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P21

Also known as P021, Ac-DGGL(adamantyl-Gly)-NH2, CNTF peptide mimetic

Preclinical CNTF-derived peptide, studied in mouse models of Alzheimer's disease.

preclinical Neuro & cognition research chemical

At a glance

Category
Neuro & cognition
Status
research chemical
Route
In animal studies mainly oral via the feed, and additionally subcutaneous
Half-life
More than 3 hours in mice; no human data
Onset
Not established; effects were assessed after weeks to many months of continuous administration, not acutely
Molecular weight
578.7 g/mol
Sequence
Ac-Asp-Gly-Gly-Leu-(adamantyl)Gly-NH2

Approved nowhere and entirely preclinical. There is not a single registered clinical study in humans: a ClinicalTrials.gov search on the intervention name P021 returns zero studies 8. No human safety, pharmacokinetic or tolerability data exist. Everything known about tolerability comes from rodents that received the compound in their feed 24. Sold exclusively as a 'research chemical'.

Doping status: Not listed by name; as a non-approved substance it falls under S0 and therefore counts as prohibited at all times

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

P21 is derived from the active portion of human ciliary neurotrophic factor (CNTF). The original 11-mer was shortened to four core residues and fitted with an adamantyl group to increase lipophilicity and passage across the blood-brain barrier. The 'AG' designation at the end stands for a single adamantylated glycine residue, not for Ala-Gly.

The design goal was to retain the neurogenic action of CNTF without its drawbacks. Full-length CNTF also activates LIF signalling, which is in fact anti-neurogenic and was responsible for the weight loss, cachexia and antibody formation that sank recombinant CNTF in ALS trials. P21 competitively inhibits LIF signalling; this is the best-supported distinguishing property of the compound.

In 3xTg-AD mice, P21 increases BDNF expression and activates the TrkB-PI3K-Akt pathway, with inhibition of GSK-3-beta as a consequence. Because GSK-3-beta is an important tau kinase, this forms the proposed link to the findings on tau.

Also reported are reduced aberrant tau phosphorylation, an increase in Ki-67- and DCX-positive cells in the dentate gyrus, and restoration of synaptic markers such as MAP2, synaptophysin, PSD-95 and NR1. The chain of LIF inhibition, BDNF increase, TrkB/Akt, GSK-3-beta inhibition, less phosphorylated tau, better cognition is coherent, but within treated animals it has largely been established correlatively and has not been disentangled with targeted knockdown and rescue experiments. Moreover, the effects concern the phosphorylation state of tau, not demonstrated clearance of neurofibrillary tangles.

What the research shows

P21 is purely preclinical. There is not a single human study and therefore no human safety data either - that has to be said without qualification. The animal literature is intact and untouched by retractions, but comes almost entirely from a single laboratory and in more than fifteen years has never progressed to human research.

Research in humans

There are no published human studies. A ClinicalTrials.gov search on the intervention name P021 returns zero studies 8. There is no pharmacokinetics, no dose finding and no tolerability research in humans.

Animal and lab research

The work comes from Khalid Iqbal's group at the New York State Institute for Basic Research in Developmental Disabilities. Models used: 3xTg-AD mice, the Ts65Dn Down syndrome model, aged wild-type rats and mice, brain trauma models and, since 2024, a model of CDKL5 deficiency 7. Administration was usually via the feed, 60 nmol per gram of feed, for periods of up to about eighteen months.

Caveats. The primary literature itself names important limitations: several key studies used female mice only; the 3xTg-AD model represents familial, mutation-driven Alzheimer's and does not model the sporadic human disease; in at least one study no littermates were used as controls; and treatment was often started before or shortly after pathology emerged - that is prevention, not treatment of established disease. Treatment durations of six to eighteen months in mice have no feasible human counterpart. Practically the entire literature comes from one laboratory, with limited independent replication. A signal that is meaningful in its own right: the compound has been in the literature since 2010 with consistently positive rodent results, and after some fifteen years it still has not reached a human study.

What it is used for

  • Studied in animal research in models of Alzheimer's disease 245, cognitive ageing 13, Down syndrome, brain trauma and CDKL5 deficiency 7
  • Used in the grey market as a supposed nootropic or neuroprotective agent - an application without any human support

Dosing

Dose
In animal studies 60 nmol per gram of feed, roughly 162 nmol per mouse per day, continuously for weeks up to eighteen months. In user protocols 100-500 mcg subcutaneously per day circulates.
Frequency
In user protocols once daily
Route
In the animal studies orally via the feed; in user protocols subcutaneous
Duration
In user protocols courses of 10 days to 6 weeks
  • The doses from user protocols were drawn up by sellers. They are not derived from the animal data, have no human pharmacokinetic basis, and were not preceded by any dose finding.
  • An exposure expressed in nmol per gram of feed, given continuously for months 24, cannot be converted into a fixed subcutaneous microgram dose in a human; the published data do not permit that step.
  • Doses are described here solely because they circulate, not because they are supported.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Reconstitution

Vial sizes
5 mg, 10 mg (lyophilised powder); alongside nasal spray and capsule forms
Solvent
bacteriostatic water (0.9% benzyl alcohol)
Storage
Lyophilised at -20 °C; reconstituted at 2-8 °C and, according to suppliers, to be used within about 14-28 days. These are general peptide rules of thumb, not validated stability data.

Worked example

5 mg vial + 2.5 ml bacteriostatic water = 2 mg/ml. 200 mcg then corresponds to 0.1 ml, that is 10 units on a U100 insulin syringe.

Let the water run down the wall of the vial, swirl gently, do not shake. The widely copied claim that P21 irreversibly denatures within one to two days above 8 °C is not credible: a modified peptide of 578 Da has no tertiary structure to denature, and the compound has in fact been described as stable in simulated gastric and intestinal fluid at 37 °C.

Work it out for P21

Safety

Side effects

  • Unknown in humans - there are no side effect data because no human study has been conducted or registered 8
  • Rodent studies report no clear toxicity, but those studies were not designed as toxicological research and contained no formal safety endpoints, histopathological panels or carcinogenicity assessment
  • That the design was specifically intended to avoid the cachexia and immunogenicity of CNTF is a design argument, not safety evidence in humans

Do not use if

  • Pregnancy - LIF plays a physiological role in embryo implantation; chronic LIF inhibition is therefore a clear theoretical contraindication
  • Breastfeeding - no data
  • Children and adolescents - no data
  • Existing or past malignancy - sustained enhancement of BDNF/TrkB has been raised as a theoretical proliferation risk in TrkB-positive tumours, but has not been studied
  • LIF also has a role in stem cell maintenance and immune regulation; chronic inhibition is not self-evidently harmless

Interactions

Not studied. No studies with concomitantly administered drugs have been conducted.

Sources