---
canonical_name: Dihexa
alternate_names: N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, PNB-0408
canonical_topic: Dihexa for Cognitive Enhancement
short_topic_lc: dihexa_cognition
creation_date: 2026-0704-0208
creator_ai_fullname: Opus 4.8
---

# Dihexa for Cognitive Enhancement

Evidence Review created on 07/04/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, PNB-0408

## Motivation

Dihexa is a small synthetic peptide (a short chain of protein building blocks) first made in a university laboratory to treat memory loss. It is a chemically stabilized relative of a natural body signal called angiotensin, redesigned so it survives digestion, enters the brain, and lasts long enough to act. Rather than nudging brain chemistry the way a stimulant does, it is thought to switch on a growth-factor system that prompts brain cells to build new connections — the physical basis of learning and memory.

The compound drew attention because, in animal experiments, it restored memory in impaired rodents at very low doses taken by mouth. That result fueled interest from Alzheimer's researchers and, separately, from a self-experimentation community that now buys the peptide from unregulated suppliers as a "smart drug." No human trials of dihexa have ever been completed, and the same growth pathway it stimulates is one that tumors exploit to grow.

This review examines what is actually known about dihexa for cognitive enhancement: how it is thought to work, what the animal evidence shows, where the safety concerns lie, and how far the current data can and cannot be stretched toward use in people.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-level, directly relevant sources that give an overview of dihexa and the growth-factor system it targets.

* [Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents](https://pubmed.ncbi.nlm.nih.gov/23055539/) - McCoy et al., 2013

  The foundational paper describing the synthesis of dihexa and its ability to reverse memory deficits in rodents at low oral doses, establishing the compound's procognitive profile.

* [The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease](https://pubmed.ncbi.nlm.nih.gov/25649658/) - Wright & Harding, 2015

  A narrative review by the originating researchers explaining why the growth-factor system dihexa engages is considered a therapeutic target, useful for understanding the intended mechanism and rationale.

* [AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway](https://pubmed.ncbi.nlm.nih.gov/34827486/) - Sun et al., 2021

  An independent group's replication showing dihexa improved memory in a genetic mouse model of Alzheimer's disease, adding external support beyond the originating laboratory.

* [Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats](https://pubmed.ncbi.nlm.nih.gov/38489193/) - Wells et al., 2024

  A recent primary study extending dihexa research into a neurodegeneration model beyond Alzheimer's, illustrating both the breadth of preclinical interest and the continued absence of human data.

Only four sources are listed. None of the priority experts (Rhonda Patrick, Peter Attia, Andrew Huberman, Chris Kresser, Life Extension) have covered dihexa, and the list has not been padded with commercial peptide-seller pages that fail the quality bar.

## Grokipedia

* [Dihexa](https://grokipedia.com/page/Dihexa)

  A comprehensive encyclopedia entry covering dihexa's chemical identity, proposed mechanism, preclinical research history, and its status as an experimental compound, providing a useful high-level orientation to the topic.

## Examine

No Examine article exists for dihexa. Examine focuses on dietary supplements and nutrients supported by human research and does not cover experimental, research-only peptides that lack human clinical data.

## ConsumerLab

No ConsumerLab article exists for dihexa. ConsumerLab independently tests commercially marketed supplements and does not cover experimental research peptides, which are not sold as regulated consumer supplements.

## Systematic Reviews

This section lists the systematic review evidence identified for dihexa and its parent compound class on PubMed.

* [Cognitive Benefits of Angiotensin IV and Angiotensin-(1-7): A Systematic Review of Experimental Studies](https://pubmed.ncbi.nlm.nih.gov/29733881/) - Ho & Nation, 2018

  A systematic review of animal experiments examining the memory effects of angiotensin IV and related peptides, including dihexa, concluding that these compounds consistently improve cognition in preclinical models while noting the complete absence of human trials.

## Mechanism of Action

Dihexa is a metabolically stabilized analog of angiotensin IV (Ang IV, a short peptide fragment of the blood-pressure hormone system). Its cognitive effects are attributed to potentiation of the hepatocyte growth factor / c-Met system (HGF is a signaling protein; c-Met, short for mesenchymal-epithelial transition factor, is the receptor it binds — together they drive cell growth, survival, and, in the brain, the formation of new synapses).

* **Primary pathway:** Dihexa is thought to bind HGF and stabilize its active dimer form, amplifying signaling through the c-Met receptor. Activated c-Met triggers two downstream cascades — the PI3K/AKT pathway (phosphoinositide 3-kinase/protein kinase B, which promotes cell survival) and the ERK/MAPK pathway (extracellular signal-regulated kinase, which drives growth signals) — leading to dendritic spine formation and synaptogenesis (growth of new connections between neurons).

* **Competing mechanistic accounts:** The compound was originally proposed to act at the AT4 receptor, identified as insulin-regulated aminopeptidase (IRAP, an enzyme that breaks down peptides). Later work by Benoist and colleagues reported that dihexa's procognitive and synapse-building effects are abolished when c-Met is blocked, indicating the HGF/c-Met system — not IRAP inhibition alone — is required; however, that 2014 paper has since been retracted, so this specific dependence claim should be treated with caution. Both accounts appear in the literature, and the HGF/c-Met system remains the more widely favored explanation, though the mechanistic evidence is not settled.

* **Reported potency:** In cell-based synaptogenesis assays, dihexa is active at sub-picomolar to picomolar concentrations, which underlies the widely repeated marketing claim that it is "seven orders of magnitude more potent than BDNF" (brain-derived neurotrophic factor, the brain's principal growth factor). This comparison reflects in-vitro assay potency, not a demonstrated real-world superiority, and is frequently overstated.

Key pharmacological properties are only partly characterized:

* **Selectivity:** Acts on the HGF/c-Met system rather than binding c-Met directly as an agonist; not a classical receptor agonist.

* **Half-life and metabolism:** Human pharmacokinetics have never been formally characterized. Dihexa was deliberately engineered for metabolic stability — an N-terminal hexanoic acid cap and a C-terminal amide protect it from aminopeptidases — which confers oral activity and resistance to rapid breakdown in preclinical models. As a small peptide it is not expected to be a major substrate of cytochrome P450 enzymes (e.g., CYP3A4).

* **Tissue distribution:** Lipophilic and blood-brain-barrier penetrant, allowing central nervous system access after oral administration in animals.

## Historical Context & Evolution

* **Original intended use:** Dihexa was developed in the laboratory of Joseph Harding and John (Jay) Wright at Washington State University in the early 2010s as a candidate treatment for Alzheimer's disease and other dementias. The goal was to convert the pro-cognitive but unstable natural peptide angiotensin IV into an orally active, metabolically stable drug.

* **Why it came to be considered for cognitive enhancement:** After McCoy and colleagues reported in 2013 that dihexa reversed memory deficits in rodents at low oral doses, and Benoist and colleagues proposed the synapse-building mechanism in 2014 (a paper later retracted), the compound attracted attention beyond dementia research. Its combination of oral activity, brain penetration, and dramatic in-vitro potency led a self-experimentation and "biohacking" community to adopt it as a nootropic (cognitive enhancer), sourced from research-chemical suppliers.

* **What the historical research actually found:** The primary studies described genuine, reproducible memory restoration in scopolamine-amnesia, aged, and lesioned rodents, plus robust synaptogenesis in cultured neurons. These are legitimate findings within their preclinical scope, not fringe claims.

* **Evolution of scientific opinion:** The originating group co-founded a company (M3 Biotechnology, later Athira Pharma) to develop the approach. Notably, the clinical program advanced a different, proprietary small molecule (fosgonimeton / ATH-1017) rather than dihexa itself, and dihexa never entered human trials. Enthusiasm has been tempered by a recognized concern — the same HGF/c-Met system is exploited by tumors — and by the later failure of the related clinical candidate to meet its primary endpoint in a large Alzheimer's trial. The current standing is that the mechanism remains scientifically interesting while human efficacy and safety for dihexa remain entirely unestablished.

## Expected Benefits

The evidence for dihexa's benefits derives almost entirely from animal and cell studies; no benefit has been confirmed in humans. Grades below reflect that ceiling.

### Low 🟩

#### Restoration of Memory in Animal Models of Cognitive Impairment

Across multiple rodent models — scopolamine-induced amnesia, aged animals, and lesion or genetic Alzheimer's models — orally administered dihexa restored learning and memory toward normal, most often measured in the Morris water maze (a spatial-memory swim test). The effect has been reported by the originating laboratory and independently replicated (e.g., Sun et al., 2021 in APP/PS1 mice), strengthening internal consistency. The limitation is fundamental: these are animal disease models, and no controlled human data exist, so relevance to a healthy person seeking enhancement is unestablished.

**Magnitude:** In rodent spatial-memory tasks, dihexa restored performance from an impaired state to near that of unimpaired controls at oral doses of roughly 1–2 mg/kg; no human effect size exists.

#### Promotion of Synaptogenesis and Neuroplasticity

In cultured hippocampal neurons, dihexa increases dendritic spine density and the number of functional synapses through the HGF/c-Met system, providing a plausible structural basis for the memory findings. This is among the best-characterized aspects of the compound mechanistically. However, the translation from dish to living human brain is unproven, and the frequently cited comparison to BDNF reflects assay potency rather than demonstrated clinical benefit.

**Magnitude:** Synaptogenic activity is reported at sub-picomolar to picomolar concentrations in vitro, with measurable increases in spine density; no in-vivo human magnitude is available.

### Speculative 🟨

#### Cognitive Enhancement in Healthy Individuals

The core reason the compound is marketed as a nootropic — improved memory, focus, or learning in people without cognitive impairment — rests entirely on mechanistic extrapolation and unverified anecdotal user reports. No controlled study has tested dihexa in healthy humans, and animal benefits were demonstrated against a backdrop of impairment, which does not predict enhancement of already-normal cognition.

#### Neuroregeneration and Recovery After Nerve or Brain Injury

Preliminary animal work suggests dihexa may aid functional recovery after peripheral nerve damage and in other neurodegeneration models (e.g., a Huntington's disease-like rat model), consistent with its growth-promoting mechanism. The basis is a small number of isolated preclinical reports with no human confirmation.

#### Disease Modification in Alzheimer's and Other Neurodegenerative Disease

Because dihexa reduced markers of pathology and improved cognition in animal Alzheimer's models, it is proposed as potentially disease-modifying. This remains speculative: dihexa itself was never trialed in humans, and the related clinical-stage molecule targeting the same pathway did not meet its primary endpoint in a pivotal Alzheimer's study.

## Benefit-Modifying Factors

Because human data are absent, the following are inferred from the mechanism and the parent compound class rather than demonstrated in people.

* **Baseline cognitive status:** Animal benefits were most pronounced against an impaired baseline (chemical amnesia, aging, lesions). Individuals with existing cognitive decline are, in principle, more likely to show a measurable effect than those with normal cognition, for whom benefit is least supported.

* **Genetic polymorphisms:** Variation in the *MET* gene (encoding the c-Met receptor) and in HGF signaling components could theoretically alter responsiveness, since the mechanism depends on this system. APOE4 carriers (the strongest common genetic risk factor for Alzheimer's) represent a population of research interest, though no dihexa data stratified by genotype exist.

* **Age:** Aged rodents were a key responsive population, and older adults at the upper end of the target range — where synaptic loss is greater — are the group for whom the mechanism is most relevant; they are also the group with the highest baseline cancer risk, complicating the risk-benefit balance.

* **Baseline biomarker levels:** No validated biomarker predicts response. Endogenous HGF and growth-factor tone could plausibly modify effect but have not been studied in this context.

* **Sex-based differences:** Preclinical studies have not systematically compared sexes, and no sex-specific efficacy data are available for dihexa.

* **Pre-existing health conditions:** Neurodegenerative disease was the modeled context; whether metabolic, vascular, or inflammatory comorbidities modify response is unknown.

## Potential Risks & Side Effects

No human safety data exist for dihexa. The risks below combine documented mechanistic concerns with the hazards inherent to an unregulated research chemical. Grades reflect the absence of clinical data.

### Low 🟥

#### Product Contamination, Mislabeling, and Dosing Errors

Dihexa is sold only as a research chemical by unregulated suppliers, with no pharmaceutical quality control. Independent testing of the broader gray-market peptide sector has repeatedly found products that are underdosed, overdosed, degraded, or contaminated with solvents, bacterial endotoxin, or incorrect compounds. Users reconstitute and dose these products themselves, adding measurement error. This is the most concrete, present-day hazard because it applies to every real-world purchase regardless of the molecule's intrinsic effects.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Cancer Promotion via HGF/c-Met Pathway Activation

The mechanism dihexa exploits is a recognized driver of cancer: HGF/c-Met signaling promotes tumor cell proliferation, survival, invasion, angiogenesis, and metastasis, and c-Met is a well-established proto-oncogene. Chronically amplifying this system throughout the body could, in principle, accelerate the growth of existing or occult tumors. No study has measured cancer outcomes with dihexa, so this remains a theoretical but mechanistically serious concern — arguably the single most important reason for caution, particularly with prolonged use or in individuals with cancer risk.

#### Unknown Human Safety Profile and Absence of Clinical Trial Data

Dihexa has never completed a human clinical trial of any phase, so there is no established safe dose, no documented adverse-event profile, no drug-interaction data, and no information on long-term consequences. Every human use is effectively uncontrolled self-experimentation.

#### Pathological Angiogenesis and Tissue Fibrosis

Beyond oncogenesis, HGF/c-Met activation can promote new blood-vessel growth and, in some tissues, fibrosis (scarring). Sustained systemic stimulation could theoretically aggravate conditions involving abnormal vascular growth (for example proliferative retinal disease) or fibrotic processes, though no clinical evidence addresses this for dihexa.

#### Overstimulation, Headache, and Neurological Effects

Anecdotal user reports describe headaches, irritability, brain fog, or a sense of overstimulation, plausibly related to growth-factor signaling or to impurities. These reports are uncontrolled, unverified, and cannot be attributed to dihexa itself with any confidence.

## Risk-Modifying Factors

As with benefits, these factors are inferred from mechanism and general pharmacology rather than demonstrated for dihexa in humans.

* **Personal or family history of cancer:** Given the HGF/c-Met oncogenic concern, individuals with active cancer, a history of cancer, or strong hereditary cancer risk represent the group in whom the theoretical harm is greatest.

* **Genetic polymorphisms:** Germline variants that increase c-Met activity or cancer susceptibility (for example hereditary cancer syndromes, or *MET* amplification-prone contexts) could plausibly heighten risk. No dihexa-specific pharmacogenetic data exist.

* **Age:** Older adults carry higher baseline prevalence of undetected malignancy and vascular disease, so the same pathway stimulation may carry greater downside at the upper end of the target range.

* **Pre-existing health conditions:** Conditions involving abnormal tissue proliferation, fibrosis, or angiogenesis (e.g., pulmonary fibrosis, proliferative retinopathy) are theoretical grounds for heightened caution.

* **Baseline biomarker levels:** No biomarker is validated to stratify risk; elevated tumor markers or unexplained abnormalities would be reasons for concern before any use.

* **Sex-based differences:** No sex-specific safety data are available for dihexa.

## Key Interactions & Contraindications

Formal interaction data do not exist for dihexa; the following are mechanistic and precautionary.

* **Prescription drug interactions:** No documented interactions. Theoretically, c-Met inhibitors used in oncology (e.g., crizotinib, cabozantinib, capmatinib) would act in direct opposition to dihexa's mechanism, and concurrent use is nonsensical and contraindicated in that clinical setting.

* **Over-the-counter medication interactions:** None documented. No specific OTC interaction is established.

* **Supplement interactions:** None documented. Supplements marketed to raise growth-factor or neurotrophic signaling (e.g., certain "BDNF-boosting" stacks) could theoretically add to growth-pathway stimulation, but this is unquantified.

* **Additive-effect substances:** Other experimental growth-factor-potentiating or synaptogenic peptides could, in principle, compound the same HGF/c-Met or neurotrophic signaling; no data confirm additive risk or benefit.

* **Other intervention interactions:** Combined use with other unregulated research peptides (a common "stacking" practice) multiplies the uncertainty and contamination risk without any supporting evidence.

* **Severity and consequence:** Because no interaction is characterized, all combinations should be treated as caution-level or higher by default; the clinical consequence of greatest concern is unmonitored stimulation of a cancer-associated pathway.

* **Mitigating actions:** Where any use occurs, avoiding co-administration with other growth-pathway agents and separating it from oncologic therapy are the only sensible precautions; no validated dose-adjustment or timing protocol exists.

* **Populations who should avoid this intervention:** Anyone with active or prior cancer, a strong hereditary cancer predisposition, pregnancy or breastfeeding (no reproductive safety data), individuals under 18, and those with proliferative or fibrotic disease. Given the complete absence of human safety data, no population can be identified for whom use is clearly safe.

## Risk Mitigation Strategies

* **Cancer risk screening before any consideration:** Because the dominant concern is HGF/c-Met-driven tumor promotion, age-appropriate cancer screening and a thorough personal and family cancer history are the logical first step, and active or prior malignancy is a reason not to use dihexa at all — this mitigates the pathway's central oncogenic risk.

* **Third-party purity and identity testing:** Since contamination and mislabeling are the most concrete hazards, obtaining an independent certificate of analysis (identity, purity ≥98%, and endotoxin testing) for any batch mitigates the risk of dosing an incorrect or contaminated compound; without such testing the product content is unknown.

* **Conservative, time-limited exposure:** Limiting any exposure to short durations rather than continuous long-term use reduces cumulative stimulation of a growth-associated pathway, addressing the theoretical concern that chronic activation is more likely to promote tumor growth.

* **Avoid stacking with other growth-pathway agents:** Not combining dihexa with other experimental peptides or neurotrophic "boosters" limits compounded, unquantified stimulation of the same signaling systems and reduces contamination exposure from multiple gray-market sources.

* **Medical supervision and baseline labs:** Undergoing baseline bloodwork and, ideally, physician oversight before and during any use provides a chance to detect adverse changes early, mitigating the risk posed by the complete absence of an established human safety profile.

## Therapeutic Protocol

There is no validated human protocol for dihexa. The intervention has never been through human trials, and the details below describe what preclinical work used and what unregulated users report — presented for completeness, not as a usable regimen.

* **Standard protocol from research:** No clinical protocol exists. Preclinical efficacy in rodents was achieved with oral or injected doses on the order of 1–2 mg/kg; leading academic work (the Harding/Wright laboratory at Washington State University) never translated this into a human dosing schedule.

* **Competing approaches:** The originating group's own translational path deliberately moved to a different, proprietary molecule (fosgonimeton) for human development rather than dihexa; the "biohacker" approach of self-dosing raw dihexa is a separate, unsanctioned practice. Neither is framed here as a default, and only the former was ever subjected to formal drug development.

* **Expert or clinic that popularized each approach:** The academic HGF/c-Met approach traces to Joseph Harding and John Wright; the nootropic self-experimentation use has no legitimate clinical sponsor and is popularized chiefly by peptide vendors and online communities.

* **Best time of day:** Not established; no chronobiological data exist for dihexa.

* **Half-life consideration:** Human half-life is uncharacterized; the molecule was engineered for metabolic stability and oral activity, but this does not translate into a known dosing interval for people.

* **Single vs. split dosing:** Not established; anecdotal users variously report once-daily oral or transdermal use, but no evidence supports any particular schedule.

* **Genetic considerations:** No pharmacogenetic guidance exists; variants in the c-Met/HGF system are of theoretical interest only.

* **Sex-based differences:** No sex-specific dosing data are available.

* **Age considerations:** No age-adjusted dosing exists; older adults face both greater potential relevance and greater theoretical cancer risk.

* **Baseline biomarkers:** No biomarker is used to guide dosing.

* **Pre-existing conditions:** No condition-specific protocol exists; cancer history is a reason to avoid rather than adjust.

## Discontinuation & Cycling

* **Lifelong vs. short-term:** No evidence supports any duration. Given the growth-pathway safety concern, indefinite continuous use is the least defensible pattern, and there is no established therapeutic course.

* **Withdrawal effects:** None are documented. As dihexa is not known to act on classical neurotransmitter or receptor-dependence systems, physical withdrawal is not an established phenomenon, but this is unstudied.

* **Tapering:** No tapering protocol exists or has been studied; there is no evidence that gradual discontinuation is necessary.

* **Cycling:** Whether cycling preserves any effect is unknown. Some users self-impose on/off cycles on the theory that this limits cumulative pathway stimulation, but no efficacy or safety data support cycling for dihexa.

* **Practical framing:** Because benefit in humans is unproven and the main safety concern scales with cumulative exposure, the discontinuation question is dominated by risk minimization rather than by any withdrawal or maintenance-of-effect consideration.

## Sourcing and Quality

* **Regulatory and supply status:** Dihexa is not an approved drug or a dietary supplement anywhere; it is sold only as a "research chemical" or "for research use only" peptide, meaning no regulator verifies its identity, purity, or safety.

* **What to look for:** Because product quality is the most concrete risk, any material should carry a batch-specific third-party certificate of analysis documenting identity (mass spectrometry), purity (typically ≥98% by high-performance liquid chromatography), and endotoxin/sterility testing; absence of such documentation should be treated as an unknown product.

* **Formulation considerations:** Dihexa is supplied variously as a raw powder, an oral solution, or a transdermal cream; the transdermal route in particular has no human absorption data, so delivered dose is highly uncertain across formulations.

* **Reputable brands or pharmacies:** There are no reputable pharmaceutical manufacturers or compounding pharmacies producing dihexa for human use; it is not a recognized compounding ingredient, and all consumer sources are unregulated research-chemical suppliers whose reliability cannot be assured.

* **Bottom line on sourcing:** The combination of no legitimate manufacturer, no regulatory oversight, and documented gray-market quality problems means sourcing risk cannot be reduced to an acceptable level through brand selection alone.

## Practical Considerations

* **Time to effect:** Not established in humans. In rodent studies, cognitive improvements were measured over days of dosing; any human timeline is unknown and anecdotal claims of rapid effects are unverified.

* **Common pitfalls:** Over-relying on the in-vitro "more potent than BDNF" marketing claim; assuming animal memory-rescue predicts enhancement in healthy people; ignoring the cancer-pathway concern; and trusting unlabeled product potency, leading to unintended over- or under-dosing.

* **Regulatory status:** Dihexa is unapproved for human use; it is neither an FDA-approved drug nor a lawful dietary supplement, and it is sold under "research use only" labeling. Personal use exists in a legal gray area and outside any medical framework.

* **Cost and accessibility:** Dihexa is comparatively expensive per gram and is accessible only through research-chemical vendors, with no insurance coverage and no pharmacy channel; supply reliability and product consistency are poor.

* **Overall practicality:** As a practical matter, dihexa is an experimental compound with no established human dose, no quality assurance, and a serious unresolved safety question, which together place it far outside routine, responsible use.

## Interaction with Foundational Habits

* **Sleep:** Interaction is indirect and unstudied. There is no evidence dihexa disrupts or improves sleep architecture; anecdotal reports of overstimulation or headache could plausibly interfere with sleep in some users, but no mechanism or study confirms a direct effect, and no timing guidance can be given.

* **Nutrition:** Interaction is indirect and unstudied. No dietary pattern is known to enhance or blunt dihexa, and no nutrient depletion is documented. As a peptide taken orally, food effects on its uncertain absorption are unknown; no foods to include or avoid are established.

* **Exercise:** Interaction is indirect and theoretically potentiating. Physical exercise independently raises endogenous growth and neurotrophic factors (including BDNF) and supports synaptic health, so exercise plausibly overlaps with dihexa's intended pathway; however, no study has examined combined effects, and exercise is the far better-evidenced route to the same cognitive goal.

* **Stress management:** Interaction is indirect and unstudied. Chronic stress suppresses neurotrophic signaling and neuroplasticity, so stress reduction is directionally complementary to dihexa's mechanism, but there is no evidence dihexa alters cortisol or the stress response, and no practical combined protocol exists.

## Monitoring Protocol & Defining Success

Given the absence of human data and the cancer-pathway concern, monitoring would be precautionary and centered on early detection of harm rather than on confirming benefit. Baseline testing before any use should establish general health and screen for contraindications.

Baseline testing should be completed before any use and reviewed with a physician; ongoing monitoring, if any use occurs, would reasonably be repeated at roughly 4–8 weeks and then every 3–6 months, alongside age-appropriate cancer screening on its standard schedule.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
|-----------|--------------------------|-----------------|---------------|
| Complete blood count (CBC) | Within standard reference range | Detects unexplained cytopenias or abnormalities before/after use | Baseline then periodic; abnormalities warrant stopping and evaluation |
| Comprehensive metabolic panel (CMP) | Fasting glucose 70–90 mg/dL; liver enzymes ALT/AST < 25 U/L | Screens general organ function, including liver where peptides are processed | Fasting sample preferred; conventional ALT/AST upper limits (~40 U/L) are higher than the functional target |
| High-sensitivity C-reactive protein (hs-CRP) | < 1.0 mg/L | General marker of systemic inflammation; unexplained rises merit attention | Avoid testing during acute illness; pair with baseline health review |
| Age-appropriate cancer screening | Per established screening guidelines | Central precaution given the HGF/c-Met tumor-promotion concern | Not a blood value; includes standard screenings for age/sex; a prior cancer history is a reason to avoid entirely |

Qualitative markers that users might track:

* Subjective memory, recall, and learning ease
* Mental clarity versus brain fog or overstimulation
* Headache frequency or new neurological symptoms
* Energy and mood stability
* Any new or changing lumps, skin lesions, or unexplained symptoms warranting prompt medical review

## Emerging Research

* **No dihexa human trials registered:** As of July 2026, a search of ClinicalTrials.gov returns no registered clinical trials of dihexa itself in any condition, underscoring that all human use remains outside formal research.

* **HGF/c-Met clinical proxy — fosgonimeton (ATH-1017):** The clinical test of dihexa's pathway advanced through a related, distinct small molecule. The Phase 2/3 LIFT-AD trial in mild-to-moderate Alzheimer's disease ([NCT04488419](https://clinicaltrials.gov/study/NCT04488419), ~554 participants) evaluated fosgonimeton; its publicly reported topline result did not meet the primary cognitive endpoint for monotherapy, a finding that weakens the near-term clinical case for the mechanism.

* **Terminated dementia programs:** Companion studies of the same molecule, including an open-label Alzheimer's study ([NCT04886063](https://clinicaltrials.gov/study/NCT04886063)) and the SHAPE trial in Parkinson's disease dementia and dementia with Lewy bodies ([NCT04831281](https://clinicaltrials.gov/study/NCT04831281)), were terminated, reflecting a contraction of the clinical program.

* **Independent preclinical replication (strengthening direction):** Work such as [Sun et al., 2021](https://pubmed.ncbi.nlm.nih.gov/34827486/) reproduced dihexa's memory benefits in a genetic Alzheimer's mouse model outside the originating laboratory, and [Benoist et al., 2014](https://pubmed.ncbi.nlm.nih.gov/25187433/) reported the HGF/c-Met dependence of the effect — though this paper has since been retracted, which weakens rather than strengthens the mechanistic case and underscores the need for independent confirmation.

* **Broadening indications (uncertain direction):** Recent primary studies extend dihexa into peripheral nerve repair ([Weiss et al., 2021](https://pubmed.ncbi.nlm.nih.gov/34703584/)) and Huntington's-like models ([Wells et al., 2024](https://pubmed.ncbi.nlm.nih.gov/38489193/)); these expand the mechanistic story but do not address human cognitive enhancement.

* **Key open questions that could change understanding:** Direct human pharmacokinetic and safety data for dihexa; long-term carcinogenicity testing given the HGF/c-Met concern; and any controlled trial in healthy people — none of which currently exist. Future evidence on the cancer question in particular could substantially strengthen or weaken the case for any human use.

## Conclusion

Dihexa is an experimental peptide, first built to treat memory loss, that is thought to work by switching on a growth-signal system in the brain to spur new connections between nerve cells. In animals, it reliably restored memory in impaired rodents at low oral doses, and it builds new nerve-cell connections powerfully in laboratory dishes. That preclinical record is genuine and has been repeated by more than one research group.

The evidence base, however, is almost entirely from animals and cells. No completed human trial exists, so there is no established dose, no safety record, and no confirmation that a healthy person's thinking would improve at all. Two concerns weigh heavily. First, the same growth system dihexa stimulates is one that tumors use to grow, making long-term or whole-body stimulation a real theoretical hazard. Second, the compound is sold only through unregulated suppliers, so what a buyer actually receives is uncertain.

Where the science is strongest — memory rescue in animals and connection-building in the lab — it is also furthest from proving anything about people. The current picture is a mechanistically intriguing compound whose promise remains unproven and whose most serious safety question is unresolved.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**


DHM
Ampelopsin
Ampeloptin
Epicelline
Vine Tea Flavonoid

---
canonical_name: Dihydromyricetin
alternate_names: DHM, Ampelopsin, Ampeloptin, Epicelline, Vine Tea Flavonoid
canonical_topic: Dihydromyricetin for Skin Rejuvenation
short_topic_lc: dihydromyricetin_skin
creation_date: 2026-0616-0427
creator_ai_fullname: Opus 4.8
ep_keywords: Flavonoids, Polyphenols
---

# Dihydromyricetin for Skin Rejuvenation

Evidence Review created on 06/16/2026 using [AI4L](https://github.com/forever-healthy/AI4L) / Opus 4.8

**Also known as:** DHM, Ampelopsin, Ampeloptin, Epicelline, Vine Tea Flavonoid

## Motivation

Dihydromyricetin (also called DHM or ampelopsin) is a plant compound extracted mainly from vine tea, a traditional Chinese herbal drink made from the leaves of the *Ampelopsis grossedentata* plant. It has long been valued as an antioxidant and anti-inflammatory agent, and it is best known in the supplement world as a liver-support and hangover aid. More recently it has drawn attention from skin-longevity researchers, who discovered that it can gently nudge the skin's chemical aging markers back toward a younger pattern.

The renewed interest comes from a specific discovery: DHM can lightly loosen the chemical tags that accumulate on skin-cell DNA with age. A consumer-skincare company built a topical serum around this finding and reported that, after eight weeks of use, the skin's measured biological age dropped while roughness and wrinkles visibly improved. DHM has also been studied for evening out skin tone and shielding skin from sun-driven aging.

This review examines what is known about dihydromyricetin applied to skin rejuvenation: the strength of the evidence behind its anti-aging claims, how it is thought to work, the practical ways it is used, and where the science is still preliminary.

**[Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol) - [Conclusion](#conclusion)**

## Recommended Reading

This section lists high-level, accessible resources that give a broad overview of dihydromyricetin and its emerging role in skin aging.

* [Reverse the Age Clock: Reverse Clinical Signs of Ageing with Epigenetic Skin Science](https://www.emjreviews.com/dermatology/symposium/reverse-the-age-clock-reverse-clinical-signs-of-ageing-with-epigenetic-skin-science-j030124/) - European Medical Journal

  A symposium summary written for clinicians that explains the epigenetic-aging concept behind dihydromyricetin and walks through the rationale for using it to reverse visible signs of skin aging.

* [Eucerin Epigenetic Serum Review](https://escentual.com/blogs/editorial/before-after-using-eucerin-epigenetic-serum-review) - Escentual

  An editorial overview describing how dihydromyricetin (branded "Epicelline") was identified through fifteen years of epigenetic research and developed into a commercial anti-aging serum.

* [Reversing Skin Aging from the Inside Out](https://www.rejuviencemedspa.com/regenerative-insider/dihydromyricetin-epigenetic-study/) - Rejuvience Med Spa

  A plain-language commentary that summarizes the dihydromyricetin epigenetic skin study for a general health-optimizing audience and places it in the context of broader longevity science.

* [Recent Advances in Research on Vine Tea, a Potential and Functional Herbal Tea with Dihydromyricetin and Myricetin as Major Bioactive Compounds](https://pubmed.ncbi.nlm.nih.gov/34765268/) - Zhang et al., 2021

  A narrative review of vine tea and its dominant compound dihydromyricetin, useful for understanding the natural source, antioxidant chemistry, and bioavailability challenges that shape its use on skin.

* [What Is Dihydromyricetin?](https://www.sanxinherbs.com/knowledge/what-is-dihydromyricetin) - Sanxin

  A concise primer covering dihydromyricetin's origin, extraction, and the range of properties (antioxidant, anti-inflammatory, depigmenting) that underlie its skincare applications.

## Grokipedia

* [Ampelopsin](https://grokipedia.com/page/Ampelopsin) - Grokipedia

  Grokipedia's dedicated page for the compound (titled by its chemical name Ampelopsin, with dihydromyricetin given as the primary synonym) covers its chemistry, natural sources, biosynthesis, and reported bioactivities, providing useful background context for its skincare applications.

## Examine

No Examine article exists for dihydromyricetin. A direct search of examine.com for "dihydromyricetin" returns no results; the compound does not currently have a dedicated Examine supplement page.

## ConsumerLab

* [Dihydromyricetin (DHM) - Does It Help and Is It Safe?](https://www.consumerlab.com/answers/dihydromyricetin-dhm-does-it-help-and-is-it-safe/dhm-supplement/) - ConsumerLab

  ConsumerLab's reviewed answer page addresses what dihydromyricetin is, its promoted uses, and safety considerations, offering an independent, consumer-focused perspective on the supplement form of the compound.

## Systematic Reviews

No systematic reviews or meta-analyses for Dihydromyricetin were found on PubMed as of 06/16/2026.

## Mechanism of Action

Dihydromyricetin is a flavanonol-type flavonoid. Several distinct, complementary mechanisms have been proposed for its effects on skin, drawn mostly from cell, animal, and early human work.

* **Epigenetic "rejuvenation" via DNMT1 inhibition.** The most novel mechanism is mild inhibition of DNA methyltransferase 1 (DNMT1, the enzyme that copies the chemical "off switches" called methyl tags onto newly made DNA). With age, skin DNA accumulates extra methyl tags that silence helpful genes. A controlled biochemical and cell screen identified dihydromyricetin as a modest DNMT1 inhibitor that produces a gentle, global reduction in these tags (hypomethylation), reactivating age-silenced genes and lowering the cells' measured biological age on DNA methylation "clocks" (molecular age estimators).

* **Inhibition of AGE-RAGE signaling.** Dihydromyricetin binds the receptor for advanced glycation end products (RAGE, a receptor that triggers inflammation and aging when sugars react with proteins). By blocking AGE-RAGE signaling, it reduces a key driver of "sugar-aged" (glycated) skin — preserving collagen and elasticity in animal and fibroblast (skin connective-tissue cell) models.

* **Antioxidant and anti-inflammatory protection.** Its multiple hydroxyl groups make it a strong scavenger of reactive oxygen species (unstable molecules that damage cells, "ROS"). This lowers ultraviolet-B (UVB)-driven oxidative stress and inflammation in skin keratinocytes (the main cells of the outer skin layer) and may engage repair-promoting TGF-β1 and Wnt signaling pathways (cell-communication routes that govern tissue growth and collagen production).

* **Inhibition of melanin production.** Dihydromyricetin suppresses tyrosinase (the rate-limiting enzyme of pigment synthesis) and downregulates the PKA, PKC, and MAPK signaling pathways (intracellular signaling routes that switch pigment genes on), reducing melanin and supporting a skin-brightening, tone-evening effect.

Where mechanisms compete, the picture is genuinely mixed: the epigenetic-demethylation model is attractive but rests on the assumption that broad, mild hypomethylation is net-beneficial rather than harmful, and critics note that DNMT1 inhibition is also the mechanism of some chemotherapeutic agents — the proposed safety margin depends on the inhibition being modest and reversible. The antioxidant and AGE-RAGE models are more conventional and overlap with how many other dietary flavonoids are thought to act.

As a pharmacological compound, dihydromyricetin has notably poor water solubility and low oral bioavailability, with a short plasma half-life (roughly 2–4 hours in human pharmacokinetic data) and rapid metabolism via glucuronidation and methylation, largely in the liver and gut. These properties are a central reason topical, encapsulated, or nano-formulated delivery has been emphasized for skin applications.

## Historical Context & Evolution

* **Original use.** Dihydromyricetin originates from vine tea (*Ampelopsis grossedentata*), a beverage consumed for centuries in southern China and used in traditional medicine for sore throat, fever, and liver complaints. Its original "intended use" was therefore as a general anti-inflammatory and hepatoprotective (liver-protecting) herbal tea, not a skincare agent.

* **Entry into supplements.** In the 2000s and 2010s, isolated dihydromyricetin became a popular Western supplement, marketed primarily for liver support and as a hangover remedy, based on animal data showing it speeds alcohol metabolism and protects liver tissue.

* **Pivot to skin science.** The reasons it came to be considered for skin optimization are recent and specific. Cosmetic-science work in the 2010s (e.g., tyrosinase/melanin inhibition in 2016 and UVB photoprotection in 2018) flagged its depigmenting and antioxidant potential. The decisive turn came in 2023, when a screen of ~1,800 natural substances and 640 approved drugs identified dihydromyricetin as a DNMT1 inhibitor with measurable rejuvenating effects on aged human skin cells, leading to its development (under the trade name "Epicelline") into a commercial epigenetic anti-aging serum and a 2026 clinical report.

* **Evolution of opinion.** The current enthusiasm is new and not yet a settled consensus. Independent dermatology groups have begun to discuss epigenetic skin rejuvenation as a plausible strategy, but the clinical evidence to date comes largely from the developing company, and longer, controlled, independent replication has not yet appeared. The historical antioxidant and depigmenting findings remain valid in their own right; the newer epigenetic claim is the part of the story still being tested, and the reader can weigh it against the relatively early stage of human data.

## Expected Benefits

### Medium 🟩 🟩

#### Reduction in Biological Skin Age (Epigenetic Rejuvenation)

This is the flagship benefit: topical dihydromyricetin appears to reduce the measured biological age of skin by gently reversing age-related DNA methylation. The mechanism (mild DNMT1 inhibition reactivating age-silenced genes) is supported by cell and 3-dimensional skin-model work, and a prospective single-cohort clinical study of 60 participants across all skin tones reported a significant drop in epidermal methylation age after 8 weeks of twice-daily serum use. The evidence is graded Medium rather than High because the pivotal human data are single-arm (no placebo control), of short duration, and generated by the product's developer.

**Magnitude:** Significant reduction in epidermal DNA-methylation age over 8 weeks in a 60-participant single-cohort study; exact years not consistently quantified across reports.

#### Improvement in Visible Aging (Wrinkles, Roughness, Skin Density)

Alongside the biological-age change, the same clinical study reported visible and structural improvements: reduced skin roughness, reduced wrinkle visibility and area, and increased dermal echogenicity (an ultrasound measure of skin density and firmness). These are the outcomes most relevant to users seeking cosmetic rejuvenation. The grade is Medium because, while the visible improvements are clinically measured, they come from an uncontrolled cohort and overlap with effects expected from the serum's co-formulated hyaluronic acid and routine daily sunscreen use.

**Magnitude:** Measurable reductions in wrinkle area/visibility and roughness plus increased dermal echogenicity over 8 weeks; effect sizes not separately reported for dihydromyricetin alone.

### Low 🟩

#### Skin Brightening and Even Tone (Reduced Hyperpigmentation)

Dihydromyricetin inhibits tyrosinase and downregulates pigment-promoting signaling (PKA, PKC, MAPK), reducing melanin production in pigment-cell models. This supports its use for evening skin tone and softening dark spots. The grade is Low because the evidence is limited to cell-culture (B16F10 melanoma cell) experiments without human skin-lightening trials.

**Magnitude:** Dose-dependent suppression of tyrosinase activity and melanin content in cultured pigment cells; no human depigmentation effect size available.

#### Protection Against Photoaging (UV-Induced Damage)

As a potent antioxidant, dihydromyricetin reduces UVB-induced oxidative stress, inflammation, and DNA damage in skin cells and mice, and may activate collagen-supporting TGF-β1 and Wnt pathways — relevant to preventing sun-driven wrinkles and skin thinning. The grade is Low because supportive data are from cell and animal models (some using oral or combination dosing with ellagic acid), not human photoaging trials.

**Magnitude:** Reduced UVB-induced epidermal thickening, inflammatory markers (IL-1β, TNF-α), and DNA damage in mouse and keratinocyte models; no human quantitative estimate.

#### Reduced Glycation-Related Skin Aging

By acting as a RAGE inhibitor and suppressing AGE-RAGE signaling, dihydromyricetin preserved skin collagen and elasticity and slowed cellular senescence in a galactose-aged rat model and in glycation-stressed human fibroblasts. This targets "sugar-aging" of skin, a recognized contributor to dullness and stiffness. The grade is Low because evidence is preclinical (rat and cell models) with no human confirmation.

**Magnitude:** Improved skin elasticity and collagen preservation at a 100 mg/kg oral dose in aged rats; ~1.5-fold increase in fibroblast proliferation in vitro; no human data.

### Speculative 🟨

#### Wound Healing and Skin Barrier Support

Dihydromyricetin has shown pro-healing and anti-inflammatory effects in wound-healing and hydrogel-delivery models, and reduces hypertrophic (raised) scar formation by targeting TGF-β/ALK5 signaling. Whether this translates into everyday barrier support or post-procedure recovery in healthy skin is unknown; the basis is mechanistic and animal-model only, with no controlled human skincare studies.

## Benefit-Modifying Factors

* **Baseline skin age and damage:** The epigenetic-rejuvenation effect is defined relative to age-accumulated methylation, so individuals with more advanced biological skin aging (and more sun and glycation damage) have more "room" for measurable improvement, while younger or minimally aged skin may show smaller changes.

* **Skin phototype and ethnicity:** The pivotal clinical study deliberately enrolled Fitzpatrick phototypes I–VI across white, African, and Asian donors and reported that age-related methylation patterns — and the response to dihydromyricetin — were broadly conserved across skin tones, suggesting benefit is not restricted to a single ethnic group.

* **Pre-existing pigmentation conditions:** Because dihydromyricetin suppresses melanin synthesis, those with hyperpigmentation concerns (melasma, post-inflammatory dark spots) may notice tone-evening benefits more than those without.

* **Concurrent sun protection:** Clinical use paired dihydromyricetin with daily sunscreen; because ultraviolet exposure actively re-drives the aging methylation and oxidative damage the compound counteracts, benefit is expected to be greater when sun protection is consistent.

* **Formulation and delivery:** Owing to poor solubility and bioavailability, benefit depends heavily on the delivery system (encapsulation, nanocarriers, penetration enhancers). Identical raw amounts in poorly formulated products may yield little skin-level effect.

* **Sex-based differences:** No skin-specific sex differences in dihydromyricetin response have been established; the clinical skin data were not reported as showing meaningful divergence by sex, and this remains an open question rather than a demonstrated modifier.

## Potential Risks & Side Effects

### Low 🟥

#### Local Skin Irritation, Redness, or Sensitization

As with most active topical botanicals, dihydromyricetin serums can cause local irritation, redness, stinging, or contact sensitization in some users, particularly on sensitive or compromised skin. The clinical serum study reported the formulation was well tolerated over 8 weeks, but the cohort was small and the product included other ingredients, so individual reactions cannot be excluded. Reactions are generally mild and reversible on discontinuation.

**Magnitude:** Not quantified in available studies.

#### Uncertainty From Mild DNA-Demethylation Mechanism

The epigenetic mechanism — deliberate, if mild, inhibition of DNMT1 — is the same class of action used by some chemotherapy demethylating drugs at much higher exposures. At the low topical doses used for skin, no genotoxic or precancerous signal has been reported, and proponents argue the effect is modest, local, and self-limiting. Nonetheless, the long-term consequences of chronically nudging skin-cell methylation are not yet established in extended human studies, making this a theoretical but non-trivial consideration.

**Magnitude:** Not quantified in available studies.

### Speculative 🟨

#### Systemic Effects From Oral Use

When dihydromyricetin is taken orally (its more common supplement form) rather than applied topically, isolated reports and supplement-safety reviews note generally good tolerability but possible mild gastrointestinal upset, and its iron-binding and enzyme-modulating properties raise theoretical concerns about nutrient interactions at high intake. These do not directly apply to topical skin use but are relevant for anyone combining an oral supplement with topical use; controlled human safety data at high oral doses remain limited.

#### Pregnancy and Lactation Safety

There is no skin-specific safety data for dihydromyricetin during pregnancy or breastfeeding, and its mechanism touches DNA methylation, a process important in fetal development. In the absence of evidence, caution during pregnancy and lactation is a reasonable default; the basis here is mechanistic precaution rather than any documented harm.

## Risk-Modifying Factors

* **Skin sensitivity and barrier status:** Those with eczema, rosacea, or a compromised skin barrier are more prone to irritation from any active serum and may need lower frequency or patch testing.

* **Concurrent use of other actives:** Layering dihydromyricetin with retinoids, exfoliating acids, or vitamin C may increase the chance of irritation through additive effects on the stratum corneum.

* **Pre-existing pigmentation disorders:** Because the compound suppresses melanin, individuals seeking even tone benefit, but those with conditions involving hypopigmentation should be aware of the depigmenting direction of effect.

* **Pregnancy and lactation:** Given the DNA-methylation mechanism and absence of data, this population represents a risk-modifying context favoring avoidance until evidence exists.

* **Sex-based differences:** No established sex-based difference in dihydromyricetin skin-related risk has been demonstrated; this remains uncharacterized rather than shown to be absent.

* **Age:** Older adults at the upper end of the target range typically have thinner, drier skin that may both benefit more and irritate more easily, warranting gradual introduction.

## Key Interactions & Contraindications

* **Prescription topical interactions:** Combining dihydromyricetin serums with prescription retinoids (tretinoin, adapalene) or topical corticosteroids has no documented direct interaction, but additive irritation is plausible — **caution**, with the consequence of increased dryness, peeling, or redness; separating application times mitigates this.

* **Over-the-counter topical interactions:** Co-use with OTC exfoliating acids (alpha-hydroxy acids such as glycolic acid, beta-hydroxy acids such as salicylic acid) or benzoyl peroxide may increase irritation — **caution**; alternating nights or applying at separate times reduces the risk.

* **Supplement interactions:** Oral dihydromyricetin can bind iron and may interact with iron supplements, potentially reducing iron absorption — **caution/monitor**; separating doses by several hours is advisable. It may also modulate drug-metabolizing enzymes, theoretically affecting other orally administered supplements.

* **Additive-effect supplements:** Other topical or oral antioxidants and tyrosinase inhibitors (vitamin C, niacinamide, alpha-arbutin, kojic acid) can have additive brightening and antioxidant effects with dihydromyricetin — generally desirable, but compounding the depigmenting effect should be considered when targeting pigmentation.

* **Other intervention interactions:** Around in-office procedures (chemical peels, lasers, microneedling) freshly treated skin is more permeable and reactive, so applying dihydromyricetin actives immediately afterward warrants **caution** to avoid stinging or irritation; spacing application until the barrier recovers is advised.

* **Populations who should avoid:** Pregnant and breastfeeding individuals (mechanistic precaution given DNA-methylation activity and absent data); those with known allergy to vine tea, *Ampelopsis* botanicals, or related flavonoids; and individuals with actively inflamed or broken skin until healed — **caution to avoid**.

## Risk Mitigation Strategies

* **Patch test before full use:** Apply a small amount to the inner forearm or behind the ear for 2–3 consecutive days before facial use, to detect irritation or sensitization before it affects a larger area — mitigates local irritation and contact sensitization.

* **Start low-frequency and titrate:** Begin with once-daily (or every-other-day) application for the first 1–2 weeks, increasing to twice daily only if well tolerated — mitigates irritation, redness, and stinging, especially in sensitive skin.

* **Separate from other strong actives:** Apply dihydromyricetin and irritating actives (retinoids, acids, benzoyl peroxide) at different times of day or on alternating nights — mitigates additive irritation from combined barrier disruption.

* **Pair with daily broad-spectrum sunscreen (SPF 30+):** Use sunscreen every morning, as in the clinical protocol — mitigates ongoing ultraviolet-driven re-aging and photodamage that would otherwise counteract the rejuvenation effect, and reduces irritation risk on actively photodamaged skin.

* **Avoid use on broken or inflamed skin and during pregnancy/lactation:** Withhold application until the skin barrier is intact and avoid during pregnancy and breastfeeding — mitigates irritation and the theoretical concern tied to the DNA-methylation mechanism where data are absent.

* **Separate oral dihydromyricetin from iron and key supplements:** If also taking it orally, space it several hours from iron supplements — mitigates reduced iron absorption from iron-binding.

## Therapeutic Protocol

* **Standard approach (topical serum):** The leading clinically described approach is a leave-on facial serum containing dihydromyricetin (trade name "Epicelline"), applied to clean skin twice daily (morning and evening), combined with daily sunscreen — the regimen used in the prospective clinical study developed by Beiersdorf for its Eucerin epigenetic serum line.

* **Alternative approach (general antioxidant/brightening use):** A second approach treats dihydromyricetin like other antioxidant/tyrosinase-inhibitor botanicals, incorporating it into a broader brightening or antioxidant routine for tone and photoprotection rather than specifically for epigenetic age reversal; this reflects the earlier cosmetic-science literature rather than a single popularizing clinic.

* **Popularizing source:** The epigenetic-serum protocol was popularized by Beiersdorf/Eucerin and the associated DKFZ (German Cancer Research Center) epigenetics collaboration; no independent clinic protocol has yet been established.

* **Best time of day:** Twice-daily (AM and PM) application was used clinically; the morning application is paired with sunscreen. No strong circadian preference has been established beyond this.

* **Half-life consideration:** Orally, dihydromyricetin has a short plasma half-life (~2–4 hours) and poor bioavailability; topically, the relevant variable is residence and penetration at the skin rather than systemic half-life, which is why a leave-on, twice-daily format is used rather than a brief rinse-off.

* **Single vs. split dosing:** For topical use, the "split" equivalent is twice-daily application; for oral supplement use, divided daily doses are typical given the short half-life, though oral dosing is not the skin-rejuvenation route of choice.

* **Genetic polymorphisms:** No validated pharmacogenetic markers (e.g., affecting DNMT activity or flavonoid metabolism) have been established to guide dihydromyricetin dose or response for skin; this is an open area.

* **Sex-based differences:** No sex-specific dosing differences have been demonstrated for topical skin use.

* **Age considerations:** Older individuals with thinner, drier skin may benefit from slower introduction and richer co-formulation; the clinical cohort spanned a broad adult age range without separate dosing by age.

* **Baseline biomarkers:** No blood biomarker guides topical dosing; the relevant "baseline" is the skin's own measured biological (methylation) age, which is a research tool rather than a routine clinical test.

* **Pre-existing conditions:** Those with sensitive-skin conditions should adopt the low-and-slow titration described in Risk Mitigation; active dermatitis is a reason to defer.

## Discontinuation & Cycling

* **Lifelong vs. short-term:** Skin rejuvenation from dihydromyricetin is presented as an ongoing cosmetic regimen rather than a fixed course; because skin continually re-accumulates age-related methylation and photodamage, benefits are expected to depend on continued use, with regression likely after stopping.

* **Withdrawal effects:** No physiological withdrawal effects are known or expected from discontinuing a topical dihydromyricetin serum; the main consequence is gradual loss of the cosmetic benefit.

* **Tapering:** No tapering protocol is needed; the product can be stopped abruptly without rebound, aside from the slow return toward baseline appearance.

* **Cycling:** There is no established evidence that cycling improves or maintains efficacy. Continuous use (as studied) is the described approach, though some users cycle actives empirically to reduce irritation rather than to preserve effect.

* **Practical note:** Because durability of the epigenetic benefit beyond 8 weeks and after cessation has not been formally studied, expectations about how long results persist off-product should remain tentative.

## Sourcing and Quality

* **Purity and standardization:** Look for products specifying dihydromyricetin (or ampelopsin/Epicelline) content and a defined purity (high-grade extracts are often standardized to ≥98% dihydromyricetin); vine tea-derived extracts vary widely in actual content.

* **Delivery system matters:** Because raw dihydromyricetin penetrates skin poorly, prefer formulations that address bioavailability (encapsulation, nanoemulsions, or paired penetration enhancers) rather than products merely listing the ingredient.

* **Third-party testing:** For supplements, choose brands that provide third-party testing and a certificate of analysis confirming identity, potency, and absence of heavy metals or solvent residues from extraction; for cosmetics, look for stability and contaminant testing.

* **Reputable sources:** The clinically studied topical is the Eucerin (Beiersdorf) epigenetic serum line; for oral supplement-grade dihydromyricetin, brands offering third-party-tested, high-purity extracts (e.g., Double Wood, SuperSmart) are commonly cited, though these are oral products not validated for skin outcomes.

* **Storage and stability:** Choose opaque, air-limiting packaging, since flavonoid antioxidants degrade with light and air exposure, reducing the active content over a product's shelf life.

## Practical Considerations

* **Time to effect:** Clinical improvements in roughness and wrinkles were measured by 8 weeks, with the manufacturer reporting some visible change by 4 weeks; biological-age and tone effects are gradual, so several weeks of consistent use are needed before judging results.

* **Common pitfalls:** Expecting rapid, dramatic change; using under-formulated products where the ingredient cannot penetrate; skipping sunscreen (which undermines the benefit); over-layering with other irritating actives; and inferring that oral supplements (studied for liver/metabolic uses) deliver the same skin effects as the topical.

* **Regulatory status:** As a topical cosmetic ingredient, dihydromyricetin is sold over the counter and is not a regulated drug; cosmetic anti-aging claims are not FDA-evaluated as drug claims. As an oral supplement it is sold as a dietary supplement, again without FDA approval for efficacy.

* **Cost and accessibility:** Branded epigenetic serums are moderately priced premium skincare, generally accessible without prescription; raw dihydromyricetin supplements are inexpensive but are not skin-validated. Neither is exceptionally costly or hard to obtain.

* **Realistic framing:** The most defensible expectation is incremental improvement in skin texture, tone, and visible aging with consistent multi-week use, rather than a one-time transformation.

## Interaction with Foundational Habits

* **Sleep:** The interaction with sleep is **indirect**. Topical dihydromyricetin is not known to affect sleep, but poor sleep accelerates skin aging and oxidative stress, which work against the compound's benefits; orally, dihydromyricetin has been studied for effects on alcohol metabolism and GABA (gamma-aminobutyric acid, the brain's main calming chemical messenger) signaling, but these do not translate into an established sleep effect for skin users.

* **Nutrition:** The interaction with nutrition is **indirect and potentiating**. A diet low in added sugars reduces the advanced glycation end products that dihydromyricetin counteracts via RAGE inhibition, so the anti-glycation benefit is amplified by lower glycemic intake; a polyphenol- and antioxidant-rich diet aligns with its antioxidant mechanism. Orally, separating it from iron-rich meals or iron supplements avoids reduced iron absorption.

* **Exercise:** The interaction with exercise is **indirect**. Regular exercise improves skin perfusion and may lower systemic inflammation, complementing dihydromyricetin's anti-inflammatory action; there is no evidence it blunts or is blunted by training, and no specific timing relative to workouts is needed for topical skin use.

* **Stress management:** The interaction with stress management is **indirect**. Chronic stress raises cortisol and oxidative load, which degrade collagen and accelerate skin aging — the same processes dihydromyricetin opposes — so stress reduction is complementary; there is no evidence dihydromyricetin itself alters cortisol or the stress response in skin users.

## Monitoring Protocol & Defining Success

Because skin rejuvenation with dihydromyricetin is a cosmetic, topical intervention, formal laboratory monitoring is generally not required for the topical use itself. Baseline assessment is best done by documenting the starting state of the skin, and ongoing assessment is mostly visual and tactile. Where oral supplementation is combined, a few labs become relevant.

Baseline assessment before starting: standardized "before" photographs in consistent lighting, a note of current skin tone evenness, roughness, and any sensitivity, and (optionally, in research settings) a skin biological-age/methylation measurement. For those also taking oral dihydromyricetin, baseline iron studies and liver enzymes are reasonable.

Ongoing monitoring cadence: reassess the skin at roughly 4 weeks and 8 weeks, then every 2–3 months, comparing against baseline photographs; for combined oral use, recheck iron studies and liver enzymes every 6–12 months.

| Biomarker | Optimal Functional Range | Why Measure It? | Context/Notes |
| --- | --- | --- | --- |
| Skin biological (methylation) age | Lower than chronological age | Tracks the targeted epigenetic-rejuvenation effect | Research tool only; not a routine clinical test; relevant to the epigenetic mechanism rather than everyday monitoring |
| Serum ferritin (if oral use) | 50–150 ng/mL | Detects reduced iron status from oral dihydromyricetin's iron-binding | Conventional lower limit (~15–30 ng/mL) is below the functional optimum; fasting not required; pair with transferrin saturation |
| ALT / AST (liver enzymes, if oral use) | ALT <25 U/L; AST <25 U/L (functional) | Confirms liver tolerance with oral supplementation | Conventional upper limits (~40 U/L) are higher than the functional target; best measured fasting |

Qualitative markers of success:

* Smoother skin texture and reduced roughness on touch and in photos
* More even skin tone and fading of dark spots
* Softened appearance of fine lines and wrinkles
* Improved skin firmness or "bounce"
* Absence of irritation, redness, or stinging (a marker of good tolerability)

## Emerging Research

* **Topical clinical evidence (recently published):** [Epigenetic Skin Aging and Its Reversal to Improve Skin Longevity across Ethnicities and Phototypes Using a Dihydromyricetin-Containing Serum: Results from a Prospective, Single-Cohort Study](https://pubmed.ncbi.nlm.nih.gov/42034839/) (Qi et al., 2026) is the pivotal prospective single-cohort study (60 participants, Fitzpatrick I–VI, 8 weeks) reporting reduced epidermal methylation age and visible improvements; it could strengthen the case, but its single-arm, manufacturer-run design means a placebo-controlled replication is the key next step.

* **Mechanistic foundation:** [Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin](https://pubmed.ncbi.nlm.nih.gov/38500495/) (Falckenhayn et al., 2023) established the DNMT1-inhibition mechanism; future work testing whether mild demethylation is durably safe in skin over years could either reinforce or weaken confidence in the approach.

* **Population-scale epigenetic signal:** [Unraveling the complexity of skin's biological aging utilizing epigenetic clocks](https://pubmed.ncbi.nlm.nih.gov/41957838/) (Bienkowska et al., 2026) found, in an 851-participant cohort, that dihydromyricetin is associated with methylation patterns consistent with decelerated skin aging — a strengthening signal — while explicitly cautioning that longitudinal and interventional designs are needed to establish causality.

* **Anti-glycation direction:** [Dihydromyricetin May Attenuate Skin Aging as a RAGE Inhibitor](https://pubmed.ncbi.nlm.nih.gov/40507131/) (Wang et al., 2025) opens a separate mechanistic avenue (AGE-RAGE blockade) that, if confirmed in humans, would broaden the rationale; as a rodent/cell study it currently neither confirms nor refutes a human benefit.

* **Future research areas:** Key open questions that could change current understanding include whether benefits persist beyond 8 weeks and after discontinuation, whether independent placebo-controlled trials reproduce the developer's findings, the long-term safety of chronic skin demethylation, and head-to-head comparison with established actives (retinoids, vitamin C).

* **Clinical-trial registry status:** A search of ClinicalTrials.gov for dihydromyricetin (ampelopsin) returned trials for alcohol-related liver disease ([NCT05623501](https://clinicaltrials.gov/study/NCT05623501)), type 2 diabetes ([NCT03606694](https://clinicaltrials.gov/study/NCT03606694)), and hangover/recovery products ([NCT06575972](https://clinicaltrials.gov/study/NCT06575972)) — but no registered trials targeting skin rejuvenation or photoaging, underscoring that the skin evidence base remains early.

## Conclusion

Dihydromyricetin is a natural plant compound from vine tea, long used as an antioxidant and liver-support agent, that has recently been repurposed as a topical skin-rejuvenation ingredient. Its appeal rests on an unusual mechanism: it gently loosens the chemical aging tags on skin-cell DNA, and it also fights sugar-driven aging, calms oxidative stress, and evens skin tone. The most relevant human evidence — a single early study of a dihydromyricetin serum — found that skin looked and measured younger after two months of twice-daily use, with smoother texture, fewer visible wrinkles, and firmer skin.

The overall quality of the evidence is still modest. The standout human study was uncontrolled, short, and run by the company that makes the product, and much of the supporting work comes from cells and animals. The available human evidence is largely single-source and uncontrolled, and the long-term effects of nudging skin aging this way remain unproven. For someone focused on skin longevity, dihydromyricetin is a promising but early option whose benefits appear real but incremental, depend on good formulation and consistent sun protection, and should be weighed against how preliminary and largely single-source the strongest evidence currently is.

**[Top](#top) - [Benefits](#expected-benefits) - [Risks](#potential-risks--side-effects) - [Protocol](#therapeutic-protocol)**