Bee Venom by Deep Blue Health

LIKELY EFFECTIVE

• Bee sting allergy. Subcutaneous use of bee venom seems to be effective for bee sting desensitization in patients with severe allergy to bee stings. Bee venom immunotherapy provides 98% to 99% protection from systemic reactions to bee stings. Once immunotherapy is stopped, the risk of a systemic reaction over the next 5 to 10 years is about 5% to 15% (6043,6075,6076). Bee venom is an FDA-approved subcutaneous injectable product for the treatment of severe allergies to bee stings (2619).

POSSIBLY INEFFECTIVE

• Multiple sclerosis (MS). Administering live bee stings in graduated doses up to 20 stings given three times weekly does not seem to improve multiples sclerosis. Treatment for 24 weeks does not seem to reduce gadolinium-enhancing lesions on MRI or improve fatigue, disability, or quality of life (13222).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Frozen shoulder. A small clinical study in patients with frozen shoulder shows that receiving bee venom diluted 1:10,000 as injections into acupuncture points twice a week for 8 weeks, as an adjunct to other therapy, improves pain and disability but not range of motion when compared with injection with normal saline. Bee venom injections diluted to 1:30,000 did not improve pain and disability when compared with placebo (96573). One year after receiving bee venom acupuncture, scores on the Shoulder Pain and Disability Index remained improved over placebo in these patients; however, verbal rating scale scores did not differ from placebo (105772).
• Hemiplegic shoulder pain. Pooled analyses of two small clinical studies shows that bee venom acupuncture modestly decreases pain, but does not affect motor function, when compared with control in patients with shoulder pain after stroke (96575,105771).
• Neck pain. In patients with chronic neck pain, receiving 6 sessions of bee venom acupuncture over a 3-week period reduces the impact of the neck pain and improves quality of life more than taking the nonsteroidal anti-inflammatory drug loxoprofen 180 mg orally daily for 3 weeks. Pain intensity and neck disability index decreased similarly with both treatments when compared to baseline (111471).
• Notalgia paresthetica. Preliminary clinical research in a small number of patients with notalgia paresthetica shows that applying a product containing bee venom 0.04% and capsaicin 0.025% to the affected skin daily for 2 weeks reduces pruritus when compared to baseline (102530). A lack of control group limits the validity of these findings. Also, it is unclear if the effects are due to bee venom, capsaicin, or the combination.
• Osteoarthritis. Preliminary clinical research on the use of injected bee venom for the treatment of osteoarthritis is mixed (6045). However, a high-quality clinical trial in patients with osteoarthritis of the knee shows that injecting bee venom 100 mcg intradermally at 15 acupuncture points on the knees and back weekly for 12 weeks reduces knee pain and increases physical function scores when compared with a histamine control injection (102531).
• Parkinson disease. Data on the effect of bee venom in patients with Parkinson disease are conflicting. Preliminary clinical studies in a small number of patients with Parkinson disease, stable on medication for at least four weeks, shows that receiving injections of dilute bee venom into 10 acupuncture points twice weekly, with or without traditional acupuncture, for 8-12 weeks improves motor symptoms, walking speed, quality of life, and ability to perform activities of daily living when compared with baseline, placebo, and/or conventional anti-Parkinson medications alone (95900,96571,102532). However, it is unclear whether bee venom acupuncture provides long-term benefits. Also, other research shows no benefit of bee venom therapy. One clinical study in patients with Parkinson disease shows that receiving a specific bee venom 100 mcg (Alyostal) injection subcutaneously once monthly for 11 months does not improve symptoms when compared with placebo. The researchers speculate that the monthly dose may have been too low to have an effect (96572). Higher quality research is needed to determine the benefits of bee venom, if any, in these patients. More evidence is needed to rate the effectiveness of bee venom for these uses.

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LIKELY EFFECTIVE

• Osteoarthritis. Oral glucosamine sulfate taken for at least 4 weeks is modestly beneficial for improving pain and function in knee osteoarthritis. However, oral glucosamine hydrochloride seems to only be beneficial when used in combination with chondroitin and other ingredients. It is unclear if glucosamine can slow disease progression or improve symptoms in other forms of osteoarthritis. Details: Meta-analyses of the available research in adults with KNEE osteoarthritis show that taking glucosamine SULFATE 1500 mg daily for up to 3 years modestly improves pain, function, and joint space narrowing when compared with placebo (14305,89521,94382,95785,99684,113636). Individual studies show 28% to 41% pain reduction and 21% to 46% improvement in function when compared with placebo (7026,8942,12461,20084,94382). Some research suggests that glucosamine sulfate reduces pain similarly to various non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen 400 mg three times daily and piroxicam 20 mg daily. However, NSAIDs appear to relieve symptoms within 2 weeks, while glucosamine sulfate takes 4-8 weeks. Notably, glucosamine sulfate appears to sustain benefit for longer after treatment withdrawal when compared with piroxicam (2604,20094,20096). Other clinical research shows that glucosamine sulfate 1500 mg once daily for 6 months might be more effective for reducing symptoms than acetaminophen 1 gram three times daily or 650 mg once daily in patients with moderate knee osteoarthritis (13578,20098). However, not all research shows benefit. One meta-analysis of clinical studies in adults with knee osteoarthritis shows that taking glucosamine sulfate 1500 mg daily for 4 weeks to 3 years reduces some, but not all, measures of pain intensity and does not reduce pain when moving or improve function when compared with placebo (113636). Furthermore, small clinical studies suggest that glucosamine sulfate 1500 mg daily for 2-6 months may NOT work for severe, long-standing osteoarthritis (1330,11459). It is unclear if glucosamine sulfate can slow disease progression. A specific crystalline glucosamine sulfate product (Dona, Rotta Pharmaceuticals) taken as 1500 mg daily for up to 3 years seems to prevent joint space narrowing of greater than 0.5 mm by up to 54% when compared with placebo (7026,8942,13719,42420). In contrast, other glucosamine sulfate formulations have not consistently been shown to improve symptoms or prevent joint space narrowing when compared with placebo (14305,89558,94382,95788). It is unclear if the benefit seen with this specific product (Dona) is due to bias introduced by industry funding or due to a higher quality product (42492). Glucosamine products associated with quality concerns have demonstrated inconsistent benefits in research (8128,102116). Limited research on the use of a different salt, glucosamine HYDROCHLORIDE, has found no benefit for knee osteoarthritis. A meta-analysis of clinical research and two other clinical trials show that taking glucosamine hydrochloride 1500 mg daily for up to 18 months does not seem to reduce pain when compared with placebo (18344,89519,89521). However, one small, unblinded clinical study in patients with mild to moderate osteoarthritis shows that taking a combination of glucosamine hydrochloride 480 mg every 12 hours and celecoxib 200 mg daily reduces pain scores, osteoarthritis severity, and inflammatory markers to a greater extent than celecoxib alone (106883). There is mixed evidence of benefit when glucosamine hydrochloride is used with chondroitin. Clinical research in patients over 40 years of age shows that taking a noncommercial preparation of glucosamine hydrochloride 1500 mg daily in combination with chondroitin sulfate 1200 mg daily for 6-24 months does not reduce pain when compared with placebo. The placebo response in these studies was sometimes as high as 60% (13579,14809,42477). However, a large, prospective observational study in adults with knee or hip osteoarthritis suggests that taking glucosamine hydrochloride 500 mg and chondroitin sulfate 400 mg (Theraflex, Bayer) three times daily for the first 3 weeks then twice daily thereafter for up to 64 weeks is associated with reductions in pain, stiffness, and the need for concomitant analgesic therapy and improvements in daily function and knee- or hip-related quality of life when compared to baseline. The most pronounced improvements were from 16-24 weeks (111647). The validity of these effects is limited by subjective outcomes, a lack of control group, and the observational design of the study. Furthermore, another clinical trial shows that taking a prescription product available in Spain (Droglican, Bioibérica S.A.), providing a similar daily dose of glucosamine hydrochloride with chondroitin sulfate for 6 months is non-inferior to celecoxib 200 mg daily for relieving pain, but not stiffness or function (89516). Small clinical studies show that taking a specific combination product (Cosamin or Cosamin DS, Nutramax Laboratories) containing glucosamine hydrochloride 1500-2000 mg, low molecular weight chondroitin sulfate 1200-1600 mg, and manganese ascorbate 228-304 mg, in 2-3 divided doses daily for 2-6 months improves pain in patients with mild or moderate, but not severe, osteoarthritis when compared with placebo (4237,7169). A different combination product (Gurukosamin & Kondoroichin, Suntory Wellness Ltd.) containing glucosamine hydrochloride 1200 mg, chondroitin sulfate 60 mg, and quercetin glycosides 45 mg, taken daily for 16 weeks, also seems to improve symptoms of knee osteoarthritis when compared with placebo (42514). It is unclear if the findings of any of these studies are due to glucosamine, chondroitin, other ingredients, or the combination. Despite evidence suggesting differing benefit (89521,94382), head-to-head comparisons of glucosamine sulfate and glucosamine hydrochloride are limited, and it is not universally acknowledged that these salts have different effectiveness profiles. One large clinical study in patients with knee osteoarthritis shows that taking a specific product (Artrolive, Aché Laboratórios Farmacêuticos S.A.) containing glucosamine sulfate 500 mg and chondroitin sulfate 400 mg three times daily for 4 months seems to be no different for reducing pain when compared with taking glucosamine hydrochloride 500 mg and chondroitin sulfate 400 mg (Cosamin DS, Nutramax Laboratories, Inc.) three times daily (89520). This study was funded by the supplement manufacturer. Many meta-analyses have pooled studies of both glucosamine salts together, producing largely inconsistent results (94381,99683,99685,112444). Experts have conflicting stances on the use of glucosamine. The American College of Rheumatology (ACR) strongly recommends against the use of any glucosamine products for any form of osteoarthritis (102114). Conversely, the European Society of Clinical and Economic Aspects of Osteoarthritis (ESCEO) strongly recommends the use of pharmaceutical-grade glucosamine sulfate products, such as Dona (Rotta Pharmaceuticals), in patients with osteoarthritis. Additionally, the ESCEO provides a weak recommendation against the use of glucosamine in combination with chondroitin (102141). These differing recommendations seem to be related to interpretation of the evidence for pharmaceutical-grade products. The ACR has determined that the inconsistent evidence may indicate the presence of industry bias; the ESCEO has determined that the inconsistent evidence is due to inconsistent product quality. Limited research has found mixed benefit of using glucosamine on osteoarthritis of the SPINE, HIP, or HAND. In one study of patients with osteoarthritis of the lumbar spine, taking glucosamine sulfate (Dona, Rotta Pharmaceuticals) 1500 mg daily for 6 weeks reduced pain in more patients when compared with placebo (1316). However, in another study, using a different glucosamine sulfate product (Glucosamine Sulfate, PharmaNord) 1500 mg daily for 6 months did not reduce pain when compared with placebo (89562). In patients with hip osteoarthritis, taking glucosamine sulfate 1500 mg once daily for 2 years did not reduce symptoms or slow disease progression when compared with placebo (16717,20100); however, there was a high rate of hip replacement, which may have confounded results (16717,16718). In patients with erosive osteoarthritis of the hand, observational research has found that taking glucosamine sulfate (Dona, Rotta Pharmaceuticals) 1500 mg daily along with conventional therapy for 6 months is associated with reduced hand pain, a shorter duration of morning stiffness, and improved hand function when compared with conventional therapy alone (108897). Limited research has also evaluated INTRAMUSCULAR and TOPICAL glucosamine sulfate. A clinical study in patients with mild to moderate knee osteoarthritis (radiological stage I-III) shows that giving intramuscular glucosamine sulfate 400 mg twice per week for 6 weeks reduces the severity of symptoms when compared with placebo (2605). There is also a small study showing that a topical preparation of glucosamine sulfate in combination with chondroitin sulfate, shark cartilage, and camphor reduces osteoarthritis symptoms when compared with placebo. However, any symptom relief is most likely due to the counterirritant effect of camphor and not the other ingredients (10327,12467). There is no evidence that glucosamine is absorbed topically. Glucosamine sulfate does not seem to PREVENT osteoarthritis. Clinical studies in overweight healthy females aged 50-60 years shows that taking crystalline glucosamine sulfate 1500 mg orally daily for 2.5 years does not reduce the incidence of osteoarthritis after a 6-7 year follow-up; however, it may reduce the percentage of patients who experience knee joint space narrowing (95789,97053).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Topical N-acetyl glucosamine has only been evaluated in combination with niacinamide for reducing hyperpigmentation and liver skin spots on aging skin; its effect when used alone is unclear. Details: A clinical study in females ages 40-60 years with skin hyperpigmentation and solar lentigines (liver spots) primarily due to aging and sun exposure shows that applying a cream containing 2% N-acetyl glucosamine and 4% niacinamide to the face twice daily with sunscreen for 10 weeks decreases facial hyperpigmentation when compared with sunscreen alone (92721). The effect of N-acetyl glucosamine alone is unclear.
• Aromatase inhibitor-induced arthralgia. Oral glucosamine sulfate has only been evaluated in combination with chondroitin; its effect when used alone is unclear. Details: A small open-label clinical study in patients with aromatase inhibitor-induced arthralgia shows that taking a combination of glucosamine sulfate 1500 mg and chondroitin sulfate 1200 mg in 2-3 divided doses daily for 24 weeks improves pain when compared to baseline in postmenopausal adults with early stage breast cancer (89561). The validity of this finding is limited by a lack of control group.
• Back pain. Although there is interest in using oral glucosamine for back pain, there is insufficient reliable information about the clinical effects of glucosamine for this condition.
• Cancer. Some low-quality observational studies have inconsistently found that glucosamine may be associated with a lower risk of different cancers; however, better quality evidence is needed. Details: A meta-analysis of observational research has found that use of glucosamine with or without chondroitin is associated with a 7% to 12% lower risk of cancer when compared with no use of glucosamine. A subgroup analysis showed a reduction in the risk of colorectal cancer, but not other types of cancer (110625). Observational research report conflicting relationships between glucosamine and cancer. Some observational research in adults in the United Kingdom has found that taking glucosamine is associated with 4% higher risk of cancer over a median follow up for 13 years. However, a subgroup analysis showed a reduction in the risk of lung cancer (110627). Other observational research in adults in the United Kingdom has found that taking glucosamine is associated with a 5% reduced risk of cancer mortality over a median follow-up of around 12 years, with reductions specifically occurring in those with kidney, lung, and rectal cancers. However, glucosamine use was not linked to a reduced risk of mortality due to bladder, brain, breast, colon, ovarian, prostate, skin, stomach, thyroid, or uterine cancer (109645). Other large, propensity-score-adjusted, observational research in adults with osteoarthritis in the United Kingdom suggests that treatment with glucosamine, with an average of 8 years of follow-up, is not associated with a reduction in cancer, including lung, colorectal, breast, or prostate cancer, when compared with patients not prescribed glucosamine (114571). These studies are limited by observational designs, which also did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Although some studies attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and the risk for cancer and/or cancer-related mortality. Of note, some researchers have called into question the results from observational research linking glucosamine use to a lower rate of cancer, claiming that these studies suffer from a high risk of selection bias (109646).
• Cardiovascular disease (CVD). It is unclear if oral glucosamine prevents fatal or non-fatal CVD events. Details: Some observational research of adults in the United Kingdom has found that taking glucosamine is associated with an overall 15% reduced risk for fatal and non-fatal CVD events, including coronary heart disease (CHD) and stroke (99682). However, this study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Conversely, an observational study in Chinese patients with osteoarthritis has found that glucosamine use is associated with a 10% increase in the risk of CVD events and a 12% increase in the risk of CHD, with no increase in the risk of stroke. The risk for these outcomes was greatest in patients with higher adherence to glucosamine and in those taking larger doses (109642). However, this study also did not clarify the form of glucosamine used or provide specifics related to the frequency or duration of use. Furthermore, glucosamine users were generally older, more likely to be on antihyperlipidemic or antiplatelet therapy, and more likely to have multiple comorbidities compared with non-users. Both studies attempted to control for the differences in characteristics between glucosamine users and non-users; despite this, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and CVD risk.
• Colorectal adenoma. Oral glucosamine has only been evaluated in combination with chondroitin; its effect when used alone is unclear. Details: An observational study in older adults has found that taking glucosamine and chondroitin is associated with a 26% reduced risk of high-risk adenoma and 10% reduced risk of conventional adenoma when compared with not using these supplements. This benefit was not seen in a subgroup of younger females (104444). This study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use.
• Colorectal cancer. It is unclear if oral glucosamine reduces the risk of colorectal cancer. Details: A meta-analysis of observational research has found that use of glucosamine with or without chondroitin is associated with a 7% to 12% lower risk of cancer when compared with no use of glucosamine. A subgroup analysis showed a reduction in the risk of colorectal cancer, but not other types of cancer (110625). However, not all research agrees. A large, observational study in adults has found that regular use of oral glucosamine is not associated with a reduced risk of colorectal cancer over a median of 7 years of follow-up, regardless of sex, age, body mass index, smoking status, or non-steroidal anti-inflammatory drug use (108018). Other large, propensity-score-adjusted, observational research in adults with osteoarthritis in the United Kingdom suggests that treatment with glucosamine, with an average of 8 years of follow-up, is not associated with a reduction in cancer, including colorectal cancer, when compared with patients not prescribed glucosamine (114571).These studies did not clarify the form or dose of glucosamine used or the frequency or duration of use.
• Coronavirus disease 2019 (COVID-19). It is unclear if oral glucosamine is beneficial for COVID-19. Details: A large observational study in adults suggests that regular glucosamine use over a median of 1.7 years is not linked to a lower odds of COVID-19 infection but is associated with a 20% lower risk of hospital admission and a 19% lower risk of mortality due to COVID-19 when compared with adults not using glucosamine (111649). This study did not clarify the form or dose of glucosamine used or the frequency or duration of use.
• Dementia. Observational studies suggest that long-term, regular glucosamine intake might reduce the risk of developing certain types of dementia. Details: An observational study has found that regularly taking glucosamine for an average of 8.9 years is associated with a 19% lower risk of developing dementia, including Alzheimer disease and vascular dementia (110630). Another large observational study in older adults without dementia suggests that regularly taking glucosamine for a median of 12 years is associated with an 18% lower risk of vascular dementia. However, habitual glucosamine consumption is not associated with a reduced risk of Alzheimer disease or frontotemporal dementia (112461).
• Depression. It is unclear if oral glucosamine hydrochloride reduces depression symptoms. Details: A small, open-label clinical trial in patients with unipolar depression shows that taking glucosamine hydrochloride 1 gram daily for 1 week, followed by 2 grams daily for 3 weeks, reduces scores on the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) by 31% or 33% when compared to baseline. However, only 20% of patients experienced a 50% or greater reduction in HAM-D scores, and there were no improvements in Clinical Global Impression scores (103281). The lack of a control group limits the validity of these findings.
• Diabetes. It is unclear if oral glucosamine reduces the risk of developing type 2 diabetes in adults. Details: Observational research in adults in the United Kingdom has found that glucosamine use is associated with a 17% lower risk of type 2 diabetes. The relationship between glucosamine use and diabetes appears to be even more pronounced in patients with high baseline levels of C-reactive protein, a marker of inflammation (103234). However, this study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Although this study attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and the risk for diabetes.
• Gout. It is unclear if oral glucosamine reduces the risk of developing gout. Details: Observational research in adults in the United Kingdom has found that glucosamine use is associated with a 19% lower risk of gout in females, but not males (109644). However, this study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. Although this study attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and the risk for gout.
• Heart failure. It is unclear if oral glucosamine prevents heart failure. Details: A large, prospective observational study in adults without heart failure suggests that taking glucosamine regularly over a median of 9 years is associated with a 13% lower risk of developing heart failure when compared with adults not taking glucosamine (111646). This study did not clarify the form or dose of glucosamine used or the frequency or duration of use.
• Hyperlipidemia. It is unclear if oral glucosamine hydrochloride improves hyperlipidemia when used with conventional medicine. Details: Preliminary clinical research shows that glucosamine hydrochloride does not reduce cholesterol or triglyceride levels in patients with hyperlipidemia. A small crossover study in older adults taking simvastatin or atorvastatin shows that adding a specific glucosamine hydrochloride product (Artrox, Pfizer) 750 mg twice daily for 4 weeks does not seem to affect lipid levels when compared with placebo (18341).
• Inflammatory bowel disease (IBD). It is unclear if oral or rectal N-acetyl glucosamine improves symptoms of IBD in children. Details: A very small clinical study in children ages 8-17 years with Crohn disease or ulcerative colitis that were unresponsive to conventional treatment suggests that oral or rectal N-acetyl glucosamine 1.5-2 grams in 10 mL water twice daily for 6 weeks might decrease symptoms of IBD when compared with baseline (10234). The validity of this finding is limited by a lack of control group.
• Interstitial cystitis. Oral glucosamine sulfate has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: An open-label clinical study in patients with interstitial cystitis shows that taking a specific product (CystoProtek, Tischon Corporation) containing glucosamine sulfate 120 mg, sodium hyaluronate 10 mg, chondroitin sulfate 150 mg, quercetin 150 mg, and rutin 20 mg per capsule, as two capsules twice daily for 12 months, reduces symptom severity by up to 52% when compared with baseline (42391). The validity of this finding is limited by a lack of control group.
• Joint pain. Oral glucosamine has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with joint pain shows that taking capsules of a specific combination product (Instaflex Joint Support, Direct Digital) containing glucosamine sulfate 1500 mg, methylsulfonylmethane 500 mg, white willow bark extract 250 mg, ginger root concentrate 50 mg, Boswellia serrata extract 125 mg, turmeric root extract 50 mg, cayenne 40 m H.U. 50 mg, and hyaluronic acid 4 mg, daily in three divided doses for 8 weeks, reduces joint pain severity by 37% compared to only 16% with placebo. However, the specific combination product does not appear to improve joint stiffness or function compared with placebo (89560).
• Kashin-Beck Disease. It is unclear if oral glucosamine hydrochloride improves Kashin-Beck Disease symptoms such as pain. Details: A small clinical study in Chinese adults with Kashin-Beck Disease shows that taking glucosamine hydrochloride 480 mg three times daily along with chondroitin sulfate 600 mg twice daily for 6 months decreases pain scores by at least 20% to 50% in more patients when compared with placebo. Taking glucosamine alone had a non-significant trend toward pain reduction in these patients (42516). An open-label study in Chinese adults with Kashin-Beck Disease shows that taking glucosamine hydrochloride 750 mg twice daily for 6 weeks seems to be no different for improving pain and physical function when compared with taking to diclofenac 50 mg twice daily or naproxen 300 mg twice daily (18339). The validity of this finding is limited by a lack of blinding.
• Kidney stones (nephrolithiasis). Oral glucosamine might reduce the risk of developing kidney stones. Details: A large observational study in adults without kidney stones suggests that regularly taking glucosamine is associated with a 28% lower risk of new-onset kidney stones in people with a total sedentary time under 3.5 hours daily. This association follows a dose-dependent relationship. However, regular glucosamine use does not seem to reduce the risk of new-onset kidney stones in people with total sedentary time exceeding 3.5 hours daily (112451).
• Knee pain. Small clinical studies suggest that oral glucosamine hydrochloride might improve exercise-induced knee pain and chronic knee pain. However, it is unclear if glucosamine sulfate, N-acetyl glucosamine, or lower doses of glucosamine hydrochloride are beneficial in these patients. Details: A small clinical study in athletes following an acute knee injury shows that taking glucosamine sulfate 500 mg three times daily for 28 days does not improve pain but might modestly improve mobility when compared with placebo (20103). Glucosamine has also been evaluated for chronic knee pain. A small clinical study in patients with chronic knee pain of unclear origin shows that taking glucosamine hydrochloride 2000 mg daily for 12 weeks might modestly improve pain when compared with placebo (10312). However, lower doses of glucosamine hydrochloride and N-acetyl glucosamine used in combination with other ingredients have not demonstrated benefit for chronic knee pain. A small clinical trial in Japanese adults over 40 with knee pain shows that taking a combination supplement with glucosamine hydrochloride and other ingredients for 16 weeks does not improve pain, function, or walking speed when compared with placebo. The combination supplement provided glucosamine hydrochloride 1200 mg, chondroitin sulfate 60 mg, type II collagen peptides 45 mg, quercetin glycosides 90 mg, imidazole peptides 10 mg, and vitamin D 200 IU daily (95784). Another small clinical study in Japanese patients over 50 years of age with chronic knee pain shows that taking a specific supplement (Walker's Glucosamine, Kyowa) containing N-acetyl glucosamine 100 mg and chondroitin sulfate 180 mg daily for 24 weeks does not reduce pain or improve knee function when compared with placebo (95795).
• Metabolic dysfunction-associated steatotic liver disease (MASLD). It is unclear if oral glucosamine is beneficial in patients with MASLD. Details: Observational research in adults with MASLD and type 2 diabetes suggests that regular use of glucosamine orally for an average follow up of 11 years is associated with a lower risk of adverse liver outcomes when compared with those not regularly using glucosamine. Non-users of glucosamine had 35% to 44% higher risk of cirrhosis, encephalopathy, and esophageal varices. This study did not report the glucosamine dose or frequency (114573).
• Multiple sclerosis (MS). It is unclear if oral glucosamine sulfate is beneficial in patients with MS. Details: A small clinical study in patients with MS shows that taking glucosamine sulfate 1000 mg once daily for 6 months modestly reduces relapse when compared to baseline, but not when compared with placebo (20104).
• Overall mortality. It is unclear if oral glucosamine reduces overall mortality. Details: An observational study in the United States has found that regular use of oral glucosamine, with or without chondroitin, for an average of 8 years is associated with a 30% lower risk of mortality when compared with no glucosamine use. However, when adjusted for covariates such as age, body-mass index, and comorbidities, there was no difference in overall mortality (110626). In contrast, a cross-sectional observational study has found that using oral glucosamine and chondroitin for at least one year is associated with 27% reduced incidence of overall mortality and 58% reduced incidence of cardiovascular mortality when compared with not using these supplements (104445). This study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine and chondroitin use also reported overall healthier lifestyle habits than those that were not taking glucosamine and chondroitin. Although this study attempted to control for these differences, higher quality, prospective research is needed to clarify the relationship, if any, with overall mortality. Of note, some researchers have called into question the results from observational research linking glucosamine use to a lower rate of overall mortality, claiming that these studies suffer from a high risk of selection bias (109646).
• Postoperative recovery. It is unclear if oral glucosamine sulfate improves recovery after surgery. Details: A small clinical study in male athletes who have undergone anterior cruciate ligament (ACL) reconstruction shows that taking glucosamine sulfate (Solgar Inc.) 1000 mg daily for 8 weeks does not improve rehabilitation outcomes such as functional ability, pain, and muscular performance when compared with placebo (95584).
• Rheumatoid arthritis (RA). It is unclear if oral glucosamine hydrochloride is beneficial in patients with RA. Details: A small clinical study in patients with RA shows that taking glucosamine hydrochloride tablets (Rohto Pharmaceutical Co.) 500 mg three times daily by mouth for 12 weeks reduces pain, but not the number of painful or swollen joints, when compared with placebo (17407).
• Stroke. It is unclear if oral glucosamine is beneficial for reducing stroke risk. Details: An observational cohort study of adults in the United Kingdom found that taking glucosamine is associated with a modest 9% reduced risk for overall stroke; however, sub-analyses show that glucosamine use is not associated with a reduced risk for fatal or non-fatal stroke, hemorrhagic stroke, or ischemic stroke (99682). This study did not clarify the form of glucosamine used, or the dose, frequency, or duration of use. Furthermore, the adults that reported glucosamine use also reported overall healthier lifestyle habits than those that were not taking glucosamine. A case-control study in Spanish patients found that glucosamine use is associated with 45% lower odds of ischemic stroke when compared with non-use; however, the benefit was only observed in patients taking glucosamine for 1 year or less (109643). This study did not clarify the form of glucosamine used or the dose or frequency of use. Furthermore, patients in the control group were generally healthier and less likely to have a history of cardiovascular disease, diabetes, or hyperlipidemia. Although both studies attempted to control for differences between patient populations, higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and stroke risk.
• Temporomandibular disorders (TMD). It is unclear if oral glucosamine sulfate is beneficial in patients with temporomandibular joint osteoarthritis. Details: A small and low-quality clinical study in patients with temporomandibular joint osteoarthritis shows that taking glucosamine sulfate 500 mg three times daily for 90 days seems to be no different than taking ibuprofen 400 mg three times daily for relieving pain and improving functional abilities such as chewing, yawning, talking, and laughing (3714). However, another small clinical study in patients with the same condition shows that taking glucosamine sulfate 1200 mg daily for 6 weeks does not improve pain or jaw opening capacity when compared with placebo (20105). Glucosamine sulfate has also been evaluated in combination with chondroitin for this condition. A meta-analysis of two small clinical studies in patients with TMD shows that taking glucosamine sulfate 1500 mg and chondroitin sulfate 1200 mg daily for 2 months does not reduce pain or increase maximum mouth opening when compared with tramadol 50-100 mg daily (109647). Other meta-analyses have reported similar results, however, these analyses may have been inadequately powered to detect a difference between groups (114572). Another small clinical trial in children aged 10-13 years with class II malocclusion shows that application of a specific combination gel product containing glucosamine, chondroitin, and essential oils (Jointace Gel, Vitabiotics) with an expander device, twice daily for 3 months does not improve temporomandibular space measures or pain or tension scores, when compared with placebo (110629).
• Wound healing. Although there is interest in using topical glucosamine for wound healing, there is insufficient reliable information about the clinical effects of glucosamine for this condition. More evidence is needed to rate glucosamine for these uses.

(Read more about GLUCOSAMINE)

LIKELY SAFE ...when FDA-approved purified bee venom is given by subcutaneous injection by a trained medical professional (2619,6070,96572).

POSSIBLY SAFE ...when applied using stings from live bees. Live bee stings have been safely administered under medical supervision in doses up to 20 bee stings three times weekly for up to 24 weeks (13222). There is insufficient reliable information available about the safety of bee venom when used topically or injected in combination with acupuncture.

PREGNANCY AND LACTATION: POSSIBLY SAFE
when used by subcutaneous injection by a trained medical professional. Significant adverse effects to fetus or mother have not been reported. However, some clinicians decrease maintenance dose by half during pregnancy (2619).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used by subcutaneous injection in high doses. High doses of bee venom can increase release of histamine, which can cause uterine contraction (2619); avoid using in high doses.

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LIKELY SAFE ...when glucosamine sulfate is used orally and appropriately. Glucosamine sulfate has been used safely in multiple clinical trials at a dose of 1000-1500 mg daily for 4 weeks to 3 years (2604,7026,8942,11340,12461)(14305,16717,89558,89567,94380,94382,95785).

POSSIBLY SAFE ...when glucosamine hydrochloride is used orally and appropriately. Glucosamine hydrochloride has been used with apparent safety at a dose of 1400-1600 mg daily for up to 2 years (4237,13579,14809,18344,42477,89516,89519,95784). Glucosamine hydrochloride 2 grams daily has also been used with apparent safety for up to 3 weeks (103281). ...when N-acetyl glucosamine is used orally and appropriately. N-acetyl glucosamine 100 mg daily has been used with apparent safety for up to 24 weeks (95795). ...when N-acetyl glucosamine is applied topically and appropriately. A 2% N-acetyl glucosamine cream has been safely used for up to 10 weeks (92721). ...when N-acetyl glucosamine is used rectally and appropriately. N-acetyl glucosamine 3-4 grams daily in 2 divided doses has been safely used (10234). ...when glucosamine sulfate is used intramuscularly and appropriately, short-term. Intramuscular glucosamine sulfate seems to be well tolerated when given twice weekly for up to 6 weeks (2605).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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ACETAMINOPHEN (Tylenol, others) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Possible •  Level of Evidence = B Acetaminophen might interfere with the activity of glucosamine sulfate by interacting with the sulfate portion.  Details Anecdotal reports suggest that adding glucosamine to an acetaminophen regimen might decrease pain control in patients with osteoarthritis (14806). Some research suggests that the sulfate portion of glucosamine sulfate might contribute to its effect in osteoarthritis. Since acetaminophen metabolism requires sulfur and reduces serum sulfate concentrations, acetaminophen could theoretically interfere with the action of glucosamine sulfate. Conversely, the administration of sulfate could theoretically decrease the effectiveness of acetaminophen in sulfate-deficient people by increasing its clearance (10313).

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Despite initial concerns, it is unlikely that glucosamine will interfere with the effects of antidiabetes drugs.  Details In vitro and animal research has suggested that glucosamine might increase insulin resistance or decrease insulin production (371,372,3406,18342,18343). This has raised concerns that taking glucosamine might worsen diabetes and decrease the effectiveness of diabetes drugs. However, clinical research suggests that glucosamine does not have adverse effects on blood glucose or glycated hemoglobin (HbA1C) in healthy, obese, or type 2 diabetes patients (7026,7075,8942,10311,10317,15111).

TOPOISOMERASE II INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically glucosamine may induce resistance to topoisomerase II inhibitors.  Details In vitro research suggests that glucosamine might induce resistance to etoposide (VP16, VePesid) and doxorubicin (Adriamycin) by reducing inhibition of topoisomerase II, an enzyme required for DNA replication in tumor cells (7639). This effect has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Glucosamine might increase the anticoagulant effects of warfarin and increase the risk of bruising and bleeding.  Details In two individual case reports, glucosamine/chondroitin combinations were associated with a significant increase in international normalized ratio (INR) in patients previously stabilized on warfarin (11389,16130). In one case, the increase in INR occurred only after tripling the dose of a glucosamine/chondroitin supplement from 500 mg/400 mg daily to 1500/1200 mg daily (16130). Additionally, 20 voluntary case reports to the U.S. Food & Drug Administration (FDA) have linked glucosamine plus chondroitin with increased INR, bruising, and bleeding in patients who were also taking warfarin (16130). There have also been 20 additional case reports to the World Health Organization (WHO) that link glucosamine alone to increased INR in patients taking warfarin (16131). The mechanism of this interaction is unclear. Glucosamine is a small component of heparin, but is not thought to have anticoagulant activity; however, animal research suggests that it might have antiplatelet activity (16131).

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General ...Purified bee venom given subcutaneously by a trained medical professional is generally well tolerated when used for diagnosis or immunotherapy of bee sting allergy.
Most Common Adverse Effects:
Parenterally: Dizziness, injection site erythema, itching, nausea and vomiting, swelling, tenderness, urticaria.
Serious Adverse Effects (Rare):
Parenterally: Anaphylaxis, asthma, chest pain or tightness, coagulation abnormalities, confusion, edema, hypotension, laryngeal edema, malaise, palpitations, respiratory distress, somnolence.

Cardiovascular ...Case reports have described stroke, and bradycardia associated with bee venom therapy (96576). Other reported adverse cardiovascular effects include cardiac dysfunction, palpitations, hypotension, and chest pain or tightness (1343,2619,6070,6078,111472,111474).

Dermatologic ...Local adverse effects of parenteral bee venom include erythema, swelling, numbness, pain, and tenderness at the injection site, itching, urticaria, and edema (1343,13222,102531). Bee stings have been associated with eosinophilic foreign body granuloma (111482), and bee venom acupuncture can cause dermatitis, contact urticaria, skin infection with Mycobacterium chelonae (11483), giant dermatofibroma, or chronic folliculitis (96576). A case report describes panniculitis associated with bee venom immunotherapy (96576).

Hematologic ...Bee venom therapy has been associated with coagulation abnormalities including intravascular hemolysis and thrombocytopenia (6046,96576,111474). Bee venom given with acupuncture can cause disseminated intravascular coagulation (6046,96576).

Hepatic ...Two case reports describe hepatotoxicity, including acute icteric hepatitis associated with bee venom acupuncture (96576). Another case report describes hepatitis B reactivation complicated by nephritic syndrome during bee venom immunotherapy (96576).

Immunologic ...Immune-mediated reactions associated with bee venom include rash, itching, generalized hypersensitivity reaction, anaphylaxis, serum sickness reaction, and immune thrombocytopenia 6077,95899,96576,11470). Estimates of the rate of immunologic reactions to various forms of bee venom range from 0.025% to 29% (96576,105770,11470,111475). They occur most frequently when doses are increased rapidly. Females and people with a c-KIT mutation may have more severe and frequent adverse effects (1343,6077,102533,11470). Doses of bee venom associated with adverse effects vary from 0.1 to 2 mL, and anaphylaxis has occurred after 1-24 doses (11470).
Bee venom is also associated with autoimmune disorders, including systemic lupus erythematosus, rheumatoid arthritis, Guillain-Barre syndrome, and pemphigus vulgaris (96574,111473). In a case report, a 68-year-old female developed Guillain-Barré syndrome with progressive quadriplegia ten days after receiving acupuncture with honeybee venom for pain (96573). In another case, a 64-year-old female developed pemphigus foliaceus, involving pruritic, erythematous, erosive skin lesions with crusting and plaques, after bee venom acupuncture twice weekly for 2 months. Immunoglobulin G was detected in the intercellular spaces between keratinocytes. Partial resolution occurred after 2 months of treatment with oral corticosteroids and azathioprine (111473).

Musculoskeletal ...Bee venom can cause rhabdomyolysis (111474). A 63-year-old female who received an accidental injection into the psoas muscle of 2 mL of normal saline containing bee venom diluted in a 1:2000 ratio, experienced severe burning pain at the injection site which persisted for 1 month, with imaging showing inflammation of the muscle. The pain gradually resolved over the following 5 months (11475).

Neurologic/CNS ...Bee venom can cause pain, headache, somnolence, and confusion (1343,2619,6070,6078,96576,111472). It has also been associated with a case of neuralgic amyotrophy (96576).

Pulmonary/Respiratory ...Bee venom has been associated with asthma, hyperventilation, respiratory distress, paralysis of respiratory muscles, and pulmonary or laryngeal edema (1343,2619,6070,6078,96576,111474).

Renal ...Bee venom immunotherapy has been associated with nephrotic syndrome, acute interstitial nephritis, and acute tubular necrosis (96576,111474). A case report describes a 50-year-old male with type 2 diabetes and normal renal function who developed acute kidney injury with combined features of interstitial nephritis and tubular necrosis after being stung by more than 1000 bees. He made a full recovery over several weeks with intermittent hemodialysis (111474).

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General ...Orally, all forms of glucosamine seem to be well tolerated. Topically and rectally, N-acetyl glucosamine also seems to be well tolerated. Intramuscularly, glucosamine sulfate seems to be well tolerated. However, a thorough evaluation of safety outcomes has not been conducted for non-oral routes of administration.
Most Common Adverse Effects:
Orally: Bloating, constipation, cramps, diarrhea, heartburn, nausea.
Serious Adverse Effects (Rare):
Orally: There have been rare reports of severe allergic reactions and hepatotoxicity.

Cardiovascular ...One case of mesenteric occlusion in a clinical trial was considered possibly related to use of oral glucosamine hydrochloride and chondroitin sulfate (89520).
Some observational research has found that glucosamine use in patients with osteoarthritis is associated with a higher risk of cardiovascular disease (CVD) events when compared with non-use (109642). However, glucosamine users tended to be older, have multiple comorbidities, and be on antihyperlipidemic or antiplatelet therapy. Furthermore, other observational research in healthy adults has found that glucosamine use is associated with a reduced risk of fatal and non-fatal CVD events (99682). Higher quality, prospective research is needed to clarify the relationship, if any, between glucosamine and CVD risk.

Dermatologic ...Orally, glucosamine might cause skin reactions, including itching, rash, and erythema (2608,20084,89567,110628,113636). Also, fingernail and toenail toughening, with an increased rate of growth, has been reported (89572). Topically, N-acetyl glucosamine 2% with niacinamide 4% cream might cause rare skin reactions (92721). Photosensitization that was reproducible with re-challenge was reported in a case report of an individual using glucosamine (form unknown) and chondroitin (10408).

Endocrine ...Orally, glucosamine does not seem to impact blood glucose. Preliminary research and anecdotal reports have found that various forms of glucosamine might increase insulin resistance or decrease insulin production, increasing fasting plasma glucose levels (22,371,372,1203,3406,5059,7637,14810). This has raised concerns that taking glucosamine sulfate might worsen diabetes and decrease the effectiveness of diabetes drugs. However, clinical research suggests that various forms of glucosamine do not have adverse effects on blood glucose or glycated hemoglobin (HbA1C) in healthy, obese, patients with type 2 diabetes or impaired glucose tolerance (7026,7075,7638,8942,10311,10317,12107,14808,15111,89563).

Gastrointestinal ...Orally, glucosamine has been associated with gastrointestinal problems, including epigastric and abdominal pain, cramps, heartburn, diarrhea, nausea, dyspepsia, vomiting, constipation, and flatulence (1520,2608,16717,20084,20104,20105,89561,89562,89567,89568)(108897,110628,111647,113636). In older persons, use of glucosamine sulfate is associated with oral dryness (89564). In a clinical trial, a case of Helicobacter pylori gastritis was considered probably related to the use of glucosamine hydrochloride (89516).

Hepatic ...Although relatively uncommon, combinations of glucosamine and chondroitin sulfate have been associated with acute liver injury that mimics autoimmune hepatitis. Of 151 patients at an outpatient clinic for liver diseases, 23 acknowledged use of products containing glucosamine (form unspecified) and/or chondroitin. However, only 2 cases had an apparent relationship between transaminase elevation and the use of recommended doses of glucosamine and chondroitin sulfate. Aminotransferase levels, which were increased by four- to seven-fold, returned to normal following discontinuation of treatment (89515). In another case, a 65-year-old male presented to the hospital with signs and symptoms of drug-induced autoimmune hepatitis. The patient had used Condrosulf, containing chondroitin sulfate, for two years, followed by Vita Mobility Complex, containing chondroitin sulfate and glucosamine sulfate, for 8 weeks. The patient required maintenance treatment with azathioprine to remain in remission (89518). A case of acute cholestatic hepatitis due to Glucosamine Forte, which contains glucosamine hydrochloride, chondroitin sulfate, Devil's claw, and shark cartilage, has been reported (89522). It is unclear whether these adverse events were related to glucosamine, other ingredients, or the combination.

Immunologic ...There is some concern that glucosamine products might cause allergic reactions in sensitive individuals. One review of glucosamine-related adverse events in Australia found that 72% of all reports involved hypersensitivity reactions. Of these reactions, 35% were mild, including pruritis, urticaria, and lip edema, 49% were moderate, including dyspnea, and 16% were severe, including gait disturbance, somnolence, and hypotension. Anaphylaxis was reported in 1.5% of cases (102115). Also, in one clinical trial, a single patient developed allergic dermatitis considered to be likely due to glucosamine hydrochloride (89516). Glucosamine is derived from the exoskeletons of shrimp, lobster, and crabs. However, it is unclear if these adverse reactions were due to a shellfish sensitivity or general atopy. Additionally, shellfish allergies are caused by IgE antibodies to antigens in the meat of shellfish, not to antigens in the exoskeleton. Regardless, it is possible that some glucosamine products might be contaminated by this allergen during production (102115).

Neurologic/CNS ...Orally, glucosamine has been reported to cause drowsiness and headache (2608,89561,113636). Glucosamine plus chondroitin combination products that also contain manganese (e.g., CosaminDS) should always be taken according to product directions. When taken at doses slightly higher than the recommended dose, these products can sometimes supply greater than the tolerable upper limit (UL) for manganese which is 11 mg/day. Ingestion of more than 11 mg/day of manganese might cause significant central nervous system toxicity (7135).

Ocular/Otic ...In older persons, use of glucosamine sulfate has been associated with ocular dryness (89564). Increased intraocular pressure has occurred with glucosamine sulfate supplementation (89573,112460). Data from the FDA MedWatch adverse event reporting system shows that 0.21% of subjects taking glucosamine reported glaucoma, which is significantly greater than the 0.08% of subjects who reported glaucoma while using any other drug (112460).

Pulmonary/Respiratory ...Cases of asthma exacerbations associated with the use of glucosamine (form unknown)-chondroitin products have been reported (10002).

Renal ...Anecdotal reports have associated glucosamine with nephrotoxicity signals such as modestly elevated creatine phosphokinase and 1+ to 2+ proteinuria, but changes in kidney function have not been reported in long-term studies (7026,8942,10408,10409). It was also noted that effects may have been due to other concurrent medications or impurities in glucosamine-chondroitin products. Cases of acute interstitial nephritis induced by glucosamine (form unknown) have also been reported (89523).

Other ...There has been concern that glucosamine might increase the risk of metabolic disturbances resulting in increased cholesterol levels and blood pressure. However, glucosamine does not appear to increase the risk of these adverse effects. Taking glucosamine sulfate for up to 3 years does not significantly increase blood glucose or lipid levels, or cause any other disturbances in metabolism (7026,7075,8942,10311,10317).

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