CLA (conjugated linoleic acid)

Conjugated Linoleic Acid (CLA)

1. Identity

Chemical Names and Classification

The term Conjugated Linoleic Acid (CLA) refers generically to a class of positional and geometric conjugated dienoic isomers of linoleic acid. CLA is a polyunsaturated fatty acid with the same chemical formula as the omega-6, 18-carbon fatty acid linoleic acid. The word "conjugated" in its name refers to the fact that CLAs have a different structural arrangement from linoleic acid. CLA is composed of a group of 28 isomers, or forms of 18-carbon polyunsaturated fatty acids, that are defined by conjugated double bonds in two different geometric or positional locations of each molecule.

The two C=C double bonds are conjugated (i.e., separated by a single bond), as opposed to more typical polyunsaturated fatty acids where double bonds are separated by two single bonds. In many natural CLAs, one of the two C=C bonds is cis and the other trans, making it technically a kind of trans fat. Conjugated trans fatty acids do not, however, appear to have the harmful effects of typical trans fats.

The systematic IUPAC name for the dominant naturally occurring isomer is (9Z,11E)-octadeca-9,11-dienoic acid. The terms "conjugated linoleic acids" and "CLA" include 9,11-octadecadienoic acid, 10,12-octadecadienoic acid, mixtures thereof, and related salts of the acids.

Key Isomers

Of the known isomers, the most studied and bioavailable are cis-9,trans-11 (abbreviated c9,t11) CLA, which constitutes 80–90% of the total CLA isomers, and trans-10,cis-12 (abbreviated t10,c12) CLA, which constitutes 3–5% of the total CLA isomers within naturally occurring forms. A number of minor isomers have also been described, including t7,t9-CLA; c9,c11-CLA; t9,t11-CLA; c10,c12-CLA; t10,t12-CLA; t11,t13-CLA; and c11,c13-CLA.

Natural Sources

The main natural sources of CLA are dairy products, beef, and lamb, whereas only trace amounts occur naturally in plant lipids. The major dietary sources of CLA are ruminant (e.g., cattle, goat, and sheep) meat and dairy products. In these species, the 9-cis,11-trans-CLA isomer is naturally produced through the fermentation, in the rumen, of unsaturated fatty acids by the bacterium Butyrivibrio fibrisolvens. In addition, some vegetables and some seafoods have also been reported to contain CLA.

Most dairy products contain about 3.5 to 6.0 mg CLA per gram of fat, or 0.35 to 0.65% of the milk fat. Homogenized whole milk contains about 5 mg CLA per gram of fat. The CLA content of meat from ruminant animals is generally less than the CLA in dairy products. Grass-fed beef tends to have small increases in CLA compared to grain-fed animals; however, if grass-fed cattle are finished on higher grain diets prior to slaughter, the CLA content in meat decreases. In general, diet has a small effect on CLA in beef compared to the dietary influence on dairy products.

The total amounts of CLA in these foods varies greatly depending on what the animals ate. The CLA content is 300–500% higher in beef and dairy from grass-fed cows than from grain-fed cows. The average intake in the US is about 151 mg per day for women and 212 mg per day for men.

Biosynthesis in Ruminants and Humans

CLA is mainly formed naturally in the rumen during ruminal biohydrogenation of polyunsaturated fatty acids. Dietary lipids, mainly linoleic acid (an indirect precursor of the CLA isomers), undergo lipolysis catalyzed by ruminal microbial lipase. Rumen bacteria play a major role in biohydrogenation. CLA is one of the intermediates of fatty acid biohydrogenation in the rumen to stearic acid. Biohydrogenation of LA begins with an isomerization reaction forming cis-9,trans-11-CLA, which is the most prevalent isomer comprising 80–90% of the total CLA in food products from ruminants; then cis-9,trans-11-CLA is reduced to trans-11 C18:1 (trans-vaccenic acid) and finally to C18:0 (stearic acid).

Trans-11 vaccenic acid can be converted to 9c,11t-CLA in the mammary gland by the tissue delta-9 desaturase enzyme. Mammary synthesis may account for up to 70 to 80% of total CLA found in milk. Non-ruminants, including humans, produce certain isomers of CLA from trans isomers of oleic acid, such as vaccenic acid, which is converted to c9,t11-CLA by delta-9 desaturase.

Common Forms and Preparations

CLA is found in supplements in the form of pills, powders, and emulsions. The type of CLA in supplements is different from natural forms from animal products. To make supplements, manufacturers create CLA by chemically altering plant sources of linoleic acid. There are also commercially available forms of CLA obtained through alkaline isomerization of linoleic acid–rich oils.

The main difference between CLA in supplement products and CLA in milk is the broader range of isomers in the synthetically produced CLA. The relative value for human health of this range of CLA isomers compared to the CLA found in ruminant milk fat is uncertain. Most of these isomers are not thought to have anti-carcinogenic properties.

Vegetable oils with high CLA content possess high nutritional value, as linoleic acid (LA) is one of the most abundant fatty acids naturally found in vegetable oils. As a result, vegetable oils with a high LA concentration such as safflower, sunflower, corn, and related oils serve as industrial substrates for CLA production.

2. Historical and Traditional Use

CLA was discovered for the first time in 1932. However, its physiological function has been emphasized since the 1980s when the antimutagenic effects of CLA in mice were first discovered. CLA was not identified as a distinct compound in the traditional pharmacopeias of any particular folk medicine system; rather, it has been consumed incidentally as a component of ruminant meat and dairy throughout human history, wherever such foods formed part of the diet.

One of the first beneficial effects formally attributed to CLA was its anti-carcinogenicity, discovered by researcher Michael Pariza. Synthetically prepared CLA isomers were applied topically to mice prior to the initiation of epidermal carcinomas. Mice that received topical CLAs developed only half the number of papillomas and exhibited a lower incidence of tumor formation relative to the control mice.

In the past thirty years, the dietary intake of CLA has drastically decreased for two fundamental reasons: firstly, the consumption of pork and milk derivatives has greatly decreased; and secondly, modern livestock rearing techniques have led pasture grass and forage to be replaced with industrially produced feedstuffs, which do not contain as much natural linoleic acid.

The National Academy of Science publication entitled "Carcinogens and Anti-carcinogens in the Human Diet" stated that "conjugated linoleic acid is the only fatty acid shown unequivocally to inhibit carcinogenesis in experimental animals." This recognition in the late twentieth century drove significant scientific and commercial interest in CLA supplementation beginning in the 1990s.

3. Key Constituents and Mechanisms of Action

Principal Bioactive Isomers

Most biological effects are attributed to the two major CLA isomers — the cis-9,trans-11 isomer (c9,t11) and the trans-10,cis-12 isomer (t10,c12) — and their mixture. CLA has different isomers that appear to have distinct characteristics, with anticarcinogenic effects more likely attributable to cis-9,trans-11 and anti-obesity effects attributable to the trans-10,cis-12 isomer.

PPAR Receptor Signaling

A key mechanism of CLA action is via the peroxisome proliferator-activated receptor (PPAR) family, which contains three isoforms (PPAR-α, PPAR-β/δ, and PPAR-γ) that control the expression of networks of genes involved in adipogenesis, lipid metabolism, and maintenance of metabolic homeostasis, as well as inflammatory regulation. PPAR-γ is expressed in adipose tissue, immune cells, and the colon, being mainly responsible for regulating adipocyte differentiation and improving insulin resistance.

The t10,c12-CLA isomer reduces adipogenesis and lipogenesis by regulating the expression of PPAR-γ target genes and modulating the transactivating activity of PPAR-γ by SIRT1 binding directly or indirectly to PPAR-γ in the adipocyte. PPAR-α and PPAR-β are involved in lipid metabolism, especially the proteins related to fatty acid oxidation and glucose metabolism, while PPAR-γ is involved in adipocyte differentiation.

Lipid and Adipose Tissue Metabolism

CLA supplementation may increase lipolysis and reduce the accumulation of fatty acids in adipose tissue; the putative mechanisms involved include reducing lipoprotein lipase activity, increasing carnitine-palmitoyl-transferase-1 (CPT-1) activity, interacting with PPAR-γ, and raising the expression of uncoupling protein-1 (UCP-1). Studies have demonstrated that the t10,c12 isomer of CLA, differently from the c9,t11 isomer, increases lipolysis significantly in human adipocytes and also functions to diminish the synthesis of fatty acids.

CLA lowered the synthesis of lipids, adipogenesis, and lipid storage in adipocytes but enhanced β-oxidation in muscles. The reduction of body fat occurs not due to a reduction in the number of adipocytes but rather by reduction of their size. Considering that the size of adipose cells is directly related to the triglyceride content inside the cells, its reduction results in a smaller cell size.

Anti-Carcinogenic Mechanisms

Additional potential mechanisms for the anti-carcinogenicity of CLA are that it induces apoptosis in tumor cells (indicated by reduced Bcl-2 expression and increased TUNEL assay and Annexin-V staining), exhibits anti-angiogenic and antioxidant effects (reduced reactive oxygen species and peroxide generation), and has altered arachidonic acid metabolism, and has been shown to promote anti-proliferation.

Bone Metabolism

The t10,c12-CLA isomer, but not c9,t11-CLA, has an anti-osteoporotic effect by modulating osteoclastogenesis, significantly inhibiting adipogenesis, and promoting osteoblastogenesis from mesenchymal stem cells via PPAR-γ-mediated mechanisms and SMAD8-mediated mechanisms.

AMPK Activation and Cardiovascular Pathways

t10c12-CLA activates 5'-adenosine monophosphate-activated protein kinase (AMPK) with concomitant increases in prostaglandin levels which are sufficient to cause lipid reductions in adipocytes. The anti-steatotic effects of trans-10,cis-12 CLA are potentially mediated via increased lipid utilization by peripheral tissues.

Gene Expression Effects

Genes of lipid metabolism regulated by CLA in human adipose tissue include: LDLR, FASN, SCD, FADS1, and UCP2, which were induced, while ABCA1, CD36, and CA3 were repressed. Transcription factors PPARγ, NFAT5, CREB5, and EBF1, the adipokine NAMPT, and members of the insulin signaling cascade SORBS1 and IGF1 were repressed, while the adipokine THBS1 and GLUT4 involved in insulin signaling were induced. Available data suggest that the isomer-specific influence of CLA on glucose and lipid metabolism is genotype-dependent and at least in part mediated by PPARγ.

4. Scientific Evidence by Area of Use

4.1 Body Composition and Weight Management

Overview of Human Evidence

Conjugated linoleic acid, a fatty acid found naturally in ruminant animal food products, has been identified as a potential anti-obesogenic agent, with substantial efficacy in mice, and modest efficacy in obese human populations. CLA has been shown to reduce body fat and increase lean body mass in mice, rats, and pigs. A recent human trial indicated that CLA may work more effectively if used for prevention of body fat deposition and weight gain rather than for active weight reduction.

Meta-Analyses and Systematic Reviews

Numerous supplements containing CLA are presently being promoted for body weight reduction. A systematic review aimed to evaluate the evidence for or against the long-term efficacy of CLA. Electronic searches were conducted to identify relevant randomized clinical trials (RCTs), with no restrictions in age, time, or language. Studies had to be at least 6 months in duration. Fifteen RCTs were identified, and seven were included. Four of the included RCTs had serious flaws in the reporting of their methodology. A meta-analysis revealed a statistically significant difference in weight loss favouring CLA over placebo (mean difference: −0.70 kg; 95% CI: −1.09, −0.32). The evidence from RCTs does not convincingly show that CLA intake generates any clinically relevant effects on body composition in the long term.

A more recent meta-analysis using random-effects modelling demonstrated that CLA supplementation significantly reduced body mass (WMD: −0.35, 95% CI −0.54 to −0.15, P < 0.001), BMI (WMD: −0.15, 95% CI −0.24 to −0.06, P = 0.001), waist circumference, fat mass, and body fat percentage, and increased fat-free mass. However, the high-quality subgroup showed that CLA supplementation fails to change fat mass and body fat percentage. According to high-quality studies, CLA intake resulted in small but significant increases in fat-free mass and decreases in body mass and BMI. This meta-analysis suggests that CLA supplementation may result in a small but significant improvement in anthropometric and body composition markers in adults. However, data from high-quality studies failed to show CLA's body fat-lowering properties.

Selected Individual Clinical Trials

A randomized, double-blind, placebo-controlled study administered 3.2 g/day CLA for 6 months in forty healthy, overweight subjects aged 18–44 years with BMI of 25–30 kg/m². Six-month change in body composition was improved with CLA compared to placebo (P = 0.02), and body fat was significantly reduced within the CLA group (−1.0 ± 2.2 kg, P = 0.05). CLA had no effect on resting metabolic rate, physical activity, or dietary intake. CLA supplementation among overweight adults significantly reduced body fat over 6 months and prevented weight gain during the holiday season.

A 24-month randomized, double-blind, placebo-controlled trial of CLA supplementation (with two groups receiving CLA in triglyceride or free fatty acid form, and one group receiving olive oil as placebo) was extended as an open study for another 12 months in 134 of 157 participants. The extension evaluated safety and effects on body fat mass, lean body mass, bone mineral mass, body weight, and BMI. All subjects were supplemented with 3.4 g CLA per day in triglyceride form. The study confirms that CLA decreases body fat mass in overweight humans and may help maintain initial reductions in body fat mass and weight in the long term.

In a 12-week trial, 74 obese or overweight women were randomly assigned to receive 3 g/day CLA or placebo. Body composition was assessed by dual-energy X-ray absorptiometry and liver function was assessed. Patients receiving CLA experienced a significant reduction of total body fat expressed as mass and percentage, android adipose tissue, gynoid adipose tissue, and visceral adipose tissue, as well as a significant increase in lean body mass to height, when compared to those receiving a placebo.

In a 13-week trial of post-weight-loss supplementation, the regain of fat-free mass was favorably and dose-independently affected by consumption of 1.8 or 3.6 g CLA/day and consequently increased resting metabolic rate. However, this did not result in improved body weight maintenance after weight loss.

It is also worth noting that the type of CLA supplement (isomer or mixture) varies in RCTs, where the trans-10 and cis-12 isomers of CLA are suggested to induce catabolic effects including enhanced lipolysis and fat oxidation, while the cis-9 and trans-11 isomers are considered anabolic agents.

Evidence strength: No consistent result was observed even in similar studies conducted at different laboratories; this may be due to variations in age, gender, racial and geographical disparities, coupled with type and dose of CLA supplemented. Supposed promising results reported in mechanistic and pre-clinical studies cannot be extrapolated to humans, mainly due to the lack of consistency in analyses, prolonged intervention studies, and follow-up studies.

4.2 Cardiovascular Health

Lipid Profile

According to a meta-analysis, foods enriched in CLA and CLA supplements have a beneficial effect on LDL-C concentration. CLA did not affect other lipids in the profile. Foods enriched in CLA increased HDL-C and tended to decrease total cholesterol non-significantly.

Adipose tissue c9,t11-CLA is associated with a lower risk of myocardial infarction. Meanwhile, c9,t11-CLA, which is present in large amounts in the milk of pasture-grazed cows, might neutralize the adverse effects of the saturated fat content of dairy products.

Atherosclerosis

In some animal studies, CLA has been shown to have a beneficial effect on sclerotic lesions associated with atherosclerosis; however, the results have been inconsistent, and the effects of CLA on atherogenesis appear to be dose-, isomer-, tissue-, and species-specific. Similarly, CLA trials in humans have resulted in conflicting findings. Both human and animal study results may be attributed to contrasting doses of CLA, isomers, the coexistence of other dietary fatty acids, length of study, and inter- and/or intra-species diversities.

The antiatherogenic effect of CLA has been demonstrated in animal models. Although there are in vitro studies suggesting profitable properties of CLA, the results in humans remain inconsistent. In one study, 74 adult female subjects with BMI ≥25 kg/m² were enrolled in a double-blind, placebo-controlled nutritional intervention. Subjects were randomly assigned to receive 3 g/day CLA or placebo (sunflower oil) for 12 weeks, and markers of atherosclerosis (hs-CRP and ADMA) were assessed. No significant differences were found in hs-CRP and ADMA levels before and after the nutritional intervention between the two groups.

Recent research advances have suggested the importance of CLA isomers in modulating gene expression involved in oxidative damage, fatty acid metabolism, immune/inflammatory responses, and ultimately atherosclerosis.

Evidence strength: Predominantly animal and in vitro evidence. Human studies on CLA and cardiovascular endpoints are limited and show mixed results.

4.3 Cancer

Most anti-carcinogens are plant products (phytochemicals); therefore, CLA isomers represent an unusual find because they occur in the highest concentration in animal products (zoochemicals) with only trace amounts found in plant lipids.

Studies have shown that murine carcinoma models show an improvement with CLA supplementation, including mammary, colon, stomach, prostate, and hepatic carcinomas.

Many studies have been carried out on the roles of CLA in the prevention of cancers. Studies on the effects of CLA on human cancers are lacking in any definitive conclusions. Correlation data on the dietary intake of CLA or tissue CLA levels and the incidences of breast cancer are inconsistent. So far, there is only one report of a CLA clinical trial for breast cancer. CLA supplementation for at least 10 days before surgery was associated with reduced S14 levels in tumor tissue in patients with higher cancer scores (II), but not in patients with lower cancer scores (I) and no changes in the expression of fatty acid synthase or lipoprotein lipase. CLA decreased Ki-67 (a tumor proliferation marker) without changing caspase 3 (an apoptosis marker) in these patients. This study concluded that CLA might be used in conjunction with current options for breast cancer treatment.

Contrary to initial studies suggesting that CLA is anti-carcinogenic, some studies have shown that CLA has no effect on tumor inhibition, and a few have even shown that CLA promotes tumor progression.

Evidence strength: Preclinical animal models and in vitro evidence are substantially positive, but human clinical data are sparse, preliminary, and inconsistent. No definitive conclusions regarding CLA's anti-cancer properties in humans can be drawn.

4.4 Insulin Sensitivity and Metabolic Health

Some animal studies have suggested that CLA supplementation may have therapeutic potential with respect to insulin sensitivity and lipid metabolism, which are important cardiovascular disease risk factors associated with type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial investigated the effect of CLA supplementation on markers of glucose and insulin metabolism, lipoprotein metabolism, and inflammatory markers of CVD in subjects with type 2 diabetes. Thirty-two subjects with stable, diet-controlled type 2 diabetes received CLA (3.0 g/day; 50:50 blend of c9,t11 CLA and t10,c12 CLA) or control for 8 weeks.

The available evidence suggests that while CLA can modestly reduce total body mass and regional body fatness, these changes do not provide the metabolic benefit of improved glucose metabolism that would be expected with weight and fat loss.

The circulating levels of 9,11-CLA and 10,12-CLA were inversely correlated with plasma lipids and hemoglobin A1c (HbA1c) levels, respectively, suggesting that the enrichment for CLA-producing gut microbes could reduce cardiovascular and diabetes risk factors, such as hyperlipidemia and insulin resistance.

Evidence strength: Animal models show insulin-sensitizing potential; however, human evidence is mixed and some studies have shown the opposite effect (see Safety section). The clinical picture for CLA and glucose metabolism in humans is unresolved.

4.5 Bone Health

The potential health benefits of CLA supplementation studied on animal models since 1987 include body fat reduction, improved insulin resistance, improved lipid profile, modulation of the immune system, stimulation of bone mineralization, anticarcinogenic effects, and prevention of atherogenesis.

CLA is a bioactive compound known for its anti-inflammatory, anti-carcinogenic, and metabolic effects, with growing interest in its role in supporting bone health. Preclinical studies, particularly those involving the t10c12 isomer, have shown that CLA can enhance bone mineral density by promoting bone formation and reducing bone resorption, indicating its potential as a therapeutic agent to improve bone health.

CLA describes a group of isomers of linoleic acid and has variable effects on bone formation and adiposity in vivo and in vitro. The variability may be due to individual effects of the predominant bioactive c9,t11 and t10,c12 CLA isomers. Preliminary data suggest CLA supplementation may improve some markers related to bone health in patients with rheumatoid arthritis.

Evidence strength: Primarily preclinical; very limited clinical data in humans. Isomer-specific effects on bone appear to exist, but human clinical trials are needed.

4.6 Immune Function

Animal studies suggest CLA supplementation may improve insulin sensitivity and blood lipid profiles, decrease body fat, and reduce risks for cancer and cardiovascular disease. However, many of these effects have not been replicated in humans, or studies show mixed results.

Research advances have suggested the importance of CLA isomers in modulating gene expression involved in oxidative damage, fatty acid metabolism, and immune/inflammatory responses. The c9,t11 isomer in particular has been associated with immune system modulation, including effects on lymphocyte populations, though much of this evidence derives from animal and in vitro experiments.

Evidence strength: Preliminary; largely preclinical and in vitro. Human immune function studies on CLA are limited.

5. Body Systems Associated with CLA

• Adipose tissue / body composition: Reduced fat mass, altered adipocyte size and lipid storage; most researched area in humans.
• Cardiovascular system: Modulation of lipid profiles, potential anti-atherosclerotic activity, platelet aggregation, and endothelial function; evidence predominantly animal-based.
• Metabolic system: Involvement in insulin signaling, glucose metabolism, and energy expenditure through AMPK and PPAR pathways.
• Immune system: Modulation of CD4/CD8 lymphocyte populations, inflammatory cytokines, and gene expression in immune-competent cells.
• Skeletal system: Promotion of osteoblastogenesis and inhibition of osteoclastogenesis, particularly via the t10,c12 isomer and PPAR-γ/SMAD8 pathways.
• Oncological: Anti-proliferative, pro-apoptotic, and anti-angiogenic effects demonstrated in vitro and in animal models; very limited human clinical data.
• Gastrointestinal system / microbiome: Certain dietary interventions have significantly increased the prevalence of CLA-producing bacteria in the gut, including species of Bifidobacteria and Lactobacillus.

6. Dosage Forms and Dosages Reported in Studies

CLA is found in supplements in the form of pills, powders, and emulsions. The following dosages are drawn directly from published studies and should not be construed as recommendations:

• A randomized, double-blind, placebo-controlled study used 3.2 g/day CLA for 6 months.
• A 24-month extension study supplemented all subjects with 3.4 g CLA per day in triglyceride form.
• A 12-week randomized trial used 3 g/day CLA.
• A 13-week study examined 1.8 or 3.6 g CLA/day following weight loss.
• A study in type 2 diabetes used 3.0 g/day of a 50:50 blend of c9,t11 CLA and t10,c12 CLA for 8 weeks.
• A one-year safety study in obese humans used 6 g/day of CLA.
• Meta-analyses of human studies concluded that CLA supplementation induced a significant reduction in body weight and body fat mass when 3.2–3.4 g/day CLA was supplemented for at least 6 months.

Optimal dietary intake has not been established for CLA. It has been hypothesized that 95 mg CLA/day is enough to show positive effects in the reduction of breast cancer in women utilizing epidemiological data linking increased milk consumption with reduced breast cancer. Ha et al. (1989) published a much more conservative estimate stating that 3 g/day CLA is required to promote human health benefits. All these values represent rough estimates and are mainly based on extrapolated animal data. What is clear is that the general population does not consume enough CLA in the diet to have a significant impact on cancer prevention or suppression.

To achieve 3 g intake of CLA per day, modifying the diet of dairy cows to increase CLA in milk and increasing consumption of higher fat dairy products would be needed.

7. Safety Considerations and Interactions

Gastrointestinal Effects

Mild side effects of CLA supplements have been seen in some human-based clinical trials. These studies indicate that even moderate doses of supplemental CLA could cause health issues like nausea, diarrhea, and stomach upset. Minor gastrointestinal symptoms and severe fatigue have been reported in clinical studies.

Insulin Resistance

Studies have shown that supplementation with CLA or the trans-10,cis-12 isomer could induce insulin resistance, lipodystrophy in animals, fatty liver, C-reactive protein enhancement, and undesirable changes in lipid profile in man. There is increasing evidence from mice and human studies that the CLA isomer trans-10,cis-12 may produce liver hypertrophy and insulin resistance via a redistribution of fat deposition that resembles lipodystrophy. In obese men, CLA has caused insulin resistance and may increase blood glucose levels.

Liver Safety

A 24-month CLA supplementation study showed that CLA supplementation in healthy, overweight adults was well tolerated. However, case reports have documented acute hepatitis in a 26-year-old female after using a CLA supplement for weight loss.

Cardiovascular Risk

There is also a concern for potential increased risk of cardiovascular disease with high CLA intake. Therefore, more well-designed studies are needed to determine under what conditions CLA supplementation demonstrates safety and any benefits. CLA should be used with caution in patients who have cardiovascular disease or diabetes, as it has increased lipid peroxidation and caused insulin resistance or decreased insulin sensitivity in some studies.

Isomer-Specific Concerns

Although studies in humans have shown some benefits of CLA supplementation, such as weight loss, the results are still discordant. Moreover, some studies have shown adverse effects, such as negative effects on glucose metabolism and lipid profile. Preclinical and clinical studies suggest that CLA may promote fat oxidation and modulate adipocyte function; however, inconsistent findings highlight dose-dependent outcomes and individual variability in response. The dual nature of CLA, showing both beneficial and adverse effects, raises questions about its long-term safety and efficacy.

Supplement vs. Food-Derived CLA

The balance of the different forms of CLA is heavily distorted in supplements. They contain types of CLA never found in large amounts in nature. For this reason, CLA supplements do not provide the same health effects as CLA from foods.

Neurological Case Reports

A case report documented severe migraine aura with visual disturbance in an older adult man without prior migraine history, which was related to several separate occasions of CLA supplement ingestion as the trigger.

General Evidence Limitations

The evidence is mixed, and many of the studies involve animals instead of humans. Consequently, the research is not yet clear about the exact health benefits of CLA. CLA has no obvious acute toxicity, subchronic, genotoxicity, or allergenicity concerns at studied doses, but long-term safety at supplemental doses — particularly of specific isomers such as t10,c12-CLA — remains an active area of investigation. The European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition, and Allergies has recognized the CLA combination (c9,t11 and t10,c12) as a safe novel food.

References

• Virginia Tech Extension: Conjugated Linoleic Acid: A Fatty Acid With Health Benefits
• Penn State Extension: Conjugated Linoleic Acid (CLA) in Animal Production and Human Health
• ScienceDirect: Conjugated linoleic acid (CLA) as a functional food: Is it beneficial or not?
• ScienceDirect Topics: Conjugated Linoleic Acid — an overview
• MDPI Foods: Production of Conjugated Linoleic Acid (CLA) by Lactiplantibacillus plantarum
• Wikipedia: Conjugated Linoleic Acid
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• PubMed (Watras et al., 2007): The role of conjugated linoleic acid in reducing body fat and preventing holiday weight gain
• PubMed (Gaullier et al., 2005): Supplementation with CLA for 24 months is well tolerated by and reduces body fat mass in healthy, overweight humans
• PubMed (Kamphuis et al., 2003): The effect of CLA supplementation after weight loss on body weight regain, body composition, and resting metabolic rate in overweight subjects
• PMC: Body Fat Changes and Liver Safety in Obese and Overweight Women Supplemented with CLA: A 12-Week Randomised, Double-Blind, Placebo-Controlled Trial
• PubMed (2023): The effects of CLA supplementation on anthropometrics and body composition indices in adults: a systematic review and dose-response meta-analysis
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• PMC: Enhancing Bone Health with Conjugated Linoleic Acid: Mechanisms, Challenges, and Innovative Strategies
• PMC: Twelve-week CLA supplementation has no effects on selected markers of atherosclerosis in obese and overweight women
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• PMC: Conjugated linoleic acid modulation of risk factors associated with atherosclerosis
• PMC: Isomer-specific effects of CLA on gene expression in human adipose tissue depending on PPARγ2 P12A polymorphism
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