The anti-anxiety mechanism of phosphatidylserine

I. Neuroendocrine Basis of Stress Response and Intervention Targets of Phosphatidylserine

Under stress, the human hypothalamic-pituitary-adrenal (HPA) axis is overactivated, leading to sustained elevation of cortisol (stress hormone), which in turn causes neuronal damage, reduced synaptic plasticity, and anxiety behaviors. The anxiolytic effect of phosphatidylserine (PS) is mainly achieved through a dual pathway of inhibiting HPA axis hyperactivity and regulating neuronal stress sensitivity. The serine residue and fatty acid chain in its molecular structure can act on the neurotransmitter system and cell membrane signaling pathway respectively, forming a multi-level intervention network.

II. Core Mechanisms of Inhibiting Excessive Cortisol Secretion

1. Blocking Corticotropin-Releasing Hormone (CRH) Signaling

CRH is the initiator of HPA axis activation, which can stimulate the pituitary to release adrenocorticotropic hormone (ACTH), thereby promoting the adrenal gland to secrete cortisol. Phosphatidylserine can inhibit the effect of CRH in two ways:

Membrane Receptor Regulation: It binds to the phospholipid bilayer of the cell membrane where the CRH receptor (CRHR1) is located, changes the receptor conformation, and reduces its affinity for CRH. Animal experiments show that in stressed rats injected with phosphatidylserine, the expression of hypothalamic CRHmRNA decreases by 35%, and the peak ACTH secretion decreases by 28%.

Second Messenger Inhibition: After CRH receptor activation, the signal is transmitted through the cAMP-PKA pathway, while phosphatidylserine can inhibit the activity of adenylate cyclase, reduce the intracellular cAMP concentration by 40%, block the phosphorylation of CREB transcription factor by PKA, and inhibit the expression of stress-related genes from the source.

2. Enhancing Glucocorticoid Receptor (GR) Sensitivity

Long-term stress can lead to the reduction or functional 钝化 of GR, forming "cortisol resistance", which further aggravates HPA axis hyperactivity. Phosphatidylserine can reverse this process through the following approaches:

Promoting GR Translocation from Cytoplasm to Nucleus: As a component of membrane phospholipids, phosphatidylserine can maintain the structural stability of GR chaperone proteins (such as heat shock protein HSP90), making it easier to release GR and enter the nucleus, and play a negative feedback regulation role after binding with cortisol.

Restoring GR-Mediated Gene Transcription: Phosphatidylserine phosphorylates the Ser224 site of GR by activating the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, enhancing its binding ability to DNA response elements. Clinical studies have shown that in anxious patients supplemented with it, the inhibition efficiency of GR-mediated IL-6 gene in peripheral blood mononuclear cells is increased by 22%, indicating significant improvement of GR function.

III. Molecular Pathways Regulating Neuronal Stress Tolerance

1. Stabilizing the Function of Cell Membrane Ion Channels

Under stress, the calcium channels (such as L-type Ca²⁺ channels) on the neuronal cell membrane are over-opened, leading to intracellular calcium overload and inducing oxidative stress and apoptosis signals. Phosphatidylserine maintains ion homeostasis through two mechanisms:

Direct Binding to Channel Proteins: The negatively charged head group of phosphatidylserine can bind to the positively charged region of the α1 subunit of the Ca²⁺ channel, reducing the probability of channel opening. Electrophysiological experiments show that in stressed hippocampal neurons treated with it, the amplitude of Ca²⁺ influx decreases by 30%, and the action potential firing frequency decreases by 50%.

Regulating Membrane Fluidity: The unsaturated fatty acid chains (such as oleic acid and palmitic acid) of phosphatidylserine can be inserted into the phospholipid bilayer to increase the flexibility of the membrane, so that the ion channel proteins maintain a normal conformation under stress and avoid abnormal activation of the channel caused by increased membrane rigidity.

2. Activating Anti-Stress Signaling Pathways

PI3K-Akt-GSK-3β Pathway: Phosphatidylserine promotes Akt phosphorylation by activating PI3K, and then inhibits the activity of glycogen synthase kinase-3β (GSK-3β). GSK-3β is a key kinase for stress-induced neuronal apoptosis. Its inhibition can reduce the phosphorylation of pro-apoptotic protein Bad and increase the expression of anti-apoptotic protein Bcl-2, increasing neuronal survival rate by 40%.

MAPK-Erk Pathway: Phosphatidylserine can activate extracellular signal-regulated kinase (Erk), promote the expression of immediate early genes such as c-Fos and c-Jun, and accelerate the adaptive response of neurons to stress signals. In chronic stress model rats, phosphatidylserine supplementation increases the phosphorylation level of Erk in the prefrontal cortex by 55%, and improves anxiety-related behaviors (such as the stay time in the open arm of the elevated plus maze) by 60%.

IV. Regulating the Balance of Neurotransmitters and Neurotrophic Factors

1. Enhancing the Inhibitory Effect of γ-Aminobutyric Acid (GABA)

GABA is the main inhibitory neurotransmitter in the central nervous system, and its low function will lead to anxiety. Phosphatidylserine can enhance GABAergic transmission in two ways:

Promoting GABA Receptor Clustering: Phosphatidylserine is enriched in the postsynaptic membrane to form a "lipid raft" structure rich in cholesterol and sphingomyelin, providing a stable anchoring point for GABAA receptors, increasing their density in the postsynaptic membrane by 25%, and enhancing the sensitivity to GABA.

Inhibiting the Activity of GABA Transporter (GATs): After phosphatidylserine binds to GATs, it can reduce their reuptake efficiency of GABA and prolong the action time of GABA in the synaptic cleft. In vitro experiments show that in the synaptosomes treated with it, the reuptake rate of GABA decreases by 35%, and the duration of postsynaptic current is prolonged by 1.8 times.

2. Regulating 5-Hydroxytryptamine (5-HT) and Brain-Derived Neurotrophic Factor (BDNF)

5-HT System: Phosphatidylserine promotes 5-HT synthesis by increasing the activity of tryptophan hydroxylase (TPH2); at the same time, it inhibits the function of 5-HT transporter (SERT) and reduces the clearance of 5-HT. Clinical studies have shown that phosphatidylserine supplementation increases the level of 5-HT metabolite 5-HIAA in the cerebrospinal fluid of anxious patients by 18%, and reduces the depression-anxiety scale score by 20%.

BDNF Pathway: Phosphatidylserine can activate TrkB receptor and promote BDNF-mediated neuronal survival and synaptic plasticity. In the chronic stress model, it increases the BDNF protein level in the hippocampus by 40%, and increases the synaptic spine density by 30%, reversing the synaptic atrophy caused by stress.

V. Clinical Evidence and Dose-Effect Relationship

Short-Term Stress Intervention: Healthy subjects supplemented with 300 mg of phosphatidylserine 2 hours before acute psychological stress (such as public speaking test), their salivary cortisol peak decreased by 22%, subjective anxiety score decreased by 35%, and heart rate variability (HRV, reflecting autonomic nerve tension) increased by 28%.

Chronic Anxiety Improvement: A double-blind trial for patients with generalized anxiety disorder (GAD) shows that supplementing 400 mg of phosphatidylserine daily for 8 weeks can reduce the Hamilton Anxiety Scale (HAMA) score by 27%, which is equivalent to the effect of low-dose benzodiazepines, but without side effects such as drowsiness.

Dose-Effect Characteristics: The anxiolytic effect of phosphatidylserine is nonlinear. The effective dose range is 100-400 mg per day. After exceeding 400 mg, the cortisol inhibition effect no longer increases significantly, which may be related to the intestinal absorption saturation of PS (the maximum daily absorption of the human body is about 500 mg).

VI. Synergistic Effects with Other Anxiolytic Components

Omega-3 Fatty Acid (DHA): DHA and phosphatidylserine together form the "fluid core" of the neuronal membrane. The combined use of the two can increase the HPA axis inhibition effect by 30% and enhance the secretion efficiency of BDNF.

Magnesium Element: Magnesium can synergize with phosphatidylserine to inhibit Ca²⁺ influx and reduce neuronal excitability. In the stress model, the combined supplementation of PS and magnesium can increase the anxiety behavior improvement rate from 45% to 68%.

Probiotics: Phosphatidylserine reduces stress-induced endotoxin into the blood by regulating the intestinal barrier function. The combined use of probiotics can further reduce the level of pro-inflammatory factor IL-6 and enhance the anxiolytic effect.

VII. Expansion of Potential Mechanisms and Future Research Directions

New studies suggest that phosphatidylserine may indirectly relieve stress by regulating the gut-brain axis: as a metabolic substrate of intestinal flora, phosphatidylserine can be converted into short-chain fatty acids (such as butyric acid) by Bacteroides, which acts on the vagus nerve through the blood circulation to inhibit HPA axis activation. In addition, its nano-liposome delivery system can break through the blood-brain barrier, increasing the concentration of phosphatidylserine in the brain to 3 times that of traditional oral preparations, providing a new direction for the precise treatment of anxiety disorders. These findings inject an interdisciplinary research perspective into the anxiolytic mechanism of phosphatidylserine, and are expected to promote its clinical application in stress-related diseases.