Fumaric acid

Fumaric Acid

1. Identity and Chemical Characterization

Chemical Names and Formula

Fumaric acid (C₄H₄O₄), also described as trans-1,2-ethylene dicarboxylic acid or (E)-2-butenedioic acid, is a widespread carboxylic acid found in nature, initially isolated from the Fumaria officinalis plant. Formally named trans-butenedioic acid and bearing the molecular formula HO₂CCH=CHCO₂H, it is the trans isomer of butenedioic acid, while maleic acid is the corresponding cis isomer. Structurally, it is a trans-alkene dicarboxylic acid comprising a central carbon chain with two carboxyl groups at the terminal ends, and the molecule exhibits geometric isomerism, existing predominantly in the trans form. Its European food additive designation is E297. The salts and esters of fumaric acid are collectively known as fumarates.

Physical Properties

Fumaric acid exists as a colorless solid at room temperature and forms white crystalline needles. It presents as a white, odorless powder with a slightly sour taste similar to citrus but milder, and is slightly soluble in water (approximately 0.63 g per 100 mL at 25 °C), but more soluble in ethanol or acetone. When used as a food additive, the hydrophobic nature of fumaric acid results in persistent, long-lasting sourness and flavor impact.

Natural Sources

Fumaric acid is found naturally in fumitory (Fumaria officinalis), bolete mushrooms (specifically Boletus fomentarius var. pseudo-igniarius), lichen, and Iceland moss. It can also be naturally found in fruits such as apple and watermelon, though it is generally less abundant in most fruits than the acidulants citric acid and malic acid. Human skin naturally produces fumaric acid when exposed to sunlight. Commercially, most fumaric acid is not harvested from natural sources because concentrations are too low.

Industrial Production

Industrially, fumaric acid is produced primarily through the isomerization of maleic acid — a process in which maleic acid is heated or treated with catalysts to convert it into fumaric acid. One of the most common industrial methods involves oxidation of maleic anhydride or maleic acid, where maleic anhydride is typically derived from the catalytic oxidation of benzene or butane. Recent trends favor microbial fermentation using Rhizopus oryzae strains, which offers renewable, sustainable production compared to petrochemical routes.

Key Derivative Forms

Through esterification with alcohols, fumaric acid forms esters including dimethyl fumarate (DMF) and diethyl fumarate, which are used in medicine and industry. Salts such as sodium fumarate, calcium fumarate, and potassium fumarate find applications in food fortification and pharmaceuticals. The pharmaceutical derivative dimethyl fumarate (Tecfidera®/Skilarence®) is distinct from fumaric acid itself and has been approved for specific clinical indications; this distinction is addressed in detail below.

2. Historical and Traditional Use

Botanical Origin and Historical Identification

Historically, fumaric acid was first isolated in the 19th century from the plant Fumaria officinalis, a flowering plant traditionally used in herbal medicine; the compound's name originates from this genus, underscoring its botanical roots. Fumaric acid was first discovered in the early 19th century by French chemist Jean-Baptiste Quéruel and German chemist Leopold Gmelin, and its chemical structure was elucidated by German chemist Adolph Strecker in 1860.

Traditional Uses of Fumaria officinalis in European Herbal Medicine

Fumitory has been used for centuries in European traditional medicine as a remedy for skin conditions, digestive issues, and liver ailments; in medieval times, it was believed to "purify the blood" and was also used as a diuretic and mild laxative. The most common traditional uses were as a digestive aid and a diuretic, but various folk traditions throughout Europe ascribed to it a multitude of uses: constipation, cystitis, arteriosclerosis, rheumatism, arthritis, as a blood purifier, for hypoglycaemia, and infections, and possibly to cleanse the kidneys. In Sicily and elsewhere it was used to treat skin blemishes, and in Britain into the modern era as an eyewash to treat conjunctivitis.

The plant contains alkaloids, potassium salts, and tannins, and is also a source of fumaric acid. Fumitory contains isoquinoline alkaloids such as protopine and fumariline, along with fumaric acid, which contribute to its pharmacological effects. It is important to note that traditional uses relate to whole-plant preparations of Fumaria officinalis, not to isolated fumaric acid. Since 1963, it has been marketed as a herbal medicine in France, and as of 2011, herbal products made from this plant are legally sold in various forms in Austria, Germany, France, and Spain.

Early Pharmaceutical Use (Mid-20th Century)

The use of fumaric acid esters in the treatment of psoriasis was first introduced in the late 1950s by the German chemist Schweckendiek, who developed a standardized fumaric acid protocol for psoriasis using fumaric acid esters (FAEs) both orally and topically (ointment and bathing solution). FAEs were introduced as a systemic psoriasis treatment in 1959 and empirically developed further between 1970 and 1990 in Germany, Switzerland, and the Netherlands; the development of FAEs as psoriasis treatment did not follow traditional drug development phases, but in 1994 FAEs were approved in Germany for the treatment of severe plaque psoriasis.

Fumaric acid has been used as a food acidulant since 1946 and is approved for use as a food additive in the EU, USA, Australia, and New Zealand.

3. Biochemistry: Fumarate as an Endogenous Metabolite

Role in the Citric Acid (Krebs) Cycle

Fumaric acid is a key intermediate in the tricarboxylic acid (TCA) cycle for organic acid biosynthesis in humans and other mammals. Fumarate is an intermediate in the citric acid cycle used by cells to produce energy in the form of adenosine triphosphate (ATP) from food. It is produced in eukaryotic organisms from succinate in complex 2 of the electron transport chain via the enzyme succinate dehydrogenase. Fumarase is the catalyst in the subsequent hydration of fumarate to malate, a reaction that is reversible. Fumarate is also a product of the urea cycle.

Signaling Functions Beyond Bioenergetics

Metabolites traditionally associated with bioenergetics or biosynthesis have been implicated in immunity and malignancy in transformed cells; among these, the Krebs cycle intermediates succinate, fumarate, itaconate, and acetyl-CoA now have extensive evidence for "non-metabolic" signaling functions in both physiological immune contexts and in disease contexts. Research has demonstrated that the Krebs cycle intermediate fumarate links metabolism to mitochondrial biogenesis through binding to malic enzyme 2 (ME2); mechanistically, fumarate binds ME2 with two complementary consequences — promoting the formation of ME2 dimers, which activate deoxyuridine 5′-triphosphate nucleotidohydrolase (DUT), fostering thymidine generation and an increase in mitochondrial DNA, and fumarate-induced ME2 dimers abrogate ME2 monomer binding to mitochondrial ribosome protein L45, freeing it for mitoribosome assembly and mtDNA-encoded protein production.

Fumarase deficiency is a rare autosomal recessive metabolic disorder of the TCA cycle due to a mutation in the FH gene, characterized by a deficiency of the enzyme fumarase hydratase, leading to fumaric acid buildup. This condition illustrates the physiological significance of tightly regulated fumarate concentrations.

4. Active Compounds and Established Mechanisms of Action

Fumaric Acid Versus Its Esters

It is important to emphasize the difference between fumaric acid and fumaric acid esters. Fumaric acid formulations are available as health supplements and often marketed as a natural alternative medicine to treat psoriasis; however, fumaric acid itself is poorly absorbed by the gut and is excreted via urine without having any therapeutic effect. Esters of fumaric acid (FAEs) — such as monoethylfumarate (MEF), monomethylfumarate (MMF), diethylfumarate (DEF), and dimethylfumarate (DMF) — are potent chemicals that have been used in the treatment of psoriasis in European countries for over 30 years.

DMF acts as a prodrug for its main metabolite monomethylfumarate (MMF); this hypothesis is supported by the observation that only monomethylfumarate was detected in the plasma of human subjects after oral administration of FAEs. In vitro data suggests that hydrolysis of DMF to the bioactive metabolite MMF occurs rapidly at pH 8 (simulating the alkaline pH found in the small intestine) but not at pH 1 (the pH found in the stomach), indicating that hydrolysis occurs mainly in the small intestine, after which MMF and MEF are absorbed into the blood circulation where they interact with blood cells.

Molecular Mechanisms: Nrf2 Pathway

MMF can bind to the hydroxy-carboxylic acid receptor 2 (HCA2) on the cell surface, and both DMF and MMF react with intracellular glutathione following cell penetration. DMF and, to some extent, MMF modulate the activity of cellular signaling proteins such as the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-κB (NF-κB), and the cellular concentration of cyclic adenosine monophosphate. After cellular uptake, the α,β-unsaturated carboxylic acid ester DMF reacts with thiol groups of glutathione (GSH) and thereby lowers GSH levels, which impacts cellular responses to oxidative stress. Activation of the Nrf2-dependent antioxidant response pathway leads to stimulation of cytoprotective and anti-inflammatory genes, and direct and/or indirect inhibition of NF-κB activity affects cytokine production, the phenotype of antigen-presenting cells, and subsequently shifts the Th1/Th17 immune response to a Th2 phenotype.

Molecular Mechanisms: NF-κB and Immune Cell Modulation

DMF inhibits NF-κB-driven cytokine production and nuclear translocation of p65 and p52 in an Nrf2-independent manner; equivalent doses of MMF and MEF do not affect NF-κB signaling. Clinical studies in psoriasis showed a reduction of peripheral CD4⁺ and CD8⁺ T-lymphocytes due to the ability of FAEs to induce apoptosis, while in vitro studies with DMF described an inhibitory effect on NF-κB-dependent transcription of tumor necrosis factor-alpha (TNF-α)-induced genes in human endothelial cells.

DMF decreases absolute lymphocyte counts but does not affect all subsets uniformly: CD8⁺ T-cells are the most profoundly affected, but reduction also occurs in the CD4⁺ population, particularly within the pro-inflammatory T-helper Th1 and Th17 subsets, creating a bias toward more anti-inflammatory Th2 and regulatory subsets; similarly, B-lymphocyte, myeloid, and natural killer populations are also shifted toward a more anti-inflammatory state.

Neuroprotective Mechanisms

In vitro and animal models demonstrate a role for DMF within the central nervous system in promoting neuronal survival in an Nrf2 pathway-dependent manner. DMF directly modifies reactive cysteine residues on multiple proteins in immune and neural cells, leading to diverse anti-inflammatory, immunomodulatory, and neuroprotective actions; recent studies revealed that DMF may affect proteins involved in inflammasome activation, glycolysis, and cell signaling pathways, including JAK-STAT and NF-κB.

5. Scientific Evidence by Area of Use

5.1 Psoriasis

Background and Historical Development

A mixture of compounds consisting of dimethylfumarate and three salts of ethylhydrogenfumarate was developed to reduce (mainly gastrointestinal) side effects and was licensed in Germany in 1994 as oral therapy for severe psoriasis under the brand name Fumaderm®. FAEs are currently one of the most commonly used treatments in Germany, and FAEs are increasingly being used as an unlicensed treatment in several other European countries.

Clinical Trial Evidence

To date, six randomized controlled trials and 29 observational studies have evaluated FAEs in a combined total of 3,439 patients. All trials were conducted in Germany or in the Netherlands, with treatment duration in RCTs ranging from 12 to 16 weeks. The largest randomized, placebo-controlled trial was a German multicenter study published in 1994, in which 100 patients with plaque psoriasis were randomized 1:1 to receive Fumaderm treatment or placebo for 16 weeks; in this RCT, the mean PASI decreased by 50%, from 21.6 at baseline to 10.8 after 16 weeks of FAE treatment.

The other placebo-controlled RCT was a small Dutch study published in 1990, in which 39 psoriasis patients were randomized to receive FAE (Fumaderm), octyl fumarate, or placebo; in contrast to the octyl fumarate and placebo groups, psoriasis improved significantly in patients treated with Fumaderm, with a 68% reduction in body surface area affected, from 21% to 6.7%.

The therapeutic effect and side effects of fumaric acid derivatives used in psoriasis treatment have been subjects of controversy for more than 30 years. In a single-centre, long-term open (12-month) clinical trial of 83 patients with severe psoriasis vulgaris evaluating the efficacy and safety profile of Fumaderm initial and Fumaderm, the antipsoriatic effect was clear, with a mean reduction of 76% in PASI. Adverse events were noted in 62% of patients (mainly flushing and gastrointestinal complaints), were dose-dependent, and decreased in frequency in the course of the study; no severe adverse events occurred.

Although data from controlled clinical trials is limited, available studies suggest that up to 50% of patients treated with Fumaderm® achieve at least a 75% reduction from their baseline PASI after 12–16 weeks of treatment. According to the German S3-guidelines on psoriasis, an evaluation of 13 studies showed a proportion of 50–70% of patients who achieved PASI 75 improvement within four months of treatment, and without any long-term toxicity, immunosuppressive effects, or increased risk of infection or malignancy.

Pediatric Evidence

A 2021 randomized, double-blinded, placebo-controlled trial published in British Journal of Dermatology evaluated FAEs in patients aged 10–17 years with moderate-to-severe plaque psoriasis. Uptitration was performed starting at 30 mg DMF and 75 mg EHF salts daily (equal to one tablet of Fumaderm Initial), with an incremental increase up to a maximum daily dosage of 480 mg DMF and 380 mg EHF salts (equal to four tablets of Fumaderm) based on individual clinical response and tolerability. The mean exposure to DMF was 301 ± 103 mg per day during weeks 5–40 in the FAE/FAE group.

Evidence Strength Assessment

The evidence base for FAEs in psoriasis is moderate in quantity but heterogeneous in quality. Randomized controlled trials are few in number and were largely conducted in Germany and the Netherlands. The lack of large, multi-national phase III trials (of the type conducted for dimethyl fumarate in MS) limits confidence levels. Long-term observational data is more abundant. The treatment is well established in German clinical guidelines but remains unlicensed in many other countries. The key caveat is that the therapeutic agent in psoriasis is the fumaric acid ester formulation (primarily DMF), not fumaric acid itself, which is poorly absorbed and exerts no documented therapeutic effect in this context.

5.2 Multiple Sclerosis (Relapsing-Remitting)

Clinical Evidence

Dimethyl fumarate is an orally available treatment option for relapsing-remitting multiple sclerosis (MS) in a formulation with improved gastroenteric coating. The mode of action comprises immunomodulatory effects and an activation of Nrf2-mediated antioxidative response pathways leading to additional cytoprotective effects.

DMF was evaluated in two phase III randomized, double-blind, placebo-controlled, 2-year trials: the DEFINE trial (1,237 patients) and the CONFIRM trial (1,430 patients); in both studies, two dosing regimens of DMF (240 mg twice and thrice daily) were compared with placebo. Both studies showed robust efficacy; DMF was associated with a 53% reduction in annualized relapse rate in DEFINE and a 44% reduction in CONFIRM (both p < 0.001). Across these two placebo-controlled phase III trials, twice-daily DMF demonstrated a 44–53% reduction in annualized relapse rate and a 71–90% reduction in new MRI lesions; in one trial, DMF slowed the accumulation of disability, but not in the other.

A phase II clinical study in relapsing-remitting multiple sclerosis (RRMS) patients with a modified fumaric acid ester, BG-12, showed as "proof of principle" a significant reduction in the number of gadolinium-enhancing lesions after 24 weeks of treatment as compared to placebo.

Brain Atrophy

A pooled analysis of brain parenchymal fraction data from DEFINE and CONFIRM showed that in weeks 48–96, estimated change in brain parenchymal fraction was −0.0021 for DMF versus −0.0033 for placebo (a 35.9% reduction; p = 0.0025); the lower rate of whole-brain volume loss with DMF in the second year is consistent with its effects on relapses, disability, and MRI lesions.

Regulatory Approval

Dimethyl fumarate (Tecfidera®) is the methyl ester of fumaric acid and was approved in 2013 for use in multiple sclerosis. Dimethyl fumarate is one of the newer additions to the armamentarium of potent immunomodulators for the treatment of relapsing-remitting multiple sclerosis.

Evidence Strength Assessment

The evidence for DMF (a derivative of fumaric acid) in RRMS is strong: it rests on two large, phase III, randomized, double-blind, placebo-controlled trials involving over 2,600 patients combined, with consistent results across multiple clinical and MRI endpoints, and supported by post-hoc analyses extending to 6 years. DMF is approved by both the FDA and EMA for RRMS. Again, it is the ester (DMF) — not fumaric acid itself — that is the active pharmaceutical agent.

5.3 Fumaric Acid as a Food Additive and Acidulant

Fumaric acid has been used as a food acidulant since 1946 and is approved for use as a food additive in the EU, USA, Australia, and New Zealand; as a food additive, it is used as an acidity regulator and can be denoted by the E number E297. It is generally used in beverages and baking powders, and is used in the making of wheat tortillas as a food preservative and as the acid in leavening. Fumaric acid is a common food additive included in many processed foods to keep them stable and to add tartness; it has a more sour flavor than citric acid, another common food additive.

5.4 Animal Feed Applications

In the food industry, fumaric acid is used as an acidifier for controlling microbial growth, adjusting pH, and improving flavor; in the animal feed industry, fumaric acid is used as an antimicrobial agent. The EFSA FEEDAP Panel concluded that fumaric acid is safe for pigs and poultry at up to 20,000 mg/kg in complete diets, with a sufficient margin of safety, and does not require a maximum content for ruminants due to higher tolerance levels. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that fumaric acid remains safe under the authorized conditions of use for terrestrial animals, consumers, and the environment; however, the Panel cannot conclude on the safety for aquatic animals under all authorized conditions of use.

5.5 Emerging and Investigational Areas

In the scientific literature, essential qualities of fumaric acid and its esters are described as neuroprotective and anticarcinogenic, efficient in psoriasis and multiple sclerosis, and capable of diminishing inflammatory cardiac diseases. Recent studies have revealed that DMF may affect proteins involved in inflammasome activation, glycolysis, and cell signaling pathways including JAK-STAT and NF-κB, which may expand the potential clinical applications of DMF in diverse pathologies including neurodegenerative, cardiovascular, and pulmonary diseases. These remain largely preclinical or investigational and are not yet established for clinical use.

6. Body Systems and Health Areas

Immune System

Evidence from recent studies points to a multifactorial working mechanism of DMF treatment in MS which leads to a restored immune balance favoring a more tolerogenic or anti-inflammatory immune profile. T-cells demonstrate increases in naïve CD4⁺ and CD8⁺ T-cells and anti-inflammatory T-regulatory and Th2 subsets, and decreases in central memory T-cells, effector memory T-cells, and pro-inflammatory Th1 and Th17 T-cell subsets; in B-cell populations, there is an increase in transitional and B-regulatory subsets and a decline in memory B-cells.

Skin (Dermatological)

FAE therapy has the longest established clinical record in dermatology. Psoriasis is a chronic immune-mediated hyperproliferative inflammatory skin disease in which a cytokine network concept is well established. Several clinical studies have shown that systemic therapy with FAEs in patients with moderate to severe psoriasis is effective and has a good long-term safety profile; for therapeutic use, tablets with a defined mixture of FAEs (dimethylfumarate and three different salts of monoethylfumarate) are registered in Germany, with evidence that DMF is the most essential component with an antipsoriatic effect.

Central Nervous System

Animal studies using a model of central nervous system demyelination (MOG-induced experimental autoimmune encephalomyelitis) revealed a reduction of microglia and macrophages in inflamed lesions following FAE treatment. The impact of DMF directly within the CNS of MS patients remains largely unknown.

Metabolic / Mitochondrial

Fumarate, citrate, and malate are all intermediates in the tricarboxylic acid cycle, used to produce energy in the form of ATP in humans and most living cells. As an endogenous metabolite produced and consumed continuously in normal cellular respiration, fumarate is integral to oxidative phosphorylation and mitochondrial function.

7. Dosage Forms and Reported Dosages

Fumaric Acid Itself (Food Use)

The Joint FAO/WHO Expert Committee on Food Additives (JECFA) recommends a daily intake of 0–6 mg of fumaric acid per kilogram of body weight; in the European Union, the safe intake is 780 micrograms per person per day.

FAE Formulations in Psoriasis

The established treatment regimen of FAEs in psoriasis proposes a gradual increase in dosage according to a published schedule, which has been shown to improve gastrointestinal tolerance; in each patient, the final daily dosage needs to be adjusted according to individual response and the onset of adverse effects. The final dosage may range up to 1–2 g/day (6 tablets of Fumaderm®); most patients treated with fumaric acids require two to four tablets of Fumaderm®, and dosage is neither related to body weight nor to the activity of the disease.

In the treatment of psoriasis, doses of several hundred milligrams are common. In the 2021 pediatric RCT, the mean exposure to DMF was 301 ± 103 mg per day during weeks 5–40 in the FAE/FAE group and 288 ± 138 mg per day during weeks 25–40 in the placebo/FAE group.

DMF in Multiple Sclerosis

In two pivotal phase III trials, dimethyl fumarate 240 mg twice daily reduced relapse rates by approximately 50% as compared with placebo. In multiple sclerosis, the dimethyl fumarate Tecfidera® is recommended at the beginning, in the first 7 days, at 2 × 1 tablet of 120 mg/day, then daily 2 tablets of 240 mg/day.

8. Safety Considerations and Known Interactions

Food-Grade Fumaric Acid

Fumaric acid holds a favorable safety status when used within established limits because the human body metabolizes it naturally; the U.S. Food and Drug Administration (FDA) has classified food-grade fumaric acid as Generally Recognized as Safe (GRAS) when used according to good manufacturing practices. Fumaric acid is generally considered nontoxic and nonirritant at food additive levels.

Gastrointestinal Effects (FAE Therapy)

The main side effects of DMF include gastrointestinal symptoms (nausea, abdominal pain, vomiting, and diarrhea) and skin flushing, which peak at treatment initiation. About one-third of patients develop flushing that tends to subside with ongoing therapy. Side effects such as flush-like sensations and sensations of heat, as well as gastrointestinal disorders, usually decrease significantly with duration of therapy.

Hematological Effects: Lymphopenia

Mild leukopenia and moderate to marked lymphopenia are regular side effects of FAE therapy, with eosinophilia occurring rarely. A mild lymphopenia is almost always present but appears to be of little consequence in most cases. Lymphopenia (a reduction in white blood cell count) is also a serious concern in pharmaceutical settings, increasing the risk of infection. In the phase III MS trials, there was no increased risk of opportunistic infections; recommended safety monitoring includes a complete blood count prior to treatment and annually while on treatment.

Risk of Progressive Multifocal Leukoencephalopathy (PML)

Despite an overall good safety profile for DMF in MS, it has become clear that necessary clinical vigilance must not be neglected; so far, reported cases of progressive multifocal leukoencephalopathy (PML), a serious condition associated with many MS therapies, warrant proper attention in updated risk management plans.

Renal and Hepatic Effects

Other more serious side effects that have occurred include kidney and liver disturbance and white blood cell abnormality (lymphopenia, eosinophilia); it is essential that kidney function, liver function, and blood count be monitored regularly when taking FAEs. Authors of a clinical series concluded that adverse effects of fumaric acid esters are limited to transient alterations of tubular function without measurable restriction of glomerular filtration rate. These changes appear to be reversible when treatment is stopped, and to date there are no reports of severe long-term toxicity. Flushing, gastrointestinal effects, lymphopenia, and increased liver enzymes are reported side effects.

Pregnancy

Tolerance for the fetus has not been systematically studied, but unpublished clinical experience with psoriasis treatment using fumaric acid dimethyl fumarate plus ethylhydrogen fumarate gave no indication of embryotoxic or teratogenic effects; treatment with fumaric acid cannot be recommended during pregnancy, though if treatment was applied accidentally, this does not justify a risk-grounded termination of the pregnancy or invasive diagnostics. Although animal studies have shown no evidence of teratogenic effects, fumarates should not be given during pregnancy.

Important Distinction: Supplement vs. Pharmaceutical Formulation

Fumaric acid formulations are available as health supplements and are often marketed as a natural alternative medicine to treat psoriasis; they are, however, poorly absorbed by the gut and are excreted via urine without having any therapeutic effect. The safety concerns summarized above — lymphopenia, renal effects, hepatic enzyme elevations — have been documented specifically in the context of pharmaceutical-grade FAE formulations (Fumaderm®, Skilarence®, Tecfidera®) used at doses of several hundred milligrams per day or more, not at food-additive or typical supplement concentrations. These two contexts should not be conflated when evaluating risk.

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