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POSSIBLY EFFECTIVE

• Athletic performance. Small studies show that taking a single oral dose of L-citrulline before anaerobic resistance exercise might reduce exhaustion and improve some performance measures. It is unclear if L-citrulline improves aerobic exercise performance; results are conflicting. Details: A meta-analysis of small clinical trials in healthy trained and untrained adults shows that taking L-citrulline prior to mostly anaerobic exercise marginally reduces perceived exhaustion and muscle soreness when compared with placebo (105965). Another meta-analysis including some of the same clinical studies shows that taking L-citrulline malate before exercise modestly increases performance on resistance exercises by an average of 6% when compared with placebo (105968). Individual studies show mixed benefit and mostly use a single dose of L-citrulline malate 8 grams 1 hour before exercise; other studies used L-citrulline 3.3-6 grams mixed in watermelon juice or sucrose water or L-citrulline malate 12 grams given 1-2 hours before exercise (94966,94957,97395,105965). L-citrulline has also been evaluated for use with aerobic exercise. A small study in healthy young adults taking L-citrulline 9 grams in 3 divided doses over 24 hours or as a single dose of 3 grams 3 hours before a treadmill test does not improve performance, but might reduce time to exhaustion, when compared with placebo (16473). Another small clinical study in healthy adults shows that taking about 6.8 grams (100 mg/kg) of L-citrulline daily for 5 days prior to a cycling trial does not improve time to exhaustion, oxygen uptake, or lactate levels when compared with taking 3 grams of glucose as placebo (105964). However, two small clinical trials in healthy males show that taking L-citrulline 2.4-6 grams daily for 7 days prior to a cycling test improves peak power by 9%, total work by 7%, and cycling time trial performance by 1.5% when compared with placebo (94954,94965). Differences in methods of testing athletic performance, the form and dose of L-citrulline used, and/or the duration of supplementation may explain the mixed results. L-citrulline has also been evaluated in combination with L-arginine. Research in male soccer players shows that taking L-citrulline 1.2 grams and L-arginine 1.2 grams daily for 7 days increases total power output over a 10-minute cycling test and improves subjective perceptions of exertion when compared with placebo (100956).

POSSIBLY INEFFECTIVE

• Sarcopenia. Oral L-citrulline does not seem beneficial for muscle strength in older adults when added to structured exercise. Details: Two small clinical studies in older adults show that taking L-citrulline in conjunction with structured exercise does not improve measures of strength, endurance, speed, or balance when compared with placebo and structured exercise (110146,110148). One study evaluated otherwise healthy adults aged 60-73 years taking L-citrulline 3 grams daily for 6 weeks (110146). The other study evaluated older adults with obesity and an average age of 68.5 years taking a specific L-citrulline product (Citrage) 10 grams daily for 12 weeks (110148).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cardiovascular disease (CVD). Although there is interest in using oral L-citrulline for CVD, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Dementia. Although there is interest in using oral L-citrulline for dementia, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Diabetes. It is unclear if oral L-citrulline is beneficial in patients with diabetes. Details: A small clinical study in adults with diabetes who are taking metformin and sulfonylureas shows that adding L-citrulline (Bulk Supplements Co., Ltd.) 3 grams daily before breakfast for 8 weeks reduces average fasting blood glucose levels by 22 mg/dL and glycated hemoglobin by 0.7%, but does not affect lipid levels, when compared with taking a microcrystalline cellulose placebo (105963).
• Erectile dysfunction (ED). It is unclear if oral L-citrulline is beneficial in patients with ED. Details: A small non-randomized crossover study in adults with mild ED shows that taking L-citrulline 1.5 grams daily for one month improves erection hardness from "mild dysfunction" to "normal function" in 50% of patients, compared with only 8% of patients taking placebo (94956). L-citrulline has also been evaluated in combination with other ingredients. A clinical study in middle-aged males with ED shows that taking a specific combination product (Revactin, MD Concepts LLC) containing L-citrulline, muira puama, ginger root, and guarana twice daily for 3 months improves scores related to erectile function and intercourse satisfaction, but does not improve sexual desire or orgasmic function scores, when compared to baseline (103224). The validity of this study is limited by the lack of a placebo control, the use of per-protocol analysis, and a high dropout rate. In fact, 44% of patients withdrew in order to resume use of phosphodiesterase type 5 (PDE5) inhibitors. Another small clinical study in adults with ED living in Japan and using PDE5 inhibitors as needed shows that taking an adjunct 50 mL drink containing L-citrulline 800 mg, a specific fenugreek extract (Testofen) 600 mg, resveratrol 300 mg, and caffeine 40 mg daily for 14 days modestly improves erectile function and satisfaction with intercourse and orgasm when compared with a placebo drink (105966). The validity of this finding may be confounded by the "as needed" use of PDE5 inhibitors, which was not reported throughout the study. Further, in both combination studies, it is unclear if these effects are due to L-citrulline, other supplement ingredients, or the combination.
• Heart failure. Small clinical studies suggest that oral L-citrulline might be beneficial in patients with heart failure. Details: A very small clinical study in patients with heart failure with preserved ejection fraction (HFpEF) shows that taking L-citrulline malate 3 grams daily for 2 months decreases systolic pulmonary arterial pressure by 16% and improves the right ventricular ejection fraction after a stress test by 27% when compared to baseline (94962). The validity of this finding is limited by the lack of a control group. Another small open-label clinical study in patients with heart failure with reduced ejection fraction (HFrEF) shows that taking L-citrulline 3 grams daily for 4 months increases left ventricular ejection fraction by about 20% at rest and 13% during the stress test, and increases the right ventricular ejection fraction by about 15%, both at rest and with the stress test, when compared with no supplementation. This improved the heart failure functional class in 35% of patients (94955).
• Hypertension. It is unclear if oral L-citrulline is beneficial for lowering blood pressure. Details: A small clinical trial in adults with prehypertension shows that taking L-citrulline 2 grams with grape and cranberry polyphenols 548 mg daily for 6 weeks does not reduce mean ambulatory blood pressure when compared with a cellulose placebo (105969). A small crossover study in postmenopausal females with hypertension shows that taking L-citrulline 6 grams as a single dose does not improve systolic or diastolic blood pressure at rest or during 5 minutes of plantar flexion exercise when compared with placebo (110147). The effects of using L-citrulline regularly or in other patients with diagnosed hypertension is unclear.
• Lysinuric protein intolerance. Although there is interest in using oral L-citrulline for lysinuric protein intolerance, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Muscle strength. It is unclear if oral L-citrulline can improve muscle strength when used in conjunction with resistance training. Details: A clinical study in healthy resistance-trained adults shows that taking L-citrulline malate 2 grams daily for 8 weeks in conjunction with resistance training does not further increase lean mass or muscle strength, measured by leg and bench presses, when compared with a cellulose placebo and resistance training (97394).
• Muscular dystrophy. It is unclear if oral L-citrulline is beneficial in patients with Duchenne muscular dystrophy. Details: A small clinical study in adults with Becker muscular dystrophy, a milder form of Duchenne muscular dystrophy (DMD), shows that taking L-citrulline 5 grams with or without metformin 500 mg three times daily for 6 weeks improves 6-minute walking distance and decreases markers of muscle necrosis when compared to baseline (100975). A small clinical study in males aged 6.5-10 years with DMD shows that taking L-citrulline 2.5 grams with metformin 250 mg three times daily for 26 weeks does not appear to slow decline in motor function when compared with placebo. However, this combination seems to slow decline in children with more stable disease, defined as those who can walk at least 350 meters in 6 minutes (100976). The reasons for these disparate results are unclear, but they may be due to the different patient populations, disease severities, doses, and durations of therapy being studied.
• Postoperative pulmonary hypertension. It is unclear if oral citrulline prevents postoperative hypertension in children undergoing heart surgery. Details: A small clinical study in children 6 years of age and younger undergoing congenital heart surgery shows that higher blood levels of L-citrulline might protect against the incidence of postoperative hypertension. L-citrulline blood levels of at least 37 micromol/L immediately after surgery, and at 12, 24, and 36 hours postoperatively, protects against its development. However, supplementation with 1.9 grams/m2 during induction of anesthesia is not necessarily protective (16467).
• Post-polio syndrome. It is unclear if oral L-citrulline is beneficial for patients with this condition. Details: A small clinical study in adults with post-polio syndrome shows that taking L-citrulline 5 grams three times daily for 24 weeks does not improve 6-minute walking distance, motor function scores, muscle strength, or quality of life when compared with placebo (110149).
• Pulmonary hypertension. It is unclear if oral L-citrulline is beneficial in patients with pulmonary hypertension. Details: A very small clinical study in patients with idiopathic arterial pulmonary hypertension or pulmonary hypertension due to Eisenmenger syndrome shows that taking L-citrulline malate 1 gram three times daily for 2 weeks increases 6-minute walking distance by 44 meters and reduces mean pulmonary arterial pressure by 5% when compared with baseline (94963). The validity of these findings is limited by the small study size and the lack of a comparator group.
• Reye syndrome. Although there is interest in using oral L-citrulline for Reye syndrome, there is insufficient reliable information about the clinical effects of L-citrulline for this condition.
• Sickle cell disease. It is unclear if oral L-citrulline is beneficial in patients with sickle cell disease. Details: A small clinical study in children ages 10-18 years shows that taking L-citrulline 90-130 mg/kg daily in 2 divided doses for up to 9 months might reduce neutrophilia and other symptoms when compared with baseline (16463). The validity of these findings is limited by the small study size and the lack of a comparator group. More evidence is needed to rate L-citrulline for these uses.

(Read more about L-CITRULLINE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related testosterone deficiency. It is unclear if oral maca is beneficial for age-related testosterone deficiency. Details: A moderate-size clinical study in eugonadal males age 65 years on average with symptoms related to late-onset hypogonadism shows that taking maca 1.66 grams three times daily for 12 weeks improves physical, sexual, and psychological symptom scores when compared with placebo. However, maca did not lead to a significant difference in testosterone levels between groups (112012). The interpretation of these findings is limited by the use of patient-reported outcomes.
• Amenorrhea. Although there has been interest in using oral maca for amenorrhea, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Anemia of chronic disease. Although there has been interest in using oral maca for anemia of chronic disease, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Antidepressant-induced sexual dysfunction. It is unclear if oral maca is beneficial in patients with sexual dysfunction due to antidepressants. Details: Preliminary clinical research shows that taking maca 1.5 grams twice daily for 12 weeks modestly increases remission rates in females experiencing antidepressant-induced sexual dysfunction (90278).
• Athletic performance. It is unclear if oral maca is beneficial for athletic performance. Details: A small clinical study in male elite athletes shows that taking maca 2500 mg twice daily for 8 weeks may improve some measures of physical performance, including grip strength, power, or agility, when compared to baseline (112014). However, the interpretation of this study is limited by the lack of a control group, inconsistent results among the various types of athletes included in the study, and unreported habitual activities, such as diet, that may confound results.
• Chronic fatigue syndrome (CFS). Although there has been interest in using oral maca for CFS, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Depression. Although there has been interest in using oral maca for depression, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Fatigue. Although there has been interest in using oral maca for fatigue, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Leukemia. Although there has been interest in using oral maca for leukemia, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Male infertility. It is unclear if oral maca is beneficial for male infertility. Details: Clinical research shows that taking a specific maca product (Maca Gelatinizada La Molina, Laboratorios Hersil) 1.5-3 grams daily for 4 months increases semen volume, sperm count, and sperm motility in healthy males aged 22-44 years (18289). Conversely, a meta-analysis of 2 small clinical studies in males with infertility shows that taking 2-2.8 grams of maca daily for 12-16 weeks does not improve the concentration of semen when compared with placebo (112011). However, the interpretation of this finding is limited by the heterogeneity of the included studies.
• Memory. Although there has been interest in using oral maca for memory, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Osteoporosis. Although there has been interest in using oral maca for osteoporosis, there is insufficient reliable information about the clinical effects of maca for this purpose.
• Postmenopausal conditions. It is unclear if oral maca is beneficial for postmenopausal conditions. Details: Two small clinical trials show that taking powdered maca (Maca Power, Incan Food, Healthychoices) 3.3 or 3.5 grams daily as a single dose or in two divided doses for 6 weeks modestly reduces anxiety, depression, and sexual dysfunction when compared with placebo (90606,99792). However, these changes are generally small and of questionable clinical significance (90606).
• Sexual desire. It is unclear if oral maca improves male sexual desire; it has not been evaluated for female sexual desire. Details: Preliminary clinical research shows that taking a specific maca product (Maca Gelatinizada La Molina, Laboratorios Hersil), 1.5-3 grams daily in three divided doses for 12 weeks can increase subjective feelings of sexual desire in healthy males aged 21 to 57 years (9928).
• Tuberculosis. Although there has been interest in using oral maca for tuberculosis, there is insufficient reliable information about the clinical effects of maca for this purpose. More evidence is needed to rate maca for these uses.

(Read more about MACA)

POSSIBLY EFFECTIVE

• Cognitive function. In middle-aged individuals, but not young adults, oral Panax ginseng seems to improve abstract thinking, attention, arithmetic skills, and reaction time. Any benefit to memory seems to be dependent on the inclusion of ginkgo. Details: Some clinical evidence shows that taking Panax ginseng orally can improve abstract thinking, attention, mental arithmetic skills, and reaction times in healthy, middle-aged people; however, Panax ginseng does not seem to improve these outcomes in young adults (2064,23596,23599,23608,23609,54374). While Panax ginseng alone does not seem to improve memory (2064), there is some evidence that a combination of Panax ginseng (G115) and ginkgo leaf (GK501) extract 80-320 mg daily for 12 weeks can improve memory in otherwise healthy people or people with neurasthenia 38-66 years of age (8591,9759,87984,88046). In clinical trials, various doses have been used. These include a specific Panax ginseng extract (G115, Pharmaton SA, Lugano) 200-400 mg once daily or in two divided doses for up to 12 weeks, or 200-960 mg administered as a single dose (8591,23596,23599,23608,23609,54374,88046). Another extract (Gerimax Ginseng Extract; Dansk Droge A/S Ishoj) 400 mg daily for 8 weeks has also been used (2064).
• Erectile dysfunction (ED). Oral Panax ginseng seems to improve sexual function in people with ED. Details: Taking Panax ginseng orally for 8 weeks seems to improve sexual function in adults with ED (8813,23637,23638,89747). Doses used in clinical research have included extract from the juice and pulp of 4 year-old Panax ginseng berry 700 mg twice daily (89747), tissue-cultured mountain ginseng extract 1000 mg twice daily (23638), and Korean red ginseng, a type of Panax ginseng, 1000-2700 mg daily (8813,112840). Panax ginseng has also been studied in adults with symptoms of ED that are associated with an enlarged prostate. A small clinical study in adult males with moderate lower urinary tract symptoms shows that taking a specific extract of Korean red ginseng (RXGIN, Jung Kwan Jang), a type of Panax ginseng, 1000 mg daily for 12 weeks improves symptoms of sexual dysfunction including erectile function, sexual desire, orgasmic function, and intercourse satisfaction when compared with placebo. However, there was no improvement reported in overall satisfaction. Most symptoms of ED except sexual desire had not significantly improved by 6 weeks, suggesting that longer durations of at least 12 weeks may be needed for Panax ginseng to significantly improve ED symptoms (112840). Additionally, Panax ginseng has been evaluated in combination with other ingredients. A moderate-sized, open-label clinical study in adults with mild-to-moderate ED shows that taking a specific combination supplement (Icarifil, Anvest Health S.p.A) containing Panax ginseng 150 mg, L-carnitine, L-citrulline, tribulus, and other ingredients daily for 3 months improves patient-reported erectile function when compared to baseline. Additionally, taking the supplement with tadalafil improves some, but not all, patient-reported assessments of erectile function when compared with taking tadalafil alone (114989). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination. Additionally, the interpretation of these results is limited by poor methodology, including the use of per-protocol analysis and lack of a placebo group.
• Influenza. Oral Panax ginseng seems to modestly reduce the risk of developing influenza. However, it might not reduce the severity or duration of symptoms. Details: Some preliminary clinical research shows that taking a specific Panax ginseng extract (G115) 200 mg daily, beginning 4 weeks prior to influenza vaccination and continuing for 8 weeks thereafter, can decrease the relative risk of getting the flu or common cold by 65% when compared with placebo (589). Also, clinical research in healthy adults shows that taking Panax ginseng extract 1 gram three times daily for 12 weeks reduces the relative risk of developing an acute influenza infection by 45% when compared with placebo. However, taking Panax ginseng does not seem to affect symptom duration or severity (89746).
• Multiple sclerosis-related fatigue. Oral Panax ginseng seems to reduce fatigue and improve quality of life in patients with multiple sclerosis. Details: Clinical research shows that taking Panax ginseng 250 mg twice daily for 3 months improves symptoms of fatigue and quality of life when compared with placebo in female patients with relapsing-remitting multiple sclerosis (RRMS). Females taking Panax ginseng experienced a 75% reduction in fatigue, compared with no change in the placebo group; quality of life was increased by 19.9 points in the Panax ginseng group, compared with only 4.2 in the placebo group (89745).
• Sexual arousal. Oral Panax ginseng, alone or in combination with other ingredients, seems to improve sexual arousal in postmenopausal adults or females with sexual dysfunction. Details: Taking Korean red ginseng, a specific form of Panax ginseng, 3 grams daily for 8 weeks seems to improve sexual arousal and satisfaction when compared with placebo in postmenopausal adults (23630). Also, other preliminary clinical research shows that taking a specific combination product (ArginMax for Women, Daily Wellness Company) containing ginkgo leaf extract, Panax ginseng root extract, damiana leaf extract, L-arginine, multivitamins, and minerals for 4 weeks can improve sexual satisfaction when compared with placebo in females who are self-reported to have sexual dysfunction (23635,46933). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination.

POSSIBLY INEFFECTIVE

• Athletic performance. Most research shows that oral Panax ginseng does not improve athletic performance. Details: Taking Panax ginseng 0.4 to 3 grams daily orally for up to 8 weeks, or as a single dose 200 mg one hour prior to exercise, does not improve aerobic exercise capacity (1427,4230,4231,23646,23647,89737,114981). Higher doses of Panax ginseng also do not seem to improve athletic performance. A small study in young athletes shows that taking Panax ginseng 100 mg/kg (about 5-7 grams, standardized to 10% ginsenosides) daily in three divided doses for 8 days does not improve squat exercise performance, although it might modestly improve perceived exertion, when compared with placebo (103045). Similarly, a small clinical study in adult male recreational athletes shows that taking Panax ginseng extract 500 mg daily for 14 days does not improve 10-kilometer running times when compared with placebo (114981).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral Panax ginseng for aging, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Anthracycline cardiotoxicity. It is unclear if oral Panax ginseng protects against anthracycline cardiotoxicity. Details: A very small clinical study in adults with non-metastatic HER-2 negative breast cancer being treated with anthracycline-based chemotherapy in Iran shows that taking Panax ginseng rhizome powder 1000 mg daily starting on the first day of doxorubicin administration until one week after completion of the eighth doxorubicin cycle improves left ventricular ejection fraction (LVEF) by 1% when compared with placebo, which was associated with a 7% reduction in LVEF. Treatment with Panax ginseng also reduces the incidence of chemotherapy-related cardiac dysfunction when compared with placebo, an effect that endured over a 6-month follow up period. However, Panax ginseng did not improve the cardiac biomarker high-sensitive cardiac troponin I or transthoracic echocardiographic measurements of left atrium diameter, left ventricular end-systolic diameter, or left ventricular end-diastolic diameter when compared with placebo (112817).
• Attention deficit-hyperactivity disorder (ADHD). Oral Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small low-quality study in children with ADHD aged 6-12 years shows that taking Panax ginseng extract 3 mg with omega-3 fatty acids 500 mg daily for 12 weeks improves overall symptoms, reduces errors of commission, and improves reaction time when compared with baseline (103049). The validity of this study was limited by the lack of a comparator group. Also, it is unclear if these changes are due to Panax ginseng, omega-3 fatty acids, or the combination.
• Age-related cognitive decline. It is unclear if oral Panax ginseng is beneficial in age-related cognitive decline. Details: Clinical research in patients over 50 years of age with memory impairments shows that taking standardized ginseng extract (G115) in combination with vitamins, minerals, and dimethylaminoethanol bitartrate may improve memory when compared to baseline (23600). The validity of this finding is limited by the lack of a comparator group. Also, it is unclear if these changes are due to Panax ginseng, other ingredients, or the combination.
• Allergic rhinitis (hay fever). It is unclear if oral Panax ginseng is beneficial in allergic rhinitis. Details: A small clinical study in adults with allergic rhinitis shows that taking Panax ginseng (Korean Ginseng Corporation) 3 mg/kg daily for 4 weeks improves rhinorrhea, nasal itch, and eye itch when compared to baseline (103047). The validity of this study is limited because it did not report statistical comparisons between the treatment and control groups.
• Alzheimer disease. Some preliminary clinical studies suggest that oral Panax ginseng might improve cognitive performance in patients with this condition. Details: Clinical research shows that taking Panax ginseng root 4.5 to 9 grams daily for 12 weeks can improve cognitive performance in patients with Alzheimer disease when compared with control (23611,23612). The validity of this finding is limited by the lack of patient and caregiver blinding.
• Androgenic alopecia. Topical Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients with androgenic alopecia shows that applying 1 mL of a topical combination product (Hirsuit hair tonic, Dermcor Pharmaceutical) containing Panax ginseng extract, biochanin A (from red clover), acetyl tetrapeptide-3, Salvia officinalis oil, and other ingredients, twice daily for 24 weeks, is similarly effective to minoxidil 3% solution for increasing hair count and mass (105672). It is unclear if the benefit is due to Panax ginseng, other ingredients, or the combination.
• Anxiety. Although there has been interest in using oral Panax ginseng for anxiety, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Aplastic anemia. Although there has been interest in using oral Panax ginseng for aplastic anemia, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Asthma. Although there has been interest in using oral Panax ginseng for asthma, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Benign prostatic hyperplasia (BPH). It is unclear if oral Panax ginseng is beneficial for treating lower urinary tract symptoms. Details: A small clinical study in adults with moderate lower urinary tract symptoms shows that taking a specific extract of Korean red ginseng (RXGIN, Jung Kwan Jang), a type of Panax ginseng, 1000 mg daily for 12 weeks reduces serum prostate-specific antigen (PSA) and improves most prostate symptoms including residual urine sensation, frequency, intermittency, urgency, weak stream, straining, and nocturia after 6 and 12 weeks when compared with placebo. However, there was no improvement in maximum urinary flow rate or post-void residual volume when compared with placebo (112840).
• Breast cancer. It is unclear if oral Panax ginseng is beneficial in breast cancer. Details: Observational research in Chinese patients with breast cancer suggests that regular use of ginseng, including either Panax ginseng or American ginseng, is associated with higher quality of life scores and a lower risk of overall mortality, breast cancer-related mortality, and breast cancer recurrence when compared with patients who do not take ginseng (14466). However, ginseng users were also significantly more likely to have been treated with tamoxifen. Another small clinical study in adults with non-metastatic breast cancer undergoing anthracycline-based chemotherapy in Iran shows that taking Panax ginseng 1 gram daily starting on the first day of chemotherapy until 1 week after completion of the final cycle at 7 or 10 weeks improves social, emotional, and functional measures of health-related quality of life but does not improve physical well-being when compared with placebo (112823).
• Bronchitis. It is unclear if oral Panax ginseng is beneficial in bronchitis. Details: One small clinical study shows that taking a specific Panax ginseng extract (G115) 100 mg twice daily for 9 days might be beneficial when used adjunctively for treating acute exacerbations of chronic bronchitis. Panax ginseng, combined with antibiotic therapy, might reduce bronchial bacterial counts more than antibiotic therapy alone (8814).
• Cancer. It is unclear if oral Panax ginseng is beneficial in preventing cancer. However, it might increase quality of life in some cancer patients. Details: Observational research has found that taking ginseng orally might decrease the incidence of cancer, specifically breast, stomach, lung, liver, ovarian, and skin cancer (2063,3122). But evidence from large-scale clinical research shows that taking Panax ginseng 1 gram once weekly for 3 years does not reduce the risk of cancer development (23622). However, some clinical research suggests that Panax ginseng may slow cancer progression or improve quality of life in patients already diagnosed with cancer. One clinical study shows that taking sun ginseng, a form of Panax ginseng that has been heat treated, 3000 mg daily orally for 12 weeks can improve quality of life for cancer patients (23643). Evidence from a case series suggests that giving Panax ginseng (also called Cultivated Wild Ginseng Pharmacopuncture) 20 mL daily by intravenous infusion for up to 13 cycles lasting 2-4 weeks each may attenuate the progression of advanced non-small cell lung cancer in some patients (23619,23620).
• Cancer-related fatigue. It is unclear if oral Panax ginseng is beneficial in cancer-related fatigue. Details: Preliminary clinical research shows that taking Panax ginseng 400 mg twice daily for 4 weeks reduces fatigue in 63% of adults with cancer-related fatigue when compared to baseline. Panax ginseng also reduces pain and improves appetite and overall quality of life when compared to baseline. The lack of a control group limits the validity of these findings (96217). Another clinical study in patients with colorectal cancer receiving the mFOLFOX-6 chemotherapy regimen shows that taking Panax ginseng 2000 mg daily for 16 weeks improves fatigue as measured on the brief fatigue inventory (BFI) when compared with placebo. However, when evaluated on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, no benefit was seen (103048).
• Chronic fatigue syndrome (CFS). It is unclear if oral Panax ginseng is beneficial in patients with severe CFS. Details: A nonblinded, observational study in patients with severe CFS, most of whom also have fibromyalgia, shows that taking Panax ginseng daily for one month improves patient reports of energy, overall wellbeing, mental clarity, sleep, pain, and stamina when compared with baseline. Patients took Panax ginseng either as capsules (Terry Naturally HRG80 Red Ginseng Energy capsules; EuroPharma, Inc) 200-400 mg daily or chewable tablets (Terry Naturally HRG80 Red Ginseng Energy chewable tablets; EuroPharma, Inc) 100-200 mg daily. There were no dose- or formulation-dependent differences between groups (107746). The validity of these findings is limited by the lack of randomization and placebo-control; additionally, the majority (89%) of patients included in this study were female.
• Chronic kidney disease (CKD). It is unclear if oral Panax ginseng prevents CKD. Details: A cross-sectional study in Korea suggests that supplemental Panax ginseng or American ginseng use is associated with a higher prevalence of CKD when compared with no supplemental ginseng use. However, no association was found when adjusting the results for potential confounders (112810). The applicability of these results is limited by a lack of subgroup analysis on the type of supplemental ginseng.
• Cognitive impairment. It is unclear if oral Panax ginseng is beneficial for the prevention or treatment of cognitive impairment. Most research has evaluated Panax ginseng in combination with other ingredients. Details: Preliminary clinical research in elderly patients with mild cognitive impairment shows that taking a specific combination product (Memo, Pharco Pharmaceuticals), which contains natural lyophilized royal jelly 750 mg, standardized ginkgo leaf extract 120 mg, and standardized Panax ginseng root extract 150 mg, orally for 4 weeks improves memory when compared with placebo (89712). It is unclear if these benefits are due to Panax ginseng, other ingredients, or the combination. A moderate-sized clinical study in older adults with subjective memory impairment shows that taking a specific Panax ginseng sprout extract (ThinkGIN, BTC Corporation) 450 mg daily for 12 weeks improves performance on some verbal and visual memory tests and cognitive function as measured with MoCA-Korean version when compared with placebo (114983).
• Common cold. It is unclear if oral Panax ginseng is beneficial in preventing the common cold. Details: Preliminary clinical research shows that taking a specific Panax ginseng extract (G115) 200 mg daily orally beginning 4 weeks prior to influenza vaccination and continuing for 8 weeks thereafter can decrease the relative risk of getting the flu or common cold by 65% when compared with placebo (589).
• Congestive heart failure (CHF). It is unclear if oral Panax ginseng is beneficial in CHF. Details: A small clinical study in adults with CHF shows that Panax ginseng 2 grams daily, with or without digoxin 0.25 mg once daily for 15 days, seems to improve heart function according to New York Heart Association (NYHA) classification when compared to baseline. Ginseng might also improve hemodynamics and may work synergistically with digoxin (4243). The validity of these findings is limited by the lack of a comparator group.
• Constipation. It is unclear if oral fermented Panax ginseng is beneficial for constipation. Details: An observational study in healthy postmenopausal adults aged 50 years and older in Korea suggests that taking fermented red ginseng 20 mL before meals daily for 3 weeks normalizes stool consistency and increases the frequency of bowel movements when compared to baseline (112837). The validity of these effects is limited by the observational study design, lack of a comparator group, and insufficient blinding.
• Chronic obstructive pulmonary disease (COPD). Oral Panax ginseng has primarily been evaluated in combination with other ingredients for improving symptoms of COPD; its effect when used alone is unclear. Taking Panax ginseng doesn't seem to prevent exacerbations. Details: A meta-analysis of clinical trials in patients with stable COPD shows that taking Panax ginseng, usually in combination with other ingredients as part of TCM formulations, significantly improves pulmonary function tests and quality of life when compared with placebo after 3-6 months of treatment. These formulations improve COPD symptoms by approximately 53% when compared with placebo. However, they only modestly improve forced expiratory volume in one second (FEV1) (17736). In contrast, Panax ginseng might not reduce the risk of COPD exacerbations. A clinical study in patients with moderate to very severe COPD shows that taking Panax ginseng 200 mg does not reduce the rate of acute COPD exacerbations over 12 months (103044).
• Depression. It is unclear if Panax ginseng is beneficial in depression. Details: In adults with treatment-resistant major depressive disorder, a small clinical study shows that taking Panax ginseng 2 grams daily in addition to current antidepressant medications for 6 weeks produces remission in 39% of patients and decreases scores on the Montgomery-Asberg Depression Rating Scale by a mean of 44% when compared with baseline (104954). The reliability of these findings is limited by the lack of a control group, randomization, blinding, and an intention-to-treat analysis, as well as a high drop-out rate.
• Diabetes. Research on the use of oral Panax ginseng for improving glycemic control in patients with diabetes is inconclusive and conflicting. Details: A meta-analysis of 6 small clinical trials in patients with type 2 diabetes using Panax ginseng for 4-24 weeks and 3 small trials using American or unidentified ginseng for 4-8 weeks, shows that taking these ingredients modestly reduces fasting blood glucose, but does not affect glycated hemoglobin (HbA1c) or insulin levels, when compared with control (105689). This analysis is limited by publication bias, as well as the heterogeneity and imprecision of the included trials. Another meta-analysis of 5 clinical studies in healthy adults and adults with a variety of metabolic disorders including diabetes and prediabetes shows that taking Panax ginseng 200 mg up to 8 grams daily for 4 to 24 weeks does not improve fasting blood glucose, 2-hour postprandial blood glucose, HbA1c, or insulin levels when compared with placebo. However, Panax ginseng might improve glucose AUC in these individuals. Subgroup analysis further suggests that the beneficial effect of Panax ginseng on glucose AUC is greater in adults with diabetes than those with prediabetes (112838). Individual small studies have shown modest glycemic benefit with fermented Panax ginseng 2.7 grams daily for 4 weeks or non-fermented Panax ginseng 6 grams daily for 8-12 weeks (23627,89740), and other studies have shown no benefit with Korean red ginseng extract or Korean black ginseng 2-8 grams daily for 4-6 weeks (17734,112839). It is unclear if the effects of Panax ginseng may be dose- or product-dependent. Panax ginseng has also shown some glycemic benefit when used in combination with other ingredients. Panax ginseng extract 750 mg (standardized to 30% ginsenosides) has been used in combination with American ginseng extract 1500 mg (standardized to 10% ginsenosides), viscous fiber 10 grams, and ground white chia seeds 60 grams daily for 24 weeks (105673). It is unclear if this benefit is due to Panax ginseng, other ingredients, or the combination.
• Diabetic neuropathy. It is unclear if oral Panax ginseng is beneficial in diabetic neuropathy. Details: A small clinical study in patients with diabetic neuropathy shows that taking Panax ginseng extract powder 1 gram daily for 24 weeks seems to improve sensory perception of electric currents, a marker for severity of diabetic neuropathy, when compared with baseline (103051). The validity of this study was limited by the lack of statistical comparison between treatment and placebo groups.
• Exercise-induced muscle damage. Although there has been interest in using oral Panax ginseng for exercise-induced muscle damage, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Fatigue. Most clinical research shows that oral Panax ginseng can reduce fatigue in adults with idiopathic chronic fatigue. However, not all research agrees. Details: Some clinical research in patients with idiopathic chronic fatigue or self-reported fatigue shows that taking Panax ginseng improves self-reported fatigue when compared with baseline or placebo (89743,23623,106665). A small clinical study in patients with idiopathic chronic fatigue shows that taking an ethanolic extract of Panax ginseng 1 gram twice daily for 4 weeks reduces self-reported fatigue by 66% and mental fatigue by 50% when compared with placebo (89743). Another clinical study in adults with chronic fatigue also shows that taking a specific combination product containing Panax ginseng (G115) 80 mg, vitamins, and minerals daily for 7 weeks alleviates fatigue symptoms in 20% more patients when compared with placebo (23623). However, not all research has been positive. A small clinical study in middle-aged patients with idiopathic chronic fatigue shows that taking Panax ginseng, steamed and aged for six years, 3 grams daily for 6 weeks is no different than placebo for reducing fatigue (103052). Notably, this clinical trial had a robust placebo effect.
• Fibromyalgia. It is unclear if oral Panax ginseng is beneficial for fibromyalgia. Details: Clinical research shows that taking Panax ginseng root extract 100 mg daily orally for 12 weeks does not improve pain, fatigue, sleep quality, anxiety, tender point count, or quality of life when compared with placebo in patients with fibromyalgia (89744). A nonblinded, observational study in patients with fibromyalgia, most of whom also have severe chronic fatigue syndrome (CFS), shows that taking Panax ginseng daily for one month improves patient reports of energy, overall wellbeing, mental clarity, sleep, pain, and stamina when compared with baseline. Patients took Panax ginseng, either as a capsule (Terry Naturally HRG80 Red Ginseng Energy capsules; EuroPharma, Inc) 200-400 mg daily, or chewable tablet (Terry Naturally HRG80 Red Ginseng Energy chewable tablets; EuroPharma, Inc) 100-200 mg daily. There were no dose- or formulation-dependent differences between groups (107746). The validity of these findings is limited by the lack of randomization and placebo-control; additionally, the majority (89%) of patients included in this study were female.
• Gallbladder disease. It is unclear if oral Panax ginseng is beneficial for gallbladder disease. Details: Clinical research shows that taking Panax ginseng 7.5 grams as an adjuvant to the bile acids chenodeoxycholic acid (CDCA) 500 mg daily plus ursodeoxycholic acid (UDCA) 500 mg daily, divided into three doses daily for 24 weeks, does not decrease the total volume of gallstones or increase gallstone dissolution when compared to use of bile acids alone (89748).
• Gastritis. Although there has been interest in using oral Panax ginseng for gastritis, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Glaucoma. It is unclear if oral Panax ginseng is beneficial for glaucoma. Details: A clinical crossover study in patients with glaucoma shows that taking oral Panax ginseng 1 gram three times daily for 4 weeks improves dry eye severity, daytime visual function, and eye pain when compared with placebo. In a sub-group of patients with early or moderate glaucoma, nighttime visual function was also improved (107744). The validity of this study is limited due to short duration of treatment.
• Halitosis. It is unclear if oral Panax ginseng is beneficial for halitosis. Details: Preliminary clinical research shows that taking Korean red ginseng, a type of Panax ginseng, 2.7 grams daily for 10 weeks helps reduce bad breath when compared with baseline, particularly in patients with bad breath caused by Helicobacter pylori (H. pylori) infection (23624). The validity of this finding is limited by the lack of a comparator group.
• Hangover. It is unclear if oral Panax ginseng is beneficial for hangover. Details: One small clinical study shows that drinking 100 mL of a drink containing Panax ginseng extract 0.321 mg/mL within 5 minutes of drinking 100 mL blended Scotch whiskey with 40% alcohol and eating a piece of cheese may reduce hangover symptoms by approximately 66% when compared with placebo in healthy males. Levels of alcohol in the blood also appear to be reduced (89742).
• Hearing loss. It is unclear if oral Panax ginseng is beneficial for hearing loss. Details: Preliminary clinical research in male textile workers exposed to continuous noise shows that taking Korean red ginseng, a type of Panax ginseng, 200 mg daily for 14 days reduces temporary hearing loss caused by noises at frequencies of 4, 6, or 16 kHz when compared with control. However, Panax ginseng may be slightly less effective than N-acetyl cysteine at preventing temporary hearing loss caused by noise at 4 kHz frequency (89739).
• HIV/AIDS. It is unclear if oral Panax ginseng is beneficial for this condition. Details: Preliminary clinical research in adults with HIV shows that taking Korean red ginseng, a particular form of Panax ginseng, along with highly active antiretroviral therapy (HAART) modestly increases CD4 count, but does not affect viral load, when compared with HAART alone (23625).
• Hyperlipidemia. It is unclear if oral Panax ginseng is beneficial for hyperlipidemia. Details: A meta-analysis of clinical studies in healthy adults and adults with a variety of metabolic disorders shows that taking Panax ginseng 200 mg to 8 grams daily for 4 to 24 weeks reduces total cholesterol by 7 mg/dL and low-density lipoprotein (LDL) cholesterol by 9 mg/dL but does not reduce triglycerides or increase high-density lipoprotein (HDL) cholesterol when compared with placebo (112838). However, a meta-analysis of up to 28 clinical studies in healthy adults and adults with a variety of metabolic disorders shows that taking Panax ginseng 300 mg to 6 grams daily for 3 to 32 weeks does not reduce total or LDL cholesterol or triglycerides or increase HDL cholesterol when compared with placebo (114985).
• Hypertension. It is unclear if oral Panax ginseng is beneficial for hypertension. Details: A meta-analysis of clinical studies in healthy adults and adults with a variety of metabolic disorders shows that taking Panax ginseng 200 mg to 8 grams daily for 4 to 24 weeks does not reduce systolic (SBP) or diastolic (DBP) blood pressure when compared with placebo. However, subgroup analysis suggests that Panax ginseng might modestly reduce SBP in people with prehypertension, hypertension, or metabolic syndrome (112838). Smaller individual studies of various forms of Panax ginseng have been evaluated in patients with mild to severe hypertension with conflicting results. Some preliminary clinical research in patients with essential hypertension shows that taking Panax ginseng 4.5 grams daily in three divided doses, alone or with a beta-blocker or calcium channel blocker for 8 weeks, moderately decreases 24-hour SBP (23632). However, in patients with prehypertension or mild hypertension, taking protopanaxatriol-enriched Panax ginseng (Ginseol K-g1) 100 mg or 300 mg daily for 8 weeks does not reduce seated SBP or DBP when compared with placebo (89741). Panax ginseng has also been evaluated in combination with American ginseng. Clinical studies in patients with hypertension with or without type 2 diabetes show that taking Panax ginseng 0.75 grams and American ginseng 1.5-2.25 grams enriched to contain 30% total ginsenosides daily for 12 weeks reduces central SBP by about 5 mmHg and 24-hour SBP by about 4 mmHg, but does not impact DBP, when compared with placebo or a control of wheat-bran (103046,107745). Patients receiving this combination also have greater reductions in daytime SBP, glycated hemoglobin, total cholesterol levels, and triglyceride levels when compared with control (107745). It is unclear if these effects are due to Panax ginseng, American ginseng, or the combination; additionally, it is unclear if enrichment with ginsenosides alters clinical effects.
• Impaired glucose tolerance (prediabetes). It is unclear if oral Panax ginseng is beneficial for impaired glucose tolerance. Details: In overweight adults with prediabetes, a small clinical study shows that taking hydrolyzed Panax ginseng extract, 320 mg three times daily before meals for 6 months, does not improve fasting blood glucose levels. However, compliance in this study was only 49% (104953). Additionally, a large, cross-over, clinical study in patients with prediabetes initiating a lifestyle intervention shows that taking a Chinese herbal medicine preparation containing Panax ginseng providing ginseng berry saponins 50 mg three times daily for 4 weeks improves 2-hour post-prandial glucose, but not fasting blood glucose, when compared with placebo (114980). Panax ginseng has also been studied in combination with other ingredients. One clinical study shows that taking a combination of Korean red ginseng, a type of Panax ginseng, and cheonggukjang, a type of fermented soybean paste, 20 grams daily for 8 weeks can decrease fasting blood glucose levels by 17% in patients with prediabetes (23640). Also, taking fermented Panax ginseng 2.7 grams daily for 4 weeks reduces 2-hour postprandial glucose by about 17% and increases 2-hour postprandial insulin levels by about 44% when compared to baseline; when compared with placebo, these changes are significant (89740). It is unclear if these effects are due to Panax ginseng, other ingredients, or the combinations.
• Inflammatory bowel disease (IBD). Although there has been interest in using oral Panax ginseng for Crohn disease and ulcerative colitis, there is insufficient reliable information about the clinical effects of Panax ginseng for these conditions.
• Insomnia. Although there has been interest in using oral Panax ginseng for insomnia, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Liver disease. Although there has been interest in using oral Panax ginseng for liver diseases, there is insufficient reliable information about the clinical effects of Panax ginseng for these conditions.
• Male infertility. It is unclear if oral Panax ginseng is beneficial for male infertility. Details: Chronic prostatitis due to Chlamydia trachomatis infection is associated with reduced male fertility due to decreased sperm concentration and motility. Preliminary clinical research in adults with this condition shows that taking 25 mL of a specific product containing L-arginine 1660 mg, L-carnitine 150 mg, acetyl-L-carnitine 50 mg, and Panax ginseng 200 mg (Fertimev) along with prulifloxacin 600 mg daily for 6 months improves sperm concentration and sperm motility when compared to treatment with prulifloxacin alone (59006). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination.
• Menopausal symptoms. Research on oral Panax ginseng for menopausal symptoms has yielded conflicting results. Details: One clinical study in postmenopausal adults shows that taking Panax ginseng extract (G115) 200 mg daily orally for 16 weeks does not improve psychological well-being or reduce vasomotor symptoms such as hot flashes when compared with placebo (10981). However, several smaller clinical studies in postmenopausal adults demonstrate beneficial effects with higher doses of Panax ginseng. One study shows that taking Panax ginseng 1 gram (containing 30 mg ginsenosides) three times daily for 12 weeks reduces hot flashes and other symptoms, as measured by the Kupperman index and the Menopause Rating Scale (MRS), when compared with placebo (89749). Another study shows that taking an extract of Korean red ginseng, a specific form of Panax ginseng, 500 mg 4 times daily for 8 weeks improves fatigue severity scores by 21%, compared with 3% in those receiving placebo (106666). In premenopausal adults with menopausal symptoms following surgery for gynecologic cancer, taking Panax ginseng 1 gram three times daily for 12 weeks reduces the total symptom score on the MRS when compared with baseline. However, there was also a robust response in the placebo group, with no significant difference in symptom reduction between groups (104596). Panax ginseng has also been evaluated for improving genitourinary syndrome and cognition after menopause. A small clinical trial in postmenopausal adults with genitourinary syndrome shows that taking a specific Panax ginseng supplement (Ruginseng, Ghaem Daru Pharmaceutical) 500 mg twice daily for 4 weeks does not affect vaginal maturation index or pH, but seems to improve patient-rated symptoms such as vaginal itching and burning, when compared with a lactose placebo (105670). This study was funded by the supplement manufacturer. In another clinical study, taking a specific combination product (Gincosan) containing Panax ginseng 200 mg and ginkgo 120 mg daily for 6-12 weeks does not improve cognition, memory, mood, anxiety, or sleep when compared with placebo (87767).
• Metabolic syndrome. It is unclear if oral Panax ginseng is beneficial for metabolic syndrome. Details: A meta-analysis of 23 clinical studies in healthy adults, menopausal adults, and adults with a variety of metabolic disorders shows that taking Panax ginseng 200 mg to 8 grams daily for 4 to 24 weeks reduces glucose area under the plasma concentration-time curve (AUC), total cholesterol, and high-density lipoprotein cholesterol, but does not improve other measures of blood glucose, insulin resistance, blood pressure, lipids, or anthropometric measures when compared with placebo (112838). Additionally, a small clinical study in adults with metabolic syndrome shows that taking Korean red ginseng, a specific form of Panax ginseng, 6 grams daily for 8 weeks modestly reduces systolic blood pressure from baseline, but not when compared with placebo. Additionally, Panax ginseng has no effect on anthropometric measurements, biochemical markers, or other vital signs when compared with placebo (106667).
• Nausea and vomiting. Although there has been interest in using oral Panax ginseng for nausea and vomiting, there is insufficient reliable information about the clinical effects of Panax ginseng for these conditions.
• Neuropathic pain. Although there has been interest in using oral Panax ginseng for neuropathic pain, there is insufficient reliable information about the clinical effects of Panax ginseng for this condition.
• Nonalcoholic fatty liver disease (NAFLD). It is unclear if oral Panax ginseng is beneficial for NAFLD. Details: A small clinical study in adults with NAFLD shows that taking Panax ginseng 2 grams (containing ginsenosides 4.5 mg/gram) daily for 30 days modestly reduces fatigue and plasma levels of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) when compared with placebo. All patients were also given milk thistle dried extract 450 mg (Legalon, Bukwang Pharmaceutical) daily and asked to exercise daily for at least 30 minutes (105671).
• Oral cancer. It is unclear if topical Panax ginseng is beneficial for oral health in patients with oral cancer. Details: A small clinical study in patients with oral cancer and poor oral hygiene shows that rinsing with a specific herbal mouthwash (Dr. Dental care liquid, Jangin Pharm Co., Ltd.) containing Panax ginseng 8 mL for 1 minute twice daily for 14 days reduces oral bacterial load and improves oral hygiene and gingival indices when compared with chlorhexidine or saline rinses (114987).
• Osteoarthritis. It is unclear if oral Panax ginseng is beneficial for osteoarthritis of the hand. Details: A small clinical study in postmenopausal adults with degenerative osteoarthritis of the hand shows that taking oral Korean red ginseng, a type of Panax ginseng, 1 gram three times daily for 12 weeks improves pain scores at rest, during daily activity, and at work or sport, and also improves disabilities of the arm, shoulder, and hand (DASH) score when compared with placebo (107747). The validity of this trial is limited due to the lack of objective outcome measures.
• Pneumonia. Injectable Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Oral Panax ginseng has not been evaluated for this use. Details: A meta-analysis of 20 small, low-quality randomized and non-randomized studies in older Chinese adults with severe pneumonia shows that administering an injection containing Panax ginseng extract 0.8 mg/mL and aconite extract 0.1 mg/mL in addition to standard treatment leads to improvement in symptoms such as fever, cough, and chest tightness in 77% of patients as compared with 61% of those who received standard treatment alone. This combination injection may also modestly reduce disease severity and the risk of mortality when compared with standard treatment alone. However, these outcomes were not evaluated in all studies, and dosing regimens were heterogenous (110472). Additionally, it is unclear whether these effects are due to Panax ginseng, aconite, or the combination.
• Premature ejaculation. Oral Panax ginseng has primarily been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Applying a multi-ingredient cream preparation containing Panax ginseng, angelica root, Cistanches deserticola, Zanthoxyl species, torlidis seed, clove flower, asiasari root, cinnamon bark, and toad venom (SS Cream) to the glans penis one hour prior to intercourse and washing off immediately before intercourse seems to improve ejaculatory latency in adults with premature ejaculation when compared with placebo (2537). It is unclear if this effect is due to Panax ginseng, other ingredients, or the combination.
• Quality of life. It is unclear if oral Panax ginseng is beneficial for quality of life. Details: While some research suggests that Panax ginseng might improve self-rated quality of life (6254,23644), other studies show no benefit (8601,10314). In studies showing benefit for quality of life, doses have included one capsule daily of a specific Panax ginseng extract (Pharmaton Capsules, Pharmaton Natural Health Products) for 12 weeks (6254) and Panax ginseng extract (G115) 40 mg twice daily for 12 weeks (23644).
• Rheumatoid arthritis (RA). It is unclear if oral Panax ginseng is beneficial for improving symptoms of RA. Details: A moderate-sized clinical study in patients with RA, Sjogren syndrome, or both shows that taking Panax ginseng 2000 mg daily for 3 months does not improve fatigue scores when compared with placebo (114984).
• Sjogren syndrome. It is unclear if oral Panax ginseng is beneficial in patients with Sjogren syndrome. Details: A moderate-sized clinical study in patients with RA, Sjogren syndrome, or both shows that taking Panax ginseng 2000 mg daily for 3 months does not improve fatigue scores when compared with placebo (114984).
• Stress. It is unclear if oral Panax ginseng is beneficial for stress. Details: A small clinical study in healthy patients with occupational stress shows that taking a specific Panax ginseng root preparation (HRG80) high in ginsenosides daily for 14 days modestly reduces perceived stress and improves attention and memory when compared with placebo. However, taking a standard Panax ginseng preparation with a lower quantity of ginsenosides was no better than placebo (103050). However, a moderate-sized clinical study in adult males shows that taking Panax ginseng 2000 mg daily for 8 weeks does not improve self-reported stress response when compared with placebo (114988).
• Stroke. It is unclear if oral Panax ginseng prevents stroke. Details: A small clinical study in adults with severe atherosclerosis in major intracranial arteries or extracranial carotid arteries at high risk for ischemic stroke shows that taking an extract of Korean red ginseng, a type of Panax ginseng, 1000 mg twice daily for 12 months does not prevent transient ischemic attack or ischemic stroke and does not improve neurological disability, cerebral blood flow, or the incidence of new ischemic brain lesions when compared with placebo (112835).
• Traumatic brain injury (TBI). It is unclear if oral Panax ginseng is beneficial for asthenic syndrome due to TBI. Details: A small study in adults with asthenic syndrome secondary to mild combat TBI shows that taking Panax ginseng improves autonomic nervous system functioning and asthenic symptoms when compared to baseline (112834). The validity of these effects is limited by a lack of a comparator group.
• Vascular dementia. Oral Panax ginseng has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients aged 60 years or older with vascular dementia shows that taking a supplement containing extracts of Panax ginseng, ginkgo, and saffron three times daily for 16 weeks modestly improves some cognitive function scores, caregiver assessed activities of daily living, and patient-reported quality of life when compared with placebo. However, these effects were not maintained after patients stopped taking the supplement (111336). Additionally, it is unclear if these effects are due to Panax ginseng, other ingredients, or the combination.
• Wrinkled skin. It is unclear if oral Panax ginseng is beneficial for wrinkled skin. Details: Preliminary clinical research shows that taking 3 grams of a combination of Korean red ginseng root with Torilus fructus and Corni fructus daily for 24 weeks may reduce wrinkles when compared with placebo. However, it does not seem to affect skin elasticity, moisture, thickness, or color (23645). It is unclear if this benefit is due to Panax ginseng, other ingredients, or the combination. More evidence is needed to rate Panax ginseng for these uses.

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POSSIBLY SAFE ...when used orally and appropriately. In clinical trials, L-citrulline has been used with apparent safety for up to 2 months at doses of 1.5-6 grams daily (94954,94956,94961,94962,100974). Doses of up to 15 grams have also been used as single doses or within a 24 hour period (16470,16473).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. L-citrulline has been used with apparent safety in infants at a dose of 0.17 grams/kg daily (16472). It has also been used in children 6.5-10 years of age at a dose of 7.5 grams daily for 26 weeks (100976). ...when used intravenously and appropriately. An intravenous bolus dose of L-citrulline 150 mg/kg followed by 9 mg/kg/hour for 48 hours has been used safely in children under 6 years of age (16469).

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

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LIKELY SAFE ...when maca is consumed in food amounts (9926).

POSSIBLY SAFE ...when used orally and appropriately, short term. Maca appears to be safe in doses up to 3 grams daily for 4 months (9928,10218,18289,90278,108603).

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

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LIKELY SAFE ...when used orally and appropriately, short-term. Panax ginseng seems to be safe when used for up to 6 months (8813,8814,17736,89741,89743,89745,89746,89747,89748,103044)(103477,114980,114981,114984,114985). Panax ginseng sprout extract has also been used with apparent safety in doses up to 450 mg daily for up to 12 weeks (114983).

POSSIBLY UNSAFE ...when used orally, long-term. There is some concern about the long-term safety due to potential hormone-like effects, which might cause adverse effects with prolonged use (12537). Tell patients to limit continuous use to less than 6 months. There is insufficient reliable information available about the safety of Panax ginseng when used topically.

CHILDREN: LIKELY UNSAFE
when used orally in infants. Use of Panax ginseng in newborns is associated with intoxication that can lead to death (12). There is limited reliable information available about use in older children (24109,103049); avoid using.

PREGNANCY: POSSIBLY UNSAFE
when used orally. Ginsenoside Rb1, an active constituent of Panax ginseng, has teratogenic effects in animal models (10447,24106,24107); avoid using.

LACTATION:
Insufficient reliable information available; avoid using.

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ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of L-citrulline with antihypertensive drugs might have additive effects and increase the chance of hypotension.  Details L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation (7822,16460,16461). However, a meta-analysis of 5 small clinical studies suggests that taking L-citrulline 3-6 grams daily for 1-8 weeks does not lower blood pressure when compared with control (100974).

PHOSPHODIESTERASE-5 INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concurrent use of phosphodiesterase-5 (PDE-5) inhibitors and L-citrulline might result in additive vasodilation.  Details L-citrulline is converted to L-arginine, which can increase nitric oxide and cause vasodilation (7822,16460,16461). Theoretically, taking L-arginine with PDE-5 inhibitors might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Although Panax ginseng has shown antiplatelet effects in the laboratory, it is unlikely to increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details In vitro evidence suggests that ginsenoside constituents in Panax ginseng might decrease platelet aggregation (1522,11891). However, research in humans suggests that ginseng does not affect platelet aggregation (11890). Animal research indicates low oral bioavailability of Rb1 and rapid elimination of Rg1, which might explain the discrepancy between in vitro and human research (11153). Until more is known, use with caution in patients concurrently taking anticoagulant or antiplatelet drugs.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking Panax ginseng with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical research suggests that Panax ginseng might decrease blood glucose levels (89740). Monitor blood glucose levels closely.

CAFFEINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking Panax ginseng with caffeine might increase the risk of adverse stimulant effects.  Details Panax ginseng has been shown to have stimulant effects (589,594). Theoretically, caffeine might have an additive effect on the stimulant effects of Panax ginseng.

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Panax ginseng might decrease levels of drugs metabolized by CYP1A1.  Details In vitro research shows that Panax ginseng can induce the CYP1A1 enzyme (24104).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, Panax ginseng might increase levels of drugs metabolized by CYP2D6. However, research is conflicting.  Details There is some evidence that Panax ginseng can inhibit the CYP2D6 enzyme by approximately 6% (1303,51331). In addition, in animal research, Panax ginseng inhibits the metabolism of dextromethorphan, a drug metabolized by CYP2D6, by a small amount (103478). However, contradictory research suggests Panax ginseng might not inhibit CYP2D6 (10847). Until more is known, use Panax ginseng cautiously in patients taking drugs metabolized by these enzymes.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, Panax ginseng might increase or decrease levels of drugs metabolized by CYP3A4.  Details Panax ginseng may affect the clearance of drugs metabolized by CYP3A4. One such drug is imatinib. Inhibition of CYP3A4 was believed to be responsible for a case of imatinib-induced hepatotoxicity (89764). In contrast, Panax ginseng has been shown to increase the clearance of midazolam, another drug metabolized by CYP3A4 (89734,103478). Clinical research shows that Panax ginseng can reduce midazolam area under the curve by 44%, maximum plasma concentration by 26%, and time to reach maximum plasma concentration by 29% (89734). Midazolam metabolism was also increased in animals given Panax ginseng (103478). Until more is known, use Panax ginseng cautiously in combination with CYP3A4 substrates.

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of large amounts of Panax ginseng might interfere with hormone replacement therapy.  Details Laboratory research and some case reports suggest that Panax ginseng can have estrogenic effects due to competition for estrogen receptors (590,591,592,6180,10982,10983,10984). The estrogenic activity is attributed to the ginsenoside constituents of Panax ginseng (10984).

FEXOFENADINE (Allegra) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, Panax ginseng might decrease blood levels of oral or intravenous fexofenadine.  Details Animal research suggests that taking Panax ginseng in combination with oral or intravenous fexofenadine may reduce the bioavailability of fexofenadine. Some scientists have attributed this effect to the ability of Panax ginseng to increase the expression of P-glycoprotein (24101).

FUROSEMIDE (Lasix) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Panax ginseng might reduce the effects of furosemide.  Details There is some concern that Panax ginseng might contribute to furosemide resistance. There is one case of resistance to furosemide diuresis in a patient taking a germanium-containing ginseng product (770).

IMATINIB (Gleevec) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, Panax ginseng might increase the effects and adverse effects of imatinib.  Details A case of imatinib-induced hepatotoxicity has been reported for a 26-year-old male with chronic myelogenous leukemia stabilized on imatinib for 7 years. The patient took imatinib 400 mg along with a Panax ginseng-containing energy drink daily for 3 months. Since imatinib-associated hepatotoxicity typically occurs within 2 years of initiating therapy, it is believed that Panax ginseng affected imatinib toxicity though inhibition of cytochrome P450 3A4. CYP3A4 is the primary enzyme involved in imatinib metabolism (89764).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Panax ginseng use might interfere with immunosuppressive therapy.  Details Panax ginseng might have immune system stimulating properties (3122).

INSULIN Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, taking Panax ginseng with insulin might increase the risk of hypoglycemia.  Details Clinical research suggests that Panax ginseng might decrease blood glucose levels (89740). Insulin dose adjustments might be necessary in patients taking Panax ginseng; use with caution.

LOPINAVIR/RITONAVIR (Kaletra) Interaction Rating = Minor Be watchful with this combination. Severity = Insignificant •  Occurrence = Unlikely •  Level of Evidence = B Although Panax ginseng has demonstrated variable effects on cytochrome P450 3A4 (CYP3A4), which metabolizes lopinavir, Panax ginseng is unlikely to alter levels of lopinavir/ritonavir.  Details Lopinavir is metabolized by CYP3A4 and is administered with the CYP3A4 inhibitor ritonavir to increase its plasma concentrations. Panax ginseng has shown variable effects on CYP3A4 activity in humans (89734,89764). However, taking Panax ginseng (Vitamer Laboratories) 500 mg twice daily for 14 days did not alter the pharmacokinetics of lopinavir/ritonavir in 12 healthy volunteers (93578).

MIDAZOLAM (Versed) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, Panax ginseng may increase the clearance of midazolam.  Details Midazolam is metabolized by cytochrome P450 3A4 (CYP3A4). Clinical research suggests that Panax ginseng can reduce midazolam area under the curve by 44%, maximum plasma concentration by 26%, and time to reach maximum plasma concentration by 29% (89734). Midazolam metabolism was also increased in animals given Panax ginseng (103478).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, Panax ginseng can interfere with MAOI therapy.  Details Concomitant use of Panax ginseng with phenelzine (Nardil) is associated with insomnia, headache, tremors (617), and hypomania (618,23650).

NIFEDIPINE (Procardia) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking Panax ginseng with nifedipine might increase serum levels of nifedipine and the risk of hypotension.  Details Preliminary clinical research shows that concomitant use can increase serum levels of nifedipine in healthy volunteers (22423). This might cause the blood pressure lowering effects of nifedipine to be increased when taken concomitantly with Panax ginseng.

QT INTERVAL-PROLONGING DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, Panax ginseng has an additive effect with drugs that prolong the QT interval and potentially increase the risk of ventricular arrhythmias. However, research is conflicting.  Details Clinical research shows that short-term use of Panax ginseng can increase the QT interval (4322,96218). However, no changes in QT interval have been identified with prolonged use (4322).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking Panax ginseng with raltegravir might increase the risk of liver toxicity.  Details A case report suggests that concomitant use of Panax ginseng with raltegravir can increase serum levels of raltegravir, resulting in elevated liver enzymes levels (23621).

SELEGILINE (Eldepryl) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Panax ginseng might increase or decrease levels of selegiline, possibly altering the effects and side effects of selegiline.  Details Animal research shows that taking selegiline with a low dose of Panax ginseng extract (1 gram/kg) reduces selegiline bioavailability, while taking a high dose of Panax ginseng extract (3 grams/kg) increases selegiline bioavailability (103053). More research is needed to confirm these effects.

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking Panax ginseng with stimulant drugs might increase the risk of adverse stimulant effects.  Details Panax ginseng has been shown to have stimulant effects (589,594).

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = B Panax ginseng might affect the clearance of warfarin. However, this interaction appears to be unlikely.  Details There has been a single case report of decreased effectiveness of warfarin in a patient who also took Panax ginseng (619). However, it is questionable whether Panax ginseng was the cause of this decrease in warfarin effectiveness. Some research in humans and animals suggests that Panax ginseng does not affect the pharmacokinetics of warfarin (2531,11890,17204,24105). However, other research in humans suggests that Panax ginseng might modestly increase the clearance of the S-warfarin isomer (15176). More evidence is needed to determine whether Panax ginseng causes a significant interaction with warfarin.

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General ...Orally, L-citrulline seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal discomfort, heartburn.

Gastrointestinal ...Orally, gastrointestinal intolerance, stomach discomfort, and heartburn have been reported with L-citrulline use (94955,94963,94966).

Genitourinary ...Orally, 2 of 25 patients with pulmonary hypertension reported increased urinary frequency and edema while taking 1 gram of powdered L-citrulline in water daily (94963).

Pulmonary/Respiratory ...Orally, 2 of 25 patients with pulmonary hypertension reported cough while taking 1 gram of powdered L-citrulline in water daily (94963).

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General ...Orally, no adverse effects have been reported with the medicinal use of maca. However, a thorough evaluation of safety outcomes has not been conducted.

Gastrointestinal ...Consumption of fresh, uncooked maca may cause stomach pain (40231).

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General ...Orally, Panax ginseng is generally well tolerated when used for up to 6 months. There is some concern about the long-term safety due to potential hormone-like effects.
Topically, no adverse effects have been reported when ginseng is used as a single ingredient. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Insomnia.
Serious Adverse Effects (Rare):
Orally: Anaphylaxis, arrhythmia, ischemia, Stevens-Johnson syndrome.

Cardiovascular ...Panax ginseng may cause hypertension, hypotension, and edema when used orally in high doses, long-term (3353). However, single doses of Panax ginseng up to 800 mg are not associated with changes in electrocardiogram (ECG) parameters or increases in heart rate or blood pressure (96218). There is a case report of menometrorrhagia and tachyarrhythmia in a 39-year-old female who took Panax ginseng 1000-1500 mg/day orally and also applied a facial cream topically that contained Panax ginseng. Upon evaluation for menometrorrhagia, the patient also reported a history of palpitations. It was discovered that she had sinus tachycardia on ECG. However, the patient was a habitual consumer of coffee 4-6 cups/day and at the time of evaluation was also mildly anemic. The patient was advised to discontinue taking Panax ginseng. During the 6 month period following discontinuation the patient did not have any more episodes of menometrorrhagia or tachyarrhythmia (13030). Also, a case of transient ischemic attack secondary to a hypertensive crisis has been reportedly related to oral use of Panax ginseng (89402).

Dermatologic ...Orally, Panax ginseng may cause itching or an allergic response consisting of systemic rash and pruritus (89743,89760,104953,114984,114985). Skin eruptions have also been reported with use of Panax ginseng at high dosage, long-term (3353). Uncommon side effects with oral Panax ginseng include Stevens-Johnson syndrome (596).
In one case report, a 6-year-old male with a previous diagnosis of generalized pustular psoriasis, which had been in remission for 18 months, presented with recurrent pustular lesions after consuming an unspecified dose of Panax ginseng. The patient was diagnosed with pityriasis amiantacea caused by subcorneal pustular dermatosis. Treatment with oral dapsone 25 mg daily was initiated, and symptoms resolved after 4 weeks (107748). In another case report, a 26-year-old female presented with itchy exanthem and oval erythematous lesions on the face, neck, and abdomen after consuming a decoction containing Panax ginseng, aconite, ginger, licorice, Cassia cinnamon, goldthread, and peony 400 mL twice daily for 1 week. Pityriasis rosea-like eruption was suspected, but the patient refused topical or oral antihistamines or corticosteroids. The patient continued taking the decoction but with Panax ginseng and aconite removed. After 6 days, symptoms began to resolve, and by 17 days symptom improvement was significant (114986). It is unclear if this reaction was due to Panax ginseng, aconite, the combination, or some other factor. Pityriasis rosea typically resolves spontaneously.
Topically, when a specific multi-ingredient cream preparation (SS Cream) has been applied to the glans penis, mild pain, local irritation, and burning have occurred (2537).

Endocrine ...The estrogenic effects of ginseng are controversial. Some clinical evidence suggests it doesn't have estrogen-mediated effects (10981). However, case reports of ginseng side effects such as postmenopausal vaginal bleeding suggest estrogenic activity (590,591,592,10982,10983).
In a 12-year-old Korean-Japanese male, enlargement of both breasts with tenderness in the right breast (gynecomastia) occurred after taking red ginseng extract 500 mg daily orally for one month. Following cessation of the product, there was no further growth or pain (89733). Swollen and tender breasts also occurred in a 70-year-old female using Panax ginseng orally (590).

Gastrointestinal ...Orally, Panax ginseng can cause decreased appetite (3353), constipation, diarrhea, dyspepsia (3353,89734,103477,112841,114980,114985), abdominal pain (89734,87984,112841,114985), and nausea (589,87984). However, these effects are typically associated with long-term, high-dose usage (3353). Some evidence suggests that fermented Panax ginseng is more likely to cause abdominal pain and diarrhea when compared with unfermented Panax ginseng (112841).

Genitourinary ...Amenorrhea has been reported with oral use of Panax ginseng (3353).
Topically, when a specific multi-ingredient cream preparation (SS Cream) has been applied to the glans penis, sporadic erectile dysfunction and excessively delayed ejaculation have occurred (2537). Less commonly, patients can experience vaginal bleeding (591,592,3354,23630).

Hepatic ...It is unclear if Panax ginseng is associated with adverse hepatic effects. Cholestatic hepatitis has been reported in a 65-year old male following oral use of a combination product containing Panax ginseng and other ingredients (Prostata). However, it is unclear if this adverse effect was due to Panax ginseng, other ingredients, or the combination (598). An elevation in liver enzymes has been rarely reported in clinical research (114985).

Immunologic ...A case of anaphylaxis, with symptoms of hypotension and rash, has been reported following ingestion of a small amount of Panax ginseng syrup (11971).

Neurologic/CNS ...Orally, one of the most common side effects to Panax ginseng is insomnia (589,89734,111336,114985). Headache (594,23638,112840,114985), vertigo, euphoria, and mania (594) have also been reported. Migraine and somnolence occurred in single subjects in a clinical trial (87984). In a case report of a 46-year-old female, orobuccolingual dyskinesia occurred following oral use of a preparation containing black cohosh 20 mg and Panax ginseng 50 mg twice daily for menopausal symptoms. The patient's condition improved once the product was stopped and treatment with baclofen 40 mg and clonazepam 20 mg daily was started (89735).

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