Dihomo-Gamma-Linolenic Acid (DGLA): A Comprehensive Reference
1. Identity, Chemical Characterization, and Nomenclature
Dihomo-γ-linolenic acid (DGLA; 20:3, ω−6) is a 20-carbon ω−6 fatty acid, also called cis,cis,cis-8,11,14-eicosatrienoic acid. Its full chemical properties are as follows: molecular weight 306.48 g/mol; molecular formula C₂₀H₃₄O₂; IUPAC name (8Z,11Z,14Z)-icosa-8,11,14-trienoic acid; CAS registry number 1783-84-2; PubChem CID 5280581. It is also known under the synonyms bishomo-gamma-linolenic acid, 8,11,14-eicosatrienoic acid, 8,11,14-all-cis-eicosatrienoic acid, and by the shorthand notation 20:3n-6. DGLA is a carboxylic acid with a 20-carbon chain and three cis double bonds; the first double bond is located at the sixth carbon from the omega end.
DGLA (20:3n-6) is a polyunsaturated fatty acid (PUFA) that is usually present in low proportions in mammals but has recently emerged as a significant molecule differentiating healthy and inflamed tissues. DGLA is an extremely uncommon fatty acid, found only in trace amounts in animal products.
1.1 Natural Sources
There are few known natural lipid sources having a high DGLA content, and minute amounts may be extracted from cow's liver, pig's kidney, and egg-yolk. DGLA is present in the human diet at levels up to 0.115 g per measure; it is also present in breast milk, with recorded levels ranging from 0.44% at week 6 of lactation to 0.27% at week 30 of lactation.
Because high-concentration dietary sources of DGLA itself are essentially absent, the practical route to increasing DGLA in the body is through its metabolic precursor, gamma-linolenic acid (GLA). Seed oils, such as borage (Borago officinalis) oil (approximately 18–26 wt-% of GLA), blackcurrant (Ribes nigrum) oil (15–20%), and evening primrose (Oenothera biennis) oil (7–10%), as well as fungal oils (23–26%), are rich sources of GLA, which the body rapidly converts to DGLA. With progress in microbial fermentation technology, DGLA may be derived from microorganisms such as fungi, bacteria, or yeast; suitable fungi belong to the order Mucorales, for example Mortierella, Pythium, or Entomophthora.
1.2 Common Forms and Preparations
DGLA is commercially available and studied primarily as an oil in which DGLA is concentrated. DGLA oil consists almost entirely of triglycerides, in which the proportion of DGLA is approximately 40%. It may also be prepared and administered as free fatty acid, as alkyl esters (e.g., methyl esters), or as glycerides. Convenient physiologically functional derivatives of dihomo-γ-linolenic acid include the C₁–C₄ alkyl (e.g., methyl) esters and the glycerides of the acid. In many research and clinical contexts, DGLA levels in the body are raised indirectly through oral supplementation with GLA-rich botanical oils (e.g., evening primrose oil, borage oil), as these are converted to DGLA in vivo. Partly because of the historical lack of a process for DGLA's mass production, fewer clinical reports have been published with DGLA directly than for γ-linolenic acid.
2. Biosynthesis and Metabolic Position
DGLA is the elongation product (by ELOVL5) of γ-linolenic acid (GLA; 18:3 ω−6). GLA, in turn, is a desaturation product (by Δ6 desaturase) of linoleic acid (18:2, ω−6). DGLA is made in the body by the elongation of GLA, by an efficient enzyme which does not appear to suffer any form of (dietary) inhibition. GLA is also formed by Δ6-desaturase, which is encoded by fatty acid desaturase 2 (FADS2), from linoleic acid (LA, 18:2n-6), the dietarily essential n-6 PUFA.
GLA is rapidly elongated (ELOVL5) to DGLA, which can be further desaturated by Δ5-desaturase (FADS1) to arachidonic acid (ARA, 20:4n-6). However, only a small fraction of DGLA is converted to ARA due to the limited activity of Δ5-desaturase and, thus, in many cell types DGLA instead of ARA becomes accumulated after dietary GLA supplementation. This positional metabolic dynamic is central to DGLA's biological significance: its position at a pivotal point of metabolic pathways leading to anti-inflammatory derivatives or via arachidonic acid (ARA) to pro-inflammatory lipid mediators makes this n-6 PUFA an intriguing research subject.
Similar to ARA, DGLA is located in cell membrane phospholipids and released as free fatty acids by phospholipase A2. DGLA is the precursor for the biosynthesis of PGE1 and 15-HETrE, which in vivo attenuate inflammatory and proliferative processes; it also competes with arachidonic acid for incorporation into membrane phospholipids, diminishing the amount of arachidonic acid, and so contributing to the maintenance of the normal fluidity of the cell membrane.
3. Traditional and Historical Use
DGLA itself has no independent history of traditional use as a purified compound, as its isolation and chemical characterization are products of modern biochemistry. However, the plant oils from which DGLA is derived via metabolic conversion — most notably evening primrose, borage, and blackcurrant seed oils — carry well-documented traditional use histories.
In the 17th century, evening primrose was introduced to Europe and became a popular folk remedy, earning the name king's cure-all. The oil of Oenothera biennis (evening primrose) was used by various indigenous peoples of North America and later adopted in European folk medicine for a range of conditions including skin complaints, wounds, and general debility. Modern scientific investigation of these oils in the second half of the 20th century revealed that their principal bioactive role was mediated through their GLA content and the downstream conversion to DGLA.
The physiological actions of the orally administered DGLA precursor γ-linolenic acid have been studied to yield numerous reports concerning hypertension, arterial infarction, complications of diabetes mellitus (neuropathy), and rheumatism; many cases have also been reported concerning diseases such as atopic dermatitis that involve allergic inflammations. The systematic scientific investigation of DGLA as a distinct entity commenced in earnest in the 1970s and accelerated through the 1980s and 1990s as the biochemical cascade from GLA to DGLA to eicosanoids became better characterized. Interest in DGLA as a separate supplemental form grew with the development of fungal fermentation processes enabling production of DGLA-enriched triglyceride oils.
4. Key Constituents, Active Compounds, and Mechanisms of Action
4.1 Principal Metabolic Products
Depending on the cell types, DGLA is cyclooxygenated (by COX-1/2) to prostaglandins of the 1-series (PGE1) and/or metabolized by the 15-lipoxygenase into 15-(S)-hydroxy-8,11,13-eicosatrienoic acid (15-HETrE). DGLA can be further converted by inflammatory cells to 15-(S)-hydroxy-8,11,13-eicosatrienoic acid and prostaglandin E1 (PGE1). These compounds possess both anti-inflammatory and anti-proliferative properties.
DGLA also produces series-1 thromboxanes and series-1 prostanoids via the COX-1 and COX-2 pathways, as well as a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to leukotrienes. All of these effects are anti-inflammatory, in marked contrast with the analogous metabolites of arachidonic acid (AA), which are the series-2 thromboxanes and prostanoids and the series-4 leukotrienes.
4.2 Competitive Inhibition of Arachidonic Acid Pathways
In addition to yielding anti-inflammatory eicosanoids, DGLA competes with AA for COX and lipoxygenase, inhibiting the production of AA's eicosanoids. The beneficial effects of DGLA presumably result from both the anti-inflammatory properties of its derivatives and the ability to compete with ARA in the synthesis of pro-inflammatory ARA mediators. An increase in DGLA relative to ARA levels can attenuate the biosynthesis of 2-series prostaglandins and 4-series leukotrienes. The anti-inflammatory activity of DGLA is obtained in three ways: it replaces ARA in inflammatory cells' membranes, blocks the metabolism of ARA by COX and lipoxygenase by competing with the latter, and forms anti-inflammatory PGE1. DGLA also forms 15-HETrE and blocks the formation of LTB4 by ARA.
4.3 Cyclooxygenase Selectivity
Increasing endogenous formation of PGE1 requires optimization of two separate processes: enrichment of cellular lipids with DGLA and effective cyclooxygenase-dependent oxygenation of substrate DGLA relative to ARA. DGLA and AA had similar affinities (Km values) and maximal reaction rates (Vmax) for COX-2, whereas AA was metabolized preferentially by COX-1. It appears that employing a dietary or a combined dietary/pharmacological paradigm to augment the cellular ratio of DGLA/AA is not an effective route to enhance endogenous synthesis of PGE1 over PGE2, at least in cells/tissues where COX-1 predominates over COX-2.
4.4 Free Radical and Apoptotic Mechanisms Relevant to Cancer
DGLA could be metabolized into the 15-lipoxygenase product 15-HETrE, which is capable of inhibiting the synthesis of AA-derived 5-lipoxygenase metabolites and further attenuates the pro-inflammatory products from AA. All types of free radicals (superoxide anion, H₂O₂, hydroxyl radicals) and lipid peroxides play a role in the induction of apoptosis of tumor cells by the metabolism of DGLA.
4.5 FADS Gene Polymorphisms and Inter-Individual Variation
DGLA is converted to AA by Δ5 desaturase (FADS1). FADS1 and ELOVL5 are differently expressed among tissues and cell types; for example, human neutrophils contain ELOVL5 but not FADS1. This tissue-specific expression means that in certain immune cell types, DGLA accumulates preferentially rather than being converted onward to pro-inflammatory ARA. A defect in the activity of Δ6-desaturase and/or Δ5-desaturase may be one factor in the initiation and progression of conditions associated with abnormal DGLA levels.
5. Scientific Evidence by Area of Use
5.1 Inflammation and Immune Regulation
The balance of ARA to DGLA is probably a critical factor affecting inflammatory processes in the body. The beneficial effects of DGLA presumably result from both the anti-inflammatory properties of its derivatives and the ability to compete with ARA in the synthesis of pro-inflammatory ARA mediators. An increase in DGLA relative to ARA levels can attenuate the biosynthesis of 2-series prostaglandins and 4-series leukotrienes.
The evidence base for DGLA's direct anti-inflammatory effects in humans consists primarily of mechanistic cell culture studies, animal experiments, and observational clinical data, with a very limited number of formal human intervention trials using DGLA itself. In vitro and in vivo animal experiments have demonstrated potentially beneficial effects of dietary GLA, the DGLA precursor, on inflammatory conditions, such as rheumatoid arthritis (RA) and atopic eczema, but clinical data are less convincing. It is now known that the earlier view of n-6 PUFAs and their derivatives being generally pro-inflammatory and, thus, harmful was an oversimplification.
5.2 Atopic Dermatitis and Skin Disease
The most extensively studied application of DGLA is probably the peroral administration of GLA oils to treat atopic dermatitis. At least in a subset of patients with atopic dermatitis (AD), a malfunction of delta-6-desaturase seems to play a pathogenetic role. This enzyme is responsible for the conversion of linoleic acid (LA) to gamma-linolenic acid (GLA), which is further metabolized to dihomo-gamma-linolenic acid (DGLA).
In an open clinical study of 21 patients with AD, researchers investigated whether evening primrose oil (EPO) supplementation results in an increase in plasma GLA and its metabolite DGLA correlating with clinical improvement, assessed by the SCORing Atopic Dermatitis (SCORAD) index. EPO (4–6 g) was administered daily for 12 weeks. A significant increase in plasma GLA and DGLA levels and a decrease in the objective SCORAD were observed 4 and 12 weeks after initiation of EPO treatment. However, this was an open (unblinded) study of limited size.
Concentrations of DGLA, an essential fatty acid, in the serum of atopic dermatitis patients are lower than those in healthy volunteers. A fermented DGLA oil was developed and examined whether oral administration of DGLA prevents development of dermatitis in NC/Nga mice, which spontaneously develop human AD-like skin lesions. Oral administration of DGLA dramatically decreases the occurrence of dermatitis in NC/Nga mice which spontaneously develop human AD-like skin lesions. However, these are animal model findings.
Supplementation with GLA-rich evening primrose oil increased the plasma levels of GLA and DGLA in patients with atopic dermatitis and induced an improvement of clinical signs. However, it is possible that a part of the patient population displays either non-compliance or failure of proper absorption or metabolization of GLA; as their erythrocyte DGLA levels are not elevated by borage oil, their eczema would not benefit from dietary GLA either. Currently, the role of GLA/DGLA in atopic dermatitis remains indefinite and continued research is warranted to study the connections between n-6 PUFAs and skin diseases.
5.3 Cardiovascular Disease and Atherosclerosis
Apolipoprotein E-deficient mice fed with a DGLA supplement in their diet for 6 months showed a significant reduction in the development of atherosclerosis that may have been mediated via PGE1. Mechanistic work in cell culture has been extensive: in vitro, DGLA has attenuated pro-inflammatory gene expression in macrophages, chemokine-driven monocytic migration, macrophage foam cell formation, endothelial cell proliferation, and vascular smooth muscle cell (VSMC) migration, as well as improved mitochondrial function.
Specifically, in human macrophage cultures, DGLA inhibits modified LDL uptake by both macropinocytosis and receptor-mediated endocytosis, the latter by reduction in expression of two key scavenger receptors (SR-A and CD36), and stimulates cholesterol efflux from foam cells. DGLA also improves macrophage mitochondrial bioenergetic profile by decreasing proton leak. The actions of DGLA extended to other key atherosclerosis-associated cell types with attenuation of endothelial cell proliferation and migration of smooth muscle cells in response to platelet-derived growth factor.
Human prognostic observational evidence: Several observational studies have examined DGLA levels and cardiovascular outcomes. Low levels of DGLA in serum have been related to poor outcome in myocardial infarction (MI) patients. In one study drawing on a randomized controlled trial database: baseline samples from 1,002 patients aged 70 to 82 years included 2–8 weeks after an MI and followed for 2 years were used; Cox regression was adjusted for age, sex, BMI, cod liver oil, hypertension, chronic kidney disease, and diabetes. Median DGLA level in serum phospholipids was 2.89%wt. There were 208 incident cases of MACE and 55 deaths. In multivariable analysis, the hazard ratio (HR) for total death in the three higher quartiles (Q2–4) of DGLA as compared to Q1 was 0.47 (95% CI 0.26–0.84), p = 0.012.
In a separate prospective observational study of patients with acute coronary syndrome: higher concentrations of DGLA in packed red blood cells were independently associated with reduced all-cause mortality [HR 0.55 (95% CI, 0.35–0.88), p = 0.012] during a median of 7 years of follow-up. In another study of 398 patients admitted with acute coronary syndrome, in a multivariable Cox regression model for total death, the hazard ratio (HR) in the highest as compared to the lowest quartile of DGLA was 0.55.
These studies are observational in design and cannot establish causality; DGLA levels may reflect overall metabolic health rather than having independent cardioprotective effects. A Cochrane review did not find suitable studies targeting DGLA as a therapeutic agent, but surmised that specific trials with DGLA and ARA would not necessarily be required as these n-6 PUFAs can be synthesized from GLA, albeit at low levels. Generally, the effects of n-6 PUFAs on cardiovascular events or deaths were negligible even though they may reduce the risk of heart attacks, but high-quality studies were absent. Evidence for the cardiovascular benefits of DGLA remains meager, and it should also be remembered that coronary disease, obesity, NAFLD, and T2D can all be associated with one another, which makes it very difficult at this stage to assess the overall benefits or potential adverse effects of DGLA supplementation in this disease continuum.
5.4 Cancer and Anti-Proliferative Activity
Evidence shows that, via COX-mediated peroxidation, DGLA and its metabolites (1-series prostaglandins) are associated with anti-tumor activity, while AA and its metabolites (2-series prostaglandins) could be tightly implicated in various cancer diseases. PGE1 could induce growth inhibition and differentiation of cancer cells. Although the mechanism of DGLA has not yet been elucidated, it is significant to anticipate the antitumor potential benefits from DGLA.
Preclinical animal experiments provide more granular data. siRNA-knockdown of delta-5-desaturase (D5D), the rate-limiting enzyme converting upstream DGLA to arachidonic acid, promoted formation of the anti-cancer byproduct 8-hydroxyoctanoic acid (8-HOA) from COX-2-catalyzed DGLA peroxidation, consequently suppressing pancreatic cancer cell growth, migration and invasion. Further investigation of this anti-tumor effect was carried out in subcutaneous xenograft tumors. In D5D-knockdown tumors, DGLA supplementation promoted 8-HOA formation to a threshold level (> 0.3 µg/g) and resulted in significant tumor reduction (30% vs. control). The promoted 8-HOA induced apoptosis associated with altered expression of Bcl-2, cleaved PARP, procaspase 3 and procaspase 9, and suppressed tumor metastatic potential via altering MMP-2 and E-cadherin expression. DGLA supplementation resulted in similar anti-tumor effects to those of gemcitabine in these experiments, while the combined treatment led to the most significant inhibitory effect on D5D-knockdown tumor growth (70% reduction vs. control).
These findings are confined to animal and in vitro models. The potential of GLA and DGLA administrations as curative or ameliorating therapies in inflammatory conditions and malignancies appears modest at best. No human clinical trial directly assessing DGLA as an anti-cancer agent has been reported in the peer-reviewed literature at this time.
5.5 Diabetic Neuropathy
Linoleic acid is metabolized to dihomo-γ-linolenic acid, which serves as an important constituent of neuronal membrane phospholipids and as a substrate for the formation of PGE, which appears to be important for preserving nerve blood flow. In diabetes, conversion of linoleic acid to γ-linolenic acid and subsequent metabolites is impaired, possibly contributing to the pathogenesis of diabetic neuropathy. In a recent multicenter, double-blind, placebo-controlled trial, patients using γ-linolenic acid for 1 year showed significant improvements in clinical measures and on electrophysiologic testing.
The most extensively cited human trial of GLA for diabetic neuropathy is the 1993 Gamma-Linolenic Acid Multicenter Trial: 111 patients with mild diabetic neuropathy from seven centers were entered into a randomized, double-blind, placebo-controlled parallel study of GLA at a dose of 480 mg/day. Motor nerve conduction velocity (MNCV), sensory nerve action potential (SNAP), compound muscle action potential (CMAP), hot and cold thresholds, sensation, tendon reflexes, and muscle strength were assessed. For all 16 parameters, the change over 1 year in response to GLA was more favorable than the change with placebo; for 13 parameters, the difference was statistically significant. Treatment was more effective in relatively well-controlled than in poorly controlled diabetic patients. GLA had a beneficial effect on the course of diabetic neuropathy.
This trial used GLA, with DGLA as the principal in vivo mediator. A 12-week double-blind trial of GLA (320 mg/day from evening primrose oil) versus alpha-lipoic acid in patients with painful diabetic peripheral neuropathy confirmed that there is a significant increase in the levels of plasma GLA and its metabolite dihomo-γ-linolenic acid (DGLA) after 4 weeks of treatment, supporting DGLA as the active intermediate. Research has confirmed that a reduced capacity to convert LA to DGLA has been associated with various physiologic and pathophysiologic states, including aging, diabetes, alcoholism, atopic dermatitis, premenstrual syndrome, rheumatoid arthritis, cancer and cardiovascular disease.
5.6 Rheumatoid Arthritis
The narrative review literature has examined the potential roles of DGLA and related n-6 PUFAs in inflammatory conditions including rheumatoid arthritis (RA). Mechanistically, the anti-inflammatory eicosanoid profile of DGLA is theoretically relevant to joint inflammation. However, the clinical evidence for direct DGLA supplementation in RA is limited. In vitro and in vivo animal experiments have demonstrated potentially beneficial effects of dietary GLA, the DGLA precursor, on inflammatory conditions such as rheumatoid arthritis, but clinical data are less convincing. The existing human trial data on GLA for RA, while sometimes positive in terms of symptom scores, generally relies on indirect DGLA generation and has methodological limitations including small sample sizes and variable outcome definitions.
5.7 Obesity, Metabolic Syndrome, NAFLD, and Type 2 Diabetes
Abnormal ARA/DGLA ratios (surrogate for Δ5-desaturase activity) and disturbed DGLA/LA ratios (surrogate for Δ6-desaturase activity) have been documented in obesity; the underlying cause for the disturbed n-6 PUFA metabolism in obesity could be related to increased Δ6-desaturase activity in parallel with decreased Δ5-desaturase activity. Abnormal desaturase levels can accompany several obesity-associated disorders. The dietary intervention of obese subjects with a very low-carbohydrate diet for 8 weeks decreased their serum DGLA concentrations together with significant improvements of clinical characteristics and metabolic markers. The relationship between DGLA levels and metabolic disease is bidirectional and complex; several disease states are characterized by abnormally low DGLA levels in the body (atopic dermatitis, cardiac disease), while some others feature elevated DGLA levels (NAFLD, T2D).
5.8 Antithrombotic Effects
Taken orally in a small study, DGLA produced antithrombotic effects. The results of perfused vascular tissue experiments show that DGLA is able to stimulate the metabolism of incorporated EPA, resulting in an increased release of antiaggregatory trienoic prostaglandins. The mechanism may be mediated via the formation of a hydroperoxide derivative of DGLA. Thus, an increased generation of antithrombotic trienoic prostaglandins may be expected under special conditions, possibly also in vivo, depending on the supply of unsaturated fatty acids. Human clinical trial evidence specifically for DGLA-mediated antithrombotic effects remains sparse.
6. Body Systems and Health Areas Associated with DGLA
- Immune and Inflammatory System: The aim of the 2023 narrative review was to examine the potential roles of DGLA and related n-6 PUFAs in inflammatory conditions such as obesity-associated disorders, rheumatoid arthritis, atopic dermatitis, asthma, cancers, and diseases of the gastrointestinal tract.
- Cardiovascular System: Anti-atherogenic and antithrombotic activity demonstrated in animal and cell models; inverse associations with mortality noted in observational studies of post-MI patients.
- Nervous System: Linoleic acid is metabolized to dihomo-γ-linolenic acid, which serves as an important constituent of neuronal membrane phospholipids and as a substrate for the formation of PGE, which appears to be important for preserving nerve blood flow.
- Skin/Integumentary System: Reduced DGLA levels have been documented in atopic dermatitis patients; animal and limited clinical data suggest a role in skin barrier integrity and inflammatory skin disease.
- Oncology: Preclinical evidence for anti-proliferative and pro-apoptotic effects, particularly via COX-2-mediated peroxidation when Δ5-desaturase activity is inhibited; no direct human trial evidence.
- Metabolic/Endocrine System: Disturbed DGLA metabolism has been documented in type 2 diabetes, NAFLD, and obesity, linked to altered desaturase enzyme activity.
7. Dosage Forms and Reported Dosages
DGLA-enriched oil (50 or 150 mg as free DGLA) was administered to healthy men for 4 weeks; the DGLA content in serum phospholipids dose-dependently increased and returned to the initial level after a 4-week washout. No side effects or changes in platelet aggregation were observed, indicating that oral supplementation with DGLA oil can safely increase serum DGLA content.
In a separate randomized controlled study in healthy adults, DGLA is expected to show anti-allergic activity. The effects of supplementation with DGLA-enriched oil (450 mg as free DGLA) for 4 weeks were examined. The DGLA composition in the total fatty acids of serum phospholipids increased from 2.0 to 3.4%, and returned to the initial level after a 4-week washout. No side effects or changes in blood biochemical parameters were observed. Serum DGLA content can be safely increased by supplementation with 450 mg DGLA under these conditions.
Currently, three intervention studies have investigated the safety of DGLA oils for humans. For the indirect supplementation route via GLA, the most frequently studied clinical dose for diabetic neuropathy was GLA at a dose of 480 mg/day over one year, and for atopic dermatitis EPO (4–6 g) daily for 12 weeks. In diabetic neuropathy comparative trials, four capsules of evening primrose oil taken twice daily corresponded to 320 mg/day of GLA.
Regarding the subchronic toxicology study: in the subchronic toxicity test in rats, DGLA oil (500, 1000, and 2000 mg/kg) was orally administered for 13 weeks; water and soybean oil (2000 mg/kg) were used for the no-oil control and soybean oil control groups, respectively.
8. Safety Considerations
8.1 Preclinical Toxicology
It is important to establish the safety levels of DGLA oil; the purposes of the 13-week study were to investigate the safety of DGLA oil by bacterial reverse mutation assay (Ames test) and acute and subchronic toxicity studies in rats. There was no death in either sex. Because of administration of large amounts of oil, food consumption was low in the soybean oil control and the three test groups, which appeared to mildly decrease urinary excretion of Na, K, and Cl, as well as total serum protein, albumin, and blood urea nitrogen levels. There were no toxicological changes in body weight, food consumption, ophthalmological examination, urinalysis, hematological examination, blood biochemical examination, necropsy, organ weight, or histopathological examination. These findings show that the no-observed-adverse-effect level (NOAEL) of the DGLA oil was 2000 mg/kg.
8.2 Human Safety Data
DGLA is a ubiquitous constituent of normal tissues with a very benign safety profile when dosed to high levels. This is supported by the results of toxicity studies on orally administered DGLA published in the scientific literature and by recently completed preclinical and clinical studies which have shown no safety concerns. In the human supplementation study with 450 mg DGLA for 4 weeks, no side effects or changes in blood biochemical parameters were observed.
8.3 Conversion to Arachidonic Acid
A safety consideration specific to DGLA is its potential conversion to the pro-inflammatory ARA. DGLA is converted to AA by Δ5 desaturase (FADS1). Supplementing dietary GLA increases serum DGLA as well as serum AA levels. However, only a small fraction of DGLA is converted to ARA due to the limited activity of Δ5-desaturase and, thus, in many cell types DGLA instead of ARA becomes accumulated after dietary GLA supplementation.
8.4 Disease States with Elevated DGLA
Several disease states feature elevated DGLA levels, including NAFLD and type 2 diabetes. The clinical significance of supplementation-induced DGLA elevation in these contexts has not been established in intervention trials, and the causal relationships between elevated DGLA and these disease states require further investigation.
8.5 Reproductive Toxicology Considerations
Data from the model organism C. elegans have revealed that dietary supplementation of DGLA induced germ cell loss; CYP-33E2 activity produces a range of epoxy and hydroxy metabolites from dietary DGLA; knockdown of cyp-33E2 suppressed the DGLA-induced sterility phenotype. Direct exposure of two specific DGLA-derived epoxy products, 8,9- and 14,15-epoxyeicosadienoic acids, produced germ cell abnormalities. It was proposed that sterility is mediated by the production of toxic DGLA-derived epoxides that trigger germ cell destruction. These effects have been described only in the invertebrate model organism C. elegans; their relevance to mammalian reproduction is unknown.
8.6 Variability Based on Genetics and Disease State
Some of the inflammatory diseases associated with DGLA are age-associated, which makes their connections to n-6 PUFAs even more complex. The circulating concentrations of GLA, DGLA, and ARA can decrease in age-associated diseases simultaneously with a gradual increase in the pro-inflammatory state of the body. A lack of GLA can occur when there is a reduction of the efficiency of the D6D conversion, for instance as people grow older or when there are specific dietary deficiencies, or in disease states wherein there is excessive consumption of GLA metabolites. These enzymatic changes affect both the efficacy and safety profile of DGLA supplementation in older or chronically ill individuals.
9. Summary of Evidence Strength
The following is an honest characterization of current evidence across studied domains:
- Biochemical/mechanistic understanding: Well established in cell and animal models. DGLA's role as an anti-inflammatory eicosanoid precursor and ARA competitor is mechanistically well supported.
- Atopic dermatitis (via GLA): Mixed human evidence. Small, mostly open or inadequately controlled trials; correlation between plasma DGLA elevation and SCORAD improvement has been shown but clinical significance in unselected populations is unclear.
- Diabetic neuropathy (via GLA): Positive evidence from a reasonably well-designed multi-center RCT (n=111), with DGLA as the presumed mediator, over 1 year. More recent comparative trials also support GLA's activity.
- Atherosclerosis/cardiovascular protection: Preclinical (animal, cell culture) evidence is robust; human evidence is observational only. No interventional trials of DGLA supplementation on cardiovascular endpoints have been published.
- Cancer: Evidence is preclinical only (cell culture and mouse xenograft models). No human clinical trial data.
- Rheumatoid arthritis: Limited and mixed human evidence, primarily for the GLA precursor; insufficient direct DGLA evidence.
- Safety (short-term human): Good; human supplementation trials with up to 450 mg DGLA/day for 4 weeks showed no adverse effects or biochemical abnormalities.
References
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