If you've been told your labs are "normal" while you're still exhausted, foggy, and crashing after ordinary activity, you're not imagining it — and you're far from alone. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are two of the most disabling, least understood conditions in medicine today. There is currently no FDA-approved treatment for either one. That's an unusual thing to say plainly on a clinic website, but it's the honest starting point for talking about these conditions well.

In 2025, one of the largest real-world studies of its kind was published, surveying 3,925 patients with ME/CFS and Long COVID about their experiences with more than 150 different treatments. This article walks through what that research actually found, in plain language, and where a root-cause, personalized approach like ours realistically fits — and where it doesn't.

Why ME/CFS and Long COVID are treated together

The study's most striking finding is how similar these two conditions look side by side. Among participants, 89.7% of ME/CFS patients and 79.4% of Long COVID patients reported post-exertional malaise (PEM) — a hallmark worsening of symptoms after physical, cognitive, or emotional exertion. Beyond that shared core symptom, the two groups reported strikingly similar rates of related conditions: anxiety or depression, postural orthostatic tachycardia syndrome (POTS), migraine, joint hypermobility, and mast cell activation syndrome (MCAS) all showed up at comparable rates in both groups.

Even more telling: when researchers compared how well each treatment worked across the two conditions, the responses were strongly correlated (statistically, R² = 0.68) — meaning a treatment that helped ME/CFS patients tended to help Long COVID patients too, and vice versa. This is a meaningful clue that the two conditions may share overlapping underlying biology, even though one starts with a known viral trigger and the other often doesn't.

A quick glossary

PEM

Post-exertional malaise — a delayed, often severe worsening of symptoms after activity that would have been easy before getting sick.

POTS

Postural orthostatic tachycardia syndrome — the heart rate spikes abnormally on standing, causing dizziness, fatigue, or fainting.

MCAS

Mast cell activation syndrome — immune cells release excess inflammatory chemicals, causing flushing, hives, digestive symptoms, and more.

Dysautonomia

A broader term for dysfunction of the autonomic nervous system, which controls heart rate, blood pressure, digestion, and temperature.

What patients said actually helped

The researchers calculated a "Net Assessment Score" (NAS) for each treatment — essentially, the percentage of patients who felt meaningfully better after trying it. It's important to be precise about what this measures: this is patient-perceived benefit from a survey, not proof of efficacy from a controlled clinical trial. With that caveat firmly in mind, a few themes stood out clearly.

ApproachReported benefit (NAS)Mainly helps with
Pacing (energy management)75.2%Fatigue, PEM prevention
Fluids & electrolytes68.6%POTS, orthostatic intolerance
Compression stockings62%POTS, circulation
IV/subcutaneous immunoglobulin (IgG)58.2%Immune dysfunction (prescription, medically supervised)
Manual lymphatic drainage55.7%Fatigue, swelling
Antihistamines51.6%MCAS-related symptoms
Low-dose naltrexone (LDN)49.4%Pain (prescription only)
Beta blockers / ivabradine47.1%POTS-related tachycardia (prescription only)
Melatonin43.3%Unrefreshing sleep

Source: Eckey, Li, Morrison, Davis & Xiao, PNAS, 2025 — see references below. Percentages reflect patient-reported perceived benefit, not clinical trial efficacy.

Notice what these fall into: energy pacing, circulation and orthostatic support, immune and mast-cell modulation, and sleep support. Several of the most-cited options — like IgG, LDN, and beta blockers — require a prescribing physician and ongoing monitoring. They are not supplements to self-start, and we won't suggest otherwise.

The finding that matters most: one profile doesn't fit all

This is where the study says something functional medicine has argued for years, now backed by real patient data. The researchers didn't just look at ME/CFS and Long COVID as single conditions — they clustered patients by their actual symptom and comorbidity patterns, and found four distinct subgroups:

  • Cluster 1 — Multisystemic: the highest overall symptom and comorbidity burden. This group responded best to IgG, manual lymphatic drainage, fluids/electrolytes, and pacing.
  • Cluster 2 — POTS-dominant: marked by the highest rates of POTS. Pacing, fluids/electrolytes, and compression stockings were most helpful here.
  • Cluster 3 — Cognitive & sleep dysfunction with pain: low POTS rates, but prominent brain fog, sleep disruption, and pain. This group responded notably to pacing and, under physician supervision, ADHD-type stimulant medication for cognitive symptoms — a response not seen in the multisystemic group.
  • Cluster 4 — Milder symptomatology: the lowest symptom burden overall, still helped most by pacing and fluids/electrolytes.

The practical takeaway: the same label ("ME/CFS" or "Long COVID") can describe genuinely different underlying pictures, and what helps one person can do nothing — or even backfire — for another. That's not a philosophical stance; it's what the data itself shows.

The label tells you what condition someone has. It doesn't tell you which of four very different pictures they're living with.

An important safety note: not everything that's popular is safe to try

The same study also found that several commonly prescribed treatments — including some SSRIs/SNRIs, certain antidepressants, gabapentin-type medications, and cognitive behavioral therapy — were reported as unhelpful or worsening by more than 20% of respondents, even though other patients found them beneficial. This cuts both ways: it's a reminder not to assume something failed because it's a "bad" treatment, and equally not to assume something is safe or effective simply because it's widely recommended.

One point deserves particular emphasis: older advice to simply "push through" fatigue with structured graded exercise has fallen out of favor for good reason. Because PEM means exertion can trigger a delayed crash, activity plans for ME/CFS and Long COVID need to be built around pacing and energy conservation first — not around gradually increasing exercise regardless of symptoms. This is a core reason physiotherapy input for these conditions looks different from a typical injury rehab plan.

Where root-cause virtual care realistically fits in

We want to be direct about this, because the field itself is still young — there is no established cure, and treatment here is genuinely a process of careful, individualized trial and adjustment, not a fixed protocol.

What we can help with

  • Detailed history and symptom-cluster mapping — understanding whether your pattern leans multisystemic, POTS-dominant, cognitive/pain-dominant, or milder, since that shapes what's worth trying first.
  • Pacing-based physiotherapy guidance — activity and energy management built around avoiding PEM, not conventional graded exercise.
  • Nutrient and inflammatory lab review — checking for contributing factors like B12 status, iron, thyroid function, and inflammatory markers that can compound fatigue.
  • Gut-immune and mast-cell-informed evaluation — given how often MCAS and digestive symptoms overlap with these conditions.
  • Coordinated care — working alongside, not instead of, any physician managing prescription treatment, since several of the more impactful options in this research require medical prescribing and monitoring.

What's outside what virtual functional medicine or physiotherapy can do alone

  • Prescribing or monitoring immunoglobulin therapy, anticoagulants, LDN, beta blockers, or other prescription medications named in this research.
  • Diagnosing or ruling out POTS and other forms of dysautonomia, which typically require in-person autonomic testing.
  • Serving as a substitute for a physician managing a complex, medically supervised treatment plan.
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This is not a treatment protocol

This article summarizes patient-reported research for educational purposes. It is not a recommendation to start, stop, or adjust any medication or supplement, several of which carry real risks and require physician supervision. If you have ME/CFS, Long COVID, or unexplained post-exertional fatigue, this is worth discussing with a qualified practitioner who can evaluate your specific case.

The honest bottom line

ME/CFS and Long COVID are conditions where the science is still catching up to the scale of patient suffering. There's no approved cure, and anyone who tells you otherwise should be treated with real skepticism. What research like this offers is something more modest but genuinely useful: real-world signal about what tends to help which kind of patient, and confirmation that a personalized, symptom-cluster-based approach — rather than a single generic protocol — lines up with what the evidence actually shows. That's the approach we bring to these cases, alongside honesty about where our role ends and a physician's needs to begin.

Written by the Akasha Clinical Team

Functional Medicine & Physiotherapy — educational content, reviewed for accuracy.

This article is written and presented within the scope of Functional Medicine practice, consultation, and patient education.

References