Hay and Su had been hungry for almost a week. Spring was in full bloom, and birds were chirping. Living in a cave was safer and warmer than outside, especially during the long winters. However, the food stock they had was almost finished. As the sun rose higher, the hunter-gatherer couple left their cave to find some food and hunt some animals to cook with the fire they had recently invented. As they searched for some fruit in the forest, they heard wood cracking and then a sudden loud growl from the bushes. The grizzly bear started to chase them, and they ran away quickly. They successfully ran back to their safe cave; however, during the chase, a tree branch scratched and wounded Su’s shoulder and she was severely bleeding. Hay first applied some ash to the wound to stop the bleeding; then he went out to the cliff, a smoking branch in his hand. He tied his rope ladder to a tree and climbed down the cliff. Once he reached the bee’s nest, he gently waved his smoky branch to numb the honeybees and collected their honey, pouring it into a carved stone. Then he rushed back to the cave, covered Su’s open wound with honey, and fed her the leftovers. The wound was closed within a couple of days without any significant inflammation, infection, or scar. Then Su and Hay carved their adventure into the wall of their cave, which is located in today’s Valencia, Spain, and was recently discovered by anthropologists – a mere 8000 years later.

Honey is a viscous, supersaturated sugar solution derived from nectar and honeydew. It’s gathered from flowers and modified by the honeybee, Apis mellifera. Honey is composed of more than 200 components, which are mostly carbohydrates (76%) and water (20%), as well as many other substances, such as amino acids, vitamins, minerals, organic acids, polyphenols, and enzymes. From ancient times, due to its high biological activity potential, honey has been used in wound care, infection control, and treatment of abdominal pains and skin and eye diseases. Thus, it was frequently mentioned in the early pharmacopeia of the Sumerians, Babylonians, Egyptians, Greeks, Romans, Indians, Chinese, Turks, Arabs, and other civilizations.

For the last two decades, scientists and healthcare professionals have studied the potential uses and benefits of honey. Cell assays, animal studies, and clinical trials have provided evidence for the use of medical grade honey in the control and treatment of wounds, cancer, diabetes, and asthma, as well as cardiovascular, neurological, and gastrointestinal diseases.

Medical grade honeys possess high bioactivity potential, which differs depending on the floral source, geographical origin, and harvest time. Worldwide, the most common honey types used for medical purposes are Manuka, Tualang, Gelam, Ulmo, Castanea (chestnut), Rhododendron (Azalea), Quercus (Oak), Acacia, Thyme, and Jungle.

Honey in wound treatment

A wound is, broadly, the destruction of the integrity of tissue, which may also include neighboring areas. This destruction can be either penetrating or non-penetrating, and induced by accidents, surgeries, or violence (Martinotti et al). Depending on the healing time, wounds are classified as acute or chronic. Generally acute wounds heal in a short and predicted amount of time without major complications. The chronic wounds take much longer to heal and present different complications such as infection, contamination of the wound bed, or ischemia, the limited supply of blood that carries oxygen and nutrients to the wounded tissue. The chronic wounds are also known as ulcers and can be grouped as pressure (bed sores), diabetic, venous, and arterial ulcers, which mostly result from chronic medical illnesses such as diabetes, atherosclerosis, thrombosis, paralysis, etc. (woundcarecenters.org). The process of wound healing is generally divided into four overlapping stages: homeostasis (seconds to minutes), inflammation (3-5 days), proliferation (4-14 days), and remodeling (8 days to 1 year) (Miguel 2017).

Different clinical trials and in vitro studies have reported the broad-spectrum antimicrobial properties of honey (Israili 2014). Moreover, honey provides hygroscopic, immunostimulatory, anti-inflammatory, and anti-oxidant properties, which are necessary for the healing of both infected and ischemic chronic wounds. Therefore, medical grade honey promotes the immune response, treats microbial infections, prevents cross-contamination, promotes autolytic debridement, balances inflammatory activity, stimulates growth of wounded tissue to hasten healing, and promotes the healing process in chronic wounds (Miguel 2017).

In a recent Cochrane review, which is considered as the highest standard in evidence-based clinical resources, Jull AB et. al. reviewed the evidence about the healing effects when applying honey on different kinds of wounds (Jull 2015). They analyzed 26 different clinical studies involving 3011 people with acute (e.g. burns, lacerations) and/or chronic (e.g. venous ulcers) wounds. Honey was compared with many alternative wound dressings and topical treatments in the included studies. They concluded that there is high quality evidence that honey heals partial thickness burns around 4 to 5 days more quickly than conventional dressings. There is also reasonable evidence that honey is more effective than antiseptic gauze for healing infected wounds (Jull 2015).

As a particular example, Yusoff KM and his colleagues treated 102 patients with untreatable chronic wounds with honey as a last resort. Most of these wounds were infected with pathogenic bacteria of 14 different strains, and two of them were antibiotic-resistant bacteria, which could not be treated using conventional antibiotics. Of the 102 patients, 100% of them were successfully cured with topical application of honey within 4 to 7 weeks of daily treatment. Moreover, limbs of the diabetic wound patients were saved from amputation after their ulcers were healed (Figure 1). 

Meanwhile, studies on different animal models provided evidence that honey accelerates wound healing in animals. Fifteen of the 16 controlled trials in five different animal models (mice, rats, rabbits, pigs, and buffalo calves) found that honey-treated incisional and excisional wounds, and that standard burns healed faster than control wounds (Jull 2015). 

Consequently, existing evidence from animal studies and clinical trials strongly suggests that medical grade honey has the potential to treat various types of wounds without causing any serious side effects.

Honey in cancer

Cancer is uncontrolled cell growth within a certain tissue or throughout the body due to mutations in the genome. As one of the major causes of death worldwide, more than 8.8 million deaths were reported in relation to cancer in 2015 (WHO). Meanwhile, cancer is not a disease occurring in one cell type only; there are more than 100 cancer types identified to date (cancer.gov). Both the genetic and environmental factors contribute to the development of cancer in different cells. There are three major steps when cancer attacks the body: initiation, proliferation, and progression. The normal cell transforms into a cancer cell due to an irreversible mutation within its genome; then it starts to replicate in an uncontrollable manner and forms a tumor mass; finally, these mutated cells invade the bloodstream and metastasize to different tissues within the body. Despite extensive research projects devoted to diagnosing and treating cancer, it remains as one of the least treatable diseases.

Conventional treatments for cancer are surgery, chemotherapy, radiotherapy, immunotherapy, and cellular therapy. Meanwhile, natural products with high anticancer potential are also being considered for research and treatment as complementary and integrative medicine (CIM) agents. Due to limitations of conventional methods, such as affordability and side effects, and promising evidence-based results of various CIM approaches, physicians and patients are getting more interested in CIM applications for the treatment of various cancer types.

Among the CIM agents, medical grade honey is one of the most promising natural products for treatment of some cancers due to its high bioactivity potential. Scientists studied the capacity of honey to both prevent tumor development and inhibit progression. Most of these studies were performed in vitro, using cell cultures in the lab. When tested on several types of human cancer cell lines (breast, prostate, liver, endometrial, cervical, lung, skin, kidney, bladder, oral squamous cell carcinoma, and osteosarcoma), honeys from diverse floral sources demonstrated potential anticancer activity (Ahmed S 2018, Erejuwa 2014). Moreover, several studies showed that different cancers, in animal models, were successfully treated with honey (Ahmed S 2018). It has been shown that honey provides antiproliferative, antitumor, antimetastatic, and anticancer effects via diverse mechanisms, including cell cycle arrest, the activation of mitochondrial pathways, induction of apoptosis, modulation of oxidative stress, amelioration of inflammation, modulation of insulin signaling, and inhibition of angiogenesis in cancer cells. It has also been shown that honey is highly and selectively cytotoxic against tumor or cancer cells while it is non-cytotoxic to normal cells. It can inhibit cancer development by modulating or interfering with the molecular processes or events of initiation, proliferation, and progression (Erejuwa 2014). In the PubMed, the largest database of biomedical research articles, there are almost 400 research papers and review articles published about the use of honey in cancer treatment. Moreover, there are more than 15 active clinical trials using honey for treatment of cancer and side effects of chemotherapy (Clinicaltrials.gov). Consequently, medical grade honey can be considered as a potential and promising anticancer agent which warrants further research—both in experimental and clinical studies.

Besides wound healing and cancer, honey is being actively studied for treatment of diabetes, neurological, cardiovascular, and metabolic disorders, as well as eye diseases.

REFERENCES

1. Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev. 2015; 3:CD005083.
2. Martinotti S.; Ranzato, E. Honey’s healing history. In Cellular and Molecular Mechanisms of Honey Wound Healing; Nova Publishers Inc.: Hauppauge, NY, USA, 2014
3. Ahmed S, Sulaiman SA, Baig AA, Ibrahim M, Liaqat S, Fatima S, Jabeen S, Shamim N, Othman NH. Honey as a Potential Natural Antioxidant Medicine: An Insight into Its Molecular Mechanisms of Action. Oxid Med Cell Longev. 2018 Jan 18. doi: 10.1155/2018/8367846.
4. Israili ZH. “Antimicrobial properties of honey,” American Journal of Therapeutics, vol. 21, no. 4, pp. 304–323, 2014.
5. Miguel MG, Antunes MD, and Faleiro ML. Honey as a Complementary Medicine. Integrative Medicine Insights 2017 Volume 12: 1–15. DOI: 10.1177/1178633717702869
6. Cutting KF. Honey and contemporary wound care: An overview. Ostomy/Wound Management 2007 Vol 53 (11): 49-54.
7. Yusoff KM, Akka ZS, Suhaimi A, Ali MRM, Yusoff MYM. The Efficacy of Honey Dressing on Chronic Wound and Ulcers. Honey: Current Research and Clinical Applications” published by NOVA Science Publishers, USA. 2012
8. https://www.woundcarecenters.org/article/wound-basics/different-types-of-wounds – accessed 6/17/2018
9. Oryan A, Alemzadeh E, Moshiri A. Biological Properties and Therapeutic Activities of Honey in Wound Healing: A narrative review and meta-analysis. 2016 Journal of tissue viability. 25. 10.1016/j.jtv.2015.12.002.
10. World Health Organization (WHO). http://www.who.int/cancer/en/ – accessed 6/17/2018
11. National Cancer Institute (NCI) https://www.cancer.gov/about-cancer/understanding/what-is-cancer#types – accessed 6/17/2018
12. Erejuwa OO, Suleiman SA, Ab Wahab MS. Effects of Honey and Its Mechanisms of Action on the Development and Progression of Cancer. Molecules 2014, 19(2), 2497-2522; https://doi.org/10.3390/molecules19022497
13. Ahmed S and Othman NH. Honey as a Potential Natural Anticancer Agent: Review of Its Mechanisms. Evidence-Based Complementary and Alternative Medicine Volume 2013. http://dx.doi.org/10.1155/2013/829070
14. https://clinicaltrials.gov – accessed on 6/18/2018

 {module Honey Pictures}

In 67 BCE, the magnificent Roman army, which was led by Pompey the Great, marched through the green mountains and blue shores of the Black Sea, chasing King Mithridates of Pontus and his Persian army. Once the Romans reached the highlands of Trabzon, now part of northeastern Turkey, they found pots full of local honey on the sides of their path. The hungry and tired Roman army, with a total of about 1000 soldiers, rushed into the pots, assuming they were gifts from the villagers. Within a couple of hours, a majority of Pompey’s soldiers were perplexed and hallucinating, and could no longer fight against Mithridates’ army. The Romans had been trapped by the “mad honey,” the first biological weapon used in history. The alkaloid grayanotoxin, of the rhododendron, locally known as the forest rose or the Kumar flower, induced aorta expansion among the Roman soldiers, which resulted in bradycardia (decrease in heart rate), hypotension, hallucinations, and eventually disorientation.[1] This mad honey is still being used, at low doses, by locals of the Black Sea region as a traditional medicine for the treatment of hypertension.

Honey is produced through enzymatic processing of the nectar or honeydew honeybees collect from various plants. The invertase enzyme within the bees’ abdomens catalyzes the conversion of sucrose – table sugar within the nectar – into glucose and fructose. Honey is supersaturated in sugars, packed with beneficial chemicals, and, thus, possesses high nutritive value. It has been used both as a nutritious food and a remedy for various ailments throughout history. Wound healing, and treatment of gastrointestinal diseases, conjunctivitis, acute fever, and pain, are just some of the disorders honey can treat.

Honeybees have been on the Earth for thousands of years due to their indispensable role as the ultimate pollinators. Bees pollinate more than 60% of the planet’s overall plants, as well as 35% of the world’s crops. Nowadays, due to a fall in productivity rates of some crops, farmers hire beekeepers to install their honeybee and bumble bee hives into their fields, allowing for more effective pollination of their crops. Between February and March each year, almond tree buds in California burst into beautiful light pink and white blossoms in preparation for pollination. As the trees blossom, honeybees forage for pollen and nectar in the orchard. When the bees move from tree to tree, they pollinate almond blossoms along the way. Each fertilized flower will grow into an almond. Honeybees also receive a great advantage from the almond pollinations. The almond pollens are rich in proteins and nutrients for the bees, and they are their first food source after the winter. Thus, the bee hives leave the almond fields stronger than they came. After almonds, beekeepers bring their honeybees to different locations across the United States, pollinating over 90 other crops and making honey.[2]

Honey in medical bibliography

Honey has been harvested by human beings for thousands of years, as was depicted at the “Man of Bicorp,” an 8000-year-old cave painting near Valencia, Spain.[3]

According to a Sumerian tablet, one of the oldest human scriptures dating back to about 2000 BC, a prescription for treating wounds reads: “grind to a powder river dust and …. (words missing) then knead it in water and honey and let plain oil and hot cedar oil be spread over it” (Jones 2001). This tablet demonstrates the oldest script about using honey for therapeutic purposes. Meanwhile, almost all great civilizations throughout history, including but not limited to Egyptians, Assyrians, Chinese, Indian, Mayan, Greek, Roman, Arabic, Ottoman, etc., praised honey in their texts; their doctors and healers used honey for treatments of various disorders. Honey was the most popular medical ingredient of the Egyptians, being mentioned in about 500 prescriptions among 900 papyri.[4]

Honey also has been praised in religious scriptures, including the Torah, Gospel, and Qur’an. In the present Torah, the Promised Land (Ha’Aretz HaMuvtahat – Ard Al-Mi’ad) is described as the land of milk and honey (Deuteronomy, 6: 3). According to the story in the Gospel, Jesus ate honey and bread to prove to the Apostles that he was not merely a spirit or figment of imagination. In the Qur’an, honey is clearly identified as “a healing for mankind”:

And your Lord inspired the (female) bee: “Take for yourself dwelling-place in the mountains, and in the trees, and in what they (human beings) may build and weave. Then eat of all the fruits, and returning with your loads, follow the ways your Lord has made easy for you. ” There comes forth from their bellies a fluid of varying color, wherein is health for human beings. Surely, in this, there is a sign for people who reflect. (16:68-69)

Moreover, Prophet Muhammad, peace be upon him, praised honey as a source of healing for both the body and spirit. In his various traditions, the Prophet encouraged his followers to consume honey for its versatile medicinal use such as abdominal pain, as well as its high potential to protect people from many illnesses, indicating honey’s significant role in preventive medicine.

Avicenna (Ibn-i Sina) is the author of “The Cannon of Medicine” (Al-Qanun fi-t-Tibb) and his five-volume-book was a reference source for medical studies in the universities of Europe between the 12^th and 18^th centuries.[5] In the 2^nd volume of “The Cannon,” where he described the preparation of various pharmaceuticals for treatment, he listed honey in more than 35 prescriptions.

Until the early 20^th century, honey was used daily by physicians as a traditional medicine. It was even used on battlefields to treat wounds and burns. During World War II, Russian army nurses gave honey to wounded soldiers.[6]

As biochemistry and pharmaceutical researchers developed and introduced new drugs into modern medicine throughout 20^th century, scientific opinions on honey’s nutritive and medical uses have differed and clashed with folklore. However, recent controversies within the scientific community have re-kindled interest in the therapeutic uses of honey in modem medicine. Recently, scientific support has emerged in a proliferation of publications on the successful therapeutic use of honey in several general medical and surgical conditions. Thus, honey has been described as, “A remedy rediscovered,” by Dr. Zumla in an article in the “Journal of Royal Society of Medicine.”[7] A complementary branch of medicine, called apitherapy, has been developed in recent years, offering treatments against many diseases based on honey and other bee products, such as propolis, royal jelly, wax, and venom.

Components of honey

As described above, honey is not only a supersaturated sugar solution, but also equipped with more than 200 various chemical and biological components. This shouldn’t be surprising, as more than 60% of medicines on the medical market are extracted from plants. As the honeybees visit the flowers and trees, they work as diligent chemists collecting various organic compounds from within the plants.

Depending on its origin of flora, geographic region, harvest time, and strain of honeybee, the components of honey differs; hence, so does its physicochemical character and biological activity potential. Besides the sugars of glucose, fructose, and sucrose, which constitute about 76% of honey’s makeup, other minor components are present in honey, such as minerals, polyphenols, carotenoids, vitamins, amino acids, specific proteins and enzymes, organic acids, and volatile compounds. Some of the vitamins present in honey are B6, thiamin, niacin, riboflavin, and pantothenic acid. The minerals include calcium, copper, iron, magnesium, manganese, phosphorus, potassium, sodium and zinc. 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. The polyphenols present in honey can act as antioxidants and they play a role in cleansing the body from the free radicals and reactive compounds, which can contribute to the development of serious illnesses such as cancer and heart disease. It is shown that honey contains a similar range of antioxidants that are found in green vegetables and fruit including broccoli, spinach, apples, oranges and strawberries.[8]

Types of honey

Since the nectar for honey is mostly collected from the various kinds of flowers within the bee’s two-mile foraging radius, not every honey is the same. Therefore, the science of melissopalynology is well developed to identify the pollen and nectar source of honey. Although there are many varieties, categories, and sub-categories of honey, all honey types can be divided into two general groups – multifloral honeys and monofloral honeys. Multifloral honeys are produced by honeybees using nectar from many different flower sources. On the other hand, honeybees can also produce honey from the nectar of one dominant flower species (>45%), which is called monofloral honey. The common monofloral honeys are acacia, eucalyptus, fir, spruce, heather, lavender, lime, linden, orange blossom, pine, rape, rosemary, sunflower, chestnut, thyme, and clover.[9] Due to easier standardization and sustainable production methods, monofloral honeys are preferable for animal studies and clinical trials. Among several monofloral types, manuka, chestnut, oak, tualang, gelam, and ulmo honeys are the most studied medical grade honeys worldwide.

Biological activity of honey

The Cochrane Reviews are systematic reviews of primary research in human healthcare and health policy and are internationally recognized as the highest standard in evidence-based healthcare resources.[10] In recent years, two reviews were published regarding the usage of honey in large clinical trials worldwide. They are titled “Honey as a topical treatment for acute and chronic wounds” [11] and “Honey for acute cough in children.”[12] These articles prove that the benefits of honey are being discussed by the major players within modern medicine.

The health benefits of uncontaminated pure honey range from antioxidant, immunomodulatory, and anti-inflammatory qualities, to antitumor actions, metabolic and cardiovascular benefits, prebiotic potentials, human pathogen control, and antiviral activity. Most of these reported biological activities are credited to the minor components present within the honey, which are mainly dependent on the floral or geographical origin of honey. Therefore, scientists and physicians admit that not every honey can be used for every disease. It has been documented that the darkness of honey positively correlates with its total phenolic contents, which significantly contributes to its biological activity potential.

In an interview with Prof. Kamaruddin Yusoff of BalMer Honey Research Center, he interprets the Quranic verse about the honey, which was described as fluid of varying color emerging from the bellies of honeybees, that different colors of honey can be used for treatment of different diseases. It has been documented that the darkness of honey positively correlates with its total phenolic contents, which significantly contributes to its biological activity potential. On the other hand, Prof. Irfan Yilmaz interprets the same verse as not only the honey but also other fluids such as propolis, royal jelly, wax, and venom are produced within different parts of the honeybee’s abdomens. Accordingly, several scientists focused on these fluids as a part of apitherapy.

Although most of the biological properties are attributed to the phenolic components, other biochemical factors may also be involved: high osmolarity and viscosity (76% sugar content), high acidity (pH 3.2 to 6.1), the glucose oxidase system (source of hydrogen peroxide), low redox potential, high carbon to nitrogen ratio, and the bee defensin-1 protein.

The osmotic pressure and viscosity of honey is due to low water (17%) and high sugar content (%76). The majority of sugars found in honey are monosaccharides, which are glucose (a range of 22-40%) and fructose (a range of 27-44%); and disaccharides, which are sucrose (a range of 1-5%) and maltose (a range of 1-5%). The high osmolarity of honey is enough to hinder the growth of microbes; thus, no bacteria, virus, or fungi can survive within honey. Consequently, honey has a very long, almost eternal shelf life. Recently, pots of honey were found by archeologists while they were excavating the pyramids in Egypt and this 3000-year-old honey was well preserved and still perfectly edible.[13] In a proverb it is said that “Noble doesn’t go astray, honey doesn’t spoil.”

The pH of honey is mostly dependent on the phenolic acids collected from the nectar sources; therefore, it changes with the foraging resources available to bees.

There are live enzymes within the honey, which are mostly introduced from the abdomens of honeybees. The predominant enzymes in honey are diastase (amylase), invertase, and glucose oxidase. Others, including catalase and acid phosphatase, can also be present, depending on the type of floral source. And recently, proteolytic enzymes have been found in honey. Among these enzymes, the glucose oxidase plays an essential role in producing hydrogen peroxide, which is critical to limit the proliferation of pathogenic bacteria. Once the honey is dissolved in water, glucose oxidase will catalyze the conversion of glucose into gluconic acid and H2O2. Since the amount of H2O2 is diminutive (0.3%) and slowly released, there is much less cytotoxic damage to the healthy cells, providing a better method than applying H2O2 directly to wounds and burns.

Researchers continue to study the potential uses and benefits of honey. Several clinical and animal studies suggest the use of honey in the control and treatment of wounds, diabetes, cancer, and asthma, as well as cardiovascular, neurological, and gastrointestinal diseases.^[14]

[1] https://today.tamu.edu/2014/10/15/expert-gives-the-buzz-on-mad-honey/

[2] http://www.almonds.com/consumers/about-almonds/bee

[3] https://en.wikipedia.org/wiki/Cuevas_de_la_Arana

[4] Grossman, R. The Other Medicines: The Penicillin of Bees. Pan Books, 1986:177

[5] http://www.muslimheritage.com/article/ibn-sinas-canon-medicine

[6] Leo A. Boсkeria, Sergey P. Glyantsev, Yan G. Kolesnikov, “Russian war surgery in 1812: 200 years since Russia’s war triumph” International Journal of Surgery, Volume 10, Issue 10, 2012, Pages 624-628, ISSN 1743-9191, https://doi.org/10.1016/j.ijsu.2012.11.001

[7] Zumla A., Lulat A. Honey- A Remedy Rediscovered. Journal of the Royal Society of Medicine. 1989 Vol 82 Pg385

[8] https://www.islamreligion.com/articles/10321/liquid-gold-benefits-of-honey/

[9] https://healthywithhoney.com/types-of-honey/

[10] http://www.cochrane.org/what-is-cochrane-evidence

[11] Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD005083. DOI: 10.1002/14651858.CD005083.pub4

[12] Oduwole O, Udoh EE, Oyo-Ita A, Meremikwu MM. Honey for acute cough in children. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD007094. DOI: 10.1002/14651858.CD007094.pub5

[13] http://www.nationalgeographic.com.au/history/honey-in-the-pyramids.aspx

[14] Samarghandian, S., Farkhondeh, T., & Samini, F. (2017). Honey and Health: A Review of Recent Clinical Research. Pharmacognosy Research, 9(2), 121–127. http://doi.org/10.4103/0974-8490.204647