3.1. INTRODUCTION

Aloe vera has a long history of popular and traditional use. It is used in traditional Indian medicine for constipation, colic, skin diseases, worm infestation, and infections (Heber 2007). It is also used in Trinidad and Tobago for hypertension (Lans 2006) and among Mexican Americans for the treatment of type 2 diabetes mellitus (DM; Coronado et al. 2004). In Chinese medicine, it is often recommended in the treatment of fungal diseases (Heber 2007). In Western society, Aloe vera is one of the few herbal medicines in common usage, and it has found widespread use in the cosmetic, pharmaceutical, and food industries. In the case of health, the therapeutic claims for the topical and oral application of Aloe vera cover a wide range of conditions, but few claims have been the subject of robust clinical investigation. The conditions for which clinical trials of Aloe vera have been conducted include skin conditions, management of burn and wound healing, constipation, DM, and gastrointestinal disorders.

3.2. TAXONOMY AND TRADITIONAL ORIGINS

Aloe vera is one of approximately 420 species of the genus Aloe (Dagne et al. 2000), which is variously classified as belonging to the Asphodelaceae, Liliaceae, or Aloaceae families. Commonly known as Aloe barbadensis Miller, its legitimate name according to the international rules of botanical nomenclature is A. vera (L.) Burm.f. (Grindlay and Reynolds 1986). The geographic origin of Aloe vera is believed to be in Sudan, with the plant subsequently being introduced in the Mediterranean region and most other warm areas of the world (Grindlay and Reynolds 1986).

Aloe has been used extensively by the Egyptians, Assyrians, Mediterranean civilizations and in Biblical times (Grindlay and Reynolds 1986). The first authentic record of Aloe as a plant with healing properties is accredited to a Mesopotamian clay tablet dated at ca 2100 bce. However, the first detailed depiction of the plant’s medicinal value is found in the Papyrus Ebers, an Egyptian document dated at ca 1550 bce, which sets out multiple Aloe-containing preparations for the treatment of external and internal ailments. The Aloe vera plant is described in detail in the Greek Herbal of Dioscorides (ca 70 ad), and its use promoted for the treatment of wounds, hair loss, genital ulcers, and hemorrhoids (Davis 1997). Aloe vera was officially listed as a purgative and skin protectant by the U.S. pharmacopoeia in 1820 (Park and Lee 2006) and was clinically used in the 1930s for the treatment of radiotherapy burns to the skin and mucous membranes (Collins and Collins 1935; Manderville 1939). Until today, Aloe is an important traditional medicine in many countries, including China, India, the West Indies, South Africa, and Japan (Grindlay and Reynolds 1986).

3.3. CURRENT USAGE

Aloe vera is one of the few herbal medicines widely used in Western society, with the manufacturing of Aloe vera extracts being one of the largest botanical industries worldwide (Grindlay and Reynolds 1986; Eshun and He 2004). In 2004, the value of the Aloe industry was estimated to be US$125 million for the cost of the raw Aloe material and US$110 billion for finished Aloe-containing products (International Aloe Science Council 2004). Aloe vera is used in the cosmetic, food, and pharmaceutical industries. In the cosmetic and toilet industry, it is used as a base material for skin moisturizers, soaps, shampoos, sun lotions, makeup creams, perfumes, shaving creams, bath aids, and many other products (Eshun and He 2004; Boudreau and Beland 2006). The food industry uses Aloe in the manufacture of functional foods, especially health drinks, and as a bitter agent (Saccu, Bogoni, and Procida 2001). Pharmaceutical products are available for topical applications (gels and ointments) and oral use (tablets and capsules; Hamman 2008).

3.4. STRUCTURE AND CHEMICAL CONSTITUENTS

Aloe vera is a perennial succulent xerophyte; it has elongated and pointed leaves that are joined at the stem in a rosette pattern and that grow to about 30–50 cm in length and 10 cm in breadth at the base in the adult plant (World Health Organization 1999). The leaf is protected by a thick, green epidermis layer (skin or rind), which surrounds the mesophyll. Immediately beneath the rind are located the vascular bundles, which are composed of three types of tubular structures: the xylem (transports water and minerals from roots to leaves), the phloem (transports starch and other synthesized products to the roots), and the large pericyclic tubules (contains the yellow leaf exudate commonly referred to as “aloes,” “sap,” or “latex”; Boudreau and Beland 2006). The pericyclic portion of the vascular bundle is adherent to the rind, whereas the remainder of the vascular bundle protrudes into the mesophyll layer (Danhof 1987). The mesophyll can be differentiated into chlorenchyma cells and thinner-walled parenchyma cells. The parenchyma (filet or pulp), which is the major part of the leaf by volume, contains a clear mucilaginous gel (known as Aloe vera gel; Femenia et al. 1999; Femenia et al. 2003).

Aloe vera is considered to be the most biologically active of the Aloe species (World Health Organization 1999). More than 75 potentially active constituents have been identified in the plant (Table 3.1) including vitamins, minerals, saccharides, amino acids, anthraquinones, enzymes, lignin, saponins, and salicylic acids. The leaf exudate contains anthraquinones, particularly barbaloin (Figure 3.1), which appear to be responsible for its bitter taste and cathartic effect (Dagne et al. 2000; Boudreau and Beland 2006). Barbaloin and other products of the phenylpropanoid pathway are commonly referred to as polyphenolic compounds. These are derived from the precursor phenolic acids, and they may act as antioxidants to inhibit free radical–mediated cytotoxicity and lipid peroxidation (Cook and Samman 1996). Aloe vera also contains products of the isoprenoid pathway, including carotenoids, steroids, terpenes, and phytosterols (Samman 1998). Isoprenoids can be regarded as sensory molecules because they contribute to the color and fragrance of the products in which they exist.

TABLE 3.1

Classes and Selected Examples of Phytochemicals in Aloe vera.

FIGURE 3.1

Structure of barbaloin (aloin), a glucoside of loe-emodin.

Aloe vera gel is rich in polysaccharides, including acemannan (partially acetylated glucomannans; Figure 3.2), which has been reported as the primary active substance in the parenchyma (t'Hart et al. 1989). However, given the number of other potentially active compounds in the plant, it is possible that the biological activities of Aloe vera result from the synergistic action of a variety of compounds, rather than from a single defined component (Dagne et al. 2000; Hamman 2008). Equally, the potential for constituents to exhibit antagonistic and competitive activities also influences the overall biological activity of particular Aloe vera preparations (Hamman 2008).

FIGURE 3.2

Structure of acemannan, a mucopolysaccharide that is extracted from Aloe vera leaves.

3.5. EFFECT OF CULTIVATION AND PROCESSING

The composition of Aloe vera extracts differs according to the plant variety, climatic and seasonal variations, and the age of the plant (Eshun and He 2004). However, the processing method has the largest effect on the number and amount of active ingredients in a product (Wang and Strong 1995). The commercial production process of Aloe vera products typically involves crushing, grinding, or pressing of the whole Aloe vera leaf to produce juice, followed by various steps of filtration and stabilization to achieve the desired extract (Eshun and He 2004). This method provides ease of processing and higher efficiency in the recovery of the solids (Agarwala 1997), but it can result in a product that contains little or no active ingredients (Eshun and He 2004). In an analysis of 18 commercial Aloe vera products, only 9 exhibited quantifiable amounts of mucilaginous polysaccharide (Ross, Elsohly, and Wilkins 1997). Only three of the nine commercial Aloe vera gel powders sourced from leading international suppliers demonstrated satisfactory amounts of the polysaccharide Acemannan (Bozzi et al. 2007). Variable polysaccharide content in Aloe vera has been attributed particularly to heating the plant extract to >60°C, which results in significant changes in molecular weight (Turner et al. 2004). A further issue with the commercial production process is that during the commercial extraction of Aloe vera gel, it is virtually impossible to prevent the contamination by leaf exudates (Eshun and He 2004). Finally, the adulteration of Aloe vera products using fillers such as maltodextrin, glucose, glycerin, and malic acid represents a major concern for the Aloe vera market (Bozzi et al. 2007). As a counter to such misrepresentations in the industry, the International Aloe Science Council developed a certification program that validates the quality and quantity of Aloe vera in approved commercial products.

3.6. HEALTH EFFECTS: THE SCIENTIFIC EVIDENCE

The therapeutic claims for Aloe vera cover a broad range of conditions. It is commonly used topically in the treatment of dermatological and wound healing conditions. The oral application of the Aloe vera latex is promoted as a laxative, whereas gel and whole-leaf oral preparations have been variously recommended for use as an adjunct to chemotherapy treatment and to ameliorate diverse disorders such as DM, infectious diseases, metastatic cancer, and ulcerative colitis. The clinical use of Aloe vera is supported primarily by anecdotal evidence and case reports. The number of clinical trials exploring its effectiveness has begun to increase (Table 3.2); however, a standardization of methodological trial quality has yet to be achieved.

TABLE 3.2

Controlled Trials Investigating the Effectiveness of Aloe vera in the Treatment of Various Health Conditions in Humans.

3.7. ACTIVE INGREDIENTS AND MECHANISMS OF ACTION

A large number of biological activities have been ascribed to Aloe vera to explain its purported health benefits, including antimicrobial, anti-inflammatory, lipid and glucose lowering, antiproliferative, immunostimulatory, and antioxidant functions. A number of potentially active ingredients in the latex and gel of Aloe vera have been identified; however, much has yet to be determined about their mechanisms of action. Further studies are also required to determine the active properties of numerous other Aloe vera constituents and to explore the competitive or synergistic actions of particular combinations of ingredients.

3.7.1. Active Latex Constituents

The major C-glycosides, barbaloin (Figure 3.1) and isobarbaloin, have been shown to be the principal agents responsible for cathartic and other effects of Aloe vera latex in humans and animals. Both barbaloin and isobarbaloin undergo decomposition in the large intestine to form the active metabolites aloe-emodin-9-anthrone and aloe-emodin (Figure 3.3), which induce laxation via multiple mechanisms. In vitro and in vivo studies in rats demonstrated that aloe-emodin-9-anthrones reduce the absorption of water from the intestinal lumen by inhibiting the activity of Na⁺, K⁺-adenosine triphosphatase (ATPase) and stimulate water secretion by increasing the paracellular permeability across the colonic mucosa (Ishii, Tanizawa, and Takino 1990). Secretion of water into the lumen by a prostaglandin-dependent mechanism has also been reported (Capasso et al. 1983). The net result is a reduction in water absorption and the formation of softer stools (Boudreau and Beland 2006). Aloe-emodin has been suggested to have antiangiogenic properties; it has been demonstrated to be a potent inhibitor of urokinase secretion and tubule formation of endothelial cells, both key events in angiogenesis (Cárdenas, Quesada, and Medina 2006).

FIGURE 3.3

Aloe-emodins (anthraquinones) isolated from Aloe vera.

3.7.2. Active Gel Constituents

Polysaccharides, particularly mannose-containing polysaccharides, cellulose, and pectic polysaccharides, comprise the major part of Aloe vera gel. Acetylated glucomannan is primarily responsible for the gel’s mucilaginous properties (Hamman 2008) and has been found in vitro and in animal studies to modulate immune function (through macrophage activation and cytokine production) and accelerate wound healing (Ulbricht et al. 2008). Veracylglucan B and veracylglucan C (Figure 3.4), two maloyl glucans isolated from Aloe vera gel, have been demonstrated in vitro to have potent anti-inflammatory effects, although their effects on cell proliferation appear antagonistic (Esua and Rauwald 2006).

FIGURE 3.4

Veracylglucan C: a maloyl glucan isolated from Aloe vera.

Among the nonpolysaccharide gel constituents, salicylic acid and other antiprostaglandin compounds may contribute to the local anti-inflammatory activity of Aloe vera via the inhibition of cyclooxygenase (Ulbricht et al. 2008). Potent antioxidant effects, including the ability to scavenge superoxide anions, have been attributed to the caffeoyl group of isorabaichromone, a derivative of aloesin (C-glycosylated 5-methylchromone). Five phytosterols have been isolated from Aloe vera gel based on their ability to decrease the HbA1c level in a mouse model (db/db) of type 2 DM. Each of the phytosterols, namely lophenol, 24-methyl-lophenol, 24-ethyl-lophenol, cycloartanol, and 24-methylene-cycloartanol, was shown to significantly decrease fasting blood glucose levels in the db/db mice compared to controls at a dose of 1 μg/day (Tanaka et al. 2006). Phytosterols are not extensively absorbed from the intestine but can bind cholesterol and prevent it from being absorbed (Ralph and Provan 2000). Phytosterols have been shown to lower plasma cholesterol concentrations, including the atherogenic LDL fraction (Moghadasian and Frohlich 1999). The mechanisms of action by which Aloe vera modulates blood glucose are unknown, but it has been suggested that it may interact with insulin. It has been hypothesized that Aloe stimulates insulin synthesis or its release from pancreatic β cells (Ajabnoor 1990). Processed Aloe vera gel was found to suppress the expression of the adipogenic genes SREBP-1a, FAS, and GPAT, suggesting that the gel improves insulin resistance by the reducing toxic effects of lipids in the liver (Kim et al. 2009).

3.8. SAFETY AND EFFICACY

Determining the safety and efficacy of Aloe vera is difficult due to the lack of standardization of commercially available Aloe vera preparations. Similarly, the need for a more detailed understanding of the plant’s active components makes it difficult to evaluate the optimal doses of particular Aloe vera preparations for the treatment of specific disorders.

Despite these challenges, a recent systematic review of Aloe vera by the Natural Standard Research Collaboration concluded that topical application of Aloe vera gel or extract is safe for the treatment of mild to moderate skin conditions, burns, wounds, and inflammation (Ulbricht et al. 2008). In terms of efficacy, reasonable evidence in humans supports the topical use of Aloe vera for the treatment of burn wounds. Evidence for its use in psoriasis, dermatitis, and surgical wound healing is conflicting.

The Natural Standard Research Collaboration further concluded that the oral use of Aloe vera gel for its potential hypoglycemic effects and the short-term use of oral Aloe latex as a laxative are possibly safe; however, prolonged use of the latex is likely to be unsafe due to a theoretical risk of dehydration and electrolyte imbalance (Ulbricht et al. 2008). The cathartic properties of anthraquinone glycosides found in Aloe vera latex are well established. However, given the potential safety concerns with its use, there is a need for further clinical trials to investigate the benefits of latex administration over conventional laxative treatments. Although inconclusive, there is some preliminary evidence of a favorable effect of Aloe vera gel taken orally in type 2 DM, ulcerative colitis and the stabilization of metastatic cancer.

3.9. DRUG/VITAMIN BIOAVAILABILITY

Aloe vera gel has been shown to enhance vitamin C and E’s bioavailability in a double-blind, randomized, controlled trial (Vinson, Al Kharrat, and Andreoli 2005). The authors suggest that Aloe vera gel protects against the degradation of vitamins in the intestinal tract and the gel polysaccharides may bind to vitamins and thereby slow down their absorption rate.

Aloe vera gel has been shown to significantly increase the transport of insulin in a cell model, and limited information suggests that if coadministered, it may also enhance the intestinal absorption of other poorly absorbed drugs (Hamman 2008).

3.10. RESEARCH NEEDS

Analysis of the potential efficacy of Aloe vera in the treatment of particular disorders is complicated by differences in Aloe vera preparations, their means of administration, and the animal model or study design employed in individual studies. Research on standardized methodological quality is, therefore, needed to identify which Aloe vera components, individually or in combination, exhibit therapeutic properties and the exact mechanisms by which they act. Controlled in vivo toxicology and safety studies of Aloe vera preparations in humans are also required.

3.11. CONCLUSIONS

Despite its long history of use, there remains a lack of consistent scientific evidence to support many of the therapeutic claims for Aloe vera. Evidence of efficacy is strongest for the laxative effects of Aloe vera latex, however, whether the latex is more efficacious than conventional laxative treatments has not yet been determined, and the anthraquinones in the latex are associated with considerable risks. The topical application of Aloe vera gel is likely safe and demonstrates overall efficacy in healing burn wounds, whereas some promising preliminary evidence suggests that the oral use of the gel may have beneficial effects in lowering blood glucose levels in type 2 DM, stabilizing metastatic cancer, and treating mild to moderate ulcerative colitis. Further research in humans is required to confirm these effects.

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