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Methionine

Nutrient Name: Methionine.
Synonyms:DL-Methionine,L-methionine.
Related Substance: S-adenosylmethionine (SAM, SAMe; AdoMet).

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Acetaminophen /	Methionine appears to reduce toxic effects of acetaminophen, especially on liver. Long-term, well-designed clinical trials are warranted.	Coadminister, possibly within same dose.
Levodopa ( L-dopa) / / /	Methionine administration (500-1000 mg/day) may benefit individuals with Parkinson’s disease, but high doses (> 4 g/day) may interfere with action of levodopa. Multinutrient support is important to protect against elevated homocysteine (Hcy) associated with Parkinson’s disease and possibly aggravated by levodopa therapy. Long-term, well-designed clinical trials are warranted.	Consider administration of methionine at low to midrange doses along with folate, B⁶, and B¹²; monitor serum total Hcy. Monitor for interference with levodopa via symptoms.

nutrient description

Chemistry and Forms

DL-Methionine,L-methionine.

Physiology and Function

Methionine is an essential sulfur-containing amino acid that facilitates and helps initiate the translation of messenger RNA (mRNA) by being the first amino acid incorporated into the N-terminal position of all proteins. The terminal methyl group of the methionine side chain often participates in biochemical methyl transfer reactions, making methionine a member of the “methyl donor” class of biochemicals.

S-adenosylmethionine (SAMe) is intimately involved in the synthesis of brain chemicals and also in detoxification reactions. Methionine is converted into SAMe, which is considered to be the activated form of methionine. This occurs in the first step of the metabolism of methionine, which requires energy in the form of adenosine triphosphate (ATP). In this activation of methionine, an adenosyl moiety is transferred from the ATP molecule. SAMe is one of the most potent methyl donors and is involved in many methylation reactions. Its methyl group, which is attached in a sulfonium linkage with high-energy characteristics, may be donated to any of a large number of methyl-group acceptors in the presence of the appropriate enzyme. DNA methylation influences the expression of many genes and depends on the availability of methyl groups from SAMe. SAMe is intimately involved in the synthesis of neurotransmitters and also in detoxification reactions.

Along with inositol, choline (tetramethylglycine), and betaine (trimethylglycine), methionine is considered a member of the group of compounds called lipotropics that are closely involved in lipid metabolism. Transmethylation metabolic pathways closely interconnect choline, methionine, methyltetrahydrofolate (methyl-THF), and vitamins B6and B12. Methionine can be formed from homocysteine using methyl groups from methyl-THF, or using methyl groups from betaine that are derived from choline. Through interrelated pathways, methyl-THF can be formed from one-carbon units derived from serine or from the methyl groups of choline via dimethylglycine, and choline can be synthesized de novo using methyl groups derived from methionine (via SAMe).

Methionine regulates several sulfur-containing compounds in the body that play an important role in liver detoxification processes and the synthesis of structural proteins and enzymes. It acts as a sulfur donor and, as such, is the source of sulfur for biosynthesis of cysteine. Methionine is also the precursor for the synthesis of cystine and taurine and is one of three amino acids required for the synthesis of creatine. Methionine may serve as a precursor for the synthesis of glutathione, which is the substrate for glutathione peroxidase, a crucial antioxidant enzyme. Methionine assists in the metabolism of homocysteine and helps reduce histamine levels.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Methionine is an essential amino acid which is primarily administered to enhance liver functions such as detoxification and lipid metabolism and to support the function of the central nervous system (CNS) and neurotransmitters. In nutritional therapeutics, methionine can be used to increase levels of SAMe, reduced glutathione (GSH), taurine, and N-acetylcysteine (NAC) and to promote detoxification of xenobiotics via the sulfation pathway.

Historical/Ethnomedicine Precedent

Not used historically as an isolated nutrient.

Possible Uses

Acrodermatitis enteropathica, AIDS-related dementia, AIDS-related nervous system degeneration, fat maldigestion, human immunodeficiency virus (HIV) support, liver detoxification, migraine headaches, pain control, pancreatitis, Parkinson’s disease, radiation effects, schizophrenia, urinary tract infections, weight loss, Wilson’s disease.

Deficiency Symptoms

Typical symptoms associated with methionine deficiency include hair loss, hepatic dysfunction, poor skin tone, and toxic elevation of metabolic waste products.

Methionine deficiency is usually related to overall protein malnutrition. Individuals with acquired immunodeficiency syndrome (AIDS) demonstrate low levels of methionine. Experimentally, a methionine deficiency causes premature atherosclerosis in monkeys, especially if they are also deficient in vitamin B6. Methionine deficiency can also cause a folate deficiency since a deficiency causes 5-methyl-THF to accumulate in the liver. Lower methionine intake during pregnancy has been associated with neural tube defects in newborns.

Dietary Sources

Dairy products, fish, and meat (beef, chicken, pork, liver) are considered the richest dietary sources of methionine. Sunflower seeds, pumpkin seeds, sesame seeds, and lentils are also good sources of methionine. Egg yolks are particularly high in sulfur. Methionine and cysteine make up 91% of the sulfur in the yolk. Endogenous gut flora may be able to synthesize significant amounts. Homocysteine in the diet can eliminate the requirement for methionine.

Soybeans are a poor source, and soy-based infant formulas are generally low in methionine.

Dosage Forms Available

Capsule, powder, tablet; oral and intravenous (IV) administration.

Source Materials for Nutrient Preparations

MostL-methionine in supplements is produced by bacterial fermentation processes in a growth medium, from which the amino acid is then purified. Methionine used in supplements is frequently of theDLform, which implies chemical synthesis, thus resulting in a racemic mixture.

Dosage Range

Adult

Dietary: No reference (recommended) daily intake (RDI) has been established. Average intake in the United States is 2.7 to 5 g per day.
Supplemental/Maintenance: Dietary sources of methionine are usually adequate so supplemental methionine is usually not considered necessary. Optimal levels of intake have not been established but probably are 800 to 1000 mg daily, depending on weight, diet, and related factors.
Pharmacological/Therapeutic: 500 to 3000 mg per day.
Toxic: No toxic dose level has been reported.

Pediatric (<18 Years)

Dietary: No minimal dietary requirement established.
Supplemental/Maintenance: Not currently recommended for children.
Pharmacological/Therapeutic: Specific treatment recommendations have not established.
Toxic: No toxic dosage level established specifically for infants and children.

Laboratory Values

Serum or Plasma Methionine

Range of normal levels for plasma methionine:

Children: 13 to 30 µmol/L
Adults: 16 to 30 µmol/L

safety profile

Overview

Methionine is usually tolerated well by most adults and generally considered to be free of adverse effects for most individuals at common dosage levels (e.g., 1-3 g/day). Toxicity is rare but possible with excessive dosage. Diets high in methionine may be associated with an increased occurrence of atherosclerosis, especially with concurrent deficiencies of vitamin B6, vitamin B12, and folic acid, resulting from elevations of blood homocysteine levels.

Nutrient Adverse Effects

General Adverse Effects

Nausea and gastrointestinal (GI) irritation are the primary signs of methionine toxicity, although occurrence is rare. Some sensitive individuals may experience gas, bloating, and digestive discomfort at levels as low as 500 mg per day. Other symptoms reportedly associated with methionine toxicity may include anorexia, ataxia, hyperactivity, reduced growth, hemosiderosis, and suppressed hematocrit. Extremely high doses may increase urinary calcium excretion and could potentially induce hallucinations. However, administration of up to 2 g daily for extended periods has not been associated with any serious adverse effects.

Rats fed methionine as 50% of dietary protein (equivalent human dose of 25 g/day) exhibited hyperactivity, anorexia, reduced growth, and iron accumulation in the spleen.

Pregnancy and Nursing

Evidence is lacking within the scientific literature to suggest or confirm any adverse effects related to fetal development during pregnancy or to infants who are breast-fed associated with methionine administration. Caution still advised.

Infants and Children

No adverse effects have been reported. However, sufficient research-based evidence is lacking to guarantee the safety of methionine in infants and children.

Contraindications

Avoid S-adenosylmethionine (SAMe) in Parkinson’s disease; administration may aggravate symptoms caused by serotonergic effect.

Precautions and Warnings

Large intakes of methionine require higher intakes of methyl donor–related nutrients, such as B12, folic acid, pyridoxine, choline (tetramethylglycine), betaine (trimethylglycine), and dimethylglycine. Large loads of dietary methionine without concomitant intake of these interdependent nutrients at adequate levels can increase the conversion of methionine to homocysteine (Hcy) and will result in higher levels of Hcy, a vasculotoxic product of intermediary metabolism. Need for methyl donor nutrients in relation to methionine intake varies according to pharmacogenomic determinants, such as methyl-THF reductase enzyme activity. In cases of strong family history of coronary heart disease, it would be judicious to check Hcy levels before and during methionine treatment, because of the potential homocysteinergic and atherogenic effects of methionine.

Animal research conducted by Toborek and Hennig ¹ suggests that high dietary intake of methionine, in the presence of B-vitamin deficiencies, may increase the risk for atherosclerosis by increasing blood levels of cholesterol and Hcy. Troen et al. ² observed that apolipoprotein E–deficient mice fed methionine-rich diets developed significant atheromatous pathology in the aortic arch, even with normal plasma Hcy levels. These findings suggest that moderate increases in methionine intake are atherogenic in susceptible mice.

Administration may be inappropriate in individuals with osteoporosis because high dosage levels increase urinary excretion of calcium.

interactions review

Strategic Considerations

The issue of methionine function and exogenous administration in individuals with Parkinson’s disease and related degenerative neurotransmitter conditions remains unclear, inconclusive, and contentious. Preliminary research by Smythies and Halsey suggests that methionine (5 g/day) may help ameliorate some symptoms of Parkinson’s disease. However, some authors have suggested that exogenous methionine, as with other amino acids, may interfere with the absorption or action of the levodopa, particularly in the treatment of individuals with Parkinson’s disease. Several studies have reported elevated plasma levels of total Hcy, along with decreased methionine and SAMe, in patients treated long term with levodopa and dopa decarboxylase inhibitors (DDIs) as a result of alterations in levels of substrates of the O-methylation cycle. ³

Several studies have investigated the use of methionine coadministration as a means of reducing toxicity caused by acetaminophen and suggested the probable benefits of such an integrative approach to prescribing.

Viewing methionine administration or supplementation within the larger context of wellness and therapeutics, it is important to note that increasing intake of methionine without providing for adequate intake of folic acid, vitamin B6, and vitamin B12can augment the conversion of methionine to Hcy and thereby increase cardiovascular risk.

nutrient-drug interactions

Acetaminophen

Acetaminophen (APAP, paracetamol; Tylenol); combination drugs: acetaminophen and codeine (Capital and Codeine; Phenaphen with Codeine; Tylenol with Codeine); acetaminophen and hydrocodone (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); acetaminophen and oxycodone (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); acetaminophen and pentazocine (Talacen); acetaminophen and propoxyphene (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic); acetaminophen, butalbital, and caffeine (Fioricet).

	Prevention or Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, Not Requiring Professional Management

Probability: 2. Probable to 1. Certain
Evidence Base:

Emerging

Effect and Mechanism of Action

Methionine appears to reduce the toxic effects of acetaminophen (paracetamol), particularly on the liver, without adversely affecting (and possibly enhancing) the drug’s pharmacokinetics and efficacy. Glutathione is most likely central to such activity, but the mechanisms involved have yet to be fully elucidated. The observed phenomenon might relate to empirical reports of methionine use in liver detoxification; however, the available evidence is not sufficient to support such an extrapolation. Further research is warranted to investigate the mechanisms of action responsible for the observed effects.

Research

Acetaminophen (paracetamol) poisoning is a major source of morbidity and mortality and represents one of the most common examples of adverse drug reactions in conventional medical practice. Numerous studies have demonstrated that coadministration of methionine may be effective in the treatment of acetaminophen toxicity. For more than a decade, various researchers and clinicians have proposed that methionine be incorporated into acetaminophen tablets routinely as a protective mechanism against acetaminophen-induced toxicity.

Skoglund and Skjelbred ⁴ conducted a randomized, single-blind, between-patient study comparing the onset of analgesia, duration, and efficacy of paracetamol versus a combination medication containing free paracetamol and its N-acetylmethionate ester (SUR 2647) in outpatients after oral surgery. Using several subjective and objective assessments, the authors reported that median onset of analgesia for both groups was approximately equivalent (i.e., ≤½ hour) and that the duration of analgesia after the combination was greater than that for paracetamol (i.e., ≥5.5 hours vs. ≥2.5 hours). Furthermore, the combination regimen reduced pain significantly more than the paracetamol from ½ to 3 hours after initiation of medication, but the mean pain scores did not show a significant difference during the remaining observation period. Subjects in both treatment groups reported mild to moderate drowsiness, but it was more common in subjects given the paracetamol/methionine combination.

Research by Neuvonen et al. ⁵ indicates that methionine might protect against the hepatotoxic effects of acetaminophen. Using a rat model, they compared the analgesic effect, toxicity, and kinetics of oral paracetamol with those of paracetamol+ L-methionine (5:1). They reported that the presence of methionine did not significantly change the analgesic effect of paracetamol, but that methionine reduced the acute toxicity (LD ⁵⁰ ) of paracetamol by 50% in nonfasted, fasted, and phenobarbital-pretreated mice. Subsequently, in a small, randomized crossover study involving 10 human subjects, they observed that coadministration of methionine (300 mg) did not alter the pharmacokinetics of paracetamol (1500 mg). Furthermore, they found that the “absorption of methionine from the combination tablets was rapid, peak concentrations occurred in plasma at 30 min and were 3-4 times higher than after paracetamol tablets not containing methionine.” ⁵ In a later paper, some of these same researchers reviewed their findings and related data and rhetorically asked, “Why not add methionine to paracetamol tablets?” ⁶

Based on these concerns and the emerging pattern of evidence supporting coadministration of methionine with acetaminophen, McAuley et al. ⁷ investigated whether methionine administration might adversely affect cardiovascular risk factors through its effect on endothelial function, plasma homocysteine (Hcy), and lipid peroxidation in 16 healthy volunteers. Their findings showed no significant difference in endothelial-dependent vascular responses after acute (250 mg orally), 1 month of low-dose (250 mg daily), or 1 week of high-dose (100 mg/kg daily) methionine. Plasma Hcy concentrations demonstrated no significant differences after acute or 1 month of low-dose methionine. However, Hcy concentrations significantly increased after 1 week of high-dose methionine (100 mg/kg) daily. Thus, methionine administration at dosage levels similar to those used in combination preparations with acetaminophen do not adversely affect plasma Hcy concentrations. The observation that high-dose methionine administration can cause elevated plasma Hcy concentrations in only 1 week is consistent with other research findings on methionine administration outside the context of synergistic nutrients.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Pending release of a commercial product combining acetaminophen and methionine, health care professionals are advised that it is reasonable to coadminister the two agents, particularly for patients who take acetaminophen on a long-term basis, such as for osteoarthritis. Although definitive conclusions from large, well-designed, controlled, double-blind clinical trials is lacking at this time, the evidence thus far available strongly indicates a pattern of clinical efficacy and lack of adverse effects associated with such coordinated use. Monitoring of Hcy would be judicious with long-term use in at-risk patients.

Levodopa

Levodopa ( L-dopa; Dopar, Larodopa); combination drugs: levodopa and benserazide (co-beneldopa; Madopar); levodopa and carbidopa (Atamet, Parcopa, Sinemet, Sinemet CR); levodopa, carbidopa, and entacapone (Stalevo).

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid
	Bimodal or Variable Interaction, with Professional Management
	Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible to 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

Depletion of dopamine in the striatum of the brain plays a central role in the symptoms of Parkinson’s disease. As a dopamine precursor, levodopa is able to cross the blood-brain barrier (BBB) to enter the CNS. After being decarboxylated to dopamine in the basal ganglia, L-dopa is able to replenish depleted dopamine stores and provide symptomatic relief. Methionine may diminish the therapeutic effect of levodopa through a mechanism that has not yet been elucidated but likely to involve S-adenosylmethionine, a methyl-activated metabolite of methionine.

Amino acids (in high-protein foods or as supplements) may compete with levodopa for transport across the BBB and thereby interfere with the drug’s therapeutic activity. ⁸

S-adenosylmethionine (SAMe) is a key metabolic contributor to the recycling of Hcy. Methylation of multiple intracellular molecules, including nucleic acids and proteins, uses SAMe as the donor, which is converted to S-adenosylhomocysteine (SAH), which in turn is in equilibrium with Hcy. The regeneration of methionine, the precursor of SAMe, occurs in neurons exclusively through methionine synthase, which requires methyl-THF aznd vitamin B ¹² . Additionally, vitamin B ⁶ deficiency results in total-Hcy elevation by preventing the conversion by cystathionine synthase of Hcy to cystathionine.

Research

The use of methionine in patients with Parkinson’s disease potentially presents both problems and opportunities as a component of an integrative therapeutic strategy and when used concomitantly with levodopa. Administration of L-methionine may benefit individuals with Parkinson’s disease. ^9,10 However, the available evidence is preliminary, contradictory, and unclear. In a preliminary clinical trial involving 15 patients who had obtained maximal improvement from L-dopa, carbidopa-levodopa, and/or anticholinergic compounds, Smythies and Halsey ¹⁰ found that 10 exhibited improvement on all measures except tremor and drooling when administered methionine (500 mg with 25 mg pyridoxine), starting at 1 g daily and gradually increasing to 5 g daily over 3 weeks. The authors cautioned that such nutrient therapy “should be avoided by patients on L-dopa or Sinemet.” In a randomized, double-blind clinical trial lasting 8 days, Pearce and Waterbury ¹¹ administered 4.5 g methionine daily or placebo to 14 Parkinson’s patients who were clinically stable after at least 3 months of levodopa therapy (1.5-5.5 g/day); all subjects were restricted to 0.5 g/day dietary methionine. Concomitant methionine decreased the therapeutic effects of levodopa and exacerbated related symptoms, such as gait disturbances, increased tremor, and rigidity. The adverse effects disappeared when methionine was discontinued, although one patient declined to a state worse than at the study onset and required 7 to 10 days to recover fully. These preliminary findings suggest that high dosage levels of methionine (≥4.5 g/day) may interfere with the therapeutic effects of levodopa, whereas lower doses may be compatible. The short duration of these studies limits the ability to extrapolate these findings over a longer period because of inability to assess whether symptoms would continue to worsen or might be modified by physiological adaptation over time.

In a clinical trial involving six children with dopamine deficiency, Surtees and Hyland ¹² demonstrated that elevating levodopa concentrations in the CNS caused a fall in cerebrospinal fluid (CSF) SAMe concentration and a rise in CSF 3-methoxytyrosine concentration. No change was observed in CSF methionine concentration, and all patients had normal CSF 5-methyl-THF concentration. These findings suggest that levodopa depletes SAMe in the CNS and may also disrupt the homeostatic regulation of Hcy.

Parkinson’s patients treated with levodopa often develop elevated plasma Hcy. ^13-16 Levodopa metabolism via catechol- O-methyltransferase increases levels of the neurotoxin Hcy, which induces an axonal-accentuated degeneration in sensory peripheral nerves in vitro. ¹⁶ This pattern of drug-related elevation in plasma Hcy suggests at least one major factor in developing an understanding of the increased mortality caused by vascular disease in individuals diagnosed with Parkinson’s disease.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The available evidence can be reasonably interpreted to suggest that physicians treating individuals with Parkinson’s disease consider prescribing methionine at doses of 500 to 1000 mg daily, i.e., within the common range, for its possible benefits without introducing significant risk of interfering with the therapeutic activity of levodopa (or levodopa/carbidopa). In cases where methionine administration may be indicated, it is essential to monitor for reduced therapeutic effect of levodopa given the potential that methionine may inhibit levodopa’s antiparkinsonian effects, especially at doses of 4.5 g/day or higher. In the event of an adverse interaction, the severity is generally moderate; the rate of onset is unknown. Given the well-established risk of elevated Hcy in such cases, health care professionals treating individuals with Parkinson’s disease receiving levodopa therapy are advised to coadminister folate and vitamin B ¹² , both of which help recycle Hcy, as well as monitor fasting plasma Hcy levels.

Furthermore, concomitant tyrosine, phenylalanine, and tryptophan should be considered because levodopa can interfere with absorption of these three amino acids, thereby inducing deficiency. Notably, L-tyrosine is a direct precursor to levodopa. However, although concomitant therapy with L-tyrosine, L-phenylalanine, and L-tryptophan may be beneficial, intake needs to be separated from L-dopa by at least 2 hours because these amino acids can compete with L-dopa for absorption.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Vidarabine

Evidence:
Vidarabine (Ara-A, arabinoside; Vira-A).
Similar properties but evidence lacking for extrapolation:
Related nucleoside antivirals.

The most common use of vidarabine is as an ophthalmic preparation for the treatment of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in acute keratoconjunctivitis and recurrent superficial keratitis. The therapeutic action of vidarabine is achieved by interfering with viral DNA synthesis, specifically inhibition of S-adenosylhomocysteine hydrolase (SAH), methionine synthesis, and SAMe-dependent DNA methylation. ^17-19 Vidarabine cannot be given orally because it is metabolized in the gut, so it is usually administered intravenously or topically.

The action of vidarabine indicates a potential risk for interfering with methionine function in humans and potentially inducing a depletion of methionine with extended use. Any such depleting effect on methionine status is likely to be gradual and cumulative, but evidence from human trials is lacking. Concomitant administration of methionine (or SAMe) could theoretically interfere with the therapeutic activity of vidarabine or related antiviral medications.

It has long been established that vidarabine is known to interfere with methionine synthesis, although recent and substantial research is lacking. ^17,18 Human studies are lacking to determine whether vidarabine might induce clinically significant methionine depletion or whether methionine administration might interfere with the medication’s antiviral activity. Further research is warranted.

Physicians prescribing vidarabine for an extended period are advised to discuss options for countering the potential adverse effects of this medication. Some nutritionally oriented physicians have found value in monitoring serum methionine in their patients taking vidarabine. Close monitoring is warranted in cases where methionine administration is indicated so as to prevent potential reduction of drug efficacy.

nutrient-nutrient interactions

Antioxidants

As with other antioxidants, methionine may work synergistically to produce an antioxidant network effect. In a small but well-controlled trial, Uden et al. ²⁰ found that 2 g/day methionine in combination with several antioxidants reduced pain and recurrent attacks of pancreatitis in patients with chronic recurring pancreatitis. In a 20-week, double-blind, double-dummy crossover trial, these researchers provided treatment as two types of tablets containing daily doses of 600 µg organic selenium, 9000 IU beta-carotene, 0.54 g vitamin C, 270 IU vitamin E, and 2 g methionine. Of the 20 patients who adhered to the full protocol, six experienced an attack while on the placebo phase of the crossover trial, compared with none while on the active-treatment phase. Despite the small number of patients in the trial, these results were statistically significant in favor of the antioxidant phase, indicating that this is a large effect. Larger trials would be warranted for this difficult-to-manage clinical problem.

Folate, Vitamin B ⁶ , and Vitamin B ¹²

Methionine works synergistically with folate, vitamin B ⁶ , and vitamin B ¹² in the management of homocysteine (Hcy) and in regulating the relationships and facilitating the functions of these interconnected nutrients.

Animal studies suggest that, in the presence of B-vitamin deficiencies, high dietary intake of methionine may produce hypercholesterolemia and hyperhomocysteinemia, thereby elevating risk for atherosclerosis. ¹ These observations have not been directly confirmed by human trials. However, McAuley et al. ⁷ found that 7 g methionine daily (i.e., megadoses) can elevate blood levels of Hcy in the absence of a deficiency of folic acid, B ⁶ , or B ¹² .

Carmel et al. ²¹ studied Hcy metabolism in 22 patients with pernicious anemia (vitamin B ¹² deficiency). They found that only levels of total Hcy and cysteine were increased and only glutathione (glutamyl-cysteinyl-glycine) was decreased in cobalamin deficiency as a whole, compared with 17 control subjects. SAMe levels correlated only with methionine levels and cysteine levels only with cysteinylglycine in healthy subjects, but in cobalamin-deficient patients, SAMe correlated instead with cysteine, cysteinylglycine, and folate levels only. Significant differences appeared in clinically subgrouped cobalamin-deficient patients. The 11 B ¹² -deficient patients with neurological damage had higher mean levels of folate, SAMe, cysteine, and cysteinylglycine than did the 11 neurologically unaffected, B ¹² -deficient patients. In all patients, cobalamin therapy restored metabolic changes to normal.

Citations and Reference Literature

1.Toborek M, Hennig B. Is methionine an atherogenic amino acid? J Opt Nutr 1994;3:80-83.
2.Troen AM, Lutgens E, Smith DE et al. The atherogenic effect of excess methionine intake. Proc Natl Acad Sci U S A 2003;100:15089-15094.View Abstract
3.Muller T, Woitalla D, Hauptmann B et al. Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson’s disease. Neurosci Lett 2001;308:54-56.
4.Skoglund LA, Skjelbred P. Comparison of a traditional paracetamol medication and a new paracetamol/paracetamol-methionine ester combination. Eur J Clin Pharmacol 1984;26:573-577.View Abstract
5.Neuvonen PJ, Tokola O, Toivonen ML, Simell O. Methionine in paracetamol tablets, a tool to reduce paracetamol toxicity. Int J Clin Pharmacol Ther Toxicol 1985;23:497-500.View Abstract
6.Neuvonen PJ, Simell O, Tokola O. Why not add methionine to paracetamol tablets? Br Med J Clin Res Ed 1986;293:958.
7.McAuley DF, Hanratty CG, McGurk C et al. Effect of methionine supplementation on endothelial function, plasma homocysteine, and lipid peroxidation. J Toxicol Clin Toxicol 1999;37:435-440.View Abstract
8.Robertson DR, Higginson I, Macklin BS et al. The influence of protein containing meals on the pharmacokinetics of levodopa in healthy volunteers. Br J Clin Pharmacol 1991;31:413-417.View Abstract
9.Meininger V, Flamier A, Phan T et al. [l-Methionine treatment of Parkinson’s disease: preliminary results]. Rev Neurol (Paris) 1982;138:297-303.
10.Smythies JR, Halsey JH. Treatment of Parkinson’s disease with l-methionine. South Med J 1984;77:1577.
11.Pearce LA, Waterbury, L.D. l-Methionine: a possible levodopa antagonist. Neurology (Minneap) 1974;24:640.
12.Surtees R, Hyland K. l-3,4-Dihydroxyphenylalanine (levodopa) lowers central nervous system S-adenosylmethionine concentrations in humans. J Neurol Neurosurg Psychiatry 1990;53:569-572.View Abstract
13.Kuhn W, Roebroek R, Blom H et al. Elevated plasma levels of homocysteine in Parkinson’s disease. Eur Neurol 1998;40:225-227.
14.Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinson’s disease. Lancet 1999;354:126-127.
15.Muller T, Woitalla D, Fowler B, Kuhn W. 3-OMD and homocysteine plasma levels in parkinsonian patients. J Neural Transm 2002;109:175-179.View Abstract
16.Muller T, Renger K, Kuhn W. Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration. Arch Neurol 2004;61:657-660.View Abstract
17.Vidarabine (Vira-A). Med Lett Drugs Ther 1977;19:42-43.
18.Cantoni GL, Aksamit RR, Kim IK. Methionine biosynthesis and vidarabine therapy. N Engl J Med 1982;307:1079.View Abstract
19.Fabianowska-Majewska K, Duley JA, Simmonds HA. Effects of novel anti-viral adenosine analogues on the activity of S-adenosylhomocysteine hydrolase from human liver. Biochem Pharmacol 1994;48:897-903.View Abstract
20.Uden S, Bilton D, Nathan L et al. Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment Pharmacol Ther 1990;4:357-371.View Abstract
21.Carmel R, Melnyk S, James SJ. Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Blood 2003;101:3302-3308.
.[No authors listed.] Vidarabine (Vira-A). Med Lett Drugs Ther 1977;19(10):42-43.
.Apeland T, Mansoor MA, Strandjord RE, et al. Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol Scand 2001;103(5):294-299.
.Ben-Shlomo Y, Marmot MG. Survival and cause of death in a cohort of patients with parkinsonism: possible clues to etiology. J Neurol Neurosurg Psychiatry 1995;58:293-299.
.Benson R, Crowell B, Hill B, et al. The effects of L-dopa on the activity of methionine adenosyltransferase: relevance to L-dopa therapy and tolerance. Neurochem Res 1993;18(3):325-330.
.Bidard JN. et al. Effect de la SAM sur le catabolisme de la dopamine. J Pharmacol (Paris) 1977; 8(I):83-93.
.Bidard JN, Fonlupt P, Cronenberger L, et al. [Effect of S-adenosyl-L-methionine on the cerebral and peripheral metabolism of L-dopa.] Arch Int Physiol Biochim 1978;86(4):715-724. [French]
.Bidard JN, Sokoloff P, Cronenberger L, et al. [Effect of S-adenosyl-L-homocysteine of dopamine catabolism.] Arch Int Physiol Biochim 1979;87(2):253-264. [French]
.Bidard JN, Fonlupt P, Cronenberger L, et al. [Effect of S-adenosyl-L-methionine on the cerebral and peripheral metabolism of L-dopa.] Arch Int Physiol Biochim 1978;86(4):715-724. [French]
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