, and that the peptide binds reversibly to plasma proteins with greater affinity in blood than in cerebrospinal fluid [5]. The 1984 reviews by Graf and Kastin [7] and by Schoenenberger [8] collate the immunohistochemical and radioimmunochemical mapping of DSIP-like material across brain, peripheral organs and plasma in several mammalian species.

Neuroendocrine and biochemical studies

Several groups examined effects on hormonal and neurochemical readouts in rodents. Graf and colleagues reported in 1985 that intravenous DSIP reduced corticotropin-releasing-factor-induced corticosterone release in rats without affecting release triggered by adrenocorticotropic hormone, and concluded the effect was located at the pituitary [10]. Iyer and McCann reported in 1987 that DSIP suppressed somatostatin release from incubated rat median eminence in a dose-dependent manner and that the dopamine antagonist pimozide blocked the effect [11].

Later Russian and Russian-collaborative work moved toward oxidative-stress readouts. Shustanova and colleagues reported in 2001 that DSIP administration shifted the prooxidant-antioxidant balance in rat tissues and restored enzyme activities disturbed by cold exposure [18]. Tukhovskaya and colleagues reported in 2021 that intranasal DSIP given to Sprague-Dawley rats before and after middle cerebral artery occlusion was associated with better performance on motor coordination and asymmetry tests, while noting explicitly that the difference in infarct volume between treated and vehicle animals was not statistically significant [20].

Human administration studies

Human studies of this exact nonapeptide exist and are not few. Between 1981 and 1998 synthetic DSIP was given intravenously to human subjects in at least seven published studies. They are, without exception, small.

Schneider-Helmert and Schoenenberger reported in 1981 on six middle-aged chronic insomniacs given a single intravenous dose, describing longer sleep duration and fewer interruptions with no daytime drowsiness [3]. A companion 1981 paper reported a randomised double-blind crossover study in six healthy volunteers, in which total sleep time rose by 59 per cent within a 130-minute interval against placebo while electroencephalographic and behavioural analysis showed no classical sedative signature [4]. Kaeser reported in 1984 an open series of seven patients with severe insomnia given ten injections, in which six of seven were described as normalised over three to seven months of follow-up [9].

The larger and better-controlled studies are more equivocal. Monti and colleagues ran a double-blind crossover polysomnographic study in chronic insomniacs in 1987 and concluded that sleep improvement under DSIP treatment is of little clinical significance, noting that the differences reaching significance were already present at baseline [12]. Schneider-Helmert’s 1987 placebo-controlled double-blind study of fourteen middle-aged chronic insomniacs over seven consecutive nights reported substantial improvement in sleep efficiency and in daytime alertness and performance, persisting into the post-treatment night [13]. Bes and colleagues ran a double-blind matched-pairs parallel-groups study in sixteen chronic insomniacs in 1992, found higher sleep efficiency and shorter sleep latency against placebo but characterised the effects as weak and partly attributable to changes in the placebo group, with no improvement in subjective sleep quality, and concluded that short-term treatment of chronic insomnia with DSIP is not likely to be of major therapeutic benefit [14].

A separate line examined withdrawal syndromes. Dick, Grandjean and Tissot reported in 1983 an open, uncontrolled series of 67 inpatients presenting with alcohol or opiate withdrawal, of whom 49 were evaluable and 48 were described as benefiting [6]. This is the largest published human series involving DSIP administration and it had no control group and lost more than a quarter of its enrolled patients to evaluation. Backmund and colleagues published a further open clinical trial of opioid detoxification with DSIP in 1998, which is indexed without an abstract [16].

One human study measured endogenous peptide rather than administering it: Vgontzas and colleagues compared morning plasma DSIP-like immunoreactivity across nine sleep apnoea patients, ten narcolepsy patients and eleven controls in 1995, found no significant differences between groups, and concluded that single plasma measurements are not useful as biological markers of sleep-disorder activity [15].

Reviews

Three reviews frame the field at three points in its history. Graf and Kastin surveyed the compound in 1984, describing a U-shaped activity curve for both dose and infusion time and cataloguing reported effects across electrophysiology, neurotransmitters, circadian rhythms, locomotion, hormones and drug interactions [7]. Schoenenberger’s 1984 review covers the same ground from the originating laboratory’s perspective and describes a phosphorylated derivative, DSIP-P [8]. Kovalzon and Strekalova’s 2006 review in the Journal of Neurochemistry is the most sceptical and the most useful: it is titled a still unresolved riddle, states that the link between DSIP and sleep has never been further characterized, describes the sleep-factor hypothesis as extremely poorly documented and still weak, and hypothesises that a distinct DSIP-like peptide may account for the observed immunoreactivity and activity [19].

Evidence gaps and limitations

The gaps here are structural rather than incidental, and several of them are the kind that would normally stop a compound being taken seriously at all.

• No gene, no precursor, no receptor. Nearly fifty years after isolation, no DSIP gene has been identified, no precursor protein isolated, and no receptor characterised. Kovalzon and Strekalova identify this as the central reason the sleep hypothesis was never resolved [19]. There is consequently no molecular mechanism on which any account of the compound rests.
• The endogenous existence of DSIP itself is contested. The reviewers who know the field best have proposed that the immunoreactivity attributed to DSIP may belong to a different, unidentified peptide [19]. That is a challenge to the premise of the entire literature, not a detail within it.
• No controlled human study since 1992. The last placebo-controlled study located is Bes and colleagues, 1992 [14]; the last human study of any design is an open trial from 1998 [16]. Nothing in the modern era of trial registration, pre-specified endpoints or CONSORT reporting exists for this compound.
• The human studies are very small and the largest is the weakest. The controlled studies enrolled six, six, fourteen and sixteen subjects [3, 4, 13, 14]. The only study with a substantial patient count — 67 — was open, uncontrolled, single-arm, and reported outcomes on 49 [6]. No human study located was multi-centre. None was registered on a trials registry, because none postdates the practice.
• The controlled results conflict. Two double-blind studies concluded the effect was of little clinical significance or unlikely to be of major therapeutic benefit [12, 14]; one concluded the opposite [13]. That disagreement has never been resolved by a larger trial, and at these sample sizes it could not be.
• No human pharmacokinetic characterisation to any modern standard. Absorption, distribution, metabolism and elimination in humans are not described in the located literature. The transport data are canine [5].
• No published GLP toxicology, no repeat-dose safety study, no long-term follow-up. Reports of tolerability in the human studies are observational statements made within trials designed to measure sleep, in samples far too small to detect anything but common events. Absence of reported adverse effects in six or sixteen subjects is not a safety dataset.
• Analytical ambiguity persists at the level of the molecule. The α- and β-aspartyl isomers are isobaric, the originating group reported that only the α-form was active in their assay [2], and much of the subsequent literature does not state which isomeric purity was verified. This is a plausible contributor to inconsistency between studies and it has not been systematically investigated.
• Publication concentration. A substantial fraction of the positive human sleep literature originates from one investigator and one collaborating laboratory [3, 4, 13], with the more sceptical conclusions coming from independent groups [12, 14].

Taken together: this is an old, small, internally inconsistent evidence base built on a molecular hypothesis that was never confirmed. It should not be described as an established or well-characterised compound.

Regulatory and standards position

United Kingdom. There is no UK marketing authorisation for emideltide or DSIP in any form. It is not an authorised medicinal product and is not a component of one. It is not a controlled drug under the Misuse of Drugs Act 1971 or the Misuse of Drugs Regulations 2001, and it is not subject to Home Office licensing. Its status is that of an unlicensed substance supplied for laboratory use. Under MHRA Guidance Note 8 and the case law on medicinal products by presentation, the determining factor is not the molecule but the claim made about it: a substance in this position becomes a medicinal product in law at the point where it is presented as having properties for treating or preventing disease, whatever its regulatory history.

European Union. No centralised or national marketing authorisation for emideltide was identified. The peptide has no approved medicinal use in the EU.

United States. DSIP is not approved by the FDA for any indication. It carries the international non-proprietary name emideltide. It was one of seven peptides considered by the FDA’s Pharmacy Compounding Advisory Committee at its meeting of 23–24 July 2026, which assessed whether they should be added to the section 503A bulk drug substances list for use in compounding. On 24 July 2026 the committee voted against recommending emideltide, by 6 in favour to 7 against with 1 abstention — the only one of the seven not recommended, the others being BPC-157, KPV, TB-500, MOTS-c, Semax and Epitalon. Reported objections included the low quality of the efficacy evidence, incomplete characterisation of the substance, the age of the supporting research, the existence of approved alternatives, and uncertainty about the regimen. The committee is advisory and its recommendation does not bind the FDA, and formal rulemaking had not concluded at the time of writing. The vote is nonetheless the most recent formal expert assessment of this compound’s evidence base, and it went against it.

Anti-doping. Delta sleep-inducing peptide, DSIP and emideltide are not named in any class of the WADA Prohibited List. That is not the end of the analysis. Section S0, Non-Approved Substances, captures any pharmacological substance which is not addressed by a subsequent section of the List and which has no current approval by any governmental regulatory health authority for human therapeutic use, and S0 substances are prohibited at all times, in and out of competition. DSIP holds no such approval in any jurisdiction identified. On the plain terms of S0 it therefore falls within a prohibited class notwithstanding that it is not listed by name. Athletes subject to anti-doping rules should treat it accordingly and verify current status directly with their anti-doping organisation.

Documented enforcement. No MHRA enforcement action, FDA warning letter or import alert naming DSIP or emideltide was identified in this review. The July 2026 PCAC vote is the substantive documented regulatory event.

Laboratory handling and safety

DSIP has no published GLP toxicology package and no established occupational exposure limit. It should be handled as a biologically active research chemical of incompletely characterised hazard, under a COSHH assessment appropriate to that description.

• Handle the lyophilised solid in a way that avoids generating airborne particulate. Low-mass peptide lyophilisates are electrostatic and disperse readily when a vial is opened sharply.
• Nitrile gloves, safety spectacles and a laboratory coat are the minimum; weighing and initial reconstitution are appropriately done in a fume hood or containment enclosure.
• Reconstitute by directing diluent down the vial wall rather than onto the cake, and dissolve by gentle swirling or inversion. Vortexing and sonication introduce shear and local heating that promote aggregation and oxidation, and the tryptophan residue makes this peptide a poor candidate for either.
• Use appropriate-grade water or buffer and aseptic technique. Aqueous peptide solutions support microbial growth; solutions held beyond a working session should be aliquoted and refrigerated, and any solution showing turbidity, particulate or discolouration discarded rather than filtered and reused.
• Label every aliquot with compound, nominal concentration, diluent and date. The arithmetic in this entry is only reliable if the vial’s nominal mass and the volume actually added are both recorded at the time.
• Dispose of peptide solutions, vials and contaminated consumables through the institution’s chemical waste stream in accordance with local regulations. Do not discharge to drain.
• Keep a safety data sheet for the specific material on file and read it before first use; formulation, counterion and residual solvent content vary between suppliers and between batches.

Nothing in this section constitutes guidance on administration to humans or animals, for which this substance is not authorised anywhere.

References

1. Schoenenberger GA, Monnier M. Characterization of a delta-electroencephalogram (-sleep)-inducing peptide. Proceedings of the National Academy of Sciences of the United States of America. 1977;74(3):1282–6. Model: rabbit, intraventricular infusion. PMID 265572
2. 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. Pflügers Archiv. 1978;376(2):119–29. Model: rabbit; chemical characterisation and synthesis. PMID 568769
3. Schneider-Helmert D, Schoenenberger GA. The influence of synthetic DSIP (delta-sleep-inducing-peptide) on disturbed human sleep. Experientia. 1981;37(9):913–7. Model: human, six subjects with chronic insomnia. PMID 7028502
4. Schneider-Helmert D, Gnirss F, Monnier M, Schenker J, Schoenenberger GA. Acute and delayed effects of DSIP (delta sleep-inducing peptide) on human sleep behavior. International Journal of Clinical Pharmacology, Therapy and Toxicology. 1981;19(8):341–5. Model: human, six healthy volunteers, randomised double-blind crossover. PMID 6895513
5. Banks WA, Kastin AJ, Coy DH. Delta sleep-inducing peptide crosses the blood-brain-barrier in dogs: some correlations with protein binding. Pharmacology, Biochemistry, and Behavior. 1982;17(5):1009–14. Model: dog. PMID 6897451
6. Dick P, Grandjean ME, Tissot R. Successful treatment of withdrawal symptoms with delta sleep-inducing peptide, a neuropeptide with potential agonistic activity on opiate receptors. Neuropsychobiology. 1983;10(4):205–8. Model: human, 67 patients, open and uncontrolled. PMID 6328354
7. Graf MV, Kastin AJ. Delta-sleep-inducing peptide (DSIP): a review. Neuroscience and Biobehavioral Reviews. 1984;8(1):83–93. Model: review. PMID 6145137
8. Schoenenberger GA. Characterization, properties and multivariate functions of delta-sleep-inducing peptide (DSIP). European Neurology. 1984;23(5):321–45. Model: review. PMID 6548966
9. Kaeser HE. A clinical trial with DSIP. European Neurology. 1984;23(5):386–8. Model: human, seven patients, open series. PMID 6391926
10. Graf MV, Kastin AJ, Coy DH, Fischman AJ. Delta-sleep-inducing peptide reduces CRF-induced corticosterone release. Neuroendocrinology. 1985;41(4):353–6. Model: rat. PMID 2995861
11. Iyer KS, McCann SM. Delta sleep inducing peptide inhibits somatostatin release via a dopaminergic mechanism. Neuroendocrinology. 1987;46(1):93–5. Model: in vitro, rat median eminence incubation. PMID 2886936
12. 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. International Journal of Clinical Pharmacology Research. 1987;7(2):105–10. Model: human, double-blind crossover polysomnography. PMID 3583493
13. Schneider-Helmert D. Effects of delta-sleep-inducing peptide on 24-hour sleep-wake behaviour in severe chronic insomnia. European Neurology. 1987;27(2):120–9. Model: human, 14 subjects, double-blind placebo-controlled. PMID 3622582
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. Model: human, 16 patients, double-blind matched-pairs parallel groups. PMID 1299794
15. Vgontzas AN, Friedman TC, Chrousos GP, Bixler EO, Vela-Bueno A, Kales A. Delta sleep-inducing peptide in normal humans and in patients with sleep apnea and narcolepsy. Peptides. 1995;16(6):1153–6. Model: human, observational plasma immunoreactivity. PMID 8532601
16. Backmund M, Meyer K, Rothenhaeusler HB, Soyka M. Opioid detoxification with delta sleep-inducing peptide: results of an open clinical trial. Journal of Clinical Psychopharmacology. 1998;18(3):257–8. Model: human, open clinical trial; indexed without abstract. PMID 9617990
17. Stanojlović OP, Zivanović DP, Susić VT. The effect of delta sleep-inducing peptide on the EEG and power spectra in rat. Indian Journal of Physiology and Pharmacology. 2000;44(4):428–34. Model: rat, adult male Wistar. PMID 11214497
18. Shustanova TA, Bondarenko TI, Milyutina NP, Mikhaleva II. Regulation of free radical processes by delta-sleep inducing peptide in rat tissues under cold stress. Biochemistry (Moscow). 2001;66(6):632–9. Model: rat. PMID 11421812
19. Kovalzon VM, Strekalova TV. Delta sleep-inducing peptide (DSIP): a still unresolved riddle. Journal of Neurochemistry. 2006;97(2):303–9. Model: review. PMID 16539679
20. Tukhovskaya EA, Ismailova AM, Shaykhutdinova ER, Slashcheva GA, Prudchenko IA, Mikhaleva II, Khokhlova ON, Murashev AN, Ivanov VT. Delta sleep-inducing peptide recovers motor function in SD rats after focal stroke. Molecules. 2021;26(17):5173. Model: rat, Sprague-Dawley, middle cerebral artery occlusion. PMID 34500605

Research use only

This entry is a record of published literature and of physical and analytical properties. It is provided for laboratory reference. Nothing here is a statement that DSIP does anything, is suitable for any purpose, or should be used in any way.

DSIP is not authorised as a medicinal product in the United Kingdom, the European Union or the United States. It is not for human or veterinary use, not for use in food, and not for any diagnostic or therapeutic application. It is not sold by NovoVita; this entry appears because the library documents the field rather than the catalogue.