Adrenal Reset by CTD Labs

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Addison disease. Although there has been interest in using oral adrenal extract for Addison disease, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Allergic rhinitis (hay fever). Although there has been interest in using oral or sublingual adrenal extract for allergic rhinitis, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Asthma. Although there has been interest in using oral adrenal extract for asthma, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Atopic dermatitis (eczema). Although there has been interest in using oral adrenal extract for eczema, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Depression. Although there has been interest in using sublingual adrenal extract for depression, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Fatigue. Although there has been interest in using oral or sublingual adrenal extract for fatigue, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Hyperkalemia. Although there has been interest in using intravenous adrenal extract for hyperkalemia, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Hypoglycemia. Although there has been interest in using sublingual adrenal extract for hypoglycemia, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Hypotension. Although there has been interest in using sublingual adrenal extract for hypotension, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Miscarriage. Although there has been interest in using intravenous adrenal extract for miscarriage, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Opioid withdrawal. Although there has been interest in using sublingual adrenal extract for opioid withdrawal, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Psoriasis. Although there has been interest in using oral adrenal extract for psoriasis, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral adrenal extract for RA, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Stress. Although there has been interest in using oral or sublingual adrenal extract for stress, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose.
• Ulcerative colitis. Although there has been interest in using intravenous adrenal extract for ulcerative colitis, there is insufficient reliable information about the clinical effects of adrenal extract for this purpose. More evidence is needed to rate adrenal extract for these uses.

(Read more about ADRENAL EXTRACT)

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.

(Read more about LICORICE)

EFFECTIVE

• Pantothenic acid deficiency. Taking pantothenic acid 5-10 mg daily is effective for treating and preventing pantothenic acid deficiency (15).

POSSIBLY INEFFECTIVE

• Radiation dermatitis. Topical dexpanthenol does not seem to be beneficial for preventing or treating radiation dermatitis. Details: Applying dexpanthenol, an analog of pantothenic acid, twice daily to areas of irradiated skin does not seem to reduce erythema, desquamation, itching, or pain following radiation treatment (7192). Also, applying dexpanthenol 0.5% cream (Bepanthen, Hoffmann LaRoche ) daily during radiation therapy and for 2 weeks after completing radiation therapy is less effective than methylprednisolone aceponate 0.1% cream (Advantan) at reducing radiation-induced skin irritation (67779).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral or topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In adults with mild to moderate acne, clinical research shows that taking a specific supplement (Pantothen, Avilan Marketing LLC) providing pantothenic acid 1.1 grams twice daily in addition to other B vitamins for 12 weeks modestly reduces total and non-inflammatory lesion counts when compared with placebo (105188). Also, in adolescents or young adults with mild to moderate acne, preliminary clinical research shows that topical application with a gel containing D-panthenol 4%, hydrogen peroxide 4%, and salicylic acid 0.5% once daily for 60 days modestly reduces acne lesions when compared with baseline (105189). The validity of this finding is limited by the lack of a comparator group.
• Alcoholism. Although there is interest in using oral pantothenic acid for improving recovery from alcoholism, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Allergic rhinitis (hay fever). Although there is interest in using oral pantothenic acid for allergic rhinitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Alopecia areata. Pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy adults with diffuse hair loss shows that intramuscular administration of dexpanthenol 250 mg and biotin 5 mg once weekly for 6 weeks reduces hair fall count at weeks 1 and 8, but only increases hair density at week 1, when compared to baseline (111366). The validity of these findings is limited by the study's small size, short duration, and lack of comparator group.
• Anxiety. Although there is interest in using oral pantothenic acid for anxiety, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Asthma. Although there is interest in using oral pantothenic acid for asthma, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Athletic performance. Although there is interest in using oral pantothenic acid to improve athletic performance, there is insufficient reliable information about the clinical effects of pantothenic acid for this purpose.
• Attention deficit-hyperactivity disorder (ADHD). Oral pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Some small outdated clinical studies in children diagnosed with hyperkinesis suggest that taking calcium pantothenate 1.2 grams, alone or in combination with niacinamide, ascorbic acid, and pyridoxine, does not improve symptoms of hyperactivity when compared with placebo (3351,9957). It is unclear what effects pantothenic may have, if any, in children with a modern diagnosis of ADHD.
• Atopic dermatitis (eczema). It is unclear if topical pantothenic acid is beneficial in infants or children with atopic dermatitis. Details: One preliminary clinical trial in infants and children with stable mild atopic dermatitis shows that topical application of an emollient containing panthenol (Bepanthen, SensiDaily, Bayer Consumer Care AG) for 3 months is as effective as a reference emollient for reducing symptoms and preventing a flare. However, the efficacy of the reference emollient (Stelatopia Emollient Cream, Mustela; Laboratoires Expanscience) is unclear based on available preliminary clinical research (105190).
• Autism spectrum disorder. Although there is interest in using oral pantothenic acid for autism spectrum disorder, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Carpal tunnel syndrome. Although there is interest in using oral pantothenic acid for carpal tunnel syndrome, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Cheilitis. Topical pantothenic acid has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small, open-label study in adults with mild-to-moderate cheilitis shows that applying a specific lip care product containing pantothenic acid and bisabolol (Eucerin Aquaphor SOS lip care) at least twice daily for 8 weeks reduces cheilitis severity scores by 5 points on a 12 point scale assessing erythema, scale, fissure, and inflammation when compared to baseline (114549). The validity of this finding is limited by the small study size and lack of a comparator group. Additionally, it is unclear if this effect is due to pantothenic acid, bisabolol, or the combination.
• Chronic fatigue syndrome (CFS). Although there is interest in using oral pantothenic acid for CFS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Conjunctivitis. Although there is interest in using oral or ocular pantothenic acid for conjunctivitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Constipation. It is unclear if oral or intramuscular dexpanthenol is beneficial for constipation. Details: Preliminary clinical research shows that administering dexpanthenol (Bepanthene), an analog of pantothenic acid, 400 mg orally or 500 mg intramuscularly daily for 5 days decreases the time to a bowel movement in patients with chronic or occasional constipation when compared with an oral placebo (67822).
• Dandruff. Although there is interest in using oral or topical pantothenic acid for dandruff, is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Depression. Although there is interest in using oral pantothenic acid for depression, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Diaper rash. Although there is interest in using topical pantothenic acid for diaper rash, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry eye. Although there is interest in using ocular pantothenic acid for dry eye, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Dry skin. It is unclear if topical dexpanthenol is beneficial for patients with dry skin. Details: A small, open-label study in healthy adults with dry skin shows that cleansing the skin with a dexpanthenol-containing liquid cleanser (DCLC, Bepanthen SensiControl Daily Gentle Body Wash) daily for 4 weeks increases stratum corneum hydration by 17% without affecting skin barrier function, pH, or microbiome when compared to baseline (111262). The validity of these findings is limited by the lack of blinding and a comparator group.
• Epilepsy. Although there is interest in using oral pantothenic acid for epilepsy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Eye trauma. It is unclear if ocular dexpanthenol is beneficial for eye trauma. Details: Some preliminary clinical research shows that using eyedrops containing dexpanthenol 5%, a derivative of pantothenic acid, two drops four times daily for 28 days following surgery for retinal detachment reduces eye pain and discomfort when compared with placebo drops (67783). However, using a specific dexpanthenol 5% ointment (Bepanthen) does not seem to improve corneal epithelial wound healing following phototherapeutic keratectomy when compared with placebo (67801).
• Heart failure. Although there is interest in using oral pantothenic acid for heart failure, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Herpes zoster (shingles). Although there is interest in using oral or topical pantothenic acid for shingles, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Insomnia. Although there is interest in using oral pantothenic acid for insomnia, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Laser skin resurfacing. It is unclear if topical dexpanthenol or pantothenic acid can reduce adverse effects after laser skin resurfacing procedures. Details: A preliminary clinical study shows that use of a dexpanthenol-containing ointment (Bepanthen Wound Healing Ointment, Bayer) once daily modestly reduces the diameter of lesions up to 3 days after fractional carbon dioxide laser resurfacing when compared with petroleum jelly (105743). Also, applying a specific cream (Cicaplast Baume B5 cream, L'Oreal) containing panthenol 5%, madecassoside, copper, zinc, and manganese to one side of the face for 28 days reduces decrustation time by approximately one day when compared with a control emollient. Redness and swelling were lower at 3 days, but there was no difference in pain and burning (105742). It is unclear if these effects are due to pantothenic acid, other ingredients, or the combination.
• Multiple sclerosis (MS). Although there is interest in using oral pantothenic acid for MS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Muscular dystrophy. Although there is interest in using oral pantothenic acid for muscular dystrophy, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Nipple fissures. Although there is interest in using topical pantothenic acid for nipple fissures, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Obesity. Although there is interest in using oral pantothenic acid for obesity, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Pain (chronic). It is unclear if oral or topical pantothenic acid is beneficial for the management of various forms of chronic pain. Details: Although there is interest in using oral or topical pantothenic acid for various forms of chronic pain, including neuropathy and arthritis, there is limited information available about the clinical effects of pantothenic acid for this purpose. One review of preliminary clinical research found that calcium pantothenate does not reduce symptoms of arthritis in patients with rheumatoid arthritis or osteoarthritis (10433).
• Parkinson disease. Although there is interest in using oral pantothenic acid for Parkinson disease, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Poison oak and poison ivy dermatitis. Although there is interest in using topical pantothenic acid for poison ivy dermatitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Postoperative pain. It is unclear if oral pantothenic acid is beneficial for postoperative pain. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily reduces pain when compared with placebo. Postoperative pain was modestly reduced at 1, 3, 7, and 14 days after surgery (105191).
• Postoperative sore throat. It is unclear if pantothenic acid lozenges are beneficial for postoperative sore throat. Details: Preliminary clinical research shows that taking two lozenges containing dexpanthenol, an analog of pantothenic acid, 200 mg 30 minutes prior to general anesthesia reduces the incidence and severity of postoperative sore throat when compared with a benzydamine hydrochloride or placebo spray (67792).
• Pregnancy-related leg cramps. Although there is interest in using oral pantothenic acid for pregnancy-related leg cramps, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Premenstrual syndrome (PMS). Although there is interest in using oral pantothenic acid for PMS, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Respiratory tract infections. Although there is interest in using oral pantothenic acid for respiratory tract infections, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Rhinosinusitis. It is unclear if nasal dexpanthenol is beneficial for rhinosinusitis. Details: Preliminary clinical research shows that using a nasal spray (MarPlus) containing dexpanthenol, an analog of pantothenic acid, on the first, second, fourth, and sixth week after endoscopic sinus surgery reduces nasal discharge, but not other symptoms associated with chronic rhinosinusitis, when compared with saline nasal spray (67808).
• Skin irritation. It is unclear if topical dexpanthenol is beneficial for preventing or treating skin irritation due to sodium lauryl sulfate. Details: Preliminary clinical research shows that applying dexpanthenol (Bepanthol Handbalsam), an analog of pantothenic acid, twice daily for 26 days does not prevent sodium lauryl sulfate-induced skin irritation (67785). However, dexpanthenol may be effective for treating skin irritation caused by sodium lauryl sulfate. Use of an ointment containing dexpanthenol 1% to 5% twice daily for up to 30 days following skin exposure to sodium lauryl sulfate seems to reduce skin water loss, skin roughness, and skin inflammation when compared to control (67802,67806).
• Ulcerative colitis. Although there is interest in using oral or rectal pantothenic acid for ulcerative colitis, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Vertigo. Although there is interest in using oral pantothenic acid for vertigo, there is insufficient reliable information about the clinical effects of pantothenic acid for this condition.
• Wound healing. Preliminary clinical research suggests that oral dexpanthenol might be beneficial for wound healing. Details: In post-tonsillectomy patients aged 5-12 years, preliminary clinical research shows that taking pastilles containing dexpanthenol (Bepanthene, Bayer) 100 mg three times daily improves wound healing when compared with placebo. Depending on the type of surgery, wound healing occurred in 2.3-2.9 times as many patients within 7 days of surgery, and in 13% to 35% more patients within 14 days, when compared with placebo (105191). More evidence is needed to rate pantothenic acid for these uses.

(Read more about PANTOTHENIC ACID)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral pregnenolone for aging, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Alcohol use disorder. It is unclear if oral pregnenolone is beneficial in patients with alcohol use disorder. Details: Preliminary clinical research in adults with alcohol use disorder undergoing guided imagery shows that taking pregnenolone 150-250 mg orally twice daily for 8 weeks improves alcohol craving severity scores and anxiety scores when compared with placebo. Taking pregnenolone also improved physiological markers of stress such as heart rate and blood pressure (112726).
• Alzheimer disease. Although there has been interest in using oral pregnenolone for Alzheimer disease, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Autism spectrum disorder. It is unclear if oral pregnenolone is beneficial in patients with autism spectrum disorder. Details: Two small clinical studies show pregnenolone as add-on therapy may improve symptoms in patients with autism spectrum disorder. One small clinical study shows that taking pregnenolone 100 mg orally twice daily as an add-on to risperidone for 10 weeks further improves ratings of irritability, stereotypy, and hyperactivity in drug-naïve adolescents aged 11-17 years with autism when compared with risperidone and placebo (104275). A very small open-label study in adults with autism shows that taking pregnenolone 50-250 mg orally twice daily as an add-on to therapy with psychotropic medications for 12 weeks may improve sensory abnormalities and symptoms of irritability and lethargy (94026). However, the lack of a control group limits the validity of these findings.
• Back pain. It is unclear if oral pregnenolone is beneficial in patients with back pain. Details: One small clinical study in otherwise healthy veterans with chronic low back pain shows that taking pregnenolone orally, titrated up to 500 mg daily, for 4 weeks reduces pain intensity by 0.56 when compared with placebo, as measured on a visual analog scale ranking pain intensity from 0 to 10. This small reduction is not likely to be considered clinically significant. Taking pregnenolone also seemed to modestly reduce the extent that pain interfered with activity or work when compared with placebo; however, there were no significant changes in the other 5 measures of pain interference (104274).
• Bipolar disorder. It is unclear if oral pregnenolone is beneficial in patients with bipolar disorder. Details: Preliminary clinical research in adults with bipolar disorder and depressive episodes shows that taking pregnenolone orally, titrated up to 500 mg daily, as add-on therapy for 12 weeks improves depression symptom scores when compared with placebo (94027).
• Cocaine dependence. It is unclear if oral pregnenolone is beneficial in patients with cocaine dependence. Details: Preliminary clinical research in adults with cocaine dependence undergoing guided imagery shows that taking pregnenolone 150-250 mg orally twice daily for 8 weeks improves cocaine craving severity scores when compared with placebo. Taking pregnenolone also improved physiological markers of stress such as heart rate and blood pressure (112728).
• Coronavirus disease 2019 (COVID-19). Oral pregnenolone has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows in adults with persistent symptoms at least 3 months after a COVID-19 infection shows that taking a combination product containing pregnenolone 40 mg, beta-caryophyllene 40 mg, and other ingredients orally twice daily for 4 weeks improves respiratory and other symptoms when compared with baseline (112727). The validity of this study is limited by the lack of a comparator group. It is unclear if this effect is due to pregnenolone, other ingredients, or the combination.
• Critical illness (trauma). Although there has been interest in using oral pregnenolone for trauma, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Depression. Although there has been interest in using oral pregnenolone for depression, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Endometriosis. Although there has been interest in using oral pregnenolone for endometriosis, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Fatigue. Although there has been interest in using oral pregnenolone for fatigue, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Fibrocystic breast disease. Although there has been interest in using oral pregnenolone for fibrocystic breast disease, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Memory. Although there has been interest in using oral pregnenolone for memory, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Menopausal symptoms. Although there has been interest in using oral pregnenolone for menopausal symptoms, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Multiple sclerosis (MS). Although there has been interest in using oral pregnenolone for MS, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Premenstrual syndrome (PMS). Although there has been interest in using oral pregnenolone for PMS, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Psoriasis. Although there has been interest in using oral pregnenolone for psoriasis, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Schizophrenia. It is unclear if oral pregnenolone is beneficial in patients with schizophrenia. Details: The effects of pregnenolone adjunctive therapy on negative symptoms of schizophrenia are conflicting. Several clinical studies in patients with schizophrenia and schizoaffective disorder and suboptimal response to previous antipsychotic treatments show that taking pregnenolone 50 mg orally daily alone or as add-on therapy with L-theanine 400 mg daily, for 8 weeks, reduces negative symptoms based on the negative symptom scale of the Positive and Negative Syndrome Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS) when compared with placebo (94029,97923). However, conflicting results exist. One study shows that taking pregnenolone 30 mg or 200 mg daily for 8 weeks does not improve negative symptoms based on the negative symptom scale of the PANSS in patients with schizophrenia and schizoaffective disorder (94028). Furthermore, another clinical study conducted in women hospitalized with an acute episode of schizophrenia shows that taking pregnenolone 50 mg orally daily for 8 weeks in combination with risperidone 2-6 mg daily does not reduce negative symptoms when compared with risperidone plus placebo (97924). Reasons for the conflicting results may relate to concomitant use of psychotropic medications such as mood stabilizers and antidepressants, prenenolone dosage, and schizophrenia subtypes of the included patients. Despite some conflicting results (94028), most research shows that taking pregnenolone orally as adjunctive therapy does not significantly improve positive symptoms based on the positive symptom subscale of the PANSS compared to placebo in patients with schizophrenia and schizoaffective disorder (94029,94032,97923,97924). One clinical study shows that taking pregnenolone 50 mg orally daily for 8 weeks in combination with antipsychotics might improve visual attention but does not appear to improve other neurocognitive symptoms of schizophrenia such as deficits in sustained attention or executive function compared with placebo (97925).
• Scleroderma. Although there has been interest in using oral pregnenolone for scleroderma, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Seizures. Although there has been interest in using oral pregnenolone for seizures, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Systemic lupus erythematosus (SLE). Although there has been interest in using oral pregnenolone for SLE, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose.
• Stress. Although there has been interest in using oral pregnenolone for stress, there is insufficient reliable information about the clinical effects of pregnenolone for this purpose. More evidence is needed to rate pregnenolone for these uses.

(Read more about PREGNENOLONE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Altitude sickness. It is unclear if oral rhodiola is beneficial for altitude sickness. Details: Preliminary clinical research shows that taking rhodiola 447 mg four times daily for 7 days does not improve blood oxygenation or markers of oxidative stress when compared with placebo in subjects exposed to simulated high-altitude conditions (25402).
• Anthracycline cardiotoxicity. It is unclear if oral rhodiola is beneficial for epirubicin-induced cardiotoxicity. Details: Preliminary clinical research in breast cancer patients shows that taking salidroside, a constituent of rhodiola, 600 mg daily, beginning one week prior to chemotherapy and continuing throughout chemotherapy administration, reduces epirubicin-induced early left ventricular regional systolic dysfunction when compared with placebo (90434).
• Anxiety. It is unclear if oral rhodiola is beneficial for anxiety. Details: Preliminary clinical research in college students with anxiety shows that taking a specific dried rhodiola extract (Vitango, Schwabe Pharma) 200 mg twice daily for 14 days modestly reduces reported levels of anxiety, anger, confusion, negative mood, and stress when compared with a control group. However, rhodiola extract does not seem to improve cognition (96462).
• Arrhythmia. Although there has been interest in using oral rhodiola for arrhythmia, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Athletic performance. The evidence related to the use of rhodiola for athletic performance is mixed, although specific standardized extracts might be beneficial for certain performance endpoints. Details: The available evidence for rhodiola in athletic performance includes small clinical trials in recreationally active or trained athletes. Trials using rhodiola extracts standardized to 3% rosavins and 1% salidroside (eg. Finzelberg, GmbH) show that taking 3 mg/kg, 200 mg, or 500 mg prior to exercise testing, either as a single dose or with a 3-day lead-in dose, modestly improves performance endpoints on a cycle ergometer. Improved endpoints included time to exhaustion, peak oxygen use, time to completion, perceived exhaustion, anaerobic capacity, and power (13109,90432,100168). However, in trials in which rhodiola was not taken the morning of testing, or when performance endpoints included forearm endurance or marathon time and recovery, rhodiola 170 mg to 1500 mg daily did not affect perceived exertion, time to exhaustion, or peak oxygen use (15574,19284,90433). A small crossover trial shows that taking 500 mg of rhodiola extract, standardized to 3% rosavins and 1% salidroside, three times daily for 3 days followed by 500 mg 30-minutes before exercise testing increases bench press velocity but decreases bench press repetition volume when compared with placebo (110543). Furthermore, limited evidence suggests that rhodiola extract does not affect muscle strength, speed of limb movement, reaction times, or attention span (13109) but might reduce plasma creatine kinase levels (19284). Also, while some evidence suggests that rhodiola extract can reduce blood lactate levels (19284), other research shows that it increases blood lactate levels after resistance training to a greater degree than placebo (110543). In general, it appears that acute doses of rhodiola may improve specific physical performance parameters, but neither acute nor chronic doses appear to notably improve muscle function. Some research has also assessed rhodiola when used in combination with other ingredients. A small clinical study in trained male cyclists shows that taking a specific combination product (Optygen, First Endurance) containing rhodiola 600 mg (standardized to 3% rosavin and 2.5% salidroside) plus cordyceps 2000 mg (standardized to 7% cordycepic acid), daily for 6 days followed by a half-dose daily for 7 days does not improve time to exhaustion or muscle tissue oxygen saturation when compared with placebo (15573). Additionally, a small crossover study in healthy, recreationally active adult males shows that taking a 30:70 blend of rhodiola and maral root extracts at a dose of 350 mg or 175 mg, ninety minutes prior to isokinetic leg strength exercises, does not influence fatigability, performance variables, or affective responses when compared with placebo (105855).
• Bladder cancer. Although there has been interest in using oral rhodiola for bladder cancer, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral rhodiola for CFS, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Coronavirus disease 2019 (COVID-19). Oral rhodiola extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults a with confirmed history of COVID-19 infection and at least 3 of 9 long COVID-19 symptoms for at least 30 days, but no longer than 3 months, after discharge shows that taking a specific combination product (ADAPT-232/Chisan, Swedish Herbal Institute), containing rhodiola extract 90 mg, schisandra extract 300 mg, and eleuthero extract 78 mg, twice daily for 14 days increases walking duration by around 13 minutes but does not reduce the duration of cough, fatigue, headache, pain, or other respiratory problems when compared with placebo (109635). It is unclear if these findings are due to rhodiola, other ingredients, or the combination.
• Depression. It is unclear if oral rhodiola is beneficial for depression. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) state that rhodiola is not currently recommended for monotherapy or adjunctive use in major depressive disorder based on mixed evidence (110318). Clinical research shows that taking a specific rhodiola extract (SHR-5, Swedish Herbal Institute) 340 mg once or twice daily reduces symptoms of mild-to-moderate depression after 6 weeks of treatment when compared with placebo. Rhodiola decreased overall depressive symptoms, emotional instability, insomnia, and somatization; however, it did not improve feelings of self-esteem (17616). Another small clinical study in patients with major depressive disorder of moderate severity shows that adding a higher dose of rhodiola 600 mg to sertraline daily for 12 weeks improves depressive symptoms when compared with either sertraline alone or sertraline with a lower dose of rhodiola (300 mg) (102283).
• Diabetes. Although there has been interest in using oral rhodiola for diabetes, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Fatigue. Preliminary clinical research suggests that oral rhodiola extract decreases fatigue in stressful situations. Details: Most preliminary clinical trials have evaluated a specific rhodiola root extract (SHR-5, Swedish Herbal Institute) in various doses and populations. Taking 50 mg of this product twice daily reduces mental fatigue and improves subjective well-being in students during an examination period (1927). Taking 144 mg twice daily for 7 days reduces fatigue, but not stress, in university students (19287). In night shift workers, 170 mg daily for 2 weeks reduces feelings of fatigue and improves mental performance (6877). In military cadets, a single dose of 370-555 mg after 24 hours without sleep improves tests of mental processing and short-term memory (16411). Finally, taking 576 mg daily for 28 days decreases symptoms of fatigue and increases attention, but does not improve quality of life or symptoms of depression, in patients with stress-related fatigue (19286). Other clinical research shows that taking a different rhodiola root extract (Rhodaxon, Teknofarm), 660 mg daily for 20 days, reduces mental fatigue by 30% in first-year university students (19288). Clinical research using another specific dried rhodiola extract (Vitango, Schwabe Pharma) also shows that taking 200 mg twice daily for 12 weeks modestly reduces perceived levels of stress, burnout, and fatigue when compared to baseline in adults experiencing symptoms of burnout. The validity of these findings is limited by the lack of a control group (96459). Rhodiola extract has also been studied in combination schisandra berry extract and Siberian ginseng root extract (ADAPT-232, Swedish Herbal Institute). However, evidence is mixed, with one study showing that 270 mg daily improves attention, accuracy, and speed in tired individuals performing stressful cognitive tasks (19289), and another study showing that 280 mg daily for 7 days does not reduce mental fatigue or stress in university students (19287).
• Generalized anxiety disorder (GAD). It is unclear if oral rhodiola is beneficial for GAD. Details: A small clinical study shows that taking a specific rhodiola extract (Rhodax, Bodyonics Ltd.) 170 mg twice daily for 10 weeks decreases anxiety and depression and improves symptom scores when compared to baseline in patients with GAD (16410). The validity of these findings is limited by the lack of a comparator group.
• Hearing loss. Although there has been interest in using oral rhodiola for hearing loss, there is insufficient reliable information about the clinical effects of rhodiola for this purpose.
• Hyperlipidemia. Although there has been interest in using oral rhodiola for hyperlipidemia, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Menopausal symptoms. Oral rhodiola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in patients experiencing menopausal symptoms shows that taking a combination product (Menopause Relief EP, EuroPharma USA) containing rhodiola extract 400 mg and black cohosh extract 13 mg daily for 12 weeks improves psychological symptoms of menopause when compared with placebo or black cohosh alone (103269). It is unclear if these findings are due to rhodiola, black cohosh, or the combination.
• Premature ejaculation. Oral rhodiola has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with lifelong premature ejaculation shows that taking a specific combination product (EndEP) containing rhodiola 200 mg, folic acid 200 mcg, zinc 10 mg, and biotin 50 mcg once daily for 90 days increases time to ejaculation by about 29 seconds and improves control of ejaculation in about 60% of participants when compared to baseline. These improvements disappear within 90 days of discontinuing treatment. The validity of these findings is limited by the lack of a control group (96460).
• Sexual arousal. Although there has been interest in using oral rhodiola for improving sexual arousal, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Stress. Preliminary clinical research suggests that oral rhodiola extract reduces feelings of stress. Details: Preliminary clinical research in adults with general stress shows that taking a specific dried rhodiola extract (Vitango, Schwabe Pharma) modestly reduces levels of stress in certain situations. Taking 200 mg twice daily before breakfast and lunch for 4 weeks improves stress, disability, and functional impairment when compared to baseline (90431). A small study in college students with anxiety shows that taking 200 mg twice daily for 14 days modestly reduces reported levels of stress, anxiety, anger, confusion, and negative mood when compared to a control group (96462). In adults experiencing symptoms of burnout, taking this specific extract 200 mg twice daily for 12 weeks modestly reduces perceived levels of stress, burnout, and fatigue and improves sexual satisfaction when compared to baseline. The validity of these findings is limited by the lack of a control group (96459). Rhodiola has also been evaluated in combination with other ingredients in individuals with stress. A small clinical study in healthy adults with chronic stress shows that taking a specific combination product (Mg-Teadiola, Sanofi-Aventis), containing rhodiola extract 222 mg, magnesium 150 mg, green tea extract 125 mg (providing theanine 50 mg), vitamin B6 0.7 mg, vitamin B9 0.1 mg, and vitamin B12 1.25 mcg, daily for 4 weeks reduces stress scores when compared with placebo (108672). It is unclear if these findings are due to rhodiola, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral rhodiola for tuberculosis, there is insufficient reliable information about the clinical effects of rhodiola for this condition.
• Upper respiratory tract infection (URTI). Although there has been interest in using oral rhodiola for URTI prevention, there is insufficient reliable information about the clinical effects of rhodiola for this purpose. More evidence is needed to rate rhodiola for these uses.

(Read more about RHODIOLA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there is interest in using oral schisandra for aging, there is insufficient reliable information about the clinical effects of schisandra for this purpose.
• Asthma. Although there is interest in using oral schisandra for asthma, there is insufficient reliable information about the clinical effects of schisandra for this condition.
• Athletic performance. Although there is interest in using oral schisandra for athletic performance, there is insufficient reliable information about the clinical effects of schisandra for this purpose.
• Coronavirus disease 2019 (COVID-19). Oral schisandra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with a history of COVID-19 infection and current symptoms of long COVID-19 shows that taking 30 mL of a specific combination product (Chisan / ADAPT-232, Swedish Herbal Institute) containing schisandra extract 300 mg, rhodiola extract 90 mg, and eleuthero extract 78 mg twice daily for 2 weeks increases exercise capacity, but does not reduce the number of days with fatigue, headache, cough, respiratory problems, or other symptoms of long COVID-19, when compared with placebo (109635).
• Cough. Although there is interest in using oral schisandra for cough, there is insufficient reliable information about the clinical effects of schisandra for this purpose.
• Diarrhea. Although there is interest in using oral schisandra for diarrhea, there is insufficient reliable information about the clinical effects of schisandra for this purpose.
• Diabetes. Although there is interest in using oral schisandra for diabetes, there is insufficient reliable information about the clinical effects of schisandra for this condition.
• Familial Mediterranean fever. Oral schisandra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: One small clinical study in children ages 3-15 years with familial Mediterranean fever shows that taking a combination product (ImmunoGuard, Inspired Nutritionals) containing schisandra extract 100 mg, andrographis, Siberian ginseng, and licorice reduces symptom duration, frequency, and severity when compared with placebo (12382). It is unclear if these effects are due to schisandra, other ingredients, or the combination.
• Hepatitis. Although there is interest in using oral schisandra for hepatitis, there is insufficient reliable information about the clinical effects of schisandra for this condition.
• Hypercholesterolemia. Although there is interest in using oral schisandra for hypercholesterolemia, there is insufficient reliable information about the clinical effects of schisandra for this condition.
• Impaired glucose tolerance (prediabetes). Oral schisandra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate sized clinical trial in adults with prediabetes shows that taking schisandra fruit extract with a soybean mixture 250 mg twice daily for 12 weeks decreases fasting plasma glucose by around 6 mg/dL and improves 30- and 60-minute post-prandial glucose levels but does not reduce glycated hemoglobin when compared with placebo (112887). The ratio of the schisandra extract to soybean mixture in the product was 5:1. It is unclear if these effects are due to schisandra, soybean, or the combination.
• Menopausal symptoms. It is unclear if oral schisandra is beneficial for improving menopausal symptoms. Details: A small clinical trial in healthy patients with moderate or severe menopausal symptoms shows that taking schisandra extract (BMO-30, Biomix Inc) 784 mg in two divided doses daily for 6 weeks improves hot flushes and other menopausal symptoms when compared with placebo (96632).
• Muscle strength. It is unclear if oral schisandra is beneficial for improving muscle strength. Details: A small clinical study in healthy middle-aged females shows that taking schisandra powdered extract (Bioport Korea Inc.) 500 mg twice daily for 12 weeks seems to modestly increase quadriceps muscle strength and grip strength, but does not affect overall muscle mass, when compared with placebo (105563).
• Myopia. Although there is interest in using topical schisandra for myopia in children, there is insufficient reliable information about the clinical effects of schisandra for this condition.
• Physical performance. It is unclear if oral schisandra is beneficial for improving physical function in older adults. Details: A small clinical study in healthy adults over 50 years of age shows that taking schisandra 500 mg twice daily, 30 minutes after breakfast and dinner, for 12 months improves knee extension peak torque, but does not improve hand grip strength or body composition, when compared with placebo (105562).
• Pneumonia. Oral schisandra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in adults with acute, nonspecific pneumonia shows that taking 20 mL of a specific combination product (ADAPT-232 CHI San, Swedish Herbal Institute) containing schisandra berry extract 51%, rhodiola root extract 27.6%, and eleuthero root extract 24.4% twice daily for 10-15 days reduces the duration of antibiotic treatment and may improve quality of life when compared with standard treatment alone (71152). It is unclear if these effects are due to schisandra, other ingredients, or the combination.
• Stress. Oral schisandra has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in healthy, fatigued females under experimental stress suggests that taking a single, 270 mg dose of a combination product (ADAPT-232, Swedish Herbal Institute) containing schisandra, rhodiola, and Siberian ginseng improves attention, as well as cognitive task speed and accuracy, when compared with placebo (19289). It is unclear if these effects are due to schisandra, other ingredients, or the combination. More evidence is needed to rate schisandra for these uses.

(Read more about SCHISANDRA)

LIKELY UNSAFE ...when used parenterally. Use of injectable adrenal extract has been associated with at least 50 cases of serious bacterial infections at injection sites (6620). Adrenal extracts are derived from animals so there is concern about contamination with diseased animal parts. So far, there are no reports of disease transmission to humans due to use of contaminated adrenal extracts. There is insufficient reliable information available about the safety of adrenal extract for its other uses.

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

(Read more about ADRENAL EXTRACT)

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)

LIKELY SAFE ...when used orally and appropriately. The pantothenic acid derivative calcium pantothenate has a generally recognized as safe (GRAS) status for use in food products (111258). While a tolerable upper intake level (UL) has not been established, pantothenic has been used in doses of 10-20 grams daily with apparent safety (15,6243,111258) ...when applied topically and appropriately, short-term. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and its derivatives are safe for use in cosmetic products in concentrations up to 5.3% (111258). Gels or ointments containing a derivative of pantothenic acid, dexpanthenol, at concentrations of up to 5%, have been used safely for up to 30 days (67802,67806,67817).

POSSIBLY SAFE ...when applied intranasally and appropriately, short-term. A dexpanthenol nasal spray has been used with apparent safety up to four times daily for 4 weeks (67826). ...when applied in the eyes appropriately, short-term. Dexpanthenol 5% eyedrops have been used with apparent safety for up to 28 days (67783). ...when injected intramuscularly and appropriately, short-term. Intramuscular injections of dexpanthenol 500 mg daily for up to 5 days or 250 mg weekly for up to 6 weeks have been used with apparent safety (67822,111366).

CHILDREN: LIKELY SAFE
when used orally and appropriately (15,6243). Calcium pantothenate is generally recognized as safe (GRAS) when used as a food additive and in infant formula (111258). However, a tolerable upper intake level (UL) has not been established (15,6243). ...when applied topically and appropriately (67795,105190,111262). Infant products containing pantothenic acid and its derivatives have been used safely in concentrations of up to 5% for infant shampoos and 2.5% for infant lotions and oils. The Cosmetic Ingredient Review Expert Panel has concluded that pantothenic acid and derivatives are safe for use in topical infant products. (111258).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. The daily adequate intake (AI) during pregnancy is 6 mg (3094).

LACTATION: LIKELY SAFE
when used orally and appropriately. The daily adequate intake (AI) during lactation is 7 mg (3094).

(Read more about PANTOTHENIC ACID)

POSSIBLY SAFE ...when used orally and appropriately, short-term. Pregnenolone has been used safely for up to 12 weeks, with doses titrated up to 500 mg daily (94026,94027,97923,104274). There is insufficient reliable information available about the safety of pregnenolone when used long-term.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Pregnenolone has been used safely for up to 10 weeks at doses of 200 mg daily in adolescents aged 11-17 years (104275). There is insufficient reliable information available about the safety of pregnenolone in younger children or when used orally for longer durations.

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

(Read more about PREGNENOLONE)

POSSIBLY SAFE ...when used orally and appropriately, short-term. There is some clinical research showing that taking rhodiola extract up to 300 mg twice daily has been used without adverse effects for up to 12 weeks (13109,16410,17616,71172,96459,102283,103269).

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

(Read more about RHODIOLA)

POSSIBLY SAFE ...when used orally and appropriately. Schisandra extract up to 1 gram daily has been used for up to 12 weeks with apparent safety (12,96632,105562,105563,112887).

PREGNANCY: POSSIBLY UNSAFE
when used orally. Some evidence suggests schisandra fruit is a uterine stimulant (11).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about SCHISANDRA)

(Read more about ADRENAL EXTRACT)

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 PANTOTHENIC ACID)

BENZODIAZEPINES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Concomitant use of pregnenolone may reduce the effects of benzodiazepines.  Details Very preliminary clinical research shows that chronic use of pregnenolone reduces sedative effects of diazepam when compared with chronic use of placebo. This effect may be related to the activity of pregnenolone at GABAA receptors (94031).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking pregnenolone might enhance the effects of estrogens.  Details Pregnenolone is a precursor for several steroid hormones, including estrogens (3008).

PROGESTERONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking pregnenolone might enhance the effects of progesterone.  Details In humans, some research shows that oral administration of pregnenolone can increase levels of progesterone (94032). However, other research shows no effect on progesterone levels (94028). It is possible the impact of pregnenolone on progesterone levels may be dose dependent.

PROGESTIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking pregnenolone might enhance the effects of progestin.  Details Pregnenolone is a precursor for several steroid hormones, including progestin (3008).

TESTOSTERONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking pregnenolone might enhance the effects of testosterone.  Details Pregnenolone is a precursor for several steroid hormones, including testosterone (3008). However, preliminary clinical research shows that taking pregnenolone 30-500 mg orally daily for up to 8 weeks does not affect testosterone levels (94028,94032).

(Read more about PREGNENOLONE)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhodiola with antidiabetes drugs might increase the risk of hypoglycemia.  Details In vitro and animal research shows that rhodiola extract can decrease blood glucose due to alpha-glucosidase activity (15717,15719).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking rhodiola with antihypertensive drugs might increase the risk of hypotension.  Details In vitro and animal research shows that rhodiola extract inhibits angiotensin-converting enzyme (ACE) and might lower blood pressure (15719,19495).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP1A2.  Details In vitro research shows that rhodiola inhibits CYP1A2. This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). However, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days does not inhibit the metabolism of caffeine, a CYP1A2 substrate (96463).

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP2C9.  Details In vitro research shows that rhodiola inhibits CYP2C9. This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). Also, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days reduces the metabolism of losartan, a CYP2C9 substrate, by 21% after 4 hours (96463).

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, rhodiola might increase levels of drugs metabolized by CYP3A4.  Details In vitro research shows that rhodiola inhibits CYP3A4 (19497,96461). This effect is highly variable and appears to be dependent on the rhodiola product studied (96461). However, a clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days does not inhibit the metabolism of midazolam, a CYP3A4 substrate (96463).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhodiola use might interfere with immunosuppressive therapy.  Details In vitro and animal research show that rhodiola has immunostimulatory effects (19498,19499,19500,19501).

LOSARTAN (Cozaar) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Rhodiola might increase the levels and adverse effects of losartan.  Details A clinical study in healthy young males found that taking rhodiola extract 290 mg daily for 14 days reduces the metabolism of losartan, a CYP2C9 substrate, by 21% after 4 hours (96463).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, rhodiola might increase levels of P-glycoprotein substrates.  Details In vitro research shows that rhodiola inhibits P-glycoprotein (19497). Theoretically, using rhodiola with P-glycoprotein substrates might increase drug levels and potentially increase the risk of adverse effects.

(Read more about RHODIOLA)

CYCLOPHOSPHAMIDE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, schisandra might increase the levels and clinical effects of cyclophosphamide.  Details In vitro research shows that schisandra increases the concentration of cyclophosphamide, likely through inhibition of cytochrome P450 3A4. After multiple doses of the schisandra constituents schisandrin A and schisantherin A, the maximum concentration of cyclophosphamide was increased by 7% and 75%, respectively, while the overall exposure to cyclophosphamide was increased by 29% and 301%, respectively (109636).

CYCLOSPORINE (Neoral, Sandimmune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Schisandra can increase the levels and clinical effects of cyclosporine.  Details A small observational study in children with aplastic anemia found that taking schisandra with cyclosporine increased cyclosporine trough levels by 93% without increasing the risk of adverse events. However, the dose of cyclosporine was reduced in 9% of children to maintain appropriate cyclosporine blood concentrations (109637).

CYTOCHROME P450 2C19 (CYP2C19) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, schisandra might increase the levels and clinical effects of CYP2C19 substrates.  Details In vitro research shows that schisandra inhibits CYP2C19, and animal research shows that schisandra increases the concentration of voriconazole, a CYP2C19 substrate (105566). Theoretically, schisandra may also inhibit the metabolism of other CYP2C19 substrates. This effect has not been reported in humans.

CYTOCHROME P450 2C9 (CYP2C9) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, schisandra might decrease the levels and clinical effects of CYP2C9 substrates.  Details In vitro and animal research suggests that schisandra induces CYP2C9 enzymes (14441). This effect has not been reported in humans.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Schisandra can increase the levels and clinical effects of drugs metabolized by CYP3A4.  Details Most clinical and laboratory research shows that schisandra, administered either as a single dose or up to twice daily for 14 days, inhibits CYP3A4 and increases the concentration of CYP3A4 substrates such as cyclophosphamide, midazolam, tacrolimus, and talinolol (13220,17414,23717,91386,91388,91387,96631,105564,109636,109638,109639,109640,109641). Although one in vitro and animal study shows that schisandra may induce CYP3A4 metabolism (14441), this effect appears to be overpowered by schisandra's CYP3A4 inhibitory activity and has not been reported in humans.

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Schisandra can increase the levels and clinical effects of midazolam.  Details A small pharmacokinetic study in healthy adults shows that taking schisandra extract (Hezheng Pharmaceutical Co.) containing deoxyschizandrin 33.75 mg twice daily for 8 days and a single dose of midazolam 15 mg on day 8 increases the overall exposure to midazolam by about 119%, increases the peak plasma level of midazolam by 86%, and decreases midazolam clearance by about 52%. This effect has been attributed to inhibition of CYP3A4 by schisandra (91388).

P-GLYCOPROTEIN SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Schisandra might increase the levels and clinical effects of P-glycoprotein substrates.  Details In vitro research shows that schisandra extracts and constituents such as schisandrin B inhibit P-glycoprotein mediated efflux in intestinal cells and in P-glycoprotein over-expressing cell lines (17414,105643,105644). Additionally, a small clinical study shows that schisandra increases the peak concentration and overall exposure to talinolol, a P-glycoprotein probe substrate (91386). Theoretically, schisandra might inhibit the efflux of other P-glycoprotein substrates.

SIROLIMUS (Rapamune) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Schisandra can increase the levels and clinical effects of sirolimus.  Details A small pharmacokinetic study in healthy volunteers shows that taking 3 capsules of schisandra (Hezheng Pharmaceutical Company) containing a total of 33.75 mg deoxyschizandrin twice daily for 13 days and then taking a single dose of sirolimus 2 mg increases the overall exposure and peak level of sirolimus by two-fold. This effect is thought to be due to inhibition of cytochrome P450 3A4 by schisandra, as well as possible inhibition of the P-glycoprotein drug transporter (105643).

TACROLIMUS (Prograf) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Schisandra can increase the levels and clinical effects of tacrolimus.  Details Clinical research in healthy children and adults, transplant patients, and patients with nephrotic syndrome and various rheumatic immunologic disorders shows that taking schisandra with tacrolimus increases tacrolimus peak levels by 183% to 268%, prolongs or delays time to peak tacrolimus concentrations, increases overall exposure to tacrolimus by 126% to 343%, and decreases tacrolimus clearance by 19% to 73% (17414,91387,15570,96631,105623,109638,109639,109640,109641,112889)(112890,112972,112973,112974). This effect is thought to be due to inhibition of P-glycoprotein drug transporter and CYP3A4 and CYP3A5 by schisandra (17414,96631,105623,105643,105644,112974). Some clinical and observational studies suggest that schisandra increases tacrolimus levels similarly in both expressors and non-expressors of CYP3A5, while other studies suggest it does so to a greater degree in CYP3A5 expressors than non-expressors (105623,109638,109639,109640,112889,112890,112973,112974). Animal research suggests that the greatest increase in tacrolimus levels occurs when schisandra is taken either concomitantly or up to 2 hours before tacrolimus (105564), and clinical and observational research in humans suggests that schisandra may increase whole blood levels of tacrolimus and decrease clearance of tacrolimus in a dose-dependent manner (109639,109640,112972).

TALINOLOL Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Schisandra can increase the levels and clinical effects of talinolol.  Details A small pharmacokinetic study in healthy volunteers shows that taking schisandra extract 300 mg twice daily for 14 days with a single dose of talinolol 100 mg on day 14 increases the peak talinolol level by 51% and the overall exposure to talinolol by 47%. This effect is thought to be due to the possible inhibition of cytochrome P450 3A4 and P-glycoprotein by schisandra (91386). tly.

VORICONAZOLE (Vfend) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, schisandra might increase the levels and clinical effects of voriconazole.  Details Animal research shows that oral schisandra given daily for 1 or 14 days increases levels of intravenously administered voriconazole, a cytochrome P450 (CYP) 2C19 substrate. This effect is thought to be due to inhibition of CYP2C19 by schisandra (105566). However, this interaction has not been reported in humans.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, schisandra might decrease the levels and clinical effects of warfarin.  Details Animal research suggests that oral schisandra extract, given daily for 6 days, reduces levels of intravenously administered warfarin. This effect might be due to the induction of cytochrome P450 (CYP) 2C9 metabolism by schisandra (14441). However, this interaction has not been reported in humans.

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General ...Orally and intravenously, adverse effects to adrenal extract seem to be rare; however, a thorough safety evaluation has not been conducted.
Most Common Adverse Effects:
Intravenously: Injection site reactions.
Serious Adverse Effects (Rare):
Intravenously: Serious bacterial infections at injection sites.

Dermatologic ...Intravenously, adrenal extract can cause infection and abscess at the site of injection (6620). In 1996, the FDA issued a nationwide alert regarding an injectable adrenal cortex extract after more than 50 cases of serious bacterial infections at injection sites were reported (6620).

Other ...Adrenal extracts are derived from raw cow, pig, or sheep adrenal glands gathered from slaughterhouses and possibly from sick or diseased animals (6620). Products made from contaminated or diseased organs might present a human health hazard. There is also some concern that adrenal extracts produced from cows in countries where bovine spongiform encephalitis (BSE) has been reported might be contaminated with diseased tissue. Countries where BSE has been reported include Great Britain, France, The Netherlands, Portugal, Luxembourg, Ireland, Switzerland, Oman, Belgium, and others (1825); however, there have been no reports of BSE transfer to humans from contaminated adrenal extract products. Until more is known, tell patients to avoid these products unless country of origin can be determined. Patients should avoid products that are produced in countries where BSE has been found.

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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).

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General ...Orally, pantothenic acid is generally well tolerated. Topically and intramuscularly, dexpanthenol, a synthetic form of pantothenic acid, seems to be well tolerated.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, eczema, irritation, and itching related to dexpanthenol.

Cardiovascular ...There is one case of eosinophilic pleuropericardial effusion in a patient taking pantothenic acid 300 mg per day in combination with biotin 10 mg per day for 2 months (3914).

Dermatologic ...Topically, dexpanthenol has been associated with itching, burning, skin irritation, contact dermatitis, and eczema (67779,67781,67788,111258,111262). Three cases of allergic contact dermatitis have been reported (111260,111261).

Gastrointestinal ...Orally, pantothenic acid has been associated with diarrhea (67822,111258).

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General ...Orally, pregnenolone is generally well tolerated.
Most Common Adverse Effects:
Orally: Acne, agitation, diarrhea, drowsiness, excitement, hair loss, skin abscess, sweating, tremor.

Cardiovascular ...A case of palpitations has been reported after oral use of pregnenolone (94031).

Dermatologic ...Orally, pregnenolone has been reported to cause skin abscesses, acne, and hair loss (94027,94031). A case of skin rash accompanied by a burning sensation on the back and sides of the hands has also been reported with oral pregnenolone use, possibly related to a photosensitivity reaction. The rash cleared on its own (94031).

Gastrointestinal ...Orally, pregnenolone may cause diarrhea. Constipation has also been reported after oral use; however, it is not certain if this effect was due to pregnenolone (94026).

Musculoskeletal ...A case of muscle pain/stiffness has been reported after oral use of pregnenolone (94032).

Neurologic/CNS ...Orally, pregnenolone has been reported to cause restlessness, tiredness, sweating, and a case of cold extremities (94026,94032). Sleep problems, drowsiness, and tremor have also been reported; however, it not certain if these effects were due to pregnenolone (94026,94031).

Psychiatric ...Orally, pregnenolone has been reported to cause depressive affect and increased appetite (94026,94031). Increased excitement, agitation, increased motor activity, and anorexia have also been reported; however, it is not certain if these effects were due to pregnenolone (94026).

Pulmonary/Respiratory ...A case of sinusitis has been reported after oral use of pregnenolone (94027).

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General ...Orally, rhodiola seems to be well tolerated.
Most Common Adverse Effects:
Orally: Dizziness, increased or decreased production of saliva.

Gastrointestinal ...Orally, rhodiola extract may cause dry mouth or excessive saliva production (16410,16411).

Neurologic/CNS ...Orally, rhodiola extract can cause dizziness (16410).

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General ...Orally, schisandra seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Decreased appetite, heartburn, stomach upset, and urticaria.

Dermatologic ...Orally, schisandra can cause urticaria in some patients (11).

Gastrointestinal ...Orally, schisandra can cause heartburn, decreased appetite, and stomach upset (11).

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