Can ADR Formula® Support Energy and the HPA Axis in Long COVID and ME/CFS?

To understand how a supplement like ADR Formula® works, we first need to explore the natural function of the systems it is designed to support. The hypothalamic-pituitary-adrenal (HPA) axis is a complex neuroendocrine network that governs how your body responds to physical, emotional, and immunological stress. When your brain perceives a stressor—whether that is a viral infection, a drop in blood pressure, or psychological trauma—the hypothalamus releases corticotropin-releasing hormone (CRH). This hormone travels a short distance to the pituitary gland, prompting it to secrete adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then acts as a messenger, traveling down to the adrenal glands, which sit like small caps on top of your kidneys.

The adrenal glands are divided into two main sections: the inner medulla, which produces rapid-response catecholamines like adrenaline, and the outer cortex, which produces steroid hormones like cortisol and aldosterone. Cortisol is often vilified as the "stress hormone" that causes weight gain, but in reality, it is a life-sustaining molecule. In a healthy body, cortisol follows a diurnal rhythm—spiking in the morning to help you wake up and gradually declining throughout the day. It regulates metabolism, reduces inflammation, manages blood sugar levels, and helps control the sleep-wake cycle. When the HPA axis is functioning optimally, the body can mount a robust defense against a stressor and then gracefully return to a state of calm homeostasis.

ADR Formula® relies heavily on a class of botanical medicines known as adaptogens, specifically Panax ginseng and Eleutherococcus senticosus (eleuthero). Adaptogens are unique natural substances that enhance the body's non-specific resistance to stress and help maintain physiological homeostasis. Unlike traditional stimulants such as caffeine or amphetamines, which force the central nervous system into overdrive and inevitably lead to a crash, adaptogens work by modulating the body's internal environment. They act like a thermostat for the HPA axis: if stress hormones are running too high, adaptogens help dial them down; if they are depleted, adaptogens help gently restore them.

At the molecular level, adaptogens interact with cellular stress sensors. For example, research indicates that adaptogens can upregulate the expression of molecular chaperones like Heat Shock Protein 70 (Hsp70). These proteins act as cellular guardians, protecting delicate enzymes and mitochondrial structures from damage during periods of extreme physiological stress. By preserving the integrity of the cell and preventing the excessive release of stress-induced nitric oxide, adaptogens help the body conserve its adenosine triphosphate (ATP) reserves. This means that instead of borrowing energy from tomorrow to survive today, the body can maintain a stable, prolonged level of equilibrium without draining its cellular batteries.

In addition to botanical adaptogens, ADR Formula® incorporates whole adrenal and adrenal cortex bovine extracts, alongside pantothenic acid (Vitamin B5). The inclusion of glandular extracts is rooted in the traditional medical concept that "like supports like." While the exact mechanisms of glandular therapy are still debated in modern allopathic medicine, the functional medicine perspective suggests that consuming specific glandular tissues provides the body with the exact raw materials, peptides, enzymes, and cofactors needed to repair and rebuild that specific organ in the human body.

Furthermore, the adrenal glands cannot manufacture stress hormones out of thin air; they require specific nutritional building blocks. Pantothenic acid is biologically non-negotiable for this process. It is the primary precursor to Coenzyme A (CoA), a molecule that sits at the crossroads of cellular metabolism. Without adequate CoA, the adrenal cortex cannot synthesize cholesterol into pregnenolone, the foundational precursor for all steroid hormones, including cortisol. By providing these essential raw materials, ADR Formula® aims to ensure that the adrenal glands are not running on empty when the brain signals them to respond to the daily demands of living with a chronic illness.

To understand why adrenal support is so critical, we must examine how conditions like Long COVID, ME/CFS, and dysautonomia disrupt the body's natural stress response. The onset of these complex chronic illnesses is frequently traced back to a severe or prolonged viral infection, such as Epstein-Barr Virus (EBV) or, more recently, SARS-CoV-2. In genetically predisposed individuals, the immune system fails to properly clear the virus or reset itself after the acute infection has passed. This leads to a state of chronic systemic inflammation, where the body is locked in a perpetual battle against perceived threats. You can learn more about this connection in our article on how Long COVID can trigger ME/CFS.

This relentless immune activation places an enormous burden on the HPA axis, creating what researchers call a high "allostatic load." Allostatic load refers to the cumulative wear and tear on biological systems caused by chronic stress. Initially, the HPA axis responds to the viral threat by pumping out high levels of cortisol to suppress the inflammatory cytokine storm. However, the adrenal glands are not designed to sustain maximum output indefinitely. Over months or years of chronic illness, the constant demand for stress hormones begins to deplete the body's nutritional reserves, including essential cofactors like Vitamin B5 and Vitamin C, leading to a state of profound physiological exhaustion.

As the chronic illness progresses, a paradoxical shift often occurs in the neuroendocrine system. Recent research into the complexities of ME/CFS and Long COVID has demonstrated that chronic systemic inflammation can eventually lead to HPA axis dysfunction characterized by hypocortisolism—abnormally low levels of circulating cortisol. This is not necessarily because the adrenal glands have failed completely (as seen in Addison's disease), but rather because the entire communication network has become desensitized. Researchers suggest that prolonged exposure to high cortisol early in the illness causes the glucocorticoid and mineralocorticoid receptors in the brain to upregulate. This creates a hyper-sensitive negative feedback loop, where the brain prematurely shuts down the release of CRH and ACTH, starving the adrenal glands of the signal they need to produce cortisol.

The clinical consequences of this hypocortisolism are devastating. Without the morning surge of cortisol (the cortisol awakening response), patients wake up feeling completely unrefreshed, as if they haven't slept at all. Without adequate cortisol to manage inflammation, patients experience widespread myalgia (muscle pain) and joint aches. Furthermore, because cortisol helps regulate vascular tone and blood pressure, its depletion significantly worsens orthostatic intolerance and conditions like Postural Orthostatic Tachycardia Syndrome (POTS). The body enters an "adrenal burnout" loop, where the lack of stress hormones makes the patient increasingly vulnerable to even minor physical or emotional stressors, triggering severe post-exertional crashes.

The impact of HPA axis dysfunction extends far beyond the adrenal glands; it deeply affects the central nervous system. When cortisol levels drop too low, the immune system loses its primary regulatory brake. This allows pro-inflammatory cytokines, such as Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α), to run rampant. Studies on the mechanisms of Long COVID indicate that these inflammatory molecules can cross the blood-brain barrier, activating specialized immune cells in the brain called microglia. This resulting neuroinflammation is a primary driver of "central fatigue"—a deep, neurological exhaustion that cannot be overcome by simply resting.

Central fatigue is fundamentally different from the peripheral muscle fatigue you might feel after a heavy workout. It alters the way the brain processes neurotransmitters like serotonin and dopamine, leading to severe cognitive impairment, commonly referred to as brain fog. It also disrupts the sleep architecture, preventing patients from entering the deep, restorative phases of sleep. Furthermore, this neuroinflammation disrupts the gut-brain axis, further impairing autonomic functions and emotional regulation. Breaking this cycle of neuroinflammation and HPA axis suppression is a critical step in managing the complex symptom clusters of Long COVID and ME/CFS, which is why targeted interventions are so heavily researched.

ADR Formula® addresses HPA axis dysfunction through multiple synergistic mechanisms, starting at the foundational level of cellular metabolism with pantothenic acid (Vitamin B5). Often referred to as the "anti-stress vitamin," B5 is biologically indispensable for adrenal function. When ingested, pantothenic acid is absorbed and converted into pantethine, which is then synthesized into Coenzyme A (CoA). CoA is a critical metabolic hub molecule required for the synthesis of cholesterol. In the adrenal cortex, specifically within the zona fasciculata, this cholesterol is transported into the mitochondria where it serves as the foundational precursor for steroidogenesis—the creation of steroid hormones.

Without adequate CoA, the enzymatic conversion of cholesterol into pregnenolone (the mother of all hormones) grinds to a halt. By supplying 100 mg of pantothenic acid, ADR Formula® ensures that the adrenal glands have the necessary metabolic resources to efficiently produce cortisol when stimulated by the brain. Animal studies have demonstrated that supplementing with pantothenic acid directly stimulates the adrenal cells' ability to secrete stress hormones, inducing a healthy "hyperresponsiveness" to ACTH signals. This means that when a patient with Long COVID encounters a stressor, their adrenal glands are better equipped biochemically to mount an appropriate, protective response rather than immediately crashing.

One of the most fascinating and powerful ingredients in ADR Formula® is licorice extract (Glycyrrhiza glabra), standardized to contain 20% glycyrrhizic acid. For patients suffering from the hypocortisolism and low blood pressure often seen in ME/CFS and dysautonomia, licorice acts as a targeted pharmacological intervention. The mechanism revolves around a "gatekeeper" enzyme in the kidneys called 11-beta-hydroxysteroid dehydrogenase type 2 (11β-HSD2). Normally, this enzyme rapidly converts active cortisol into inactive cortisone to prevent cortisol from overwhelming the mineralocorticoid receptors that control fluid balance.

When you consume licorice extract, gut bacteria hydrolyze the glycyrrhizic acid into active metabolites that are highly potent, competitive inhibitors of the 11β-HSD2 enzyme. By temporarily blocking this enzyme, licorice prevents the breakdown of cortisol. This effectively prolongs the half-life of whatever cortisol the patient's struggling adrenal glands are able to produce, allowing it to circulate longer and exert its much-needed anti-inflammatory and energy-regulating effects. Furthermore, because the active cortisol is allowed to bind to mineralocorticoid receptors, it promotes sodium and water retention. For a patient with POTS or orthostatic hypotension who struggles with low blood volume, this mild fluid retention can significantly improve vascular tone, increase blood pressure, and reduce dizziness upon standing.

To address the profound cellular energy deficits and neuroinflammation, ADR Formula® includes Panax ginseng (Asian ginseng) extract. The active compounds in ginseng, known as ginsenosides, are powerful adaptogens with multi-target mechanisms. At the cellular level, fatigue in Long COVID and ME/CFS is heavily linked to mitochondrial dysfunction and poor ATP production. Ginsenosides have been shown to directly promote ATPase activities and regulate the PI3K/AKT/mTOR signaling pathway. This complex biochemical pathway is a central regulator of cell metabolism, growth, and survival. By activating this pathway, ginseng helps accelerate physical recovery and optimizes how the cells utilize energy, directly combating peripheral fatigue. If you are interested in other ways to support cellular energy, you can read our guide on how CoQ10 supports mitochondrial function.

Beyond energy production, Panax ginseng plays a crucial role in modulating the central nervous system. Research indicates that ginsenosides can cross the blood-brain barrier and exert powerful anti-neuroinflammatory effects. They reduce the expression of pro-inflammatory cytokines like IL-6 and TNF-α within the brain tissue. By dampening this neuroinflammation, ginseng helps clear the "brain fog" that plagues so many patients. Additionally, it helps regulate glucocorticoid receptors in the hypothalamus, assisting the brain in re-establishing a healthy communication loop with the adrenal glands, thereby treating the root cause of the HPA axis dysfunction rather than just masking the symptoms.

The final major botanical component is Eleutherococcus senticosus (eleuthero), standardized to contain 0.8% eleutherosides. Eleuthero is a classic adaptogen that excels at improving physical endurance and resilience to stress. Its primary mechanism of action involves the upregulation of molecular chaperones, specifically Heat Shock Protein 70 (Hsp70). During periods of intense physical or immunological stress, cells can become damaged and trigger apoptosis (programmed cell death). Hsp70 acts as a cellular shield, protecting delicate proteins and enzymes from stress-induced degradation.

Furthermore, eleuthero plays a vital role in preserving mitochondrial ATP reserves. During chronic stress, the body typically increases the production of nitric oxide (NO), a signaling molecule that, in excess, can severely impair mitochondrial energy production. Studies have shown that eleutherosides inhibit the expression of NO synthase via the Hsp70 and JNK pathways, effectively preventing this damaging nitric oxide spike. By protecting the mitochondria and preventing the wasteful depletion of ATP, eleuthero helps patients maintain a steadier baseline of energy throughout the day, reducing the severity and frequency of post-exertional crashes.

Because ADR Formula® acts on multiple interconnected pathways—from mitochondrial ATP production to central neuroinflammation and renal enzyme inhibition—it has the potential to address a wide array of symptoms associated with complex chronic illnesses. Here are the primary symptoms this formulation may help manage:

When incorporating a complex supplement like ADR Formula® into your management plan, understanding the specific forms and standardization of the ingredients is crucial. Pure Encapsulations utilizes standardized herbal extracts, which is a vital marker of quality in botanical medicine. For example, the Panax ginseng is standardized to contain 5% total ginsenosides, and the eleuthero is standardized to 0.8% eleutherosides. Standardization ensures that every capsule contains a consistent, clinically relevant dose of the active phytochemicals responsible for the therapeutic effects, rather than just inert plant fiber. This consistency is essential when trying to modulate delicate systems like the HPA axis.

The formula also includes 150 mg of whole adrenal and 75 mg of adrenal cortex, both sourced from bovines. Glandular therapy is designed to provide tissue-specific nutrients. Because these are complex biological materials, their absorption relies on healthy digestive function. The proteins and peptides in the glandular extracts must be broken down by stomach acid and pancreatic enzymes before they can be absorbed in the small intestine. For patients with Long COVID or ME/CFS who also struggle with gastrointestinal issues or low stomach acid, taking the supplement with a digestive enzyme or a small amount of food might improve the assimilation of these glandular components.

The timing of adrenal support supplements can significantly impact their efficacy. The suggested use for ADR Formula® is one capsule daily, between meals. However, because the primary goal is to support the natural diurnal rhythm of cortisol—which should be highest in the morning and lowest at night—many practitioners recommend taking adrenal support formulas early in the day. Taking adaptogens and glandulars in the morning or early afternoon helps mimic and support the natural cortisol awakening response. Taking them too late in the evening could potentially overstimulate the nervous system and interfere with sleep architecture, which is already fragile in patients with chronic fatigue.

Because the formula contains water-soluble nutrients (like Vitamin B5) alongside complex botanical extracts, taking it "between meals" as suggested helps prevent the active compounds from competing with dietary proteins and fibers for absorption in the gut. However, if taking it on an empty stomach causes mild nausea—a common sensitivity for patients with dysautonomia or MCAS—taking it with a small, easily digestible snack is a perfectly acceptable modification. Consistency is key; adaptogens generally require several weeks of continuous use to build up in the system and exert their full homeostatic effects on the HPA axis.

Safety and medical supervision are paramount when using formulations containing licorice root. As discussed, the glycyrrhizic acid in licorice inhibits the 11β-HSD2 enzyme, which can lead to a condition known as Apparent Mineralocorticoid Excess (AME). While this fluid-retaining effect is often highly beneficial for patients with POTS and low blood pressure, it can be dangerous for individuals who already have essential hypertension (high blood pressure). Ingesting licorice can cause significant dose-dependent spikes in systolic blood pressure and lead to the excessive excretion of potassium (hypokalemia), which can trigger cardiac arrhythmias.

Therefore, ADR Formula® is strictly contraindicated for individuals with pre-existing high blood pressure, kidney disease, or cardiovascular disease, unless explicitly managed by a physician. It is also contraindicated for pregnant or lactating women. If you and your healthcare provider decide this formula is appropriate for your condition, it is highly recommended to monitor your blood pressure regularly at home, especially during the first few weeks of use. If you notice a sudden, sustained increase in blood pressure, increased swelling (edema) in your lower legs, or unexplained muscle weakness, you should discontinue the supplement and consult your doctor immediately.

The scientific community has increasingly focused on the use of adaptogens for managing the complex fatigue associated with post-viral syndromes. A highly relevant 2021 prospective, open-label clinical trial investigated the effects of a specialized Panax ginseng root extract on 188 patients suffering from severe ME/CFS and Fibromyalgia, including subgroups specifically dealing with post-viral fatigue. Patients were administered daily doses ranging from 100 to 400 mg over the course of one month. The results were striking: 60.1% of the subjects rated themselves as improved. Among the responding group, researchers recorded a 67% average increase in energy, a 72% increase in stamina, and a 48% improvement in mental clarity. The study authors explicitly noted the urgency of these findings for the growing population of COVID-19 patients developing post-viral fatigue syndromes.

These clinical outcomes are supported by robust preclinical data. A 2023 study published in Pharmaceutical Biology explored the exact cellular pathways of P. ginseng in animal models of chronic fatigue. Researchers found that the ginseng extract significantly decreased serum triglycerides and directly promoted ATPase activities. It effectively relieved chronic physical fatigue by activating the PI3K/AKT/mTOR signaling pathway, providing hard biochemical evidence that ginseng accelerates recovery from exhaustion at the cellular level, rather than just acting as a central nervous system stimulant.

The efficacy of Eleutherococcus senticosus (eleuthero) has also been evaluated in the context of physical stamina and cardiovascular endurance, which is particularly relevant for patients struggling with exertion intolerance. A randomized, double-blind, crossover study tested the effects of 800 mg/day of eleuthero over 8 weeks. The researchers found that supplementation significantly elevated cardiovascular function, resulting in a 12% increase in VO₂ peak and a 23% improvement in time to exhaustion compared to the placebo. While this study was conducted on healthy individuals, the demonstrated ability of eleuthero to improve oxygen utilization and delay fatigue highlights its potential utility for patients whose aerobic energy systems have been compromised by chronic illness.

While large-scale human trials on Vitamin B5 for "adrenal fatigue" are limited, its biochemical necessity is undisputed in the scientific literature. Extensive animal studies have demonstrated that pantothenic acid supplementation directly dictates the adrenal glands' capacity to respond to stress. In a series of studies, subjects given drinking water supplemented with pantothenic acid exhibited significantly higher baseline and stimulated levels of corticosteroids when their adrenal cells were exposed to ACTH. This confirms that B5 acts as a vital rate-limiting nutrient; without it, the adrenal cortex simply cannot synthesize the cholesterol required to produce the cortisol necessary for managing systemic inflammation and stress.

Living with the invisible, unpredictable, and often debilitating symptoms of Long COVID, ME/CFS, and dysautonomia is an incredibly heavy burden to carry. When your body's primary stress response system—the HPA axis—is depleted, every day can feel like an uphill battle against your own physiology. It is entirely valid to feel frustrated when standard blood tests come back "normal," yet you are too exhausted to stand up in the shower or hold a conversation. The neuroinflammation, the hypocortisolism, and the cellular energy deficits you are experiencing are real, measurable biological phenomena, not character flaws or signs of deconditioning. Acknowledging the physiological reality of your symptoms is the first and most important step toward finding effective management strategies.

While comprehensive formulations like ADR Formula® offer powerful, science-backed support for the adrenal glands and the HPA axis, it is crucial to remember that no single supplement is a cure-all for complex chronic illness. Adaptogens and glandulars are most effective when utilized as one piece of a much larger, holistic management puzzle. They provide the biochemical scaffolding your body needs, but they cannot out-supplement the damage caused by continuously pushing past your energy envelope. If you want to learn more about comprehensive diagnostics, you can read our guide on how doctors diagnose Long COVID.

True symptom management requires a multi-disciplinary approach. This includes strict adherence to pacing and energy conservation to prevent post-exertional malaise, optimizing your sleep hygiene, managing comorbid conditions like MCAS or POTS, and working with a knowledgeable healthcare team to monitor your progress. Symptom tracking is an invaluable tool in this process; by keeping a daily log of your activities, supplement intake, and symptom severity, you can begin to identify patterns and determine exactly which interventions are moving the needle for your unique biology.

If you are struggling with profound fatigue, orthostatic intolerance, and signs of HPA axis dysfunction, targeted adrenal support may be a valuable addition to your protocol. Always consult with your primary care physician or a specialist before introducing new supplements, especially those containing licorice root, to ensure they are safe for your specific cardiovascular and metabolic profile. By combining targeted nutritional support with compassionate, comprehensive medical care, you can begin to restore balance to your stress response systems and improve your overall quality of life.