Synthetic ACTH analogue Semax displays nootropic-like activity in humans
Kaplan AY, Kochetova AG, Nezavibatko VN, Ryasina TV, Ashmarin IP
Neuroscience Research Communications (1996) · n=36
The first international report of Semax cognitive effects in humans, from the Ashmarin inventor group at Moscow State University — three sub-studies (operator performance, EEG during cognitive load, EEG under post-hyperventilation cerebral ischaemia) establishing a long-lasting (20-24 hr post single intranasal dose) cognitive signal at 0.25-1.0 mg.
This 1996 paper from the Kaplan / Kochetova / Nezavibatko / Ryasina / Ashmarin group at Moscow State University is the foundational international report describing the cognitive and EEG effects of the synthetic heptapeptide Semax (Met-Glu-His-Phe-Pro-Gly-Pro), an ACTH(4-10) analogue, in healthy human volunteers. Three sub-studies are reported: (1) a 2-day double-blind placebo-controlled parallel-group operator-performance trial at a power plant (n=16; 8 Semax, 8 placebo) in Perm, Russia, in which a single intranasal 1.0 mg dose preserved sensorimotor accuracy across an 8-hour shift and into the next morning 20-24 hours later; (2) a within-subject EEG study during a visual-memory task (n=11; 6 Semax, 5 placebo) showing that a 0.25 mg intranasal dose suppressed delta-band power and increased alpha-band power, a spectral signature the authors classify as nootropic-like per the Hock 1987 and Kaplan 1989 pharmaco-EEG criteria; (3) a double-blind three-visit EEG study (n=9) under post-hyperventilation transient cerebral ischaemia showing that Semax attenuated the hyperventilation-induced increase in slow rhythms by roughly 60-80% relative to placebo, with full normalization of the ischaemic EEG shift in 4 of 9 subjects.
The paper situates Semax within the ACTH(4-7) analogue family and motivates the C-terminal Pro-Gly-Pro extension as a stability modification (the structural rationale is in the Ashmarin et al. 1995 design paper, Neurosci Res Commun 16(2):105-112). It does not report hormonal (HPA-axis) activation, consistent with the design goal of decoupling ACTH cognitive effects from corticotropic activity. The paper is the canonical citation for Semax's claim to "nootropic-like" cognitive enhancement in humans and the anchor reference for the subsequent Russian regulatory approval pathway.
Small samples across all three sub-studies (n = 16, 11, 9). The operator study is the only one that is genuinely double-blind and placebo-controlled with random allocation; the EEG-cognitive sub-study has a placebo arm but the methods do not state whether allocation was blinded to the subject. The hyperventilation sub-study is described as "double-blind, control regime" with three visits 7-8 days apart, implying a within-subject crossover but the structure is not made fully explicit.
The operator task is a custom number-image recognition battery ("computational reactography"), not a standardized neuropsychological assessment. Baseline (first morning) is the 100% reference for each subject, and all subsequent measurements are expressed as percentage change against that subject's own baseline — this normalizes individual variation but does not give absolute reaction times or accuracy rates that would let an outside reader independently judge effect-size context.
Statistical analyses use the Wilcoxon test (operator data) and Student's t-test (EEG spectra). No effect sizes (Cohen's d or equivalents) are reported; only p-values. The hyperventilation table uses an unusual derived metric "ES" — the proportional correction of the hyperventilation-induced EEG shift attributable to Semax. Beta-band cells are blank, meaning the placebo-vs-Semax difference for beta-1 and beta-2 did not reach statistical significance.
The paper does not develop a mechanistic claim beyond pharmaco-EEG classification (alpha-up, delta-down → nootropic-like). It explicitly raises but does not resolve the question of whether Semax acts directly on cognitive circuits or indirectly via improved cerebral oxygen supply.
Dose-response is not characterized: the operator study uses 1.0 mg, the EEG-cognitive study uses 0.25 mg, and the hyperventilation study uses an unspecified dose within the 0.25-1.0 mg range stated in the abstract. The authors are also the inventor group at the molecule's home institution — the routine institutional conflict-of-interest applies in the same way it does for any sponsor-affiliated Phase 1/2 trial.
Independent Western RCT replication of these findings in healthy adults has not occurred in the 30 years since publication. The subsequent Russian clinical literature uses Semax for stroke recovery, cognitive-impairment populations, and other indications, but the healthy-adult nootropic claim rests substantially on this paper.
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