Benefits
Knee comfort and function during activity
In 105 overweight adults with knee discomfort only during activity, 250 mg or 500 mg twice daily for 84 days improved a knee comfort and function score and a knee discomfort rating more than placebo; on the knee score, the 500 mg group alone did not differ. The maker funded that trial. A 12-week trial in 100 adults with knee osteoarthritis also reported larger knee score drops than placebo.
Serum uric acid levels over 24 weeks
In 110 adults with high serum uric acid split across five groups, 500 mg twice daily for 24 weeks lowered uric acid from 7.76 to 6.42 mg/dL (about 16%), while it rose about 7% on placebo, and 22% of the extract group reached 6 mg/dL or less. A related Terminalia bellerica extract lowered it about twice as much. The maker supplied the capsules.
Walking distance and knee soreness after exercise
In the same 84-day trial, 6-minute walk distance improved more than placebo in the 250 mg group and in both groups combined, and knee soreness after a leg extension test fell more than placebo at both doses. Knee range of motion, knee mobility and low back ratings, willingness to exercise and leg extension repetitions did not differ from placebo.
Blood inflammation markers (CRP and TNF-alpha) over 84 days
In the 84-day joint trial, C-reactive protein (CRP) and TNF-alpha did not differ between the extract and placebo; TNF-alpha fell within the 500 mg twice daily group only, which is not a comparison with placebo. A cartilage turnover marker (COMP) fell on 250 mg twice daily while it rose on placebo, but not in the 500 mg or combined groups.
Pain threshold after a single dose in laboratory tests
In two small crossover studies, each in 12 healthy volunteers, a single 1,000 mg dose raised pain threshold and pain tolerance more than placebo 3 hours later, in a mechanical pressure test and a hot air test. A one-dose laboratory pain model in healthy people says little about daily joint comfort, and longer studies are needed.
Mechanism of action
Inflammatory signaling in cell studies
In mouse macrophage cells stimulated with bacterial endotoxin, chebulagic acid, one of the tannins the extract is standardized to, lowered nitric oxide and PGE2 output, reduced COX-2, 5-LOX, TNF-alpha and IL-6, and blocked NF-kappaB activation. These are cell results; in the human joint trial, blood CRP and TNF-alpha did not differ from placebo.
Nrf2 antioxidant signaling in liver cells
In human liver cells (HepG2) exposed to an oxidant, chebulic acid from T. chebula raised cell glutathione, increased heme oxygenase-1 activity and moved the transcription factor Nrf2 into the nucleus, switching on its antioxidant target genes in a dose-dependent way. Whether supplement doses do this in people has not been measured.
Clinical trials
Randomized, double-blind, placebo-controlled trial with a two-week placebo lead-in: AyuFlex 250 mg or 500 mg twice daily versus placebo for 84 days; funded by Natreon through a restricted grant; registered NCT02589249. (Lopez et al. 2017, BMC Complement Altern Med)
105 apparently healthy overweight adults aged 35 to 70 with knee discomfort during activity but none at rest; the main results tables report 86 participants (28, 33 and 25 per group).
Comparing change from baseline at day 84 against placebo, the combined extract groups improved the modified KOOS knee score (p = 0.023; 250 mg group p = 0.011, 500 mg group not significant), total modified WOMAC (p = 0.042) and its physical function subscale (p = 0.046), knee discomfort with activity (p < 0.001), whole-body joint function (p = 0.029), knee soreness after leg extensions (p = 0.039) and 6-minute walk distance (p = 0.022). Knee mobility, low back health, willingness to exercise, range of motion, CRP and TNF-alpha did not differ from placebo; a cartilage turnover marker (COMP) differed from placebo only in the 250 mg group (p = 0.033). The abstract describes several of these results as relative to baseline, but the full text reports them as change scores compared with placebo. A few mild or moderate side effects (such as heartburn, reflux, headache and cramps) occurred in all three groups at similar rates, and none were serious.
Randomized, double-blind, placebo- and positive-controlled pilot trial in Hyderabad, India, registered with CTRI: AyuFlex 500 mg twice daily, Terminalia bellerica extract 250 mg or 500 mg twice daily, a prescription uric acid lowering drug, or placebo for 24 weeks; all capsules supplied by Natreon. (Usharani et al. 2016, Clin Pharmacol)
110 adults aged 18 to 69 with serum uric acid of 6 to 12 mg/dL who were not taking uric acid lowering medicine; 88 completed 24 weeks, 18 of them on AyuFlex.
On AyuFlex, serum uric acid fell from week 4 compared with baseline (p<0.01) and went from 7.76 to 6.42 mg/dL at 24 weeks (about 16%), while it rose about 7% on placebo; levels leveled off after 16 weeks. The reduction was about half that of T. bellerica 500 mg. By week 24, 22.2% on AyuFlex reached 6 mg/dL or less, versus none on placebo. One person on AyuFlex had mild gastrointestinal intolerance, and no one withdrew because of adverse events.
Randomized, double-blind, placebo-controlled crossover with a washout between treatments (one week in the abstract, two weeks in the methods): one 1,000 mg dose (two 500 mg capsules) of the standardized aqueous extract or placebo, tested 3 hours later with a pressure device (Randall Selitto test); capsules supplied by Natreon. (Pokuri et al. 2016, J Anaesthesiol Clin Pharmacol)
12 healthy men aged 18 to 40.
Compared with placebo, the extract raised pain threshold force and time (by 20.8% and 21.0%) and pain tolerance force and time (by 13.4% each; p<0.001). No adverse reactions were reported. A one-dose laboratory pain model in healthy volunteers says nothing direct about the effects of regular daily use.
Randomized, double-blind, placebo-controlled crossover with a two-week washout: one 1,000 mg dose (two 500 mg capsules) of a standardized aqueous T. chebula extract or placebo, tested with a hot air pain device before and 180 minutes after dosing. (Kumar et al. 2015, J Clin Diagn Res)
12 healthy adult participants.
The extract raised mean pain threshold time from 34.06 to 41.00 seconds and pain tolerance time from 49.67 to 57.30 seconds (percentage increases of 20.42% and 17.50%; p<0.001), significantly more than placebo. Study capsules were well tolerated. The abstract does not name the brand; a later Natreon-funded study cites it as AyuFlex research.
Randomized, double-blind, double-dummy, placebo-controlled trial at Nizam's Institute of Medical Sciences, Hyderabad, India, registered with CTRI: AyuFlex 500 mg or 250 mg twice daily, AyuFlex 500 mg twice daily plus a Natreon chromium complex, the chromium complex alone, or placebo for 12 weeks; published in a journal not indexed in PubMed. (Nutalapati et al. 2016, Asian J Pharm Clin Res)
100 adults aged 40 to 70 with knee discomfort for at least 6 months and X-ray signs of knee osteoarthritis (Kellgren and Lawrence grade II to IV); 22 on 500 mg, 17 on 250 mg and 20 on placebo.
At 12 weeks, the modified WOMAC score fell 19.82 points on 500 mg twice daily and 10.47 points on 250 mg twice daily, versus 2.45 points on placebo (p<0.001 for each dose versus placebo), and 500 mg did better than 250 mg. The knee swelling index fell more than placebo at both doses. Pain, stiffness and disability ratings fell more on 500 mg than on placebo; on 250 mg, stiffness and disability but not pain differed from placebo. Adding the chromium complex gave no extra benefit. Two people on 500 mg reported indigestion and one diarrhea; none were serious and no one withdrew. It has not been repeated.