IngredientsPhosphatidic acid (PA) is a diacyl-glycerophospholipid, in which two fatty acids and a phosphate group are covalently bonded to a glycerol molecule through ester linkages. More precisely, PA is the simplest diacyl-glycerophospholipid and occurs only in small amounts — often less than a few mol% — in biological membranes, yet is crucial for cell survival. Its chemical structure consists of glycerol, to which two fatty acids (acyl-chains) and a phosphate are esterified at positions 1, 2, and 3, respectively. The anionic phosphate headgroup is attached as a phosphomonoester, and it is this defining feature that sets PA apart from all other diacyl-glycerophospholipids.
At its core, phosphatidic acid comprises a glycerol backbone esterified with two fatty acid chains at the sn-1 and sn-2 positions, and a phosphate group at the sn-3 position. This tripartite structure renders PA amphipathic, with hydrophobic tails derived from fatty acids and a hydrophilic phosphate head group. Distinctively, while phospholipids typically possess a polar head group that imparts unique chemical properties to different phospholipid species, phosphatidic acid lacks a polar head group in the conventional sense, contributing to its amphipathic nature and distinctive role in cellular physiology.
The compound is known under several designations in the scientific and regulatory literature, including phosphatidic acid, diacylglycerol-3-phosphate, 1,2-diacyl-sn-glycero-3-phosphate, and phosphatidate (the ionised form). Its CAS registry number is 645-36-3 (for the general class). In commercial supplement contexts, soy-derived PA is often sold under the branded tradename Mediator®.
PA can act as a signaling lipid, it is a precursor for the biosynthesis of other lipids, and it is a major constituent of cell membranes. It is therefore present to some degree in virtually all biological tissue. In practical dietary terms, however, PA concentrations in most common foods are low.
The glycerophospholipid phosphatidic acid has been identified as a potential nutritional treatment for gastrointestinal disorders. Dietary food sources rich in PA include cabbage and radish leaves, as well as Mallotus japonicus, a Japanese edible herb historically used for the treatment of stomach ulcers. Additionally, lecithin — as found in soybeans and eggs — normally comprises a variety of phosphatides, in particular phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidic acid (PA).
The chief sources of commercial natural phospholipids are soybean, egg yolk, and cows (brain and liver). Globally, over 90% of commercial lecithin comes from soybeans; sunflower and egg are common alternatives. Egg yolk lecithin is particularly phospholipid-dense: the content of lecithin in egg yolk is three times higher than the content of lecithin in soybean.
Commercial PA supplements are primarily manufactured by enzymatic conversion of soy lecithin. Due to concerns regarding bovine spongiform encephalopathy, PA produced by enzymatic conversion of soybean lecithin is considered a safer alternative to animal-brain-derived sources. Although PS (and PA) from both sources can be considered safe, currently from a regulatory point of view only non-bovine brain-derived PS/PA is permitted as a dietary supplement. The development of practical enzymatic conversion of soybean lecithin to PS and PA followed these regulatory constraints; the first company to commercially produce soy lecithin-derived PS was Lipogen Ltd. (Haifa, Israel) in 1991.
PA supplements are sold primarily in capsule and powder form. The predominant branded form studied in clinical trials is Mediator® Phosphatidic Acid, derived from soy lecithin. Research has demonstrated that soy-derived PA stimulated mTOR signaling substantially more than egg-derived PA in cell-culture models. PA supplements are also sold as complexes with phosphatidylserine (PS), under names such as PAS (phosphatidylserine/phosphatidic acid complex) or MemreePlus™.
Phosphatidic acid as a chemically identified entity is a product of 20th-century biochemistry; it was not known, named, or deliberately isolated by pre-modern healers. Unlike many herbal ingredients, PA has no documented history as a standalone remedy in any traditional medicine system. However, several important contextual points apply:
In sum, there is no documented traditional use of purified phosphatidic acid per se. Its intentional use as a dietary supplement dates to the early 2010s, following the publication of preclinical and early human data on its role in mTORC1-mediated muscle protein synthesis.
PA holds a central role in membrane glycerophospholipid and triacylglycerol synthesis as their biosynthetic precursor, and can be generated by three major mechanisms. These three principal pathways are:
PA can be produced by multiple enzymes, including two well-known families: phospholipase D (PLD) and diacylglycerol kinase (DGK). PA is extremely short-lived and is rapidly hydrolysed by the enzyme phosphatidate phosphatase to form diacylglycerol (DAG).
Signaling PA generated by PLD, DGK, and LPAAT has been implicated in cytoskeletal organization, cell survival and proliferation, and membrane and vesicle trafficking. Because PA is implicated either directly or indirectly in the biosynthesis of most phospholipids and triacylglycerols, its potential signaling functions may not be mutually exclusive from its intermediate biosynthetic role. At the molecular level, PA has been found to interact with or regulate at least 50 different partners present in all organisms from yeasts and plants to mammals.
Phospholipase D activity plays essential roles in membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, cell migration, and broader signal transduction pathways. PLD-generated phosphatidic acid not only acts as a signaling lipid itself but also serves as a precursor for the biosynthesis of other lipid second messengers, including diacylglycerol (DAG) and lysophosphatidic acid (LPA).
The mechanistic target of rapamycin complex 1 (mTORC1) has received much attention in exercise physiology as a master regulator of skeletal muscle hypertrophy. The multiprotein complex is regulated by growth factors, energy status, amino acids, and mechanical stimuli. Importantly, PA appears to play an important role in mTORC1 activation by mechanical stimulation. PA has been shown to modulate mTOR activity by direct binding to its FKBP12-rapamycin binding domain.
Because of its central role in regulating various anabolic pathways, activation of mTORC1 is critical in mediating the anabolic response to perturbations that promote tissue hypertrophy. 4E-BP1 and S6K1 phosphorylation are increased in skeletal muscle in various animal models of resistance exercise. Additionally, S6K1 phosphorylation is increased in humans after exercise, showing that mTORC1 signaling is increased by exercise. Treatment with the selective mTORC1 inhibitor rapamycin dramatically attenuates exercise-induced mTORC1 activation and muscle hypertrophy.
The mechanism through which exercise promotes activation of mTORC1 is incompletely defined and may be multifactorial. Research has shown that, in vivo, electrically induced muscle contraction resulted in activation of phospholipase D (PLD), leading to increased phosphatidic acid (PA) production.
Recent studies have shown that mechanical stimuli can induce an increase in intracellular levels of PA, and that the increase in intracellular PA contributes to the activation of mTOR-dependent signaling events such as ribosomal S6 kinase 1 (p70) threonine 389 phosphorylation. It has also been shown that PA can directly bind to the FKBP12-rapamycin binding (FRB) domain of mTOR, and in doing so activates mTOR signaling.
The precise mechanism by which exogenously supplemented PA reaches and activates mTOR is debated. PA has been shown to modulate mTOR activity by direct binding to its FKBP12-rapamycin binding domain. Additionally, it has been suggested that exogenous PA activates mTORC1 via extracellular conversion to lysophosphatidic acid and subsequent binding to endothelial differentiation gene receptors on the cell surface.
The DGK ζ-isoform has received special attention: overexpression in serum-deprived HEK293 cells led to an increase in p70S6K1 phosphorylation in an mTOR-dependent manner. Moreover, DGKζ has been shown to be necessary for a mechanically induced increase in PA-mTOR signaling. Overexpression of DGKζ was sufficient to induce muscle fiber hypertrophy through an mTOR-dependent mechanism. Current evidence indicates that PA synthesized by DGKζ, but not PLD, is responsible for the mechanical activation of mTOR signaling and hypertrophy.
PA stimulates the activity of phosphatidylinositol 4-phosphate 5-kinase (PI4P5K), producing PI 4,5-bisphosphate, an additional important signaling lipid. Many survival signals including hormones and growth factors activate PA synthesis through the stimulation of PLD activity. Mitogenic signals trigger cell proliferation, suppression of cell cycle arrest, and prevention of apoptosis. The PLD–PA–Rheb–mTOR and PLD–PA–MAP kinase pathways are the two main downstream pathways of PLD involved in mitogenic signals.
Diacylglycerol (DAG) and phosphatidic acid (PA) are bioactive lipids synthesized when the T cell receptor binds to a cognate peptide-MHC complex. DAG triggers signaling by recruiting Ras guanyl-releasing protein 1, PKCθ, and other effectors, whereas PA binds to effector molecules that include mechanistic target of rapamycin, Src homology region 2 domain-containing phosphatase 1, and Raf1.
Evidence on the effectiveness of PA as an anabolic supplement is equivocal. A scoping review published in Journal of Sports Sciences aimed to systematically assess the effect of PA on performance and body composition; due to the small number of studies, this could only be characterized as a scoping review. A comprehensive search was performed in PubMed, SPORTDiscus, and Web of Science, from 1 January 2010 to 31 August 2020, retrieving 2,009 articles, which when filtered resulted in six studies published between 2012 and 2019.
Five studies were performed in adult male populations and one in an elderly male population. Of these, three studies suggested no effect of PA on lean body mass, while the remaining showed a possible positive effect on body composition and performance improvements. After thorough analysis of the included studies, the evidence does not support the supplementation with PA to increase performance or improve body composition in young or elderly men.
Phosphatidic acid was reported to activate the mTOR signaling pathway and is thought to enhance the anabolic effects of resistance training. This pilot study examined whether oral PA administration could enhance strength, muscle thickness, and lean tissue accruement during an 8-week resistance training program. Sixteen resistance-trained men were randomly assigned to consume 750 mg of PA (n=7) or 750 mg rice flour placebo (n=9). Subjects ingesting PA demonstrated a 12.7% increase in squat strength and a 2.6% increase in LBM, while subjects consuming placebo showed a 9.3% improvement in squat strength and a 0.1% change in LBM. Although parametric analysis was unable to demonstrate significant differences, magnitude-based inferences indicated positive trends. The results do not provide support to the previously discussed mechanisms of action, but provide some evidence of proof of concept. Additional research was identified as needed, including a bioavailability study to investigate the absorption profile of orally administered PA and a muscle biopsy study.
The purpose of this study was to compare the effects of various PA precursors and phospholipids on their ability to stimulate mTOR signaling and to augment resistance training-induced changes in body composition and performance. In phase one, C2C12 myoblasts were stimulated with different phospholipids derived from soy and egg sources; the ratio of phosphorylated p70 to total p70 was used as readout for mTOR signaling. In phase two, resistance-trained subjects (n=28, 21±3 years) consumed either 750 mg PA daily or placebo and participated in an 8-week periodized resistance training program. In phase one, soy-PA stimulated mTOR signaling by 636%, significantly greater than egg-PA at +221%. In phase two, PA significantly increased lean body mass (+2.4 kg), cross-sectional area (+1.0 cm), and leg press strength (+51.9 kg) over placebo. The authors concluded that PA significantly activates mTOR and significantly improved responses in skeletal muscle hypertrophy, lean body mass, and maximal strength to resistance exercise.
This study investigated the effects of PA supplementation on muscle thickness and strength following an 8-week supervised resistance-training program. Fifteen resistance-trained men were randomly assigned to consume 750 mg of PA or placebo. Testing was carried out before and after training for muscle thickness and strength, including 1RM of squat, deadlift, and bench press. Analysis of covariance did not reveal any group differences for measures of muscle thickness in the rectus femoris (PA: 3.6% ± 5.2%; PL: 3.2% ± 4.2%, p=0.97) or vastus lateralis (PA: 23.4% ± 18.1%; PL: 12.5% ± 15.4%, p=0.37). This trial found no statistically significant benefit of PA supplementation.
This investigation studied the effects of a dietary supplement (MaxxTOR®, containing PA along with other potentially anabolic compounds including L-leucine, HMB, and vitamin D3) in conjunction with a 3-day per week total body resistance training program on muscular strength, endurance, power, vertical jump, agility, lean body mass, thigh muscle mass, and fat mass in resistance-trained men. Eighteen participants completed the trial. The results of this eight-week trial suggested that the addition of MaxxTOR® to a 3-day per week resistance training program can positively impact lean body mass and strength beyond the results found with exercise alone. However, since the product contained multiple potentially anabolic ingredients, no isolated conclusion about PA can be drawn.
A significant main effect for time was observed for improvements in total body mass (p=0.003), lean mass (p=0.008), rectus femoris cross-sectional area (p=0.011), and lower-body strength (p<0.001), but no significant interactions between PA and placebo groups were present (p>0.05). Magnitude-based inferences determined both doses of PA to have a likely impact on increasing body mass (74.2%), lean mass (71.3%), rectus femoris cross-sectional area (92.2%), and a very likely impact on increasing lower-body strength (98.1% beneficial). When combined with resistance training, PA appeared to have a more than likely impact on improving lower-body strength.
The overall body of human clinical evidence for PA supplementation on muscle hypertrophy and strength is preliminary and mixed. There are only a small number of relevant RCTs, most involve exclusively young adult males, sample sizes are small (typically 15–28 completers), and the studies span only 8 weeks. Multiple trials report null or non-significant primary outcomes, while a minority show statistically positive effects. The scoping review published in Journal of Sports Sciences (2021) concluded that the available evidence does not support the use of PA supplementation to improve performance or body composition.
PA has been studied not as an isolated supplement but as a component of a combined phosphatidylserine/phosphatidic acid (PAS) complex in the context of chronic stress and HPA axis dysregulation.
Supplementation with a phosphatidylserine/phosphatidic acid complex (PAS) has been observed to normalize stress-induced dysregulations of the hypothalamus-pituitary-adrenal axis (HPAA). Prolonged stress first induces a hyper-activation of the HPAA, which can then be followed by a state of hypo-activation. This study examined the effects of an oral supplementation with 400 mg PS and 400 mg PA (PAS 400) per day on the endocrine stress response — measured as ACTH, saliva cortisol, and serum cortisol — to a psychosocial stressor, with a focus on analyzing subgroups of low versus high chronically stressed subjects, as well as testing the efficacy of 200 mg PS and 200 mg PA (PAS 200).
75 healthy male volunteers were enrolled for this double-blind, placebo-controlled study, stratified by chronic stress level, and randomly allocated to one of three arms (placebo, PAS 200, or PAS 400 per day). Supplementation was administered for 42 days for each participant. Chronic stress was measured with the Trier Inventory for Chronic Stress (TICS), and an acute stress test (Trier Social Stress Test, TSST) followed six weeks of supplementation.
Chronic stress levels and other baseline measures did not differ between treatment groups. Acute stress was successfully induced and resulted in a hyper-responsivity of the HPAA in chronically stressed subjects. Compared to placebo, supplementation with PAS 400 was effective in normalizing the ACTH (p=0.010), salivary (p=0.043), and serum cortisol responses (p=0.035) to the TSST in chronically high but not in low stressed subjects. PAS 200 did not result in any significant differences.
There were no significant effects of supplementation with PAS on heart rate, pulse transit time, or psychological stress response.
An important limitation of this evidence is that the studied intervention was a combined PS+PA complex, making it impossible to attribute observed effects specifically to PA rather than to PS, the better-established phospholipid for this indication.
A small number of pilot studies have examined the combined PS/PA complex in elderly patients with Alzheimer's disease and dementia. Early pilot studies were performed with a brain-health food supplement containing a proprietary blend of 100 mg phosphatidylserine (PS) and 80 mg phosphatidic acid (PA) produced from soy lecithin. These studies reported observations on memory, cognition, daily functioning, and mood in Alzheimer's patients, but the evidence base is at an early, hypothesis-generating stage, and the specific contribution of PA to any observed effects cannot be disentangled from that of PS. No large-scale RCTs isolating PA for cognitive outcomes have been published to date.
The glycerophospholipid phosphatidic acid has been identified as a potential nutritional treatment for gastrointestinal disorders. Dietary food sources rich in PA include cabbage and radish leaves as well as Mallotus japonicus, a Japanese edible herb historically used for the treatment of stomach ulcers. This application remains at a very early stage; no human clinical trial evidence for PA supplementation in GI conditions was identified.
The following dosages are drawn directly from published human studies and should not be interpreted as prescriptive recommendations.
The PA supplement used in the Hoffman et al. 2012 pilot study (Mediatorâ„¢) was obtained from Chemi Nutra (White Bear Lake, MN). Both the PA and placebo were in capsule form and were similar in appearance. Subjects were required to consume five capsules of the treatment once per day.
In the Hoffman et al. (2012) pilot study, PA and placebo were very well tolerated and no adverse events were reported. This finding is consistent across the small number of published 8-week trials, none of which reported serious adverse events at 750 mg/day.
Commercial lecithin, defined as a naturally-occurring mixture of the phosphatides of choline, ethanolamine, and inositol, is a direct food substance affirmed as generally recognized as safe (GRAS). The WHO places no limit on the oral intake of lecithin. Regulatory agencies (FDA and EFSA) regard lecithin as safe (GRAS/E322) at typical use levels. However, these GRAS designations apply to lecithin in the context of food use; there is no specific GRAS or regulatory approval for concentrated, isolated PA supplements at supplemental doses.
The longest published human trials using PA supplementation have been 8 weeks in duration. No long-term safety data from controlled studies in humans (beyond 8 weeks) has been identified for supplemental doses of isolated PA. The lack of long-term data is an acknowledged gap in the evidence base.
Soy lecithin (the primary PA source) contains only trace soy proteins and rarely triggers soy allergy, but still carries a "contains soy" label requirement in the US; egg lecithin must be labeled as eggs (a major allergen), while sunflower lecithin is generally hypoallergenic. Individuals with diagnosed soy or egg allergies should consider the source material of any PA supplement.
Due to concerns regarding bovine spongiform encephalopathy, PA produced by enzymatic conversion of soybean lecithin is considered a safer alternative to animal-brain-derived sources. Currently, from a regulatory point of view, only non-bovine brain-derived PS/PA is permitted as a dietary supplement.
How orally supplemented PA reaches skeletal muscle and other target tissues remains incompletely characterised. A bioavailability study to investigate the absorption profile of orally administered PA was identified as an outstanding research need by the authors of the 2012 pilot study. The cell-culture evidence shows that exogenous PA activates mTOR through multiple mechanisms including potential conversion to lysophosphatidic acid prior to receptor engagement, as demonstrated by Winter and colleagues who showed that the exogenous addition of PA to fibroblasts results in activation of mTOR signaling via an indirect mechanism dependent on PA being metabolised to lysophosphatidic acid (LPA) and activating LPA family receptors.
The following limitations are critical for accurate interpretation of the PA literature:
Health conditions that Phosphatidic acid may help support.
Body systems that Phosphatidic acid may help support.
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