DSIP

DSIP: what the published research shows

Compiled by NADA-Labs from the peer-reviewed literature cited below. No own study data.

DSIP (Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu) is a nonapeptide isolated from cerebral venous blood of rabbits during sleep induced by thalamic stimulation and named after the slow-wave (delta) EEG activity it produced after intraventricular infusion¹. No gene, precursor or receptor has been identified, and its role as an endogenous sleep factor is unresolved (Kovalzon 2006, PMID 16539679). Mechanisms discussed in the research literature include modulation of the pituitary-adrenal axis — lower plasma ACTH in healthy men⁵ and inhibition of CRF-stimulated ACTH release from rat pituitary tissue in vitro (Okajima 1986, PMID 3017833) — and changes in EEG and autonomic activity⁶. It has been studied in rabbit, rat and cat sleep models (see below), in rat models of stroke and myocardial ischaemia-reperfusion^7,8 and in small controlled human studies^2,5,6.

Evidence base: About ten small double-blind or placebo-controlled human studies from 1981-1995 (n = 6 to 20 where reported) and one randomised study under general anaesthesia (2009, n = 24)^2,3,4,5,6, plus uncontrolled clinical series (Dick 1984, PMID 6548969; Larbig 1984, PMID 6548970). The positive sleep findings come mainly from investigators working with the group that isolated the peptide^2,3; independent double-blind insomnia studies found weak effects or changes of little clinical significance⁴ (Monti 1987, PMID 3583493). Animal work covers sleep and EEG in rabbits, rats and cats with conflicting results, and ischaemia models, including two recent rat studies from one research group^7,8. No controlled human study published after 2009 was identified.

Key studies at a glance

Other controlled human studies: sleep and hormone secretion

Effects reported in the studies

• EEG delta activity and sleep in animals. In rabbits, intraventricular DSIP raised EEG delta activity by a mean of 35 % versus vehicle or eight related peptides¹. Total slow-wave sleep rose by 20 % in rats (Ursin 1983, PMID 6688864) and sleep increased after intraventricular injection in cats (Susić 1987, PMID 3620931), but other rat studies found no increase (Tobler 1980, PMID 7405185; Obál 1985, PMID 3841214) and intraperitoneal DSIP reduced sleep in cats (Sommerfelt 1985, PMID 3840239).
• Sleep in healthy volunteers. In six healthy volunteers (double-blind crossover), median total sleep time in the 130 min after administration was 59 % higher than with placebo; the next night showed shorter sleep onset and better sleep efficiency, and no classic pharmacological sedation was found².
• Sleep in chronic insomnia (conflicting results). In 14 patients with chronic insomnia (placebo-controlled, double-blind, 7 nights), night sleep improved, also in the first placebo night afterwards, and daytime alertness and performance increased³. An independent study in 16 patients found higher sleep efficiency and shorter latency, but the effects were weak and possibly partly due to a chance change in the placebo group, and subjective sleep was unchanged⁴.
• Pituitary-adrenal axis. In 11 healthy men (randomised, double-blind crossover), plasma ACTH-like immunoreactivity was lower for at least 3 h while cortisol was unaffected⁵; further controlled studies found lower ACTH (Chiodera 1994, PMID 7698722) or no effect on stimulated ACTH and cortisol (Späth-Schwalbe 1995, PMID 7777652).
• EEG and autonomic effects under anaesthesia. In 24 women under general anaesthesia (randomised, saline-controlled), DSIP increased heart rate and reduced heart-rate variability and, contrary to the authors’ hypothesis, reduced EEG delta activity and raised the bispectral index at the lowest dose studied, i.e. it lightened anaesthesia⁶.
• Motor recovery after experimental stroke (rat). After 90-min middle cerebral artery occlusion, rotarod fall latency rose from 11 s (day 1) to 25 s (day 21) with DSIP (p < 0.01 vs. day 1 on days 7 and 21) and from 13 to 18 s with vehicle; infarct volume (20.9 vs. 24.1 %) and rotation asymmetry did not differ significantly⁷.
• Myocardial ischaemia-reperfusion (rat). Given once at the start of reperfusion, DSIP lowered infarct area relative to the area at risk to 28.7 % versus 42.1 % with saline (p = 0.01), and the analogue KND to 19.1 %; in a pilot experiment, all 10 rats given DSIP during the occlusion died within 30 min⁸.

Adverse effects and tolerability reported

• Tolerability in small human studies. No psychological, physiological or biochemical side effects were observed in six healthy volunteers²; an uncontrolled series of 107 inpatients in alcohol or opiate withdrawal reported good tolerance apart from headaches in a few patients (Dick 1984, PMID 6548969). No systematic adverse-event data were identified; the largest controlled study (n = 24) does not mention adverse events in its abstract⁶.
• Paradoxical arousal and autonomic effects. In women under isoflurane anaesthesia, DSIP raised heart rate and lightened anaesthesia instead of deepening it⁶; in six insomniacs a slight arousing effect was noted in the first hour after administration (Schneider-Helmert 1981, PMID 7028502).
• Deaths when given during acute ischaemia (rat). All 10 rats given DSIP during coronary artery occlusion died within 30 min; as all 4 mice given the analogue KND during middle cerebral artery occlusion also died, the authors regard use of these peptides during acute myocardial or cerebral ischaemia as dangerous⁸.
• Non-linear dose-response (animals). Experiments in rabbits, cats and mice gave indications of bell-shaped dose-response curves in most test situations (Scherschlicht 1984, PMID 6548967), and a review reports a U-shaped activity curve for both dose and time of infusion (Graf 1984, PMID 6145137).
• Endocrine activity. Besides lowering ACTH in healthy men⁵, DSIP injected into the third ventricle raised plasma LH and GH in ovariectomised rats (Iyer 1987, PMID 3121137; Iyer 1987, PMID 3575154); GH and prolactin were unchanged in healthy women (Giusti 1993, PMID 8475226).
• Interactions with centrally acting drugs (rodents). In rats, DSIP reversed d-amphetamine-induced hyperthermia to hypothermia at 22 °C (Yehuda 1980, PMID 6894196), and in morphine-dependent mice it attenuated naloxone-precipitated withdrawal jumping (Scherschlicht 1984, PMID 6548967).

Limitations of the evidence. Apart from the concentration of positive sleep data in one group^2,3, the human studies are small (n = 6 to 24 where reported), mostly from 1981-1995, and rarely report effect sizes. In several rat studies DSIP itself, unlike some analogues, did not increase sleep, possibly because it is degraded quickly (Obál 1986, PMID 3754970); in vitro it was degraded in human and rat blood (Graf 1987, PMID 3628078) and by aminopeptidases of rat brain membranes (Nakamura 1993, PMID 8474631), and its plasma half-life was 2-4 min in dogs, rats and one monkey (Kato 1984, PMID 6379493). The two recent rat studies come from one research group and use 5-10 animals per group^7,8; the stroke study found no significant change in infarct volume and reported rotarod significance only within groups (versus day 1, and for the regression slope over the 21 days), with no direct statistical comparison of DSIP versus vehicle⁷. None of the findings summarised here establish efficacy or safety for any use outside the described research models.

References

1. Schoenenberger GA, Maier PF, Tobler HJ, Wilson K, Monnier M (1978). The delta EEG (sleep)-inducing peptide (DSIP). XI. Amino-acid analysis, sequence, synthesis and activity of the nonapeptide. Pflügers Archiv: European Journal of Physiology. PMID 568769 DOI
2. Schneider-Helmert D, Gnirss F, Monnier M, Schenker J, Schoenenberger GA (1981). Acute and delayed effects of DSIP (delta sleep-inducing peptide) on human sleep behavior. International Journal of Clinical Pharmacology, Therapy, and Toxicology. PMID 6895513 human study
3. Schneider-Helmert D (1987). Effects of delta-sleep-inducing peptide on 24-hour sleep-wake behaviour in severe chronic insomnia. European Neurology. PMID 3622582 DOI human study
4. Bes F, Hofman W, Schuur J, Van Boxtel C (1992). Effects of delta sleep-inducing peptide on sleep of chronic insomniac patients. A double-blind study. Neuropsychobiology. PMID 1299794 DOI human study
5. Bjartell A, Ekman R, Bergquist S, Widerlöv E (1989). Reduction of immunoreactive ACTH in plasma following intravenous injection of delta sleep-inducing peptide in man. Psychoneuroendocrinology. PMID 2554357 DOI human study
6. Pomfrett CJ, Dolling S, Anders NR, Glover DG, Bryan A, Pollard BJ (2009). Delta sleep-inducing peptide alters bispectral index, the electroencephalogram and heart rate variability when used as an adjunct to isoflurane anaesthesia. European Journal of Anaesthesiology. PMID 19142086 DOI human study
7. Tukhovskaya EA, Ismailova AM, Shaykhutdinova ER, Slashcheva GA, Prudchenko IA, Mikhaleva II, Khokhlova ON, Murashev AN, Ivanov VT (2021). Delta Sleep-Inducing Peptide Recovers Motor Function in SD Rats after Focal Stroke. Molecules. PMID 34500605 DOI
8. Tukhovskaya EA, Shaykhutdinova ER, Ismailova AM, Slashcheva GA, Prudchenko IA, Mikhaleva II, Khokhlova ON, Murashev AN, Ivanov VT (2021). DSIP-Like KND Peptide Reduces Brain Infarction in C57Bl/6 and Reduces Myocardial Infarction in SD Rats When Administered during Reperfusion. Biomedicines. PMID 33918965 DOI

This section summarises findings published in the cited peer-reviewed literature for informational purposes. It is not a claim of efficacy or safety, contains no dosing or administration information by design, and does not constitute medical, veterinary or scientific advice. Results in cell cultures or animal models do not predict effects in humans.