Bone Mend by Advanced Orthomolecular Research (AOR)

POSSIBLY EFFECTIVE

• Generalized anxiety disorder (GAD). Oral ashwagandha may modestly improve symptoms of anxiety in patients with GAD. Details: Clinical practice guidelines from the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Treatments (CANMAT) provisionally recommend ashwagandha root extract at doses of 300-600 mg, standardized to 5% withanolides, daily as monotherapy or adjunctive therapy in patients with GAD. This recommendation is based on a review of three preliminary clinical trials with consistent results (110318). Two of these studies are described below. A small clinical trial in patients with GAD who are taking selective serotonin reuptake inhibitors (SSRIs) shows that taking ashwagandha 1 gram daily for 6 weeks reduces symptoms of anxiety by 48%, compared with a 27% reduction in patients taking placebo. Furthermore, by the end of treatment, 72% of patients taking ashwagandha were determined to have mild symptoms of GAD, compared with only 32% of those taking placebo (102687). Another preliminary clinical trial in patients aged 16 years and older with GAD shows that taking ashwagandha root powder granules 4 grams three times daily for 60 days moderately improves anxious mood in 58% of patients, compared with no moderate improvement in the placebo group. Mild improvement occurred in 82% of patients in the placebo group and 40% of patients in the ashwagandha group (90654).
• Insomnia. Oral ashwagandha may modestly improve sleep in patients with insomnia or non-restorative sleep. Details: A small meta-analysis in patients with insomnia and healthy patients shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 250-600 mg daily or a specific root and leaf extract (Shoden, Arjuna Natural) 120 mg daily for 6-12 weeks modestly improves overall sleep, as well as sleep quality, sleep latency, total sleep time, wake time after sleep onset, and sleep efficiency, when compared with placebo. Effects were more pronounced in those with insomnia, with doses of at least 600 mg daily, and with treatment durations of at least 8 weeks (106784). These findings may be limited by heterogeneity of the included studies. In patients with non-restorative sleep, clinical research shows that taking a specific ashwagandha extract (Shoden, Arjuna Natural Private Ltd) 125 mg daily for 6 weeks increases sleep quality by 72%, compared with an improvement of 29% in patients taking placebo. Small to moderate improvements also occurred in total sleep time, sleep latency, and number of times awake (103476).
• Stress. Oral ashwagandha seems to help reduce stress and may also reduce stress-related weight gain. Details: A meta-analysis of seven small clinical studies in healthy adults, patients with chronic stress, or patients with psychiatric conditions shows that taking ashwagandha 240-1000 mg daily for 8-12 weeks improves stress when compared with placebo (109587). Clinical studies included in this meta-analysis that evaluated adults with chronic stress show that taking specific ashwagandha root extracts 240 mg daily (Shoden, Arjuna Natural Ltd.) or 300 mg twice daily (KSM-66, Ixoreal Biomed) for 60 days reduces perceived stress levels by 30% to 44% and decreases cortisol levels by 22% to 28% when compared with baseline. These improvements remain significant when compared with the changes seen for patients treated with placebo (90652,95617,101816,102682). In adults reporting moderate to high stress levels, clinical research shows that treatment with specific slow-release capsules containing another ashwagandha root extract (Prolanza), 300 mg daily for 90 days, lowers perceived stress scores and cortisol levels when compared with placebo (107371). In healthy college students, clinical research also shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves qualitative perceptions of stress management, but not stress scores, when compared with placebo (109589,109590). Other clinical research shows that taking ashwagandha root extract 500 mg twice daily may prevent stress-related weight gain when compared with placebo (95617).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. A small clinical study suggests that oral ashwagandha may modestly improve well-being, sleep, and alertness in elderly patients. Details: A small clinical trial in individuals aged 65-80 years shows that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 600 mg daily for 12 weeks improves overall well-being, sleep quality, and mental alertness by small to moderate amounts when compared with placebo (102684).
• Antipsychotic-induced metabolic side effects. It is unclear if ashwagandha is beneficial for attenuating the metabolic side effects of antipsychotic agents. Details: One preliminary clinical trial shows that taking a specific ashwagandha extract (Cap Strelaxin, M/s Pharmanza Herbal Pvt. Ltd.) 400 mg three times daily for one month reduces serum triglycerides by 12% and fasting blood glucose by 15% when compared with baseline levels. Patients were taking atypical antipsychotics and had modestly elevated triglycerides and fasting blood glucose levels at baseline (90649). The validity of these findings is limited by the lack of a comparator group.
• Anxiety. It is unclear if oral ashwagandha is beneficial for reducing anxiety. Details: One small clinical study shows that taking ashwagandha root (Swiss Herbals) 300 mg twice daily for 12 weeks, in combination with standard psychotherapy interventions, including dietary counseling, deep breathing exercise instruction, and a multivitamin, reduces anxiety scores when compared with standard psychotherapy interventions and placebo (19271). However, other clinical research in young adults shows that a specific ashwagandha root and leaf extract (NooGandha, Specnova LLC) 225 mg or 400 mg daily for 30 days produces similar improvements in self-reported anxiety, stress, and depression scores when compared with placebo (107370).
• Asthma. Although there has been interest in using oral ashwagandha for asthma, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Athletic performance. It is unclear if ashwagandha is beneficial for improving athletic performance. Details: A meta-analysis of four small clinical trials shows that taking ashwagandha increases aerobic capacity in athletes and non-athletes based on the measurement of maximum oxygen consumption. Effective doses ranged from 500-1000 mg daily for up to 12 weeks (102683). Another meta-analysis shows that taking ashwagandha in doses of 120-1250 mg daily, as a single dose or divided twice daily, for up to 6 months seems to improve muscle strength, speed, time to exhaustion, recovery time, and cardiorespiratory fitness in athletes and non-athletes (105824). However, the validity of this analysis is reduced by the lack of a control group, the varied training levels of the subjects, and the wide range of outcomes assessed. More research is needed to determine whether taking ashwagandha can improve athletic performance.
• Attention deficit-hyperactivity disorder (ADHD). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In a preliminary clinical trial, children with ADHD were given a combination herbal extract formula (Nurture & Clarity), containing ashwagandha, white peony root, gotu kola, blue-green algae, bacopa, and sage, 3 mL three times daily for 4 months. Measures of attention, cognition, and impulse control improved significantly in children receiving ashwagandha when compared with placebo (19272). The dose of ashwagandha in the combination product was not reported, and the effect of ashwagandha alone in ADHD is unclear.
• Back pain. Although there has been interest in using oral or topical ashwagandha for back pain, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Bipolar disorder. It is unclear if oral ashwagandha is beneficial for improving cognitive function in adults with bipolar disorder. Details: Clinical research shows that taking ashwagandha extract (Sensoril, Natreon, Inc.) 250 mg daily for 1 week and then 250 mg twice daily for 7 weeks, improves some, but not all, measures of cognition by a small-to-moderate amount when compared with placebo (90653).
• Bronchitis. Although there has been interest in using oral ashwagandha for bronchitis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Cerebellar ataxia. It is unclear if oral ashwagandha is beneficial for improving balance in patients with cerebellar ataxia. Details: A small, open-label study evaluating ashwagandha 500 mg three times daily in combination with Ayurvedic therapy for one month showed improvement in balance indices in subjects with cerebellar ataxia when compared with baseline (19273). The validity of this finding is limited by the lack of a comparator group. Additionally, it is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Chemotherapy-related fatigue. Evidence is limited to one small clinical study in patients with breast cancer. Details: In preliminary clinical research in patients with breast cancer, taking ashwagandha powdered root extract 2 grams (Himalaya Drug Co) three times daily through six cycles of chemotherapy decreases chemotherapy-related fatigue when compared with no treatment. Fatigue scores were 16% to 52% higher in the control group when compared to the ashwagandha group (90651).
• Chronic obstructive pulmonary disease (COPD). It is unclear if oral ashwagandha is beneficial in patients with COPD. Details: A small clinical study in patients with stable COPD shows that taking ashwagandha root extract 250 mg twice daily for 12 weeks, along with conventional therapy, improves measures of lung function and exercise tolerance, but not quality of life, when compared with conventional therapy alone (109588).
• Cognitive function. Although there has been interest in using oral ashwagandha for cognitive function, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Constipation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in adults with constipation shows that taking a combination product containing ashwagandha root and ambrette fruit extracts 300 mg or 500 mg daily for 14 days improves bowel movement frequency and abdominal, rectal, and stool symptoms when compared with placebo (112114). It is unclear if these effects are due to ashwagandha, ambrette, or the combination. The validity of these effects is limited by the small sample size.
• Coronavirus disease 2019 (COVID-19). Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults hospitalized with COVID-19 shows that taking a specific combination product, (Artovid-20, Bioved Pharmaceuticals) containing ashwagandha, ginger, turmeric, and Boswellia, 1,776 mg orally twice daily for 14 days shortens the duration of symptoms by 0.9 days when compared with placebo. Taking the combination product also modestly reduced the severity ratings of some symptoms, such as sore throat and cough, however, these improvements are unlikely to be clinically relevant (109899). Another small clinical study in adults with mild to moderate COVID-19 shows that taking ashwagandha 500 mg and ginger 1000 mg twice daily for 15 days reduces time to recovery by around 6 days and increases the rate of clinical cure 14-fold and 2.6-fold at days 5 and 7, respectively, when compared with a control. However, taking this combination does not appear to improve the proportion of patients with a negative COVID-19 test, viral clearance, serum antibodies, chest findings, or disease progression when compared with control (112094). The validity of these findings is limited by a lack of blinding, and the study may have been inadequately powered to detect a difference between groups. Additionally, it is unclear if these effects are due to ashwagandha, ginger, or the combination.
• Diabetes. It is unclear if oral ashwagandha is beneficial for type 2 diabetes. Details: In patients with type 2 diabetes, preliminary clinical research shows that ashwagandha 3 grams daily for 30 days decreases blood glucose to a degree similar to oral hypoglycemic drugs (19274). However, this study did not compare ashwagandha directly to a group taking oral hypoglycemic drugs.
• Fibromyalgia. Although there has been interest in using oral ashwagandha for fibromyalgia, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hiccups. Although there has been interest in using oral ashwagandha for hiccups, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Hypercholesterolemia. It is unclear if ashwagandha is beneficial for hypercholesterolemia. Details: A very small clinical study in subjects with hypercholesterolemia shows that ashwagandha 3 grams daily for 30 days decreases serum cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL) cholesterol levels when compared with baseline (19274). The validity of these findings is limited by the lack of a comparator group.
• Hypothyroidism. It is unclear if ashwagandha is beneficial for hypothyroidism. Details: Preliminary clinical research in adults with subclinical hypothyroidism shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks increases triiodothyronine (T3) and thyroxine (T4) levels by 42% and 20%, respectively, and reduces serum TSH levels by 17% from baseline. These changes are significant when compared with placebo (97292). However, the effects of ashwagandha on thyroid hormone levels in patients with overt hypothyroidism, or in patients taking prescription thyroid hormones, is unknown.
• Infertility. Although there has been interest in using oral ashwagandha for infertility in females, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Male infertility. It is unclear if oral ashwagandha is beneficial for male infertility. Details: Preliminary clinical research in males with infertility shows that taking ashwagandha root powder for approximately 3 months modestly improves hormone levels, as well as sperm count and motility, when compared with baseline (19275,90650). The validity of these findings is limited by the lack of a comparator group. One study used a specific ashwagandha root extract (KSM-66 Ashwagandha, Ixoreal Biomed) 225 mg three times daily; another study provided doses of 5 grams daily (19275,90650).
• Menopausal symptoms. Oral ashwagandha may be beneficial for menopausal symptoms. Details: A small clinical study in healthy adults in perimenopause shows that taking a specific ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily for 8 weeks improves menopausal symptom severity by 24%, compared with 11% in those receiving placebo. Quality of life and hot flashes also were improved in those taking ashwagandha (106785).
• Obsessive-compulsive disorder (OCD). It is unclear if ashwagandha is beneficial for OCD. Details: Preliminary clinical research shows that taking ashwagandha root extract 120 mg after meals for 6 weeks, in conjunction with prescribed selective-serotonin reuptake inhibitors (SSRIs), might reduce OCD symptom severity when compared with prescribed SSRIs alone. The dose was initiated at 30 mg daily and increased by 30 mg every 4 days. Although OCD scores were significantly reduced when compared with placebo, it should be noted that scores were already significantly lower in the placebo group at baseline (95618).
• Osteoarthritis. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with osteoarthritis, taking a specific combination supplement, containing ashwagandha 450 mg, Ayurvedic zinc complex 50 mg, guggul 100 mg, and turmeric 50 mg (Articulin-F) two capsules three times daily for 3 months reduces symptoms of pain and swelling when compared with placebo. However, there were no radiological improvements (19276). It is unclear if this effect is due to ashwagandha, other ingredients, or the combination.
• Parkinson disease. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: In patients with Parkinson disease, a small clinical study shows that taking a product containing ashwagandha 14.5 grams, cowhage 4.5 grams, Hyoscyamus reticulantus 0.75 grams, and Sida cordifolia 14.5 grams in lukewarm milk twice daily for 56 days improves symptoms like tremor, stiffness, and cramps when compared with baseline. The therapy followed 28 days of cleansing or eliminative therapy using Ayurvedic remedies (6899). The validity of these findings is limited by the lack of a comparator group. Also, it is unclear if these effects are due to ashwagandha, other ingredients, or the combination. Cowhage contains levodopa, which may contribute to any benefit seen with this combination product.
• Psychological well-being. It is unclear if oral ashwagandha is beneficial for improving psychological well-being in college students. Details: A small clinical study in healthy college students shows that taking ashwagandha root extract 350 mg twice daily for 30 days improves perceptions of well-being, including improvements in energy, mental clarity, food cravings, and sleep quality, when compared with placebo. Qualitative analysis also suggests these students had improvements in stress management, but stress scores were not reduced when compared with placebo (109589,109590).
• Rheumatoid arthritis (RA). It is unclear if ashwagandha is beneficial for improving symptoms of RA. Details: Preliminary clinical research shows that taking ashwagandha powder 5 grams twice daily for 3 weeks, followed by 4 weeks of sidh makardhwaj (a mixture of gold, mercury, and sulfur) 100 mg with honey daily, modestly improves symptoms in about 50% of males and 60% of females with RA when compared with baseline (95620). The lack of a control group limits the validity of this finding. Additionally, the effect of ashwagandha powder alone is unclear.
• Sexual dysfunction. Small clinical studies suggest that oral ashwagandha root extract may help improve sexual arousal and sexual desire in some females and males with sexual dysfunction. Details: Two, small clinical studies in adult females with sexual dysfunction show that taking ashwagandha root extract (KSM-66, Ixoreal Biomed) 300 mg twice daily with food for 8 weeks in conjunction with or without counseling increases the number of successful sexual encounters and improves orgasms, satisfaction, lubrication, and arousal when compared with placebo or counseling alone (95619,110492). Also, a small clinical study in adult males with low sexual desire shows that taking the same ashwagandha root extract 300 mg twice daily after meals for 8 weeks improves subjective sexual functioning scores, including measures of sexual arousal, sexual desire, sexual behavior, and orgasm, when compared with placebo (109586).
• Smoking cessation. Oral ashwagandha has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with a history of smoking 5 or more cigarettes daily for at least 3 years shows that taking a specific combination product containing ashwagandha 100 mg, Indian gooseberry, tribulus, bacopa, Albizia lebbeck, licorice, clove, ginger, cowhage, holy basil, and turmeric (Smotect, Smotect India) 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 ashwagandha, other ingredients, or the combination.
• Tuberculosis. Although there has been interest in using oral ashwagandha for tuberculosis, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Vitiligo. Although there has been interest in using oral ashwagandha for vitiligo, there is insufficient reliable information about the clinical effects of ashwagandha for this condition.
• Wrinkled skin. It is unclear if topical ashwagandha is beneficial in individuals with wrinkled skin. Details: A small clinical study in healthy adults with photoaged skin shows that applying ashwagandha root extract 8% lotion daily for 60 days improves physician-rated scores for skin wrinkles, hydration, brightness, tone, and pigmentation and improves other measures of skin elasticity and hydration when compared with placebo. However, changes in melanin content did not differ between treatment groups (111538).
• Wound healing. Although there has been interest in using topical ashwagandha for healing of skin ulcers and skin sores, there is insufficient reliable information about the clinical effects of ashwagandha for this condition. More evidence is needed to rate ashwagandha for these uses.

(Read more about ASHWAGANDHA)

POSSIBLY EFFECTIVE

• Obesity. Several small clinical studies suggest that oral Cissus quadrangularis extract, taken with or without other ingredients, can decrease body weight in those who are overweight or obese. Details: Two small clinical studies in adults with overweight or obesity shows that taking a specific Cissus quadrangularis extract standardized to 2.5% keto-steroids and 15% soluble plant fiber (CQR-300, Gateway Health Alliance) 300 mg daily for 6-8 weeks with a reduced calorie diet decreases body weight by around 4% to 11%, compared with a 0% to 3% reduction with reduced calorie dieting alone (15609,93637). Other small clinical studies in patients with overweight or obesity shows that taking 300 mg of this product daily for 8-10 weeks without following any specific diet decreases body weight by about 8% to 9%, compared with about 2% in those taking placebo (16457,99257). Taking this product also appears to reduce body fat by about 13%, compared with no decrease in those taking placebo (99257). However, most of these studies are of moderate to low quality, and all are short-term, limiting the reliability of the findings. Cissus quadrangularis has also been evaluated in combination with other ingredients. Several small clinical studies show that taking a specific combination product containing Cissus quadrangularis (standardized to 2.5% keto-steroids and 15% soluble plant fiber), green tea, soy, chromium, selenium, and B-vitamins (Cylaris, Iovate Health Sciences International) 1028 mg daily, taken in single or divided doses, for 8 weeks reduces weight by around 7% or 6.6 kg when used alone. When used with a reduced calorie diet, body weight is reduced by 8.5% or 8.1 kg (15608,15609,95921). It is unclear if these findings are due to Cissus quadrangularis, other ingredients, or the combination.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Asthma. Although there has been interest in using oral Cissus quadrangularis for asthma, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Cancer. Although there has been interest in using oral Cissus quadrangularis for cancer, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Diabetes. Although there has been interest in using oral Cissus quadrangularis for diabetes, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Epilepsy. Although there has been interest in using oral Cissus quadrangularis for epilepsy, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Fractures. Several small, low-quality clinical trials suggest that oral Cissus quadrangularis may accelerate the healing of various types of fractures and reduce pain and swelling. Details: Two small clinical studies in patients with jaw fractures in India show that taking powdered Cissus quadrangularis whole herb 500 mg three times daily for 6 weeks or a different Cissus quadrangularis preparation containing dried stem 600 mg twice daily for 8 weeks reduces pain, swelling, and healing time when compared with placebo (93634,95923). In patients with single, simple bone fractures, a small clinical study in India shows that taking an Ayurvedic preparation of crude, powdered Cissus quadrangularis (Asthishrunkhala churna), 10 grams divided into three doses daily for 30 days, accelerates bone healing and reduces analgesic requirements when compared with placebo (95921). Another small clinical trial in patients with distal radius fractures shows that taking the same Ayurvedic preparation orally, 3-4 grams twice daily for 6 weeks, with or without a topical preparation of Cissus quadrangularis, 15 grams applied once daily for 2 weeks, seems to decrease subjective measures of pain and swelling when compared to baseline (95922). The validity of this finding is limited by the lack of a comparator group. In patients with a fracture of the long bones of the leg, a very small clinical study in India shows that taking a specific Cissus quadrangularis extract (Calzbone, Verdure Sciences) 250 mg orally three times daily decreases the average fracture healing time from 16-20 weeks to 12-14 weeks (43216). Cissus quadrangularis has also been evaluated in combination with other ingredients. A small, open label trial in India among patients with jaw fractures shows that taking Cissus quadrangularis 500 mg and Dalbergia sissoo 400 mg twice daily for 4 weeks improves bite force restoration when compared with placebo, but not when compared with teriparatide. Improvements in pain, fracture site mobility, and bone healing were lacking in all groups (112139). The study may have been inadequately powered to detect differences between the groups, and it is unclear if these findings are due to Cissus quadrangularis, Dalbergia sissoo, or the combination.
• Gout. Although there has been interest in using oral Cissus quadrangularis for gout, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Hemorrhoids. Small clinical studies suggest that oral or topical Cissus quadrangularis extracts may not improve symptoms of hemorrhoids. Details: Several small clinical studies in patients with acute, symptomatic hemorrhoids show that taking Cissus quadrangularis extract as either 100 mg daily for 1 week, 180 mg daily for 2 weeks, or 1 gram three times daily for 3 days followed by 1 gram twice daily for 4 days, does not improve symptoms of hemorrhoids when compared with placebo (43204,95921). Using a topical preparation of Cissus quadrangularis extract three times daily for 1 week also seems to be no better than placebo (95921). Another small clinical study in this population shows that rectal administration of a suppository containing Cissus quadrangularis extract 1% and Amcella paniculata extract 1% twice daily for 7 days results in similar improvements in anal pain, bleeding, and prolapse size when compared with a commercial suppository containing hydrocortisone 5 mg and cinchocaine 5 mg (108548). It is unclear if these findings are due to Cissus quadrangularis, Amcella paniculate, or the combination.
• Hyperlipidemia. Although there has been interest in using oral Cissus quadrangularis for hyperlipidemia there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Joint pain. It is unclear if oral Cissus quadrangularis is beneficial in patients with joint pain. Details: A small clinical study in males with exercise-related chronic joint pain shows that taking two 800 mg capsules of a specific Cissus quadrangularis product (SuperCissus, USPlabs) twice daily for 8 weeks decreases pain by 31% and stiffness by 23% when compared to baseline (93633). The validity of these findings is limited by the lack of a comparator group.
• Metabolic syndrome. Although there has been interest in using oral Cissus quadrangularis for metabolic syndrome, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Muscle strength. Although there has been interest in using oral Cissus quadrangularis to improve muscle strength, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Osteopenia. It is unclear if oral Cissus quadrangularis is beneficial for osteopenia. Details: A moderate-sized clinical trial in Thailand among postmenopausal patients with osteopenia shows that taking Cissus quadrangularis 1200 or 1600 mg daily for 24 weeks does not improve bone mineral density (BMD) when compared with placebo. However, Cissus quadrangularis does seem to improve markers of bone turnover, suggesting that longer-term use might lead to improvements in BMD (112140). Also, a small clinical study in patients with low BMD shows that taking a combination of Cissus quadrangularis, ashwagandha, and holy basil once daily for 6 months seems to improve BMD, T-score, and Z-score when compared with placebo (43217). However, it is unclear if these findings are due to Cissus quadrangularis, other ingredients, or the combination.
• Osteoporosis. Although there has been interest in using oral Cissus quadrangularis for osteoporosis, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Peptic ulcers. Although there has been interest in using oral Cissus quadrangularis for peptic ulcers, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral Cissus quadrangularis for RA, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose.
• Wound healing. Although there has been interest in using topical Cissus quadrangularis for wound healing, there is insufficient reliable information about the clinical effects of Cissus quadrangularis for this purpose. More evidence is needed to rate Cissus quadrangularis for these uses.

(Read more about CISSUS QUADRANGULARIS)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Aging. Although there has been interest in using oral holy basil for aging, there is insufficient reliable information about the clinical effects of holy basil for this purpose.
• Asthma. Although there has been interest in using oral holy basil for asthma, there is insufficient reliable information about the clinical effects of holy basil for this condition.
• Dental plaque. Small clinical studies suggest that topical use of holy basil mouthwash, gel, or toothpaste may modestly reduce the severity of dental plaque. Details: Small clinical studies in patients with mild to moderate dental plaque or gingivitis shows that using 10 mL of a mouthwash containing holy basil leaf extract 4% twice daily for 30 days reduces plaque severity by about 17% to 28% when compared with baseline (91570,103621). In one study, this effect was significant when compared with a placebo mouthwash and similar to a mouthwash containing chlorhexidine 0.12% (91570), whereas the other study did not conduct comparisons between study groups (103621). A small clinical study in patients with chronic gingivitis shows that applying holy basil extract 2% gel as a gingival massage twice daily for 30 days reduces plaque severity when compared with baseline (110030). The validity of this finding is limited by the lack of statistical comparison to the other study groups. Also, a small clinical trial in children 14-15 years of age shows that brushing with toothpaste containing holy basil leaf extract 4% twice daily for 3 weeks reduces plaque severity when compared with placebo, with similar improvements when compared with a fluorinated toothpaste (104183). Holy basil has also been evaluated in combination with other ingredients. A small study shows that rinsing with 10 mL of a solution containing tea tree oil, clove, and holy basil (0.2% to 0.3% of each), for 30 seconds twice daily for 21 days, reduces plaque formation by 64%. This reduction is similar to a 72% reduction seen in the active control group using a mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate (91446).
• Diabetes. Small clinical studies suggest that oral holy basil may modestly improve glycemic control in patients with diabetes. Details: One small clinical trial in adults with type 2 diabetes shows that taking holy basil dried leaf powder 2.5 grams daily for 4 weeks decreases fasting and postprandial blood glucose by 18%, compared with a 7% reduction in those taking placebo (12242). Another small clinical study in patients with type 2 diabetes shows that taking holy basil 250 mg twice daily in combination with glyburide 5 mg daily for 3 months reduces fasting blood glucose by 16%, postprandial blood glucose by 13%, and glycated hemoglobin (HbA1c) levels by 18% when compared with glyburide alone (91571).
• Dyspepsia. Although there has been interest in using oral holy basil for dyspepsia, there is insufficient reliable information about the clinical effects of holy basil for this purpose.
• Generalized anxiety disorder (GAD). It is unclear if oral holy basil is beneficial in patients with GAD. Details: One small, uncontrolled clinical study in patients with GAD shows that taking holy basil leaf extract 500 mg twice daily following meals for 60 days reduces anxiety and associated symptoms of stress and depression when compared to baseline (19575). The validity of these findings is limited by a lack of control group.
• Gingivitis. Small clinical studies suggest that topical use of holy basil mouthwash or toothpaste may modestly improve gingivitis. Details: Small clinical studies in patients with mild to moderate dental plaque or gingivitis shows that using 10 mL of a mouthwash containing holy basil leaf extract 4% twice daily for 30 days reduces gingivitis by about 23% to 40% when compared with baseline (91570,103621). In one study, these effects were significant when compared with placebo mouthwash and similar to those of a mouthwash containing chlorhexidine 0.12% (91570), whereas the other study did not conduct statistical comparisons between study groups (103621). A small clinical trial in children 14-15 years of age shows that brushing with toothpaste containing holy basil leaf extract 4% twice daily for 3 weeks reduces the severity of gingivitis when compared with placebo, with similar improvements when compared with a fluorinated toothpaste (104183). However, a small clinical study in patients with chronic gingivitis shows that applying holy basil leaf extract 2% gel as a gingival massage twice daily for 30 days does not reduce gingivitis severity when compared with baseline (110030). Holy basil has also been evaluated in combination with other ingredients. A small clinical study shows that rinsing with 10 mL of a solution containing tea tree oil, clove, and holy basil (0.2% to 0.3% of each), for 30 seconds twice daily for 21 days, reduces gum inflammation by 76%. This reduction is similar to a 70% reduction seen in the active control group using a mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate (91446).
• Headache. Although there has been interest in using oral holy basil for headache, there is insufficient reliable information about the clinical effects of holy basil for this purpose.
• Hepatitis. Although there has been interest in using oral holy basil for hepatitis, there is insufficient reliable information about the clinical effects of holy basil for this condition.
• Hypercholesterolemia. Although there has been interest in using oral holy basil for hypercholesterolemia, there is insufficient reliable information about the clinical effects of holy basil for this purpose.
• Hypertension. Although there has been interest in using oral holy basil for hypertension, there is insufficient reliable information about the clinical effects of holy basil for this purpose.
• Insect repellent. Although there has been interest in using topical holy basil as an insect repellent, there is insufficient reliable information about the clinical effects of holy basil for this purpose.
• Insomnia. It is unclear if oral holy basil is beneficial for sleep problems. Details: A moderate-sized clinical study in adults with stress and sleep problems (i.e., unrefreshing sleep or difficulty falling or staying asleep) shows that taking holy basil 125 mg twice daily for 8 weeks does not improve patient-reported or wearable tracker scores related to sleep when compared with placebo (112416). However, the interpretation of these results is limited by self-reported outcomes and use of a non-validated measurement tool for sleep (i.e., Fitbit device).
• Obesity. It is unclear if oral holy basil is beneficial in overweight or obese patients. Details: One small clinical study in individuals with overweight or obesity shows that taking holy basil extract 250 mg twice daily for 8 weeks slightly reduces body weight and improves levels of triglycerides or low-density lipoprotein (LDL) cholesterol and certain glycemic indices when compared to baseline, but not when compared with no treatment. Holy basil extract also did not improve liver enzymes when compared to baseline or with no treatment (96944).
• Oral submucous fibrosis. It is unclear if topical holy basil paste is beneficial for oral submucous fibrosis. Details: A moderate-sized clinical study in adults with oral submucous fibrosis conducted in India shows that applying a paste containing holy basil extract 250 mg intraorally twice daily for 1 month modestly improves mouth opening scores and patient-reported burning sensation at the 3 month follow up when compared to baseline (112424). However, the validity of these findings is limited by poor methodology and lack of a comparator group.
• Respiratory tract infections. Although there has been interest in using oral holy basil for respiratory tract infections, including bronchitis, common cold, influenza, and tuberculosis, there is insufficient reliable information about the clinical effects of holy basil for these conditions.
• Stress. It is unclear if oral holy basil is beneficial in patients with stress. Details: One small clinical trial in patients experiencing various symptoms of stress shows that taking a specific holy basil extract (OciBest, Natural Remedies Pvt. Ltd.) 400 mg in the morning and 800 mg at night for 6 weeks decreases self-reported symptoms of stress, including forgetfulness, sexual problems and sleep problems of recent origin, and frequency of exhaustion, when compared with placebo (18107). A moderate-sized clinical study in adults with stress and sleep problems shows that taking holy basil 125 mg twice daily for 8 weeks modestly improves stress scores but does not improve individual symptoms related to stress including anxiety, mood disturbance, physical function, depression, fatigue, or sleep disturbance when compared with placebo (112416). However, the interpretation of these findings is limited by self-reported outcome measures and unclear clinical significance.
• Tinea corporis. Although there has been interest in using topical holy basil for tinea corporis, there is insufficient reliable information about the clinical effects of holy basil for this purpose. More evidence is needed to rate holy basil for these uses.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Ashwagandha has been used with apparent safety in doses of up to 1250 mg daily for up to 6 months (3710,11301,19271,90649,90652,90653,97292,101816,102682,102683) (102684,102685,102687,103476,105824,109586,109588,109589,109590). ...when used topically. Ashwagandha lotion has been used with apparent safety in concentrations up to 8% for up to 2 months (111538).

PREGNANCY: LIKELY UNSAFE
when used orally. Ashwagandha has abortifacient effects (12).

LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Preparations of Cissus quadrangularis dried herb have been used with apparent safety in doses up to 1600 mg for 24 weeks (93634,95923,112140). An Ayurvedic preparation of the dried herb has been used with apparent safety in doses of 6-10 grams daily for 4-6 weeks (95921,95922). Some research shows that a specific Cissus quadrangularis product (SuperCissus, USPlabs) can be used safely in a dose of 3.2 grams daily for up to 8 weeks (93633). Other research shows that another specific Cissus quadrangularis extract (CQR-300; Gateway Health Alliance) has been used with apparent safety in a dose of 300 mg daily for up to 10 weeks (15609,16457,93637,99257).

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

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POSSIBLY SAFE ...when used orally, short-term. Holy basil leaf extract has been used with apparent safety at a dose of 500 mg daily for 60-90 days (12242,18107,19575,91571,96944). ...when used topically in the mouth, short-term. Holy basil has been used with apparent safety as a 4% mouthwash solution for up to 30 days (91570,103621).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used in high doses during pregnancy or when trying to conceive. Animal research suggests that relatively high doses of holy basil extract (200 mg/kg) may reduce implantation rate when used for one week, while long-term use of higher doses (2-4 grams/kg) may decrease the number of full-term pregnancies (55040,91569). There is insufficient reliable information available regarding the safety of holy basil during lactation; avoid using.

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, taking ashwagandha with antidiabetes drugs might increase the risk of hypoglycemia.  Details There is preliminary clinical evidence suggesting that ashwagandha might lower blood glucose levels. Theoretically, ashwagandha might have additive effects when used with antidiabetes drugs and increase the risk of hypoglycemia (19274,90649,102685).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha with antihypertensive drugs might increase the risk of hypotension.  Details Animal research suggests that ashwagandha might lower systolic and diastolic blood pressure (19279). Theoretically, ashwagandha might have additive effects when used with antihypertensive drugs and increase the risk of hypotension.

BENZODIAZEPINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of benzodiazepines.  Details There is preliminary evidence that ashwagandha might have an additive effect with diazepam (Valium) and clonazepam (Klonopin) (3710). This may also occur with other benzodiazepines.

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might increase the sedative effects of CNS depressants.  Details Ashwagandha seems to have sedative effects. Theoretically, this may potentiate the effects of barbiturates, other sedatives, and anxiolytics (3710).

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking ashwagandha might decrease the effects of immunosuppressants.  Details Ashwagandha has demonstrated immunostimulant effects in humans (3710,3711,4114,11301,106786). Animal research has shown that ashwagandha can attenuate the immunosuppression caused by cyclophosphamide (3711,4114).

THYROID HORMONE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Ashwagandha might increase the effects and adverse effects of thyroid hormone.  Details Concomitant use of ashwagandha with thyroid hormones may cause additive therapeutic and adverse effects. Preliminary clinical research and animal studies suggest that ashwagandha boosts thyroid hormone synthesis and secretion (19281,19282,97292). In one clinical study, ashwagandha increased triiodothyronine (T3) and thyroxine (T4) levels by 41.5% and 19.6%, respectively, and reduced serum TSH levels by 17.4% from baseline in adults with subclinical hypothyroidism (97292).

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ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, Cissus quadrangularis might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Small clinical studies suggest that Cissus quadrangularis might reduce fasting blood glucose in individuals with overweight or obesity (16457,99257).

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, holy basil seed oil might increase the risk of bleeding when used with anticoagulant or antiplatelet drugs.  Details Animal research shows that holy basil seed oil can prolong bleeding time, possibly due to inhibition of platelet aggregation (13251). However, it is not known if this occurs in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, holy basil might increase the risk of hypoglycemia when taken with antidiabetes drugs.  Details Small clinical studies show that taking holy basil can decrease fasting blood glucose and other measures of glycemic control in patients with type 2 diabetes (12242,91571).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, holy basil seed oil might increase the sedative effects of pentobarbital.  Details Animal research shows that holy basil seed oil increases pentobarbitone-induced sleeping time (13056,13251). However, it is not known if this occurs in humans or if this applies to other barbiturates or sedatives.

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General ...Orally, ashwagandha seems to be well-tolerated. Topically, no adverse effects have been reported. However, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Diarrhea, gastrointestinal upset, nausea, and vomiting. However, these adverse effects do not commonly occur with typical doses.
Serious Adverse Effects (Rare):
Orally: Some case reports raise concerns about acute liver failure, hepatic encephalopathy, and the need for liver transplantation with ashwagandha treatment.

Dermatologic ...Orally, dermatitis has been reported in three of 42 patients in a clinical trial (19276).

Endocrine ...A case report describes a 73-year-old female who had taken an ashwagandha root extract (unspecified dose) for 2 years to treat hypothyroidism which had been previously managed with levothyroxine. The patient was diagnosed with hyperthyroidism after presenting with supraventricular tachycardia, chest pain, tremor, dizziness, fatigue, irritability, hair thinning, and low thyroid stimulating hormone (TSH) levels. Hyperthyroidism resolved after discontinuing ashwagandha (108745).

Gastrointestinal ...Orally, large doses may cause gastrointestinal upset, diarrhea, and vomiting secondary to irritation of the mucous and serous membranes (3710). When taken orally, nausea and abdominal pain (19276,110490) and gastritis and flatulence (90651) have been reported.

Genitourinary ...In one case report, a 28-year-old male with a decrease in libido who was taking ashwagandha 5 grams daily over 10 days subsequently experienced burning, itching, and skin and mucous membrane discoloration of the penis, as well as an oval, dusky, eroded plaque (3 cm) with erythema on the glans penis and prepuce (32537).

Hepatic ...Orally, ashwagandha in doses of 154-1350 mg daily has played a role in several case reports of liver injury. In most of these cases, other causes of liver injury were excluded, and liver failure did not occur. Symptoms included jaundice, pruritus, malaise, fatigue, lethargy, weight loss, nausea, diarrhea, abdominal pain, stool discoloration, and dark urine. Symptom onset was typically 5-180 days from first intake, although in some cases onset occurred after more than 12 months of use (102686,107372,110490,110491,111533,111535,112111). Laboratory findings include elevated aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, and serum bilirubin (112111). In most cases, liver enzymes normalized within 1-5 months after discontinuation of ashwagandha (102686,107372,110491,111535,112111). However, treatment with corticosteroids, lactulose, ornithine, ursodeoxycholic acid, and plasmapheresis, among other interventions, was required in one case (111533). Rarely, use of oral ashwagandha has been reported to cause hepatic encephalopathy and liver failure requiring liver transplantation (110490).

Neurologic/CNS ...Orally, ashwagandha has been reported to cause drowsiness (110492). Headache, neck pain, and blurry vision have been reported in a 47-year-old female taking ashwagandha, cannabis, and venlafaxine. Imaging over the course of multiple years and hospital admissions indicated numerous instances of intracranial hemorrhage and multifocal stenosis of intracranial arteries, likely secondary to reversible cerebral vasoconstriction syndrome (RCVS) (112113). It is unclear whether the RCVS and subsequent intracranial hemorrhages were precipitated by ashwagandha, cannabis, or venlafaxine.

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General ...Orally, Cissus quadrangularis seems to be well tolerated.

Gastrointestinal ...Orally, Cissus quadrangularis has been reported to cause flatulence (15608,16457), diarrhea (15608,112140), gastritis (43204), and dry mouth (15608). However, the rates of these adverse effects are similar to or lower than that observed with placebo (15608,16457,43204,112140).

Neurologic/CNS ...Orally, Cissus quadrangularis has been reported to cause headache and insomnia. However, the rates of these adverse effects are similar to or lower than that observed with placebo (15608,16457).

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General ...Orally and topically, holy basil extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Loose stools and nausea.
Topically: Bitter taste with oral application.

Gastrointestinal ...Orally, two out of 24 participants taking capsules containing holy basil extract in one clinical study experienced nausea or loose stools (55037).
Topically, holy basil mouthwash has been reported to cause a bitter taste in clinical trials (55038).

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