Bee Venom

Scientific Name(s): Apis mellifera
Common Name(s): Bee venom, Honeybee venom

Medically reviewed by Drugs.com. Last updated on Mar 22, 2024.

Clinical Overview

Use

Bee venom is used to hyposensitize individuals highly sensitive to bee stings. Systematic reviews suggest anti-inflammatory and analgesic effects. See also the Honeybee Products monograph for information related to honey, propolis, and royal jelly.

Dosing

Clinical evidence is lacking to guide dosing of bee venom.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

Avoid use. Documented adverse reactions.

Interactions

None well documented.

Adverse Reactions

Various adverse reactions have been reported with bee venom from a sting or therapy.

Toxicology

Published data regarding toxicity with bee venom therapy are lacking. Bee venom from a sting or therapy can cause anaphylaxis and death in sensitive individuals (ie, with Hymenoptera venom allergy). Refining bee venom to remove harmful substances may limit toxicity.

Source

Honeybee venom is obtained from A. mellifera, the common honeybee. Other venoms are derived from related members of the insect order Hymenoptera.(Jang 2020) Honey bee venom is a bitter, colorless liquid. Compositions of fresh and dried bee venom differ mainly with regard to the volatile components; however, the overall biological activities are similar.(Zolfagharian 2015)

History

Bee venom is one of the most common animal venoms encountered. Anaphylaxis to insect stings is relatively uncommon, affecting approximately 0.4% of the general US population. It is the cause of an estimated 40 deaths per year in the United States.(Park 2015, Reisman 1992) Allergic reactions to bee venom are mediated by immunoglobulin E (IgE) antibodies directed at constituents of honeybee, yellow jacket, hornet, and wasp venoms.(Muller 1992)

Use of bee products, including bee venom, dates back thousands of years, with medicinal properties cited in the Bible and Quran. Apitherapy is an alternative therapy that relies on honeybee products (honey, pollen, propolis, royal jelly, bee venom [also known as apitoxin]). It has been suggested that honeybee venom may alleviate the symptoms and slow the progression of immune-modulated diseases such as arthritis. Use of bee venom for this purpose was an idea raised from observations that beekeepers rarely experience rheumatism or joints problems.(Wehbe 2019) In one survey of a random sampling of the general population, 83% of respondents believed that bee venom could be an effective treatment for arthritis based on information they had read in the lay press.(Price 1983)

Bee venom immunotherapy has also been used for desensitization to bee stings, thus inhibiting allergic reactions.(Park 2015) The strategy consists of either indirect application, by extracting bee venom with an electric stimulus followed by its injection into the body, or directly via bee stings. In order to minimize allergic reactions, hyposensitizing bee venom immunotherapy techniques consist of administration of small doses of the venom under controlled conditions over a period of months to years. Patients allergic to honeybee venom may be particularly sensitive to Hymenoptera venoms in general and have been found to be at a higher risk of developing systemic adverse reactions to venom immunotherapy than patients who are sensitive to yellow jacket venom.(Muller 1992, Wehbe 2019)

Chemistry

Venom is collected from the insects and diluted to standardized concentrations. Bee venom consists of mast cell degranulation peptide, adolapin, melittin, apamin, histamine, phospholipase A2, hyaluronidase, acid phosphatase, and nonpeptide components such as glucose and fructose.(Jang 2020, Zahran 2021) Melittin, a phospholipase-activating protein in bee venom, has been shown to induce neutrophil degranulation(Bomalaski 1989) and to increase(Bomalaski 1989) or inhibit(Somerfield 1986) the formation of superoxide. This variation in activity appears to depend upon the test method employed. Melittin induces neutrophil degranulation with subsequent superoxide formation in vitro(Bomalaski 1989); however, melittin binds to calmodulin, an effect associated with inhibition of superoxide production.(Somerfield 1986)

Uses and Pharmacology

See also the Honeybee Products monograph for information related to honey, propolis, and royal jelly.

Acne

Clinical data

A Cochrane review of complementary therapies for acne identified 1 low-quality randomized trial (N=12) that showed a statistically significant reduction in numbers of skin lesions in acne vulgaris with purified bee venom compared with control (P=0.01). Cosmetics with or without the intervention were applied for 2 weeks; concentration of purified bee venom was 0.06 mg/mL in bee venom–containing cosmetics.(Cao 2015)

Analgesic effects

Clinical data

Systematic reviews of randomized controlled trials employing bee venom for various pain conditions identified 1 trial that assessed bee venom ultrasound gel in 30 patients with pelvic inflammatory disease. Compared with a 7-day regimen of oral doxycycline only, adjunctive use of topical bee venom gel applied with phonophoresis for 4 weeks resulted in significantly lower C-reactive protein as well as pain intensity (P<0.0001 each). Additional studies used bee venom acupuncture (2 studies; N=114), ultrasound gel (1 study; N=20), and ointment (N=68) in patients with low back pain, delayed-onset muscle soreness, and temporomandibular joint (TMJ) disorder, respectively. Compared with controls, significant improvement in pain scores was reported with bee venom therapy in the low back pain and muscle soreness trials (P=0.012, P<0.05, and P<0.05, respectively). In contrast, both the intervention and the control groups with TMJ disorder experienced significant pain improvement; between-group differences were not reported.(Jang 2020, Mena 2020) Another systematic review that assessed the efficacy of bee venom acupuncture for shoulder pain identified 7 studies total, 4 of which were included for meta-analyses (N=128). The majority of studies investigated poststroke shoulder pain, while 2 studies enrolled patients with adhesive capsulitis; duration of therapy ranged from 2 to 12 weeks. Pain reduction was significantly greater in the bee venom groups compared to saline injection with or without conventional therapy (P values ranged from 0.0007 to 0.02), but not compared with physiotherapy. Heterogeneity was high and study numbers and population sizes were small, making firm conclusions difficult.(Shen 2020) One additional single-blind, randomized controlled study using bee venom acupuncture was identified in a systematic review of nonpharmacological therapies for central poststroke pain. Compared with normal saline, the bee venom group experienced significantly better pain reduction (P=0.009).(Xu 2020)

Antinociceptive effects resulting from desensitization after repeated bee venom administration have been demonstrated in experimental and clinical models. In a single-blind, randomized, comparator trial in adults with nonspecific chronic neck pain (N=60), patients were randomized to receive bee venom acupuncture, nonsteroidal anti-inflammatory drugs (NSAIDs), or combined treatment (bee venom acupuncture plus NSAIDs) for 3 weeks. Bee venom acupuncture alone significantly reduced bothersomeness and pain intensity compared to the combination treatment (P<0.05 each) at week 4. By week 8, reductions in bothersomeness and neck disability scores were significantly better with bee venom acupuncture than with NSAIDs alone (P<0.05 each). Scores for health-related quality of life as well as depressive mood also improved significantly with bee venom acupuncture compared to NSAID monotherapy (P<0.05 each). Three cases of mild itching and redness at the injection site were reported in the bee venom acupuncture and bee venom acupuncture plus NSAIDs groups and were deemed definitely related to bee venom acupuncture treatment.(Lee 2021)

Anti-inflammatory effects

Animal and in vitro data

The polypeptide adolapin isolated from bee venom inhibits inflammation (carrageenan, prostaglandin, and adjuvant rat paw edema models) and appears to inhibit the prostaglandin synthase systems.(Shkenderov 1982)

In a study using the mouse air pouch model, diluted bee venom treatment produced a potent anti-inflammatory effect, as indicated by a marked reduction in leukocyte migration compared with that of saline pretreatment. Diluted bee venom's anti-inflammatory effect is reversed by intrathecal pretreatment with atropine but not with hexamethonium, indicating that diluted bee venom stimulates an increase in spinal acetylcholine, specifically activating spinal muscarinic receptors. Intrathecal administration of a muscarinic type 2 (M₂) receptor antagonist (methoctramine), but not M₁ or M₃ receptor antagonists, abolished the anti-inflammatory effect, indicating that spinal M₂ receptors are specifically involved.(Yoon 2005)

In a mouse inflammatory air pouch model, systemic pretreatment with the beta-adrenergic receptor antagonist propranolol, but not the corticosteroid antagonist RU-486, inhibited diluted bee venom's anti-inflammatory effect, suggesting the effect is mediated by adrenal medullary catecholamines acting through beta-adrenoreceptors expressed by immune cells and not dependent on corticosteroid release from the adrenal cortex.(Kwon 2003) A study in mice demonstrated that bee venom–induced anti-inflammatory effects are dependent on activation of capsaicin-insensitive primary afferent fibers and the central noradrenergic system, including the locus coeruleus. These findings demonstrate the complex nature of the neuroimmune interactions that underlie the anti-inflammatory effect produced by subcutaneous bee venom administration.(Kwon 2006)

Transection of the sciatic nerve completely eliminated the bee venom anti-inflammatory effect on zymosan-induced inflammation, indicating a dependence on peripheral nerve integrity and not a locally mediated anti-inflammatory effect.(Kwon 2006) A study in Sprague-Dawley rats showed that sciatic nerve transaction, L4-L6 dorsal rhizotomy, and local treatment of the sciatic nerve with capsaicin produced a depression of bee venom subcutaneous injection–induced inflammation, indicating that neurogenic components are involved in the bee venom–induced inflammatory response. Dorsal root reflex together with axon reflex conducted by capsaicin-sensitive primary afferents are the potential mechanisms underlying the generation of neurogenic inflammation. It is further suggested that capsaicin-sensitive primary afferents may play differential roles in the development of dynamic and static mechanical allodynia in the bee venom test.(Chen 2006)

Arthritis therapy

Animal and in vitro data

Honeybee venom administered to rats with adjuvant arthritis resulted in suppression of disease.(Yiangou 1993) In human neutrophils, melittin blocked the production of superoxide and hydrogen peroxide; melittin and other agents that bind calmodulin have decreased superoxide production. Honeybee venom also decreased the production of the inflammatory mediator interleukin 1 in rat splenocytes. In rats with adjuvant arthritis, honeybee venom treatment inhibited certain macrophage activities and thus, indirectly inhibited the activation of T and B cells.(Hadjipetrou-Kourounakis 1988)

Treatment with bee venom resulted in a reduction of tissue swelling and osteophyte formation in a rat model of chronic arthritis, as well as reduction of edema formation in a model of acute arthritis.(Park 2004)

Bee venom inhibited lipopolysaccharide-induced prostaglandin E₂ and nitric oxide production in the Raw 264.7 murine macrophage cell line. The inhibitory actions of bee venom on the generation of inflammation mediators were also effective in synoviocytes obtained from rheumatoid arthritis patients. The inhibitory effect of bee venom was consistent with that of indomethacin.(Park 2004)

Clinical data

A systematic review of randomized controlled trials using bee venom therapy noted improvements in Shoulder Pain and Disability Index score (P=0.017) as well as pain at rest (P=0.029) after 12 weeks of bee venom acupuncture injections and at the 1-year follow-up in patients with adhesive capsulitis. In another trial included in the systematic review, significant improvements in pain, physical function, walking (P=0.001 each), and patient global assessment (P=0.0001) were documented in patients with knee osteoarthritis after bee venom injections for 12 weeks.(Jang 2020)

Atopic dermatitis

Clinical data

In patients with atopic dermatitis randomized to receive bee venom emollient in a 4-week, double-blind, controlled trial (N=114), Eczema Area and Severity Index (EASI) score was significantly improved. The improvement in EASI scores was significantly larger than in the control group at both 2 and 4 weeks (P=0.023 and P=0.022, respectively). At week 3, itching visual analog score was also significantly reduced in the experimental group (P=0.03). Adverse drug reactions (ie, irritation, pruritus, erythema, urticaria, disease exacerbation) occurred in 35.2% of participants in the bee venom group compared with 23.1% of controls.(You 2016)

Immunotherapy

Hypersensitivity to honeybee venom is mediated by a number of antibodies and immunomodulators, the most important of which appears to be IgE. Venom immunotherapy (VIT) reduces the likelihood of systemic response in patients with systemic allergic reactions to insect venom. Criteria to precisely identify the point in time when protection becomes persistent are unknown. Despite the remote possibility of severe reaction, the supervised sting challenge test is the only current method for evaluating the efficacy of VIT. Identification of markers that can be used to predict protection is needed.(Konno 2005)

Clinical data

Passive infusion of beekeepers' plasma has demonstrated protection against systemic reactions that can occur during active immunotherapy. In a study conducted in one patient, decreased sensitivity to honeybee venom was noted in the days after passive infusion of beekeeper plasma; modified rush immunotherapy with honeybee venom was then initiated, with increases in anti-idiotypic antibodies and decreases in specific antibodies to honeybee venom (IgG and IgE) observed over the following 76 weeks. These findings suggest that several mechanisms play an interrelated role in the development of immunity to honeybee venom.(Boutin 1994) An upregulation of osteopontin expression associated with successful VIT has been reported, suggesting a potential role of osteopontin as a biomarker in VIT. In addition to its known regulatory role in bone metabolism, osteopontin has been postulated to be a Th1 cytokine and is involved in Th1-associated immune responses.(Konno 2005)

The European Academy of Allergy and Clinical Immunology (EAACI) Taskforce on Venom Immunotherapy guideline on allergen immunotherapy for Hymenoptera venom allergy (2018) recommends VIT in the following populations:

• Adults (level I evidence, grade A recommendation [strong to moderate recommendation strength]) and children (level III evidence, grade B recommendation [weak recommendation strength]) with detectable sensitization and systemic sting reactions that exceed generalized skin symptoms;

• Adults with systemic sting reactions confined to generalized skin symptoms if quality of life is impaired (level I evidence, grade A recommendation [strong to moderate recommendation strength]);

• Adults with recurrent, troublesome large local reactions to reduce the duration and size of such reactions in the future (level II evidence, grade B recommendation [moderate/low recommendation strength]).

The EAACI Taskforce does not recommend the use of VIT in the following populations:

• Asymptomatic individuals with incidentally detected sensitization to insect venom (level IV evidence, grade C recommendation [weak recommendation strength]);

• Patients with unusual reactions who do not represent immediate type systemic reactions (level V evidence, grade D recommendation [weak recommendation strength]).(Sturm 2018)

Metabolic dysfunction

Animal data

In a type 2 diabetic hyperlipidemic rat model, intraperitoneal administration of bee venom for 4 weeks significantly reduced fasting blood glucose (FBG) compared to untreated rats. By week 4, FBG was reduced by 69.6% and 77.16% in the low- and high-dose bee venom groups, respectively, compared to untreated controls (P<0.001 each), with a similar reduction observed in the metformin-atorvastatin group (−79.06%; P<0.001). Additionally, insulin profile, lipid parameters, and cardiac dysfunction parameters were significantly improved in the bee venom and metformin-atorvastatin groups compared to untreated controls (P<0.0001 for all). Based on improvements in the antioxidant status of cardiac tissue, the mechanism was observed to include modulation of the nuclear factor kappa B signaling system.(Zahran 2021)

Multiple sclerosis

Uses for bee venom, although poorly substantiated, include the treatment of diseases of the locomotor system,(Mund-Hoym 1982) particularly multiple sclerosis. Despite widespread anecdotal reports, there is no scientific consensus regarding safety and effectiveness of bee venom in the management of multiple sclerosis.(Wesselius 2005)

Clinical data

In a study of 26 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis, bee sting therapy had no effect on disease activity, as measured using gadolinium-enhanced magnetic resonance imaging of the brain.(Wesselius 2005)

Parkinson disease

Clinical data

Data results from 3 randomized controlled trials (N=138) identified in systematic reviews evaluating use of bee venom to treat Parkinson disease are equivocal. The individual trials employed bee venom acupuncture/injection or bee venom injection. Study periods ranged from 8 weeks to 11 months.(Cho 2018, Jang 2020)

Systemic sclerosis

Clinical data

In a 64-year-old female with systemic sclerosis, superficial circumscribed lesions were treated with bee venom acupuncture along the margins of the patches. Average itch and sleep disturbance scores improved by at least 50% after the first treatment, with amelioration (scores of 0) of both symptoms after the fifth visit. At 3-month follow-up, the patient's skin condition had improved to resemble normal skin.(Hwang 2018)

Dosing

Clinical evidence is lacking to guide dosing of bee venom.

Pregnancy / Lactation

Avoid use. Documented adverse reactions.

Interactions

None well documented.

Adverse Reactions

Immediate effects after multiple stings include localized pain, swelling, and erythema at individual sting sites. Stings to the eyes can result in corneal edema and ulceration. When bees are swallowed, life-threatening pharyngeal edema and respiratory obstruction may occur. Early systemic symptoms after large-volume envenomation include fatigue, dizziness, nausea, vomiting, and diarrhea. Within 24 hours, hemolysis, hemoglobinuria, rhabdomyolysis, and hepatic transaminase enzyme elevations may develop. Subendocardial damage and cardiac enzyme elevations seen in human case reports and animal studies may result from direct venom effects in the absence of anaphylaxis and hypotension. Renal insufficiency and electrolyte abnormalities such as hyperkalemia, may occur secondary to rhabdomyolysis, hemolysis, and acute tubular necrosis. Nonanaphylactic responses to multiple stings often will be apparent within the first several hours; however, severe systemic signs and symptoms have been delayed for up to 24 hours or more.(Betten 2006)

In a systematic review and meta-analysis of randomized controlled trials, itchiness occurred significantly more often with bee venom therapy than with control, with a risk ratio (RR) of 6.68 (95% CI, 2.37 to 18.84; P<0.0003) based on data from 4 trials (N=687; low heterogeneity). Total events also occurred significantly more often with bee venom (RR, 1.55 [95% CI, 1.03 to 2.34]; P=0.04; N=2,535; moderate heterogeneity). No difference was found between groups specifically for rash, edema, or headache.(Jang 2020)

Toxicology

Published data regarding toxicity with bee venom therapy are lacking. Bee venom from a sting or therapy can cause anaphylaxis and death in sensitive individuals. Refining bee venom to remove harmful substances may limit toxicity.(Cherniack 2018)

Bee stings cause human reactions in 2 distinct patterns: One or a few stings may induce allergic responses that are sometimes severe or fatal; and massive attacks with hundreds to thousands of stings can cause severe systemic injury affecting many organs, resulting in high mortality. Melittin and phospholipase A2 have been shown to be the main lethal components in bee venom.(Jang 2020, Tunget 1993)

Signs and symptoms of multiple stings include urticaria (hives), nausea, vomiting, diarrhea, hypotension, confusion, seizures, and renal failure. Treatment is supportive, with attention to blood pressure, renal function, and maintenance of an open airway. Stingers should be removed with gentle scraping to prevent further venom injection.(Tunget 1993) Massive inoculation of bee venom may induce acute renal failure, adult respiratory distress syndrome, liver injury, cardiac damage, pancreatitis, skin necrosis, shock hypertension, bleeding, thrombocytopenia, hemolysis, and rhabdomyolysis. Bee venom–induced acute renal failure after multiple stings has been sporadically reported in Europe, Africa, and Asia.(Grisotto 2006)

Animal studies have shown a decrease in glomerular filtration rate and urinary volume after bee venom infusion. Venom also caused a sharp and immediate decrease in renal blood flow. Experimental injection of bee venom caused a reaction similar to that observed in patients with bee venom–induced acute renal failure.(Grisotto 2006)

Because cardiac levels of noradrenaline have increased dramatically in animals following bee venom injection, it is suggested that all individuals, regardless of sensitivity history, undergo cardiac monitoring in the case of multiple bee stings.(Ferreira 1994) Rare cases of anuria and rhabdomyolysis/rhabdomyonecrosis have been reported.(Azevedo-Marques 1992, Beccari 1992)

Index Terms

• Hymenoptera

References

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