What randomized clinical trials have been registered to test natural products (including honey) for Alzheimer’s prevention?
Executive summary
Systematic reviews and recent literature show that several randomized clinical trials (RCTs have been registered testing natural products for Alzheimer’s prevention or early-stage intervention — most prominently trials of curcumin, omega‑3 fatty acids (DHA), Ginkgo biloba, vitamin D combinations, and various herbal extracts such as ginseng — but results are mixed and large, definitive prevention trials are largely absent [1] [2] [3] [4]. The field is characterized by small, often short-duration RCTs, variable endpoints and bioavailability problems (notably with curcumin), and calls across reviews for larger, biomarker‑driven prevention trials [1] [5] [6].
1. What the registries and reviews actually document: named RCTs and their natural-product targets
Reviews that synthesize registered and published clinical trials list curcumin trials by registry identifiers (example trial identifiers cited in the review include NCT99710 and NCT164749 for curcumin) and describe multiple clinical-stage studies of botanical extracts such as Ginkgo biloba, Panax ginseng, and other phytoconstituents [1] [3] [6]. Large federally funded RCTs testing nutritional compounds are documented as well: the Alzheimer’s Disease Cooperative Study (ADCS) evaluated DHA (an omega‑3 fatty acid) versus placebo and showed no overall benefit in mild–moderate AD in the large federally funded trial summarized by the Alzheimer’s Association and reviews [4]. A named prevention trial in the prevention literature (A4; NCT02008357) is an antibody trial rather than a natural-product study but illustrates the scale and design standards that natural-product prevention trials would need to meet [7].
2. Trials with negative or mixed outcomes that reshaped expectations
Large, well‑conducted studies of natural products have tempered early enthusiasm: a multicenter Phase 3 RCT of Ginkgo biloba found no benefit in preventing or delaying Alzheimer’s disease, a conclusion emphasized by the Alzheimer’s Association and trial reviews [4]. Similarly, the ADCS DHA trial did not show overall cognitive benefit versus placebo in the enrolled population [4]. These outcomes are repeatedly cited in systematic reviews as evidence that single‑agent nutraceutical approaches have so far failed to deliver robust prevention signals [4] [2].
3. Promising candidates hampered by design or delivery problems
Curcumin and other polyphenols recur in reviews as biologically plausible agents with antioxidant and anti‑inflammatory effects; curcumin has multiple registered clinical studies (the reviews cite NCT identifiers) but investigators repeatedly flag poor bioavailability and variable formulations as key limitations that complicate interpretation of RCT results [1] [6]. Huperzine A and rosmarinic acid have strong preclinical rationales and small clinical assessments, but reviews note many clinical trials did not include biomarker endpoints or were too small to be definitive [1]. Panax ginseng and Ginkgo also have multiple clinical-stage evaluations but with mixed outcomes across trials [3] [4].
4. Why the registry landscape is still incomplete for prevention trials of “natural products”
Recent comprehensive reviews and pipeline analyses stress that most registered prevention trials in AD are pharmaceutical candidates and that only a minority of natural‑product studies meet the rigorous, biomarker‑based, multicenter designs now expected for prevention work [8] [5]. The reviews repeatedly call for larger, longer, randomized, double‑blind prevention trials with standardized formulations, dose‑finding, and biomarker outcomes — precisely what is largely missing from the current registry corpus for natural products [5] [9].
5. Bottom line and limits of the reporting
Existing systematic reviews and authoritative summaries document multiple randomized clinical trials testing natural products — including curcumin (registered trials cited by identifier), omega‑3 DHA (ADCS trial), Ginkgo biloba (large Phase 3 prevention/efficacy trials), vitamin D co‑therapy pilots, ginseng and other botanicals — but most are small, produce mixed or negative results, and suffer from formulation and endpoint heterogeneity; the literature and registry reviews therefore call for larger, biomarker‑driven prevention RCTs to move the field forward [1] [2] [3] [4] [5]. The sources reviewed summarize and name several registered trials but do not provide a single exhaustive, up‑to‑the‑minute registry list, so this account reflects what the cited reviews record rather than a complete clinicaltrials.gov sweep [1] [9] [8].