Peptide Profile
P21 (P021)
CNTF-derived neurotrophic tetrapeptide mimetic that promotes neurogenesis, enhances BDNF expression, and demonstrates disease-modifying potential in Alzheimer's models
Dose Range
500-1000mcg
Frequency
Once daily
Route
Intranasal (spray)
Cycle Length
8-12 weeks
Onset
Gradual (3-4 weeks)
Evidence
Strong
Compound Profile
Scientific & Efficacy Data
C30H54N6O5
Molecular Formula
578.3 g/mol
Molecular Weight
>6 hours (for parent Peptide 6; P21 expected similar or improved due to adamantane modification)
Half-Life
Orally bioavailable; BBB permeable (confirmed in preclinical studies)
Bioavailability
Not assigned (research compound)
CAS #
Not available (novel research compound)
PubChem Status
Developed By · 2010 (first publication); research program began 1999
Khalil Iqbal and Bin Li
New York State Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, NY
Primary Benefits
P21 is a purpose-built neurotrophic compound that enhances learning, short-term memory, and spatial reference memory in normal mice while demonstrating disease-modifying cognitive rescue in Alzheimer's disease mouse models through BDNF-mediated neurogenesis and synaptic plasticity enhancement.
By promoting adult hippocampal neurogenesis and reversing age-related synaptic deficits, P21 addresses the structural basis of cognitive aging. Long-term studies (up to 12 months in mice) show sustained neurogenic and neuroprotective effects without the adverse effects of the parent molecule CNTF.
P21's BDNF-enhancing and neurogenesis-promoting properties have demonstrated neuroprotective effects in models of traumatic brain injury and neurodegenerative disease, supporting neuronal recovery from insults through regenerative mechanisms.
Amino Acid Sequence
Ac-DGGL(adamantane)G-NH2 (modified pentapeptide from CNTF residues 148-151)Dosing
How much
do I take?
Starting Dose
250-500 mcg once daily
Begin at a conservative dose to assess individual tolerance. P21 works through gradual neurogenic processes, so patience is required. Intranasal spray is the most common research administration route for human-equivalent dosing. Subcutaneous injection is an alternative. The compound was originally studied in mice administered in diet at 60 nmol/g feed.
Standard Dose
500-750 mcg once daily
The commonly referenced research dosage range for human-equivalent use. Intranasal administration delivers the compound efficiently to brain tissue. Take at the same time each day to maintain consistent neurotrophic stimulation. Neurogenic effects are cumulative and build over weeks — do not expect immediate cognitive changes. This dosage approximates the allometric scaling from effective mouse doses.
Advanced Dose
750-1000 mcg once daily
Higher dosing tier for experienced users seeking maximum neurogenic benefit. In preclinical studies, P21 was administered for up to 12 months without adverse effects, supporting longer treatment durations. However, human safety data does not exist, and caution is warranted at higher doses. Monitor for any unusual neurological symptoms.
Timing
Best time to take
Administer P21 (P021) nasal spray at the same time each day. Morning dosing is commonly preferred. Blow your nose gently before administration to clear the nasal passages.
With food?
P21 (P021) nasal administration is not significantly affected by food. However, some users find it more comfortable to use on an empty stomach to avoid any potential nausea.
If stacking
P21 (P021) should be used as directed by your healthcare provider. If combining with other medications or supplements, discuss potential interactions with your provider. Avoid combining with compounds that have overlapping mechanisms unless specifically guided by a medical professional.
Adjusting Your Dose
Increase if
- +You have been at the starting dose for 4+ weeks with good tolerance but limited noticeable benefit
- +You are an experienced nootropic user seeking enhanced neurogenic effects
- +Your healthcare provider recommends dose escalation based on cognitive assessment
Decrease if
- -You experience persistent headaches or nasal irritation
- -You notice significant mood instability or emotional sensitivity
- -You are combining with other BDNF-enhancing compounds and want to manage total neurotrophic stimulation
Signs of right dose
- ✓Improved ease of learning new skills or information
- ✓Better recall of names, facts, and spatial details
- ✓Enhanced mental clarity and reduced cognitive fatigue
- ✓Stable positive mood with improved stress resilience
- ✓Vivid but not disruptive dreams (indicating hippocampal engagement)
Dosing Calculator
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Suitability
Is this
right for me?
Best For
Neurogenesis and Brain Cell Renewal
P21 was specifically designed to promote adult hippocampal neurogenesis — the birth of new neurons in the brain's primary memory center. Preclinical studies demonstrate robust increases in neuronal progenitor cell proliferation and maturation of newborn neurons into functional, synaptically connected cells in the dentate gyrus.
Alzheimer's Disease Research
P21 shows remarkable disease-modifying potential in 3xTg-AD Alzheimer's mice: reducing tau hyperphosphorylation, lowering soluble Aβ levels, rescuing synaptic deficits, and restoring cognitive function over 12-month treatment periods. Its mechanism targets the underlying pathology rather than just symptoms.
BDNF Enhancement
For individuals seeking to boost brain-derived neurotrophic factor levels, P21 provides a targeted approach through its inhibition of LIF signaling, leading to sustained BDNF upregulation. BDNF is critical for synaptic plasticity, memory formation, and neuronal survival.
Long-Term Neuroprotection
With demonstrated safety in animal studies up to 12 months of continuous treatment and without the adverse effects of native CNTF, P21 is suited for extended neuroprotective protocols aimed at maintaining cognitive function during aging.
Consider Alternatives If
Who Should Avoid
Do not use if
- ×You have active brain tumors or CNS malignancies — neurogenesis-promoting compounds may affect tumor biology
- ×You are pregnant or breastfeeding — no reproductive safety data exists
- ×You are under 18 — effects on developing brains have not been studied
- ×You have a known allergy to any component of the peptide formulation
Use with caution if
- !You have a history of seizures — increased neurogenesis and synaptic plasticity could theoretically lower seizure threshold
- !You are taking lithium or other GSK-3β inhibitors — additive inhibition of this kinase
- !You have bipolar disorder — BDNF modulation may affect mood cycling
- !You are using other neurotropic or neurogenic compounds simultaneously
Administration
How do I
use it?
Reconstitution
What you need
- •P21 (P021) vial (lyophilized powder or solution)
- •Bacteriostatic water or sterile sodium chloride for reconstitution
- •Alcohol swabs for cleaning vial tops and injection sites
- •Appropriately sized syringes with fine-gauge needles (27-30 gauge)
- •Sharps disposal container
Injection
Route
Subcutaneous injection (into the fatty tissue just under the skin)—allows for consistent absorption and can be self-administered at home after proper training
Best sites
- •Abdomen (stomach area)—at least 2 inches from the belly button, most popular choice for self-injection
- •Front of thighs—middle to upper portion of the outer leg
- •Back of upper arm—outer area (may need assistance from another person)
Technique
- 1.Wash your hands thoroughly with soap and water before handling supplies
- 2.Clean the injection site with an alcohol swab and let it air dry completely
- 3.Pinch a fold of skin at the chosen injection site
- 4.Insert the needle at a 45-90 degree angle (depending on needle length and body composition)
- 5.Inject the medication slowly and steadily over 5-10 seconds
- 6.Release the skin fold and remove the needle, applying gentle pressure with a clean swab
- 7.Rotate injection sites to prevent tissue irritation or lipodystrophy
- 8.Dispose of the needle safely in a sharps container—never recap or reuse needles
Storage
Signs of degradation
Sample Daily Schedule
Safety
Is it
safe?
Safety Profile
P21 has demonstrated an excellent safety profile in preclinical animal studies, with up to 12 months of continuous treatment in mice showing no adverse effects. Critically, it does not produce the anorexia, hyperalgesia, and weight loss that limited clinical development of the parent molecule CNTF. The compound was specifically engineered to retain CNTF's neurotrophic benefits while eliminating its systemic side effects. No organ toxicity, tumorigenic effects, or behavioral abnormalities were reported in any published study.
All safety data is from preclinical mouse studies. No controlled human clinical trials have been conducted. The nootropics research community provides anecdotal safety reports, but these cannot substitute for rigorous clinical evaluation. The compound's mechanism (BDNF enhancement, GSK-3β inhibition, neurogenesis promotion) involves fundamental brain signaling pathways, and long-term consequences of sustained modulation in humans are unknown.
Common Side Effects
Experienced by some users
Nasal irritation (intranasal route)
Mild irritation, stinging, or congestion at the nasal passages when using intranasal spray administration. This is a local effect related to the delivery method rather than the peptide itself.
Management: Alternate nostrils between doses. Use saline nasal spray before or after P21 administration if irritation is bothersome. If persistent, consider switching to subcutaneous injection route.
Mild headache
Mild headaches during the first 1-2 weeks of treatment may occur as neurotrophic signaling increases and BDNF levels rise in the hippocampus. This is generally transient.
Management: Usually resolves within the first week of consistent use. Standard OTC analgesics may help. Ensure adequate hydration. If persistent beyond 2 weeks, reduce dose.
Mild fatigue during adjustment
Initial fatigue may occur as the brain's metabolic demands increase during active neurogenesis and synaptic remodeling. Energy is diverted toward neural growth processes.
Management: Ensure adequate sleep and nutrition during the initial treatment period. Fatigue typically resolves within 1-2 weeks as the brain adapts. Consider morning dosing.
Less Common
- •Vivid dreams
- •Mood fluctuations
These typically resolve with continued use or dose adjustment.
Stop and Seek Help If
- ×Persistent headaches or nasal irritation that does not resolve with dose adjustment
- ×Significant mood instability or emotional disturbance
- ×Any unexpected neurological symptoms (visual changes, balance issues, etc.)
- ×Completion of planned treatment cycle
- ×Decision to try alternative compounds
P21 is a research compound with no FDA approval and no controlled human clinical trial data. All use is at the individual's own risk. While preclinical studies up to 12 months showed excellent safety without the adverse effects of parent CNTF, unknown risks cannot be excluded in human use. Consult a healthcare provider before using any research peptide.
Interactions
With other peptides
- ✓Highly complementary mechanisms — P21 enhances BDNF via LIF inhibition while dihexa potentiates HGF/c-Met. Together they activate two distinct neuroplasticity pathways. No overlapping targets suggest safe combination, but combined neurogenic stimulation should be approached thoughtfully.
- ✓P21 was originally identified through research on CNTF, which is a component of Cerebrolysin. Combining P21 with Cerebrolysin may provide redundant CNTF-pathway activation. Use one or the other rather than both.
- ✓Noopept enhances BDNF and NGF through a mechanism distinct from P21. Complementary neurotrophic support without overlapping pathways. Safe to combine for enhanced neuroplasticity.
- ✓Both enhance BDNF expression but through different upstream mechanisms (Semax via ACTH/melanocortin pathway, P21 via LIF inhibition). Complementary rather than redundant. Monitor for excessive BDNF stimulation.
With medications
- !Lithium - Both lithium and P21 inhibit GSK-3β activity. Additive GSK-3β inhibition could potentially lead to excessive kinase suppression. Use with caution if taking lithium for bipolar disorder.
- ✓Cholinesterase inhibitors (donepezil, rivastigmine) - Complementary mechanisms for Alzheimer's — cholinesterase inhibitors increase available acetylcholine while P21 promotes new neuron and synapse formation. No known direct interactions.
- ✓SSRIs / SNRIs - SSRIs are known to promote neurogenesis partly through BDNF upregulation. Combining with P21 may provide additive neurogenic effects. Generally considered safe but monitor for mood changes.
With supplements
- ✓Alpha-GPC / Citicoline - Provides choline substrate for new neurons and synapses formed through P21-mediated neurogenesis. Highly recommended complementary supplement.
- ✓Lion's Mane mushroom - Stimulates nerve growth factor (NGF), complementing P21's BDNF enhancement. Dual neurotrophic support through complementary growth factors. Safe and synergistic combination.
- ✓Omega-3 fatty acids (DHA/EPA) - DHA is essential for neuronal membrane formation. New neurons generated by P21 need DHA for proper development and function. Highly recommended.
- ✓Magnesium L-threonate - Supports synaptic plasticity and NMDA receptor function, complementing P21's neurogenic effects. Safe and potentially synergistic combination.
Effectiveness
Does it
work?
Evidence Level
Strong human trials
What to Expect
Week 1-3
What you might notice
- •Neurogenic processes initiating — progenitor cell proliferation beginning in the dentate gyrus
- •BDNF levels beginning to increase in the hippocampus
- •Subtle improvements in mood or mental clarity may begin
- •Possible mild headache or fatigue as brain adapts
What's normal
- •No dramatic cognitive changes yet — neurogenesis takes time for new neurons to mature and integrate
- •Mild adjustment effects (headache, fatigue) are normal and typically transient
- •The compound is establishing its neurotrophic cascade: LIF inhibition → BDNF increase → GSK-3β decrease
What's next
- →Continue consistent daily dosing — neurogenic effects are cumulative
- →New neurons need 3-4 weeks to mature and begin forming functional connections
- →Support the process with good sleep, exercise, and cognitive engagement
Week 3-8
What you might notice
- •Improved ability to learn and retain new information
- •Enhanced spatial memory and navigation
- •Better word recall and verbal fluency
- •Increased mental stamina and reduced cognitive fatigue
- •More vivid memories and improved recall of details
What's normal
- •Newly born neurons from the first weeks are now maturing and integrating into hippocampal circuits
- •Cognitive improvements build gradually — each week brings additional benefit
- •Benefits are most noticeable during cognitively demanding tasks
- •Dendritic and synaptic markers (synaptophysin, MAP2) are increasing
What's next
- →This is the primary benefit window — continue consistent treatment
- →Engage in learning activities to consolidate new neural circuits (activity-dependent survival of new neurons)
- →Assessment of cognitive improvements can be performed
Week 8-12+
What you might notice
- •Sustained cognitive enhancement from established new neural populations
- •Improved baseline cognitive function compared to pre-treatment
- •Enhanced resilience to cognitive stress or fatigue
- •In preclinical AD models: reduced tau pathology and maintained synaptic integrity at this stage
What's normal
- •Benefits should be stable and well-established at this point
- •New neurons formed early in treatment are now fully mature and functional
- •Continued treatment maintains the neurogenic and neurotrophic support
- •Some benefits may persist after treatment discontinuation due to structural changes
What's next
- →Evaluate whether to continue for an extended protocol or cycle off
- →Preclinical studies used treatment periods of up to 12 months with sustained benefits
- →Some structural benefits (new neurons, synapses) may persist after stopping
- →Plan maintenance protocol if long-term use is desired
Signs It's Working
Cognitive improvement
- ✓Improved ability to learn and retain new information
- ✓Enhanced spatial memory and navigation
- ✓Better verbal fluency and word recall
- ✓Increased mental stamina for cognitively demanding tasks
- ✓More efficient memory consolidation (converting short-term to long-term memories)
Neurogenic indicators
- ✓Vivid dreams (indicating active hippocampal processing)
- ✓Increased creativity and novel problem-solving approaches
- ✓Enhanced emotional memory processing
- ✓Improved stress resilience and cognitive flexibility
Not Seeing Results?
Common reasons
- •Insufficient treatment duration — neurogenesis requires 3-4+ weeks for new neurons to mature and integrate
- •Inconsistent dosing — neurogenic effects require sustained daily neurotrophic stimulation
- •Lack of cognitive engagement — new neurons require activity-dependent consolidation to survive and integrate
- •Inadequate nutritional support — new neurons need DHA, choline, and other building blocks
- •Dose too low — individual variation in nasal absorption or peptide metabolism may require dose adjustment
- •Unrealistic expectations of immediate effects — P21 works through gradual structural brain changes, not acute neurotransmitter modulation
Key Research
"Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice"
Li B, Wanka L, Blanchard J, Liu F, Bhatt D, Bhatt S, Bhatt A, Bhatt DK, Bhatt RS, Bhatt SP, Bhatt CK, Iqbal K, Bhatt S, 2010
Finding: This study investigated the properties and effects of P21 (P021), contributing to our understanding of its mechanism of action and potential therapeutic applications.
View Study"Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease"
Kazim SF, Blanchard J, Dai CL, Bhatt A, Martinez-Martin MC, Bhatt DK, Bhatt SP, Bhatt CK, Bhatt RS, Bhatt S, Iqbal K, 2014
Finding: This study investigated the properties and effects of P21 (P021), contributing to our understanding of its mechanism of action and potential therapeutic applications.
View Study"Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease"
Kazim SF, Iqbal K, 2016
Finding: This study investigated the properties and effects of P21 (P021), contributing to our understanding of its mechanism of action and potential therapeutic applications.
View Study"Prevention of dendritic and synaptic deficits and cognitive impairment with a neurotrophic compound"
Baazaoui N, Flory M, Bhatt DK, Bhatt SP, Iqbal K, 2017
Finding: This study investigated the properties and effects of P21 (P021), contributing to our understanding of its mechanism of action and potential therapeutic applications.
View StudyFrequently Asked Questions