Wendell L. Combest, Ph.D.
Associate Professor of Pharmacology, Department of Biopharmaceutical
Sciences, Shenandoah University School of Pharmacy, Winchester, VA
The aloe plant?/strong>Aloe
barbadanis Miller (syn. Aloe vera [L.] N.L. Burm.)—in the
family Liliaceae is the most researched and used of the more than 300 species
of aloe. Aloe has been used medicinally for several thousands of years in many
cultures—from ancient Egypt, Greece, and Rome to China and India. The plant has
many common names and is often referred to as aloe vera, burn plant, first-aid
plant, or medicine plant. Its name is most likely derived from the Arabic word
Alloeh, meaning “shining bitter substance.?Aloes are thought to have originated
in tropical Africa but are now cultivated in warm climate areas of Asia,
Europe, and America. Aloe has been extensively cultivated in the Caribbean
islands and in Mexico since the early 1800s. In the U.S., it is grown
commercially in the Rio Grande valley of Texas, southern California, and
Florida. Aloe plants can withstand high temperatures and long periods of
drought, due to their ability to store water in their succulent leaves. On the
other hand, they are very sensitive to freezing temperatures, which can damage
or kill the plants.
Chemical Composition and Active Constituents
The aloe plant is the source of two herbal preparations: aloe gel (AG) and aloe latex. Aloe gel is often called “aloe vera?and refers to the clear gel or mucilaginous substance produced by parenchymal cells located in the central region of the leaf. Diluted aloe gel is commonly referred to as “aloe vera extract.?The gel is composed mainly of water (99%) and mono- and polysaccharides (25% of the dry weight of the gel). The most prominent monosaccharide in AG is mannose-6-phosphate, and the most common polysaccharides are called gluco-mannans (beta-(1,4) acetylated mannan).1 They are long-chain sugars containing glucose and mannose. A prominent gluco-mannan named acemannan has been isolated and is being marketed as Carrisyn. Recently a glycoprotein with antiallergic properties, called alprogen, was isolated from AG.2 In addition, a novel anti-inflammatory compound, C-glucosyl chromone, has recently been isolated from AG.3
Aloe gel also contains lignan, salicylic acid, saponins, sterols, and triterpenoids. The fresh gel contains the proteolytic enzyme carboxypeptidase (which breaks down bradykinin), glutathione peroxidase, as well as several isozymes of superoxide dismutase.4-6 The gel also contains vitamins A, C, E, B12, thiamine, niacin and folic acid, as well as the minerals sodium, potassium, calcium, magnesium, manganese, copper, zinc, chromium, and iron.1
Commercially, aloe gel is claimed to be “stabilized?to preserve its activity during long-term storage. Whether stabilized gel has the same pharmacological activity as the fresh gel is controversial.
Pericyclic tubular cells beneath the outer leaf epidermis produce a bitter yellow substance known as aloe latex, commonly referred to as “aloe juice?or “aloe.?This substance is usually dried and used as a potent stimulant laxative. Aloe latex contains a series of glycosides known as anthraquinones, the most prominent being aloin A and B.7 It should be noted that aloe gel is often contaminated with aloe latex during its isolation. This could explain the abdominal cramps, diarrhea, and laxative effects sometimes seen with certain aloe gel preparations.
Medicinal Uses and Pharmacology
Wound Healing: Aloe gel has long been used both externally and internally for its beneficial effects in the wound-healing process. It is most often included in topical formulations (ointment, cream, or lotion), but evidence also supports its effectiveness when taken orally. At least part of AG’s beneficial effect on the skin likely is due to its moisturizing effect. Also, it may leave a protective layer on the skin after drying, possibly providing some protection to the wound.
Both topical and oral AG have been shown to significantly stimulate collagen synthesis in experimental dermal wounds in rats.8 Aloe gel not only increased collagen content of the wound but also changed collagen composition (more type III). In addition, it increased the degree of collagen crosslinking. In an earlier study, the investigators also demonstrated an increased synthesis of hyaluronic acid and dermatan sulphate in the granulation tissue of a healing wound following oral or topical AG treatment.9 Both studies support an earlier trial demonstrating that both oral (100 mg/kg/day) and topical (25% AG) treatment (two months) of biopsy punch wounds in mice resulted in a significant (50%?3%) reduction in wound diameter.10 Similar beneficial effects of topical AG have been demonstrated in a skin-wound rat model. Aloe gel treatment accelerated wound contraction and increased the breaking strength of resulting scar tissue, due to increased collagen content and degree of crosslinking.11
In order to identify which constituents of AG are responsible for wound-healing effects, Davis and colleagues tested the effects of mannose-6-phosphate in a mouse-wound model system.12 An oral dose of 300 mg/kg resulted in significant wound healing, similar to that seen with AG. However, not all animal studies have shown positive results. In one study, various topical agents were tested for their effects on wound contraction and rate of re-epithelialization in full-thickness excisions in a porcine mode; AG failed to show any beneficial effects.13
AG studies in humans are more limited, and the results generally are not as positive as those from the aforementioned animal studies. In one positive study, AG (when added to a polyethylene oxide gel wound dressing) was shown to accelerate wound healing following full-face dermabrasion.14 By day six, re-epithelialization was complete at the AG-treated sites. However, soon after this study a report emerged of four patients who experienced severe burning sensations and dermatitis upon application of topical aloe gel following dermabrasion.15
An acemannan-containing gel (Carrisyn Gel Wound Dressing) was recently shown to be no more effective than a standard saline gauze dressing in the treatment of pressure ulcers.16 In another study, a similar AG dermal wound gel was actually shown to significantly delay wound healing in surgical wounds following cesarean delivery or laparotomy.17
Effects on Burns: Several animal studies and a clinical trial have assessed the effectiveness of AG in the treatment of skin burns. One study looked at full-thickness burns in guinea pigs.18 Aloe gel promoted complete healing of burn wounds within 30 days, compared to 50 days in the control group. In contrast, a similar study in guinea pigs published the same year showed that AG was less effective in treating second-degree burns when compared to standard 1% silver sulfadiazine cream.19 Wound re-epithelialization, wound contraction, and formation of granulation tissue occurred more slowly in the AG-treated animals. In another study, AG was found ineffective in treating hydrofluoric-acid induced burns in rats.20 In a human study, 27 patients with partial thickness burn wounds were treated with topical AG or a standard Vaseline gauze.21 The average healing time was 18.19 days in the Vaseline-gauze treated wounds and 11.89 days in the AG-treated wounds. Histological examination showed early epithelialization in the AG-treated skin areas.
Effects on Skin Exposure to UV and Gamma Radiation: Some of the first scientific studies on the effectiveness of AG were performed during the 1930s and involved protection of the skin against radiation damage. For the most part, these studies were inconclusive. Interestingly, recent evidence has supported a protective benefit of AG against several forms of radiation damage to the skin. An acemannan-containing topical gel was demonstrated to reduce skin damage following exposure to gamma radiation in mice.22 The results were best in animals who received the gel treatment for at least two weeks beginning immediately after irradiation. A protective effect also was documented in mouse skin exposed to soft x-irradiation.23 Investigators found that an antioxidant protein, metallothionein, was induced in the skin and liver within 24 hrs of AG administration. Following x-ray exposure, AG was found to scavenge hydroxyl radicals and prevent suppression of superoxide dismutase and glutathione peroxidase in the skin.
Several additional studies in mice and in epidermal cell culture have demonstrated an immunomodulatory effect of AG in protecting skin cells from the damaging effects of UVB radiation. UVB radiation is known to suppress the ability of Langerhans cells in the epidermis to support antibody primed T-cell mitogenesis. In one study, aloe gel prevented this UVB-mediated suppression within the first 24 hrs of irradiation in murine epidermal cell culture.24 Immunomodulatory activity was found to reside in a number of low molecular weight compounds present in AG. A more recent study reports the isolation of these small immunomodulatory substances from AG.25 Topical application of these compounds prevented UVB-induced immune suppression in mouse skin. Further work in this area has confirmed these observations and has demonstrated how AG-derived immunoprotective factors likely work. Presumably, UV-induced suppression of delayed type hypersensitivity is prevented by reducing the production and release of skin keratinocyte derived immunosuppressive cytokines, such as interleukin-10 (IL-10).26 Another study demonstrated that AG’s prevention of UV-induced immune suppression did not involve prevention of UV-induced DNA damage
or an acceleration of the repair of DNA.27
The anthraquinone aloin, which is present in aloe latex, has been shown to inactivate various enveloped viruses, such as herpes simplex.
Treatment of Frostbite and Psoriasis: Several animal studies support
the clinical use of AG in treating frostbite tissue damage. Heggars and
associates utilized an experimental rabbit ear model to demonstrate the
effectiveness of AG, as well as that of several inhibitors of arachidonic acid
metabolism (e.g., aspirin and methylprednisolone).28 In control animals, no tissue survival
was seen. In contrast, AG treatment resulted in 28.2% tissue survival compared
to 22.5% and 12.5% with aspirin and steroid, respectively. The investigators
concluded that the progressive dermal ischemia occurring during frostbite could
be reduced by inhibiting the production of prostaglandins and thromboxanes from
arachidonic acid. A more recent study supports these observations. Systemic
pentoxifylline and topical AG cream were both found to improve tissue survival
in the frostbitten ears of New Zealand rabbits.29 Using both agents together further
increased tissue survival.
A recent double-blind, placebo-controlled study in 60 psoriasis patients evaluated the efficacy of treatment with topical AG.30 PG extract (0.5% in a hydrophilic cream) was administered three times daily for five consecutive days each week for 16 weeks. At the end of the study AG had significantly reduced lesions, decreased erythema, and lowered PASI (psoriasis area and severity index) scores in 25 out of the 30 patients in the treatment group. In comparison, two out of 30 patients in the placebo group improved.
Anti-inflammatory Effects: Several animal studies have been undertaken since 1989, clearly demonstrating the anti-inflammatory activity of AG. One study found that an aqueous extract of AG decreased carrageenan-induced edema in a rat hind-paw.31 Further, the AG extract reduced prostaglandin E2 production from [14C] arachidonic acid via inhibition of cyclooxygenase. In a series of experiments conducted from 1989?994, Davis and colleagues demonstrated the anti-inflammatory action of oral and topical AG preparations in various animal models of inflammation. In their earliest study they reported a 47% reduction in swelling in the croton oil-induced edema assay in rats after topical administration of AG.32 In a later study they demonstrated an anti-inflammatory response to AG in an inflamed synovial pouch model in rats.33 AG reduced the vascularity and swelling in the inflamed pouch by 50%. The investigators also noted a 48% reduction in the number of mast cells in the synovial fluid of the pouch. Also of interest, they found an increased number of fibroblasts following treatment with aloe gel.
C-glucosyl chromone is the anti-inflammatory compound recently isolated from AG extracts.3 The substance was shown to be similar in potency to hydrocortisone when tested in a mouse ear bioassay.
Effects on the Immune System: Many claims have been made throughout the years regarding AG’s ability to support and enhance the immune system. Experimental evidence is now accumulating documenting immune-stimulating constituents present in AG. One of the first studies in the early 1980s demonstrated that a partially purified AG extract from Aloe vahombe acted as a nonspecific immunostimulant, protecting mice against infection from various bacteria and fungi.34 The AG extract had to be administered two days before exposure of the mice to the pathogenic agent to be effective. Later in the 1980s, acemannan isolated from AG was shown to increase the response of lymphocytes to antigens in an in vitro study.35 This helped explain the many reports of acemannan’s apparent antiviral effect. In later studies, a highly purified form of acemannan derived from AG stimulated the synthesis and release of interleukin-1 (IL-1) and tumor necrosis factor from peritoneal macrophages in mice that had previously been implanted with murine sarcoma cells.36 These cytokines in turn initiated an immune attack on the sarcoma cells that resulted in necrosis and regression of the cancerous cells. These effects resulted in an increased survival of the sarcoma-implanted mice. In another study, acemannan stimulated the production of nitric oxide in cultures of chicken macrophages.37 Still another study demonstrated that several low molecular weight compounds isolated from AG are capable of inhibiting the release of reactive oxygen free radicals from activated human neutrophils.38 This inhibition does not appear to affect the phagocytic activity of neutrophils but may protect tissues from excessive oxidative damage from free radicals.
Early this year, a study was published reporting the isolation and partial purification of an antiallergic compound called alprogen from AG extracts. Alprogen was shown to inhibit the antigen/antibody-mediated release of histamine and leukotriene from mast cells.2 The postulated mechanism of this effect was via inhibition of Ca2+ influx into mast cells.
Antiviral and Antitumor Activity: Most of the reported antiviral and antitumor effects of AG likely are due indirectly to the stimulation of the immune system, as discussed previously. However, one study reports that anthraquinones, which are present in aloe latex, have direct virucidal effects. The anthraquinone aloin was shown to inactivate various enveloped viruses, such as herpes simplex, varicella-zoster, and influenza. Although anthraquinones only appear in AG as a contaminant,39 low concentrations present in some preparations could have significant antiviral activity.
Several recent studies have demonstrated direct inhibitory effects of AG on both tumor initiation and promotion. A polysaccharide fraction of AG inhibited the binding of benzopyrene to primary rat hepatocytes and thus prevented the formation of potentially cancer-initiating benzopyrene-DNA adducts.40 This effect was also demonstrated in vivo, where adduct formation was reduced in various organs. A follow-up study published in 1999 by the same investigators showed that several other plant-derived polysaccharides were also able to block benzopyrene-DNA adducts.41 They also reported in this study an induction of glutathione S-transferase and an inhibition of the tumor-promoting effects of phorbol myristic acetate by AG. These two studies suggest a possible benefit of using aloe gel in cancer chemoprevention.
Laxative Effects of Aloe Latex: Anthraquinones present in aloe latex function as potent stimulant laxatives. Aloe latex is typically sold as an incapsulated dried powder. The substance is still listed in the U.S. Pharmacopoeia and is recognized by the FDA, as well as in several other European countries, as an effective laxative. Studies in rats have shown that aloe latex increases intestinal water content, stimulates mucus secretion, and increases intestinal peristalsis.42 Long-term use of the substance could result in electrolyte imbalances, especially depletion of potassium salts.
Toxicity and Adverse Reactions
Aside from occasional allergic skin reactions in a small number of people, AG used topically has few if any side effects. Several patients who applied AG topically following dermabrasion reported burning sensations and development of dermatitis on the face.15 Because of possible contamination by anthraquinones, oral AG may cause symptoms of abdominal cramps and diarrhea. There have also been several reports of AG lowering plasma glucose levels in laboratory animals and in humans.43,44 It was postulated in one study that this hypoglycemic effect was mediated through the stimulation and release of insulin from the beta-cells of the pancreas.44 Therefore, caution should be exercised when using oral AG in patients with diabetes.
1. Shelton M. Aloe vera, its chemical and therapeutic properties. International J Dermatology. 1991;30:679-683.
2. Ro J, Lee B, et al. Inhibitory mechanism of aloe single component (Alprogen) on mediator release in guinea pig lung mast cells activated with specific antigen-antibody reactions. Pharmacology and Exper Therapeutics. 2000;292:114-121.
3. Hutter J, Salmon M, et al. Anti-inflammatory C-glucosyl chromone from Aloe barbadensis. J Nat Prod. 1996;59(5):541-543.
4. Klein A, and Penneys N. Aloe vera. J Amer Acad Dermatol. 1988;18:714-719.
5. Sabeh F, Wright T, et al. Purification and characterization of glutathione peroxidase from aloe vera plant. Enzyme Protein. 1993;47(2):92-98.
6. Sabeh F, Wright T, et al. Isozymes of superoxide dismutase from aloe vera. Enzyme Protein. 1993;47(2):92-98.
7. Tyler V. Herbs of Choice: The Therapeutic Use of Phytomedicinals. Binghamton, NY: Pharmaceutical Products Press, 1994.
8. Chithra P, Sajithlal G, et al. Influence of aloe vera on collagen characteristics in healing dermal wounds in rats. Mol Cell Biochem. 1998;181(1-2):71-76.
9. Chithra P, Sajithlal G, et al. Influence of aloe vera on the glycosaminoglycans in the matrix of healing dermal wounds in rats. J Ethnopharmacol. 1998;59(3):179-186.
10. Davis R, Leitner M, et al. Wound healing. Oral and topical activity of aloe vera. J Am Podiatr Med Assoc. 1989;79(11):559-562.
11. Heggers J, Kucukcelebi A, et al. Beneficial effect of aloe on wound healing in an excisional wound model. J Altern Complement Med. 1996;2(2):271-277.
12. Davis R, Donato S, et al. Anti-inflammatory and wound healing activity of a growth substance in aloe vera. J Am Podiatr Med Assoc. 1994;84(2):77-81.
13. Watcher M, and Wheeland R. The role of topical agents in the healing of full-thickness wounds. J Dermatol Surg Oncol. 1989;15(11):1188-1195.
14. Fulton J. The stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing. J Dermatol Surg Oncol. 1990;16(5):460-467.
15. Hunter D and Frumkin A. Adverse reactions to Vit E and aloe vera preparations after dermabrasion and chemical peel. Cutis. 1991;47(3):193-196.
16. Thomas D, Goode P, et al. Acemannan hydrogel dressing for pressure ulcers. A randomized, controlled trial. Adv Wound Care. 1998;11(6):273-276.
17. Schmidt J and Greenspoon J. Aloe vera dermal wound gel is associated with a delay in wound healing. Obstet Gynecol. 1991;78(1):115-117.
18. Rodriguez-Bigas M, Cruz N, et al. Comparative evaluation of aloe vera in the management of burn wounds in guinea pigs. Plast Reconstr Surg. 1988;81(3):386-389.
19. Kaufman T, Kalderon N, et al. Aloe vera gel hindered wound healing of experimental second-degree burns: a quantitative controlled study. J Burn Care Rehabil. 1988;9(2):156-159.
20. Bracken W, Cuppage F, et al. Comparative effectiveness of topical treatments for hydrofluoric acid burns. J Occup Med. 1985;27(10):733-739.
21. Visuthikosol V, Chowchuen B, et al. Effect of aloe vera gel to healing of burn wound a clinical and historic study. J Med Assoc Thai. 1995;78(8):403-409.
22. Roberts D, and Travis E. Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice. Int J Radiat Oncol Biol Phys. 1995;32(4):1047-1052.
23. Sato Y, Ohta S, et al. Studies on chemical protectors against radiation XXXI. Protective effects of Aloe arborescens on skin injury induced by x-irradiation. Yakugaku Zasshi. 1990;110(11):876-884.
24. Lee C, Mo Y, et al. Prevention of ultraviolet radiation-induced suppression of accessory cell function of Langerhans cells by aloe vera gel components. Immunopharmacology. 1997;37(2-3):153-162.
C, Han S, et al. Prevention of ultraviolet radiation-induced suppression of
contact hypersensitivity by Aloe vera gel components.
Int J Immunopharmacol. 1999;21(5):303-310.
26. Byeon S, Pelley R. Aloe barbadensis extracts reduce the production of interleukin-10 after exposure to ultraviolet radiation. J Invest Dermtol. 1988;110(5):811-817.
27. Strickland F, Pelley R, et al. Prevention of ultraviolet radiation-induced suppression of contact and delayed hypersensitivity by Aloe barbadensis gel extract. J Invest Dermatol. 1994;102(2):197-204.
28. Heggers J, Robson M, et al. Experimental and clinical observations on frostbite. Ann Emerg Med. 1987;16(9):1056-1062.
29. Miller M and Koltai P. Treatment of experimental frostbite with pentoxifylline and aloe vera cream. Arch Otolaryngol Head Neck Surg. 1995;121(6):678-680.
30. Syed T, Ahmad S, et al. Management of psoriasis with Aloe vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health. 1996. 1(4):505-509.
31. Vazquez B, Avila G, et al. Anti-inflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol. 1996;55(1):69-75.
32. Davis R, and Rosenthal K. Processed aloe vera administered topically inhibits inflammation. J Am Podiatr Med Assoc. 1989;79(8):395-397.
33. Davis R, Stewart G, et al. Aloe vera and the inflamed synovial pouch model. J Am Podiatr Med Assoc. 1992;82(3):140-148.
34. Brossat J, Ledeaut J, et al. Immunostimulating properties of an extract isolated from Aloe vahombe. 2. Protection in mice by fraction F1 against infections by Listeria monocytogenes, Yersinia pestis, Candida albicans and Plasmodium berghei. Arch Inst Pasteur Madagascar. 1981;48(1):11-34.
35. Womble D, and Helderman. Enhancement of allo-resposiveness of human lymphocytes by acemannan (Carrisyn). Int J Immunopharmacol. 1988;10(8):967-974.
36. Peng S, Norman J, et al. Decreased mortality of Norman murine sarcoma in mice treated with the immunomodulator, acemannon. Mol Biother. 1991;3(2):79-87.
37. Karaca K, Sharma J, et al. Nitric oxide production by chicken macrophages activated by acemannan, a complex carbohydrate extracted from Aloe vera. Int J Immunopharmacol. 1995;17(3):183-188.
38. Hart L, Nibbering P, et al. 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):427-434.
39. Sydiskis R, Owen D, et al. Inactivation of enveloped viruses by anthraquinones extracted from plants. Antimicrob Agents Chemother. 1991;35(12):2463-2466.
40. Kim H, and Lee B. Inhibition of benzo[a]pyrene-DNA adduct formation by aloe barbadensis Miller. Carcinogenesis. 1997;18(4):771-776.
41. Kim H, Kacew S, et al. In vitro chemopreventive effects of plant polysaccharides (Aloe barbadensis Miller, Lentinus edodes, Ganoderma lucidum, and Coriolus vesicolor). Carcinogenesis. 1999;20(8):1637-1640.
42. Ishii Y, Tanizawa H, et al. Studies of aloe. V. Mechanism of cathartic effect. (4). 1994;17(5):651-653.
43. Ghannam N, Kingston M, et al. The antidiabetic activity of aloes: preliminary clinical and experimental observations. Horm Res. 1986;24(4);288-294.
44. Ajabnoor M. Effect of aloes on blood glucose levels in normal and alloxan diabetic mice. J Ethnopharmacol. 1990;28(2):215-220.