Aloe Vera Gel Research Review

An overview of its clinical uses and proposed mechanisms of action

By Oliver Grundmann, BPharm,ms,PHD

Abstract

Aloe vera, commonly known as Barbados or Curaçao Aloe, is an herbal medicine with a long tradition of use by a variety of cultures. The succulent plant grows in arid and subtropical climates and is best known for 2 distinct preparations: the clear mucilaginous gel that is widely used for the treatment of minor burns, especially sunburns, and the thick sap of the leaves that turns yellow-brown and has strong laxative effects that caution its use. The traditional uses of the clear mucilaginous gel are manifold, ranging from topical applications to reduce perspiration to oral dosing for diabetes and a range of gastrointestinal ailments. The efficacy of aloe vera gel to treat burn wounds, genital herpes, and seborrheic dermatitis have been shown in clinical trials, but other indications such as psoriasis or internal application for the treatment of type 2 diabetes remain inconclusive. The main limitation of the current clinical knowledge about aloe vera gel is small clinical studies that often lack rigorous methodology. Several clinical trials are being conducted to further evaluate the use of aloe vera gel for a variety of disorders, as well as to further confirm traditional uses of the plant extract.

Introduction

Aloe vera (syn. Aloe barbadensis Mill., Fam. Liliaceae), also known as Barbados or Curaçao Aloe, has been used in traditional and folk medicines for thousands of years to treat and cure a variety of diseases. Although the plant is native to northern parts of Africa, it has rapidly spread across the world because its cultivation is easy. An important distinction has to be made between the strongly laxative and purgative latex derived from the bundle-sheath cells and the clear mucilaginous gel. The plant has been used by Egyptians, Assyrians, and Mediterranean civilizations, as well as in Biblical times. A variety of aloe species are still used in folk medicines of Africa and Asia. Hunters in the Congo reportedly rub their bodies in the clear mucilaginous gel to reduce perspiration; some African tribes apply the gel for chronic conjunctivitis; the gel is used in India for the treatment of asthma.1

Aloe vera gel is used as an ethnomedicine in Trinidad and Tobago for hypertension.2 The most common folk use of aloe has been for the treatment of burn wounds and specifically to aid in the healing process, reduce inflammation, and tissue scaring. The gel was described by Dioscorides and used to treat wounds and mouth infections, soothe itching, and cure sores.3 The use of aloe vera gel as a household remedy in the United States was triggered by reports of its beneficial effect on radiation dermatitis4 followed by a boom in cultivation in the 1930s; it remains a common plant and for burns and abrasions.1,5 Important contemporary uses of the gel exist in traditional medicines of India, China, and Mexico, as well as Middle America and the West Indies. Mexico is producing roughly 47% of aloe worldwide with a total sales volume of $123.5 million US dollars as of 2008.6

Despite its widespread popularity, scientific evidence on the aloe vera gel remains sparse. Aloe vera gel is regarded as safe if applied topical with only a few allergic reactions being reported.7 The efficacy of aloe vera gel to treat burn wounds, genital herpes, and seborrheic dermatitis have been shown in clinical trials, but other indications such as psoriasis or internal application for the treatment of type 2 diabetes remain inconclusive. The major application of aloe vera gel remains as a skin moisturizer in cosmetics and as an après treatment for sunburns, for which it has proven its effectiveness.8,9

Description

Aloe vera is a succulent plant with thick, fleshy, serrated, lanceolate-shaped leaves of green-greyish color. Aloe vera inner gel is obtained from the lower leaves of the plant by slicing the leaf open. The gel is clear, odorless, and tasteless and should be free of leaf skin or yellow parts. No consistent standardization has been established, but the International Aloe Science Council (IASC), a trade association of internationally based aloe producers and marketers, requires adherence to certain specifications for the product to be certified.10 Other preparations include a hydrophilic cream containing 0.5% aloe vera gel and an emulsion consisting of 30% aloe vera gel.

Primary Uses

(determined by clinical trials)

External

  • Mild to moderate burns11–13 as well as erythema14
  • Genital herpes15,16
  • Seborrheic dermatitis17

Internal

  • Adjunct therapy of spontaneous fibrosarcomas in dogs and cats18,19

Other Potential Uses

(determined by clinical trials and/or official monographs and/or empirical use)

  • Psoriasis vulgaris20
  • Skin moisturizer8
  • Type 2 diabetes21–23
  • Malignancies and immunodeficiency viruses in cats24,25
  • Oral lichen planus infections26,27
  • Angina pectoris23
  • Ulcerative colitis28–31
  • UV-induced erythema14 Kidney stones32,33
  • Alveolar osteitis34

Dosage

External

  • For burns: Clear mucilaginous gel (pure aloe vera inner gel or preparations containing 10%–70% aloe inner gel). Gel must be stabilized by pasteurization at 75–80°C for less than 3 minutes3 and applied on affected area 3 times daily.
  • For seborrheic dermatitis: 30% aloe vera in a hydrophilic emulsion twice daily to affected area17
  • For psoriasis and genital herpes: Hydrophilic cream containing 0.5% aloe gel 3 times daily to affected area16,20

Internal

  • Treatment of diabetes and angina pectoris: recommended in humans, 100 mg of fresh inner gel each day or 1 tablespoon twice daily.23,35
  • For ulcerative colitis and irritable bowel syndrome: a dose of 25–50 ml of 95% aloe inner gel is recommended 3 times daily.28
  • Adjuvant therapy in feline and canine malignancies: Acemannan Immunostimulant®, a special preparation of the clear mucilaginous gel specifically for injection, for intraperitoneal injection in cats and dogs following chemotherapy. Weekly injections over at least 6 weeks; recommended dose is 1 mg/kg body weight of animal.18,19

Duration of Administration

External administration 3–4 times daily to affected area until improvement is seen.15,17,20 No information for duration after oral application in humans is available, but generally the gel is taken as long as the symptoms persist.23

Chemistry

The fresh gel mainly consists of water (99.1%) and mesophyll cells (0.9% dry matter), which can be divided into 3 distinct fractions: cell wall, microparticles, and liquid gel [accounting for 16.2%, 0.7%, and 83.1% of dry pulp (w/w), respectively]. The predominant sugar component is mannose as mannose-6-phosphate36 in all 3 fractions [20.4% in cell wall, 32.2% in microparticles, and 62.9% in the liquid gel (% of total sugars)], followed by other sugars in varying concentrations depending on the fraction. Overall, the 5 neutral sugars (ie, arabinose, xylose, mannose, galactose, glucose) account for 69.2% of the total sugars in the gel.37 Mucopolysaccharides are mainly present as acemannan [a highly acetylated, β-1-4-linked polysaccharide (> 1kDa) made mainly of mannose] with various side chain glycosylation patterns.38 The anthraquinone content should be below 50 ppm and is considered an impurity from the leaf extract of aloe vera.7 Other ingredients include various amino acids, enzymes, and vitamins, which have not been quantified. The IASC maintains a certification program, in which “whole aloe vera leaf gel” has to adhere to the following specifications: solids (0.46%–1.31%); pH (3.5–4.7); calcium (98.2–448 mg/L); magnesium (23.4–118 mg/L; malic acid (817.8–3,427.8 mg/L); acemannan in raw materials (≥5% by dry weight); isocitrate (≤5% for inner leaf by dry weight); raw materials ash content (≤40%); aloin (≤10 ppm in 0.5% aloe vera solids solution for oral consumption). Quality products should contain high amounts (95%) of pure aloe vera gel.39 One way of quantifying aloe polysaccharides is a colorimetric assay, which has been suggested for use in quality control of commercial products.40 Quality control and identification of commercial aloe vera products has also been accomplished by nuclear magnetic resonance spectrometry.41

Pharmacological Actions

Note: Information on the precise chemical composition of the aloe vera inner gel used for most of the below listed observed pharmacological activities is lacking. Therefore, results should be interpreted with caution in regard to reproducibility of the stated effect.

Human

Mild (first degree) to moderate (second degree) burn wounds;11–13,42 genital herpes at first onset;16,20 seborrheic dermatitis;17 oral lichen planus infections;26 postdermabrasion wound healing;43 normalization of gastric pH;44 treatment of diabetes and angina pectoris.23

Animal

Acceleration of wound healing in mice and rats;36,45–47 reduction of radiation-induced skin reactions in irradiated mice and rats;48–50 prevention of progressive dermal ischaemia caused by burns and frostbite in rats and guinea pigs; 51–53 antidiabetic in type-2 diabetic and insulin-resistant mice;21,54–57 chemopreventive in skin papillomagenesis in mice;58,59 anti-inflammatory in mice;36,60–64 enhancement of immune responsiveness in chicks and mice;65,66 amelioration of UV-induced immune suppression in mice;67 promotion of gastric ulcer healing in rats;68,69 protection of alcohol dehydrogenase and reduction of blood ethanol concentrations in rats;70 reduction of salmonella-mediated inflammation in mice;71 antioxidant and cholesterol-lowering effects in aged rats.72

In vitro

Inhibits collagenase and metalloproteinase activity in Clostridium histolyticum;73 exerts cytotoxic effects in normal and malignant tissues;74 suppresses bactericidal inflammation in human leukocytes;75,76 causes antioxidant activities and enhanced phagocytosis in human neutrophils;77-79 cell wall material stabilizes growth factors;80 inhibits pro-inflammatory cytokines;81-83 acemannan enhances T cell response through monocyte activation;84,85 induces hematopoietic and hematologic activity of carbohydrate fraction;86 acts as antifungal;87,88 stimulates cell proliferation in keratinocytes by glycoprotein fraction;47 accelerates wound healing in diabetic human skin fibroblasts;89 di(2-ethylhexyl)phthalate isolated from aloe vera leaves exerts antitumor activity;90 Aloe vera gel fraction on calf pulmonary artery endothelial cells has angiogenic activity.91

Proposed Mechanisms of Action

  • Stimulation of macrophage and fibroblast activity, increased collagen and proteoglycan synthesis36,62,85
  • Mannose-6-phosphate binds to growth factor receptor on fibroblasts and enhances their activity36,92
  • Macrophage activation through increased nitric oxide synthase activity by acemannan, leading to release of fibrogenic cytokines49,93,94
  • Upregulation of phagocytosis and fungicidal activity of macrophages by acemannan95
  • Acemannan and other cell wall biomaterial may promote stability of growth factors and prolong stimulation of granulation tissue48,80
  • Inhibition of Thromboxan A236,53
  • May promote hypoglycemic effect by normalizing membrane-bound enzyme activities of phosphatases and hydrolases and increased glucose metabolism;55,56 potential active compounds include the phytosterols lophenol, cycloartenol and their alkylated derivatives21
  • Anti-inflammatory effect of plant sterols like lupeol, campesterol, and β-sitosterol92 through bradikinase activation,61 prostaglandin F2 and E2, as well as thromboxane A2 inhibition45,81,96 and inhibition of IL-10 secretion83
  • Inhibitory effect on release of reactive oxygen species from human neutrophils by reducing intracellular free calcium levels77
  • Increase in mRNA expression of metalloproteinases and plasminogen activator may lead to angiogenic activity in endothelial cells91

Contradictions

Known allergy against aloe vera; discontinue use if skin irritation develops or worsens97

Pregnancy and Lactation

It is not recommended to use aloe vera gel during pregnancy or while breastfeeding.7 There is, however, no evidence that suggests a reproductive or genotoxic effect of topical aloe vera inner gel preparations. Internal use in combination with digoxin is contraindicated due to possible acceleration of potassium depletion.98

Adverse Effects

In general, topical application of aloe vera preparations has been regarded as safe as assessed by the Cosmetic Ingredient Review Expert Panel.7 However, several case reports of the development of hypersensitivity reactions and contact dermatitis in response to topically applied aloe gel preparations have been published.99–103 This allergic reaction has been attributed in most cases to anthraquinone contaminations in the gel.97 Macrophage infiltration and emesis has been observed in dogs treated intravenously with acemannan.104 Oral application of aloe vera gel may lower blood glucose levels and enhance the activity of antidiabetic treatments.23 No genotoxic effects have been observed following oral administration of an aloe vera inner leaf gel (Qmatrix® by Aloecorp, Inc., which is a standardized inner gel extract that has not been heated after extraction from the leaf) to rats after 90 days.105 An important factor for adverse effects is the purity of the aloe vera gel used, since anthraquinones like aloin might be related to the development of hypersensitivity reactions.99,106

Drug Interactions

When aloe vera gel is administered topical, it is generally regarded as safe.7 Aloe gel might enhance the ability of hydrocortisone to reduce swelling if applied topically.107 If ingested, it might lead to increased hypoglycemia in conjunction with oral antidiabetics or insulin.97 The American Pharmaceutical Association rates aloe vera gel for external use in category 2, meaning that “according to a number of well-designed studies and common use, this substance appears to be relatively effective and safe when used in recommended amounts.”39 Aloe vera inner gel may significantly increase the absorption of vitamins C and E after oral application.108 Aloe vera gel for systemic application is not recommended in combination with antidiabetic, diuretic, or laxative drugs; sevoflurane; or digoxin.107 In general, a 2-hour time period is recommended between oral drug application and aloe vera ingestion due to increased intestinal motility and reduced drug absorption.98 If aloe vera gel is used with any other prescription drug, the patient should inform the physician and/or pharmacist.

Clinical Review

Clinical data on aloe vera gel is sparse, which might be in part due to the many possible indications for the gel. The table outlines 18 clinical trials on a total of 7,297 subjects conducted for various types of aloe gel-derived preparations on numerous indications. The design of the clinical studies evaluated ranges from placebo-controlled, double-blind, multicenter studies to equivalence investigations. One of the most important factors is the composition of the aloe vera preparation used, which in most cases is a certain purity aloe vera gel without further elucidation of compound quantity. This discrepancy complicates a direct comparison of the studies.

Three randomized studies on the efficacy of aloe vera gel for radiation-induced dermatitis109–111 reported either a delayed onset of skin changes if aloe vera gel was applied in addition to mild soap against mild soap alone111 or no efficacy of the gel against a placebo gel or aqueous cream.109,110 A review of aloe vera for radiation-induced skin damage concluded that there is no evidence for a protective effect of the gel and that more research with well-designed studies is needed to evaluate potential benefits.112 Similar results were obtained from a clinical study evaluating the use of aloe vera gel for the treatment of radiation-induced oral mucositis with no significant differences from the placebo group.113

The historical application of aloe vera gel for the treatment of wounds has been evaluated in surgical wounds and the randomized study concluded that there was a significant delay in complete wound healing for the aloe vera gel compared to standard treatment.114

The use of aloe vera gel for the treatment of lichen planus lesions was examined in 2 clinical trials with small sample sizes. One study examined the use of aloe vera gel (containing 70% mucilage) in oral lichen planus lesions compared to placebo over 8 weeks and found a significant improvement in 88% of patients versus 4% in the placebo group.26 Another study used a similar design but with unspecified composition of the aloe vera gel and reported significant improvement in 82% of patients versus 5% in the placebo group over a period of 8 weeks.115

Three clinical trials on the effect of aloe vera gel for the treatment of psoriasis vulgaris were inconclusive. One study reported a significant beneficial effect of aloe vera extract 0.5% in hydrophilic cream compared to hydrophilic cream alone in reducing psoriatic plaques and inflammation,20 while the other study did not find a significant benefit of 98% pure aloe vera gel versus placebo after 12 weeks.116 A third study compared aloe vera cream containing 70% mucilage to 0.1% triamcinolone acetonide cream over the course of 8 weeks and found it to be equally effective.117

One study evaluated the effect of aloe vera 0.5% in hydrophilic cream and aloe vera gel versus placebo for the treatment of genital herpes15 and concluded that aloe vera in hydrophilic cream is more effective than aloe vera gel, but that both resulted in faster healing times compared to placebo.

An aloe vera emulsion showed significant benefits for the treatment of seborrheic dermatitis in a double-blind, randomized study compared to placebo,17 but the placebo formulation was different from the base used for the emulsion.

A randomized, double-blind clinical trial evaluated the effectiveness of a prepared 70% aloe vera gel for the treatment of oral lichen planus infections compared to the base gel alone and reported a significant improvement of symptoms in the aloe vera group.26

The use of aloe vera gel in the traditional medicine of India has triggered an observational, inter-patient control study using fresh aloe vera inner gel in addition to adding psyllium (Plantago ason, Plantaginaceae) seeds to the daily diet of 5,000 patients diagnosed with angina pectoris. Over the course of 5 years, patients were observed and blood cholesterol, glucose, and triglyceride levels evaluated. A cofounding variable was the influence of aloe vera gel on diabetes mellitus. Aloe vera gel had a significant influence on normalizing blood parameters and relief of angina pectoris symptoms, as well as diabetic symptoms.23 In many patients, the continued use of aloe vera gel daily led to the discontinuation of prescription medications. An important drawback of the study is the absence of a control group and no chemical definition of the aloe vera gel used in the study.

The widespread use of aloe vera gel as moisturizer and for the treatment of xerosis was evaluated in two studies.8,118 The moisturizing effects of aloe vera resulted in increased water content in the stratum corneum after short-term and long-term application of a hydrophilic cream containing various concentrations of freeze-dried aloe vera concentrate compared to the base cream alone.8 A partially blinded, non-placebo study suggests a benefit of freeze-dried aloe vera gel on the inner side of a glove to dry skin, although this study lacks both control and complete blinding.118

In addition, aloe vera gel lotions are popular for the treatment of sunburn (UV-induced erythema). One randomized, double-blind, placebo-controlled trial compared the anti-inflammatory effect of 97.5% pure aloe vera gel to 1% hydrocortisone and a placebo gel. Aloe vera gel, if applied under an occlusive bandage for 2 days following UV exposure, significantly reduced inflammation compared to placebo gel or 1% hydrocortisone in placebo gel, but was less effective than 1% hydrocortisone cream. The authors suggest that aloe vera gel might be useful for the treatment of inflammatory skin conditions.14

Two studies evaluated beneficial effects of aloe vera gel on irritable bowel syndrome30 and ulcerative colitis,28 which resulted in no significant effect for either indication, although a patient-evaluated improvement was seen for the treatment of ulcerative colitis after 1 month.

Based on its immunomodulatory effect, acemannan was evaluated for the adjunct treatment of HIV infections in addition to standard treatment (either zidovudine or didanosine).119 The one-year, double-blind, placebo-controlled, randomized trial concluded that there were no differences in CD4 count or survival after 48 weeks between acemannan capsules and placebo.

A non-controlled trial reported a positive influence of nutritional dietary supplements partially containing aloe vera on fibromyalgia and chronic fatigue syndrome, but failed to differentiate between the various supplements.

Since acemannan has been shown to stimulate macrophage activation and enhances wound healing, 1 study evaluated the use of acemannan hydrogel in a patch for the treatment of alveolar osteitis after oral surgery.34 Acemannan significantly reduced the incidence and severity of the inflammatory process compared to clindamycin Gelfoam patches. Although the study lacks a complete clinical design, the comparison between the treatment groups showed an impressive advantage of acemannan in the prevention of alveolar osteitis in a large patient collective (n=1,194).

One randomized, double-blind, placebo-controlled study investigated the use of aloe vera inner leaf gel for its anti-hyperglycemic and anti-hypercholesteremic effects in a small study population and found a slight decrease in fasting blood glucose, HbA1C, total cholesterol, and LDL levels, although this may be attributed to a restricted diet that patients in both groups were prescribed.120

Two promising clinical trials with fresh aloe vera gel in healthy adult33 and pediatric32 volunteers showed increased calcium and oxalate urinary secretions, which might confirm the traditional use of aloe vera gel in the treatment of kidney stones.1 However, confirmation through clinical studies for this indication in patients suffering from kidney stones is lacking to date.

A non-controlled trial reported a positive influence of nutritional dietary supplements partially containing aloe vera on fibromyalgia and chronic fatigue syndrome, but failed to differentiate between the various supplements.121

Conclusions

In conclusion, the use of aloe vera gel or its components for the treatment of a variety of conditions and diseases needs further clinical evidence through well-designed studies with defined aloe extracts and matching placebo controls. Currently (June 2012), 5 national and international clinical studies are listed by the United States National Institutes of Health clinical trial database with a major emphasis on the use of aloe vera in the treatment of wounds.122 This indicates the scientific significance of aloe vera gel and the need to establish it as a valid treatment option for wounds. However, the use of aloe vera gel in topical applications has widely been confirmed in the clinical studies as safe.

Clinical Studies on Aloe vera (Aloe barbadensis Mill.) Inner Gel

External Applications* of Aloe Vera Formulations in Clinical Trials

Author/Year Subject Design Duration Dosage Preparation Results/Conclusion
Syed et al, 1996 Genital herpes R, DB, PC, PG, N=120 2 weeks 3x/day to herpetic lesions, max. 30 applications Aloe extract 0.5% in hydrophilic cream or gel Both aloe cream & gel were effective in reducing healing time compared to placebo (4.8 vs. 7.0 vs. 14.0 days, respectively), aloe cream was more efficacious in number of cured patients compared to gel (70% vs. 45% vs. 7%, respectively, no side effects observed.
Choonhakarn et al, 2009 Lichen planus R, DB, PC, SC, N=54 8 weeks 2x/day to erosive and ulcerative lesions Aloe vera gel (containing 70% of aloe mucilage) Lesions were significantly reduced in Aloe vera gel group compared to placebo with complete remission or good response in 88% of patients compared to 4% in placebo group
Rajar et al, 2008 Lichen planus R, DB, PC, SC, N=34 8 weeks 2x/day to erosive and ulcerative lesions Aloe vera gel, not further specified Lesions were significantly reduced in Aloe vera gel group compared to placebo with good response (at least 50% improvement) in 82% of patients compared to 5% in placebo group
Syed et al, 1996 Psoriasis vulgaris R, PC, PG, N=60 4 weeks 3x/day to lesions, max. 15 applications per week Aloe extract 0.5% in hydrophilic cream Aloe hydrophilic cream cured 83.3% of patients treated vs. 6.6% in the control group. Psoriatic plaques were significantly (P<0.001) reduced and biopsies presented with reduced inflammation and parakeratosis.
Paulsen et al, 2005 Psoriasis vulgaris DB, R, PC, SC, IC, N=40 4 weeks 2x/day to left or right arm, treatment with emollients and Vaseline allowed ACTIV aloe® (Aloe vera group ApS, Søborg, Denmark) with 98% aloe leaf gel Placebo was more effective than aloe gel (P<0.0197) at first follow up visit (week 8), but not different at later time point (week 12).
Choonhakarn et al, 2010 Psoriasis vulgaris DB, R, SC, N=80 8 weeks 2x/day to affected area, no other treatment allowed Aloe vera cream (containing 70% of aloe mucilage) compared to 0.1% triamcinolone acetonide cream Aloe vera cream was at least as effective in reducing psoriatic plaque in patients as triamcinolone acetonide cream with significant more reduction in psoriasis area severity index and equal reduction in dermatology life quality index
Reuter et al, 2008 UV-induced erythema R, DB, PC, SC, N=40 2 days Occlusive bandage for 2 days 97.5% aloe gel compared to 0.25% prednicarbate, 1% hydrocortisone in placebo gel, 1% hydrocortisone cream, & placebo gel Significant reduction of erythema by aloe gel compared to 1% hydrocortisone in placebo gel after 2 days, 1% hydrocortisone cream was more effective.
Vardy et al, 1999 Seborrheic dermatitis DB, R, PC, N=44 4-6 weeks 2x/day to affected areas Aloe emulsion (30% crude extract) in defined base, different base as placebo Responder percentage higher in aloe group vs. placebo (58 vs. 15% assessed by physician), significant decrease in scaliness (P<0.008) and pruritus (P<0.046) in aloe group
Heggie et al, 1998 Radiation-induced dermatitis R, DB, PC, MC, N=208 Duration of radiation treatment & 2 weeks post-treatment 3x/day to affected area 98% aloe gel & aqueous cream as placebo No differences between aloe & placebo in severity of itching, erythema, or moist desquamation, but aqueous cream was significantly better in reducing moderate pain and dry desquamation.
Olsen et al, 2001 Radiation-induced dermatitis R, SB, SC, N=70 Duration of radiation treatment 6-8x/day to irradiated area 100% pure aloe gel (Fruit of the Earth) in addition to mild soap or mild soap alone, patients could use prescribed skin care products Delayed onset of skin changes in aloe gel group (P=0.013), no placebo gel used, so effect not clearly associated with aloe.
Williams et al, 1996 Radiation-induced dermatitis R, DB, PC, N=191 Duration of radiation treatment 2x/day to irradiated area 98% pure, fresh aloe gel with added inert gel, patients could use hydrocortisone cream No significant improvement in all parameters evaluated for aloe gel vs. placebo inert gel.
Schmidt et al, 1991 Surgical wounds R, SC, N=21 Time to complete healing Initially change of wound dressing every 8 hours until granulation tissue established, thereafter every 12 hours Carrington Dermal wound gel®, standard treatment as control Significant delay in wound healing for aloe gel group compared to standard treatment (P=0.003).
Poor et al, 2002 Alveolar osteitis R, N=1,194 7 days post-surgery SaliCept Patch® applied to surgery site SaliCept patch contained acemannan hydrogel, compared to clindamycin Gelfoam, concurrent pain & antibiotic medication was identical Significantly lower incident of alveolar osteitis & symptoms in SaliCept patch group compared to clindamycin Gelfoam group. Parameters used were based on physician evaluation & patient survey.
West et al, 2003 Xerosis PB, SC, N=29 30 days, 30 days rest, 10 days Wearing glove with aloe gel for 8h/day Aloetouch®, glove with dried, pure freeze-dried aloe gel which converts to a gel upon contact with skin moisture, no placebo One hand covered in Aloetouch glove for 8h while other hand served as control—no placebo, baseline evaluation unblinded, outcome evaluation by photography and blinded, significant improvement for Aloetouch hand vs. uncovered hand (P<0.0001), but questionable since no placebo for general moisturizing effect used.
Dal’Belo et al, 2006 Moisturizer R, SB, PC, N=20 Short-term (0-3h) & long-term (2 weeks) Single application & 2x/day for 2 weeks 0.1%, 0.25%, or 0.5% of freeze-dried 200:1 concentrate ACTIValoe® aloe GEL FD200 in hydrophilic cream Short-term significant increase in water content of the stratum corneum for 0.25 and 0.5% of aloe at 1, 2, and 3h after application (at least P<0.01), long-term increase in water content for all 3 Aloe vera creams after 1 and 2 weeks (at least P<0.01) compared to placebo, no changes in transepidermal water loss during entire trial

Internal Applications+ of Aloe Vera Formulations in Clinical Trials

Author/Year Subject Design Duration Dosage Preparation Results/Conclusion
Davis et al, 2006 Irritable Bowel Syndrome R, DB, PC, N=41 1 month 4x/day 50 ml Aloe gel Natural Living Products® formulation Patients recruited from refractory pool, no significant changes in IBS or pain scores (P=0.46 & P=0.12 respectively) between aloe & placebo group at 3 months after treatment
Langmead et al, 2004 Ulcerative colitis R, DB, PC, N=44 1 month 2x/day 100 ml Aloe gel Natural Living Products® formulation 2:1 aloe gel & placebo ratio in study, improvements in clinical response (P=0.048), but not for histological or sigmoidoscopic evaluations
Montaner et al, 1996 HIV infection R, DB, PC, MC, N=63 48 weeks 4x/day capsules 100 mg acemannan in capsules or equivalent placebo Acemannan or placebo in addition to standard treatment showed no differences in CD4 count or survival after 48 weeks.
Choonhakarn et al, 2008 Oral lichen planus infections R, DB, PC, N=54 8 weeks 2x/day to affected area 70% aloe mucilage in hydrophilic gel base, gel base as placebo control 81% of aloe patients showed good response to treatment vs. 4% in placebo group (P<0.001) with no side effects.
Su et al, 2004 Radiation-induced mucositis R, DB, SC, PC, N=58 Duration of radiation treatment & 6 weeks post-treatment 4x/day 20 ml p.o. Lily of the Desert® 94.5% aloe vera gel No significant differences in mucositis parameters between aloe & placebo group.
Huseini et al, 2012 Hypercholesteremia and diabetes R, SC, DB, PC, IC, N=60 8 weeks 2x/day 300 mg aloe powder, restricted diet Freshly prepared aloe inner leaf powder after removal of aloin and anthraquinones and concentration of acemannan confirmed by HPLC Significantly lower fasting blood glucose, HbA1C, total cholesterol, and LDL levels in patients taking aloe after intervention, but only minimal improvements in glucose levels and HbA1C compared to placebo.
Agarwal, 1985 Angina pectoris and diabetes IC, R, N=5,000 5 years 100mg fresh inner gel in combination with bread containing seeds from Plantago ovata Fresh flesh gelatin from Aloe vera, not chemically defined Improvement after 2 weeks persisted for whole observation period with diabetic patients benefiting most from the Aloe and Plantago treatment, clinical parameters including cholesterol, triglycerides, and blood glucose levels normalized over time.

* Please note: in most external studies, the exact amount for topical application was not defined. It is assumed that the amount is equal to what would be applied as a standard topical cream about 1/8 inch thick to the affected area. 

+ Please note: for oral application of the inner gel the exact dose equivalent of mucopolysaccharides was not provided. In many studies it is assumed that the dose corresponds to fresh Aloe inner leaf gel, the composition of which is described in the section “chemistry” above. There is significant variation among products and therefore the instructions of the manufacturer should be followed.

Abbreviation Key: IC – interpatient control, PB – partially blinded, SC – single-center, MC – multi-center, R – randomized, DB – double-blinded, PC – placebo-controlled, SB – single-blinded, PG – parallel group

About the Author

Oliver Grundmann, BPharm, MS, PhD, is a clinical assistant professor at the University of Florida in the Department of Medicinal Chemistry, College of Pharmacy, and assistant professor in the Department of Adult and Elderly Nursing, College of Nursing, as well as adjunct assistant professor at Midwestern University College of Pharmacy. He is involved in several collaborative research projects on natural products both in preclinical and clinical stages, especially the treatment of irritable bowel syndrome and other intestinal disorders using complementary and alternative medicine, as well as herbal medicines for the treatment of neurological disorders. He has been a fellow of the Japan Society for the Advancement of Science and the German Academic Exchange Program while studying at Tokushima University in 2006. His teaching involvement covers areas related to medicinal chemistry, natural products, forensic toxicology, and clinical toxicology, as well as general pharmaceutical sciences.

References

1.         Morton JF. Folk uses and commercial exploitation of Aloe leaf pulp. Economic botany. 1961;15(4):311-19.
2.         Lans CA. Ethnomedicines used in Trinidad and Tobago for urinary problems and diabetes mellitus. J Ethnobiol Ethnomed. 2006;2:45.
3.         Grindlay D, Reynolds T. The Aloe vera phenomenon: a review of the properties and modern uses of the leaf parenchyma gel. J Ethnopharmacol. 1986;16(2-3):117-51.
4.         Collins CE, Collins C. Roentgen dermatitis treated with fresh whole leaf of Aloe vera. American Journal of Roentgenology. 1935;33(3):396-97.
5.         Halles JS. A drug for all seasons. Medical and pharmacological history of aloe. Bull N Y Acad Med. 1990;66(6):647-59.
6.         Rodriguez S. How Large is the Aloe Market. [PowerPoint presentation]. 2008. Accessed 07/03/2008, 2008.
7.         CIREP CIREP. Final Report on the Safety Assessment of Aloe Andongensis Extract, Aloe Andongensis Leaf Juice, Aloe Arborescens Leaf Extract, Aloe Arborescens Leaf Juice, Aloe Arborescens Leaf Protoplasts, Aloe Barbadensis Flower Extract, Aloe Barbadensis Leaf. Int J Toxicol. 2007;26:1-50.
8.         Dal'Belo SE, Gaspar LR, Maia Campos PM. Moisturizing effect of cosmetic formulations containing Aloe vera extract in different concentrations assessed by skin bioengineering techniques. Skin Res Technol. 2006;12(4):241-46.
9.         Thornfeldt C. Cosmeceuticals containing herbs: fact, fiction, and future. Dermatol Surg. 2005;31:873-80.
10.       Diehl B, Teichmueller EE. Aloe vera, Quality inspection and identification. Agro Food Ind Hi Tech. 1998;9:14-6.
11.       Thamlikitkul V, Bunyapraphatsara N, Riewpaiboon W, Theerapong S, Chantrakul C, Thanaveerasuwan T. Clinical trial of aloe vera Linn. for treatment of minor burns. Siriraj Hosp Gaz. 1991;43(5):313-316.
12.       Visuthikosol V, Chowchuen B, Sukwanarat Y, Sriurairatana S, Boonpucknavig V. Effect of aloe vera gel to healing of burn wound a clinical and histologic study. J Med Assoc Thai. Aug 1995;78(8):403-09.
13.       Akhtar MA, Hatwar SK. Efficacy of aloe vera extract cream in management of burn wound. J Clin Epidemiol. 1996;49:24.
14.       Reuter J, Jocher A, Stump J, Grossjohann B, Franke G, Schempp CM. Investigation of the anti-inflammatory potential of Aloe vera gel (97.5%) in the ultraviolet erythema test. Skin Pharmacol Physiol. 2008;21(2):106-10.
15.       Syed TA, Afzal M, Ashfaq AS. Management of genital herpes in men with 0.5% Aloe vera extract in a hydrophilic cream. A placebo-controlled double-blind study. J Derm Treatment. 1997;8(2):99-102.
16.       Syed TA, Cheeman KM, Ahmad SA, Holt AH. Aloe vera extract 0.5% in hydrophilic cream versus Aloe vera gel for the management of genital herpes in males. A placebo-controlled, doubleblind, comparative study. J Eur Acad Dermatol Venereol. 1996;7:294-95.
17.       Vardy AD, Cohen AD, Tchetov T. A double-blind, placebo-controlled trial of Aloe vera (A. barbadensis) emulsion in the treatment of seborrheic dermatitis. J Derm Treatment. 1999;10(1):7-11.
18.       King GK, Yates KM, Greenlee PG, et al. The effect of Acemannan Immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas. J Am Anim Hosp Assoc. 1995;31(5):439-47.
19.       Harris C, Pierce K, King G, Yates KM, Hall J, Tizard I. Efficacy of acemannan in treatment of canine and feline spontaneous neoplasms. Mol Biother. 1991;3(4):207-13.
20.       Syed TA, Ahmad SA, Holt AH, Ahmad SA, Ahmad SH, Afzal M. Management of psoriasis with Aloe vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health. 1996;1(4):505-09.
21.       Tanaka M, Misawa E, Ito Y, et al. Identification of five phytosterols from Aloe vera gel as anti-diabetic compounds. Biol Pharm Bull. 2006;29(7):1418-22.
22.       Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in diabetes. Diabetes Care. 2003;26(4):1277-94.
23.       Agarwal OP. Prevention of atheromatous heart disease. Angiology. 1985;36(8):485-92.
24.       Sheets MA, Unger BA, Giggleman GF, Jr., Tizard IR. Studies of the effect of acemannan on retrovirus infections: clinical stabilization of feline leukemia virus-infected cats. Mol Biother. 1991;3(1):41-5.
25.       Yates KM, Rosenberg LJ, Harris CK, et al. Pilot study of the effect of acemannan in cats infected with feline immunodeficiency virus. Vet Immunol Immunopathol. 1992;35(1-2):177-89.
26.       Choonhakarn C, Busaracome P, Sripanidkulchai B, Sarakarn P. The efficacy of aloe vera gel in the treatment of oral lichen planus: a randomized controlled trial. Br J Dermatol. 2008;158(3):573-77.
27.       Hayes SM. Lichen planus--report of successful treatment with aloe vera. Gen Dent. May- 1999;47(3):268-72.
28.       Langmead L, Feakins RM, Goldthorpe S, et al. Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis. Aliment Pharmacol Ther. 2004;19(7):739-47.
29.       Blitz JJ, Smith JW, Gerard JR. Aloe vera gel in peptic ulcer therapy: preliminary report. J Am Osteopath Assoc. 1963;62:731-35.
30.       Davis K, Philpott S, Kumar D, Mendall M. Randomised double-blind placebo-controlled trial of aloe vera for irritable bowel syndrome. Int J Clin Pract. 2006;60(9):1080-86.
31.       Avijgan M. Phytotherapy: an alternative treatment for non-healing ulcers. J Wound Care. 2004;13(4):157-58.
32.       Kirdpon S, Kirdpon W, Airarat W, Thepsuthammarat K, Nanakorn S. Changes in urinary compositions among children after consuming prepared oral doses of aloe (Aloe vera Linn). J Med Assoc Thai. 2006;89(8):1199-205.
33.       Kirdpon S, Kirdpon W, Airarat W, Trevanich A, Nanakorn S. Effect of aloe (Aloe vera Linn.) on healthy adult volunteers: changes in urinary composition. J Med Assoc Thai. 2006;89 Suppl 2:S9-14.
34.       Poor MR, Hall JE, Poor AS. Reduction in the incidence of alveolar osteitis in patients treated with the SaliCept patch, containing Acemannan hydrogel. J Oral Maxillofac Surg. 2002;60(4):374-79.
35.       Elton B Stephens Company (EBSCO) Commodity Research Bureau (CRB). Aloe. 2008. Accessed 08/03/2008, 2008.
36.       Davis RH, Donato JJ, Hartman GM, Haas RC. Anti-inflammatory and wound healing activity of a growth substance in Aloe vera. J Am Podiatr Med Assoc. 1994;84(2):77-81.
37.       Ni Y, Turner D, Yates KM, Tizard I. Isolation and characterization of structural components of Aloe vera L. leaf pulp. Int Immunopharmacol. 2004;4(14):1745-55.
38.       Tai-Nin Chow J, Williamson DA, Yates KM, Goux WJ. Chemical characterization of the immunomodulating polysaccharide of Aloe vera L. Carbohydr Res. 2005;340(6):1131-42.
39.       Peirce A. The American Pharmaceutical Association Practical Guide to Natural Medicines. Vol 1. First ed: William Morrow; 1999.
40.       Eberendu AR, Luta G, Edwards JA, et al. Quantitative colorimetric analysis of aloe polysaccharides as a measure of Aloe vera quality in commercial products. J AOAC Int. 2005;88(3):684-91.
41.       Bozzi A, Perrin C, Austin S, Arce Vera F. Quality and authenticity of commercial aloe vera gel powders. Food Chem. 2006;103(1):22-30.
42.       Mantle D, Gok MA, Lennard TW. Adverse and beneficial effects of plant extracts on skin and skin disorders. Adverse Drug React Toxicol Rev. 2001;20(2):89-103.
43.       Fulton JE, Jr. The stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing. J Dermatol Surg Oncol. 1990;16(5):460-67.
44.       Bland J. Effect Of Orally Consumed Aloe Vera Juice On Gastrointestinal Function In Normal Humans. Preventive Medicine. 1985;14(2).
45.       Shelton RM. Aloe vera. Its chemical and therapeutic properties. Int J Dermatol. 1991;30(10):679-83.
46.       Heggers JP, Kucukcelebi A, Listengarten D, et al. Beneficial effect of Aloe on wound healing in an excisional wound model. J Altern Complement Med. 1996;2(2):271-77.
47.       Choi SW, Son BW, Son YS, Park YI, Lee SK, Chung MH. The wound-healing effect of a glycoprotein fraction isolated from aloe vera. Br J Dermatol. 2001;145(4):535-45.
48.       Tizard IR, Busbee D, Maxwell B, Kemp MC. Effects of acemannan, a complex carbohydrate, on wound healing in young and aged rats. Wounds. 1995;6:201-09.
49.       Roberts DB, Travis EL. Acemannan-containing wound dressing gels reduce radiation-induced skin reactions in C3H mice. Int J Radiat Oncol Biol Phys. 1995;15:1047-52.
50.       Wang ZW, Zhou JM, Huang ZS, et al. Aloe polysaccharides mediated radioprotective effect through the inhibition of apoptosis. J Radiat Res. 2004;45(3):447-54.
51.       Somboonwong J, Thanamittramanee S, Jariyapongskul A, Patumraj S. Therapeutic effects of Aloe vera on cutaneous microcirculation and wound healing in second degree burn model in rats. J Med Assoc Thai. 2000;83(4):417-25.
52.       Rodriguez-Bigas M, Cruz NI, Suarez A. Comparative evaluation of aloe vera in the management of burn wounds in guinea pigs. Plast Reconstr Surg. 1988;81(3):386-89.
53.       McCauly R. Frostbite-methods to minimize tissue loss. Postgrad Med. 1990;88:67-70.
54.       Perez YY, Jimenez-Ferrer E, Zamilpa A, et al. Effect of a polyphenol-rich extract from Aloe vera gel on experimentally induced insulin resistance in mice. Am J Chin Med. 2007;35(6):1037-46.
55.       Rajasekaran S, Sivagnanam K, Ravi K, Subramanian S. Hypoglycemic effect of Aloe vera gel on streptozotocin-induced diabetes in experimental rats. J Med Food. 2004;7(1):61-6.
56.       Rajasekaran S, Sriram N, Arulselvan P, Subramanian S. Effect of aloe vera leaf gel extract on membrane bound phosphatases and lysosomal hydrolases in rats with streptozotocin diabetes. Pharmazie. 2007;62(3):221-25.
57.       Beppu H, Shimpo K, Chihara T, et al. Antidiabetic effects of dietary administration of Aloe arborescens Miller components on multiple low-dose streptozotocin-induced diabetes in mice: investigation on hypoglycemic action and systemic absorption dynamics of aloe components. J Ethnopharmacol. 2006;103(3):468-77.
58.       Chaudhary G, Saini MR, Goyal PK. Chemopreventive potential of Aloe vera against 7,12-dimethylbenz(a)anthracene induced skin papillomagenesis in mice. Integr Cancer Ther. 2007;6(4):405-12.
59.       Akev N, Turkay G, Can A, et al. Tumour preventive effect of Aloe vera leaf pulp lectin (Aloctin I) on Ehrlich ascites tumours in mice. Phytother Res. 2007;21(11):1070-75.
60.       Udupa SI, Udupa AL, Kulkarni DR. Anti-inflammatory and wound healing properties of Aloe vera. Fitoterapia. 1994;65:141-45.
61.       Fujita K, Teradaira R, Nagatsu T. Bradykinase activity of aloe extract. Biochem Pharmacol. 1976;25(2):205.
62.       Davis RH, Stewart GJ, Bregman PJ. Aloe vera and the inflamed synovial pouch model. J Am Podiatr Med Assoc. 1992;82(3):140-48.
63.       Davis RH, Maro NP. Aloe vera and gibberellin. Anti-inflammatory activity in diabetes. J Am Podiatr Med Assoc. 1989;79(1):24-6.
64.       Davis RH, Rosenthal KY, Cesario LR, Rouw GA. Processed Aloe vera administered topically inhibits inflammation. J Am Podiatr Med Assoc. 1989;79(8):395-97.
65.       Chinnah AD, Baig MA, Tizard IR, Kemp MC. Antigen dependent adjuvant activity of a polydispersed beta-(1,4)-linked acetylated mannan (acemannan). Vaccine. 1992;10(8):551-57.
66.       t'Hart LA, van den Berg AJ, Kuis L, van Dijk H, Labadie RP. An anti-complementary polysaccharide with immunological adjuvant activity from the leaf parenchyma gel of Aloe vera. Planta Med. 1989;55(6):509-12.
67.       Strickland FM, Pelley RP, Kripke ML. Prevention of ultraviolet radiation-induced suppression of contact and delayed hypersensitivity by Aloe barbadensis gel extract. J Invest Dermatol. 1994;102(2):197-204.
68.       Eamlamnam K, Patumraj S, Visedopas N, Thong-Ngam D. Effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing in rats. World J Gastroenterol. 2006;12(13):2034-39.
69.       Korkina L, Suprun M, Petrova A, Mikhal'chik E, Luci A, De Luca C. The protective and healing effects of a natural antioxidant formulation based on ubiquinol and Aloe vera against dextran sulfate-induced ulcerative colitis in rats. Biofactors. 2003;18(1-4):255-64.
70.       Sakai K, Saitoh Y, Ikawa C, Nishihata T. Effect of water extracts of aloe and some herbs in decreasing blood ethanol concentration in rats. II. Chem Pharm Bull (Tokyo). 1989;37(1):155-59.
71.       Rishi P, Rampuria A, Tewari R, Koul A. Phytomodulatory potentials of Aloe vera against Salmonella OmpR-mediated inflammation. Phytother Res. 2008;22(8):1075-82.
72.       Lim BO, Seong NS, Choue RW, et al. Efficacy of dietary aloe vera supplementation on hepatic cholesterol and oxidative status in aged rats. J Nutr Sci Vitaminol (Tokyo). 2003;49(4):292-96.
73.       Barrantes E, Guinea M. Inhibition of collagenase and metalloproteinases by aloins and aloe gel. Life Sci. 2003;72(7):843-50.
74.       Winters WD, Benavides R, Clouse WJ. Effects of aloe extracts on human normal and tumor cells in vitro. Economic Botany. 1981;35:89-95.
75.       Habeeb F, Stables G, Bradbury F, et al. The inner gel component of Aloe vera suppresses bacterial-induced pro-inflammatory cytokines from human immune cells. Methods. 2007;42(4):388-93.
76.       Habeeb F, Shakir E, Bradbury F, et al. Screening methods used to determine the anti-microbial properties of Aloe vera inner gel. Methods. 2007;42(4):315-20.
77.       t Hart LA, Nibbering PH, van den Barselaar MT, van Dijk H, van den Berg AJ, Labadie RP. Effects of low molecular constituents from Aloe vera gel on oxidative metabolism and cytotoxic and bactericidal activities of human neutrophils. Int J Immunopharmacol. 1990;12(4):427-34.
78.       Shida T, Yagi A, Nishimura H, Nishioka I. Effect of aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Med. 1985;51(3):273-75.
79.       Yagi A, Shida T, Nishimura H. Effect of amino acids in Aloe extract on phagocytosis by peripheral neutrophil in adult bronchial asthma. Arerugi. 1987;36(12):1094-101.
80.       Ni Y, Turner D, Yates K, Tizard I. Stabilization of growth factors relevant to wound healing by a plant cell wall biomaterial. Planta Med. 2007;73(12):1260-66.
81.       Vazquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol. 1996;55(1):69-75.
82.       Strickland FM, Darvill A, Albersheim P, Eberhard S, Pauly M, Pelley RP. Inhibition of UV-induced immune suppression and interleukin-10 production by plant oligosaccharides and polysaccharides. Photochem Photobiol. 1999;69(2):141-47.
83.       Byeon SW, Pelley RP, Ullrich SE, Waller TA, Bucana CD, Strickland FM. Aloe barbadensis extracts reduce the production of interleukin-10 after exposure to ultraviolet radiation. J Invest Dermatol. 1998;110(5):811-17.
84.       Womble D, Helderman JH. Enhancement of allo-responsiveness of human lymphocytes by acemannan (Carrisyn). Int J Immunopharmacol. 1988;10(8):967-74.
85.       Zhang L, Tizard IR. Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe vera gel. Immunopharmacol. 1996;35(2):119-28.
86.       Talmadge J, Chavez J, Jacobs L, et al. Fractionation of Aloe vera L. inner gel, purification and molecular profiling of activity. Int Immunopharmacol. 2004;4(14):1757-73.
87.       Ali MI, Shalaby NM, Elgamal MH, Mousa AS. Antifungal effects of different plant extracts and their major components of selected aloe species. Phytother Res. 1999;13(5):401-07.
88.       Rosca-Casian O, Parvu M, Vlase L, Tamas M. Antifungal activity of Aloe vera leaves. Fitoterapia. 2007;78(3):219-22.
89.       Abdullah KM, Abdullah A, Johnson ML, et al. Effects of Aloe vera on gap junctional intercellular communication and proliferation of human diabetic and nondiabetic skin fibroblasts. J Altern Complement Med. 2003;9(5):711-18.
90.       Lee KH, Kim JH, Lim DS, Kim CH. Anti-leukaemic and anti-mutagenic effects of di(2-ethylhexyl)phthalate isolated from Aloe vera Linne. J Pharm Pharmacol. 2000;52(5):593-98.
91.       Lee MJ, Lee OH, Yoon SH, et al. In vitro angiogenic activity of Aloe vera gel on calf pulmonary artery endothelial (CPAE) cells. Arch Pharm Res. 1998;21(3):260-65.
92.       Davis RH, DiDonato JJ, Johnson RW, Stewart CB. Aloe vera, hydrocortisone, and sterol influence on wound tensile strength and anti-inflammation. J Am Podiatr Med Assoc. 1994;84(12):614-21.
93.       Karaca K, Sharma JM, Nordgren R. Nitric oxide production by chicken macrophages activated by Acemannan, a complex carbohydrate extracted from Aloe vera. Int J Immunopharmacol. 1995;17(3):183-88.
94.       Ramamoorthy L, Kemp MC, Tizard IR. Acemannan, a beta-(1,4)-acetylated mannan, induces nitric oxide production in macrophage cell line RAW 264.7. Mol Pharmacol. 1996;50(4):878-84.
95.       Stuart RW, Lefkowitz DL, Lincoln JA, Howard K, Gelderman MP, Lefkowitz SS. Upregulation of phagocytosis and candidicidal activity of macrophages exposed to the immunostimulant acemannan. Int J Immunopharmacol. 1997;19(2):75-82.
96.       Robson MC, Heggers J, Hagstrom WJ. Myth, magic, witchcraft or fact? Aloe vera revisited. J Burn Care Rehabil. 1982;3:157-62.
97.       World Health Organization (WHO), ed WHO Monographs on Selected Medical Plants, Vol 1. 1 ed. Geneva, Switzerland: World Health Organization; 1999. Organization WH, ed. WHO Monographs on Selected Medical Plants; No. 1.
98.       Jellin JM. Aloe. In: Database NMC, ed. Natural Medicines Comprehensive Database: Therapeutic Research Faculty; 2008.
99.       Morrow DM, Rapaport MJ, Strick RA. Hypersensitivity to aloe. Arch Dermatol. 1980;116(9):1064-65.
100.     Shoji A. Contact dermatitis to Aloe arborescens. Contact Dermatitis. 1982;8(3):164-67.
101.     Nakamura T, Kotajima S. Contact dermatitis from aloe arborescens. Contact Dermatitis. 1984;11(1):51.
102.     Hunter D, Frumkin A. Adverse reactions to vitamin E and aloe vera preparations after dermabrasion and chemical peel. Cutis. 1991;47(3):193-96.
103.     Ferreira M, Teixeira M, Silva E, Selores M. Allergic contact dermatitis to Aloe vera. Contact Dermatitis. 2007;57(4):278-79.
104.     Fogleman RW, Chapdelaine JM, Carpenter RH, McAnalley BH. Toxicologic evaluation of injectable acemannan in the mouse, rat and dog. Vet Hum Toxicol. 1992;34(3):201-05.
105.     Williams LD, Burdock GA, Shin E, et al. Safety studies conducted on a proprietary high-purity aloe vera inner leaf fillet preparation, Qmatrix. Regul Toxicol Pharmacol. 2010;57(1):90-8.
106.     Fujii S. Evaluation of hypersensitivity to anthraquinone-related substances. Toxicol. 2003;193(3):261-67.
107.     Brinker F. Herb Contraindications and Drug Interactions. 2nd ed: Eclectic Medical Publications; 1998.
108.     Vinson JA, Al Kharrat H, Andreoli L. Effect of Aloe vera preparations on the human bioavailability of vitamins C and E. Phytomedicine. 2005;12(10):760-65.
109.     Heggie S, Bryant GP, Tripcony L, et al. A Phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue. Cancer Nurs. 2002;25(6):442-51.
110.     Williams MS, Burk M, Loprinzi CL, et al. Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity. Int J Radiat Oncol Biol Phys. 1996;36(2):345-49.
111.     Olsen DL, Raub W, Jr., Bradley C, et al. The effect of aloe vera gel/mild soap versus mild soap alone in preventing skin reactions in patients undergoing radiation therapy. Oncol Nurs Forum. 2001;28(3):543-47.
112.     Richardson J, Smith JE, McIntyre M, Thomas R, Pilkington K. Aloe vera for preventing radiation-induced skin reactions: a systematic literature review. Clin Oncol (R Coll Radiol). 2005;17(6):478-84.
113.     Su CK, Mehta V, Ravikumar L, et al. Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms. Int J Radiat Oncol Biol Phys. 2004;60(1):171-77.
114.     Schmidt JM, Greenspoon JS. Aloe vera dermal wound gel is associated with a delay in wound healing. Obstet Gynecol. 1991;78(1):115-17.
115.     Rajar UD, Majeed R, Parveen N, Sheikh I, Sushel C. Efficacy of aloe vera gel in the treatment of vulval lichen planus. J Coll Physicians Surg Pak. 2008;18(10):612-14.
116.     Paulsen E, Korsholm L, Brandrup F. A double-blind, placebo-controlled study of a commercial Aloe vera gel in the treatment of slight to moderate psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2005;19(3):326-31.
117.     Choonhakarn C, Busaracome P, Sripanidkulchai B, Sarakarn P. A prospective, randomized clinical trial comparing topical aloe vera with 0.1% triamcinolone acetonide in mild to moderate plaque psoriasis. J Eur Acad Dermatol Venereol. 2010;24(2):168-72.
118.     West DP, Zhu YF. Evaluation of aloe vera gel gloves in the treatment of dry skin associated with occupational exposure. Am J Infect Control. 2003;31(1):40-2.
119.     Montaner JS, Gill J, Singer J, et al. Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;12(2):153-7.
120.     Huseini HF, Kianbakht S, Hajiaghaee R, Dabaghian FH. Anti-hyperglycemic and anti-hypercholesterolemic effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. Planta Med. 2012;78(4):311-16.
121.     Dykman KD, Tone C, Ford C, Dykman RA. The effects of nutritional supplements on the symptoms of fibromyalgia and chronic fatigue syndrome. Integr Physiol Behav Sci. 1998;33(1):61-71.
122.     ClinicalTrials.gov. National Institues of Health (NIH), National Library of Medicine (NLM), Department of Health and Human Service (HHS); 2008. Accessed 08/03/2008.