DSIP vs PE-22-28.

DSIP (Delta Sleep-Inducing Peptide) is a small endogenous nonapeptide with the amino acid sequence Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu (WAGGDASGE), molecular weight roughly 850 Da. It was first isolated in 1974 by Schoenenberger, Monnier and colleagues in Switzerland from the cerebral venous blood of rabbits placed in an electrically induced state of slow-wave (delta) sleep, and named for that apparent sleep-promoting property. DSIP-like immunoreactive material has since been detected in various mammalian tissues and human fluids (including breast milk), but it remains a biochemical "riddle": no gene, precursor protein, or specific receptor for it has been definitively identified.

PE-22-28 is a synthetic seven-residue peptide corresponding to residues 22 to 28 of spadin, itself a fragment derived from the sortilin propeptide (also called neurotensin receptor-3). It was developed as a shortened, more stable analog of spadin intended to block the TREK-1 potassium channel. It has been studied as a fast-acting antidepressant candidate in rodent models. It is a preclinical research compound with no human data.

DSIP has no single confirmed receptor or signaling pathway; its mechanism remains genuinely unresolved despite decades of study. Reported preclinical interactions are diffuse and concentration-dependent, including modulation of NMDA-receptor activity, effects on glucocorticoid/stress-axis regulation, and engagement of MAPK signaling cascades, along with proposed influences on GABAergic, opioid/enkephalin, and somatostatin systems. It does not behave like a classical hypnotic acting at a defined target; instead it has been framed as a neuromodulator or "homeostatic" regulator with dose- and timing-dependent, sometimes bidirectional, effects on arousal. Its very short circulating half-life (on the order of minutes) further complicates any straightforward receptor-occupancy mechanism.

PE-22-28 acts by inhibiting the TREK-1 two-pore-domain potassium channel, which is implicated in mood regulation and in resistance to conventional antidepressants. By blocking TREK-1, it is proposed to increase serotonergic neurotransmission and promote hippocampal neurogenesis. Reported potency is high, with a sub-nanomolar IC50 and improved metabolic stability compared with spadin. These effects are characterized in cell and animal systems.

Human data exist but are old, small, and mixed. Small studies from the early 1980s (e.g., Schneider-Helmert and colleagues, Experientia 1981; Int J Clin Pharmacol Ther Toxicol 1981) reported acute and delayed improvements in sleep efficiency, latency and continuity in insomniac and normal subjects after intravenous DSIP, with good tolerability. However, a later double-blind matched-pairs study in 16 chronic insomniacs (Neuropsychobiology, 1992) found higher sleep efficiency and shorter latency yet concluded short-term DSIP is "not likely to be of major therapeutic benefit." A 1984 clinical trial (European Neurology) and a pilot study in chronic pain also reported effects, and a 2009 anaesthesia study (European Journal of Anaesthesiology) found DSIP altered bispectral index/EEG as an isoflurane adjunct. A 2006 Journal of Neurochemistry review explicitly calls DSIP "a still unresolved riddle," underscoring that no modern, adequately powered, registration-quality trial has confirmed a clinical sleep benefit.

Evidence for PE-22-28 is preclinical only. In the foundational study, shortened spadin analogs including PE-22-28 showed stronger TREK-1 inhibition, longer in-vivo stability and antidepressant-like activity in behavioral tests such as forced swim and novelty-suppressed feeding, along with induction of neurogenesis after a short treatment course (Djillani et al., Frontiers in Pharmacology 2017). A review of TREK-1 blockers situates spadin and its analogs within antidepressant drug discovery (Djillani et al., Pharmacology and Therapeutics 2019). Related work describes the sortilin/NTSR3 origin of spadin and its role in the membrane expression of TREK-1, which supplies the mechanistic rationale for the shortened analogs (Frontiers in Pharmacology, 2018). Separate mouse work using genetic and pharmacological inhibition of TREK-1 reported changes in depression-related behavior and hippocampal neuronal plasticity (CNS Neuroscience and Therapeutics, 2021); that work supports the target as biologically interesting but does not test this peptide. The design of the supporting studies limits the conclusions available. They are rodent experiments run in academic laboratories, largely the group that originated spadin, over short treatment courses. The behavioral readouts are screening assays rather than models of depression: forced swim, tail suspension and novelty-suppressed feeding are sensitive to known antidepressants, which makes them useful filters, but a long list of compounds that performed well in them has failed in human trials. The reports are not blinded multi-centre studies, are not pre-registered, and have not been replicated head to head by an independent group. No completed or registered human clinical trial exists for PE-22-28. There is consequently no Phase 1 safety or tolerability dataset, no human pharmacokinetic profile, no measured central nervous system exposure in people, and no published toxicology package. This is a weaker position than that of compounds it is informally compared with: approved rapid-acting antidepressants such as esketamine were established through randomized, placebo-controlled trials with standard depression rating scales before approval, and even TREK-1 or novel-mechanism candidates that ultimately failed generally reached Phase 1 and produced human exposure and tolerability data. Antidepressant-like signals in rodents do not establish human efficacy or safety.

In the small historical human studies DSIP was generally described as well tolerated with few reported acute side effects, including reports of no daytime sedation hangover. However, these trials were tiny, short-term, and decades old, so the safety database is thin and there is essentially no modern controlled long-term safety, immunogenicity, or chronic-exposure data. Material sold for "research" is unregulated, of unverified purity and identity, and not produced to pharmaceutical standards, which introduces contamination and mislabeling risks independent of the peptide itself. Long-term effects, drug interactions, and effects in any specific population remain unknown.

No human safety data exist for PE-22-28; all information comes from short-term rodent studies. There is no published Phase 1 tolerability study, no human pharmacokinetic or elimination data, no immunogenicity assessment, and no repeat-dose or reproductive toxicology package in the public literature. Because TREK-1 is expressed in tissues outside the brain, including cardiovascular, smooth muscle and immune-related tissues, systemic and off-target effects are theoretically possible; the channel also contributes to cellular responses to mechanical and thermal stimuli, so blocking it chronically could have consequences that short rodent behavioral experiments were never designed to detect. Effects on mood-related circuitry are themselves a caution: psychoactive compounds acting on serotonergic signaling and neurogenesis can produce agitation, sleep disruption or worsening mood, and no monitored human exposure exists to characterize any of this. Purity, identity and long-term toxicology of material sold as a research chemical are not controlled. Such products are made outside pharmaceutical good manufacturing practice, carry no verified certificate of analysis for peptide content, impurity profile or endotoxin, and are labeled for laboratory use only. Buyers cannot confirm what the vial holds or whether a reconstituted solution is sterile. The lack of reported adverse events reflects the lack of supervised human use rather than a safety record. With no clinical trials, no pharmacovigilance reporting and no registry, harms occurring in unsupervised use would not be captured. It is not a medicine and is not intended for human use.

DSIP is not approved by the FDA (or, to public knowledge, any major regulator) as a drug for sleep or any other indication; it has only ever been an investigational/experimental compound and is currently sold as a research-use-only chemical. It is not a WADA-prohibited substance by name, but it is not a legitimate, quality-controlled medicine.

PE-22-28 is not approved by the FDA or any other regulator and has no approved medical use. It exists only as a preclinical research compound. This summary is educational and includes no dosing guidance.