Herbal formulas used in traditional East Asian medicine have now been compared against standard dementia drugs in a substantial number of randomized trials. Pooled analyses favour them on the cognitive endpoint most often used as a primary measure in Alzheimer’s registration trials, with adverse event rates indistinguishable from active comparators. The trials carry well-documented methodological weaknesses, and the finding is worth examining rather than dismissing on that basis.

Findings

The larger of two recent syntheses pooled 57 randomized controlled trials of herbal medicine in Alzheimer’s disease (Lee et al., 2022). Relative to conventional treatment, herbal medicine improved both the Mini-Mental State Examination and the Alzheimer’s Disease Assessment Scale cognitive subscale. Among trials comparing herbal medicine directly against donepezil, the agent most widely prescribed for the condition, MMSE scores were equivalent and ADAS-cog scores favoured the herbal arm. Given as an adjunct rather than a substitute, herbal medicine improved both scales beyond conventional treatment alone and lowered plasma amyloid beta.

A second synthesis covering 23 trials and approximately 2,000 patients reported a standardized mean difference of −0.22 on ADAS-cog favouring herbal treatment, together with a benefit on the Hasegawa Dementia Scale (Wang et al., 2025). Adverse event rates did not differ between arms, and heterogeneity on that outcome was zero, the only such value in either analysis.

The ADAS-cog result is the most durable finding in this literature. It appears independently in both syntheses and survives direct comparison against active drug rather than placebo. ADAS-cog is the more sensitive of the two instruments in common use and the one generally preferred as a primary endpoint in Alzheimer’s trials, which lends the convergence some weight.

Two endpoints showed no benefit. MMSE improved in the larger synthesis but not in the smaller one. Behavioural and psychological symptoms, assessed by the Neuropsychiatric Inventory, did not differ from placebo. Cognitive and behavioural domains in dementia respond to different mechanisms and dissociate routinely in trials of approved agents, so a cognitive signal unaccompanied by a behavioural one is an ordinary pattern rather than an internal inconsistency.

Why dementia tests the multi-target hypothesis

The plausibility of these results rests on what kind of disease dementia is. Alzheimer’s disease involves amyloid deposition and tau pathology alongside chronic neuroinflammation, cerebrovascular insufficiency, mitochondrial dysfunction, impaired synaptic maintenance and the accumulation of senescent cells. Several of these processes are also hallmarks of biological aging, which places age-related cognitive decline within aging biology rather than beside it.

Agents directed at single nodes within that network have produced limited clinical benefit. Cholinesterase inhibitors and memantine yield small, temporary symptomatic effects without altering disease course. Anti-amyloid monoclonal antibodies, developed over decades of work on one hypothesis, slow decline by margins that remain contested in clinical significance and carry amyloid-related imaging abnormalities as a recognized risk.

Multi-target interventions have a structural rationale under these conditions. Traditional East Asian medicine has produced such interventions empirically for roughly two millennia, selecting and refining multi-herb formulas by observed response. The trials summarized above represent the first substantial attempt to evaluate that inheritance against modern comparators.

Pharmacological basis

The case for multi-herb formulas is usually made by observing that they contain many compounds acting on many targets. Stated that way the claim carries little information, since the same is true of most foods. Two distinctions make it testable.

Pharmacokinetic against pharmacodynamic synergy. Interactions between constituents of a formula frequently concern absorption and clearance rather than target biology. One compound inhibits the enzyme that metabolizes another, and systemic exposure to the second rises accordingly. The Alzheimer’s formula Bushen-Yizhi provides a well-characterized example. Screening its constituents for CYP3A4 inhibition identified four active compounds, of which a Schisandra lignan proved the most potent, with an IC50 of 0.339 µM. In rats, administration of the whole formula raised the area under the curve for osthole, its principal active constituent, from 228 to 2,196 ng/L·h, an approximately tenfold increase. The isolated lignan achieved 1,053, while ketoconazole, a clinical CYP3A4 inhibitor used as a positive control, reached only 463 (Liu et al., 2022).

The classical framework anticipated this category of interaction. Formula construction in traditional practice assigns constituent herbs to four roles, the fourth of which, conventionally translated as envoy, denotes the herb that directs the others to their site of action. A system with no concept of hepatic metabolism nonetheless reserved a functional position for delivery.

Characterized against uncharacterized polypharmacology. Dasatinib engages dozens of kinases, as does a decoction. The two differ in documentation rather than in promiscuity. Dasatinib’s target profile has been mapped across the kinome at known affinities and known dose, and several of its adverse effects are attributable to specific off-target activity. A decoction engages a comparably broad target range at unknown occupancies from a dose that varies between batches. The limitation of traditional formulas lies in characterization, and that limitation is tractable.

Summary of endpoints

Taken together, the evidence supports a modest cognitive benefit on the more sensitive of the two standard instruments, in Chinese trial populations, with a safety profile comparable to approved agents. It does not support benefit for behavioural symptoms or daily function.

Two methodological cautions

Two observations from our own work on senescence-targeting formulations bear on how evidence of this kind should be read.

The first concerns transcriptional readouts. A published approach proposed identifying natural substitutes for a synthetic senolytic by matching gene-expression signatures. Reproducing that logic, the compounds under evaluation failed to rank, which initially appeared to be a negative result about the compounds. The better interpretation is that the readout was mismatched to the endpoint. Senolysis proceeds through protein-level machinery already present in the cell and does not require a distinctive transcriptional program, while bulk transcriptomics systematically loses the dying subpopulation it is meant to detect. Gene expression remains well suited to measuring suppression of inflammatory signalling, which genuinely is transcriptional. The same caution applies to network-pharmacology analyses of traditional formulas, where a map of converging targets constitutes a mechanistic hypothesis rather than evidence of effect.

The second concerns exposure. Quercetin, fisetin and curcumin all engage relevant targets in vitro at concentrations that human plasma does not reach following oral administration. Target engagement established in cell culture should therefore be filtered by achievable systemic exposure before a compound advances. This constraint applies with particular force to decoctions, which deliver variable doses of multiple poorly absorbed constituents, and it is the reason the osthole pharmacokinetic result described above carries weight: a tenfold increase in exposure represents substantive pharmacological work.

Limitations

The trials supporting these findings are methodologically weak, and the weaknesses are consistent across both syntheses. In the 2025 analysis, 15 of 23 trials scored 3 or below on a 7-point quality scale. Ten described their randomization procedure adequately. Nineteen reported a random-number method without establishing that allocation was concealed from enrolling investigators. Blinding was seldom reported and only two trials employed a placebo. Heterogeneity reached 81 percent on MMSE and 94 percent on the Hasegawa scale, levels at which pooled estimates become difficult to interpret. All participants were recruited in China, so generalization to other populations is untested. Publication bias cannot be excluded: the authors report none overall, though their test on the headline effectiveness measure falls close to the conventional threshold, and a literature composed largely of small trials carries that risk independent of any single statistic. The 2022 authors state directly that concrete conclusions cannot be drawn from their inputs. These limitations constrain the confidence attachable to the effect size; they do not explain away a result that replicates across two independent pools of trials against an active comparator, and they are addressable by better trial conduct rather than inherent to the subject.

What would settle the question

Four changes in trial design would convert this from a promising signal into a decided question.

1. Blinded, placebo-controlled trials. Two of 23 trials used a placebo. Matching the appearance and taste of a decoction is genuinely difficult, which partly explains the omission, though encapsulated standardized extracts remove most of that difficulty.
2. Concealed allocation, documented. The least expensive correction available and the most consistently omitted. Nineteen trials described randomization without establishing that allocation was hidden from enrolling investigators.
3. One standardized formula tested repeatedly. Much of the heterogeneity that makes pooling unreliable arises because each trial evaluates a different preparation. A single characterized formula with quantified marker compounds, examined across several independent centres, would yield evidence that can legitimately be combined.
4. Replication outside China. An effect observed only within one country’s trial system remains a finding about that trial system until demonstrated elsewhere.

None of this requires methodological innovation. It requires the standard apparatus of clinical research applied to a subject that has largely been studied without it. The obstacle is economic rather than scientific, since an unpatentable formula seldom attracts funding sufficient for a definitive trial. That explains why the evidence is thin without making thin evidence stronger than it is.

Sources

• Lee J, Kwon S, Jin C, et al. Traditional East Asian Herbal Medicine Treatment for Alzheimer’s Disease: A Systematic Review and Meta-Analysis. Pharmaceuticals 2022;15(2):174.
• Wang Q, Wang D-L, Zhang X-C, et al. Efficacy and safety of traditional Chinese medicine and Western medicine in Alzheimer’s disease: a systematic review and meta-analysis. Frontiers in Neurology 2025;16:1607945.
• Liu JM, Chen JM, Lin MJ, et al. Screening and verification of CYP3A4 inhibitors from Bushen-Yizhi formula to enhance the bioavailability of osthole in rat plasma. Journal of Ethnopharmacology 2022;282:114643.
• Jiang W, Tang M, Yang L, et al. Analgesic Alkaloids Derived From Traditional Chinese Medicine in Pain Management. Frontiers in Pharmacology 2022;13:851508.
• Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015;14(4):644–658.
• Meiners F, Hinz B, Boeckmann L, et al. Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data. Scientific Reports 2024;14:6286.

These statements have not been evaluated by the Food and Drug Administration. Nothing here is intended to diagnose, treat, cure or prevent any disease, and nothing here is medical advice. Dementia is a serious condition that warrants care from a qualified clinician.

The seeds of a West African legume concentrate a single active compound to 20 percent of their weight, and that compound enters serotonin synthesis at the one point the body does not throttle. Among everything sold without a prescription, very little has pharmacology this direct.

What makes 5-HTP unusual

Most supplements are plant extracts in which the active fraction is a small percentage of the material, often under one percent, and frequently a mixture rather than a single compound. Griffonia simplicifolia, a climbing legume from the forests of West Africa, concentrates 5-hydroxytryptophan in its seeds at 6 to 20 percent of wet weight (Cunningham et al., 2021). The market has never needed a synthetic route for it, because the plant outperforms one.

The second unusual property is what the compound does once absorbed. Serotonin is built from the amino acid tryptophan in two steps, and the body regulates the first one tightly. Tryptophan hydroxylase is rate limiting, and the tryptophan reaching it is continually diverted into the kynurenine pathway by two other enzymes. Supplementing tryptophan therefore means pushing against a throttle the body controls. 5-HTP arrives on the far side of it (Turner et al., 2006). It also crosses into the brain without competing against the other large neutral amino acids for transport, which is why a protein-containing meal blunts tryptophan and does not blunt 5-HTP.

Third, and rarest of all in this field, the effect has been measured in people. In a trial across thirteen hospitals, 166 participants taking 100 mg twice daily showed serum 5-HTP higher by an estimated 52.66 ng/mL and serum serotonin higher by 3.0 ng/mL against placebo, both at p < 0.001 (Truyens et al., 2022). Most natural compounds are sold on mechanism inferred from cell culture. This one has been shown to reach circulation and convert, at a margin that leaves no room for argument.

Who it suits

5-HTP is for adults looking to support mood, appetite regulation and sleep onset through the serotonin pathway rather than through stimulants or sedatives. It suits people who find their appetite hardest to manage in the evening or who crave carbohydrate specifically, since that is the pattern the satiety research describes. It suits people interested in the serotonin system as it changes with age, for the reasons set out further down.

One group should not take it without speaking to a prescriber first. 5-HTP increases serotonin synthesis, so it adds to anything else doing the same, and this is the one caution on this compound that genuinely warrants space. Anyone taking an SSRI, SNRI, MAO inhibitor, tricyclic antidepressant, tramadol, dextromethorphan, linezolid, lithium or a triptan should clear it with their doctor before starting, and the combination with an MAO inhibitor should be avoided. That interaction exists precisely because the compound is pharmacologically active, which is the same reason the rest of this page is worth reading.

What it is known to do

Where 5-HTP has been tested in randomized, placebo-controlled trials against the outcomes people actually buy it for, the results have generally favoured it.

The satiety result is the one people underestimate. Early satiety and a specific reduction in carbohydrate intake, achieved without a stimulant and without appetite suppression of the jittery kind, is an unusual pharmacological profile, and it was reproduced across two consecutive study periods in the same cohort.

Sleep is the other common reason people reach for it. Serotonin is the direct precursor to melatonin, so supporting serotonin synthesis in the evening supplies the substrate for the body’s own melatonin production, which is a different approach from taking melatonin itself and overriding the signal.

How it does it

The two-step pathway runs tryptophan, then 5-HTP, then serotonin. The second step is catalysed by aromatic L-amino acid decarboxylase, an enzyme that uses pyridoxal 5′-phosphate, the active form of vitamin B6, as its cofactor. Patients with inherited disorders of B6 metabolism show reduced activity of this enzyme, and B6-deficient human cells show reduced enzyme activity and protein (Allen et al., 2010). Adequate B6 status is the nutritional input that matters for making the conversion efficiently.

Serotonin made this way acts on the full range of serotonergic targets, which is why the reported effects span mood, appetite and sleep rather than sitting in one category. Melatonin synthesis follows from serotonin through two further enzymatic steps in the pineal gland, which places sleep downstream of the same pathway.

How this relates to aging

The serotonin system is one of the first to decline. Serotonin transporter binding falls roughly 10 percent per decade in the thalamus and midbrain of healthy men across the adult lifespan (Yamamoto et al., 2002). In Down syndrome, where Alzheimer’s pathology develops on a predictable schedule and can therefore be studied at every stage, tau pathology appears in the dorsal raphe nucleus, the origin of the brain’s serotonergic projections, early enough that it may predate the entorhinal and hippocampal changes or coincide with them (Davidson et al., 2018).

That decline tracks real consequences. Among 28 people with mild cognitive impairment and 28 matched controls, serotonin transporter loss was larger and more widespread than grey matter atrophy or reduced blood flow measured in the same participants, and lower cortical binding went with worse verbal and spatial memory (Smith et al., 2017). Serotonergic signalling also appears to act on the pathology itself: raising synaptic serotonin with citalopram arrested the growth of existing amyloid plaques and cut new plaque formation by 78 percent in transgenic mice, and slowed cerebrospinal amyloid-beta production by 37 percent in healthy human volunteers (Sheline et al., 2014).

Serotonergic tone is therefore not a peripheral detail of brain aging. It is an early-affected system with measurable links to memory performance and to amyloid handling, and supporting the substrate for its synthesis is a rational thing to be interested in as that system changes.

Sourcing and testing

Griffonia seeds are wild harvested rather than cultivated. Five West African countries export them, extraction is now concentrated in China, and roughly 48 percent of the finished material is exported onward to North America (Cunningham et al., 2021). A wild-harvested botanical moving through a chain of that length varies from lot to lot, which is why we run identity and impurity testing on incoming material rather than accepting a supplier certificate of analysis. No confirmed case of toxicity from 5-HTP has been established across decades of widespread use.

Our 5-HTP

MDS Labs supplies 5-HTP at 200 mg per serving, 60 capsules per bottle, available on our shop. The randomized trials behind the uses above are small and several are decades old, and no trial has yet tested 5-HTP against a direct measure of biological aging. Readers interested in how we appraise evidence may find our other research articles useful.

These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. Consult a healthcare professional before use, particularly if you take prescription medication.

Research suggests that fisetin has strong senolytic activity, which means it can selectively induce the death of senescent cells. Senescent cells are damaged cells that cease to divide but do not die as they should. They release inflammatory factors that lead to tissue dysfunction and age-related diseases, and subsequently, play a major role in the aging process. By clearing these cells, clearing these cells reduced inflammation and improved tissue function in animal models, with effects on lifespan reported in mice.

A 2018 study [1] set out to test ten flavonoids for their senolytic properties. The study acknowledged that the combination of Dasatinib, (when combined with the flavonoid quercetin) is a potent senolytic, improving numerous age-related conditions including frailty, osteoporosis, and cardiovascular disease. However, the goal of this study was to identify natural flavinoids with even more potent senolytic activity.

The study examined critical connectivity tissue (human fibroblasts) that had become senescent from oxidative and genotoxic stress. They further tested the flavinoids on mice, evaluating age-related histopathology, disease markers, health span and lifespan.

Of the 10 flavonoids tested, fisetin was the most potent senolytic. When they treated the old mice. Fisetin reduced senescent markers in multiple tissues, consistent with a hit-and-run senolytic treatment like Dasatinib + Quercetin. It was determined that fisetin demonstrates senotherapeutic activity in both human and mice tissue. In mice, it was found that fisetin restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.

Additionally, fisetin is known for its antioxidant properties. It combats oxidative stress, a key contributor to aging and chronic disease, by neutralizing free radicals and reducing oxidative damage. Antioxidant activity of this kind has been studied in relation to aging and cognitive function, though these remain preclinical findings.

Fisetin has been reported to act on AMPK, MAPK and mTOR signalling while also inhibiting CDK1, and CDK4 kinase enzymes. [4] A 2015 study indicated that AMPK activation can delay aging [2], while a 2019 study demonstrated mTOR inhibition has profound effects on life span and age-associated phenotypes across a wide array of organisms. [3]

Natural senolytic supplements are widely available, but notably, NEUROmergence®, which contains fisetin, is formulated with seven additional compounds thought to have the ability to affect similar pathways as Dasatinib. NEUROmergence® also contains quercetin to further align the formulation to D+Q.

1. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PMID: 30279143; PMCID: PMC6197652. https://pubmed.ncbi.nlm.nih.gov/30279143/

2. Stancu AL. AMPK activation can delay aging. Discoveries (Craiova). 2015 Dec 31;3(4):e53. doi: 10.15190/d.2015.45. PMID: 32309575; PMCID: PMC6941559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941559/

3. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette FA, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res. 2019 Jul 2;8:F1000 Faculty Rev-998. doi: 10.12688/f1000research.17196.1. PMID: 31316753; PMCID: PMC6611156.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611156/

4. Baier A, Szyszka R. Compounds from Natural Sources as Protein Kinase Inhibitors. Biomolecules. 2020 Nov 12;10(11):1546. doi: 10.3390/biom10111546. PMID: 33198400; PMCID: PMC7698043. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698043/

Update, November 2026

Two things have changed since this article was written, and they point in opposite directions.

The rodent evidence has strengthened. A 2025 study in Aging Cell tested intermittent oral fisetin, one week on and two weeks off, in old mice and reported improved frailty scores and grip strength, with RNA sequencing of skeletal muscle identifying the senescence-related pathways involved. The study benchmarked fisetin against two established methods of removing senescent cells, including genetic clearance in a transgenic model, which is a more demanding comparison than most natural-compound work attempts (Murray et al., 2025).

Human efficacy evidence remains absent. Randomized trials in people are underway rather than reported. One registered triple-blind placebo-controlled trial is giving 100 mg of fisetin daily for seven weeks to adults aged 50 and over, with a circulating inflammation marker as its primary endpoint, and its protocol was published in 2026 (Tavenier et al., 2026). Notably, that trial uses 100 mg daily, far below the intermittent high-dose regimens discussed in the senolytic literature.

The accurate position is therefore narrower than this article originally implied. Fisetin has replicated, mechanistically characterized senolytic activity in mice, benchmarked against genetic controls. Whether any of that transfers to humans is an open question that the running trials are designed to answer, and no published randomized trial has yet demonstrated a clinical benefit in people.