S-methylmethionine

Other Names

(3-Amino-3-carboxy-propyl)-dimethyl-sulfonium(3-Amino-3-carboxypropyl)(dimethyl)sulfonium3-amino-3-carboxypropyl dimethylsulfoniumAnti-peptic ulcer dietary factorAnti-ulcer factorL-form S-methylmethionine sulfonium chlorideMethionine S-methyl sulfoniumMethylmethionineMethylmethionine sulfoniumMethylmethionine sulfonium chlorideMMSMMSCS-Methyl methionine sulfonium chlorideS-Methyl methionine sulphonium chlorideS-Methyl-L-methionineS-Methylmethionine sulfoniumS-Methylmethionine sulfonium chlorideSMMSMMSSulfonium, (3-amino-3-carboxypropyl)dimethyl-Vitamin U

Synopsis

S-Methylmethionine (Vitamin U): A Comprehensive Reference

1. Identity, Nomenclature, and Chemical Characterization

S-methylmethionine (SMM) is referred to in the literature also as methylmethionine sulfonium chloride (MMSC) and "vitamin U," and is a methylated derivative of the essential amino acid methionine belonging to the class of sulfonium compounds. SMM is a derivative of methionine with the chemical formula (CH₃)₂S⁺CH₂CH₂CH(NH₃⁺)CO₂⁻. When isolated as a salt for supplemental or pharmaceutical use, it is commonly encountered as the chloride form — methylmethionine sulfonium chloride — with CAS number 1115-84-0.

Its full IUPAC-generated name is (3-amino-3-carboxypropyl)(dimethyl)sulfonium; additional synonyms include S-methyl-L-methionine and sulfonium, (3-amino-3-carboxypropyl)dimethyl-.

S-Methylmethionine is sometimes referred to as vitamin U, but it is not considered a true vitamin. The term was coined in 1950 by Garnett Cheney for uncharacterized anti-ulcerogenic factors in raw cabbage juice that may help speed healing of peptic ulcers. Vitamin U is a highly active compound but may not have any essential function in the body. The name is given to MMSC, a molecule with many biological activities; it does not have an essential function and is not currently accepted as a true vitamin.

1.1 Biosynthesis and Natural Occurrence

All flowering plants produce S-methylmethionine (SMM) from methionine and have a separate mechanism to convert SMM back to methionine. It is biosynthesized from L-methionine and S-adenosylmethionine by the enzyme methionine S-methyltransferase. S-Methylmethionine arises via the methylation of methionine by S-adenosylmethionine (SAM), with S-adenosylhomocysteine as the coproduct.

S-Methylmethionine is particularly abundant in plants, being more abundant than methionine itself. By use of the aphid stylet collection method with mass spectral and radiolabeling analyses, SMM has been established as a major constituent of the phloem sap moving to wheat ears; the SMM level in the phloem (approximately 2% of free amino acids) was 1.5-fold that of glutathione, indicating that SMM could contribute approximately half the sulfur needed for grain protein synthesis.

Dietary sources rich in SMM include: vegetables such as cabbage, kohlrabi, turnip, tomatoes, and celery. S-Methylmethionine is also found in barley and is further created during the malting process; SMM can be subsequently converted to dimethyl sulfide (DMS) during the malt kilning process, causing an undesirable flavor. Lightly kilned malts such as pilsner or lager malts retain much of their SMM content, while darker kilned malts such as Munich malt have virtually no SMM content since most has been converted to DMS.

Animals lack a dedicated enzyme for SMM biosynthesis, with no significant MmtN or MMT homologs identified in mammals. However, incidental SMM formation may arise non-enzymatically or through methylation by gut microbiota harboring MmtN-producing bacteria, contributing trace levels in animal tissues.

1.2 Common Forms and Preparations

Raw vegetable juice (historically, especially cabbage juice): the original therapeutic preparation used in clinical investigations of the 1940s–1950s.
Oral tablets and capsules: in modern applications, MMSC is utilized primarily for gastrointestinal disorders as an over-the-counter supplement in countries like Japan, where it is commonly available in oral formulations.
Topical preparations: investigated in dermatological research for wound healing and photoprotection; research has demonstrated that SMMS confers wound-healing and photoprotective effects on the skin, suggesting it can be used as a cosmetic raw material, though it has an unpleasant odor. Derivatives have been synthesized to address this limitation.
Combined formulations: clinical research has examined a combination of vitamin B5 and vitamin U in therapeutic doses for healing erosions of the gastrointestinal mucosa.

2. Historical and Traditional Use

Long before its isolation as a specific compound, cabbage and its juice had been used in European folk medicine for treating stomach ailments, indigestion, and inflammation. In traditional herbal texts, raw cabbage was often recommended for both internal ulcerations and external wounds. Folk remedies often included cabbage juice or raw cabbage as central components, particularly in European and Asian traditional medicine, to ease stomach discomfort and promote overall digestive wellness.

Interest in SMM arose in the mid-twentieth century due to observations of accelerated healing of gastric ulcerations upon consumption of plant-derived foods rich in this factor. Historically derived from observations of antiulcer activity in plant-derived foods, SMM has been studied in preclinical models and limited clinical settings.

The term "Vitamin U" was coined in the early 1950s by Dr. Garnett Cheney at Stanford University, who conducted clinical research on cabbage juice therapy for peptic ulcers. Dr. Garnett Cheney, a professor of medicine at Stanford University School of Medicine, embarked on a series of pioneering clinical investigations that led to the discovery of a potent anti-ulcer agent found in fresh cabbage juice. Initially termed "vitamin U" for its remarkable ulcer-healing properties, this compound was later identified as S-methylmethionine (SMM).

It was discovered as an anti-peptic ulcer factor during the 1940s–1950s by Dr. Garnett Cheney. The initial study, entitled "Rapid Healing of Peptic Ulcers in Patients Receiving Fresh Cabbage Juice," was considered of inadequate interest by the medical establishment to make these experiences better known. The primary author further demonstrated with two more studies done in 1952 and 1956, with identical outcomes, that vitamin U is an effective treatment — and this was before the idea that bacteria may be a deterministic causal factor.

3. Key Constituents, Active Form, and Mechanisms of Action

3.1 Chemical Activity as a Methyl Donor

The vitamin-like compound S-methyl-L-methionine (SMM, historically called vitamin U) is a metabolic agent that affects metabolic processes, causing a wide variety of effects. Data from studies demonstrate a gastroprotective effect, hypolipidemic and antioxidant effect, participation in regulation of adipocyte function, and involvement in homocysteine exchange. SMM is involved in all methylation reactions in which another activated form of methionine, S-adenosylmethionine, normally participates.

SMM is a derivative of L-methionine catabolism: methionine is first methylated to S-adenosylmethionine (SAM), and then the adenosyl group is replaced by a methyl group, catalyzed by the enzyme methionine S-methyltransferase, making this molecule a potent methyl donor. SMM has been characterized as a vitamin-like metabolic agent involved in methylation processes, homocysteine metabolism, and antioxidant defense, with functional parallels to S-adenosylmethionine.

3.2 Gastroprotective Mechanisms

Investigation carried out on piglet jejunal epithelial cells (IPEC-J2) treated with different concentrations of S-methylmethionine sulfonium chloride demonstrated that vitamin U could stimulate the expression of Mucin-2 (MUC2), epidermal growth factor (EGF), glucagon-like peptide-2 (GLP-2), and insulin-like growth factor-1 (IGF-1), while inhibiting the expression of transforming growth factor beta (TGF-β1) at both the mRNA and protein level — outcomes of potential importance to mucosal repair.

SMM has a variety of documented effects including stimulating the formation of gastric mucus, serving as an antioxidant, and acting as a methyl donor for a variety of acceptors.

3.3 Antioxidant and Anti-Inflammatory Mechanisms

Combined administration of S-methylmethionine has been shown in preclinical models to lead to significant reduction in malondialdehyde levels and xanthine oxidase activity, and restoration of glutathione content and activity of antioxidant enzymes including catalase and superoxide dismutase. Furthermore, SMM reduced levels of pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) and fibrosis markers including TGF-β and collagen I, indicating a combination of antioxidant, anti-inflammatory, and anti-fibrotic mechanisms.

3.4 Dermal and Tissue Regeneration Mechanisms

A single SMMS treatment was sufficient to promote the growth of human dermal fibroblasts (hDFs) as well as the migration of hDFs, which are indispensable steps for skin wound healing. The promotion of hDF proliferation and migration resulted from considerable activation of ERK1/2 by SMMS; inhibition of ERK activity by a chemical inhibitor significantly abrogated both the promoted proliferation and migration of hDFs. SMMS was thus concluded to facilitate the repair process of skin damage by activation of dermal fibroblasts.

3.5 Metabolic and Hepatic Pathways

Biotransformation of vitamin U activity proceeds in the liver, kidneys, and digestive tract. Metabolism of vitamin U in the liver and kidneys was found to proceed via methylation of homocysteine with the formation of methionine, and via enzymatic hydrolysis to dimethylsulfide and homoserine.

The biological roles of S-methylmethionine are not well understood. Speculated roles include methionine storage, use as a methyl donor, and regulation of SAM. A few plants also use S-methylmethionine as a precursor to the osmolyte dimethylsulfoniopropionate (DMSP).

3.6 Adipocyte Regulation

An in vitro investigation using the 3T3-L1 pre-adipocyte cell line demonstrated that introducing varying concentrations of MMSC (10 to 100 mM) into fat differentiation-inducing media led to a significant reduction in triglyceride levels and the expression of key adipogenic factors such as C/EBP-α, PPAR-γ, adipsin, ADD-1, and glycerol-3-phosphate dehydrogenase (GPDH) activity. Additionally, higher MMSC concentrations resulted in increased AMP-activated protein kinase (AMPK) activity.

4. Scientific Evidence by Area of Use

4.1 Gastrointestinal Health: Peptic Ulcers and Gastritis

Historical clinical evidence: In a seminal study by Cheney (1949), 13 patients with peptic ulcers treated with approximately 1 liter of cabbage juice daily achieved an average gastric ulcer healing time of 7.3 days, compared to 42 days with standard bed-rest therapy; duodenal ulcers healed in an average of 10.4 days versus 37 days. This work was expanded to 100 patients in subsequent studies, which highlighted the anti-ulcerogenic properties of cabbage-derived factors and prompted the isolation of MMSC as the primary active compound.

The initial study used a liter of raw cabbage juice consumed throughout each day. Based upon the results of the studies, the authors suggested a protocol lasting 10–13 days.

Limitations of Cheney's work: The scientific evidence supporting its efficacy is limited and largely dated. Most research consists of uncontrolled or poorly designed studies from several decades ago, with few modern clinical trials to validate its benefits. These early studies also tested whole cabbage juice — a complex mixture — rather than isolated SMM, making it difficult to attribute effects solely to this compound.

More recent clinical evidence: One clinical study was designed to evaluate the effect of S-methylmethionine sulfonium chloride intake on the symptoms of dyspepsia and quality of life in patients with chronic gastritis. The study included 37 patients (21 men and 16 women) aged 35–60 years with chronic gastritis of various etiologies, all prescribed S-methylmethionine at a dose of 300 mg per day. The study showed that taking a vitamin U dietary supplement for 6 months helps to reduce the severity of dyspeptic symptoms in patients with chronic gastritis.

The protective and restoring effects of vitamin U in erosive disorders of the gastrointestinal mucosa are described as well-documented in recent review literature. A 2025 review analyzed the mechanisms of action of vitamin B5 and vitamin U and provided clinical evidence for the combined application of these compounds in the management of erosive gastrointestinal diseases.

Animal studies: A controlled study assessed the value of SMMSC at 200 mg/kg on nutritional performance of pigs and as prevention or therapy for oesophagogastric ulcers; 60 pigs from a high-health-status herd were endoscopically assessed for the presence or absence of oesophagogastric ulcers. There was no difference over the 49-day period in weight gain, feed intake, and backfat in pigs with and without SMMSC supplementation, between pigs with or without fully developed oesophagogastric ulcers at the start of the study.

Evidence strength: The evidence for gastroprotective and antiulcer effects in humans is historically suggestive but methodologically weak by modern standards. The pivotal Cheney studies lacked adequate controls, used whole vegetable juice rather than isolated compound, and are decades old. A small modern study at 300 mg/day for 6 months provides preliminary support for benefit in chronic gastritis. Well-designed Phase II randomized controlled trials and innovative pharmaceutical formulations are urgently needed to translate preclinical promise into clinical benefits.

4.2 Skin: Wound Healing and Photoprotection

Preclinical (in vivo and in vitro) evidence: A key study by Kim et al. demonstrated that topical application of S-methylmethionine accelerates healing of both physical and chemically induced skin wounds in animals. Treatment was accompanied by faster wound surface closure and enhanced re-epithelialization compared to control groups. In vitro experiments showed that a single exposure to SMM stimulated the proliferation and migration of human dermal fibroblasts, which are key processes for granulation tissue formation and restoration of the dermal matrix.

In investigations of photoprotective effects, SMMS increased the viability of keratinocyte progenitor cells (KPCs) and human dermal fibroblasts (hDFs) following ultraviolet B (UVB) irradiation and reduced UVB-induced apoptosis in these cells. SMMS increased phosphorylation of extracellular signal-regulated kinases (ERK), and the inhibitor of the mitogen-activated protein kinase pathway significantly decreased the SMMS-induced viability of KPCs and hDFs. SMMS also attenuated UVB-induced reactive oxygen species (ROS) generation in KPCs and hDFs. Furthermore, SMMS induced collagen synthesis and reduced matrix metalloproteinase-1 expression in UVB-irradiated hDFs.

In animal studies, application of 5% and 10% SMMS before and after UVB-irradiation significantly decreased the UVB-induced erythema index and depletion of Langerhans cells.

Evidence strength: All wound healing and photoprotective evidence is preclinical (animal models and cell culture). No peer-reviewed human clinical trials assessing wound healing or photoprotection with topical SMMS have been identified. SMMS has been used as a cosmetic raw material, but UVB-protective effects in humans have not been fully investigated in controlled trials.

4.3 Liver Protection (Hepatoprotection)

Pharmacological review literature highlights hepatoprotection as one of the important protective effects of MMSC across organ systems. A study carried out on 60 male Wistar albino rats divided into four groups — including a hepatocellular carcinoma group induced by diethyl nitrosamine and carbon tetrachloride and a group treated with MMSC — revealed that MMSC administration after HCC induction significantly improved liver function biomarkers, including AST, GGT, albumin, globulin, and albumin/globulin ratio, in comparison with the HCC group.

Protective effects of SMMS in valproic acid-induced liver injury have been reported in experimental models. Experimental studies on mice have shown positive regulation of Sult1e1, Phlda1, and Ciart genes in the liver with vitamin U food supplementation, suggesting that vitamin U may regulate xenobiotic, glucose, and circadian rhythm pathways.

Evidence strength: All hepatoprotective evidence is from animal or in vitro studies. No human clinical trials specifically assessing liver protection with SMM supplementation have been identified in available literature.

4.4 Kidney Protection (Nephroprotection)

Studies have shown that prolonged administration of valproic acid was accompanied by pronounced histopathological changes in renal tissue, decreased Na⁺/K⁺-ATPase activity, enhanced oxidative stress, inflammatory reaction, and fibrosis. Combined administration of S-methylmethionine led to significant reduction in malondialdehyde levels and xanthine oxidase activity, and restoration of glutathione content and activity of antioxidant enzymes including catalase and superoxide dismutase. Furthermore, SMM reduced levels of pro-inflammatory cytokines (TNF-α, IL-1β, MCP-1) and fibrosis markers including TGF-β and collagen I, indicating antioxidant, anti-inflammatory, and anti-fibrotic mechanisms of nephroprotective action.

Evidence strength: Nephroprotective evidence is from animal experiments only. No human data are available.

4.5 Lipid Metabolism and Adipocyte Function

S-methylmethionine sulfonium chloride, originally called vitamin U because of its inhibition of ulceration in the digestive system, is ubiquitously expressed in the tissues of flowering plants; while there have been reports on its hypolipidemic effect, its precise function remains unknown.

Hypolipidemic effects and inhibitory effects of SMMS on differentiation of 3T3-L1 pre-adipocytes have been reported. The in vitro study using varying concentrations of MMSC (10–100 mM) confirmed significant reductions in triglyceride levels and key adipogenic factor expression, along with increased AMPK activity — findings of potential metabolic relevance but not yet confirmed in humans.

A diet containing foods that are sources of S-methylmethionine, and its use as a dietary supplement, have demonstrated beneficial health effects in animal studies. To evaluate whether SMM alone is responsible for these effects, the compound was evaluated as a dietary supplement in C57BL/6J high-fat-fed mice divided into low-fat, high-fat, and high-fat plus SMM groups maintained for 10 weeks.

Evidence strength: Preclinical only (cell culture and mouse models). No human trials have assessed SMM specifically for lipid-lowering or anti-obesity outcomes.

4.6 Neuroprotection

Organ-specific protection in the nervous system has been noted in review literature, although human evidence remains scarce. Neuroprotective effects are among the pharmacological protective effects highlighted for MMSC in recent reviews. No peer-reviewed human clinical trials investigating neuroprotective outcomes of SMM supplementation were identified in available sources.

Evidence strength: Extremely preliminary; limited to mention in review literature with no identifiable controlled human data.

4.7 Homocysteine Metabolism

Data from studies demonstrate SMM's involvement in homocysteine exchange and methylation processes. SMM is involved in all methylation reactions in which S-adenosylmethionine normally participates. Because SMM can donate a methyl group to homocysteine to regenerate methionine, it has been proposed as a modulator of homocysteine levels. However, formal clinical studies specifically measuring the effect of SMM supplementation on plasma homocysteine in humans were not identified in available sources.

5. Body Systems and Health Areas Associated with SMM

The most consistently reported effects are gastroprotective and antiulcer effects, as well as antioxidant, anti-inflammatory, cytoprotective, and regenerative activities. Particular attention has been paid to organ-specific protection in the nervous system, liver, kidneys, lungs, skin, eyes, and oral tissues, although human evidence remains scarce.

Gastrointestinal system: Ulcer healing, gastric mucosa protection, erosive gastritis, dyspepsia — the most historically and clinically documented area.
Integumentary system (skin): Wound healing acceleration, UVB photoprotection — supported by preclinical and in vitro data; used in cosmetic formulations.
Liver: Hepatoprotection against toxin-induced injury; hepatic gene expression modulation — preclinical evidence only.
Kidneys: Nephroprotection against drug-induced damage — preclinical evidence only.
Cardiovascular/metabolic: Homocysteine metabolism modulation, lipid-lowering, adipogenesis inhibition — preclinical evidence only.
Nervous system: Proposed neuroprotective role — mentioned in review literature, no controlled human evidence identified.
Eyes: Protective effects for the eyes are among the organ-specific effects highlighted in pharmacological review literature. No independent human evidence identified.

6. Dosage Forms and Reported Dosages

The following dosages are reported exclusively as stated in the sources identified; they are not recommendations.

Cheney's clinical studies (1949–1956): The initial study used a liter of raw cabbage juice consumed throughout each day, with a protocol lasting 10–13 days. These studies used whole cabbage juice, not isolated SMM.
Oral supplementation for chronic gastritis (clinical study): A clinical study of 37 patients with chronic gastritis prescribed S-methylmethionine at a dose of 300 mg per day for 6 months.
Porcine oesophagogastric ulcer study: SMMSC was used at 200 mg/kg body weight in a 49-day pig trial assessing prevention or therapy for oesophagogastric ulcers.
In vitro adipocyte study: Concentrations of 10, 50, 70, 90, and 100 mM were tested in the 3T3-L1 pre-adipocyte cell line model.
Animal topical wound/UVB studies: Application of 5% and 10% SMMS concentrations before and after UVB irradiation were used in animal photoprotection studies.

It is essential to explore the effectiveness of MMSC in new dosage forms with different doses and via alternative administration methods, alongside the conventional external application and oral administration utilized in preclinical research.

7. Safety Considerations and Interactions

7.1 General Safety Profile

Despite the small amount of articles and research studies, the notable antioxidant and anti-inflammatory properties of SMM, along with its extensive range of target organs and tissues and its low toxicity, position it as a promising candidate for the development of novel medicines.

Vitamin U is reported to be safe when eaten directly from whole foods. However, little is known about its safety or potential side effects in dietary supplement form. According to the European Chemicals Agency, vitamin U may cause eye, skin, or lung irritation if it comes into contact with these tissues in an undiluted form.

7.2 Relationship to Methionine Metabolism and Homocysteine

Because SMM participates in the same metabolic cycle as methionine and SAM, considerations relevant to methionine excess are pertinent. Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels. The role of methionine as a precursor of homocysteine is the most notable cause for concern with excess methionine-family compounds.

Longer-term studies in adults indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, B-12, C, and folic acid.

Importantly, unlike SAM, S-methylmethionine does not affect the functional activity of the liver's isoenzymes and does not have an inhibitory effect on methylation processes, making its use preferable and safe as a nutrient.

7.3 Schizophrenia and Psychopathological Symptoms

Although methionine is known to exacerbate psychopathological symptoms in schizophrenic patients, there is no evidence of similar effects in healthy subjects. This mechanistic concern, based on methionine's role as a methyl donor in the brain, has not been directly studied for isolated SMM supplementation in psychiatric populations, and direct extrapolation should be made cautiously.

7.4 Odor Characteristics

Research has confirmed that SMMS confers wound-healing and photoprotective effects on the skin for cosmetic applications; however, it has an unpleasant odor — a practical consideration addressed in pharmaceutical derivative development for topical use.

7.5 Regulatory Status

Despite over 70 years of investigation, SMM has not achieved Western drug registration, and translational and regulatory barriers remain a significant obstacle to its wider pharmaceutical use. Mainstream medical guidelines do not recommend vitamin U for acid indigestion, and it is not recognized as an essential nutrient. With the advent of effective pharmacological treatments for ulcers, such as proton pump inhibitors and antibiotics for Helicobacter pylori, interest in "vitamin U" has waned in mainstream medicine.

8. Overall Characterization of the Evidence Base

SMM has been studied in preclinical models and limited clinical settings for its multilevel pharmacological effects. This narrative review evidence critically evaluates SMM's pharmacological actions across organ systems with explicit differentiation between preclinical and clinical data.

The most promising outcomes warranting additional investigation are antioxidant, anti-inflammatory, gastroprotective, hepatoprotective, nephroprotective, photoprotective, and wound healing effects. The existing body of research is insufficient and necessitates further exploration of alternative disease models, as well as a more comprehensive examination of the characteristics of this substance in vitro and in vivo.

While some animal and in vitro studies suggest that methylmethionine sulfonium chloride may have a protective effect on the gastric mucosa, these findings have not been robustly confirmed in large, well-controlled human studies. As a result, its continued use is primarily justified by tradition and anecdotal reports rather than strong scientific validation.

References

Health Conditions

Health conditions that S-methylmethionine may help support.

UlcersScientific
S-Methylmethionine (vitamin U), found abundantly in cabbage juice, was historically used and studied in the 1950s–1970s as a specific antiulcer factor. Early clinical trials reported significantly faster healing of peptic and duodenal ulcers with vitamin U compared to placebo. It strengthens gastric mucosal integrity and promotes mucosal repair.

Body Systems

Body systems that S-methylmethionine may help support.

No body systems available.