DREN by MHP (Maximum Human Performance)

POSSIBLY EFFECTIVE

• Depression. Oral 5-HTP seems to improve symptoms of depression. Details: A meta-analysis of preliminary clinical research shows that taking 5-HTP for up to 8 weeks might improve symptoms of depression in some patients. The pooled remission rate across 13 studies was 65%, and the pooled effect size across 7 studies assessing the change in depressive symptom scores from baseline was large (102854). In most studies, the dose of 5-HTP administered ranged from 150-800 mg daily, although doses as high as 3 grams daily have been used (903,30000,30125,30138,102854). Some research has compared 5-HTP to conventional antidepressants. In one clinical trial of adults experiencing a first episode of depression, taking 5-HTP orally, titrated up to a daily dose of 400 mg, decreased depression symptoms similarly to fluoxetine titrated up to 40 mg daily (30112). Limited research also suggests that taking 5-HTP 300-800 mg daily seems to work similarly to fluvoxamine 50 mg (2203) or imipramine 150 mg daily (30125). Adding 5-HTP 300 mg orally daily to clomipramine 50 mg daily for 28 days has also been shown to reduce depressive symptoms when compared with clomipramine alone (6245).

POSSIBLY INEFFECTIVE

• Down syndrome. Oral 5-HTP does not seem to improve muscle tone or cognitive skills in patients with this condition. Details: Although early reports suggested that 5-HTP might improve muscle tone and activity levels in infants with Down syndrome (88172), other research has shown no benefit. One small clinical study suggests that taking 5-HTP 0.5-5 mg/kg daily orally from early infancy until 3-4 years of age does not improve muscle tone or developmental ability scores in children with Down syndrome when compared with a control group (88173). Also, a prospective, double-blind study shows that taking 5-HTP 1-2 mg/kg daily orally, alone or with pyridoxine 5-10 mg/kg daily orally, beginning at birth and continuing until 3 years of age, does not improve muscle tone or development of cognitive, social, or language skills when compared with placebo (30153).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a food supplement containing 5-HTP 5 mg, phenylalanine 300 mg, and glutamine 150 mg daily for 40 days during alcohol detoxification therapy reduces withdrawal symptoms when compared with alcohol detoxification therapy alone (30100). However, taking a combination of 5-HTP 25-100 mg with carbidopa 25 mg four times daily for one year does not seem to improve alcohol abstinence rates when compared with placebo (30007). The effect of 5-HTP alone is unclear.
• Alzheimer disease. Although there has been interest in using oral 5-HTP for Alzheimer disease, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Anxiety. It is unclear if oral 5-HTP is beneficial in patients with anxiety disorders. Details: A small clinical study in people with anxiety disorders shows that taking 5-HTP 25-150 mg daily with carbidopa 150 mg daily for 8 weeks reduces anxiety when compared with baseline, but not when compared with clomipramine 25-150 mg daily (30124).
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral 5-HTP for ADHD, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Cerebellar ataxia. It is unclear if oral 5-HTP reduces cerebellar ataxia symptoms. Details: One small clinical trial in people with cerebellar ataxia of various etiologies shows taking 5-HTP orally 10 mg/kg daily for 4 months improve quantitative ataxia scores when compared with placebo. Further improvement was noted in subjects continuing treatment for another 8 months (916). However, in a subsequent trial in this population, taking 5-HTP orally 1 gram daily for 10 months did not improve symptom scores when compared with placebo (30164). Also, a small clinical study in people with Friedreich's ataxia shows that taking 5-HTP 200-300 mg daily for 1 month, then 600-900 mg daily for 5 months (depending on body weight), does not improve symptoms when compared with placebo (30165).
• Fibromyalgia. Small clinical studies suggest that oral 5-HTP may improve symptoms of primary fibromyalgia syndrome. Details: Small clinical studies in people with primary fibromyalgia syndrome suggest that taking 5-HTP 100 mg orally three times daily for 30-90 days might improve pain, tenderness, sleep, anxiety, fatigue, and morning stiffness when compared with baseline or placebo (913,10286).
• Inflammatory bowel disease (IBD). It is unclear if oral 5-HTP is beneficial for IBD. Details: Preliminary clinical research in adults with stable IBD and fatigue shows that taking a specific 5-HTP (Levotonine, Panpharma) 100 mg orally twice daily for 8 weeks does not improve fatigue scores when compared with placebo. However, the validity of this study is limited by high patient drop-out (111311).
• Menopausal symptoms. It is unclear if oral 5-HTP is beneficial for symptoms of menopause. Details: A small clinical study in postmenopausal patients shows that taking 5-HTP orally 50 mg three times daily for 4 weeks does not reduce hot flash frequency when compared with placebo (30061).
• Migraine headache. It is unclear if oral 5-HTP reduces frequency of migraines. Details: Preliminary clinical research shows that taking 5-HTP 600 mg daily decreases migraine attack frequency similarly to methysergide 3 mg daily (30129). However, other small clinical studies show that taking 5-HTP 400 mg daily does not reduce the frequency or severity of migraine attacks when compared with placebo (30130,30184). Also, in children 6-12 years of age, one very small clinical study shows that taking 5-HTP 5 mg/kg daily in 3 divided doses for 12 weeks does not reduce the frequency or severity of migraine attacks when compared with placebo (30128).
• Obesity. It is unclear if oral 5-HTP is beneficial in for weight loss. Details: Some very small clinical studies show that taking 5-HTP orally, 300 mg three times daily 30 minutes before meals for 2-12 weeks, improves early satiety and decreases daily caloric intake in females with obesity when compared with placebo (914,30018). 5-HTP was also associated with a mean weight loss of 1.7 kg over 6 weeks when caloric intake was not restricted, and a mean weight loss of 3.3 kg over 6 weeks when caloric intake was restricted to about 1200 calories daily (914,30114). In moderately overweight adults with type 2 diabetes, taking 5-HTP 250 mg three times daily 30 minutes before meals for 2 weeks reduces caloric intake by about 22% and decreases body weight by about 2 kg when compared to baseline (30175).
• Obsessive-compulsive disorder (OCD). It is unclear if oral 5-HTP is beneficial in patients with OCD. Details: A small clinical study in patients with moderate to severe OCD shows that adding 5-HTP 200 mg orally daily to fluoxetine, titrated up to 60 mg daily, for 12 weeks reduces symptom severity when compared with placebo and fluoxetine. A complete response, defined as greater than or equal to 35% improvement in overall Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score, was seen in 54% of those taking 5-HTP at week 12, compared with only 12% of those taking placebo (104250). These results were not observed until week 12, which indicates that a longer treatment period may be needed to see the full effects of the intervention.
• Opioid withdrawal. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in Chinese males undergoing detoxification for heroin addiction shows that taking 5-HTP 200 mg orally daily for 6 days, in combination with tyrosine, phosphatidylcholine, and L-glutamine, might reduce insomnia and withdrawal symptoms and improve mood when compared with a control group (88178).
• Panic disorder. It is unclear if intravenous 5-HTP is beneficial for reducing anxiety in panic disorder. Details: A small clinical trial in females with panic disorders shows that receiving an intravenous (IV) infusion of 5-HTP, 60 mg over 30 minutes after premedication with carbidopa 100 mg orally, does not appear to reduce anxiety when compared with control (30093).
• Parkinson disease. It is unclear if oral 5-HTP is beneficial for improving Parkinson disease symptoms. Details: Two preliminary clinical trials show that taking 5-HTP 50 mg daily for 1 month seems to improve levodopa-induced dyskinesia and symptoms of depression, but not motor functioning or apathy, when compared with placebo in patients with Parkinson disease (102853,104251). Both studies used a crossover design to correct for the small sample size, but may still have been inadequately powered to detect small changes in these outcomes. However, in another study, taking larger doses of 5-HTP, 275-1500 mg orally daily along with carbidopa 150-1000 mg daily for up to 38 days, worsened rigidity, bradykinesia, and functional disability (30140). Other research has evaluated 5-HTP in patients with Parkinson disease and REM sleep behavior disorder (RBD). A small crossover study in these patients shows taking oral 5-HTP 50 mg daily for 4 weeks does not improve the percentage of REM sleep without atonia or the frequency of RBD events when compared with baseline or placebo. Patients taking 5-HTP report modest improvements in part II (motor function; e.g. swallowing, walking, and dressing) of the Unified Parkinson Disease Rating Scale (UPDRS), but not other parts of the UPDRS, when compared with placebo (107793). This study may have been inadequately powered to detect a difference between groups.
• Premenstrual syndrome (PMS). Although there is interest in using oral 5-HTP for PMS, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Seizures. Although there is interest in using oral 5-HTP for seizures, there is insufficient reliable information about the clinical effects of 5-HTP for this condition.
• Tension headache. It is unclear if oral 5-HTP reduces tension headache severity. Details: A small clinical study in adults with a history of chronic tension headaches suggests that taking 5-HTP 100 mg three times daily for 8 weeks does not reduce pain intensity or the number of days with headache when compared with placebo (2204).
• Tinnitus. Oral 5-HTP has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Research has evaluated a specific capsule formulation (Tinnitan Duo; Laboratorios Salvat) containing 5-HTP, ginkgo extract, magnesium, melatonin, pantothenic acid, vitamin B6, and zinc at undeclared doses. A small clinical trial in patients with subjective tinnitus shows taking this product as one capsule twice daily for 3 months improves Tinnitus Handicap Inventory (THI) total score and THI emotional subscale score at 3 months when compared with baseline. Patients also report improvement in tinnitus-related distress (107792). The validity of this study is limited by the lack of randomization and placebo-control; additionally, it is unclear if any effects are due to 5-HTP, other ingredients, or the combination. More evidence is needed to rate 5-HTP for these uses.

(Read more about 5-HTP)

EFFECTIVE

• Migraine headache. Oral caffeine in combination with acetaminophen, aspirin, and/or sumatriptan is approved by the US Food and Drug Administration (FDA) for treating migraine headache. Details: Taking caffeine 100-260 mg orally in combination with acetaminophen 500-2000 mg, aspirin 500 mg, and/or sumatriptan 50-100 mg is effective for treating migraine headache (2715,2716,2717,37614,37626,37816,91068). Some evidence shows that caffeine in combination with aspirin and acetaminophen may be more effective than sumatriptan in treating a migraine attack (37666). However, taking caffeine 200 mg plus ergotamine seems to be less effective than sumatriptan or calcium carbasalate plus metoclopramide (37685,38312). Caffeine is an FDA-approved product for use with analgesics for the treatment of migraine.
• Neonatal apnea. Oral or intravenous caffeine citrate is approved by the US Food and Drug Administration (FDA) for the short-term treatment of neonatal apnea in very preterm infants. Details: Using caffeine orally or intravenously improves apnea of prematurity in very preterm infants and reduces the risk of bronchopulmonary dysplasia, invasive mechanical ventilation, and neurodevelopmental impairment (6023,6371,37857,37906,38124,38344,98807,100364,114658). The dosage approved in the FDA labeling is a single loading dose of caffeine citrate 20 mg/kg (10 mg/kg caffeine base), followed by 5 mg/kg of caffeine citrate (2.5 mg/kg caffeine base) every 24 hours for maintenance. Clinical research shows that caffeine citrate dose-dependently reduces the number of apnea episodes by at least 50% over 7-10 days of treatment (6371). Most research suggests that doses above 10 mg/kg daily reduce the risk of apnea, bronchopulmonary dysplasia, and problematic extubation when compared with doses below 10 mg/kg/day (98807,100364,114658). Additional clinical research shows that reinitiating caffeine treatment after termination of the original caffeine regimen, and continuing until 40 weeks postmenstrual age, reduces the incidence of intermittent hypoxia in premature infants by 46% when compared to standard care (91073). At 18-21 months of age, a history of neonatal caffeine treatment reduces the risk of long-term complications of apnea of prematurity, such as cerebral palsy or cognitive delay (37722,38340). At 11 years of age, individuals born prematurely and treated with caffeine have improved visuomotor, visuoperceptual, and visuospatial abilities when compared to those who received placebo (97452). At 6-11 years of age, these individuals may also have a reduced risk of motor impairment (114658). Data on the prophylactic use of caffeine in very low birth-weight infants (less than 1500 grams and 32 weeks' gestation) are conflicting. In a meta-analysis of 11 studies, 5 show a reduced risk of apnea of prematurity, oxygen therapy, bronchopulmonary dysplasia, patent ductus arteriosus, and retinopathy of prematurity, and a reduced duration of mechanical ventilation (111491). However, other studies do not show any benefit (38125,111491). A study of infants born at 34-36 weeks' gestation shows that caffeine citrate, 10 or 20 mg/kg orally daily, reduces the number of intermittent hypoxemia episodes per hour by 61% and 67% respectively, when compared with placebo (111493). Caffeine and aminophylline have similar effectiveness for management of apnea, bradycardia, and hypoxemia, but caffeine has a wider range of safe plasma levels and lower rates of tachycardia and feeding intolerance (111492).
• Postoperative headache. Oral or intravenous caffeine is approved by the US Food and Drug Administration (FDA) for preventing headache in postoperative patients who regularly consume caffeinated products. Details: Clinical research shows that using caffeine is effective for preventing postoperative headache in patients who regularly consume caffeinated products. Intravenous caffeine does not seem to be effective in non-regular caffeine consumers. Studied doses have included 200 mg intravenously or oral doses calculated based on average daily consumption (2725,2726). Caffeine is an FDA-approved product for preventing headache in postoperative patients who regularly consume caffeinated products.
• Tension headache. Oral caffeine in combination with analgesics is approved by the US Food and Drug Administration (FDA) for treating tension headache. Details: Taking caffeine orally in combination with analgesics is effective for treating simple tension headache. Taking caffeine 100 mg alone is more effective at reducing tension headache pain when compared with placebo, but less effective than the combination of caffeine and analgesics. Caffeine 130 mg has been used with acetaminophen 1000 mg or with acetaminophen 500 mg and aspirin 500 mg. Caffeine 50 mg has been used with acetylsalicylic acid 250 mg and acetaminophen 200 mg (2718,11832,37668,37773).

LIKELY EFFECTIVE

• Athletic performance. Oral caffeine taken as a single dose of at least 2-3 mg/kg can modestly improve endurance, muscle strength, power output, and overall athletic performance when taken prior to certain forms of athletic activity or exercise. However, the magnitude and duration of effect is variable and may be dependent on the form and dose of caffeine, as well as various individual- and activity-specific factors. Caffeine intake in excess of 800 mg daily can result in blood levels greater than those allowed by the National Collegiate Athletic Association. Details: Clinical research and meta-analyses of clinical research show that taking caffeine 2-10 mg/kg modestly improves work produced, aerobic endurance, muscle strength and endurance, power output, and overall athletic performance (10203,11832,37648,37894,38054,38063,95955,100362,100365,100371)(103701,103703,108798,111250,114655,114657,114661,114673). According to the International Society of Sports Nutrition, the most consistent and measurable effects are seen in aerobic endurance; the minimal effective dose for any form of exercise is unclear, but benefits have been most consistent at doses of 3-6 mg/kg (114673). Meta-analyses of studies using caffeine 3-9 mg/kg as a single dose prior to endurance time trials report variability in results. Sports studied included running, rowing, cycling, swimming, and Nordic skiing, and included both recreational and trained athletes. Overall there was a small positive effect on time to exhaustion, endurance performance, and mean power output, and a decrease in the time needed to complete the trials when compared with placebo (98808,111497,114655). One meta-analysis of studies that evaluated cycling time trial performance found that doses of 4-6 mg/kg, but not doses of 1-3 mg/kg, improved performance (114655). A separate meta-analysis of 14 clinical studies shows that taking caffeine 2-11 mg/kg approximately 45-60 minutes before exercise improves muscle strength and endurance in the upper and lower body when compared with placebo. However, a sub-group analysis shows that muscle strength only improves with caffeine doses of at least 6 mg/kg (114657). Another meta-analysis of small clinical trials shows that the benefit of caffeine on athletic performance seems to increase with increased duration of activity. This suggests that caffeine can improve physical endurance during athletic activities (100371). In these trials, caffeine is typically provided as a single dose 30-150 minutes prior to testing (98808), although one study suggests that taking caffeine 60 minutes prior to peak activity has the most consistent ergogenic benefits (104577). Caffeine might improve performance in some athletic activities but not others. Some research shows that caffeine does not improve performance during athletic activities requiring a high amount of exertion over a short period of time. Such activities include sprinting and lifting (11832,37564,37758,37837,37841,37890,38319,95963,97459,112740). However, it is possible that the negative lifting studies were underpowered. Ballistic exercise, such as jumping or throwing, requires rapid increases in velocity, force, and muscle activation. A meta-analysis of 10 studies shows that caffeine in a range of doses (mean: 3 mg/kg) has a significant ergogenic effect on throwing performance and velocity (111488). A meta-analysis of small studies shows that caffeine modestly improves bench press repetitions and maximum strength, but not perceived exertion, when compared with placebo. Caffeine also tends to improve these parameters for leg presses, but the improvement does not reach significance when compared with placebo (103701). A meta-analysis of small clinical studies in female team-sport athletes shows that caffeine improves specific team-sport skills but has no effect on perceived exertion or agility tests performed after exertion (108799). Conversely, a small individual clinical study shows that taking caffeine 6.5 mg/kg 60 minutes before strength training decreases perceived exertion while increasing the number of repetitions of both upper and lower limb exercises by 17% to 33% over placebo (104581). Some clinical research also shows that taking caffeine can decrease subjective feelings of exertion and fatigue during exercise such as fencing and cycling (17618,37656,91026,91058,91062). Although some other clinical studies show that caffeine does not affect perceived exertion, caffeine does seem to improve performance and cause small increases in the amount of physical work done when compared with placebo in various athletes, including cyclists, runners, basketball players, and golfers (37702,37860,37872,38031,38119,38320,91037,91077,97457,97459)(104580,108800,108804). These effects do not seem to be dependent upon the dose of caffeine (97459), although some research shows that the timing of caffeine intake and exercise may alter overall benefit, with a greater effect seen in the morning compared to the evening (97457,104580). Most research has investigated the acute effects of a single dose of caffeine. The evidence is mixed as to whether chronic intake of caffeine could induce tolerance and reduce any acute ergogenic benefits (114673). One study shows that the consistent consumption of caffeine 3 mg/kg daily for 28 days eliminates the acute benefits of caffeine in work produced when compared with placebo, suggesting the development of tolerance (95955). However, chronic use of caffeine at a dose of 6 mg/kg for 4 days does not seem to induce tolerance to an acute dose of caffeine 6 mg/kg taken 60 minutes prior to a cycling time trial in males who are moderate to high users of caffeine (104576). Similarly, a small clinical study in trained individuals shows that acute supplementation with oral caffeine 6 mg/kg about 1 hour prior to performance improves strength and endurance when compared with placebo or control, regardless of habitual caffeine consumption (108804). Differences may be due to the type of exercise, the acute dose of caffeine, the length of the chronic intake period, and/or the normal caffeine intake of the athlete. Most studies suggest that there is significant inter-individual variability in response to caffeine for improvement of athletic performance (100365). These differences might be due, at least in part, to genotype (100370,114673), although research is conflicting. Caffeine is metabolized by the cytochrome P450 1A2 (CYP1A2) enzyme. One small clinical trial in resistance-trained males shows that taking caffeine 6 mg/kg improves resistance exercise performance in those homozygous for the CYP1A2 rs762551 polymorphism (AA) when compared with those without or heterozygous for that polymorphism (CC or A/C, respectively) (100370). However, another clinical study in trained male athletes shows that taking oral caffeine 4 mg/kg about 30 minutes prior to performance decreases handgrip strength by about 13% in individuals with the CC genotype when compared with placebo, but not in those with the AA or A/C genotypes. No groups experienced an improvement in vertical jump performance (108803). Another small clinical study suggests that CYP1A2 genotype does not affect exercise performance in athletes 60 minutes after taking caffeine 3 mg/kg. In addition, the ADORA2A genotype, which plays a role in caffeine sensitivity, does not seem to affect exercise performance benefits from caffeine (104578). However, these studies are small and used different performance protocols; further research is needed to clarify how these polymorphisms may impact the athletic performance benefits of caffeine (114673). Limited research has also evaluated the use of a caffeine mouth rinse, with mixed findings. Two very small clinical studies in healthy trained males shows that rinsing the mouth with 25 mL of water containing caffeine 85 or 300 mg for 5-10 seconds does not affect athletic performance or time to exhaustion while cycling when compared with placebo (103709,108801). However, another small study in healthy Taekwondo athletes fasting for Ramadan suggests that using a mouth rinse containing caffeine 6 mg/kg, ten seconds prior to exertion, modestly reduces perceived exertion and modestly improves kick performance when compared with using a placebo rinse (103710). Similarly, another small clinical study in healthy, resistance-trained males shows that rinsing the mouth with 25 mL of a solution containing caffeine 3%, but not 1% or 2%, reduces perceived exertion and increases muscular endurance, but not strength, when compared with placebo. The mouth rinse was used for 5 seconds immediately prior to a strength test or once per minute for 2 minutes during a muscular endurance test (108802). Preliminary clinical research has also investigated the use of caffeine in combination with other ingredients, such as sodium bicarbonate or creatine. However these studies have not demonstrated clear benefits in athletic performance over taking caffeine alone (112740,114673).
• Mental alertness. Oral caffeine increases mental alertness. However, it might not improve performance or accuracy to the same extent achieved through adequate sleep. Details: Consumption of caffeinated beverages or caffeine supplements seems to prevent a decline in alertness and cognitive capacity when consumed throughout the day (4221,4224,36439,37727,37757,37759,38070,38075,38158,91093)(91075). Caffeine appears to be especially effective in individuals that are not regular users (91074). Taking caffeine 100-600 mg can improve alertness and speed following prolonged sleep deprivation but usually does not affect mental performance or accuracy (10205,37716,37755,37806,37992,38007,38035,38139,91049,91072)(103706,112736). Drinking coffee containing caffeine 100 mg prior to a cognitive performance test improves reaction times in people with recent poor sleep quality, and in those with adequate sleep. However, the increase in vigilance occurring in the sleep-deprived people does not bring their performance up to the level seen with adequate sleep. Also, the number of errors made by sleep-deprived people seems to increase, suggesting that caffeine may have a detrimental effect on inhibitory control (98809). Caffeine also appears to reduce cognitive impairment caused by medications such as chlorpheniramine (91058). Combining caffeine with certain other supplements may improve mental performance. Taking caffeine 80 mg with taurine seems to provide a small improvement in mental performance (9899), although this effect is not observed in sleep deprived subjects (38154). Some clinical research shows that combining caffeine 40-75 mg with glucose 37.5 grams or L-theanine 97-100 mg improves mental performance better than placebo or either substance alone (13732,37762,37903,38116); however, other clinical research shows no additional benefit from combining L-theanine and caffeine (91045).

POSSIBLY EFFECTIVE

• Bronchopulmonary dysplasia. Intravenous caffeine may reduce the risk for bronchopulmonary dysplasia in preterm infants. Details: Population research has found that initiating caffeine treatment prior to the third day of life in premature infants is associated with a reduced risk of developing bronchopulmonary dysplasia compared to later initiation of treatment with caffeine. Additionally, a meta-analysis of available clinical research shows that high-dose caffeine (40-80 mg/kg loading dose, 20 mg/kg daily maintenance) lowers the risk of bronchopulmonary dysplasia when compared with standard dosing (20 mg/kg loading dose, followed by 5-10 mg/kg daily maintenance). However, small sample sizes and high heterogeneity limit the validity of these findings (97462,100364).
• Diabetes. Dietary caffeine seems to be beneficial for the prevention of type 2 diabetes; it is unclear if it is beneficial for the prevention of gestational diabetes. Also, it is unclear if oral caffeine is beneficial in patients with type 1 or type 2 diabetes. Details: Total caffeine consumption from beverages such as coffee or tea is associated with a lower risk of developing type 2 diabetes. This effect appears to be dose-dependent (11353,14313,37850,37871,91040,100368). For example, an increase of 200 mg daily caffeine intake seems to be associated with a 14% decrease in the incidence of type 2 diabetes (91055). Additionally, in North American males, consuming caffeine 417 mg daily from coffee or tea is associated with a 20% lower risk of developing type 2 diabetes when compared with those consuming less than 37 mg daily. North American females consuming at least 258 mg of caffeine daily from coffee or tea seem to have a 10% to 30% lower risk of developing type 2 diabetes when compared with those consuming less than 140 mg daily (11353). Japanese adults who consume at least 416 mg of caffeine daily from beverages including coffee or green tea seem to have a 33% lower risk of developing type 2 diabetes compared to those who consume no more than 57 mg daily. The risk reduction appears to be more pronounced in Japanese females when compared with males (14313). It is unclear if caffeine is beneficial in adults with diabetes. A few small studies show that caffeine consumption may further reduce insulin sensitivity in patients with type 2 diabetes, gestational diabetes, or those at risk for developing diabetes (13744,37653,37820). Caffeine consumption has also been evaluated during pregnancy. An observational study has found that self-reported consumption of beverages containing up to 100 mg of caffeine at 16-22 weeks' gestation is associated with a 47% lower risk of developing gestational diabetes when compared with no intake (108814). Research regarding the effects of caffeine in patients with type 1 diabetes shows conflicting results. One study shows that taking caffeine 250 mg twice daily for 2 weeks can reduce the incidence of elevated blood sugar at night in patients with type 1 diabetes (37660). However, another study in patients with type 1 diabetes shows that taking caffeine 200 mg daily for 3 months may increase the ability to perceive hypoglycemic symptoms when compared with placebo, although overall glycemic control does not seem to be affected (6024). A small clinical crossover study evaluated caffeine for the prevention of exercise-induced hypoglycemia in adults with type 1 diabetes using ultra-long-acting insulin. This study shows that consuming a beverage containing caffeine 250 mg, glucose 10 grams, and aspartame 30 minutes before a moderate intensity cycling exercise does not reduce the risk of exercise-related hypoglycemia, alter the time to hypoglycemia, or increase peak plasma glucose levels during exercise when compared with taking glucose and aspartame (114662).
• Memory. Oral caffeine seems to be beneficial for short-term memory recall in college students and extroverted personalities. It is unclear if oral caffeine is beneficial for introverted personalities or other populations. Details: Taking a single dose of caffeine 65-200 mg orally daily seems to improve memory function in some individuals such as college students and people with extroverted personalities. A small study shows that taking caffeine does not improve memory function in individuals with introverted personalities (37845,38071,91080).
• Obesity. Oral caffeine, when taken in combination with ephedrine or as a component of green tea, seems to be beneficial for weight loss, short-term. Details: Taking caffeine orally, in combination with ephedrine or as a component of green tea, seems to help reduce weight, short-term (695,696,1704,8647,16892,37617,37831). Caffeine 192 mg in combination with ephedra 20-90 mg per day for 6 months seems to cause a modest weight reduction (5.3 kg) in people with a body mass index (BMI) between 25-40 kg/m². This combination, along with limiting fat intake to 30% of calories and moderate exercise, also seems to reduce body fat, decrease low-density lipoprotein (LDL) cholesterol, and increase high-density lipoprotein (HDL) cholesterol. However, even in carefully screened and monitored otherwise healthy adults, caffeine/ephedra combinations can cause small changes in blood pressure and heart rate (8647). Preliminary clinical research also shows that taking 1000 mg of a proprietary combination product containing caffeine and multiple other ingredients (Prograde Metabolism) twice daily for 8 weeks in conjunction with dieting reduces body weight, fat mass, waist circumference, and hip circumference by 1.5%, 5%, 1.8%, and 1.3%, respectively, when compared with dieting alone (40802).
• Pain (acute). Oral caffeine, when taken in combination with acetaminophen, propyphenazone, ibuprofen, or other pain-relieving agents, seems to be beneficial for acute pain. Details: Clinical research shows that taking caffeine 50-130 mg in combination with acetaminophen, propyphenazone, ibuprofen, or other pain-relieving agents can reduce acute pain when compared with the effects of pain-relieving agents alone (37587,37904,38036,38303,91038). Adding ≥100 mg caffeine to treatment with acetaminophen or ibuprofen results in 5% to 10% more patients that achieve at least 50% of maximum pain relief for over 4 hours when compared to treatment with acetaminophen or ibuprofen alone (91038).
• Postdural puncture headache. Oral or intravenous caffeine seem to be beneficial for preventing postdural puncture headache. Details: Using caffeine 300 mg orally or 500 mg in 1,000 mL normal saline intravenously seems to help treat and prevent postdural puncture headache (2727,2728). Using a combination of ergotamine and caffeine seems to be less effective than gabapentin for treating this condition (38147). Lower doses of oral caffeine may not be beneficial. Clinical research shows that oral caffeine, 75-125 mg, does not decrease the risk of postdural headache (91022).

POSSIBLY INEFFECTIVE

• Atrial fibrillation. Oral caffeine does not seem to prevent atrial fibrillation after cardiopulmonary bypass. In addition, it might increase the risk of gastrointestinal side effects. Details: In adults undergoing surgery with cardiopulmonary bypass, taking caffeine 400 mg every 8 hours for 6 doses does not seem to reduce the risk of developing atrial fibrillation during the first three post-operative days. This clinical study was stopped prior to the completion of recruitment after an interim analysis showed increased incidence of postoperative nausea and vomiting, and no effect on the incidence of atrial fibrillation (97451).
• Attention deficit-hyperactivity disorder (ADHD). Oral caffeine does not seem to reduce symptoms of ADHD in children. Details: Most research suggests caffeine does not significantly reduce ADHD symptoms in children when used at tolerable doses (10755,10756,10757,10758,10759,10760). The use of caffeine in adolescents and adults with ADHD has not been studied.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral caffeine prevents cognitive decline with aging. Details: Population research from a small cohort of elderly females shows that caffeine intake of more than 371 mg daily is associated with an attenuation in cognitive decline when compared to less than 30 mg daily. This is equivalent to the difference seen over a 7 year span of age. Caffeinated coffee consumption, but not caffeinated chocolate, tea, or cola, was associated with this attenuation in cognitive decline (91088).
• Alzheimer disease. It is unclear if oral caffeine is beneficial for preventing dementia; the available research is conflicting. Details: Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 24% to 34% reduced risk of developing Alzheimer disease when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 41% increased risk of developing Alzheimer disease when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810).
• Asthma. Oral caffeine seems to modestly improve airway function for up to 4 hours in patients with mild to moderate asthma. However, it is unclear if oral caffeine has a clinically significant effect on asthma symptoms or quality of life. Details: Taking caffeine 9 mg/kg orally appears to modestly improve airway function for up to 4 hours in people with mild to moderate asthma (37907,37915). However, more research is needed to determine the appropriate dose, whether any benefit is clinically significant, or whether tolerance occurs with chronic dosing.
• Cancer pain. It is unclear if intravenous caffeine is beneficial for cancer pain. Details: Clinical research shows that receiving caffeine 200 mg intravenously once daily for 2 days results in a significant reduction in pain intensity by 0.833 points on the NRS scale when compared with control in patients receiving opioids for pain from advanced cancer (91081).
• Cognitive function. It is unclear if oral caffeine improves cognitive performance in trained athletes. Details: A meta-analysis of small studies in trained adult athletes shows that consumption of a low to moderate amount of caffeine 15-60 minutes prior to exercise and during exercise improves attention performance, but not reaction time or inhibitory control, when compared with placebo (108797). The validity of these findings is limited by unclear reporting.
• Dementia. It is unclear if oral caffeine is beneficial for preventing dementia or improving behavior in patients with dementia. Details: Population research from the Women's Health Initiative has found that caffeine intake of more than 175 mg daily is associated with a 26% reduced risk of developing probable dementia or global cognitive impairment when compared to less than 175 mg daily in postmenopausal adults 65-80 years of age (97458). Population research from the UK Biobank has found that caffeine intake up to 400 mg daily is associated with a 17% to 26% reduced risk for developing all-cause dementia when compared with lower intake. Conversely, population research from the Rush Memory and Aging Project in the US has found that caffeine intake of more than 100 mg daily is associated with a 35% increased risk of developing all-cause dementia when compared with lower intake. However, when those with mild cognitive impairment at baseline or cases diagnosed within 2 years of follow-up are excluded, these findings become insignificant (108810). Caffeine consumption has also been evaluated in patients with dementia. A cross-sectional study in patients with dementia in a care home has found that intake of 'normal' to 'high' amounts of caffeine are associated with reduced agitation and other behavioral symptoms when compared to 'low' intakes of caffeine (104574).
• Depression. It is unclear if oral caffeine is beneficial for depression prevention. Details: Some population research found that caffeine intake is associated with an increased incidence of depressive symptoms in pediatric patients (37839,38162). However, other population research found that caffeinated beverage intake is associated with a decreased incidence of depression in adults (37969,38165,91067,100366).
• Electroconvulsive therapy (ECT) augmentation. Although there has been interest in using intravenous caffeine sodium benzoate to augment electroconvulsive therapy, there is insufficient reliable information about the clinical effects of caffeine for this condition.
• Exercise-induced hypoxemia. It is unclear if oral caffeine is beneficial for hypoxemia associated with exercise. Details: Preliminary clinical research in athletes experiencing exercise-induced hypoxemia shows that taking caffeine 8 mg/kg can improve exercise ventilation, but not ventilatory response or oxygen saturation, when compared with placebo (37750).
• Exercise-induced muscle soreness. It is unclear if oral caffeine is beneficial for reducing muscle soreness during exercise. Details: There is conflicting clinical evidence as to whether caffeine can reduce exercise-induced muscle pain. Some evidence shows that taking caffeine 100 mg or 10 mg/kg can reduce muscle pain during exercise when compared with placebo (37622,38146). However, the effect of lower doses is unclear. Some evidence shows that taking caffeine 5 mg/kg may reduce exercise-induced muscle pain when compared with placebo (37747,91050), while other evidence suggests that taking caffeine 2-5 mg/kg does not affect muscle pain during exercise (38141).
• Gallbladder disease. It is unclear if increased dietary caffeine intake reduces the risk of developing gallstones. Details: Consumption of caffeinated beverages that provide 400 mg or greater of caffeine per day is associated with a significantly reduced risk of developing symptomatic gallstone disease (3345,8032). The effect seems to be dose-dependent; consumption of 800 mg caffeine per day has the greatest reduction in risk (3345).
• Hepatitis C. It is unclear if increased dietary caffeine reduces the risk for hepatitis C-associated severe liver inflammation, although it may reduce the risk of developing advanced fibrosis. Details: A meta-analysis of population research has found that regular consumption of caffeine at doses of at least 123 mg daily is associated with a 48% reduced risk of advanced liver fibrosis when compared to lower caffeine intake in patients with hepatitis C virus (95947). An individual population study also found that higher intake of caffeine from coffee is associated with reduced severity of liver fibrosis in patients with chronic hepatitis C virus. For these patients, the risk of advanced fibrosis is reduced by 14% for each 67 mg of caffeine (37896). However, caffeine intake does not appear to be associated with a reduced risk of moderate to severe liver inflammation in patients with hepatitis C (95947).
• Hypnic headache. It is unclear if oral caffeine reduces the pain associated with this rare condition. Details: Anecdotal evidence suggests that drinking a cup of coffee containing caffeine before bed or upon waking up may help alleviate pain associated with hypnic headaches (38078).
• Hypotension. It is unclear if oral caffeine is beneficial in people with low blood pressure. Details: Preliminary clinical research shows that consuming caffeinated beverages increase blood pressure in elderly people with postprandial hypotension (11834,11835).
• Intermittent claudication. It is unclear if oral caffeine is beneficial for intermittent claudication. Details: Taking a single dose of caffeine 6 mg/kg orally seems to improve walking distance, muscular strength, and endurance in patients with intermittent claudication; however, balance seems to be reduced (38038).
• Liver disease. It is unclear if oral caffeine is beneficial for liver disease prevention. Details: Population research found that there is an inverse association between intake of coffee and the incidence of liver cirrhosis (37576,37608). However, it is unclear if this effect of coffee is attributable to caffeine, since other caffeinated beverages do not show this effect.
• Multiple sclerosis (MS). It is unclear if oral caffeine is beneficial for the symptoms of multiple sclerosis (MS). Details: A small crossover study in adults with MS shows that taking caffeine 200 mg daily for 12 weeks may modestly improve balance, functional mobility, and MS-related quality of life, but not walking function, when compared to a 2-week placebo run-in period. All patients were told to eliminate all other forms of caffeine from their diets; however, baseline caffeine intake was not recorded (114663). The validity of this study is limited by the small size and heterogeneous nature of the study population, which included patients with various forms of MS at varying levels of severity.
• Narcolepsy. It is unclear if oral caffeine is beneficial for narcolepsy. Details: A small clinical study in patients with narcolepsy shows that taking caffeine 200 mg daily in the morning for 1 week does not affect reaction time, but modestly reduces drowsiness, when compared with baseline (103698). The validity of this finding is limited by the lack of a statistical comparison between the treatment and placebo groups.
• Neonatal resuscitation. It is unclear if oral caffeine improves the likelihood for successful extubation in preterm infants. Details: Preliminary clinical research in extremely preterm infants requiring mechanical ventilation within the first 5 days of birth shows that early administration of caffeine, given as a loading dose of caffeine citrate 20 mg/kg followed by a maintenance dose of 5 mg/kg daily until extubation, does not reduce mortality or shorten time to first successful extubation when compared to giving a bolus dose of caffeine citrate 20 mg/kg just prior to extubation (97461).
• Nocturnal enuresis. Reducing caffeine intake might reduce the frequency of nocturnal enuresis episodes in children. Details: Preliminary clinical research in children aged 6-15 years with primary nocturnal enuresis shows that limiting caffeine intake to less than 30 mg daily reduces the mean number of bedwetting episodes from 3.5 to 2.4 per week, when compared with no change in the group with intakes of 80-100 mg daily. The probability of bedwetting in the caffeine restricted group was about 14% lower than that in the control group (111495).
• Nonmelanoma skin cancer. It is unclear if oral caffeine is beneficial for nonmelanoma skin cancer prevention. Details: A review of available population research shows that increased caffeine intake from any source is associated with a 14% reduction in the risk of developing nonmelanoma skin cancer. Consumption of caffeinated coffee, but not decaffeinated coffee, is associated with an 18% reduced risk (97465).
• Parkinson disease. Although consuming caffeinated beverages might reduce the risk of developing Parkinson disease, it is unclear if oral caffeine is beneficial for improving symptoms. Also, oral caffeine does not seem to prevent tardive dyskinesia. Details: It is unclear whether caffeine improves some symptoms of Parkinson disease, as results from clinical research are conflicting (91069,95951,95954,103705). One clinical study in Parkinson disease patients with extreme daytime somnolence shows that taking caffeine 100 mg twice daily for 3 weeks and then 200 mg twice daily for 3 weeks results in modest improvements in rigidity and bradykinesia, but inconsistent improvements in drowsiness, when compared with placebo (91069). Other clinical research shows that caffeine 200 mg twice daily does not lead to improvements in motor severity, cognition, or somnolence after 6, 12, or 18 months when compared with placebo (95954). Furthermore, a large retrospective study has found that caffeine consumption of more than 300 mg daily for 18 months in conjunction with dopaminergic therapy does not slow the rate of Parkinson disease progression. This research also shows that a reported consumption of caffeine greater than 300 mg, in conjunction with creatine 10 grams daily for 18 months, may accelerate the rate of Parkinson disease progression (95951). The retrospective nature of this study limits the validity of these findings. Caffeine does not appear to be helpful for reducing the risk of tardive dyskinesia. A retrospective analysis has found no definitive difference in onset of tardive dyskinesia in Parkinson patients consuming more than 204 mg caffeine daily when compared with those consuming less than 68 mg daily (91090). Despite these mainly negative findings, large-scale epidemiological studies have found that people who consume caffeinated beverages, such as coffee, tea, and cola, have a decreased risk of Parkinson disease (37931,91060,91071,103705). Males consuming 3-4 cups (28 oz) of caffeinated coffee per day, or 421-2716 mg total caffeine, seem to have the lowest risk of developing this condition. However, a lower risk is also associated with consumption of as little as 124-208 mg of caffeine (6022). In females, more moderate caffeinated coffee consumption, such as 1-3 cups per day, seems to be best (1238). Caffeine does not appear to provide additional protection from Parkinson disease in cigarette smokers (9236,91060).
• Postoperative ileus. It is unclear if oral caffeine is beneficial for improving bowel recovery following colorectal surgery. Research is conflicting and may vary depending on the type of procedure performed. Details: A meta-analysis of two small clinical trials in adults undergoing elective laparoscopic colorectal resection shows that taking caffeine 100-200 mg three times daily, starting on postoperative day 1, does not reduce the time to the first stool, time to first flatus, or length of hospital stay (LOS) when compared with placebo (112732). Another meta-analysis of 8 trials, including the 2 trials discussed previously, pooled 610 patients undergoing open and laparoscopic colorectal procedures. The analysis shows that caffeine taken three times daily, starting either on the day of surgery or on postoperative day 1, reduces LOS and the time to first bowel movement when compared with placebo, tea, or decaffeinated coffee. However, a sub-analysis of only laparoscopic procedures shows no difference in LOS between groups. These findings are limited by high heterogeneity, which appears to be due primarily to differences between open and laparoscopic procedures (114660).
• Postoperative pain. It is unclear if intravenous caffeine is beneficial for reducing opioid consumption in adults undergoing surgery. Details: A small clinical study in adults undergoing laparoscopic colorectal and gastrointestinal surgery shows that intravenous caffeine citrate 200 mg at the initiation of surgical closure has no effect on cumulative opioid consumption through postoperative day 3 when compared with placebo. In fact, post-hoc analysis with adjustment for age, sex, comorbidities, history of anxiety or depression, and open surgical conversion suggests an increase in opioid consumption with administration of caffeine when compared with placebo (108809).
• Pre-eclampsia. It is unclear if oral caffeine intake affects the risk of gestational hypertension or pre-eclampsia. Details: a meta-analysis of 10 observational studies including about 115,000 pregnant people did not find an association between the level of caffeine intake during pregnancy and the risk of developing gestational hypertension or pre-eclampsia (111485).
• Stroke. It is unclear if oral caffeine is beneficial for stroke prevention. Details: Population research has found that increased intake of either caffeinated or decaffeinated coffee is associated with a decreased risk of stroke in females (37804). However, it is not clear if the effect of coffee is attributable to the caffeine component.
• Tinnitus. It is unclear if oral caffeine is beneficial in patients with chronic tinnitus. Details: A small clinical study in adults with chronic tinnitus shows that taking a single dose of caffeine 300 mg improves mood and quality of life at 1 hour when compared with baseline. (108805). The lack of statistical comparison to the placebo group limits the validity of these findings. More evidence is needed to rate the effectiveness of caffeine for these uses.

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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.

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POSSIBLY SAFE ...when used orally and appropriately. 5-HTP has been used safely in doses up to 400 mg daily for up to one year (913,30007,30130). Doses up to 1.2 grams daily have been used with apparent safety for up to 10 months (914,30018,30125,30164,30165). Doses of 3 grams daily have been used safely for 3 weeks (30138). There is some controversy about the safety of 5-HTP due to concerns for eosinophilia myalgia syndrome (EMS) (902,919,7067,10084,30178). There is speculation that only certain, contaminated 5-HTP products may cause this serious adverse effect (88174). So far, there is not enough evidence to know if EMS is caused by 5-HTP, contaminants, or other unknown factors (919,7067,10084).

POSSIBLY UNSAFE ...when used orally in large doses. Doses of 6-10 grams daily have been associated with severe gastrointestinal effects and hyperkinesis (30139,30183). The risk may be reduced if the dose is increased gradually.

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

CHILDREN: POSSIBLY SAFE
when used orally and appropriately. Doses of 5-HTP up to 5 mg/kg daily have been used safely for up to 3 years in infants and children up to 12 years old (30128,30153,88173). There is some controversy about the safety of 5-HTP due to concerns for eosinophilia myalgia syndrome (EMS) (902,919,7067,10084,30178). There is speculation that only certain, contaminated 5-HTP products may cause this serious adverse effect (88174). So far, there is not enough evidence to know if EMS is caused by 5-HTP, contaminants, or other unknown factors (919,7067,10084).

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LIKELY SAFE ...when used orally, parenterally, or rectally and appropriately. Caffeine has Generally Recognized As Safe (GRAS) status in the US (4912,98806). Caffeine is also an FDA-approved product and a component of several over-the-counter and prescription products (4912,11832). According to a review by Health Canada, and a subsequent large meta-analysis conducted in the US, doses of caffeine up to 400 mg daily are not associated with significant adverse cardiovascular, bone, behavioral, or reproductive effects in healthy adults (11733,98806). The US Dietary Guidelines Advisory Committee states that there is strong and consistent evidence that consumption of caffeine 400 mg daily is not associated with increased risk of major chronic diseases, such as cardiovascular disease or cancer, in healthy adults (98806). This amount of caffeine is similar to the amount of caffeine found in approximately 4 cups of coffee. Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine from caffeine-containing natural ingredients such as coffee or green tea does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

POSSIBLY UNSAFE ...when used orally, long-term or in high doses (91063). Chronic use, especially in large amounts, can produce tolerance, habituation, psychological dependence, and other adverse effects (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). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine from caffeine-containing natural ingredients such as coffee or green tea does not need to be provided. This can make it difficult to determine the total amount of caffeine in a given product.

LIKELY UNSAFE ...when used orally in very high doses. The fatal acute oral dose of caffeine is estimated to be 10-14 grams (150-200 mg/kg). Serious toxicity can occur at lower doses depending on variables in caffeine sensitivity such as smoking, age, or prior caffeine use (11832,95700,97454,104573). Caffeine products sold to consumers in highly concentrated or pure formulations are considered to a serious health concern because these products have a risk of being used in very high doses. Concentrated liquid caffeine can contain about 2 grams of caffeine in a half cup. Powdered pure caffeine can contain about 3.2 grams of caffeine in one teaspoon. Powdered pure caffeine can be fatal in adults when used in doses of 2 tablespoons or less. As of 2018, these products are considered by the FDA to be unlawful when sold to consumers in bulk quantities (95700).

CHILDREN: POSSIBLY SAFE
when used orally or intravenously and appropriately in neonates under the guidance of a healthcare professional (6371,38340,38344,91084,91087,97452). ...when used orally in amounts commonly found in foods and beverages in children and adolescents (4912,11833,36555). Daily intake of caffeine in doses of less than 2.5 mg/kg daily are not associated with significant adverse effects in children and adolescents (11733,98806). Keep in mind that only the amount of ADDED caffeine must be stated on product labels. The amount of caffeine from caffeine-containing natural ingredients such as coffee or green tea 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 commonly found in foods. Intakes of caffeine should be monitored during pregnancy. Caffeine crosses the human placenta, but is not considered a teratogen (38048,38252,91032). Fetal blood and tissue levels are similar to maternal concentrations (4260). The use of caffeine during pregnancy is controversial; however, moderate consumption has not been associated with clinically important adverse fetal effects (2708,2709,2710,2711,9606,16014,16015,98806,108814). In some studies consuming amounts over 200 mg daily is associated with a significantly increased risk of miscarriage (16014,37960). This increased risk seems 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, up to 300 mg daily can be consumed during pregnancy without an increased risk of spontaneous abortion, stillbirth, preterm birth, fetal growth retardation, or congenital malformations (11733,98806). However, observational research in a Norwegian cohort found that caffeine consumption is associated with a 16% increased odds of the baby being born small for gestational age when compared with no consumption (100369,103707). The same Norwegian cohort found that low to moderate caffeine consumption during pregnancy is not associated with changes in neurodevelopment in children up to 8 years of age (103699). Advise patients to keep caffeine consumption below 300 mg daily during pregnancy. This is similar to the amount of caffeine in about 3 cups of coffee or tea.

PREGNANCY: POSSIBLY UNSAFE
when used orally in amounts over 300 mg daily. Caffeine crosses the placenta, producing fetal blood concentrations similar to maternal levels (4260,98806). Consumption of caffeine in amounts over 300 mg daily is associated with a significantly increased risk of miscarriage in some studies (16014,98806). Advise patients to keep caffeine consumption below 300 mg daily during pregnancy. This is similar to the amount of caffeine in about 3 cups of coffee or tea. Additionally, 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). In a cohort of mother/infant pairs with a median maternal plasma caffeine level of 168.5 ng/mL (range 29.5-650.5 ng/mL) during pregnancy, 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 another 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 commonly found in foods. Caffeine intake should be closely monitored while breast-feeding. During lactation, breast milk concentrations of caffeine are thought to be approximately 50% of serum concentrations and caffeine peaks in breastmilk approximately 1-2 hours after consumption (23590).

LACTATION: POSSIBLY UNSAFE
when used orally in large amounts. Caffeine is excreted slowly in infants and may accumulate. Caffeine can cause sleep disturbances, irritability, and increased bowel activity in breast-fed infants exposed to caffeine (2708,6026).

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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).

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CARBIDOPA (Lodosyn) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Combining 5-HTP and carbidopa can increase the risk of serotonergic side effects.  Details Carbidopa is sometimes used with 5-HTP to minimize peripheral 5-HTP metabolism and boost the amount that reaches the brain. However, this combination might also increase the risk of some side effects including hypomania, restlessness, rapid speech, anxiety, insomnia, and aggressiveness (30076,30132,30158). Combining carbidopa and 5-HTP might also increase the risk of scleroderma-like skin changes due to elevated serotonin levels (1403).

CNS DEPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use of 5-HTP with medications that cause sedation might have additive effects.  Details In clinical trials, 5-HTP has been associated with drowsiness and somnolence (914,30093,30129,30130).

SEROTONERGIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Combining serotonergic drugs with 5-HTP might cause additive serotonergic effects.  Details 5-HTP can increase serotonin levels and cause serotonergic effects (901). Theoretically, combining serotonergic drugs with 5-HTP might increase the risk of serotonergic side effects, including serotonin syndrome and cerebral vasoconstrictive disorders (8056). However, serotonin syndrome with 5-HTP has not yet been reported in humans (104941). Monitor patients for signs of serotonin syndrome and other serotonergic side effects if using 5-HTP with serotonergic drugs.

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ADENOSINE (Adenocard) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, caffeine might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.  Details Some evidence shows that caffeine is a competitive inhibitor of adenosine and can reduce the vasodilatory effects of adenosine in humans (38172). However, other research shows that 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 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 = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase levels and adverse effects of caffeine.  Details Alcohol reduces caffeine metabolism. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects (6370).

ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.  Details Caffeine is reported to have antiplatelet activity. Theoretically, it might increase the risk of bleeding when used concomitantly with these agents (8028,8029); however, 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 caffeine with antidiabetes drugs might interfere with blood glucose control.  Details Data are conflicting. Reports claim that caffeine might increase or decrease blood sugar (6024,8646,114662).

CARBAMAZEPINE (Tegretol) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of carbamazepine and increase the risk for convulsions.  Details 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 = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Likely •  Level of Evidence = B Theoretically, cimetidine might increase the levels and adverse effects of caffeine.  Details 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 Caffeine might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.  Details Caffeine might increase the effects and toxicity of clozapine. Caffeine doses of 400-1000 mg per day inhibit clozapine metabolism (5051). Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2). Although researchers speculate that caffeine might inhibit CYP1A2, there is no reliable evidence that caffeine affects CYP1A2. There is also speculation that genetic factors might make some patients more sensitive to an interaction between clozapine and caffeine (13741). In one case report, severe, life-threatening clozapine toxicity and multiorgan system failure occurred in a patient with schizophrenia stabilized on clozapine who consumed caffeine 600 mg daily (108817).

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

CYTOCHROME P450 1A2 (CYP1A2) INHIBITORS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, concomitant use might increase the levels and adverse effects of caffeine.  Details Caffeine is metabolized by CYP1A2. Theoretically, drugs that inhibit CYP1A2 may decrease the rate of caffeine clearance and increase caffeine levels (5051,11741).

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

DISULFIRAM (Antabuse) Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = B Theoretically, disulfiram use might increase the levels and adverse effects of caffeine.  Details 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 caffeine with diuretic drugs might increase the risk of hypokalemia.  Details Caffeine, especially in excessive amounts, can reduce potassium levels due to stimulation of the sodium-potassium pump (23579,37905,37953,38003,38034). Diuretics can also cause lower potassium levels.

EPHEDRINE Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Theoretically, concomitant use might increase the risk for stimulant adverse effects.  Details Use of ephedrine with caffeine can increase the risk of stimulatory adverse effects. 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 caffeine.  Details Estrogen inhibits caffeine metabolism (2714,23570).

ETHOSUXIMIDE (Zarontin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of ethosuximide and increase the risk for convulsions.  Details 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, caffeine might reduce the effects of felbamate and increase the risk for convulsions.  Details 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 caffeine.  Details Fluconazole decreases caffeine clearance by approximately 25% (11022).

FLUTAMIDE (Eulexin) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, caffeine might increase the levels and adverse effects of flutamide.  Details In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). However, 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 caffeine.  Details Fluvoxamine reduces caffeine metabolism (6370).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Abrupt caffeine withdrawal might increase the levels and adverse effects of lithium.  Details Caffeine has diuretic activity. When abruptly discontinued, caffeine may alter the clearance of lithium (609). There are two case reports of lithium tremor that worsened upon abrupt coffee withdrawal (610) and 6 case reports of elevated serum lithium levels after reducing or eliminating caffeine intake (114665). In one case, a male with schizoaffective disorder stabilized on lithium had an elevated lithium level after reducing his caffeine intake by 87%. At a later date, he increased his caffeine intake by 6-fold, resulting in a subtherapeutic lithium level and a recurrence of psychiatric symptoms (114665).

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 caffeine.  Details Animal research suggests that metformin can reduce caffeine metabolism (23571). However, this effect has not been reported in humans.

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 caffeine.  Details Methoxsalen reduces 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 caffeine.  Details Mexiletine reduces caffeine metabolism (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 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 = B Theoretically, concomitant use might increase the risk of hypertension.  Details 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, caffeine might decrease the effects of pentobarbital.  Details Caffeine might negate the hypnotic effects of pentobarbital (13742).

PHENOBARBITAL (Luminal) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, caffeine might reduce the effects of phenobarbital and increase the risk for convulsions.  Details Animal research suggests that caffeine can decrease the anticonvulsant activity of phenobarbital (23558,23559,23561). However, the exact mechanism of this interaction is unclear.

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 caffeine.  Details Phenothiazines, including perazine, chlorpromazine, levomepromazine, and thioridazine, 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 caffeine.  Details 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, caffeine might reduce the effects of phenytoin and increase the risk for convulsions.  Details 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, caffeine might increase the levels and clinical effects of pioglitazone.  Details 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 caffeine.  Details Quinolones (also called fluoroquinolones) can decrease caffeine clearance by inhibiting cytochrome P450 1A2 (CYP1A2) enzyme (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 Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce the 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 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 caffeine.  Details Terbinafine decreases the clearance of intravenous caffeine by 19% (11740).

THEOPHYLLINE Interaction Rating = Moderate Be cautious with this combination. Severity = Mild •  Occurrence = Probable •  Level of Evidence = C Theoretically, caffeine might increase the levels and adverse effects of theophylline.  Details 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, caffeine might increase the levels and adverse effects of tiagabine.  Details 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 caffeine.  Details 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, caffeine might reduce the effects of valproate and increase the risk for convulsions.  Details Animal research suggests that caffeine can decrease the anticonvulsant activity of valproate (23558,23559,23561,37882). However, the exact mechanism of this interaction is unclear.

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

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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 = Probable •  Level of Evidence = B CYP2D6 inhibitors may 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). Paroxetine, a cytochrome P450 (CYP) 2D6 inhibitor, increases the maximum serum concentration of yohimbine and reduces the clearance of yohimbine compared to yohimbine alone in patients who are extensive CYP2D6 metabolizers. (114932).

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).

PAROXETINE (Paxil) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Paroxetine decreases the clearance of yohimbine and may increase its effects.  Details Paroxetine, a cytochrome P450 (CYP) 2D6 inhibitor, increases the maximum serum concentration of yohimbine by about 350% and reduces the clearance of yohimbine by about 80% compared to yohimbine alone in patients who are extensive CYP2D6 metabolizers. No significant changes in pharmacokinetic parameters of yohimbine were observed with coadministration of paroxetine in patients who are poor CYP2D6 metabolizers (114932).

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).

(Read more about YOHIMBE)

General ...Orally, 5-HTP is generally well tolerated, short-term.
Most Common Adverse Effects:
Orally: Abdominal pain, anorexia, dizziness, diarrhea, drowsiness, fatigue, headache, insomnia, nausea, and vomiting. Severity appears to be dose-dependent.
Serious Adverse Effects (Rare):
Orally: Aggression, hallucinations, mania, severe gastrointestinal complaints.

Cardiovascular ...Orally, palpitations have been reported with 5-HTP (30076,30130,30167). Conversely, bradycardia has been reported in patients taking 5-HTP 0.4-2 grams daily in combination with carbidopa 100-300 mg daily (30132). In patients with schizophrenia, a combination of 5-HTP in doses up to 6 grams daily and carbidopa 150 mg daily was associated with diaphoresis and mild diastolic hypotension, especially when doses were increased at a rate faster than 200 mg per day (30183).

Dermatologic ...Orally, 5-HTP has been reported to cause urticaria, other allergic-type skin reactions, and flushing (2204,30000,30140). A scleroderma-like illness was reported in a 70-year-old man who had been taking 5-HTP 1400 mg daily and carbidopa 150 mg daily for 20 months. Elevated serotonin levels may be linked to this condition (1403).

Gastrointestinal ...Orally, 5-HTP has been reported to cause gastrointestinal side effects such as nausea, vomiting, abdominal or epigastric pain, heartburn, constipation, diarrhea, flatulence, anorexia, and taste alteration at any dose (2203,2204,30000,30112,30114,30125,30132,30139,30140)(30165,30183,104250). Severity may be dose-dependent and also related to how quickly doses are increased (30183). Some data suggests that these effects may diminish or disappear with continued use of 5-HTP (30132).

Hematologic ...Symptoms suggestive of eosinophilia myalgia syndrome (EMS) have been reported in some patients using 5-HTP (902,10084,30178,88174,90927). In one case, a woman was exposed to 5-HTP, tetrahydrobiopterin, carbidopa, and levodopa while administering them to her children for 2 years (90927). Her diagnosis was not confirmed, and the validity of the tests performed on the 5-HTP product has been questioned (88174). Other cases of eosinophilia or EMS in patients taking 5-HTP have been attributed to impurities that resemble previously identified contaminants found in L-tryptophan products (902,919,7067,10084). The L-tryptophan contaminants associated with EMS were linked to a specific manufacturer's production method that is not used in the preparation of 5-HTP (88174). Although 5-HTP supplements have been associated with EMS, it seems that this adverse effect is likely due to the presence of contaminants in the 5-HTP products, not 5-HTP itself.

Musculoskeletal ...Orally, rhabdomyolysis was noted in one patient with progressive myoclonus epilepsy who was treated with 5-HTP 300 mg daily for 21 days (30162).

Neurologic/CNS ...Orally, 5-HTP has been reported to cause drowsiness, dizziness, insomnia, fatigue, and headache (30076,30112,30132).

Psychiatric ...Orally, 5-HTP has been associated with euphoria, hypomania and mania, anxiety, insomnia, and aggressiveness (30076,30132,30158,88179). In patients with schizophrenia, a combination of high-dose 5-HTP, up to 6 grams daily, and carbidopa 150 mg daily was associated with transient increases in hallucinations, delusions, marked confusion, looseness of associations, flight of ideas, and a hyperkinetic syndrome consisting of restlessness, hand wringing, pacing, and an inability to sit quietly in a chair (30183).

(Read more about 5-HTP)

General ...Caffeine in moderate doses is typically well tolerated.
Most Common Adverse Effects:
Orally: Anxiety, dependence with chronic use, diarrhea, diuresis, gastric irritation, headache, insomnia, muscular tremors, nausea, and restlessness.
Serious Adverse Effects (Rare):
Orally: Stroke has been reported rarely.

Cardiovascular ...Caffeine can temporarily increase blood pressure. Usually, blood pressure increases 30 minutes after ingestion, peaks in 1-2 hours, and remains elevated for over 4 hours (36539,37732,37989,38000,38300).
Although acute administration of caffeine can cause increased blood pressure, regular consumption does not seem to increase either blood pressure or pulse, even in mildly hypertensive patients (1451,1452,2722,38335). However, the form of caffeine may play a role in blood pressure increase after a more sustained caffeine use. In a pooled analysis of clinical trials, coffee intake was not associated with an increase in blood pressure, while ingesting caffeine 410 mg daily for at least 7 days modestly increased blood pressure by an average of 4.16/2.41 mmHg (37657). Another meta-analysis of clinical research shows that taking caffeine increases systolic and diastolic blood pressure by approximately 2 mmHg when compared with control. Preliminary subgroup analyses suggest that caffeine may increase blood pressure more in males or at doses over 400 mg (112738).
When used prior to intensive exercise, caffeine can increase systolic blood pressure by 7-8 mmHg (38308). The blood pressure-raising effects of caffeine are greater during stress (36479,38334) and after caffeine-abstinence of at least 24 hours (38241).
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 found that regular caffeine intake of up to 400 mg daily is not associated with increased incidence of atrial fibrillation (38018,38076,91028,91034,97451,97453,103708), atherosclerosis (38033), cardiac ectopy (91127), stroke (37804), ventricular arrhythmia (95948,97453), and cardiovascular disease in general (37805,98806). One clinical trial shows that in adults with diagnosed heart failure, consumption of 500 mg of coffee does not result in an increased risk for arrhythmia during exercise (95950). However, caffeine intake may pose a greater cardiovascular risk to subjects that are not regular users of caffeine. For example, in one population study, caffeinated coffee consumption was associated with an increased risk of ischemic stroke in subjects that don't regularly drink coffee (38102). In a population study in Japanese subjects, caffeine-containing medication use was modestly associated with hemorrhagic stroke in adults that do not consume caffeine regularly (91059).
The most common side effect of caffeine in neonates receiving caffeine for apnea is tachycardia (98807,114658).

Dermatologic ...There are several case reports of urticaria after caffeine ingestion (36546,36448,36475).

Endocrine ...Some evidence shows caffeine is associated with fibrocystic breast disease or breast cancer in females; however, this is controversial since findings are conflicting (8043,108806). Restricting caffeine in females with fibrocystic breast conditions doesn't seem to affect breast nodularity, swelling, or pain (8996). 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 2 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 an increase consumption of caffeine results in increased insulin resistance (91023).

Gastrointestinal ...Gastrointestinal upset, nausea, diarrhea, abdominal pain, and fecal incontinence may occur with caffeine intake (36466,37755,37806,37789,37830,38138,38136,38223,95956,95963). Also, caffeine may cause feeding intolerance and gastrointestinal irritation in infants (6023). Perioperative caffeine during cardiopulmonary bypass surgery seems to increase the rate of postoperative nausea and vomiting (97451). Caffeine and coffee consumption have been associated with an increase in the incidence of heartburn (37545,37575,38251,38259,38267) and gastrointestinal esophageal reflux disease (GERD) (38329,37633,37631,37603).

Genitourinary ...Caffeine, a known diuretic, may increase voiding, give a sense of urgency, and irritate the bladder (37874,37961,104580). In men with lower urinary tract symptoms, caffeine intake increased the risk of interstitial cystitis/painful bladder syndrome (38115). Excessive caffeine consumption may worsen premenstrual syndrome. Consumption of up to 10 cups of caffeinated drinks daily was associated with increased severity of premenstrual syndrome (38177). Finally, population research shows that exposure to caffeine was not associated with an increased risk of endometriosis (91035).

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

Musculoskeletal ...Caffeine can induce or exacerbate muscular tremors (38136,37673,38161). There has also been a report of severe rhabdomyolysis in a healthy 40-year-old patient who consumed an energy drink containing 400 mg of caffeine (4 mg/kg) and then participated in strenuous weightlifting exercise (108818).
Epidemiological evidence regarding the relationship between caffeine use and the risk for osteoporosis is contradictory. Caffeine can release calcium from storage sites and increase its urinary excretion (2669,10202,11317,111489). Females 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, less than 300 mg daily, does not seem to significantly increase osteoporosis risk in most postmenopausal adults with normal calcium intake (2669,6025,10202,11317). Premature infants treated with intravenous caffeine for apnea of prematurity, have a lower bone mineral content compared with infants who are not treated with caffeine, especially when treatment extends beyond 14 days (111489).

Neurologic/CNS ...Caffeine can cause headaches, anxiety, jitteriness, restlessness, and nervousness (36466,37694,37755,37806,37865,37830,37889,38223,95952). In adolescents, there is an inverse correlation between the consumption of caffeine and various measurements of cognitive function (104579). Insomnia is a frequent adverse effect in children (10755). Caffeine may result in insomnia and sleep disturbances in adults as well (36445,36483,36512,36531,37598,37795,37819,37862,37864,37890)(37968,37971,38091,38242,91022,92952). Additionally, caffeine may exacerbate sleep disturbances in patients with acquired immunodeficiency syndrome (AIDS) (10204). Combining ephedra with caffeine can increase the risk of adverse effects. Jitteriness, hypertension, seizures, temporary loss of consciousness, and hospitalization requiring life support has been associated with the combined use of ephedra and caffeine (2729). Finally, epidemiological research suggests that consuming more than 190 mg of caffeine daily is associated with an earlier onset of Huntington disease by 3.6 years (91078).

Ocular/Otic ...In individuals with glaucoma, coffee consumption and caffeine intake has been found to increase intraocular pressure (8540,36464,36465,37670). 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 ...Most human studies which have examined caffeine or methylxanthine intake have found that they do not play a role in the development of various cancers, including breast, ovarian, brain, colon, rectal, or bladder cancer (37641,37737,37775,37900,38050,38169,38220,91054,91076,108806).

Psychiatric ...Caffeine may lead to habituation and physical dependence (36355,36453,36512,36599), with amounts as low as 100 mg daily (36355,36453). An estimated 9% to 30% of caffeine consumers could be considered addicted to caffeine (36355). Higher doses of caffeine have caused nervousness, agitation, anxiety, irritability, delirium, depression, sleep disturbances, impaired attention, manic behavior, psychosis and panic attacks (36505,37717,37818,37839,37857,37982,38004,38017,38028,38072)(38079,38138,38306,38325,38331,38332,97464). Similar symptoms have been reported in a caffeine-naïve individual experiencing fatigue and dehydration after a dose of only 200 mg, with resolution of symptoms occurring within 2 hours (95952).
Withdrawal: The existence or clinical importance of caffeine withdrawal is controversial. Some researchers think that if it exists, it appears to be of little clinical significance (11839). Headache is the most common symptom, due to cerebral vasodilation and increased blood flow (37769,37991,37998). Other researchers suggest symptoms such as tiredness and fatigue, decreased energy, alertness and attentiveness, drowsiness, decreased contentedness, depressed mood, difficulty concentration, irritability, and lack of clear-headedness are typical of caffeine withdrawal (13738). Withdrawal symptoms typically occur 12-24 hours after the last dose of caffeine and peak around 48 hours (37769,36600). Symptoms may persist for 2-9 days. Withdrawal symptoms such as delirium, nausea, vomiting, rhinorrhea, nervousness, restlessness, anxiety, muscle tension, muscle pains, and flushed face have been described. However, these symptoms may be from nonpharmacological factors related to knowledge and expectation of effects. Clinically significant symptoms caused by caffeine withdrawal may be uncommon (2723,11839). In a case report, caffeine consumption of 560 mg daily was associated with increased suicidality (91082).

Renal ...Data on the relationship between caffeine intake and kidney stones are conflicting. Some clinical research shows that caffeine consumption may increase the risk of stone formation (37634,111498), while other research shows a reduced risk with increasing caffeine intakes (111498). A meta-analysis of 7 studies found that overall, there is an inverse relationship, with a 32% decrease in the risk of kidney stones between the lowest and highest daily intakes of caffeine (111498).

Other ...People with voice disorders, singers, and other voice professionals are often advised against the use of caffeine; however, this recommendation has been based on anecdotal evidence. One small exploratory study suggests that caffeine ingestion may adversely affect subjective voice quality, although there appears to be significant intra-individual variability. Further study is necessary to confirm these preliminary findings (2724).

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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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