Alpha-Linolenic Acid (DB00132): A Comprehensive Scientific Review

I. Introduction to Alpha-Linolenic Acid (ALA)

Alpha-linolenic acid (ALA) is an 18-carbon polyunsaturated fatty acid (PUFA) belonging to the omega-3 (n-3) family.[1] It holds the distinction of being an essential fatty acid (EFA) for humans and other mammals, meaning it is indispensable for normal physiological function but cannot be synthesized de novo within the body.[3] Consequently, ALA must be obtained entirely from dietary sources. This inherent biological limitation underscores ALA's critical nutritional status and necessitates its inclusion in dietary recommendations to prevent deficiency and support overall health.

ALA serves as the parent compound for the entire omega-3 fatty acid series. While it can be metabolically converted into longer-chain, more unsaturated omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), this conversion process is notably limited in humans.[2] Nevertheless, ALA itself, along with its metabolites, plays significant roles in human nutrition and physiology.[1] It is a structural component of cell membranes and is involved in various signaling pathways.

Found predominantly in plant-based foods, ALA is abundant in certain vegetable oils (flaxseed, canola, soybean), nuts (walnuts), and seeds (flax, chia, hemp).[1] Its presence in common dietary components makes it the most prevalent omega-3 fatty acid in many Western diets.[17] Chemically, ALA is identified by the Chemical Abstracts Service (CAS) number 463-40-1 and the DrugBank identifier DB00132.[1] Its molecular formula is C18​H30​O2​.[1] This report provides a comprehensive overview of the chemical properties, metabolism, dietary sources, physiological functions, health effects, safety considerations, and dietary recommendations pertaining to alpha-linolenic acid.

II. Chemical Properties and Structure

Alpha-linolenic acid is characterized by its specific chemical structure, which dictates its physical properties and biological functions.

Detailed Structure:

ALA is a carboxylic acid featuring an 18-carbon aliphatic chain.5 Its defining feature is the presence of three double bonds located at the 9th, 12th, and 15th carbon atoms when numbered from the carboxyl (COOH) end (denoted as Δ9,12,15). Crucially, all three double bonds possess a cis configuration (Z configuration).1 This cis geometry introduces kinks into the hydrocarbon chain, preventing the molecules from packing tightly together and contributing significantly to the fluidity of biological membranes into which ALA is incorporated.2 This contrasts sharply with trans fatty acids, which lack these kinks and behave more like saturated fatty acids.

The systematic IUPAC name for ALA is (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid.[1] In nutritional nomenclature, it is commonly referred to as 18:3n-3 (or 18:3ω-3). This notation indicates an 18-carbon chain with 3 double bonds, with the first double bond positioned at the third carbon atom counting from the methyl (CH3) or omega (n) end of the molecule.[1] ALA is a regioisomer of gamma-linolenic acid (GLA), which is an omega-6 fatty acid (18:3n-6) with double bonds at the 6th, 9th, and 12th positions.[5]

For precise chemical identification, the InChI string is InChI=1S/C18​H30​O2​/c1−2−3−4−5−6−7−8−9−10−11−12−13−14−15−16−17−18(19)20/h3−4,6−7,9−10H,2,5,8,11−17H2​,1H3​,(H,19,20)/b4−3−,7−6−,10−9− and the InChIKey is DTOSIQBPPRVQHS-PDBXOOCHSA-N.[1] The canonical SMILES representation is CC/C=C\C/C=C\C/C=C\CCCCCCCC(=O)O.[1]

Physicochemical Properties:

At standard room temperature, ALA exists as a clear, colorless liquid.1 Its molar mass is approximately 278.436 g/mol.1 It has a low melting point of −11 °C (12 °F) and boils at 232 °C (450 °F) under reduced pressure (17 mmHg).5 Its density is approximately 0.9164 g/cm³.5 As a long-chain fatty acid, its solubility characteristics are typical, being poorly soluble in water but soluble in organic solvents.

Stability and Oxidation:

The presence of three double bonds makes ALA highly susceptible to oxidation when exposed to air, heat, or light, leading to rancidity more quickly than saturated or monounsaturated fats.5 This oxidative instability presents challenges in food processing and storage. To enhance stability and shelf-life, oils rich in ALA, such as soybean oil, have historically been partially hydrogenated. However, this process generates detrimental trans fatty acids.5 Consequently, there has been development of soybean varieties with modified fatty acid profiles (lower ALA content) to improve oil stability without requiring hydrogenation.5 The inherent instability necessitates careful handling, storage (e.g., refrigeration, protection from light and air), and potentially the use of antioxidants when formulating products containing ALA-rich oils. This chemical characteristic directly impacts the quality, sensory properties, and nutritional value of ALA-containing foods and supplements.

Table 1: Key Identifiers and Chemical Properties of ALA

Property	Value	Reference(s)
IUPAC Name	(9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid	1
Common Name	alpha-Linolenic acid (ALA), Linolenic acid	1
CAS Number	463-40-1	1
DrugBank ID	DB00132	1
PubChem CID	5280934	1
Molecular Formula	C18​H30​O2​	1
Molar Mass	~278.4 g/mol	1
Physical State (Room Temp.)	Clear, colorless liquid	1
Melting Point	-11 °C	5
Boiling Point	232 °C (at 17 mmHg)	5
Key Structural Features	18 carbons, 3 cis double bonds (Δ9,12,15), omega-3 (n-3) position	1

III. Biological Significance and Metabolism

Alpha-linolenic acid holds a unique position in human nutrition as an essential fatty acid, forming the foundation for the synthesis of other vital omega-3 fatty acids and participating directly in various physiological processes.

Essential Nutrient Role:

As established, ALA cannot be synthesized by the human body and must be obtained from the diet, classifying it as indispensable for human health.4 It plays a fundamental role in normal growth and development.11 While overt deficiency is rare in populations consuming varied diets, insufficient intake can theoretically lead to symptoms such as rough, scaly skin, dermatitis, and potentially visual or neurological problems, although these are more strongly associated with deficiencies of its longer-chain derivatives, EPA and DHA.2

Metabolic Pathway: Conversion to EPA and DHA:

Upon ingestion, ALA enters a metabolic pathway primarily located in the liver, where it can be elongated and further desaturated to produce longer-chain omega-3 PUFAs.3 This pathway involves a series of enzymatic steps:

1. Delta-6 Desaturation: ALA is first converted to stearidonic acid (SDA, 18:4n-3) by the enzyme delta-6 desaturase (D6D), encoded by the FADS2 gene. This step is considered rate-limiting for the overall pathway.[2]
2. Elongation: SDA is elongated to eicosatetraenoic acid (ETA, 20:4n-3) by elongase enzymes, primarily ELOVL5.[3]
3. Delta-5 Desaturation: ETA is then converted to eicosapentaenoic acid (EPA, 20:5n-3) by the enzyme delta-5 desaturase (D5D), encoded by the FADS1 gene.[3]
4. Further Elongation and Desaturation: EPA can be further elongated and desaturated through a series of steps involving elongases (ELOVL2/5) and desaturases (FADS2), potentially including peroxisomal beta-oxidation, to form docosapentaenoic acid (DPA, 22:5n-3) and ultimately docosahexaenoic acid (DHA, 22:6n-3).[6]

A critical aspect of this pathway is its limited efficiency in humans.[6] Studies consistently show that only a small fraction of dietary ALA is converted to EPA, with estimates typically ranging from less than 5% to perhaps 10-15% in some studies.[6] The conversion to DHA is even more restricted, often estimated at less than 1%, and sometimes reported as negligible (0-4%).[8] This metabolic bottleneck means that while ALA contributes to the body's pool of longer-chain omega-3s, relying solely on ALA intake is generally insufficient to achieve the higher tissue levels of EPA and particularly DHA associated with certain health benefits, especially those related to brain and retinal function where DHA plays a crucial structural role.[6] Consequently, direct dietary consumption of preformed EPA and DHA from marine or algal sources is the most effective strategy to increase their levels in the body.[6]

Factors Affecting Conversion:

The efficiency of ALA conversion is influenced by several factors:

• Dietary Competition: Linoleic acid (LA, 18:2n-6), the essential omega-6 fatty acid, competes with ALA for the same D6D and D5D enzymes.[3] Typical Western diets are often high in LA relative to ALA (high LA:ALA ratio), which can saturate these enzymes and significantly suppress the conversion of ALA to EPA and DHA.[25] This highlights that the balance of dietary fatty acids, not just absolute ALA intake, is crucial for omega-3 metabolism. Dietary stearidonic acid (SDA), found in sources like echium oil, bypasses the rate-limiting D6D step and is more readily converted to EPA compared to ALA.[9]
• Biological Factors: Studies indicate that women, particularly those of reproductive age, generally exhibit higher conversion rates of ALA to EPA and especially DHA compared to men.[8] This may be related to hormonal influences (e.g., estrogen) or reflect an adaptation to meet the high demands for DHA during pregnancy and lactation for fetal and infant development.
• Genetic Factors: Genetic variations (polymorphisms) within the FADS1 and FADS2 genes, which encode the D5D and D6D enzymes, significantly impact individual conversion capacity.[25] Certain haplotypes are associated with higher enzyme activity and more efficient conversion than others.[25] This genetic variability suggests that population-average conversion rates may not apply equally to all individuals, potentially necessitating personalized dietary approaches in the future.
• Health Status: Pathophysiological states, such as obesity or metabolic syndrome, may alter desaturase and elongase activities, potentially further impairing the already limited conversion of ALA.[10]

Tissue Distribution and Incorporation:

Following absorption, ALA, along with EPA and DHA (whether from diet or conversion), is incorporated into the phospholipid bilayers of cell membranes throughout the body.2 This incorporation modifies membrane composition and influences properties like fluidity and the function of embedded proteins.2 DHA shows preferential accumulation in neural tissues, particularly the brain and retina, where it constitutes a major structural component of neuronal membranes.6

Beta-Oxidation:

Like other fatty acids, ALA can be catabolized for energy production through the process of beta-oxidation, primarily in mitochondria and peroxisomes.8

IV. Dietary Sources of ALA

Alpha-linolenic acid is unique among omega-3 fatty acids in that its primary dietary sources are plant-based. Understanding these sources is crucial for dietary planning and ensuring adequate intake.

Primary Plant Sources:

The most concentrated sources of ALA are found in specific plant oils, nuts, and seeds 4:

• Oils: Flaxseed oil stands out as the richest known source of ALA. Other significant contributors include canola (rapeseed) oil, soybean oil, and walnut oil.[4] Olive oil contains ALA, but typically in much lower amounts compared to these other oils.[4]
• Nuts and Seeds: Flaxseeds (whole or ground), chia seeds, English walnuts, and hemp seeds are excellent sources of ALA.[4] Black walnuts also contain ALA, though less than English walnuts.[6]
• Legumes and Vegetables: Soybeans (including edamame) and kidney beans contain ALA.[6] Leafy green vegetables also provide ALA, but generally in smaller quantities compared to oils and seeds.[6]

Other Sources:

ALA is present in some animal fats, particularly from grass-fed animals, as they consume ALA-containing plants.17 However, the amount of ALA in grass-fed beef, for example, is considerably lower than in concentrated plant sources like walnuts or flaxseed oil, and also much lower than the EPA and DHA content found in fatty fish.6

Fortified Foods:

Consumers may also find ALA, along with EPA and DHA, added to certain fortified foods such as eggs, yogurt, juices, milk, soy beverages, and infant formulas.7 Label reading is necessary to determine the type and amount of omega-3 added.

Quantitative Data:

The ALA content varies significantly among sources. Table 2 provides approximate ALA amounts in common foods, based primarily on USDA data compiled by the NIH.6 Achieving the recommended daily intake (e.g., 1.1-1.6 g/day for adults) typically requires regular consumption of specific ALA-rich foods. For instance, a single tablespoon of flaxseed oil far exceeds the daily AI, while one ounce of walnuts or chia seeds provides a substantial portion of the daily need. Relying solely on leafy vegetables or typical Western dietary patterns without specific inclusion of these concentrated sources might result in lower ALA intake.

Table 2: Dietary Sources and Approximate ALA Content of Selected Foods

Food	Serving Size	ALA Content (grams)	Reference(s)
Flaxseed oil	1 tablespoon (tbsp)	7.26	6
Chia seeds	1 ounce (oz)	5.06	6
English walnuts	1 oz	2.57	6
Flaxseed, whole	1 tbsp	2.35	6
Canola oil	1 tbsp	1.28	6
Soybean oil	1 tbsp	0.92	6
Black walnuts	1 oz	0.76	6
Mayonnaise	1 tbsp	0.74	6
Edamame, frozen, prepared	½ cup	0.28	6
Refried beans, vegetarian	½ cup	0.21	6
Kidney beans, canned	½ cup	0.10	6
Ground beef, 85% lean, cooked	3 oz	0.04	6
Bread, whole wheat	1 slice	0.04	6
Milk, low-fat (1%)	1 cup	0.01	6

Note: Values are approximate and can vary based on specific product, processing, and preparation methods.

Comparison with EPA/DHA Sources:

It is crucial to distinguish ALA sources from those providing preformed EPA and DHA. The latter are primarily found in fatty, cold-water fish (like salmon, mackerel, herring, sardines, tuna), shellfish (like oysters, shrimp), fish oil supplements, krill oil, and algal oil.6 Algal oil is a significant source for vegetarians and vegans seeking direct EPA and DHA intake.7 This distinction is fundamental for dietary guidance, as individuals who do not consume fish or algae-derived supplements rely entirely on the limited endogenous conversion of dietary ALA to obtain EPA and DHA.6

V. Physiological Functions

Alpha-linolenic acid, both directly and through its metabolites EPA and DHA, participates in a wide array of physiological processes critical for maintaining health. Its functions extend from basic cellular structure to complex signaling pathways.

Membrane Structure and Fluidity:

A primary role of ALA and other PUFAs is their incorporation into the phospholipid bilayers that form cellular membranes.2 The cis double bonds in ALA introduce kinks in the fatty acid chain, disrupting tight packing and thereby increasing membrane fluidity and flexibility.2 This property is vital for the proper functioning of membrane-bound proteins, including receptors, ion channels, and enzymes, influencing processes like signal transduction and transport across the membrane.2 DHA, in particular, is highly concentrated in membranes of the retina and brain, contributing significantly to the fluidity required for visual transduction and neuronal signaling.6

Eicosanoid Production and Signaling:

While the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid EPA are the major precursors for the most widely studied eicosanoids (prostaglandins, thromboxanes, leukotrienes), ALA can also serve as a substrate for these pathways, albeit leading to different series of compounds.2 Eicosanoids derived from ALA may possess distinct, potentially weaker, biological activities compared to those derived from AA or EPA.2 Some evidence suggests that ALA metabolites might inhibit the production of pro-inflammatory eicosanoids derived from AA, such as prostaglandin E2 (PGE2) and leukotriene B4 (LTB4).2 Furthermore, the longer-chain derivatives of ALA, EPA and DHA, are precursors to specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins. These lipid mediators actively orchestrate the resolution phase of inflammation, promoting tissue repair and return to homeostasis.12

Gene Expression Regulation:

ALA and its metabolites, EPA and DHA, act as signaling molecules that can modulate the expression of numerous genes.2 They exert this control by interacting with and altering the activity of specific nuclear transcription factors. Key among these are the Peroxisome Proliferator-Activated Receptors (PPARs, particularly PPAR-alpha and PPAR-gamma) and Nuclear Factor kappa B (NF-κB).2 PPARs regulate genes involved in lipid metabolism, glucose homeostasis, and inflammation, while NF-κB is a central regulator of inflammatory gene expression. By influencing these transcription factors, omega-3 fatty acids can orchestrate broad changes in metabolic and inflammatory pathways at the genetic level, providing a molecular basis for many of their observed physiological effects.

Anti-inflammatory and Immunomodulatory Roles:

Through the mechanisms described above (modulation of eicosanoid production, SPM generation, and gene expression), ALA and its derivatives exhibit anti-inflammatory and immunomodulatory properties.2 Evidence suggests potential inhibition of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β).2 Importantly, research indicates that ALA itself, not just its longer-chain metabolites, can be metabolized via lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome P450 (CYP450) pathways into various oxylipins, such as 9-hydroxy-octadecatrienoic acid (9-HOTrE) and 13-HOTrE.12 These ALA-derived oxylipins have demonstrated immunomodulating effects in experimental models 12, suggesting that ALA possesses intrinsic biological activity beyond simply serving as a precursor to EPA and DHA.

Cardiovascular System Effects:

ALA and its metabolites contribute to cardiovascular health through several mechanisms. An antithrombotic effect, involving the inhibition of platelet aggregation, has been described.1 This, along with anti-inflammatory actions and potential improvements in lipid profiles and endothelial function, likely contributes to the observed association between ALA intake and reduced cardiovascular disease risk.

Central Nervous System (CNS):

The high concentration of DHA in the brain underscores the importance of omega-3 fatty acids for neurological function. While direct evidence for ALA's role is less extensive than for DHA, ALA contributes to the overall omega-3 pool available for brain development and maintenance. Potential positive impacts on CNS function and behavior have been suggested, likely mediated through membrane structural effects and the provision of DHA.6

VI. Health Effects and Clinical Evidence

The consumption of alpha-linolenic acid has been linked to various health outcomes, particularly concerning cardiovascular disease, inflammation, and metabolic health. However, the evidence base varies in strength, and some areas, such as cancer risk, remain controversial.

Cardiovascular Health:

• Mortality: A significant body of evidence from prospective cohort studies suggests that higher dietary intake or tissue biomarker levels of ALA are associated with a reduced risk of mortality. Systematic reviews and meta-analyses consistently report a lower risk of death from all causes, cardiovascular disease (CVD), and specifically coronary heart disease (CHD) with higher ALA exposure.[5] One large meta-analysis quantified this association, finding that each 1 g/day increase in ALA intake was linked to an approximately 5% lower risk of both all-cause and CVD mortality.[29] This association with mortality appears more robust than the effects observed on some individual cardiovascular risk factors, suggesting that ALA's protective mechanisms might be multifactorial, potentially involving anti-arrhythmic effects, membrane stabilization, or cumulative small benefits across various pathways rather than large changes in single markers.[2]
• Lipid Profile: ALA intake appears to favorably modulate blood lipid profiles, although the effects are generally considered more modest than those achieved with direct EPA and DHA supplementation.[8] Meta-analyses of randomized controlled trials (RCTs) indicate that ALA supplementation significantly reduces serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C).[5] No consistent effect on high-density lipoprotein cholesterol (HDL-C) has been observed.[12] The magnitude of these effects may vary depending on the population studied, with potentially greater benefits seen in individuals with pre-existing hyperlipidemia or hyperglycemia, and possibly in Asian populations.[30]
• Blood Pressure: Some sources suggest a potential benefit of ALA in lowering blood pressure [32], similar to other omega-3s, although the evidence specifically for ALA might be less extensive compared to that for fish oil.[33]
• Mechanisms: The cardioprotective effects are likely mediated through a combination of factors including anti-thrombotic (anti-platelet) actions [1], potential anti-arrhythmic effects [2], anti-inflammatory properties [2], improvements in lipid profiles [12], and possibly enhanced endothelial function.

Inflammation and Immune Response:

Evidence suggests ALA can exert anti-inflammatory effects. A meta-analysis focusing on individuals with overweight or obesity found that ALA supplementation significantly reduced levels of C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α).31 However, results regarding CRP have been inconsistent across different meta-analyses 12, potentially reflecting differences in study populations, ALA dosage, or duration.

Neurological Function and Development:

While omega-3 fatty acids, particularly DHA, are crucial for brain development and function 6, the direct contribution of ALA itself, independent of its conversion to DHA, is less clearly defined. Its essentiality implies a fundamental role, but specific neurological benefits are more strongly attributed to DHA.

Cancer Risk:

The relationship between ALA and cancer risk is complex and somewhat controversial. While higher ALA intake is linked to lower overall and CVD mortality, one large meta-analysis reported a potential slight increase in cancer mortality associated with higher ALA intake.29 The most discussed concern relates to prostate cancer. Several observational studies and meta-analyses have suggested an association between higher ALA intake or tissue levels and an increased risk of prostate cancer.23 However, it is crucial to interpret this association cautiously. Observational studies cannot establish causation, and confounding factors may play a significant role. For example, dietary sources of ALA vary; higher tissue levels might sometimes correlate with higher red meat consumption (an animal source containing ALA but also other factors linked to cancer risk) rather than plant sources like flaxseed oil.23 The biological mechanism remains unclear, and further research is needed to determine if a causal link exists and whether the source of ALA (plant vs. animal) matters. Until then, caution regarding high-dose ALA supplementation, particularly for men at high risk of prostate cancer, is warranted.23

Metabolic Syndrome and Obesity:

Given its beneficial effects on lipid profiles and inflammation, ALA may play a role in managing metabolic syndrome.13 Some studies suggest ALA supplementation can improve insulin sensitivity and increase serum adiponectin levels in patients with type 2 diabetes 32, indicating potential benefits for glucose metabolism beyond its lipid-lowering and anti-inflammatory actions.

VII. Safety, Tolerability, and Interactions

Alpha-linolenic acid, particularly when consumed as part of a normal diet, is generally considered safe. However, considerations regarding high-dose supplementation, potential side effects, and drug interactions are important.

General Safety Profile:

ALA obtained from food sources in typical dietary amounts is regarded as safe and well-tolerated by most adults.23 The U.S. Food and Drug Administration (FDA) recognizes ALA as safe and effective for its nutritional role.34

Supplement Safety and Tolerability:

The safety profile of ALA consumed in high doses via supplements is less well-established compared to dietary intake.23 While one study suggested doses up to 2400 mg/day were safe in adults 34, exceeding dietary levels may increase the likelihood of side effects and potential risks. High doses generally do not appear to offer additional benefits.34 Mild side effects associated with omega-3 supplements (including ALA, though perhaps less frequently causing fishy aftertaste than fish oil) can include 33:

• Unpleasant aftertaste or bad breath
• Heartburn
• Nausea
• Diarrhea
• Headache
• Rash (rare)

Due to its caloric density, excessive intake of ALA-rich oils or supplements could contribute to weight gain if not accounted for in overall energy balance.[23]

Bleeding Risk:

Omega-3 fatty acids, including ALA and its metabolites, possess antiplatelet properties.2 High doses, generally considered to be 3 grams per day or more of combined EPA/DHA, but potentially applicable to high ALA intake as well, may increase the risk of bleeding.32 This is particularly relevant for individuals taking anticoagulant or antiplatelet medications or those scheduled for surgery. Discontinuation of high-dose supplements prior to surgical procedures is often recommended.32

Drug Interactions:

Potential interactions include:

• Anticoagulant/Antiplatelet Drugs: Concurrent use of ALA supplements with medications like warfarin, clopidogrel, aspirin, or other blood thinners may potentiate their effects and increase bleeding risk.[32] Close monitoring and physician consultation are advised.
• Blood Pressure Medications: ALA may have a mild blood pressure-lowering effect, potentially adding to the effect of antihypertensive drugs.[33]
• Statins: Preliminary evidence suggests ALA might enhance the cholesterol-lowering efficacy of statin medications.[32]

Contraindications and Precautions:

Caution or avoidance of high-dose ALA supplementation is advised in certain situations:

• Prostate Cancer: Due to the unresolved association observed in some studies, men with existing prostate cancer or at high risk should avoid ALA supplements until more definitive data are available.[23]
• Surgery: Supplements should typically be stopped before elective surgery due to bleeding risk.[32]
• Pregnancy and Breastfeeding: While dietary ALA is essential, the safety of high-dose supplements during pregnancy and lactation has not been established. It is prudent to rely on food sources and avoid supplementation unless specifically advised by a healthcare provider.[23]
• Kidney Transplant: One report noted a potential increased risk of mortality with high ALA consumption post-transplant; avoidance of supplements is suggested pending further research.[23]
• Other Conditions: Consultation with a healthcare provider before starting ALA supplementation is recommended for individuals with liver disease, high alcohol consumption, diabetes (due to potential effects on blood sugar), thyroid disorders, or thiamine deficiency.[34] One source lists dyslipidemia as a contraindication, possibly reflecting the superior triglyceride-lowering effects of EPA/DHA.[32]

Toxicity:

ALA is generally considered non-toxic at dietary levels. Human toxicity from overdose is extremely rare.34 Animal studies indicate that very high intravenous doses can cause toxicity, including hepatic necrosis in primates (~90-100 mg/kg).34 While no lethal dose is established in humans, very high intakes (e.g., 121 mg/kg/day) have been associated with altered liver enzymes, suggesting potential hepatotoxicity at extreme doses.34 Monitoring may be advisable for individuals consuming very high supplemental doses.34

VIII. Dietary Recommendations and Intake Levels

Establishing precise dietary requirements for alpha-linolenic acid is complicated by its metabolic relationship with EPA and DHA. However, authoritative bodies have set reference values based on observed intakes in healthy populations and the prevention of deficiency.

Established Dietary Reference Intakes (DRIs):

Due to insufficient data to determine an Estimated Average Requirement (EAR), an Adequate Intake (AI) level has been established for ALA. The AI represents an intake level assumed to ensure nutritional adequacy.35

• U.S. Institute of Medicine (IOM) / National Institutes of Health (NIH): The AI for adults is set at 1.6 grams per day for males and 1.1 grams per day for females.[7] Specific AIs are also established for different life stages:
• Pregnancy: 1.4 g/day [23]
• Lactation: 1.3 g/day [23]
• Infants (0-12 months): 0.5 g/day
• Children (1-18 years): AIs range from 0.7 g/day to 1.6 g/day, increasing with age.[7]
• European Food Safety Authority (EFSA): EFSA recommends an AI for ALA of 0.5% of total daily energy intake (E%) for adults and children.[35] For context, EFSA also sets an AI for linoleic acid (LA, omega-6) at 4 E% and for combined EPA plus DHA at 250 mg/day for adults.[35] For infants (7-11 months) and young children (1-3 years), EFSA recommends an AI for DHA of 100 mg/day.[35]

The use of an AI rather than a Recommended Dietary Allowance (RDA) reflects the difficulty in defining a specific biochemical or functional endpoint solely dependent on ALA intake, separate from the effects of its conversion products, EPA and DHA.[35]

Meeting Recommendations:

Most individuals in developed countries like the United States likely consume enough ALA to meet the established AI levels through their regular diet.7 However, achieving intakes associated with potential cardiovascular benefits observed in some epidemiological studies (e.g., >1 g/day) may require conscious dietary choices.29 Prioritizing ALA-rich foods such as flaxseeds, chia seeds, walnuts, and canola or soybean oil is the most effective way to ensure adequate or optimal intake.6 Studies in European children suggest that ALA intake can often be below the EFSA recommendation of 0.5 E%.38

Tolerable Upper Intake Level (UL):

Currently, neither the IOM nor EFSA has established a Tolerable Upper Intake Level (UL) for ALA or other omega-3 fatty acids.36 This is primarily due to a lack of consistent evidence demonstrating adverse effects from high dietary intakes across populations. However, this does not imply that unlimited supplemental intake is without risk; potential side effects like increased bleeding risk and concerns regarding prostate cancer warrant caution with high-dose supplementation, as discussed in the Safety section.23 EFSA considers supplemental intakes of combined EPA and DHA up to 5 g/day to not raise safety concerns for adults.39

Table 4: Dietary Reference Intakes (Adequate Intake - AI) for ALA

Age Group / Life Stage	IOM/NIH AI (g/day)	EFSA AI (% Energy)	Reference(s)
Infants 0-6 months	0.5	--	7
Infants 7-12 months	0.5	0.5% E	7
Children 1-3 years	0.7	0.5% E	7
Children 4-8 years	0.9	0.5% E	7
Males 9-13 years	1.2	0.5% E	7
Males 14-18 years	1.6	0.5% E	7
Females 9-13 years	1.0	0.5% E	7
Females 14-18 years	1.1	0.5% E	7
Adult Males (≥19 yrs)	1.6	0.5% E	7
Adult Females (≥19 yrs)	1.1	0.5% E	7
Pregnancy	1.4	0.5% E	7
Lactation	1.3	0.5% E	7

IX. ALA in Context: Comparison with EPA and DHA

While ALA is the parent omega-3 fatty acid, understanding its relationship and distinctions compared to its longer-chain derivatives, EPA and DHA, is crucial for appreciating their respective roles in nutrition and health.

Key Differences Summarized:

• Source: ALA is primarily derived from plants (seeds, nuts, vegetable oils), whereas EPA and DHA are mainly found in marine sources (fatty fish, fish oil, krill oil) and algal oil.[6]
• Structure: They differ in chain length and degree of unsaturation: ALA is 18:3n-3, EPA is 20:5n-3, and DHA is 22:6n-3.[5]
• Metabolism: ALA serves as the precursor, but its conversion to EPA and especially DHA is inefficient in humans. EPA and DHA can be obtained directly from the diet or synthesized (inefficiently) from ALA.[6] EPA can also be retro-converted from DHA.[25]
• Tissue Accumulation: While all can be incorporated into membranes, DHA shows marked preferential uptake and retention in the brain and retina.[6]
• Physiological Potency and Roles: EPA and DHA are generally considered more biologically potent than ALA for specific functions. EPA plays significant roles in inflammation and cardiovascular health, serving as a precursor to series-3 eicosanoids and certain SPMs.[2] DHA is critical for neural structure (brain, retina) and function, and also gives rise to specific SPMs.[6] ALA contributes to membrane fluidity and acts as a precursor, but also appears to have independent effects, potentially mediated by its own oxylipin metabolites.[12] EPA and DHA have more established evidence for potent triglyceride lowering.[2]

Table 3: Comparison of Key Omega-3 Fatty Acids: ALA, EPA, and DHA

Feature	Alpha-Linolenic Acid (ALA)	Eicosapentaenoic Acid (EPA)	Docosahexaenoic Acid (DHA)
Structure	18:3n-3	20:5n-3	22:6n-3
Essentiality	Essential	Conditionally Essential (via ALA conversion)	Conditionally Essential (via ALA conversion)
Primary Dietary Sources	Flaxseed, chia, walnuts, canola/soybean oils	Fatty fish, fish oil, krill oil, algal oil	Fatty fish, fish oil, krill oil, algal oil
Conversion Efficiency (from ALA)	N/A (Precursor)	Limited (<5% to ~15%)	Very Limited (<1% to ~5%)
Key Physiological Roles	Membrane structure/fluidity, Precursor to EPA/DHA, Energy source, Potential direct signaling (oxylipins)	Membrane structure, Precursor to eicosanoids (Series-3) & SPMs (Resolvins E-series), Inflammation modulation, Cardiovascular function	Membrane structure (esp. brain/retina), Precursor to SPMs (Resolvins D-series, Protectins, Maresins), Neural development & function, Visual acuity
Major Established Health Benefits	↓ CVD/All-cause mortality, Modest ↓ Lipids, Potential anti-inflammatory	↓ Triglycerides, ↓ Inflammation, Cardiovascular health support, Mood support	↓ Triglycerides, Brain development & cognitive function, Visual health, Cardiovascular health support

Relative Importance and Complementary Roles:

It is inaccurate to view ALA merely as a poor substitute for EPA and DHA. ALA is essential in its own right, and its dietary intake is necessary regardless of EPA/DHA consumption.5 It contributes to the overall omega-3 pool, influences membrane properties, and likely has intrinsic biological activities mediated by its own metabolites.8 The conversion pathway, although limited, provides a baseline endogenous source of EPA and DHA, which is particularly important for individuals like vegetarians or non-fish eaters who do not consume preformed EPA/DHA.22 However, for achieving therapeutic levels associated with significant triglyceride reduction or robust anti-inflammatory effects, or for ensuring optimal brain and retinal DHA levels, direct intake of EPA and DHA is generally required.8 Therefore, ALA, EPA, and DHA should be considered distinct yet interconnected nutrients with both overlapping and unique contributions to human health.

X. Conclusion and Future Perspectives

Alpha-linolenic acid (ALA), an essential omega-3 polyunsaturated fatty acid (DB00132, CAS 463-40-1), is a vital component of the human diet, obtainable primarily from plant sources like flaxseed, walnuts, chia seeds, and certain vegetable oils. Its essentiality stems from the human inability to synthesize it de novo. ALA serves critical functions as a structural component of cell membranes, influencing fluidity and function, and as the metabolic precursor to the longer-chain omega-3 fatty acids, EPA and DHA.

While the conversion of ALA to EPA and particularly DHA is metabolically constrained in humans, ALA intake remains crucial. Epidemiological evidence strongly links higher ALA intake and biomarker levels to a reduced risk of mortality from all causes, cardiovascular disease, and coronary heart disease. Mechanistically, these benefits may arise from ALA's modest positive effects on lipid profiles (reducing TG, TC, LDL-C), potential anti-thrombotic and anti-arrhythmic properties, and anti-inflammatory actions, possibly mediated through modulation of eicosanoid pathways, gene expression (via PPARs and NF-κB), and its own specific oxylipin metabolites.

Dietary ALA is generally considered safe and well-tolerated. However, caution is warranted regarding high-dose ALA supplementation due to potential increased bleeding risk (especially with anticoagulant medications), unresolved concerns about a possible link to increased prostate cancer risk observed in some epidemiological studies, and lack of established safety data in pregnancy/lactation beyond food amounts. Established Adequate Intakes (AIs) range from 1.1 to 1.6 g/day for adults, levels generally achievable through conscious inclusion of ALA-rich foods.

Compared to EPA and DHA, ALA exhibits lower efficiency in conversion and may have less potent effects on certain outcomes like triglyceride lowering or inflammation resolution. Direct intake of EPA and DHA from marine or algal sources remains the most effective way to increase tissue levels of these long-chain omega-3s, which have distinct and critical roles, particularly DHA in neural tissues. Nevertheless, ALA's essentiality, its contribution to the overall omega-3 pool via conversion, and its independent association with reduced mortality underscore its unique nutritional importance.

Future research should focus on further elucidating the specific mechanisms underlying ALA's health benefits independent of EPA/DHA conversion, particularly the role of ALA-derived oxylipins. Resolving the ambiguity surrounding the association between ALA and prostate cancer risk, including potential confounding by dietary source, is critical. Investigating genetic, dietary, and physiological factors that may optimize the limited ALA-to-EPA/DHA conversion pathway could inform personalized nutrition strategies. Finally, more research on the long-term safety and efficacy of ALA supplementation at doses exceeding typical dietary levels is needed.

In conclusion, alpha-linolenic acid is an indispensable nutrient. Ensuring adequate intake through dietary sources like flaxseed, chia seeds, walnuts, and canola/soybean oils is a cornerstone of a healthy eating pattern. While direct sources of EPA and DHA are often recommended for specific therapeutic goals or for populations with limited conversion capacity or intake, the fundamental role and observed health benefits associated with ALA solidify its position as a key fatty acid for human health.

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