Soft Tissue Soother [Discontinued] by Herb Pharm

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.

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POSSIBLY EFFECTIVE

• Burns. Topical gotu kola seems to improve the rate of burn healing. Details: Clinical research shows that applying a cream containing gotu kola 3% once daily to second degree burns increases the rate of re-epithelialization and complete healing by about 7 days when compared with silver sulfadiazine (SSD) 1% cream. Gotu kola cream also seems to reduce dryness, itching, irritation, and scar severity when compared with SSD (97027). Other research in adults with second degree burns shows that applying a gauze dressing containing gotu kola 5% and aloe 2.5%, covered with absorbent cotton wool and changed every 3 days, reduces time to healing by 1.5 days and length of hospital stay by 1.7 days when compared with the use of a gauze dressing containing chlorhexidine acetate 0.5% (97028).
• Venous insufficiency. Oral gotu kola seems to improve symptoms of venous insufficiency. Details: Clinical research shows that taking gotu kola or a specific extract of gotu kola (Centellase) 60-180 mg daily orally for 4-8 weeks seems to improve measures of circulation and decrease symptoms such as edema in patients with venous insufficiency (6887,9786,11063,11064,11066,11070,52894,52909).

POSSIBLY INEFFECTIVE

• Cognitive function. Oral gotu kola does not seem to be beneficial for cognitive function. Details: A meta-analysis of a small number of generally moderate quality clinical trials shows that taking a single dose of gotu kola, alone or in combination with other ingredients, does not improve cognitive function when compared with placebo (105334). In one study, gotu kola was taken in combination with ginkgo and docosahexaenoic acid (DHA) for 4 months by healthy, cognitively intact older adults (52880).
• Radiation dermatitis. Topical gotu kola does not seem to reduce symptoms of radiation dermatitis. Details: Clinical research in females undergoing radiotherapy for breast cancer shows that applying a cream containing gotu kola extract 7% once daily during and up to 4 weeks following radiotherapy does not reduce the severity of dermatitis when compared with no treatment or applying a moisturizing cream (102792).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging skin. Oral gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy, middle-aged females shows that applying a topical emulsion containing extracts of gotu kola 3% and Indian gooseberry 3% twice daily for 60 days improves skin hydration, some measures of skin wrinkles, and elasticity of the cheek (but not the eye) when compared with placebo (111571). It is unclear if these effects are due to gotu kola, Indian gooseberry, or the combination.
• Alzheimer disease. Although there is interest in using oral gotu kola for Alzheimer disease, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Anal fissures. It is unclear if topical gotu kola is beneficial for anal fissures. Details: In patients with chronic anal fissures who are using standard dietary and hygiene treatments, preliminary clinical research shows that taking gotu kola extract 60 mg twice daily for 8 weeks and locally applying an ointment containing gotu kola does not reduce the mean time to bleeding cessation when compared with standard treatments alone. However, pain may be modestly improved. Also, gotu kola was less effective than an unspecified flavonoid mixture used both orally and topically (105332).
• Atherosclerosis. It is unclear if oral gotu kola is beneficial for slowing the progression of atherosclerotic plaques. Details: Some preliminary clinical research shows that taking gotu kola extract 60 mg orally three times daily for 12 months helps stabilize low-density atherosclerotic plaques when compared with placebo (11062,11069). Gotu kola has also been evaluated in combination with a specific maritime pine bark product (Pycnogenol, Horphag Research). A non-randomized clinical trial shows that taking gotu kola 225 mg and Pycnogenol 150 mg in two divided doses daily for 3 months reduces plaque height and length and increases plaque echogenicity and stability when compared to control (97030). Another non-randomized clinical study in adults with atherosclerotic plaques and no other cardiovascular risk factors shows that taking gotu kola extract 100 mg and Pycnogenol 100 mg daily for up to 4 years reduces plaque progression and increases plaque echogenicity when compared with Pycnogenol alone or no treatment at all. Taking gotu kola and Pycnogenol is also associated with a reduced rate of clinical vascular events, including angina, myocardial infarction, minor transient ischemic attacks (TIAs), and minor strokes when compared with taking Pycnogenol alone or receiving no treatment at all (97029). It is unclear how these outcomes would compare to the use of gotu kola alone.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral gotu kola for ADHD, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Atopic dermatitis (eczema). Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying an ointment containing 5% each of the extracts of heart's ease, gotu kola, and Oregon grape twice daily for 4 weeks does not improve eczema when compared with a base cream. However, patients with eczema on skin exposed to cold weather might experience some improvement (67372).
• Depression. Although there is interest in using oral gotu kola for depression, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Diabetic foot ulcers. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with deep diabetic foot ulcers, preliminary clinical research shows that applying a cream (WH-1 cream) containing 1.25% of gotu kola and Plectranthus amboinicus extracts in a 4:1 ratio twice daily for 2 weeks after surgical debridement is as effective as the use of a standard hydrocolloid fiber wound dressing for improving wound size. However, when compared with baseline, changes in wound size were not statistically significant (105335).
• Diabetic microangiopathy. It is unclear if oral gotu kola is beneficial for diabetic microangiopathy. Details: Preliminary clinical research shows that taking gotu kola extract 60 mg orally twice daily for 6-12 months helps increase measures of circulation and decrease edema in patients with diabetic microangiopathy (11065,11068,52917).
• Dry skin. It is unclear if topical gotu kola is beneficial for dry skin. Details: In patients with dry skin associated with type 2 diabetes, clinical research shows that topical application with 0.25 grams of a gotu kola 1% ointment twice daily, either alone or with oral gotu kola 1100 mg twice daily, for 28 days does not improve dry skin when compared with placebo. However, in a sub-group of patients with well-controlled diabetes, the combination of oral and topical gotu kola modestly improved dry skin (105329). Additionally, a small clinical study in individuals with dry skin due to working with synthetic and natural dyes shows that application of a gotu kola 2% ceramide-based cream to the hands and arms twice daily for 4 weeks improves skin barrier hydration, as measured by hydration of the stratum corneum and skin acidity, when compared to baseline. These improvements were similar to those seen with a ceramide 5% cream (109554). As the gotu kola cream was formulated with ceramide, it is unclear if these findings are due to gotu kola, ceramide, or the combination.
• Epilepsy. Although there is interest in using oral gotu kola for epilepsy, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Generalized anxiety disorder (GAD). It is unclear if oral gotu kola is beneficial for GAD. Details: In patients with GAD, preliminary clinical research shows that taking gotu kola extract 500 mg twice daily for 60 days reduces symptoms of anxiety, depression, and stress by 22% to 26% when compared with baseline (105333). The validity of these findings is limited by the lack of a comparator group.
• Hemorrhoids. It is unclear if topical gotu kola is beneficial for hemorrhoids. Details: Preliminary clinical research in patients with chronic hemorrhoids, as well as patients with acute symptoms following a hemorrhoidectomy or surgical treatment for hemorrhoidal thrombosis, shows that taking gotu kola extract (Centella complex) 60 mg twice daily for 15 weeks and locally applying an ointment (Proctocella) containing gotu kola, arnica, and aloe, in conjunction with standard treatments, does not reduce the mean time to bleeding cessation when compared with standard treatments alone. Anal irritation was modestly improved in the patients with chronic hemorrhoids and in those undergoing treatment for hemorrhoidal thrombosis, but not in those that had undergone a hemorrhoidectomy (105336).
• Herpes zoster (shingles). Although there is interest in using oral gotu kola for shingles, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Hypertension. It is unclear if oral gotu kola is beneficial for hypertension. Details: Preliminary clinical research in patients with hypertension shows that drinking a tea made by boiling gotu kola 4 grams in 250 mL water three times daily for 3 days modestly reduces systolic and diastolic blood pressure when compared with baseline. After consuming the tea, about 40% of patients had normal or high-normal systolic blood pressure and 77% had optimal or normal diastolic blood pressure, compared with 0% and 45%, respectively, prior to consumption (105330). The validity of these findings is limited by the lack of a comparator group.
• Hypertrophic scars. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that topical use of a specific silicone gel (Bangkok Botanica) containing 15% extracts of gotu kola, onion, aloe, and paper mulberry, starting 2 weeks after surgery and continuing for 6 months, moderately improves the height and pliability of the post-surgical hypertrophic scar when compared with a silicone placebo gel. There was no effect on pigmentation or vascularity (102793). It is unknown whether any benefit is related to gotu kola, other ingredients, or their combination.
• Idiopathic interstitial pneumonia. Oral gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational registry study in males less than 65 years old with idiopathic interstitial pneumonia has found that taking a specific gotu kola extract (Centellicum; Horphag Research) 225 mg three times daily in combination with a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 8 months is associated with a modest improvement in Karnofsky Performance Scale scores and a reduction in fatigue when compared with pirfenidone (108862). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Keloids. It is unclear if oral or topical gotu kola are beneficial for keloids. Details: There is some early evidence that applying a specific extract of gotu kola (Madecassol) topically might help reduce keloids and hypertrophic scarring (13558). Gotu kola has also been taken orally for keloids. Preliminary clinical research in patients at high risk for keloids shows that taking a specific extract of gotu kola (Centellicum, Horphag Research Ltd) 450 mg daily for 4 weeks starting on the second week after surgery seems to improve scar homogeneity and regularity (99756). However, the reliability of these results is limited because patients in this study were not randomized or blinded to different interventions.
• Laser skin resurfacing. It is unclear if topical gotu kola is beneficial for recovery from laser skin resurfacing. Details: A small clinical trial shows that applying a gel containing gotu kola extract (ECa 233) 0.05% four times daily for 7 days, then twice daily for 3 months, improves wound healing following laser resurfacing for facial acne. Redness returned to baseline levels by day 7, in contrast to day 28 on the side treated with a placebo gel. The general wound appearance and crusting were also improved on the side on which the gotu kola extract gel was applied (102794).
• Osteoarthritis. Topical gotu kola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A large, single-blind clinical study in adults with knee osteoarthritis causing moderate pain shows that applying a specific cream (TMP-4) containing extracts of gotu kola leaf, sesame seed, soybean, and mangosteen peel four times daily for 4 weeks provides similar improvement in pain scores when compared with diclofenac 1% gel. Topical TMP-4 cream also seems to improve knee stiffness, stair climbing, and mobility similarly to diclofenac gel. However, patient impression of overall improvement was higher with diclofenac (110128). The validity of this study is limited by inadequate blinding.
• Scarring. It is unclear if topical gotu kola is beneficial for scarring or tenderness from scarring. Details: Preliminary clinical research in patients without a history of keloid formation suggests that applying a specific cream (Alpha Centella, not available in the US) containing gotu kola and Bulbine frutescens extracts twice daily for 6-8 weeks following suture removal might help to reduce scarring (11072). Also, a large clinical study in adults who underwent carpal tunnel release surgery shows that applying gotu kola cream 1% three times daily for 6 months after suture removal marginally improves self-reported scar tenderness pain when compared with control, and modestly improves scarring scores when compared to baseline (112425). However, the interpretation of these findings is limited by patient-reported outcomes and insufficient validity of the scar scoring tool in this population.
• Skin grafts. Although there is interest in using topical gotu kola for skin graft recovery, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Stretch marks (striae gravidarum). It is unclear if oral gotu kola is beneficial for stretch marks; topical gotu kola has only been evaluated in combination with other ingredients. Details: Preliminary clinical research in females with stretch marks shows that taking a specific extract of gotu kola (Centellicum, Horphag Research Ltd) 225 mg three times daily for 6 weeks increases skin thickness, elasticity, and perfusion when compared with a stretch mark minimizer cream (Clarins) and regular control cream (99757). The validity of these results is limited by the fact that patients were not randomized or blinded to the different interventions. Gotu kola has also been evaluated topically in combination with other ingredients. Preliminary clinical research shows that applying a specific mixture of gotu kola, vitamin E, and collagen-elastin hydrolysates in a cream (Trofolastin, not available in the US) daily during the second and third trimesters reduces stretch marks when compared with a placebo cream (13559). Another small clinical study shows that applying a specific mixture of gotu kola, vitamin E, essential fatty acids, hyaluronic acid, elastin, and menthol in an ointment (Verum, not available in the US) helps decrease the formation of stretch marks during pregnancy when compared with placebo (11073). Other preliminary clinical research in patients without previous striae shows that applying a specific formula containing hydroxyprolisilane C, rosehip oil, gotu kola triterpenes, and vitamin E (Velastisa Antiestrías, ISDIN) twice daily, beginning at week 10-14 and continuing throughout pregnancy, decreases the severity of both new and old stretch marks and the incidence of stretch marks when compared with placebo (92507). It is unclear if the effects seen in these studies are due to gotu kola, other ingredients, or the combinations.
• Systemic lupus erythematosus (SLE). Although there is interest in using oral gotu kola for SLE, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Tonsillitis. Although there is interest in using oral gotu kola for tonsillitis, there is insufficient reliable information about the clinical effects of gotu kola for this condition.
• Venous thromboembolism (VTE). It is unclear if oral gotu kola is beneficial for VTE prevention. Details: Preliminary clinical research shows that gotu kola decreases edema and improves measures of circulation in patients traveling on airplanes for more than 3 hours when compared to a control group receiving no treatment (11067). However, it is unknown if these changes reduce the incidence of clots.
• Wound healing. Although there is interest in using topical gotu kola for wound healing, there is insufficient reliable information about the clinical effects of gotu kola for this purpose.
• Wrinkled skin. It is unclear if topical gotu kola is beneficial for wrinkled skin. Details: Small, low-quality studies in healthy adults suggest that topical formulations of gotu kola extract or the constituent asiaticoside 0.1% or 0.2% applied 1-3 times daily have shown modest benefit for wrinkled skin. Cream or gel formulations were used for 12 weeks for periorbital wrinkles and a lipstick was used for 8 weeks for lip wrinkles. However, the extent of benefit is not clear and meta-analyses are limited to a very small number of studies with varied comparator groups, including placebo, vehicle, tretinoin 0.02%, and Pueraria mirifica extract (106639). More evidence is needed to rate gotu kola for these uses.

(Read more about GOTU KOLA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angina. It is unclear if oral hawthorn is beneficial in patients with angina. Details: Preliminary clinical research in patients with angina taking chronic beta-adrenergic receptor blockers or ACE inhibitor therapy shows that taking a hawthorn (Crataegus pinnatifada) extract 100 mg orally three times daily for four weeks improves angina and electrocardiogram (ECG) findings and reduces nitroglycerin intake when compared with placebo (19242). Other preliminary clinical research in patients with unstable angina shows that taking hawthorn 10 grams and hu zang 15 grams orally daily for 4 weeks does not reduce the frequency of angina pectoris attacks when compared with control. However, taking hawthorn and hu zang improved some subjective symptom scores and quality of life scores (109610).
• Anxiety. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A clinical study in adults with mild to moderate generalized anxiety shows that taking a specific product (Sympathyl, not available in the US) containing hawthorn, magnesium, and California poppy for 90 days modestly improves anxiety scores when compared with placebo (12583). Also, a clinical study in adults with adjustment disorder and anxious mood shows that hawthorn, in combination with black horehound, passion flower, valerian, kola nut, and guarana, modestly improves anxiety scores when compared with placebo (6250). It is unclear if these effects are due to hawthorn, other ingredients, or the combination. Another small clinical study in healthy adults shows that taking a combination of herbal extracts containing hawthorn, passionflower, ballota, and valerian root daily for 14 days reduces subjective anxiety and objective sympathetic and autonomic nervous system activation in response to a psychosocial stressor when compared with placebo (111222). It is unclear if these effects are due to hawthorn, other ingredients, or the combination.
• Arrhythmia. Although there has been interest in using oral hawthorn for arrhythmia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Atherosclerosis. Although there has been interest in using oral hawthorn for atherosclerosis, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cardiovascular disease (CVD). Although there has been interest in using oral hawthorn for CVD, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Cognitive function. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, a single dose of 25 drops of a combination product of D-camphor and hawthorn berry extract (Korodin) was superior to placebo for increasing cognitive performance in elderly female patients as measured by visuomotor speed and information processing capacity. The active treatment group showed an improvement in attentional and mental performance (19240,91504).
• Congestive heart failure (CHF). The evidence on the effects of oral hawthorn in patients with CHF is conflicting. Although some older research suggests it may be beneficial, more recent, larger studies suggest it may actually increase the risk for complications. Details: There is contradictory evidence about the effects of hawthorn extract in heart failure patients. Several clinical studies show that taking specific hawthorn leaf and flower extracts (LI 132, Faros 300, Lichtwer Pharma; WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; or HeartCare, Nature's Way) 240-600 mg daily improves ejection fraction and exercise tolerance, reduces subjective symptoms, and decreases the risk of death in patients with New York Heart Association (NYHA) stage II heart failure. In these studies, the maximum effect was usually seen after 6-12 weeks of treatment (8279,8280,11449,19221,19223,19225,19226,19227,19228). Another clinical trial shows that hawthorn extract (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals or HeartCare, Nature's Way) 1800 mg daily, combined with diuretic therapy, improves exercise tolerance and reduces subjective symptoms in NYHA stage III heart failure. In this study, maximum effect was usually seen after 16 weeks of treatment (8281). In another trial, patients with NYHA II heart failure taking either hawthorn (LI 132, Faros) 300 mg three times daily or captopril 12.5 mg three times daily experienced similar improvements in cardiac performance and symptoms (19230). However, other clinical research suggests no benefit and possible harm with hawthorn. A large-scale clinical trial (SPICE) in patients with NYHA stage II or III heart failure shows that taking specific hawthorn extracts (WS 1442, Crataegutt forte, Dr. Willmar Schwabe Pharmaceuticals; HeartCare, Nature's Way) 900 mg daily for 24 months, in combination with conventional treatment, does not decrease hospitalization due to progressive heart failure, non-fatal myocardial infarction, or cardiac death (17203). Another clinical trial in patients with NYHA stage II or III heart failure shows that taking these same specific hawthorn extracts at the same dose for up to 6 months does not slow the progression of heart failure when compared with placebo (19222). In a retrospective analysis of this study, it was shown that heart failure progression was significantly increased in patients taking hawthorn when compared with placebo. The rate of death was also increased by 1.7% over placebo, and heart failure-related hospitalizations increased by 8% over placebo in patients treated with hawthorn (16824).
• Hyperlipidemia. Although there has been interest in using oral hawthorn for hyperlipidemia, there is insufficient reliable information about the clinical effects of arrhythmia for this condition.
• Hypertension. It is unclear if oral hawthorn is beneficial for lowering blood pressure. Details: One preliminary clinical trial showed that taking hawthorn standardized extract 1,000-2,500 mg daily for three days does not significantly reduce blood pressure in hypertensive or prehypertensive patients when compared with placebo (19244). However, another study in patients with diabetes and hypertension shows that taking a specific hawthorn extract (LI 132) 1,200mg daily for 16 weeks significantly decreased diastolic, but not systolic, blood pressure when compared with placebo (19245).
• Orthostatic hypotension. Oral hawthorn has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in older adults with orthostatic hypotension shows that taking a specific combination product containing hawthorn and camphor (Korodin Herz-Kreislauf-Tropfen) 25 drops orally three times daily for 7 days attenuates the blood pressure reduction upon standing when compared with placebo. Signs and symptoms of orthostatic hypotension such as dizziness, blurry vision, and falls also seem to be reduced when compared with baseline (39614,39617). A meta-analysis of 4 studies shows that giving single doses of 20-25 drops of the same combination product increases systolic and diastolic blood pressure when compared with placebo (103620). However, the studies have methodologic problems and, while 2 were conducted in females with orthostatic hypotension, the others involved health young adults or normotensive elderly subjects. The effect of hawthorn alone for treatment of orthostatic hypotension has not been determined. The combination product used in these studies is not available in the US. More evidence is needed to rate hawthorn for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Androgenic alopecia. Although there is interest in using oral horsetail for alopecia, there is insufficient reliable information about the clinical effects of horsetail for this condition.
• Hypertension. Oral horsetail seems to reduce blood pressure in patients with hypertension. Details: A clinical trial in patients with stage 1 systemic arterial hypertension shows that taking horsetail extract 900 mg daily for 3 months decreases systolic and diastolic blood pressure by 13 mmHg and 8 mmHg, respectively, and is similarly effective to hydrochlorothiazide 25 mg daily (108849). The validity of this finding is limited due to high withdrawal rates and low adherence to treatment protocols.
• Kidney stones (nephrolithiasis). Although there is interest in using oral horsetail for kidney stones, there is insufficient reliable information about the clinical effects of horsetail for this condition.
• Obesity. Although there is interest in using oral horsetail for weight loss, there is insufficient reliable information about the clinical effects of horsetail for this purpose.
• Osteoporosis. It is unclear if oral horsetail is beneficial for osteoporosis. Details: Preliminary clinical research shows that taking two tablets of either dried horsetail extract or a specific combination of horsetail extract with calcium (Osteosil Calcium) daily for 2-month intervals separated by 2 weeks of no treatment for up to one year can increase bone density when compared with no treatment in postmenopausal patients with osteoporosis. The effect of horsetail extract plus calcium (Osteosil Calcium) seems to be greater than the effect of dried horsetail extract alone (55578).
• Tonsillitis. Oral horsetail has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with acute non-bacterial tonsillitis shows that taking a specific combination product (Imupret) for 10 days in addition to standard symptomatic therapy accelerates recovery by a small amount when compared with symptomatic therapy alone. Overall treatment response after 10 days occurred in 82% of patients taking the combination product compared with 65% of patients receiving symptomatic therapy alone. Withdrawal from antipyretic drugs occurred approximately one day earlier in children using the horsetail product. Per 100 grams, Imupret provides 29 grams of an alcoholic extract produced from horsetail 0.5 grams, marshmallow root 0.4 grams, chamomile flowers 0.3 grams, walnut leaves 0.4 grams, English walnut leaves 0.4 grams, yarrow 0.4 grams, oak bark 0.2 grams, and dandelion 0.4 grams. In children aged 6-11 years, 15 drops 6 times daily for 5 days and then 15 drops 3 times daily for 5 days was used. In children aged 12-18 years, 25 drops 6 times daily for 10 days was used. (100347). Due to the small difference between the two groups and the open-label design, the clinical relevance of this study is unclear. Also, it is unclear if these benefits are due to horsetail, the other ingredients, or the combination.
• Urinary incontinence. Oral horsetail 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 supplement (Urox, Seipel Group) 840 mg, containing a combination of horsetail stem, three-leaf caper, and lindera root daily with food for 8 weeks modestly decreases urinary frequency, stress incontinence, and urgency incontinence when compared with placebo in patients with urinary incontinence and/or overactive bladder (97575). It is unclear if these effects are due to horsetail, the other ingredients, or the combination.
• Urinary tract infections (UTIs). Although there is interest in using oral horsetail for UTIs, there is insufficient reliable information about the clinical effects of horsetail for this condition. More evidence is needed to rate horsetail for these uses.

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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)

POSSIBLY SAFE ...when used topically and appropriately. Gotu kola has been used safely in a cream or ointment for up to 10 weeks (11072,11073,67372,102792,105329,105335). An emulsion containing gotu kola extract 3% and other ingredients has been applied safely to the skin twice daily for up to 60 days (111571). ...when used orally and appropriately. Gotu kola extract has been used with apparent safety in doses of up to 180 mg daily for up to 12 months or 1000 mg daily for 60 days. Dried gotu kola has been used with apparent safety in doses of up to 2200 mg daily for 4 weeks (6887,11062,11063,11064,11065,11066,11067,11068,11069,11070)(11071,99756,99757,99758,105329,105332,105333). A specific gotu kola extract (Centellicum, Horphag Research Ltd) 450-675 mg daily has been used with apparent safety for up to 6 weeks (99756,99757).

PREGNANCY: POSSIBLY SAFE
when used topically and appropriately (11073,13559). There is insufficient reliable information available about the safety gotu kola when used orally during pregnancy; avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Hawthorn preparations in doses of up to 1800 mg daily seem to be safe when used for up to 16 weeks. Although hawthorn might be safe for long-term use, current studies have not evaluated safety past 16 weeks (8279,8280,8281,10144,17203,104689). There is insufficient reliable information available about the safety of hawthorn when used topically.

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

(Read more about HAWTHORN)

POSSIBLY UNSAFE ...when horsetail products containing thiaminase are used orally, long-term. Thiaminase is an enzyme that destroys thiamine, which could theoretically lead to thiamine deficiency. In Canada, horsetail products are required to be thiaminase-free (105301).

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

(Read more about HORSETAIL)

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)

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gotu kola might increase the sedative effects of CNS depressants.  Details In vitro research suggests that gotu kola may have sedative effects via binding of GABA receptors (6887,11071).

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking gotu kola with hepatotoxic drugs might have additive adverse effects.  Details There are at least four case reports of hepatotoxicity associated with the use of gotu kola. However, more information is needed to determine if gotu kola was the causative factor in these cases (13182,92506).

(Read more about GOTU KOLA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro and animal research shows that hawthorn can inhibit platelet aggregation (95528,95529,95530,95531). However, its effect in humans is unclear. One observational study shows that patients taking hawthorn shortly before undergoing coronary artery bypass graft (CABG) surgery or valve replacement surgery have a 10% incidence of postoperative bleeding, compared with 1% in those who never consumed hawthorn extract (95527). However, clinical research shows that taking a specific preparation of dried hawthorn leaves and flowers (Crataesor, Soria Natural Lab) 800 mg three times daily for 15 days does not affect platelet aggregation or levels of thromboxane B2, the metabolite of thromboxane A2, in healthy humans (54664).

BETA-BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive effects on blood pressure and heart rate.  Details Some evidence shows that hawthorn might lower blood pressure and heart rate (12595,19245).

CALCIUM CHANNEL BLOCKERS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilation and hypotensive effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, hawthorn might potentiate the effects and adverse effects of digoxin.  Details Hawthorn appears to improve cardiac output (12595); however, hawthorn does not appear to affect digoxin pharmacokinetics (19249).

NITRATES Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might cause additive coronary vasodilatory effects.  Details Some evidence shows that hawthorn might lower blood pressure due to vasodilatory effects (12595,19245).

PHOSPHODIESTERASE-5 INHIBITORS Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might result in additive vasodilation and hypotension.  Details Hawthorn might inhibit PDE-5 and cause vasodilation (12595).

(Read more about HAWTHORN)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking horsetail with antidiabetes drugs might increase the risk of hypoglycemia.  Details Equisetum myriochaetum has demonstrated hypoglycemic activity in clinical research (13576). In an animal diabetic model, Equisetum giganteum had hypoglycemic effects (105300). It is unclear whether other horsetail species have hypoglycemic effects.

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking horsetail with diuretic drugs might increase potassium loss and the risk of hypokalemia.  Details Laboratory research shows that various species of horsetail have diuretic properties (13574,13575). Due to its diuretic effects, there has been concern that taking horsetail along with potassium-depleting diuretics might increase the risk for hypokalemia. However, pharmacokinetic research in humans shows that taking horsetail 900 mg daily for 4 days does not affect urinary excretion of electrolytes, including potassium and sodium, despite having a diuretic effect similar to taking hydrochlorothiazide 25 mg daily (92288). It is unclear if taking horsetail for a longer duration would affect electrolyte levels. Until more is known, use with caution.

EFAVIRENZ (SUSTIVA) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, horsetail might decrease the levels and clinical effects of efavirenz.  Details In two case reports, patients were found to have detectable viral loads when taking horsetail-containing supplements along with an antiretroviral regimen that included efavirenz. In one case, the antiretroviral regimen included zidovudine, lamivudine, and efavirenz; in the other case, the regimen consisted of emtricitabine, tenofovir disoproxil fumarate, and efavirenz. One month after discontinuing horsetail, the viral loads became undetectable in both cases. The exact mechanism of this interaction is unknown (97573). It is also unclear if this interaction is specific to efavirenz or if it is related to various components of antiretroviral therapy.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, horsetail might increase the levels and adverse effects of lithium.  Details Animal research suggests that horsetail has diuretic properties (13574). Theoretically, due to these potential diuretic effects, horsetail might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, horsetail might decrease the levels and clinical effects of NRTIs.  Details In two case reports, patients were found to have detectable viral loads when taking horsetail-containing supplements along with an antiretroviral therapy. In one case, the antiretroviral regimen included zidovudine, lamivudine, and efavirenz; in the other case, the regimen consisted of emtricitabine, tenofovir disoproxil fumarate, and efavirenz. One month after discontinuing the supplement, the viral loads became undetectable in both cases. The exact mechanism of these interactions is unknown (97573). It is also unclear if these interactions are specific to NRTIs or if they are related to various components of antiretroviral therapy.

(Read more about HORSETAIL)

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 and topically, gotu kola seems to be well tolerated.
Most Common Adverse Effects:
Orally: Gastric irritation and nausea.
Topically: Eczema.
Serious Adverse Effects (Rare):
Orally: Hepatotoxicity.

Dermatologic ...Topically, gotu kola may cause eczema (10277,10278). Also, gotu kola can cause allergic contact dermatitis, characterized by erythema, itching, papules, and a burning sensation (4,6887,9789,52875,52887,52896,52902). One specific gotu kola product (Blasteostimulina,Almirall, S. A.) has been reported to cause allergic contact dermatitis. However, not all patients with reactions to this product are sensitive to gotu kola; some patients are sensitive to neomycin, another ingredient in the product (52875). Madecassol ointment (Rona Laboratories Limited) is another gotu kola product that has resulted in allergic contact dermatitis. Controlled testing suggests that this product can cause this adverse effect in about 8% of patients (9789). Centellase cream has also caused allergic contact dermatitis in at least two cases (52887,52888).

Gastrointestinal ...In some patients, gotu kola can extract cause gastrointestinal upset and nausea (780,6887,52894).

Hepatic ...There is concern that gotu kola may cause liver toxicity in some patients. There are at least four case reports of hepatotoxicity associated with gotu kola; however, hepatotoxic contaminants cannot be ruled out, as laboratory analysis was not conducted on the products used. Additionally, the doses of gotu kola used in these cases were not reported (13182,92506). In a clinical trial where liver function was monitored, taking gotu kola 120 mg daily for 6 months was not associated with changes in liver function (11065).
In one case of hepatotoxicity, a 61-year-old female developed elevated liver transaminase and total bilirubin levels after taking gotu kola tablets for 30 days. Liver biopsy showed granulomatous acute hepatitis. Months later, the patient took gotu kola again and developed elevated liver transaminases after 2 weeks. In another case, a 52-year-old female developed symptoms of hepatitis and increased liver transaminases after taking gotu kola for 3 weeks. Biopsy indicated chronic hepatitis and granulomas, areas of necrosis, and cirrhotic transformation. Liver function normalized after discontinuation of gotu kola. In a third case, a 49-year-old female developed symptoms of hepatitis after taking gotu kola for 2 months. Biopsy revealed granulomatous hepatitis. Liver function normalized after discontinuation of gotu kola (13182). In a fourth case, a 15-year-old female taking an unknown dose of gotu kola and lymecycline for 6 weeks for acne experienced acute liver failure with abdominal pain and vomiting, as well as elevated liver transaminases, bilirubin, international normalized ratio (INR), and prothrombin. Liver function returned to normal after both products were discontinued (92506).

Immunologic ...Topically, gotu kola can cause allergic contact dermatitis, characterized by erythema, itching, papules, and a burning sensation (4,6887,9789,52875,52887,52896,52902). One specific gotu kola product (Blasteostimulina, Almirall, S. A.) has been reported to cause allergic contact dermatitis in some patients. However, not all patients who react to this product are sensitive to gotu kola; some are sensitive to neomycin, another ingredient in the product (52875). Madecassol ointment (Rona Laboratories Limited) is another gotu kola product that has resulted in allergic contact dermatitis. Controlled testing suggests that this product can cause this adverse effect in about 8% of patients (9789). Centellase cream has also caused allergic contact dermatitis in at least two cases (52887,52888).

Psychiatric ...A case of night eating syndrome has been reported for a 41-year-old female who had been taking a gotu kola tincture (dose not specified) for 2 years. Symptoms resolved after gotu kola use was discontinued (52878).

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General ...Orally, hawthorn seems to be well tolerated when used appropriately. Topically, no adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Multiorgan hypersensitivity reactions resulting in acute renal failure have been reported rarely.

Cardiovascular ...Orally, tachycardia (with facial pains) of uncertain relationship to hawthorn was reported in a multicenter clinical trial (54640). Palpitations (19244) were reported in three patients in a large surveillance trial of 3,664 patients with cardiac failure (54692) and in 11 patients with congestive heart failure (CHF) in a literature review of 5,577 patients (19247). Circulation failure has been reported in two patients with CHF in a literature review of 5,577 patients (19247). Incidences of hospitalization, hospitalization due to CHF, worsening of CHF, angina, and atrial fibrillation have also been reported with the use of hawthorn extract WS 1442 (Crataegutt forte), although it is unclear if these events are related to hawthorn supplementation or existing CHF (19222). In clinical trials, chest pain (8281), short-term increases in blood pressure (19240), and other non-specific heart problems (17203) have also been reported following the use of various hawthorn preparations (e.g. WS 1442, Korodin).

Dermatologic ...Orally, erythematous rash has been reported in patients with CHF in a literature review of 5,577 patients (19247). Non-specific rashes and itching (19222,19243) as well as toxiderma from the fruits of hawthorn (54670) have also been reported.

Gastrointestinal ...Orally, rare abdominal discomfort of uncertain relationship to hawthorn has been reported in a large clinical trial, surveillance study, and a literature review (19247,54640,54692). Digestive intolerance (19241), diarrhea (19243), flatulence (8281), gastroenteritis (8281), increased bowel movements (19243), obstipation (8281), mild and rare nausea (10144,19247,19244), nutritional and metabolic problems (17203), and other non-specific gastrointestinal effects (19222), have also been reported. Furthermore, gastrointestinal hemorrhage has been reported in two patients with CHF in a literature review of 5,577 patients (19247).

Musculoskeletal ...In clinical trials, arthritis (8281), back pain (8281), weakness (19243), and other non-specific musculoskeletal effects (19222) have been reported following the use of various hawthorn preparations g. WS 1442, CKBM-A01).

Neurologic/CNS ...Orally, headache and dizziness/vertigo were reported in two patients in a large surveillance trial of 3,664 patients with cardiac failure (54692), in 15 patients with CHF as reported in a literature review of 5,577 patients (19247), and in a varying number of clinical trial participants (8281,19222,19244). Incidences of fainting (19222), fever (17203), and infrequent, mild and transient sleepiness have also been reported (19221,54692).

Psychiatric ...Orally, agitation was reported in a large surveillance trial of 3,664 patients with cardiac failure (54692).

Pulmonary/Respiratory ...Orally, bronchitis has been reported following the use of hawthorn extract WS 1442 (8281).

Renal ...A case of multiorgan hypersensitivity reaction and acute renal failure following the consumption of C. orientalis has been reported (54654).

Other ...Flu-like syndrome (8281) and other non-specific infections have been reported following the use of the hawthorn extract WS 1442 (17203,19222). Hawthorn has also been reported to cause nosebleeds (8281,10144).

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General ...There is limited clinical research evaluating the safety of horsetail.
Most Common Adverse Effects:
Orally: Abdominal distension, increased bowel movements, and nausea.

Dermatologic ...In one case report, a patient developed seborrheic dermatitis after topical application of horsetail, requiring treatment with local epinephrine and oral antihistamines. The nicotine component of horsetail was determined to be the likely cause of this reaction (13563).

Gastrointestinal ...Orally, horsetail has been associated with mild gastrointestinal side effects including abdominal distension, increased frequency of bowel movements, and nausea (55576). Orally, chronic consumption of horsetail infusion has been associated with acute pancreatitis. In a case report, a 56-year-old female presenting with recurrent mild acute pancreatitis every 6-7 months, previously thought to be drug-induced, discontinued ingesting horsetail infusions. The patient had a history of bilateral adrenal gland removal and was being treated for hypertension, dyslipidemia, and hormone replacement, and then self-medicated with horsetail infusions. After discontinuing horsetail infusions, there were no further recurrences of pancreatitis during a 14-month follow-up (97574).

Hepatic ...In one case report, a patient with asymptomatic hepatitis B developed symptomatic liver failure following consumption of boiled horsetail juice 500 mL daily for 2 weeks. Liver enzymes returned to normal following discontinuation of the juice (92291). It is not known if the horsetail juice was contaminated or mixed with other ingredients.

Immunologic ...Horsetail has been associated with cross-allergenicity with carrots (13577).

Renal ...There are at least 4 case reports of hyponatremia thought to be at least partially associated with horsetail consumption. In one case report, an elderly patient who had taken oral horsetail 15 mg daily for 10 years presented with hyponatremia and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) secondary to reduced oral intake and nausea for the previous 2 days. Horsetail was thought to be a contributing factor. The patient's symptoms resolved after 5 days of treatment with oral sodium chloride and fluid restriction (108851).

Other ...Crude horsetail contains thiaminase, which can cause thiamine deficiency with prolonged consumption. Canadian Equisetum arvense products are required to be certified as free from thiaminase-like activity (55579,105301). In one case report, the development of autism in a child exposed to both horsetail and alcohol during pregnancy was thought to be caused by thiamine deficiency attributed to this combination (92292). However, it is not known if other genetic or environmental factors were involved in the development of this condition in utero.

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