P021

updated

P021 is a small adamantane-containing peptide mimetic, described in one paper as a tetra-peptide derived from the active region of human ciliary neurotrophic factor. It improved learning and memory in normal adult mice and aged rats and reduced tau pathology in an Alzheimer mouse model, almost all in work from one laboratory. No controlled human study exists, and in the one outside model that measured BDNF, chronic in vivo treatment did not raise it.

Adamantane-containing peptide mimetic, proposed BDNF-pathway modulator

  • PubChem lists P021 as CID 56599151, C27H42N6O8, molecular weight 578.7, CAS 1246751-68-7; at 578.7 Da with an adamantane group it is a small molecule peptide mimetic, not a conventional peptide drug.
  • In normal adult C57Bl6 mice, peripherally administered P21 enhanced learning and short-term and spatial reference memory and enhanced neurogenesis in the dentate gyrus.
  • In 22 to 24-month-old Fisher rats, chronic oral P021 reduced the age-dependent decline in learning and memory and increased BDNF expression.
  • In 3xTg-AD mice given P021 in the diet for 12 months, abnormal tau hyperphosphorylation fell significantly, while the amyloid-beta effect was limited to lower soluble amyloid-beta and a trend toward reduced plaque load.
  • In Cdkl5 knockout mice, chronic in vivo P021 failed to increase BDNF levels and did not improve neuroanatomical defects, with limited behavioral benefit; the compound's inventor was a co-author.
  • ClinicalTrials.gov queries on 9 October 2026 returned no studies, and the records reviewed hold no human dose, pharmacokinetics or safety data 16 years after the discovery paper.

What is P021, and is it approved for anything?

P021 is a small adamantane-containing peptide mimetic of 578.7 Da, described in the literature in more than one way. No approval for any use appears in the records reviewed, and ClinicalTrials.gov queries on 9 October 2026 returned no studies.

PubChem lists P021 as CID 56599151, C27H42N6O8, molecular weight 578.7, CAS 1246751-68-7, with synonyms including P-21, P021 and P-21 nootropic peptide. At 578.7 Da with an adamantane group, it is a small molecule peptide mimetic, not a conventional peptide drug.

The published descriptions are not consistent. The 2010 discovery paper writes it as Ac-DGGLAG-NH2 and calls it P21, a 2014 paper writes P021 (Ac-DGGL(A)G-NH2), and a 2024 paper calls it a tetra-peptide derived from the biologically active region of human ciliary neurotrophic factor. In the wider literature the string P-21 also denotes p21 (CDKN1A), an unrelated cell cycle protein, so secondary sources should be read against the compound actually studied.

ClinicalTrials.gov queries on 9 October 2026 for P021 neurotrophic peptide and P021 Alzheimer peptide returned no studies. A PubMed search for P021 or Ac-DGGL restricted to the clinical trial publication type or the humans MeSH term returned 18 records, none a human study of P021. No approval for any use appears in the records reviewed.

PubChem: P021 identity, small adamantane-containing peptide mimetic

Chemical identity record

National Library of Medicine. PubChem compound record CID 56599151 (P021).

PubChem lists P021 as CID 56599151, C27H42N6O8, molecular weight 578.7, CAS 1246751-68-7, with synonyms including P-21, P021 and P-21 nootropic peptide. At 578.7 Da with an adamantane group, this is a small molecule peptide mimetic, not a conventional peptide drug. The published descriptions of it are not consistent: the 2010 discovery paper writes it as Ac-DGGLAG-NH2 and calls it P21, a 2014 paper writes P021 (Ac-DGGL(A)G-NH2), and a 2024 paper calls it a tetra-peptide derived from the biologically active region of human ciliary neurotrophic factor.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined adamantane-containing peptide mimetic
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

In the wider literature the string P-21 also denotes p21 (CDKN1A), an unrelated cell cycle protein, so secondary sources should be read against the compound actually studied.

Read the original source
Searches, 9 October 2026: no registered study, no human study of P021

PubMed search record

PubMed search run on 9 October 2026: (P021 OR Ac-DGGL) AND (clinical trial publication type OR humans MeSH term), 18 records. ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide run the same day.

ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide returned no studies. A PubMed search for P021 or Ac-DGGL restricted to the clinical trial publication type or the humans MeSH term returned 18 records. The ones concerning this compound are two reviews, the Cdkl5 study and an aged rat cerebrospinal fluid tau study, and the remainder are unrelated papers on spinal muscular atrophy genetics, puberty timing, saliva virology and pneumococcal serotypes. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for P021, 16 years after the discovery paper. No study combined P021 with a TrkB agonist or any other BDNF-pathway compound.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

What did mouse and rat studies find?

In normal adult mice P021 enhanced learning, memory and neurogenesis, in aged rats chronic oral dosing reduced the age-related decline in learning and memory, and in an Alzheimer mouse model 12 months in the diet reduced tau pathology. No study gave it to a person.

The discovery paper reported that Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and enhanced neurogenesis and maturation of newly born neurons in the dentate gyrus. This is the only record located in which the compound was given to healthy, unimpaired animals. The abstract does not state the route beyond peripheral administration.

Chronic oral P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed a significant reduction in myoinositol concentration, which was increased in aged compared with young animals. These were aged rats, not healthy young ones.

In the longest exposure study, 3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. Abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites fell significantly. The effect on amyloid-beta was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Almost all of this record comes from one laboratory.

Discovery paper: normal adult C57Bl6 mice, learning, memory and neurogenesis

Animal study

Li B et al. FEBS Lett. 2010;584(15):3359-65. PMID 20600002.

Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Participants / model
Normal adult C57Bl6 mice
Treatment
Peripheral administration; route not stated beyond peripherally in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only record located in which the compound was given to healthy, unimpaired animals, which is the closest analogue to the supplier's use case. The abstract does not state the route beyond peripheral administration.

Read the original source
Cognitive aging: 22 to 24-month-old Fisher rats, chronic oral dosing

Animal study

Bolognin S et al. Neurobiol Aging. 2014;35(9):2134-46. PMID 24702821.

Chronic oral administration of P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression, and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed P021 significantly reduced myoinositol concentration, which was increased in aged compared with young animals.

Participants / model
22 to 24-month-old Fisher rats
Treatment
Chronic oral administration
Follow-up
Chronic; length not stated in the available record
Study design
Original preclinical study
Funding
not stated in the source

The route was oral, and the animals were aged rats, not healthy young ones.

Read the original source
Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source

Did the BDNF finding hold up outside the original program?

In one model, no. In Cdkl5 knockout mice, chronic in vivo P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects, with limited behavioral benefit, although it restored deficits in cultured neuronal cells.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling.

In vivo the result reversed. Chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

This is the only BDNF test outside the originating program that the records reviewed contain. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source

By which routes was P021 given to animals?

By mouth, either in the diet or as chronic oral dosing, or by an unspecified peripheral route. No study used injection or a nasal spray, so no vendor route is supported by the published work.

The rodent studies used oral dosing, in the diet for the 12-month Alzheimer-model study and chronic oral administration in aged rats, or peripheral administration whose specific route the discovery abstract does not state. The Cdkl5 knockout study does not state a route in the information reviewed.

No study in the records reviewed used injection or nasal delivery, so no vendor route is supported by the published work, and no dose is converted from the rodent studies here.

Discovery paper: normal adult C57Bl6 mice, learning, memory and neurogenesis

Animal study

Li B et al. FEBS Lett. 2010;584(15):3359-65. PMID 20600002.

Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Participants / model
Normal adult C57Bl6 mice
Treatment
Peripheral administration; route not stated beyond peripherally in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only record located in which the compound was given to healthy, unimpaired animals, which is the closest analogue to the supplier's use case. The abstract does not state the route beyond peripheral administration.

Read the original source
Cognitive aging: 22 to 24-month-old Fisher rats, chronic oral dosing

Animal study

Bolognin S et al. Neurobiol Aging. 2014;35(9):2134-46. PMID 24702821.

Chronic oral administration of P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression, and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed P021 significantly reduced myoinositol concentration, which was increased in aged compared with young animals.

Participants / model
22 to 24-month-old Fisher rats
Treatment
Chronic oral administration
Follow-up
Chronic; length not stated in the available record
Study design
Original preclinical study
Funding
not stated in the source

The route was oral, and the animals were aged rats, not healthy young ones.

Read the original source
Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source
Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source

Do the memory, learning and neuroprotection claims hold up?

In rodents only. Memory and learning improvement is supported in normal adult mice and aged rats, neuroprotection in a rodent Alzheimer model, and none of it has been tested in a person. The proposed BDNF effect did not reproduce in the one outside model that measured it.

Sellers describe P021 for memory, learning and neuroprotection, used alongside TrkB or BDNF-pathway compounds.

Memory and learning improvement is supported in normal adult mice and in aged rats, by peripheral and oral dosing respectively. Neuroprotection is supported in a rodent model of Alzheimer disease. None of it has been tested in a person, and the proposed BDNF mechanism did not reproduce in the one in vivo model outside the originating program that measured it.

ClinicalTrials.gov queries on 9 October 2026 returned no studies, and the records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for P021, 16 years after the discovery paper. No study combined P021 with a TrkB agonist or any other BDNF-pathway compound, so the pairing has no study behind it.

Discovery paper: normal adult C57Bl6 mice, learning, memory and neurogenesis

Animal study

Li B et al. FEBS Lett. 2010;584(15):3359-65. PMID 20600002.

Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Participants / model
Normal adult C57Bl6 mice
Treatment
Peripheral administration; route not stated beyond peripherally in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only record located in which the compound was given to healthy, unimpaired animals, which is the closest analogue to the supplier's use case. The abstract does not state the route beyond peripheral administration.

Read the original source
Cognitive aging: 22 to 24-month-old Fisher rats, chronic oral dosing

Animal study

Bolognin S et al. Neurobiol Aging. 2014;35(9):2134-46. PMID 24702821.

Chronic oral administration of P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression, and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed P021 significantly reduced myoinositol concentration, which was increased in aged compared with young animals.

Participants / model
22 to 24-month-old Fisher rats
Treatment
Chronic oral administration
Follow-up
Chronic; length not stated in the available record
Study design
Original preclinical study
Funding
not stated in the source

The route was oral, and the animals were aged rats, not healthy young ones.

Read the original source
Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source
Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source
Searches, 9 October 2026: no registered study, no human study of P021

PubMed search record

PubMed search run on 9 October 2026: (P021 OR Ac-DGGL) AND (clinical trial publication type OR humans MeSH term), 18 records. ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide run the same day.

ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide returned no studies. A PubMed search for P021 or Ac-DGGL restricted to the clinical trial publication type or the humans MeSH term returned 18 records. The ones concerning this compound are two reviews, the Cdkl5 study and an aged rat cerebrospinal fluid tau study, and the remainder are unrelated papers on spinal muscular atrophy genetics, puberty timing, saliva virology and pneumococcal serotypes. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for P021, 16 years after the discovery paper. No study combined P021 with a TrkB agonist or any other BDNF-pathway compound.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

How does P021 work?

The proposed mechanism is increased BDNF expression and decreased GSK3-beta activity, which the Alzheimer-model authors credited for the tau effect. In one model outside the originating program, chronic in vivo treatment did not raise BDNF.

The authors of the 12-month Alzheimer-model study attributed the effect of P021 to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity. In aged rats, chronic oral P021 increased BDNF expression and restored synaptic deficits in cortex and hippocampus, and in normal mice it enhanced neurogenesis and maturation of newly born neurons in the dentate gyrus.

In Cdkl5 knockout mice, chronic in vivo treatment failed to increase BDNF levels and did not improve neuroanatomical defects, although P021 restored the altered GSK3-beta signaling in cultured cells.

No pharmacokinetic parameter is reported in the sources reviewed for any species, so no half-life or Tmax is given.

Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source
Cognitive aging: 22 to 24-month-old Fisher rats, chronic oral dosing

Animal study

Bolognin S et al. Neurobiol Aging. 2014;35(9):2134-46. PMID 24702821.

Chronic oral administration of P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression, and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed P021 significantly reduced myoinositol concentration, which was increased in aged compared with young animals.

Participants / model
22 to 24-month-old Fisher rats
Treatment
Chronic oral administration
Follow-up
Chronic; length not stated in the available record
Study design
Original preclinical study
Funding
not stated in the source

The route was oral, and the animals were aged rats, not healthy young ones.

Read the original source
Discovery paper: normal adult C57Bl6 mice, learning, memory and neurogenesis

Animal study

Li B et al. FEBS Lett. 2010;584(15):3359-65. PMID 20600002.

Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Participants / model
Normal adult C57Bl6 mice
Treatment
Peripheral administration; route not stated beyond peripherally in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only record located in which the compound was given to healthy, unimpaired animals, which is the closest analogue to the supplier's use case. The abstract does not state the route beyond peripheral administration.

Read the original source
Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source

What is known about the risks of P021?

Almost nothing. No human dose, pharmacokinetics or safety data exist, and the animal studies used oral or unspecified peripheral dosing, so nothing is known about injection or nasal delivery.

The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for P021.

The rodent studies used oral dosing in diet or unspecified peripheral administration. Nothing is known about injection or nasal delivery, which are the routes sellers use. In Cdkl5 knockout mice, chronic in vivo treatment failed to increase BDNF levels and did not improve neuroanatomical defects, with limited behavioral benefit.

The published descriptions of the structure are not consistent, and the string P-21 also denotes the unrelated cell cycle protein p21 (CDKN1A), so a vial or a paper labeled P-21 may not be the compound described here.

Searches, 9 October 2026: no registered study, no human study of P021

PubMed search record

PubMed search run on 9 October 2026: (P021 OR Ac-DGGL) AND (clinical trial publication type OR humans MeSH term), 18 records. ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide run the same day.

ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide returned no studies. A PubMed search for P021 or Ac-DGGL restricted to the clinical trial publication type or the humans MeSH term returned 18 records. The ones concerning this compound are two reviews, the Cdkl5 study and an aged rat cerebrospinal fluid tau study, and the remainder are unrelated papers on spinal muscular atrophy genetics, puberty timing, saliva virology and pneumococcal serotypes. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for P021, 16 years after the discovery paper. No study combined P021 with a TrkB agonist or any other BDNF-pathway compound.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source
Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source
Discovery paper: normal adult C57Bl6 mice, learning, memory and neurogenesis

Animal study

Li B et al. FEBS Lett. 2010;584(15):3359-65. PMID 20600002.

Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Participants / model
Normal adult C57Bl6 mice
Treatment
Peripheral administration; route not stated beyond peripherally in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only record located in which the compound was given to healthy, unimpaired animals, which is the closest analogue to the supplier's use case. The abstract does not state the route beyond peripheral administration.

Read the original source
Cognitive aging: 22 to 24-month-old Fisher rats, chronic oral dosing

Animal study

Bolognin S et al. Neurobiol Aging. 2014;35(9):2134-46. PMID 24702821.

Chronic oral administration of P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression, and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed P021 significantly reduced myoinositol concentration, which was increased in aged compared with young animals.

Participants / model
22 to 24-month-old Fisher rats
Treatment
Chronic oral administration
Follow-up
Chronic; length not stated in the available record
Study design
Original preclinical study
Funding
not stated in the source

The route was oral, and the animals were aged rats, not healthy young ones.

Read the original source
Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source
PubChem: P021 identity, small adamantane-containing peptide mimetic

Chemical identity record

National Library of Medicine. PubChem compound record CID 56599151 (P021).

PubChem lists P021 as CID 56599151, C27H42N6O8, molecular weight 578.7, CAS 1246751-68-7, with synonyms including P-21, P021 and P-21 nootropic peptide. At 578.7 Da with an adamantane group, this is a small molecule peptide mimetic, not a conventional peptide drug. The published descriptions of it are not consistent: the 2010 discovery paper writes it as Ac-DGGLAG-NH2 and calls it P21, a 2014 paper writes P021 (Ac-DGGL(A)G-NH2), and a 2024 paper calls it a tetra-peptide derived from the biologically active region of human ciliary neurotrophic factor.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined adamantane-containing peptide mimetic
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

In the wider literature the string P-21 also denotes p21 (CDKN1A), an unrelated cell cycle protein, so secondary sources should be read against the compound actually studied.

Read the original source

Why does P021 sit in C tier?

The animal record is long and the compound is a defined small molecule with oral activity, but almost all of it is from one laboratory, the one outside model that measured BDNF did not show a rise, and there is no registered trial or human exposure.

The animal record is long for a research compound: a defined small molecule with a PubChem entry and a CAS number, oral activity, a 12-month dosing study in an Alzheimer model, results in normal mice and aged rats, and a consistent proposed mechanism through BDNF and GSK3-beta.

Almost all of it comes from one laboratory, and the one study that tested the mechanism in a new disease model found that chronic in vivo treatment failed to raise BDNF and did not improve neuroanatomy, with only limited behavioral benefit. There is no registered trial and no human exposure of any kind.

PubChem: P021 identity, small adamantane-containing peptide mimetic

Chemical identity record

National Library of Medicine. PubChem compound record CID 56599151 (P021).

PubChem lists P021 as CID 56599151, C27H42N6O8, molecular weight 578.7, CAS 1246751-68-7, with synonyms including P-21, P021 and P-21 nootropic peptide. At 578.7 Da with an adamantane group, this is a small molecule peptide mimetic, not a conventional peptide drug. The published descriptions of it are not consistent: the 2010 discovery paper writes it as Ac-DGGLAG-NH2 and calls it P21, a 2014 paper writes P021 (Ac-DGGL(A)G-NH2), and a 2024 paper calls it a tetra-peptide derived from the biologically active region of human ciliary neurotrophic factor.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined adamantane-containing peptide mimetic
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

In the wider literature the string P-21 also denotes p21 (CDKN1A), an unrelated cell cycle protein, so secondary sources should be read against the compound actually studied.

Read the original source
Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source
Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source
Searches, 9 October 2026: no registered study, no human study of P021

PubMed search record

PubMed search run on 9 October 2026: (P021 OR Ac-DGGL) AND (clinical trial publication type OR humans MeSH term), 18 records. ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide run the same day.

ClinicalTrials.gov queries for P021 neurotrophic peptide and P021 Alzheimer peptide returned no studies. A PubMed search for P021 or Ac-DGGL restricted to the clinical trial publication type or the humans MeSH term returned 18 records. The ones concerning this compound are two reviews, the Cdkl5 study and an aged rat cerebrospinal fluid tau study, and the remainder are unrelated papers on spinal muscular atrophy genetics, puberty timing, saliva virology and pneumococcal serotypes. The records reviewed contain no human dose, no human pharmacokinetics, no human safety data and no clinical trial for P021, 16 years after the discovery paper. No study combined P021 with a TrkB agonist or any other BDNF-pathway compound.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Literature and registry searches
Funding
not stated in the source

A search result shows what the databases returned on that date. It is not proof that no unindexed study exists.

Read the original source

Studies and sources

PubChem: P021 identity, small adamantane-containing peptide mimetic

Chemical identity record

National Library of Medicine. PubChem compound record CID 56599151 (P021).

PubChem lists P021 as CID 56599151, C27H42N6O8, molecular weight 578.7, CAS 1246751-68-7, with synonyms including P-21, P021 and P-21 nootropic peptide. At 578.7 Da with an adamantane group, this is a small molecule peptide mimetic, not a conventional peptide drug. The published descriptions of it are not consistent: the 2010 discovery paper writes it as Ac-DGGLAG-NH2 and calls it P21, a 2014 paper writes P021 (Ac-DGGL(A)G-NH2), and a 2024 paper calls it a tetra-peptide derived from the biologically active region of human ciliary neurotrophic factor.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined adamantane-containing peptide mimetic
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

In the wider literature the string P-21 also denotes p21 (CDKN1A), an unrelated cell cycle protein, so secondary sources should be read against the compound actually studied.

Read the original source
Discovery paper: normal adult C57Bl6 mice, learning, memory and neurogenesis

Animal study

Li B et al. FEBS Lett. 2010;584(15):3359-65. PMID 20600002.

Ac-DGGLAG-NH2, called P21, administered peripherally, enhanced learning and both short-term and spatial reference memories of normal adult C57Bl6 mice, and induced enhancement of neurogenesis and maturation of newly born neurons in the granular cell layer and subgranular zone of the dentate gyrus.

Participants / model
Normal adult C57Bl6 mice
Treatment
Peripheral administration; route not stated beyond peripherally in the abstract
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only record located in which the compound was given to healthy, unimpaired animals, which is the closest analogue to the supplier's use case. The abstract does not state the route beyond peripheral administration.

Read the original source
Cognitive aging: 22 to 24-month-old Fisher rats, chronic oral dosing

Animal study

Bolognin S et al. Neurobiol Aging. 2014;35(9):2134-46. PMID 24702821.

Chronic oral administration of P021 significantly reduced the age-dependent decline in learning and memory in 22 to 24-month-old Fisher rats, inhibited the deficit in neurogenesis, increased brain derived neurotrophic factor expression, and restored synaptic deficits in both cortex and hippocampus. In vivo magnetic resonance spectroscopy showed P021 significantly reduced myoinositol concentration, which was increased in aged compared with young animals.

Participants / model
22 to 24-month-old Fisher rats
Treatment
Chronic oral administration
Follow-up
Chronic; length not stated in the available record
Study design
Original preclinical study
Funding
not stated in the source

The route was oral, and the animals were aged rats, not healthy young ones.

Read the original source
Alzheimer model: 3xTg-AD mice, 12 months in the diet, tau pathology reduced

Animal study

Kazim SF et al. Neurobiol Dis. 2014;71:110-30. PMID 25046994.

3xTg-AD and wild type female mice were treated for 12 months with P021 or vehicle in the diet starting at 9 to 10 months of age. There was a significant reduction in abnormal hyperphosphorylation and accumulation of tau at known major neurofibrillary pathology sites. The effect on amyloid-beta pathology was limited to a significant decrease in soluble amyloid-beta and a trend toward reduced plaque load in hippocampal CA1, consistent with reduced generation rather than clearance. The authors attributed the effect to increased BDNF expression and decreased glycogen synthase kinase-3-beta activity, and reported rescue of deficits in cognition, neurogenesis and synaptic plasticity.

Participants / model
3xTg-AD and wild type female mice
Treatment
P021 in the diet
Follow-up
12 months, starting at 9 to 10 months of age
Study design
Original preclinical study
Funding
not stated in the source

This is the longest exposure study. The route is oral, in food.

Read the original source
Cdkl5 knockout mice: cells improved, in vivo BDNF did not rise, limited behavioral benefit

Animal study

Mottolese N et al. J Neurodev Disord. 2024;16(1):65. PMID 39592934.

A 2024 study used SH-CDKL5-KO cells and Cdkl5 knockout mice. In vitro, P021 restored neuronal proliferation, survival and maturation deficits and the altered GSK3-beta signaling. In vivo the result reversed: chronic P021 treatment failed to increase BDNF levels and did not improve neuroanatomical defects in Cdkl5 knockout mice, resulting in limited behavioral benefit. The authors left open whether earlier or longer treatment would be needed.

Participants / model
SH-CDKL5-KO human neuronal cells; young and adult Cdkl5 knockout mice
Treatment
Chronic in vivo treatment as dosed in the report; media exposure in vitro; in vivo route not stated in the information reviewed
Follow-up
not stated in the source
Study design
Original preclinical study
Funding
not stated in the source

This is the only BDNF test outside the originating program. The compound's inventor is a co-author, with an affiliation to Phanes Biotech Inc, so it is not a hostile replication.

Read the original source

Why is P021 in C tier?

C fits a long animal record with no human exposure. P021 has a defined PubChem entry, oral activity, a 12-month dosing study in an Alzheimer mouse model and results in normal mice and aged rats, but almost all of it comes from one laboratory, and the one model outside the originating program that measured BDNF found no rise. There is no registered trial and no human dose 16 years after the discovery paper.