Stone age paintings in several locations dating to 6000 BC or earlier depict honey hunting, documenting
human use of honey for at least 8000 years. References to honey as a medicine are found in ancient scrolls,
tablets and books—Sumarian clay tablets estimated to be 6200 BC, Egyptian papyri dated from 1900-1250
BC, Veda (Hindu scripture) about 5000 years old,2 the Holy Koran,3,4 the Talmud, both the old and new testaments of the Bible, sacred books of India, China, Persia and Egypt3,4 and Hippocrates 460-357 BC.2
Clearly, honey was ubiquitous and our ancestors’ use of it for medicinal purposes was universal.
Honey was prescribed for a variety of uses including baldness, contraception and as a wound treatment.
Frequently, honey was mixed with herbs, grains and other botanicals from the geographic area. Table 1 summarizes some of the ways honey has been used through the ages. Uses that have continued into modern folk medicine include treatment for coughs and sore throats, lotus honey for eye diseases in India, infected leg ulcers in Ghana, earaches in Nigeria, topical treatment of measles in the eyes to prevent corneal scarring, gastric ulcers and constipation. 20th Century practices and research Much of the literature in the early part of the 20th Century contains reports of antimicrobial and wound healing properties of honey. In 1919, Sackett reported that antibacterial activity increased in diluted honey.11 Russian soldiers during World War I used honey to prevent infections in wounds and to accelerate healing.12 Germans used honey and cod liver oil for
ulcerations, burns, fistulas and boils in addition to a honey salve (mixed with egg yolk and flour) for boils
and sores. In a 1992 review by Molan, it was noted that in 1937, Dold, et al. began intensive study on the antimicrobial activity of honey and called it “inhibine”.11 In 1963, White, et al, identified “inhibine” as hydrogen peroxide, which is formed by the glucose oxidase system.13 Throughout the 1930s, there were numerous medical journal reports on the effectiveness of honey in clearing bacterial infection in wounds. Intensive laboratory studies for the treatment of infections became available in the mid-1940s with the medical profession taking note of the value of honey.

However, the introduction of antibiotics shifted the focus to synthetic and massproduced treatments. During the 1930s, 1940s and 1950s, researchers were documenting the wound healing properties of honey, leading to a treatment still in practice today. The past two decades have brought a resurgence
of interest in learning more about antimicrobial and wound healing properties of honey.
Reports from different parts of the world generally affirmed the effectiveness of honey in treating various
wounds, burns and serious infections. Research objectives have included comparisons of honey wound dressings to other treatments as well as identification of more effective honeys. Other research focused on the pathogens against which honey acted and the mechanisms by which it acts. In studies that compared it to a solution of sugar with similar osmotic pressures, honey was shown to be particularly active against gram negative bacteria and higher fungi while sugar solutions did not have the antimicrobial activity.32,42 In addition, research on Salmonella, Escherichia coli, Aspergillus flavus, Aspergillus niger and Penicillium chrysogenum showed honey to have more pronounced inhibitory effect than individual sugars.42,43 Other aspects of honey and its use in various clinical conditions have also been investigated. For example, the carbohydrate absorption from a commercial brand of honey (blossom honeydew honey) in Greece was studied in 20 normal, white subjects. The results of a breath hydrogen test, reports of loose stools within 10 hours of consumption of the test doses of honey vs. glucose and fructose mixture demonstrated carbohydrate malabsorption. The researchers suggested that fructose was the malabsorbed carbohydrate leading to
the laxative effect of honey. This study provides scientific support for the common Greek practice of treating constipation with honey.44,45 In recent years, with the advent of functional foods, research expanded to include the health promoting aspects of honey. A number of studies on the phytochemical and antioxidant content of honey and its impact on gastrointestinal health and energy metabolism have identified potential new roles for honey in diets.

Composition of Honey
Nutrients

Honey is a supersaturated sugar solution with approximately 17.1 percent water. Fructose is the predominant sugar at 38.5 percent, followed by glucose at 31 percent. Disaccharides, trisaccharides and oligosaccharides are present in much smaller quantities. Besides carbohydrates, honey contains small amounts of protein, (including enzymes), vitamins and minerals. Honey yields 64 calories per tablespoon, making it a more concentrated source of energy than other common sweeteners. While the amino acid content is minor, the broad spectrum of approximately 18 essential and nonessential amino acids present in honey is unique and varies by floral source. Proline is the primary amino acid with lysine being the second most prevalent. Other amino acids found in honey include phenylalanine, tyrosine, glutamic and aspartic acids. The glutamic acid is a product of the glucose oxidase reaction.13 Proline and other amino acids are concontributed by pollens, nectar or by the bees themselves. Bees use a variety of plants to create honey and consequently, the nutritional profile of honey varies accordingly. Some studies have been done on honeys from different botanical origins to evaluate the differences in sugar content, 52 amino acid content 53 and other components. These compositional differences can influence the value of a specific honey for medicinal
or health-promoting purposes.

Phytochemicals
In recent years, research has identified a number of phytochemicals in various foods, including honey.
Phytochemicals are substances in plants. It is now recognized that many phytochemicals can have
health-promoting activities. Antioxidants, a major group of phytochemicals, reduce the risk of tissue oxidative
damage. Honey is known to be rich in both enzymatic and non-enzymatic antioxidants, including catalase, ascorbic acid, flavonoids and alkaloids.46,54,55 A unique flavonoid, pinocembrin, is present in high quantities
in propolis and honey. Other flavonoids found in honey are pinobanksin, chrysin, galangin, quercetin, luteolin and kaempferol. Different honeys have different flavonoid profiles, depending on the floral source
for the nectar. Similarly, the ascorbic acid content of honey ranges from 0.5-6.5mg/100g with an average of
2.4mg/100g or 5mg/ml.56 However, some specific varieties of honey have been reported to contain as much as 75-150mg ascorbic acid per 100g, while most honey contain less than 5mg/100g.57 In vitro experiments on the inhibition of oxidation in a model system using various honeys demonstrated a wide variation in the antioxidant capacity among floral sources. Honey made by bees fed herbal extracts exhibited
greater antioxidant activity than normal honey.58 In general, higher antioxidant content was found in darker
honeys and in honeys with higher water content.59 Some honeys, such as buckwheat honey, are comparable to fruits and vegetables, such as orange pulp, broccoli and sweet peppers, in their antioxidant content on a weight basis.

Enzymes

Honey contains a number of enzymes including glucose oxidase, invertase, diastase (amylase), catalase and
acid phosphatase.46 The glucose oxidase reaction produces glutamic acid and hydrogen peroxide from glucose. It also produces glucolactone that equilibrates with gluconic acid. The hydrogen peroxide contributes
to the antimicrobial properties of honey.

Invertase converts sucrose to fructose and glucose. It is added to the nectar by the bees as either gluco-invertase or fructo-invertase.60 Some invertase is found in honey and may continue its activity in extracted honey. However, high temperatures will inactivate it. Diastase (amylase) splits starch chains to randomly
produce dextrins and maltose. Originating from bees and pollen,46 it is added during the ripening of nectar.
The diastase content varies according to floral source. Long storage periods and exposure to high temperatures for a prolonged period of time inactivate diastase.

Researchers recommend 85 °C for 5 minutes to denature diastase in honey; also a pH outside the optimum
range of 5.3-5.6 will decrease diastase activity. Catalase, found in small amounts in honey, produces
oxygen and water from hydrogen peroxide. The inverse relationship between catalase activity and hydrogen perperoxide content has been used to determine the hydrogen peroxide level of honey, formerly called the “inhibine
number”.

Organic acids

Organic acids contribute a slight tartness to the flavor of honey and add to its antimicrobial properties.
Gluconic acid, the major organic acid, is the product of the enzymatic glucose oxidase reaction. It has been
shown to increase calcium absorption.63 Honey contains many other organic acids—butyric, acetic, formic,
lactic, succinic, malic, citric, maleic, oxalic and pyroglutamic. As with many other components in honey, the
organic acid content varies according to the floral source.

Other relevant properties (pH, osmotic pressure, water activity)
Honey possesses a number of properties that contribute to its various roles in human health.
Actual values vary by floral source.

Acidic environment (average values)
• Low pH 3.9 Range 3.4-6.1
• Acids 0.57% Range: 0.017-1.17% (primarily gluconic acid)
High osmotic pressure and low water activity Aw51
• 0.5 (16% water) to 0.6 (18.3% water) in the 40-100 °F (4-37 °C) temperature range,
depending on its water content, temperature, floral source and other factors.
Viscosity, which decreases rapidly as temperature rises; 1% moisture is equivalent to about 3.5 °C in its effect
on viscosity.

Antimicrobial Activity Mechanisms

A number of characteristics of honey contribute to its antimicrobial activity. The enzymatic glucose oxidation
reaction and some of its physical properties are considered to be the major factors. Other factors include
high osmotic pressure/low water activity (Aw), low pH/acidic environment, low protein content, high
carbon to nitrogen ratio, low redox potential due to the high content of reducing sugars, a viscosity that
limits dissolved oxygen and other chemical agents/ phytochemicals.

Honey researcher, Peter Molan, PhD, has written an extensive review of the research on the antimicrobial
factors in honey67,68 and has summarized the key aspects of his research on a Web site at the University of
Waikato, Hamilton, New Zealand:
• Honey is a supersaturated sugar solution with a low water activity (Aw), which means that there is little
water available to support the growth of bacteria and yeast. Many species of bacteria will grow if the
Aw is between 0.94-0.99 and the Aw of ripened honey (0.56-0.62) does not support the growth of
yeast. Diluted honey with a higher Aw will not be effective against those species of bacteria that grow
most rapidly at an Aw of 0.99.

• The natural acidity of honey will inhibit many pathogens. The minimum pH value for some species that commonly infect wounds ranges from 4.0-4.5. Dilution of honey, especially with body fluids, will raise the pH and lessen the antibacterial effectiveness that results from its acidity.

• Glucose oxidase is an enzyme secreted by the bees to form honey from nectar. It converts glucose in
the presence of water and oxygen to gluconic acid and hydrogen peroxide. The resulting acidity and
hydrogen peroxide preserve and sterilize the honey during the ripening process. Full-strength honey
has negligible amounts of hydrogen peroxide and active glucose oxidase. Transition ions and ascorbic
acids rapidly decompose hydrogen peroxide to oxygen and water while the low pH inactivates the
enzyme. However, dilution of honey results in a 2,500-50,000 increase in enzyme activity and a
“slow-release” antiseptic that does not damage tissue.

• The peroxide-generating system does not account for all of the observed antibacterial activity. Several
substances with antibacterial activity are found in honey in small quantities that are too low to concontribute
significantly to antibacterial activity:

pinocembrin, terpenes, benzyl alcohol, 3,5- dimethoxy-4-hydroxybenzoic acid (syringic acid),
methyl-3,5-dimethoxy-4-hydroxybenzoate (methyl syringate), 3,4,5-trimethoxybenzoic acid, 2- hydroxy-3-phenylpropionic acid, 2-hydroxybenzoic acid and 1,4-dihydroxybenzene. Support for the existence of non-peroxide antimicrobial factors comes from reports of continued activity after
honey has been treated with heat, thereby inactivating the glucose oxidase, and after honey
has been treated with catalase to remove the peroxide activity.

Not all honeys are created equal in antimicrobial activity due to differences in levels of peroxide production
and non-peroxide factors, which vary by floral source and processing. The presence of metal ions,
ascorbic acid and catalase from the nectar can destroy the hydrogen peroxide. Heat and light can destroy the
glucose oxidase enzyme. The original method for measuring antibacterial activity was to determine the “inhibine number” defined as the degree of dilution (done in a stepwise fashion) to which a honey will retain its antibacterial activity. Most studies now report antimicrobial activity as minimum inhibitory concentration (MIC), the minimum concentration necessary for complete inhibition of growth. Studies on large numbers of
honey samples show a wide range of activity and many with only a low level of activity. While there are insufficient data to clearly identify the antibacterial activity of all honeys, there is some evidence of high levels in honeydew honey (a sweet liquid excreted by sucking insects72 which tap into leaves) from the conifer forests of the mountainous regions of central Europe and manuka honey (honey from the
Leptospermum species) from New Zealand. In a study by Willex, et al, manuka honey had the highest
levels of non-peroxide activity among 26 different types of honey from various floral sources. It strongly inhibited two strains of bacteria (Escherichia coli and Staphylococcus aureus). An in vitro study compared the antibacterial action of a pasture honey (a polyfloral honey in which the nectar comes from various clovers and pasture weeds such as thistle and dandelion) and manuka honey on coagulase

Wound Healing
Properties and mechanisms

Empirical evidence established honey as a treatment for wounds and sores in ancient times. Today an extensive body of scientific literature on the wound healing capabilities of honey confirms its value as both an
antimicrobial agent and a promoter of healing. A multitude of wound types have successfully been treated with honey dressings.

There have only been a few cases reported where improvement did not occur—a Buruli ulcer, a small
group in which only a small amount of honey was applied, two cases with immunodepression, one who
stopped treatment because of a painful reaction to honey, one burn that had only a good initial response
and an ulcer complicated by the presence of varicose veins.

Clearly, the antimicrobial activity in honey that prevents and treats infections is fundamental to its wound
healing properties. However, scientific evidence points to a more diverse role for honey in the process.
Observed therapeutic effects attributed to using honey as a wound dressing include rapid healing, stimulation of the healing process, clearance of infection, cleansing action on wounds, stimulation of tissue regeneration, reduction of inflammation, and the comfort of the dressings due to lack of adhesion to the tissues.
Healing is a complex, dynamic process that involves many systems and cell types. Molecular and cellular components are responsible for the degradation and repair of tissues that occur during healing. While the
exact mechanisms for all the observed effects of honey when applied to wounds, burns and skin ulcers are yet to be defined, recent research clarifies and elucidates some possible explanations.

As a medical treatment, honey is rather innocuous. Other than occasional stinging when applied to wounds
and redness in the eye, no adverse affects have been reported. In addition, allergy to honey is rare. In theory, wound botulism from naturally occurring Clostridium botulinum spores is possible but in practice,
this has never been reported. Since high heat is known to inactivate the antimicrobial factors in honey, pasteurization or other heat treatments are not sterilization options. However, treatment with gamma-irradiationwill kill the spores while leaving the components responsible for antimicrobial activity intact.

Much of the literature on the use of honey in wound healing (and in other areas of research) does not give
the type of honey used. All honey is not equal in its effectiveness and care must be taken to ensure that the
type used has adequate antimicrobial activity.

Extensive research at the University of Waikato, Hamilton, New Zealand, has demonstrated the value of manuka honey (not found in the United States) from the Leptospermum species as a wound dressing.
Commercial standardized and sterilized versions of manuka or other Leptospermum honey in squeeze-out
tubes, syringes and impregnated dressings are available from several manufacturers by mail order. In New
Zealand, active manuka honey with a rating of UMF 10 or higher is commonly used in these products.

In recent years, honey has been rediscovered as a treatment for wound healing. Laboratory research
has verified its efficacy against many of the common pathogens that infect wounds, including some of the
antibiotic resistant bacteria such as MRSA (Methicillanresistant Staphylococcus aureus) and VRE (Vancomycinresistant enterococci). In these studies, an artificial honey, a supersaturated sugar solution that mimics the composition and osmolarity of honey, is used as thecontrol to demonstrate the antimicrobial components in honey that are not related to its osmotic pressure. As can be seen in Table 8, honey at less than 10 percent (v/v) concentration inhibited the pathogens including the MRSA with manuka honey exhibiting inhibition at the lowest concentrations (2.3-6.6 percent v/v).

Promotion of Healing

Clinically, there are numerous reports of healing severe wounds with honey wound dressings. Most striking
was the remarkable recovery of an adolescent boy in the United Kingdom who had chronic infected lesions
caused by meningococcal septicemia that resulted in extensive tissue necrosis, necessitating amputations of
his legs below the knees and distal and middle phalanges on both hands. After several months, numerous
skin grafts on his legs and a pressure ulcer were heavily infected by Pseudomonas and Staphylococcus aureus and failed to heal with conventional treatment. Treatment with dressingpads impregnated with sterilized active manuka honey from New Zealand led to complete healing within 10 weeks.

In order to capitalize on all the advantages honey offers as a wound dressing, its application needs to be
tailored to the type of wound and its degree of severity. The exudate from the wound will dilute the honey, sothe fluid outflow will determine the frequency of dressing changes. Honey needs to be in contact with the wound; inflamed and deep wounds require more honey so it can diffuse into the tissues. Cavities and depressions
in a wound bed need to be filled with honey before the dressing is applied. It is best to apply the honey to the dressing instead of the wound itself.

Dressings should extend beyond the edges and surround affected tissues. Occlusive or other secondary
bandages help to prevent honey from oozing out from the dressing. Patients are encouraged to discuss honey as a potential therapeutic agent with their physicians.

Burns

Burns have more adverse effects on the body than just damage to the skin and tissues. Hemodynamic (heart),
hematological, gastrointestinal, endocrinologic, and neurologic systems are all affected as well. Management
of burn victims requires re-establishment of a barrier that will protect the internal environment from external
contaminants but also help hold in and regulate fluids and tissues under repair.

Honey may be able to heal burns as well or better than conventional dressings.116 A series of studies by
Subrahmanyam in India has shown that dressings with pure, unprocessed, undiluted honey obtained from
hives (floral origin and antimicrobial activity of the honey not specified in the reports) had advantages over
standard medical treatments such as OpSite®,26 silver sulfadiazine29 and traditional, low-cost treatments such as boiled potato peels30 but not over early tangential excision and skin grafting of moderate burns.

Results from the studies comparing different dressings demonstrated that honey is an effective dressing which speeds healing, sterilizes wounds, reduces pain with enhanced formation of granulation tissue and lessens inflammation and scarring. Its viscous quality protects the surface
from infection and scraping. Other benefits are the ease of dressing changes and its lower cost. Additionally, skin grafts were successfully held at room temperature in honey prior to grafting instead of being rehydrated in
saline solution.

Minimal scarring has been observed when wounds and burns are treated with honey Subrahmanyam25
noted less scarring in burn patients, including deep wound patients and patients with second and third
degree burns.

In regulatory terms, honey is considered to be a medical device as are wound dressings such as OpSite®.
In 1999, the Therapeutic Goods Administration of Australia approved the use of Medihoney®, which is
100 percent honey, as a primary wound dressing. Two new products were introduced in The Netherlands
during 2001. One is Medisoft®, a plaster containing a neutral woven carrier of ethylvinylacetate (EVC) and
pure honey. The other is a sterile mix of honey and other substances such as lanolin, sunflower oil and
zinc oxide.

Infected Wounds and Burns

Of course, infected wounds and burns are more difficult to manage clinically. Honey has been evaluated
recently for its usefulness in dealing with these conditions. Research in the 1990s found honey to be effective
in healing infected non-healing skin wounds. Studies on Fournier’s gangene treated with topical unprocessed honey showed rapid improvement with decreased edema and discharge, rapid regeneration with
little or no scarring, wound debridement and reduced mortality. Animal studies with buffalo calves compared
honey to ampicillin and nitrofuazone in treating infection and found that honey decreased infection and
healing time and was generally more effective.

Surgical Wounds
In 1955, Bulman used honey as surgical dressing for vulvectomies because of its bactericidal capabilities. He
also noted success in treating ulcerations following radical surgery for carcinoma of the breast and varicose
veins with honey.18 In 1970, other researchers reported using undiluted honey following radical operations for
carcinoma of the vulva, resulting in no infections, minimal debridement and reduced hospital stays. In the
1980s, a number of studies used mice to investigate honey in surgical wound healing and found that there
was more granulation, smaller wounds and more rapid healing. Other research evaluated the use of honey
and microtape for wound closure in women with wounds.

Antioxidant Activity
Antioxidants in food preservation and human health

Antioxidants play a role in combating damage caused by oxidizing agents, such as oxygen, in foods and in the
human body. Natural and synthetic antioxidants have a long history as preservatives in the food supply. Their
role in the human body has yet to be fully elucidated but much evidence indicates a role in countering the
effects of naturally occurring free radicals that are associated with a number of diseases and the aging
process.

Antioxidants are used as preservatives in foods to specifically retard deterioration, rancidity or discoloration
due to oxidation caused by light, heat and some metals. Rancid food generally lacks eating quality and
can contain potentially toxic substances that can be harmful if consumed. Antioxidants buffer the oxidizing
agent to prevent reactions with unsaturated fatty acids. In the body, highly reactive compounds derived from
oxygen, called free radicals and reactive oxygen species (ROS), are formed during metabolism. These compounds are then free to interact with a number of lipid and protein components in cell membranes and
enzymes as well as DNA. These damaging reactions may result in cancer, heart disease, stroke, cataracts,
Alzheimer’s, arthritis and some of the symptoms of old age. Antioxidants intercept free radicals before
they can do damage. The protective antioxidant mechanisms employ both enzymatic (such as catalase) and
non-enzymatic substances (such as tocopherols, phenolics, flavonols, catechins, ascorbic acid and carotenoids).

Antioxidant content of various honeys Research from the Departments of Plant Biology and Entomology at the University of Illinois at Urbana- Champaign has shown that antioxidant capacity of different honeys varies by floral source and is positively correlated with color and water content. When the water-soluble content of 14 unifloral honeys was measured, a 20-fold variation existed between the highest, 1995 Illinois buckwheat honey, and the lowest, 1994 California button sage honey. Darker honeys were higher in antioxidants as were those with higher water content.

Another study from the Department of Food Science and Human Nutrition at the University of Illinois at
Urbana-Champaign set out to isolate and characterize the antioxidants present in seven different honeys.
Components that were identified and/or quantified included phenolic compounds, ascorbic acid and the
enzymes glucose oxidase, catalase and peroxidase. The oxygen radical absorbance capacity (ORAC) assay was used to measure antioxidant properties of the honeys.

Bioactivity and Bioavailability of Honey Antioxidants

Additional research on bioactivity was conducted on the honeys for which ORAC values were determined in
the above study. Two different measures were made on the honeys and a sugar analogue. The in vitro lipoprotein oxidation test measured oxidative reactions when serum is exposed to copper and the Ames mutagenicity assay measured inhibition of Trp-p-1 mutagenicity.

Results showed that the honeys were more effective at inhibiting lipoprotein oxidation than the sugar analogue, indicating that honey has potential as a biological antioxidant. There were differences in the antioxidant activity as measured by the ORAC assay of specific honeys, which may be due to the difference in phenolic profile. The honeys and the sugar analogue exhibited significant antimutagenicity activity to Trp-p-1. It
seems that the sugar components may partly be responsible for the antimutagenicity of honey as opposed to
the antioxidant phenolics.

Further research on the health promoting components in honey has begun. In a study designed to assess
the potential of honey as a dietary antioxidant, in vitro antioxidant capacity of honey from various floral sources was measured in a biologically relevant system and the acute effect of black tea with the honeys was measured ex vivo in a controlled human intervention study. All honeys exhibited a dose-dependant inhibition
of lipoprotein oxidation in vitro. A slight increase of water-soluble plasma antioxidants followed the consumption of black tea with honey but did not affect lipoprotein oxidation dramatically when measured
ex vivo.

Researchers from the Department of Nutrition and Internal Medicine at the University of California at
Davis studied the bioavailability and efficacy of honey antioxidants. The effects on plasma phenolic content
and plasma antioxidant capacity in healthy human subjects were measured after consumption of corn syrup
and buckwheat honey at 1.5g/kg body weight. Results demonstrated the bioavailability and bioactivity of phenolic antioxidants in honey on an acute basis and suggest a high efficiency of anitoxidant transfer from
honey. Future research needs include determining the efficacy of different floral sources, assessing the longterm antioxidant protection afforded by honey and the antioxidant potential of honey when used as a food
additive.

More resources:

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