Aloe

Scientific Name(s): Aloe vera L., Aloe perryi Baker (Zanzibar or Socotrine aloe), Aloe barbadensis Miller (also called A. vera Tournefort ex Linne or Aloe vulgaris Lamark; Curacao or Barbados aloe), or Aloe ferox Miller (Cape aloe). A. vera Miller and A. vera L. may not be the same species. Family: Liliaceae

Common Name(s): Cape , Zanzibar , Socotrine , Curacao , or Barbados aloes ; aloe vera

Uses

Topical aloe appears to inhibit infection and promote healing of minor burns and wounds, frostbite, as well as in skin affected by diseases such as psoriasis and seborrheic dermatitis, although studies have had conflicting results. Dried aloe latex should be ingested with caution as a drastic cathartic, but its use is not recommended. In 2002, the US Food and Drug Administration required all over-the-counter aloe laxative products to be removed from the US market or reformulated because manufacturers have not provided the necessary safety data.

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Dosing

As a gel, A. vera may be applied externally. The resin product is cathartic and not recommended for internal use.

Contraindications

Ingestion is contraindicated in pregnant and breast-feeding women, children younger than 12 years of age, patients with inflammatory bowel disease, and elderly patients with suspected intestinal obstruction.

Pregnancy/Lactation

Documented adverse effects with ingestion; do not use. Cathartic, reputed abortifacient.

Interactions

Potential interactions between ingested aloe resin and the following medications have been identified: digoxin, furosemide, thiazide diuretics, sevoflurane stimulant laxatives, and antidiabetic agents.

Adverse Reactions

There has been 1 report that aloe gel as standard wound therapy delayed healing. The gel may cause burning sensations in dermabraded skin, and redness and itching also can occur. Use caution with cosmetic products containing A. vera gel. A case of acute hepatitis induced by aloe vera ingestion has been reported.

Toxicology

The resin product is cathartic at doses of 250 mg and is not recommended for internal use.

Botany

Aloes, of which there are approximately 500 species, belong to the Liliaceae family. 1 The name, meaning “bitter and shiny substance,” derives from the Arabic alloeh . Indigenous to the Cape of Good Hope, these perennial succulents grow throughout most of Africa, southern Arabia and Madagascar, and are cultivated in Japan, North and South America, and in the Caribbean and Mediterranean regions. Often attractive ornamental plants, their fleshy leaves are stiff and spiny along the edges and grow in a rosette. Each plant has 15 to 30 tapering leaves, each up to 0.5 m long and 8 to 10 cm wide. Beneath the thick cuticle of the epidermis lies the chlorenchyma. Between this layer and the colorless mucilaginous pulp containing the aloe gel are numerous vascular bundles and inner bundle sheath cells from which a bitter yellow sap exudes when the leaves are cut. 2

History

Drawings of aloe have been found in the wall carvings of Egyptian temples erected in the 4th millennium BC. Called the “Plant of Immortality,” it was a traditional funerary gift for the pharaohs. The Egyptian Book of Remedies (ca. 1500 BC) notes the use of aloe in curing infections, treating the skin, and preparing drugs that were chiefly used as laxatives. In the Bible, Nicodemus provided a mixture of myrrh and aloes for the preparation of Christ's body. Alexander the Great (356 to 323 BC) is said to have conquered the island of Socotra to obtain control of aloe. In 74 AD, the Greek physician Dioscorides recorded its use to heal wounds, stop hair loss, treat genital ulcers, and eliminate hemorrhoids. In the 6th century AD, Arab traders carried it to Asia. From the Mediterranean region, it was carried to the New World in the 16th century by Spanish explorers and missionaries. In the modern era, its clinical use began in the 1930s as a treatment for roentgen dermatitis. 2

Chemistry

The aloe plant yields 2 commercially important products. Aloe resin is the solid residue obtained by evaporating the latex from the pericyclic cells beneath the skin. 3 The bitter yellow latex contains the anthraquinone barbaloin (a glucoside of aloe-emodin) and iso-barbaloin, as well as a series of O-glycosides of barbaloin (called aloinosides), chrysophanic acid, and up to 63% resin. The filtering of resins from the exudate and concentrating the remaining anthraglycoside material, which is up to 25% barbaloin, into crystalline form produces aloin, a mixture of water-soluble glycosides.

A second product, aloe gel, is a clear, thin, gelatinous material obtained by crushing the mucilaginous cells found in the inner tissue of the leaf. The gel is the product used most frequently in the cosmetic and health food industries. It is generally devoid of anthraquinone glycosides. The gel contains a polysaccharide glucomannan, similar to guar gum, that is believed to contribute mostly to the emollient effect. Aloe vera gel “extract” is not actually an extract, but rather the pulverized whole leaves of the plant.

Allantoin is a primary mucilaginous substance in aloe and an important proliferating agent.

Other compounds, such as tannins, polysaccharides, organic acids, enzymes, vitamins, and steroids, have been identified. 4 Aloe contains bradykininase, which relieves pain and decreases swelling and redness. Magnesium lactate may contribute to the antipruritic effect of aloe by blocking histamine production. An antiprostaglandin that reduces inflammation has also been isolated. Anthraquinones are local irritants in the GI tract but have been used in treating certain skin diseases, such as psoriasis.

Chemical composition differs among the species of aloe. For example, A. barbadensis Miller may contain 2.5 times the aloe-emodin of A. ferox Miller; the time of harvest also factors into the composition.

Uses and Pharmacology

Aloe latex has been used internally for centuries as a potent cathartic. The aloinosides exert strong purgative effects by irritating the large intestine. In 2002, the US Food and Drug Administration required all over-the-counter aloe laxative products to be removed from the US market or reformulared because manufacturers have not provided the necessary safety data. 5

Burns/skin irritation

Aloe gel is most commonly used to treat minor burns and skin irritation. Early studies of its use generally were poorly controlled, and the data were incomplete and conflicting. These reports described the use of aloe in the treatment of radiation-induced dermatitis. 6

Animal data

A. barbadensis extracts in a murine model prevented ultraviolet radiation-induced suppression of contact and delayed hypersensitivity by reducing the production of interleukin-10. 7 , 8 However, a small study in 10 healthy volunteers did not support this observation. 9 Subsequent reports of the use of topical aloe in treating human and animal radiation burns suggested that although healing occurred, a clear advantage over aggressive wound care was not established.

Clinical data

In a study of 27 patients, aloe vera gel-treated, partial thickness burn wounds healed in an average of 12 days as opposed to the Vaseline -gauze-treated area of the same burn, which healed in an average of 18 days. 10

There are 5 published and 2 unpublished randomized controlled trials evaluating the effectiveness of aloe vera for the prevention and/or minimization of radiation-induced skin reactions in cancer patients. From the trials reviewed, there was no evidence to suggest that aloe vera gel is effective for the prevention and/or treatment of radiation-induced skin reactions in either adults or children. Furthermore, in 2 of the studies, aloe vera gel was shown to be less effective than other creams (aqueous cream and anionic phospholipid-based cream). 11 Although no serious adverse effects were reported in the literature, 5 patients had an allergic reaction to aloe vera gel.

A systematic review was carried out to determine the efficacy of aloe vera in burn wound healing. Only 4 studies of burns were identified in humans. Two of these studies used time to wound healing as an outcome measure. Based on a meta-analysis of these 2 studies, the summary-weighted mean difference in healing time of the aloe vera group was 8.79 days shorter than of those in the control group ( P = 0.006). The other 2 studies showed that treatment in the aloe vera group was better than that of the control group. One study reported a success rate with aloe vera of 95% compared with 83% with silver sulfadiazine. The other showed that the epithelialization rate measured by the healing size of the aloe wound was higher than that of the Vaseline gauze group on both day 5 and day 8 after skin grafting.

The findings also suggest that aloe vera products are safe for topical use. There were no withdrawal or serious adverse reactions, and only irritation, itching, discomfort, and minimal transient pain were reported. However, these events were common signs and symptoms in burns and were present in both the aloe vera and control groups. None of the included studies standardized the amount of active ingredients of aloe vera in the products used. 12

The activity of aloe in treating burns may stem from its moisturizing effect, which prevents air from drying the wound. 13 One study used skin bioengineering techniques to evaluate the effects of cosmetic formulations containing different concentrations of freeze-dried aloe vera extract on skin hydration. After a single application, formulations containing 0.25% and 0.5% of aloe vera extract increased the water content of the stratum corneum, while after a 2-week period of application, all 3 formulations (0.1%, 0.25%, and 0.5%) had the same effect. It was proposed that freeze-dried aloe vera extract improved skin moisture by a humectant mechanism. 14 Its activity has also been ascribed to its chlorophyll content and that of other minor components, but this has not been adequately substantiated. Current theory suggests that healing is stimulated by mucopolysaccharides in combination with sulfur derivatives and nitrogen compounds. Topical aloe treatment for burns has not been adequately documented. Two FDA advisory panels found insufficient evidence to show that A. vera is useful in the treatment of minor burns, cuts, or vaginal irritations.

Wound healing

Other studies have generally found preparations containing aloe to accelerate wound healing.

Animal data

A number of animal studies provide evidence that aloe vera, or one or more of its constituents, promotes wound healing in animal models.

A study in mice found that acemannan, the major carbohydrate fraction isolated from aloe vera gel, stimulates macrophage cytokine production, nitric oxide release, and morphologic cellular changes that varied proportionally with increasing dosages. Another study in Sprague-Dawley rats showed that the combination of hypochlorite and aloe increased wound contraction when compared with controls, indicating that this combination stimulated collagen activity and strengthened the collagen matrix of the wound, enhancing its tensile strength.

Another study in mice identified the glycoprotein fraction (G1G1M1D12) that was thought to provide the wound healing effects of aloe vera. In addition, mannose 6-phosphate, the primary sugar in aloe vera, has been identified as an active wound healing component.

Aloe vera also blocked the suppressive effects of hydrocortisone on wound healing in animal studies. 15

When used to treat frostbite in a study with rabbits, the addition of oral pentoxifylline showed additional improvement in tissue survival. 16

Clinical data

In patients who underwent dermabrasion, aloe accelerated skin healing by approximately 72 hours compared with polyethylene oxide gel dressing, 17 and aloe has been found to accelerate wound healing in patients with frostbite. 18 Aloe vera applied to debrided white or clear blisters and to intact hemorrhagic blisters every 6 hours has been part of the treatment protocol for frostbite. 19 , 20

A study of 133 patients with pressure ulcers higher than grade 1 compared Vulnopur spray (a saline spray with aloe vera, silver chloride, and decyl glucoside) with isotonic saline for cleaning wounds. The Vulnopur spray was found to improve pressure score status tool scores when used to cleanse pressure ulcers, compared with wounds that were cleansed with isotonic saline. The mean percentage change from baseline to day 14 in the control group was −20.5% while the mean percentage change for Vulnopur spray was −27.8%. 21

A small study compared the mean healing times of surgical wounds treated with aloe vera gel plus traditional wet-to-dry treatment to traditional wet-to-dry treatment alone. The mean time to healing was reported as greater in the aloe vera group; however, the results were flawed by differential loss to follow up. 22

Controlled clinical trials in humans demonstrated no benefit when aloe vera was incorporated into topical therapy, 15 and at least 1 study found that aloe applied as standard wound therapy delayed wound healing (83 vs 53 days). 23

Seborrheic dermatitis/Psoriasis
Animal data

Research reveals no animal data regarding the use of aloe for the treatment of seborrheic dermatitis or psoriasis.

Clinical data

The efficacy of aloe vera for the treatment of psoriasis has been studied in 2 placebo-controlled, double-blind trials. Aloe vera in a hydrophilic cream base was applied 3 times daily for 4 weeks to 60 patients with slight to moderate psoriasis (psoriasis area sensitivity index [PASI] score 4.8 to 16.7). Compared with the placebo group, the aloe vera group had more patients with a positive response (83.3% vs 6.6%, P < 0.001). The mean PASI score decreased from 9.7 to 2.2 in the aloe vera group compared with 8.9 to 8.2 among the placebo-treated group. 24

Another study of 41 patients investigated the application of aloe vera gel twice daily for 4 weeks. In an as-treated analysis, a score sum of erythema, infiltration, and desquamation decreased in 72.5% of aloe vera-treated patients compared with 82.5% of placebo-treated patients ( P = 0.0197). The magnitude of change was moderate in most patients, with only 10% to 15% of patients in the aloe vera and placebo groups, respectively, achieving a 50% reduction from baseline scores. 25

A double-blind, randomized, placebo-controlled trial demonstrated the effectiveness of an aloe vera crude extract emulsion in reducing scaliness and pruritus, as well as the number of involved sites in 44 patients with seborrheic dermatitis. 26

Diabetes/Hyperglycemia
Animal data

A study in rats examined the effects of 2 minor phytosterols of aloe vera gel, lophenol (Lo) and cycloartanol (Cy), in an obese animal model of type 2 diabetes. Consecutive treatment with phytosterols suppressed hyperglycemia and random blood glucose levels 39.6% and 37.2% lower than control in Lo and Cy treatment groups, respectively, after 35 days of treatment. Glycosolated hemoglobin (HbA 1c ) values were also lower in phytosterol-treated rats than in the control group. In addition, the weights of total abdominal fat tissues were significantly lower in the treatment groups than in the control group in rats treated with phytosterols. 27

Clinical data

Aloe gel contains glucomannan, a hydrosoluble fiber that may, in part, account for its hypoglycemic effects. Two nonrandomized clinical trials (N = 40 and N = 76) reported improved blood glucose levels with 6 weeks of juice made from aloe gel. Case reports of 5 patients with type 2 diabetes reported decreases in fasting blood glucose as well as in HbA 1c . No adverse effects were reported in these trials. The preliminary data suggest a potential effect of aloe vera in glycemic control; however, further information is needed. 28

Anti-inflammatory effects
Animal data

Arthritic mice were injected subcutaneously with a 150 mg/kg suspension of anthraquinones once a day for 13 days. This aloe extract resulted in a 48% inhibition of inflammation, caused by anthraquinone and cinnamic acid, and a 72% inhibition of arthritis, caused by anthranilic acid, which also had an anti-inflammatory effect. A. vera extracts have bradykininase activity in vitro. 29

A study evaluating the modulation of Salmonella OmpR-medicated inflammation by aloe vera was also conducted in mice. Aloe vera applied topically, administered intraperitoneally, or a combination of the two routes modulated the inflammatory response. The maximum effect was seen with the combined routes, indicating modulation at local as well as systemic levels. This modulation could be due to the potential of aloe vera to decrease perioxidative damage via a decrease in the levels of monokines (tissue necrosis factor [TNF]-alpha, IL-1, and IL-6) and an increase in the level of superoxide dismutase. No change in catalase activity was observed by aloe vera treatment. 30

Topical administration of aloe extracts reduced swelling in an animal model 29%. 31 Investigations have established that certain components of aloe inhibit the complement system, thereby reducing inflammatory responses. 32 , 33

Alprogen, a single inhibitory component in aloe vera, strongly inhibited histamine and leukotriene releases during the activation of mast cells by specific antigen-antibody reactions.

Alprogen also appeared to inhibit multiple signals as well as block calcium ion influx, and protein kinase C and phospholipase D activities were decreased in a dose-dependent manner. Alprogen also inhibited mass 1,2-diacylglycerol formation and phospholipase A 2 activity during mast cell activation. 34

Clinical data

Research reveals no clinical data regarding the use of aloe for the treatment of inflammation.

Anticancer effects
Animal data

Aloe emodin is a hydroxyanthraquinone in aloe vera leaves. Studies revealed that aloe emodin selectively inhibits human neuroectodermal tumor cell growth in tissue cultures and in animal models, 35 and is antileukemic in vitro. 36

Aloe emodin displayed a dose-dependent cytotoxic effect on neuroblastoma and Ewing sarcoma cells, whereas malignant human cells from epithelial and blood-derived tumors, as well as human hemopoietic progenitors and normal fibroblasts, were not sensitive to this compound. 35

In Merkel cell carcinoma, a striking inhibitory effect of aloe emodin on viable cell numbers after 72 hours of treatment was demonstrated. The results were statistically significant ( P < 0.02) for 10 mcmol aloe emodin and with higher drug concentrations ( P < 0.001). Aloin, the glycosidic derivative of aloe emodin, has no effect. 37

Other studies showed A. vera gel to be less cytotoxic 38 than indomethacin or prednisolone in tissue cultures. The National Cancer Institute concluded that A. vera latex was not worthy of further study as a cancer treatment. However, in 2000 the US Department of Agriculture approved A. vera as an adjunctive treatment for fibrosarcoma in animals. 39

Clinical data

Research reveals no clinical data regarding the use of aloe for the treatment of cancer.

Antibacterial/Anti-infective effects
Animal data

Studies of the antibacterial activity of aloe have yielded conflicting results. Tests found that Aloe chinensis inhibited growth of Staphylococcus aureus , Escherichia coli , and Mycobacterium tuberculosis , but that A. vera was inactive. 40 Furthermore, these extracts lost their in vitro activity when mixed with blood. The latex has shown some activity against pathogenic strains. 41

The in vitro effects of aloe vera leaf extract against axenic amastigotes of the parasite Leishmania were studied. The aloe vera leaf extract had a direct parasiticidal effect on promastigotes and was effective against Leishmania donovani axenic amastigotes. The extract also modulated the immune function of murine peritoneal macrophages by increasing the generation of reactive oxygen species. Activation of the macrophage is the primary mechanism for elimination of the Leishmania parasite that is possibly accelerated by toxic metabolites of oxygen (eg, superoxide, hydrogen peroxide, nitric oxide). However, the parasite is able to deactivate these functions of the macrophage, thus allowing itself to survive. Activation of macrophages can be viewed as a de novo therapeutic strategy in leishmaniasis. 42

Effective growth inhibition for up to 24 hours was achieved with a concentration of aloe vera gel more than 100 mg/mL for Shigella flexeri and aloe vera 25 mg/mL for Streptococus pyogenes . The reduction in the amount of aloe vera needed to suppress the growth of the gram-positive bacterium was attributed to the structural differences between the 2 organisms. 43

A hydroalcoholic plant extract obtained from fresh aloe vera leaves had antifungal activity against the myceial growth of Botrytus gladiolorum , Fusarium oxysporum , Heterosporium pruneti , and Penicillium gladioli . The minimum fungicidal concentration varied between 80 and 100 mcg/mL, depending on the fungal species. 44

Aloe is more effective than sulfadiazine and salicylic acid creams in promoting wound healing and as effective as silver sulfadiazine in reducing wound bacterial counts. 45

Clinical data

Research reveals no clinical data regarding the use of aloe as an antibacterial.

Gastrointestinal/Inflammatory bowel disease
Animal data

A study assessed the antioxidant activity of aloe vera gel on colorectal mucosal biopsies. Aloe vera had a dose-dependent inhibitory effect on reactive oxygen metabolite production, and it also inhibited the production of prostaglandin E 2 by 30% at a 1 in 50 dilution ( P = 0.03). No effect was seen on thromboxane B 2 production. The anti-inflammatory actions of aloe vera gel demonstrated in vitro support the proposal that it may have a therapeutic effect in inflammatory bowel disease. 46

Clinical data

A double-blind, randomized, placebo-controlled study of 44 hospital outpatients with mild to moderately active ulcerative colitis was performed. Patients were randomly given oral aloe vera gel or placebo 100 mL twice daily for 4 weeks. Primary outcome measures were clinical remission (Simple Clinical Colitis Activity Index 2 or less), sigmoidoscopic remission (Baron score 1 or less), and histological remission (Saverymuttu score 1 or less). Secondary outcome measures included changes in the Simple Clinical Colitis Activity Index (improvement was defined as a decrease of 3 or more points; response was defined as remission or improvement), Baron score, and histology score. The Simple Clinical Colitis Activity Index and histological scores decreased significantly during treatment with aloe vera ( P = 0.01 and P = 0.03, respectively), but not with placebo. Sigmoidoscopic scores and laboratory variables showed no statistically significant differences. Although clinical remission, improvement, and response occurred more frequently in aloe vera-treated patients, the differences did not reach statistical significance. 47

An emulsion of the gel was reported to cure 17 of 18 patients with peptic ulcers, but no control agent was used in this study. 48 Additionally, pretreatment with an A. vera extract reduced aspirin-induced injury in a study with rats. 49 Further human studies are needed to establish this potential protective property.

Other uses

Other health claims are generally poorly documented.

A Cochrane review of interventions for preventing oral mucositis found 1 study that compared aloe vera with placebo for mild versus moderate/severe mucositis (0 to 1 vs 2+) dichotomy. Because no statistically significant difference was found, it was concluded that aloe vera was neither more nor less effective than placebo. 50

The hepatoprotective potential of aqueous extracts of A. babadensis against the hepatotoxin carbon tetrachloride (CCl4) has been reported. A. babadensis shortened the hexobarbitone sleeptime and zoxazolamine “paralysis time” as compared with CCl4-treated animals, possibly due to the ability of A. babadensis to protect hepatic drug metabolizing enzymes. 51

A small study found that parenteral administration of aloe extract protects the liver from chemical injury and has been shown to dramatically ameliorate ALT levels in patients with chronic hepatitis. 52

In a laboratory experiment, rats injected subcutaneously with doses of A. vera 1, 10, or 100 mg/kg/day without anthraquinones for 7 days showed improved circulation and wound healing. 53

In a study of rats (N = 16), the administration of an intravenous infusion of drag-reducing polymers extracted from aloe vera preserved mean arterial pressure and tissue perfusion, and resulted in improved acid-base status after acute myocardial ischemia by ligation of the left anterior coronary artery. All rats in the drag-reducing polymers infusion group survived, while half of the control group died from congestive heart failure within 60 minutes. 54

A placebo-controlled study of A. vera extract 0.5% in a hydrophilic cream shortened time to healing in men with first episodes of genital herpes. 55 A gel containing A. vera extract 0.125%, allantoin 0.35%, and silicon dioxide was found effective in decreasing the duration of lesions associated with aphthous stomatitis. 56

Lyophilized A. barbadensis combined with zinc acetate has been studied in rabbits for use as a vaginal contraceptive. 57

Dosage

As a gel, A. vera may be applied externally. The resin product is cathartic and is not recommended for internal use. 58

Pregnancy/Lactation

Documented adverse effects with ingestion; do not use. Cathartic, reputed abortifacient. 59

Interactions

Potential interactions between aloe ingestion and the following medications have been identified:

Digoxin, furosemide, hydrochlorthiazide, and other thiazide diuretics

Aloe may cause hypokalemia, altering drug effects.

Stimulant laxatives

Increased laxative effect may cause excessive fluid/electrolyte loss.

Sevoflurane

Concurrent use of oral aloe vera and sevoflurane may have contributed to excessive bleeding in a 35-year-old woman undergoing excision of a thigh hemangioma. 60

Antidiabetic agents

Glimepiride, glyburide, insulin, metformin, pioglitazone, rosiglitazone: May potentate hypoglycemia. 61

Adverse Reactions

Because aloe has been used extensively as a folk medicine, its adverse effects are well documented. Except for dried latex, aloe is not approved as an internal medication. The external use of aloe has not been associated with severe adverse reactions; the majority are relatively mild and reversible upon cessation of application. 62 Reports of burning sensations following topical application of aloe gel to dermabraded skin have been described. 63 Contact dermatitis from the related Aloe arborescens has been reported. 1 Erythema, edema, urticaria, and eczematous rash have also been reported following A. vera application. 64 , 65

In one report, the use of aloe gel as standard wound therapy delayed healing. The gel may cause burning sensations in dermabraded skin, and redness and itching can also occur. Use caution with cosmetic products containing A. vera gel. 66

Prolonged ingested aloe use has resulted in adverse effects. Patients can develop bloody diarrhea, potassium depletion, albuminuria, hematuria, muscle weakness, weight loss, and cardiac effects. Prolonged use of high-dose aloe, greater than 1 g/day, has reportedly caused hemorrhagic gastritis, nephritis, and acute renal failure 61 in some patients.

A case of acute hepatitis induced by aloe vera ingestion has been reported. 67

Toxicology

Although anthranoid laxative (aloe-emodin) use has not been shown to be a risk factor for the development of melanosis coli, colorectal adenomas, or carcinomas, 68 aloe-emodin and other anthraquinones may cause severe gastric cramping and aloe has been associated with congenital malformations. 69 Its use is contraindicated in pregnant and breast-feeding women, 70 children younger than 12 years of age, 71 , 72 patients with inflammatory bowel disease, 49 and elderly patients with suspected intestinal obstruction. 72 In 2002, the US Food and Drug Administration required all over-the-counter aloe laxative products to be removed from the US market or reformulated because manufacturers have not provided the necessary safety data. 5

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