Cracking the Code on Long COVID: An Integrative Medicine Framework Built from the Roots Up

By Allison Proffitt 

For the millions of patients still struggling with fatigue, brain fog, racing hearts, and a constellation of other symptoms months or years after a COVID infection, Dr. George Schatz has a message: the conventional medicine playbook isn’t enough. Speaking at last week’s Integrative Healthcare Symposium, the physician from the Andrew Weil Center for Integrative Medicine laid out a systematic, layered framework for understanding and treating long COVID—one that starts not with prescription pads, but with tree roots. 

“When a tree starts to lose its leaves, we don’t pick up the leaves and paint them green and tape them back up on the tree with supplements and/or medications,” Schatz told the audience. “Sometimes we have to do that to alleviate suffering—and that’s okay in the short term—but we treat the roots of the tree.” 

Root Cause Over Symptom Management 

Schatz opened by challenging the standard clinical approach to long COVID, arguing that a symptom-to-diagnosis-to-treatment model fails these patients. A single individual can rack up dozens of diagnoses based on symptoms alone, he said, while the underlying drivers remain unaddressed. His alternative: a functional medicine approach that works backwards from symptoms through mechanisms to pathophysiology. 

The clinical framework he described operates as a pyramid. First, he advised, rule out any significant pathology with lab work. In his practice, he’s looking for organ dysfunction, unmasked underlying comorbidities, metabolic dysfunction, and autoimmune disease.  

Then build the foundation of basics: sleep, stress management, diet, and movement. “These things are necessary for good health, but not sufficient,” Schatz emphasized. “If you are not sleeping eight hours a night, if you’re not moving your body, if you’re not managing stress — it is going to be very hard to help you, and there’s really no way around that.” 

He noted that he has seen patients invest in expensive, sophisticated treatments that ultimately failed because the foundational work was never done. “They crumbled,” he said, “because they didn’t put the steps in first.” 

The Middle Layers: Identifying the Root Causes 

Once the foundations are solidly in place, Schatz turns to identifying what he described as the most prevalent underlying mechanisms in long COVID patients. Three phenotypes stood out in his clinical experience—all common phenotypes but hard to evaluate or treat: Dysautonomia or POTS, Tryptophan Metabolism Dysregulation, and Mast Cell Dysfunction.   

Postural Orthostatic Tachycardia Syndrome, or POTS. One of the most frequently encountered issues in his practice, Schatz said he rarely needs a formal tilt-table test to identify POTS. If a patient has post-COVID fatigue and reports a heart rate that spikes dramatically with activities like showering, “you’ve got this — let’s not waste time figuring out anything else except which sub-type of POTS it is.” 

He presented several patient cases where thiamine (vitamin B1) supplementation proved transformative. Drawing on work by researchers Derrick Lonsdale and Chandler Marrs, Schatz described patients with hypovolemic POTS — a subtype driven by thiamine deficiency affecting the brainstem structures that regulate heart rate. The mechanism, he explained, is that without adequate thiamine, the brain cannot properly metabolize glucose; the result is mitochondrial dysfunction, impaired autonomic reflexes, cerebral hypoperfusion, and ultimately the classic POTS symptom cluster. One patient experienced complete resolution of his tachycardia and associated symptoms within two weeks of starting thiamine supplementation. Another, with overlapping EDS and mast cell activation, saw significant objective improvement in heart rate and even a reversal of a heart failure diagnosis after thiamine doses were carefully titrated. 

“Not all thiamine is thiamine,” Schatz cautioned, noting that the most bioavailable form — allithiamine — outperforms standard preparations because of its superior absorption and ability to cross the blood-brain barrier. He uses thiamine both therapeutically and diagnostically: if a patient improves by 50%, that tells him roughly how much of their picture is driven by this mechanism. 

Mast Cell Activation. The second major phenotype Schatz addressed was mast cell activation disorder (MCAD), which he said must be ruled out in long COVID patients — particularly because mast cell reactivity can prevent patients from tolerating other treatments. He described a simple clinical heuristic for suspicion: symptoms spanning skin (hives, flushing), respiratory (allergic-type reactions), and GI (IBS-like symptoms) together point strongly toward mast cell involvement. He relies heavily on clinical diagnosis and response to treatment rather than the cumbersome lab workup traditionally required, and emphasized low-histamine dietary approaches alongside targeted medications. 

Tryptophan Metabolism Dysregulation. Perhaps the most biochemically detailed portion of the talk, Schatz described what he called the third most common phenotype: disruption of the kynurenine pathway. Most people know tryptophan as a precursor to serotonin and melatonin — but Schatz pointed out that only about 5–10% of tryptophan goes that route. The lion’s share, roughly 90%, flows toward NAD+ production via the kynurenine pathway. 

In long COVID, he explained, viral infection and the resulting immune activation upregulate the enzyme IDO (indoleamine 2,3-dioxygenase) in the periphery and TDO (tryptophan 2,3-dioxygenase) in the brain. This shunts tryptophan sharply toward the kynurenine pathway — and toward the production of quinolinic acid, a neurotoxin and NMDA receptor agonist. The result is brain fog, depression, neuronal damage, and depletion of both serotonin and melatonin. Simultaneously, the pathway becomes less efficient at producing NAD+, leading to cellular energy deficits and profound fatigue. 

Elevated kynurenic acid levels are actually more predictive of long COVID than a positive antigen test, Schatz said, citing emerging research. The clinical hallmark constellation — fatigue, brain fog, depression, and disrupted sleep — maps almost perfectly onto this biochemical picture. 

His therapeutic approach targets multiple points in the pathway simultaneously: suppressing IDO/TDO activity with certain supplements and medications, including low-dose naltrexone, pushing tryptophan toward the serotonin/melatonin branch, raising NAD+ levels with precursors, and antagonizing the NMDA receptor to counter quinolinic acid’s neurotoxic effects. He noted that ketamine, increasingly used in long COVID clinics, works substantially through this last mechanism. Resveratrol also featured in his protocol for several patients, with notable improvements in fatigue and depression. 

Putting It Together: Cases and Caution 

Throughout the talk, Schatz wove in patient cases that illustrated both the framework’s power and its complexity. A college student with two years of brain fog and depression saw meaningful improvement through tryptophan pathway-targeted supplementation. A 46-year-old woman with fibromyalgia and worsening anxiety, low energy, and sleep disturbance responded rapidly to a targeted supplement protocol addressing the same pathway. A patient with EDS, mast cell activation, POTS, and liver complications — who couldn’t tolerate most treatments — finally found a foothold when her GI mast cell reactivity was addressed first, allowing her to tolerate everything else. 

The Takeaway 

Schatz closed by returning to his pyramid metaphor: build from the bottom, one block at a time. The foundational work comes first, always. Then identify the root-cause mechanisms — dysautonomia, mast cell activation, tryptophan pathway disruption — that are maintaining the illness. Address those specifically and systematically, and “you give the body enough of what it needs to be able to heal, and then you move on from there.”