Immune Alert by Herbs, Etc.

POSSIBLY EFFECTIVE

• Common cold. Oral andrographis, taken alone or as part of a specific combination product (Kan Jang, Swedish Herbal Institute) also containing eleuthero, seems to improve symptoms of the common cold. It is unclear if oral andrographis is beneficial for preventing the common cold. Details: Most clinical research shows that taking andrographis alone or as part of a combination herbal supplement improves cold symptoms (2744,2773,2774,5784,10795,12380,12381,98222). Taking a specific combination product (Kan Jang, Swedish Herbal Institute) containing andrographis extract, standardized to andrographolides 4-5.6 mg, and eleuthero three times daily seems to improve symptoms of the common cold when started within 72 hours of symptom onset. Some symptoms can improve after 2 days of treatment, but it typically takes 4-5 days of treatment for maximal symptom relief (2744,2773,2774,5784,10795,12380). This combination also seems to relieve cold symptoms better than echinacea or placebo in children (12381). Other clinical research shows that taking a specific andrographis extract (KalmCold) 200 mg daily for 5 days reduces cold symptoms by approximately two-fold and increases the number of patients who respond to treatment when compared with placebo (31222). Preliminary clinical research shows that taking andrographis (Kan Jang, Swedish Herbal Institute) prophylactically might decrease the risk of developing a cold by about 50% after 2 months of continuous treatment (2772); however, more evidence is needed to confirm these results.
• Osteoarthritis. Oral andrographis extract has been evaluated for the treatment of osteoarthritis, with promising results. Details: In patients with mild to moderate osteoarthritis of the knee, clinical research shows that taking a specific brand of andrographis extract (ParActin, HP Ingredients) 300 mg and 600 mg daily for 12 weeks reduces pain and stiffness by approximately 40% and 46%, respectively, compared with changes of less than 10% with placebo (101116).
• Tonsillopharyngitis. Oral andrographis has been evaluated for the management of fever and sore throat associated with tonsillopharyngitis, with promising results. Details: Some clinical research shows that andrographis 6 grams daily is comparable to acetaminophen for reducing fever and sore throat associated with tonsillopharyngitis after 3 and 7 days of treatment (2748).
• Ulcerative colitis. Oral andrographis extract has been evaluated for the management of ulcerative colitis symptoms, with promising results. Details: Some clinical research shows that taking andrographis extract 1200-1800 mg daily for 8 weeks reduces symptoms of mild to moderate ulcerative colitis, but does not affect remission rates, when compared with placebo (31231). Additional clinical research also shows that taking andrographis extract 1200 mg daily for 8 weeks is as effective as mesalamine for reducing symptoms in patients with ulcerative colitis (31223).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acute bronchitis. Although there has been interest in using oral andrographis for acute bronchitis, there is insufficient reliable information about the clinical effects of andrographis for this purpose.
• Cognitive impairment. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in a small number of patients with mild cognitive impairment shows that taking a combination product (Adaptra Forte, Europharma USA) containing andrographis extract 400 mg, standardized to andrographolides 40 mg, and ashwagandha extract 150 mg twice daily for 4 weeks modestly improves some measures of concentration and sleep quality when compared with placebo (104822).
• Coronavirus disease 2019 (COVID-19). It is unclear if oral andrographis is beneficial in mild to moderate COVID-19. Details: A moderate-sized clinical study in adults with mild to moderate COVID-19 receiving standard of care conducted in India shows that taking andrographis raw plant part extract 200 mg twice daily for 14 days improves the time to clinical improvement by 2-points on the World Health Organization (WHO) scale to about 4 days compared with about 6 days in the control group (112920). However, the interpretation of this finding is limited by unbalanced groups with sicker patients in the control group. Additionally, a large observational study conducted in Thailand in unvaccinated hospitalized adults with mild COVID-19 suggests that taking andrographis, dosed as andrographolide 60 mg, three times daily for 5 days is not associated with a decrease in the risk of developing pneumonia when compared with standard of care (112919).
• Diabetes. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial in adults with type 2 diabetes who are taking metformin 1000 mg daily shows that taking a combination product containing andrographis and Syzygium polyanthum leaf extracts, 900 mg daily for 8 weeks, does not improve fasting blood glucose levels, glycated hemoglobin (HbA1c), blood pressure, or blood lipid levels when compared with placebo (101117).
• Familial Mediterranean fever. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children 3-15 years of age shows that taking a combination product (ImmunoGuard, Inspired Nutritionals) containing andrographis 16 mg, eleuthero, schisandra, and licorice daily for 1 month reduces the duration, frequency, and severity of attacks of familial Mediterranean fever (12382).
• Hypertriglyceridemia. It is unclear if oral andrographis is beneficial in patients with hypertriglyceridemia. Details: A small clinical study in adults with hypertriglyceridemia shows that taking andrographis, standardized to contain andrographolide 119.64-120.36 mg, by mouth daily for 8 weeks decreases triglycerides by 42 mg/dL, demonstrating comparable effects to gemfibrozil. However, compared to baseline, total cholesterol was increased by 15 mg/dL and low-density lipoprotein (LDL) cholesterol was increased by 21 mg/dL, suggesting that the benefits of lower triglycerides may be offset by elevations in other lipid levels. Taking a lower daily dose of andrographis, standardized to contain andrographolide 71.64-72.36 mg, does not seem to affect lipid levels (91839).
• Impaired glucose tolerance (prediabetes). It is unclear if oral andrographis is beneficial in patients with prediabetes. Details: A small crossover clinical study in adults with prediabetes conducted in Indonesia shows that taking andrographis 550 mg for 14 days increases glucagon-like peptide 1 (GLP-1) levels but does not statistically improve measures of insulin resistance (i.e., fasting insulin, fasting glucose, 2-hour postprandial glucose, 2-hour postprandial insulin, homeostatic model assessment for insulin resistance [HOMA-IR]) when compared with placebo (112918). However, it is unclear whether this improvement is clinically significant. In addition, the frequency of andrographis dosing is unclear.
• Influenza. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that patients with influenza who take a specific product (Kan Jang, Swedish Herbal Institute) containing andrographis extract, standardized to andrographolides 4-5.6 mg, and eleuthero three times daily for 3-5 days have more rapid symptom relief when compared with patients taking amantadine. Taking this combination product also seems to reduce the risk of post-influenza complications such as rhinosinusitis or bronchitis when compared with amantadine (10441).
• Migraine headache. Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Research has evaluated a combination product (Vivinor, Brain Therapeutics; Partena, FB Health) containing andrographis 100 mg, magnesium 281 mg, riboflavin 5 mg, feverfew 150 mg, and coenzyme Q10 20 mg. A nonblinded, clinical study in patients with episodic migraines shows that taking 1-2 tablets of this product daily for 3 months decreases monthly average migraine days, migraine severity, and the number of days an acute migraine medication is used when compared with baseline. In the third month of treatment, 57% of patients had at least a 50% reduction in average migraine days (107473). The validity of this study is limited by the lack of randomization and placebo-control; additionally, it is unclear if any effects are due to andrographis, the other ingredients, or the combination.
• Multiple sclerosis (MS). It is unclear if oral andrographis is beneficial in patients with MS. Details: A small clinical study in patients with relapsing-remitting MS currently receiving interferon-beta shows that taking andrographis dried extract (Innobioscience Spa) 170 mg, standardized to contain andrographolides 85 mg, twice daily for 12 months decreases fatigue by 44%, but does not affect relapse rate or disability, when compared with placebo (91838). Another small clinical study of patients with primary or secondary, but not active, progressive MS shows that taking andrographolide, a constituent of andrographis, 140 mg twice daily for 24 months slows the progression of disability when compared with placebo (104821).
• Rheumatoid arthritis (RA). It is unclear if oral andrographis is beneficial in patients with RA. Details: Preliminary clinical research shows that taking andrographis extract 90 mg daily for 14 weeks reduces symptoms of RA when compared to baseline, but not when compared with placebo (31220).
• Rhinosinusitis. Although there has been interest in using oral andrographis for rhinosinusitis, there is insufficient reliable information about the clinical effects of andrographis for this purpose.
• Upper respiratory tract infection (URTI). Oral andrographis has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in adults with uncomplicated URTI shows that a specific combination product (Kan Jang, Swedish Herbal Institute) containing andrographis 195 mg and eleuthero root 11.4 mg per capsule, taken as two capsules three times daily for 5 days, reduces the median number of sick leave days to 2 days, compared with 3 days in the placebo group. It also increases the total number of recovered patients on day 3 to 75%, compared with 55% of those taking placebo (107471). More evidence is needed to rate andrographis for these uses.

(Read more about ANDROGRAPHIS)

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).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• 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.

(Read more about ECHINACEA)

POSSIBLY EFFECTIVE

• Influenza. Although some small clinical studies show that elderberry extracts can improve influenza symptoms in otherwise healthy adults, a small clinical study enrolling adults and children with or without high risk medical conditions shows it does not reduce the duration of symptoms. Details: Small clinical studies in otherwise healthy adults with influenza presenting within 48 hours of symptom onset show that taking elderberry extract syrup (Sambucol, Nature's Way) 15 mL four times daily for 5 days improves patient ratings of symptoms such as aches and pains, cough, and nasal congestion an average of 4 days earlier than in control groups. It also reduced the use of rescue medications (5260,12235). Another small clinical study in adults shows that taking an elderberry extract lozenge (ViraBLOC, HerbalScience) 175 mg four times daily for 2 days, starting within 24 hours of symptom onset, improves flu-like symptoms, typically within 48 hours, when compared with placebo (17022). However, in a small clinical study in children and adults 5 years and older with influenza, including those with high-risk conditions such as asthma, chronic lung disease, and heart disease, using Sambucol for 5 days starting within 48 hours of symptom onset did not reduce the time to complete resolution of symptoms for a 24-hour period when compared with placebo (103831). These negative findings may be due to the age and baseline health status of the enrolled patients, as well as the use of symptom resolution, as opposed to symptom improvement, as the primary outcome. Elderberry has also been evaluated in combination with echinacea for treating influenza symptoms (95650), but it is not clear whether the combination is better than either ingredient alone.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). Although there is interest in using oral elderberry for allergic rhinitis, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Asthenopia (eye strain). Oral elderberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults without dry eye disease with occupations requiring the use of video display terminals shows that taking a specific combination product containing elderberry fruit extract 300 mg, zinc 10 mg, L-carnitine 50 mg, currant 100 mg, and Eleutherococcus root 50 mg (Meramirt CM) once daily for 1 month improves measures of eye strain and contrast sensitivity when compared to baseline. Improvements in these measures were lacking in the control group (111295). Statistical comparison between the two groups was not reported. It is unclear if these effects are due to elderberry, other ingredients, or the combination.
• Cardiovascular disease (CVD). It is unclear whether elderberry has any benefit in CVD. In one small study it did not alter disease markers. Details: Preliminary clinical research in postmenopausal women shows that taking elderberry extract 500 mg daily for 12 weeks does not significantly improve markers of CVD, including inflammatory biomarkers, vascular activity, or plasma lipid or glucose levels, when compared with placebo (21141).
• Chronic obstructive pulmonary disease (COPD). Elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in men aged 40-70 years with a history of smoking and Stage 2 COPD, shows that a combination of elderberry 165 mg, heart's ease herb 165 mg, and calendula flowers 165 mg (Inflaminat, INAT-Farma), 3 capsules daily for 6 months modestly improves the score on the 5-point breathlessness, cough, and sputum scale (BCSS) and modestly increases the mean forced expiratory volume in 1 second (FEV1), compared with no changes in the placebo group. However, the number of COPD exacerbations per month is not affected (103629). It is unclear if these effects are due to elderberry, the other ingredients, or the combination.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral elderberry for CFS, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Common cold. Oral elderberry extract does not seem to PREVENT colds when taken prophylactically, but it may reduce the duration and severity of existing colds. Details: Clinical research in healthy adults shows that taking capsules containing elderberry extract (BerryPharma, Iprona AG) 600 mg daily for 8 days before overseas air travel, and then 900 mg daily starting 1 day before traveling and continuing for 4-5 days after arriving at the destination, does not reduce the number of colds or impact quality of life when compared with placebo. However, this product does reduce the duration of colds by about 2 days and the severity of colds by about 58% when compared with placebo (91374).
• Constipation. Oral elderberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial among airline flight crew shows that taking a specific product (ACTIVE) containing elderberry extract 70 mg and a specific probiotic formulation (SYNBIO) daily for 1 month improves constipation, stool volume and consistency, ease of defecation, intestinal regularity, flatulence, and diarrhea compared to baseline, but not when compared with placebo (112134). It is unclear if these effects are due to elderberry, the probiotics, or the combination.
• Gingivitis. Elderberry has been evaluated as a mouthwash or patch in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a mouth rinse (HM-302, Izun Pharmaceuticals) containing elderberry, echinacea, and gotu kola 15 mL three times daily for 14 days might prevent worsening of gingivitis when compared with a placebo rinse. However, it only minimally improves symptoms (20069). Other preliminary clinical research shows that applying a periodontal patch (PerioPatch, Izun Pharmaceuticals) containing elderberry, echinacea, and gotu kola either as a single dose, or three times daily for 1 day then once daily for 2 days, reduces some, but not all, measures of inflammation and gingivitis when compared with no treatment (20068,20070).
• HIV/AIDS. Although there has been interest in using oral elderberry for HIV/AIDS, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Hyperlipidemia. It is unclear if elderberry is beneficial for the treatment of hyperlipidemia. Details: One preliminary clinical study in patients with hyperlipidemia shows that taking capsules containing spray-dried elderberry 400 mg, providing 10% anthocyanins, three times daily for 2 weeks does not reduce serum lipids when compared with placebo (21142).
• Lower respiratory tract infections. Oral elderberry extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children aged 2-6 years with recurrent respiratory tract infections shows that adding a specific combination product (Stimunex gocce) containing elderberry extract, beta-glucans, zinc, and vitamin D3 to standard therapy does not reduce the number or duration of lower respiratory tract infections when compared with standard therapy alone. In the four months after treatment completion, the number of infections was reduced by about 50%; however, the total number of infections in each group was small. The dose was 1 drop/kg daily for one month, followed by 1 drop/kg daily for 15 consecutive days each month for the next three months (109212). The validity of this study is limited by lack of blinding.
• Obesity. Elderberry has been studied for weight loss in combination with other ingredients; its effect when used alone is unclear. Details: Observational research in overweight adults shows that replacing all meals for 8 days with a kit containing elderberry juice (from 120 grams of elderberries/day), dried elderberry (225 mg/day), dried elderflower (3.9 grams/day), elderflower extract (600 mg/day), and dried asparagus (40.5 grams/day), while also taking psyllium 2-3 teaspoons daily for 2 weeks, is associated with a mean decrease in body weight of 3.2 kg over 14 days when compared with baseline (94939). The validity of this study is limited by the lack of a comparator group. Also, it is unclear whether this effect is due to elderberry, other ingredients, the combination, or fasting from regular food.
• Psychological well-being. Oral elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical trial among airline flight crew shows that taking a specific product (ACTIVE) containing elderberry extract 70 mg and a specific probiotic formulation (SYNBIO) daily for 1 month improves scores on the Psychological General Well Being Index when compared with placebo. The index measures symptoms of anxiety and depression, general health status, and feelings of vitality and general self-control (112134). It is unclear if these effects are due to elderberry, the probiotics, or the combination.
• Respiratory tract infections. Oral elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children aged 2-6 years with recurrent respiratory tract infections shows that adding a specific combination product (Stimunex gocce) containing elderberry extract, beta-glucans, zinc, and vitamin D3 to standard therapy reduces the duration of respiratory tract infections by about 1.7 days and modestly improves parent-perceived symptom severity when compared with standard therapy alone. However, there was no effect on the number of total, upper, or lower respiratory tract infections, the use of antibiotics or antipyretics, or the number of days missed from school. The product was dosed as 1 drop/kg daily for one month, followed by 1 drop/kg daily for 15 consecutive days each month for the next three months (109212). The validity of this study is limited by lack of blinding.
• Rhinosinusitis. Although there has been interest in using oral elderberry for rhinosinusitis, there is insufficient reliable information about the clinical effects of elderberry for this purpose.
• Upper respiratory tract infection (URTI). Oral elderberry has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in children aged 2-6 years with recurrent respiratory tract infections shows that adding a specific combination product (Stimunex gocce) containing elderberry extract, beta-glucans, zinc, and vitamin D3 to standard therapy does not reduce the number or duration of upper respiratory tract infections when compared with standard therapy alone. At four months after treatment completion, the number of infections was reduced by about 44%; however, the total number of infections in both groups was small. The product was dosed as 1 drop/kg daily for one month, followed by 1 drop/kg daily for 15 consecutive days each month for the next three months (109212). The validity of this study is limited by lack of blinding. More evidence is needed to rate elderberry for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dyspepsia. Oral olive leaf extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small study in healthy adults shows that taking a specific combination product containing olive leaf extract 24% and prickly pear cactus 33% (Mucosave, Bionap S.R.L.) 400 mg daily for 8 weeks seems to improve dyspepsia and other gastrointestinal symptoms when compared with placebo (105904). It is unclear if this benefit would occur in patients with clinically diagnosed dyspepsia.
• Exercise-induced respiratory infections. It is unclear if oral olive leaf extract is beneficial for reducing respiratory infections from exercise. Details: A small clinical study in high school athletes shows that taking one tablet of olive leaf extract providing eleuropein 100 mg daily for 2 months during training season does not reduce the incidence of the common cold when compared with placebo. While it may reduce the number of sick days by 28%, a sub-group analysis suggests that this reduction is only evident in female athletes (101860).
• Gastroesophageal reflux disease (GERD). Although there is interest in using oral olive leaf for GERD, there is insufficient reliable information about the clinical effects of olive for this condition.
• Herpes zoster (shingles). Although there is interest in using oral olive leaf for shingles, there is insufficient reliable information about the clinical effects of olive for this condition.
• Influenza. Although there is interest in using oral olive leaf for influenza, there is insufficient reliable information about the clinical effects of olive for this condition.
• Metabolic syndrome. It is unclear if oral olive leaf extract is beneficial for improving body composition and cardiovascular risk factors in patients with metabolic syndrome. Details: A small clinical trial in overweight, middle-aged males at risk for metabolic syndrome shows that taking four capsules of olive leaf extract providing oleuropein 51.1 mg and hydroxytyrosol 9.7 mg daily for 12 weeks improves insulin sensitivity by 15% when compared with placebo. However, body composition, blood pressure, cholesterol levels, and other cardiovascular risk factors were not improved (92245).
• Osteoarthritis. It is unclear if oral olive fruit or leaf extract is beneficial for improving osteoarthritis. Details: Preliminary clinical research shows that taking a freeze-dried aqueous extract of olive fruit 400 mg daily for 8 weeks decreases pain and increases mobility in people with osteoarthritis (14844). Other preliminary clinical research in adults with knee osteoarthritis shows that taking olive leaf extract 50.1 mg daily for 4 weeks improves overall pain measurements by 14%, compared to only 4% in the placebo group. However, many individual measurements of pain are not improved (92252).
• Osteoporosis. It is unclear if oral olive leaf extract is beneficial for osteoporosis. Details: Clinical research shows that taking olive leaf extract (Bonolive, BioActor BV) 250 mg daily for 12 months, along with elemental calcium 400 mg daily, increases osteocalcin levels by about 32% when compared to baseline; this increase was significant when compared to those taking calcium 400 mg plus placebo, who showed a 6% decrease in osteocalcin levels. However, taking olive leaf extract does not significantly increase bone mineral density of the lumbar spine or femur neck when compared with placebo (92247).
• Rheumatoid arthritis (RA). It is unclear if oral olive fruit extract is beneficial for improving RA symptoms. Details: Preliminary clinical research in adults with RA shows that taking an aqueous freeze-dried extract of olive fruit 400 mg daily for 8 weeks does not improve symptoms when compared with control (14844). More evidence is needed to rate the effectiveness of olive for these uses.

(Read more about OLIVE)

LIKELY SAFE ...when used orally and appropriately, short-term. Andrographis has been used with apparent safety in doses of up to 6 grams daily for up to 7 days. Andrographis extract has been used with apparent safety at doses of up to 340 mg daily for up to 12 months, 600 mg daily for up to 3 months, or 1200 mg daily for up to 8 weeks (2748,31220,31223,31231,91838,91839,101116). Andrographolide, a constituent of andrographis, has been used with apparent safety at a dose of 280 mg daily for 24 months (104821). A specific combination product containing andrographis extract 178-206 mg and eleuthero (Kan Jang, Swedish Herbal Institute) has been taken three times daily with apparent safety for up to 4-7 days (2744,2748,2773,2774,10441,10795,13016).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Andrographis, in combination with other herbs, has been used with apparent safety in clinical trials at doses up to 48 mg daily in children 3-15 years of age for up to one month (12381,12382).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Andrographis is thought to have abortifacient effects (12); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about ANDROGRAPHIS)

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.

(Read more about ECHINACEA)

LIKELY SAFE ...when used orally in the amounts typically found in foods. Elderberry has generally recognized as safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when elderberry fruit extract is used orally, short-term. One specific elderberry fruit extract (Sambucol, Nature's Way) has been used with apparent safety for up to 5 days (5260,12235,103831); another (BerryPharma, Iprona AG) has been used with apparent safety for up to 15 days (91374). A specific elderberry fruit extract lozenge (ViraBLOC, HerbalScience) has been used with apparent safety for 2 days (17022). Other elderberry fruit extracts have been used with apparent safety for up to 12 weeks (21141,21142).

POSSIBLY UNSAFE ...when elder tree leaves and stems, or unripe or uncooked elderberries, are consumed. The unripe green fruit, as well as the leaves and stems of the elder tree, contain a cyanide-producing chemical, which can cause serious toxicity (17020,17021,21143,21144,91374). Cooking eliminates the toxin.

CHILDREN: LIKELY SAFE
when consumed in the amounts typically found in foods.

CHILDREN: POSSIBLY SAFE
when used orally for up to 3 days. A specific fruit extract (Sambucol, Nature's Way) has been used in doses of 15 mL twice daily for 3 days in children 5 years and older (5260,103831).

CHILDREN: POSSIBLY UNSAFE
when unripe or uncooked elderberries are consumed. The unripe green fruit, as well as the leaves and stems of the elder tree, contain a cyanide-producing chemical , which can cause serious toxicity (17020,17021,21143,21144,91374). Cooking eliminates the toxin.

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in the amounts typically found in foods. There is insufficient reliable information available about the safety of elderberry when used for medicinal purposes; avoid using in amounts greater than those found in foods.

(Read more about ELDERBERRY)

LIKELY SAFE ...when olive fruit is used orally and appropriately in amounts commonly found in foods.

POSSIBLY SAFE ...when olive leaf extract is used orally and appropriately. Olive leaf extract providing 51-100 mg oleuropein daily has been used with apparent safety for 6-8 weeks (92245,92247,101860). There is insufficient reliable information available about the safety of olive fruit extract when used in amounts greater than those found in foods.

PREGNANCY AND LACTATION:
Insufficient reliable information available; stick with amounts commonly found in foods.

(Read more about OLIVE)

ACECLOFENAC Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis extract might increase the maximum concentration and decrease the area under the curve of aceclofenac. The clinical significance of these changes is unclear.  Details Animal research suggests that andrographis extract taken orally increases the maximum concentration and decreases the area under the curve of aceclofenac (112916).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Animal and laboratory studies suggest that andrographis has antiplatelet effects (2758,2759).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might increase the risk of hypotension when used with antihypertensive drugs.  Details Animal research suggests that andrographis has hypotensive effects (2755,2760).

CELECOXIB (Celebrex) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis extract might increase the maximum concentration and time to peak concentration of celecoxib. The clinical significance of these changes is unclear.  Details Animal research suggests that andrographis extract taken orally increases the maximum concentration and time to peak concentration of celecoxib but does not appear to impact the area under the curve (112916).

ETORICOXIB (Arcoxia) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might decrease the absorption of etoricoxib, although the clinical significance is unclear.  Details Animal research shows that andrographis extract, or the constituent andrographolide, taken orally with etoricoxib decreases the bioavailability of etoricoxib. However, this reduced bioavailability is not correlated with a reduction in the anti-inflammatory effects of etoricoxib in arthritic mice models (91837). The clinical significance of this interaction is unclear.

GLIPIZIDE (Glucotrol) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis extract might increase the maximum concentration and area under the curve of glipizide; however, opposite effects are seen with the constituent, andrographolide. The clinical significance of this interaction is unclear.  Details Animal research suggests that andrographis extract taken orally with glipizide in diabetes-induced rats increases the maximum concentration and area under the curve of glipizide. However, the opposite effect is seen with the constituent, andrographolide, in which the maximum concentration and area under the curve are decreased when taken with glipizide (112917).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, andrographis might interfere with the effects of immunosuppressive drugs.  Details Laboratory research suggests that andrographolide has immunostimulant activity (2766).

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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).

(Read more about ECHINACEA)

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, elderberry might interfere with immunosuppressant therapy due to its immunostimulant activity.  Details Elderberry has immunostimulant activity, increasing the production of cytokines, including interleukin and tumor necrosis factor (10796).

(Read more about ELDERBERRY)

(Read more about OLIVE)

General ...Orally, andrographis is generally well tolerated. Adverse effects are more likely when doses reach or exceed 5-10 mg/kg of andrographolide content and when treatment duration exceeds 14 days.
Most Common Adverse Effects:
Orally: Abdominal discomfort, altered taste, diarrhea, dizziness, fatigue, headache, nausea and vomiting, pruritus, rash, and urticaria.
Serious Adverse Effects (Rare):
Orally: Severe allergic reactions, including anaphylaxis.

Cardiovascular ...Orally, andrographis has been reported to cause vasculitis, edema, and increased sweating (12380,13016,91841).

Dermatologic ...Orally, andrographis has been frequently reported to cause maculopapular, erythematous rash, pruritus, and urticaria (31223,31222,31233,12380,31231,31220,13016,91838,91841,104821)(107783,112921). Andrographis consumption has also been reported to cause angioedema, exfoliative dermatitis, skin exfoliation, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, bullous eruption, fixed eruption, stomatitis, allergic purpura, flushing, and swelling (91841).
Parenterally, there have been reports of maculopapular rash, urticaria, pruritus, and flushing with the use of andrographolide derivative injections; about one-third of patients experienced skin or subcutaneous reactions (112921).

Gastrointestinal ...Orally, andrographis has been reported to cause nausea, vomiting, diarrhea, dyspepsia, flatulence, altered or metallic taste, and abdominal discomfort (6767,31213,2748,13016,31220,31222,91841,104821,107783,112921). Andrographis intake has also been reported to cause epigastric pain, ulcerative stomatitis, melena, dry mouth, and dry lips (31213,10795,13016,91841).
Parenterally, there have been reports of diarrhea, nausea, vomiting, and abdominal discomfort with the use of andrographolide derivative injections; over 40% of patients experienced gastrointestinal events (112921).

Genitourinary ...Orally, there is one case report of increased urinary frequency associated with andrographis use (91841)

Hematologic ...Orally, there is one case report of epistaxis (nosebleed) associated with andrographis use (31222).

Hepatic ...Orally, there is one case report of hepatitis associated with andrographis use (91841).

Immunologic ...Orally, andrographis has been reported to cause anaphylactic shock in 2 cases with determined causality, and 7 cases with probable causality. Anaphylactic shock developed in 5 minutes to one day after oral intake, and included symptoms such as hypotension, chest pain, urticaria, angioedema, wheezing, and tachycardia (91841). Additionally, andrographis intake has been associated with cases of eosinophilia and fever (91841,107783). High doses of the andrographolide constituent (5-10 mg/kg daily) have been associated with two cases of lymphadenopathy and three cases of lymph node pain (6767).
Parenterally, there have been 97 cases reporting severe or life-threatening anaphylaxis after andrographolide derivative injections, 3 of which resulted in death (112921).

Musculoskeletal ...Orally, andrographis has been associated with case reports of pain, muscle weakness, cramps, and paralysis (31220,91841,107783).

Neurologic/CNS ...Orally, andrographis has been reported to cause headache, fatigue, anorexia, somnolence, insomnia, lethargy, malaise, and drowsiness (2748,5784,6767,10795,12380,13016,31220,31213,31222,91841,107783). Headache and fatigue occurred more often with high doses of the andrographolide constituent (5-10 mg/kg daily) in one clinical trial (6767).

Pulmonary/Respiratory ...Orally, andrographis has been reported to cause dyspnea, coughing, bronchospasm, increased sputum, and nasal congestion (10795,13016,31213,91841,107783).

(Read more about ANDROGRAPHIS)

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).

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General ...Orally, elderberry extracts prepared from ripe fruit seem to be well tolerated.
Most Common Adverse Effects:
Orally: When adverse effects occur, they are likely due to ingestion of raw and unripe elderberries, or seeds, leaves, and other plant parts. Due to cyanogenic glycosides, these may cause nausea, vomiting, severe diarrhea, weakness, dizziness, numbness, and stupor. Cooking eliminates the toxin.

Gastrointestinal ...Orally, nausea and vomiting have been reported after consuming a specific elderberry and echinacea product Vogel Bioforce AG) (95650). However, it is unclear if this was due to the elderberry or Echinacea contained in the product.
Raw and unripe elderberries, and the seeds, leaves, and other elder tree parts might cause nausea, vomiting, or severe diarrhea due to cyanogenic glycosides (17020,17021). Cooking eliminates the toxin.

Hepatic ...In one case report, a 60-year-old female with underlying autoimmune disease presented with autoimmune hepatitis after taking elderberry at an unknown dose for several years. The patient presented with nausea, jaundice, abdominal pain, and abdominal distention. Liver function tests returned to baseline 4 weeks after initiating treatment with prednisone 40 mg daily and discontinuing elderberry (110123).

Immunologic ...Elder tree pollen might cause an allergic reaction characterized by rhinitis and dyspnea in some patients who are allergic to grass pollen. These patients might also experience an allergic reaction to elderberry extracts (11095).

Neurologic/CNS ...Raw and unripe elderberries might cause weakness, dizziness, numbness, and stupor due to cyanogenic glycosides (17020,17021). Cooking eliminates the toxin.

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General ...Orally, olive fruit is well tolerated when used in typical food amounts. Olive leaf extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Headache and stomach discomfort.

Dermatologic ...Orally, one patient in one clinical trial reported bad skin and acne after using olive leaf extract (101860).

Gastrointestinal ...Orally, three patients in one clinical trial reported stomach ache after using olive leaf extract (101860).

Neurologic/CNS ...Orally, three patients in one clinical trial reported headache after using olive leaf extract (101860).

Psychiatric ...In one case report, a 67-year-old female experienced irritability, anger, a lack of control, and feelings of sadness and negativity after consuming a multi-ingredient product containing olive leaf extract 5 grams, horseradish root, and eyebright daily for 38 days. All psychiatric symptoms disappeared within days of stopping the combined product. It is hypothesized that the hydroxytyrosol component of olive leaf extract contributed to these symptoms due to its chemical similarity to dopamine; however, it is not clear if these symptoms were due to the olive leaf extract or to the other ingredients (96245).

Pulmonary/Respiratory ...Olive tree pollen can cause seasonal respiratory allergy (1543).

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