Honeybee Products

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

Medically reviewed by Drugs.com. Last updated on Nov 30, 2022.

Clinical Overview

Use

Honeybee products have been used historically worldwide, both topically and internally, as remedies for a variety of illnesses. Limited data from mainly small trials of varying quality indicate that honeybee products may be of some benefit for conditions including seasonal allergy symptoms (honey), herpetic lesions and warts (propolis), cough (honey), dry eye (royal jelly, honey), dry mouth (honey), eye surgery antibacterial prophylaxis (honey), oral mucositis (propolis, royal jelly), and rosacea (honey). Data supporting the use of honeybee products for other indications are equivocal and/or not well substantiated.

Dosing

Use of honey is not recommended in children younger than 12 months due to increased risk of botulism/paralysis.

The type of honeybee product, plant species of origin, methods of processing, and doseform have all been shown to affect the appropriate dose and duration, safety, and effectiveness. See specific indications in Uses and Pharmacology section.

Contraindications

The American Academy of Pediatrics and the World Health Organization (WHO) recommend that honey not be given to infants younger than 12 months due to the potential for botulism. 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 honeybee 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 propolis. Case reports of warfarin potentiation have been documented with bee pollen and royal jelly.

Adverse Reactions

Allergic reactions to pollen may occur when honey is 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 following ingestion of bee pollen have been reported. 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. Increased rates of infection, peritonitis, and parathyroidectomy were reported in diabetic patients who received daily application of Medihoney to peritoneal dialysis exit sites during a clinical trial. Case reports of propolis-induced fixed-drug eruption, erythema multiforme–like contact dermatitis, and necrotizing mediastinitis with concomitant aspiration pneumonia have been published.

Toxicology

Contaminated honey containing botulism spores can be toxic to infants. The American Academy of Pediatrics and the WHO recommend that honey not be given to infants younger than 12 months due to the potential for botulism. Honey made from the nectar of poisonous plants can be poisonous. Information regarding the toxicology of bee pollen or royal jelly is lacking.

Scientific Family

• Apidae

Source

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., family: Apidae), as well as a few other species of bee in the tropics, and primarily consists of sugars. Composition varies with the pollen source, climate, environmental conditions, and processing.Osol 1960, Viuda-Martos 2008

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; lay approximately 2,000 eggs a day (female worker bees are infertile); and live 5 to 8 years, approximately 40 times longer than worker bees.Tyler 1987

History

Honey use dates to ancient times; it was historically used as a sweetening agent and then as flavoring for medicinal preparations. 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. It was once officially listed in the National Formulary.Carper 1988 Honey is used directly as a sweetener and is also fermented into the sweet-tasting beverages of mead, cyser, or metheglin.Klein 1987

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.Campos 2010, Kostic 2020

Royal jelly was used in traditional medicine for longevity in Europe and Asia. In many countries, royal jelly has been widely promoted as a commercially available medicine, health food, cosmetic emollient, moisturizer, and source of nourishment. Royal jelly has been sold as a skin tonic and hair growth stimulant.Inoue 2003, Tyler 1987, Viuda-Martos 2008

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).Honey 1999 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 dextrose and levulose, occurring in a mixture ranging from 65% to 80% of one or the other. Sucrose content ranges from 0.5% to 8%, and dextrin content ranges from 1% to 10%. Minor components include phenols, glucose oxidase and catalase, ascorbic acid, carotenoids, organic acids, amino acids, proteins, and alpha-tocopherol.Osol 1960 There have been numerous reports on an antimicrobial honey distillate fraction and related antifungal compounds.Efem 1992, Elbagoury 1993, Obaseiki-Ebor 1984, Radwan 1984 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.Mirkin 1989 Vitamin C concentrations of 3.6% to 5.9% have also been found in some samples.Tyler 1992 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.Kimura 2006, Schönleben 2007, Viuda-Martos 2008 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 (MRJPs) (including MRJP 1 to 9) have been identified.Bilikova 2002, Hattori 2006, Izuta 2009, Kodai 2007, Schmitzova 1998, Suzuki 2008, Zhang 2009

Uses and Pharmacology

Acne

Clinical data

A Cochrane systematic review of trials published up to mid-January 2014 assessed complementary and alternative medicines for acne vulgaris. Among the 35 studies that met inclusion criteria, a single small, low-quality study (N=12) was identified that used bee venom. Topical application of purified bee venom to the face for 2 weeks significantly improved the number of lesions compared with no bee venom (mean difference [MD], −1.17; 95% CI, −2.06 to −0.28; P=0.01).(Cao 2015) In contrast, in a New Zealand single-blind, randomized, controlled trial in adults in with acne (N=68), no difference was observed between medical-grade topical kanuka honey applied as an adjunct to standard therapy (antibacterial soap) and standard therapy alone. Outcomes assessed included investigator-based severity scores as well as subject-rated improvements. The number of treatment-related adverse events was similar between groups.(Semprini 2016)

Allergies

Clinical data

In a single-blind, randomized controlled trial of patients 8 to 79 years of age with a long history of birch pollen allergies (N=61), administration of honey (up to 8 g/day) with and without enrichment with bee-collected birch pollen in 44 patients significantly improved symptoms of birch pollen seasonal allergies as well as decreased the use of antihistamine medications compared with controls (17 patients continuing their usual allergy medicines). Patients also experienced more asymptomatic days with honey enriched with birch pollen (P<0.01) or without (P<0.05) compared with controls. Adverse events correlated with honey consumption were mild itching in the mouth or skin or runny nose.(Saarinen 2011) Similarly, in a double-blind, randomized, placebo-controlled trial of adults with confirmed allergic rhinitis (N=40), symptom scores were significantly improved in those randomized to 1 g/kg/day of tualang honey (unprocessed, multifloral) for 4 weeks compared with those who consumed honey-flavored corn syrup (placebo group).(Asha'ari 2013)

Analgesic effects

Clinical data

Compared with standard postsurgical therapy alone (antibiotic plus acetaminophen), adjunctive use of 5 mL of honey orally for 10 days significantly decreased the average time to relieve pain (7.65 vs 5.53 days, respectively; P<0.001) and average acetaminophen use (17.53 vs 12.1 times, respectively; P<0.001) in 80 Iranian children who underwent tonsillectomy.(Mohebbi 2014) 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 following surgery with the use of honey compared with controls (P=0.05 to P<0.0001). However, after subgroup analyses by intervention and blinded studies, significant pain reduction was seen only with honey plus antibiotics and not for honey alone, and for only 1 day post surgery (day 2). Similarly, the number of analgesics used was statistically significantly lower with honey plus antibiotics compared with controls on 2 postsurgery 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 the studies was rated as poor.(Lal 2017) In a double-blind, randomized clinical trial conducted in 120 nulliparous women, no significant differences were observed in episiotomy pain intensity among 3 treatment groups: topical honey 30% cream, phenytoin 1% cream, and placebo cream.(Lavaf 2017) Similarly, in a smaller unblinded, randomized comparator crossover study, no significant difference in pain relief was observed between honey (1.2 mg/kg) or mefenamic acid (250 mg) for 2 menstruation cycles in 60 young women with primary dysmenorrhea.(Amiri Farahani 2017)

Antibacterial activity

Apidaecins and abaecin, potent antibacterial peptides, have been isolated and characterized in the honeybee (A. mellifera L.) itself,(Casteels 1989, Casteels 1990) and the potent antibacterial protein royalisin has been found in the royal jelly of the honeybee.(Fugiwara 1990) Antibacterial activity in diluted honey with a pH range of 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.(Krell 1996, Molan 1996) 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.(Viuda-Martos 2008) 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(Mandal 2011); manuka honey has a high level of activity against a variety of bacteria, including Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, and Enterobacteriaceae.(Allen 2000, Cooper 1999, Molan 2020, Quadri 1998) Active manuka honey and its Australian equivalent are the only commercially available types of honey 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."(Molan 2012)

In vitro data

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 S. 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.(Boukraa 2009, Supabphol 1995)

In a systematic review of randomized controlled trials and in vitro controlled trials assessing periodontal pathogens, an overall antimicrobial effect of pure or diluted honey was evident, particularly in the in vitro studies. Heterogeneity was high and susceptibility appeared to vary between clinical and reference microbial strains.(Hbibi 2020) Honey has also been effective for inhibiting growth of Helicobacter pylori.(al Somal 1994, Ali 1991) When honeys from the United States and New Zealand were compared against glucose-fructose solutions, the growth inhibition of H. pylori was shown to be related to the osmotic effects of the carbohydrates in the solutions instead of elements (ie, hydrogen peroxides) present in honey.(Osato 1999)

Clinical data

When applied topically, manuka honey was a safe alternative antibiotic compared with povidone iodine for the prophylaxis of dialysis catheter–related sepsis.(Quadri 1998) Similarly, in the HONEYPOT international randomized controlled trial, daily application of Medihoney (80% antibacterial honey plus natural oils and waxes) to peritoneal dialysis exit sites for 12 to 24 months had anti-infective efficacy equal to standard exit-site care, which included nasal mupirocin for carriage of S. aureus. In contrast, subgroup analysis revealed that patients with diabetes who received honey experienced higher rates of infection and peritonitis as well as higher rates of study withdrawal compared with controls. Additionally in patients with diabetes, incidence of parathyroidectomy was higher in the honey group than with control (7 vs 0 patients, respectively). Local reactions to honey led to a 6% dropout rate.(Johnson 2014) Similarly, results of the open-label HONEYPOT substudy in nasal S. aureus carriers demonstrated comparable rates between honey and mupirocin controls for organism-specific peritonitis, organism-specific exit-site infections, hospitalizations due to peritonitis or infection, and conversion to hemodialysis. Withdrawal rates were also similar between groups.(Zhang 2015) 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 a standard site dressing of chlorhexidine 0.5% in 70% alcohol.(Kwakman 2012)

In a randomized comparator study, 101 patients scheduled for cataract surgery or vitrectomy received topical prophylactic application of honey 25% eye drops (monofloral derived from the honeydew Abias species) or ofloxacin 0.3% eye drops starting 7 days prior to surgery. A significant reduction in ocular bacterial isolates was observed compared with baseline (P<0.001), with no significant difference seen between treatment groups. Isolates completely eradicated in the honey group were S. aureus, Corynebacterium species, Proteus species, and Enterococcus species.(Cernak 2012)

In a small single-blind, randomized, controlled pilot study (n=13) in patients with cystic fibrosis-associated chronic rhinosinusitis, sinus irrigation with manuka honey (Medihoney) for 30 days led to a clinically significant improvement in sinusitis-related quality of life scores compared to baseline, but the difference between groups was not significant. However, endoscopic scores were statistically significantly better with honey than saline (P=0.006) with the biggest improvement observed in the "crusting" subcategory. Post-treatment culture negativity rates were similar between groups.(Lee 2021)

Antifungal activity

Clinical data

An antimycotic effect similar to that with miconazole was demonstrated when Brazilian green propolis extract was applied topically for 2 weeks in 7 students from the Republic of Congo. Statistically significant improvements in the clinical severity of Trichophyton rubrum caused by Tinea pedis interdigitalis and Tinea corporis were documented in patients receiving either the propolis extract or miconazole compared with petroleum jelly (P<0.001, unpaired t test). Additionally, propolis extract was observed to be significantly more effective than miconazole with regard to clinical severity of desquamation, incrustation, erythema, and pruritus.(Ngatu 2012) Similarly, in a study of 69 patients (88% female) with fungated malignant wounds, no significant differences were observed between application of manuka honey–coated and silver-coated dressings regarding effects on exudate, malodor, and wound pain.(Adderley 2014)

Antioxidant activity

The production of free radicals, which leads to oxidative stress, plays a major role in most diseases, including cardiovascular disease, cancer, and diabetes. Honeybee products such as honey and royal jelly have a naturally high antioxidant potential.(Vuida-Martos 2008)

Animal and in vitro data

Antioxidant activity has been demonstrated with royal jelly using various in vitro and plant models,(El-Nekeety 2007, Jamnik 2007, Liu 2008, Nagai 2006) while protection against oxidative stress–induced injury has been demonstrated in animal experiments.(El-Nekeety 2007, Kanbur 2009, Kanbur 2009, Silici 2009) In in vitro studies and experiments in rats, royal jelly inhibited lipid peroxidation.(Guo 2008)

Bee pollen may possess antioxidant effects,(Nakajima 2009) 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.(Alivazicioglu 2005) 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.(Saric 2009)

Clinical data

In an 8-week, double-blind, randomized, controlled trial in male long-distance cyclists (N=39), several biomarkers indicated that antioxidant activity was improved in seminal plasma with supplementation of 70 g of unprocessed honey compared with placebo administered 90 minutes prior to exercise. Outcomes were measured immediately and at 12 hours and 24 hours after the intervention. Specifically, levels of superoxide dismutase, catalase, reactive oxygen species, malondialdehyde (MDA), and total antioxidant capacity were improved. Improvements were also documented in seminal anti-inflammatory markers.(Tartibian 2012) In a 5-hour pilot study, the acute effect of high- or low-dose honey (1.5 or 0.75 mg/kg body weight, respectively) on oxidative parameters was assessed in 20 female athletes. The area under the curve (AUC) of MDA, an end product of lipid peroxidation, was significantly lower with low-dose honey compared with high-dose honey (P<0.05), whereas no significant differences were found between groups for AUCs of other parameters. High-dose honey also produced a significant reduction in MDA levels at 1, 2, and 3 hours, with a maximum reduction of 31.2% at 2 hours post honey consumption. However, no significant differences in plasma levels of antioxidant biomarkers were observed between the 2 groups.(Ahmad 2017) The impact of 900 mg/day of propolis given for 18 weeks on antioxidant parameters in type 2 diabetes patients produced equivocal but mostly insignificant results in a randomized, controlled study (N=65). The control was undefined but was noted in the study limitations to not be a placebo.(Zhao 2016)

Antiviral activity

The antiviral activity of propolis was previously identified to include prevention of cellular entry, interference with virus cell membranes, and conversion of the viral envelope, as well as a direct effect on free virions.

Clinical data

A 2019 systematic review of controlled trials studying the use of bee products for treating herpes skin infections (herpes simplex and zoster) identified 9 studies that met inclusion criteria; 3 evaluating honey and 6 evaluating propolis. Controls in 8 of the 9 studies were acyclovir and/or placebo; one study was a propolis dose-finding study comparing propolis 0.5% as the intervention against propolis 0.1% and 1%. All 8 of the non–dose-finding studies reported either overall better or equal efficacy with application of topical honey or propolis (cream or ointment) compared with acyclovir for pain relief, pain duration, and/or healing time of herpetic lesions of the mouth, skin, and genitalia. The 2 studies including placebo reported that both honey alone and honey in combination with acyclovir provided better effects than placebo. In the dose-finding study, propolis 0.5% ointment was more effective for healing than propolis 0.1% or 1% concentrations. The majority of the studies were of good quality, and while the propolis study sample sizes ranged from 60 to 400, 2 of the 3 honey studies were small crossovers with 15 or 16 patients.(Munstedt 2019)

In a single-blind, randomized, placebo-controlled trial, the effect of propolis was also studied on plane, plantar, and common warts. Data from 90 participants who completed the study demonstrated that a 3-month regimen of oral propolis 500 mg/day produced complete clearing of common and plane warts in significantly more participants (62%) than either echinacea (22%) or placebo (12%) (P<0.05). No adverse events were observed.(Zedan 2009)

Cataracts

Clinical data

A number of related activities and unique medical applications include the successful use of honey in treating senile cataracts(Golychev 1990) and postherpetic opacities of the cornea.(Mozherenkov 1984)

Cough

Clinical data

Cochrane updated reviews of data from a few randomized controlled trials published through 2014 reported potential benefits of honey over placebo, no treatment, salbutamol, and diphenhydramine for symptomatic relief of acute cough in children, but little or no difference compared with dextromethorphan.(Oduwole 2014, Oduwole 2018) Another 2014 Cochrane review of OTC preparations for acute cough identified one new randomized, controlled trial evaluating honey (N=300), the results of which indicated a benefit in total symptom scores for nocturnal acute cough in children 1 to 5 years of age who took 10 g of honey (eucalyptus honey, citrus honey, or labetiae honey) as a single dose or diluted in a noncaffeinated drink 30 minutes before bed compared with placebo (silan date extract).(Smith 2014) Similar results were reported in another, more recently published unblinded randomized trial of children with cough due to upper respiratory tract infections.(Ayazi 2017)

Dentistry

Clinical data

A systematic review identified limited data describing a number of propolis applications in dentistry, including use as a storage medium for avulsed teeth, intracanal irrigation and medication, caries prevention, dentin hypersensitivity, pulp capping, periodontitis treatment, recurrent aphthous stomatitis, and wound healing.(Abbasi 2018) In another systematic review (N=67) reporting on natural products used as an effective medium for the storage and transport of avulsed teeth, propolis was recommended by 6 of 22 studies and royal jelly was recommended by one.(Adnan 2018) Effects of propolis on oral infection, dental plaque, and stomatitis were discussed in an earlier meta-analysis; however, limited data and/or heterogeneity in outcome measures prevented meta-analyses for most of the data. Data that could be pooled from 3 studies evaluating use for dental plaque revealed a nonsignificant reduction with propolis.(Hwu 2014) Data from 19 twin pairs enrolled in a double-blind, randomized controlled equivalence trial showed propolis 2% mouth rinse resulted in a reduction in induced gingivitis similar to that with positive control (sodium fluoride with CPC rinse) after 21 days of treatment.(Bretz 2014)

According to a prospective, cross-sectional survey (N=250) analyzing use of 31 complementary and alternative medicine (CAM) remedies for dental or mouth issues, propolis was recommended by 33% of German dentists and maxillofacial surgeons. As would be expected, perceived effectiveness was rated higher among CAM proponents than opponents.(Baatsch 2017)

Diabetes mellitus/Glycemic effects

The glycemic index of a variety of German and Greek honeys has been found to be negatively correlated with the fructose content, sucrose content, fructose to glucose ratio, and sucrose to oligosaccharides ratio in healthy volunteers. For a portion size of 20 g of honey, glycemic loads varied among the varieties and was less than 10 (on glucose scale) for fir, chestnut, linden (heated and not heated), multifloral, acacia, heather, and sweet chestnut.(Deibert 2010, Gourdomichai 2018) Similarly, the insulinemic index of a variety of German honeys was found to be negatively correlated to the fructose content of each honey, although no correlation was identified between the glycemic and insulinemic values.(Deibert 2010) Reactive hypoglycemia has been negatively correlated with salivary insulin levels and honey glucose content.(Gourdomichai 2018)

Animal data

Limited data from a systematic review of animal studies reported a reduction in fasting blood glucose for royal jelly supplementation, but inconsistent results were reported for insulin levels, insulin resistance, and lipid parameters in diabetic animal models.(Maleki 2019)

Clinical data

A 2019 systematic review and meta-analysis included 6 randomized, controlled trials (N=373) assessing the effect of propolis on glycemic control in patients with type 2 diabetes from Iran, Egypt, Japan, and China. Pooled data revealed a reduction only in fasting plasma glucose (−13.51 mg/dL) and hemoglobin A_1C (HbA_1C) (−0.52%); however, heterogeneity was high. Significance was lost in subgroup and sensitivity analyses when non–East Asian countries were excluded. Additionally, no association was found between fasting glucose or HbA_1C and propolis dosage (range, 226 to 1,500 mg/day) or duration of therapy (range, 56 to 180 days).(Karimian 2019) Results from a systematic review of clinical trials are mixed with regard to the effect of royal jelly (1 to 3 g/day for 8 weeks) on glycemic parameters in patients with type 2 diabetes. Similarly, limited data report equivocal effects on lipid parameters as well as oxidative stress and inflammatory markers in this patient population.(Maleki 2019) Long-term effects of honey on cardiovascular parameters and anthropometric measurements were evaluated in 100 postmenopausal women 45 to 65 years of age enrolled in a double-blind, randomized comparator study. Only diastolic blood pressure and fasting glucose were significantly improved from baseline at 12 months with a tualang honey sachet (100% honey) compared with a honey mixture (95% honey, 4% bee bread, 1% royal jelly). Fasting blood glucose decreased 0.4 mmol/L (7.2 mg/dL; P=0.021). No significant changes were found for systolic blood pressure or any lipid parameters.(Ab Wahab 2018)

Dry eye syndrome

Clinical data

Effective use for signs and symptoms of dry eye have been documented for royal jelly oral supplementation as well as a honey topical eye product (gel and drops).(Albietz 2017, Inoue 2017) In a double-blind, randomized, controlled study (N=43), Japanese adults with of mild or moderate dry eye symptoms were administered placebo or 2,400 mg/day of standardized royal jelly tablets (800 mg 3 times daily after meals) for 8 weeks. At 8 weeks, only tear volume was significantly improved with administration of oral royal jelly compared with 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 at weeks 4 and 8 compared with baseline (P=0.0324 and P=0.0396, respectively) and versus 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.(Inoue 2017) A prospective, open-label, randomized controlled trial conducted in 114 patients with dry eye due to moderate to advanced meibomian gland dysfunction (MGD) reported significant improvements with the 3 treatment groups evaluated: Optimel (standardized product approved in Australia, New Zealand, and Europe approved for MGD) eye gel (98% manuka honey) or drops (16% manuka honey) in conjunction with conventional treatment (warm, wet compress; lid massage; lubricant) and control (conventional therapy alone) for 8 weeks. Significant improvements in symptoms, tear osmolarity, tear break-up time, meibum quality, inflammation (lid margin redness, bulbar redness, limbal redness), and corneal staining were observed at 8 weeks with the 3 treatments compared with baseline (P≤0.05 for all parameters in all 3 groups). Improvement in staining was significantly greater with adjunctive Optimel drops (P=0.035). Significant improvements (P<0.05) in meibomian gland expressibility and InflammaDry occurred for both Optimel treatment groups. Optimel gel was significantly more effective in improving meibum quality (P=0.005) and gland expressibility (P=0.042). Total eyelid marginal bacterial colony counts reduced significantly with Optimel drops (P=0.03) but not the other treatments. S. epidermidis counts reduced significantly in the Optimel drops (P=0.041) and gel (P=0.027) groups. Both Optimel treatments significantly reduced the need for lubricants, with drops decreasing lubricant use most (P=0.001). Temporary stinging and redness were the only reported adverse effects related to the honey products.(Albietz 2017)

Dry mouth/Xerostomia

Clinical data

The effect of thyme honey on the intensity of radiotherapy-induced xerostomia in patients treated in the oral cavity for cancer of the head and neck was observed to be significantly more beneficial than control in a randomized, single-blind trial (N=72). Saline or filtered pure honey was used as an oral rinse and topically applied immediately before, immediately after, and 6 hours after each radiotherapy session, then for 4 more weeks at home following completion of radiotherapy. At the end of the 7-week treatment period, mean xerostomia grade was significantly improved in the honey group compared with control and was maintained through week 26, with grades of 0.22 and 1.28 for honey and saline (control), respectively (P<0.0001). No patients in the treatment group had grade 3 or 4 xerostomia at the end of week 7 compared with 25% in the control arm. Patient-assessed symptomatology, quality of life, and general satisfaction were also significantly improved compared with controls, with an increased effect size at 6 months post treatment. No adverse effects to honey were reported.(Charalambous 2017)

Dysphagia

Clinical data

Honey is often used to modify the consistency of food and fluids for patients with dysphagia in an effort to reduce the incidence of aspiration, particularly in those with dementia. Limited data reflect likely greater risks than any long-term benefit when honey is used to thicken fluids in dysphagic patients with dementia and/or Parkinson disease. Results from systematic reviews, including a Cochrane review, and a case report reveal low-quality evidence that reduced aspiration following administration of honey-thickened fluids does not necessarily reduce the immediate or long-term risk of pneumonia and may instead increase the risk of dehydration, malnutrition, and pneumonia.(Flynn 2018, Wang 2016)

Estrogenic activity

Animal and in vitro data

Effects of royal jelly on estrogen receptors are weak compared with the effects of diethylstilbestrol and phytoestrogens; however, stimulation of mRNA expression in estrogen-responsive genes and enhanced MCF-7 cell proliferation, which can be blocked by concomitant use of tamoxifen, has been demonstrated in vitro.(Mishima 2005, Suzuki 2008) 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,(Suzuki 2008) while effects in ewes varied. The effect of royal jelly supplementation on the onset of estrus has shown mixed results in ewes, with 1 trial showing no effect and another exhibiting a shorter time to estrus compared with control and no difference compared with gonadotropin.(Husein 2006, Kridli 2006, Kridli 2003) In both experiments, positive effects on pregnancy and lambing rates were demonstrated.

Hypertension

Animal data

Following GI enzymatic hydrolysis, peptides derived from royal jelly demonstrated angiotensin I–converting enzyme inhibitory activity in spontaneously hypertensive rats. 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.(Librowski 2000, Matsui 2002, Takaki-Doi 2009)

Clinical data

Long-term effects of honey on cardiovascular parameters and anthropometric measurements were evaluated in 100 postmenopausal women 45 to 65 years of age enrolled in a double-blind, randomized comparator study. Only diastolic blood pressure and fasting glucose were significantly improved from baseline at 12 months with administration of a tualang honey sachet (100% honey) compared with a honey mixture (95% honey, 4% bee bread, 1% royal jelly). Diastolic blood pressure decreased by 4.5 mm Hg in the honey group compared with the honey mixture group (P=0.047). No significant changes were found for systolic blood pressure or any lipid parameters.(Ab Wahab 2018)

Immunoregulatory activity

Animal and in vitro data

Various in vitro experiments examined the actions of royal jelly and its constituents on the immune system.(Gasic 2007, Kimura 2006, Oka 2001, Okamoto 2003, Taniguchi 2003, Vucevic 2007) Animal experiments demonstrated immunoregulatory activities, with administration of royal jelly 500 to 1,500 mg/kg/day resulting in increased survival in tumor-bearing mice and demonstrating positive effects on bone marrow stem cells and tumor-induced splenic hematopoiesis.(Bincoletto 2005) Additionally, autoimmunity was inhibited in systemic lupus erythematous–prone mice, with a delay in disease progression, decrease in proteinuria, and increase in survival.(Mannoor 2009) Increased healing rates were observed in guinea pig tympanic membrane perforation.(Calli 2008)

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.(Erem 2006)

Clinical data

A positive immunomodulatory effect has been demonstrated in protein energy–malnourished patients. In a small randomized study (N=50), administration of honey (2 mL/kg/day) plus a conventional nutritional rehabilitation program for 2 weeks improved phagocytic function and rate of improvement compared with patients who received nutritional rehabilitation without honey.(Shaaban 2012) A significant improvement (P<0.001) was also reported by patients with atopic dermatitis for lesions treated with honey compared with no improvement in the untreated lesions. Data from 14 patients who completed this pilot study suggest multiple mechanisms, including dose-dependent inhibition of mast cell degranulation and subsequent histamine release, as well as downregulation of interleukin 4 (IL-4)–induced chemokine ligand 26 (CCL26) protein release from keratinocytes.(Alangarie 2017)

In an open-label study in Malaysian adults 20 to 50 years of age, the effects of 12-week honey supplementation on plasma inflammatory markers were evaluated in 64 chronic smokers (at least 10 cigarettes/day for more than 5 years). Blood was obtained from the 64 chronic smokers and from 32 nonsmokers for purposes of a preintervention status assessment; chronic smokers had significantly higher high-sensitivity C-reactive protein (hsCRP) levels at baseline, whereas there were no differences in preintervention tumour necrosis factor alpha (TNF-alpha) or IL-6 levels between the smokers and nonsmokers. Smokers were then randomly assigned to 20 g/day of honey or no honey for 12 weeks; a significant increase in TNF-alpha and a significant reduction in hsCRP were seen compared with baseline; however, no change was observed in IL-6. In contrast, no significant differences were observed in smokers without honey supplementation for any of the 3 measures.(Ghazali 2017)

In an 8-week, double-blind, randomized controlled trial in male long-distance cyclists (N=39), several biomarkers indicated improved anti-inflammatory activity in seminal plasma with supplementation of 70 g of unprocessed honey compared with placebo administered 90 minutes prior to each training session. Outcomes were measured immediately and at 12 hours and 24 hours after the intervention. Specifically, seminal plasma levels of IL-1beta, IL-6, IL-8, and TNF-alpha were improved, suggesting honey may have an immunomodulatory effect.(Tartibian 2012)

Data pooled from 6 clinical trials (N= 406) in a meta-analysis that evaluated the effect of propolis on C-reactive protein and TNF-alpha levels reported a significant reduction in both parameters (P<0.0001 and P=0.01, respectively). Heterogeneity was moderate. Propolis regimens varied from 66 mg/day given for 104 weeks to 1,500 mg/day for 8 weeks. Trials were conducted across 5 countries and enrolled predominantly diabetic patients (N=234) but also included healthy, asthmatic, and elderly individuals (mean age range, 19 to 73 years).(Jalali 2020)

Infertility, male

Clinical data

Increasingly, evidence supports the role of inflammation and oxidative stress in the damage to spermatozoa and subsequent etiology of male infertility. In an 8-week, double-blind, randomized controlled trial in 39 male long-distance cyclists, the effects of supplementation with 70 g of unprocessed honey on semen parameters as well as seminal inflammatory and oxidative biomarkers were explored. Outcomes were measured immediately and at 12 hours and 24 hours after the intervention. Overall, the mixed model analysis adjusted for baseline revealed that exercise plus honey improved semen volume as well as sperm motility, morphology, concentration, and absolute numbers compared with exercise plus placebo. Several antioxidant and anti-inflammatory outcomes were also shown to be improved in the honey group compared with placebo.(Tartibian 2012)

Lipid profile

Clinical data

Small clinical trials have demonstrated mixed effects on lipid profiles in humans receiving royal jelly. In a review investigating the ways royal jelly modulates age-related mechanisms, royal jelly administered at 10 g/day for 14 days increased serum high-density lipoprotein (HDL) levels in elderly participants, while a trend toward improved low-density lipoprotein (LDL) levels was seen with no effect on serum triglycerides.(Münstedt 2009) 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.(Guo 2007) In a randomized, single-blind trial, administration of 350 mg/day of royal jelly capsules for 3 months to mildly hypercholesterolemic (n=20) individuals produced a reduction in total and LDL cholesterol compared with baseline (−11.5% and −4.8%, respectively), whereas no changes were observed in the placebo group (n=20). No between-group comparisons were reported. Additionally, dehydroepiandrosterone sulfate (DHEA)-S levels were increased with royal jelly compared with baseline levels. No other lipid, sex hormone, hepatic, renal, or physiologic parameters were impacted in either group.(Chiu 2017) In a double-blind, randomized comparator study evaluating effects on cardiovascular parameters and anthropometric measurements in 100 postmenopausal women 45 to 65 years of age, administration of a tualang honey sachet (100% honey) or a honey mixture (95% honey, 4% bee bread, 1% royal jelly) for 12 months resulted in no changes for any lipid parameters.(Ab Wahab 2018)

Menopausal symptoms

Clinical data

Data regarding use of honey in menopause are equivocal. Limited data report improvement as well as worsening of some climacteric symptoms, and in CNS and cardiovascular outcomes.(Ab Wahab 2018, Georgiev 2004, Othman 2011) In an open, multicenter, uncontrolled, prospective observational study, the effects of Melbrosia (pollen, perga [propolis], royal jelly) on menopausal symptoms and cardiovascular risk markers were assessed. 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. Of the 55 total patients enrolled, 27 underwent laboratory assessment of cardiovascular risk markers, including cholesterol and CRP levels. Significant reductions in the standardized Kupperman score (P<0.001) and other symptom measuring tools (ie, Zerssen symptoms list and Zung depression score) were noted compared with before 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).(Georgiev 2004) In a double-blind, randomized comparator study of 100 postmenopausal women 45 to 65 years of age who consumed either a tualang honey sachet (100% honey) or a honey mixture (95% honey, 4% bee bread, 1% royal jelly) for 12 months, both treatments helped reduce some cardiovascular risk factors.(Ab Wahab 2018)

In a 16-week study of 102 postmenopausal women evaluating the effects of honey as an alternative to standard estrogen plus progestin therapy and to no treatment, some, but not all, verbal learning and immediate memory performance scores were significantly improved (after controlling for educational differences), in those assigned to receive 20 g of tualang honey compared with the untreated controls (P<0.05); no significant differences were observed in scores between those receiving honey and those receiving estrogen-progestin therapy, including regarding total learning score, which was significantly improved in both the honey and the estrogen-progestin groups compared with untreated controls. Additionally, no significant differences were observed between the honey and estrogen-progestin groups for any of the 10 outcome measures. Plasma estradiol levels were significantly increased only in the estrogen-progestin group, suggesting a mechanism for honey that is not dependent on estrogenic effects alone.(Othman 2011)

The North American Menopause Society position statement for nonhormonal management of menopause-associated vasomotor symptoms (2015) states that evidence from one small study suggests benefit of pollen extracts for menopausal vasomotor symptoms and other quality-of-life parameters (level II evidence).(NAMS 2015) The Society of Obstetricians and Gynaecologists of Canada's updated guideline on managing menopausal vasomotor symptoms (2021) notes that efficacy data are insufficient to recommend pollen extract.(Yuksel 2021)

Neurological activity

Animal and in vitro data

Traditional use of royal jelly in ameliorating various effects of 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.(Hashimoto 2005) In addition, 10-hydroxy-trans-2-decanoic acid increased the generation of neurons from neural stem (progenitor) cells in vitro,(Hattori 2011) while adenosine monophosphate stimulated neuronal differentiation of pheochromocytoma PC12 cells.(Hattori 2007) Activity on the pituitary gland in middle-aged rats has also been demonstrated,(Narita 2009) and orally administered royal jelly increased granule cell content in the hippocampus, with an observed improvement in induced cognitive impairment in mice.(Hattori 2011)

Oral mucositis

Clinical data

An assessment of interventions for preventing oral mucositis in patients receiving cancer treatment reported some weak statistical evidence of benefit with honey used to either prevent or reduce the severity of mucositis compared with placebo or no treatment.(Worthington 2011) Additionally, in a randomized controlled trial (N=103), mean time to resolution of oral mucositis (grades 1 to 3) was reduced in patients undergoing radio- and chemotherapy who rinsed orally with royal jelly 1 g/day in addition to standard mouthwash therapy with benzydamine hydrochloride and nystatin rinses.(Erdem 2014) In a meta-analysis of 9 randomized clinical trials published through June 2014 evaluating the effects of honey on oral mucositis in patients with head and neck cancer undergoing radio- or chemoradiotherapy, improvements (lower incidence of moderate to severe mucositis, later onset time, lower 3-week mean grade) were seen with honey compared with placebo or no treatment. Subgroup analysis of honey efficacy according to type of treatment found that honey produced no statistically significant effect in patients receiving chemotherapy but a significantly greater effect in preventing moderate to severe mucositis in patients undergoing radiotherapy alone compared with chemoradiotherapy.(Cho 2015)

Similar equivocal results were published in 2 systematic reviews and/or meta-analyses reporting on the effects of honey, royal jelly, and/or propolis on chemotherapy/radiotherapy-induced mucositis.(Kuo 2018, Yang 2019) In a standard meta-analysis of 16 randomized controlled trials (N=1,200), moderate evidence supported a significant effect of honey in treating moderate to severe oral mucositis induced by chemo-/radiotherapy; however, heterogeneity was substantial. The various types of honey used affected the results, prompting further assessment via network meta-analysis. Of 13 treatment and control arms, pure natural honey ranked second only to chamomile; 3 other types of honey (dabur, local, manuka) ranked fourth, fifth, and seventh after benzocaine compared with usual care. Propolis ranked least effective followed by kanuka honey, both of which ranked lower than "usual care." Honey was also found to reduce the onset time of oral mucositis (odds ratio [OR], 0.41; 95% CI, 0.08 to 0.73) without increasing the risk of adverse effects.(Yang 2019) Another meta-analysis of 5 randomized controlled trials (N=209) evaluating the efficacy of propolis mouthwash showed a significant reduction in risk of severe cancer therapy–induced oral mucositis with propolis compared with control (OR, 0.35; 95% CI, 0.18 to 0.7; P=0.003). Overall, mean Jadad score for these studies reflected evidence of high methodological quality (mean, 3.6).(Kuo 2018)

Osteoporosis

Animal and in vitro data

In tissue culture models and ovariectomized rats, a positive effect on osteoporosis was demonstrated with royal jelly. The increased calcium content and recovered bone mass were suggested to be results of enhanced intestinal calcium absorption rather than of antagonism of the parathyroid hormone.(Hidaka 2006)

Performance enhancement

Clinical data

Limited data reflect an overall lack of effect of honey or honeybee products on athletic performance.(Blustein 1981, Maughan 1982, Meng 2017, Montgomery 1977) A 2-year, double-blind study found bee pollen was "absolutely not a significant aid in the metabolism, workout training, or performance" of athletes.(Montgomery 1977) The results of another study conducted in track athletes suggested that runners who took bee pollen recovered faster after exercise (ie, regarding relief of common tiredness and lack of energy). Critics of this study found the test group to be small, the blinding inadequate, and the conclusions premature.(Blustein 1981) 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).(Winther 2002)

Animal and experimental studies previously showed that using proteolytic enzymes to reduce royal jelly proteins into smaller peptide molecules and/or amino acids facilitated digestion and absorption. As a follow-up to these studies, low- and high-dose protease-treated royal jelly (1.2 and 4.8 g/day, respectively) was administered for 1 year in a double-blind, randomized, placebo-controlled, dose-response study evaluating effects on muscle strength and physical performance in elderly nursing home residents. Data from 163 participants reflected no differences in hand grip or physical performance tests. No treatment-related adverse effects were observed.(Meng 2017)

Premenstrual syndrome and menopausal symptoms

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 alternative treatment for 2 more consecutive cycles. Results indicate Femalhad an overall beneficial effect, with 8 of 10 symptom scores (eg, irritability, dysphoria) reduced by 27% to 57% with active treatment. Femal was associated with 50% less premenstrual weight gain compared with placebo. Results did show strong evidence of a protracted carryover effect. In the group receiving placebo first, the change in individual VAS scores was always between 3 and 4 points (P<0.01); in contrast, in the group that received Femal before placebo, change in individual VAS scores was less than 1 point, with only sleep disturbance showing a significant change in favor of Femal (P<0.04). Although results suggest that Femal may be beneficial in improving PMS symptoms, the findings should be interpreted cautiously because no washout period was implemented, which results in the risk of a carryover effect; also, a preliminary phase designed to eliminate placebo responders was not conducted.(Winther 2002)

Prostate conditions

Cernilton, an extract of bee pollen, has been used in prostate conditions for its presumed anti-inflammatory and antiandrogenic effects.(Dhar 2007) 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 is thought to possess antiandrogenic effects, may relax urethral smooth muscle tone and increase bladder muscle contraction, and/or may act on alpha-adrenergic receptors and relax internal and external sphincter muscles.(MacDonald 2000)

Clinical data

Some evidence is available regarding 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 study limitations include short duration, small numbers of participants, and questionable standardization of preparations.(Elist 2006, MacDonald 2000, Shoskes 2002, Shoskes 2003, Wilt 2000)

Two placebo-controlled trials and 2 comparative trials enrolling 444 participants with BPH were included in a systematic review published in 2000; patients received Cernilton or either placebo or pharmacologic therapy (control) for 12 to 24 weeks. Weighted mean risk ratio (RR) for self-improvement was 2.4 (range, 1.21 to 4.75) for Cernilton versus placebo, and was 1.42 (range, 1.21 to 4.75) versus 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.(MacDonald 2000)

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. Those receiving the higher dose of Cernilton experienced a greater improvement in international prostate symptom score (IPSS), prostate volume, postvoid residual urine, and maximal flow rate (Q_max) assessments compared with those receiving the lower dose (P<0.0001). Additionally, patients receiving the higher dose of Cernilton experienced improvements in IPSS and Q_max after 3 and 6 months of therapy, compared with after 6 and 9 months in those receiving the lower dose.(Xu 2008)

The efficacy of Cernilton N (administered as 1 tablet 3 times daily for a 6-month period) for the treatment of chronic prostatitis syndrome was assessed in 90 patients. 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; 36% 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.(Rugendorff 1993)

Respiratory infections

Clinical data

A double-blind, randomized, controlled trial conducted in 64 Iranian adults 18 to 65 years of age in whom standard medical treatment for chronic rhinosinusitis had failed showed improved endoscopic scores following endoscopic surgery in those treated with thyme honey nasal spray (honey 35% w/v, thymol 200 mcg/mL) compared with placebo. However, no differences were seen in sinonasal outcome test, endoscopy, or computerized tomography scan scores between the groups.(Hashemian 2015)

A systematic review and meta-analysis that investigated the use of honey for upper respiratory tract infections among 14 randomized controlled trials concluded that evidence was too limited and/or too heterogeneous to draw strong conclusions for honey compared to placebo. Excluding the 4 studies that used honey in combination with other ingredients, meta-analyses of honey compared to "usual care" indicated benefit in combined symptom score (mean difference [MD], −4.47; 95% CI, −6.47 to −2.48; 2 studies, n=192), cough frequency (standard MD, −0.4; 95% CI, −0.58 to −0.21; 6 studies, n=586), and cough severity (standardized median difference, −0.44; 95% CI, −0.7 to −0.17; 4 studies, n=457). Data for all 3 outcomes were homogeneous. Similarly, subgroup analysis indicated benefit for cough frequency in patients using honey compared to diphenhydramine (MD, −0.41; 95% CI, −0.69 to −0.14; 3 studies, n=280, low heterogeneity).(Abuelgasim 2020)

Rosacea

Clinical data

A placebo-controlled, randomized trial investigated the efficacy of topical 90% medical-grade kanuka honey (with glycerine 10%) applied twice daily for 8 weeks as a treatment for rosacea in 138 adults in New Zealand. Participants were predominantly between the ages of 50 and 70 years, with a mean duration of rosacea of 15 years. The proportion of participants who experienced a clinically important improvement was significantly higher in the treatment group (34.3%) compared with 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 with placebo.(Braithwaite 2015)

Smoking detoxification

Clinical data

In 50 male Korean smokers (20 to 28 years of age), urinary excretion of a major tobacco carcinogen (bone alkaline phosphatase [BaP]) increased marginally by 1.3-fold in a time-dependent manner over 4 weeks with the administration of propolis 600 mg/day (0.34 to 0.43 ng/mL) compared with baseline (P<0.01). However, BaP levels increased by 2.23-fold following administration of aloe polysaccharide (0.34 to 0.75 ng/mL; P<0.01) and by 2.33-fold with a mixture of propolis and aloe polysaccharide (0.33 to 0.77 ng/mL; P<0.01). No changes were observed in nonsmoking controls or in smokers given placebo. Similar time-dependent increases were observed in urinary excretion of cotinine, with 2.08-, 2.64-, and 2.28-fold increases compared with baseline levels following administration of propolis, aloe polysaccharide, and the combination, respectively (P<0.01 each). Other biochemistry changes included an approximate 16% time-dependent decrease in mean creatinine levels among smokers in the supplementation groups, with levels that approached those of nonsmokers by the end of the treatment period. Baseline glucose and bilirubin levels, which were significantly higher in smokers than nonsmokers, also decreased in smokers over time to levels comparable to those of nonsmokers. Smokers enrolled in the study had smoked more than 20 cigarettes/day for the last year, with an average of 23 cigarettes/day for 5 years.(Koo 2019)

Wound healing

Properties of honey, including acidic pH, high viscosity, high osmolarity, and the presence of hydrogen peroxide, have been shown to collectively impart antibacterial effects; phenolic compounds and other nonperoxide components (ie, methylglyoxal, bee defensin-1) have been identified as contributors to the intensity of these effects.(Wang 2019)

Clinical data

A review of the literature through September 2016 found numerous articles of low to high quality supporting the use of honey in wound healing; a representative sample includes Cochrane meta-analyses showing benefit for managing venous ulcers, acute wounds, pressure ulcers, diabetic ulcers, arterial ulcers, partial thickness burns, and Fournier gangrene(Brölmann 2012, Jull 2015, Norman 2017); an analysis of 40 cases in which honey showed a positive (88% healing) effect on wounds of various origin(Ndayisaba 1993); and many other reports of positive effects in leg ulcers,(Bourne 1991) wounds and ulcers (including superficial),(Dunford 2000, Greenwood 1993, Kolmos 1993, Postmes 1993, Zhang 2015) skin graft preservation,(Postmes 1993) burns,(Subrahmanyam 1994, Subrahmanyam 1993, Subrahmanyam 1991) fungated wounds,(Adderley 2014) mandibular surgical wounds,(Anyanechi 2015) and abdominal wound disruption (in 15 patients after Cesarean delivery).(Phuapradit 1992)

In contrast, 2 Cochrane reviews found no difference in postoperative pain, healing rates, or infection of ingrown toenails among patients receiving honey gauzes compared with other standard interventions or controls(Eekhof 2012); or in time to healing or complete healing of venous leg ulcers compared with usual care.(O'Meara 2014) Similarly, results from a randomized, controlled trial reported no difference in postoperative wound healing or scarring between manuka honey and control (Vaseline) in patients who underwent bilateral blepharoplasty.(Malhotra 2017)

In patients with diabetes, data are equivocal regarding use of honey in ulcers. Some data supported reduced healing time of lower leg ulcers in patients with type 2 diabetes but no difference in percent of healed ulcers with manuka honey–impregnated dressings compared with conventional dressings,(Kamaratos 2014) whereas a large (N=348), unblinded study in patients with Wagner's grade 1 or 2 diabetic foot ulcers reported improved healing time and a greater number of healed wounds with beri honey (Ziziphus jujuba)–impregnated dressings compared with saline dressings.(Imran 2015) Benefit of honey dressings for the treatment of diabetic foot ulcers was also supported by results of a 2019 systematic review and meta-analysis (5 studies; N=756). The quality of included studies was rated as grade B, sample sizes ranged from 20 to 348, and duration of follow-up was 4 to 17 weeks. The outcomes of wound healing rate and time, bacterial clearance rate and time, and wound debridement time were all significantly improved with honey dressings (1 study used royal jelly) compared with controls (P<0.01 for each). Controls varied and consisted of functional, conventional iodine, saline, nanocrystalline silver, and placebo dressings.(Wang 2019)

In a double-blind, placebo-controlled trial, application of 5% topical royal jelly over 12 weeks did not provide benefit in healing parameters in patients with type 2 diabetes with one or multiple foot ulcers.(Siavash 2015)

An aqueous propolis liquid applied approximately every 10 days for 6 weeks to chronic foot ulcers in patients with type 1 or 2 diabetes led to significantly improved rates of healing and percentage of fully healed ulcers compared with controls (P<0.001 for each). These results remained significant for propolis in the presence of systemic antibiotics compared with antibiotic therapy alone, as well as within the propolis group with or without antibiotics. Compared with historic controls, both the bacterial load and proinflammatory proteinase were also significantly reduced by propolis.(Henshaw 2014)

A subgroup analysis of the HONEYPOT multicenter trial revealed that diabetic patients receiving peritoneal dialysis who also received honey as topical exit-site treatment experienced higher rates of infection and peritonitis, as well as higher rates of study withdrawal compared with mupirocin controls. Additionally, incidence of parathyroidectomy in patients with diabetes was higher for honey than with control (7 vs 0 patients, respectively).(Johnson 2014)

The Scottish Intercollegiate Guidelines Network (SIGN) 2010 guidelines 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.(SIGN 2010) It was also reported that while honey may be superior to some conventional dressing materials, the reproducibility of results is uneven.(Jull 2013)

Dosing