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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Amenorrhea. Although there has been interest in using oral cassia cinnamon for amenorrhea, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Angina. Although there has been interest in using oral cassia cinnamon for angina, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Common cold. Although there has been interest in using oral cassia cinnamon for the common cold, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Diabetes. Several clinical trials have evaluated oral cassia cinnamon for type 2 diabetes, but results are conflicting. Details: Some clinical studies and meta-analyses of cassia cinnamon have found significant benefits in patients with diabetes (11347,17011,21914,21918,89646,89649,111692), while others have not (14344,16010,17689,21915,21916,89650). Results from meta-analyses are also mixed with respect to lowering fasting blood glucose and lipid levels (89647,108264). Meta-analyses including more than 1500 adults with type 2 diabetes show that taking cassia cinnamon 120 mg To 14.4 grams daily for 4-18 weeks reduces fasting blood glucose by an average of 25 mg/dL, total cholesterol by 16 mg/dL, low-density lipoprotein (LDL) cholesterol by 9 mg/dL, and triglycerides by 30 mg/dL, and increases high-density lipoprotein (HDL) cholesterol by 2 mg/dL (89647,111692). Analyses included studies examining either extract or powder, and two of the studies included used an unspecified type of cinnamon. In contrast, a more recent meta-analysis of studies limited to cassia cinnamon ground bark powder 1-2 grams daily for 40-90 days shows no benefit on fasting blood glucose or lipid levels (108264). Evidence regarding cassia cinnamon's effect on glycated hemoglobin (HbA1c) is mixed, with one meta-analysis of 15 clinical studies suggesting that it moderately lowers HbA1c, while other studies suggest that it does not, although some of the studies were too short to detect a change (89647,108264,111692). One meta-analysis found that cassia cinnamon was most beneficial for adults with HbA1c of 8% or higher (111692). The individual studies included in the meta-analyses were also small, and very heterogenous in relation to dose, duration, use of conventional medications, and diabetes control at baseline (89647,108264). Cassia cinnamon has also been evaluated in combination with other ingredients. A study in treatment-naïve adults newly diagnosed with type 2 diabetes shows that taking a combination product containing cassia cinnamon extract 100 mg, black seed extract, and ficin extract (NW Low-Glu) 4-5 times daily for 12 weeks reduces HbA1c by 0.6-0.8% and 2-hour postprandial glucose by 25-35 mg/dl when compared to baseline, with similar findings when compared with metformin. However, there were no notable differences in fasting blood glucose, insulin resistance, and beta cell function (111710). It is unclear if these effects are due to cassia cinnamon, other ingredients, or the combination. In patients with type 1 diabetes, clinical research shows that taking cassia cinnamon daily does not improve fasting blood glucose, HbA1c, insulin sensitivity, or the rate of hypoglycemic episodes (16010,89648).
• Diarrhea. It is unclear if oral cassia cinnamon is beneficial for diarrhea. Details: A moderate-sized clinical study in adults with diarrhea shows that taking cinnamon water extract 1200 mg twice daily for 8 weeks increases colonic transit time by about 10 hours but does not improve other symptoms of diarrhea including percentage of bowel movements with diarrhea, Bristol stool scale score, abdominal pain, bowel urgency, or abdominal distension when compared with placebo (111712).
• Dyslipidemia. It is unclear if oral cassia cinnamon is beneficial for dyslipidemia. Details: A meta-analysis of 12 clinical studies in adults with metabolic syndrome, polycystic ovary syndrome (PCOS), nonalcoholic fatty liver disease (NAFLD), type 2 diabetes, prediabetes, and overweight or obesity shows that taking cassia cinnamon daily for 2-4 months reduces total cholesterol by 7 mg/dL, triglycerides by 9 mg/dL, and low-density lipoprotein (LDL) cholesterol by 6 mg/dL but does not increase high-density lipoprotein (HDL) cholesterol. Subgroup analysis suggests that cassia cinnamon improves lipid profiles of Asian patients but not European or American patients. Additionally, higher doses appear to regulate lipid profiles better, and cassia cinnamon doses above 1.5 grams daily increase high-density lipoprotein cholesterol by about 2.5 mg/dL. Subgroup analysis also shows that cassia cinnamon only reduces triglycerides for patients with metabolic syndrome and increases HDL cholesterol for patients with PCOS but does not impact total cholesterol for those with type 2 diabetes (111709).
• Erectile dysfunction (ED). Although there has been interest in using oral cassia cinnamon for ED, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Hypertension. Although there has been interest in using oral cassia cinnamon for hypertension, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Impaired glucose tolerance (prediabetes). The effects of cassia cinnamon in patients with impaired glucose tolerance are unclear; results from clinical research are conflicting. Details: A small clinical study in patients with impaired glucose tolerance shows that taking cassia cinnamon powder 6 grams twice daily for 12 weeks does not improve fasting plasma glucose or insulin sensitivity when compared with placebo (96280). However, another clinical study in overweight or obese patients with impaired fasting blood glucose shows that taking a dried aqueous extract of cassia cinnamon 250 mg twice daily for 12 weeks reduces fasting blood glucose by about 12 mg/dL when compared with baseline, but does not affect fasting insulin levels (93118). Another preliminary clinical trial in overweight or obese patients with impaired glucose tolerance shows that taking two capsules of a specific combination product, (Glycabiane, PiLeJe) containing cassia cinnamon extract 228 mg, chromium chloride 10 mcg, and carnosine 100 mg per capsule, daily for 4 months decreases fasting blood glucose by 6.5 mg/dL but has no effect on glycated hemoglobin (HbA1c), insulin sensitivity, or body weight, when compared with placebo (94234). It is unclear whether these effects are due to cassia cinnamon, ingredients, or the combination.
• Mosquito repellent. It is unclear if topical cassia cinnamon is beneficial as a mosquito repellent. Details: Preliminary clinical research suggests that applying a cream containing cassia cinnamon oil 5% to the skin provides protection from mosquito bites. However, the repellency of this cream appears to decrease more quickly over time compared to MeiMei cream (containing citronella and geranium oils) and Repellan S aerosol (containing 19% N,N-diethyl-m-toluamide (DEET)) (59580).
• Muscle cramps. Although there has been interest in using oral cassia cinnamon for muscle cramps, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Nausea and vomiting. Although there has been interest in using oral cassia cinnamon for nausea and vomiting, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose.
• Obesity. It is unclear if oral cassia cinnamon is beneficial for weight loss. Details: A meta-analysis of 7 clinical studies shows that cassia cinnamon reduces body mass index (BMI) when compared with placebo (111692). However, preliminary clinical research in a small number of patients with overweight or obesity and impaired glucose tolerance shows that taking two capsules of a specific combination product (Glycabiane, PiLeJe) containing cassia cinnamon extract 228 mg, chromium chloride 10 mcg, and carnosine 100 mg per capsule, daily for 4 months does not decrease body weight, BMI, fat mass, or lipid levels when compared with placebo (94234). A very small clinical study in healthy adults shows that drinking a single dose of cinnamon infusion containing 2 grams of powdered cinnamon served along with breakfast does not increase energy expenditure, diet-induced thermogenesis, respiratory quotient, or lipid and carbohydrate oxidation and does not affect appetite responses including hunger, fullness, desire to eat, macronutrient intake, and food intake throughout the day when compared with control. Furthermore, cassia cinnamon intake reduces feelings of satiety and increases energy intake in the first meal after the intervention when compared with control (111707). The validity of these findings is limited by a lack of blinding.
• Polycystic ovary syndrome (PCOS). It is unclear if oral cassia cinnamon is beneficial for patients with PCOS. Details: A small observational study in adults with PCOS suggests that taking cinnamon 500 mg three times daily for 8 weeks is associated with decreased body weight, body mass index, insulin resistance, and testosterone but does not appear to alter levels of luteinizing hormone, follicle-stimulating hormone, dehydroepiandrosterone (DHEA), insulin, or lipids when compared with placebo (113514).
• Stroke. It is unclear if oral cassia cinnamon is beneficial for stroke prevention. Details: Preliminary clinical research in patients with a mild ischemic stroke or transient ischemic attack shows that taking cinnamon (Chinese herbal formula granules, Guangdong Yifang Pharmaceutical Co, Ltd) 5 grams with aspirin 100 mg daily for 90 days, starting within 24 hours of the ischemia, reduces the percentage of patients with a recurrent stroke to 3%, compared with 15% of those taking aspirin plus placebo. There were also modest improvements in levels of plasma lipids, glucose, and glycated hemoglobin, as well as a reduced likelihood of identifying unstable or severe plaques on carotid ultrasound (108265). The use of cassia cinnamon, specifically, was not confirmed; however, this species of cinnamon is commonly used in traditional Chinese medicine, as indicated in the study.
• Urinary incontinence. Although there has been interest in using oral cassia cinnamon for urinary incontinence, there is insufficient reliable information about the clinical effects of cassia cinnamon for this purpose. More evidence is needed to rate cassia cinnamon for these uses.

(Read more about CASSIA CINNAMON)

POSSIBLY EFFECTIVE

• Ventilator-associated pneumonia (VAP). Clove mouthwash might reduce the risk of acquiring pneumonia in patients on mechanical ventilation. Details: A large clinical trial in adults in the intensive care unit on mechanical ventilation shows that administration of a clove extract 6.66% mouthwash, 15 mL twice daily for 5 days, results in a 2-fold lower incidence of ventilator-associated pneumonia when compared with chlorhexidine mouthwash (112151).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alveolar osteitis. Although there has been interest in using topical clove for alveolar osteitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Anal fissures. It is unclear if topical clove oil is beneficial in patients with anal fissures. Details: Preliminary clinical research in patients with chronic anal fissures shows that applying clove oil 1% cream for 6 weeks heals fissures in 60% of patients by the 3-month follow-up, compared with only 12% of patients who used topical lidocaine 5% cream and stool softeners (43487).
• Cough. Although there has been interest in using oral clove for cough, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dental plaque. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that using a specific toothpaste (Sudantha, Link Natural Products Ltd.) containing a combination of clove, Acacia chundra Willd., malabar nut, bullet wood tree, black pepper, Indian beech, gall oak, Terminalia, and ginger twice daily for 12 weeks can reduce dental plaque, bleeding, and bacteria counts in the mouth when compared with placebo (43570). Other clinical research shows that administration of a mouth rinse containing clove, tea tree oil, and basil 10 mL twice daily for 21 days is as effective as a commercially available mouth rinse containing thymol, eucalyptol, menthol, and methyl salicylate in reducing dental plaque and gum inflammation (92160). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Diarrhea. Although there has been interest in using oral clove for diarrhea, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Dyspepsia. Although there has been interest in using oral clove for dyspepsia, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Flatulence. Although there has been interest in using oral clove for flatulence, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Gingivitis. Although there has been interest in using topical clove for gingivitis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Halitosis. Although there has been interest in using oral clove for halitosis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Hangover. It is unclear if oral clove flower extract is beneficial for reducing hangover severity. Details: Preliminary clinical research in a very small number of healthy males with a history of hangovers shows that taking a clove flower bud polyphenol extract 250 mg prior to drinking brandy (42.8% alcohol) decreases hangover severity scores by around 55% when compared with placebo (100597).
• Hyperhidrosis. It is unclear if topical clove oil is beneficial in patients with hyperhidrosis. Details: Preliminary clinical research in patients with hyperhidrosis of the palms shows that topical application of clove oil 45% in liposome base twice daily for 2 weeks improves hyperhidrosis severity and decreases the rate of sweating by around 34% when compared with a saline control (100596). The validity of these findings is limited by a lack of subject randomization.
• Impaired glucose tolerance (prediabetes). It is unclear if oral clove flower extract is beneficial in patients with prediabetes. Details: Preliminary clinical research in a very small number of patients with prediabetes shows that taking a polyphenolic extract from clove flower buds 250 mg daily for 30 days decreases pre-prandial plasma glucose by 14 mg/dL and postprandial plasma glucose by 40 mg/dL when compared to baseline (100595). The validity of these findings is limited by the very small size of the study and the lack of a control group.
• Mosquito repellent. Small clinical studies suggest that topical clove oil may repel mosquitos for up to 4-5 hours. Details: Preliminary clinical research shows that topical application of undiluted clove oil can repel 100% of mosquitoes for up to 4 hours (43427). Other preliminary research shows that topical application of gel containing clove oil 20% can repel 86% to 97% of mosquitoes for 5 hours (43411).
• Nausea and vomiting. Although there has been interest in using oral clove for nausea and vomiting, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Oral mucositis. Although there has been interest in using topical clove for oral mucositis, there is insufficient reliable information about the clinical effects of clove for this purpose.
• Pain (acute). It is unclear if topical clove is beneficial in patients with acute pain. Details: Preliminary clinical research shows that topical application of a gel containing ground cloves, applied as 4 grams of gel for 5 minutes prior to dental anesthesia injection, can reduce needle stick pain when compared with placebo. The effect of the clove gel on pain seems to be comparable to benzocaine 20% gel (43448).
• Premature ejaculation. Topical clove has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that administration of a multi-ingredient cream preparation (SS Cream) containing clove flower, Panax ginseng root, Angelica root, Cistanches deserticola, Zanthoxyl species, Torlidis seed, Asiasari root, cinnamon bark, and toad venom to the glans penis, one hour prior to intercourse and washed off immediately before intercourse, increases ejaculatory latency time by over 4-fold when compared with placebo in adults with premature ejaculation (2537). It is unclear whether clove, another ingredient, or a combination of these ingredients is responsible for these effects.
• Pruritus. There is limited evidence on the topical use of clove oil in patients with chronic pruritus. Details: Preliminary clinical research in patients with chronic pruritus shows that applying clove oil 10% in petroleum jelly to the skin twice daily for 2 weeks reduces the daily duration of itching by 48 minutes and improves symptom severity and disability scores when compared with placebo (96950). More evidence is needed to rate clove for these uses.

(Read more about CLOVE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Obesity. Oral cola nut has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in overweight and obese adults shows that taking cola nut 1500 mg daily for 3 months, in combination with ephedra and willow bark, modestly increases weight loss (12811). Other preliminary clinical research shows that taking an herbal treatment containing ephedra and cola nut for 6 months reduces body weight by 2.7 kg and body fat by 1.6 kg when compared with placebo in overweight and obese individuals (8647). Ephedra is banned in the US due to the risk for severe adverse effects (10055). More evidence is needed to rate cola nut for this use.

(Read more about COLA NUT)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Obesity. A small clinical study in overweight adults shows that taking a combination product containing damiana, guarana, and yerba mate for 45 days increases weight loss when compared with placebo (11866). It is not clear if this effect is due to damiana, other ingredients, or the combination.
• Sexual dysfunction. Preliminary clinical research shows that taking a specific combination product containing damiana, L-arginine, Panax ginseng, ginkgo, vitamins, and minerals (ArginMax for Women, Daily Wellness Co.) improves sexual satisfaction and desire, increases orgasm frequency, and reduces vaginal dryness when compared with placebo in women interested in improving their sexual function (46933). It is not clear if these effects are due to damiana, other ingredients, or the combination. More evidence is needed to rate damiana for these uses.

(Read more about DAMIANA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dysmenorrhea. In patients with dysmenorrhea, preliminary clinical research shows that taking a palm sap-sweetened herbal decoction 180 mL made with a combination of mace 3 grams and Cassia fistula 21 grams for 3 days starting just before expected menstruation and repeating for two menstrual cycles reduces pain by a large amount and the duration of pain by a small amount when compared with the same three days of the menstrual cycle at baseline. In addition, it was as effective as taking mefenamic acid 500 mg twice daily for 3 days starting on the first day of menstruation. When the average 3-day pain was compared, the decoction was slightly more effective than mefenamic acid (103376). It is unclear if these are effects are due to mace, Cassia fistula, or the combination.
• Urinary incontinence. In women with mixed urinary incontinence of at least 2 months duration, preliminary clinical research shows that taking mace powder 1.5 grams twice daily for 3 months, in addition to doing pelvic floor muscle training, has a large benefit on severity of symptoms when compared with those using pelvic floor training alone (103377). More evidence is needed to rate mace for these uses.

(Read more about MACE)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Dental caries. It is unclear if topical nutmeg is beneficial in children with dental caries. Details: A small clinical study in children aged 6-9 years shows that use of a nutmeg 2% extract gel as pulpotomy for a primary molar is as effective as formocresol for preventing pain, swelling, and root problems for 12 months (103371).
• Diarrhea. Although there has been interest in using oral nutmeg for diarrhea, there is insufficient reliable information about the clinical effects of nutmeg for this purpose.
• Halitosis. It is unclear if nutmeg is beneficial for halitosis. Details: A small clinical study in patients in India with plaque and plaque-induced halitosis shows that rinsing with 10 mL of a mouthwash containing nutmeg 2%, olive oil, menthol, orange oil, and other ingredients twice daily for 3 weeks reduces plaque and halitosis scores when compared to baseline, but not when compared with chlorhexidine gluconate 0.2% (111749). More evidence is needed to rate nutmeg for these uses.

(Read more about NUTMEG)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Cancer. Although there has been interest in using oral sarsaparilla for cancer, there is insufficient reliable information about the clinical effects of sarsaparilla for this purpose.
• Psoriasis. Although there has been interest in using oral sarsaparilla for psoriasis, there is insufficient reliable information about the clinical effects of sarsaparilla for this purpose.
• Rheumatoid arthritis (RA). Although there has been interest in using oral sarsaparilla for RA, there is insufficient reliable information about the clinical effects of sarsaparilla for this purpose. More evidence is needed to rate sarsaparilla for these uses.

(Read more about SARSAPARILLA)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Antidepressant-induced sexual dysfunction. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for patients with antidepressant-induced sexual dysfunction. Details: Small clinical trials suggest that taking yohimbine, a constituent of yohimbe, improves sexual dysfunction associated with selective serotonin reuptake inhibitors (SSRIs) (3305,3306,3307,3311,3313,3970,3971,3972,3973). It is unclear if yohimbe bark is beneficial.
• Anxiety. There is limited evidence on the oral use of yohimbine, a constituent of yohimbe, for the management of various phobias. Details: A small clinical study in healthy adults with a fear of flying shows that taking yohimbine hydrochloride 10 mg as an adjunct to virtual reality exposure therapy (VRET) does not improve anxiety measures when compared with VRET alone (86819). However, another small clinical study in healthy adults with claustrophobia shows that taking yohimbine hydrochloride 10.8 mg prior to exposure-based treatment reduces peak fear after one week when compared with exposure-based treatment alone (86794). The effect of yohimbe bark has not been investigated in clinical research.
• Athletic performance. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for athletic performance. Details: A small clinical study in professional soccer players shows that taking yohimbine, a constituent of yohimbe, 20 mg daily for 3 weeks does not improve exercise performance or build muscle mass when compared with placebo (86785). However, a small crossover study in physically active females undergoing an anaerobic exercise test shows that taking a single dose of oral yohimbine 2.5 mg 20 minutes prior to repeated sprints increases average power output, total work, and heart rate and decreases average fatigue index when compared with placebo. Additionally, taking yohimbine decreases lactic acid levels and increases epinephrine levels when compared with baseline or placebo (107849). Due to the single-dose nature of this study, the effects of continued administration of yohimbine on athletic performance are unclear. The effects of yohimbe bark have not been investigated in clinical research.
• Depression. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial in patients with depression. Details: A very small clinical study in patients with treatment-resistant major depressive disorder shows that taking yohimbine, a constituent of yohimbe, 30 mg daily for 10 days along with desipramine does not improve symptoms of depression when compared with desipramine alone (86834). Also, a small crossover trial in patients with major depressive disorder and/or a history of adverse childhood experiences shows that taking yohimbine 10 mg once does not alter approach-avoidance behaviors normally associated with depression when compared with placebo (111402). The effects of yohimbe bark have not been investigated in clinical research.
• Dry mouth. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for dry mouth. Details: A very small clinical study shows that taking yohimbine, a constituent of yohimbe bark, 18 mg daily for 5 days improves symptoms of dry mouth in individuals treated with antidepressants when compared with placebo (86886). The effect of yohimbe bark has not been investigated in clinical research.
• Erectile dysfunction (ED). It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial for ED. Details: The effects of yohimbe bark have not been investigated in clinical research. Most small clinical studies suggest that taking yohimbine, a constituent in yohimbe bark, seems to improve symptoms in adults with various types of ED, including organic, psychogenic, mixed, and others (3305,3307,3309,3311,3312,3313,10629,86827,86831,86878)(86882,86888,86896). A meta-analysis in patients with ED shows that taking 5-100 mg of oral yohimbine for 2-10 weeks increases the probability of erectile function improvement when compared with placebo. Also, the use of yohimbine in combination with either L-arginine or trazodone, but not as monotherapy, improves sexual function when compared with placebo (107848). These findings are limited by the high heterogeneity of the included studies. Due to insufficient data, guidelines from the American Urological Association do not recommend yohimbine as a treatment option for ED (86881).
• Fatigue. Although there is interest in using oral yohimbe for fatigue, there is insufficient reliable information about the clinical effects of yohimbe for this purpose.
• Obesity. Although there is interest in using oral yohimbe for obesity, there is insufficient reliable information about the clinical effects of yohimbe for this condition.
• Orthostatic hypotension. It is unclear if oral yohimbine, a constituent of yohimbe, is beneficial in patients with orthostatic hypotension. Details: Some preliminary clinical research shows that taking a single dose of yohimbine 5.4 mg increases systolic blood pressure and standing diastolic blood pressure in patients with orthostatic hypotension when compared with placebo or pyridostigmine (86811,86890). However, other preliminary clinical research shows that taking yohimbine does not improve blood pressure in patients with orthostatic hypotension due to autonomic failure when compared with placebo (86821). The effect of yohimbe bark has not been investigated in clinical research. More evidence is needed to rate yohimbe for these uses.

(Read more about YOHIMBE)

LIKELY SAFE ...when consumed in amounts commonly found in foods. Cassia cinnamon has Generally Recognized As Safe (GRAS) status in the US for use as a spice or flavoring agent (4912) ...when used orally and appropriately, short-term. Cassia cinnamon 1-2 grams daily has been used safely for up to 3 months (17011,21914). Cassia cinnamon 3-6 grams daily has been used safely for up to 6 weeks (11347,14344). Cassia cinnamon extract corresponding to 3 grams daily of cassia cinnamon powder has also been used safely for up to 4 months (21916).

POSSIBLY SAFE ...when used topically, short-term. Cassia cinnamon oil 5% cream applied topically to the legs has been used safely in one clinical trial (59580).

POSSIBLY UNSAFE ...when used orally in high doses, long-term. Some cassia cinnamon products contain high levels of coumarin. Coumarin can cause hepatotoxicity in animal models (15299,21920). In humans, very high doses of coumarin from 50-7000 mg daily can result in hepatotoxicity that resolves when coumarin use is discontinued (15302). In most cases, ingestion of cassia cinnamon will not provide a high enough amount of coumarin to cause significant toxicity; however, in especially sensitive people, such as those with liver disease, prolonged ingestion of large amounts of cassia cinnamon might exacerbate the condition.

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. Cassia cinnamon 1 gram daily has been used safely in adolescents 13-18 years of age for up to 3 months (89648).

PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods (4912). There is insufficient reliable information available about the safety of cassia cinnamon when used in medicinal amounts during pregnancy and breast-feeding. Stay on the safe side and stick to food amounts.

(Read more about CASSIA CINNAMON)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912).

POSSIBLY SAFE ...when clove oil is applied topically (272). A clove oil 1% cream has been applied to the anus with apparent safety for up to 6 weeks (43487). A liposome-based product containing clove oil 45% has been applied to the palms with apparent safety for up to 2 weeks (100596).

LIKELY UNSAFE ...when clove smoke is inhaled. Smoking clove cigarettes can cause respiratory injury (17,43599). ...when clove oil is injected intravenously. This can cause pulmonary edema, hypoxemia, and acute dyspnea (16384). There is insufficient reliable information available about the safety of using clove orally in medicinal amounts.

CHILDREN: LIKELY UNSAFE
when clove oil is taken orally. Ingesting 5-10 mL of undiluted clove oil has been linked to reports of coagulopathy, liver damage, and other serious side effects in infants and children up to 3 years of age (6,17,43385,43395,43419,43457,43652).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally in amounts found in foods (4912). Clove, clove oil, and eugenol have Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of using clove in medicinal amounts during pregnancy and lactation; avoid using.

(Read more about CLOVE)

LIKELY SAFE ...when used in amounts commonly found in foods. Cola nut extract has Generally Recognized As Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately, short-term. Cola nut has been used with apparent safety for up to 12 weeks (12811).

POSSIBLY UNSAFE ...when used orally, long-term, or in large amounts. Chewing cola nut is associated with an increased risk of mouth cancer and gastrointestinal cancer (11963). Cola nut also contains caffeine. Chronic use of caffeine, especially in large amounts, can sometimes produce tolerance, habituation, and psychological dependence (3719). Acute use of high doses, typically above 400 mg daily, has been associated with significant adverse effects such as tachyarrhythmia and sleep disturbances (11832). Abrupt discontinuance of caffeine can cause physical withdrawal symptoms (11733). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cola nut, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

PREGNANCY: POSSIBLY SAFE
when used orally in amounts found in foods. Due to the caffeine content of cola nut, pregnant patients should closely monitor their intake to ensure moderate consumption. Fetal blood concentrations of caffeine approximate maternal concentrations (4260). The use of caffeine during pregnancy is controversial; however, moderate consumption has not been associated with clinically important adverse fetal effects (2708,2709,2710,2711,9606,11733,16014,16015). In some studies, consuming amounts over 200 mg daily is associated with a significantly increased risk of miscarriage (16014). This increased risk may be most likely to occur in those with genotypes that confer a slow rate of caffeine metabolism (98806). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, most healthy pregnant patients can safely consume caffeine in doses up to 300 mg daily without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). Advise keeping caffeine consumption below 300 mg daily. This is similar to the amount of caffeine in about 3 cups of coffee or tea. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cola nut, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

PREGNANCY: POSSIBLY UNSAFE
when caffeine, a constituent of cola nut, is used orally in amounts over 300 mg daily. Caffeine crosses the placenta, producing fetal blood concentrations similar to maternal levels (4260). Advise keeping caffeine consumption from all sources below 300 mg daily (2708). High doses of caffeine throughout pregnancy have resulted in symptoms of caffeine withdrawal in newborn infants (9891). High doses of caffeine have also been associated with spontaneous abortion, premature delivery, and low birth weight (2709,2711,91033,91048,95949). Keep in mind that only the amount of added caffeine must be stated on product labels. The amount of caffeine found in ingredients such as cola nut, which naturally contains caffeine, does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product. In a study that included 2 large cohorts of mother/infant pairs, the first cohort with a median maternal plasma caffeine level of 168.5 ng/mL (range 29.5-650.5 ng/mL) during pregnancy, suggests birth weights and lengths were lower in the 4th quartile of caffeine intake compared with the 1st. By age 7, heights and weights were lower by 1.5 cm and 1.1 kg, respectively. In the second cohort of mother/infant pairs with higher maternal pregnancy plasma caffeine levels, median 625.5 ng/mL (range 86.2 to 1994.7 ng/mL), heights at age 8 were 2.2 cm lower, but there was no difference in weights (109846).

LACTATION: POSSIBLY SAFE
when used orally in amounts found in foods. Due to the caffeine content of cola nut, caffeine intake should be closely monitored while nursing. Breast milk concentrations of caffeine are thought to be approximately 50% of maternal serum concentrations. Minimal consumption would likely result in limited exposure to a nursing infant (9892).

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Consumption of cola nut might cause sleep disturbances, irritability, and increased bowel activity in nursing infants due to its caffeine content (6026). Large doses or excessive intake of cola nut should be avoided during lactation. It is unknown whether potentially carcinogenic constituents of cola nut are transferred via breast milk.

(Read more about COLA NUT)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Damiana has Generally Recognized As Safe status (GRAS) for use in foods in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts (12,46933,11866).

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

(Read more about DAMIANA)

LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. Mace is commonly used as a spice. Mace and mace oil have Generally Recognized as Safe (GRAS) status in the US (4912).

POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Mace powder in doses of up to 1.5 grams twice daily has been used with apparent safety for up to 3 months (103377). There is insufficient reliable information available about the safety of larger doses of mace. However, severe cardiovascular, gastrointestinal, neurologic, ocular, and psychiatric adverse events have been reported following high intake of the related herb nutmeg (19293,19492,25538). Theoretically, high doses of mace may have similar effects, although there have been no reported cases in humans. There is insufficient reliable information available about the safety of mace when used topically.

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Mace might have abortifacient activity, and its safrole content might be mutagenic (12).

LACTATION:
Insufficient reliable information available; avoid using.

(Read more about MACE)

LIKELY SAFE ...when used orally and appropriately in amounts commonly found in foods. Nutmeg is commonly used as a spice. Nutmeg and nutmeg oil have Generally Recognized as Safe (GRAS) status in the US (4912). There is insufficient reliable information available about the safety of nutmeg when used orally in larger doses, up to 120 mg daily. These doses have not been adequately evaluated in clinical research. However, doses at or above 120 mg daily have been associated with serious adverse effects (19292).

POSSIBLY UNSAFE ...when used orally in doses of 120 mg or greater. Chronic use of nutmeg in these doses has been associated with psychotic episodes and hallucinations (19292,19296,19487). Acute intoxication from nutmeg has been described in several case reports in which subjects ingested a single dose of 5-80 grams (2563,19297,19300,19491,111750). Symptoms of toxicity ranged from nausea, dry mouth, and dizziness to palpitations, agitation, and hallucinations (2563,3494,19293,19294,19295,19297,19298,19299,19489,19490)(19491,103373,111750). Two deaths involving nutmeg intoxication have also been reported (19300,112016) . Symptoms generally start 0.5-8 hours after ingestion and last up to 24-48 hours (19298,19488,19491,103372,103373). There is insufficient reliable information available about the safety of nutmeg when used topically.

PREGNANCY: LIKELY SAFE
when used orally and appropriately in amounts commonly found in foods.

PREGNANCY: POSSIBLY UNSAFE
when used orally in medicinal amounts. Nutmeg might have abortifacient activity, and its safrole content might be mutagenic (12).

LACTATION: LIKELY SAFE
when used orally and appropriately in amounts commonly found in foods. There is insufficient reliable information available about the safety of nutmeg when used in larger, medicinal amounts during lactation; avoid using.

(Read more about NUTMEG)

LIKELY SAFE ...when used orally in amounts commonly found in foods. Sarsaparilla has Generally Recognized As Safe (GRAS) status for use in foods in the US (4912). There is insufficient reliable information available about the safety of sarsaparilla when taken orally in medicinal amounts.

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

(Read more about SARSAPARILLA)

POSSIBLY UNSAFE ...when used orally. Yohimbine, a constituent of yohimbe, has been associated with serious adverse effects including cardiac arrhythmia, agitation, myocardial infarction, seizure, and others (17465). Some research shows that yohimbine can be safely used under close medical supervision for up to 10 weeks (3305,3307,3311,3313). However, due to safety concerns, yohimbe should not be used without medical supervision.

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally. Yohimbe might have uterine relaxant effects and also cause fetal toxicity (19).

(Read more about YOHIMBE)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cassia cinnamon may have additive effects with antidiabetes drugs.  Details Cassia cinnamon may lower blood glucose levels, and have additive effects in patients treated with antidiabetic agents (11347,17011,21914,21918,89649). Dose adjustments to diabetes medications might be necessary.

HEPATOTOXIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, large doses of cassia cinnamon might cause additive effects when used with hepatotoxic drugs.  Details There is some concern that ingesting large amounts of cassia cinnamon for an extended duration might cause hepatotoxicity in some people. Cassia cinnamon contains coumarin, which can cause hepatotoxicity in animal models (15299,21920). In humans, very high doses of coumarin from 50-7000 mg/day can result in hepatotoxicity that resolves when coumarin use is discontinued (15302,97249). Lower amounts might also cause liver problems in sensitive people, such as those with liver disease or those taking potentially hepatotoxic agents.

(Read more about CASSIA CINNAMON)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, clove oil may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Laboratory research suggests that eugenol, a constituent of clove, has antiplatelet activity (12889,43558,43650,43654). This interaction has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of clove extracts with antidiabetes drugs might increase the risk of hypoglycemia.  Details Clinical and laboratory research suggest that polyphenol extracts from clove flower buds might lower blood glucose levels (100595). Dosing adjustments for insulin or oral hypoglycemic agents may be necessary when taken with clove. Monitor blood glucose levels closely.

IBUPROFEN (Advil, others) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, topical application of clove oil with ibuprofen might increase the absorption and side effects of topical ibuprofen.  Details Laboratory research shows that topical application of clove oil increases the absorption of topical ibuprofen (98854). This interaction has not been reported in humans.

(Read more about CLOVE)

ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cola nut might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Cola nut contains caffeine. Caffeine is a competitive inhibitor of adenosine at the cellular level. However, caffeine does not seem to affect supplemental adenosine because high interstitial levels of adenosine overcome the antagonistic effects of caffeine (11771). It is recommended that methylxanthines and methylxanthine-containing products (including cola nut) be stopped 24 hours prior to pharmacological stress tests (11770). However, methylxanthines appear more likely to interfere with dipyridamole (Persantine) than adenosine-induced stress testing (11771).

ALCOHOL (Ethanol) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, alcohol might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Concomitant use of alcohol and caffeine can increase caffeine serum concentrations and the risk of caffeine adverse effects. Alcohol reduces caffeine metabolism (6370).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, cola nut may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Cola nut contains caffeine. Caffeine is reported to have antiplatelet activity (8028,8029). This interaction has not been reported in humans.

ANTIDIABETES DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = B Theoretically, taking cola nut with antidiabetes drugs might interfere with blood glucose control.  Details Cola nut contains caffeine. Some conflicting reports claim that caffeine might increase or decrease blood sugar (6024,8646).

BETA-ADRENERGIC AGONISTS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, the caffeine in cola nut might increase the clinical effects of beta-adrenergic agonists.  Details Cola nut contains caffeine. Theoretically, concomitant use of large amounts of caffeine might increase the cardiac inotropic effects of beta-agonists (15).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might reduce the effects of carbamazepine and increase the risk for convulsions.  Details Cola nut contains caffeine. Animal research suggests that taking caffeine can lower the anticonvulsant effects of carbamazepine and can induce seizures when taken in doses above 400 mg/kg (23559,23561). Human research has shown that taking caffeine 300 mg in three divided doses along with carbamazepine 200 mg reduces the bioavailability of carbamazepine by 32% and prolongs the plasma half-life of carbamazepine 2-fold in healthy individuals (23562).

CIMETIDINE (Tagamet) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, cimetidine might increase the effects and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Cimetidine decreases the rate of caffeine clearance by 31% to 42% (11736).

CLOZAPINE (Clozaril) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Theoretically, cola nut might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.  Details Cola nut contains caffeine. Caffeine can increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg daily inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Researchers speculate that caffeine might inhibit CYP1A2. However, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients more sensitive to the interaction between clozapine and caffeine (13741).

CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, contraceptive drugs might increase the effects and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Oral contraceptives can decrease the rate of caffeine clearance by 40% to 65% (2714,11737).

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP1A2 inhibitors might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Caffeine is metabolized by CYP1A2 (3941,5051,11741,23557,23573,23580,24958,24959,24960,24962), (24964,24965,24967,24968,24969,24971,38081,48603).

DIPYRIDAMOLE (Persantine) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, cola nut might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.  Details Cola nut contains caffeine. Caffeine may inhibit dipyridamole-induced vasodilation (11770,11772). It is recommended that methylxanthines and methylxanthine-containing products, such as cola nut, be stopped 24 hours prior to pharmacological stress tests (11770). Methylxanthines appear more likely to interfere with dipyridamole than with adenosine-induced stress testing (11771).

DISULFIRAM (Antabuse) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, disulfiram might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. In human research, disulfiram decreases the rate of caffeine clearance (11840).

DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, using cola nut with diuretic drugs might increase the risk of hypokalemia.  Details Cola nut contains caffeine. In excessive amounts, caffeine can reduce potassium levels due to stimulation of the sodium-potassium pump (23579,37905,37953,38003,38034). Certain diuretics can also lower potassium levels.

EPHEDRINE Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk for stimulant adverse effects.  Details Cola nut contains caffeine. There is evidence that using ephedrine with caffeine might increase the risk of serious life-threatening or debilitating adverse effects such as hypertension, myocardial infarction, stroke, seizures, and death (1275,6486,10307).

ESTROGENS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, estrogens might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Estrogen inhibits caffeine metabolism (2714).

ETHOSUXIMIDE (Zarontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might reduce the effects of ethosuximide and increase the risk for convulsions.  Details Cola nut contains caffeine. Animal research suggests that caffeine 92.4 mg/kg can decrease the anticonvulsant activity of ethosuximide (23560). However, this effect has not been reported in humans

FELBAMATE (Felbatol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might reduce the effects of felbamate and increase the risk for convulsions.  Details Cola nut contains caffeine. Animal research suggests that a high dose of caffeine 161.7 mg/kg can decreases the anticonvulsant activity of felbamate (23563). However, this effect has not been reported in humans.

FLUCONAZOLE (Diflucan) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, fluconazole might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Fluconazole decreases caffeine clearance by approximately 25% (11022).

FLUTAMIDE (Eulexin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might increase the levels and adverse effects of flutamide.  Details Cola nut contains caffeine. In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). This effect has not been reported in humans.

FLUVOXAMINE (Luvox) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = D Theoretically, fluvoxamine might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Fluvoxamine reduces caffeine metabolism (6370).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, abrupt cola nut withdrawal might increase the levels and adverse effects of lithium.  Details Cola nut contains caffeine. Abrupt caffeine withdrawal can increase serum lithium levels. There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (609,610).

METFORMIN (Glucophage) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, metformin might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Animal research suggests that metformin can reduce caffeine metabolism (23571).

METHOXSALEN (Oxsoralen) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, methoxsalen might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Methoxsalen can reduce caffeine metabolism (23572).

MEXILETINE (Mexitil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, mexiletine might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Mexiletine can decrease caffeine elimination by 50% (1260,11741).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the risk of a hypertensive crisis.  Details Cola nut contains caffeine. Caffeine has been shown to inhibit monoamine oxidase (MAO) A and B in laboratory studies (37724,37877,37912,38108). Concomitant intake of large amounts of caffeine with MAOIs might precipitate a hypertensive crisis (15). In a case report, a patient that consumed 10-12 cups of caffeinated coffee and took the MAOI tranylcypromine presented with severe hypertension (91086). Hypertension was resolved after the patient switched to drinking decaffeinated coffee.

NICOTINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase the risk of hypertension.  Details Cola nut contains caffeine. Concomitant use of caffeine and nicotine has been shown to have additive cardiovascular effects, including increased heart rate and blood pressure. Blood pressure was increased by 10.8/12.4 mmHg when the agents were used concomitantly (36549).

PENTOBARBITAL (Nembutal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, cola nut might decrease the effects of pentobarbital.  Details Cola nut contains caffeine. Theoretically, caffeine might negate the hypnotic effects of pentobarbital (13742).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might reduce the effects of phenobarbital and increase the risk for convulsions.  Details Cola nut contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of phenobarbital (23558,23559,23561). However, this effect has not been reported in humans.

PHENOTHIAZINES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, phenothiazines might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Phenothiazines can reduce the metabolism of caffeine by inhibiting cytochrome P450 1A2 (CYP1A2) (23573,23574).

PHENYLPROPANOLAMINE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Concomitant use of phenylpropanolamine and caffeine might cause an additive increase in blood pressure (11738). Phenylpropanolamine also seems to increase caffeine serum levels (13743).

PHENYTOIN (Dilantin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might reduce the effects of phenytoin and increase the risk for convulsions.  Details Cola nut contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of phenytoin (23559,23561). The effect does not seem to be related to the seizure threshold-lowering effects of caffeine. However, the exact mechanism of this interaction is unclear.

PIOGLITAZONE (Actos) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might increase the levels and clinical effects of pioglitazone.  Details Cola nut contains caffeine. Animal research suggests that caffeine can modestly increase the maximum concentration, area under the curve, and half-life of pioglitazone, and also reduce its clearance. This increased the antidiabetic effects of pioglitazone (108812). However, the exact mechanism of this interaction is unclear.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, quinolone antibiotics might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Quinolones (also called fluoroquinolones) can decrease caffeine clearance by inhibiting cytochrome P450 1A2 (CYP1A2) (606,607,608,23554,23555,23556).

RILUZOLE (Rilutek) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.  Details Cola nut contains caffeine. Caffeine and riluzole are both metabolized by cytochrome P450 1A2, and concomitant use might reduce metabolism of one or both agents (11739).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Theoretically, concomitant use might increase stimulant adverse effects.  Details Cola nut contains caffeine. Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects (11832).

TERBINAFINE (Lamisil) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = B Theoretically, terbinafine might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. Terbinafine decreases the rate of intravenous caffeine clearance by 19% (11740).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, cola nut might increase the levels and adverse effects of theophylline.  Details Cola nut contains caffeine. Large amounts of caffeine might inhibit theophylline metabolism (11741).

TIAGABINE (Gabitril) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might increase the levels and adverse effects of tiagabine.  Details Cola nut contains caffeine. Animal research suggests that chronic caffeine administration can increase the serum concentrations of tiagabine. However, concomitant use does not seem to reduce the antiepileptic effects of tiagabine (23561).

TICLOPIDINE (Ticlid) Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, ticlopidine might increase the levels and adverse effects of the caffeine in cola nut.  Details Cola nut contains caffeine. In vitro evidence suggests that ticlopidine can inhibit caffeine metabolism (23557). However, this effect has not been reported in humans.

VALPROATE Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, cola nut might reduce the effects of valproate and increase the risk for convulsions.  Details Cola nut contains caffeine. Animal research suggests that caffeine can decrease the anticonvulsant activity of valproate (23558,23559,23561,37882). However, this effect has not been reported in humans.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of both verapamil and caffeine.  Details Cola nut contains caffeine. Verapamil increases plasma caffeine concentrations by 25% (11741).

(Read more about COLA NUT)

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, damiana may lower blood glucose levels (4,25016). This might increase the risk of hypoglycemia in patients taking antidiabetes drugs.  Details Some antidiabetes drugs include glimepiride (Amaryl), glyburide (Diabeta, Glynase PresTabs, Micronase), insulin, metformin (Glucophage), pioglitazone (Actos), rosiglitazone (Avandia), and others.

(Read more about DAMIANA)

(Read more about MACE)

ANTICHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of nutmeg and anticholinergic drugs might decrease the effectiveness of either agent.  Details Animal research suggests that nutmeg extract can inhibit acetylcholinesterase and might increase acetylcholine levels (25549).

CHOLINERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of nutmeg with other cholinergic drugs might have additive effects and increase the risk of cholinergic side effects.  Details Animal research suggests that nutmeg extract can inhibit acetylcholinesterase and might increase acetylcholine levels (25549).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, nutmeg might increase the risk of additive sedation when taken with CNS depressants.  Details Animal studies suggest that nutmeg extracts and several volatile oils in nutmeg, such as methyleugenol, isoeugenol, safrole, myristicin, trimyristin, 1,8-cineole, and geranyl acetate, have sedative effects (2563,25544,25545,25547,25548). One animal study shows that petroleum ether extracts of nutmeg can potentiate the effects of pentobarbital or phenobarbital (25547). However, evidence from other animal research suggests that the nutmeg constituent myristicin can actually reduce sleeping time in rats pretreated with phenobarbital (3492,3493).

CYTOCHROME P450 1A1 (CYP1A1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, nutmeg might decrease the levels and clinical effects of drugs metabolized by CYP1A1.  Details Animal research suggests that intraperitoneal injections of myristicin, a constituent of nutmeg, can induce CYP1A1 (3493).

CYTOCHROME P450 1A2 (CYP1A2) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, nutmeg might decrease levels of drugs metabolized by CYP1A2.  Details Animal research suggests that intraperitoneal injections of myristicin, a constituent of nutmeg, can induce CYP1A2 (3493).

CYTOCHROME P450 2B1 (CYP2B1) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, nutmeg might decrease levels of drugs metabolized by CYP2B1.  Details Animal research suggests that intraperitoneal injections of myristicin, a constituent of nutmeg, can induce CYP2B1 (3493).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, nutmeg might increase or decrease the effects and adverse effects of phenobarbital.  Details Some animal research suggests that myristicin, a constituent of nutmeg, can reduce sleeping time in rats pretreated with phenobarbital (3492,3493). However, other animal research suggests that petroleum ether extract of nutmeg can potentiate the effects of phenobarbital (25547).

(Read more about NUTMEG)

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of sarsaparilla with digoxin might increase the risk of cardiac toxicity.  Details Sarsaparilla is thought to have diuretic properties, which could potentially cause potassium loss. Overuse or misuse of sarsaparilla with cardiac glycoside therapy might increase the risk of cardiac toxicity due to potassium loss (2,11).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, sarsaparilla might increase the effects and adverse effects of lithium.  Details Sarsaparilla is thought to have diuretic properties (11). Due to these effects, sarsaparilla might reduce excretion and increase levels of lithium. The dose of lithium might need to be decreased.

(Read more about SARSAPARILLA)

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, combining yohimbe bark with antiplatelet or anticoagulant drugs might have additive effects; however, this has not been reported in clinical research.  Details Research in healthy adults shows that taking yohimbine, a constituent of yohimbe bark, in doses of 8 mg or more, seems to inhibit platelet aggregation in vitro by binding to the alpha-2 adrenoceptor (86773,86806,86835,86853). The effects of yohimbe bark itself are unclear; yohimbe bark contains 0.6% to 1.38% yohimbine, but it is unclear how much is absorbed (86862,89263).

ANTIHYPERTENSIVE DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, yohimbe might reduce the effects of antihypertensive drugs.  Details Yohimbine, a constituent of yohimbe, is an alpha-2 adrenoceptor antagonist and has been reported to increase blood pressure in clinical research. Theoretically, concomitant use of yohimbe and antihypertensive drugs can interfere with blood pressure control (11,17465).

CLONIDINE (Catapres) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might precipitate clonidine withdrawal.  Details Chronic clonidine use can downregulate alpha-2 adrenoreceptors. Animal research and one human case report suggest that concomitant administration of yohimbine, an alpha-2 adrenoceptor antagonist, may precipitate clonidine withdrawal and lead to sympathomimetic toxicity, including hypertensive crisis (111406).

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

CYTOCHROME P450 2D6 (CYP2D6) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP2D6 inhibitors might increase the levels and adverse effects of yohimbine, a constituent of yohimbe.  Details In vitro and clinical research shows that the yohimbe bark constituent, yohimbine, is metabolized by CYP2D6 isoenzymes (105688,105697,105698).

CYTOCHROME P450 2D6 (CYP2D6) SUBSTRATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might increase the levels and adverse effects of CYP2D6 substrates.  Details In vitro research suggests that yohimbine, a constituent of yohimbe bark, inhibits CYP2D6 enzyme activity (23117).

CYTOCHROME P450 3A4 (CYP3A4) INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, CYP3A4 inhibitors might increase the levels and adverse effects of yohimbine, a constituent of yohimbe bark.  Details In vitro and clinical research shows that the yohimbe bark constituent, yohimbine, is metabolized by CYP3A4 enzymes (105688,105698). Theoretically, drugs that inhibit CYP3A4 might increase the levels and adverse effects of yohimbine.

CYTOCHROME P450 3A4 (CYP3A4) SUBSTRATES Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, yohimbe might decrease the levels and clinical effects of CYP3A4 substrates.  Details In vitro research shows that yohimbe extract induces CYP3A4 enzymes (111404).

MONOAMINE OXIDASE INHIBITORS (MAOIs) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Likely •  Level of Evidence = D Concomitant use of MAOIs with yohimbe can result in additive effects.  Details Yohimbine, a constituent of yohimbe, has MAO inhibitory effects. At high doses, yohimbine is a non-selective inhibitor of MAO (11,12).

PHENOTHIAZINES Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, using yohimbine with phenothiazines might have additive effects.  Details Yohimbine, a constituent of yohimbe, has alpha-2 adrenergic antagonist effects. Theoretically, combining it with phenothiazines can cause additive alpha-2 adrenergic antagonism (19).

STIMULANT DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking yohimbe with stimulant drugs can have additive effects.  Details Yohimbine, a constituent of yohimbe, has sympathomimetic effects and increases blood pressure in a dose-dependent manner. Theoretically, taking yohimbe with stimulant drugs can have additive stimulant and hypertensive effects (11,12,105698).

TRICYCLIC ANTIDEPRESSANTS (TCAs) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking yohimbe with TCAs can increase adverse effects.  Details A small clinical study in patients taking TCAs for at least 4 weeks shows that receiving doses of intravenous yohimbine 2.5-20 mg daily for up to 7 days precipitates severe anxiety, agitation, and tremor (105881). The effects of yohimbe bark itself are unclear; oral yohimbe bark contains 0.6% to 1.38% yohimbine, but it is unclear how much is absorbed (86862,89263).

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General ...Orally, cassia cinnamon appears to be well-tolerated. Significant side effects have not been reported in most patients.
Most Common Adverse Effects:
Topically: Burning mouth, stomatitis.

Dermatologic ...In one clinical trial, a rash was reported in one patient taking cassia cinnamon 1 gram daily for 90 days (17011).
In one case, a 58-year-old female with a documented allergy to topically applied cinnamic alcohol presented with eyelid dermatitis, which was found to be a manifestation of systemic contact dermatitis to cinnamon in the diet. Symptoms improved in two days and completely cleared five days after discontinuing the addition of cinnamon to food products (95599). In other case reports, two adults presented with allergic contact cheilitis following the ingestion of chai tea with cinnamon and yogurt with cinnamon. Cinnamon components were confirmed as the causative allergic agents with patch tests, and both cases of allergic contact cheilitis completely resolved upon cessation of the cinnamon-containing products (113516,113515).
Topically, allergic skin reactions and stomatitis from toothpaste flavored with cassia cinnamon have been reported (11915,11920). Intraoral allergic reactions with symptoms of tenderness and burning sensations of the oral mucosa have also been reported in patients using breath fresheners, toothpaste, mouthwash, candy, or chewing gum containing cinnamon, cinnamic aldehyde or cinnamic alcohol as flavoring agents. Glossodynia, or burning mouth syndrome, has also been reported in a 62-year-old female who ate apples dipped in cinnamon nightly (95598), and allergic contact dermatitis has been reported in a teenage female using a homemade cinnamon sugar face scrub (95596).

Endocrine ...In one clinical trial, a hypoglycemic seizure was reported in one patient taking cassia cinnamon 1 gram daily for 3 months. The event occurred one day after enrolling in the study (89648). It is unclear if cassia cinnamon caused this event.

Hepatic ...There is some concern about the safety of ingesting large amounts of cassia cinnamon for extended durations due to its coumarin content. Coumarin can cause hepatotoxicity in animal models (15299). In humans, very high doses of coumarin from 50-7000 mg/day can result in hepatotoxicity that resolves when coumarin is discontinued (15302). In clinical trials, taking cassia cinnamon 360 mg to 12 grams daily for 3 months did not significantly increase levels of aspartate transaminase (AST) or alanine transaminase (ALT) (21918,96280,108259). However, in one case report, acute hepatitis with elevated AST and ALT occurred in a 73-year-old female who started taking a cinnamon supplement (dose unknown) one week prior to admission. The cinnamon supplement was added on to high-dose rosuvastatin, which may have led to additive adverse hepatic effects. After discontinuing both products, liver function returned to normal, and the patient was able to restart rosuvastati without further complications (97249). In most cases, ingestion of cassia cinnamon won't provide a high enough amount of coumarin to cause significant toxicity; however, in especially sensitive people, such as those with liver disease or taking potentially hepatotoxic agents, prolonged ingestion of large amounts of cassia cinnamon might exacerbate the condition.

Immunologic ...An unspecified allergic reaction was reported in one patient taking cassia cinnamon 1 gram daily for 3 months (89648).

(Read more about CASSIA CINNAMON)

General ...Orally, clove is well tolerated when consumed as a spice; however, clove oil in doses of only 5-10 mL can be toxic in children. Topically, clove is generally well tolerated. When inhaled or used intravenously, clove may be unsafe.
Most Common Adverse Effects:
Topically: Burning, contact dermatitis, dental decay, itching, mucous membrane irritation, tingling, ulcers.
Inhaled: Dental decay, hypertension, itching, tachycardia.
Serious Adverse Effects (Rare):
Orally: Liver failure, respiratory distress.
Inhaled: Pneumonitis, pulmonary edema, respiratory distress.

Cardiovascular ...Smoking clove cigarettes increases heart rate and systolic blood pressure (12892).

Dental ...Population research has found that the risk of dental decay is increased in clove cigarette smokers (43332). Repeated topical application of clove in the mouth can cause gingival damage and skin and mucous membrane irritation (4,272,512). Eugenol, a constituent of clove and a material commonly found in dentistry, has been associated with side effects including gum inflammation and irritation (43365,43373,43522).

Dermatologic ...The American Dental Association has accepted clove for professional use, but not nonprescription use, due to potential damage to soft tissue that may be induced by clove application. In clinical research, small aphthous-like ulcers appeared in the area of the mouth where clove gel was applied in four participants (43448). Skin irritation and stinging have been reported with clove oil application (43338,43626). In a 24-year-old, exposure to a clove oil spill resulted in permanent local anesthesia and anhidrosis, or lack of sweating, at the affected area (43626).

Endocrine ...A case of hypoglycemia and metabolic acidosis have been reported after administration of one teaspoon of clove oil to a seven-month-old infant (43457). A case of electrolyte imbalance following accidental ingestion by a seven-month-old has also been reported (6).

Hematologic ...A case of disseminated intravascular coagulation has been reported in a 2-year-old patient after consuming between 5-10 mL of clove oil. The patient was treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III. On the fifth day, the patient started to improve and made a full recovery (43652).

Hepatic ...There are three cases of hepatic failure occurring in children after ingestion of 5-10 mL of clove oil (43395,43419,43652). Liver injury also occurred in a 3-year-old male (96949). These patients were successfully treated with N-acetylcysteine. The course of liver injury seems to be milder and shorter with early N-acetylcysteine treatment (43395,43419,96949). Another patient, who also presented with disseminated intravascular coagulation, was successfully treated with heparin, fresh frozen plasma, protein C, factor VII, and antithrombin III (43652).

Immunologic ...Contact dermatitis and urticaria has been reported following topical exposure to clove oil or eugenol, a constituent of clove oil (12635,43339,43606,43346).

Neurologic/CNS ...CNS depression has been reported in a 7-month-old who was given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457). A case of confusion and inability to speak has been reported secondary to oral exposure to clove oil and alcohol. The patient required intubation and was successfully treated with thiamine and normal saline (43580). Seizure and coma have been reported in a two-year-old male after ingesting 5-10 mL of clove oil (43652).

Pulmonary/Respiratory ...Clove cigarettes have been associated with throat and chest tightness (43337), pulmonary edema (43618), and fatal aspiration pneumonitis (43599). The causative factor may be clove alone or clove along with other substances found in cigarettes. Clove cigarettes contain significant amounts of nicotine, tar, and carbon monoxide and increase plasma levels of nicotine and exhaled carbon monoxide, which might cause long-term health effects similar to tobacco smoking (12892). According to the American Medical Association, inhaling clove cigarette smoke has been associated with severe lung injury in a few susceptible individuals with prodromal respiratory infection. Also, some individuals with normal respiratory tracts have apparently suffered aspiration pneumonitis as the result of a diminished gag reflex induced by a local anesthetic action of eugenol, which is volatilized into the smoke (43602).
Intravenous injection of clove oil in a 32-year-old female resulted in hypoxia, acute dyspnea, interstitial and alveolar infiltrates, and non-cardiogenic pulmonary edema. The patient was managed with supplemental oxygen and recovered over the next seven days (16384).
Occupational exposure to eugenol, a constituent of clove, has also been reported to cause asthma and rhinitis (43492).

Renal ...Proteinuria and other urinary abnormalities were observed in a seven-month-old infant given one teaspoon of clove oil accidentally in place of mineral oil for diarrhea. The patient was successfully treated with supportive care and gastric lavage (43457).

(Read more about CLOVE)

General ...Orally, cola nut is well tolerated when eaten in the amounts found in food. It seems to be well tolerated when used medicinally and appropriately, short-term. However, the caffeine found in cola nut may cause adverse effects when taken in large amounts.
Most Common Adverse Effects:
Orally: Dyspepsia, skin discoloration.
Serious Adverse Effects (Rare):
Orally: Increased risk of oral cancer, gastrointestinal cancer, and West African crystalline retinopathy with long-term use.

Cardiovascular ...Orally, acute administration of caffeine can cause increased blood pressure. However, regular consumption of caffeine does not seem to increase either blood pressure or pulse, even in mildly hypertensive patients (1451,1452,2722). Epidemiological research suggests there is no association of caffeine consumption with incidence of hypertension (38190). Habitual coffee consumption also doesn't seem to be related to hypertension, but habitual consumption of sugared or diet cola is associated with development of hypertension (13739).
Epidemiological research has also found that regular caffeine intake of up to 400 mg daily is not associated with an increased incidence of atrial fibrillation (38018,38076,91028,91034,97451,97453), atherosclerosis (38033), cardiac ectopy (91127), stroke (37804), ventricular arrhythmia (95948,97453), or cardiovascular disease in general (37805,98806).

Dermatologic ...Orally, chewing cola nut has been reported to cause bright yellow skin pigmentation (57680).

Endocrine ...Some evidence shows that caffeine, which is found in cola nut, is associated with fibrocystic breast disease, breast cancer, and endometriosis; however, this is controversial since findings are conflicting (8043). Restricting caffeine in people with fibrocystic breast conditions doesn't seem to affect breast nodularity, swelling, or pain (8996). Also, a population analysis of the Women's Health Initiative observational study has found no association between consumption of caffeine-containing beverages and the incidence of invasive breast cancer in models adjusted for demographic, lifestyle, and reproductive factors (108806). Also, a dose-response analysis of two low-quality observational studies has found that high consumption of caffeine is not associated with an increased risk of breast cancer (108807).
Clinical research in healthy adults shows that increased consumption of caffeine results in increased insulin resistance (91023).

Gastrointestinal ...Orally, cola nut may induce gastric acid secretion and cause dyspepsia and peptic ulceration (57672,57674,57683). The caffeine found in cola nut may cause feeding intolerance and gastrointestinal irritation in infants (6023).

Genitourinary ...Orally, the caffeine in cola nut may increase voiding, give a sense of urgency, and irritate the bladder (37874,37961,104580). In males with lower urinary tract symptoms, caffeine intake increased the risk of interstitial cystitis/painful bladder syndrome (38115).

Immunologic ...Cola nut contains caffeine. Caffeine can cause anaphylaxis in sensitive individuals, although true IgE-mediated caffeine allergy seems to be relatively rare (11315).

Musculoskeletal ...Cola nut contains caffeine. Epidemiological evidence regarding the relationship between caffeine use and the risk for osteoporosis is contradictory. Caffeine can increase urinary excretion of calcium (2669,10202,11317). Females identified with a genetic variant of the vitamin D receptor appear to be at an increased risk for the detrimental effect of caffeine on bone mass (2669). However, moderate caffeine intake of less than 400 mg daily does not seem to significantly increase osteoporosis risk in most postmenopausal adults with normal calcium intake (2669,6025,10202,11317,98806).

Neurologic/CNS ...Orally, cola nut may prolong sleep latencies and suppress REM and 3rd and 4th stages of sleep (57697). Cola nut has also been reported to cause insomnia in children (10755) and may exacerbate sleep disturbances in patients with acquired immunodeficiency syndrome (AIDS) (10204). Caffeine, a constituent of cola nut, can cause headaches, anxiety, jitteriness, restlessness, and nervousness (36466,37694,37755,37806,37865,37830,37889,38223,95952).

Ocular/Otic ...Orally, cola nut has been associated with an increased risk for West African crystalline retinopathy in one retrospective, observational case series (57667).
Cola nut contains caffeine. In individuals with glaucoma, caffeine intake has been found to increase intraocular pressure. This did not occur in patients without glaucoma (36462,36464,36465,37670). The magnitude of this effect seems to depend on individual tolerance to caffeine. Some research in healthy young adults shows that caffeine increases intraocular pressure to a greater degree in low-consumers of caffeine (i.e., 1 cup of coffee or less daily) when compared to high-consumers (i.e., those consuming 2 cups of coffee or more daily) (100371). The peak increase of intraocular pressure seems to occur at about 1.5 hours after caffeine ingestion, and there is no notable effect 4 hours after ingestion (36462,100371).

Oncologic ...Orally, chewing cola nut has been associated with an increased risk of oral and gastrointestinal cancer. Cola nut contains high amounts of tannins and N-nitroso compounds, which are carcinogenic. The risk may be even higher in smokers (11963).

Psychiatric ...Cola nut contains caffeine. Caffeine may lead to habituation and physical dependence with amounts as low as 100 mg daily (36353,36355). Higher doses of caffeine have caused nervousness, agitation, anxiety, irritability, delirium, depression, sleep disturbances, impaired attention, psychosis, and panic attacks (36505,37717,37818,37839,37857,37982,38004,38017,38028,38072). Abrupt discontinuation of caffeine may result in physical withdrawal symptoms, including headache, fatigue, drowsiness, decreased physical energy, difficulty concentrating, depression, anxiety, irritability, and reduced alertness (13738).

(Read more about COLA NUT)

General ...Orally, damiana is generally well tolerated. In a rare case, 200 grams of damiana extract has caused tetanus-like convulsions and paroxysms resulting in symptoms similar to rabies or strychnine poisoning (4).

Neurologic/CNS ...Orally, 200 grams of damiana extract has caused tetanus-like convulsions and paroxysms resulting in symptoms similar to rabies or strychnine poisoning (4).

(Read more about DAMIANA)

General ...Orally, mace seems to be well tolerated when consumed in appropriate amounts. No adverse effects have been reported, although a thorough evaluation of safety outcomes has not been conducted. However, severe cardiovascular, gastrointestinal, neurologic, ocular, and psychiatric adverse events have been reported following high intake of the related herb nutmeg (19293,19492). Theoretically, high doses of mace may have similar effects, although there have been no reported cases in humans.
Topically, contact and systemic contact-type dermatitis to mace has occurred in rare cases (39898).

Cardiovascular ...There are no reports of adverse cardiovascular events due to ingestion of mace. However, mace contains myristicin, which is structurally similar to certain hallucinogenic chemicals. High intake of nutmeg, a related herb, has been associated with non-specific electrocardiographic changes, tachycardia, palpitations, weak pulse, hypotension, chest pain, and flushing (12,19293,19300,25547,25943). Theoretically, high intake of mace may have similar effects.

Dermatologic ...Topically, contact and systemic contact-type dermatitis to mace has occurred in rare cases (39898).

Gastrointestinal ...There are no reports of adverse gastrointestinal events due to ingestion of mace. However, mace contains myristicin, which is structurally similar to certain hallucinogenic chemicals. High intake of nutmeg, a similar spice, has been reported to cause nausea and vomiting, epigastric pain, and gastroenteritis (2563,19294,19300). Theoretically, high intake of mace may have similar effects.

Immunologic ...In a case report, inhalation of mace induced an immediate asthmatic reaction (46245).

Musculoskeletal ...There are no reports of adverse musculoskeletal events due to ingestion of mace. However, mace contains myristicin, which is structurally similar to certain hallucinogenic chemicals. High intake of nutmeg, a similar herb, has been reported to cause involuntary eye movement (nystagmus), muscle weakness, numbness, and ataxia (2563). Theoretically, high intake of mace may have similar effects.

Neurologic/CNS ...There are no reports of adverse neurologic or central nervous system (CNS)-related events due to ingestion of mace. However, mace contains myristicin, which is structurally similar to certain hallucinogenic chemicals. High intake of nutmeg, a similar herb, has been reported to cause headache, dizziness, drowsiness, hot and cold sensations, sensations of limb loss, convulsions, and coma (2563,19294,19300,19487). Theoretically, high intake of mace may have similar effects.

Ocular/Otic ...There are no reports of adverse ocular events due to ingestion of mace. However, mace contains myristicin, which is structurally similar to certain hallucinogenic chemicals. High intake of nutmeg, a similar herb, has been reported to cause blurred vision, double and triple vision, and pupil dilation or constriction (2563,25948). Theoretically, high intake of mace may have similar effects.

Psychiatric ...There are no reports of adverse psychiatric events due to ingestion of mace. However, mace contains myristicin, which is structurally similar to certain hallucinogenic chemicals. High intake of nutmeg, a similar herb, has been reported to cause mild to intense visual hallucinations, auditory hallucinations, feelings of impending doom, euphoria, anxiety, disorientation, stupor, agitation, insomnia, and restlessness (12,2563,19300,19489,19492). Theoretically, high intake of mace may have similar effects.

(Read more about MACE)

General ...Orally, nutmeg is generally well tolerated when used as a spice in foods. Acute or chronic use of nutmeg at high doses is unsafe.
Most Common Adverse Effects:
Topically: Allergic contact dermatitis in sensitive individuals.
Serious Adverse Effects (Rare):
Orally: Accidental or intentional overdose with nutmeg has been associated with several serious adverse cardiovascular, gastrointestinal, neurological, and psychiatric events. Death due to overdose has also been reported.

Cardiovascular ...Orally, in cases of nutmeg overdose, tachycardia, palpitations, weak pulse, hypotension, and nonspecific electrocardiographic changes have been reported (3494,19293,19295,19299,19300,19488,19489,25943,103372,103373)(111750).

Dermatologic ...Topically, allergic contact dermatitis to nutmeg has been reported (25945,25946).

Gastrointestinal ...Orally, nausea was reported in a 13-year-old female consuming nutmeg capsules while smoking cannabis (2563). Vomiting was reported in a case of a 19-year-old female using high doses of nutmeg with a history of lysergic acid diethylamide (LSD) and cannabis use (19294). Burning epigastric pain, gastroenteritis, diarrhea, nausea, and increased thirst have been reported in other cases of intentional or unintentional nutmeg overdose (19293,19299,19300,19489,19490,103372,103373). Vomiting has been reported in a 17-year-old male who snorted at least 15 grams of nutmeg powder (103372).

Hematologic ...Orally, hyponatremia and leukocytosis with neutrophilia associated with nutmeg overdose have been rarely reported (103372).

Hepatic ...Orally, elevated liver enzymes associated with nutmeg overdose have been reported rarely (103372).

Immunologic ...Topically, allergic contact dermatitis to nutmeg has been reported (25945,25946).

Musculoskeletal ...Orally, muscle weakness, numbness, and ataxia were reported in a 13-year-old female consuming nutmeg capsules while smoking cannabis (2563). An ataxic gait has been reported in a 17-year-old male who snorted at least 15 grams of nutmeg powder (103372).

Neurologic/CNS ...Orally, headache, dizziness, and drowsiness were reported in a 13-year-old female consuming nutmeg capsules while smoking cannabis (2563). Adverse effects associated with high intake of nutmeg have included confusion, dizziness, drowsiness, hallucinations, headache, incoherent speech, hot and cold sensations, sensations of limb loss, convulsions, and coma (19294,19299,19300,19487,19489,19490,103372,103373,111750). Sweating and hypothermia have also been reported following intake of high doses of nutmeg (19293,19294). Lethargy has been reported in a 17-year-old male who snorted at least 15 grams of nutmeg powder (103372).

Ocular/Otic ...Orally, a case of double, triple, and blurred vision has been reported for a 13-year-old female who consumed nutmeg capsules while smoking cannabis (2563). Pupil dilation and pupil constriction has been reported from exposure to nutmeg (25948). Involuntary eye movement has been reported in a 17-year-old male who snorted at least 15 grams of nutmeg powder (103372).

Psychiatric ...Orally, visual, auditory, and tactile hallucinations, depression, suicidal ideation, insomnia, restlessness, and bizarre behavior have been reported following nutmeg intoxication in various reports (12,2563,19300,19492,103372,103373). Other adverse effects associated with high intake of nutmeg have included disorientation, stupor, euphoria, anxiety, and agitation (19300,19489,103373,103374). Chronic psychosis has been associated with rare cases of prolonged abuse of nutmeg (103372). However, some researchers suggest that nutmeg does not have significant psychological or behavioral effects, even when taken at high doses (25939,25947). Restlessness and anxiety have been reported in a 17-year-old male who snorted at least 15 grams of nutmeg powder (103372).

Other ...Orally, fatal poisoning associated with nutmeg is rare (19300,103372,103373).

(Read more about NUTMEG)

General ...Orally, sarsaparilla seems to be well tolerated.

Gastrointestinal ...Orally, there is some concern that sarsaparilla may cause GI irritation when used in large amounts (11,18). However, these claims cannot be substantiated.

Pulmonary/Respiratory ...Occupational exposure to sarsaparilla root dust can cause rhinitis and asthma symptoms (4111).

Renal ...Orally, there is some concern that sarsaparilla may cause temporary kidney impairment and diuresis, possibly leading to shock, when used in large amounts (11,18). However, these claims cannot be substantiated.

(Read more about SARSAPARILLA)

General ...Orally, there is limited information available about the adverse effects of yohimbe. Yohimbine, a constituent of yohimbe, might be unsafe; most reported adverse effects are dose-related.
Most Common Adverse Effects:
Orally: Yohimbine, a constituent of yohimbe, has been associated with anxiety, agitation, diaphoresis, diarrhea, flushing, headache, hypertension, increased urination, nausea, tachycardia, tremors, vertigo, and vomiting.
Serious Adverse Effects (Rare):
Orally: Yohimbine, a constituent of yohimbe, has been associated with atrial fibrillation, hypertensive crisis, myocardial infarction, and QT interval prolongation.

Cardiovascular ...Orally, yohimbine, a constituent of yohimbe, has been associated with hypertension, especially at higher doses (3312,17465,86801,86802,86804,86811,86820,86822,86834,86856)(86786,86896). A case of hypertensive crisis was reported in a 63-year-old male taking a yohimbine-containing herbal product once daily for one month. The patient was successfully managed with intravenous nitroprusside followed by clonidine (91521). Tachycardia, fluid retention, palpitations, and chest discomfort have also been reported (3312,17465,86786,86793,86801,86802,86804,86822,86843,86854)(86856,86866,86867,86869,86871,86874,86875). Conduction abnormalities have also been reported (86856,86786). There have been some reports of myocardial infarction, atrial fibrillation, and QT interval prolongation (17465). In theory, these effects may also occur with the use of yohimbe bark extract.

Dermatologic ...Orally, yohimbine, a constituent of yohimbe, may cause rash, erythrodermic skin eruption, and exanthema (3312,3971,86804,86896,86878).

Gastrointestinal ...Orally, yohimbine, a constituent of yohimbe, may cause nausea, vomiting, increased salivation, diarrhea, and gastrointestinal distress (3970,17465,49902,86780,86781,86786,86801,86804,86824,86827)(86828,86829,86863,86878,86882,86896).

Genitourinary ...Orally, yohimbine may cause dartos contraction or decreased libido in some patients (86786,86882). A case of severe intractable priapism has been reported for a 42-year-old male who took a supplement containing yohimbe extract the previous day for sexual enhancement. Treatment with phenylephrine 400 mcg was unsuccessful at resolving the priapism, so surgical insertion of a proximal cavernosal spongiosum shunt was needed (86804).

Hematologic ...A case of drug-induced agranulocytosis has been reported following prolonged use of oral yohimbine, a constituent of yohimbe (86877).

Immunologic ...There is one report of a hypersensitivity reaction including fever; chills; malaise; itchy, scaly skin; progressive renal failure; and lupus-like syndrome associated with ingestion of a one-day dose of yohimbine, a constituent of yohimbe (6169).

Musculoskeletal ...Orally, yohimbine, a constituent of yohimbe, may cause muscle aches (86850).

Neurologic/CNS ...Orally, yohimbine, a constituent of yohimbe, has been associated with reports of general central nervous system (CNS) and autonomic excitation, tremulousness, head twitching, seizure threshold changes, enhanced brain norepinephrine release, decreased energy, dizziness, vertigo, and headache (3312,3971,86774,86779,86786,86804,86827,86857,86870,86882)(86883). Cold feet and chills have also been reported with yohimbine (86827,86896). Other adverse reactions include flushing and diaphoresis (17465). Excessive doses of yohimbine can also cause paralysis (11,18). A case of acute neurotoxicity characterized by malaise, vomiting, loss of consciousness, and seizures has been reported for a 37-year-old bodybuilder who ingested a single dose of yohimbine 5 grams. Improvement was seen within 12 hours following treatment with furosemide, labetalol, clonidine, urapidil, and gastrointestinal decontamination (86801).

Psychiatric ...Orally, yohimbine, a constituent of yohimbe, may increase malaise, fatigue, insomnia, restlessness, agitation, and anxiety (3312,3970,3971,17465,86786,86801,86804,86822,86827,86834)(86868,86878,86882,86896). In a clinical study of healthy subjects, administration of yohimbine increased impulsivity, with larger doses increasing impulsivity more than 50% (86784,86810).

Pulmonary/Respiratory ...Orally, yohimbine, a constituent of yohimbe, may cause bronchospasm, tachypnea, cough, and rhinorrhea (17465,86825,86850). A case of sinusitis characterized by pain and discomfort above both eyes has been reported for a 59-year-old male taking yohimbine 5.4 mg three times daily to treat erectile dysfunction. Symptoms resolved within 24 hours of discontinuing yohimbine. The effect was attributed to the alpha-2 adrenergic antagonist effects of yohimbine (94112). Excessive doses of yohimbine can cause respiratory depression (1118).

Renal ...Orally, yohimbine, a constituent of yohimbe, may increase urinary frequency (3312,3970,3971,17465,86804,86827,86850,86861,86882). A case of acute renal failure has been reported for a 42-year-old male taking yohimbine. Normalization of renal function was achieved following 2 weeks of treatment with corticosteroids. The renal dysfunction was attributed to yohimbine-induced systemic lupus erythematosus (6169).

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