Infrared Sauna and NADPH in Human Metabolism: Benefits, Risks, and the Hormesis Curve

Infrared sauna therapy is a form of controlled hyperthermia—a deliberate, time-limited heat stress that can trigger hormesis: a beneficial adaptive response to a mild stressor. Heat exposure affects many metabolic systems, but one of its most clinically relevant targets is NADPH physiology.

NADPH sits at the crossroads of antioxidant defence (glutathione/thioredoxin), nitric oxide production, mitochondrial redox stability, and detoxification capacity. Infrared sauna exposure can either strengthen these systems through adaptive upregulation—or strain them through excessive ROS production and redox imbalance—depending on the individual’s metabolic reserve, baseline redox status, genetics, and protocol design.

This article outlines both the positive and negative effects of infrared sauna on NADPH-dependent systems, and provides a clinically grounded framework for safe, effective application.

Infrared sauna therapy creates thermal stress that increases metabolic demand. Acute heat exposure can raise energy expenditure, increase circulation, and stimulate cellular stress-response programs. This stress affects NADPH systems in two ways:

1. Adaptive response (benefit): mild stress → stronger antioxidant enzyme capacity, improved endothelial function, enhanced mitochondrial resilience.
2. Overload response (risk): excessive stress → acute NADPH depletion, glutathione collapse, NOX hyperactivation, redox imbalance, cardiovascular strain.

The clinical question is not whether infrared sauna “works,” but where an individual sits on the hormetic curve—the zone where stress improves resilience versus the zone where stress becomes destabilizing.

Far-infrared therapy has been associated with reduced oxidative stress markers and improved vascular function in clinical contexts, particularly in populations with cardiovascular risk factors. One central mechanism is upregulation of antioxidant enzymes, including glutathione-related pathways.

Heat exposure can increase expression of enzymes such as glutathione peroxidase (GPx-1). This matters because GPx relies on reduced glutathione (GSH) to neutralize peroxides, and maintaining GSH depends on NADPH-driven recycling via glutathione reductase.

A clinically important pattern is often seen with hormesis:

• early sessions may temporarily increase oxidative markers (a controlled oxidative challenge),

• repeated exposure then produces a “rebound” strengthening of antioxidant capacity.

This is not paradoxical—it is the intended adaptive outcome of properly dosed heat stress.

Infrared sauna robustly activates heat shock proteins (HSPs), especially HSP70. Heat stress triggers heat shock factor 1 (HSF1) signalling, increasing HSP expression even with relatively short exposures (often 15–30 minutes depending on protocol).

HSPs are molecular chaperones. Their relevance to NADPH physiology is indirect but powerful:

• They reduce accumulation of misfolded or damaged proteins, lowering oxidative burden.

• They support cellular repair processes that would otherwise drain antioxidant reserves.

• They improve “proteostasis,” which reduces chronic redox pressure.

HSP90 also has particular cardiovascular relevance because it supports endothelial nitric oxide synthase (eNOS) stability. Since eNOS is NADPH-dependent, stabilizing eNOS helps preserve nitric oxide signalling, vascular tone, and endothelial function—especially important in cardiometabolic risk states.

Infrared exposure has been associated with improved mitochondrial function and biogenesis in experimental models. The clinical relevance is the downstream impact: more robust mitochondria can expand capacity for mitochondrial NADPH production through systems such as:

• nicotinamide nucleotide transhydrogenase (NNT)

• mitochondrial isocitrate dehydrogenase (IDH2)

• mitochondrial malic enzyme (ME3)

Mitochondrial biogenesis is also linked to PGC-1α, a central regulator of mitochondrial adaptation. Heat shock proteins, particularly HSP70, support mitochondrial biogenesis by protecting mitochondrial proteins and assisting assembly/repair processes.

The practical translation is important: when adaptation occurs, people may experience improved energy output, improved exertional tolerance, and improved recovery—because mitochondrial antioxidant stability and ATP production are more resilient under stress.

Detoxification is often simplified in popular health discussions, but the biochemical reality is more specific: Phase II detox pathways frequently rely on glutathione conjugation, and glutathione functionality depends on NADPH availability.

Infrared sauna can support detoxification indirectly via:

• increased circulation and tissue perfusion

• improved elimination through sweat

• potential heat-shock-mediated protection of hepatic cells

• enhanced glutathione system efficiency in those who adapt well

Some clinical protocols pair sauna use with glutathione support strategies (including IV glutathione in certain settings) based on the rationale that glutathione binds/reacts with reactive intermediates and sauna may improve elimination—though this must be individualized and clinically supervised.

Infrared sauna therapy has been studied in cardiovascular contexts, including heart failure, showing improvements in symptoms, exercise tolerance, and vascular function in controlled settings.

Mechanistically, improvements appear tied to:

• reduced oxidative stress burden,

• improved endothelial function (eNOS stability and NO signalling),

• favourable shifts in metabolic regulation.

A nuanced point: NADPH oxidase isoforms differ. While NOX hyperactivation is associated with pathology, certain isoforms (e.g., NOX4 in specific contexts) may contribute to adaptive metabolic regulation and stress tolerance in cardiovascular tissue. The clinical implication is that context and dose determine whether NADPH oxidase activity is helpful or harmful.

Heat stress and exercise share a common feature: controlled oxidative challenge can activate Nrf2, the master regulator of antioxidant response elements.

Nrf2 upregulates a coordinated network including:

• NADPH-generating enzymes (PPP-related and other pathways)

• glutathione synthesis enzymes

• NADPH-utilizing antioxidant enzymes (glutathione and thioredoxin systems)

This “system-wide upregulation” is one reason properly dosed sauna therapy can enhance resilience over time rather than merely providing temporary symptom relief.

The same mechanisms that produce benefit can also produce harm when the load exceeds adaptive capacity.

Heat stress increases metabolic demand and can acutely increase ROS production. Mechanisms include:

• increased mitochondrial electron transport activity

• higher membrane potential states

• increased oxygen flux

• increased fatty acid transport and β-oxidation

This initial ROS rise can consume NADPH through antioxidant defence pathways and can also stimulate NADPH oxidase activity, creating a feed-forward cycle of ROS generation and NADPH consumption.

In healthy individuals, this is often followed by adaptive rebound. In vulnerable individuals, it may produce symptomatic worsening—especially with prolonged sessions, high temperatures, dehydration, or baseline redox depletion.

Excessive NADPH oxidase activation (particularly NOX2-driven patterns) can promote pathological oxidative stress and apoptosis signalling through MAPK pathways and other systems.

One of the most clinically concerning downstream effects is eNOS uncoupling. When eNOS loses its essential cofactors (including tetrahydrobiopterin integrity), it can shift from producing nitric oxide to producing superoxide. This represents a metabolic failure mode where a protective NADPH-dependent enzyme becomes a ROS generator—consuming NADPH while increasing oxidative injury.

For individuals with cardiometabolic disease, endothelial dysfunction, or autonomic instability, sauna exposure that pushes NOX activation beyond compensatory capacity may increase risk rather than deliver benefit.

Oxidative stress gets most attention, but reductive stress (excess reduced cofactors or imbalanced redox ratios) is also harmful.

Heat stress can substantially shift redox couple ratios (NADH/NAD⁺, NADPH/NADP⁺, GSH/GSSG). Short-term ratio shifts may reflect adaptive responses. Prolonged or extreme shifts can indicate reductive stress that disrupts mitochondrial metabolism and cellular signalling.

Individuals with impaired metabolic flexibility, NAD⁺ dysregulation, or certain mitochondrial disorders may be more vulnerable to reductive stress effects from heat exposure.

G6PD catalyses the rate-limiting step of the pentose phosphate pathway and is the sole NADPH source in red blood cells. In G6PD deficiency, erythrocytes cannot generate adequate NADPH to maintain reduced glutathione, making them vulnerable to oxidative stress from multiple triggers—including heat stress.

Clinical concerns include increased vulnerability to oxidative injury and severe hyperthermic reactions in susceptible contexts. Because sauna therapy can provoke oxidative challenge, G6PD deficiency should be treated as a major contraindication unless a specialist explicitly deems otherwise.

Moderate sauna exposure may upregulate glutathione systems. Excessive exposure can deplete glutathione faster than it can be regenerated—especially in individuals with already-low glutathione reserve (malnutrition, chronic disease, heavy toxic burden, chronic alcohol exposure, frequent acetaminophen use, genetic polymorphisms affecting glutathione synthesis).

When total glutathione pools fall, NADPH cannot “solve the problem” because the substrate pool is depleted. At that point, redox collapse can worsen rapidly.

Infrared sauna creates cardiovascular demand: vasodilation and increased heart rate can be beneficial for many, but risky for those with limited cardiac reserve or unstable physiology.

Risks increase with:

• dehydration and electrolyte loss

• hypotension and fainting tendencies

• uncontrolled hypertension

• kidney disease and impaired fluid handling

• arrhythmia risk states

Warning signs include dizziness, heavy fatigue, nausea, cramps, headache, rapid pulse, and confusion—signals that the stress has exceeded hormetic range.

NADP⁺ is synthesized from NAD⁺ (via NAD kinase). Heat stress can reduce NAD⁺ availability in prolonged stress contexts, and NAD⁺ depletion can therefore limit NADP⁺ pools, reducing maximal NADPH regeneration capacity.

This matters clinically because a person can appear “fine” initially, then deteriorate with repeated exposures if precursor pools are being chronically depleted without recovery.

Many beneficial adaptations occur at relatively moderate infrared sauna ranges:

• Temperature: commonly effective ranges are ~43–54°C (109–129°F)

• Duration: often 15–30 minutes, depending on tolerance and health status

• Frequency: protocols vary from 2–7 sessions/week depending on goal and population

• Progression: start low (10–15 minutes) and build gradually as adaptation develops

This progression allows NADPH-dependent antioxidant systems to “learn” the stressor without being overwhelmed.

Hydration supports cardiovascular stability and redox function. Electrolyte depletion worsens fatigue and increases strain. Individuals prone to hypotension or dizziness require extra caution.

Clinically, support may include:

• glutathione precursors (e.g., NAC in suitable individuals)

• B-vitamins that support NAD⁺/NADP⁺ metabolism

• magnesium as relevant enzymatic cofactor support

• antioxidant nutrients (context-specific; avoid oversimplification)

The principle is not “more supplements,” but ensuring the redox system has the raw materials and cofactors needed to adapt.

• G6PD deficiency

• pregnancy (hyperthermia risk)

• unstable cardiovascular disease or recent acute events

• severe kidney or liver disease

• history of severe heat intolerance or malignant hyperthermia concerns

• chronic heart failure (may benefit but must be supervised)

• diabetes (monitor dehydration and hypoglycaemia risk)

• mitochondrial disorders

• severe metabolic syndrome or autonomic dysfunction

• chronic fatigue syndromes with strong oxidative stress phenotype (may worsen before improving)

A clinical approach focuses on:

• baseline blood pressure response and symptoms

• hydration status and electrolyte stability

• heat strain symptoms vs adaptive “post-session calm”

• oxidative stress markers and glutathione status in complex cases

• G6PD status in at-risk individuals

The goal is not to “tough it out,” but to remain within the adaptive range.

Infrared sauna therapy is a powerful hormetic tool with meaningful effects on NADPH metabolism. Properly applied, it can:

• upregulate NADPH-dependent antioxidant defences,

• increase mitochondrial resilience and biogenesis capacity,

• improve endothelial function through stable NO signalling,

• support detoxification processes through glutathione-dependent pathways.

However, the same physiology can flip into harm if exposure exceeds adaptive capacity, resulting in:

• acute NADPH depletion,

• NOX hyperactivation and potential eNOS uncoupling,

• glutathione pool collapse,

• redox imbalance (including reductive stress),

• cardiovascular strain and dehydration.

The clinical reality is that NADPH metabolism is dynamic and balanced. Heat stress can strengthen this balance—or overwhelm it. Genetics (particularly G6PD), baseline redox reserve, cardiovascular fitness, NAD⁺ metabolism, and protocol design determine where a person lands on the hormesis curve.

For practitioners, the safest path is clear: assess metabolic reserve, use graduated protocols, support redox capacity, and monitor responses—so sauna therapy remains a metabolic ally rather than a stress amplifier.