Launch — Access limited to 250 Members to ensure personalized follow-up quality.
The three selection filtersInsufficient bioavailability: the first wallInsufficient human clinical evidence: the second filterUnfavorable benefit/risk ratio: the third filterWhat science will illuminate nextFrequently asked questions

What We Chose Not to Include, and Why

By The Scientific Editorial TeamEditorial policyMarch 11, 2026Updated on August 5, 202636 min read
Row of botanical extracts in petri dishes swept away by a beam of light, only a few remaining

Every molecule that applies for inclusion in our formulas passes through the same evaluation framework. Some do not make it through, not because they lack scientific interest, but because scientific interest alone is not sufficient justification for a formula intended for a human being.

Selecting a bioactive is an act of rigor, not an act of marketing. The supplement market operates on an inverse logic: popularity often precedes evidence. Molecules present in countless products have never demonstrated robust human clinical efficacy. Some carry risk signals that the industry consistently minimizes.

This article is an inventory of what we have chosen not to include, organized by reason for exclusion.

Insufficient bioavailability:

Insufficient clinical evidence or incompatible modality:

Unfavorable benefit/risk ratio:

The three selection filters

Before entering a precision formula, a bioactive must clear three successive barriers.

The first filter is documented bioavailability. A molecule with remarkable laboratory properties produces no effect if it cannot reach its biological target in active form after oral ingestion. Pharmacokinetics (what happens to a molecule once ingested: absorption, transformation, distribution, elimination) is often the first point of failure.

The second filter is human clinical evidence, required at a level proportionate to the bioactive's class and the claimed use. A biomarker establishes benefit only when it is a validated surrogate for the intended conclusion. A biochemical change confirming target engagement is therefore insufficient on its own. Animal and mechanistic data can support the file without replacing this human evidence floor.

The third filter is a favorable benefit/risk ratio. Even an effective molecule can be excluded if its documented adverse effects create a risk signal that outweighs the expected benefit, particularly in unselected populations.

The filters are sequential: a candidate that fails the first does not proceed to the next two; if it fails the second, the third is not applicable.

Insufficient bioavailability: the first wall

Green tea EGCG

Epigallocatechin gallate (EGCG, the primary polyphenol in green tea) has accumulated preclinical data on inflammation, metabolism, and neuroprotection. Its oral bioavailability ranges from approximately 2 to 13%, depending on the individual and dietary conditions (PubMed).

This degree of variability is problematic for a precision formula. It makes real systemic exposure unpredictable. Added to this are documented drug interactions with anticoagulants (warfarin) and drugs transported by P-glycoprotein (a cellular transporter that regulates the absorption of many molecules).

Green tea also contains L-theanine, an amino acid whose plasma exposure rises in proportion to the dose and which the delivery matrix does not alter (PubMed), and whose human clinical literature is substantial. It is possible to extract the documented benefit of a plant without carrying along its pharmacokinetic limitations.

Oral glutathione

Glutathione is the body's primary intracellular antioxidant. Supplementing it directly via the oral route seems logical. It runs into a fundamental biochemical obstacle: gastrointestinal peptidases (digestive enzymes) break down the tripeptide glutathione (composed of three amino acids: glycine, cysteine, and glutamic acid) before it reaches the bloodstream (PubMed).

N-acetylcysteine (NAC), a direct precursor of glutathione, is absorbed by the oral route and has a substantial human clinical literature. This is a rational substitution: when the direct target is inaccessible, the precursor with a documented pathway is selected.

Pterostilbene

Pterostilbene is a stilbenoid structurally similar to resveratrol but with two methoxy groups replacing the hydroxy groups. This structural difference confers higher oral bioavailability (approximately 80% in some animal models) (PubMed). Human pharmacokinetic data remain limited, however, and controlled clinical trials on primary health outcomes are still insufficient to justify formulation. A molecule to watch.

Insufficient human clinical evidence: the second filter

A molecule can clear the first wall, be adequately absorbed, and still remain outside a precision formula. Either because the human evidence remains immature. Or because its relevant mode of use is not sustained daily oral intake. Quercetin and fisetin illustrate this second case.

Quercetin and fisetin

Quercetin is one of the best-selling antioxidants in the world. The long-held reading of an "inactive" quercetin held back by poor bioavailability is now outdated. It belongs to a different logic than absorption.

First factual point: quercetin is adequately absorbed. In volunteers, measured absorption ranges from 17% for the rutinoside to 52% for onion glucosides, with the aglycone at 24% (PubMed). Its circulating glucuronidated metabolites are not a dead end: they are deconjugated into active aglycone directly at the tissue site, through the action of β-glucuronidase, in inflammatory macrophages (PubMed) as well as at the vascular wall, where the vasodilation observed after oral intake correlates with this deconjugation (PubMed). Oral supplementation, from 500 mg per day, measurably lowers blood pressure (PubMed) and C-reactive protein (PubMed) in randomized human trials. The bioavailability argument therefore does not hold.

The real reason for exclusion lies in the modality. Quercetin's most-studied longevity lever is senolytic: the selective elimination of senescent cells (aged cells that stop dividing but persist in tissues, secreting an inflammatory cocktail). Yet this mechanism operates through short, intermittent pulses, the "hit-and-run" paradigm: in the first human trial, three days of an oral protocol combining dasatinib and quercetin were enough to reduce the senescent cell burden, with no chronic exposure (PubMed). By construction, this intermittent modality sits outside the canon of a formula designed for sustained daily intake. Added to this is a pharmacological caution: quercetin inhibits CYP3A4 and P-glycoprotein, an interaction profile that calls for prudence in polymedicated individuals.

Fisetin follows the same senolytic logic. In 2018, it was identified as the most potent senolytic flavonoid among ten flavonoids tested, extending the median and maximum lifespan of aged mice (PubMed). But its human record amounts to a handful of small pilot studies. The human clinical evidence remains immature, and the relevant mode of use is, here again, intermittent rather than daily. Neither molecule therefore enters the daily oral canon: not for lack of absorption, but because their relevant use belongs to a logic different from that of a precision formula taken regularly.

Trehalose

Trehalose offers the cleanest case of this first filter: a molecule that never reaches the bloodstream intact.

This disaccharide of two glucose units owes its reputation to a remarkable physico-chemical property. Under dehydration it forms a glassy matrix that preserves the conformation of proteins, a property used in biotechnology to stabilise vaccines and enzymes without a cold chain. From this arose a hypothesis of autophagy induction, long repeated in the longevity field.

The obstacle is enzymatic and it is absolute. Trehalase, an enzyme of the small-intestine brush border, hydrolyses the molecule into two glucoses before any absorption. What rises in the blood is glucose. Two facts corroborate this almost to excess: research had to engineer analogues resistant to that enzyme in order to bypass the degradation, and the entire therapeutic development of the hypothesis went through the intravenous route.

The hypothesis is moreover not merely undemonstrated: it has been tested and disproved. A phase 2/3 trial in 325 participants by the intravenous route concludes to the absence of any effect, with an excess of serious adverse events (PubMed). The only oral trial that looked for a change in autophagy markers, at 4 g per day over six months, found none (PubMed).

A final word on the "microbiota" promise sometimes advanced: no human trial has ever measured gut microbiota composition under oral trehalose, neither on PubMed nor among registered trials.

Boron

Astragaloside IV and TA-65

Astragaloside IV (the primary saponin from astragalus root) is presented in certain circles as a telomerase activator (the enzyme that lengthens telomeres, the protective ends of chromosomes). TA-65, its patented derivative, sells for several thousand euros per year.

The literature is unambiguous: no randomized clinical trial has demonstrated measurable benefit on longevity, telomere length, or any other primary health outcome in humans. Available studies are observational or trials without robust control groups (PubMed). The mechanistic hypothesis is interesting. The clinical proof is absent.

0
Randomized clinical trials

No randomized controlled clinical trial has demonstrated a benefit of astragaloside IV on a primary health outcome in humans to date.

Ergothioneine

Ergothioneine is a sulfur-containing amino acid found in mushrooms and certain microorganisms. It is actively absorbed via a specific transporter and accumulates in tissues with high oxidative demand. Epidemiological data show a correlation between plasma ergothioneine levels and reduced all-cause mortality (PubMed).

Correlation is not causation. These observational studies cannot distinguish whether ergothioneine actively protects or whether it is simply a marker of a diet rich in vegetables and mushrooms. Controlled intervention trials in humans are essentially absent. A molecule to monitor, not to formulate.

Apigenin

Apigenin is a flavone found in parsley, chamomile, and celery. Preclinical data on neuroprotection and circadian rhythm modulation (the 24-hour biological clock) are promising. In vitro studies also suggest activity on the CD38/NAD+ axis (a NAD+ degradation pathway, where NAD+ is the central coenzyme of cellular energy metabolism).

Controlled human clinical trials are virtually nonexistent. The biohacking community has preceded clinical validation by several years. This gap between preclinical enthusiasm and clinical proof is a pattern we know well.

Acetyl-L-carnitine

Acetyl-L-carnitine (ALCAR) is a form of carnitine that crosses the blood-brain barrier (the biological boundary protecting the brain) and shows neuroprotective effects in animal models. Meta-analyses of human clinical trials show heterogeneous results. A Cochrane review published in 2003 concluded that a possible benefit on cognition in patients with mild cognitive impairment was present, but highlighted the poor methodological quality of available studies (PubMed).

In healthy subjects without documented cognitive impairment, the evidence is insufficient. A signal exists in certain pathological populations. It does not justify a general-public formulation.

Coenzyme Q10 (ubiquinone and ubiquinol)

Coenzyme Q10 is a cofactor of the mitochondrial respiratory chain (the cellular system that converts nutrients into energy as ATP). It exists in two interconvertible forms: ubiquinone (oxidized) and ubiquinol (reduced, biologically active). Endogenous production declines from around age twenty, an argument routinely used by the industry to justify supplementation.

The most robust clinical trial is Q-SYMBIO: 420 patients with severe heart failure, 300 mg/day for two years, significant reduction in cardiovascular mortality (PubMed). A solid result. But this is a treatment trial for advanced cardiovascular disease, not a demonstration of longevity benefit.

The KiSel-10 study, frequently cited in the anti-aging context, combined CoQ10 (200 mg) and selenium (200 µg) in elderly Swedish subjects. Cardiovascular mortality was halved after twelve years of follow-up (PubMed). However, the study population lived in a region with selenium-poor soils, and selenium deficiency itself is associated with cardiovascular mortality. The effect of selenium alone cannot be separated from that of CoQ10. This confounder is systematically omitted by supplementation advocates.

In healthy adults, no randomized trial has measured a longevity benefit. Systematic reviews conclude that there is insufficient evidence to recommend CoQ10 as an anti-aging therapy (PubMed). A paradox from animal models further complicates the picture: organisms carrying partial CoQ10 biosynthesis deficiencies live longer, likely through mitohormesis (moderate mitochondrial stress triggering protective adaptive responses). If partial deficiency extends lifespan, the rationale for systematic supplementation becomes hard to defend.

One final note: the marketing distinction between ubiquinol ("the active form") and ubiquinone is fragile. The body converts both forms in both directions. Galenic formulation quality influences bioavailability more than the choice of chemical form (PubMed).

Ca-AKG (calcium alpha-ketoglutarate)

Alpha-ketoglutarate is a central intermediate of the Krebs cycle and the obligate co-substrate of the enzymes that regulate epigenetics. The mechanistic file is impeccable, which is what makes its case instructive.

A study published in 2020 reported lifespan extension and morbidity compression in mice (PubMed). It is what launched the molecule onto the longevity market. The Interventions Testing Program of the National Institute on Aging retested the compound at the exact dose of that study, in genetically heterogeneous mice, across three centres and at two starting ages. No lifespan extension, in males or in females (PubMed).

The positive study this replication contradicts is single-centre, restricted to females for survival, and co-funded by the company that sells the product. On the human side, the only double-blind randomised trial rests on a bone-remodelling marker, at six times the dose of common supplements, and has never been replicated in nineteen years (PubMed). Animal data, whether positive or negative, are not sufficient to clear our second filter. The cited human trial uses an intermediate bone-remodelling endpoint that is not validated as a surrogate for the claimed benefit; it therefore does not document the clinical or functional benefit required to justify inclusion.

Reishi (Ganoderma lucidum)

Reishi holds a particular position on this list: its human evidence is not absent, it is abundant and weak. The distinction is worth stating, because it recurs often in the supplement field.

A meta-analysis conducted under the GRADE framework in 2025 assembled seventeen randomised trials and 971 participants, across doses from 200 to 11,200 mg per day. It concludes to "very low" certainty on every endpoint, notes that sixteen of the seventeen trials are of insufficient quality, and finds no effect on high-sensitivity C-reactive protein, TNF-alpha, the lipid profile or glycaemia (PubMed). For the intended use, this corpus therefore does not establish a relevant clinical or functional benefit; the cited biomarkers are not, on their own, validated surrogate endpoints.

The most favourable trial also illustrates a formulation pitfall that reaches well beyond reishi. It administered a purified isolate titrated at 75 percent beta-glucan, not a fruiting-body extract, and its funder is tied to the manufacturer of the tested product (PubMed). The activity of these polysaccharides depends on molecular weight, degree of branching and solubility, not on mass alone. Mapping those 200 mg onto the titrated fraction of a crude extract would treat two distinct materials as interchangeable. Equal milligrams do not make equal doses.

Maitake (Grifola frondosa)

Maitake holds a particular place on this list. It is a mushroom that functional mycology often pairs with reishi. The two evidence packages are not equivalent, however, and the cultural proximity of the two species does not stand in for evidence.

This large edible Japanese mushroom, nicknamed “hen of the woods,” concentrates branched high-molecular-weight beta-glucans grouped under the name D-fraction. The preclinical file on immune modulation and glycemic regulation is real, and Japanese mycological tradition has long paired it with reishi.

The human trial presented here is a phase I/II study conducted at the Memorial Sloan-Kettering Cancer Center in 34 patients. It documents a differential modulation of circulating cytokines (the signaling molecules of the immune system) under a polysaccharide extract of Grifola frondosa (PubMed). This is a dose escalation on an immunological marker, in a selected population followed in oncology. On its own, this trial does not establish a relevant clinical or functional benefit for daily intake in healthy adults. Animal longevity data, whether present or absent, do not replace the human evidence base required by the second filter.

A family-level argument is not sufficient either. Mushroom beta-glucans are not interchangeable: their activity depends in particular on the fraction, molecular weight, degree of branching, and solubility. Proximity to reishi therefore does not, on its own, allow its results to be transposed to maitake.

Spermidine

Spermidine is an endogenous polyamine (naturally produced by the body and the gut microbiome) involved in inducing autophagy (the cellular recycling program). Its preclinical record is among the strongest in the field of nutritional longevity. Adding spermidine to the drinking water of mice extended their lifespan and reduced age-related cardiovascular decline (PubMed). In 2024, a study published in Nature Cell Biology showed that spermidine is essential to the mechanism by which fasting triggers autophagy, via hypusination of the eIF5A protein (a post-translational modification conserved from yeast to humans) (PubMed). The Bruneck cohort (829 participants, 20-year follow-up) associates high dietary spermidine intake with a mortality reduction equivalent to 5.7 years of age (PubMed).

Despite these converging signals, human intervention trials do not follow. The SmartAge Phase IIb trial (100 participants, wheat germ extract, 12 months) did not meet its primary endpoint on memory (PubMed). Of the three published randomized trials, two show a positive signal in small samples and the third (the largest and longest) finds no significant effect.

The underlying problem is pharmacokinetic. A randomized controlled study showed that 15 mg/day of spermidine for five days does not raise plasma spermidine levels (PubMed). The molecule is converted to spermine in the gut before reaching systemic circulation. At 40 mg/day for 28 days, circulating polyamine levels barely change. The human body regulates polyamines homeostatically, rendering oral supplementation largely ineffective at tissue-level concentrations.

A recent signal warrants additional caution. A study from Tokyo University of Science published in the Journal of Biological Chemistry in 2025 showed that polyamines activate two distinct pathways depending on cellular context: in healthy cells, they stimulate eIF5A1, which promotes autophagy; in cancer cells, they increase production of eIF5A2, a related protein that facilitates tumor growth (PubMed). This does not prove that spermidine causes cancer in healthy subjects. It establishes that in a pre-existing tumoral context (including undiagnosed tumors), polyamines could fuel progression.

The POLYCAD trial (Aarhus, Denmark), testing 24 mg/day for 48 weeks in 187 coronary patients, is expected to deliver results in 2026. It is the first long-duration, high-dose trial. Its conclusions could alter this assessment.

Nicotinamide riboside (NR)

Nicotinamide riboside clears the bioavailability filter. In an eight-week randomized trial involving 140 overweight but otherwise healthy adults, 100 and 300 mg per day raised whole-blood NAD+ by 22% and 51% after two weeks. These increases were maintained throughout the trial (PubMed).

That result documents exposure and engagement of the NAD+ pathway. It does not demonstrate a functional benefit. At 1,000 mg per day for 21 days in twelve older men, the skeletal-muscle NAD+ metabolome changed without an improvement in mitochondrial bioenergetics or systemic metabolism (PubMed).

A 2026 study reinforces this distinction. Across seven independent human cohorts, whole-blood NAD+ remained stable with age and lifestyle interventions. The authors therefore challenge its use as a biomarker of aging or lifestyle (PubMed). An NR-induced increase is not, on current evidence, a validated surrogate for clinical benefit.

We distinguish engagement of a biological target from evidence of a human benefit. For the evaluated use, 100 to 300 mg per day in the intended general population, NR clears the first filter and fails the second. The third filter opens only after the second has been passed, so it is not applicable here. This decision does not settle the possible value of higher doses in selected pathological populations, which involve different objectives, doses, and monitoring conditions.

Rutin

Rutin is not excluded for lack of exposure. In a six-week randomised trial in 18 healthy women, 500 mg per day increased plasma flavonoids without significantly changing plasma antioxidant status (PubMed). Exposure is documented; the claimed human benefit is not.

A double-blind trial in 50 patients with type 2 diabetes reported improvements in several glycaemic, lipid, and inflammatory markers after three months at 500 mg per day (PubMed). This small pathological population and these endpoints do not establish a benefit from daily longevity supplementation in unselected adults. Rutin therefore stops at filter two; filter three does not open.

Inulin

Inulin clears the first filter through local action in the colon, without needing to be absorbed into the systemic circulation. Its best-established human benefit is specific: in 44 adults with constipation, 12 g per day of chicory inulin for four weeks increased median stool frequency from three to four per week (PubMed). This result supports bowel function in that population; it does not demonstrate a longevity effect.

For the metabolic promise associated with healthy ageing, results remain population-dependent and rely on intermediate endpoints. In 24 adults at risk of type 2 diabetes, 10 g per day for six weeks increased bifidobacteria and reduced HOMA-IR, but did not improve directly measured peripheral insulin sensitivity (PubMed). In a randomised trial of 131 adults, 44 of whom received 15 g per day of inulin for four weeks, a glycaemic signal appeared in the overweight or obese subgroup but not in normal-weight adults (PubMed). These trials do not establish a clinical or functional longevity benefit in unselected adults. Inulin therefore stops at filter two; filter three does not open.

This exclusion concerns inulin as a potential longevity bioactive. Its use as a technological excipient serves a different purpose, based on its formulation properties and without a bioactive longevity claim. The two statuses are not contradictory.

Trimethylglycine (betaine)

Betaine clears the first filter without difficulty. Oral ingestion raises serum betaine within two hours, in proportion to the dose (PubMed). This methyl group donor, present in beetroot, spinach and quinoa, opens a homocysteine remethylation route that does not depend on folate.

Its file stops at a threshold, and that threshold has been measured. In 34 healthy adults receiving 1, then 3, then 6 g per day, plasma homocysteine fell by 10 % and 14 % at the two higher doses; at 1 g, the change reached 1.1 % and did not attain significance (PubMed). A controlled trial in 76 adults places the lowest genuinely active dose at 1.5 g per day, for a 12 % fall after six weeks (PubMed).

Yet the quantity of betaine permitted per day in a food supplement, in France, does not exceed 400 to 500 mg. The dose that carries the effect is three times that ceiling, and the lowest dose tested without result is already two and a half times it. Ordinary dietary intake, 0.5 to 2 g per day, itself exceeds what supplementation allows.

For the use evaluated, namely a supplemental intake capped at 400-500 mg per day in the general adult population, betaine clears the first filter and fails the second. The third does not open. The benefit is real and has been documented for twenty years; it lies beyond what the applicable condition of use permits delivering.

Unfavorable benefit/risk ratio: the third filter

Beta-carotene

Beta-carotene is a precursor of vitamin A found in carrots, spinach, and many multivitamin supplements. Its reputation as a protective antioxidant seemed solid until the publication of two major clinical trials.

The ATBC trial (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study), conducted in 29,000 Finnish smokers, showed an 18% increase in lung cancer incidence in the group supplemented with 20 mg/day of beta-carotene (PubMed). The CARET trial (Beta-Carotene and Retinol Efficacy Trial), conducted in 18,000 smokers and asbestos-exposed workers, confirmed this signal with a 28% increase in lung cancer risk, leading to early termination of the trial (PubMed).

High-dose vitamin A (retinol)

Vitamin A is essential. It is also one of the most hepatotoxic (liver-toxic) vitamins at excessive doses. The review by Penniston and Tanumihardjo published in the American Journal of Clinical Nutrition documents a narrow therapeutic window: intakes exceeding 10,000 IU/day of preformed retinol over the long term carry documented dose-dependent hepatotoxicity and teratogenic risk (toxic to fetal development) (PubMed).

Provitamin A (dietary beta-carotene) does not carry the same risk because conversion to active retinol is regulated by the body. Preformed retinol supplementation at common marketing doses, however, regularly exceeds this safety threshold.

High-dose vitamin E (alpha-tocopherol)

Vitamin E in its alpha-tocopherol form (the most common in supplements) long benefited from an assumed protective status. The meta-analysis by Miller et al., published in the Annals of Internal Medicine in 2005, ended this assumption. Drawing on 135,967 participants from 19 randomized clinical trials, it showed that doses of 400 IU/day or more of alpha-tocopherol were associated with a statistically significant increase in all-cause mortality (PubMed).

The suspected mechanism involves high-dose alpha-tocopherol interfering with other vitamin E isomers (notably gamma-tocopherol), reducing their plasma availability. This is an example of the complexity of interactions between forms of the same nutrient that simplified supplementation protocols overlook.

Alpha-lipoic acid

Alpha-lipoic acid (ALA) is an endogenous liposoluble (fat-soluble) antioxidant involved in mitochondrial metabolism. Its clinical profile is limited by multiple drug interactions: it potentiates the hypoglycemic effect of insulin and oral antidiabetic drugs, and can interfere with levothyroxine (a thyroid hormone treatment).

Cases of autoimmune insulin syndrome (a rare form of hypoglycemia linked to anti-insulin antibodies) have been reported in connection with ALA supplementation, primarily in Asian populations (PubMed). This signal, rare but severe, combined with the heterogeneity of clinical trial results on primary outcomes of interest, leads to its exclusion from a formula intended for an unselected audience.

Ashwagandha (Withania somnifera)

Ashwagandha is the best-selling adaptogen in the world. Randomized clinical trials confirm a significant reduction in serum cortisol and measurable decreases in anxiety scores (PubMed). Short-term anxiolytic efficacy is documented.

The problem lies elsewhere. Ashwagandha acts simultaneously on three neuroendocrine systems: it suppresses the hypothalamic-pituitary-adrenal (HPA) axis (the central stress response system), directly activates GABA-A receptors (the same receptors targeted by benzodiazepines) (PubMed), and modulates serotonergic 5-HT1A receptors through a mechanism shared with SSRI antidepressants.

This triple mechanism produces, in a subset of users on continuous intake, emotional blunting. Not merely a reduction in anxiety: a dampening of the entire emotional spectrum, including positive emotions. Published cases document measurable adrenal hypofunction after 10 weeks of supplementation, reversible upon discontinuation. Clinical trials reveal a telling finding: cortisol decreases significantly and reproducibly, but perceived stress reduction does not always follow (PubMed). The body produces less cortisol. The subject does not necessarily feel better.

No clinical trial has measured emotional blunting using validated instruments. The absence of measurement is not the absence of effect. For a precision formula intended for continuous daily use, the risk of chronic endocrine suppression is a signal we cannot ignore.

Rhodiola rosea

Rhodiola rosea is a Scandinavian and Siberian adaptogen with solid short-term clinical data. Randomized trials show sustained anti-fatigue effects over periods of 4 to 12 weeks (PubMed).

Two problems prevent its inclusion in a precision formula.

The first is the complete absence of data beyond 12 weeks. No study has measured the safety or efficacy of continuous long-term use. Traditional Siberian and Scandinavian usage was seasonal and situational, never daily year-round. Modern practitioners recommend cycling (typically 12 weeks on, 1 to 2 weeks off) (PubMed). This mode of administration is incompatible with a formula designed for regular daily intake.

The second is pharmacological. Rhodiola significantly inhibits monoamine oxidases A and B (MAO, the enzymes that degrade serotonin, dopamine, and norepinephrine) in vitro. This inhibition creates a potential for interactions with serotonergic antidepressants, opioids, and sympathomimetics. The lack of thorough human pharmacokinetic data makes it impossible to reliably model these interactions, even within an individualized health profile.

Berberine

Berberine is the file most thoroughly documented by the agencies on this entire list, and the only one ruled out on a mainly regulatory ground.

This alkaloid holds converging randomised trials on glycaemia and lipids, at doses of 1,000 to 1,500 mg per day in split intakes. France's national food safety agency nonetheless concluded in 2019 that, in the absence of new data, the safety of use of these supplements cannot be guaranteed. It recommends abstention for pregnant and breastfeeding women, for people with hepatic or cardiac disorders, and for people with diabetes.

That last recommendation is decisive for a precision formula. It sets aside exactly the population in whom efficacy has been demonstrated. A formula that triggered berberine on an elevated glycaemic profile would serve it to the very group the agency asks to exclude.

Three elements consolidate this position. The drug interactions are established in humans, not inferred from cell models: 900 mg per day over fourteen days in eighteen healthy volunteers inhibits cytochromes CYP2D6, CYP3A4 and CYP2C9 (PubMed), which exposes statins, immunosuppressants and anticoagulants. Glucose-6-phosphate dehydrogenase deficiency, common in several populations, exposes to haemolytic anaemia. Finally, a draft opinion of the European Food Safety Authority, endorsed in January 2026, concludes that the available data do not allow any safe intake for humans to be established, whatever the preparation.

That opinion also records indications of genotoxicity observed in vitro. Confirmation in the whole animal is lacking and the opinion remains under public consultation, which forbids making it the principal argument. It is enough not to set it aside.

Boron falls under a distinct case: that of an element whose nutritional status is itself contested.

The European Food Safety Authority explicitly classifies it as non-essential. No physiological or biochemical function has been identified in humans, no dietary reference value has been derived for it, and it does not appear on the positive list of minerals authorised in food supplements.

The clinical file closes on two replication failures at the exact dose of common supplements. The founding 1987 effect, a reduction in calcium excretion, was conditional on a prior experimental depletion of one hundred and nineteen days, a condition unrelated to a European adult whose diet already supplies 1.5 to 3.5 mg per day. A metabolic-ward study then finds no effect on minerals, steroids or bone markers. A randomised trial in nineteen men finds no effect on testosterone, even as blood boron concentration rose. To this day there exists no meta-analysis of boron supplementation, on any endpoint.

One last observation disqualifies the bone argument in the context of a complete formula: the calcium sparing attributed to boron is observed only under a magnesium-poor diet, and it reverses under magnesium supplementation. The presumed benefit therefore disappears exactly where it would be claimed.

What science will illuminate next

Several molecules absent today are the subject of ongoing clinical trials. Fisetin is being studied in a randomized trial funded by the National Institute on Aging (NIA) on markers of cellular senescence in older adults. Ergothioneine is entering pilot intervention protocols. Apigenin is being tested in sleep trials.

If these trials produce data that meet the three selection criteria, the conclusions will evolve. The selection process is not a fixed list, but a method of continuous evaluation.

The principle governing this inventory of exclusions is straightforward: a rigorous formula in which every bioactive has passed all three filters, at the level of evidence attainable for its class, is preferable to an extended list of molecules half of which rest on a preclinical promise never confirmed in humans. The value of a formula is not measured by the length of its ingredient list. It is measured by the solidity of each of its choices, including its choices of exclusion.

Frequently asked questions

References

  1. Nakagawa K, Ninomiya M, Okubo T, et al. Tea catechin supplementation increases antioxidant capacity and prevents phospholipid hydroperoxidation in plasma of humans. J Agric Food Chem. 1999;47(10):3967-73 (PubMed).
  2. Scheid L, Ellinger S, Alteheld B, et al. Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea. J Nutr. 2012;142(12):2091-2096 (PubMed).
  3. Meister A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther. 1991;51(2):155-94 (PubMed).
  4. Rimando AM, Cuendet M, Desmarchelier C, et al. Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally occurring analogue of resveratrol. J Agric Food Chem. 2002;50(12):3453-7 (PubMed).
  5. Hollman PC, de Vries JH, van Leeuwen SD, Mengelers MJ, Katan MB. Absorption of dietary quercetin glycosides and quercetin in healthy ileostomy volunteers. Am J Clin Nutr. 1995;62(6):1276-82 (PubMed).
  6. Ishisaka A, Kawabata K, Miki S, et al. Mitochondrial dysfunction leads to deconjugation of quercetin glucuronides in inflammatory macrophages. PLoS One. 2013;8(11):e80843 (PubMed).
  7. Perez A, Gonzalez-Manzano S, Jimenez R, et al. The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: correlation with beta-glucuronidase activity. Pharmacol Res. 2014;89:11-18 (PubMed).
  8. Serban MC, Sahebkar A, Zanchetti A, et al. Effects of quercetin on blood pressure: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2016;5(7):e002713 (PubMed).
  9. Mohammadi-Sartang M, Mazloom Z, Sherafatmanesh S, Ghorbani M, Firoozi D. Effects of supplementation with quercetin on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2017;71(9):1033-39 (PubMed).
  10. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456 (PubMed).
  11. Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28 (PubMed).
  12. HEALEY ALS Platform Trial Study Group. Safety and efficacy of trehalose in amyotrophic lateral sclerosis (HEALEY ALS Platform Trial): an adaptive, phase 2/3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2025;24(6):500-511 (PubMed).
  13. Della Vecchia S, Gammaldi N, Ricca I, et al. Open-label evaluation of oral trehalose in patients with neuronal ceroid lipofuscinoses. J Neurol. 2025;272(1):94 (PubMed).
  14. Fauce SR, Jamieson BD, Chin AC, et al. Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol. 2008;181(10):7400-6 (PubMed).
  15. Cheah IK, Halliwell B. Could ergothioneine aid in the treatment of coronavirus patients? Antioxidants. 2020;9(10):595 (PubMed).
  16. Montgomery SA, Thal LJ, Amrein R. Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease. Int Clin Psychopharmacol. 2003;18(2):61-71 (PubMed).
  17. Mortensen SA, Rosenfeldt F, Kumar A, et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2014;2(6):641-9 (PubMed).
  18. Alehagen U, Aaseth J, Alexander J, Johansson P. Still reduced cardiovascular mortality 12 years after supplementation with selenium and coenzyme Q10 for four years: a validation of previous 10-year follow-up results of a prospective randomized double-blind placebo-controlled trial in elderly. PLoS One. 2018;13(4):e0193120 (PubMed).
  19. López-Lluch G. Coenzyme Q homeostasis in aging: Response to non-genetic interventions. Free Radic Biol Med. 2021;164:285-302 (PubMed).
  20. Langsjoen PH, Langsjoen AM. Comparison study of plasma coenzyme Q10 levels in healthy subjects supplemented with ubiquinol versus ubiquinone. Clin Pharmacol Drug Dev. 2014;3(1):13-7 (PubMed).
  21. Asadi Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metab. 2020;32(3):447-456.e6 (PubMed).
  22. Korstanje R, Strong R, Salmon AB, et al. Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice. Geroscience. 2026;48(3):3821-3830 (PubMed).
  23. Filip RS, Pierzynowski SG, Lindegard B, et al. Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: six-month study. Int J Vitam Nutr Res. 2007;77(2):89-97 (PubMed).
  24. Jafari A, Mardani H, Mirzaei Fashtali Z, et al. The nutritional significance of Ganoderma lucidum on human health: a GRADE-assessed systematic review and meta-analysis of clinical trials. Food Sci Nutr. 2025;13(6):e70423 (PubMed).
  25. Chen SN, Nan FH, Liu MW, et al. Evaluation of immune modulation by beta-1,3; 1,6 D-glucan derived from Ganoderma lucidum in healthy adult volunteers, a randomized controlled trial. Foods. 2023;12(3) (PubMed).
  26. Deng G, Lin H, Seidman A, et al. A phase I/II trial of a polysaccharide extract from Grifola frondosa (maitake mushroom) in breast cancer patients: immunological effects. J Cancer Res Clin Oncol. 2009;135(9):1215-21 (PubMed).
  27. Eisenberg T, Abdellatif M, Schroeder S, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22(12):1428-38 (PubMed).
  28. Hofer SJ, Kroemer G, Kepp O, et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nat Cell Biol. 2024;26(9):1571-84 (PubMed).
  29. Kiechl S, Pechlaner R, Willeit P, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018;108(2):371-80 (PubMed).
  30. Wirth M, Schwarz C, Benson G, et al. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge): a randomized, double-blind, placebo-controlled, phase 2 trial. Alzheimers Dement (N Y). 2022;8(1):e12262 (PubMed).
  31. Senekowitsch S, Wietkamp E, Grimm M, et al. High-dose spermidine supplementation does not increase spermidine levels in blood plasma and saliva of healthy adults: a randomized, placebo-controlled pharmacokinetic and metabolomic study. Nutrients. 2023;15(8):1852 (PubMed).
  32. Higashi K, et al. Polyamines enhance translation of eIF5A2 through inhibition of miR-6514-5p in cancer cells. J Biol Chem. 2025;301(8):110453 (PubMed).
  33. Conze D, Brenner C, Kruger CL. Safety and metabolism of long-term administration of NIAGEN (nicotinamide riboside chloride) in a randomized, double-blind, placebo-controlled clinical trial of healthy overweight adults. Sci Rep. 2019;9(1):9772 (PubMed).
  34. Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome and induces transcriptomic and anti-inflammatory signatures. Cell Rep. 2019;28(7):1717-1728.e6 (PubMed).
  35. Trętowicz MM, Scantlebery AML, Schomakers BV, et al. Human whole-blood NAD+ levels do not vary with age or lifestyle interventions. Nat Metab. 2026;8(6):1282-1290 (PubMed).
  36. Boyle SP, Dobson VL, Duthie SJ, et al. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr. 2000;54(10):774-782 (PubMed).
  37. Bazyar H, Moradi L, Zaman F, Zare Javid A. The effects of rutin flavonoid supplement on glycemic status, lipid profile, atherogenic index of plasma, brain-derived neurotrophic factor (BDNF), some serum inflammatory, and oxidative stress factors in patients with type 2 diabetes mellitus: a double-blind, placebo-controlled trial. Phytother Res. 2023;37(1):271-284 (PubMed).
  38. Micka A, Siepelmeyer A, Holz A, Theis S, Schön C. Effect of consumption of chicory inulin on bowel function in healthy subjects with constipation: a randomized, double-blind, placebo-controlled trial. Int J Food Sci Nutr. 2017;68(1):82-89 (PubMed).
  39. Mitchell CM, Davy BM, Ponder MA, et al. Prebiotic inulin supplementation and peripheral insulin sensitivity in adults at elevated risk for type 2 diabetes: a pilot randomized controlled trial. Nutrients. 2021;13(9):3235 (PubMed).
  40. Li J, Liu F, Luo Y, et al. Differential effects of inulin and fructooligosaccharides on gut microbiota composition and glycemic metabolism in overweight/obese and healthy individuals: a randomized, double-blind clinical trial. BMC Med. 2025;23(1):372 (PubMed).
  41. Schwab U, Törrönen A, Meririnne E, et al. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans. J Nutr. 2006;136(1):34-8 (PubMed).
  42. Alfthan G, Tapani K, Nissinen K, Saarela J, Aro A. The effect of low doses of betaine on plasma homocysteine in healthy volunteers. Br J Nutr. 2004;92(4):665-9 (PubMed).
  43. Olthof MR, van Vliet T, Boelsma E, Verhoef P. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr. 2003;133(12):4135-8 (PubMed).
  44. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330(15):1029-35 (PubMed).
  45. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-5 (PubMed).
  46. Penniston KL, Tanumihardjo SA. The acute and chronic toxic effects of vitamin A. Am J Clin Nutr. 2006;83(2):191-201 (PubMed).
  47. Miller ER 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46 (PubMed).
  48. Takeuchi Y, Miyamoto T, Kakizawa T, Shigematsu S, Hashizume K. Insulin Autoimmune Syndrome possibly caused by alpha lipoic acid. Intern Med. 2007;46(5):237-9 (PubMed).
  49. Chandrasekhar K, Kapoor J, Anishetty S. A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults. Indian J Psychol Med. 2012;34(3):255-62 (PubMed).
  50. Candelario M, Cuellar E, Reyes-Ruiz JM, et al. Direct evidence for GABAergic activity of Withania somnifera on mammalian ionotropic GABAA and GABAρ receptors. J Ethnopharmacol. 2015;171:264-72 (PubMed).
  51. Lopresti AL, Smith SJ, Malvi H, Kodgule R. An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: a randomized, double-blind, placebo-controlled study. Medicine. 2019;98(37):e17186 (PubMed).
  52. Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract SHR-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009;75(2):105-12 (PubMed).
  53. Panossian A, Wikman G, Sarris J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine. 2010;17(7):481-93 (PubMed).
  54. Guo Y, Chen Y, Tan ZR, et al. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol. 2012;68(2):213-7 (PubMed).

Related Articles

Nutrition laboratory workstation with data visualizations and capsules
Inside the Lab

From Data to Molecule: The Algorithm Behind Your Precision Formulation

How does a blood value translate into milligrams in your jar? Behind every Singular formulation, an algorithmic framework transforms biological data into personalized bioactive calibration.

January 27, 20267 min read
Cluster of dark red grapes on slate with one grape cut in half, chiaroscuro lighting
Inside the Lab

Why We Banned Resveratrol from Our Formulas (Despite Its Popularity)

Resveratrol is one of the most popular bioactives on the global supplement market. We chose not to include it. Here is why.

December 22, 20257 min read
Miron violet glass bottle protecting bioactives from photonic degradation
Inside the Lab

Photonic Degradation: Why We Protect Your Bioactives in Miron Glass

Visible light destroys sensitive molecules within hours. Understanding photodegradation is essential for evaluating the true quality of any supplementation formula.

November 9, 20257 min read