Table 1.
Effects of antioxidant supplements on gastrointestinal diseases (see footnote for explanations)
| Ref. | Disease | Trial characteristics | Outcome measures | Observation summary | Rating and comments |
|---|---|---|---|---|---|
| Allopurinol | |||||
| 44 | IBD | O: combination therapy after failed azathioprine monotherapy (n = 11) up to 8 months | 6-TGN levels in erythrocytes | 50 mg allopurinol with 50 mg azathioprine sufficient to raise 6-TGN level | ++** Small sample size, no clinical results |
| 45 | IBD | O: combination therapy after failed monotherapy, given allopurinol + thiopurine (n = 77) up to 5 years | 6-TGN levels in erythrocytes | Long-term combination therapy effective and well tolerated | ++** No clinical results |
| 46 | IBD | O: azathioprine combination therapy (n = 10; 8 CD, 2 UC), 12 weeks | 6-TGN levels in erythrocytes and hypoxanthine-guanine phosphoribosyltransferase | Increased hypoxanthine-guanine phosphoribosyltransferase and 6-TGN levels | ++** No clinical results |
| 85 | UC | RDBP: prophylactic use of pouchitis (n = 273), 2 years | Pouchitis incidence and pouch function | No effects | ±***** Restorative surgery in UC may result in pouchitis |
| 48 | UC | RDBP: combination therapy with mesalamine, patients in remission (n = 199), 12 months | Clinical and endoscopy after 1, 6 and 12 months | Combination therapy better for 6 but not 12 months | +***** High relapse rate in mesalamine alone in first 3 months |
| 47 | UC | RDB: sulfasalazine and prednisol enema (n = 45) ± allopurinol (n = 46) or DMSO (n = 45), 12 months | Remission and relapse rate | 2 weeks: 51% in remission vs. 84% with allopurinol or DMSO; over 12 months 5% relapse with allopurinol or DMSO vs. 25% without | ++*** No placebo, limited measurements |
| Aloe vera | |||||
| 86 | IBS | RDBP: (n = 58), 1–3 months | IBS, pain and distension scores, bowel habit satisfaction | Effects similar to placebo | ±*** |
| 87 | IBS | RDBP crossover: (n = 110), 5 + 5 months | Gastrointestinal Symptoms Rating Score, IBS Quality of Life, EuroQol | Effects similar to placebo | ±**** Subjective questionnaires, high dropout |
| 88 | IBS | O: constipation-predominated refractory patients (n = 33), 8 weeks | Self-rated VAS scores | Pain and discomfort decreased significantly | +* No placebo, subjective questionnaires |
| 89 | UC | RDBP: (n = 44), 4 weeks | SCCAI, sigmoidoscope scores, and histological scores | Better than placebo for SCCAI and histological scores not for sigmoidoscopic scores | +*** Small sample size and short time |
| Andrographis paniculata (Indian echinacea, kirayat) | |||||
| 90 | UC | RDBC: compared with mesalamine (n = 120), 8 weeks | Colonoscopy, stools, abdominal pain, and distension | Effects similar to mesalamine | ++**** This was a pilot study |
| 91 | UC | RDBP: extract 1,200 or 1,800 mg or placebo (n = 224), 8 weeks | Colonoscopy, stools, abdominal pain, and distension | 1,800 mg gave better clinical response but adverse effects in half the patients | -**** Has in vitro inhibitory activity against TNF-α, IL-1P, and NF-κB |
| Vaccinium myrtillus (bilberry) | |||||
| 92 | IBS | O: bilberry and other compounds D-IBS (n = 21) and C-IBS (n = 10), 3 weeks | Stool frequency and consistency | Small improvement in C-IBS but not in D-IBS | ±** Small sample, no control |
| 93 | UC | O: mild to moderate active UC (n = 13), 6 weeks treatment + 3 weeks | Remission, CAI, SIBDQ fecal calprotectin, endoscopy, histology score | 63% remission at 6 weeks which did not last in the follow-up | +** No control, small sample size |
| Boswellia serrata (frankincense, shallaki, salai) | |||||
| 52 | CC | RDBP: extract vs. placebo in collagenous colitis (n =26), 6 weeks | Clinical remission, SF-36 questionnaire, colonoscopy, stools | More patients in remission 63.6 vs. 26.7%; no effect on colonoscopy or SF-36 | ++**** Small sample |
| 94 | CC | RDBP: collagenous colitis in remission (n = 82), 52 weeks | Remission maintenance, time to relapse, CDAI and IBDQ | Terminated early due to no difference | ±**** Good safety profile |
| 49 | CD | RDBC: extract (n = 44) vs. mesalamine (n = 39), 8 weeks | CDAI noninferiority vs. mesalamine | CDAI decreased: 90 (treated) and 53 points (controls) | ++*** |
| 53 | CD | O: diet with curcumin, vitamins, microbiotics and others, juvenile CD (n = 6) | Clinical remission, weight gain | Prolonged remission (years) in most with continued therapy; improved patient growth | ++** Small sample, requires maintaining diet, role of Boswellia not clear |
| 54 | UC | O: active UC, resin (n = 20) vs. sulfasalazine (n = 10), 6 weeks | Remission, stool properties, histopathology, serum and blood biochemistry | More effective for remission (14/20) than sulfasalazine (4/10) | ++** Small trial, short time period |
| Capsicum annuum (chili pepper) | |||||
| 95 | IBS | RDBP: red pepper (n = 23) vs. placebo (n = 27), 6 weeks | Likert scale, pain, and bloating | Low efficacy at low doses, abdominal pain at higher doses | -*** Doses need to be optimized |
| 96 | IBS | RDBP: red pepper (n = 15) vs. placebo (n = 15), 5 weeks | Symptom score, epigastric pain, fullness, nausea | Relief more significant in pepper (60%) than placebo (30%) | +*** Small sample |
| 97 | IBS | RP crossover: Guajillo chili vs. placebo (n = 10), 7 days each phase | Rectal pain threshold and upper abdominal discomfort | Decreased pain threshold, but increased upper abdominal discomfort | -*** Small sample |
| Carn osine | |||||
| 98 | IBS | RDBP: dose escalation study 500, 1,000, 1,500 mg (n = 25), 12 weeks | Diarrhea symptoms | Diarrhea decreased after 1,500 mg | ++*** Gulf War syndrome |
| Matricaria chai nomilla (chamomile | |||||
| 62 | UC | RDBC: chamomile + myrrh + coffee charcoal vs. mesalamine (n = 96), 12 months | Noninferiority measured by CCAI and relapse rates | Relapse rates similar to mesalamine | ++***** Role of chamomile not clear |
| 61 | UC | RDBC: chamomile + myrrh + coffee charcoal vs. mesalamine (n = 39), 12 months | CD4 + T-cell compartment | With mesalamine there was a steady decrease with flare but different patterns with chamo. | ++***** Role of chamomile not clear |
| Curcumin (isolated from Curcuma longa which is turmeric) | |||||
| 58 | IBD | O: UC (n = 5), CD (n = 5), 3 months | Clinical assessment and blood parameters | Improvement with curcumin | +* No controls, very small sample |
| 59 | IBD | O: pediatric UC/CD patients (n = 11), 6 weeks | Tolerability in pediatric patients and disease indices | Improvement in some patients, 3 g/day tolerated in all patients | ±* Small study, no controls, limited determinations |
| 55 | IBS | RB: turmeric extract (72 or 144 mg) (n = 207), 8 weeks | Questionnaires on pain and discomfort, self-reported effectiveness | Similar improvement at both doses compared to initial baseline | ++** IBS symptoms can fluctuate over time; no controls |
| 56 | UC | RDBP: mesalamine plus curcumin/placebo refractory to mesalamine (n = 50), 1 month | Remission, SCCAI and endoscopy | Effective for all parameters | ++**** Short duration of study |
| 57 | UC | RDBP: mesalamine with curcumin enema or placebo (n = 45), 8 weeks | UCDAI, improvement in endoscopic activity, remission | More improvement in all parameters than by placebo | ++*** Short study duration |
| Ferrous fumarate | |||||
| 99 | IBD | O crossover: ferrous fumarate vs. iron sucrose (n = 19), 14 days each in iron deficiency anemia IBD | CDAI, UCDAI, general well-being, abdominal pain, vascular oxidative stress | Ferrous fumarate increased disease activity, iron sucrose increased oxidative stress | _** |
| Camellia sinensis (green tea) | |||||
| 100 | UC | RDBP: EGCG (n = 15) or placebo (n = 4), 7 weeks | Remission, UCDAI; IBD questionnaire | Remission 8/15 vs. placebo 0/4 (p = 0.1); UCDAI decrease in 10/15 vs. 0/4 with placebo | ++*** Small sample and short duration |
| Actinidia deliciosa (kiwifruit) | |||||
| 101 | IBS | O: IBS (constipation/ diarrhea) patients (n = 41), 5 weeks | Stool properties and frequency | Improved bowel function | +* Small sample size, no controls |
| Pistacia lentiscus (mastic gum) | |||||
| 102 | CD | O: active CD patients (n = 18), 4 weeks | CDAI, IL-6, TNF-α, CRP and total antioxidant potential | Improvement in all parameters | +** No adverse effects, small sample size, no controls |
| N-acetyl cysteine | |||||
| 103 | UC | RDBP: combination therapy with mesalamine (n = 37), 4 weeks | Modified Truelove Witts Severity Index, remission | Small benefits for the measured parameters | +*** Small sample and short duration |
| Oxpentifylline | |||||
| 104 | CD | O: active CD patients (n = 16), 4 weeks | CDAI, endoscopic inflammation | No improvement | ±* It is a TNF-α inhibitor |
| Mentha piperita (peppermint) | |||||
| 72 | IBS | RDBP: oil vs. placebo (n = 90), 8 weeks | Pain and quality of life based on three types of questionnaires | Severity of pain decreased vs. placebo | +** High dropout rate |
| 69 | IBS | RDBP: oil vs. placebo, D-IBS patients (n = 74), 6 weeks + 2 week follow-up | Change in symptoms at 3, 6 and 8 weeks | Small but significant difference at 6 weeks; none after the follow-up | +*** Abstract only available, dose not quoted |
| 71 | IBS | RDBP: oil (n = 35) vs. placebo (n = 37) IBS-mixed or D-IBS, 4 weeks | Total IBS Symptom Score | Significantly better at 24 h; at 4 weeks: 40% reduction vs. 24% with placebo (p = 0.0246) | +*** Used a sustained release preparation |
| 105 | IBS | RDBP: oil vs. placebo, pediatric IBS (n = 42), 2 weeks | Neurological exam, gastrointestinal symptom rating scale, other variables | Pain decreased in 75% of treated group vs. 19% of placebo; no other changes | +*** Short and small trial |
| 67 | IBS | RDBP: oil (n = 52) vs. placebo (n = 49), 1 month | Pain, distension, stool frequency, flatulence, borborygmi | Symptoms improved significantly compared to placebo (p < 0.05) | ++*** Well tolerated, short duration |
| 68 | IBS | RDBP: oil vs. placebo (n = 18), 3 weeks | Symptom severity, stool frequency | Worked better than placebo | +*** Small sample and short duration |
| 70 | IBS | RDBP oil vs. placebo (n = 57), 4 weeks + 4 week follow-up | Symptom changes and Total IBS Symptom Score at 0, 4, 8 weeks | Score decreased more at 4 (and 8 weeks) vs. 0 weeks (p < 0.01) vs. no change in placebo | ++*** Even at 8 weeks still partial effect |
| Punica granatum (pomegranate) | |||||
| 106 | UC | RBP: peel extract vs. placebo (n = 78), 4 weeks + 6 week follow-up | Lichtiger CAI | CAI decreased marginally, better than placebo at 4 but not 10 weeks | ±** |
| Plantago ovata (psyllium, isabgol) | |||||
| 107 | IBS | RDBP: chronic constipation with/without IBS (n = 20), 1 month | Fecal weight and colonic transit time | Stool frequency increased and transit time decreased vs. no change with placebo | ++*** Small sample |
| 108 | UC | OR: psyllium (n = 35) or mesalamine (n = 37) or both (n = 30), 1 year | Maintenance of remission | Failure rate: psyllium (40%), mesalamine (35%) vs. both (30%) | ++*** |
| Pycnogenol | |||||
| 109 CD | O: pediatric patients in remission (n = 15) vs. healthy controls (n = 15), 10 weeks | Oxidative stress markers | Positive improvement | +* Small study, good study on CDAI vs. oxidative stress | |
| Resveratrol (red wine) | |||||
| 110 | UC | RDBP: resveratrol vs. placebo, active UC (n = 50), 6 weeks | Serum inflammatory markers, IBDQ-9, CCAI | Greater reduction in TNF-α, CRP, NF-kB and CCAI vs. placebo, increase IBDQ | +**** Short duration, all changes were small |
| Superoxide dismutase | |||||
| 11, 111 | CD | O: 2 trials; patients refractory to steroids (n = 26), used with desferroxamine | CDAI, anatomic healing | No relapse in 12 and 1 relapse in 9 patients | +* Open trials, placebo, more recent trials not found |
| Potentilla erecta (Tormentil) | |||||
| 112 | UC | O: escalating dose trial 1,200; 1,800; 2,400; 3,000 mg (n = 16), 3 weeks each with 4 week washout | Side effects, CAI, CRP, tannins | CAI decreased during treatment and increased during washout, no side effects | +** Safety trial, small sample |
| Artemesia species (Wormwood) | |||||
| 64 | CD | RDBP: wormwood (n = 20) vs. placebo (n = 20) with decreasing steroids 10 weeks + 10 weeks no steroids, no wormwood | Change in prednisone use, CDAI, HAMD, IBDQ, VAS | 18 treated patients stayed off steroids, CDAI, HAMD, IBDQ, and VAS improved, placebo patients deteriorated without steroids | ++**** Longer duration study would be beneficial |
| 65 | CD | OC: usual medications with (n = 10) or without wormwood (n = 10), 6 weeks | TNF-a levels, CDAI, Hamilton Depression Scale, IBDQ | Improvement in all parameters with wormwood | ++** Small sample and short duration |
Types of trials: O, open, R, random, B, blind, DB, double blind, C, controlled, P, placebo controlled. Benefit ratings: ++, clear benefit, +, some benefit, ±, no benefit, –, adverse effects outweigh benefits. Quality of studies: *****, RDBP or RDB crossover or RDBC trials with good sample size and duration of several weeks to years, the number of stars decrease with the quality of trial. Indices and scoring systems of GI diseases: IBDQ (inflammatory bowel disease questionnaire) is the most comprehensive and contains 60 questions on current status and history of GI health, bowel movements and anxiety, general health, energy, ability to focus, medication, and other diseases [113]; CDAI (Crohn's Disease Activity Index) is a weekly sum of the scores based on lost fluid or the number of very soft stools, abdominal pain, arthritis/arthralgia, mucocutaneous lesions, iritis/uveitis, anal disease, external fistula, fever over 37.8°C, antidiarrheal use, abdominal mass, low hematocrit, and body weight [114]; CDEIS (Crohn's Disease Endoscopic Index of Severity) is based on locations of deep or superficial lengths of the surface involved in the disease and ulcerated surface [115]; IBS score is based on stomach pain, distension, bowel movement satisfaction and comfort, bowel habits and structure including passing of mucus and blood, effect of bowel movements on pain, and history of absence from work due to stomach problems [116]; SCCAI (Simple Clinical Colitis Activity Index) is based on bowel frequency during the day and during the night, urgency for defection, blood in stool, general well-being, and extracolonic features [117]; SIBDQ is a shorter version of the CDAI questionnaire; UCDAI (Ulcerative Colitis Disease Activity Index) is based on stool frequency, rectal bleeding, mucosal appearance, and the physician's rating of disease activity [118]; Rutgeerts score, NRI (Nutrition Risk Index) EuroQol, Modified Truelove Witts Severity Index (also called Lichtiger CAI), DAI (Disease Activity Index), VAS score for pain, and Likert scale pain and bloating have also been used.