P21

P21 is a short peptide derived from the brain-derived neurotrophic factor (BDNF) sequence. It is composed of 21 amino acids and was designed to mimic certain biological effects of BDNF while being more stable and easier to study.

P21 is believed to support neurogenesis and improve cognitive function by promoting neuronal growth and synaptic plasticity. Research suggests it may enhance learning, memory, and mental clarity by activating pathways involved in brain repair and regeneration.

Research in animal models shows that P21 (also called P021) can increase neurogenesis and enhance synaptic plasticity. For example, in the commonly used 3×Tg-AD mouse model of Alzheimer’s disease, chronic P21 treatment improved cognitive function, restored levels of neurotrophic markers such as BDNF and synaptic proteins, and reduced phosphorylation of tau protein and accumulation of soluble Aβ ¹. In another study P21 was shown to rescue neuronal proliferation and maturation deficits in a mouse model of CDKL5 deficiency disorder (although it did not increase BDNF in that case) ². These findings suggest that P21 supports brain cell growth, improves synaptic health, and may counter neurodegenerative changes.

Beyond neurogenesis and synaptic repair, P21 has shown potential to reduce hallmark pathologies of neurodegeneration. In the 3×Tg-AD mice P21 treatment led to lower levels of tau pathology, less β-amyloid production (though not necessarily clearance), and improved markers of neuronal connectivity and memory retention ³.

One review of preclinical work in mice reports that chronic treatment did not alter body weight, food consumption, anxiety behavior, or motor behavior in wild-type and transgenic animals ⁴. Another study in a knockout mouse model found that P021 did not increase BDNF expression and did not improve outcomes in that disorder, which suggests limited efficacy in certain conditions rather than obvious adverse events ⁵. Overall, current evidence does not show significant adverse effects associated with P21 in laboratory settings. However, because no formal clinical trials have been conducted in humans, data on potential negative side effects remain incomplete and inconclusive.

CDKN1A, encoding the protein p21, is transcriptionally induced by TP53 (p53) in response to DNA damage and other stress signals. Once produced, p21 binds to and inhibits the activity of cyclin–CDK complexes (such as cyclin-CDK2 and cyclin-CDK4/6), which prevents phosphorylation of the retinoblastoma protein (RB), thus enforcing a G₁-phase cell cycle arrest ^{6, 7}. In addition to cell-cycle control, p21 interacts with proliferating cell nuclear antigen (PCNA), limiting DNA replication and facilitating DNA repair processes; evidence shows that p21 knockout cells display genomic instability and altered replication fork dynamics ⁸.

P21 is considered a research chemical in the United States and is not FDA-approved for human use, with suppliers and literature labeling it “for research use only.” For athletes, WADA’s Prohibited List and USADA guidance make clear that whole classes of peptide hormones and biologics are banned when they enhance performance or have similar biological effects to listed agents; even if a peptide is not named individually, it may still fall under a prohibited category. Because P21 is a biologically active peptide with reported neurotrophic/nootropic effects, anti-doping authorities would treat it as at least restricted/monitored and potentially prohibited depending on interpretation and future additions to the Prohibited List. Athletes should not assume it is allowed.