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Honeybee Products

Scientific Name(s): Apis mellifera L.
Common Name(s): Honig, Miel blanc, Bee pollen, Clarified honey, Honey, Honeybee pollen, Mel, Purified honey, Royal jelly, Strained honey

Clinical Overview

Use

Honeybee products have been used topically and internally for hundreds of years worldwide as remedies for a variety of illnesses; however, clinical trials are lacking for most uses. Honey and royal jelly exhibit antibacterial properties, and there is some evidence that honey might have a role in wound healing. Discrepancies among studies evaluating honey for wounds may be due to variations in the source and preparation of the honey. Bee pollen is most often used for its nutritional properties, and although it is nutritionally rich, claims that it enhances every-day and athletic performance have not been reliably verified. Data supporting the use of honeybee products for other indications are not well substantiated.

Dosing

Honey is a common food and there are no dose restrictions on its use. It has been ingested and used topically.

The ideal dose of bee pollen is unknown, with doses varying among products because tablets contain differing amounts. Manufacturers' recommendations on product labeling may provide more guidance.

Clinical trials are generally lacking to recommend dosage for royal jelly. Small clinical trials have used royal jelly 6 to 10 g/day for 14 to 28 days when evaluating the effect on hyperlipidemia. A randomized, controlled trial investigating use of royal jelly for oral mucositis in patients receiving chemotherapy and radiation used a dose of 1 g/day in addition to standard mouthwash therapy. A dose of 2,400 mg/day for 8 weeks showed promise for patients with symptoms of dry eye in a controlled trial.

Contraindications

Honey should be used with caution in infant formulations. Allergy to bee venom is considered a relative contraindication to royal jelly. Other contraindications have not been identified for honey, bee pollen, or royal jelly.

Pregnancy/Lactation

Clinical data regarding safety and efficacy of these products in pregnancy and lactation are lacking. Honey is generally recognized as safe (GRAS) during pregnancy and lactation when used as food.

Interactions

None well documented for honey or bee pollen. Case reports of hematuria due to potentiation of warfarin have been documented with royal jelly.

Adverse Reactions

Allergic reactions may occur to pollen in honey when ingested. Attempts to hyposensitize patients by administering bee pollen may produce severe anaphylaxis and other acute or chronic responses. Although rare, bee pollen can cause serious, sometimes fatal, adverse reactions. Some case reports of acute hepatitis and photosensitivity following ingestion of bee pollen have been reported. In many allergic patients, skin tests are positive for royal jelly. Occupational allergic respiratory disease from the inhalation of powdered royal jelly has been reported in workers. Case reports exist of allergy, acute exacerbation of asthma, anaphylaxis, and death.

Toxicology

Contaminated honey containing botulism spores can poison infants. The American Academy of Pediatrics and the World Health Organization recommend that honey should not be given to an infant younger than 12 months due to the potential for botulism. Honey made from the nectar of poisonous plants can be poisonous. Information on the toxicology of bee pollen or royal jelly is lacking.

Botany

Honey is a bee-concentrated and processed product of nectar from the flowers of numerous plants. This sweet secretion is deposited in honeycombs by honeybees (A. mellifera L., Fam. Apidae), as well as a few other species of bee in the tropics, and primarily consists of sugars. Minor components include phenols, glucose oxidase and catalase, ascorbic acid, carotenoids, organic acids, amino acids, proteins, and alpha-tocopherol. Composition varies with the pollen source, climate, environmental conditions, and processing.1, 2

Bee pollen consists of plant pollens collected by worker bees combined with plant nectar and bee saliva, usually a mixture of pollen species from several different plants. The pollens are packed by the insects into small dust pellets that are then used as a food source for male drones.

Royal jelly is a milky-white secretion produced by the hypopharyngeal and mandibular glands of worker honeybees (A. mellifera L.). It is the principal food of the honeybee queen, inducing differentiated growth and development. Because of this specialized nutrition, queen bees differ from workers in several ways: they are approximately twice the size of worker bees; they lay approximately 2,000 eggs a day (female worker bees are infertile); and they live 5 to 8 years, approximately 40 times longer than worker bees.3

History

Honey as flavoring for medicinal preparations was first known historically as a sweetening agent and was once officially listed in the National Formulary. Its use dates to ancient times.4 Early cultures universally hailed honey for its sweetening and nutritional qualities, as well as for its topical healing properties for sores, wounds, and skin ulcers.4 Honey is used directly as a sweetener and is also fermented into the sweet-tasting beverages of mead, cyser, or metheglin.5

The use of bee pollen increased during the late 1970s following testimonials by athletes that supplementation increased stamina and improved athletic ability. Products containing bee pollen have become widely available in health food stores and drugstores, as well as online.

In many countries, royal jelly has been widely promoted as a commercially available medicine, health food, cosmetic emollient, moisturizer, and source of nourishment. It is used in traditional medicine for longevity in Europe and Asia. Royal jelly has been sold as a skin tonic and hair growth stimulant.1, 3, 6

Chemistry

Bees and other insects extract thin, aqueous fluid nectar from the nectaries of various flowers. Some types of honey can be poisonous if the nectar is obtained from poisonous plants (eg, mountain laurel, jimson weed, azalea, rhododendron).7 When taken in by the bee, the nectar is modified by enzymes from glands in the head and thorax, forming levulose, dextrose, and sucrose. Honey is a thick, syrup-like liquid ranging in color from light yellow to golden brown. It is translucent when fresh, but darkens to opacity when old and can become granular through the crystallization of dextrose. Generally, honey has a characteristic odor and a sweet, faintly acrid taste. Honey is naturally mildly acidic. While honey varies in composition, its principle constituents are a mixture of dextrose and levulose in almost equal amounts ranging from 65% to 80% of one or the other. Sucrose ranges from 0.5% to 8%; dextrin from 1% to 10%.2 There have been numerous reports on an antimicrobial honey distillate fraction and related antifungal compounds.8, 9, 10, 11 The active antimicrobial principles have not been fully identified.

Bee pollen is a nutritional source for drone bees. It is a highly concentrated food source rich in vitamins, minerals, trace elements, enzymes, and amino acids. It contains approximately 30% protein, 55% carbohydrate, 1% to 2% fat, and 3% minerals and trace vitamins.12 Vitamin C concentrations of 3.6% to 5.9% have also been found in some samples.13 Bee pollen preparations often contain mixtures of pollens from diverse types of plants that vary with geographic origin.

Royal jelly is composed of a complex mixture of water (50%), proteins (approximately 15%), sugars, lipids, vitamins, pheromones, amino acids, and minerals.1, 14, 15 In addition, fatty acids (including hydroxydecanoic acids) and sterols (including sitosterol, desmosterol, and methylenecholesterol), tryptophan, organic acid glycosides and monoglycosides, glycopeptides, N-glycans, adenosine monophosphate N-oxide, apisimin, and a variety of major royal jelly proteins (MRJP) (including MRJP 1 to 9) have been identified.16, 17, 18, 19, 20, 21, 22, 23

Uses and Pharmacology

While more information is available on honey and bee pollen products, recent clinical trials evaluating these products are lacking, and suggested pharmacologic effects are largely based on in vitro and animal model experiments.

Analgesia

Compared to standard postsurgical therapy alone (antibiotic plus acetaminophen), adjunctive use of 5 mL of oral honey for 10 days significantly decreased average time of pain relief (7.65 vs 5.53 days, respectively, P < 0.001) as well as average acetaminophen use (17.53 vs 12.1 times, respectively, P < 0.001) in 80 Iranian children who underwent tonsillectomy.148 A systematic review and meta-analysis of 8 randomized controlled trials that evaluated the use of honey after tonsillectomy reported significant improvements overall in postoperative pain during the first 7 days postop with the use of honey compared to controls (P=0.05 to P<0.0001). However, after subgroup analyses by intervention and blind studies, significant pain reduction was seen only with honey plus antibiotics and not honey alone, and for only 1 day postop (day 2). Similarly, the number of analgesics used were statistically significantly lower with honey plus antibiotics for 2 postop days (days 1 and 3) with a mean difference of −1.39 and −1.03, respectively (P=0.0001 to P=0.005). Doses were highly variable across the studies and the quality of studies was rated as poor.154

Anti-aging

Bee pollen administered to rats was also found to possibly have antiaging effects.118

Antibacterial activity

Apidaecins and abaecin, potent antibacterial peptides, have been isolated and characterized in the honeybee (A. mellifera L.) itself,24, 25 and a potent antibacterial protein named royalisin has been found in the royal jelly of the honeybee.26 The antibacterial activity in diluted honey with the right pH (range, 3.2 to 5) is attributed to hydrogen peroxide (H2O2), an enzymatic byproduct of the formation of gluconic acid from glucose. However, most of the hydrogen peroxide–related antibacterial activities of honey are lost after heating or prolonged exposure to sunlight.27, 28 A second mechanism, nonperoxide antimicrobial activity, is independent of light, heat, and storage time, but dependent on the flower source of the nectar. As a result, not all honey possesses this activity. Other characteristics that may contribute to honey's antibacterial activity are the presence of lysozymes and honey's low pH and high osmolarity.1 Honeydew honey from the conifer forests of the mountainous regions of central Europe and honey from manuka (Leptospermum scoparium) in New Zealand have particularly high antibacterial activity.29

The protein royalisin found in royal jelly has potent in vitro antibacterial activity against gram-positive bacteria, but is inactive against gram-negative bacteria. Hydroxydecanoic acid has in vitro bacteriostatic activity against Streptococcus aureus and Escherichia coli, which may modestly enhance host defenses in honeybees. Additive or synergistic effects have been demonstrated in vitro with starch and honey.30, 31, 32

Animal data

Manuka honey has a high level of activity against a variety of bacteria including S. aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Enterobacteriaceae.33, 34, 35, 36 Active manuka honey and its Australian equivalent are the only commercially available types of honey that are tested for antibacterial activity. Manuka honey contains an additional antibacterial component found only in honey produced from Leptospermum plants known as the "unique manuka factor."37

Clinical data

Manuka honey is a safe alternative topical antibiotic when compared with povidone iodine for the prophylaxis of dialysis catheter–related sepsis.38 However, 2 g of medical-grade honey from The Netherlands had no effect on reducing colonization of skin at central venous catheter sites in intensive care unit patients when used in combination with standard site dressing of 0.5% chlorhexidine in 70% alcohol.142 Honey has also been used for treating Helicobacter pylori, the gastric ulcer causative agent.39, 40, 41

Antioxidant activity

The growing interest in the antioxidant properties of foods is based on an attempt to protect cells against the damage caused by oxygen. The production of free radicals, which leads to oxidative stress, plays a part in many diseases, including cardiovascular disease, cancer, and diabetes. Oxidation in foods also leads to undesirable effects, such as reduced shelf life and unpleasant odors and flavors. Honeybee products such as honey and royal jelly have a naturally high antioxidant potential.1

Animal and in vitro data

Antioxidant activity has been demonstrated with royal jelly using different in vitro and plant models,42, 43, 44, 45 while protection against oxidative stress–induced injury has been demonstrated in animal experiments.43, 46, 47, 48 Using royal jelly, lipid peroxidation was inhibited in vitro and in experiments in rats.49

Bee pollen may possess antioxidant effects50 possibly attributed to polyphenolic substances, such as quercetin, caffeic acid, pinocembrin, and galangin, among others. One study found that bee pollen and propolis extracts inhibited respiratory burst, a transient increase in oxygen consumption following the production of reactive oxygen species within cancer cell lines, an effect attributed to the antioxidant potential.51 Another study found that bee pollen modulated antioxidant enzymes in the livers, brains, and lysates of erythrocytes in mice, and also decreased hepatic lipid peroxidation.52

Antitumor activity

Animal and in vitro data

Honey has demonstrated moderate antitumor and pronounced antimetastatic effects in rat and mouse tumors.53 A study showed that application of commercial honey to surgical wounds in mice impeded subsequent tumor implantation.54 Royal jelly exhibited antitumor activity in experimental mouse leukemias55; antiangiogenesis activity has been demonstrated in vitro.18 In human cervical/uterine carcinoma cells, some royal jelly fractions actively inhibited tumor growth.20 One study found that royal jelly inhibited the growth-promoting effect of bisphenol on breast cancer MCF-7 cell lines, although another study showed that royal jelly enhanced MCF-7 proliferation.23, 56

Cataracts

A number of related activities and unique medical applications include the successful use of honey in treating senile cataracts113 and postherpetic opacities of the cornea.114

Cough

Based on data in a few randomized, controlled trials, honey may offer benefits over placebo, no treatment, salbutamol, and diphenhydramine for symptomatic relief of acute cough in children, and may have similar effecacy as dextromethorphan.116, 140, 155 Results from a randomized, controlled trial (N = 300) indicated a significant benefit in total symptom scores for nocturnal acute cough in children 1 to 5 years of age who took 10 g of honey (eucalyptus, citrus, or labetiae) as a single dose or diluted in a noncaffeinated drink 30 minutes before bed compared with placebo (silan date extract).138

Dry eye syndrome

The safety and efficacy of royal jelly oral supplementation used for signs and symptoms of dry eye was investigated in a double-blind, randomized, placebo-controlled study (n=43) and followed with a mouse model to explore underlying mechanisms of action. Japanese adults complaining of mild or moderate dry eye symptoms were administered placebo or 2,400 mg/day of enzyme-treated royal jelly tablets (800 mg 3 times daily after meals) for 8 weeks; the tablets were standardized to a minimum of 3.5% (E)-10-hydroxy-2-decenoic acid and 0.6% 10-hydroxy-decanoic acid. At 8 weeks, only tear volume was significantly improved with administration of oral royal jelly compared to both baseline and placebo, and only for patients with an initial Schirmer score of 10 or less (P=0.0005 each). Tear film break-up time was significantly improved with royal jelly compared to baseline and placebo at 4 weeks (P=0.0271) but not at 8 weeks. No adverse events were observed. The mechanism appears to involve restoration of the lacrimal gland function by royal jelly.152

Estrogenic activity

Animal and in vitro data

Effects on estrogen receptors are weak compared with the effects of diethylstilbestrol and phytoestrogens; however, stimulation of messenger ribonucleic acid (mRNA) expression in estrogen-responsive genes and enhanced MCF-7 cell proliferation, which could be blocked by tamoxifen, has been demonstrated in vitro.23, 57 Animal experiments in rats and ewes have also been conducted. Mild hypertrophy of the uterine luminal epithelium was achieved in rats supplemented with royal jelly,23 while effects in ewes were varied. The effect of royal jelly supplementation on the onset of estrus has shown mixed results in ewes, with 1 trial showing no effect, while another exhibiting a shorter time to estrus compared with control and no difference compared with gonadotropin.58, 59, 60 In both experiments, positive effects on pregnancy and lambing rates were demonstrated.

Clinical data

A number of studies evaluated royal jelly for the relief of menopausal symptoms in the 1970s. However, recent clinical trials are lacking.

Hypertension

Animal data

Following GI enzymatic hydrolysis, peptides derived from royal jelly demonstrated angiotensin 1–converting enzyme inhibitory activity in the spontaneously hypertensive rat. Other studies suggest that trans-2-octenoic acid and hydroxydecanoic acid may account for the antihypertensive activity, but different fractions exert lesser or greater effects on duration of action. Royal jelly was also associated with protective action and therapeutic activity in adrenaline-induced arrhythmia; however, no effect on heart rate has been observed.61, 62, 63, 64

Immunoregulatory activity

Animal and in vitro data

Various in vitro experiments examined the actions of royal jelly and its constituents on the immune system.14, 65, 66, 67, 68, 69 Animal experiments demonstrated immunoregulatory activities, with the administration of royal jelly at 500 to 1,500 mg/kg/day, increasing survival in tumor-bearing mice and demonstrating positive effects on bone marrow stem cells and tumor-induced splenic hematopoiesis.70 Additionally, autoimmunity was inhibited in systemic lupus erythematous–prone mice, with a delay in disease progression, decreased proteinuria, and increased survival.71 Increased healing rates were observed in guinea pig tympanic membrane perforation.72

In an in vitro study using lymphocytes from healthy volunteers and patients with Graves disease, royal jelly caused lymphocytes to proliferate and certain cytokines to be secreted, suggesting a potential immunomodulatory role in the management of the disease.73

Insulin-like activity

Animal and in vitro data

In rats and in vitro experiments, insulin-like activity has been shown with royal jelly, and components may be structurally and functionally related to insulin. In an insulin-resistance model in rats, royal jelly reduced plasma insulin and triglycerides without affecting plasma glucose levels.20, 64

Lipid profile

Clinical data

Small clinical trials have demonstrated mixed effects on lipid profile in humans receiving royal jelly. Royal jelly administered at 10 g/day for 14 days increased serum high-density lipid (HDL) levels in elderly participants, while a trend toward improved low-density lipid (LDL) levels was seen with no effect on serum triglycerides.74 In another trial, 6 g/day for 4 weeks resulted in decreased serum total cholesterol and LDL, but had no effect on HDL or triglycerides.75

Neurological activity

Animal data

Traditional use of royal jelly in preventing aging has led to experiments regarding neuronal activities. Stimulation of production of glial cell line–derived neurotrophic factor has been demonstrated in the adult mouse brain, with a prediction of a neuroprotective role for royal jelly.76 In addition, 10-hydroxy-trans-2-decanoic acid increased the generation of neurons from neural stem (progenitor) cells in vitro,77 while adenosine monophosphate stimulated neuronal differentiation of pheochromocytoma PC12 cells.78 Activity on the pituitary gland in middle-aged rats has also been demonstrated,79 and orally administered royal jelly increased granule cell content in the hippocampus, with an observed improvement in induced cognitive impairment in mice.77

Oral mucositis

An assessment of interventions for preventing oral mucositis for patients receiving cancer treatment reported some weak statistical evidence of the benefits for honey used to either prevent or reduce the severity of mucositis compared with either a placebo or no treatment.115 Additionally, in a randomized controlled trial (N = 103), the mean time to resolution of oral mucositis (grade 1 to 3) was significantly reduced in patients undergoing radio- and chemotherapy who rinsed orally with royal jelly 1 g/day in addition to standard mouthwash therapy of benzydamine hydrochloride and nystatin rinses.141 However, subgroup analysis of 9 randomized clinical trials published up through June 2014 evaluating the effects of honey on oral mucositis in patients with head and neck cancer undergoing radio- or chemoradiotherapy found no significant effect in patients receiving chemotherapy. In contrast, significant improvements (lower incidence of moderate to severe mucositis, later onset time, lower 3-week mean grade) was seen in the honey groups compared to placebo or no treatment, with greater effects in patients undergoing radiotherapy alone compared with chemoradiotherapy.145

Osteoporosis

In tissue culture models and ovariectomized rats, a positive effect on osteoporosis was demonstrated with royal jelly. Increased calcium content and recovered bone mass were suggested as results of enhanced intestinal calcium absorption, rather than antagonism of the parathyroid hormone.117

Performance enhancement

Articles in the popular press have suggested that athletes could enhance performance by ingesting bee pollen; however, 1 investigation found no beneficial effect.80

Animal data

In a pilot study, 10 Arabian horses were randomized to receive either Dynamic Trio, a product containing 55% bee pollen or placebo consisting of 50% red wheat bran, 25% evaporated cane juice crystal sugar, 17% baking flour, and 8% powdered apple peels for 42 days. At baseline, the horses performed a standard exercise test. During the study, they continued to participate in horsemanship classes and were ridden throughout the week. Additionally, the horses performed the standard exercise test twice weekly, with a gradual increase in exercise intensity. At the end of this study, there were no treatment differences for V150 and V200, values of projected velocities at heart rates of 150 and 200 beats per minute, respectively. No changes were noted in heart rate, or in lactate, hematocrit, or hemoglobin levels. Horses receiving bee pollen tended to digest more neutral detergent fiber and acid detergent fiber. Additionally, they had less phosphorus excretion and tended to retain nitrogen. Thus, the product containing bee pollen may only have been beneficial in the performance of horses by stimulating food intake and nutrient retention.81

Clinical data

A 2-year, double-blind study found bee pollen "absolutely not a significant aid in the metabolism, workout training, or performance" of athletes.82 The results of another study conducted in track athletes suggested that runners who took bee pollen recovered faster after exercise, therefore being of value in relieving common tiredness and lack of energy. Critics of this study found the test group to be small, the blinding inadequate, and the conclusions premature.83 Another 6-week study in 20 competitive swimmers found no differences in strength and endurance tests between those treated with bee pollen and those treated with placebo (cod liver oil). However, it was noted in a post hoc analysis that swimmers treated with bee pollen missed fewer days (4 days) of training due to upper respiratory tract infections compared with those treated with placebo (27 days).84

Premenstrual syndrome and menopausal symptoms

Animal data

In a study of mice, Melbrosia, a product containing pollen, perga-pollen (bee bread), and royal jelly, was given in doses of 6, 60, and 600 mg/kg orally for 3 days to groups of 10 immature rats. Melbrosia was administered subcutaneously in the same doses to groups of 12 ovariectomized rats for 3 days. Estrogenic effects were not evident with Melbrosia therapy.85

Clinical data

In a randomized, double-blind, placebo-controlled, crossover study, the effect of Femal (an herbal remedy containing pollen extract 36 mg, combined pollen and pistil extract 120 mg, and royal jelly 6 mg) on premenstrual syndrome (PMS) was assessed in 32 women with regular menstrual cycles. Each participant received Femal or placebo for 2 consecutive menstrual cycles, followed by the alternate treatment for 2 more consecutive cycles. Three women dropped out of the study, and 29 participants were included in the analysis. Overall symptoms such as irritability and dysphoria were improved, and 6 of 9 symptom scores were reduced by 27% to 57%. Evidence also suggested a slow onset of action (no effect was noted between Femal and placebo after the first cycle of treatment), and protracted effect, considering that the placebo group first experienced a reduction in symptoms. Except for sleep quality, there were no differences in symptoms in participants receiving Femal before placebo. Weight gain was reduced by 50% in participants treated with Femal compared with placebo. Although the results suggest that Femal may be beneficial in improving PMS symptoms, they should be interpreted cautiously because there was no washout period, which raises doubt that the authors found a carry-over effect, and a preliminary phase designed to eliminate placebo responders was not conducted.86

Melbrosia is used in Europe and contains the active ingredients phytosterols, phytoestrogens, amino acids, oligopeptides, and enzymes.87 The effects of Melbrosia on ameliorating climacteric symptoms were clinically assessed. Two groups of women were followed; 32 served as a control group and 34 received Melbrosia. Patients receiving therapy experienced a reduction in the Kupperman menopausal index. Specifically, Melbrosia was most effective on nervousness, anxiety, irritability, headache, and hot flashes. No changes were noted in gonadotropin, estradiol, or lipid values. Thus, products containing bee pollen may serve as potential treatment options for patients suffering from climacteric symptoms associated with menopause.88 Similarly, another randomized, placebo-controlled study in women with severe menopausal symptoms found that the use of Melbrosia resulted in improvements in headache, urinary incontinence, vaginal dryness, and decreasing vitality. However, no changes in biochemical parameters were noted.89

In an open, multicenter, uncontrolled, prospective observation study, the effects of Melbrosia on menopausal symptoms and cardiovascular risk markers were assessed. Fifty-five postmenopausal women with climacteric complaints received 2 capsules of Melbrosia once daily for the first 2 weeks, followed by 1 capsule daily for the remaining 10 weeks. Twenty-seven of the 55 patients underwent laboratory assessment of cardiovascular risk markers, including cholesterol and C-reactive protein (CRP) levels. A significant reduction in the standardized Kupperman score (P < 0.001) and other symptom measuring tools (ie, Zerssen symptoms list and Zung depression score) were noted with treatment. Improvements were also demonstrated in problem-solving (P = 0.0015) but not in self-esteem or self-assessment. Additionally, patients experienced worsening irritability with Melbrosia therapy (P < 0.001). Total cholesterol (P = 0.03), LDL (P = 0.0053), and HDL (P = 0.018) improved with Melbrosia. However, triglyceride levels increased significantly (P = 0.0088). CRP levels did not significantly differ with Melbrosia therapy (P = 0.37). Thus, products containing bee pollen may not only improve menopausal symptoms, but also may improve cholesterol parameters.87

Prostate conditions

Cernilton, an extract of bee pollen, has been used in prostate conditions for its presumed anti-inflammatory and antiandrogenic effects.90 A single dose of Cernilton contains 60 mg of cernitin T60 (a water soluble pollen extract fraction) and 3 mg of cernitin GBX (an acetone-soluble pollen extract fraction). Cernilton has antiandrogenic effects via relaxation of urethral smooth muscle tone and increases in bladder muscle contraction and/or acts on alpha-adrenergic receptors and relaxes internal and external sphincter muscles.91

Clinical data

There is some evidence involving the use of bee pollen for the management of prostatitis and benign prostatic hyperplasia (BPH). Studies using Cernilton have shown modest improvement in urological symptoms, but have been limited by their short duration, small number of participants, and questionable standardization of preparations.91, 92, 93, 94, 95

Two placebo-controlled trials and 2 comparative trials enrolling 444 participants receiving treatment for 12 to 24 weeks were included in a systematic review published in 2000. The weighted mean relative risk (RR) of self-improvement for those receiving Cernilton versus placebo was 2.4 (range, 1.21 to 4.75) versus 1.42 (range, 1.21 to 4.75) with Tadenan (an extract from the African plum plant). Nocturia was reduced with Cernilton therapy compared with placebo, with an RR of 2.05 (range, 1.41 to 3). When compared with Paraprost (a mixture of amino acids), the weighted mean difference for nocturia was −0.4 times per evening (range, −0.73 to 0.07). Cernilton did not improve urinary flow rates, residual volume, or prostate size when compared with placebo or active comparators. The only reported adverse effect with Cernilton was nausea.91

Different doses of Cernilton for the prevention of BPH progression were assessed in a comparative study. Men with BPH (N = 240) received Cernilton 375 or 750 mg twice daily for 4 years. Patients receiving the higher dose of Cernilton experienced a greater improvement in the international prostate symptom score (IPSS), prostate volume, postvoid residual urine, and maximal flow rate (Qmax) assessments compared with those receiving the lower dose (P < 0.0001). Additionally, patients receiving the higher dose of Cernilton experienced improvements in IPSS and Qmax after 3 and 6 months of therapy, compared with 6 and 9 months in those receiving the lower dose.96

The efficacy of Cernilton N for the treatment of chronic prostatitis syndrome was assessed in 90 patients. The supplement was administered as 1 tablet 3 times daily for a 6-month period. The participants were divided into 2 groups: those with complicating factors (n = 18), such as urethral strictures, prostatic calculi, and bladder neck sclerosis; and those without complicating factors (n = 72). Seventy-eight percent of patients without complicating factors experienced a favorable response with Cernilton N therapy. Thirty-six percent were cured of their symptoms, and 42% improved in measures such as flow rate, leukocyturia in postprostate massage urine, and complement C3/coeruloplasmin in ejaculate fluid. Only 1 patient with complicating factors demonstrated a response. Thus, consideration for complicating factors may be an important determinant for successful treatment.97

One study evaluating the effects of the chloroform extract of bee pollen from Brassica campestris, a plant used as an herbal cancer chemopreventative in China, found that the steroid-containing extract could induce cytotoxicity in prostate cancer PC-3 (human) cells via apoptosis.98 Additional studies of bee pollen in the treatment of prostate cancer are needed.

Respiratory infections

Other potential uses of bee pollen include combating the effects of aging, treating respiratory infections and endocrine disorders, and relief of enteritis, colitis, and constipation. A double-blind, randomized, controlled trial conducted in 64 Iranian adults 18 to 65 years of age who had failed standard medical treatment for chronic rhinosinusitis found significantly improved endoscopic scores post-endoscopic surgery in the group treated with thyme honey nasal spray (35% w/v honey, 200 microg/mL thymol) compared to placebo. However, no significant differences were seen in sinonasal outcome test, endoscopy, or computerized tomography scan scores between the groups.146

Rosacea

A placebo-controlled randomized trial investigated the efficacy of topical 90% medical-grade kanuka honey (with 10% glycerine) applied twice daily for 8 weeks as a treatment for rosacea in 138 adult New Zealanders. Participants were predominantly between the ages of 50 and 70 years of age with a mean duration of rosacea of 15 years. The proportion of participants who experienced a clinically significant improvement was significantly higher in the treatment group (34.3%) compared to placebo (17.4%) (P = 0.02). Additionally, the proportion of patients who demonstrated full resolution of rosacea was 13.2% versus 2.9% in the honey versus placebo groups, respectively (P = 0.031). Both the investigator-rated and participant-rated severity scores were also significantly improved at weeks 2 and 8 in the treatment group compared to placebo.119

Wound healing

Wound healing activity, particularly anti-ulcerous properties, of honeybee products is attributed primarily to the presence of phenolic compounds.1

Clinical data

A review of literature through March 2001 found numerous articles verifying the use of honey in wound healing. A representative sample includes articles on honey for wounds, ulcers, and skin graft preservation99; an analysis of 40 cases in which honey was used on wounds and showed a positive (88% healing) effect100; honey and its healing properties for leg ulcers101; the successful use of honey for superficial wounds and ulcers102; honey as a wound-healing agent with antibacterial activity103; the use of honey in wound management104 and treating burns105, 106, 107; and usefulness of honey in managing abdominal wound disruption in 15 patients after cesarean delivery.108 The Scottish Intercollegiate Guidelines (SIGN, 2010) for the management of chronic venous leg ulcers state that honey dressings are not recommended in the routine treatment of patients with venous leg ulcers; no recommendation can be made for manuka honey as a debridement agent.109 A Cochrane systematic review of evidence-based decisions for local and systemic wound care found strong evidence for the use of honey and included venous ulcers, acute wounds, pressure ulcers, diabetic ulcers, and arterial ulcers.110 However, a Cochrane review of treatments for venous leg ulcers alone found that honey-based preparations offered no benefit in time to healing or complete healing when compared with usual care.111 An updated Cochrane review evaluated clinical data in 26 trials (N = 3,011) on the use of honey as a topical treatment for acute and chronic wounds. High-quality evidence favored improved healing with honey for partial thickness burns compared to conventional dressings in addition to a reduced overall risk of adverse events relative to treatment with silver sulfadiazine. Low-quality data supported improved healing of burns as well as mixed population acute and chronic wounds with honey compared to silver sulfadiazine. Other favorable outcomes were seen for Fournier’s gangrene with honey versus Eusol soaks, improved pressure ulcers with honey versus saline soaks, and healing of infected postoperative wounds with honey versus antiseptic washes; fewer adverse events were also seen with honey when used for postoperative wound infection. Beyond these, results were unclear due to poor quality of the evidence.144 It was also reported that while honey may be superior to some conventional dressing materials, the reproducibility of results is uneven.112 Other data support reduced healing time, but not healing rate, of lower leg ulcers in patients with type 2 diabetes.139 Whereas a small double-blind, randomized, controlled trial (N = 25) in patients with type 2 diabetes found no significant difference in healing parameters with application of 5% topical royal jelly over 12 weeks.147 A larger randomized controlled trial (unblended) conducted in 348 patients with Wagner’s grade 1 or 2 foot ulcers reported significantly improved wound healing and healing time honey-impregnated dressings compared to saline dressings. Only beri honey (Ziziphus jujuba) samples that provided at least an 18 mm zone of inhibition at 50% w/v against Staphylococcus aureus in agar diffusion test were used for the study. Maximum follow up was 120 days. Significantly more wounds healed with honey-impregnated dressings than saline dressings (75.97% vs 57.39%, respectively, P=0.001). Additionally, the number of wounds that were incompletely healed were significantly lower with honey (17.87%) compared to saline (31.36%; P=0.001). Mean wound healing time was also significantly shorter with honey than saline (18 vs 29 days, P<0.001).150

Dosing

Honey is a common food and there are no dose restrictions on its use. It has been ingested and used topically, sometimes on surgical dressings.120

The ideal dose of bee pollen is unknown, with doses varying among products because tablets contain differing amounts. Manufacturers' recommendations on product labeling may provide more guidance.

Clinical trials are generally lacking to recommend dosage for royal jelly. Small clinical trials have used 6 to 10 g/day for 14 to 28 days when evaluating the effect on hyperlipidemia.74, 75 A randomized, controlled trial investigating use of royal jelly for oral mucositis in patients receiving chemotherapy and radiation used a dose of 1 g/day in addition to standard mouthwash therapy.98 Whereas 2,400 mg/day (800 mg 3 times daily with meals) was used safely for 8 weeks in a double-blind, randomized, placebo-controlled trial with some benefit in improving tear volume in patients with dry eye.152

Pregnancy / Lactation

Honey is GRAS when used as food. Safety and efficacy for dosages above those in foods is unproven.

Pregnant Sprague-Dawley rats fed bee pollen had fetuses with higher birth weights and decreased death rates, suggesting that bee pollen may be an effective prenatal nutrient.121 Human data regarding safety and efficacy of bee pollen in pregnancy and lactation are lacking.

Information regarding safety and efficacy of royal jelly in pregnancy and lactation is lacking. Estrogenic effects of royal jelly and its constituents have been demonstrated in animals.23, 57, 58, 59, 60, 117

Interactions

No interactions have been well-documented for honey.

Warfarin: Bee pollen may enhance the anticoagulant effect of warfarin. Monitor therapy.156, 157, 158

Case reports of hematuria due to potentiation of warfarin have been documented with royal jelly.122 Based on a few animal experiments, potentiation of insulin activity may exist.20, 64

Other interaction data

Some studies have reported insignificant pharmacokinetic drug interactions with natural products. Limited information as well as potentially high interpatient variability in clinical response warrants cautious interpretation and/or application of these data in practice.

Nigerian honey consumption resulted in a dose-related variable, but had a statistically nonsignificant effect on quinine metabolism to 3-hydroxquinine in a 3-phase randomized crossover trial in 10 healthy volunteers. Young adult Nigerians 20 to 28 years of age consumed 10 or 20 mL of honey twice daily for 1 week prior to administration of quinine; the quinine metabolic ratio increased by 24.4% after the 10 mL phase and decreased 23.9% after the 20 mL phase (P = 0.15).143

Adverse Reactions

Honey

Pollen in honey may cause allergic reactions.

Bee Pollen

There have been numerous case reports of adverse reactions related to allergic reactions after ingestion of bee pollen by sensitive individuals. Single doses of bee pollen as low 5 mL have precipitated acute allergic reactions, including anaphylaxis.12, 123, 124, 125 The development of hypereosinophilia and neurologic and GI symptoms were reported in a woman who ingested bee pollen for more than 3 weeks.126 Allergic symptoms resolved upon discontinuation. The reactivity of bee pollen was assessed in 145 atopic patients and 57 healthy volunteers. All patients received skin-prick testing with 6 standard aeroallergens (olive, grasses mix, Parietaria, mugwort, Dermatophagoides pteronyssinus, and Dermatophagoides farinae) and homemade bee pollen extracts. There was a strong correlation between cutaneous reactions to bee pollen extracts and olive, grasses mix, and mugwort. Additionally, strong cutaneous reactions to bee pollen were observed in atopic patients compared with healthy volunteers.127

Two case reports of acute hepatitis following bee pollen ingestion have been reported. In 1 report, a 33-year-old woman had been taking 2 tablespoons of pure bee pollen daily for several months and subsequently developed sharp midepigastric and right upper quadrant pain. Liver function tests (LFT) were elevated. Although she was taking several other medications, only the bee pollen was discontinued. Within 6 weeks, a complete resolution with normalization of laboratory values occurred. In the second report, a 69-year-old man was taking 14 tablets daily of a mixed herbal product containing bee pollen. He developed worsening pruritus and nausea, followed by anorexia, weight loss, and jaundice, as well as elevated LFT. His only other medication was metoprolol tartrate. Within 8 weeks of discontinuation of only the herbal product, his symptoms dissipated and LFTs normalized.128

Royal Jelly

Although skin tests were positive for royal jelly in many allergy patients, some have been able to consume honey with no problems. Allergy, acute exacerbation of asthma, anaphylaxis, and death have been reported. Some occupational allergic respiratory cases have been reported in workers handling powdered royal jelly.122, 129, 130, 131, 132, 133, 153

Toxicology

Generally, honey is considered safe as a sweet food product, gargle, cough-soothing agent, and a topical product for minor sores and wounds. However, medical reports indicate that honey can be harmful when fed to infants because some batches contain spores of Clostridium botulinum, which can multiply in the intestines and result in botulism poisoning.134, 135, 136 The American Academy of Pediatrics and the World Health Organization recommend that honey should not be given to an infant younger than 12 months due to the potential for botulism. Research regarding toxicity with the use of bee pollen and royal jelly is lacking. A case report described mucosal hemorrhage, edema, and inflammation attributed to royal jelly consumption. A drug-induced lymphocyte stimulation test for royal jelly was positive.137

Honey made from the nectar of poisonous plants can be poisonous. This is most commonly seen in Turkey, with honeys produced from the genus Rhododendron in the Eastern Black Sea region; 15 to 20 cases per year of "mad honey" intoxication are reported that result from consumption of honey containing grayanotoxin that blocks sodium channels and most often leads to bradycardia, hypotension, nausea, vomiting, syncope, and possibly also mild hypothermia.149 Three cases of honey poisoning, including 1 fatality, were reported in Southwest China from consumption of honey contaminated with pollen from Tripterygium wilfordii Hook F. The patients, who were young males otherwise previously healthy, presented with frequent vomiting, acute renal failure, and toxic myocarditis.151

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