Each 1 scoop (10 grams) serving contains: MethylFire brand Super Intense Matrix 9000 mg: Creatine Monohydrate , Arginine Alpha-Ketoglutarate (A-AKG), L-Arginine , L-Leucine , Beta-Alanine , Caffeine alpha-ketoglutarate, Alpha-GPC (alpha-glycerophosphocholine), 1,3-Dimethylamylamine (geranium stem), Beta-P (PEA phenylethylamine), DMAE (dimethylaminoethanol), cAMP (Cyclic Adenosine Monophosphate), L-Glutamine , 1,3 N-Dipropyl-7-Propargylxanthine , R-Beta-Methylphenylethylamine HCl , N-Methyl-Beta-Phenylethylamine . Other Ingredients: Citric Acid, Natural Lemon-Lime Flavor, Sucralose.
Brand name products often contain multiple ingredients. To read detailed information about each ingredient, click on the link for the individual ingredient shown above.
This product contains 1,3-dimethylamylamine (DMAA), also known as methylhexanamine or geranium extract. There are serious safety concerns about DMAA. It is a stimulant that can potentially increase blood pressure and increase the risk of adverse cardiovascular events. DMAA-containing products have been linked to over 40 serious adverse event reports including adverse cardiovascular, metabolic, nervous system, and psychiatric events. Reports of death have also occurred (17660,17663,17904,17906,17907,17908,17958). In 2011, US Department of Defense (DoD) temporarily banned the sale of DMAA-containing supplements in military stores due to safety concerns. Sales of these products will be prohibited until the DoD investigates reports of potential serious adverse outcomes related to this product (17904,17909). On April 9, 2012, DMAA was also banned in New Zealand due to safety concerns (17960). Due to its stimulant effects, DMAA was added to the World Anti-Doping Agency's prohibited substances list for 2010. It is listed using the name methylhexaneamine on the prohibited list (17600).
Supplements that contain DMAA often list rose geranium oil, geranium oil, or geranium stems on the label. Some supplement manufacturers claim that this is because rose geranium oil contains a small amount of dimethylamylamine. However, this has not been verified by laboratory analysis. Some laboratories have not been able to detect dimethylamylamine in geranium oil. There is concern that some supplement manufacturers may be artificially spiking their supplements with this synthetic drug (17661,17662). In 2011, Health Canada determined that there is no credible evidence that DMAA is derived from the geranium plant. Therefore, DMAA is considered a drug and is not allowed in dietary supplements in Canada (17959).
For more information about DMAA, see the complete scientific monograph
This product has been discontinued by the manufacturer.
Below is general information about the effectiveness of the known ingredients contained in the product MethylFire. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
INSUFFICIENT RELIABLE EVIDENCE to RATE
Below is general information about the safety of the known ingredients contained in the product MethylFire. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
LIKELY UNSAFE ...when used orally. 1,3-DMAA is a drug originally used as a stimulant nasal decongestant. There is concern that it increases the risk of serious adverse cardiovascular events, similar to other stimulants such as synephrine in bitter orange and ephedrine alkaloids from ephedra. There are several case reports linking 1,3-DMAA to serious adverse events including lactic acidosis, hemorrhagic stroke, heat stroke, and death (17599,17660,17662,17663,17904,94361,94369,94374). Although some supplement manufacturers claim that 1,3-DMAA is a natural compound found in geranium oil, this has not been verified by laboratory analysis. Some laboratories have not been able to detect 1,3-DMAA in geranium oil (94370,94372). There is concern that some supplement manufacturers may be artificially spiking their supplements with this synthetic drug (17661,17662). The New Zealand government restricted sales of supplements containing 1,3-DMAA to prevent the sale to people under 18 years of age due to concerns about safety (17599). The FDA has declared products containing 1,3-DMAA to be illegal and potential health risks (94383). Avoid using.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately. Alpha-GPC has been used with apparent safety at doses of 400 mg three times daily (1200 mg/day) for up to 6 months (12102,12176). ...when used intramuscularly and appropriately. Alpha-GPC has been administered intramuscularly with apparent safety at doses of 1000-1200 mg/day for 28 to 90 days (12100,12102).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately for up to 3 years (5311,18113,30784,30785,30778). When used topically for up to 8 weeks (111125). ...when used intravenously and appropriately (5308,5309,5310,5311,5312,5313).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately, short-term. Oral beta-alanine, including a specific commercial product (CarnoSyn, Natural Alternatives International), has been used with apparent safety in doses up to 6.4 grams daily for 12 weeks in younger adults (14611,16025,16439,16441,18227,94357,97972,101028,101029,104144,106717), and up to 3.2 grams daily for 12 weeks in adults aged 55 years and older (16442,97955,97961,97965).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using in medicinal amounts.
POSSIBLY UNSAFE .... ..when used orally. BMPEA is an amphetamine-like compound that has been shown to have stimulant properties and is associated with severe cardiovascular adverse effects (29823,94317).
PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally.
BMPEA is an amphetamine-like compound that has been shown to have stimulant properties and is associated with severe cardiovascular adverse effects (29823,94317).
LIKELY SAFE ...when used orally and appropriately. BCAAs 12 grams daily have not been associated with significant adverse effects in studies lasting for up to 2 years (68,72,73,74,10117,10146,10147,37120,92643,97531,103351,103352). ...when used intravenously and appropriately. BCAAs are an FDA-approved injectable product (13309).
CHILDREN: LIKELY SAFE
when used orally in dietary amounts of 71-134 mg/kg daily (11120,13308).
CHILDREN: POSSIBLY SAFE
when larger, supplemental doses are used orally and appropriately for up to 6 months (13307,13308,37127).
PREGNANCY:
Insufficient reliable information available; avoid using amounts greater than those found in food.
Although adverse effects have not been reported in humans, some animal research suggests that consumption of supplemental isoleucine, a BCAA, during the first half of pregnancy may have variable effects on birth weight, possibly due to abnormal placental development (103350).
LACTATION:
Insufficient reliable information available; avoid using amounts greater than those found in food.
Although the safety of increased BCAA consumption during lactation is unclear, some clinical research suggests that a higher concentration of isoleucine and leucine in breastmilk during the first 6 months postpartum is not associated with infant growth or body composition at 2 weeks, 2 months, or 6 months (108466).
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).
LIKELY SAFE ...when used orally and appropriately, short-term. Creatine supplementation appears to be safe when used at loading doses of up to 25 grams daily or 0.3 grams/kg daily for up to 14 days in healthy adults (1367,2100,2101,3996,4569,10064,15354,15520,46570,46587)(46673,46688,46719,46753,46801,103278,103279,108336). Creatine supplementation also appears to be safe when used at maintenance doses of 4-5 grams daily for up to 18 months (2101,4578,15353,15354,15520,46587,46673,46690,46753,46838,102164,103278,108336).
POSSIBLY SAFE ...when used orally and appropriately, long-term. Creatine supplementation has been safely used at doses of up to 10 grams daily for up to 5 years in some preliminary clinical research (1367,3996). There is insufficient reliable information available about the safety of creatine when used topically.
CHILDREN: POSSIBLY SAFE
when used orally and appropriately.
Creatine supplementation appears to be safe when used in appropriate doses in infants and children. Creatine 3-5 grams daily for 2-6 months has been safely used in children 5-18 years of age (6182,46596,46739,46841). Creatine 2 grams daily for 6 months has been safely used in children 2-5 years of age (46841). Additionally, weight-based dosing of creatine 0.1-0.4 grams/kg daily in infants and children or 4.69 grams/m2 in children weighing over 40 kg has been used safely for up to 6 months (46623,46629,46694,46759,104672).
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
POSSIBLY SAFE ...when used orally and appropriately. Deanol has been safely used at doses up to 2 grams daily for up to 4 weeks and doses up to 500 mg daily for up to 3 months (1668,1671,1672,1673,1674,1675,1676,1679,1680,1681). There is insufficient reliable information available about the safety of deanol when used topically.
PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.
LIKELY SAFE ...when used orally and appropriately. Glutamine has been safely used in clinical research in doses up to 40 grams per day or 1 gram/kg daily (2334,2337,2338,2365,5029,5462,7233,7288,7293), (52288,52307,52308,52311,52313,52337,52349,52350,96516,97366). A specific glutamine product (Endari) is approved by the US Food and Drug Administration (FDA) (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 600 mg/kg daily in clinical trials (2363,2366,5448,5452,5453,5454,5458,7293,52272,52275), (52283,52289,52304,52306,52316,52341), (52359,52360,52371,52377,52381,52284,52385,52408,96637,96507,96516).
CHILDREN: LIKELY SAFE
when used orally and appropriately.
Glutamine has been shown to be safe in clinical research when used in amounts that do not exceed 0.7 grams/kg daily in children 1-18 years old (11364,46657,52321,52323,52363,86095,96517). A specific glutamine product (Endari) is approved by the US Food and Drug Administration for certain patients 5 years of age and older (96520). ...when used intravenously. Glutamine has been safely incorporated into parenteral nutrition in doses up to 0.4 grams/kg daily in clinical research (52338,96508). There is insufficient reliable information available about the safety of glutamine when used in larger amounts in children.
PREGNANCY AND LACTATION: LIKELY SAFE
when consumed in amounts commonly found in foods.
There is insufficient reliable information available about the safety of glutamine when used in larger amounts as medicine during pregnancy or lactation.
POSSIBLY SAFE ...when used orally and appropriately. L-arginine has been used safely in clinical studies at doses of up to 24 grams daily for up to 18 months (3331,3460,3595,3596,5531,5532,5533,6028,7815,7816)(8014,8473,13709,31943,91195,91196,91963,99264,99267,110380)(110387). A tolerable upper intake level (UL) for arginine has not been established, but the observed safe level (OSL) of arginine intake established in clinical research is 20 grams (31996). ...when used intravenously and appropriately. Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically and appropriately. L-arginine appears to be safe when 5 grams is applied as a topical cream twice daily for 2 weeks or when a dentifrice is used at a dose of 1.5% w/w for up to 2 years (14913,96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks (96807).
CHILDREN: POSSIBLY SAFE
when used orally in premature infants and children (8474,32286,96803,97392,110391).
...when used intravenously and appropriately (97392). Parenteral L-arginine is an FDA-approved prescription product (15). ...when used topically, short-term. A dentifrice containing L-arginine appears to be safe when used at a dose of 1.5% w/w for up to 2 years in children at least 3.7 years of age (96806). ...when inhaled, short-term. L-arginine appears to be safe when inhaled twice daily at a dose of 500 mg for up to 2 weeks in children at least 13 years of age (96807).
CHILDREN: POSSIBLY UNSAFE
when used intravenously in high doses.
Parenteral L-arginine is an FDA-approved prescription product (15). However, when higher than recommended doses are used, injection site reactions, hypersensitivity reactions, hematuria, and death have occurred in children (16817).
PREGNANCY: POSSIBLY SAFE
when used orally and appropriately, short-term.
L-arginine 12 grams daily for 2 days has been used with apparent safety in pregnancy during the third trimester (11828). L-arginine 3 grams daily has been taken safely during the second and/or third trimesters (31938,110379,110382). ...when used intravenously and appropriately, short-term. Intravenous L-arginine 20-30 grams daily has been used safely in pregnancy for up to 5 days (31847,31933,31961,31978).
LACTATION:
Insufficient reliable information available; avoid using.
Below is general information about the interactions of the known ingredients contained in the product MethylFire. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
1,3-DMAA strongly inhibits cytochrome P450 2D6 (CYP2D6) enzymes in vitro (91878). Theoretically, 1,3-DMAA can increase levels of CYP2D6 substrates. Some of drugs that are CYP2D6 substrates include amitriptyline (Elavil), clozapine (Clozaril), codeine, desipramine (Norpramin), donepezil (Aricept), fentanyl (Duragesic), flecainide (Tambocor), fluoxetine (Prozac), meperidine (Demerol), methadone (Dolophine), metoprolol (Lopressor, Toprol XL), olanzapine (Zyprexa), ondansetron (Zofran), tramadol (Ultram), trazodone (Desyrel), and others.
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1,3-DMAA is thought to have stimulant effects (94367). There is concern that taking 1,3-DMAA with stimulant drugs might increase the risk of adverse cardiovascular effects. Some preliminary research shows that taking 1,3-DMAA 50 mg daily in combination with caffeine 250 mg daily does not increase respiratory rate, blood pressure, or other cardiovascular outcomes compared to taking caffeine alone in healthy men (94364). However, a number of cardiovascular side effects have been reported for patients taking 1,3-DMAA in combination with other stimulants including caffeine (17660,91680,94362,94365,94371,94377). Theoretically, combining 1,3-DMAA with stimulant drugs might increase the risk of adverse cardiovascular effects. Some stimulant drugs include amphetamine, caffeine, diethylpropion (Tenuate), methylphenidate, phentermine (Ionamin), pseudoephedrine (Sudafed, others), and many others.
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Theoretically, alpha-GPC might decrease the effects of scopolamine.
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A small clinical study shows that alpha-GPC can partially counteract the attention and memory impairment effects caused by scopolamine given intramuscularly (12103). Whether alpha-GPC can decrease the beneficial anti-motion sickness effects of the scopolamine patch (Transderm Scop) is unclear.
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Theoretically, BMPEA might increase the levels and clinical effects of CYP2D6 substrates.
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In vitro research shows that BMPEA strongly inhibits CYP2D6 (91878).
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Theoretically, BMPEA might increase the levels and clinical effects of CYP3A4 substrates.
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In vitro research shows that BMPEA inhibits CYP3A4 by up to 37% (91878).
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Theoretically, taking BMPEA with other stimulant drugs might increase the risk of adverse cardiovascular effects.
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Theoretically, BCAAs might alter the effects of antidiabetes medications.
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BCAAs in large doses can reduce the effects of levodopa.
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BCAAs may compete with levodopa for transport systems in the intestine and brain and decrease the effectiveness of levodopa (66,2719). Small clinical studies how that concomitant ingestion of protein or high doses of leucine or isoleucine (100 mg/kg) and levodopa can exacerbate tremor, rigidity, and the "on-off" syndrome in patients with Parkinson disease (3291,3292,3293,3294).
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Theoretically, caffeine might decrease the vasodilatory effects of adenosine and interfere with its use prior to stress testing.
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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).
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Theoretically, concomitant use might increase levels and adverse effects of caffeine.
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Alcohol reduces caffeine metabolism. Concomitant use of alcohol can increase caffeine serum concentrations and the risk of caffeine adverse effects (6370).
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Theoretically, caffeine may increase the risk of bleeding if used with anticoagulant or antiplatelet drugs.
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Theoretically, taking caffeine with antidiabetes drugs might interfere with blood glucose control.
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Theoretically, large amounts of caffeine might increase the cardiac inotropic effects of beta-agonists (15).
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Theoretically, caffeine might reduce the effects of carbamazepine and increase the risk for convulsions.
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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).
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Theoretically, cimetidine might increase the levels and adverse effects of caffeine.
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Cimetidine decreases the rate of caffeine clearance by 31% to 42% (11736).
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Caffeine might increase the levels and adverse effects of clozapine and acutely exacerbate psychotic symptoms.
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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).
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Theoretically, contraceptive drugs might increase the levels and adverse effects of caffeine.
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Theoretically, concomitant use might increase the levels and adverse effects of caffeine.
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Theoretically, caffeine might decrease the vasodilatory effects of dipyridamole and interfere with its use prior to stress testing.
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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).
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Theoretically, disulfiram use might increase the levels and adverse effects of caffeine.
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Disulfiram decreases the rate of caffeine clearance (11840).
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Theoretically, using caffeine with diuretic drugs might increase the risk of hypokalemia.
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Theoretically, concomitant use might increase the risk for stimulant adverse effects.
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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).
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Theoretically, estrogens might increase the levels and adverse effects of caffeine.
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Theoretically, caffeine might reduce the effects of ethosuximide and increase the risk for convulsions.
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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.
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Theoretically, caffeine might reduce the effects of felbamate and increase the risk for convulsions.
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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.
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Theoretically, fluconazole might increase the levels and adverse effects of caffeine.
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Fluconazole decreases caffeine clearance by approximately 25% (11022).
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Theoretically, caffeine might increase the levels and adverse effects of flutamide.
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In vitro evidence suggests that caffeine can inhibit the metabolism of flutamide (23553). However, this effect has not been reported in humans.
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Theoretically, fluvoxamine might increase the levels and adverse effects of caffeine.
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Fluvoxamine reduces caffeine metabolism (6370).
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Abrupt caffeine withdrawal might increase the levels and adverse effects of lithium.
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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).
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Theoretically, metformin might increase the levels and adverse effects of caffeine.
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Animal research suggests that metformin can reduce caffeine metabolism (23571). However, this effect has not been reported in humans.
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Theoretically, methoxsalen might increase the levels and adverse effects of caffeine.
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Methoxsalen reduces caffeine metabolism (23572).
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Theoretically, mexiletine might increase the levels and adverse effects of caffeine.
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Theoretically, concomitant use might increase the risk of a hypertensive crisis.
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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.
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Theoretically, concomitant use might increase the risk of hypertension.
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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).
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Theoretically, caffeine might decrease the effects of pentobarbital.
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Caffeine might negate the hypnotic effects of pentobarbital (13742).
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Theoretically, caffeine might reduce the effects of phenobarbital and increase the risk for convulsions.
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Theoretically, phenothiazines might increase the levels and adverse effects of caffeine.
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Theoretically, phenylpropanolamine might increase the risk of hypertension, as well as the levels and adverse effects of caffeine.
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Theoretically, caffeine might reduce the effects of phenytoin and increase the risk for convulsions.
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Theoretically, caffeine might increase the levels and clinical effects of pioglitazone.
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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.
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Theoretically, quinolone antibiotics might increase the levels and adverse effects of caffeine.
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Theoretically, concomitant use might increase the levels and adverse effects of both caffeine and riluzole.
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Caffeine and riluzole are both metabolized by cytochrome P450 1A2 (CYP1A2), and concomitant use might reduce the metabolism of one or both agents (11739).
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Theoretically, concomitant use might increase stimulant adverse effects.
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Due to the central nervous system (CNS) stimulant effects of caffeine, concomitant use with stimulant drugs can increase the risk of adverse effects (11832).
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Theoretically, terbinafine might increase the levels and adverse effects of caffeine.
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Terbinafine decreases the clearance of intravenous caffeine by 19% (11740).
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Theoretically, caffeine might increase the levels and adverse effects of theophylline.
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Large amounts of caffeine might inhibit theophylline metabolism (11741).
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Theoretically, caffeine might increase the levels and adverse effects of tiagabine.
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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).
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Theoretically, ticlopidine might increase the levels and adverse effects of caffeine.
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In vitro evidence suggests that ticlopidine can inhibit caffeine metabolism (23557). However, this effect has not been reported in humans.
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Theoretically, caffeine might reduce the effects of valproate and increase the risk for convulsions.
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Theoretically, verapamil might increase the levels and adverse effects of caffeine.
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Verapamil increases plasma caffeine concentrations by 25% (11741).
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Theoretically, deanol might decrease the effectiveness of anticholinergic drugs.
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Deanol is thought to increase acetylcholine levels (1669).
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Theoretically, deanol might increase the effects and adverse effects of cholinergic drugs.
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Deanol is thought to increase acetylcholine levels (1669).
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Theoretically, glutamine might antagonize the effects of anticonvulsant medications.
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Theoretically, concomitant use of L-arginine and ACE inhibitors may increase the risk for hypotension and hyperkalemia.
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Combining L-arginine with some antihypertensive drugs, especially ACE inhibitors, seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916). Furthermore, ACE inhibitors can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ACE inhibitors with L-arginine may increases the risk of hyperkalemia.
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Theoretically, concomitant use of L-arginine and ARBs may increase the risk of hypotension and hyperkalemia.
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L-arginine increases nitric oxide, which causes vasodilation (7822). Combining L-arginine with ARBs seems to increase L-arginine-induced vasodilation (31854). Furthermore, ARBs can increase potassium levels. Use of L-arginine has been associated with hyperkalemia in some patients (32213,32218). Theoretically, concomitant use of ARBs with L-arginine may increases the risk of hyperkalemia.
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Theoretically, concomitant use of L-arginine with anticoagulant and antiplatelet drugs might have additive effects and increase the risk of bleeding.
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Theoretically, concomitant use of L-arginine might have additive effects with antidiabetes drugs.
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Theoretically, concomitant use of L-arginine and antihypertensive drugs may increase the risk of hypotension.
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L-arginine increases nitric oxide, which causes vasodilation (7822). Clinical evidence shows that L-arginine can reduce blood pressure in some individuals with hypertension (7818,10636,31871,32201,32167,32225,31923,32232,110383,110384). Furthermore, combining L-arginine with some antihypertensive drugs seems to have additive vasodilating and blood pressure-lowering effects (7822,20192,31854,31916).
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Theoretically, concurrent use of isoproterenol and L-arginine might result in additive effects and hypotension.
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Preliminary clinical evidence suggests that L-arginine enhances isoproterenol-induced vasodilation in patients with essential hypertension or a family history of essential hypertension (31932).
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Theoretically concomitant use of potassium-sparing diuretics with L-arginine may increases the risk of hyperkalemia.
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Theoretically, concurrent use of sildenafil and L-arginine might increase the risk for hypotension.
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In vivo, concurrent use of L-arginine and sildenafil has resulted in increased vasodilation (7822,8015,10636). Theoretically, concurrent use might have additive vasodilatory and hypotensive effects. However, in studies evaluating the combined use of L-arginine and sildenafil for erectile dysfunction, hypotension was not reported (105065).
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Theoretically, concomitant use of L-arginine and testosterone might have additive effects.
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Below is general information about the adverse effects of the known ingredients contained in the product MethylFire. Some ingredients may not be listed. This information does NOT represent a recommendation for or a test of this specific product as a whole.
General
...Orally, taking 1,3-DMAA combination products (OxyELITE Pro, AmphetaLean, or Jack3d, USPlabs) has been reported to cause cardiac arrest, atrial fibrillation, chest pressure, angina, tachycardia, palpitations, hypertension, hypotension, myocardial infarction, and acute coronary syndrome (17660,91680,94361,94362,94365,94369,94371,94377).
Increased heart rate and blood pressure have also been reported. Other reported adverse effects associated with the use of 1,3-DMAA-containing products have included life-threatening lactic acidosis (17660), nausea, vomiting, diarrhea, and abdominal pain (17663,17907,17908,94365,94371,94377), urinary changes (17663,94365,94371,94377), liver injury (94367,94368,94369), anaphylaxis (94365), muscle symptoms such as spasm or weakness (94377), neurological symptoms including tremors, insomnia, sweating, tiredness, confusion, headache, and chills (17907,17663), hemorrhagic stroke (17663,90318), pupil dilation or tinnitus (94365,94371), psychiatric symptoms such as anxiety, agitation, paranoia, and aggression (17660,17907,94365,94371,94377), or rapid breathing (17660,94371). The dose of 1,3-DMAA at which such adverse effects occur is not clear (94368).
Death has occurred in some cases following organ failure and cardiac arrest (17904,94361,94369,94374).
Topically, rubbing an eye while mixing a drink with a 1,3-DMAA-containing combination product (Jack3d) has caused pupil dilation (94368).
Cardiovascular
...Due to the stimulant effects of 1,3-DMAA, there is concern that it might increase the risk of adverse cardiovascular events similar to synephrine from bitter orange or ephedrine from ephedra.
Cardiovascular outcomes have rarely been assessed in patients taking 1,3-DMAA alone. Most adverse effects are linked to 1,3-DMAA-containing combination products. Palpitations and tachycardia are some of the most common side effects reported for adults and children taking 1,3-DMAA-containing combination products (17660,91680,94365,94371). Other less common adverse effects have included chest pressure, angina, atrial fibrillation, hypertension, hypotension, myocardial infarction, and acute coronary syndrome (17660,91680,94362,94365,94371,94377).
There is inconsistent data about the effects of 1,3-DMAA on heart rate and blood pressure (94368). For example, some research suggests that taking specific 1,3-DMAA-containing combination products (OxyELITE Pro or Jack3d, USPlabs) significantly increases systolic blood pressure and increases heart rate within 1-2 hours of taking a dose. These increases appear to be dose dependent (17906,17907,17908). However, in an 8-week study, heart rate was significantly increased, but blood pressure was not (17907). Other research shows that neither acute nor chronic intake of 1,3-DMAA increases heart rate or blood pressure (17908,94364,94368,94376). Overall, it seems that oral intake of a single dose of a 1,3-DMAA-containing product is more likely to increase systolic blood pressure. Resting blood pressure is less likely to remain increased following chronic use (94368,94379). Higher doses are more likely to increase heart rate and blood pressure. Although most sports supplements contain 25-65 mg/dose, some contain as much as 285 mg/dose (94377).
In case reports of healthy young adults taking 1,3-DMAA-containing combination products prior to exercise, cardiac arrest causing death has occurred (94361,94369).
Endocrine ...In one report, a patient who took a specific combination product containing 1,3-DMAA (Jack3d by USP Labs) prior to intense exercise experienced life-threatening lactic acidosis (17660).
Gastrointestinal ...Orally, taking 1,3-DMAA-containing combination products has been reported to cause nausea (17907,17908,94365,94371,94377), vomiting (17663,94365,94371,94377), diarrhea (94365), vomiting blood (94371), and abdominal pain (94371).
Genitourinary ...Urinary hesitancy (94365), urinary retention (94371), and uncontrolled urination (94377), have been reported following ingestion of 1,3-DMAA-containing combination products.
Hepatic ...Acute liver injury, in some cases requiring a liver transplant, has been reported following oral intake of 1,3-DMAA-containing products (94367,94368,94369).
Immunologic ...An anaphylactic reaction has been reported following oral intake of 1,3-DMAA-containing products (94365).
Musculoskeletal ...Orally, dimethylamine-containing products have caused muscle spasm (94365), muscle weakness (94377), and leg pains (94377).
Neurologic/CNS ...Orally, taking specific 1,3-DMAA-containing combination products (OxyELITE Pro or Jack3d, USPlabs) has been reported to cause feelings of jitters, sleeplessness, shakiness, chills, sweating, fatigue, tingling, and lack of focus in clinical trials (17907). Other adverse effects reported for products containing 1,3-DMAA have included headache, dizziness, tremor, numbness, flushing, seizure, blacking out, visual disturbances, confusion, and lethargy (17660,17908,94365,94368,94371,94377). In a case report, a 26 year old male reported with a hemorrhagic stroke linked to taking the supplement Jack3d, which contains 1,3-DMAA, schizandrol A, caffeine, beta-alanine, creatine, and L-arginine alpha-ketoglutarate (90318). In another report, a patient experienced a hemorrhagic stroke after taking two tablets of a product containing 1,3-DMAA 278 mg each along with caffeine 150 mg and a can of beer (17663).
Ocular/Otic ...Orally, dimethylamine-containing products have caused tinnitus (94365) and pupil dilation (94371). Pupil dilation also occurred after rubbing an eye while mixing a drink with the specific product Jack3d, containing 1,3-DMAA (94368).
Psychiatric ...Orally, taking 1,3-DMAA-containing combination products has been reported to cause feelings of anxiety (17907,94365), suicidal behavior (94365), agitation or irritability (94365,94371,94377), paranoia (94377), depression (94377), panic (94377), and aggression or combativeness (17660,94365).
Pulmonary/Respiratory ...Orally, combination products containing 1,3-DMAA have caused rapid breathing and hyperventilation (17660,94371).
Other ...There are at least two reports of death in US Army soldiers who took 1,3-DMAA supplements and suffered heat stroke and related complications following physical fitness training (17904).
General
...Orally, alpha-GPC seems to be well tolerated.
Serious Adverse Effects (Rare):
Orally: Stroke.
Dermatologic ...Orally, some patients can experience skin rash (12102). Intramuscularly, alpha-GPC can cause erythema at the injection site (12101).
Gastrointestinal
...Orally, alpha-GPC has been rarely associated with diarrhea, heartburn, nausea, and vomiting (12102).
Intramuscularly, alpha-GPC has been rarely associated with diarrhea, heartburn, nausea, and vomiting (12102).
Neurologic/CNS
...Orally, alpha-GPC has been rarely associated with dizziness, excitation, headache, and insomnia (12102).
Alpha-GPC use for at least 2 months has also been associated with an elevated risk of stroke when compared with non-users or those who used alpha-GPC for less than 2 months (108883).
Intramuscularly, alpha-GPC has been rarely associated with confusion, excitation, fainting, headache, and insomnia (12102).
General ...Orally, topically, and intravenously, alpha-ketoglutarate seems to be well tolerated.
General
...Orally, beta-alanine seems to be generally well tolerated.
Most Common Adverse Effects:
Orally: Flushing, paresthesia.
Gastrointestinal ...While rare, digestion problems have been reported with oral beta-alanine use (94341).
Neurologic/CNS ...Orally, beta-alanine can cause a dose-dependent feeling of pins and needles (paresthesias) along with skin flushing (16438,94333,94335,94338,94341,94342,94349,101028,101029,106711). This generally starts on the scalp within 20 minutes of the dose, spreading to most of the body, and lasting for about an hour. This was described as severe at a dose of 40 mg/kg, tolerable at a dose of 20 mg/kg, and very mild at a dose of 10 mg/kg. At the lowest dose it only occurred in 25% of subjects (16438). In some studies, beta-alanine has been given as frequently as 8 times per day so that each dose can be kept below 10 mg/kg (16438,16439). Other clinical research shows that taking beta-alanine in a tablet formulation eliminates the presence of parasthesias at a dose of 1.6 grams when compared with a solution made from powdered beta-alanine. This effect may be due to delayed absorption (97974,97975). Although paresthesias still occur with sustained-release formulations, their presence is less frequent when compared with immediate-release formulations (101029).
General
...BMPEA is an amphetamine derivative which can cause serious stimulant adverse effects.
Most Common Adverse Effects:
Hypertension and tachycardia.
Serious Adverse Effects (Rare):
Cardiac arrest, stroke.
Cardiovascular ...Hemorrhagic stroke was reported in a healthy 53-year-old female who took a specific supplement (Jacked Power, MM sports) 30 minutes prior to exercise. It was not labeled as containing BMPEA, but testing showed a level of 290 mg per dose (89219). A combination of BMPEA with other stimulants including synephrine, yohimbine, and caffeine has been associated with cardiac arrest and several reports of tachycardia and palpitations (21079).
General
...Orally or intravenously, BCAAs are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal distension, diarrhea, nausea, vomiting.
All routes of administration: High doses can lead to fatigue and loss of motor coordination.
Cardiovascular ...Orally, a single case of hypertension following the use of BCAAs has been reported (37143).
Dermatologic ...Orally, a single case of skin blanching following the use of BCAAs has been reported (681). It is not known if this effect was due to use of BCAAs or other factors.
Gastrointestinal ...Orally, BCAAs can cause nausea, vomiting, diarrhea, and abdominal distension. Nausea and diarrhea has been reported to occur in about 10% of people taking BCAAs (10117,37143,92643,97531).
Neurologic/CNS ...Orally and intravenously, BCAAs can cause fatigue and loss of motor coordination due to increased plasma ammonia levels (693,694,10117). Short-term use of 60 grams of BCAAs containing leucine, isoleucine, and valine for 7 days in patients with normal metabolic function seems to increase levels of ammonia, but not to toxic plasma levels (10117). However, liver function should be monitored with high doses or long-term use (10117). Due to the potential of increased plasma levels of ammonia and subsequent fatigue and loss of motor coordination, BCAAs should be used cautiously before or during activities where performance depends on motor coordination (75). Orally, BCAAs may also cause headache, but this has only been reported in one clinical trial (681).
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).
General
...Orally, creatine is generally well-tolerated.
Topically, a thorough evaluation of safety outcomes has not been conducted.
Most Common Adverse Effects:
Orally: Dehydration, diarrhea, gastrointestinal upset, muscle cramps, and water retention.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about interstitial nephritis, renal insufficiency, rhabdomyolysis, and venous thrombosis.
Cardiovascular
...Some research suggests that creatine supplementation can cause edema.
In a randomized controlled trial, 26% of patients with amyotrophic lateral sclerosis (ALS) receiving creatine 10 grams daily reported edema after 2 months of treatment compared to 9% with placebo. The difference between groups was statistically significant at 2 months but not at month 4 and beyond. Creatine is believed to cause slight water retention, which may have been more apparent in patients who were immobilized due to ALS (46647). While this adverse drug reaction did not lead to worsening cardiac function in these patients, theoretically, creatine-related water retention could worsen congestive heart failure or hypertension.
There is one case report of lone atrial fibrillation in a 30-year-old male vegetarian. He started powdered creatine 20 grams daily for 5 days, followed by 2.5 grams daily for a month. However, he discontinued powdered creatine due to severe cramping and diarrhea, and reinitiated creatine supplementation a month later with an encapsulated formulation. Aside from gelatin in the capsule, creatine was the only ingredient listed in both formulations. During the loading dose phase, the patient developed dyspnea and palpitations and was diagnosed with lone atrial fibrillation in the emergency department. Symptoms resolved with treatment and supplement discontinuation (13187). Theoretically, alterations in electrolyte balance due to dehydration or diarrhea could lead to conduction abnormalities and arrhythmia; however, in this case, the patient had normal electrolyte levels. Contaminants in dietary supplements might also be responsible for adverse reactions; this specific creatine product was not tested for contaminants. It remains unclear whether creatine was associated with this event.
Theoretically, taking creatine nitrate might reduce blood pressure and heart rate due to its nitrate component. However, clinical research shows that creatine nitrate 12 grams daily for 7 days followed by 3 grams daily for 21 days does not lower blood pressure or heart rate acutely or chronically when compared to creatine monohydrate or placebo (95959).
Dermatologic
...In a small clinical trial of older, healthy males, one subject out of the 10 receiving creatine 5 grams four times daily for 10 days followed by 4 grams daily for 20 days reported a skin rash during the study.
The type and severity of rash and whether it resolved after creatine was discontinued were not discussed (4572). Also, skin rash has been reported by patients taking celecoxib and creatine; however, whether this effect was due to creatine or celecoxib is unclear (46706).
Topically, burning, itching, redness, irritation, and perception of changes in skin temperature have been reported (104669).
Endocrine ...Creatine may influence insulin production (11330). In human research, insulin levels increased 120 and 240 minutes after creatine supplementation (46760); however, there was no effect in another trial (46732). In a clinical study, 0.3 grams/kg of creatine daily for one week significantly increased cortisol levels by 29%. However, the levels returned to baseline at week 2 (46615).
Gastrointestinal
...Some small clinical studies have reported diarrhea and vomiting with oral creatine supplementation (4584,11332,46562,46684,46698,46704,104673).
Also, gastrointestinal distress, transient abdominal discomfort, constipation, heartburn, and nausea have been reported by a small number of individuals in randomized, controlled clinical trials (4572,11332,46527,46528,46573,46589,46622,46668,46684,46695), (46704,46771,95964,104668,104669,104673,108316). However, most high-quality clinical research shows that creatine does not increase the incidence of gastrointestinal upset (103102,103278,103279).
Undissolved creatine powder may cause gastroenteritis (1368). Additionally, simultaneous intake of creatine and caffeine powder may increase the occurrence of gastrointestinal distress (95964).
Hematologic ...There are two case reports of creatine-related venous thrombosis in otherwise healthy adults. In the first case, an active 18-year-old male who had been taking an unspecified dose of creatine daily for 3 months was diagnosed with venous thrombosis via MRI. The patient reported increased thirst and fluid consumption when taking creatine. In the second case, an active 31-year-old male who had recently taken a 5-hour flight was diagnosed with deep vein thrombosis. He had been taking an unspecified dose of creatine. After stopping creatine and receiving anticoagulation therapy for 6 months, both patients' thromboses were resolved and did not recur. Researchers speculate that dehydration might be to blame for these adverse events, as dehydration increases the risk of thrombosis. In both cases, thrombophilic conditions were ruled out, and a temporal relationship between creatine consumption and thrombosis was established (90301). However, it remains unclear if creatine was responsible for these thrombotic events.
Hepatic
...Despite two case reports describing hepatic injury in patients taking creatine (46701,90319), meta-analyses and clinical studies specifically evaluating the safety of creatine have not identified an increased risk for hepatic injury (103278,103279).
In addition, population research suggests that there is not an association between creatine intake and liver fibrosis, cirrhosis, or hepatic steatosis. However, this study largely included subjects consuming less than 4 grams daily (112208).
One preliminary clinical trial specifically evaluated the effect of creatine loading and maintenance doses on hepatic function indices in healthy adults. No clinically significant changes in hepatic indices were reported in patients taking creatine loading doses of 20 grams daily for 5 days followed by maintenance doses of 3 grams daily for 8 weeks (46521). Another clinical study evaluated the impact of creatine monohydrate and creatine nitrate on liver function enzymes, showing no change in levels within 5 hours after the first dose of 12 grams or after continued consumption of 12 grams daily for 7 days followed by 3 grams daily for 21 days (95959). The patients that experienced hepatic injury in the available case reports were also taking other exercise supplements. Whether the reported adverse hepatic effects were due to creatine or the other supplements patients were taking is unclear. Also, neither of these case reports addressed whether the supplements were tested for contamination (46701,90319).
Musculoskeletal ...Creatine-associated increase in body mass is well documented in randomized, controlled clinical trials and is often as large as 1-2 kg during the five-day loading period of creatine (2101,4569,4589,4591,4600,4605,46504,46561,46815,46827)(46830,46843,95962,103279,112201). This may be considered an unwanted adverse reaction in some individuals and a desired effect of supplementation in others. This weight gain may interfere with mass-dependent activities such as running and swimming (46504,46823). Muscle cramping due to creatine supplementation has been reported in controlled clinical trials and may result from water retention in skeletal muscle (2104,4572,4584,30915,46562,46695,46826,46827,104673). However, most high quality clinical research shows that creatine does not increase the incidence of musculoskeletal injuries or muscle cramping (103102). In one case report, rhabdomyolysis in a weight lifter using creatine 25 grams daily over a one-year period has been reported (12820). Another case report describes an adult male who developed acute compartment syndrome of the leg after regular consumption of an unspecified amount of creatine and cocaine (112210).
Neurologic/CNS ...In clinical research, thirst, sleepiness, mild headache, and syncope have been reported for patients taking creatine, although the events were uncommon (46578,46615,46820). More serious adverse events have been reported for patients taking creatine in combination with other ingredients. A case of ischemic stroke has been reported for an athlete who consumed creatine monohydrate 6 grams, caffeine 400-600 mg, ephedra 40-60 mg, and a variety of other supplements daily for 6 weeks (1275). In another case, a 26 year old male reported with a hemorrhagic stroke linked to taking the supplement Jack3d, which contains creatine, DMAA, schizandrol A, caffeine, beta-alanine, and L-arginine alpha-ketoglutarate (90318). It is likely that these adverse events were due to other ingredients, such as caffeine, ephedra, and DMAA, which are known to have stimulant and vasoconstrictive properties.
Oncologic ...Population research shows that use of muscle building supplements such as creatine, protein, and androstenedione is associated with an increased odds of testicular germ cell cancer. This risk appears to be more apparent in early users, those using two or more muscle building supplements, and those with long-term use of the supplements. The odds of testicular germ cell cancer may be increased by up to 155% in males taking both creatine and protein supplements (90329). The risk of testicular germ cell cancer from creatine alone is unclear from this study.
Psychiatric ...Anxiety, irritability, depression, aggression, and nervousness have been reported in clinical research for patients taking creatine, although the effects are not common (46518). A case of acute organic psychosis was reported in a 32-year-old soldier in Iraq who was consuming excessive amounts of caffeine coupled with use of creatine (Creatamax, MaxiNutrition) one tablet twice daily for 3 weeks plus a specific stimulant containing bitter orange, guarana seed extract, and St. John's wort extract (Ripped Fuel Ephedra Free, Twinlabs) two tablets three times daily for 2 days prior to admission. The psychosis was considered likely due to caffeine consumption in combination with the stimulant supplement rather than creatine (37982).
Renal
...Isolated cases of renal dysfunction in patients taking creatine have been reported, including a case of interstitial nephritis in a healthy male (184) and a case of renal insufficiency in a football player (46828).
In contrast to these cases, several clinical studies and case reports have shown that creatine does not affect markers of renal function in healthy adults (2120,3996,4573,16535,46735,46749,46758,46779,46813,95959,103279). Doses studied included 5- to 7-day loading regimens of 12 to 21 grams daily (2120,46813), or maintenance doses of 3-10 grams daily for up to 2 years (16535,46712,46758,95959). In two additional studies, creatine supplementation 15.75 grams for 5 days followed by 4.25 grams daily for 20 days with carbohydrate and protein ingestion led to no change of renal stress markers (46844). Other clinical research has shown that ingestion of creatine up to 30 grams daily for 5 years is not associated with an increased incidence of renal dysfunction (103102).
Other case reports involve patients with pre-existing renal dysfunction. For example, in one case, a patient with a history of recurrent renal failure developed relapsing steroid-responsive nephritis syndrome after taking creatine (1368,2118). In another case, a patient with diabetic nephropathy who was taking creatine and metformin developed severe metabolic acidosis and acute renal failure. It is unclear if creatine contributed to this event, as metformin alone is known to cause metabolic acidosis (46738). These case reports have raised concern that individuals with pre-existing renal dysfunction may be at increased risk for renal injury with creatine supplementation. However, no prospective clinical trials have been conducted in this population to clarify this concern.
In addition, two cases of acute kidney injury and hypercalcemia have been reported in 16 year old males that took 1-4 servings of creatine for less than 4 weeks; however, the creatine product contained unlabeled, very high doses of vitamin D, which is the likely cause of these symptoms (109739).
In one survey, 13% of male collegiate athletes taking creatine reported dehydration (4584). The Association of Professional Team Physicians has warned that creatine may cause dehydration, heat-related illnesses, and electrolyte imbalances, and reduce blood volume. Mild transient dehydration resulting in an elevated serum creatinine was also reported in a single person in a clinical trial (104672). However, a study found that creatine supplementation during preseason football training had no effect on fluid or electrolyte status (46845). Additionally, most high quality clinical research shows that creatine does not increase dehydration (103102). A theoretical increase in risk of dehydration due to intracellular fluid shifts has led most creatine manufacturers to caution about adequate hydration with creatine supplementation (4576).
Other
...There have been reports of heat intolerance with oral creatine supplementation (46505).
Increases in formaldehyde production have been reported with creatine use. A-24 year-old man taking supratherapeutic doses of creatine monophosphate in combination with an energy supplement developed malignant hyperthermia after undergoing anesthesia. His symptoms included tachycardia, hypertension, hypercarbia, and hyperthermia. Environmental factors are suspected to have played a role in the development of malignant hyperthermia, so whether this adverse event was due to creatine at all is unclear (46717).
In 1997, three collegiate wrestlers died after engaging in a rapid weight-loss program in order to qualify for competition (93628). Initially creatine supplementation was considered to have contributed to or caused these deaths (12820,93629); however, investigations by the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) did not confirm this belief (12820,93630). It appears that only one of the three wrestlers had been using creatine. Instead, the deaths were related to drastic, short-term weight loss in which the wrestlers wore rubber suits, avoided hydration, and performed workouts in rooms with temperatures up to 33 °C (1368,93631).
General
...Orally, deanol seems to be well tolerated (1668,1671,1672,1673,1674,1675,1676,1679,1680,1681).
However, deanol has been reported to cause constipation, diarrhea, urticaria, headache, drowsiness, insomnia, overstimulation, lucid dreams, confusion, motor retardation, depression, hypomania, and an increase in schizophrenia symptoms (1674,1680,1684,1685,1686,2706).
Most Common Adverse Effects:
Orally: Abdominal cramps, abdominal pain, diarrhea, drowsiness, nausea, vomiting.
Cardiovascular ...Orally, small elevations in blood pressure have been reported in some patients taking deanol up to 1800 mg daily. These effects improved after deanol discontinuation (1680).
Gastrointestinal ...Orally, deanol has been reported to cause diarrhea, abdominal cramps, abdominal pain, nausea, and vomiting (1674,1680).
Musculoskeletal ...Orally, deanol up to 1800 mg daily has been reported to cause motor retardation in a small number of patients. This effect improved after deanol discontinuation (1680).
Neurologic/CNS ...Orally, deanol has been reported to cause drowsiness, apathy, and confusion (1674,1680). In one case report, a physician promoted the use of deanol to induce lucid dreams, which may be considered an undesirable outcome for some patients (1686).
Psychiatric ...Orally, taking deanol at doses greater than 1000 mg daily has been reported to cause mood changes, including depression and hypomania, in patients with psychiatric conditions (1685). Deanol 1500 mg daily has been reported to increase schizophrenic symptoms in patients with chronic schizophrenia (1674).
General
...Orally and intravenously, glutamine is generally well tolerated.
Most Common Adverse Effects:
Orally: Belching, bloating, constipation, cough, diarrhea, flatulence, gastrointestinal pain, headache, musculoskeletal pain, nausea, and vomiting.
Endocrine ...One case of hot flashes has been reported in a patient taking glutamine 5-15 grams orally twice daily for up to 1 year (96520).
Gastrointestinal ...Orally, glutamine has been associated with belching, bloating, constipation, flatulence, nausea, vomiting, diarrhea, and gastrointestinal (GI) pain. Nausea, vomiting, constipation, diarrhea, and GI pain have been reported in clinical trials using high-dose glutamine 10-30 grams (0.3 grams/kg) in two divided doses daily to treat sickle cell disease (99414). One case of dyspepsia and one case of abdominal pain have been reported in patients taking glutamine 5-15 grams twice daily orally for up to 1 year (96520). In a small trial of healthy males, taking a single dose of about 60 grams (0.9 grams/kg of fat free body mass [FFM]) was associated with a 50% to 79% incidence of GI discomfort, nausea, and belching, compared with a 7% to 28% incidence with a lower dose of about 20 grams (0.3 gram/kg FFM). Flatulence, bloating, lower GI pain, and urge to regurgitate occurred at similar rates regardless of dose, and there were no cases of heartburn, vomiting, or diarrhea/constipation (105013). It is possible that certain GI side effects occur only after multiple doses of glutamine.
Musculoskeletal ...Orally, glutamine 30 grams daily has been associated with cases of musculoskeletal pain and non-cardiac chest pain in clinical trials for patients with sickle cell disease (99414).
Neurologic/CNS ...Orally, glutamine has been associated with dizziness and headache. A single case of dizziness has been reported in a patient treated with oral glutamine 0.5 grams/kg. However, the symptom resolved after reducing the dose to 0.25 grams/kg (91356). Mania and hypomania have been reported in 2 patients with bipolar disorder taking commercially purchased glutamine up to 4 grams daily (7291). Glutamine is metabolized to glutamate and ammonia, both of which might have neurological effects in people with neurological and psychiatric diseases or in people predisposed to hepatic encephalopathy (7293).
Oncologic ...There is some concern that glutamine might be used by rapidly growing tumors and possibly stimulate tumor growth. Although tumors may utilize glutamine and other amino acids, preliminary research shows that glutamine supplementation does not increase tumor growth (5469,7233,7738). In fact, there is preliminary evidence that glutamine might actually reduce tumor growth (5469).
Other ...Orally, glutamine has been associated with cough when a powdered formulation is used. It is unclear if this was due to accidental inhalation. One case of a burning sensation and one case of hypersplenism has been reported in a patient taking glutamine 5-15 grams twice daily orally for up to 1 year (96520).
General
...Oral, intravenous, and topical L-arginine are generally well tolerated.
Most Common Adverse Effects:
Orally: Abdominal pain, bloating, nausea, diarrhea, headache, insomnia, flushing.
Intravenously: Excessively rapid infusion can cause flushing, headache, nausea and vomiting, numbness, and venous irritation.
Cardiovascular ...L-arginine taken orally by pregnant patients in a nutrition bar containing other antioxidants was associated with a 36% greater risk of palpitations when compared with a placebo bar (91197). It is unclear if this effect was due to L-arginine, other ingredients, or other factors.
Dermatologic ...Orally, arginine can cause flushing, rash, and hives (3460,32138,102587,104223). The skin reactions were likely of allergic etiology as oral L-arginine has been associated with eosinophilia (32138). In one case report, intravenous administration caused allergic reactions including urticaria, periorbital edema, and pruritus (11830). Excessively rapid infusion of L-arginine has caused flushing, local venous irritation, numbness. Extravasation has caused necrosis and superficial phlebitis (3330,16817).
Gastrointestinal
...Orally, L-arginine has been reported to cause nausea, diarrhea, vomiting, dyspepsia, gastrointestinal discomfort, and bloating (1363,31855,31871,31972,31978,32261,90198,91197,96811,99243)(102587,102592).
Orally, L-arginine has been reported to cause esophagitis in at least six adolescents. Symptoms, which included pain and dysphagia, occurred within 1-3 months of treatment in most cases (102588). There are at least two cases of acute pancreatitis possibly associated with oral L-arginine. In one case, a 28-year-old male developed pancreatitis after consuming a shake containing 1.2 grams of L-arginine daily as arginine alpha-ketoglutarate. The shake also contained plant extracts, caffeine, vitamins, and other amino acids. Although there is a known relationship between L-arginine and pancreatitis in animal models, it is not clear if L-arginine was directly responsible for the occurrence of pancreatitis in this case (99266).
Intravenously, excessively rapid infusion of L-arginine has been reported to cause nausea and vomiting (3330,16817).
Musculoskeletal ...Intravenous L-arginine has been associated with lower back pain and leg restlessness (32273). Orally, L-arginine has been associated with asthenia (32138).
Neurologic/CNS ...Orally, L-arginine has been associated with headache (31855,31955,32261,91197,102587,102592), insomnia, fatigue (102587,102592), and vertigo (32150,102592).
Oncologic ...In breast cancer patients, L-arginine stimulated tumor protein synthesis, which suggests stimulated tumor growth (31917).
Pulmonary/Respiratory ...When inhaled, L-arginine can cause airway inflammation and exacerbation of airway inflammation in asthma (121). However, two studies assessing oral L-arginine in patients with asthma did not detect any adverse airway effects (31849,104223).
Renal ...Intravenously, L-arginine has been associated with natriuresis, kaliuresis, chloruresis, and systemic acidosis (32225). Orally, L-arginine can cause gout (3331,3595).
Other ...Orally, L-arginine has been associated with delayed menses, night sweats, and flushing (31855).
