By Justin Yamashita, MSc. Benchtop, site, CRO: three levels of basic and clinical research, explained without spin.

The deeper dive: trial methodology, mechanisms, and the science behind the story.

Last week's Informed ended by saying we were leaving the safety room and going somewhere the money is louder. Here it is. Monday asked whether a company would already be selling a remedy if it really worked. Wednesday laid out the economics and named who pays when nobody can own the answer. This is the evidence underneath both of them, including the one case where the whole thing actually worked, and who paid.

The premise that nobody screens plants is false, and the counter-evidence is publicly funded and publicly available. The National Cancer Institute's Natural Products Repository holds over 230,000 unique extracts from plant, marine and microbial organisms collected from biodiverse regions worldwide, which NCI describes as one of the largest collections of its kind in the world. Its Program for Natural Product Discovery is prefractionating over 125,000 of those extracts toward a publicly accessible library of more than 1,000,000 fractions, supplied to the research community free of charge in 384-well plates for screening against all disease states (NCI Center for Cancer Research, Molecular Targets Program).

That is worth sitting with before any suppression argument. A programme built to bury natural compounds would not prefractionate them, catalogue them, and mail them to anyone who asks. The bottleneck this issue is about sits after this step, not at it.

Traditional preparations are usually complex mixtures rather than single molecules, and that is a measurement problem before it is anything else. A 2022 review in Metabolites concluded that the therapeutic potential of a plant extract cannot be explained by the sum of its parts alone, and noted that some isolated compounds showed lower therapeutic activity than the extract they were isolated from, which points to synergy between constituents rather than one clean active ingredient (Rajcevic et al., 2022). A 2018 review in the International Journal of Molecular Sciences makes the same structural point: modern drug development is built to isolate one or two compounds, while traditional medicine uses whole preparations (Thomford et al., 2018).

Then add standardisation. When Cohen and colleagues measured monacolin K across 28 commercial red yeast rice products, the content varied more than 60-fold between brands, the same variability this newsletter documented back in Issue 016 (Cohen et al., 2017). That is a finding about the supplement industry rather than a statement about every plant, but it shows the problem cleanly: if you cannot say what is in the bottle, you cannot say what was tested. That is a real quality-control problem, not evidence of a cover-up.

Tu Youyou searched a 1,600-year-old traditional Chinese medicine text for a malaria remedy, identified Artemisia annua, and isolated artemisinin. She shared the 2015 Nobel Prize in Physiology or Medicine for it, and the drug family built on it has saved an enormous number of lives. That much of the story gets told often, and it is true.

The part usually left out is who paid. Artemisinin came out of Project 523, a Chinese government and military research programme launched in 1967. Nobody involved was chasing an exclusive licence. A state decided the problem was worth solving and funded the search, which is precisely the answer to who pays for a cure that nobody can own.

The patent question came afterwards, and it is worth being exact about, because the loose version of this story gets it backwards. Artemisinin itself is a natural product, and under U.S. patent law you generally cannot own something you simply found in nature and pulled out of the ground. What became ownable were the semisynthetic derivatives built from it, artemether, artesunate and dihydroartemisinin, along with manufacturing processes and combination therapies. Those are made in a lab and markedly different from the plant compound, which is why manufacturers existed to scale them.

So the honest reading is not "a folk remedy proved itself and got rewarded." It is two separate things stacked. Public money paid for the discovery, because no private money was ever going to. Private money arrived once there was something ownable to manufacture. Trial-ability tracks a chemical profile and a funder, not a continent, and that is the real answer to "Western medicine won't touch Eastern remedies."

Curcumin (turmeric) is the cautionary case for enthusiasm. A 2017 review in the Journal of Medicinal Chemistry laid out why: it is poorly absorbed when taken orally, it is unstable, and it is a notorious source of false positives in laboratory screening assays, which means a great deal of the promising lab work may have been measuring the assay rather than the compound (Nelson et al., 2017). Critical reviews of the human trial record have not found convincing evidence of benefit in cancer. That review drew a published rebuttal arguing it went too far, and some placebo-controlled trials in inflammatory and metabolic conditions do report benefit, so the record is genuinely mixed rather than settled. Treat it as an open question, not a win.

St. John's Wort is the clearer warning. It induces the liver enzyme CYP3A4 strongly enough that the FDA issued a public health advisory over it dropping blood levels of HIV antiretrovirals, and it has caused documented transplant-organ rejections by lowering cyclosporine levels. "Natural" and "no drug interactions" are not the same claim.

Tier 1, peer-reviewed: Rajcevic et al. 2022 (Metabolites, synergy between constituents); Cohen et al. 2017 (Eur J Prev Cardiol, red yeast rice brand variability); JAMA Network Open 2025 (development cost); Garcia-Diaz et al. 2025 (Frontiers in Pharmacology, off-patent repurposing); Nelson et al. 2017 (J Med Chem, curcumin bioavailability and assay interference).

Tier 2, regulatory and programme record: USPTO patent-eligibility guidance; the NCI Center for Cancer Research Molecular Targets Program record for the Natural Products Repository and the Program for Natural Product Discovery; the FDA St. John's Wort public health advisory; the Nobel Foundation record for the 2015 prize; the published history of Project 523.

Tier 3, company or institutional press release: none used in this issue.

Tier 4, individual case or self-reported: none used in this issue.

Development cost: direct costs median $150M and mean $369M; after cost-of-capital and discontinuation adjustments, median $708M and mean $1.31B, all 2019 dollars, from 38 drugs approved in 2019. Tier 1. NCI Natural Products Repository holds over 230,000 unique extracts, and the Program for Natural Product Discovery is prefractionating over 125,000 of them toward more than 1,000,000 fractions supplied free to researchers: Tier 2, NCI Center for Cancer Research. Monacolin K varied more than 60-fold across 28 red yeast rice brands: Tier 1. Tu Youyou shared the 2015 Nobel Prize in Physiology or Medicine: Tier 2, Nobel Foundation. Project 523 launched 1967 under Chinese government and military direction: Tier 2, published historical record including Tu Youyou's own 2011 account in Cell. St. John's Wort CYP3A4 interaction advisory: Tier 2, FDA.

Q4, who funded this, and do they have a stake in the answer? Run it in reverse. Ask who COULD have funded a trial on something nobody can own, and the answer is usually nobody, which is the finding.

Q6, am I seeing the full picture, or only part of the evidence? The suppression story looks only at natural remedies and never mentions that unpatentable, off-patent Western drugs hit the identical funding wall.

Next issue: the FDA's pivot toward non-animal preclinical models, and what actually replaces a mouse.

These 3 issues give you the foundation for everything in this arc.

Issue 003b: How to evaluate any health claim using the Skeptic's Toolkit. Start here.

Issue 001: Why medical distrust is rational, and what to do with it anyway.

Issue 004: How a drug gets from a lab to your pharmacy. The pipeline in plain language.

All back issues are at RootToRx.com.

1. "Use of Clinical Trial Characteristics to Estimate Costs of New Drug Development." JAMA Network Open. Published 6 January 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC11704977/
2. Garcia-Diaz M, Epstein D, Espin J. "Overcoming barriers to off-patent drug repurposing: a lifecycle-based policy solutions." Frontiers in Pharmacology. 2025. doi:10.3389/fphar.2025.1670845
3. Rajcevic N, Bukvicki D, Dodos T, Marin PD. "Interactions between Natural Products, A Review." Metabolites. 2022;12(12):1256. doi:10.3390/metabo12121256
4. Thomford NE, et al. "Natural Products for Drug Discovery in the 21st Century." International Journal of Molecular Sciences. 2018.
5. Cohen PA, et al. "Variability in strength of red yeast rice supplements." European Journal of Preventive Cardiology. 2017;24(13):1431.
6. USPTO, Manual of Patent Examining Procedure 2106.04(b), "Laws of Nature, Natural Phenomena and Products of Nature," November 2024 revision. uspto.gov
7. Tu Y. "Artemisinin, A Gift from Traditional Chinese Medicine to the World." Nobel Lecture, 2015, nobelprize.org. See also Tu Y, "Artemisinin: Discovery from the Chinese Herbal Garden," Cell. 2011;146(6):855-858, for her own account of Project 523.
8. FDA public health advisory, St. John's Wort and drug interactions. fda.gov
9. Nelson KM, Dahlin JL, Bisson J, Graham J, Pauli GF, Walters MA. "The Essential Medicinal Chemistry of Curcumin." Journal of Medicinal Chemistry. 2017;60(5):1620-1637. doi:10.1021/acs.jmedchem.6b00975
10. National Cancer Institute, Center for Cancer Research, Molecular Targets Program: the NCI Natural Products Repository and the Program for Natural Product Discovery. ccr.cancer.gov/molecular-targets-program

If this was worth your time, the best thanks is a referral. Series 1 cards are the reward.

New here? Root to Rx runs three pieces a week. Monday you watch a real health claim try to work on someone. Wednesday you get the tools to run it yourself. Thursday you get the full evidence so you can check my work. Written by a clinical researcher, free, at RootToRx.com.

For educational purposes only. Nothing in this newsletter is medical advice. Talk to your doctor before making any health decision.

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Disclosure: Root to Rx is published independently by Open Label Media LLC. Views expressed are personal views of Justin Yamashita and do not represent his employer or any affiliated organization. No employer resources or proprietary information are used. Every claim is sourced from publicly available materials.

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