Arachidonic acid

Arachidonic Acid (ARA): A Comprehensive Reference

1. Identity and Chemical Characterization

Names and Nomenclature

Arachidonic acid (ARA) is a 20-carbon chain fatty acid with four methylene-interrupted cis double bonds, the first of which — with respect to the methyl (omega, ω or n) end — is located between carbon 6 and 7. It belongs to the omega-6 (n-6) polyunsaturated fatty acids (PUFAs), is designated as 20:4ω-6, and carries the biochemical nomenclature of all-cis-5,8,11,14-eicosatetraenoic acid. Due to their 20-carbon-atom length, ARA and its derivatives are known as eicosanoids, as "eicos" in Greek means the number 20.

The term "arachidonic acid" refers to an omega-6 fatty acid having the chemical formula C₂₀H₃₂O₂, also given the name 20:4(n-6). It is structurally related to the saturated arachidic acid found in cupuaçu butter (named after L. arachis, peanut). The molecular weight is approximately 304.47 g/mol.

In all eukaryotes, ARA is naturally found incorporated in phospholipids of the cell membrane, conferring it with fluidity and flexibility, so necessary for the function of all cells. The membrane and cytosolic phospholipids of mammalian cells and tissues are rich in ARA, usually localized at the glycerol backbone sn-2 position. Platelets, mononuclear cells, neutrophils, liver, brain, and muscle have up to 25% of phospholipid fatty acids as ARA.

Natural Sources

ARA is found only in animal-derived foods because plants cannot synthesize C-20 long-chain PUFAs. The main food sources of ARA are meat, poultry, eggs, fish, and dairy foods. ARA is contained in most animal foods; however, the contents are moderate, generally below 200 mg per 100 g of food. Little or no ARA is found in plants.

Arachidonic acid is obtained from food such as poultry, animal organs and meat, fish, seafood, and eggs, and is incorporated in phospholipids in the cells' cytosol, adjacent to the endoplasmic reticulum membrane that is studded with the proteins necessary for phospholipid synthesis and their allocation to diverse biological membranes.

Endogenous Biosynthesis

Arachidonic acid is synthesized from linoleic acid (LA) via a process starting with the conversion of LA into gamma-linolenic acid (GLA), effected by Δ6 desaturase. GLA is further elongated by the enzyme elongase to form dihomo-gamma-linolenic acid (DGLA, 20:3n-6), which is then desaturated by delta-5-desaturase (D5D) to form arachidonic acid (AA, 20:4n-6). The delta-5-desaturase enzyme is encoded by the FADS1 gene.

Linoleic acid, with a Dietary Reference Intake (DRI) of 12–17 g/day, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid — being the metabolic precursor of arachidonic acid — is that its consumption may enrich tissues with arachidonic acid and contribute to chronic overproduction of bioactive eicosanoids. However, a systematic review of human clinical trials found that modifying current intakes of dietary linoleic acid does not appear to have an effect on changing levels of arachidonic acid in plasma/serum or erythrocytes in adults consuming Western-type diets.

Supplement Forms and Production

Mortierella alpina is the most efficient production organism for arachidonic acid presently known. Since ARA is being developed as a food ingredient, and M. alpina has no history of use for such applications, safety evaluations have been undertaken. M. alpina is a common soil fungus to which humans are frequently exposed. High-ARA oil has been commercially produced under the trade name ARASCO® (Martek Biosciences).

One commercially available ingredient is produced by the fungus Mortierella alpina, with specifications stipulating a minimum of 40% arachidonic acid in the oil. Multiple GRAS (Generally Recognized as Safe) notices for ARA-rich fungal oils have received "no questions" letters from the United States Food and Drug Administration (FDA).

The filamentous fungus Mortierella alpina 1S-4 is capable of accumulating a large amount of triacylglycerol containing C20 polyunsaturated fatty acids. Triacylglycerol production by M. alpina 1S-4 can reach 20 g/L of culture broth, and arachidonic acid comprises 30%–70% of the total fatty acid.

As a dietary supplement, ARA is most commonly available in capsule or softgel form as an ARA-enriched oil, with some products offering the free acid form. Supplemental doses used in published human studies have ranged from 1.0 to 1.5 g per day (see Dosage section below).

2. Traditional and Historical Use

Arachidonic acid was not historically recognized as a distinct compound or used as an isolated preparation in any traditional medical system. Its isolation and biochemical characterization as a distinct 20-carbon polyunsaturated fatty acid occurred in the context of modern biochemical science. It was not until the 1930s and 1940s that researchers began to identify and classify individual fatty acids, thanks to the groundbreaking work of biochemists such as George and Mildred Burr.

While ARA was not used in traditional herbal or folk medicine as an isolate, the animal-derived foods that provide it — organ meats, eggs, fatty fish, and red meat — have featured prominently across diverse culinary and therapeutic traditions worldwide. In ancient and pre-modern cultures, organ meats such as liver (a source of ARA) were valued for vitality and strength, and eggs were prized for nutritional completeness. However, these uses were made without knowledge of ARA as a specific active component.

The scientific study of ARA as a biologically active molecule began in earnest in the mid-20th century with the discovery of prostaglandins, for which Sune Bergström, Bengt Samuelsson, and John Vane were awarded the Nobel Prize in Physiology or Medicine in 1982. The isolation and characterization of ARA as the central precursor to prostaglandins, thromboxanes, and leukotrienes established it as an essential molecular target for pharmaceutical and nutritional research. Dietary supplementation with isolated ARA as a health strategy emerged in the late 20th century, driven primarily by interest in infant nutrition and, subsequently, sports performance.

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

The Arachidonic Acid Cascade

The arachidonic acid pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma and arthritis. Esterified ARA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs).

Arachidonic acid-derived eicosanoids belong to a complex family of lipid mediators that regulate a wide variety of physiological responses and pathological processes. They are produced by various cell types through distinct enzymatic pathways and act on target cells via specific G-protein-coupled receptors. Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa, and platelet aggregation, eicosanoids are now understood to regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodeling, cancer, asthma, rheumatoid arthritis, and autoimmune disorders.

Release from Membranes

Arachidonic acid is a PUFA that acts as a second messenger. After the release of AA from the stereospecific sn-2 position of the membrane phospholipids by the enzyme cytosolic phospholipase A2 (PLA2) — which is activated in response to various cellular activation signals from receptor-dependent events requiring G protein-coupled transducing proteins, such as toll-like receptor 4 (TLR4), purinergic receptors, and inflammatory stimulation (e.g., tumour necrosis factor α, TNF-α) — ARA is either transformed by beta-oxidation to eicosanoids and other metabolites or is incorporated back into membrane phospholipids.

Three Major Enzymatic Pathways

The COX Pathway: ARA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Eicosanoids derived from this pathway have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. The COX pathway generates prostaglandins (PGE₂, PGI₂, PGF₂α) and thromboxanes (TXA₂). Aspirin and NSAIDs exert their anti-inflammatory and antiplatelet effects primarily by inhibiting this pathway.

The LOX Pathway: The synthesis of eicosanoids is catalysed primarily by cyclooxygenases (COX), which are involved in the production of pro-inflammatory AA metabolites, including prostaglandins and thromboxanes. Moreover, eicosanoid synthesis is catalysed by lipoxygenases (LOXs), which generate both leukotrienes and anti-inflammatory derivatives such as lipoxins.

The CYP Pathway: The cytochrome P450 branch metabolizes ARA to epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs), which have roles in vascular tone regulation and kidney function.

Membrane Structure and Direct Signaling

Surrounding inflammation activates phospholipase A2, which cleaves and releases arachidonic acid from cell membranes. The four cis double bonds are instrumental in ARA susceptibility to oxidation, resulting in the generation of numerous bioactive metabolites of critical importance for the immune system, namely inflammation in response to pathogens, resolution of inflammation, wound healing, and mood and energy balance.

Free ARA modulates the function of ion channels and several receptors and enzymes, via stimulation as well as inhibition.

Pro-inflammatory and Pro-resolving Duality

ARA metabolites have double-edged pro-inflammatory and anti-inflammatory, pro-resolving properties, and an imbalance between these metabolites has been proposed as a central mechanism in various disease states. ARA is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E₂ (PGE₂) and lipoxin A₄ (LXA₄), the latter being a potent pro-resolution mediator.

4. Scientific Evidence by Area of Use

4a. Skeletal Muscle Growth, Strength, and Exercise Performance

The hypothesis underlying ARA supplementation in exercise contexts is that increasing endogenous ARA availability may enhance prostaglandin synthesis, thereby influencing muscle remodeling and recovery. ARA serves as a metabolic precursor for prostaglandins such as PGE₂ and PGF₂α, which have been implicated in the regulation of skeletal muscle adaptations to resistance exercise. On this basis, ARA supplementation has been proposed as a potential ergogenic aid in resistance training, under the hypothesis that increasing endogenous ARA availability through supplementation may enhance PG synthesis, thereby potentially influencing muscle remodeling and recovery processes.

Eicosanoids produced from ARA — prostaglandins PGF₂α, PGE₂, and PGI₂ — display essential roles in skeletal muscle development and growth by controlling proliferation, differentiation, migration, fusion, and survival of myoblasts. Eicosanoids produced from ARA tend to promote muscle growth during and after physical activity in healthy humans.

Key human clinical studies:

• Roberts et al. (2007) — Journal of the International Society of Sports Nutrition: In a randomized and double-blind manner, 31 resistance-trained male subjects (22.1 ± 5.0 years) ingested either a placebo (1 g/day corn oil, n=16) or AA (1 g/day AA, n=15) while participating in a standardized 4-day/week resistance training regimen. Wingate relative peak power was significantly greater after 50 days of supplementation, while the inflammatory cytokine IL-6 was significantly lower after 25 days of supplementation in the AA group. PGE₂ levels tended to be greater in the AA group. However, no statistically significant differences were observed between groups in body composition, strength, anabolic and catabolic hormones, or markers of muscle hypertrophy. The authors concluded that ARA supplementation during resistance training may enhance anaerobic capacity and lessen the inflammatory response to training, but did not promote statistically greater gains in strength, muscle mass, or influence markers of muscle hypertrophy.

• Morales et al. (2016) — PLOS ONE: Thirty strength-trained males (age: 20.4 ± 2.1 years) were randomly divided into ARA or placebo groups. Both groups underwent an 8-week, 3-day per week, non-periodized training protocol; quadriceps muscle thickness, whole-body composition (DEXA), muscle strength, and power were assessed at baseline and post-test. Lean body mass (2.9%, p<0.0005), upper-body strength (8.7%, p<0.0001), and peak power (12.7%, p<0.0001) increased only in the ARA group. Results suggest that strength-trained individuals can have a beneficial effect on lean body mass and muscle power supplementing with ARA; however, the study had inherent limitations, including an inability to determine if ARA supplementation increased membrane phospholipid levels of ARA in either trial. Thus, it remains to be determined whether ARA supplementation increases the ARA content in membrane phospholipids.

• Markworth et al. (2018) — Journal of Applied Physiology: Nineteen men with ≥1 year of resistance-training experience were randomized to consume either 1.5 g daily ARA or a corn-soy-oil placebo in a double-blind manner for 4 weeks. Four weeks of daily arachidonic acid supplementation in trained men did not alter their acute muscle protein synthetic or anabolic signaling response to resistance exercise. However, 48 h after exercise, men supplemented with arachidonic acid showed greater ribosome biogenesis and a trend toward greater change in satellite cell content. Chronic arachidonic acid supplementation does not appear to regulate the acute anabolic response to resistance exercise but may augment muscle adaptation in the following days of recovery.

• Cholewa et al. (2018) — PubMed (muscle lipid profile study): Resistance-trained men (≥1 year) received dietary supplementation with 1.5 g/day ARA (n=9, 24 ± 1.5 years) or placebo (n=10, 26 ± 1.3 years) for 4 weeks while continuing their normal training regimen. Compared to placebo, ARA supplementation reduced circulating platelet and monocyte numbers, and decreased the mRNA expression of the immune cell surface markers neutrophil elastase/CD66b and interleukin 1-beta in peripheral blood mononuclear cells. In muscle, ARA supplementation increased mRNA expression of the myogenic regulatory factors MyoD and myogenin, but had no effect on a range of immune cell markers or inflammatory cytokines. These data show that dietary ARA supplementation can rapidly and safely modulate plasma and muscle fatty acid profile and promote myogenic gene expression in resistance-trained men, without a risk of increasing basal systemic or intramuscular inflammation.

Evidence strength assessment: The limited available studies provide preliminary mechanistic observations suggesting that ARA supplementation may be associated with changes in muscle strength and anaerobic performance and with modulation of the acute inflammatory response to exercise, without affecting chronic inflammation. Conversely, findings related to body composition and muscle hypertrophy remain inconsistent and a significant effect has not been consistently observed. Despite these preliminary insights, the current body of evidence is insufficient and heterogeneous, precluding the recommendation of routine clinical or practice-based use.

4b. Infant Nutrition: Neurodevelopment and Growth

Arachidonic acid (ARA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) are long-chain polyunsaturated fatty acids (LCPUFAs) that are present in breast milk and have important structural and physiological roles in early development. ARA and DHA are universal and prominent components of breast milk of well-nourished humans.

The DIAMOND trial (a large dose-response study) used 0.32%, 0.64%, or 0.96% of total fatty acids as DHA and 0.64% as ARA, compared with a formula without DHA and ARA. The trial began in 2003 and was conducted at two sites in the United States. DHA and ARA supplementation significantly enhanced visual acuity at 12 months of age, confirming earlier studies.

Concerns about providing DHA without ARA in infant formula include the possibility of undesirable outcomes such as decreased concentrations of ARA in the brain, as well as potential negative impacts on neurodevelopment, growth, and immunity. Supplementation with ARA and DHA did not differentially affect immune responses, but ARA levels in red blood cells and prefrontal cortex were reduced when DHA was provided without ARA.

In 2009, EFSA concluded that a cause-and-effect relation has been established between the intake of infant and follow-on formula supplemented with DHA at amounts of approximately 0.3% of total fatty acids and visual function at 12 months in term infants fed formula for ≤12 months, including infants who were initially breastfed and then fed formula after weaning. Regulatory decisions on ARA as a mandatory additive to infant formula have been more contentious. In 2016, the European Commission adopted legislation stipulating that from February 2020 onwards, all infant and follow-on formula marketed in the EU must contain DHA at higher amounts (20–50 mg/100 kcal) without any requirement for also providing ARA.

Evidence strength assessment: Evidence for the combined supplementation of ARA and DHA in infant formula in supporting visual and neurodevelopmental outcomes is moderately strong and supported by multiple randomized controlled trials. The regulatory picture is complex, with the EU mandating DHA but not ARA, and ongoing scientific debate about the implications of omitting ARA from formulas that contain DHA.

4c. Brain Function and Neurological Health

The conditionally essential PUFA arachidonic acid and docosahexaenoic acid together make up approximately 20% of fatty acids in the mammalian brain. During neurotransmission, the brain AA cascade is initiated when AA is released from synaptic membrane phospholipid by neuroreceptor-initiated activation of cytosolic PLA2.

Glutamate stimulates the production of arachidonic acid by activation of NMDA, AMPA, and metabotropic glutamate receptors, leading to an elevation in intracellular Ca²⁺, which is necessary for activation of phospholipase A2 and arachidonic acid release.

Alzheimer's Disease (AD): Alzheimer's disease is associated with neuroinflammation and excitotoxicity, and the postmortem Alzheimer brain demonstrates elevated expression of cPLA2, sPLA2, and COX-2. Consistent with these findings, PET demonstrated increased brain ARA incorporation in patients with Alzheimer's disease compared with healthy age-matched controls, particularly in neocortical regions reported to have activated microglia and high levels of inflammatory cytokines.

AD frontal cortex showed significant increases in protein and mRNA levels of cPLA2-IVA, secretory sPLA2-IIA, cyclooxygenase-1 and -2, membrane prostaglandin (PG) synthase-1, and lipoxygenase-12 and -15. These findings suggest upregulation of the ARA cascade in the AD brain, which may contribute to neuroinflammation. Genetic deletion of cPLA2 has been shown to improve cognitive performance in a transgenic animal model of AD. Moreover, drugs that decrease turnover and metabolites of the AA cascade, such as lithium and valproate, have been reported to have beneficial effects in patients with HIV-associated dementia. However, these are primarily preclinical and post-mortem findings; large clinical trials of ARA supplementation in AD are lacking.

Although many neuroscientists have investigated the effect of DHA on cognitive aptitude in older individuals and patients with Alzheimer's disease, research on the effect of ARA on learning and memory is limited. Although some noteworthy studies have been published, their results have not been conclusive. Whether ARA itself or ARA-derived lipid mediators are responsible for changes in the brain underlying changes in cognition remains to be determined.

Evidence strength assessment: Evidence for the role of ARA in brain health is predominantly mechanistic and derived from animal models and post-mortem tissue studies. Human clinical intervention trials directly testing ARA supplementation on cognitive or neurological outcomes are sparse and insufficient to draw firm conclusions. The observed upregulation of the ARA cascade in Alzheimer's brain tissue suggests pathological relevance, but the direction of causality and the potential benefit or harm of ARA supplementation in these populations remain unclear.

4d. Immune Function

ARA is an n-6 essential fatty acid that plays an important role in human and animal growth and development. ARA present in membrane phospholipids can be released by phospholipase A2. These free arachidonic acid molecules are then used to produce eicosanoids through three different pathways. Previous studies have demonstrated that eicosanoids have a wide range of physiological functions. Although they are generally considered to be pro-inflammatory molecules, recent advances have elucidated they also have an effect on innate immunity via regulating the development and differentiation of innate immune cells and the function of the intestinal epithelial barrier.

One key human dietary supplementation study was conducted to determine the effects of ARA supplementation on human immune response and on the secretion of prostaglandin E₂ (PGE₂) and leukotriene B4 (LTB4). Ten healthy men (20–38 years) participated in the study and lived at the Metabolic Suite of the Western Human Nutrition Research Center. They were fed a basal diet containing 200 mg/day of ARA for the first 15 days of the study. Additional ARA (1.5 g/day) was added to the diet of six men from day 16 to 65, while the remaining four subjects remained on the basal diet. The diets of the two groups were crossed over from day 66 to 115. The study found that ARA supplementation enhanced the synthesis of eicosanoids without suppressing immune functions in young healthy men.

Evidence strength assessment: Human evidence is limited to small, controlled metabolic studies. Results suggest that supplemental ARA does not impair immune responses at doses of up to 1.5 g/day, and may enhance eicosanoid synthesis. However, the study populations are small and the findings cannot be broadly generalized.

4e. Platelet Aggregation and Cardiovascular Function

Stimulation of platelet aggregation by various agonists leads to the activation of membrane phospholipases, with the consequent release of arachidonic acid and its cyclooxygenation to form the prostaglandin endoperoxides PGG₂ and PGH₂. ARA liberated from phospholipids, in the presence of the enzyme cyclooxygenase-1 (COX-1), incorporates oxygen to form the endoperoxide prostaglandin G2 (PGG₂). PGG₂ is then quickly transformed to prostaglandin H₂ (PGH₂), which in turn is converted to thromboxane A₂ — a potent inducer of platelet aggregation.

ARA-induced platelet aggregation ex vivo is an established pharmacological assay widely used to monitor aspirin therapy. Arachidonic acid-induced aggregation is the widely accepted standard test to control for aspirin resistance.

Excessive consumption of AA can result in increased platelet aggregation and vasoconstriction by thromboxane A₂, which can lead to thrombogenesis and myocardial infarction. In contrast, however, several clinical studies have also reported that the use of AA supplements showed no significant adverse effects on kidney or liver function, serum lipids, immunity, or platelet aggregation.

A 2009 review indicated that consumption of 5–10% of food energy from omega-6 fatty acids including arachidonic acid may reduce the risk of cardiovascular diseases compared to lower intakes.

Evidence strength assessment: The role of ARA in platelet physiology is well established mechanistically; however, whether dietary supplementation with isolated ARA at commonly studied doses (1–1.5 g/day) significantly increases thrombotic risk in healthy adults is not clearly supported by clinical evidence. Large-scale intervention trials are absent.

4f. Psychiatric Conditions

Beneficial effects of the COX-2 inhibitor celecoxib as add-on therapy have been reported in early stage schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. The COX/prostaglandin E pathway plays an important role in synaptic plasticity and may be implicated in the pathophysiology of autism spectrum disorders (ASD).

Eicosanoids are arachidonic acid derivatives belonging to a family of lipid signaling mediators that are engaged in both physiological and pathological processes in the brain. Their implication in the prolonged inflammatory response has become a focus of particular interest because, in contrast to acute inflammation, chronic inflammatory processes within the central nervous system (CNS) are crucial for the development of brain pathologies including depression.

Evidence strength assessment: The ARA cascade is mechanistically implicated in neuropsychiatric disorders through its regulation of neuroinflammation and prostaglandin signaling. The clinical evidence, however, concerns interventions targeting the ARA pathway (such as COX-2 inhibitors), not ARA supplementation itself. No human clinical trials testing ARA supplementation specifically for psychiatric outcomes were identified in the searched literature.

5. Body Systems and Health Areas Associated with Arachidonic Acid

• Musculoskeletal system: ARA and its prostaglandin metabolites regulate satellite cell activity, myoblast proliferation and differentiation, muscle repair, and adaptation to exercise.
• Immune system: Eicosanoids derived from ARA regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodeling, cancer, asthma, rheumatoid arthritis, and autoimmune disorders.
• Central nervous system: ARA and DHA together make up approximately 20% of fatty acids in the mammalian brain, and ARA is involved in neurotransmission, synaptic plasticity, and neuroinflammation.
• Cardiovascular system: ARA is the substrate for thromboxane A₂ (pro-aggregatory) and prostacyclin PGI₂ (anti-aggregatory), and its cascade metabolites are critical regulators of vascular tone and platelet function.
• Gastrointestinal system: Prostaglandins derived from ARA contribute to the protection of the gastric mucosa and intestinal epithelial barrier integrity.
• Reproductive system: Prostaglandins derived from ARA have well-established roles in uterine contraction, ovulation, and parturition.
• Neonatal and pediatric development: ARA is a structural component of developing brain and retinal tissue and is present in human breast milk as a consistent component.

6. Dosage Forms and Studied Dosages

Arachidonic acid is available as a dietary supplement in the following forms:

• Softgel capsules containing ARA-enriched fungal oil (typically from Mortierella alpina)
• Blended oils containing ARA for food fortification or infant formula
• Powdered supplement products (less common, typically combined with other performance ingredients)

The following dosages have been used in published human clinical studies:

• 1.5 g/day of additional ARA for 50 days in a controlled crossover metabolic study in healthy adult men (on top of a basal diet containing 200 mg/day).
• 1.5 g/day of AA in the form of a triglyceride containing 50% AA in a 130-day controlled crossover design study.
• 1 g/day of AA for up to 50 days in resistance-trained males.
• 1.5 g/day ARA for 4 weeks in men with ≥1 year of resistance-training experience.
• 1.5 g/day ARA for 4 weeks in resistance-trained men.

A 2019 review of clinical studies investigating the potential health effects of arachidonic acid supplementation of up to 1,500 mg per day on human health found there were no clear benefits. There were no adverse effects in adults using high daily doses (1,500 mg) of arachidonic acid on several biomarkers of blood chemistry, immune function, and inflammation.

In the context of infant formula, doses are expressed as a percentage of total fatty acids. Studied doses include 0.64% of total fatty acids as ARA alongside varying doses of DHA (0.32%, 0.64%, or 0.96% of total fatty acids as DHA).

7. Safety Considerations and Drug Interactions

General Adult Safety

A 2019 review of clinical studies found there were no adverse effects in adults using high daily doses (1,500 mg) of arachidonic acid on several biomarkers of blood chemistry, immune function, and inflammation. Several clinical studies have reported that the use of AA supplements showed no significant adverse effects on kidney or liver function, serum lipids, immunity, or platelet aggregation.

Production Source Safety

The production strains of Mortierella alpina used to manufacture ARA are non-pathogenic and do not form potentially allergenic spores under production conditions. There are no reliable reports in the literature connecting the species with disease or allergenic responses. No production of mycotoxins was observed, in line with the absence of literature reports describing such products.

Safety assessments of ARA-enriched oil from Mortierella alpina have included gene mutation assays in bacteria and mammalian cells in vitro, chromosome aberration assays both in vitro and in vivo, and acute and subacute (4-week) oral toxicity studies in rats. No known mycotoxins were produced by the production strains under the conditions tested.

Platelet and Cardiovascular Considerations

Excessive consumption of ARA can theoretically result in increased platelet aggregation and vasoconstriction by thromboxane A₂, which can lead to thrombogenesis and myocardial infarction. However, human clinical trials at supplemental doses of 1–1.5 g/day have not consistently demonstrated this effect. The theoretical concern is nonetheless relevant for individuals with pre-existing cardiovascular disease or those at elevated thrombotic risk.

Interaction with NSAIDs and Aspirin

Aspirin is widely used for its antiplatelet effects in patients with acute coronary syndromes. The clinical benefits of aspirin in ACS are due in part to its ability to inhibit thromboxane A₂ — known to cause platelet aggregation — by the irreversible acetylation of the COX-1 enzyme. Because the ARA cascade is the direct biochemical target of NSAIDs and aspirin (via COX inhibition), high supplemental doses of ARA may theoretically counteract or reduce the efficacy of these drugs by increasing substrate availability for COX enzymes.

AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX), and NSAIDs function by blocking this conversion. Supplemental ARA taken concurrently with aspirin, ibuprofen, naproxen, celecoxib, or other COX inhibitors may represent a pharmacodynamic interaction, though the clinical magnitude of this interaction has not been directly studied in human trials.

Omega-3 to Omega-6 Ratio Considerations

The concern with dietary linoleic acid — being the metabolic precursor of arachidonic acid — is that its consumption may enrich tissues with arachidonic acid and contribute to chronic overproduction of bioactive eicosanoids. Supplementation with ARA increases the ratio of omega-6 to omega-3 fatty acids; omega-3 fatty acids (EPA and DHA) compete with ARA for the same enzymatic pathways, and higher EPA status is associated with reduced generation of ARA-derived pro-inflammatory eicosanoids. The direction and magnitude of this interaction in humans consuming typical Western diets and taking supplemental ARA are not fully characterized.

Psychiatric and Neuroinflammatory Considerations

Given the evidence that the ARA cascade is upregulated in Alzheimer's disease and other neuroinflammatory conditions, some observations support the notion that selective inhibition of neuroinflammatory and ARA cascade pathways may alleviate cognitive impairment. The implication for ARA supplementation in such populations is unclear, and the evidence is insufficient to draw conclusions about benefit or harm.

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