Methionine supplement, amino acid health benefit and side effects
September 20 2016 by
Ray Sahelian, M.D.

L Methionine is an essential sulfur-containing amino acid. Supplementation increases homocysteine plasma concentrations. An optimal vitamin supplementation, especially with folate, might prevent such an increase.

Cysteine and Methionine - Function in the body
The carbons and nitrogen for the synthesis of cysteine are provided by serine and the sulfur is provided by methionine. Serine reacts with homocysteine to form cystathionine. This reaction is catalyzed by cystathionine synthase. Cleavage of cystathionine by cystathionase produces cysteine and alpha ketoglutarate, which forms succinyl CoA via propionyl CoA. Since cysteine dreives its sulfur from teh essential amino acid methionine, cysteine becomes essential if it is low in the diet and the supply of mehtioninen is inadequate for cysteine synthesis. An adequate supply of of cysteine spares methionine, that is, it decreases the amount of methionine that must be degrades to produce cysteine. When cysteine is degraded, the nitrogen is converted to urea, the carbons to pyruvate, and the sulfur to sulfate, which is excreted in the urine.

At this time I am not fully clear for which clinical conditions l methionine supplementation would be of definitive benefit. I need to see many more studies to know how useful this amino acid can be when used as a single supplement.

J Neural Transm. 2014. Antioxidants L-carnitine and D-methionine modulate neuronal activity through GABAergic inhibition. Antioxidants are well known for their neuroprotective properties against reactive oxygen species in cortical neurons and auditory cells. We recently identified L-carnitine and D-methionine to be among agents that provide such protection. Here, we investigated their neuronal modulatory actions. We used cultured neuronal networks grown on microelectrode arrays to assess the effects of L-carnitine and D-methionine on network function. Spike production and burst properties of neuronal networks were used as parameters to monitor pharmacological responses. We showed that the antioxidants L-carnitine and D-methionine modulate cortical electrical spike activity primarily through GABA A receptor activation. Our findings suggest the involvement of GABAergic mechanisms that perhaps contribute to the protective actions of these compounds.

L Methionine and pancreatic cancer
Higher levels of the essential amino acid methionine in the diet is apparently associated with a reduction in pancreatic cancer risk. Previous studies have shown that alterations in the methyl group metabolism may contribute to pancreatic diseases, including pancreatic cancer. Methyl group donors could influence the risk of pancreatic cancer. Dr. Susanna C. Larsson from the Karolinska Institute, Stockholm, and associates examined the dietary levels of methionine and vitamin B6, along with the pancreatic cancer rates in two large studies -- Swedish Mammography Cohort and Cohort of Swedish Men. This comprised nearly 82,000 men and women ages 45 to 83 years. During an average follow-up of 7 years, 147 cases of pancreatic cancer were diagnosed. The risk of pancreatic cancer was 56 percent lower for individuals with the highest levels of methionine in the diet compared with those with the lowest levels, the researchers found. Foods rich in methionine include fish, poultry, meat, legumes, and dairy products. However, it is possible other factors besides methionine played a role. Gastroenterology, 2007.

Transplant Proc. 2013 June. Higher serum methionine levels as a predictive factor in patients with irreversible fulminant hepatic failure. Fulminant hepatic failure (FHF) which is characterized by acute massive liver necrosis in the absence of chronic liver disease, shows an imbalance of amino acid levels resulting from acute hepatocyte necrosis.  The markedly increased serum levels of methionine may be associated with the severity of liver damage, which could lead to impaired liver regeneration and multiple organ failure among FHF patients.

Methionine oxidation and aging.
Biochim Biophys Acta. 2005.
It is well established that many amino acid residues of proteins are susceptible to oxidation by various forms of reactive oxygen species (ROS), and that oxidatively modified proteins accumulate during aging, oxidative stress, and in a number of age-related diseases. Methionine residues and cysteine residues of proteins are particularly sensitive to oxidation by ROS. However, unlike oxidation of other amino acid residues, the oxidation of these sulfur amino acids is reversible. Oxidation of methionine residues leads to the formation of both R- and S-stereoisomers of methionine sulfoxide. We summarize here results of studies, by many workers, showing that the methionine sulfoxide content of proteins increases with age in a number of different aging models, including replicative senescence and erythrocyte aging, but not in mouse tissues during aging. Aging is associated with a loss of methionine sulfoxide reductase activities in a number of animal tissues, and mutations in mice leading to a decrease in the Msr levels lead to a decrease in the maximum life span, whereas overexpression of methionine sulfoxide reductase leads to a dramatic increase in the maximum life span.

Methionine oxidation, alpha-synuclein and Parkinson's disease.
Biochim Biophys Acta. 2005.
The aggregation of normally soluble alpha-synuclein in the dopaminergic neurons of the substantia nigra is a crucial step in the pathogenesis of Parkinson's disease. Oxidative stress is believed to be a contributing factor in this disorder. Because it lacks Trp and Cys residues, mild oxidation of alpha-synuclein in vitro with hydrogen peroxide selectively converts all four methionine residues to the corresponding sulfoxides. Both oxidized and non-oxidized alpha-synucleins have similar unfolded conformations; however, the fibrillation of alpha-synuclein at physiological pH is completely inhibited by methionine oxidation. The inhibition results from stabilization of soluble oligomers of methionine -oxidized alpha-synuclein. Furthermore, the methionine -oxidized protein also inhibits fibrillation of unmodified alpha-synuclein. The degree of inhibition of fibrillation by Met-oxidized alpha-synuclein is proportional to the number of oxidized methionines. However, the presence of metals can completely overcome the inhibition of fibrillation of the methionine -oxidized alpha-synuclein. Since oligomers of aggregated alpha-synuclein may be cytotoxic, these findings indicate that both oxidative stress and environmental metal pollution could play an important role in the aggregation of alpha-synuclein, and hence possibly Parkinson's disease. In addition, if the level of Met-oxidized alpha-synuclein was under the control of methionine sulfoxide reductase (Msr), then this could also be factor in the disease.

The critical role of methionine 35 in Alzheimer's amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity.
Biochim Biophys Acta. 2005. Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, KY
Amyloid beta-peptide has been proposed to play a central role in the pathogenesis of Alzheimer's disease, a neurodegenerative disorder associated with cognitive decline and aging. AD brain is under extensive oxidative stress, and Abeta(1-42) has been shown to induce protein oxidation, lipid peroxidation, and reactive oxygen species formation in neurons and synaptosomes, all of which are inhibited by the antioxidant vitamin E. Additional studies have shown that Abeta(1-42) induces oxidative stress when expressed in vivo in Caenorhabditis elegans, but when methionine 35 is replaced by cysteine, the oxidative stress is attenuated. This finding coupled with in vitro studies using mutant peptides have demonstrated a critical role for methionine 35 in the oxidative stress and neurotoxic properties of Abeta(1-42). In this review, we discuss the role of methionine 35 in the oxidative stress and neurotoxicity induced by Abeta(1-42) and the implications of these findings in the pathogenesis of AD.

Risks of excess
Nutr Res Pract. 2015. Effects of excessive dietary methionine on oxidative stress and dyslipidemia in chronic ethanol-treated rats. The aim of this study was to examine the effect of high dietary methionine (Met) consumption on plasma and hepatic oxidative stress and dyslipidemia in chronic ethanol fed rats. Male Wistar rats were fed control or ethanol-containing liquid diets supplemented without (E group) or with DL-Met at 0.6% (EM1 group) or 0.8% (EM2 group) for five weeks. Plasma aminothiols, lipids, malondialdehyde (MDA), alanine aminotransferase (ALT), and aspartate aminotransferase were measured. Hepatic folate, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured. DL-Met supplementation was found to increase plasma levels of homocysteine (Hcy), triglyceride (TG), total cholesterol (TC), and MDA compared to rats fed ethanol alone and decrease plasma ALT. However, DL-Met supplementation did not significantly change plasma levels of HDL-cholesterol, cysteine, cysteinylglycine, and glutathione. In addition, DL-Met supplementation increased hepatic levels of folate, SAM, SAH, and SAM:SAH ratio. Our data showed that DL-Met supplementation can increase plasma oxidative stress and atherogenic effects by elevating plasma Hcy, TG, and TC in ethanol-fed rats. The present results demonstrate that Met supplementation increases plasma oxidative stress and atherogenic effects by inducing dyslipidemia and hyperhomocysteinemia in ethanol-fed rats.

Q. Hi, I would like to ask why on your website you don't mention methionine as one way to increase SAM-e levels? You mention that TMG should help and I agree. But SAM-e is supposedly synthesized primarily out of methionine. Is it
because increased homocysteine levels associated with methionine supplementation?
   A. This is a good question, we just don't have enough experience and knowledge on the interaction with methionine supplmentation and its influence on SAM-e to say much at this time.

Q. Can a methionine supplement be used the same day as curcumin or the herb saw palmetto extract?
   A. I don't see why not.

I am currently being treated for undermethylation by a GP in London who also has a side-interest in alternative medicine. After postulating that i had high histamine levels via a questionnaire supplied by the Pfeiffer institute, as well as conducting a blood test which confirmed as much, i was assigned to take each morning 2 x L-Methionine (500mg), p5p, Cal/Mag, vit C 500mg, and each evening 2x L-Methoinine (500mg), chelated zinc, cal/mag, vit C 500mg. Unfortunately, since this is the only doctor i've come across in my area interested in treating histamine levels, it's difficult to cross-check facts, which is why I have e-mailed you. My questions are as follows: i was told that it did not matter whether i take the L-Methionine on an empty stomach. i was under the impression that all amino acids needed to be taken in such a state in order to maximise absorption; unfortunately, if i do take the l-methoinine first thing upon waking i experience side effects of intense feelings of nausea. However, these symptoms fail to appear (or are tempered at least) if i take the l-methionine after a meal. Do you agree that it's okay to take the L-methionine with food? I am experiencing intense feelings of anger and frustration ever since coming off Nardil. it's been 2 weeks since i discontinued the medication (after 6 weeks at a dose of 75mg), and this lack of emotional resiliency has yet to abate. Do you see any potential way in which L-methionine might be aggravating these symptoms since i know that SAM-e pills can be quite activating? if so, would another methyl donor like TMG or maybe even SAM-e viably be able to 'take the place' of L-methionine in this regime?
   Not enough human studies with l methionine supplements have been done to determine whether it is better to take it on an empty stomach or with food. Most amino acids are more effective when used on an empty stomach. As a physician I treat the whole person as opposed to specifically trying to influence levels of one or two blood study results. It is difficult to predict a person's response to the other supplements you mention without giving them a try.

I tried a TMG and methionine supplement together two days ago and got one of the worst headaches I've had in a while and no other effect. I realize it probably takes a few days to kick in but it made me feel so ill that I am not going to take it again for a while. I'm continuing to take the DMG with good results although I hurt my back recently and it doesn't seem to help the pain much - I am only taking one sublingual pill a day of 125 mg so I may try more but I'm afraid it will keep me up if I do. I will probably try the TMG / methionine again when my back is better but not sure - it really did have a weird effect on me.

Source Naturals L-Methionine supplement, 3.53 oz (100 grams)
L-Methionine is an essential sulfur-containing, free-form amino acid. It contributes to the synthesis of S-adenosyl-Lmethionine (SAMe), which is necessary for normal brain function, and L-cysteine, which is a component of glutathione, an important antioxidant molecule in the body. It is also a transporter of the antioxidant mineral, selenium.

Suggested Use: 1/4 to half teaspoon of L Methionine amino acid powder between meals, or as recommended by your health care professional. If you experience stomach irritation, take with meals.

Supplement Facts:
Serving Size 1/2 Teaspoon (approx. 1.5 g)
Servings Per Container 66
Amount Per Serving
L-Methionine 1.5 g

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