Concept:Folic Acid and TrPs

Folic acid (pteroylglutamic acid; folate; folacin) is a water-soluble B-complex vitamin whose insufficiency is the most common vitamin inadequacy and among those most likely to perpetuate myofascial trigger points (TrPs). Its metabolism is inseparably intertwined with that of vitamin B₁₂ — the two vitamins share critical pathways, and treatment of one without establishing the status of the other risks precipitating a deficiency of the second. This page focuses on the distinct biology and clinical profile of folic acid; for the shared metabolic pathways with cobalamin, see Vitamin B₁₂ (Cobalamin) and Trigger Points.

Patients with myofascial pain who have marginally low serum folate levels — still within the "normal" range but in the lowest quartile — tire easily, sleep poorly, feel discouraged and depressed, frequently feel cold, and have a reduced basal temperature. These symptoms are similar to, but less intense than, those of patients with obvious neurological disorders responsive to folic acid therapy. In the clinical experience of Travell, Simons, and Gerwin, be sure to check your patients with chronic myofascial TrPs for low normal or abnormal serum folate levels.

Discovery and History

Pteroylglutamic (folic) acid was purified in 1943 by Stokstad and was crystallised from liver in the same year by Pfiffner and associates. By 1948, Angier and his coworkers synthesised it and identified its structure. It then became clear that folic acid was the Wills factor — the vitamin M previously found in dry brewers' yeast, and the vitamin B_c of yeast identified in chick experiments — that had enabled Lucy Wills in 1931 to cure macrocytic anaemia of pregnancy in Indian women by feeding them Marmite.

The name derives from the Latin folium (leaf), reflecting that leafy green vegetables are the primary dietary source.

Biochemical Functions

Folate acts as a carrier of single-carbon units — one-carbon fragments — at various levels of oxidation, and transfers them in biosynthetic reactions. The active form in the body is tetrahydrofolate (THF), which is produced by the reduction of dietary folate by dihydrofolate reductase.

The principal biochemical roles of folate are:

1. DNA Synthesis — Thymidylate Synthesis

Folate is essential for the synthesis of thymidylate (the thymidine nucleotide unique to DNA) via the thymidylate synthase reaction. In this reaction, the methylene group of 5,10-methylenetetrahydrofolate is transferred to deoxyuridylate to form thymidylate, oxidising THF to dihydrofolate in the process.

Folate deficiency impairs the synthesis of deoxyribonucleic acid, causing megaloblastosis in all duplicating cells of the body, most commonly observed in bone marrow cells. The impaired haematopoiesis produces a pancytopenia.

2. Purine Synthesis

Two steps in purine synthesis require folate-mediated one-carbon transfers. Purines are the building blocks of both DNA and RNA, so folate deficiency affects RNA synthesis as well as DNA replication.

3. The Methionine Cycle and DNA Methylation

The conversion of 5-methyltetrahydrofolate (5-Me-THF) to THF is coupled to the remethylation of homocysteine to methionine, which requires vitamin B₁₂ as cofactor. This reaction is the point of convergence of folate and cobalamin metabolism.

Methionine is metabolised to S-adenosylmethionine (SAM), the universal methyl donor for DNA methylation and for the synthesis of myelin, neurotransmitters (epinephrine, melatonin, creatine, phospholipids), and many other methylated compounds.

Failure of this cycle (from either folate or B₁₂ deficiency) results in:

• Accumulation of homocysteine — a cardiovascular risk factor
• Reduced SAM — impairing all methylation reactions
• Impaired DNA methylation — affecting gene expression in dividing tissues

4. The Methyl-Folate Trap

When cobalamin is lacking, 5-Me-THF cannot be demethylated. Since the polyglutamated form of THF is needed for intracellular enzyme cofactor function and cannot be formed from 5-Me-THF directly, the polyglutamated THF pool is depleted — even when serum folate levels appear normal or elevated. This is the methyl-folate trap:

• Serum folate can appear high in cobalamin deficiency (because 5-Me-THF accumulates in serum rather than being converted)
• Intracellular folate function is simultaneously impaired
• Large doses of folic acid given to a cobalamin-deficient patient will further deplete cobalamin reserves by increasing the demand for cobalamin in the methylation cycle

This is why: Never give folic acid without first establishing the vitamin B₁₂ status.

5. Amino Acid Metabolism

• Folate is required for the conversion of homocysteine to methionine
• It participates in the catabolism of histidine — in folate deficiency, formiminoglutamic acid (FIGLU) accumulates in the urine after a histidine load (the FIGLU test)
• Serine–glycine interconversion requires THF as a one-carbon acceptor

6. Neural Tube Development

Adequate folate in the periconceptional period (before and in the first weeks after conception) is essential for normal closure of the neural tube. Deficiency at this critical stage causes neural tube defects (anencephaly, spina bifida). This is the biological rationale for folate supplementation of 400–800 μg/day recommended for all women of childbearing age.

Insufficiency and Deficiency in the Context of Myofascial Pain

Insufficiency (Low Normal / Lower Quartile)

Patients with chronic MPS who have marginally low serum folate levels show a characteristic cluster of symptoms that overlap with, but are less severe than, frank deficiency:

• Increased muscular irritability and susceptibility to myofascial TrPs
• Easy fatigue
• Poor sleep
• Discouragement and depression
• Frequent sensation of cold; reduced basal temperature (mimicking thyroid hypofunction — the two conditions may coexist)
• These symptoms are often relieved by multivitamin therapy including folic acid

A disproportionately high percentage of psychiatric patients are folic acid deficient. Depression is their most probable psychiatric diagnosis.

Established Deficiency

The documented timeline of folate deprivation (from experimental studies):

• Week 3: Low serum folate
• Week 7: Hypersegmentation of polymorphonuclear leukocytes (earliest haematological sign)
• Week 14: Increased urinary excretion of FIGLU
• Week 18: Low erythrocyte folate and macroovalocytosis
• Week 19: Megaloblastic bone marrow and anaemia

Neuropsychiatric symptoms preceding haematological changes (fourth and fifth months):

• Sleeplessness and forgetfulness, gradually increasing
• Mental symptoms disappeared within 48 hours after starting oral folic acid therapy

Full clinical deficiency presents as:

• Megaloblastic anaemia (macrocytic) — large, structurally abnormal red cells; reduced oxygen-carrying efficiency per red cell
• Fatigue, diffuse muscular pain, restless legs
• Peripheral sensory neuropathy (less common than with B₁₂, but documented in 21% of one group of folate-deficient patients)
• Depression; peripheral sensory loss; diarrhoea
• In children with congenital enzyme deficiencies: severe and often irreversible mental retardation and/or megaloblastic anaemia

Specific Enzyme Deficiencies

Congenital abnormalities in folate-dependent pathways are generally seen initially in children with severe and often irreversible mental retardation and/or megaloblastic anaemia. Some are greatly improved by megadoses of folic acid or folacin:

• Methylenetetrahydrofolate reductase (MTHFR) deficiency — impairs the synthesis of 5-Me-THF; patients exhibit homocystinuria responsive to folate therapy; a common polymorphism (C677T) in this gene affects a significant proportion of the population and reduces folate utilisation
• 5-Methyltetrahydrofolate transferase deficiency — liver enzyme studies reveal markedly decreased activity; causes increased excretion of homocysteine
• Glutamic formiminotransferase deficiency — blocks formation of glutamate from histidine, causing increased formiminoglutamate (FIGLU) in urine; congenital expression can significantly increase the dietary folate requirements of an individual
• Cystathionine synthase deficiency — also causes homocystinuria; requires supplemental vitamin B₆ (see Vitamin B₆)

Low Serum Cholesterol as a Marker

Low serum cholesterol levels were correlated with low serum folate values at or below 6.2 ng/ml in 46 patients (r = 0.58). No such correlation was obtained between cobalamin deficiency and serum cholesterol level. Low thyroid function of thyroid (but not of pituitary) origin is likely to be associated with an increased serum cholesterol — providing a useful clinical differentiator.

Laboratory Tests

Serum and Red Cell Folate

• Routine laboratory testing of folate levels in blood serum and in blood cells (tissue level) is now available
• Normal human serum contains approximately 7–16 ng/ml of folate
• Serum folate reflects recent dietary intake; it falls rapidly with dietary restriction
• Red cell (erythrocyte) folate reflects tissue stores accumulated over the lifespan of the red cell (approximately 120 days) — a more reliable indicator of chronic folate status

FIGLU Test

After a histidine load, urinary excretion of formiminoglutamic acid (FIGLU) is measured. In folate deficiency, histidine catabolism is blocked at the step requiring THF, and FIGLU accumulates and spills into the urine. Elevated FIGLU at 14 weeks of deficiency provides biochemical evidence before anaemia develops.

MCV and Its Limitations

Contrary to expectation, among hospitalised patients, a high MCV of 95 cu mm or more had only a 0.18 correlation with folate deficiency, and therefore would not have been useful to screen for it. In some patients, other conditions caused the macrocytosis despite the folate deficiency; in other patients, the tissue folate had not yet been sufficiently depleted to produce macrocytosis.

Absence of macrocytosis does not exclude folate deficiency.

Homocysteine

Homocysteine accumulates in the serum and urine when homocysteine cannot be converted to methionine (a folate-dependent step). Elevated homocysteine is found in both folate and vitamin B₁₂ deficiency, making it a sensitive but non-specific marker. Its elevation in folate deficiency (without B₁₂ deficiency) distinguishes folate from B₁₂ as the limiting factor, since methylmalonic acid only accumulates in B₁₂ deficiency.

Requirements

The total folacin activity recommended as a daily dietary allowance:

• Adults and adolescents: 400 μg/day
• During pregnancy: 800 μg/day
• During lactation: 500 μg/day

Evidence of depleted body stores of folacin appear in 2 months and symptoms become severe after 4 months of folic acid deprivation. Body stores are therefore not large.

Sources

Best Dietary Sources

The dietary sources of folate are leafy vegetables (foliage — the name is literal). Sources include:

• Yeast, liver, and other organ meat
• Fresh or fresh-frozen uncooked fruit or fruit juice
• Lightly cooked fresh green vegetables: broccoli, asparagus, spinach, Brussels sprouts
• Beans and lentils

Folate Destruction in Food Preparation

Although folates are ubiquitous in nature, being present in nearly all natural foods, they are highly susceptible to oxidative destruction:

• 50–95% of the folate content of foods may be destroyed in processing and preparation
• All folate is lost from refined foods — hard liquor and hard candies contain none
• Heat, prolonged cooking, and oxidation destroy folate rapidly
• Food should be stored in a cool, dark place and consumed as fresh as possible
• Cooking water should not be discarded — the pot liquor of cooked vegetables contains substantial folate

This extraordinary vulnerability to destruction means that a diet dominated by cooked, processed, and refined foods is structurally deficient in folate regardless of the nominal food variety consumed.

Folate in Specific Foods

Food	Approximate folate content
Liver (beef, 100g)	220 μg
Spinach (raw, 100g)	194 μg
Asparagus (cooked, 4 spears)	89 μg
Broccoli (cooked, 100g)	71 μg
Lentils (cooked, 100g)	181 μg
Orange juice (250ml)	55 μg
Avocado (half)	59 μg

Causes of Insufficiency and Deficiency

The four commonest causes are:

1. Advanced age — an increasing segment of the population; decreased nutritional intake, decreased absorption (partly due to folate deficiency itself impairing the dividing GI mucosal cells), and increased need
2. Pregnancy or lactation — the demand for rapid cellular division in fetal tissue and placenta dramatically increases folate requirement
3. Dietary indiscretion — restrictive diets, food faddism, economic disadvantage, social isolation
4. Drug abuse — most commonly alcohol, which impairs folate absorption, reduces dietary folate intake, and interferes with folate metabolism

Additional causes:

• Malabsorption syndromes — coeliac disease, Crohn's disease, tropical sprue
• Drugs: methotrexate and other dihydrofolate reductase inhibitors; phenytoin and other anticonvulsants (increase folate catabolism); oral contraceptives; sulfasalazine; trimethoprim
• Dialysis — folate is lost in dialysate

The Alcohol–Folate Interaction

Alcohol impairs folate status through multiple mechanisms simultaneously:

1. Reduced dietary intake of folate (alcohol displaces food)
2. Impaired absorption from the small intestine
3. Interference with the enterohepatic recirculation of folate
4. Direct inhibition of dihydrofolate reductase at high concentrations
5. Increased urinary excretion of folate

This multi-level impairment explains why alcoholism is one of the most potent causes of folate deficiency, and why the folate–alcohol interaction is clinically critical in patients with chronic musculoskeletal pain who drink regularly.

Therapy

Oral Supplementation

• Standard replacement: 1 mg/day orally
• The Schilling test is an unreliable indicator of oral absorption of vitamin B₁₂, and oral supplementation should always be monitored by subsequent serum levels of the vitamin
• It is wise to routinely prescribe adequate amounts of vitamin B₁₂ and folic acid together, not just one — a 500 μg tablet of B₁₂ and a 1 mg tablet of folic acid daily is safe and effective
• Patients should be cautioned that folic acid absorption is impaired by the simultaneous ingestion of antacids

The Homocysteine Rationale for Higher Doses

Reduction of elevated homocysteine levels to the point that there is no increased mortality from cardiac and cerebral thrombosis requires a higher daily dose of about 700 μg. Hence, a daily dose of 1 mg has been considered adequate.

The B₁₂ First Rule

Never administer folic acid without first checking the vitamin B₁₂ level.

Daily intake of 400 μg of folic acid can:

• Aggravate the effects of vitamin B₁₂ deficiency
• Obscure the early haematological warning signs of possible combined degeneration of the spinal cord, by correcting the megaloblastic anaemia while the neurological damage progresses undetected
• In the presence of already-depleted cobalamin reserves, precipitate serious cobalamin deficiency

Pregnancy

Folate supplementation of 400–800 μg/day is recommended for all women of childbearing age, and should be started before conception since neural tube closure occurs in the first 28 days after fertilisation — before most pregnancies are confirmed. Supplementation to 800 μg/day is maintained throughout pregnancy and reduced to 500 μg/day during lactation.

The Biology of Starvation: Folic Acid

Folic acid stands at the intersection of starvation biology and cell survival because it governs the capacity of dividing cells to replicate their DNA. When dietary folate fails — whether from outright starvation, food processing, or malabsorption — the consequences unfold through a distinctive hierarchy of vulnerable tissues:

Fastest-dividing tissues fail first:

1. Bone marrow — megaloblastic arrest of erythropoiesis; the red cells produced are large, short-lived, and oxygen-inefficient; anaemia follows within weeks to months of depletion. This directly impairs oxygen delivery to skeletal muscle, creating or worsening the local energy crisis at TrP endplates
2. Gastrointestinal epithelium — villous atrophy and impaired absorption develop, creating a vicious cycle: folate deficiency destroys the absorptive surface that would absorb replacement folate
3. Lymphoid tissue and immune cells — impaired immune surveillance

Neural consequences: Unlike vitamin B₁₂ deficiency, folate deficiency causes peripheral neuropathy less frequently, and the spinal cord lesions of subacute combined degeneration only in the most severe cases. However, folate deficiency impairs brain function through SAM depletion — reducing methylation capacity throughout the nervous system, affecting neurotransmitter turnover and myelin maintenance.

The specific vulnerability in starvation is that folate stores last only 2–4 months — far shorter than the 1–3 years required to exhaust vitamin B₁₂ stores. In conditions of restricted fresh vegetable and fruit intake (sieges, famines, long sea voyages without fresh provisions, prolonged institutional catering, restricted diets, excessive alcohol), folate depletion is the first B-vitamin crisis to emerge neurologically.

The evolutionary logic: folate is abundant in the fresh plant matter that constitutes the natural human diet; its destruction by heat and oxidation is a product of cooking and food storage. In this sense, folate deficiency is a disease of civilisation — specifically, of cooked and processed food — rather than true starvation.

In the chronic pain patient, the relevance is that folate insufficiency — even at low-normal levels — directly predicts increased TrP irritability, impaired treatment response, depression, fatigue, and poor sleep. These are simultaneously the most common complaints of patients with chronic myofascial pain and the most common symptoms of subclinical folate insufficiency. Correcting folate status is therefore both diagnostically informative and therapeutically necessary.

Related Pages

• Perpetuating Factors — Overview
• Vitamin B₁₂ (Cobalamin) and Trigger Points — inseparable metabolic partner
• Vitamin B₆ (Pyridoxine) and Trigger Points
• Vitamin C (Ascorbic Acid) and Trigger Points
• Folate — Wikipedia
• Folate deficiency — Wikipedia
• Folate metabolism — Wikipedia
• MTHFR — Wikipedia
• Neural tube defect — Wikipedia
• Homocysteine — Wikipedia
• Tetrahydrofolate — Wikipedia
• Megaloblastic anaemia — Wikipedia

References

• Travell JG, Simons DG. Myofascial Pain and Dysfunction: The Trigger Point Manual, Volume 1. 2nd ed. Baltimore: Williams & Wilkins; 1999. Chapter 4, Section C.