Cellular Energy Metabolism and the TCA Cycle
Chronic fatigue cannot be explained by nutritional deficiency alone. The TCA cycle (tricarboxylic acid cycle, also called the Krebs cycle) is the core circuit through which cells generate energy, and when this cycle runs poorly inside the mitochondria, fatigue follows directly.
The TCA cycle operates within the mitochondria, converting glucose, fatty acids, and amino acids into ATP — the cell's primary energy currency. Each turn of the cycle produces NADH and FADH₂, which then feed into the electron transport chain to drive ATP synthesis. When this cycle runs smoothly, the heart, brain, and muscles all function normally.
AMPK (AMP-activated protein kinase, a key enzyme that senses the cell's energy status) governs the speed of this cycle. AMPK continuously monitors the ATP-to-AMP ratio inside the cell and, when energy falls low, sends signals to adjust metabolic pathways.(Steinberg Gregory R et al., 2023) Think of it as the cell's fuel warning light. The problem arises when that warning light stays on — that is, when chronic energy deficiency persists.
Oxidative stress and chronic inflammation add further strain on the TCA cycle. Reactive oxygen species (ROS) can damage key enzymes at intermediate steps of the cycle, and inflammatory cytokines (signaling proteins that drive inflammation) can reduce the electrochemical gradient across the inner mitochondrial membrane — known as the membrane potential.(Haque Parsa S et al., 2024) When membrane potential drops, the enzyme responsible for making ATP cannot function properly, and energy output falls.
As this vicious cycle accumulates, fatigue and cognitive decline appear together. Muscles feel heavy, concentration fades, and immune responses slow down. What many people call "burnout" may partly reflect an imbalance in cellular energy metabolism. Addressing energy metabolism means engaging the underlying mechanistic pathways — not just relieving the symptom of tiredness.
NAD+ IV Therapy — Why Directly Replenishing the TCA Cycle's Coenzyme Matters
The TCA cycle cannot complete a single turn without NAD+. Several key enzymes at critical steps use NAD+ as an electron acceptor. When NAD+ runs low, these reactions stall or slow considerably, dragging down overall energy production efficiency.
As we age — and as chronic inflammation persists — intracellular NAD+ levels decline. An enzyme called CD38 becomes more active in inflammatory environments and breaks down NAD+. At the same time, the enzymes responsible for synthesizing new NAD+ lose function with age. Supply drops while consumption rises.
Oral NAD+ precursors such as NMN (nicotinamide mononucleotide) or NR (nicotinamide riboside) are one option. However, intestinal absorption rates and first-pass metabolism through the liver affect how much actually reaches the bloodstream. Intravenous administration bypasses the digestive route and can raise NAD+-related plasma concentrations more rapidly, though the pathways by which this translates into intracellular NAD+ elevation remain under active debate. Further research is ongoing.
NAD+ replenishment may affect more than the TCA cycle alone. Proteins called sirtuins (SIRT1, SIRT3) require NAD+ to function, and they play roles in mitochondrial biogenesis (the process of forming new mitochondria) and antioxidant defense. The AMPK pathway also participates in energy balance through its regulation of mitochondrial biogenesis and fatty acid oxidation.(Steinberg Gregory R et al., 2023) NAD+ IV therapy is being studied from the perspective of coenzyme replenishment, and its relationship with mitochondrial function and intracellular signaling pathways continues to be explored. Individual responses may vary depending on each person's condition and the underlying cause of their fatigue.
Myers' Cocktail and High-Dose Vitamin C — Supplying Cofactors and Antioxidant Defense
If NAD+ serves as the TCA cycle's electron acceptor, magnesium and B vitamins are the components that keep the cycle turning. Myers' Cocktail is a combination IV infusion that typically contains magnesium, calcium, B vitamins, and vitamin C, though the exact formulation and doses vary by clinical setting and individual patient needs. This section focuses on magnesium and B vitamins; high-dose vitamin C is discussed separately as an extended or add-on component.
Magnesium acts as a metal cofactor (a helper mineral) for many metabolic enzymes. For a cell to actually use ATP, it needs ATP bound to magnesium — written as Mg-ATP. When magnesium is deficient, ATP cannot be properly utilized even when present in adequate amounts, creating a paradoxical form of energy deficiency.
B vitamins each play specific roles at different steps of the cycle. Vitamin B1 (thiamine) supports the gateway reaction that allows glucose to enter the TCA cycle; when this step is blocked, glucose cannot feed into the circuit. Vitamin B2 (riboflavin) provides the raw material for FADH₂, which is needed by the electron transport chain. Vitamin B5 (pantothenic acid) is the building block for CoA (coenzyme A), a carrier molecule that appears at multiple points throughout the TCA cycle.
When these cofactors are insufficient, the cycle struggles to run at full capacity even when NAD+ is available. This is why the combination infusion is considered a complementary approach to NAD+ therapy. Whether and how a patient responds depends on the presence of actual deficiencies, underlying medical conditions, and current medications.
High-dose vitamin C may be added to or given alongside Myers' Cocktail as an extended formulation. Intravenous administration at high concentrations can raise plasma levels far beyond what oral dosing can achieve. Some preclinical and early-stage research has reported distinct effects in tumor cell models, but these findings cannot be directly applied to chronic fatigue. From an energy metabolism perspective, vitamin C may support antioxidant defense and help protect metabolic enzymes that are vulnerable to oxidative stress.(Haque Parsa S et al., 2024)
Vitamin C is also required for synthesizing carnitine, a molecule that transports fatty acids into the mitochondria — the gateway through which fatty acids enter the TCA cycle. When magnesium deficiency and B vitamin insufficiency are both suspected, considering cofactor supply alongside NAD+ represents a broader metabolic approach than focusing on NAD+ alone.
Laennec (Human Placenta-Derived) and Glycyrrhizin — Cellular Recovery Environment and Inflammation Modulation
Where NAD+ and Myers' Cocktail supply fuel and components to the TCA cycle, Laennec and glycyrrhizin address the surrounding environment in which that cycle operates.
Laennec is a human placenta-derived hydrolysate (a preparation made by breaking down placental proteins). Its approved indications in South Korea cover liver disease-related conditions such as improving liver function in chronic liver disease; it is not approved as a treatment for chronic fatigue. Preclinical research has suggested it may influence cell-protective and regenerative signaling pathways. Some studies discuss mechanisms resembling hepatocyte growth factor (HGF) activity or involvement in PGC-1α, a pathway that coordinates mitochondrial biogenesis — but most of this evidence comes from animal experiments or in vitro (test tube) studies. Whether these effects translate to improvements in chronic fatigue or mitochondrial function in humans requires further clinical investigation. Laennec is best understood as an agent being explored for its potential role in the cellular recovery environment. Individual responses may vary.
Glycyrrhizin is a compound extracted from licorice root. Studies have reported that it may reduce the release of HMGB1 (a key mediator of inflammatory signaling) or modulate the NF-κB pathway (a major switch that activates inflammatory responses). These mechanisms have also been identified primarily in animal models and in vitro studies, and direct clinical evidence for its effects on chronic fatigue in humans remains limited. Glycyrrhizin should be understood in terms of its mechanistic potential against low-grade chronic inflammation.
The connection between inflammation control and energy metabolism becomes clear when considering how vulnerable mitochondria are to inflammatory signals. Persistent inflammatory environments reduce mitochondrial energy production efficiency and increase ROS generation.(Haque Parsa S et al., 2024) When energy-sensing pathways including AMPK are disrupted by chronic inflammation, overall metabolic homeostasis becomes unstable.(Steinberg Gregory R et al., 2023) Evaluating inflammatory burden is therefore an integral part of understanding TCA cycle and mitochondrial function.
Laennec and glycyrrhizin can be thought of as a complementary approach that assesses the oxidative and inflammatory load within the cellular environment where NAD+ and Myers' Cocktail act — similar to checking for buildup around an engine before refueling it. That said, appropriateness varies considerably depending on individual health status, underlying conditions, and current medications.
Combining All Four as a Protocol — Selection Criteria and the Logic of Combination
Each of the four IV therapies has a distinct mechanism of action, yet they connect within a coherent logical framework. NAD+ relates to TCA cycle coenzyme availability; Myers' Cocktail supplies the broader range of cofactors that keep the cycle running; Laennec's cellular recovery mechanisms are under ongoing investigation; and glycyrrhizin's potential for modulating inflammatory signaling has been proposed mainly at the preclinical level. AMPK is one energy-sensing pathway where all four approaches may theoretically converge.(Steinberg Gregory R et al., 2023)
Which combination is appropriate depends entirely on the patient's current condition. The following situations call for a diagnosis of underlying disease before any IV therapy is considered — and if an underlying cause is identified, treating that cause takes priority. Fatigue persisting for two to four weeks or more despite adequate rest, recurring episodes of reduced concentration, heavy muscles, or severe post-exertional exhaustion, or possible abnormalities in liver function, anemia, thyroid function, or inflammatory markers all require specialist evaluation first. Symptoms suggesting other conditions — such as unintentional weight loss, fever, chest pain, shortness of breath, or severe depression — also require medical attention.
Following acute burnout or a short period of extreme overwork, a coenzyme- and cofactor-focused approach may be considered in some patients, though responses vary and a physician's judgment must come first. When low-grade chronic inflammation is suspected as a background contributor — as in cases resembling chronic fatigue syndrome — or when liver function sits at a borderline level, these approaches may be mechanistically relevant to consider. Direct clinical evidence for chronic fatigue syndrome specifically remains limited, and specialist diagnosis must precede any treatment plan. Responses differ between individuals, and no particular combination guarantees the same outcome for everyone.
A comprehensive mechanistic understanding of mitochondrial function calls for evaluating both substrate supply and the inflammatory microenvironment.(Haque Parsa S et al., 2024) That principle is the theoretical basis for discussing this four-therapy combination.
Since each therapy has its own mechanism even when used alone, there is no need to start all four simultaneously. A realistic approach involves the clinician comprehensively evaluating the patient's metabolic status, underlying conditions, lifestyle, and treatment goals — then setting priorities and adjusting based on observed response. Addressing energy metabolism is a process that combines cause evaluation, lifestyle modification, and, where appropriate, an IV therapy plan — not a one-time injection. Treatment intervals and frequency depend on individual test results and symptom changes, so please consult a specialist to establish a personalized plan.
This content is provided for informational purposes only. Individual responses may vary. Please consult a qualified physician for accurate diagnosis and treatment.
References
- Steinberg Gregory R, Hardie D Grahame (2023). New insights into activation and function of the AMPK. Nat Rev Mol Cell Biol. PMID: 36316383
- Haque Parsa S, Kapur Neeraj, Barrett Terrence A (2024). Mitochondrial function and gastrointestinal diseases. Nat Rev Gastroenterol Hepatol. PMID: 38740978
Frequently Asked Questions
A significant portion of oral supplements is broken down during intestinal absorption, limiting how much actually reaches the cells. IV infusion bypasses the digestive route and can raise blood concentrations more rapidly. This difference may be clinically meaningful in cases where intracellular NAD+ depletion is severe.
The magnesium and B vitamins in Myers' Cocktail serve as metal cofactors and coenzymes for TCA cycle enzymes. These components must be adequately supplied for the entire cycle to run smoothly — even when electron acceptors like NAD+ are present. The fact that Myers' Cocktail delivers multiple nutrients together, rather than any single ingredient, is its defining characteristic.
Laennec may be considered for patients whose chronic fatigue has persisted long enough to suggest a possible decline in mitochondrial quantity or quality, or for those whose fatigue is accompanied by reduced liver function. It is reviewed as an option in situations where restoring the cellular recovery environment may need to precede straightforward nutritional supplementation.
Glycyrrhizin has been reported to modulate overactivated NF-κB signaling in chronic inflammatory environments and to inhibit expression of CD38, the enzyme that breaks down NAD+. Through these mechanisms, it may help slow the rate of intracellular NAD+ depletion and reduce the inflammatory burden that interferes with normal mitochondrial function.
All four therapies do not need to be administered simultaneously. The combination and sequence can vary depending on each patient's current condition and the nature of their fatigue. In some cases, therapies are prioritized and introduced stepwise rather than all on the same day. Determining the right combination requires integrating an individual's metabolic status with clinical findings.