By Ming Tao Jiang, MD, PhD
Around 2010, I proposed that many of the seemingly unrelated effects of American ginseng could be connected through nitric oxide, or NO.
NO is a small gaseous signaling molecule involved in vascular relaxation, regional blood flow, platelet activity, immune defense and neural communication. It offered a common physiological explanation for several familiar observations associated with ginseng:
- improved circulation and physical energy;
- increased alertness and mental sharpness;
- effects on blood pressure and sexual function;
- altered platelet and coagulation behavior;
- and, at excessive exposure, headache, insomnia, nasal congestion or nosebleeding—some manifestations traditionally described as “上火.”
That original hypothesis remains relevant. But recent research and our clinical observations suggest that NO is only one component of a much broader physiological response.
The updated hypothesis is that American ginseng may help restore the coordination among innate immunity, pulmonary gas exchange, microvascular perfusion, barrier integrity and mitochondrial energy production.
From NO production to NO preservation
My original hypothesis emphasized the possibility that ginseng stimulates NO generation, leading to vascular and possibly airway smooth-muscle relaxation.
New work involving pseudoginsenoside F11 (PF11), a characteristic component of American ginseng, suggests an additional pathway. PF11 may protect mitochondrial SIRT3/SOD2 signaling, reduce mitochondrial oxidative stress and preserve endothelial function.
This matters because excessive reactive oxygen species rapidly inactivate NO.
American ginseng may therefore support NO signaling through two complementary mechanisms:
- stimulating or regulating NO production; and
- preserving NO bioavailability by reducing its oxidative destruction.
This connects endothelial physiology with mitochondrial function. It also provides a possible explanation for why ginseng’s circulatory effects may be more complex than those of a simple vasodilator.
The oxygen–barrier–host-resilience hypothesis
Effective tissue oxygenation depends on an entire physiological chain:
Ventilation → alveolar gas exchange → pulmonary perfusion → systemic microcirculation → mitochondrial oxygen utilization
A failure at any point can produce organ dysfunction. American ginseng may influence several parts of this chain simultaneously.
1. Protecting the alveolar and endothelial barriers
During severe pneumonia, sepsis and respiratory failure, inflammation damages the pulmonary vascular endothelium and alveolar epithelium. Protein-rich fluid enters the interstitial space and alveoli.
The lungs become heavy and may appear “white” on imaging. The diffusion distance for oxygen increases, alveoli become flooded or collapse, and ventilation–perfusion matching deteriorates.
Recent studies of individual ginsenosides have reported preservation of junctional proteins such as:
- VE-cadherin;
- ZO-1;
- occludin;
- claudins;
- and E-cadherin.
These proteins help maintain the pulmonary endothelial and epithelial barriers. Their preservation could reduce vascular leakage, alveolar flooding and pulmonary edema.
The resulting improvement in oxygenation would not require an immediate resolution of the underlying infection. It could occur because more alveoli remain available for gas exchange:
Less leakage → less alveolar flooding → shorter oxygen-diffusion distance → better gas exchange
This may be one of the most clinically important extensions of the original NO hypothesis.
2. Promoting pulmonary fluid clearance
Reducing leakage addresses only one side of pulmonary edema. The lung must also remove fluid already present in the interstitial space.
Recent Rg1 research suggests that ginsenosides may promote pulmonary lymphangiogenesis and lymphatic remodeling through VEGFC/D–VEGFR3 signaling.
If this pathway is confirmed, ginseng components may simultaneously:
- decrease fluid entry into the lung;
- preserve endothelial and epithelial junctions;
- and enhance the clearance of accumulated interstitial fluid.
Reduced leakage combined with increased lymphatic clearance could improve oxygen exchange before structural lung injury has fully resolved.
3. Supporting airway function and mucociliary defense
The airway has both muscular and mechanical defense components.
Earlier work demonstrated that ginsenoside preparations can relax precontracted human bronchial tissue through an epithelial NO-dependent pathway. This supports the possibility that NO contributes to airway smooth-muscle relaxation.
More recent work with ginsenoside Rd adds another mechanism. In primary human bronchial epithelial cells, Rd increased ciliary beat frequency and promoted FOXJ1 and acetylated α-tubulin, markers associated with ciliated-cell function.
These are two distinct effects:
- smooth-muscle relaxation may reduce airway resistance;
- enhanced ciliary activity may improve mucus and particle clearance.
Together, they could improve ventilation and airway defense without requiring a direct antimicrobial effect.
4. Restoring and regulating innate immune responses
The immune system is not simply “on” or “off.”
During severe infection, an initially excessive inflammatory response can injure the lungs, endothelium and other organs. This may be followed by immune exhaustion or immunoparalysis, leaving the patient unable to clear pathogens or resist secondary infections.
The desired response is neither maximum stimulation nor broad suppression. It is restoration of effective immune regulation.
Experimental ginsenoside studies have reported effects on:
- macrophage activity;
- alveolar macrophage extracellular-vesicle signaling;
- TLR4/NF-κB pathways;
- NLRP3 inflammasome activation;
- inflammatory cytokine production;
- neutrophil accumulation;
- and lymphocyte balance.
These observations suggest that American ginseng may function as a state-dependent regulator—restraining destructive inflammation while helping the host return toward effective innate immune function.
This concept is closer to restoration of “元气” than the popular phrase “immune boosting.” The goal is coordinated defense, not indiscriminate activation.
To test this hypothesis, future studies should measure:
- monocyte HLA-DR expression;
- ex-vivo stimulated cytokine responses;
- neutrophil phagocytosis and oxidative burst;
- natural-killer-cell activity;
- lymphocyte exhaustion markers;
- pathogen clearance;
- and secondary infection rates.
5. Improving microvascular oxygen delivery
Blood pressure alone does not tell us whether tissues are receiving oxygen.
In sepsis and other forms of critical illness, microvascular flow becomes heterogeneous. Some capillaries remain open while others are obstructed by endothelial swelling, edema, platelet adhesion or microthrombosis.
American ginseng may improve microvascular function through several converging mechanisms:
- preservation of endothelial NO;
- reduced mitochondrial oxidative stress;
- stabilization of endothelial junctions;
- decreased leukocyte and platelet adhesion;
- and regulation of vascular smooth-muscle tone.
The most useful concept is not generalized vasodilation. It is restoration of appropriately distributed perfusion.
This distinction is particularly important in the lung. Increasing blood flow to well-ventilated alveoli could improve oxygenation, whereas indiscriminate dilation of vessels supplying poorly ventilated regions could worsen ventilation–perfusion mismatch.
The hypothesis must therefore be tested with regional perfusion and oxygenation measurements, not blood pressure alone.
6. Helping mitochondria use delivered oxygen
Oxygen delivery is beneficial only when cells can use that oxygen to generate ATP.
Recent mechanistic research connects ginsenosides with:
- SIRT3/SOD2 regulation;
- reduced mitochondrial reactive oxygen species;
- normalization of excessive RhoA/ROCK/Drp1-mediated mitochondrial fission;
- preservation of mitochondrial membrane potential;
- increased ATP production;
- and improved oxidative phosphorylation.
This completes the connection between pulmonary function, circulation and cellular energy production:
Gas exchange × microvascular delivery × oxygen extraction × mitochondrial efficiency = effective organ oxygenation
A patient may have an acceptable arterial oxygen saturation while cells remain metabolically impaired. Conversely, improved mitochondrial function and microvascular distribution could contribute to falling lactate, improved organ function and regained consciousness before major radiographic changes become apparent.
This mitochondrial component may help explain why the clinical response appears broader than a conventional pulmonary or cardiovascular drug effect.
7. Hemostasis as a dynamic balance
American ginseng’s relationship with coagulation is also unlikely to be one-directional.
Different ginsenosides may influence:
- platelet activation and aggregation;
- endothelial platelet adhesion;
- inflammatory microthrombosis;
- PAI-1 and fibrinolysis;
- vascular permeability;
- and anticoagulant-drug metabolism.
Some isolated ginsenosides inhibit platelet activation. American ginseng has also reduced warfarin exposure and INR in a human study, which could decrease anticoagulant protection.
Our proposed dose-dependent or biphasic hemostatic effect remains a hypothesis. It should be examined through direct clinical measurements rather than inferred from PT or aPTT alone.
A future protocol should include platelet function, fibrinogen, D-dimer, thrombin generation, PAI-1/tPA and preferably TEG or ROTEM.
Why dose, preparation and timing are essential
American ginseng is not a single molecule. Whole root contains multiple ginsenosides, polysaccharides and other constituents that may act on different targets and sometimes in different directions.
Recent human-airway cell research illustrates this complexity. Rd increased ciliated-cell markers as its concentration rose to approximately 10 μM, but the effect became smaller at 30 μM.
This is an example of a non-monotonic response: more compound did not necessarily produce a larger effect.
The clinical response may therefore depend on:
- root age and origin;
- cultivated versus wild material;
- ginsenoside and polysaccharide composition;
- processing and drying;
- decoction method;
- dose and treatment duration;
- gastrointestinal absorption and microbial metabolism;
- and the patient’s physiological state when treatment begins.
This may explain why traditional low-dose supplementation and high-dose Du Shen Tang should not automatically be considered the same intervention.
From clinical observation to testable science
Our clinical observations suggest that high-dose American ginseng may be associated with improvements in oxygenation, consciousness and overall recovery in some critically ill patients.
The next step is to convert these observations into measurable biological questions.
A prospective case series or physician-sponsored trial should include:
- PaO₂/FiO₂ or SpO₂/FiO₂;
- oxygen flow, FiO₂, PEEP and ventilator settings;
- airway resistance and lung compliance;
- serial chest imaging and pulmonary-edema assessment;
- daily fluid balance;
- vasopressor-equivalent dose;
- lactate and peripheral-perfusion measurements;
- endothelial-injury and glycocalyx markers;
- innate immune-function assays;
- mitochondrial respiration or metabolic markers;
- comprehensive coagulation testing;
- and chemical characterization of the American ginseng administered.
The updated hypothesis
My original hypothesis was that American ginseng produces many of its effects through nitric oxide.
The updated hypothesis is:
American ginseng may function as a multicomponent regulator of host resilience. By preserving nitric-oxide signaling, stabilizing the alveolar and endothelial barriers, supporting pulmonary fluid and mucus clearance, restoring and regulating innate immune responses, improving microvascular perfusion and protecting mitochondrial energy production, it may help recouple ventilation, circulation and cellular oxygen utilization during severe physiological stress.
NO remains an important messenger—but it is now part of a larger system.
The developing picture is not of American ginseng acting on one pathogen or one receptor. It is of American ginseng helping multiple physiological systems recover their coordination: the airway brings in oxygen, the alveolus transfers it, the circulation delivers it, innate immunity protects the host, and mitochondria convert it into the energy required for recovery.
That is the hypothesis we now need to test.
This article presents a scientific hypothesis for discussion. It is not medical advice and does not describe the effects of any product sold on this site. These statements have not been evaluated by the Food and Drug Administration. Our products are not intended to diagnose, treat, cure or prevent any disease. Critically ill patients should be treated only under the care of their physicians. If you take warfarin or other anticoagulants, talk with your doctor before using ginseng.