Regardless of their specialty, if there’s one thing most functional medicine practitioners encounter in their patients on a daily basis, it’s fatigue. “Sick and tired of feeling sick and tired” is a refrain medical and nutrition professionals might hear multiple times a day. Even if someone makes an appointment for a different specific reason—digestive problems, for example, or improving blood sugar control—it’s common for feeling tired to come up during the exam. Some people have had low energy for so long that they may not even remember what it’s like not to feel like they’re dragging through the day. The good news is, there are nutritional interventions that can help people get their “oomph” back if serious conditions that impair energy generation have been ruled out.

It’s important to remember that energy generation involves biochemical processes that take place at the cellular level. When critical elements essential for these processes are lacking or are in short supply, energy generation will be compromised. When someone reports that “their get up and go got up and went,” something relatively simple to identify and easy to correct might be responsible—for example, iron deficiency, or B12 inadequacy. For long-term improvement of quality of life, helping patients address their flagging energy at its root causes is a more effective way to go than them covering up the symptoms with caffeine and energy drinks.

Energy generation ultimately comes down to one thing: synthesizing ATP. And this comes down to converting the stored chemical energy in foods into molecules individual cells can use to do work. In looking at the various ways ATP is produced, several nutrients are required for different pathways and mechanisms, such as glycolysis, beta-oxidation, and the citric acid (or Krebs) cycle. It’s basic physiology and biochemistry, but these things are easy to forget when you’re face-to-face with a patient whom you see as a cohesive, singular human rather than a 200-pound pile of cells with a couple billion mitochondria. 

Glycolysis, the anaerobic process by which glucose is converted to pyruvate with a net yield of 2 ATP, requires several molecules of magnesium. Pyruvate dehydrogenase, the multi-enzyme complex that converts pyruvate to acetyl-CoA, requires coenzymes made from B-vitamins, including thiamine (thiamine pyrophosphate), riboflavin (FAD), niacin (NAD⁺) and pantothenic acid (coenzyme A). Some of these B-vitamins are also essential for the redox reactions of the citric acid cycle, which generates high-energy electrons that then participate in the electron transport chain, whose final player is ATP synthase. Additional enzymes in the citric acid cycle are iron- or manganese-dependent, and the crucial cytochrome proteins and cytochrome C oxidase require iron and copper for proper functioning of the “proton pump” that establishes the critical electrochemical gradient that drives ATP synthesis. The essentiality of iron in these reactions may underlie fatigue as a hallmark of iron-deficiency anemia.

Insufficient levels of B vitamins could also be responsible for low energy, for reasons discussed above. Low B12 status, specifically, may lead to fatigue, muscle weakness, and neurological and neurodegenerative symptoms, likely owing to neurons’ high energy demands. It’s necessary to keep in mind that some experts believe the typical lab reference ranges for B12 are too wide, and that the lower cutoff for “normal” should be raised. Some labs have a reference range of 200 to 900 pg/mL while other sources suggest that as low as 160 pg/mL may be considered “normal.” The nurse and osteopathic physician who wrote the book Could it Be B12? suggest that anyone presenting with cognitive, neurological or neurodegenerative symptoms with a level under 450 pg/mL should be considered deficient and begin supplementation. The American Academy of Family Physicians acknowledged that patients in the gray area of “low normal” (200-350 pg/mL) might benefit from supplementation if they show elevated homocysteine or methylmalonic acid (MMA) even if they’re asymptomatic.

Turning away from glucose metabolism and toward harnessing energy from fats, the modified amino acid carnitine is essential for facilitating transport of fatty acids across mitochondrial membranes. Beta-oxidation, the breaking down of fatty acids into 2-carbon building blocks for acetyl-CoA, takes place in the mitochondrial matrix, so fatty acids first have to get inside. Once beta-oxidation has taken place, the fat-derived acetyl-CoA follows the same pathway into the citric acid cycle as acetyl-CoA derived from glucose. Beta-oxidation also requires B vitamin-derived FAD and NAD coenzymes.    

The broad spectrum of micronutrients needed for cellular energy generation can be obtained from a diet of whole, unprocessed foods. While vegetarian or strictly vegan diets provide iron, zinc, and other crucial minerals, these are less bioavailable from plant foods than from animal foods, so individuals consuming low amounts of animal foods or avoiding them completely may need to take special care to supplement strategically, particularly if they begin to experience signs and symptoms of inadequacies. However, even those consuming omnivorous diets may be at risk for deficiencies due to malabsorption, increased demand from stress or athletic activity, poor digestive function, or use of medications known to deplete certain nutrients.

For patients struggling with low energy, an emphasis on unprocessed, nutrient-rich foods, improving digestive efficiency, and targeted supplementation if warranted addresses the fundamental causes, rather than masking the symptoms and “making do” with energy drinks in the short term.