Digestrin by Selmedica Healthcare

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about BROMELAIN)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. Although there has been interest in using oral cowhage for anxiety, there is insufficient reliable information about the clinical effects of cowhage for this purpose.
• Erythema. Although there has been interest in using topical cowhage for erythema, there is insufficient reliable information about the clinical effects of cowhage for this purpose.
• Hyperprolactinemia. Although there has been interest in using oral cowhage for hyperprolactinemia, there is insufficient reliable information about the clinical effects of cowhage for this purpose.
• Myalgia. Although there has been interest in using topical cowhage for myalgia, there is insufficient reliable information about the clinical effects of cowhage for this purpose.
• Parkinson disease. It is unclear if oral cowhage is beneficial in patients with Parkinson disease. Details: Very small clinical studies in patients with Parkinson disease suggest that taking a specific cowhage seed extract standardized to 3.3% levodopa (Zandopa, formerly HP-200; Zandu Pharmaceuticals), or other cowhage products that contain levodopa 75-400 mg orally once daily for up to 12 weeks modestly improves Parkinson disease scores when compared with baseline (7020,7203). Two very small clinical trials enrolling a total of 26 patients with Parkinson disease suggests that taking a single dose of cowhage powder, providing levodopa 1000-2000 mg or 12.5-17.5 mg/kg, is similarly effective after 90 minutes when compared with prescription levodopa 200 mg or 3.5 mg/kg as a single dose, with or without carbidopa and benserazide (12232,97266). It is unclear how these products would compare if they provided similar amounts of levodopa, or if they were taken for an extended duration.
• Rheumatoid arthritis (RA). Although there has been interest in using topical cowhage for RA, there is insufficient reliable information about the clinical effects of cowhage for this purpose.
• Sexual desire. Although there has been interest in using oral cowhage to increase sexual desire, there is insufficient reliable information about the clinical effects of cowhage for this purpose. More evidence is needed to rate cowhage for these uses.

(Read more about COWHAGE)

LIKELY EFFECTIVE

• Dyspepsia. Over-the-counter oral antacid products containing sodium bicarbonate are considered effective by the US Food and Drug Administration (FDA). Details: Over-the-counter oral antacid products containing sodium bicarbonate are considered effective by the US Food and Drug Administration (FDA) when taken for up to 2 weeks at a maximum daily dosage of 200 mEq sodium and 200 mEq bicarbonate by patients up to 60 years old and when taken at a maximum daily dosage of 100 mEq sodium and 100 mEq bicarbonate by patients over 60 years old (90912).

POSSIBLY EFFECTIVE

• Athletic performance. Oral sodium bicarbonate seems to improve athletic performance in most populations. It is unclear if topical or intravenous sodium bicarbonate is beneficial for athletic performance. Details: Although conflicting research exists, oral sodium bicarbonate seems to improve athletic performance in males and females. This conclusion is the position of the International Society of Sports Nutrition (ISSN) based on a comprehensive review of the literature (106250). The greatest evidence of benefit, with the lowest risk of adverse effects, is shown for single-dose protocols using 300 mg/kg 60-180 minutes before exercise, or protocols involving intakes of 100-200 mg/kg 2-3 times daily for 3-7 days, for a total daily dose of 400-500 mg/kg. Generally, increasing the dose of sodium bicarbonate above 300 mg/kg does not improve athletic performance and may increase the severity of gastrointestinal adverse effects (25706,104850,106250). Multiple meta-analyses of clinical research in male athletes and non-athletes shows that acute doses of oral sodium bicarbonate, taken as 200-400 mg/kg 40-120 minutes prior to exercise, improves mean performance on sprint exercises by 2% to 16% when compared with controls (25706,104847). Another meta-analysis shows that oral or intravenous sodium bicarbonate 100-400 mg/kg, taken within 3 hours of exercise, modestly improves exercise performance, total work, performance time, and power, and increases time to exhaustion when compared with placebo (25707). Although the majority of research has been conducted in males, most available evidence also supports the ergogenic effects of sodium bicarbonate in females (25706,106250,106252). In general, the ergogenic benefits of sodium bicarbonate have been shown in muscular endurance-type activities, as well as high-intensity activities, such as cycling and running, and are especially relevant for single exercise sessions lasting 30 seconds to 12 minutes or for repeated exercise measures (106250). One meta-analysis of clinical research shows that sodium bicarbonate does not improve mean power during sprint tests lasting 10 minutes or longer (25706). Also, although some individual research disagrees (104849), meta-analyses of research assessing athletic performance on Wingate tests, generally lasting up to 30 seconds, shows that acute sodium bicarbonate ingestion does not improve peak or mean power when compared with placebos such as calcium carbonate or sodium chloride (101265,106243). However, it does produce modest improvements in these measures for repeated performance (106243) or when ingested for 5-7 days (101265). In addition to cycling and running, the ergogenic benefits of sodium bicarbonate have been shown in some studies for activities such as swimming and rowing (106250). Although a small study in highly trained rowers found no benefit with sodium bicarbonate (97732), more recent research and a meta-analysis shows that taking sodium bicarbonate 100-300 mg/kg up to 4 hours prior to competition seems to be beneficial for improving mean power during a 2000-meter rowing performance (106245,106250,106253). Also, in elite level rowers, clinical research shows that taking sodium bicarbonate 300 mg/kg prior to competition, on an individualized schedule based on time to peak bicarbonate levels, improves rowing performance when compared with using a standardized administration time of 60 minutes prior to performance (106245). The ergogenic effects of sodium bicarbonate have also been shown for middle-distance, but not short-distance, swimming competitions (106249,106250). A meta-analysis of small clinical trials shows that taking sodium bicarbonate 200-300 mg/kg 60-120 minutes prior to competition has a small benefit on 200-meter and 400-meter swim tests, but not on tests of 100 meters or less (106249). Research related to the ergogenic effects of sodium bicarbonate for combat sports or martial arts is mixed (106244,106250,109691). Although the ISSN have suggested that the available clinical research shows that sodium bicarbonate is beneficial for combat sports (106250), a recent meta-analysis of clinical research in combat sport athletes, including judo, wrestling, and others, shows that sodium bicarbonate as single or multiple doses does not improve athletic performance, power, or perceived exertion when compared with placebo (109691). Also, a small clinical trial in jiu-jitsu athletes shows that taking sodium bicarbonate before testing does not improve muscle contractions (106244). One meta-analysis suggests that the ergogenic effects of sodium bicarbonate are associated with the degree of alkalosis (25707). However, initial research in male athletes shows that although taking 200 mg/kg sodium bicarbonate for 8 days does not significantly increase blood pH, it still improves performance on the Wingate test when compared with a single dose (104849). More research is needed to determine if taking sodium bicarbonate during training improves adaptations to exercise or whether sodium bicarbonate is beneficial in multi-sport or multi-day events (106250). Sodium bicarbonate has also been investigated in combination with other ergogenic compounds. There is some clinical evidence showing that combining sodium bicarbonate with beta-alanine or creatine may have additive effects (106250). Although most of the individual studies disagree with these findings, one meta-analysis of small clinical trials shows that taking a combination of sodium bicarbonate, usually a single dose, along with beta-alanine has a moderately greater ergogenic effect than taking beta-alanine alone (94357). Also, a small number of individual studies shows that taking sodium bicarbonate as a single dose or along with creatine improves performance in various sports (106250). More research is needed to determine any additional benefit of combining sodium bicarbonate with caffeine or nitrates (106250). Topical sodium bicarbonate has also been evaluated. Preliminary clinical research in healthy adults shows that topical application of 0.9036 grams/kg of sodium bicarbonate as a specific sodium bicarbonate 33.2% lotion (PR Lotion; Amp Human Performance) 30 minutes prior to exercise does not improve performance on the Wingate test when compared with placebo. This lotion also led to smaller increases in blood pH and bicarbonate ion levels when compared with a single oral dose of sodium bicarbonate 0.3 grams/kg (104848).
• Drug-induced sodium channel blockade. Intravenous sodium bicarbonate seems to be beneficial for the management of drug-induced sodium channel blockade. Details: Preliminary clinical studies show that intravenous sodium bicarbonate treats QRS widening following exposure to various drugs, including tricyclic antidepressants (TCAs), cocaine, diphenhydramine, citalopram, some antiarrhythmics, and others. Benefits of sodium bicarbonate may be related to an increased sodium concentration and/or a change in pH. The best evidence of effectiveness of sodium bicarbonate is for TCA-induced sodium channel blockade. Further research is needed to determine the most effective dosing regimen (106257,106258).
• Gingivitis. Brushing the teeth with sodium bicarbonate seems to be beneficial for gingivitis. Details: A meta-analysis of seven clinical trials in patients with mild to moderate gingivitis shows that using a 67% bicarbonate toothpaste twice daily for 3-24 weeks has a small beneficial effect on gingivitis, plaque, and bleeding when compared with placebo toothpaste (109692), One specific toothpaste (Parodontax Daily Toothpaste, GlaxoSmithKline) was used in some of the individual studies (98210,109692).

POSSIBLY INEFFECTIVE

• Cardiac arrest. Intravenous sodium bicarbonate does not seem to improve survival in children or adults with an out-of-hospital cardiac arrest. Details: A meta-analysis of randomized controlled trials and observational research shows that sodium bicarbonate administration during cardiopulmonary resuscitation in adults does not improve the survival rate until hospital discharge in patients that had an out-of-hospital cardiac arrest when compared with no sodium bicarbonate administration. There was also no difference in the rate of return to spontaneous circulation (ROSC), with some preliminary evidence suggesting that the use of sodium bicarbonate actually reduces the incidence of sustained ROSC and the incidence of good neurological outcome at discharge (106247). There is also concern regarding the use of sodium bicarbonate in pediatric cardiac arrest. American Heart Association Pediatric Life Support (PLS) guidelines state that sodium bicarbonate administration is not recommended for routine management of cardiac arrest in pediatric patients (106254). A meta-analysis of seven observational studies has found that intravenous administration of sodium bicarbonate during pediatric resuscitation actually led to a moderate reduction in the rate of survival until hospital discharge (106246). The effect of sodium bicarbonate administration on neurological outcomes in adults with an out-of-hospital cardiac arrest has also been evaluated. Observational research in a French dataset has found that sodium bicarbonate administration is not associated with neurological outcome after 30 days. However, in North America, sodium bicarbonate administration is associated with 55% decreased odds of having a favorable functional outcome and a 41% reduction in survival (109693).
• Ischemia-reperfusion injury. Intravenous sodium bicarbonate does not seem to prevent ischemia-reperfusion kidney injury in patients undergoing cardiac surgery. Details: A meta-analysis of clinical research shows that administering intravenous sodium bicarbonate does not prevent ischemia-reperfusion kidney injury when compared with placebo in adults undergoing cardiac surgery (97733).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Atopic dermatitis (eczema). Although there is interest in using topical sodium bicarbonate for eczema, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Bowel preparation. Sodium bicarbonate is an ingredient in some approved medications for bowel cleansing. However, there is insufficient reliable information about the clinical effects of sodium bicarbonate alone for this use.
• Burns. Although there is interest in using topical sodium bicarbonate for burns, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Cancer. Although there is interest in using intratumoral sodium bicarbonate for cancer, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Chronic kidney disease (CKD). It is unclear if oral sodium bicarbonate is beneficial for CKD. Details: Preliminary clinical studies in adults with stage 3-5 CKD and low serum bicarbonate levels show that taking oral sodium bicarbonate 5.95-11.9 mEq three times daily or 0.4 mEq/kg daily for 12 months increases serum bicarbonate levels, but does not improve kidney function, quality of life, bone mineral density, or physical functioning scores, when compared with placebo (104845,104851). Some clinical research in adults undergoing continuous ambulatory peritoneal dialysis shows that adding oral sodium bicarbonate 900 mg three times daily for 12 months to prescription dialysis improves nutritional status and reduces the duration of hospitalization, but not number of hospitalizations, when compared with placebo (29940). One preliminary clinical trial shows that taking sodium bicarbonate, titrating up to an average of 3.7 grams daily in two divided doses, for 12 weeks reduces the frequency of hyperkalemia from 11% of measurements at baseline to 4%. Also, pre-dialysis bicarbonate levels were increased by 2.12 mmol/L (109689). However, the target bicarbonate level of 22 mmol/L was not consistently achieved and there was no benefit in lean body mass, muscle strength, or electrocardiogram changes (109689). Also, other clinical research in patients with metabolic acidosis prior to dialysis shows that administering dialysate bicarbonate 40 mEq/L with or without oral sodium bicarbonate 1 mEq/kg daily in three divided doses for 16 weeks does not improve nutritional parameters when compared with dialysate bicarbonate 35 mEq/L alone (29939).
• Constipation. Although there is interest in using oral and topical sodium bicarbonate for constipation, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Contrast induced nephropathy. It is unclear if intravenous sodium bicarbonate is beneficial for contrast induced nephropathy prevention. Details: Clinical trials evaluating the use of intravenous sodium bicarbonate report conflicting results and utilize heterogeneous doses, comparators, and concomitant therapies. Meta-analyses of clinical research show that intravenous sodium bicarbonate (sodium concentration 80-154 mEq/L) 1 mL/kg/hr for up to 12 hours or 3 mL/kg/hr for 1 hour prior to cardiac angiography, followed by 1 mL/kg/hour for 6-12 hours following cardiac angiography, reduces the risk of contrast induced nephropathy when compared to hydration with normal saline (25714,25715,25717,25718,25721,25754,97036). However, when only studies that compared the effects of sodium bicarbonate plus N-acetylcysteine to normal saline plus N-acetylcysteine are considered, the favorable effect of sodium bicarbonate was less significant or not significantly different (25715,25717), suggesting that N-acetylcysteine may have been responsible for the enhanced effectiveness shown in other studies. Additionally, most of the analyses note that significant heterogeneity exists among the published studies. When only large, higher methodological quality, randomized controlled trials are considered, sodium bicarbonate does not appear to reduce the risk of contrast induced nephropathy when compared to hydration with sodium chloride (25716,25721,97036). Clinical research shows that sodium bicarbonate does not appear to reduce the risk of congestive heart failure, the need for renal replacement therapy, or mortality when compared with normal saline (25711,25713,25714,25717,25718,25721,25754). Preliminary clinical research in patients with stage 3 chronic kidney disease also shows that no hydration is similar to hydration with 250 mL of sodium bicarbonate (sodium concentration 170 mEq/L). Follow up after 2-5 days and 7-14 days shows that the relative increase in serum creatinine with no hydration is non-inferior to sodium bicarbonate. However, the volume and concentration of sodium bicarbonate used in this trial was lower than many trials that previously demonstrated benefits (104846). Finally, a meta-analysis of the available literature suggests that xanthine and statins are superior to both sodium bicarbonate and normal saline for the treatment of contrast induced nephropathy (97036).
• Dental plaque. It is unclear if brushing the teeth or rinsing the mouth with sodium bicarbonate is beneficial for dental plaque reduction. Details: A meta-analysis of clinical research shows that brushing teeth one time with 1.5 grams of toothpaste containing sodium bicarbonate 20% to 65% removes plaque better than brushing teeth with toothpaste containing triclosan/copolymer or fluoride/silica and no sodium bicarbonate, particularly for teeth that are difficult to reach with a toothbrush (25708). Products assessed in the analysis included Arm & Hammer Dental Care, Arm & Hammer Advanced White Brilliant Sparkle, Arm & Hammer Advance White Baking Soda and Peroxide, and Arm & Hammer Liquid Gel (Church & Dwight Co. Inc.). However, the meta-analysis is limited by the fact that most studies were only single-brushing crossover comparisons. Therefore, it is not clear if sodium bicarbonate-containing toothpastes are significantly better than toothpastes that do not contain sodium bicarbonate when used long-term. Additionally, some limited research suggests that sodium bicarbonate seems to work as well as fluoride in toothpaste for removing dental plaque. One small clinical study shows that brushing teeth once with toothpaste containing sodium bicarbonate 20% to 67% is no different for reducing plaque than brushing teeth with control toothpaste containing 0.312% fluoride (101264). Preliminary clinical research also shows that using an oral rinse (Periogen) containing sodium bicarbonate, sodium fluoride, and multiple other ingredients for 60 seconds, twice daily for 3 days, decreases dental plaque and bleeding by a small amount when compared with baseline in healthy patients who did not brush their teeth during the study (97731).
• Earwax. It is unclear if ear drops containing sodium bicarbonate are beneficial for removing earwax. Details: Preliminary clinical research shows that treatment with sodium bicarbonate solution four drops twice daily for 5 days prior to irrigation improves earwax clearance better than no treatment and similar to Cerumol ear drops. The percentage of ears completely cleared by irrigation after treatment with Cerumol, sodium bicarbonate, and no treatment is 22%, 20%, and 5%, respectively (29936). Other clinical research shows that administering 10% sodium bicarbonate solution four drops daily for 14 days is similarly effective to 2.5% acetic acid solution for reducing the degree of earwax in children and adults with occlusive earwax (29937). However, treatment with sodium bicarbonate solution prior to irrigation may make syringing more difficult when compared to other methods. Some clinical research shows that administering Cerumol ear drops once daily for 3 days prior to syringing makes syringing easier when compared to administering sodium bicarbonate for the same treatment duration in elderly patients (29938).
• Gastroesophageal reflux disease (GERD). Sodium bicarbonate is an ingredient in some approved medications for GERD. However, there is insufficient reliable information about the clinical effects of sodium bicarbonate alone for this use.
• Hyperkalemia. Although there is interest in using oral and intravenous sodium bicarbonate for hyperkalemia, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Infertility. Although there is interest in using intravaginal sodium bicarbonate for infertility, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Insect bite. Although there is interest in using topical sodium bicarbonate for insect bite treatment, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Jellyfish stings. It is unclear if topical sodium bicarbonate is beneficial for jellyfish stings. Details: Preliminary clinical research shows that topical application of a sodium bicarbonate 50% slurry on gauze, replaced every 2 minutes for 30 minutes, does not reduce pain associated with jellyfish stings when compared with placebo. However, application of the slurry reduces overall redness (97730).
• Kidney stones (nephrolithiasis). Although there is interest in using oral sodium bicarbonate for kidney stones, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Muscle Strength. It is unclear if oral sodium bicarbonate is beneficial for muscle strength. Details: A meta-analysis of small clinical studies in healthy adults shows that taking sodium bicarbonate 300-400 mg/kg 1-2 hours before exercise does not improve mean muscle strength when compared with placebo (104852).
• Neonatal resuscitation. It is unclear if intravenous sodium bicarbonate improves outcomes in neonates requiring resuscitation. Details: Preliminary clinical research in asphyxiated newborns still requiring positive pressure ventilation at 5 minutes of life shows that intravenous sodium bicarbonate 4 mL/kg (1.8 mEq/kg) for 3-5 minutes does not improve survival or reduce the risk of neurological abnormality, encephalopathy, cerebral edema, need for inotropic support, or risk of intraventricular hemorrhage when compared with 5% dextrose (25692).
• Oral mucositis. It is unclear if rinsing the mouth with sodium bicarbonate is beneficial for chemotherapy-associated oral mucositis. Details: Clinical research in patients with chemotherapy-induced oral mucositis shows that using 7.5 mL of a mouthwash containing sodium bicarbonate 5% for 3 weeks has a moderate to large beneficial effect on the severity of mucositis and quality of life when compared with placebo. The mouthwash was swished for two, two-minute sessions separated by 15 minutes, repeated every 8 hours (109690).
• Organophosphorus pesticide poisoning. Although there is interest in using intravenous sodium bicarbonate for organophosphorus pesticide poisoning, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Peptic ulcers. Sodium bicarbonate is an ingredient in some approved medications for peptic ulcers. However, there is insufficient reliable information about the clinical effects of sodium bicarbonate alone for this use.
• Poison oak and poison ivy dermatitis. Although there is interest in using topical sodium bicarbonate for poison oak and poison ivy dermatitis, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Pruritus. Although there is interest in using topical sodium bicarbonate for pruritus, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Psoriasis. It is unclear if topical sodium bicarbonate is beneficial for psoriasis. Details: In patients with mild to moderate stable plaque psoriasis, a small clinical trial shows that topical sodium bicarbonate 30% does not improve symptoms of psoriasis when compared with a lanette wax vehicle only (106256).
• Rhabdomyolysis. Although there is interest in using intravenous sodium bicarbonate for preventing rhabdomyolysis-induced kidney injury, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Salicylate intolerance. Although there is interest in using intravenous sodium bicarbonate for salicylate intolerance, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Tooth discoloration. It is unclear if brushing the teeth with sodium bicarbonate is beneficial for tooth discoloration. Details: Preliminary clinical research shows that using a specific toothpaste containing 35% sodium bicarbonate (Arm & Hammer Truly Radiant Toothpaste, Church & Dwight Co. Inc.) for 2 minutes twice daily for 6 weeks reduces tooth staining by approximately 45% when compared to baseline. This product was more beneficial than a non-whitening toothpaste control, as well as a positive control that reduced staining by approximately 38% over baseline (97736). However, preliminary clinical research shows that using a toothpaste containing sodium bicarbonate 67% (Corsodyl Daily Gum and Toothpaste, GSK Consumer Healthcare) for one minute twice daily for 6 weeks does not reduce staining associated with use of a chlorhexidine 0.2% mouthwash when compared with a control toothpaste without sodium bicarbonate (97727).
• Urinary tract infections (UTIs). Although there is interest in using oral sodium bicarbonate for UTIs, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition.
• Ventilator-associated pneumonia (VAP). It is unclear if rinsing the mouth with sodium bicarbonate reduces the risk of VAP. Details: Preliminary clinical research in adults who have been mechanically ventilated for at least 4 days shows that using an oral rinse containing sodium bicarbonate 0.13 grams in 20 mL every 2 hours, in conjunction with tooth brushing three times daily, does not reduce the risk of VAP when compared with sterile water and tooth brushing (97737).
• Wound healing. Although there is interest in using topical sodium bicarbonate for wound healing, there is insufficient reliable information about the clinical effects of sodium bicarbonate for this condition. More evidence is needed to rate sodium bicarbonate for these uses.

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POSSIBLY EFFECTIVE

• Insomnia. Most research shows that taking valerian whole root extract 300-600 mg daily modestly improves subjective sleep quality, although it might take up to 4 weeks to provide benefit. Valerian does not seem to improve sleep latency, sleep duration, or insomnia severity. Details: Although there is a great deal of conflicting research, overall, taking valerian 300-600 mg before bedtime seems to improve sleep quality when compared with placebo. In contrast, no consistent benefit has been seen for sleep latency, sleep duration, or insomnia severity (15046,17577,19406,19409,104010). Older meta-analyses show that valerian root improves sleep quality regardless of its formulation. However, the most recent meta-analysis shows that valerian whole root extract improves sleep quality, while it's unclear whether an unspecified valerian extract is effective (17577,19406,104010). These analyses are limited by significant heterogeneity in valerian dosage and formulation, treatment duration, and included patient populations. Some experts claim that valerian does not work acutely for sleep, and it can take up to 4 weeks for a benefit to be seen (10209,104010). Indeed, most short-term studies assessing valerian as a single dose, or used daily for up to one week, show no benefit for sleep quality when compared with placebo (19407,19408,19411,19414). However, a meta-analysis of studies lasting 4 weeks or longer also did not find a consistent benefit (104010). The benefits of valerian for sleep might vary in different patient populations. A large post-marketing surveillance study in children with restlessness or dyssomnia under the age of 12 has found that taking a specific combination product (Euvegal Forte, Dr. Willmar Schwabe Pharmaceuticals) containing valerian root extract 160 mg and lemon balm extract 80 mg 1-2 tablets once or twice daily is associated with moderate sleep improvement (14416). Also, one clinical study in postmenopausal adults shows that taking valerian root extract 530 mg (Sadamine) twice daily for 28 days moderately improves sleep quality when compared with placebo (19425). Another clinical study in patients undergoing treatment for cancer shows that taking valerian 450 mg 1 hour before bedtime for 8 weeks does not improve objective sleep measures, but might improve subjective sleep ratings and mood, when compared with placebo (19424). Small clinical studies in adults on hemodialysis show that taking valerian 530 mg before bedtime for 1 month improves sleep quality when compared with baseline or placebo. (105718,110712). In one of these studies, improvements in sleep quality were similar when compared with gabapentin (110712). Research also shows that taking specific combination products containing valerian and other ingredients can improve sleep quality. These combination products have combined valerian with hops; lemon balm (Euvegal Forte); lemon balm and hops (Valerina Natt); or passionflower and hops (NSF-3, M/s Tablets India) (10423,15018,19413,19417,19418,19419,88193,89408). Finally, limited research has compared valerian to benzodiazepines. A small clinical study in patients with non-organic insomnia shows that taking valerian extract (LI 156, Sedonium) 600 mg daily for 6 weeks seems to be no different for improving sleep quality when compared with taking low-dose oxazepam 10 mg (19416). Valerian might also improve sleep quality in patients who are resistant to chronic benzodiazepine therapy. In one small study, after tapering the benzodiazepine over two weeks, valerian extract 100 mg three times daily for 15 days improves sleep quality when compared with placebo (8006).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Anxiety. It is unclear if valerian is beneficial for anxiety. Details: Meta-analyses of heterogeneous clinical research show that there is insufficient and contradictory evidence on the use of valerian root for anxiety (104010,110711). However, one analysis suggests that using whole root preparations seems to have greater efficacy than valerian extracts (104010). These meta-analyses are limited by significant heterogeneity in valerian dosage and formulation, treatment duration, and patient populations and concerns related to publication bias (104010,110711). One small clinical study in patients with generalized anxiety disorder (GAD) shows that taking valerian extract containing 81.3 mg valepotriates daily for 4 weeks is no different for reducing anxiety scores when compared with diazepam 6.5 mg or placebo (9896). This study was not adequately powered to detect a difference between groups. Also, a small, quasi-randomized trial in adults with poor sleep quality who are undergoing hemodialysis shows that taking a specific valerian root product (Sedamin, Goldaru Company) 530 mg daily for 1 month improves anxiety scores by 2-3.9 times when compared with placebo. However, not all patients reported anxiety at baseline (105718). In contrast, a small clinical study in healthy adults shows that taking a combination of herbal extracts containing valerian root, passionflower, ballota, and hawthorn (Euphytose) 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 valerian, other ingredients, or the combination.
• Delirium. Oral valerian has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adult intensive care unit (ICU) patients with agitation and delirium receiving quetiapine 50-200 mg every 12 hours shows that taking 5 mL of syrup containing valerian root 625 mg and an extract of lemon balm leaf 50 mg every 12 hours improves agitation from baseline similarly to placebo. It is unclear if the improvement from baseline differed between groups (106627).
• Depression. It is unclear if valerian is beneficial in patients with depression. Details: A retrospective case series in patients with mild to moderate depression and reports of anxiety has found that taking high-dose valerian 1000 mg with St. John's wort is associated with more rapidly improved depressive symptoms than low-dose valerian 500 mg with St. John's wort (19402). The validity of this study is limited by its retrospective nature and small size. Also, it is unclear if this effect is due to valerian, St. John's wort, or the combination. One small, quasi-randomized trial in adults with poor sleep quality who are undergoing hemodialysis shows that taking a specific valerian root product (Sedamin, Goldaru Company) 530 mg daily for 1 month improves depression scores by 2-3.9 times when compared with placebo. However, not all patients reported depression at baseline (105718).
• Dysmenorrhea. One small study suggests that oral valerian may reduce symptoms of dysmenorrhea. Details: A small clinical study shows that taking powdered valerian root 255 mg three times daily for two menstrual cycles reduces pain severity associated with menstruation when compared with placebo (19342).
• Menopausal symptoms. Two small studies suggest that oral valerian may reduce hot flashes. Details: Two small clinical studies in postmenopausal adults show that taking valerian root (Zardband or Goldaroo Co.) 225 mg three times daily or 530 mg twice daily for 2 months moderately reduces hot flash frequency and severity when compared with placebo (89407,96243). Both studies were conducted in Iran, so it is unclear if these results are generalizable to other geographic locations.
• Premenstrual syndrome (PMS). One small study suggests that oral valerian may reduce PMS symptoms. Details: A small clinical study in young adults with PMS shows that taking valerian root extract (Goldaroo Co.) 530 mg twice daily on the last 7 days of the menstrual cycle for 3 cycles moderately reduces the severity of self-reported PMS symptoms when compared with placebo (96239).
• Pre-procedural anxiety. One small study suggests that oral valerian may reduce anxiety during wisdom tooth extraction. Details: A small crossover clinical study in patients undergoing impacted mandibular molar extraction shows that taking valerian extract (Dermatologica Ltda.) 100 mg one hour prior to the extraction reduces physiological responses to anxiety to a satisfactory but lesser degree than midazolam 15 mg. Patients expressed no clear preference for either valerian or midazolam for reducing perioperative anxiety (102242). The validity of these findings is limited by the use of subjective outcome measures.
• Restless legs syndrome (RLS). It is unclear if oral valerian is beneficial in patients with RLS. Details: A small clinical study in patients with RLS shows that taking valerian (Pharmavite, LLC) 800 mg daily for 8 weeks does not improve RLS symptoms or sleep latency when compared with placebo (19422). However, this study was not adequately powered to detect a difference in RLS symptoms between groups. Conversely, another small clinical study in adults with RLS on hemodialysis shows that taking valerian 530 mg nightly before bed for 1 month reduces symptoms of RLS when compared to baseline; however, valerian's effects were weaker when compared with gabapentin 100 mg nightly (110712). The validity of this study is limited by a lack of a placebo group and a small sample size.
• Stress. Two small studies suggest that oral valerian may reduce the stress response in healthy adults who are performing a stressful mental task or a verbal presentation. Details: Two small clinical studies in healthy volunteers shows that taking valerian 100 mg once or 600 mg daily for 7 days prior to participating in a mental stress task or public verbal test reduces physiologic responses to stress and feelings of anxiety when compared to baseline (9893,9895). The validity of these findings is limited by the lack of statistical comparison to the control group. Another small study in healthy volunteers shows that taking a specific combination product containing valerian 360 mg and lemon balm 240 mg (Songha Night, Pharmaton Natural Health Products) reduces anxiety associated with laboratory-induced stress. However increasing the dose to valerian 1080 mg and lemon balm 720 mg seems to increase anxiety (19405).
• Tension headache. One small study suggests that oral valerian may reduce tension headache. Details: A small clinical study in patients with frequent tension headaches shows that taking valerian root extract (Sedamin, Goldaru Pharmaceutical Company) 1060 mg daily after dinner for one month modestly reduces headache severity and disability when compared with placebo (103221). More evidence is needed to rate valerian for these uses.

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

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

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POSSIBLY SAFE ...when used orally and appropriately. Powdered formulations of cowhage seed that are standardized to provide levodopa 75-400 mg daily have been used with apparent safety for up to 20 weeks (7020,7203,97266).

POSSIBLY UNSAFE ...when the hair of the cowhage bean pod is used orally or topically. The bean pod hairs are strong irritants and can cause severe itching, burning, and inflammation (18).

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

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POSSIBLY UNSAFE ...when used orally in excessive amounts. Over 20 cases of stomach rupture have been reported for patients who used sodium bicarbonate to relieve stomach discomfort after eating large meals (29414,29415,29416,29962,90913). In some of these cases, it is believed that the patients consumed dry sodium bicarbonate or a sodium bicarbonate suspension rather than a completely dissolved sodium bicarbonate solution. Ingestion of undissolved or partially undissolved sodium bicarbonate is believed to produce excess carbon dioxide and corresponding gastric dilation, leading to stomach rupture (90913). There is also concern that excessive or prolonged use of oral sodium bicarbonate may cause metabolic alkalosis characterized by hypokalemia, hypochloremia, and hypernatremia (25733,29962,90913). There is insufficient reliable information available about the safety of sodium bicarbonate when used topically.

CHILDREN: POSSIBLY SAFE
when used intravenously and appropriately with proper medical supervision. Intravenous sodium bicarbonate solutions are approved by the US Food and Drug Administration (FDA) to be used in infants and children (13309).

CHILDREN: POSSIBLY UNSAFE
when used topically. At least two cases of hypernatremia resulting from topical application of sodium bicarbonate (baking soda) have been reported (29962,90914). There is insufficient reliable information available about the safety of sodium bicarbonate when used orally; avoid using unless advised by a physician.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally or intravenously during pregnancy. There is concern that sodium bicarbonate may increase the risk of metabolic alkalosis or fluid retention when used orally during pregnancy (90915). There is insufficient reliable information available about the safety of oral or intravenous sodium bicarbonate when used in medicinal amounts during lactation.

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LIKELY SAFE ...when used orally and appropriately, short-term. Valerian 300-600 mg daily has been safely used in clinical studies in over 12,000 patients for up to 6 weeks (2074,3484,3485,4032,15018,17577,17578,19409,96242,103221)(104010,105718). There is insufficient reliable information available about the safety of valerian when used orally for longer than 6 weeks.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Valerian 160-320 mg has been used with apparent safety in children under 12 years of age for 4-8 weeks (14416).

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

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Bromelain may have antiplatelet effects and may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details There is one case report of a patient experiencing minor bruising while taking bromelain with naproxen (14806). Bromelain is thought to have antiplatelet activity (10639,14806,18285,18286,37234). Whether this interaction is of concern with topical bromelain is unclear. Interference with coagulation of burn wounds has been reported in a patient receiving bromelain-based enzymatic debridement. However, observational research has found that topical bromelain debridement is not associated with increases or decreases in laboratory markers of coagulation when compared with surgical debridement (110547).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, bromelain might increase levels of tetracycline antibiotics.  Details Laboratory research suggests that bromelain might increase the absorption of tetracycline antibiotics. However, a study in healthy adults reported no difference in tetracycline plasma levels when a 500 mg dose was taken with or without bromelain 80 mg (14296).

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ANESTHESIA Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of cowhage and anesthesia might increase the risk of arrhythmias.  Details Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of levodopa with cyclopropane or halogenated hydrocarbon anesthesia has led to arrhythmias. Other anesthetics have not been implicated (15). Use other anesthetics in patients taking cowhage or tell patients to stop taking cowhage at least 2 weeks before surgery.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of cowhage and antidiabetes drugs might increase the risk of hypoglycemia.  Details Animal research shows that cowhage might have hypoglycemic effects (7221).

ANTIPSYCHOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of cowhage might decrease the clinical effects of antipsychotic drugs.  Details Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of levodopa might counteract the antidopaminergic effects of antipsychotic medications (15).

GUANETHIDINE (Ismelin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of cowhage and guanethidine might increase the risk of hypotension.  Details Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of levodopa with guanethidine might cause additive hypotension (15); avoid using.

LEVODOPA Interaction Rating = Major Do not take this combination. Severity = Moderate •  Occurrence = Likely •  Level of Evidence = D Concomitant use can increase the risk of levodopa-related adverse effects.  Details Cowhage contains levodopa. Some cowhage products have been standardized to contain 75-400 mg of levodopa per dose (7020,7205,46334,46336,94723,94724).

METHYLDOPA (Aldomet) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of cowhage and methyldopa might increase the risk of hypotension.  Details Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of levodopa with methyldopa might cause additive hypotension. In addition, methyldopa may inhibit peripheral decarboxylation of levodopa and increase levodopa levels in the central nervous system (15); avoid using.

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use of cowhage and non-selective MAOIs might increase the risk of hypertensive crisis.  Details Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of levodopa with non-selective MAOIs might cause hypertensive crisis. However, this interaction has not been reported with MAO-B selective inhibitors such as selegiline (15).

TRICYCLIC ANTIDEPRESSANTS (TCAs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, use of TCAs might reduce the levels and clinical effects of cowhage.  Details Cowhage contains levodopa (7020,7205,46334,46336,94723,94724). Use of TCAs might reduce the absorption of levodopa. Some case reports describe patients that developed hypertension and dyskinesia when taking both levodopa and TCAs (15).

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AMINOGLYCOSIDE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk for hypokalemia in patients receiving aminoglycosides.  Details Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, when administered intravenously, the most common complication of sodium bicarbonate is hypokalemia (25709). Nephrotoxicity caused by aminoglycosides may lead to increased urinary losses of various electrolytes, including potassium (9519).

AMPHOTERICIN-B (Abelcet, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk for hypokalemia in patients receiving amphotericin B.  Details Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, when administered intravenously, the most common complication of sodium bicarbonate is hypokalemia (25709). Amphotericin B increases urinary potassium losses due to toxic effects on renal tubular epithelium. Hypokalemia can occur in up to 50% of patients (9519).

ASPIRIN Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, sodium bicarbonate may reduce the levels and clinical effects of aspirin.  Details In humans, oral or intravenous administration of sodium bicarbonate increases salicylate elimination. Although the exact mechanism of this effect is not clear, some researchers hypothesize that sodium bicarbonate increases urinary pH, which increases salicylate ionization and subsequent excretion by the kidneys. In patients with urine pH of about 5.5, renal clearance of salicylate is approximately 55 mL/min. When urine pH is increased with oral sodium bicarbonate to about 7.5, renal clearance of salicylate increases to approximately 100 mL/min. Similarly, urine alkalinization with sodium bicarbonate increases the mean total body clearance of salicylate by approximately 60% compared with urine acidification (29410,29411).

BETA-ADRENERGIC AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk for hypokalemia in patients taking beta-adrenergic agonists.  Details Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common adverse effect of intravenous sodium bicarbonate is hypokalemia (25709). Oral, parenteral, or inhaled beta-adrenergic agonists can reduce serum potassium levels, especially during acute use of high doses (6217,7001,8880,8881,8882,8883,8884,8885,8886,8889)(8890,9534,9599).

CEFPODOXIME PROXETIL (Vantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, sodium bicarbonate might reduce the levels and clinical effects of cefpodoxime.  Details Cefpodoxime proxetil is an oral prodrug that is de-esterified in the intestine to the active drug cefpodoxime. Drugs or supplements that increase gastric pH can inhibit the activation of cefpodoxime proxetil and reduce the peak plasma concentrations of cefpodoxime. In humans, taking sodium bicarbonate 12.6 grams orally along with cefpodoxime proxetil 200 mg reduces peak plasma concentrations and area under the plasma concentration-time curve (AUC) of cefpodoxime by 35% to 50% (25740).

CHLORPROPAMIDE (Diabinese) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, sodium bicarbonate might reduce the levels and clinical effects of chlorpropamide.  Details The elimination of chlorpropamide by the kidneys depends strongly on urine pH. At a pH of 5, the renal clearance of chlorpropamide ranges from 0.5 to 3 mL/hr. At a pH of 8, renal clearance of chlorpropamide ranges from 500 to 1000 mL/hr. When taken in combination with oral sodium bicarbonate, the elimination half-life of chlorpropamide is shortened from 49.7 to 12.8 hours and urinary excretion of chlorpropamide is increased four-fold (25741).

CISPLATIN (Platinol-AQ) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk of hypokalemia in patients receiving cisplatin.  Details Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common complication of intravenous sodium bicarbonate is hypokalemia (25709). Cisplatin can cause renal tubular damage, with increased losses of electrolytes including potassium (15509,15510,15511).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk of hypokalemia in patients taking corticosteroids.  Details Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common intravenous complication of sodium bicarbonate is hypokalemia (25709). Some glucocorticoids (corticosteroids) can also cause hypokalemia by causing sodium retention, resulting in compensatory renal potassium excretion. It is most common with hydrocortisone, cortisone, and fludrocortisone, followed by prednisone and prednisolone (4425).

LOOP DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk of hypokalemia in patients taking loop diuretics.  Details Loop diuretics increase urinary potassium excretion (4412,4425,4449). Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common complication of intravenous sodium bicarbonate is hypokalemia (25709).

METHYLXANTHINES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk of hypokalemia in patients taking methylxanthines.  Details Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common complication of intravenous sodium bicarbonate is hypokalemia (25709). Theophylline and related drugs can reduce serum potassium levels, possibly by increasing intracellular uptake of potassium. Hypokalemia is most likely to occur after acute overdose of these drugs (17). However, reduced potassium levels can occur with therapeutic doses, and the incidence and degree of hypokalemia increases with increasing serum theophylline levels (9534,9537,9538,9539).

PSEUDOEPHEDRINE (Sudafed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, sodium bicarbonate may increase levels and adverse effects of pseudoephedrine.  Details In humans, intravenous or oral administration of sodium bicarbonate can increase urinary pH. Clinical evidence shows that urine alkalinization increases the serum elimination half-life of pseudoephedrine by approximately 10-fold (29412). In one patient with persistently alkaline urine, treatment with pseudoephedrine resulted in hallucinations and personality changes (29412).

SODIUM-CONTAINING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Concomitant use of sodium-containing drugs with additional sodium from dietary or supplemental sources may increase the risk of hypernatremia and long-term sodium-related adverse effects.  Details The Chronic Disease Risk Reduction (CDRR) intake level of 2.3 grams of sodium daily indicates the intake at which it is believed that chronic disease risk increases for the apparently healthy population (100310). Some medications contain high quantities of sodium. When used in conjunction with sodium bicarbonate, the CDRR may be exceeded. Additionally, concomitant use may increase the risk for hypernatremia; this risk is highest in the elderly and people with other risk factors for electrolyte disturbances.

STIMULANT LAXATIVES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk of hypokalemia in patients taking stimulant laxatives.  Details Long-term use of stimulant laxatives, or acute use of high doses (e.g., in bowel-cleansing regimens), can result in potassium loss and hypokalemia (4411,4412,4425). Orally, use of excessive sodium bicarbonate (such as intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common complication of intravenous sodium bicarbonate is hypokalemia (25709).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, sodium bicarbonate may increase the risk of hypokalemia in patients taking thiazide diuretics.  Details Thiazide diuretics increase urinary potassium excretion (4412,4425,4449). Orally, use of excessive sodium bicarbonate (such as the intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with cases of hypokalemia (25733). Furthermore, the most common complication of intravenous sodium bicarbonate is hypokalemia (25709).

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ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Valerian can have additive sedative effects when used concomitantly with alcohol.  Details Valerian has sedative effects (9894). Theoretically, valerian might have an additive sedative effect when combined with alcohol. Excessive sedation has been reported in an alcohol-abusing individual who took valerian and Gingko biloba (19426). However, the potential interaction between valerian and alcohol has been disputed in other research. Limited evidence suggests that a combination of valerian 160 mg and lemon balm 80 mg (Euvegal) does not cause further deterioration in reaction ability and reaction rate when taken with alcohol as compared to the effects of alcohol alone (19427).

ALPRAZOLAM (Xanax) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Valerian can have additive sedative effects when used with alprazolam. Also, valerian in high doses might modestly increase alprazolam levels, though this is not likely to be clinically significant.  Details Valerian has sedative effects (9894). Theoretically, valerian might cause additive sedation when combined with alprazolam. Also, a small pharmacokinetic study shows that taking valerian extract 1000 mg daily (providing 11 mg valerenic acid) might increase alprazolam levels by about 19%. This might be due to valerian's mild inhibition of cytochrome P450 3A4 (CYP3A4) (13014). Despite being statistically significant, this increase is not likely to be clinically significant.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Valerian can have additive sedative effects when used concomitantly with CNS depressant drugs.  Details Theoretically, concomitant use of valerian and drugs with sedative and anesthetic properties may cause additive therapeutic and adverse effects (3486,12720,19429).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Unlikely •  Level of Evidence = B Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP2D6.  Details Although some in vitro evidence suggests that valerian affects CYP2D6, clinical pharmacokinetic (PK) studies show that valerian is unlikely to affect the CYP2D6 enzyme (13014,13536,19430,19431). In one PK study, taking valerian 1000 mg (providing about 11 mg valerenic acid) nightly for 14 days did not affect the metabolism of dextromethorphan, a CYP2D6 substrate. In another PK study, taking valerian 125 mg three times daily for 28 days did not affect metabolism of debrisoquine, an accepted CYP2D6 probe-substrate (13014,13536).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Valerian does not seem to have a clinically relevant effect on levels of drugs metabolized by CYP3A4.  Details Although some in vitro evidence suggests that valerian extract might inhibit or induce CYP3A4, clinical pharmacokinetic (PK) studies show that valerian does not have a clinically significant effect on the CYP3A4 enzyme (6450,12214,13014,13536,19431). In one PK study, taking valerian 125 mg three times daily for 28 days did not affect metabolism of midazolam, an accepted CYP3A4 probe-substrate. In another PK study, taking valerian 1000 mg (providing about 11 mg valerenic acid) nightly for 14 days modestly increases levels of alprazolam, a CYP3A4 substrate, suggesting mild inhibition of CYP3A4 (13014,13536). However, this mild inhibition is unlikely to be clinically relevant.

GLUCURONIDATED DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Valerian might weakly inhibit glucuronidation and increase concentrations of drugs metabolized by UGT1A1 and UGT2B7.  Details In vitro research shows that methanolic valerian extract and valerenic acid might competitively inhibit UDP-glucuronosyltransferase (UGT) 1A1 (UGT1A1) and UGT2B7 (81685).

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

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

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

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

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General ...Orally, adverse effects to cowhage seem to be rare; however, a thorough safety evaluation has not been conducted. Topically, cowhage bean pod or seed may be unsafe.
Most Common Adverse Effects:
Orally: Diarrhea, flatulence, mucosal irritation.
Topically: Erythema, pruritus, rash.

Cardiovascular ...Orally, cowhage has been reported to cause palpitations (7021,7203)

Dermatologic ...Orally, ingestion of hairs from the bean pod or seed can result in significant mucosal irritation and should be avoided.
Topically, hairs on cowhage bean pod or seed can cause severe pruritus (6898). Symptoms include severe itching, burning, inflammation, and erythematous macular rashes (18,6898). Symptoms resolve spontaneously within several hours, but may also be relieved with antihistamines (6898). The hairs can be removed from the skin by washing, but the hairs can also be retained, and transferred to other people, in fabrics and carpets. Clothing and other materials that come in contact with cowhage hairs should also be thoroughly washed (6898).

Gastrointestinal ...Orally, cowhage has been reported to cause flatulence, diarrhea, and dry mouth (7021,7203). Orally, a specific powdered cowhage seed extract (Zandopa, formerly HP-200; Zandu Pharmaceuticals) has been reported to cause nausea, abdominal distention, and vomiting in clinical research when taken in amounts of 22.5-67.5 grams divided into 2-5 doses per day (7020).

Musculoskeletal ...Orally, dyskinesia has been reported in clinical research in about 3% of patients taking a specific powdered cowhage seed extract (Zandopa, formerly HP-200; Zandu Pharmaceuticals) 22. 5-67.5 grams divided into 2-5 doses daily (7020).

Neurologic/CNS ...Orally, cowhage has been reported to cause headaches (7021,7203). Orally, insomnia has been reported in clinical research in about 3% of patients taking a specific powdered cowhage seed extract (Zandopa, formerly HP-200; Zandu Pharmaceuticals) 22.5 grams to 67.5 grams divided into 2-5 doses daily (7020).

Psychiatric ...In a case report, cowhage caused an outbreak of acute toxic psychosis. Symptoms of psychosis included confusion, giddiness, agitation, hallucinations, and paranoid delusions. The cowhage-induced psychosis was successfully treated with intravenous chlorpromazine (7021).

Other ...Orally, cowhage has been reported to cause sweating and changes in urine color, (7021,7203). Theoretically, due to the levodopa constituent, cowhage is likely to cause the same adverse effects that have been attributed to purified, prescription levodopa. Some of these side effects include elevated liver enzymes, respiratory disturbances, urinary retention, muscle cramps, and priapism (15). However, these effects have not yet been reported for cowhage.

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General ...Orally, sodium bicarbonate is generally well tolerated when used in over-the-counter antacid products. However, it is possibly unsafe when used in excessive amounts. Intravenously, sodium bicarbonate is generally well tolerated when used appropriately with proper medical supervision. Topically, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, diarrhea, flatulence, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Metabolic alkalosis and stomach rupture.
Intravenously: Alkalotic tetany, hypernatremia, hypocalcemia, hypokalemia, and metabolic alkalosis.

Cardiovascular ...Orally, sodium bicarbonate has been reported to cause increased blood pressure (109689).

Gastrointestinal ...Orally, sodium bicarbonate may cause mild adverse effects including gastrointestinal disturbance such as bloating, nausea, vomiting, and abdominal pain (25706,106250). The severity of these effects appears to increase with dose (104850). When taken in large amounts (300 mg/kg as a single dose, 4 ounces over a 24-hour time period, or 10-12 ounces over 5 days), sodium bicarbonate can cause diarrhea, nausea, vomiting, bloating, flatulence, and abdominal pain (29962,104853,104850). Gastrointestinal side effects during exercise can be reduced when single doses of 200-300 mg/kg are taken 3 hours before with a high-carbohydrate meal (106250). Taking enteric-coated or delayed-release formulations may also reduce the incidence and severity of mild gastrointestinal symptoms (104853,106250), but enteric-coated formulations may also reduce overall absorption of bicarbonate (104853).
Sodium bicarbonate antacids may cause serious gastrointestinal effects, including stomach rupture, if taken orally as a partially dissolved slurry rather than a solution, especially if taken when overly full from food or drink (25735,25736,29414,29415,29416,90913).

Hematologic ...In patients with normal kidney function, appropriate use of oral sodium bicarbonate may not cause significant alkalosis, although it may increase loss of sodium, chloride, potassium, and volume due to diuresis (25733). However, excessive use or chronic oral intake of sodium bicarbonate may induce metabolic alkalosis characterized by levels of sodium bicarbonate ≥40 mEq/L, hypokalemia, hypochloremia, and hypernatremia (25733,29962,106255). When administered intravenously, the most common complication of sodium bicarbonate is hypokalemia (25709). Hypocalcemia or hypernatremia may also occur, although these effects are less common and typically associated with overaggressive therapy (25709,106255).
At least two cases of hypernatremia resulting from topical application of sodium bicarbonate (baking soda) have been reported (29962,90914).

Musculoskeletal ...Metabolic alkalosis induced by sodium bicarbonate has reportedly been associated with tetany that results from hypocalcemia; however, this condition is rare (25709).

Neurologic/CNS ...Orally, concomitant use of excessive sodium bicarbonate (intake of "tablespoons" of sodium bicarbonate daily or up to one box of baking soda weekly) has been associated with at least two cases of hypercalcemia-induced metabolic alkalosis, characterized by dizziness, headache, and loss of consciousness with shivering (25733). Rare symptoms include drowsiness, lethargy, seizures, and coma (106255). Sodium bicarbonate may also cause metabolic alkalosis and the associated symptoms when administered intravenously (13309). However, these effects are typically associated with therapy that is overaggressive.

Ocular/Otic ...At least three cases of otitis externa have been reported following the use of eardrops containing sodium bicarbonate (25696).

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General ...Orally, valerian is generally well-tolerated.
Most Common Adverse Effects:
Orally: Dizziness, drowsiness, and mental slowness. Other reported side effects include headache, gastrointestinal upset, excitability, and vivid dreams. When used chronically and abruptly stopped, symptoms of withdrawal such as tachycardia, anxiety, irritability, and insomnia might occur. Advise patients to taper doses slowly after extended use.
Serious Adverse Effects (Rare):
Orally: Several case reports raise concerns about hepatotoxicity after the use of valerian and valerian-containing multi-ingredient dietary supplements. Withdrawal from chronic valerian use has been associated with cases of cardiac failure and hallucinations.

Cardiovascular ...When used orally in high doses for an extended period of time, valerian withdrawal has been associated with tachycardia and high output cardiac failure in one patient with a history of coronary artery disease (3487). Chest tightness has been reported for an 18-year-old female who took 40-50 capsules containing valerian 470 mg/capsule (659). A case of severe hypotension, suspected to be due to vasodilation, hypocalcemia, and hypokalemia, has been reported for a patient who injected an unknown quantity of a crude tap water extract of raw valerian root (81734).

Dermatologic ...Orally, valerian might rarely cause a rash. A case of valerian-related rash that resolved after valerian root discontinuation was reported in clinical research (19422).

Gastrointestinal ...Orally, valerian has been associated with increased incidence of gastrointestinal problems including diarrhea, nausea, vomiting, and stomach pain (15046,19406,19407,19422,110712). In one individual, taking 20 times the normal dose caused abdominal cramping (659).

Hepatic ...There have been several case reports of hepatotoxicity associated with the use of multi-ingredient oral preparations containing valerian (8243,96241). In one case report, a 57-year-old man presented with acute hepatitis after consuming a cold and flu remedy containing valerian 2 grams for 3 days; the remedy also contained white willow, elderberry, and horseradish. Although the use of the cold and flu remedy was discontinued one month prior to symptom presentation, the acute hepatitis was attributed to valerian root and treated with steroids (96241). It is possible, however, that some of these preparations may have been adulterated with hepatotoxic agents (8243).
Hepatotoxicity involving long-term use of single-ingredient valerian preparations has also been reported (3484,17578). Also, a case of a 38-year-old female with liver insufficiency and cirrhosis of a vascular parenchymal nature who developed hepatotoxic symptoms following valerian and ethyl-alcohol abuse has been reported (81697). Symptoms resolved and laboratory values normalized following intense plasmapheresis treatment. Another case of acute hepatitis characterized by elevated aminotransferases, mild fibrosis, and liver inflammation has been reported for a 50-year-old female who consumed valerian root extract 5 mL three times weekly along with 10 tablets of viamine, a product containing dry valerian extract 125 mg/tablet, for 2 months (81696). Because a variety of doses were used in these cases, and many people have used higher doses safely, these hepatotoxic reactions might have been idiosyncratic. Tell patients the long-term effect of valerian on liver function is unknown.

Musculoskeletal ...In a case report, combined intake of valerian and passionflower caused throbbing and muscular fatigue when taken concomitantly with lorazepam (19429).

Neurologic/CNS ...Orally, valerian might cause dizziness, headaches, fatigue, sleepiness, and mental dullness (3484,17578,19411,19422,81723,89407). The severity of adverse effects appears to increase with higher doses (19411). However, taking valerian extracts in doses up to 1800 mg does not appear to significantly affect mood or psychomotor performance (10424,15044). Valerian does not usually have a negative impact on reaction time, alertness, and concentration the morning after intake (2074,8296). Clinical research shows that a single dose of valerian root 1600 mg is not associated with any changes in sleepiness, reaction time, or driving performance within 1-4 hours after intake (96240). More serious side effects may occur when valerian is taken at higher doses. In one individual, 20 times the normal dose caused tremor of the hand and foot and lightheadedness (659). In a case report, combined intake of valerian and passionflower caused shaking of the hands and dizziness when taken concomitantly with lorazepam (19429).

Psychiatric ...Orally, valerian has been associate with reports of restlessness, excitability, uneasiness, agitation, and vivid dreams (3484,17578,19411,19422). Chronic use and rapid cessation can lead to withdrawal syndrome with symptoms of agitation, insomnia, and hallucinations (104003). There appears to be a trend towards increased severity of adverse effects with higher doses (19411). A case of acute hypomania has been reported for a 21-year-old female patient who took a valerian decoction in water each night for one month to treat subclinical anxiety. Symptoms included euphoric mood, rapid speech, and increased sociability and sexual interest. Following cessation of valerian use and treatment with quetiapine 100 mg daily for two weeks, the patient recovered (89405). In another case report, an 85-year-old male with mild cognitive impairment, major depression, anxiety, and chronic kidney disease presented to the emergency department with hallucinations, confusion, and agitation thought to be due to abrupt cessation after taking valerian 600 mg daily for about 6 months. The symptoms resolved in about 5 days (104003).

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