DSIP

What it is

DSIP is a nine-residue peptide isolated in 1977 from the cerebral venous blood of rabbits. The original experiment was elegant: a peptide that enhanced slow-wave (delta) and spindle EEG patterns after infusion into the brain ventricles. The researchers synthesised the nonapeptide along with five possible metabolic products, two analogues with amino acid substitutions and a related tripeptide, then infused all nine into 58 rabbits under double-blind conditions with computer-analysed EEG. Only the synthetic DSIP produced significant and specific enhancement of delta and spindle patterns.

That is a careful 1977 study, and it gave the molecule its name. Everything since has struggled to build on it. In FDA documents it appears under the name emideltide.

What it does in the body

The honest answer is that this remains unresolved — and the people who have worked on it longest say so most clearly.

A 2006 review in the Journal of Neurochemistry, titled “Delta sleep-inducing peptide (DSIP): a still unresolved riddle”, laid out the problem. The link between DSIP and sleep has never been further characterised, in part because the DSIP gene, protein and any related receptor have never been isolated. The authors described the hypothesis regarding DSIP as a sleep factor as “extremely poorly documented and still weak”. Its structure is unlike any other known peptide family. Its natural occurrence and biological activity remain obscure.

The reviewers went further and proposed that DSIP-like immunoreactivity and activity may belong to some other, unidentified peptide. Their reasons are worth noting: DSIP-like immunoreactivity is distributed in neurosecretory hypothalamic nuclei that are not particularly relevant to sleep regulation; certain artificial structural analogues promoted slow-wave sleep in rabbits and rats while DSIP itself did not; and a naturally occurring dermorphin decapeptide similar to DSIP in five of nine positions promoted slow-wave sleep while its optical isomer suppressed it.

Fifty years after isolation, the mechanism is not merely unproven. The molecule’s identity as a signalling peptide is itself in question.

What the human evidence shows

Unusually for this atlas, there is a double-blind trial. It is small and it is essentially negative.

Chronic insomnia, 1992. Sixteen chronic insomniac patients in a double-blind matched-pairs parallel-groups design slept five consecutive nights in a laboratory — one adaptation night, one baseline night, then three nights after intravenous DSIP at 25 nmol/kg or a glucose placebo. Polysomnography showed higher sleep efficiency and shorter sleep latency with DSIP, and one measure of subjective tiredness decreased. But the authors stated that the statistically significant effects were weak and in part could be due to an incidental change in the placebo group, and that no other measure — including subjective sleep quality — changed. Their conclusion: short-term treatment of chronic insomnia with DSIP is not likely to be of major therapeutic benefit.

Earlier open studies. A 1986 sleep-laboratory study gave 18 chronic psychophysiological insomniacs intravenous DSIP for a week with a week of follow-up, reporting normalisation of sleep, more so in the more severely affected. These were open, uncontrolled, and from a single investigator.

Withdrawal syndromes, 1984. One hundred and seven inpatients with alcohol (47) or opiate (60) withdrawal received intravenous DSIP. Assessment was by clinical evaluation by physicians and nursing staff — no blinding, no control group. Roughly 13% and 22% of the two groups could not be evaluated. Of those assessed, symptoms reportedly disappeared or improved markedly and rapidly in 97% of opiate and 87% of alcohol patients, with anxiety slower to resolve and headaches in a few patients. In an unblinded, uncontrolled study of withdrawal — a condition that resolves on its own over days — those numbers cannot be attributed to the drug.

Claims and what backs them

Risks and unknowns

The deepest unknown here is what the molecule is. For every other entry in this atlas there is at least a defined target or mechanism. For DSIP there is a sequence, a name based on a 1977 rabbit EEG experiment, and fifty years of inability to find the gene, the receptor or a convincing physiological role.

Tolerability in the old studies was reported as acceptable. Across the withdrawal study and the insomnia studies, the main adverse events noted were headaches in a few patients. These were small, short, mostly unblinded studies with no systematic safety monitoring, so “well tolerated” means “nothing obvious was recorded”.

All human studies used intravenous administration. That is how it was given in 1984 and 1992, under supervision, in hospital. Material sold today is for self-administered subcutaneous injection — a different route with no supporting data, and the FDA committee specifically noted that the withdrawal studies it reviewed had used intravenous dosing.

Supply. DSIP has no legitimate pharmaceutical source. Anything available is grey-market, with the identity and contamination concerns that apply across this category.

Where regulators stand

The bottom line

DSIP is the weakest entry in this atlas, and it is instructive precisely because it is not a modern invention — it has had half a century. In that time nobody has found its gene, its receptor, or a reliable physiological function, and the researchers closest to it published a review arguing that the activity attributed to DSIP may belong to a different molecule entirely.

The one blinded human trial found effects its own authors described as weak and possibly an artefact of the placebo group. And when a committee that had just voted six other peptides onto a compounding list reached this one, it said no.

References

1. Schoenenberger GA, Monnier M. Characterization of a delta-electroencephalogram (-sleep)-inducing peptide. Proc Natl Acad Sci USA. 1977;74(3):1282–1286 PMID 265572
2. Kovalzon VM, Strekalova TV. Delta sleep-inducing peptide (DSIP): a still unresolved riddle. J Neurochem. 2006;97(2):303–309 PMID 16539679
3. 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):193–197 PMID 1299794
4. Schneider-Helmert D. Efficacy of DSIP to normalize sleep in middle-aged and elderly chronic insomniacs. Eur Neurol. 1986;25(6):448–453 PMID 3792404 — open-label
5. Dick P, Costa C, Fayolle K, et al. DSIP in the treatment of withdrawal syndromes from alcohol and opiates. Eur Neurol. 1984;23(5):364–371 PMID 6548969 — uncontrolled, unblinded