Similase Sensitive Stomach by Integrative Therapeutics

POSSIBLY EFFECTIVE

• Dyslipidemia. Small studies show that oral gamma-oryzanol might decrease total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels in patients with dyslipidemia. Details: Most clinical research in patients with dyslipidemia, comprised of small clinical studies, shows that gamma-oryzanol 100-300 mg daily for up to 2-6 months decreases total cholesterol, LDL cholesterol, and triglyceride levels, although effects on high-density lipoprotein (HDL) cholesterol levels are mixed (752,757,51108,51109). Other preliminary clinical evidence in patients with dyslipidemia shows that taking gamma-oryzanol 40.2 mg with vitamin E 4 mg, omega-3 fatty acids 1100 mg, and niacin 18 mg daily for 4 months reduces LDL cholesterol by an additional 23 mg/dL when compared with vitamin E and omega-3 fatty acids (51073). Gamma-oryzanol as a component of rice brain oil has also been evaluated. While rice bran oil has been shown to lower lipid levels, it is unclear if gamma-oryzanol content alters outcomes (51066,100481). One small clinical study in males with mild hypercholesterolemia shows that consuming rice bran oil containing a high amount of gamma-oryzanol (0.8 grams daily) as part of the diet for 4 weeks lowers LDL and total cholesterol to the same degree as rice bran oil low in gamma-oryzanol (0.05 grams daily) (51066). However, another small clinical study in patients with hyperlipidemia shows that taking rice brain oil 30 mL containing 8000 or 11000 ppm gamma-oryzanol daily for 4 weeks decreases LDL-C levels to a greater extent than oil containing 4000 ppm gamma-oryzanol (100481).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Athletic performance. Although there is interest in using oral gamma-oryzanol to improve athletic performance, there is insufficient reliable information about the clinical effects of gamma-oryzanol for this purpose.
• Atopic dermatitis (eczema). It is unclear if topical gamma-oryzanol is beneficial for eczema in children. Details: A small clinical study in children shows that bathing in bathwater containing 20 mL of a solution containing gamma-oryzanol 0.5% daily for up to 6 months appears to improve symptoms of atopic dermatitis when compared with baseline (51112). The validity of this finding is limited by the lack of a comparator group.
• Hypertension. Oral gamma-oryzanol has only been evaluated in combination with sesame oil; its benefits when used alone are unclear. Details: Preliminary clinical research in patients with hypertension shows that using a 20:80 blend of sesame oil and gamma-oryzanol-rich rice bran oil (Vivo, Adani Wilmar) as cooking oil for 8 weeks improves blood pressure and lipid profile. In patients using a low dose of nifedipine, 20 mg daily, adding the oil blend seems to further reduce blood pressure when compared with nifedipine alone (96180).
• Menopausal symptoms. Although there is interest in using oral gamma-oryzanol for symptoms of menopause, there is insufficient reliable information about the clinical effects of gamma-oryzanol for this purpose.
• Muscle strength. It is unclear if oral gamma-oryzanol is beneficial for improving muscle strength. Details: Preliminary clinical research in well-trained male athletes over 40 years old shows that taking gamma-oryzanol 500 mg daily for 9 weeks while participating in a resistance exercise program does not improve muscle strength or vertical jump power when compared with placebo (751). Conversely, a small clinical study in young healthy males shows that taking gamma-oryzanol 600 mg daily for 9 weeks during resistance training modestly increases muscular strength when compared with placebo (100482). More evidence is needed to rate gamma-oryzanol for these uses.

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POSSIBLY EFFECTIVE

• Atopic dermatitis (eczema). Some clinical research suggests that topical licorice seems to improve symptoms of atopic dermatitis. Details: Applying gel formulations containing 1% or 2% licorice root extract three times daily for 2 weeks seems to reduce erythema by 35% to 61%, edema by 57% to 84%, and itching by 44% to 73%. The 2% gel seems to be more effective than the 1% gel (59732).
• Canker sores. Some clinical research suggests that topical licorice patches and mouth rinses seems to reduce ulcer size and pain in patients with recurrent aphthous stomatitis. Details: Clinical research shows that applying an oral patch containing licorice 0.015-0.229 mg/kg for 16 hours each day for 8 days does not affect ulcer healing time, but reduces ulcer size and post-stimulus pain, when compared with placebo (59769). A small clinical study also shows that applying bioadhesive hydrogel patches containing 1% licorice extract reduces the pain, as well as the diameter of necrosis and inflammatory halo of recurrent canker sores, when compared to baseline (59781). Mouth rinses containing licorice have also been used. One clinical study shows that swishing a diphenhydramine and 5% licorice extract solution around the mouth for about 3 minutes four times daily until the sores have healed reduces the average time to healing by 1.5 days when compared to a solution containing diphenhydramine alone. Pain was reduced by up to 69% more in those using licorice extract (104564). Another small clinical study shows that gargling with licorice extract four times daily for 2 days has a large beneficial effect on pain and ulcer size when compared with using a placebo gargle. The licorice extract was made by boiling licorice root 40 grams in one liter of water for 30 minutes and cooled (110319). In addition, preliminary clinical research shows that gargling with warm water containing deglycyrrhizinated licorice powder 200 mg four times daily for 7 days improves pain in 75% of patients by day one and results in complete healing in 75% of patients by day three (59857).
• Endotracheal intubation-related adverse effects. Some clinical research suggests that using licorice as a gargle or lozenge prior to endotracheal intubation can reduce adverse effects like sore throat and cough. Details: A meta-analysis of 5 clinical trials in patients undergoing elective surgical procedures shows that topical use of licorice, either as a gargle or lozenge, prior to endotracheal intubation reduces the risk for sore throat by 56% and reduces the risk for cough by 39% when compared with a control group at 24 hours post-extubation (100985). One clinical study included in this analysis shows that sucking on a single lozenge (Sualin, Hamdard Pharma) containing licorice extract 97 mg beginning 30 minutes prior to intubation reduces the risk for cough immediately after extubation by 56% when compared with a sugar candy lozenge. However, it doesn't seem to reduce cough at 30 minutes, 12 hours, or 24 hours post-extubation. This lozenge also appears to reduce the risk for sore throat by about 32% at 12 and 24 hours post-extubation, but not immediately or 30 minutes after extubation (25670). Additional clinical studies included in the meta-analysis show that gargling with fluid prepared with licorice 0.5 grams for at least one minute beginning 5 minutes prior to endotracheal intubation reduces the incidence and severity of post-extubation sore throat and coughing when compared with a water control (26464,59793).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Topical licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research in patients with mild to moderate acne associated with mask wearing shows that topical application of a combination of licorice root extract 0.3%, calendula 4%, and snail secretion filtrate 40% (AI complex) to the face twice daily for 12 weeks modestly reduces inflammatory, but not non-inflammatory or total, acne lesions when compared with placebo. There was no difference in overall treatment success, defined as at least almost clear skin or a large improvement (110322). It is unclear if any benefits are due to licorice, other ingredients, or the combination.
• Addison disease. Although there has been interest in using oral licorice for Addison disease, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Adrenal insufficiency. Although there has been interest in using oral licorice for adrenal insufficiency, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Allergic rhinitis (hay fever). It is unclear if using a licorice-containing nasal irrigation suspension improves symptoms in patients with allergic rhinitis. Details: A clinical study in patients with allergic rhinitis shows that using a nasal irrigation suspension containing licorice extract 900 mg daily for 1 month improves symptoms such as nasal blockage, rhinorrhea, sneezing, postnasal discharge, and olfactory disturbance when compared with baseline (108569). Although the study also utilized mometasone 2 mg nasal spray and isotonic saline nasal irrigation as comparators, symptom improvement was observed in all three groups, and there was no statistical comparison of outcomes between groups.
• Antipsychotic-induced hyperprolactinemia. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in females with risperidone-induced hyperprolactinemia shows that taking a combination of licorice and peony (Peony-Glycyrrhiza Decoction; PGD) 45 grams daily for 4 weeks reduces prolactin levels to a similar extent as bromocriptine (59775). However, another study shows that taking the same product at the same dose for 16 weeks has no effect on prolactin levels in females with antipsychotic-induced hyperprolactinemia when compared with placebo. Although the prolactin-related adverse event questionnaire total score was moderately improved, there was no effect on clinically meaningful symptoms or menstrual resumption (97219). Both studies show no effect on psychotic symptoms (59775,97219). Preliminary clinical research in male patients with antipsychotic-induced hyperprolactinemia shows that taking an herbal extract containing licorice and peony (shakuyaku-kanzo-to) 2.5 grams three times daily reduces prolactin levels after 4 weeks, but does not have a significant effect on prolactin levels 4 weeks after treatment cessation (59907).
• Asthma. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study conducted in Iran in children and adolescents aged 6-18 years old with mild-to-moderate asthma shows that taking a combination of licorice, sweet violet, and jalap (Anti-Asthma, Sinafaravar) twice daily for a month in addition to standard therapy reduces cough severity but does not change shortness of breath frequency or severity, rescue inhaler use, respiratory indices, or perceptions of asthma severity when compared with placebo (113569). It is unclear whether this effect is due to licorice, other ingredients, or the combination.
• Bleeding. Topical licorice might reduce bleeding when used in combination with other ingredients; its effect when used alone is unclear. Details: Some preliminary clinical research shows that topically applying 4 mL of a specific product (Ankaferd Blood Stopper, Mefar Ilaç Sanayi A.S.) containing licorice, Alpinia, thyme, stinging nettle, and common grape vine reduces bleeding, but does not improve the surgical time for episiotomy repair, when compared with saline (31010). Other preliminary clinical research shows that ampules of this same product placed in empty alveolus for up to 20 minutes reduces bleeding in postsurgical dental patients with increased bleeding tendency (31002).
• Cancer-related pain. It is unclear if oral licorice is beneficial for pain in patients with cancer. Details: Preliminary clinical research shows that taking a 1:1 combination of licorice root and peony root, along with a Taiwanese tonic vegetable soup comprised of lily bulb, lotus seed, and jujube fruit, reduces pain levels in terminal cancer patients when compared with patients consuming only the soup or the regular hospital diet (59770).
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral licorice for CFS, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Colic. Although there has been interest in using oral licorice for colic, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Coronavirus disease 2019 (COVID-19). It is unclear whether oral licorice is beneficial for COVID-19. Details: A small open-label study in adults in Iran with moderate COVID-19 shows that taking licorice (D-Reglis, Irandarouk Pharmaceutical Company) 760 mg three times daily for 7 days in addition to standard treatment with hydroxychloroquine 200 mg twice daily for 7 days does not improve oxygen saturation, temperature, respiratory rate, clinical symptoms, length of hospital stay, or mortality, when compared with standard treatment alone (113633). As part of a combination treatment, a small clinical study in patients hospitalized in Egypt with moderate COVID-19 shows that administering oral licorice extract 300 mg (standardized to contain glycyrrhizin 60 mg) once daily and Boswellia serrata extract 300 mg twice daily for 14 days, along with following an institution-based COVID-19 treatment protocol, may modestly improve mortality and time to recovery when compared with patients receiving the standard protocol alone. The standard treatment protocol included acetaminophen, azithromycin, vitamin C, zinc, and enoxaparin (108579). It is unclear if any effect is due to licorice, Boswellia serrata, or the combination.
• Dental caries. It is unclear if oral licorice is beneficial for the prevention of dental caries. Details: One clinical study in adults shows that swishing 15 mL of a solution containing licorice extract 1% once nightly before bed for 5 days may reduce the acid production of cavity-causing bacteria, which may modestly reduce cavity risk, when compared with using a saline solution (108567). The validity of this study is limited by the short duration of treatment and follow-up.
• Dental plaque. It is unclear if licorice toothpaste or mouthwash is beneficial for reducing plaque. Details: Preliminary clinical research shows that using 0.25% or 0.50% glycyrrhizin-containing toothpaste twice daily does not reduce the amount of plaque, gingivitis, or bleeding in patients with proper dental hygienic measures when compared with the same toothpaste without glycyrrhizin (59812). Also, other preliminary clinical research shows that using glycyrrhizin-containing mouthwash for 3 days does not significantly reduce plaque levels (59855).
• Depression. It is unclear if adding oral licorice to standard treatment is beneficial for improving depression. Details: A very small, nonblinded clinical study in hospitalized adults with major depressive disorder shows that adding licorice extract 1400 mg daily, standardized to glycyrrhizin 7% to 8%, to standard treatment for 2 weeks improves depression rating scores when compared with baseline, although these improvements were numerically similar to those seen with standard treatment alone. Patients in the treatment group also took oral magnesium citrate 300 mg daily to prevent magnesium depletion. The validity of this finding is limited due to the small size of the study, short duration of treatment, and unclear reporting (108575).
• Diabetes. Although there has been interest in using oral licorice for diabetes, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Dry mouth. It is unclear if rinsing the mouth with licorice is beneficial for dry mouth in people on hemodialysis. Details: Preliminary clinical research in hemodialysis patients with dry mouth shows that rinsing with a licorice mouthwash containing 8.34 grams of licorice concentrate per 500 mL of water with every meal for 10 days does not affect salivary flow rate, but reduces subjective feelings of dry mouth by about 28%, when compared with a water-based mouthwash and control group (97220).
• Dysmenorrhea. It is unclear if oral licorice is beneficial for reducing pain. Details: Preliminary clinical research shows that taking a syrup providing licorice extract 750 mg twice daily for the first 5 days of the menstrual cycle reduces pain as effectively as ibuprofen 400 mg every 8 hours in patients with moderate or severe dysmenorrhea (104558).
• Dyspepsia. Oral licorice might improve symptoms of dyspepsia when used in combination with other ingredients; its effect when used alone is unclear. Details: Various combination products manufactured by Steigerwald Arzneimittelwerk GmbH have been evaluated for dyspepsia. Two specific combination products containing licorice root (Iberogast; STW-5-S) seem to improve symptoms of dyspepsia. The combinations include licorice plus milk thistle, peppermint leaf, German chamomile, caraway, celandine, angelica, and lemon balm either with (Iberogast) or without clown's mustard plant (STW-5-S) 1 mL three times daily for 4 weeks (19532). A meta-analysis of studies using the Iberogast product shows that taking 1 mL orally three times daily over a period of 4 weeks reduces severity of acid reflux, epigastric pain, cramping, nausea, and vomiting when compared with placebo (13089). Also, using a preparation containing clown's mustard plant, German chamomile, peppermint, caraway, licorice, and lemon balm (STW 5-II) 1 mL three times daily for up to 12 weeks improves dyspepsia symptoms in 40% more patients when compared with placebo (12724).
• Familial Mediterranean fever. It is unclear if oral licorice is beneficial for familial Mediterranean fever. Details: Preliminary clinical research shows that taking a combination of licorice, andrographis, Siberian ginseng, and schisandra (ImmunoGuard, Inspired Nutritionals) four tablets three times daily for one month reduces the duration, frequency, and severity of attacks of familial Mediterranean fever in children when compared with placebo (12382). It is unclear if these effects are due to licorice, other ingredients, or the combination.
• Helicobacter pylori. It is unclear if oral licorice is beneficial for Helicobacter pylori eradication. Details: Some preliminary clinical research shows that adding licorice (D-Reglis, Iran Darouk Pharmaceutical Co.) 380 mg twice daily to conventional clarithromycin-based triple therapy for 14 days improves eradication rate by an additional 21% when compared with conventional treatment alone. However, any additional benefit might be limited to patients with peptic ulcer disease (97221). Other preliminary clinical research shows that taking a combination of licorice extract 100 mg and Lactobacillus paracasei HP7 in 150 mL of fermented milk daily for 8 weeks does not increase eradication rates when compared with fermented milk alone, although it may improve gastrointestinal symptom scores, decrease the gastric load of Helicobacter pylori, and improve some measures of inflammation when compared to baseline (100984).
• Hepatitis. Evidence for the use of intravenous licorice in the management of hepatitis B and C is mixed. Details: In some preliminary clinical research, a specific glycyrrhizin-containing intravenous preparation (Stronger Neominophagen C, Minophagen Pharmaceutical Co. Ltd.) appears to reduce mortality due to viral hepatitis by about 50% (3250). Other clinical research suggests that this same product reduces serum alanine aminotransferase (ALT) in hepatitis C patients but does not improve hepatitis C virus (HCV)-RNA levels (3247,59712,59721,59920). When used long-term, this preparation seems to reduce the risk of hepatocellular carcinoma in hepatitis C patients when compared to long-term use of other supplements, such as vitamin K (59905). This product has been used in various doses: 40 or 100 mL, containing 2 mg glycyrrhizin, 1 mg cysteine, and 20 mg of glycine per mL of solution, administered daily for 4-8 weeks, followed by 40 or 100 mL 2-7 times weekly for 2-16 weeks, has been used (3250,59905,59915); 40-120 mL diluted in 100 mL of 5% glucose solution and administered three times weekly for 4 weeks (59712,59721); 100 mL, which contained 200 mg glycyrrhizin, administered undiluted six times weekly for 4 weeks (59721); or 60 mL administered three times weekly for 16 weeks (59920). Other research shows that this preparation reduces ALT, aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) in patients with hepatitis B virus (59915). Oral licorice has not been evaluated for this purpose.
• Hypercholesterolemia. It is unclear if oral licorice is beneficial for improving cholesterol. Details: Preliminary clinical research shows that taking licorice root extract 0.1 grams daily for one month reduces plasma total cholesterol levels by 5%, plasma low-density lipoprotein (LDL) cholesterol levels by 9%, and plasma triglyceride levels by 14% when compared with baseline in patients with moderate hypercholesterolemia (59725). The validity of these findings is limited by the lack of a comparator group.
• Hyperkalemia. It is unclear if oral licorice is beneficial for reducing potassium levels. Details: Some clinical research in adults with diabetes and hypoaldosteronism suggests that taking glycyrrhizin 150 mg daily decreases potassium levels when compared with calcium polystyrene sulfonate (59897). Also, one very small clinical study in patients with anuria shows that taking glycyrrhetinic acid 1 gram daily for 2 weeks seems to decrease plasma potassium, but does not improve blood pressure, when compared with placebo (59723).
• IgA vasculitis. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small retrospective study in patients aged 5-36 years with newly diagnosed IgA vasculitis shows that taking compound glycyrrhizin (Eisai Pharmaceutical Co, Ltd) three times daily along with loratadine, calcium, vitamin C, rutin, and other unspecified conventional treatments is associated with an improvement in cutaneous purpura symptoms and time to symptom regression when compared with placebo. After 1 month, the rate of complete resolution and time to regression in the treatment group was 82% and 5 days, respectively, compared with 65% and 8 days, respectively, in the placebo group. Compound glycyrrhizin contained glycyrrhizin, glycine, and methionine and was dosed by age, with a dose of 25 mg daily in those 12 years or younger and 50 mg daily in those over 12 years (108580).
• Irritable bowel syndrome (IBS). Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that a formulation containing licorice root, slippery elm bark, lactulose, and oat bran daily for 2 weeks improves stool consistency and increases bowel movement frequency by 20% in individuals with constipation-predominant IBS when compared to baseline. Symptoms of abdominal pain, bloating, straining, and global severity might also be reduced (35462). The validity of these findings is limited by the lack of a comparator group. Additionally, it is unclear if any benefits are due to licorice, other ingredients, or the combination.
• Lichen planus. It is unclear if intravenous licorice is beneficial for lichen planus. Details: A very small clinical study shows that intravenous administration of 0.2% glycyrrhizin solution, 40 mL daily for 4 weeks, improves clinical symptoms of oral lichen planus in a greater percentage of patients with chronic hepatitis C when compared with dental cleaning (59903). There is no evidence suggesting that oral licorice is beneficial.
• Liver cancer. Although there has been interest in using oral or intravenous licorice preparations for liver cancer, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Melasma. Topical licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that applying a topical cream (Clariderm Clear, Stiefel Laboratories Inc.) containing 7% licorice, emblica, and belides twice daily for 60 days is as effective as a cream containing 2% hydroquinone for lightening the skin in patients with melasma (59824). It is unclear if this effect is due to licorice, other ingredients, or the combination.
• Menopausal symptoms. It is unclear if oral licorice is beneficial for reducing hot flash frequency or severity. Details: In one preliminary clinical study, taking licorice root extract 330 mg orally three times daily for 8 weeks modestly reduces the frequency of hot flashes by about 1.3 per day and the severity of hot flashes by about 40% when compared with placebo (94659). However, another preliminary clinical study shows that taking a specific licorice root extract (D-Reglis, Iran Darouk Pharmaceutical Co.) 650 mg orally daily for 90 days does not reduce the number or severity of hot flashes when compared to baseline (25694).
• Muscle cramps. It is unclear if oral licorice is beneficial for muscle cramps due to cirrhosis or hemodialysis. Details: Preliminary clinical research shows that taking a specific combination of licorice and peony (shakuyaku-kanzo-to) might reduce muscle cramps in patients with hepatic cirrhosis or in patients undergoing hemodialysis when compared to baseline (13550,13551,13552). This combination was taken as 6-7.5 grams daily in up to three divided doses for 2-4 weeks in two studies (13550,13552). In a third study, the combination was taken as 2.5 grams during hemodialysis with self-administration at the onset of muscle cramping (13551).
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral licorice is beneficial for NAFLD. Details: A small clinical trial in females with NAFLD shows that taking licorice extract (Shirin Darou Company, Shiraz, Iran) 500 mg twice daily for 12 weeks improves some measures of liver health and glycemic control when compared with placebo. Modest improvements occurred in levels of alanine aminotransferase, as well as in measures of insulin resistance and severity of liver steatosis based on ultrasonographic evaluation. There were no effects on body mass index (BMI), plasma lipids, fasting blood glucose, or other liver enzymes. All patients were also given weight loss and healthy lifestyle advice (110320). Preliminary clinical research shows that taking licorice root extract 2 grams daily for 2 months reduces liver function enzyme levels in patients with NAFLD when compared to pre-treatment (59841). It is unclear if this reduction is clinically significant.
• Obesity. It is unclear if oral licorice is beneficial for weight loss. Details: Preliminary clinical research shows that taking a specific licorice flavonoid oil (Glavonoid) 300 mg daily for 8 weeks has no effect on weight or body fat when compared with placebo in obese patients (17727).
• Oral mucositis. It is unclear if oral or topical licorice is beneficial for the prevention or treatment of chemotherapy- or radiation-induced oral mucositis. Details: In patients with head and neck cancer undergoing chemoradiation, preliminary clinical research shows that using oral and topical licorice powder twice daily in addition to conventional treatments for 6 weeks reduces the overall incidence of mucositis and also reduces the risk of developing severe oral mucositis to 15.5%, compared with 20% in those using topical honey and 43% in those using conventional treatments alone. Licorice treatment consisted of yastimadhu powder 5 grams mixed in honey for topical application in the mouth, as well as yastimadhu capsule 500 mg twice daily orally (104562). A small clinical trial in patients with head and neck cancer and oral mucositis currently undergoing radiation therapy shows that applying a mucoadhesive film containing licorice to the upper lip mucosal surface four times daily for 4 weeks, in conjunction with standard oral care, improves pain scores, mucositis grading, and ulcer size when compared with placebo film (108572). The validity of this finding is limited due to the short duration of treatment and exclusion of patients with severe mucositis.
• Osteoarthritis. Although there has been interest in using oral licorice for osteoarthritis, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Osteoporosis. Although there has been interest in using oral licorice for osteoporosis, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Parkinson disease. It is unclear if oral licorice is beneficial for improving Parkinson disease symptoms. Details: A small clinical study in patients with Parkinson disease shows that taking licorice extract 136 mg (containing glycyrrhizin 12.14 mg, polyphenols 136 mcg, and flavonoids 2.6 mcg) in a 5 mL syrup twice daily for 6 months improves Parkinson symptoms, tremor, and overall daily activities when compared with placebo (102961).
• Peptic ulcers. Evidence for the use of oral licorice for peptic ulcers is mixed. Details: There is some evidence that taking 6-12 tablets each containing deglycyrrhizinated licorice 380 mg, bismuth subnitrate 100 mg, aluminum hydroxide gel 100 mg, magnesium carbonate 200 mg, sodium bicarbonate 100 mg, and powdered alder buckthorn bark 30 mg (Caved-S, Cedona) in up to three divided doses daily for 4-16 weeks might accelerate the healing of peptic ulcers (11312,11313). Some clinical research also shows that this product is as effective as carbenoxolone sodium (Biogastrone) when taken at doses of two tablets three times daily after meals for 4 weeks (59871). In contrast, taking deglycyrrhizinated licorice (Ulcedal, Cedona, and others) 450-1000 mg three to five times daily for 4-8 weeks or glycyrrhizinic acid-reduced licorice 760 mg three times daily for 6 weeks does not seem to reduce the need for medication, pain, burning, or other discomfort in patients with peptic ulcers when compared with placebo (59864,59865,59873,59874).
• Physical performance. It is unclear if oral licorice is beneficial for improving physical performance in older females. Details: A small clinical trial in healthy females 59 years and older shows that taking licorice flavonoid oil 300 mg orally daily for 16 weeks in addition to strength training does not improve walking speed or other measures of functional mobility when compared with strength training alone (102960).
• Polycystic ovary syndrome (PCOS). Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Clinical research shows that taking licorice root extract 2250 mg daily along with Ceylon cinnamon, levant berry, St. John's Wort, peony, and tribulus for 3 months with lifestyle modification improves symptoms of PCOS, including a reduction in oligomenorrhea/amenorrhea by 33% and the number of days between menstrual cycles by 43 days when compared with lifestyle modification alone. Although conception rate increased 4-fold in the intervention group, live birth rate was similar between groups (97216). The effect of licorice alone for the treatment of PCOS is unknown.
• Prostate cancer. Although there has been interest in using oral licorice for prostate cancer, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Psoriasis. It is unclear if topical licorice is beneficial for improving psoriasis symptoms. Details: Preliminary clinical research shows that using a topical cream containing licorice extract and milk proteins twice daily for 4 weeks does not reduce the duration of corticosteroid cream therapy in patients with palmar and/or plantar psoriasis, but may improve skin peeling, the area of skin affected, and some subjective symptoms, when compared with corticosteroid cream alone (59823).
• Smoking cessation. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults in India with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing licorice 200 mg, ashwagandha, cowhage, ginger, turmeric, and other herbal extracts (Smotect, Smotect India) twice daily for 3 months reduces the number of cigarettes smoked daily and levels of alveolar carbon monoxide and carboxyhemoglobin but does not improve lung capacity when compared with placebo (112115). It is unclear if these effects are due to licorice, other ingredients, or the combination.
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral licorice for SLE, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Tuberculosis. Although there has been interest in using oral licorice for tuberculosis, there is insufficient reliable information about the clinical effects of licorice for this condition.
• Urticaria. Oral licorice has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A meta-analysis of clinical research in adults with chronic urticaria shows that taking compound glycyrrhizin, containing glycyrrhizin, N-acetyl cysteine, and glycine, as 50-75 mg three times daily along with desloratadine 5-8.8 mg daily for 4 weeks improves response rate, cure rate, and recurrence rate when compared with desloratadine alone (108571). Another meta-analysis of clinical research in pediatric and adult patients with chronic urticaria shows that taking compound glycyrrhizin 25-75 mg 2-3 times daily improves efficacy rate of symptom reduction, increases cure rate, and decreases recurrence rate when compared with second-generation antihistamine monotherapy (113634). However, most studies included in the meta-analyses were low quality, and all studies were conducted in China. Higher quality studies in other geographic locations are needed to confirm these findings.
• Vitiligo. It is unclear if the licorice constituent compound glycyrrhizin is beneficial for vitiligo. Details: A meta-analysis of 14 clinical studies in patients aged 3-68 years old with vitiligo shows that taking licorice constituent compound glycyrrhizin 25-75 mg 3 times daily for 2-6 months with standard treatment improves effectiveness, cure rate, and immune-mediated inflammatory markers when compared with standard treatment alone (112232). Additionally, a meta-analysis of clinical studies conducted in China in adults with vitiligo suggests that taking oral or intramuscular compound glycyrrhizin for 10 weeks to 6 months in combination with conventional therapies, including phototherapy, immunosuppressants, or traditional Chinese medicine, increases the percentage of patients with more than 50% regimentation when compared with conventional treatments alone (113635). More evidence is needed to rate licorice for these uses.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Celiac disease. Although there has been interest in using oral lipase for celiac disease, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Dyspepsia. It is unclear if oral lipase is beneficial for improving symptoms of postprandial distress syndrome. Details: A small clinical trial shows that taking a specific acid-resistant lipase (Amano Enzyme USA) 280 mg immediately before a high-fat meal does not reduce postprandial bloating and nausea when compared with placebo in individuals with postprandial distress syndrome (101900).
• Inflammatory bowel disease (IBD). Although there has been interest in using oral lipase for IBD, there is insufficient reliable information about the clinical effects of lipase for this purpose.
• Prematurity. It is unclear if adding a specific form of lipase, recombinant human bile salt-stimulated lipase (rhBSSL), to infant formula improves outcomes in premature infants. Some research suggests a potential increased risk for adverse effects. Details: Human breast milk contains rhBSSL, but it is inactivated when breast milk is pasteurized for donation. Clinical research in infants born before 32 weeks' gestation shows that adding rhBSSL as 8700 units per 100 mL formula or pasteurized breast milk, for 4 weeks does not increase growth velocity, body length, or head circumference over the next 12 months when compared with formula or pasteurized breast milk devoid of lipase. However, the infants who were small for gestational age (SGA), which made up approximately 15% of the study population, grew by an additional 1.9 grams/kg daily on average when compared with placebo (101940). More evidence is needed to rate lipase for these uses.

(Read more about LIPASE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about MARSHMALLOW)

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

(Read more about SLIPPERY ELM)

POSSIBLY SAFE ...when used orally and appropriately. Gamma-oryzanol 300 mg daily has been used most commonly in clinical research without reports of adverse events (751,752,753,754,755,51111). ...when used topically and appropriately (51112).

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

(Read more about GAMMA-ORYZANOL)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Licorice has Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when licorice products that do not contain glycyrrhizin (deglycyrrhizinated licorice) are used orally and appropriately for medicinal purposes. Licorice flavonoid oil 300 mg daily for 16 weeks, and deglycyrrhizinated licorice products in doses of up to 4.5 grams daily for up to 16 weeks, have been used with apparent safety (6196,11312,11313,17727,100984,102960). ...when licorice products containing glycyrrhizin are used orally in low doses, short-term. Licorice extract 272 mg, containing glycyrrhizin 24.3 mg, has been used daily with apparent safety for 6 months (102961). A licorice extract 1000 mg, containing monoammonium glycyrrhizinate 240 mg, has been used daily with apparent safety for 12 weeks (110320). In addition, a syrup providing licorice extract 750 mg has been used twice daily with apparent safety for 5 days (104558). ...when applied topically. A gel containing 2% licorice root extract has been applied to the skin with apparent safety for up to 2 weeks. (59732). A mouth rinse containing 5% licorice extract has been used with apparent safety four times daily for up to one week (104564).

POSSIBLY UNSAFE ...when licorice products containing glycyrrhizin are used orally in large amounts for several weeks, or in smaller amounts for longer periods of time. The European Scientific Committee on Food recommends that a safe average daily intake of glycyrrhizin should not exceed 10 mg (108577). In otherwise healthy people, consuming glycyrrhizin daily for several weeks or longer can cause severe adverse effects including pseudohyperaldosteronism, hypertensive crisis, hypokalemia, cardiac arrhythmias, and cardiac arrest. Doses of 20 grams or more of licorice products, containing at least 400 mg glycyrrhizin, are more likely to cause these effects; however, smaller amounts have also caused hypokalemia and associated symptoms when taken for months to years (781,3252,15590,15592,15594,15596,15597,15599,15600,16058)(59731,59740,59752,59785,59786,59787,59792,59795,59805,59811)(59816,59818,59820,59822,59826,59828,59849,59850,59851,59867)(59882,59885,59888,59889,59895,59900,59906,97213,110305). In patients with hypertension, cardiovascular or kidney conditions, or a high salt intake, as little as 5 grams of licorice product or 100 mg glycyrrhizin daily can cause severe adverse effects (15589,15593,15598,15600,59726).

PREGNANCY: UNSAFE
when used orally. Licorice has abortifacient, estrogenic, and steroid effects. It can also cause uterine stimulation. Heavy consumption of licorice, equivalent to 500 mg of glycyrrhizin per week (about 250 grams of licorice per week), during pregnancy seems to increase the risk of delivery before gestational age of 38 weeks (7619,10618). Furthermore, high intake of glycyrrhizin, at least 500 mg per week, during pregnancy is associated with increased salivary cortisol levels in the child by the age of 8 years. This suggests that high intake of licorice during pregnancy may increase hypothalamic-pituitary-adrenocortical axis activity in the child (26434); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about LICORICE)

There is insufficient reliable information available about the safety of lipase.

CHILDREN: POSSIBLY UNSAFE
when recombinant human bile salt-stimulated lipase (rhBSSL) is used orally by premature infants. Adding rhBSSL to infant formula or pasteurized breast milk increases the risk for serious gastrointestinal adverse effects in premature infants (101940).

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

(Read more about LIPASE)

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

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

PREGNANCY AND LACTATION:
Insufficient reliable information available.

(Read more about MARSHMALLOW)

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

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

(Read more about SLIPPERY ELM)

(Read more about GAMMA-ORYZANOL)

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, licorice might reduce the effects of antihypertensive drugs.  Details In human research, licorice increases blood pressure in a dose-dependent manner (1372,7620,59877).

CISPLATIN (Platinol-AQ) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might reduce the effects of cisplatin.  Details In animal research, licorice diminished the therapeutic efficacy of cisplatin (59763).

CORTICOSTEROIDS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of licorice and corticosteroids might increase the side effects of corticosteroids.  Details Case reports suggest that concomitant use of licorice and oral corticosteroids, such as hydrocortisone, can potentiate the duration of activity and increase blood levels of corticosteroids (3252,12672,20040,20042,48429,59756). Additionally, in one case report, a patient with neurogenic orthostatic hypertension stabilized on fludrocortisone 0.1 mg twice daily developed pseudohyperaldosteronism after recent consumption of large amounts of black licorice (108568).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease the levels and clinical effects of CYP1A2 substrates.  Details In vitro research shows that licorice induces CYP1A2 enzymes (111404).

CYTOCHROME P450 2B6 (CYP2B6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase levels of drugs metabolized by CYP2B6.  Details In vitro research shows that licorice extract and glabridin, a licorice constituent, inhibit CYP2B6 isoenzymes (10300,94822). Licorice extract from the species G. uralensis seems to inhibit CYP2B6 isoenzymes to a greater degree than G. glabra extract in vitro (94822). Theoretically, these species of licorice might increase levels of drugs metabolized by CYP2B6; however, these interactions have not yet been reported in humans.

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase levels of drugs metabolized by CYP2C19.  Details In vitro, licorice extracts from the species G. glabra and G. uralensis inhibit CYP2C19 isoenzymes in vitro (94822). Theoretically, these species of licorice might increase levels of drugs metabolized by CYP2C19; however, this interaction has not yet been reported in humans.

CYTOCHROME P450 2C8 (CYP2C8) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase levels of drugs metabolized by CYP2C8.  Details In vitro, licorice extract from the species G. glabra and G. uralensis inhibits CYP2C8 isoenzymes (94822). Theoretically, these species of licorice might increase levels of drugs metabolized by CYP2C8; however, this interaction has not yet been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase or decrease levels of drugs metabolized by CYP2C9.  Details There is conflicting evidence about the effect of licorice on CYP2C9 enzyme activity. In vitro research shows that extracts from the licorice species G. glabra and G. uralensis moderately inhibit CYP2C9 isoenzymes (10300,94822). However, evidence from an animal model shows that licorice extract from the species G. uralensis can induce hepatic CYP2C9 activity (14441). Until more is known, licorice should be used cautiously in people taking CYP2C9 substrates.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, licorice might increase or decrease levels of drugs metabolized by CYP3A4.  Details Pharmacokinetic research shows that the licorice constituent glycyrrhizin, taken in a dosage of 150 mg orally twice daily for 14 days, modestly decreases the area under the concentration-time curve of midazolam by about 20%. Midazolam is a substrate of CYP3A4, suggesting that glycyrrhizin modestly induces CYP3A4 activity (59808). Animal research also shows that licorice extract from the species G. uralensis induces CYP3A4 activity (14441). However, licorice extract from G. glabra species appear to inhibit CYP3A4-induced metabolism of testosterone in vitro. It is thought that the G. glabra inhibits CYP3A4 due to its constituent glabridin, which is a moderate CYP3A4 inhibitor in vitro and not present in other licorice species (10300,94822). Until more is known, licorice should be used cautiously in people taking CYP3A4 substrates.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of licorice with digoxin might increase the risk of cardiac toxicity.  Details Overuse or misuse of licorice with cardiac glycoside therapy might increase the risk of cardiac toxicity due to potassium loss (10393).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of licorice with diuretic drugs might increase the risk of hypokalemia.  Details Overuse of licorice might compound diuretic-induced potassium loss (10393,20045,20046,59812). In one case report, a 72-year-old male with a past medical history of hypertension, type 2 diabetes, hyperlipidemia, arrhythmia, stroke, and hepatic dysfunction was hospitalized with severe hypokalemia and uncontrolled hypertension due to pseudohyperaldosteronism. This was thought to be provoked by concomitant daily consumption of a product containing 225 mg of glycyrrhizin, a constituent of licorice, and hydrochlorothiazide 12.5 mg for 1 month (108577).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might increase or decrease the effects of estrogen therapy.  Details Theoretically, licorice might interfere with estrogen therapy due to estrogenic and anti-estrogenic effects (7860,16058).

LOOP DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, loop diuretics might increase the mineralocorticoid effects of licorice.  Details Theoretically, loop diuretics might enhance the mineralocorticoid effects of licorice by inhibiting the enzyme that converts cortisol to cortisone; however, bumetanide (Bumex) does not appear to have this effect (3255).

METHOTREXATE (Trexall, others) Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, licorice might increase levels of methotrexate.  Details Animal research suggests that intravenous administration of glycyrrhizin, a licorice constituent, and high-dose methotrexate may delay methotrexate excretion and increase systemic exposure, leading to transient elevations in liver enzymes and total bilirubin (108570). This interaction has not yet been reported in humans.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, licorice might decrease levels of midazolam.  Details In humans, the licorice constituent glycyrrhizin appears to moderately induce the metabolism of midazolam (59808). This is likely due to induction of cytochrome P450 3A4 by licorice. Until more is known, licorice should be used cautiously in people taking midazolam.

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease the absorption of P-glycoprotein substrates.  Details In vitro research shows that licorice can increase P-glycoprotein activity (104561).

PACLITAXEL (Abraxane, Onxol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease plasma levels and clinical effects of paclitaxel.  Details Multiple doses of licorice taken concomitantly with paclitaxel might reduce the effectiveness of paclitaxel. Animal research shows that licorice 3 grams/kg given orally for 14 days before intravenous administration of paclitaxel decreases the exposure to paclitaxel and increases its clearance. Theoretically, this occurs because licorice induces cytochrome P450 3A4 enzymes, which metabolize paclitaxel. Notably, a single dose of licorice did not affect exposure or clearance of paclitaxel (102959).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, licorice might decrease plasma levels and clinical effects of warfarin.  Details Licorice seems to increase metabolism and decrease levels of warfarin in animal models. This is likely due to induction of cytochrome P450 2C9 (CYP2C9) metabolism by licorice (14441). Advise patients taking warfarin to avoid taking licorice.

(Read more about LICORICE)

(Read more about LIPASE)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, marshmallow flower might have antiplatelet effects.  Details Animal research suggests that marshmallow flower extract has antiplatelet effects (92846). However, the root and leaf of marshmallow, not the flower, are the plant parts most commonly found in dietary supplements. Theoretically, use of marshmallow flower with anticoagulant/antiplatelet drugs can have additive effects, and might increase the risk for bleeding in some patients.

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, due to potential diuretic effects, marshmallow might reduce excretion and increase levels of lithium.  Details Marshmallow is thought to have diuretic properties. To avoid lithium toxicity, the dose of lithium might need to be decreased when used with marshmallow.

ORAL DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, mucilage in marshmallow might impair absorption of oral drugs.  Details Marshmallow contains mucilage which can affect oral drug absorption (1,11,12,19). To avoid changes in absorption, take marshmallow 30-60 minutes after oral medications.

(Read more about MARSHMALLOW)

ORAL DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, slippery elm may slow the absorption and reduce serum levels of oral drugs.  Details Slippery elm inner bark contains mucilage, which may interfere with the absorption of orally administered drugs (19).

(Read more about SLIPPERY ELM)

General ...Gamma-oryzanol is generally well tolerated. No adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.

(Read more about GAMMA-ORYZANOL)

General ...Orally, licorice is generally well tolerated when used in amounts commonly found in foods. It seems to be well tolerated when licorice products that do not contain glycyrrhizin (deglycyrrhizinated licorice) are used orally and appropriately for medicinal purposes or when used topically, short-term.
Most Common Adverse Effects:
Orally: Headache, nausea, and vomiting.
Topically: Contact dermatitis.
Intravenously: Diarrhea, itching, nausea, and rash.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about acute renal failure, cardiac arrest, cardiac arrhythmias, hypertension, hypokalemia, muscle weakness, paralysis, pseudohyperaldosteronism, and seizure associated with long-term use or large amounts of licorice containing glycyrrhizin.

Cardiovascular ...Orally, excessive licorice ingestion can lead to pseudohyperaldosteronism, which can precipitate cardiovascular complications such as hypertension and hypertensive crisis, ventricular fibrillation or tachycardia, sinus pause, and cardiac arrest. These effects are due to the licorice constituent glycyrrhizin and usually occur when 20-30 grams or more of licorice product is consumed daily for several weeks (781,15590,15592,15594,15596,15597,15599,15600,16835,97213) (104563,108574,108576,110305,112234). In one case report, an 89-year-old female taking an herbal medicine containing licorice experienced a fatal arrhythmia secondary to licorice-induced hypokalemia. The patient presented to the hospital with recurrent syncope, weakness, and fatigue for 5 days after taking an herbal medicine containing licorice for 2 months. Upon admission to the hospital, the patient developed seizures, QT prolongation, and ventricular arrhythmia requiring multiple defibrillations. Laboratory tests confirmed hypokalemia and pseudohyperaldosteronism (112234).
However, people with cardiovascular or kidney conditions may be more sensitive, so these adverse events may occur with doses as low as 5 grams of licorice product or glycyrrhizin 100 mg daily (15589,15593,15598,15600,59726). A case report in a 54-year-old male suggests that malnutrition might increase the risk of severe adverse effects with excessive licorice consumption. This patient presented to the emergency room with cardiac arrest and ventricular fibrillation after excessive daily consumption of licorice for about 3 weeks. This caused pseudohyperaldosteronism and then hypokalemia, leading to cardiovascular manifestations. In spite of resuscitative treatment, the patient progressed to kidney failure, refused dialysis, and died shortly thereafter (103791).

Dermatologic ...There have been reports of contact allergy, resulting in an itchy reddish eruption, occurring in patients that applied cosmetic products containing oil-soluble licorice extracts (59912). There have also been at least 3 cases of allergic contact dermatitis reported with the topical application of glycyrrhizin-containing products to damaged skin. In one case report, a 31-year-old female with acne presented with a 2-year history of pruritic erythematous-scaly plaques located predominantly on the face and neck after the use of a cosmetic product containing licorice root extract 1%. The patient had a positive skin patch test to licorice root extract, leading the clinicians to hypothesize that the use of benzoyl peroxide, a strong irritant, might have sensitized the patient to licorice (108578). Burning sensation, itching, redness, and scaling were reported rarely in patients applying a combination of licorice, calendula, and snail secretion filtrate to the face. The specific role of licorice is unclear (110322).
In rare cases, the glycyrrhizin constituent of licorice has caused rash and itching when administered intravenously (59712).

Endocrine ...Orally, excessive licorice ingestion can cause a syndrome of apparent mineralocorticoid excess, or pseudohyperaldosteronism, with sodium and water retention, increased urinary potassium loss, hypokalemia, and metabolic alkalosis due to its glycyrrhizin content (781,10619,15591,15592,15593,15594,15595,15596,15597,15598)(15600,16057,16835,25659,25660,25673,25719,26439,59818,59822)(59832,59864,91722,104563,108568,108574,110305,112234). These metabolic abnormalities can lead to hypertension, edema, EKG changes, fatigue, syncope, arrhythmias, cardiac arrest, headache, lethargy, muscle weakness, dropped head syndrome (DHS), rhabdomyolysis, myoglobinuria, paralysis, encephalopathy, respiratory impairment, hyperparathyroidism, and acute kidney failure (10393,10619,15589,15590,15593,15594,15596,15597,15599)(15600,16057,16835,25660,25673,25719,26439,31562,59709,59716)(59720,59740,59787,59820,59826,59882,59889,59900,91722,97214,100522) (104563,108576,108577). These effects are most likely to occur when 20-30 grams of licorice products containing glycyrrhizin 400 mg or more is consumed daily for several weeks (781,15590,15592,15594,15596,15597,15599,15600,16835,108574). However, some people may be more sensitive, especially those with hypertension, diabetes, heart problems, or kidney problems (15589,15593,15598,15600,59726,108576,108577) and even low or moderate consumption of licorice may cause hypertensive crisis or hypertension in normotensive individuals (1372,97213). The use of certain medications with licorice may also increase the risk of these adverse effects (108568,108577). One case report determined that the use of large doses of licorice in an elderly female stabilized on fludrocortisone precipitated hypokalemia and hypertension, requiring inpatient treatment (108568). Another case report describes severe hypokalemia necessitating intensive care treatment due to co-ingestion of an oral glycyrrhizin-specific product and hydrochlorothiazide for 1 month (108577). Glycyrrhetinic acid has a long half-life, a large volume of distribution, and extensive enterohepatic recirculation. Therefore, it may take 1-2 weeks before hypokalemia resolves (781,15595,15596,15597,15600). Normalization of the renin-aldosterone axis and blood pressure can take up to several months (781,15595,108568). Treatment typically includes the discontinuation of licorice, oral and intravenous potassium supplementation, and short-term use of aldosterone antagonists, such as spironolactone (108574,108577).
Chewing tobacco flavored with licorice has also been associated with toxicity. Chewing licorice-flavored tobacco, drinking licorice tea, or ingesting large amounts of black licorice flavored jelly beans or lozenges has been associated with hypertension and suppressed renin and aldosterone levels (12671,12837,97214,97215,97217,108574). One case report suggests that taking a combination product containing about 100 mg of licorice and other ingredients (Jintan, Morishita Jintan Co.) for many decades may be associated with hypoaldosteronism, even up to 5 months after discontinuation of the product (100522). In another case report, licorice ingestion led to hyperprolactinemia in a female (59901). Licorice-associated hypercalcemia has also been noted in a case report (59766).

Gastrointestinal ...Nausea and vomiting have been reported rarely following oral use of deglycyrrhizinated licorice (25694,59871). Intravenously, the glycyrrhizin constituent of licorice has rarely caused gastric discomfort, diarrhea, or nausea (59712,59915).

Immunologic ...There have been reports of contact allergy, resulting in an itchy reddish eruption, occurring in patients that applied cosmetic products containing oil-soluble licorice extracts (59912). There have also been at least 3 cases of allergic contact dermatitis reported with the topical application of glycyrrhizin-containing products to damaged skin. In one case report, a 31-year-old female with acne presented with a 2-year history of pruritic erythematous-scaly plaques located predominantly on the face and neck after the use of a cosmetic product containing licorice root extract 1%. The patient had a positive skin patch test to licorice root extract, leading the clinicians to hypothesize that the use of benzoyl peroxide, a strong irritant, might have sensitized the patient to licorice (108578).

Musculoskeletal ...In a case report, excessive glycyrrhizin-containing licorice consumption led to water retention and was thought to trigger neuropathy and carpal tunnel syndrome (59791).

Neurologic/CNS ...Orally, licorice containing larger amounts of glycyrrhizin may cause headaches. A healthy woman taking glycyrrhizin 380 mg daily for 2 weeks experienced a headache (59892). Intravenously, the glycyrrhizin constituent of licorice has rarely caused headaches or fatigue (59721). In a case report, licorice candy ingestion was associated with posterior reversible encephalopathy syndrome accompanied by a tonic-clonic seizure (97218).

Ocular/Otic ...Orally, consuming glycyrrhizin-containing licorice 114-909 grams has been associated with transient visual loss (59714).

Pulmonary/Respiratory ...Orally, large amounts of licorice might lead to pulmonary edema. In one case report, a 64-year old male consumed 1020 grams of black licorice (Hershey Twizzlers) containing glycyrrhizin 3.6 grams over 3 days, which resulted in pulmonary edema secondary to pseudohyperaldosteronism (31561). Intravenously, the glycyrrhizin constituent of licorice has caused cold or flu-like symptoms, although these events are not common (59712,59721).

(Read more about LICORICE)

General ...No adverse effects have been reported in adults. However, a thorough evaluation of safety outcomes has not been conducted.
Serious Adverse Effects (Rare):
Orally: Gastrointestinal adverse effects, such as necrotizing enterocolitis, when recombinant human bile salt-stimulated lipase is used in premature infants.

Gastrointestinal ...Orally, when added to the formula or pasteurized breast milk consumed by premature infants, recombinant human bile salt-stimulated lipase (rhBSSL) can cause gastrointestinal adverse effects, including abdominal distension, flatulence, constipation, colic, abdominal pain, gastroenteritis, vomiting, regurgitation, and rectal bleeding (101940). Premature infants receiving rhBSSL also had a slightly higher rate of necrotizing enterocolitis (NEC) when compared with those receiving placebo. After review by a panel of experts, it was determined that the rate of confirmed or suspected NEC in infants consuming rhBSSL was 3.3%, compared with 0.5% in those receiving placebo. Although this rate of NEC is lower than the historical rate of occurrence in premature infants (11%), a possible increased risk for NEC cannot be ruled out (101940).

(Read more about LIPASE)

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

(Read more about MARSHMALLOW)

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

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

(Read more about SLIPPERY ELM)