RF Plus by Integrative Therapeutics

Allergic rhinitis (hay fever). Although there has been interest in using oral bromelain for allergic rhinitis, there is insufficient reliable information about the clinical effects of bromelain for this condition.
Aromatase inhibitor-induced arthralgia. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with aromatase inhibitor-induced arthralgia shows that taking a specific combination product (Opera, Gam Farma), providing bromelain 20 mg, alpha-lipoic acid 240 mg, Boswellia serrata 40 mg, and methylsulfonylmethane 200 mg, daily for 6 months reduces arthralgia symptoms when compared to baseline (109570). The validity of these findings is limited by a lack of placebo control group. Further, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
Burns. Preliminary clinical research shows that topical bromelain is beneficial for burn debridement. It is unclear if topical bromelain is beneficial for scar prevention. Details: Preliminary clinical research and chart reviews show that gels formulated with proteolytic enzymes derived from bromelain (Debridase or NexoBrid, MediWound Ltd.), applied under an occlusive dressing for 4 hours, help debride burns, including chemical and electrical burns, in children and adults (18275,91113,103297,108149). However, only one of these studies compared the bromelain-based enzymatic debridement product to standard of care. In this study, which included surgical excision or non-surgical debridement, bromelain-derived gel decreased the time to complete debridement by 6.5 days, reduced the risk of surgical excision by 65%, and reduced the risk for autografts by 48%. However, in the long-term, there appeared to be no difference in quality of life or scarring between groups (91113).
Cancer. Although there has been interest in using oral bromelain for cancer, there is insufficient reliable information about the clinical effects of bromelain for this condition.
Chemotherapy-induced peripheral neuropathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with chemotherapy-induced peripheral neuropathy shows that taking a specific product (Opera, Gamfarma s.r.l.) containing bromelain 20 mg, alpha-lipoic acid 240 mg, methylsulfonylmethane (MSM) 200 mg, and boswellia 40 mg daily for 12 weeks reduces overall pain when compared with baseline (96449). The validity of these findings is limited by the lack of a control group. Additionally, it is not clear if benefit is due to alpha-lipoic acid, the other ingredients, or the combination.
Diabetes. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with a family history of type 1 diabetes found that taking a specific product (Mucos Pharma) containing bromelain 90 mg. rutin 100 mg, and trypsin 48 mg daily for 24 months is not associated with reduced incidence of type 1 diabetes at 8 years (99472).
Diabetic foot ulcers. Although there has been interest in using topical bromelain for diabetic foot ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
Exercise-induced muscle soreness. It is unclear if oral bromelain is beneficial for preventing exercise-induced muscle soreness. Details: One small clinical study shows that taking bromelain 300 mg three times daily, immediately following an intense exercise regimen, does not reduce delayed onset muscle soreness and has no effect on pain, flexibility, or skeletal weakness when compared with either ibuprofen 400 mg three times daily or placebo (10622). However, a small clinical study shows that taking a combination protease tablet containing bromelain 50 mg, trypsin 75 mg, papain 50 mg, amylase 10 mg, lipase 10 mg, lysosome 10 mg, and chymotrypsin 2 mg, four times in one day before downhill running, can improve recovery of contractile muscle function and decrease muscle soreness when compared with placebo (67838). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
Exercise-induced respiratory infections. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in non-elite male runners shows that taking a combination product (Wobenzym Plus, Mucos Pharma) providing bromelain 540-1080 mg, rutin 600-1200 mg, and trypsin 288-576 mg daily for 3 weeks, starting one week before a marathon, does not reduce the risk of a post-race respiratory tract infection when compared with placebo (96766).
Kidney stones (nephrolithiasis). It is unclear if oral bromelain is beneficial for kidney stone expulsion. Details: Observational research in patients with 4-10 mm kidney stones found that adding bromelain to tamsulosin is associated with a 12% increased rate of spontaneous stone expulsion when compared to tamsulosin alone (100752).
Knee pain. It is unclear if oral bromelain is beneficial for knee pain. Details: Preliminary clinical research shows that taking bromelain (Bromelin, Lichtwer Pharma Ltd.) orally for 30 days can reduce mild, acute (duration of less than 3 months) knee pain in otherwise healthy patients when compared to baseline. A daily dose of 400 mg seems to be more effective than 200 mg daily for relieving pain, stiffness, and physical function of the knee, with reductions in symptom scores of 59% and 41%, respectively (11457).
Lymphedema. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some clinical research in patients who have undergone a mastectomy shows that taking a specific combination product containing bromelain, rutin, pancreatin, papain, trypsin, and chymotrypsin (Wobenzym N, Mucos Pharma) daily for 7 weeks reduces arm swelling associated with lymphedema when compared with diuretics (24560). Other preliminary clinical research in patients with primary or secondary lymphedema of the upper or lower limbs shows that taking a different combination product containing bromelain 100 mg, rutin 300 mg, and sweet clover 100 mg daily for 6 months decreases pitting, limb volume, pain, and quality of life when compared to baseline (103298). The validity of these results is limited by the lack of a control group. Additionally, it is unclear if these findings are due to bromelain, other ingredients, or the combination.
Multiple sclerosis (MS). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with relapsing-remitting MS shows that taking an enzyme combination containing bromelain 90 mg, rutin 100 mg, and trypsin 48 mg per tablet for at least 3 months does not affect the progression of disability, relapse rate, or central nervous system lesions when compared with placebo (99468). The validity of these results is limited by the short duration of treatment.
Ocular floaters. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in patients with spontaneous symptomatic vitreous opacities (ocular floaters) shows that taking oral mixed fruit enzyme capsules containing bromelain 190 mg, papain, and ficin once, twice, or three times daily for 3 months eliminates floaters in 55%, 63%, and 70% of patients, respectively, when compared with an elimination rate of 5% with vitamin C as a control. Additionally, patients with vitreous hemorrhage-induced symptomatic vitreous opacities taking the mixed fruit enzyme capsules 3 times daily for 3 months reduced intraocular blood by 56% and improved visual acuity, but these effects were not found for lower doses and shorter durations when compared with a control (111650). It is unclear if these effects are due to bromelain, other ingredients, or the combination.
Osteoarthritis. It is unclear if oral bromelain is beneficial for osteoarthritis. Details: A small clinical trial shows that taking bromelain 800 mg daily for 12 weeks as an adjunctive treatment for moderate to severe knee osteoarthritis is no more effective than placebo for improving symptom scores (18274). Other preliminary clinical research shows that taking bromelain 500 mg daily for 4 weeks for mild to moderate knee osteoarthritis is less effective than diclofenac 100 mg daily for improving quality of life, joint pain, and joint function (96216). However, preliminary clinical research shows that oral combination products containing bromelain can reduce pain and improve function in knee osteoarthritis (6252,91104,91106,92235,99467,99477,103299). Bromelain 180 mg has been used in combination with trypsin 144 mg and rutin 200 mg (Phlogenzym, Mucos Pharma GMBH; Wobenzym, Mucos Pharma GmbH) three times daily for 3-12 weeks, with effects comparable to diclofenac, usually taken as 50 mg three times daily for one week, then twice daily thereafter. This product also reduces the need for rescue analgesics by 95% when compared with placebo (6252,91104,92235,99467,99477). Other studies have used a specific combination supplement (AINAT, Laboratoire de Rhumatologie Appliquée) containing Devil's claw 600 mg, turmeric 400 mg, and bromelain 300 mg, taken 2-3 times daily for 2-8 weeks (91106) or a combination of bromelain 250 mg and papain 250 mg (Nature's Life Bromelain & Papain, NutraMarks, Inc.) twice daily, plus aceclofenac 100 mg twice daily for 6 weeks (103299).
Pain (acute). It is unclear if oral bromelain is beneficial for acute pain. Details: A meta-analysis of 9 small clinical studies in patients experiencing acute pain due to various etiologies shows that taking bromelain slightly improves subjective pain scores and allows patients to open their mouth wider after oral operations when compared with a control (113513).
Parturition. Although there has been interest in using oral bromelain for shortening the duration of labor, there is insufficient reliable information about the clinical effects of bromelain for this purpose.
Periodontitis. It is unclear if oral bromelain is beneficial for periodontitis. Details: A very small clinical study in adults with periodontitis shows that taking bromelain 500 mg (Anaheal) twice daily for one week after undergoing pocket elimination surgery reduces bleeding on probing but does not improve gingival index, plaque index, or probing pocket depth when compared with placebo when assessed five weeks after surgery (111691). The validity of these effects is limited by a very small sample size and inadequate statistical power.
Pityriasis lichenoides chronica (PLC). It is unclear if oral bromelain is beneficial for PLC. Details: A case series suggests that taking bromelain 40 mg orally three times daily for one month, then twice daily for a second month, then once daily for a third month, helps treat episodes of PLC when compared to baseline (18280).
Postoperative pain. While evidence is mixed, some small clinical studies suggest that oral bromelain reduces postoperative pain after wisdom tooth extraction. It is unclear if bromelain improves pain after other surgical procedures. Details: Meta-analyses and clinical research in a small number of patients undergoing wisdom tooth extraction shows that bromelain modestly reduces pain for up to 8 days when compared with control (91109,91110,100750,100751). Also, three small clinical trials show that bromelain 160-1500 mg, taken in 3-4 divided doses daily for 4-6 days, reduces dental pain and swelling similarly to taking ketoprofen 100 mg twice daily, diclofenac sodium 25 mg four times daily, or aceclofenac 100 mg twice daily (91109,91110,110546). In contrast, several other small clinical studies show that taking bromelain does not reduce swelling or pain after wisdom tooth extraction when compared with placebo (91107,96214,96215). These studies might have not been sufficiently powered to detect a smaller effect. Meta-analyses also suggest that bromelain does not appear to have a significant effect on postoperative swelling or trismus (100750,100751). However, a more recent study in patients undergoing wisdom tooth extraction shows that taking bromelain 500 mg three times daily for 5 days reduces the severity of postoperative swelling and trismus when compared with aceclofenac, a nonsteroidal anti-inflammatory drug (NSAID) used in some European and Asian countries (110546). Bromelain, in combination with other ingredients, has also been evaluated for reducing pain after rotator cuff tear repair. Clinical research shows that taking a specific supplement (Tenosan, Agave) containing bromelain 50 mg, arginine-L-alpha-ketoglutarate 500 mg, methylsulfonylmethane (MSM) 550 mg, hydrolyzed collagen type I 300 mg, vitamin C 60 mg, and Vinitrox 125 mg daily for 3 months decreases shoulder pain, but does not improve shoulder function, in postoperative patients (19322).
Postoperative swelling. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small preliminary clinical study in patients undergoing surgery of the jaw shows that taking an enzyme combination of bromelain 180 mg, rutin 200 mg, and trypsin 96 mg twice daily for 5 days in addition to standard treatment reduces soft-tissue thickness (indicating the amount of swelling) at most of the nine assessed facial points when compared to control (99476).
Rhinosinusitis. It is unclear if oral bromelain is beneficial for rhinosinusitis. Details: Several small clinical trials show that short-term and long-term use of bromelain reduces symptoms of acute and chronic sinusitis, especially nasal mucosal inflammation and edema (18276,18277,18278,18279,91105). The trials used bromelain 40 mg orally (usually the product Ananase) four times daily for six days as an adjunct to antibiotics (18276,18278,18279) or 6 bromelain tablets each containing enzymes of 500 International Pharmaceutical Federation (FIP) units for 12 weeks (91105). Bromelain is usually taken in combination with decongestants, antihistamines, and/or antibiotics. However, the studies have a number of methodological problems, and results are inconsistent. Bromelain has also been evaluated as part of a combination product. A small study in patients over 12 years old with chronic sinusitis shows that taking a combination product containing bromelain 200 mg, Boswellia serrata, black currant, and vitamin D (Flogostop Forte, Humana Italia S.p.A) 1-2 times daily for 15-30 days as an adjunctive therapy to inhaled corticosteroids modulates hyperemia of the mucosa, rhinorrhea, and local inflammation when compared with inhaled corticosteroids alone and baseline (111501). It is unclear if these findings are due to bromelain, other ingredients, or the combination.
Sprains. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A preliminary clinical study in patients with a sprained ankle shows that taking a specific enzyme combination (Phlogenzym, Mucos Pharma) containing bromelain 90 mg, trypsin 48 mg, and rutin 100 mg, or taking different combinations of the individual enzymes three times daily for 10 days, is no more effective for relieving pain than placebo (99473).
Tendinopathy. Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with Achilles tendon insertional tendinopathy shows that taking two sachets of a specific supplement (Tenosan, Agave, Prato, Italy) containing a total of bromelain 100 mg, arginine-L-alpha-ketoglutarate 1000 mg, methylsulfonylmethane (MSM) 1100 mg, hydrolyzed collagen type I 600 mg, vitamin C 120 mg, and Vinitrox 25 mg orally for 60 days improves function and pain when compared with placebo (19321).
Urinary tract infections (UTIs). Oral bromelain has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial shows that a combination of bromelain 50 mg and trypsin 1 mg (Kimotab, Mochida Pharmaceutical), taken in a dose of 8 tablets daily for 2 days, does not improve subjective symptoms of UTIs when compared with placebo (18282).
Venous leg ulcers. Although there has been interest in using topical bromelain for venous leg ulcers, there is insufficient reliable information about the clinical effects of bromelain for this condition.
Wound healing. It is unclear if enzymatic debridement with bromelain improves the healing of various types of chronic wounds. Details: A meta-analysis of 12 small clinical studies shows that topical bromelain reduces time to complete debridement by around 6 days but has no effect on time to healing when compared with a control (113513). However, the validity of these effects is limited by significant publication bias and a small number of studies per outcome. One small clinical study, included in the analysis above, of patients with chronic wounds related to diabetes, surgery, trauma, or venous insufficiency shows that use of bromelain-based enzymatic debridement (EscharEx, MediWound Ltd), administered as up to ten daily applications of 4 hours each, increases the incidence of complete debridement over the next 6 months to 55% of patients, compared with only 29% of those using the bromelain-free gel. However, there was no difference in changes in wound area, non-viable tissue area, or the incidence or time to complete wound closure (108148). More evidence is needed to rate bromelain for these uses.

CABBAGE

POSSIBLY EFFECTIVE

Breast engorgement. Most research shows that applying cabbage leaves to engorged breasts reduces pain and hardness to the same degree as cold compresses in lactating females with breast engorgement. Details: Several small clinical studies suggest that applying whole cabbage leaves to the engorged breasts of lactating females produces subjective relief similar to the use of chilled gel-packs (6781,6784,93677). Both chilled and room temperature cabbage leaves seem to provide the same relief (6782). Another small clinical study shows that whole cabbage leaves also seem to improve breast pain and hardness when compared with general nursing care (93673). When compared with hot and cold compresses, one small clinical study found that using chilled cabbage leaves reduces postnatal breast engorgement to a similar degree, but is not as effective for reducing pain (101966). The preparation of cabbage leaves for this purpose sometimes includes stripping out the large vein of the cabbage leaf and cutting a hole for the nipple. Cabbage leaves are rinsed and chilled. The chilled cabbage leaf is worn inside the bra or as a compress under a cool towel. This procedure is typically repeated 1-4 times daily for 1-3 days (6781,6784,93673,93677,101966). A cabbage leaf extract applied as a cream has also been tried. The cabbage leaf extract cream seems to provide subjective relief when compared to baseline, but it does not provide superior relief when compared with a placebo cream (6783).

Bladder cancer. It is unclear if consuming cabbage is effective for the prevention of bladder cancer. Details: Observational research has found that eating about 1.75 cups of cruciferous vegetables such as cabbage or broccoli is associated with a 30% reduced risk of bladder cancer in men and women (14864).
Colorectal cancer. It is unclear if consuming cabbage is effective for the prevention of colorectal cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing colorectal cancer (6792).
Gastric cancer. It is unclear if consuming cabbage is effective for the prevention of gastric cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing stomach cancer (6792).
Gastritis. Although there has been interest in using oral cabbage for gastritis, there is insufficient reliable information about the clinical effects of cabbage for this purpose.
Hyperlipidemia. It is unclear if oral cabbage is beneficial in patients with hyperlipidemia. Details: A small clinical study in Japanese adults with hyperlipidemia shows that adding broccoli and cabbage to a beverage consisting of fruits and vegetables for 3-9 weeks reduces low-density lipoprotein (LDL) cholesterol levels by 8.5% when compared to baseline. The reduction in LDL cholesterol was significant when compared with the same beverage without broccoli and cabbage added (25423).
Knee pain. It is unclear if topical cabbage is beneficial in patients with knee pain. Details: A small clinical study in males with an acute mild to moderate traumatic knee ligament injury shows that use of crushed fresh cabbage leaf and cooling dressing wraps improves recovery over the first 24 hours of use by a moderate amount when compared with the cooling dressing alone. Normal fluid release occurred in 67% to 80% of patients using crushed cabbage leaf compared with 47% to 50% of those given the cooling dressing alone (101969).
Lung cancer. It is unclear if consuming cabbage is effective for the prevention of lung cancer. Details: Observational research has found that consuming large amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is associated with a lower risk of developing lung cancer (6792).
Osteoarthritis. Small clinical studies suggest that topical cabbage leaf modestly improves pain and other symptoms in patients with osteoarthritis of the knee. Details: A small clinical study in patients with osteoarthritis of the knee shows that applying cabbage leaf wraps to the knees for at least 2 hours daily for 4 weeks decreases pain by around 12 points on a 100 mm visual analog scale when compared with usual care. The analgesic effect of cabbage leaf wraps in these patients appears to be similar to treatment with topical gel containing the nonsteroidal anti-inflammatory drug diclofenac 10 mg/gram (93671). Another small, open-label clinical study in patients with moderate to severe osteoarthritis of the knee shows that applying cabbage leaf wraps to the knees for 1 hour daily for 4 weeks reduces knee pain and improves symptom severity when compared with diclofenac gel applied four times daily. Improvements in pain and overall symptoms were similar between cabbage leaf and the use of cooling gel pads (110558). The validity of these findings is limited by a lack of blinding.
Pancreatic cancer. It is unclear if consuming cabbage is effective for the prevention of pancreatic cancer. Details: Observational research in elderly and middle-aged individuals has found that consuming one or more servings of cabbage per week is associated with a 38% lower risk of developing pancreatic cancer when compared with those who do not eat cabbage (25422).
Peptic ulcers. Although there has been interest in using oral cabbage for peptic ulcers, there is insufficient reliable information about the clinical effects of cabbage for this purpose.
Prostate cancer. It is unclear if consuming cabbage is effective for the prevention of prostate cancer. Details: Some observational research has found that consuming higher amounts of cabbage and other Brassica vegetables such as kale, broccoli, and cauliflower is not associated with a lower risk of prostate cancer (25417,25419). However, other observational studies have found that consuming higher amounts of cabbage and other Brassica vegetables is associated with a lower risk of developing prostate cancer (25418,25420,25421). More evidence is needed to rate cabbage for these uses.

ECHINACEA (Echinacea angustifolia root extract)

POSSIBLY EFFECTIVE

Common cold. Taking echinacea orally while still healthy may help prevent the common cold, but the benefit is probably modest. Echinacea does not seem to have a significant benefit for treating colds that have already developed. Details: Three meta-analyses show a 10% to 58% reduction in the risk of developing a cold when taking various forms of echinacea (17520,17522,95652). A large clinical study shows that adults who use a specific echinacea extract (Echinaforce, A. Vogel Bioforce AG) 0.9 mL three times daily (2400 mg echinacea daily) for 4 months, with an increase to 0.9 mL five times daily (4000 mg echinacea daily) at the first sign of a cold, have 59% fewer cold episodes and 26% fewer days with cold symptoms than those taking placebo (18225). Many smaller studies have shown a non-significant trend toward a prophylactic benefit, but they were likely underpowered to detect a statistically significant difference (3282,6386,17521,95652). Research in adults who are deliberately infected with cold viruses shows that taking echinacea products either does not reduce the incidence of colds, or has a limited effect which is not statistically significant. Products used include E. angustifolia root extract 300 mg three times daily for 7 days before and 5 days after experimental infection (13419), an alcoholic extract of E. purpurea above-ground parts (EchinaGuard, Madaus AG) 2.5 mL three times daily for 7 days before and 7 days after experimental infection (12354), or echinacea 300 mg three times daily for 14 days before and 5 days after experimental infection (8228). These studies are small and have methodological problems. Some small clinical studies have suggested that taking E. purpurea extracts as a tincture or tea to treat the common cold modestly reduces symptom severity and reduces cold duration by a couple of days (6384,10320,10802,12355,14419,20062,111530). Specific products used in these studies include Echinilin by Inovobiologic Inc., and Echinacin and EchinaGuard by Madaus AG (10320,10802,12355,20062). In contrast, higher quality clinical research shows that taking E. purpurea alone or with E. angustifolia does not reduce duration or severity of cold symptoms when compared with placebo (10800,11970,17519,20059). Echinacea has also been evaluated in children. Preliminary clinical research in healthy children 4-12 years old shows that taking a specific E. purpurea product (Echinaforce Junior, A. Vogel) 400 mg three times daily for 4 months reduces the occurrence of cold symptoms, respiratory complications (such as pneumonia and otitis media), and antibiotic prescriptions by 30%, 52%, and 62%, respectively, when compared with vitamin C 50 mg three times daily. Taking echinacea also reduces the average duration of symptoms during respiratory illness by an average of 1.4 days when compared with vitamin C (105719). However, other clinical research in children has found no benefit with a specific E. purpurea product (Echinacin, Madaus AG) (4989,95653).

Anxiety. It is unclear if oral echinacea reduces anxiety. Details: Preliminary clinical research shows that taking a specific E. angustifolia extract (ExtractumPharma ZRT) 40 mg once or twice daily for 7 days reduces anxiety scores on the State-Trait Anxiety Inventory scale when compared with placebo (20064,103233). This extract seems to be more effective in patients with high baseline anxiety scores (103233). A lower dose of 20 mg daily appears to be ineffective (20064). Conversely, a small clinical study in physically healthy adults with mild to moderate anxiety shows that taking the same E. angustifolia extract at doses of 20 or 40 mg twice daily for 6 weeks does not reduce anxiety when compared with placebo (106626).
Athletic performance. It is unclear if oral echinacea improves athletic performance in healthy, recreationally active males. Details: Preliminary clinical research in healthy, recreationally active males shows that taking echinacea (Puritan's Pride) 2 grams four times daily for 28 days increases serum erythropoietin levels and maximal oxygen consumption (VO2max) during exercise tests (20066). However, two small clinical studies in endurance trained athletes and in non-athletes with high aerobic fitness show that taking E. purpurea 8 or 16 grams once daily for 35 days in combination with other ingredients (Biomedical Research Lab), or taking E. purpurea (Puritan's Pride) 8 grams daily for 42 days, has no effect on erythropoietin levels, VO2max, or aerobic capacity (95651,101593).
Atopic dermatitis (eczema). Some evidence shows that an echinacea cream may be effective in mild disease, but it has not been compared to conventional treatments such as corticosteroids. Details: Preliminary clinical research in patients with mild atopic dermatitis shows that applying a cream containing echinacea (Linola Plus Cream, Dr. August Wolff GmbH & Co) 2-3 times daily for 12 weeks reduces symptoms such as erythema, edema, pruritus, and dryness when compared with a cream containing birch bark extract (Imlan Crème Pur, Birken AG). However, the echinacea product was no different to the comparator cream at the 4- and 8-week assessments, indicating that it might take up to 12 weeks to show benefit (97499).
Attention deficit-hyperactivity disorder (ADHD). Although there has been interest in using oral echinacea for ADHD, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Burns. Although there has been interest in using topical echinacea for burns, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Chronic fatigue syndrome (CFS). Although there has been interest in using oral echinacea for CFS, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Coronavirus disease 2019 (COVID-19). It is unclear if oral echinacea is beneficial for preventing or treating COVID-19. Details: A moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiraA moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiratory tract infection, this study also shows that taking the same echinacea extract 4000 mg daily for up to 10 days speeds viral clearance compared with usual care when all virus types were analyzed; however, clearance of SARS-CoV-2 was not improved. Echinacea may also reduce the number of days with a fever, but not other symptoms (111174). The validity of this study is limited by lack of blinding. Further, most patients were unvaccinated against COVID-19; it is unclear whether these results can be extrapolated to vaccinated patients.
Genital herpes. It is unclear if oral echinacea is beneficial for genital herpes in patients with herpes simplex virus (HSV) type 1 or 2. Details: Some clinical research shows that a specific E. purpurea extract (Echinaforce, A. Vogel Bioforce AG) 800 mg orally twice daily for 6 months does not seem to prevent or reduce the frequency or duration of recurrent genital herpes in patients with herpes simplex virus (HSV) type 1 or 2 (7087).
Gingivitis. Echinacea, in a mouth rinse or periodontal patch, has only been studied in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a mouth rinse containing echinacea, gotu kola, and elderberry (HM-302, Izun Pharmaceuticals) 15 mL three times daily for 14 days might prevent worsening of gingivitis when compared with a placebo rinse, but it produces only minimal improvement in symptoms (20069). Applying a periodontal patch containing echinacea, gotu kola, and elderberry (PerioPatch, Izun Pharmaceuticals) either as a single dose, or three times daily for 1 day then once daily for 2 days seems to reduce some measures of inflammation and gingivitis at some time points, but effects lack consistency (20068,20070).
Herpes labialis (cold sores). Although there has been interest in using topical echinacea for herpes labialis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
HIV/AIDS. Although there has been interest in using oral echinacea for HIV/AIDS, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Human papillomavirus (HPV). Oral echinacea has only been studied in combination with other ingredients; its benefit when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing echinacea, andrographis, grapefruit, papaya, pau d'arco, and cat's claw (Immune Act, Erba Vita SpA) three tablets daily for one month reduces the recurrence of anal condylomata in patients following surgical removal. After one month, the recurrence rate was about 4% in the echinacea group compared with 18% in the control group; after 6 months the recurrence rates were about 7% and 27%, respectively (20073). However, poor study methodology limits the validity of these findings.
Influenza. Limited data suggest that oral echinacea may improve the response to influenza vaccine, and that a combination product containing echinacea may improve rates of recovery from influenza. Details: Preliminary clinical research shows that a taking a specific echinacea product (Monoselect Echinacea, PharmExtracta) 200 mg orally daily for 15 days, then 100 mg daily for 15 days, followed by 100 mg every other day for 60 days, might improve the response to influenza vaccine in people with chronic bronchitis or asthma (18226). Higher quality research is needed to confirm these results. Taking a specific combination product (Echinaforce Hot Drink, A. Vogel Bioforce AG), containing elderberry juice and extracts of E. purpurea above-ground parts and roots, 5 mL five times daily for 3 days, then three times daily for 7 days, improves rates of recovery and influenza-related respiratory complications similarly to oseltamivir 75 mg twice daily for 5 days (95650). However, due to the lack of a placebo group, it is unclear if both treatments were beneficial or if the outcomes represent the natural progression of influenza.
Insect bite. It is unclear if topical homeopathy with a gel containing echinacea is beneficial for insect bite treatment. Oral echinacea has not been evaluated for this use. Details: Preliminary clinical research shows that using a homeopathic after-bite gel, containing echinacea, marsh Labrador tea, and stinging nettle, on affected areas does not reduce erythema or itching after a mosquito bite when compared with placebo (89235).
Lichen planus. It is unclear if oral echinacea is beneficial for patients with this condition. Details: A small clinical study in adults with erosive oral lichen planus in Iran shows that taking a specific echinacea extract tablet (Immustim, Goldaru Corp.) 114 mg three times daily for 35 days decreases pain scores, number of lesions, and symptom severity when compared with placebo. However, all patients also used a mouthwash containing betamethasone, diphenhydramine, nystatin, and aluminum-magnesium suspension three times daily (111173).
Malaria. Although there has been interest in using oral echinacea for malaria, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Migraine headache. Although there has been interest in using oral echinacea for migraine headache, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Otitis media. Oral echinacea does not seem to reduce the rate of recurrence of otitis media in young children, and may actually increase it. Details: Preliminary clinical research shows that taking a specific liquid extract of echinacea fresh roots and dried mature seeds, 0.5 mL three times daily for 3 days at the first sign of a common cold, followed by 0.25 mL three times daily for 7 days, does not prevent otitis media in children 1-5 years of age with a history of recurrent otitis media. In fact, the risk of an episode of otitis media during the 6 month follow-up seemed to increase by 59% in those taking echinacea when compared with placebo (20063).
Psoriasis. Although there has been interest in using topical echinacea for psoriasis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Respiratory tract infections. It is unclear if oral echinacea is beneficial for patients with respiratory tract infections. Details: A large clinical study in adults with respiratory tract infections shows that using echinacea spray or taking echinacea lozenges 16,800 mg daily during days 1-3 and 2240-3360 mg daily afterward for up to 10 days does not improve time to recovery, symptom relief, or number of sick days when compared with echinacea tablets or drops at a prophylactic dose of 2400 mg daily for 10 days. However, the higher dose from days 1-3 is associated with faster viral clearance than the prophylactic dose (111540). The validity of these effects is limited by insufficient blinding and a lack of a placebo group.
Rheumatoid arthritis (RA). Although there has been interest in using oral echinacea for RA, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Tonsillitis. Oral echinacea has been used with azithromycin to reduce relapses of recurrent tonsillitis in children. A throat spray containing echinacea has also been evaluated for tonsillitis-associated sore throat. It is unclear if echinacea is beneficial for either purpose. Details: Preliminary clinical research in children with recurrent tonsillitis shows that adding echinacea suspension, 250 mg root powder per 5 mL, orally 3 times daily for 10 consecutive days per month for 6 months, to azithromycin 10 mg/kg/day for 6 consecutive days per month for 6 months reduces the number of tonsillitis attacks when compared with azithromycin alone (104127). However, the study was not blinded and the number of tonsillitis episodes in both groups was very low. Other preliminary clinical research shows that applying a throat spray containing sage and echinacea whole plant extract every 2 hours up to 10 times daily for up to 5 consecutive days is as effective as a chlorhexidine-lidocaine spray in patients with sore throat due to acute pharyngitis or tonsillitis (20077).
Tonsillopharyngitis. Oral echinacea has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized study in patients aged 12-75 years with acute tonsillopharyngitis shows that taking lozenges containing echinacea extract 800 mg and sage extract 5 times daily for 4 days reduces throat pain and tonsillopharyngitis symptoms when compared to baseline, both acutely within 90 minutes and after 4 days of treatment (111530). The validity of these effects is limited by a lack of a comparator group. It is unclear if these effects are due to echinacea, sage, or the combination.
Upper respiratory tract infection (URTI). It is unclear if oral echinacea is beneficial for preventing or treating URTIs. Details: A moderate-size open-label clinical study tested the effects of echinacea to prevent or treat respiratory viruses. This study of otherwise healthy adults in Bulgaria shows that taking echinacea extract (Echinaforce, A. Vogel AG) 2400 mg daily for cycles of 2, 2, and 1 months, with a 1-week break between each cycle, does not reduce symptomatic respiratory tract infections, including SARS-CoV-2, or respiratory virus detection overall when compared with usual care. However, echinacea extract does reduce the risk of a positive test for coronaviruses or SARS-CoV-2 by 48% and 63%, respectively. In patients who develop a symptomatic respiratory tract infection, this study also shows that taking the same echinacea extract 4000 mg daily for up to 10 days speeds viral clearance compared with usual care when all virus types were analyzed; however, clearance of SARS-CoV-2 was not improved. Echinacea may also reduce the number of days with a fever, but not other symptoms (111174). The validity of this study is limited by lack of blinding. Further, most patients were unvaccinated against COVID-19; it is unclear whether these results can be extrapolated to vaccinated patients. Another large study in adults with URTIs shows that taking a combination product containing echinacea 1100-2200 mg, zinc, and vitamin C (EZC Pak) daily for 5 days reduces time to recovery by 1.4 days but does not reduce symptom severity when compared with placebo (111512). The validity of these effects is severely limited by multiple instances of selection bias. Additionally, it is unclear if these effects are due to echinacea, other ingredients, or the combination.
Urinary tract infections (UTIs). Although there has been interest in using oral echinacea for UTIs, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Vaginal candidiasis. Although there has been interest in using oral echinacea for vaginal candidiasis, there is insufficient reliable information about the clinical effects of echinacea for this purpose.
Warts. It is unclear if oral echinacea is beneficial for warts when used alone or in combination with other ingredients. Details: Preliminary clinical research shows that taking echinacea 600 mg orally once daily for up to 3 months does not clear common, plantar, or plain cutaneous warts any more effectively than placebo (20080). Other preliminary clinical research shows that taking an oral supplement containing echinacea with methionine, zinc, probiotics, antioxidants and immunostimulants for 6 months, in addition to using conventional topical therapy to treat cutaneous warts, seems to increase the rate of complete remission from 54% to 86% when compared with conventional therapy alone (20071). It is unclear if these effects are due to echinacea, other ingredients, or the combination.
Water warts. It is unclear if oral echinacea is beneficial for water warts (molluscum contagiosum). Details: In children who have been successfully treated with curettage for molluscum contagiosum, taking a combination of E. angustifolia and E. purpurea orally daily for 2 months is associated with a relapse rate of about 39%, compared with a rate of 68% in a control group that received no oral treatment (104128). The validity of this finding is limited by the lack of a placebo control. E. angustifolia and E. purpurea were taken in doses of 200 mg each in children under 20 kg and 400 mg each in children over 20 kg. More evidence is needed to rate echinacea for these uses.

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 and function when compared with placebo (14305,89521,94382,95785,99684). 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. 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).

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). 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 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). This study 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).
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). 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.

GOLDENSEAL (Goldenseal (Hydrastis canadensis) root extract)

POSSIBLY INEFFECTIVE

Urine drug tests. Drinking water with goldenseal or adding goldenseal tea to urine does not appear to cause a false negative urine drug screen for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or tetrahydrocannabinol (THC). Details: Goldenseal is often promoted to mask illicit drugs in the urine, but drinking one gallon of water with goldenseal or adding goldenseal tea to urine samples does not seem to cause a false negative immunoassay (EMIT and TDx) for cocaine, amphetamines, barbiturates, benzodiazepines, or opiates. It also does not produce a false negative for Microgenics CEDIA DAU assays for amphetamines, barbiturates, benzodiazepines, cocaine, opiates, phencyclidine, or THC (260,261,52599). Although adding goldenseal tea to urine samples at 15 grams per liter may produce a false-negative EMIT reading for the presence of THC, the adulteration is obvious due to a brownish color in the urine (52599). Some people also claim that goldenseal can cause a false positive on a drug screen. However, goldenseal does not seem to cause false positives for the fluorescent polarization immunoassay (FPIA) or thin-layer chromatography (TLC) assays for amphetamines, opiates, cocaine, methadone, or their metabolites (2590).

Acne. Although there has been interest in using topical goldenseal for acne, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Allergic rhinitis (hay fever). Although there has been interest in using oral goldenseal for allergic rhinitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Anorexia nervosa. Although there has been interest in using oral goldenseal for anorexia nervosa, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Atopic dermatitis (eczema). Although there has been interest in using topical goldenseal for atopic dermatitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Chronic fatigue syndrome (CFS). Although there has been interest in using oral goldenseal for CFS, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Conjunctivitis. Although there has been interest in using goldenseal as an eye drop for conjunctivitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Dandruff. Although there has been interest in using topical goldenseal for dandruff, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Flatulence. Although there has been interest in using oral goldenseal for flatulence, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Gastritis. Although there has been interest in using oral goldenseal for gastritis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Gingivitis. Although there has been interest in using goldenseal as a mouthwash for gingivitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Hemorrhoids. Although there has been interest in using oral goldenseal for hemorrhoids, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Herpes labialis (cold sores). Although there has been interest in using topical goldenseal for herpes labialis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Menorrhagia. Although there has been interest in using oral goldenseal for menorrhagia, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Otitis media. Although there has been interest in using goldenseal as an ear drop for otitis media, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Peptic ulcers. Although there has been interest in using oral goldenseal for peptic ulcers, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Respiratory tract infections. Although there has been interest in using oral goldenseal for various respiratory tract infections, including influenza, pneumonia, rhinosinusitis, and the common cold, there is insufficient reliable information about the clinical effects of goldenseal for these conditions.
Tinnitus. Although there has been interest in using goldenseal as an ear drop for tinnitus, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Urinary tract infections (UTIs). Although there has been interest in using oral goldenseal for UTIs, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Uveitis. Although there has been interest in using goldenseal as an eye drop for uveitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Vaginitis. Although there has been interest in using oral goldenseal for vaginitis, there is insufficient reliable information about the clinical effects of goldenseal for this purpose.
Wound healing. Although there has been interest in using topical goldenseal for wound healing, there is insufficient reliable information about the clinical effects of goldenseal for this purpose. There is insufficient reliable information available about the effectiveness of goldenseal for its other uses.

MARSHMALLOW

ACE inhibitor-induced cough. It is unclear if oral marshmallow root is beneficial in patients with cough due to ACE inhibitors. Details: A small clinical study in patients with ACE inhibitor-induced cough shows that taking marshmallow root 40 mg (20 drops) three times daily for 4 weeks improves cough when compared to baseline (62027). The validity of this finding is limited by the lack of a control group.
Atopic dermatitis (eczema). It is unclear if topical marshmallow is beneficial in children with eczema. Details: A very small clinical study in children ages 3 months to 12 years with a recent diagnosis of mild to moderate eczema shows that applying a marshmallow 1% ointment twice daily for 1 week and then three times weekly for 3 weeks seems to reduce symptoms, as measured on the SCORing Atopic Dermatitis (SCORAD) scale, when compared with applying hydrocortisone 1% ointment (105437). This finding is limited by the large number of drop-outs due to non-compliance, most of which were in the marshmallow group.
Breast engorgement. It is unclear if topical marshmallow is beneficial in women with this condition. Details: A small clinical study in breastfeeding women with breast engorgement shows that applying a compress containing 40-50 mL of a solution made from marshmallow leaves and stems 3 times daily for 2 days in conjunction with standard treatment improves patient-reported breast engorgement scores when compared with standard treatment alone. Standard treatment consisted of massage and alternating warm and cold compresses before and after breastfeeding (92845).
Constipation. Although there is interest in using oral marshmallow for constipation, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
Cough. Although there is interest in using oral marshmallow for cough, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
Diarrhea. Although there is interest in using oral marshmallow for diarrhea, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
Fever. It is unclear if topical marshmallow is beneficial for pediatric fever. Details: A moderate-sized clinical study in children aged 6 months-10 years with fever receiving rectal acetaminophen shows that applying marshmallow extract body wash and lukewarm water reduces the time to defervescence by 8 minutes when compared with lukewarm water alone, but does not improve the change in body temperature, number of acetaminophen doses given, or incidence of fever recurrence (112375). However, the interpretation of these findings is limited to patients without fevers greater than 40 degrees Celsius or history of febrile seizures since these patients were not studied.
Leishmania lesions. Topical marshmallow has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research suggests that the topical application of an herbal extract containing a combination of marshmallow and Althaea rosa to affected areas for 5 days can help promote curing of Leishmania lesions (62020).
Respiratory tract infections. Although there is interest in using oral marshmallow for respiratory tract infections, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
Vaginal candidiasis. It is unclear if vaginal marshmallow is beneficial for vulvovaginal candidiasis. Details: A small clinical study in adults with vulvovaginal candidiasis shows that applying a vaginal cream comprised of marshmallow extract 4% and clotrimazole 1% daily for 7 days improves itching, dyspareunia, and dysuria at 7 days when compared with clotrimazole 1% alone. At 30 days, the marshmallow intervention also results in fewer positive yeast cultures and sustained reduction in itching (112371). However, the validity of these results is limited by significant differences between groups at baseline for dyspareunia and dysuria, and lack of adjustment for multiple comparisons which can increase false positive findings. Additionally, all primary outcomes were patient-reported.
Venous leg ulcers. Although there is interest in using topical marshmallow for venous leg ulcers, there is insufficient reliable information about the clinical effects of marshmallow for this condition.
Wounds. Although there is interest in using topical marshmallow for wounds, there is insufficient reliable information about the clinical effects of marshmallow for this condition. More evidence is needed to rate marshmallow for these uses.

SLIPPERY ELM

Cancer. Oral slippery elm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Retrospective population research has found that taking a specific product containing burdock root, Indian rhubarb, sheep sorrel, and slippery elm bark (Essiac, Resperin Canada Limited) does not improve quality of life in breast cancer patients and may have a negative effect on physical well-being (37419).
Constipation. Although there has been interest in using oral slippery elm for constipation, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
Cough. Although there has been interest in using lozenges containing slippery elm for cough, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
Diarrhea. Although there has been interest in using oral slippery elm for diarrhea, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
Inflammatory bowel disease (IBD). Although there has been interest in using oral slippery elm for IBD, including Crohn disease and ulcerative colitis, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
Irritable bowel syndrome (IBS). Oral slippery elm has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific formulation containing slippery elm inner bark, lactulose, oat bran, and licorice root can improve stool frequency by 20% and reduce abdominal pain and bloating in people with constipation-predominant IBS when compared to baseline. Also, taking a different formulation containing slippery elm inner bark, bilberry fruit, cinnamon quilts, and agrimony aerial parts can reduce abdominal pain, bloating, and flatulence in people with diarrhea-predominant IBS when compared to baseline, although stool frequency is increased in these individuals as well (35462). It is unclear if these findings are due to slippery elm, other ingredients, or the combination.
Peptic ulcers. Although there has been interest in using oral slippery elm for peptic ulcers, there is insufficient reliable information about the clinical effects of slippery elm for this purpose.
Pharyngitis. It is unclear if lozenges containing slippery elm are beneficial in patients with sore throat. Details: Slippery elm has demulcent properties and, when added to lozenges, may soothe sore throats (272,512,1740). However, clinical research is lacking. More evidence is needed to rate slippery elm for these uses.

SPOTTED GERANIUM (Cranesbill (Geranium maculatum) root powder)

There is insufficient reliable information available about the effectiveness of spotted geranium.

Safety view details

Below is general information about the safety of the known ingredients contained in the product RF Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROMELAIN

POSSIBLY SAFE ...when used orally and appropriately. Doses up to 240 mg daily have been used safely for up to a year (6252,6253,10622,11457,18281,18284,91104,91105,91106,91111)(96449,103298). Higher doses up to 3200 mg daily have been used safely, short-term (18283,110546). ...when used topically and appropriately. Bromelain has been used safely as a debriding agent for up to 4 hours (18275,91113,103297,108148,108149).

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

CABBAGE

LIKELY SAFE ...when used orally in amounts commonly found in foods.

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (18). ...when used topically and appropriately, short-term. Topical application of cabbage leaves has been general well-tolerated in short-term studies (6781,6782,6783,6784,93671,110558). However, pain, itching, and burning with topical use of cabbage leaves have been reported in some patients leaving cabbage leaf wraps in place for 2-4 hours (93671,93675).

PREGNANCY:
There is insufficient reliable information available about using cabbage in medicinal amounts during pregnancy; avoid using.

LACTATION: LIKELY SAFE
when used topically and appropriately, short-term. Significant adverse effects have not been reported in short-term studies (6781,6782,6783,6784,93673,93677). There is insufficient reliable information available about using cabbage orally in medicinal amounts during lactation; avoid using.

ECHINACEA (Echinacea angustifolia root extract)

LIKELY SAFE ...when used orally and appropriately, short-term. Various liquid extracts of Echinacea purpurea have been used safely for up to 10 days, including EchinaGuard (Madaus AG) 20 drops every 2 hours for 1 day, then three times daily (10320), or Echinilin (Inovobiologic Inc.) 40 mL in divided doses for 1 day, then 15 mL in divided doses daily thereafter (12355,20062). Other liquid extracts have been used safely for relatively longer periods, including Echinaforce (A. Vogel Bioforce AG) 2.4 grams daily for 4 months or 1.6 grams daily for 6 months (7087,18225), and Echinacin (Madaus AG) 5 mL twice daily for 10 days, or 4 mL twice daily for 8 weeks (3282,10802). Specific solid dosage forms of echinacea that have been used safely for up to 10 days include Echinacea purpurea above-ground parts (EchinaFresh, Enzymatic Therapy) 300 mg daily (11970), and mixtures of Echinacea purpurea and Echinacea angustifolia herb in divided doses of 6 grams to 10.5 grams for 1 day then 3 grams to 5.1 grams daily (10800,17519,20059). A specific Echinacea angustifolia extract (ExtractumPharma ZRT) has also been used with apparent safety at a dose of 40 mg once or twice daily for up to 7 days (20064,103233). An Echinacea purpurea product (Natures Resource) has been used safely at a dose of 1.8 grams daily for 8 weeks (17521), and echinacea (Puritan's Pride) has been used safely at 8 grams daily for 28 days (20066).

POSSIBLY SAFE ...when used topically, short-term. A specific cream (Linola Plus Cream, Dr. August Wolff GmbH & Co.) containing echinacea extract (WO 3260) has been applied to the skin safely 2-3 times daily for up to 12 weeks (97499). There is insufficient reliable evidence about the safety of echinacea when used parenterally.

CHILDREN: POSSIBLY SAFE
when used orally, short-term. Some clinical research shows that an extract of the above-ground parts of Echinacea purpurea (EC31J2, Echinacin Saft, Madaus AG) in a dose of 3.75 mL twice daily (for ages 2 years to 5 years) or 7.5 mL twice daily (for ages 6 years to 11 years) is safe when used for up to 10 days (4989). However, about 7% of children experienced a rash after taking echinacea, which might have been caused by an allergic reaction (4989). There is concern that allergic reactions could be severe in some children. The Medicines and Healthcare Products Regulatory Agency in the United Kingdom recommends against the use of oral echinacea products in children under 12 years of age due to this risk of allergic reaction (18207). In contrast, another clinical study in children 4-12 years old shows that a specific Echinacea purpurea product (Echinaforce Junior, A. Vogel) does not cause allergic or urticarial reactions more frequently than vitamin C (105719).

PREGNANCY: POSSIBLY SAFE
when used orally, short-term. There is preliminary evidence that mothers can safely use echinacea in the form of E. purpurea or E. angustifolia solid dosage forms, 250-1000 mg daily, or tinctures, up to 30 drops daily, for 5 days to 7 days during the first trimester without adversely affecting the fetus (7056,13418,15123). There is insufficient reliable information available about the safety of echinacea when used for longer than 7 days.

LACTATION:
Insufficient reliable information available; avoid using.

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.

GOLDENSEAL (Goldenseal (Hydrastis canadensis) root extract)

POSSIBLY SAFE ...when used orally and appropriately as a single dose (260,261). There is insufficient reliable information available about the safety of goldenseal when used as more than a single dose.

CHILDREN: LIKELY UNSAFE
when used orally in newborns. The berberine constituent of goldenseal can cause kernicterus in newborns, particularly preterm neonates with hyperbilirubinemia (2589).

PREGNANCY: LIKELY UNSAFE
when used orally. Berberine is thought to cross the placenta and may cause harm to the fetus. Kernicterus has developed in newborn infants exposed to goldenseal (2589).

LACTATION:
LIKELY UNSAFE when used orally. Berberine and other harmful constituents can be transferred to the infant through breast milk (2589). Use during lactation can cause kernicterus in the newborn and several resulting fatalities have been reported (2589).

MARSHMALLOW

LIKELY SAFE ...when marshmallow root and leaf are used in amounts commonly found in foods. Marshmallow root has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when marshmallow root and leaf are used orally in medicinal amounts (4,12). ...when used topically (4,62020). There is insufficient reliable information available about the safety of marshmallow flower.

PREGNANCY AND LACTATION:
Insufficient reliable information available.

SLIPPERY ELM

POSSIBLY SAFE ...when used orally and appropriately (4,12,272,512,1740).

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using. Slippery elm bark has historically been inserted into the cervix to induce abortion. As a result, slippery elm has been reported in some sources to have abortifacient activity. However, there is no reliable information available about whether slippery elm has abortifacient activity when taken orally.

SPOTTED GERANIUM (Cranesbill (Geranium maculatum) root powder)

There is insufficient reliable information available about the safety of spotted geranium.

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

Interactions with Drugs view details

Below is general information about the interactions of the known ingredients contained in the product RF Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROMELAIN

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Bromelain may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.

Details

There is one case report of a patient experiencing minor bruising while taking bromelain with naproxen (14806). Bromelain is thought to have antiplatelet activity (10639,14806,18285,18286,37234). Whether this interaction is of concern with topical bromelain is unclear. Interference with coagulation of burn wounds has been reported in a patient receiving bromelain-based enzymatic debridement. However, observational research has found that topical bromelain debridement is not associated with increases or decreases in laboratory markers of coagulation when compared with surgical debridement (110547).

TETRACYCLINE ANTIBIOTICS

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = B

Theoretically, bromelain might increase levels of tetracycline antibiotics.

Details

Laboratory research suggests that bromelain might increase the absorption of tetracycline antibiotics. However, a study in healthy adults reported no difference in tetracycline plasma levels when a 500 mg dose was taken with or without bromelain 80 mg (14296).

CABBAGE

ACETAMINOPHEN (Tylenol, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Cabbage might increase clearance and reduce the effects of acetaminophen.

Details

A small clinical study shows that daily consumption of cabbage and Brussels sprout decreases acetaminophen levels by as much as 16%, with some evidence suggesting that this effect is due to increased elimination through glucuronide conjugation (3952).

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, cabbage might increase the risk of hypoglycemia when taken with antidiabetes drugs.

Details

Animal and in vivo research suggests that cabbage might have hypoglycemic effects (25424).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, cabbage might decrease levels of drugs metabolized by CYP1A2.

Details

Some animal research suggests that cabbage or its constituent indole-3-carbinol might increase drug metabolism and elimination by stimulating CYP1A2 activity (7176,7187,51183).

GLUCURONIDATED DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Theoretically, cabbage might increase clearance and decrease the effects of drugs metabolized through glucuronide conjugation.

Details

A small clinical study shows that daily consumption of cabbage and Brussels sprout decreases levels of some drugs metabolized through glucuronide conjugation (3952).

OXAZEPAM (Serax)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Cabbage might increase clearance and reduce the effects of oxazepam.

Details

A small clinical study shows that daily consumption of cabbage and brussels sprout decreases oxazepam levels by as much as 17%, with some evidence suggesting that this effect is due to increased elimination through glucuronide conjugation (3952).

WARFARIN (Coumadin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, cabbage might decrease the anticoagulant effects of warfarin.

Details

Cabbage contains vitamin K. If consumed in large quantities, cabbage might decrease the anticoagulant effects of warfarin (19).

ECHINACEA (Echinacea angustifolia root extract)

CAFFEINE

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Echinacea can increase plasma levels of caffeine by inhibiting its metabolism.

Details

Echinacea seems to increase plasma concentrations of caffeine by around 30% (12155). This is likely due to inhibition of cytochrome P450 1A2 (CYP1A2) by echinacea.

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Echinacea might inhibit the metabolism of CYP1A2 and increase plasma levels of some drugs.

Details

Echinacea appears to inhibit CYP1A2 enzymes in humans. Additionally, echinacea seems to increase plasma concentrations of caffeine, a CYP1A2 substrate, by around 30% (12155). Theoretically, echinacea might increase levels of other drugs metabolized by CYP1A2.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Echinacea may induce hepatic CYP3A4 and inhibit intestinal CYP3A4. This may increase or decrease levels of drugs metabolized by CYP3A4.

Details

Several clinical trials have shown that taking echinacea for up to one month does not significantly affect the metabolism of various CYP3A4 substrates, including midazolam, docetaxel, etravirine, lopinavir-ritonavir, and darunavir-ritonavir (13712,48618,88164,88165). However, other clinical research shows that echinacea may increase the clearance of midazolam, suggesting that echinacea might induce CYP3A4 (48618). The discrepancy is thought to be due to differing effects of echinacea on intestinal versus hepatic CYP3A4 enzymes. Echinacea appears to induce hepatic CYP3A4 but inhibit intestinal CYP3A4 (12155). In some cases, these effects might cancel each other out, but in others, drug levels may be increased or decreased depending on the level of effect at hepatic and intestinal sites. The effect of echinacea on CYP3A4 activity may differ depending on the CYP3A4 substrate (6450,11026,88162,88167).

DARUNAVIR (Prezista)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Unlikely • Level of Evidence = B

Theoretically, echinacea may interfere with the metabolism of darunavir; however, a small clinical study found no effect.

Details

Darunavir is metabolized by cytochrome P450 3A4 (CYP3A4) and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Echinacea has variable effects on CYP3A4, but administration of an E. purpurea root extract (Arkocapsulas Echinacea, Arkopharma) 500 mg four times daily for 14 days did not affect darunavir/ritonavir pharmacokinetics in 15 HIV-infected patients (88163,93578).

DOCETAXEL (Taxotere)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Unlikely • Level of Evidence = B

Theoretically, echinacea may interfere with the metabolism of docetaxel; however, a small clinical study found no effect.

Details

Docetaxel is metabolized by cytochrome P450 3A4 (CYP3A4). Echinacea has variable effects on CYP3A4, but taking E. purpurea whole plant extract (Echinaforce, A. Vogel Biopharma AG) 20 drops three times daily for 2 weeks did not alter the pharmacokinetics of docetaxel in one clinical study (88164).

ETOPOSIDE (VePesid)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Echinacea may increase levels of etoposide.

Details

In one report, concomitant use of etoposide and echinacea was associated with more severe thrombocytopenia than the use of etoposide alone, suggesting inhibition of etoposide metabolism (20082). Etoposide is a cytochrome P450 3A4 (CYP3A4) substrate. Echinacea has variable effects on CYP3A4, but some studies have reported inhibition of the enzyme (6450,11026,12155,88162,88167).

ETRAVIRINE (Intelence)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Unlikely • Level of Evidence = B

Theoretically, echinacea may interfere with the metabolism of etravirine; however, a small clinical study found no effect.

Details

Etravirine is metabolized by cytochrome P450 3A4 (CYP3A4). Echinacea has variable effects on CYP3A4, but taking E. purpurea root extract (Arkocapsulas Echinacea, Arkopharma) 500 mg three times daily for 14 days did not alter the pharmacokinetics of etravirine in HIV-infected patients (88165,93578).

IMMUNOSUPPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = B

Echinacea has immunostimulant activity which may interfere with immunosuppressant therapy.

Details

Theoretically, echinacea may interfere with immunosuppressant therapy because of its immunostimulant activity (3279,6388,6389,12639).

LOPINAVIR/RITONAVIR (Kaletra)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Unlikely • Level of Evidence = B

Theoretically, echinacea may interfere with the metabolism of lopinavir; however, a small clinical study found no effect.

Details

Lopinavir is metabolized by cytochrome P450 3A4 (CYP3A4) and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Echinacea has variable effects on CYP3A4, but taking E. purpurea (Echinamide, Natural Factors Nutritional Products, Inc.) 500 mg three times daily for 14 days did not alter the pharmacokinetics of lopinavir/ritonavir in healthy volunteers (48618,93578).

MIDAZOLAM (Versed)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Possible • Level of Evidence = B

Theoretically, echinacea may increase the metabolism of intravenous midazolam.

Details

Echinacea induces hepatic CYP3A4 and might decrease plasma levels of midazolam by about 20%, reducing the effectiveness of intravenous midazolam (12155). Echinacea also appears to inhibit intestinal CYP3A4, which could theoretically increase the bioavailability of oral midazolam. This may cancel out the decrease in availability caused by induction of hepatic CYP3A4, such that overall plasma levels after oral administration of midazolam are not affected by echinacea.

WARFARIN (Coumadin)

Interaction Rating = Minor Be watchful with this combination.

Severity = Insignificant • Occurrence = Possible • Level of Evidence = B

Echinacea seems to increase the clearance of warfarin, although the effect may not be clinically significant.

Details

Preliminary clinical research in healthy male volunteers suggests that taking echinacea increases the clearance of the active S-isomer of warfarin after a single dose of warfarin, but there was not a clinically significant effect on the INR (20083).

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).

GOLDENSEAL (Goldenseal (Hydrastis canadensis) root extract)

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.

Details

Goldenseal contains berberine. In vitro and animal research shows that berberine can inhibit platelet aggregation (33660,33694). However, this effect has not been reported in humans.

ANTIDIABETES DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase the risk of hypoglycemia when used with antidiabetes drugs.

Details

Goldenseal contains berberine. Clinical research shows that berberine can lower blood glucose levels (20579,34247,34265,34282). However, this effect has not been reported with goldenseal.

ANTIHYPERTENSIVE DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase the risk of hypotension when taken with antihypertensive drugs.

Details

Goldenseal contains berberine. Animal research shows that berberine can have hypotensive effects (33692,34308). Also, an analysis of clinical research shows that taking berberine in combination with amlodipine can lower systolic and diastolic blood pressure when compared with amlodipine alone (91956). However, this effect has not been reported with goldenseal.

CNS DEPRESSANTS

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase the sedative effects of CNS depressants.

Details

Goldenseal contains berberine. Animal research shows that berberine can have sedative effects (13519,33650,33664,33692). However, this effect has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase serum levels of drugs metabolized by CYP2C9.

Details

In vitro research shows that goldenseal root extract can modestly inhibit CYP2C9. This effect may be due to its alkaloid constituents, hydrastine and berberine (21117). However, this effect has not been reported in humans.

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = B

Goldenseal might increase serum levels of drugs metabolized by CYP2D6.

Details

Clinical and in vitro research shows that goldenseal can significantly inhibit CYP2D6 enzymes, potentially increasing levels of drugs metabolized by CYP2D6 (13536,16848,35907).

CYTOCHROME P450 2E1 (CYP2E1) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase serum levels of drugs metabolized by CYP2E1.

Details

In vitro research shows that goldenseal root extract can inhibit the activity of CYP2E1 (94140). However, this effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = B

Goldenseal might increase serum levels of drugs metabolized by CYP3A4.

Details

Most clinical and in vitro research shows that goldenseal inhibits CYP3A4 enzyme activity and increases serum levels of CYP3A4 substrates, such as midazolam (6450,13536,21117,91740,111725). However, in one small clinical study, goldenseal did not affect the levels of indinavir, a CYP3A4 substrate, in healthy volunteers (10690,93578). This is likely due to the fact that indinavir has a high oral bioavailability, making it an inadequate probe for CYP3A4 interactions (13536,91740) and/or that it is primarily metabolized by hepatic CYP3A, while goldenseal has more potential to inhibit intestinal CYP3A enzyme activity (111725). Both goldenseal extract and its isolated constituents berberine and hydrastine inhibit CYP3A, with hydrastine possibly having more inhibitory potential than berberine (111725).

DEXTROMETHORPHAN (Robitussin DM, others)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase serum levels of dextromethorphan.

Details

Goldenseal contains berberine. A small clinical study shows that berberine can inhibit cytochrome P450 2D6 (CYP2D6) activity and reduce the metabolism of dextromethorphan (34279).

DIGOXIN (Lanoxin)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Goldenseal might increase serum levels of digoxin, although this effect is unlikely to be clinically significant.

Details

Clinical research shows that goldenseal modestly increases digoxin peak levels by about 14% in healthy volunteers. However, goldenseal does not seem to affect other pharmacokinetic parameters such as area under the curve (AUC) (15132). This suggests that goldenseal does not cause a clinically significant interaction with digoxin. Digoxin is a P-glycoprotein substrate. Some evidence suggests that goldenseal constituents might affect P-glycoprotein; however, it is unclear whether these constituents inhibit or induce P-glycoprotein.

LOSARTAN (Cozaar)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might decrease the conversion of losartan to its active form.

Details

Goldenseal contains berberine. A small clinical study shows that berberine inhibits cytochrome P450 2C9 (CYP2C9) activity and reduces the metabolism of losartan (34279). However, this effect has not been reported with goldenseal.

METFORMIN (Glucophage)

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might reduce blood levels of metformin.

Details

In vitro research shows that goldenseal extract decreases the bioavailability of metformin, likely by interfering with transport, intestinal permeability, or other processes involved in metformin absorption. It is unclear which, if any, of metformin's transporters are inhibited by goldenseal. Goldenseal does not appear to alter the clearance or half-life of metformin (105764).

OSELTAMIVIR (Tamiflu)

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might reduce the therapeutic effects of oseltamivir by decreasing its conversion to its active form.

Details

In vitro evidence suggests that goldenseal reduces the formation of the active compound from the prodrug oseltamivir (105765). The mechanism of action and clinical relevance is unclear.

P-GLYCOPROTEIN SUBSTRATES

Interaction Rating = Moderate Be cautious with this combination.

Severity = Mild • Occurrence = Probable • Level of Evidence = B

Theoretically, goldenseal might increase or decrease serum levels of P-glycoprotein (P-gp) substrates.

Details

There is conflicting evidence about the effect of goldenseal on P-gp. In vitro research suggests that berberine, a constituent of goldenseal, modestly inhibits P-gp efflux. Other evidence suggests that berberine induces P-gp. In healthy volunteers, goldenseal modestly increases peak levels of the P-gp substrate digoxin by about 14%. However, it does not seem to affect other pharmacokinetic parameters such as area under the curve (AUC) (15132). This suggests that goldenseal is not a potent inhibitor of P-gp-mediated drug efflux. Until more is known, goldenseal should be used cautiously with P-gp substrates.

PENTOBARBITAL (Nembutal)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase the sedative effects of pentobarbital.

Details

Animal research shows that berberine, a constituent of goldenseal, can prolong pentobarbital-induced sleeping time (13519). However, this effect has not been reported with goldenseal.

TACROLIMUS (Prograf)

Interaction Rating = Moderate Be cautious with this combination.

Severity = High • Occurrence = Possible • Level of Evidence = D

Theoretically, goldenseal might increase serum levels of tacrolimus.

Details

Goldenseal contains berberine. In a 16-year-old patient with idiopathic nephrotic syndrome who was being treated with tacrolimus 6.5 mg twice daily, intake of berberine 200 mg three times daily increased the blood concentration of tacrolimus from 8 to 22 ng/mL. Following a reduction of tacrolimus dosing to 3 mg daily, blood levels of tacrolimus decreased to 12 ng/mL (91954).

MARSHMALLOW

ANTICOAGULANT/ANTIPLATELET DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Moderate • Occurrence = Unlikely • Level of Evidence = D

Theoretically, marshmallow flower might have antiplatelet effects.

Details

Animal research suggests that marshmallow flower extract has antiplatelet effects (92846). However, the root and leaf of marshmallow, not the flower, are the plant parts most commonly found in dietary supplements. Theoretically, use of marshmallow flower with anticoagulant/antiplatelet drugs can have additive effects, and might increase the risk for bleeding in some patients.

LITHIUM

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Probable • Level of Evidence = D

Theoretically, due to potential diuretic effects, marshmallow might reduce excretion and increase levels of lithium.

Details

Marshmallow is thought to have diuretic properties. To avoid lithium toxicity, the dose of lithium might need to be decreased when used with marshmallow.

ORAL DRUGS

Interaction Rating = Minor Be watchful with this combination.

Severity = Mild • Occurrence = Possible • Level of Evidence = D

Theoretically, mucilage in marshmallow might impair absorption of oral drugs.

Details

Marshmallow contains mucilage which can affect oral drug absorption (1,11,12,19). To avoid changes in absorption, take marshmallow 30-60 minutes after oral medications.

SLIPPERY ELM

ORAL DRUGS

Interaction Rating = Moderate Be cautious with this combination.

Severity = Moderate • Occurrence = Possible • Level of Evidence = D

Theoretically, slippery elm may slow the absorption and reduce serum levels of oral drugs.

Details

Slippery elm inner bark contains mucilage, which may interfere with the absorption of orally administered drugs (19).

SPOTTED GERANIUM (Cranesbill (Geranium maculatum) root powder)

None known.

Report an Adverse Reaction to RF Plus

Adverse Effects view details

Below is general information about the adverse effects of the known ingredients contained in the product RF Plus. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.

BROMELAIN

General ...Orally, bromelain seems to be well tolerated.
Most Common Adverse Effects:
Orally: Diarrhea, flatulence, gastric upset, headache.
Topically: Pruritus, urticaria.

Dermatologic ...Topically, bromelain may cause dermal allergic reactions including urticaria, pruritus, and skin swelling (9184). Redness, swelling, burning, pain at the application site, and cellulitis have also been reported rarely (108148,113513). In one case, a fixed drug eruption with pruritis near the groin was reported in a 33-year-old male taking bromelain 50 mg orally daily for 10 days. After discontinuation of bromelain and treatment with topical corticosteroid, the lesion resolved. Upon re-challenge with bromelain, the lesion reappeared in the same area (103300).
In another case report, a 61-year-old male with a history of chronic lower leg ulceration secondary to chronic venous hypertension and recurrent deep vein thrombosis on rivaroxaban presented with a deep-dermal burn on his lower calf. Bromelain-based topical enzymatic debridement agent Nexobrid 2 grams was applied to the burn site. Thirty minutes later, the patient experienced two instances of hemorrhage at the site of debridement. The patient was stabilized and treated with fluids, packed red cells, and tranexamic acid, and then the Nexobrid was removed (111656). Caution should be used in patients with underlying coagulopathies.

Gastrointestinal ...Orally, bromelain may cause gastrointestinal disturbances, including diarrhea, nausea, vomiting, flatulence, and abdominal pain (9184,18274,18282,96216,113513).

Immunologic ...Immunoglobulin E (IgE)-mediated allergic reactions to bromelain may occur (9184).
If inhaled, bromelain may cause sensitization and allergic reactions such as asthma (37199,37215,37233). In case reports of occupational inhalation of bromelain, additional allergic symptoms included difficulty swallowing, throat itching, eye irritation, and rhinitis (37214).

CABBAGE

General ...Topically, cabbage leaf seems to be well-tolerated.

Dermatologic ...Some preliminary clinical research shows that application of cabbage leaf wraps to knee joints for at least 2 hours daily for 4 weeks is generally well-tolerated. Of the 27 patients using cabbage leaf wraps in this study, one patient reported an itching and burning sensation during the application. This patient was later found to have shingles, which may explain the adverse event (93671). However, in another case, a patient applying fresh Savoy cabbage leaves on his knee to reduce joint pain reported pain and burning after 4 hours of use. Skin patch and prick tests did not indicate an allergic reaction, and the patient's lesion improved with wet dressings, topical antibiotics, and oral antibiotics (93675).

Immunologic ...Topically, cabbage may cause contact dermatitis (93675). Allergic reactions to cabbage-related vegetables are rare. However, anaphylactic reactions to broccoli and cauliflower have been reported. Because the surface proteins believed to cause allergic reactions to brocolli are also found in cabbage, some patients allergic to brocolli or other vegetables in the Brassicaceae family may also be allergic to cabbage (92516).

Other ...Topical application of cabbage leaves to the breasts has been reported to stain clothes and put off an unpleasant smell (6781,6782).

ECHINACEA (Echinacea angustifolia root extract)

General ...Orally, echinacea is well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, heartburn, nausea and vomiting, rashes, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions and hepatitis have been reported.

Dermatologic ...Itching, urticaria, tingling, and allergic rashes have been reported with various echinacea preparations (8225,12355,17519,20059,20077,101592,111530,111540). In a study of children aged 2-11 years, rash occurred in about 7% of children treated with an extract of the above-ground parts of E. purpurea (EC31J2, Echinacin Saft, Madaus AG), compared with about 3% of those treated with placebo (4989,95652). There is concern that allergic reactions could be severe in some children. The Medicines and Healthcare Products Regulatory Agency in the United Kingdom (UK) recommends against the use of oral echinacea products in children under 12 years of age due to this risk of allergic reaction (18207). However, another study in children 4-12 years old shows that a specific E. purpurea product (Echinaforce Junior, A. Vogel) did not cause allergic or urticarial reactions more frequently than vitamin C (105719).

Gastrointestinal ...Gastrointestinal adverse effects include nausea and vomiting, abdominal pain, stomach upset, heartburn, diarrhea, and constipation (10802,11970,12355,13419,17519,20059,48680,105719,106626). An unpleasant taste, dry mouth, and burning, tingling or numbness of the tongue also occur (11970,12355,17519,20059,20070,20077).

Hematologic ...A 51-year-old female presented with leukopenia after taking echinacea 450 mg three times daily for 2 months, along with ginkgo biloba, multivitamins, and calcium. Her leukocyte count recovered upon stopping these supplements, but dropped again when she restarted echinacea alone about a year later. The problem resolved when echinacea was stopped permanently (48533). A 32-year-old male presented with severe thrombotic thrombocytopenic purpura (TTP) about 2 weeks after using an extract of E. pallida to treat a cold. He required admission to an intensive care unit and extensive plasmapheresis. The authors speculate that immunostimulant effects of echinacea induced or exacerbated the TTP (48572).

Hepatic ...Although uncommon, cases of echinacea-induced hepatitis have been reported. One case report describes acute cholestatic autoimmune hepatitis in a 45-year-old male who had been taking an echinacea root extract 1500 mg daily for about 2 weeks. He presented with significantly elevated liver function tests (LFTs), elevated immunoglobulin G (IgG) levels, and a positive test for anti-smooth muscle antibodies, indicating an autoimmune process. Elevated LFTs and IgG levels returned to normal within one month of stopping echinacea (17518). Another case report describes acute cholestatic hepatitis in a 44-year-old male who had taken echinacea root tablets 600 mg daily for 5 days to treat flu-like symptoms. He presented with elevated LFTs, prothrombin time, and international normalized ratio (INR). His condition gradually improved after stopping echinacea, and his LFTs normalized within 3 months (91528).
Seven cases of hepatitis associated with echinacea use were reported to the Australian Adverse Drug Reactions Advisory Committee between 1979 and 2000, but specific details are lacking (8225).
One case report describes acute liver failure in a 2 year-old child who had been given about 100 mg of echinacea daily for 2 weeks. The patient presented with jaundice, diarrhea, lethargy, anorexia, and significantly elevated LFTs. A liver biopsy showed hepatocyte swelling, spotty necrosis, and inflammatory infiltrate with eosinophils. A full recovery was made over a 2-week period (88166).

Immunologic ...Allergic reactions, including urticaria, runny nose, dyspnea, bronchospasm, acute asthma, angioedema, and anaphylaxis, have been reported with various echinacea preparations (638,1358,8225). Atopic individuals and those sensitive to other members of the Asteraceae family (ragweed, chrysanthemums, marigolds, daisies) seem to be at higher risk for these reactions (1358,8225).
A case report describes a 36-year-old female who presented with muscle weakness, electrolyte abnormalities, renal tubular acidosis, fatigue, and dry mouth and eyes after taking echinacea, kava, and St. John's Wort for 2 weeks., She also had a positive antinuclear antibody (ANA) test, with elevated anti-dsDNA antibodies SSA and SSB. Sjogren syndrome was diagnosed; the authors hypothesize that it may have been triggered by the immunostimulant effects of echinacea (10319). A 55-year-old male with a history of pemphigus vulgaris in remission for about a year experienced a flare of the disease after taking an echinacea supplement for one week. After stopping echinacea, medical treatment resulted in partial control of the disease (12171). Another case report describes a 58-year-old male who presented with marked eosinophilia and elevated immunoglobulin E (IgE) levels while taking an echinacea supplement. He required prednisone therapy until he stopped taking echinacea 3 years later, at which time his eosinophils and IgE normalized (48623). A 41-year-old male experienced four episodes of erythema nodosum, each occurring after he had taken echinacea for early symptoms of influenza. After stopping echinacea, he had no further exacerbations of erythema nodosum, suggesting that it had been triggered by the immunostimulant effects of echinacea (7057).

Musculoskeletal ...Reports of arthralgia and myalgia have been associated with echinacea (13418).

Neurologic/CNS ...Headache has been reported in people taking various echinacea preparations orally (3282,11970,17519,20059,20064). Dizziness has also been reported (3282,8225,11970). In one study using an alcoholic extract of the above-ground parts of E. purpurea (EC31J0, Echinacin, Madaus AG), somnolence and a tendency to aggressiveness were reported (3282).

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). 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). 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). 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).

GOLDENSEAL (Goldenseal (Hydrastis canadensis) root extract)

General ...There is limited reliable information available about the safety of goldenseal when used in more than a single dose. Berberine, a constituent of goldenseal, is generally well tolerated when used orally.
Most Common Adverse Effects:
Orally: Berberine, a constituent of goldenseal, can cause abdominal distension, abdominal pain, bitter taste, constipation, diarrhea, flatulence, headache, nausea, and vomiting.

Dermatologic ...Orally, berberine, a constituent of goldenseal, may cause rash. However, this appears to be rare (34285). A case of photosensitivity characterized by pruritic, erythematous rash on sun-exposed skin has been reported in a 32-year-old female taking a combination product containing goldenseal, ginseng, bee pollen, and other ingredients. The rash resolved following discontinuation of the supplement and treatment with corticosteroids (33954). It is not clear if this adverse effect is due to goldenseal, other ingredients, or the combination.

Endocrine ...A case of severe, reversible hypernatremia has been reported in an 11-year-old female with new-onset type 1 diabetes and diabetic ketoacidosis who took a goldenseal supplement (52592).

Gastrointestinal ...Orally, berberine, a constituent of goldenseal, may cause diarrhea, constipation, flatulence, vomiting, abdominal pain, abdominal distention, and bitter taste (33648,33689,34245,34247,34285,91953). Theoretically, these effects may occur in patients taking goldenseal. However, this hasn't been reported in clinical research or case reports.

Neurologic/CNS ...Orally, berberine, a constituent of goldenseal, may cause headache when taken in a dose of 5 mg/kg daily (33648). Theoretically, this may occur with goldenseal, but this hasn't been reported in clinical research or case reports.

MARSHMALLOW

General ...Orally and topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

SLIPPERY ELM

General ...Orally, slippery elm seems to be well tolerated. A thorough evaluation of safety outcomes with topical use of slippery elm has not been conducted.

Dermatologic ...Topically, slippery elm extracts can cause contact dermatitis. The pollen is an allergen (6). Contact dermatitis and urticaria have been reported after exposure to slippery elm or an oleoresin contained in the slippery elm bark (75131).

SPOTTED GERANIUM (Cranesbill (Geranium maculatum) root powder)

General ...No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

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