DSIP (Delta Sleep-Inducing Peptide): Research Guide

In 1977, a team of Swiss researchers electrically stimulated the thalamus of a sleeping rabbit, collected the blood draining from its brain, and found something unexpected: a tiny peptide that, when injected into the brain ventricles of awake rabbits, produced the slow, rolling delta waves of deep sleep. They named it Delta Sleep-Inducing Peptide, or DSIP.

Nearly fifty years later, DSIP remains one of the strangest molecules in neuroscience. No one has identified its gene. No one has found its receptor. Some researchers have called it a sleep breakthrough; others have called it a flop. And yet, study after study turns up biological activity that goes far beyond sleep -- from stress protection to addiction recovery to tumor suppression in aging mice.

Quick Facts

Property	Detail
Full name	Delta Sleep-Inducing Peptide (emideltide)
Type	Nonapeptide (9 amino acids)
Sequence	Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu (WAGGDASGE)
Molecular weight	~849 Da
Molecular formula	C35H48N10O15
Found in	Hypothalamus, limbic system, pituitary, gut, pancreas, peripheral blood
Plasma half-life	7-8 minutes
Blood-brain barrier	Crosses freely
Gene identified	No (the only neuropeptide with an unknown gene)
Receptor identified	No
FDA approved	No
First isolated	1977 by Schoenenberger and Monnier (Basel, Switzerland)

What Is DSIP?

DSIP is a naturally occurring peptide made of nine amino acids. It was the first substance ever isolated from brain tissue specifically because it appeared to promote deep sleep. You will sometimes see it called "emideltide" in pharmaceutical literature.

What makes DSIP unusual among peptides:

It crosses the blood-brain barrier freely. Most peptides cannot do this. DSIP also survives passage through the gut without being destroyed by digestive enzymes, which is rare for any peptide.
It has no known gene. Every other neuropeptide in biology can be traced back to a gene that encodes it. DSIP cannot. Researchers have proposed it might be a fragment of a larger, undiscovered precursor protein, but no one has found that protein either.
It has no identified receptor. Unlike most signaling molecules, DSIP has never been shown to bind directly to any specific receptor. This makes its mechanism of action genuinely mysterious.
It is amphiphilic. The molecule has both water-soluble and fat-soluble properties, which may help explain how it moves so easily between blood and brain tissue.

DSIP appears throughout the body -- in the hypothalamus, limbic system, pituitary gland, gut (where it co-localizes with glucagon in pancreatic cells), and various peripheral organs and body fluids. This widespread distribution suggests it does more than just promote sleep.

Discovery and History

The story begins in the early 1970s at the University of Basel in Switzerland. Researchers G.A. Schoenenberger and M. Monnier were studying the neurochemistry of sleep by electrically stimulating the intralaminar thalamic area of rabbits. They dialyzed the blood flowing from the sleeping rabbits' brains, collected the dialysate, and infused it into the brain ventricles of awake rabbits. The awake rabbits showed a clear increase in delta-wave EEG activity -- the electrical signature of deep sleep.

By 1977, the team had isolated and sequenced the responsible molecule. When they synthesized DSIP in the lab and tested it under double-blind conditions, the synthetic version produced a 35% increase in delta EEG activity in the neocortex and limbic cortex compared to controls. Only the pure alpha-aspartyl form was active; its beta-Asp isomer had no effect.

The Rise and Decline of Research

Through the 1980s, DSIP research was active and optimistic. Multiple labs explored its effects on sleep, hormones, pain, and addiction. By the 1990s, interest had faded.

The reasons depend on who you ask. Professor Alexander Borbely of the University of Zurich was blunt: DSIP "turned out to be a flop as a sleep substance and any interest was lost." Schoenenberger himself disagreed.

In 2006, Russian researchers Kovalzon and Strekalova published an influential review titled "DSIP: A Still Unresolved Riddle." They argued that the hypothesis of DSIP as a sleep factor was "extremely poorly documented and still weak." But they raised a tantalizing possibility: maybe the original isolation identified the wrong molecule. They proposed that an undiscovered DSIP-like peptide might exist in the brain -- structurally related but not identical -- that could explain the biological effects attributed to DSIP.

This remains an open question. Research continues at lower intensity, primarily in Russia and a few European labs, with recent work on neuroprotection, antioxidant activity, and fusion peptides designed to improve DSIP's stability.

How DSIP Works (Mechanism of Action)

Nobody fully understands how DSIP works. Without a known gene, receptor, or clear signaling pathway, researchers have pieced together a partial picture from decades of pharmacological studies.

GABA and Glutamate

DSIP boosts GABA-activated currents in hippocampal and cerebellar neurons while blocking NMDA-activated (glutamate) responses in cortical areas. In plain terms, it turns up the brain's main "calm down" signal and turns down its main "get excited" signal. This dual action could explain effects on sleep, seizure protection, and anxiety. Two rodent studies in the 1990s supported this: DSIP prevented convulsions triggered by GABA-A antagonists.

Endogenous Opioid System

DSIP does not bind directly to opioid receptors. Instead, it indirectly stimulates the release of Met-enkephalin, one of the body's own opioid peptides. This indirect activity may account for DSIP's pain-reducing effects and its apparent usefulness in addiction withdrawal -- without the tolerance and dependence problems of direct opioid drugs.

Endocrine Regulation

DSIP suppresses ACTH, stimulates growth hormone and luteinizing hormone release, and interacts with the hypothalamic-pituitary-adrenal (HPA) axis. Some researchers believe these endocrine effects, rather than direct neural activity, may be the primary way DSIP influences sleep. Sleep quality is heavily affected by hormones like growth hormone-releasing hormone (GHRH), which promotes slow-wave sleep.

The Stability Problem

DSIP has a plasma half-life of just 7-8 minutes. A specific aminopeptidase-like enzyme chews it up by splitting off the N-terminal tryptophan. Researchers suspect that in the living body, DSIP complexes with carrier proteins to avoid rapid degradation, but no one has identified these carriers. This instability has been a major obstacle to research.

Sleep Research: Promise and Controversy

The name "Delta Sleep-Inducing Peptide" sets up an expectation that the research only partly delivers.

What the Positive Studies Show

Early human studies found DSIP increased total sleep time by 59% (median) within a 130-minute window after treatment compared to placebo. But DSIP does not act like a sedative. Researchers describe it as a sleep-modulating substance: a dose given during the day improved sleep quality on the following night and for several nights afterward. The effects were strongest when sleep was already disrupted; in healthy sleepers, DSIP had minimal effects.

The most rigorous human study was a double-blind trial in chronic insomniacs. Objective measurements showed higher sleep efficiency and shorter sleep latency with DSIP compared to placebo. But most other measures, including patients' own ratings of sleep quality, showed no change. The researchers concluded that "short-term treatment of chronic insomnia with DSIP is not likely to be of major therapeutic benefit."

The Replication Problem

Some labs simply could not reproduce the original sleep-promoting findings. The Kovalzon review noted that certain synthetic analogues of DSIP actually produced stronger sleep effects than DSIP itself, raising questions about whether the original molecule was really the active agent.

DSIP probably does something to sleep architecture, but it is not a powerful or reliable sleep aid. It appears to nudge the system toward deeper sleep under stress or disruption, rather than knocking someone out. For researchers interested in other neuromodulatory peptides, Selank and Semax have more consistent evidence bases.

Stress, Mood, and the HPA Axis

While the sleep story is complicated, DSIP's effects on stress are more consistent across studies.

DSIP reduces basal ACTH (adrenocorticotropic hormone) levels and blocks its release. In human studies, ACTH-like immunoreactivity dropped significantly for at least 3 hours after injection. Since ACTH drives cortisol production, this dampening of the HPA axis may buffer the body against chronic stress. Low plasma DSIP concentrations have been found in patients with Cushing's syndrome, a condition defined by excess cortisol.

DSIP levels appear altered in major depressive disorder (MDD), though the data are contradictory -- some studies find elevated levels, others find decreased levels. Either way, the alteration suggests a link between this peptide and mood regulation.

Animal studies show anxiolytic signals too. Mice receiving lifetime DSIP treatment spent 73% more time in the open arms of the elevated plus maze (a standard anxiety test) and explored exposed areas 9 times more often than controls. For readers interested in peptides with stronger anxiety data, Selank has a more established evidence base.

Pain and Opioid Withdrawal Research

Some of the most striking DSIP research involves substance dependence, though the quality of the evidence demands careful reading.

In animal studies, DSIP has a potent antinociceptive effect when administered directly into the brain, working at the supraspinal level through the opioid system via Met-enkephalin release.

Withdrawal Trials

The most cited withdrawal study is Dick et al. (1984), published in European Neurology. DSIP was given intravenously to 107 inpatients withdrawing from alcohol (47 patients) or opiates (60 patients). Clinical symptoms disappeared or improved "markedly and rapidly" in 97% of evaluable opiate-dependent patients and 87% of alcoholics. An earlier trial in 49 patients found similarly positive results. A separate patent-documented trial of 56 patients reported that delirium tremens was terminated in 6 of 8 cases.

These results sound remarkable, but they were mostly open-label, conducted in the early 1980s with small samples, and have never been replicated in large randomized trials. The 97% response rate is unusually high for any addiction treatment. Still, the consistency across multiple small studies suggests something real is happening, even if the magnitude may be inflated.

For perspective on peptides studied in other recovery contexts, BPC-157 and TB-500 have been investigated for tissue healing, though their applications differ from DSIP's neurological focus.

Endocrine Effects: Growth Hormone, LH, and Cortisol

DSIP has measurable effects on several hormones, though animal results do not always translate to humans.

Growth hormone: In rats, DSIP produced a dose-dependent GH increase through a hypothalamic dopaminergic mechanism. It stimulates GHRH release and inhibits somatostatin. But a study in eight healthy women found no effect on GH or prolactin, even at doses that altered EEG patterns. This disconnect between animal and human findings is a recurring theme.

Luteinizing hormone: In ovariectomized rats, DSIP caused a significant LH elevation within 30 minutes through a hypothalamic mechanism (LHRH release), not a direct pituitary effect. Since LH release increases during sleep, researchers proposed DSIP may contribute to sleep-related LH surges.

Cortisol and ACTH: DSIP suppresses ACTH clearly, but in one human study, plasma cortisol followed its normal diurnal decline regardless of DSIP. The upstream ACTH effect is clear; the downstream cortisol impact is less so.

Neuroprotection and Antioxidant Activity

Some of the most promising recent DSIP research focuses on brain protection.

A 2011 study concluded DSIP has a "strong antioxidant effect" through increased gene expression for superoxide dismutase (SOD1) and glutathione peroxidase (GPX1) -- enzymes whose expression normally declines with aging. DSIP reversed this decline in rats and reduced accumulation of lipid peroxidation products.

Khvatova et al. showed that pretreating rats with DSIP before hypoxia completely prevented the reduction in mitochondrial respiratory activity, meaning DSIP may help brain cells maintain energy production even when oxygen drops.

A 2021 study in Molecules tested intranasal DSIP in a rat stroke model. Over 8 days, DSIP-treated animals showed significantly better motor coordination recovery. The intranasal route is noteworthy because it bypasses the blood-brain barrier.

For other peptides with neuroprotective research, Semax has been studied more extensively in stroke contexts, and Epitalon has been investigated for aging-related neurodegeneration.

Anti-Tumor and Longevity Research

One of the most surprising DSIP findings comes from V.N. Anisimov and colleagues at the Petrov Research Institute of Oncology in St. Petersburg. Starting at 3 months of age, female SHR mice received monthly subcutaneous DSIP injections (as "Deltaran," ~100 mcg/kg, 5 days per month) until natural death.

The results:

Tumor suppression: Spontaneous tumor incidence dropped 2.6-fold, driven by reductions in mammary carcinomas and leukemias.
Maximum lifespan extension: The longest-lived 10% of DSIP mice lived 17.1% longer than the longest-lived controls. Maximum lifespan increased 24.1%.
Chromosomal protection: Bone marrow chromosome aberrations decreased 22.6%.
Preserved reproductive function: Age-related shutdown of estrous cycling was slowed.

Mean lifespan was not significantly affected -- DSIP did not make average mice live longer, but it extended maximum lifespan and reduced cancer across the group. The researchers proposed DSIP's effects might work partly through melatonin, since DSIP stimulated pineal melatonin synthesis.

This remains a single study in one mouse strain. But a 2.6-fold reduction in spontaneous tumors and 24% maximum lifespan extension are not trivial findings. For context on longevity peptides, Epitalon has been studied for telomerase activation, and Thymosin Alpha-1 is researched for immune modulation relevant to aging.

Safety and Side Effects

In a 2001 editorial in the European Journal of Anaesthesiology, Pollard and Pomfrett described DSIP as "incredibly safe," noting its LD50 could not be determined because it proved impossible to kill an animal with DSIP regardless of dose.

Reported side effects in human studies: transient headache, mild nausea, temporary vertigo, injection-site redness, and daytime drowsiness at excessive doses. Studies report DSIP does not produce pharmacological tolerance, which is unusual for substances interacting with opioid and GABA systems.

The FDA's view is different. DSIP is on the FDA's list of bulk drug substances with safety risks. The primary concern is immunogenicity -- the possibility the body could mount a dangerous immune response. This has not occurred in existing studies, but those were small and short-term.

Important unknowns: No long-term safety data exists. Combining DSIP with sleep medications, alcohol, or sedatives could produce unpredictable effects given its GABA and NMDA activity. DSIP's effects can be blocked by naloxone, consistent with its indirect opioid activity.

Legal and Regulatory Status

DSIP is not FDA-approved for any use. It carries unapproved new drug status, and the FDA issued warning letters in 2024 to firms marketing DSIP products. Since January 2025, stricter peptide compounding rules mean pharmacies cannot legally prepare DSIP for human use -- it lacks FDA approval, GRAS status, a USP monograph, or 503A Bulks List placement.

DSIP is available from online research suppliers under "for research use only" labeling, but using research peptides for human consumption violates federal regulations. It is similarly unapproved in Europe, Canada, and Australia. In Russia, the Deltaran preparation has been used in research but lacks full drug approval.

DSIP is not specifically named on the WADA prohibited substances list, but given its potential effects on recovery and growth hormone, this could change.

Frequently Asked Questions

Is DSIP a sleeping pill?

No. It is better described as a sleep modulator. It does not cause immediate drowsiness like a benzodiazepine. Research suggests it nudges the brain toward deeper sleep when sleep is already disrupted, with minimal effects in healthy sleepers.

Can DSIP be taken orally?

DSIP can survive gut passage without being destroyed, which is rare for peptides. But oral bioavailability is poorly characterized. Most research used intravenous or subcutaneous injection. The 2021 stroke study used intranasal delivery in rats successfully.

Does DSIP cause dependence?

Published studies consistently report no pharmacological tolerance or dependence, despite its indirect opioid activity. Long-term human data is lacking.

How does DSIP compare to melatonin?

Different mechanisms. Melatonin signals your body clock that it is nighttime (circadian rhythm). DSIP appears to affect sleep depth and architecture, particularly slow-wave sleep. Melatonin has decades more clinical data and an established safety profile. DSIP remains experimental.

The Bottom Line

DSIP is a genuinely unusual molecule. After nearly fifty years, we still do not know its gene, its receptor, or exactly how it works. Some researchers think the original isolation may have identified the wrong peptide, and that a related but undiscovered molecule is the true endogenous signal.

The biological activity is real. Across dozens of studies, DSIP shows effects on sleep architecture (modest and inconsistent), stress hormone regulation, pain modulation, opioid withdrawal, antioxidant defense, neuroprotection, and tumor suppression in mice. The problem is that very few findings come from large, well-controlled human trials.

For now, DSIP remains in the "fascinating but unproven" category. It is not approved for therapeutic use anywhere, and the FDA has flagged safety concerns. What DSIP's story does offer is a reminder of how much we still do not understand about the brain's own chemistry -- and how a tiny peptide discovered in the blood of sleeping rabbits can keep scientists puzzled for half a century.

This article is for educational and informational purposes only. It is not medical advice. DSIP is not approved by the FDA or any major regulatory body for therapeutic use. Consult a qualified healthcare provider before considering any peptide-based intervention.

References

Schoenenberger GA, Monnier M. "The delta EEG (sleep)-inducing peptide (DSIP). XI. Amino-acid analysis, sequence, synthesis and activity of the nonapeptide." Proc Natl Acad Sci USA. 1977;74(3):1282-6. PubMed
Kovalzon VM, Strekalova TV. "Delta sleep-inducing peptide (DSIP): a still unresolved riddle." J Neurochem. 2006;97(2):303-309. PubMed
Schneider-Helmert D. "Effects of delta sleep-inducing peptide on sleep of chronic insomniac patients. A double-blind study." Psychopharmacology. 1987;91(4):485-492. PubMed
Dick P, et al. "DSIP in the treatment of withdrawal syndromes from alcohol and opiates." Eur Neurol. 1984;23(5):364-71. PubMed
Larbig W, et al. "Successful treatment of withdrawal symptoms with delta sleep-inducing peptide." Br Med J. 1984;289(6441):321-2. PubMed
Anisimov VN, et al. "Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice." Mech Ageing Dev. 2003;124(6):721-31. PubMed
Tukhovskaya EA, et al. "Delta Sleep-Inducing Peptide Recovers Motor Function in SD Rats after Focal Stroke." Molecules. 2021;26(17):5173. PMC
Pollard BJ, Pomfrett CJD. "Delta sleep-inducing peptide." Eur J Anaesthesiol. 2001;18(7):419-422. EJA
Iyer KS, et al. "Delta sleep-inducing peptide (DSIP) stimulates growth hormone (GH) release in the rat." Peptides. 1988;9(2):249-53. PubMed
Ramirez VD, et al. "Delta sleep inducing peptide (DSIP) stimulates the release of LH but not FSH via a hypothalamic site of action in the rat." Brain Res Bull. 1987;19(5):589-93. PubMed
Fiorina P, et al. "Delta sleep-inducing peptide administration does not influence growth hormone and prolactin secretion in normal women." Horm Metab Res. 1993;25(3):175-6. PubMed
Yang J, et al. "Pichia pastoris secreted peptides crossing the blood-brain barrier and DSIP fusion peptide efficacy in PCPA-induced insomnia mouse models." Front Pharmacol. 2024;15:1439536. Frontiers