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Aliment Pharmacol Ther 2004; 19: 739–747.
Randomized, double-blind, placebo-controlled trial of oral aloe vera gelfor active ulcerative colitis L . L A N G M E A D * , R . M . F E A K I N S * , S . G O L D T H O R P E   , H . H O L T   , E . T S I R O N I * , A . D E S I L V A * ,D . P . J E W E L L   & D . S . R A M P T O N **Centre for Gastroenterology, Institute of Cellular and Molecular Science, Barts and The London, Queen MarySchool of Medicine and Dentistry, London, UK;  Department of Gastroenterology, John Radcliffe Hospital,Oxford, UK haemoglobin, platelet count, erythrocyte sedimentation rate, C-reactive protein and albumin.
Background: The herbal preparation, aloe vera, has been Results: Clinical remission, improvement and response claimed to have anti-inflammatory effects and, despite a occurred in nine (30%), 11 (37%) and 14 (47%), lack of evidence of its therapeutic efficacy, is widely used respectively, of 30 patients given aloe vera, compared by patients with inflammatory bowel disease.
with one (7%) [P ¼ 0.09; odds ratio, 5.6 (0.6–49)], one Aim: To perform a double-blind, randomized, placebo- (7%) [P ¼ 0.06; odds ratio, 7.5 (0.9–66)] and two controlled trial of the efficacy and safety of aloe vera gel (14%) [P < 0.05; odds ratio, 5.3 (1.0–27)], respectively, for the treatment of mildly to moderately active of 14 patients taking placebo. The Simple Clinical Colitis Activity Index and histological scores decreased sig- nificantly during treatment with aloe vera (P ¼ 0.01 were randomly given oral aloe vera gel or placebo, and P ¼ 0.03, respectively), but not with placebo.
100 mL twice daily for 4 weeks, in a 2 : 1 ratio. The Sigmoidoscopic scores and laboratory variables showed primary outcome measures were clinical remission no significant differences between aloe vera and pla- (Simple Clinical Colitis Activity Index £ 2), sigmoido- cebo. Adverse events were minor and similar in both scopic remission (Baron score £ 1) and histological remission (Saverymuttu score £ 1). Secondary out- Conclusion: Oral aloe vera taken for 4 weeks produced a come measures included changes in the Simple Clinical clinical response more often than placebo; it also reduced Colitis Activity Index (improvement was defined as a the histological disease activity and appeared to be safe.
decrease of ‡ 3 points; response was defined as remis- Further evaluation of the therapeutic potential of aloe sion or improvement), Baron score, histology score, vera gel in inflammatory bowel disease is needed.
been used medicinally for over 5000 years by Egyptian, Indian, Chinese and European cultures. Aloe vera gel is Aloe vera is a stemless, drought-resisting succulent of the mucilaginous aqueous extract of the leaf pulp of Aloe the lily family. It is indigenous to hot countries and has barbadensis Miller. It contains over 70 biologically activecompounds and is claimed to have anti-inflammatory,anti-oxidant, immune boosting, anti-cancer, healing, Correspondence to: Professor D. S. Rampton, Endoscopy Unit, Royal anti-ageing and anti-diabetic properties.1 Aloes, by London Hospital, London E1 1BB, UK.
E-mail: d.rampton@qmul.ac.uk contrast, is an anthraquinone derivative of the sap of the aloe leaf which has been used for centuries as a the John Radcliffe Hospital, Oxford, between March 1999 and July 2003. The diagnosis of ulcerative colitis Aloe vera gel is widely promoted for the treatment of was confirmed by standard clinical, radiological, endo- digestive disorders, skin diseases and wound healing.
scopic and histological criteria prior to inclusion in the Although there is, as yet, little scientific evidence to trial; demographic and clinical details are shown in support these claims, in vitro studies have shown that Table 1. The Ethics Committee at each centre approved aloe vera has anti-oxidant and other anti-inflammatory the study. Patients gave written informed consent effects (see ‘Discussion’ section), and a randomized trial and the study was conducted according to the principles has shown that topical aloe vera gel is superior to of the Second Declaration of Helsinki.
placebo in the treatment of plaque psoriasis.2 The trial profile is shown in Figure 1. The inclusion Because conventional therapies for inflammatory criteria were an age of 18–80 years, mildly to moder- bowel disease are not always successful in achieving ately active ulcerative colitis [as defined by a modified remission or preventing relapse, and may cause serious (see below) Simple Clinical Colitis Activity Index side-effects, up to 50% of patients seek alternative (SCCAI) ‡ 3]7 and no recent changes in conventional options.3–5 In our own survey, aloe vera was the single most widely used herbal therapy.6 This, and the The exclusion criteria were as follows: acute severe beneficial effect of aloe vera in psoriasis, led us to ulcerative colitis requiring hospital admission (SCCAI > investigate the efficacy and safety of oral aloe vera gel, 12); inactive disease (SCCAI < 3); positive stool exami- given for 4 weeks, in a randomized, double-blind, nation for pathogens; Crohn’s disease or indeterminate placebo-controlled trial in patients with mildly to colitis; use of antibiotics, warfarin, cholestyramine, moderately active ulcerative colitis.
sucralfate, anti-diarrhoeal drugs (loperamide, codeinephosphate, diphenoxylate), non-steroidal anti-inflam-matory drugs, aspirin > 75 mg/day, aloe vera or other herbal remedies; alcohol or drug abuse; pregnancy orbreast feeding; female of child-bearing age not taking adequate contraception; participation in another drug Patients who met the inclusion criteria shown below trial in the previous 3 months; and serious liver, renal, and consented to participate were consecutively recrui- cardiac, respiratory, endocrine, neurological or psychi- ted at Barts and The London NHS Trust, London, and atric illness. Patients were also excluded if they hadaltered their dosage of aminosalicylates in the previous4 weeks, had taken > 10 mg/day or had altered their Table 1. Demographic details of patients recruited to the trial oral prednisolone dosage in the previous 4 weeks, had Patients not fulfilling inclusion criteria 2 Patients lost immediately from further review 3 Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747 A L O E V E R A F O R U L C E R A T I V E C O L I T I S changed their dose of azathioprine or 6-mercaptopurine cyte sedimentation rate were measured. Diary cards in the previous 3 months, or had used more than five were issued for the next 2 weeks. Aloe vera or placebo corticosteroid or aminosalicylate enemas in the previous was dispensed with instructions about dosage. Patients were instructed to continue any long-term prophylacticmedication (see inclusion criteria above) unalteredthroughout the 4-week trial.
Patients were reviewed at 2 and 4 weeks after starting Treatments consisted of a liquid to be taken orally. The treatment. At each visit, diary cards were collected to active treatment was aloe vera gel (kindly provided by calculate the SCCAI and to record compliance with Dr Peter Atherton, Forever Living Products, Jersey, the study medication. The interviewing doctor made a Channel Islands). The placebo consisted of a liquid global assessment of disease activity (physician’s global preparation containing flavourings, but no known assessment, scored thus: much better, + 2; slightly better, active agents (synthesized by Flavex International Ltd, + 1; the same, 0; slightly worse, ) 1; much worse, ) 2).
Hereford, UK), which was identical in taste and Blood count and routine biochemistry were checked appearance to the aloe vera preparation. The dose used for safety purposes. After 4 weeks of treatment, all the was 100 mL twice daily, this being the maximum dose procedures undertaken at weeks 0 and 2 were repeated.
tolerated and commonly employed by individuals usingaloe vera gel for a range of indications. Patients were advised to start with 25–50 mL twice daily for up to3 days to ensure tolerability and to minimize the risk of To minimize the risk of adverse effects of the trial side-effects. The daily dosage of trial medication was medication on their well-being, patients were with- recorded by participants on their daily symptom diary drawn if, at any time, they or their physician believed that they had deteriorated substantially. These patientswere then given topical or oral conventional therapy.
Patients who were withdrawn were offered continued follow-up in the out-patient clinic to ensure their well- Eligible patients were interviewed and informed of the being and the absence of side-effects of the study details of the trial verbally and in writing. Those agreeing to participate were issued with a writteninformation sheet prior to signing a consent form. They underwent history review and physical examinationand were issued with a symptom diary card for the Disease activity scores were calculated using the SCCAI.7 SCCAI (see below); a stool specimen was sent for culture This was modified to allow inclusion of patients with for pathogens, including Clostridium difficile (Figure 1).
active proctitis, but without increased stool frequency.
Patients were reviewed after 1 week (i.e. at week 0 of The modification involved altering the scores for stool the treatment period). Those meeting the inclusion frequency so that patients recording zero or one bowel criteria were randomized by a trial pharmacist at Barts movement in a day scored zero, those with 2–3 stools and The London NHS Trust, using a computer-gener- scored 1 point, those with 4–6 scored 2, those with 7–9 ated, block-design, randomization sequence, to receive scored 3 and those with > 9 scored 4. To confirm the active herbal remedy or placebo; a ratio of 2 : 1 for aloe validity of this minor modification, we showed that, in patients at baseline, the SCCAI was significantly Patients completed the Inflammatory Bowel Disease negatively correlated with the IBDQ8 (R ¼ ) 0.63, Questionnaire (IBDQ) for the quality of life.8 At the same P < 0.0001); it also correlated positively with the Baron visit, rigid sigmoidoscopy was performed and mucosal sigmoidoscopic score9 (R ¼ + 0.35, P < 0.03).
appearances were assessed using the Baron score.9 Arectal biopsy was taken for histological scoring of disease activity.10 The SCCAI for the preceding week,blood count, routine biochemistry including serum The primary outcome measures were clinical remission albumin concentration, C-reactive protein and erythro- (defined as SCCAI £ 2), sigmoidoscopic remission Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747 [Baron score of zero (normal-looking mucosa) or one Wilcoxon signed rank test was used to assess changes (mucosal oedema as indicated by loss of the normal from baseline to week 4 in SCCAI, IBDQ, physician’s vascular pattern)]9 and histological remission (Savery- global assessment, sigmoidoscopic score, histological muttu score of £ 1, i.e. no loss of colonocytes, absence grade and blood test results. Where data at the week 4 of crypt inflammation, and normal lamina propria visit were missing because of earlier patient withdrawals content of mononuclear cells and neutrophils).10 All or other reasons, the last-value-carried-forward tech- histological grades were assessed by the same experi- nique was used. All analysis was undertaken on an enced histopathologist (RMF) blind to the treatment Statistical calculations were made using computer The secondary outcome measures included changes in software programs (Microsoft Excel and GraphPad the clinical condition, assessed by the SCCAI (improve- Prism 3.02). Numerical results are expressed as the ment defined as a reduction in score of ‡ 3 points; median and interquartile range. Because all the com- response defined as remission or improvement), physi- parisons to be made were planned prospectively, no cian’s global assessment and IBDQ; changes in the correction for multiple comparison was applied.12 All tests were two-tailed and significance was reported at decrease of ‡ 2 points) and histological score (improve- ment defined as a decrease of ‡ 3 points); and changesin laboratory measures of inflammation, haemoglobin,platelet count, erythrocyte sedimentation rate, C-react- Possible adverse effects of the trial medications were The flow of the patients through the trial is shown inFigure 1. Of the 49 patients assessed and entered intothe trial, five were excluded from further analysis after Power calculations and statistical analysis randomization. Of these, two patients were found, on On the assumption of a 10% clinical remission rate with analysis of their case record forms, to have inactive placebo11 and a 50% remission rate with aloe vera disease at entry (SCCAI ¼ 1) and three patients failed to gel, and with the use of a 2 : 1 aloe vera : placebo return for review after the trial consultation at week 0 randomization scheme, 45 patients were required to despite repeated attempts to make contact with them.
detect this difference at the 5% level of significance (two- Forty-four evaluable patients were therefore randomly tailed) with 80% power. All patients who met the given aloe vera gel (n ¼ 30) or placebo (n ¼ 14). There inclusion criteria and were effectively followed up were were no significant differences between the two treat- ment groups at baseline in relation to age, gender, Fisher’s exact test was used to compare treatment and disease extent, current conventional therapy, disease placebo groups with respect to gender. The chi-squared activity, sigmoidoscopic score, histological grade or test was used to compare treatment and placebo groups in relation to baseline disease extent and therapy. TheMann–Whitney U-test was used to compare the groups at baseline in relation to age, SCCAI, IBDQ, sigmoido-scopic score, histological grade and blood results.
Six patients (20%) given aloe vera gel and three patients Correlations at baseline between SCCAI, IBDQ and (21%) given placebo withdrew from the study because sigmoidoscopic score were assessed by Spearman’s rank of deterioration or a failure to improve sufficiently.
Variables recorded at the time of their withdrawal were Fisher’s exact test was used to compare the proportions included in the data analyses shown below.
of patients in each group who achieved clinical,sigmoidoscopic or histological remission, improvement or response after 4 weeks. Odds ratios (with 95%confidence limits) were calculated to compare the effects After 2 weeks of therapy, clinical remission (SCCAI of aloe vera and placebo. For each treatment group, the £2 points), improvement (fall in SCCAI of ‡ 3 points) Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747 A L O E V E R A F O R U L C E R A T I V E C O L I T I S oral aloe vera gel and placebo showingclinical, sigmoidoscopic and histological CL, confidence limit; OR, odds ratio; SCCAI, Simple Clinical Colitis Activity Index.
Numbers of patients for each measure vary as not all patients underwent follow-up sig-moidoscopy or rectal biopsy; numbers recorded (n) are those with paired data. P values(Fisher’s exact test) and OR (95% CL) are shown.
Table 3. Numerical values of all measures assessed before and after 4 weeks of treatment with oral aloe vera gel or placebo CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IBDQ, Inflammatory Bowel Disease Questionnaire; PGA, physician’s globalassessment; SCCAI, Simple Clinical Colitis Activity Index.
Medians (interquartile range) are shown.
* P < 0.05 from pre-treatment value.
and response were noted in three (10%), five (17%) and [P ¼ 0.048; OR, 5.3 (1.0–27)]. The median SCCAI five (17%) patients taking aloe vera gel, but in no showed a small but statistically significant fall after patients given placebo. These apparent differences did 4 weeks of treatment with aloe vera (P ¼ 0.01), but not not reach statistical significance (data not shown).
Clinical remission (SCCAI £ 2 points) at 4 weeks The physician’s global assessment showed no change occurred in nine of 30 patients (30%) given aloe vera during the treatment period in either patient group gel, compared with one of 14 patients (7%) given (Table 3). The IBDQ was also unaltered during 4 weeks placebo [P ¼ 0.09; odds ratio (OR), 5.6 (0.6–49)] of treatment with aloe vera. In contrast, in the eight (Table 2, Figure 2). Clinical improvement after 4 weeks placebo-treated patients who completed the IBDQ before (fall in SCCAI of ‡ 3 points) was recorded in 11 patients and after the trial period, the median score rose (37%) on aloe vera and in one patient (7%) on placebo significantly (P ¼ 0.03); unfortunately, however, the [P ¼ 0.06; OR, 7.5 (0.9–66)]. Fourteen patients (47%) three patients in the placebo group who withdrew from given aloe vera showed a clinical response at 4 weeks, the trial failed to return the questionnaires they were compared with two (14%) of those taking placebo Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747 protein or serum albumin concentration, most of whichwere normal or only marginally abnormal on recruit- Adverse effects recorded in the patients taking aloe veragel and placebo were minor, similar and not clearly related to the study medications. Of the 30 patientsrandomized to aloe vera gel, one complained of abdominal bloating, one of pain in her feet, one of sore throat, one of transient ankle swelling, one of acne andone of worsening eczema. Of the 14 patients taking placebo, two reported bloating, one foot pain and oneacne. No patients developed abnormal blood tests attributable to aloe vera gel or placebo, or were withdrawn from the trial because of adverse effects.
Herbal therapies in general, and aloe vera in particular, are already widely used by patients with inflammatorybowel disease.3–5 Previous clinical trials of varying design and accessibility have claimed that Boswellia approaches are beneficial in active ulcerative coli- tis.14, 15 In this randomized, double-blind, placebo- controlled clinical trial, treatment for 4 weeks with oral Figure 2. Changes in the Simple Clinical Colitis Activity Index aloe vera gel produced a symptomatic clinical response (SCCAI) induced by 4 weeks of treatment with oral (a) aloe vera more frequently than did placebo. In addition, the gel (n ¼ 30) or (b) placebo (n ¼ 14). The dotted line denotes the clinical (SCCAI) and histological disease activity scores fell in the aloe vera-treated group of patients, but not inthose given placebo. The magnitude of the effect of aloe Sigmoidoscopic and histological appearances vera, as indicated by a clinical response rate of nearly There were no significant differences in the proportions 50%, and an odds ratio over placebo of over five, of patients in the two treatment groups entering resembles that reported for mesalazine in a meta- sigmoidoscopic remission (Baron score of 0 or 1) or showing sigmoidoscopic improvement (defined by a fall The sample size and power calculation for this study in Baron score of ‡ 2 points) (Table 2). The same was were influenced by our desire to restrict to a minimum true for the histological scores (Table 2). However, the number of patients needed to be treated with aloe although the sigmoidoscopic score showed no signifi- vera or placebo in order to obtain a meaningful result.
cant changes in either treatment group, the histological At the outset, we had no pointers as to either the score fell significantly in patients given aloe vera gel for therapeutic efficacy or safety of aloe vera in patients with active ulcerative colitis. To minimize the number ofpatients exposed to aloe vera, were it to prove to beineffective or unsafe, we decided to use a placebo- controlled trial design rather than one using an active Neither aloe vera gel nor placebo had a significant effect comparator, such as mesalazine. In order to minimize on the patients’ haemoglobin, platelet count, C-reactive the number of patients given placebo, we used a 2 : 1 Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747 A L O E V E R A F O R U L C E R A T I V E C O L I T I S aloe vera to placebo ratio, aiming for an absolute between response to aloe vera and disease activity at improvement in outcome of 40% for the active over recruitment, disease extent and use, or not, of concur- In some trials in inflammatory bowel disease, the The preparation of aloe vera given in this trial is response (as opposed to remission) rate in patients given reported to contain a high proportion (> 95%) of the placebo has approached 50%. However, in designing active ingredient, namely the pulp of the leaf of the aloe this trial in 1998, we focused specifically on the placebo- vera plant; some commercially available preparations related remission rate in out-patients with active ulcer- contain far less (International Aloe Science Council, ative colitis. In the event, our placebo rate for remission http://www.iasc.org).17 The dose of aloe vera gel used (7%) closely resembled the 10% figure which was taken in this trial was the maximum recommended by the for our power calculations from the meta-analysis manufacturers, and was at the top of the range of doses published in 1997 of 44 placebo-controlled trials in used and tolerated by the large numbers of individuals out-patients with active ulcerative colitis.11 taking this agent for this and other indications. It is In retrospect, it is to be regretted that our trial was not conceivable, however, that a higher dose might have larger, as the clinical remission and improvement rates been more efficacious, albeit possibly at the expense of on aloe vera gel failed to reach statistical significance.
more side-effects, of which none of note occurred during Nevertheless, several factors support the view that aloe this trial. Conversely, any conclusions drawn from this vera has a genuine, albeit modest, anti-inflammatory study cannot necessarily be extrapolated to other therapeutic effect in mildly to moderately active ulcer- preparations or lower doses of aloe vera.
ative colitis. First, there was a trend in favour of aloe The mechanisms by which aloe vera gel may act are vera for these two variables at 2 weeks as well as at unclear. In vivo, aloe vera reduces irritant-induced 4 weeks. Second, the improvement in SCCAI after production of inflammatory mediators in paw, ear and 4 weeks of aloe vera covered all the domains of the synovial models of inflammation in animals.18–20 Aloe scoring system, and was not due solely, for example, to vera gel and its components also ameliorate ultraviolet- a reduction in stool frequency, as might have occurred with a constipating agent such as loperamide. Third, In vitro, several fractions of aloe vera, as well as the the histological scores showed a small, but statistically unfractionated whole gel, have anti-oxidant effects.25– significant, improvement in patients given aloe vera for 27 Aloe vera gel contains peroxidase activity,28 several 4 weeks. Finally, the sigmoidoscopic appearances also superoxide dismutase enzymes29 and a phenolic anti- showed a trend in favour of aloe vera at 4 weeks. In the latter context, the standard scoring system which was Aloe vera appears to have various immuno-inhibitory used to assess the mucosal appearance macroscopically effects. Extracts of the gel reportedly deplete complement is known to be prone to inter-observer variability at its in pooled human serum by an effect on the alternative lower grades:10 this factor could conceivably have pathway,30 inhibit ultraviolet irradiation-induced re- prevented the detection of a significant improvement lease of tumour necrosis factor-a by human epidermoid carcinoma cells,24 and reduce histamine and leukotri- Despite the significant inverse correlation between ene release from guinea pig mast cells.31 SCCAI and IBDQ scores pre-treatment, the improvement Finally, and in contrast, aloe vera gel and one of its (rise) in median IBDQ in the aloe vera gel-treated principal components, acemannan, have been reported patients failed to reach statistical significance. This to possess immuno-stimulatory properties. Acemannan finding may represent a type 2 statistical error, as the up-regulates nitric oxide production by chicken spleen trial was not powered specifically for changes in IBDQ.
cells and HD11 cell lines, an effect mediated through Conversely, as indicated in the ‘Results’ section, the mannose receptors.32 In addition, acemannan stimu- apparent improvement in quality of life in the placebo- lates the release of reactive oxygen metabolites, inter- treated subjects is likely to have been a consequence of leukin-1, interleukin-6 and tumour necrosis factor-a incomplete IBDQ data collection in the individuals from murine macrophages.33–35 Acemannan also pro- withdrawing from the trial prematurely.
motes differentiation and maturation of dendritic cells34 Because the trial was small, sub-group analysis was and increases human T-cell responsiveness to allo- inappropriate. However, there was no obvious relation Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747 In designing this trial, we were in agreement with 4 Hilsden RJ, Meddings JB, Verhoef MJ. Complementary and pharmaceutical commentators17, 37 and the Medicines alternative medicine use by patients with inflammatory boweldisease: an internet survey. Can J Gastroenterol 1999; 13(4): Control Agency that there was an urgent need to evaluate formally the efficacy and safety of aloe vera gel 5 Moser G, Tillinger W, Sachs G, et al. Relationship between the in the treatment of ulcerative colitis. We felt that the use of unconventional therapies and disease-related concerns: demonstration of the efficacy of aloe vera, a ‘natural’ a study of patients with inflammatory bowel disease. J Psy- product, would be helpful for the many patients currently using herbal therapy and specifically this 6 Langmead L, Chitnis M, Rampton DS. Use of complementary therapies by patients with IBD may indicate psychosocial preparation. In contrast, a failure to show benefit, or the distress. Inflamm Bowel Dis 2002; 8(3): 174–9.
identification of adverse effects, would have resulted in 7 Walmsley R, Ayres R, Pounder R, Allen R. A simple clinical advice to patients to avoid using this expensive product colitis activity index. Gut 1998; 43: 29–32.
(up to £20 per week, depending on the dose and 8 Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment ofinflammatory bowel disease. Canadian Crohn’s Relapse Pre- Our results are encouraging, although not conclusive.
vention Trial Study Group. Gastroenterology 1994; 106(2): They indicate the need for further larger controlled trials of aloe vera gel, not only in moderately active 9 Baron J, Connell A, Lennard-Jones A. Variation between ulcerative colitis, but also in the maintenance of observers in describing mucosal appearances in proctocolitis.
remission in ulcerative colitis and in Crohn’s disease; direct comparisons with mesalazine would be worth- 10 Saverymuttu S, Camilleri M, Rees H, et al. Indium-111 gra- nulocyte staining in the assessment of disease extent and while. Until such studies are performed, patients with activity in inflammatory bowel disease. Gastroenterology inflammatory bowel disease should be advised to exercise caution and, in particular, should not use aloe 11 Ilnyckyj A, Shanahan F, Anton P, Cheang N, Burnstein C.
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for Healthcare Professionals. London: The Pharmaceutical An anti-complementary polysaccharide with immunological Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 739–747

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