Compounds with a graded row

Ordered by rung, strongest first. The rung rates the study design; the chip beside it says what the study measured. Both are needed.

1. N-Acetylcysteine (NAC)

   human RCT Direct outcome Not approved for this condition

   Who was studied

   adults with vascular mild cognitive impairment enrolled in an exercise-based cardiac rehabilitation programme, n=59, 69.5% male, mean age 67.6 years, 2,400 mg/day orally for 24 weeks

   This 24-week randomised, double-blind, placebo-controlled trial measured an executive function composite plus verbal memory, working memory, non-verbal memory, attention and global cognition. Executive function improved over time in both arms and there was no significant difference between N-acetylcysteine and placebo (p=0.8), so the improvement belongs to the rehabilitation both groups received rather than to the compound. A companion imaging analysis of the same trial reported that lower frontal white-matter hyperintensity volume predicted greater Trail Making Test B improvement at 3 months on N-acetylcysteine than on placebo, with no difference at 6 months or on the other measures. N-acetylcysteine is approved as a mucolytic and as the paracetamol-overdose antidote; no regulator has approved it for a cognitive indication.

   Source PubMed 2 primary sources read for this row

2. NAD+ Boosting / Precursor Peptides

   human RCT Direct outcome Not approved for this condition

   Who was studied

   adults over 55 with subjective cognitive decline or mild cognitive impairment, n=46 randomised and 37 completing, nicotinamide riboside 1 g/day for 8 weeks in a double-blind placebo-controlled crossover; sex distribution and mean age not reported in the abstract

   The Repeatable Battery for the Assessment of Neuropsychological Status was the primary outcome and did not differ between nicotinamide riboside and placebo, and neither did Lumosity gameplay scores; plasma p-tau217 fell 7% on nicotinamide riboside against an 18% rise on placebo (p=0.02). Two further randomised placebo-controlled trials in mild cognitive impairment agree on the cognitive result: 1 g/day for 10 weeks in 20 patients left the Montreal Cognitive Assessment and every other neurocognitive metric unchanged while raising blood NAD+ 2.6-fold, and a 12-week trial in 42 patients with amnestic mild cognitive impairment doubled blood NAD+ with no improvement in its primary cognitive outcome. All three administered nicotinamide riboside; no trial of nicotinamide mononucleotide in this population is on file.

   Source PubMed 3 primary sources read for this row

3. Testosterone

   human RCT Direct outcome Not approved for this condition

   Who was studied

   men aged 65 and over with low serum testosterone on two measurements and age-associated memory impairment, n=493 of the 788 men randomised, mean age 72.3 years (SD 5.8), 12 months of 1% testosterone gel titrated to a target of 500-800 ng/dL; women were not enrolled

   The Cognitive Function Trial of the Testosterone Trials measured delayed paragraph recall as its primary outcome and found no difference from placebo at 6 or 12 months (adjusted difference -0.07, 95% CI -0.92 to 0.79, p=0.88). Visual memory on the Benton Visual Retention Test (p=0.24), executive function on Trail Making B minus A (p=0.14) and spatial ability on the Card Rotation Test (p=0.89) did not differ either. Entry required both a subjective memory complaint and objective memory more than 1 SD below men aged 20-24, so this is the impaired-memory population rather than a healthy one; testosterone products are approved for male hypogonadism and no regulator has approved testosterone for memory or cognition.

   Source PubMed Central 1 primary source read for this row

4. Cerebrolysin

   human observational Direct outcome Not approved for this condition

   Who was studied

   elderly patients with amnestic mild cognitive impairment, n=100 (50 given annual courses of 20 intravenous infusions of 20 mL over 4 weeks, 50 observed without therapy), followed 3 years with annual examinations; sex distribution and mean age not reported in the abstract

   The one located study in this population reported a lower conversion rate to dementia and less progression of cognitive deficit in the treated group over three years, and its authors describe the effect as disease-modifying. Allocation was open and not randomised and there was no placebo arm, so the untreated group differs from the treated one by whatever decided who was treated; the report is published in Russian and only the English abstract could be read, so the psychometric instruments and the numbers behind the result are not on file. Cerebrolysin has no FDA or EMA marketing authorisation, it is marketed under national registrations in Russia, China and elsewhere, and no regulator document naming mild cognitive impairment as an indication was located.

   Source PubMed 1 primary source read for this row

Recorded absences

6 compounds are listed here without a rung. Each row exists to mark a distinction a reader would otherwise draw wrongly, and each says what is missing rather than leaving the compound off the page.

1. CRH (Corticotropin-Releasing Hormone)

   No rung — nothing on file to grade Not approved for this condition

   Nothing located. CRH and its receptors are studied in Alzheimer's tissue as pathology, not given as treatment.

2. Dihexa

   No rung — nothing on file to grade Not approved for this condition

   Dihexa is sold for memory and no human study of it exists on file, in mild cognitive impairment or in any other population. The published record is rodent and cell work, and the 2014 paper in the Journal of Pharmacology and Experimental Therapeutics that established the procognitive claim carried an expression of concern in 2021 and was retracted in April 2025, which removes the study most often cited for it. The remaining animal work is in scopolamine-treated and aged rats and in APP/PS1 mice, which are models of dementia rather than of mild cognitive impairment.

3. GHRH (Growth Hormone-Releasing Hormone)

   No rung — nothing on file to grade Not approved for this condition

   Same reason as above: the mild cognitive impairment arms of those trials received tesamorelin, not native GHRH, so the row belongs to that compound.

4. IGF-1

   No rung — nothing on file to grade Not approved for this condition

   No trial has administered IGF-I to a cognitively impaired population. The IGF-I cognition literature is observational — blood IGF-I measured as a correlate, not given as a treatment.

5. Noopept

   No rung — nothing on file to grade Not approved for this condition

   Two comparative trials against piracetam in patients with mild-to-moderate cognitive impairment of vascular and traumatic origin are indexed in PubMed without abstracts, so the design, the number of patients, the doses and the rating instruments could not be read and no rung can honestly be attached to them. No trial in amnestic mild cognitive impairment and no placebo-controlled trial in any cognitive population could be located. Noopept is a proline-containing dipeptide ester rather than a peptide as sold; it is not approved by the FDA or the EMA, and a Russian registration is widely asserted but no regulator document was located.

6. P21

   No rung — nothing on file to grade Not approved for this condition

   Every located study of P021, the adamantylated tetrapeptide Ac-DGGLAG-NH2, is in mice or rats: 3xTg-AD and Ts65Dn mouse models, a Cdkl5 knockout model and aged rats. No human study of any kind is on file, and none of the animal work models mild cognitive impairment. Part of the literature attributed to this record concerns Peptide 6, the longer ciliary neurotrophic factor fragment P021 was derived from, which is a different and longer molecule.

Checked, and nothing recorded

30 compounds were checked against mild cognitive impairment and produced no gradeable row.

• Adamax — checked, no row on file
• Angiotensin II — checked, no row on file
• Bombesin — checked, no row on file
• C-Max — checked, no row on file
• Carnosic Acid — checked, no row on file
• Cholecystokinin (CCK) — checked, no row on file
• Cortexin — checked, no row on file
• Dynorphin A — checked, no row on file
• Epitalon — checked, no row on file
• Galantide — checked, no row on file
• GHRP-1 — checked, no row on file
• GHRP-2 — checked, no row on file
• Humanin — checked, no row on file
• Irisin — checked, no row on file
• Leu-Enkephalin — checked, no row on file
• Met-Enkephalin — checked, no row on file
• Nesfatin-1 — checked, no row on file
• Neurotensin — checked, no row on file
• Nociceptin — checked, no row on file
• Orexin-A — checked, no row on file
• Oxytocin — checked, no row on file
• PACAP (Pituitary Adenylate Cyclase-Activating Peptide) — checked, no row on file
• PEA — checked, no row on file
• Pinealon — checked, no row on file
• Selank — checked, no row on file
• Semax — checked, no row on file
• Simonson Alpha 1 — checked, no row on file
• Substance P — checked, no row on file
• VIP — checked, no row on file
• β-Endorphin — checked, no row on file

A compound is here because someone looked and the sources did not support a row — not because nobody looked. Under the rubric, uncertainty resolves to no row, and a row resting on a vendor page or a clinic blog is worse than no row at all.