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Ndg3.0
NDGA (Nordihydroguaiaretic acid) Research
Mostly mechanism / observational
11 peer-reviewed studies
What the evidence says
Mostly mechanism / observational
Most NDGA (Nordihydroguaiaretic acid) studies are mechanism or observational rather than RCTs that measure a clinical effect — keep findings provisional.
Most evidence is from medium-quality randomised trials published 1991–2024.
Based on 11 studies · 1 RCT
Confidence
Low confidence
By outcome
Safety profile
Mostly mechanism / observational10 studies
Longevity & aging (male-mouse signal, unproven in humans)Extended lifespan in MALE mice only (ITP) via antioxidant/5-LOX inhibition; no human longevity evidence and a serious, FDA-documented hepatotoxicity/liver-failure record. · Not established (animal-only, hepatotoxic)
Mostly mechanism / observational3 studies
Liver health & hepatotoxicity
Too few graded studies2 studies
Glucose & triglyceride lowering (animal)
Too few graded studies1 study
Inflammation & antioxidant activity
Too few graded studies1 study
Steady research
3 studies in the last 5 years
199120072024
1Systematic Review2021
In plain English: Therefore, increasing the number of studies targeting the 5-LOX pathway would largely expand our knowledge on the anti-inflammatory mechanisms of (poly)phenols.
Giménez-Bastida JA et al. · International journal of molecular sciences (2021)
The number of studies identified is low (5, 24, and 127 human, animal, and cellular studies, respectively) compared to the thousands of studies focusing on the COX-2 pathway.
Some (poly)phenolics such as caffeic acid, hydroxytyrosol, resveratrol, curcumin, nordihydroguaiaretic acid (NDGA), and quercetin have been reported to reduce the formation of 5-LOX eicosanoids in vitro.
However, the in vivo evidence is inconclusive because of the low number of studies and the difficulty of attributing effects to (poly)phenols.
Ahluwalia MS et al. · Cell reports. Medicine (2024)
Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3).
These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential.
Mala John GS et al. · Current cancer drug targets (2020)
NDGA derivatives have been developed as better alternatives to NDGA.
Although several NDGA derivatives have been chemically synthesized as evidenced by recent literature, there is a paucity of information on their therapeutic efficacies.
This review is to highlight the medicinal applications of NDGA, its toxicity evaluations and discuss the chemical derivatives of NDGA synthesized and studied so far and suggest to continue research interests in the development of NDGA analogs for therapeutic applications.
In plain English: Among the most promising and widely reported metabolites from L. tridentata, are: 3'-demethoxy-6-O-demethylisoguaiacin, 3'-O-methyldihydroguaiaretic acid, meso-dihydroguaiaretic acid, and tetra-O-methylnordihydroguaiaretic acid.
Reyes-Melo KY et al. · Current topics in medicinal chemistry (2021)
Among the most promising and widely reported metabolites from L. tridentata, are: 3'-demethoxy-6-O-demethylisoguaiacin, 3'-O-methyldihydroguaiaretic acid, meso-dihydroguaiaretic acid, and tetra-O-methylnordihydroguaiaretic acid.
These have been reported to exhibit antibacterial, antiprotozoal, anthelmintic, antifungal, antiviral, anticancer, and antioxidant activities.
In plain English: Only male UM-HET3 mice receiving N-acetyl-L-cysteine had significantly increased life span ... The other agents had no significant effects on life span.
Flurkey K, Astle CM, Harrison DE. · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences (2010)
THE HONEST COUNTERPOINT: a later lifespan study in the same UM-HET3 genetically heterogeneous stock tested several anti-aging treatments including NDGA — and found NDGA had NO significant effect on lifespan
Only N-acetyl-L-cysteine extended male lifespan (and the authors note this may have been due to treatment-related inadvertent diet restriction); aspirin, nitroflurbiprofen, 4-OH-PBN and NDGA all showed no significant effect
Shows the NDGA mouse-lifespan signal is NOT unconditional — it was not reproduced here, tempering the longevity claim
In plain English: Males in the NDGA group had significantly improved survival (P = 0.0004) ... None of the other agents altered survival ... the current data show that NDGA reduces early life mortality risks in genetically heterogeneous mice at multiple test sites.
Miller RA, Harrison DE, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Strong R. · Aging Cell (2007)
FIRST-COHORT INTERIM REPORT of the NIA Interventions Testing Program, describing its design (genetically heterogeneous mice, three test sites, power to detect 10% lifespan changes) and the first agents tested (aspirin, nitroflurbiprofen, 4-OH-PBN, NDGA)
NDGA was the standout: male mice on NDGA had significantly improved survival (P = 0.0004), with significant effects at two of the three sites — none of the other three agents altered survival
Framed cautiously as reducing early-life mortality; the authors note more data are needed to determine whether NDGA extends MAXIMUM lifespan
In plain English: Of 18 reports of illnesses associated with the ingestion of chaparral, there was evidence of hepatotoxicity in 13 cases ... in 4 individuals, there was progression to cirrhosis; and in 2 individuals, there was acute fulminant liver failure that required liver transplants.
Sheikh NM, Philen RM, Love LA. · Archives of Internal Medicine (1997)
THE DECISIVE HARM SIGNAL: a review of adverse-event reports to the FDA (1992-1994) on chaparral (Larrea tridentata, the source of NDGA), documenting serious liver injury
Of 18 reports, 13 showed hepatotoxicity — a toxic/drug-induced cholestatic hepatitis with jaundice appearing 3 to 52 weeks after ingestion and resolving 1-17 weeks after stopping
SEVERE OUTCOMES: 4 individuals progressed to cirrhosis and 2 developed acute fulminant liver failure requiring liver transplantation — chaparral/NDGA can cause irreversible liver damage
9AnimalCited 281×2008
In plain English: Pooling data from all three sites, a log-rank test showed that both NDGA (p=0.0006) and aspirin (p=0.01) led to increased lifespan of male mice. Comparison of the proportion of live mice at the age of 90% mortality ... neither NDGA (p=0.12) nor aspirin (p=0.16) had a significant effect in this test.
Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE. · Aging Cell (2008)
THE HEADLINE LONGEVITY RESULT: in the NIA Interventions Testing Program (ITP) — a rigorous multi-site mouse-lifespan program in genetically heterogeneous mice — NDGA significantly increased lifespan of MALE mice when data were pooled across all three test sites (p=0.0006)
MALE-ONLY: NDGA did not increase lifespan in females; the authors suggest sex differences in drug disposition/metabolism may explain the lack of female effect
DID NOT CLEARLY EXTEND MAXIMUM LIFESPAN: using survival at 90% mortality as a surrogate for maximum lifespan, NDGA had no significant effect (p=0.12) — the effect was on median/mean survival, not the upper limit
In plain English: At the molecular level, NDGA is a potent scavenger of reactive oxygen species. Lipoxygenase inhibition by NDGA has been broadly studied ... related with its role as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidant pathway. In contrast, in tumor cells NDGA exerts pro-apoptotic activity.
Hernández-Damián J, Andérica-Romero AC, Pedraza-Chaverri J. · Archiv der Pharmazie (2014)
MECHANISM REVIEW: characterises NDGA as a potent reactive-oxygen-species scavenger and a broadly studied inhibitor of lipoxygenases (including 5-LOX), and as an activator of the Nrf2/ARE endogenous antioxidant response in non-tumour cells
'PARADOXICAL': the same compound is cytoprotective and mitochondria-sparing in non-tumour cells but pro-apoptotic and mitochondria-impairing in tumour cells — a double-edged chemistry
Catalogues preclinical interest across cancer, renal damage, Huntington's and Alzheimer's models — all preclinical, none establishing human benefit
In plain English: Masoprocol (nordihydroguaiaretic acid), a pure compound isolated from the creosote bush (Larrea tridentata), decreases serum glucose and triglyceride (TG) levels when administered orally in rodent models of type 2 diabetes ... masoprocol at a dose of 40 or 80 mg/kg twice daily, significantly reduced hepatic TG secretion and liver TG content.
Scribner KA, Gadbois TM, Gowri M, Azhar S, Reaven GM. · Metabolism (2000)
METABOLIC ACTIVITY (ANIMAL): masoprocol (NDGA) lowered serum triglycerides in a stepwise, dose-dependent way in rats with fructose-induced hypertriglyceridemia, and reduced hepatic triglyceride secretion and liver triglyceride content at higher doses
Consistent with the creosote bush's folk use for type 2 diabetes — NDGA also lowers serum glucose in rodent diabetes models
Provides a mechanism (reduced hepatic TG secretion) for NDGA's lipid-lowering effect in animals