Ebiratide
A brain-active fragment of the stress hormone ACTH, built to work without raising cortisol, that made people more alert but did not help memory
Ebiratide, code name Hoe 427, is a synthetic analogue of ACTH(4-9), a six-residue piece of the pituitary hormone corticotropin. Fragments of this kind were studied because they seemed to act on behaviour and attention without the full hormone's effect on the adrenal glands. Ebiratide was made more stable and fatty enough to cross into the brain. In rats it improved avoidance learning at very small doses and raised the enzyme that makes acetylcholine. In people, single intravenous doses did not change cortisol, made patients feel less tired, disturbed the first hours of sleep and did not improve memory in Alzheimer's disease. Development stopped in the 1990s.
Used in human trials: 60, 300 or 600 micrograms, Once per study day, with placebo on another day, Intravenous (Alzheimer's disease or depression, crossover (8 patients)) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
Corticotropin (ACTH) is the 39-amino-acid pituitary hormone that tells the adrenal glands to make cortisol. Short pieces of it, from residue 4 to residue 9 or 10, were studied because they act on behaviour without driving the adrenal gland; a 1993 trial report calls ebiratide endocrinologically inert but behaviourally active. That made the fragments candidates for treating poor attention and memory in older people. The early versions, ACTH(1-10) and the analogue Org 2766, were broken down quickly and gave inconsistent results in patients, including no clear benefit in Alzheimer's disease, according to a 1991 report on ebiratide's first clinical use.
Ebiratide was the next attempt. Its sequence keeps the ACTH(4-9) core but oxidises the first methionine to a sulfone, swaps lysine for its D-form and ends in an eight-carbon amine chain. The 1991 report describes the result as far more stable and more lipophilic than earlier fragments and much more potent in animal memory models. In 1988 rat and mouse studies, injections under the skin of 1 to 10 micrograms per kilogram worked best across five avoidance and maze tasks, and doses down to 0.01 micrograms per kilogram lowered brain acetylcholine content while raising the activity of choline acetyltransferase, the enzyme that makes it.
A Japanese group spent much of the 1990s on how it reaches the brain. In isolated bovine brain capillaries and cultured capillary cells it was taken up by adsorptive endocytosis, a route open to positively charged peptides that other basic peptides compete for. In rats, radiolabelled ebiratide entered brain tissue at about seven times the volume of a sugar marker that barely crosses, and most of what reached brain fluid was intact. Four weeks of continuous infusion in aged rats raised choline acetyltransferase in the septum, neocortex and hippocampus by 35% to 89%. Other papers from the programme tested ways to give it by mouth or through the skin, with poor absorption across rat intestine unless an enhancer was added.
Six papers describe it in people, all from 1989 to 1996 and all with single intravenous doses or one night of doses. They agree on two points. It did not change cortisol or growth hormone, which was the design goal, and it did act on the brain: it altered attention-related brain waves in healthy men, made sleep lighter and slower to start in the first three hours of the night, and left patients with Alzheimer's disease or depression reporting less tiredness and more alertness. In the one placebo-controlled patient study, none of the eight patients improved on cognitive tests.
No trial of repeated dosing, no registry record and no approval exist. ChEMBL records a maximum clinical phase of 2, and the last paper found is from 1998. For anyone who meets the name today, the important facts are that the human data are a few dozen people given one dose each, that the cognitive benefit hoped for was not seen, and that one study found an analogue dose impaired a marker of focused attention rather than helping it.
Mechanism of Action
Ebiratide was designed to keep the brain effects attributed to ACTH(4-9) and drop the hormone's action on the adrenal glands. The receptor it acts on was not identified in the abstracts read; what was measured is below.
No adrenal signal
In people it left nighttime cortisol and growth hormone secretion unchanged (1991) and did not raise plasma cortisol, unlike corticotropin-releasing hormone given the same way (1996).
Acetylcholine turnover
In rats single injections lowered acetylcholine content in several brain areas for up to 24 hours while raising choline acetyltransferase and cyclic GMP, which the authors read as faster acetylcholine use (1988). Four weeks of infusion raised choline acetyltransferase in aged rats, and in septal cell cultures it partly prevented nerve-cell loss (1995).
Crossing into the brain
Brain capillary cells took it up by a saturable endocytosis shared with other basic peptides such as protamine and poly-lysine, not by insulin or transferrin routes (1991, 1992). In rats brain levels peaked five minutes after an intravenous dose and fell in step with plasma (1991).
Arousal rather than memory
In people the effects measured were on arousal and attention: lighter early sleep, changed auditory evoked potentials, and less reported tiredness, with no cognitive improvement in patients (1989-1996).
Published Research
These are the studies of ebiratide read from their PubMed abstracts on October 30, 2026: the six human reports first, then the animal, tissue and formulation work. Four human papers title it only as an ACTH 4-9 analogue or fragment; they are carded because each abstract names ebiratide or Hoe 427 as the substance given.
Alzheimer's disease and depression, placebo-controlled
Three patients with probable Alzheimer's disease and five with retarded depression received 60, 300 and 600 micrograms intravenously and placebo in a double-blind crossover. No adverse effect was detected and no patient improved on neuropsychological tests, but all reported feeling less tired and more alert after every dose and not after placebo. The authors concluded it may activate but showed no anti-dementia or antidepressant effect when given once.
Sleep and night-time hormones
Four intravenous pulses of 120 micrograms between 22:00 and 01:00, against placebo, lengthened the time to fall asleep, increased waking during the night and reduced slow-wave sleep, but only in the first three hours. Night-time cortisol and growth hormone secretion did not change.
Attention brain waves in 20 healthy men
In a double-blind Latin-square study, each man received placebo, ACTH 4-10 (1 mg) and Hoe 427 at 60 and 200 micrograms intravenously. Both ACTH 4-10 and the higher Hoe 427 dose reduced the event-related potentials that mark selective attention during a listening task; the authors read this as an impairing influence, with the analogue more potent than the natural fragment.
Auditory evoked potentials in 10 men
On separate days ten men received placebo, corticotropin-releasing hormone (100 micrograms) or Hoe 427 (300 micrograms) intravenously. Corticotropin-releasing hormone raised cortisol and ACTH; Hoe 427 did not change cortisol, yet both changed late auditory evoked potentials in a similar pattern, which the authors attributed to a direct action of the fragment on the brain.
First clinical impressions in Alzheimer's disease
A report on the first clinical work: single-dose studies in mildly cognitively impaired older people and in patients with Alzheimer's disease found slight but significant effects on attention and mood, less consistent in patients than in healthy subjects. It frames the compound as a more stable, more lipophilic successor to ACTH(1-10) and Org 2766, which had failed to show efficacy.
Sleep-endocrine research programme
A summary of a Munich programme of sleep EEG and night-time hormone studies in healthy men and in depression reports that sleep became shallower under ebiratide while hormone secretion stayed unchanged, in contrast to corticotropin-releasing hormone, which mimicked some features of depression.
Learning and memory in mice and rats
Across five tasks, including avoidance tests with shock- or scopolamine-induced amnesia and an eight-arm radial maze, ebiratide worked best at 1 to 10 micrograms per kilogram injected under the skin.
Acetylcholine in rat brain
Injected at 0.01 to 10 micrograms per kilogram, it lowered acetylcholine content in several brain areas within half an hour for up to a day, more so after dexamethasone, and raised choline acetyltransferase activity and cyclic GMP. The authors concluded it speeds acetylcholine metabolism.
Septal cultures and aged rats
In sparse fetal rat septal cultures it partly prevented nerve-cell degeneration and raised choline acetyltransferase and acetylcholinesterase up to 1.5 and 1.2 times control. Infused under the skin at 10 nmol per hour for four weeks, it raised choline acetyltransferase in aged rats' septum by 35%, neocortex by 79% and hippocampus by 89%.
How much reaches the rat brain
After intravenous doses of 2 to 20 mg per kilogram, brain levels peaked at five minutes and fell in step with plasma, with a brain-to-plasma ratio near 0.05 ml/g. Unlabelled peptide reduced the uptake of a labelled dose, most in the hippocampus, pointing to a specific uptake.
Uptake by isolated brain capillaries
Bovine brain capillaries bound and internalised it in a temperature-dependent, saturable way that an endocytosis inhibitor blocked. ACTH, poly-lysine and protamine competed; insulin and transferrin did not, pointing to adsorptive endocytosis of basic peptides.
Cultured brain capillary cells
In monolayers of bovine brain capillary endothelial cells it was not broken down and was internalised by a saturable, energy-dependent process that basic peptides inhibited, confirming the adsorptive endocytosis route.
Brain microdialysis in rats
Infused into the carotid artery, labelled ebiratide reached brain tissue at about seven times the distribution volume of sucrose, and at least 80% of the radioactivity collected from brain fluid was intact peptide. Its brain-fluid-to-blood ratio was about eight times sucrose's.
Spinal cord injury in mice
The blood-spinal cord barrier was more permeable to ebiratide in the cervical and lumbar cord than in the thoracic cord and brain. After a complete lumbar transection, permeability to ebiratide did not change, which the authors read as its transport system being unaffected by the injury.
Alcohol drinking in male and female rats
Daily intraperitoneal doses of 0.03 mg per rat, like ACTH 4-10, reduced free-choice ethanol drinking without changing saccharin intake. After four days male rats showed a rebound rise in drinking that females did not.
Alcohol drinking in two rat strains
In Lewis and Sprague-Dawley rats, four days of intraperitoneal Hoe-427 reduced ethanol drinking in a dose-dependent way, as immobilisation and isolation stress did, with no effect on saccharin.
Stability in rat intestine
It was very stable in rat intestinal fluid but broken down by intestinal lining homogenates, two to three times faster in jejunum and ileum than in duodenum and colon; aminopeptidase inhibitors such as bestatin and puromycin largely prevented this.
Absorption across rat intestine
In Ussing chambers its permeation through rat intestinal membranes was poor overall, best in jejunum. Glycocholate and caprate improved passage only through colon; a maltoside surfactant improved both jejunum and colon with little membrane damage.
Through rat skin
Gels with absorption enhancers carried labelled ebiratide through rat skin at a steady rate; patches with enhancers raised plasma radioactivity well above an enhancer-free gel, and a very small amount reached the brain.
Dosing Data
These are the amounts the published human studies gave, each once or over a single night, to measure brain and hormone responses. Ebiratide was never approved and no study gave it for longer, so there is no treatment dose.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes Ebiratide is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
No worked example: none of the doses on this page is a fixed amount in mg or mcg injected under the skin or into a muscle (the routes given are: intravenous). There is no home-mixing step to show. The reconstitution calculator does the arithmetic for any vial.
Source: the route and amount of each dose row in Dosing Data below.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store Ebiratide, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long Ebiratide stays intact once mixed.
How it is taken
As it was given in human studies: Intravenous (Once per study day, with placebo on another day; Alzheimer's disease or depression, crossover (8 patients)).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Alzheimer's disease or depression, crossover (8 patients): Single doses; Sleep EEG study: One night; Attention study, 20 healthy men: Single doses.
When effects appear: unknown; no source on this page gives a time to effect for Ebiratide. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: No adverse effect detected in eight patients given up to 600 micrograms (PMID 8394847); Lighter, more broken sleep and slower sleep onset in the first three hours after night-time doses (PMID 1666179); Reduced markers of focused attention at 200 micrograms in healthy men, which the authors read as impairment (PMID 2556725); Feeling less tired and more alert, reported by patients after every dose (PMID 8394847); No change in cortisol or growth hormone (PMID 1666179, PMID 8927235). Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping Ebiratide. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the human studies above, all with single doses or one night of doses”).
Interactions
Unknown: a PubMed search for human interaction studies of Ebiratide (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of Ebiratide products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against Ebiratide's expected mass, 996.2 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Discontinued (Never approved: Drugs@FDA and the EMA medicines list hold no record (searched October 28, 2026), and ClinicalTrials.gov lists no trial (October 30, 2026)). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the human studies above, all with single doses or one night of doses.
Contraindications & Cautions
There is no label. These cautions follow from what was and was not studied.
Legal Status
Ebiratide reached early clinical study in the late 1980s and early 1990s and was never approved.
Frequently Asked Questions
?What is ebiratide?
A synthetic analogue of ACTH(4-9), a short piece of the pituitary hormone corticotropin, modified to resist breakdown and reach the brain. Its development code was Hoe 427.
?Does it raise cortisol like ACTH?
No. In the human studies it did not change cortisol or growth hormone, which was the point of the design.
?Did it improve memory?
Not in people. Rats learned avoidance tasks better at tiny doses, but in a 1993 placebo-controlled study none of eight patients with Alzheimer's disease or depression improved on cognitive tests after single doses, though all felt more alert.
?What doses were used in people?
Single intravenous doses of 60 to 600 micrograms, or four 120-microgram pulses over one night. These were experiments measuring brain and hormone responses, not treatments.
?How is it related to Semax?
Both come from the same ACTH(4-10) region. Semax is a different, Russian-developed analogue with its own entry; the two have separate literatures.
?Can it be bought?
It was never approved, and no regulated product exists. Anything sold under the name would be an unregulated research chemical of unknown content.
References
- [other] PubChem CID 6918103, Ebiratide: formula C48H73N11O10S, molecular weight 996.2. Read October 28, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/6918103
- [rct] Heuser I, et al. "Behavioral effects of a synthetic corticotropin 4-9 analog in patients with depression and patients with Alzheimer's disease." J Clin Psychopharmacol, 1993;13(3):171-4. PMID: 8394847.
- [clinical-trial] Steiger A, et al. "Effects of an ACTH/MSH(4-9) analog (HOE 427) on the sleep EEG and nocturnal hormonal secretion in humans." Peptides, 1991;12(5):1007-10. PMID: 1666179.
- [clinical-trial] Born J, et al. "Fragments of ACTH affect electrophysiological signs of controlled stimulus processing in humans." Psychopharmacology (Berl), 1989;99(4):439-44. PMID: 2556725.
- [clinical-trial] Hartmann A, et al. "Changes in late auditory evoked potentials induced by corticotropin-releasing hormone and corticotropin fragment 4-9 in male controls." Neuropsychobiology, 1996;33(2):90-6. PMID: 8927235.
- [review] Siegfried KR. "First clinical impressions with an ACTH analog (HOE 427) in the treatment of Alzheimer's disease." Ann N Y Acad Sci, 1991;640:280-3. PMID: 1663715.
- [review] Steiger A, et al. "The sleep EEG and nocturnal hormonal secretion studies on changes during the course of depression and on effects of CNS-active drugs." Prog Neuropsychopharmacol Biol Psychiatry, 1993;17(1):125-37. PMID: 8416599.
- [pubmed] Hock FJ, et al. "Learning and memory processes of an ACTH4-9 analog (ebiratide; Hoe 427) in mice and rats." Peptides, 1988;9(3):575-81. PMID: 2843833.
- [pubmed] Wiemer G, et al. "Neurochemical effects of the synthetic ACTH4-9-analog Hoe 427 (Ebiratide) in rat brain." Peptides, 1988;9(5):1081-7. PMID: 2854245.
- [pubmed] Matsumoto T, et al. "The neurotrophic effects of ebiratide, an analog of ACTH4-9, on cultured septal cells and aged rats." J Neural Transm Gen Sect, 1995;100(1):1-15. PMID: 8748659.
- [pubmed] Shimura T, et al. "Brain transfer of a new neuromodulating ACTH analog, ebiratide, in rats." Peptides, 1991;12(3):509-12. PMID: 1681522.
- [pubmed] Shimura T, et al. "Transport mechanism of a new behaviorally highly potent adrenocorticotropic hormone (ACTH) analog, ebiratide, through the blood-brain barrier." J Pharmacol Exp Ther, 1991;258(2):459-65. PMID: 1650827.
- [pubmed] Terasaki T, et al. "Absorptive-mediated endocytosis of an adrenocorticotropic hormone (ACTH) analogue, ebiratide, into the blood-brain barrier: studies with monolayers of primary cultured bovine brain capillary endothelial cells." Pharm Res, 1992;9(4):529-34. PMID: 1323100.
- [pubmed] Shimura T, et al. "In-vivo blood-brain barrier transport of a novel adrenocorticotropic hormone analogue, ebiratide, demonstrated by brain microdialysis and capillary depletion methods." J Pharm Pharmacol, 1992;44(7):583-8. PMID: 1357139.
- [pubmed] Pan W, et al. "Blood-brain barrier permeability to ebiratide and TNF in acute spinal cord injury." Exp Neurol, 1997;146(2):367-73. PMID: 9270046.
- [pubmed] Krishnan S, et al. "The effect of Hoe-427 (an ACTH4-9 analog) on free-choice ethanol consumption in male and female rats." Life Sci, 1991;49(26):2005-11. PMID: 1660954.
- [pubmed] Sprague JE, et al. "Effects of stress and ebiratide (Hoe-427) on free-choice ethanol consumption: comparison of Lewis and Sprague-Dawley rats." Life Sci, 1994;55(11):873-8. PMID: 8072388.
- [pubmed] Okagawa T, et al. "Susceptibility of ebiratide to proteolysis in rat intestinal fluid and homogenates and its protection by various protease inhibitors." Life Sci, 1994;55(9):677-83. PMID: 8065230.
- [pubmed] Yamamoto A, et al. "Effects of different absorption enhancers on the permeation of ebiratide, an ACTH analogue, across intestinal membranes." J Pharm Pharmacol, 1997;49(11):1057-61. PMID: 9401937.
- [pubmed] Ogiso T, et al. "Percutaneous absorption of physiologically active peptides, ebiratide and elcatonin, in rats." Biol Pharm Bull, 1994;17(8):1094-100. PMID: 7820115.
- [other] ChEMBL CHEMBL2106396, ebiratide: maximum clinical phase 2 in the ChEMBL molecule record, read October 2, 2026 (the Registry's ChEMBL harvest). https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2106396/
Sources & Citations
Every study on this page was read from its PubMed record on October 30, 2026. The structure is from the 1992 and 1988 papers; the formula and weight are PubChem's; the clinical phase is ChEMBL's. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.