ACTH (4-10)

De Wied's work in the 1960s and 70s established that the behavioural effects of ACTH could be separated from its steroidogenic effects, and that residues 4-10 carried the behavioural activity. The fragment influences attention, motivation and avoidance learning in rodents through central melanocortin signalling, with additional effects on nerve regeneration. In humans, studies by Sandman, Kastin and others found measurable effects on attention, visual discrimination and reaction time, but essentially no durable effect on memory consolidation - the disappointment that eventually killed the programme. Its lasting significance is structural: adding a Pro-Gly-Pro tail to this fragment produced Semax, and adding it to tuftsin produced Selank.

Targets: Melanocortin receptors (MC3R/MC4R), Attention and arousal circuitry, Peripheral nerve regeneration pathways

• · The 1970s and 80s human attention studies used single parenteral doses in the tens of milligrams. That is enormous compared to how the grey market doses it, and reflects how fast the unmodified fragment is destroyed.
• · Dosed by analogy with Semax, which is not a sound basis - Semax was specifically engineered because this fragment does not survive long enough to work at those amounts. Expect much less than you would from Semax.

Work out your exact syringe units →

• commonNasal irritation
• uncommonRestlessness or arousal
• uncommonHeadache
• rareSkin darkening with prolonged high-dose use— A theoretical consequence of melanocortin activity; the fragment is far weaker at MC1R than the melanotans.
• rareNo cortisol elevation— Listed for clarity rather than as a side effect - the 4-10 fragment lacks the residues required for steroidogenesis, so it does not raise cortisol.

• Pregnancy and breastfeeding - no data.
• Melanoma or a history of atypical naevi - the melanocortin mechanism argues for caution even though this fragment is a weak MC1R ligand.

• redundantsemax — Semax is this fragment with a protective tail. Running both is pointless; Semax simply works better.
• cautionmelanotan-ii — Overlapping melanocortin activity; stacking increases pigmentation and nausea risk for no cognitive gain.

• · No bloodwork established. Cortisol testing is not required - this fragment does not stimulate the adrenal cortex.
• · Skin checks if you are using any melanocortin-active compound long term.

Not approved anywhere. Sold as a research chemical.

• de Wied, behaviourally active ACTH fragments and neuropeptide effects on learning - review of the Utrecht programme (review)
• Sandman & Kastin, effects of ACTH 4-10 on attention and visual discrimination in humans (trial)

The historical importance of ACTH(4-10) is that De Wied's Utrecht group used it to prove behavioural and steroidogenic activity could be separated - the fragment influences attention, motivation and avoidance learning through central melanocortin signalling without touching the adrenal cortex. That proof of principle launched the entire neuropeptide-fragment field this class is built on. What is less often said is how the human story actually ended, and it is more informative than the summary suggests. Sandman and Kastin's work in the 1970s reported enhanced attention on behavioural and physiological measures. But a well-designed double-blind study in 60 healthy adults, published in 2000, compared single-dose and prolonged intranasal ACTH(4-10) against desacetyl-alpha-MSH and placebo using event-related potentials: ACTH(4-10) enhanced the positive slow wave to target stimuli, left the classic P3 unchanged, increased error rates during vigilance testing, and temporarily reduced recall of neutral words. That is not a clean nootropic result. It is a peptide that changes attentional processing and makes performance somewhat worse on the measures that matter. The same study found desacetyl-alpha-MSH produced almost no effect on brain activity despite stronger melanocortin receptor binding, which argues the classical melanocortin receptors are not what mediates these cognitive effects - an important and underappreciated finding that also applies to Semax. Two things follow for anyone considering this compound. The human memory literature is genuinely negative, which is why the programme was abandoned. And the structural lesson is that Semax exists because this molecule does not survive long enough to be useful, so dosing this by analogy with Semax is backwards.

The core error is dosing by analogy with Semax. Semax was engineered specifically because this fragment does not survive long enough to work at those amounts, and taking 600 mcg of ACTH(4-10) intranasally expecting a Semax-like effect is asking a molecule to do the thing it was proven unable to do. The second problem is the evidence itself, which people quote selectively: the human attention literature includes a well-controlled study where the compound increased vigilance error rates and temporarily reduced word recall, and the programme was abandoned because there was no durable memory effect. Feeling more aroused while performing worse is the documented pattern. Third is chemical fragility - the fragment contains methionine and tryptophan, both readily oxidised, so it degrades faster than Semax in the same conditions and a warm spray bottle will destroy it. Reconstituted solution should be treated as a two to three week product at most, kept cold and dark.

1. 300 mcgDays 1-5 — Single morning intranasal dose. Understand that this is dosing by analogy with Semax, which is not a sound basis - the fragment is destroyed far faster and the historical human studies that produced any effect used doses three orders of magnitude higher parenterally.
2. 1 mgWeek 2 onward — Top of the grey-market range, once or twice daily. Expect substantially less than an equivalent Semax dose. There is no modern dose-response data by any practical route, so this ladder is convention rather than derivation.
3. 30 mgHistorical research dosing, for context only — The 1970s and 80s human attention studies used single parenteral doses of 15-30 mg per test session. Included to show the scale of the mismatch with grey-market dosing, not as a protocol - and remembering that those doses produced increased vigilance errors and reduced word recall in the better-controlled work.

• Melanocortin receptors (MC3R/MC4R) — Weak. The critical comparative finding is that desacetyl-alpha-MSH, which binds melanocortin receptors more strongly, produced almost no cognitive or electrophysiological effect in a direct human comparison - which argues these receptors are not the route

  Contributes to arousal. The mechanistic account resting on melanocortin receptors is weaker than usually presented, for this compound and for Semax.

• Melanocortin MC1R (pigmentation) — Far weaker than the melanotans

  Theoretical pigmentation effect at high prolonged doses. Not a realistic concern at grey-market intranasal dosing.

• Melanocortin MC2R (adrenal ACTH receptor) — No meaningful activity - the fragment lacks the residues needed for steroidogenesis

  No cortisol release. Cortisol testing is not required on this compound and a normal result proves nothing you did not already know.

• Attention and arousal circuitry — Not receptor-defined

  Altered attentional processing measured on event-related potentials - enhanced positive slow wave to targets with unchanged P3, alongside increased vigilance error rates and transiently reduced word recall.

• Peripheral nerve regeneration pathways — Not quantified

  ACTH fragments have documented effects on peripheral nerve regeneration in animal models, which is a genuine and separate line of work from the cognitive one.

• Event-related brain potentials and working memory after single-dose and prolonged intranasal ACTH(4-10) and desacetyl-alpha-MSH in healthy humans (Smolnik et al.) Double-blind, randomised, placebo-controlled · n=60 · 2000

  Event-related potentials and working memory function in healthy adults after single-dose and prolonged intranasal administration. ACTH(4-10) enhanced the positive slow wave in ERPs to target stimuli with unchanged P3, increased error rates during vigilance testing, and temporarily reduced recall of neutral words. Desacetyl-alpha-MSH showed minimal effects despite stronger receptor binding, suggesting melanocortin receptors may not mediate the cognitive effects of this peptide family.

• MSH/ACTH 4-10 influences behavioral and physiological measures of attention (Sandman, Kastin et al.) Experimental human study · 1977

  Behavioural and physiological measures of attention in humans. Part of the 1970s series that established measurable attentional effects of the fragment and led to the broader clinical programme.

Attentional effects in the classic human studies were measured within 30-60 minutes of parenteral administration and were short-lived, consistent with a peptide that is degraded within minutes. The intranasal study assessed both single-dose and prolonged administration and found effects on event-related potentials without durable cognitive benefit. There is no meaningful chronic timeline because the historical use was single-dose experimental and the programme did not proceed to chronic dosing for lack of an effect worth chasing.

There is very little reason to stack this with anything, because there is very little reason to use it. Running it with Semax is pointless - Semax is this fragment with a protective tail and simply works better at any given dose. Combining it with melanotan-II or another melanocortin agonist increases pigmentation and nausea risk for no cognitive gain, since the human data suggest melanocortin receptors are not where the cognitive effects come from anyway. If you have this compound and want to use it sensibly, the honest advice is to treat it as a historical curiosity or a cheaper way to test whether the ACTH-fragment pharmacophore does anything for you, and to move to Semax if it does.

Against Semax, which is the only comparison that matters: Semax is this molecule with a Pro-Gly-Pro tail replacing the last three residues, added specifically to survive exopeptidases. Semax lasts longer, works at lower doses, has a Russian registration and human stroke data, and is usually cheaper per effective dose. There is no scenario where the parent fragment is the better buy. Against the melanotans, which share the melanocortin core: those are far stronger MC1R ligands with real pigmentation effects and a completely different use case; ACTH(4-10) is a weak melanocortin ligand and the human data suggest its cognitive effects are not melanocortin-mediated at all. Against nothing at all: the honest read of the human literature is that this fragment produces measurable changes in attentional electrophysiology, no durable memory benefit, and in the best-controlled study a decrement in vigilance accuracy and word recall. The programme was abandoned for good reasons. Its lasting value is structural - adding a Pro-Gly-Pro tail to this gave Semax and adding it to tuftsin gave Selank, and understanding that explains most of this class.

$20–$60/month. A 10 mg vial typically runs 40-70 USD. At 600 mcg daily that is roughly two weeks, so 60-120 USD monthly at grey-market dosing - which is more expensive than Semax for an effect that is by design weaker. Reproducing the historical 15-30 mg parenteral research doses would consume two to three vials per single dose and is not a realistic proposition.

• ?No modern pharmacokinetic data exists - no measured half-life, bioavailability, volume of distribution, clearance or protein binding by any route.
• ?Participant numbers and design details of the Sandman and Kastin studies I did not fully verify beyond the titles and journals.
• ?The grey-market intranasal dose range of 300-1000 mcg has no evidential basis at all and is derived by analogy with a different, more stable molecule.
• ?How the intranasal route compares with the parenteral route used in the historical studies has not been characterised for this fragment.
• ?Whether the melanocortin receptors mediate any of the cognitive effect is genuinely in doubt following the comparison with desacetyl-alpha-MSH.
• ?The nerve regeneration effects of ACTH fragments are a separate literature I did not verify in detail.
• ?The molecular weight of 962.1 Da in the Core record is plausible for the heptapeptide sequence but I did not verify it against a primary characterisation.
• ?There is no data on chronic use because chronic use was never studied - the programme stopped when the memory effects did not materialise.

• Event-related brain potentials and working memory function in healthy humans after single-dose and prolonged intranasal administration of adrenocorticotropin 4-10 and desacetyl-alpha-melanocyte stimulating hormone Smolnik R, Perras B, Molle M, Fehm HL, Born J, Journal of Clinical Psychopharmacology, 2000 · PMID 10917406

  The best-controlled human study of intranasal ACTH(4-10), and the most useful. 60 healthy adults, double-blind, and the results are not flattering - increased vigilance errors and reduced word recall. Also the source of the finding that a stronger melanocortin binder does less, which undermines the melanocortin mechanism for this whole peptide family.

• MSH/ACTH 4-10 influences behavioral and physiological measures of attention Sandman CA, George J, McCanne TR, Nolan JD, Kaswan J, Kastin AJ, Journal of Clinical Endocrinology and Metabolism, 1977 · PMID 192754

  The positive-side human attention work from the original programme. Read alongside the 2000 study rather than instead of it.

• Neuropeptide MSH/ACTH 4-10 enhances attention in the mentally retarded Sandman CA, George J, Walker BB, Nolan JD, Kastin AJ, Pharmacology Biochemistry and Behavior, 1976 · PMID 189328

  The earlier study in a clinical population. Historically important as one of the first demonstrations of a behaviourally active peptide fragment in humans; the terminology is of its period.