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EFFECTIVE

• Homocystinuria. Oral betaine anhydrous is effective at reducing plasma homocysteine levels in patients with homocystinuria associated with cystathionine beta-synthase (CBS) deficiency, 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency, or cobalamin cofactor metabolism (cbl) defect. Details: Clinical research shows that taking oral betaine anhydrous reduces plasma homocysteine levels by 20% to 30% when compared with placebo in adults and children with several types of homocystinuria, including CBS deficiency, MTHFR deficiency, and cbl defect (698). Observational studies have also found that betaine anhydrous reduces plasma homocysteine levels as monotherapy, in combination with other treatments, such as pyridoxine, folate, and cobalamin, and in patients refractory to pyridoxine treatment (145,698,34956). A specific betaine anhydrous product (Cystadane, Recordati Rare Diseases Inc.) is approved by the US FDA for homocystinuria. Oral betaine anhydrous is initiated at a dose of 100 mg/kg daily in children under 3 years of age and a dose of 3 grams twice daily in children 3 years and older, then titrated to effect. Although some patients have taken up to 20 grams daily, some clinical research suggests that doses above 150 mg/kg daily do not provide additional benefit (698).

POSSIBLY EFFECTIVE

• Hyperhomocysteinemia. Oral betaine anhydrous decreases plasma homocysteine levels in people with hyperhomocysteinemia; however, any effects on cardiovascular sequela and other clinical outcomes are unclear. Details: Most clinical research in adults with normal or mildly elevated plasma homocysteine levels (<25 micromol/L) shows that taking betaine anhydrous 3-6 grams daily orally for up to 12 weeks can modestly decrease plasma homocysteine levels by 5.5% to 15% when compared with control (6810,16451,16452,34894,34896,34902,34904,34925,34936). Some research indicates that oral doses of betaine anhydrous up to 4 grams daily can lower plasma homocysteine levels without an adverse effect on lipid levels (105813). However, it is not clear whether any reduction in plasma levels of homocysteine results in a decreased risk for cardiovascular disease. In patients with kidney failure, clinical research shows that taking betaine anhydrous 4 grams daily lowers levels of plasma homocysteine after methionine loading, but does not affect fasting levels, when compared with control (16455). However, taking this dose of betaine anhydrous in combination with folate 5 mg daily does not seem to have additive homocysteine-lowering effects in patients with kidney failure when compared with folate alone (34885,34957,34963). A very small clinical study in children with hyperhomocysteinemia secondary to pyridoxine non-responsive cystathionine beta-synthase (pnrCBS) or cobalamin C (cblC) deficiencies shows that taking betaine anhydrous 100 or 250 mg/kg daily in divided doses for one month leads to similar reductions in total plasma homocysteine concentrations, suggesting that an increased dose is not beneficial in the setting of pediatric pnrCBS and cblC deficiencies. The researchers noted that increased doses of betaine anhydrous cause proportional increases in methionine concentrations, which can induce severe hypermethioninemia in patients with pnrCBS, possibly leading to increased intracranial pressure and cerebral edema. In contrast, increases in methionine and S-adenosylmethionine concentrations are desirable in patients with cblC deficiency since low concentrations of both are implicated in the pathology of cblC deficiency (111374).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Angelman syndrome. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in children with Angelman syndrome shows that taking betaine anhydrous (Cystadane, Recordati Rare Diseases, Inc.) 100-200 mg/kg daily or betaine anhydrous 6-12 grams daily for 12 months, in combination with folate, folic acid derivatives, creatine, and/or vitamin B12, does not prevent seizures or improve cognitive, motor, or language development, when compared with placebo or baseline (34932,34945).
• Athletic performance. It is unclear if oral betaine anhydrous improves athletic performance; small clinical trials have yielded conflicting findings that may be related to age, training status, and biological sex. Details: Small clinical trials in males with and without strength training experience shows that taking betaine anhydrous 2-2.5 grams daily for 10-15 days, either alone or in combination with resistance training or blood flow restriction, does not improve muscle power, strength, or performance on bench press, leg press, or squat exercises when compared with placebo (34940,34941,34947,34954,111373). In aerobic exercise training, a small clinical study in healthy untrained males shows that taking betaine anhydrous 1.25 grams twice daily with 300 mL of a sports beverage for 2 weeks does not improve aerobic capacity or performance during exhaustive endurance exercise when compared with placebo (105550). Similarly, a small clinical study in trained male runners shows that taking betaine anhydrous 5 grams once with 1000 mL of a sports beverage after becoming dehydrated does not improve long-distance running or sprinting after rehydration when compared with placebo (34916). Additional clinical research in males and females who have undergone at least 6 months of CrossFit training shows that taking betaine anhydrous 1.25 grams twice daily for 6 weeks while continuing to train does not improve muscle strength, body composition, aerobic capacity, or anaerobic performance when compared with placebo (105549). However, other research shows that betaine anhydrous benefits certain aspects of athletic performance in particular subgroups. One small clinical study in healthy, active males shows that taking betaine anhydrous 2.5 grams daily for 2 weeks improves subjective fatigue scores during exercise when compared with placebo (34941). Another small clinical study in active but untrained young females shows that taking betaine anhydrous (BetaPower, Finnfeeds) 2.5 grams daily for 8 weeks in combination with a structured resistance training program reduces body fat percentage and body fat mass, but does not improve muscle strength, when compared with placebo (98525). Another small clinical study in active females shows that taking betaine anhydrous 1.2 grams twice daily for 2 weeks improves power output during sprinting, but not oxygen uptake, when compared with placebo (107950). Betaine anhydrous has also been studied in adolescents. Preliminary clinical research in trained adolescent soccer players shows that taking betaine 1 gram twice daily orally with 300 mL water for 14 weeks improves muscle power, agility, and sprint time, but not muscle strength, when compared with placebo (108654).
• Colorectal adenoma. It is unclear if oral betaine anhydrous reduces the risk of colorectal adenoma. Details: Preliminary population research has found that high dietary betaine intake is not associated with a reduced risk of colorectal adenoma when compared with low dietary betaine intake (14845).
• Depression. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in adults with major depression shows that taking a specific combination product (DDM Metile, Omeopiacenza) containing betaine anhydrous 125 mg and S-adenosyl-L-methionine (SAMe) 250 mg orally twice daily for 12 months improves depression symptoms when compared with amitriptyline 75 mg daily. After 12 months, patients treated with the combination product showed an average improvement in depression scores of 38%, compared with 18% in patients treated with amitriptyline (90107). It is unclear if this effect is due to betaine anhydrous, SAMe, or the combination.
• Dry mouth. It is unclear if topical betaine anhydrous is beneficial in patients with dry mouth. Details: Applying betaine anhydrous 4% topically twice daily in a toothpaste for 2 weeks reduces symptoms of dry mouth when compared with baseline (6812). Other preliminary clinical research in adults with dry mouth shows that using a specific mouthwash product (Xeros Dentaid) that contains betaine anhydrous 1.33%, xylitol 3.3%, and sodium fluoride 0.05%, each evening for 4 weeks improves dry mouth symptoms when compared with baseline (34944). It is unclear if this effect is due to betaine anhydrous, other ingredients, or the combination. Additionally, the validity of the findings from these studies is limited by the lack of a comparator group.
• Fibrocystic breast disease. Although there has been interest in using oral betaine anhydrous for fibrocystic breast disease, there is insufficient reliable information about the clinical effects of betaine anhydrous for this purpose.
• Gastroesophageal reflux disease (GERD). Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a combination of betaine anhydrous 100 mg, melatonin 6 mg, L-tryptophan 200 mg, vitamin B6 25 mg, folic acid 10 mg, vitamin B12 50 mcg, and methionine 100 mg daily for 40 days reduces symptoms of GERD in more patients when compared with omeprazole 20 mg daily. Symptom improvement occurred in 100% of patients who took this combination supplement, compared with only 66% of patients taking omeprazole (16011). It is unclear if this effect is due to betaine anhydrous, other ingredients, or the combination.
• Gingivitis. Topical betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study of patients with gingivitis shows that brushing with a toothpaste containing a combination of extra virgin olive oil, xylitol, and betaine anhydrous daily for 4 months decreases gingival bleeding and improves markers associated with gingival health when compared with placebo and commercial toothpaste (111372).
• Hepatitis C. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking pegylated interferon alpha and ribavirin in combination with betaine anhydrous (Cystadane, Recordati Rare Diseases, Inc.) and S-adenosyl-L-methionine (SAMe) daily for 12 months induces early virological response in approximately 60% of patients with hepatitis C who were previously unresponsive to treatment with pegylated interferon alpha and ribavirin. However, sustained virological response only occurred in 10% of these patients (20465). The validity of this study is limited by the lack of a comparator group. Also, it is unclear if this effect is due to betaine anhydrous, SAMe, or the combination.
• Metabolic Syndrome. It is unclear if oral betaine anhydrous is beneficial in patients with metabolic syndrome. Details: A large observational study in older adults with overweight or obesity and metabolic syndrome has found that increased dietary intake of betaine for 1 year is associated with reduced body weight, waist circumference, glycated hemoglobin (HbA1c), body weight, and triglycerides and increased levels of high-density lipoprotein (HDL) cholesterol (111375).
• Nonalcoholic steatohepatitis (NASH). It is unclear if oral betaine anhydrous is beneficial in patients with NASH. Details: Preliminary clinical research shows that taking betaine anhydrous 10 grams twice daily orally for 12 months improves NASH scores when compared with placebo (34928). Taking betaine anhydrous also normalizes liver enzyme levels and reduces inflammation and fibrosis when compared with baseline (10631,34928).
• Obesity. It is unclear if oral betaine anhydrous is beneficial in patients with obesity. Details: Preliminary clinic research in obese adults on a reduced-calorie diet shows that taking betaine anhydrous 3 grams orally twice daily for 12 weeks does not reduce body weight or fat mass or improve resting energy expenditure when compared with placebo (16452). A meta-analysis of small randomized controlled trials that studied the effects of betaine anhydrous on body composition also shows that taking betaine 1.5-20 grams daily for 2-52 weeks does not reduce body mass, fat mass, or fat-free mass when compared with control. However, the validity of this study is limited by inclusion of obese, non-obese, and healthy patients (108653).
• Osteoarthritis. Although there has been interest in using oral betaine anhydrous for osteoarthritis, there is insufficient reliable information about the clinical effects of betaine anhydrous for this purpose.
• Rett syndrome. Oral betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in female children with Rett syndrome shows that taking a combination of folate 15 mg and betaine anhydrous 6-12 grams orally daily for 12 months does not improve motor function, growth, or development when compared with placebo. In addition, one subgroup analysis suggests that taking the combination product may reduce head circumference growth rate (34922).
• Sunburn. Topical betaine anhydrous has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research in healthy adults shows that applying a specific cream (Physiogel AI), which contains betaine anhydrous 0.36%, N-palmitoylethanolamine 0.3%, N-acetylethanolamine 0.21%, and sarcosine 0.24%, daily for one month prior to ultraviolet (UV) light exposure can reduce UV-induced redness when compared with placebo. However, application of this cream only once 20 minutes prior to UV exposure does not have any effect (34905). It is unclear if any benefits are due to betaine anhydrous, other ingredients, or the combination. More evidence is needed to rate betaine anhydrous for these uses.

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POSSIBLY EFFECTIVE

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

POSSIBLY INEFFECTIVE

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

INSUFFICIENT RELIABLE EVIDENCE to RATE

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

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LIKELY SAFE ...when used orally and appropriately in doses of up to 6 grams daily (698,10631). However, some patients have used up to 20 grams daily with apparent safety (698). Betaine anhydrous is available as an FDA-approved prescription product (Cystadane) (698), and also as a supplement. The European Food Safety Authority states that betaine anhydrous is safe to use in doses up to 6 mg/kg daily, in addition to usual dietary intake (105548). There is insufficient reliable information available about the safety of topical betaine anhydrous.

CHILDREN: LIKELY SAFE
when used orally and appropriately in doses up to 150 mg/kg daily (698). However, some patients have used up to 20 grams daily with apparent safety (698). Prescription betaine anhydrous (Cystadane) is approved by the US FDA for use in infants and children (698).

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

(Read more about BETAINE ANHYDROUS)

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

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

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

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

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

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General ...Orally, betaine anhydrous is generally well tolerated.
Most Common Adverse Effects:
Orally: Body odor, diarrhea, elevated cholesterol levels, GI distress, nausea, vomiting.
Serious Adverse Effects (Rare):
Orally: Cerebral edema.

Cardiovascular ...Betaine anhydrous might have adverse effects on the plasma lipid profile. Some studies have reported a 3% to 4% increase in total and low-density lipoprotein (LDL) cholesterol levels with betaine anhydrous 6 grams daily (16452,16455,16456,34904). A meta-analysis of 6 studies in adults, some with obesity and/or prediabetes, shows that taking betaine anhydrous 4-6 grams daily for 6-24 weeks is associated with a mean increase in total cholesterol of 4 mg/dL, with no significant change in LDL cholesterol, high-density lipoprotein (HDL) cholesterol, or triglyceride levels (105814). Another meta-analysis of 12 studies, some in healthy adults and others in adults with various disease states, shows that taking betaine anhydrous 1.5-20 grams daily for 2-52 weeks is associated with a mean increase in total cholesterol of 14 mg/dL, and a mean increase in LDL cholesterol of 10 mg/dL, with no change in triglyceride or HDL cholesterol levels (105813).

Gastrointestinal ...Orally, betaine anhydrous can cause vomiting, nausea, GI distress, and diarrhea (698,10631,34888,34928,111374).

Neurologic/CNS ...When used orally to treat homocystinuria due to cystathionine beta-synthase deficiency, elevated plasma methionine concentrations can occur following use of betaine anhydrous, which might lead to cerebral edema (698,111374).

Other ...Orally, betaine anhydrous can cause body odor (698,10631).

(Read more about BETAINE ANHYDROUS)

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

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

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

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

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