Therapeutic Interventions in Long COVID: A Guide for Patients to current research

Author: Based on original work by Dr Graham Exelby, with contributions from Dr Valerio Vittone (PhD) Date: September 05, 2025

Purpose: This guide simplifies the therapeutic ideas for Long COVID for patients who are actively researching and managing their condition. It explains the 3-phase model, symptoms, and potential treatments in clear language, helping you discuss options with your doctor. Remember, these are research-level proposals—always consult your healthcare team before trying anything.

What Is Long COVID and Why This Guide?

Long COVID isn't just leftover symptoms from COVID-19—it's an ongoing condition where inflammation, low oxygen (hypoxia), and body changes keep problems going. It affects millions, causing fatigue, post-exertional malaise (PEM—crashing after activity), brain fog, heart rate issues (dysautonomia), stiff muscles/tissues, and head pressure. It overlaps with conditions like POTS, ME/CFS, and fibromyalgia.

This paper proposes a 3-phase model to explain it:

1. Acute Phase: Intense immune reaction (cytokine storm), leaky vessels, histamine release.

2. Transition Phase: Lingering inflammation, energy (mitochondrial) problems, early brain waste buildup.

3. Chronic Phase: Low oxygen drives inefficient energy use, scarring (fibrosis), ongoing loops.

These phases involve overlapping "hubs" (like STAT3, CCL2, RAGE, NLRP3) creating vicious cycles. Single treatments often fail because of backups; need combined approaches.

For you: Understanding phases helps track your symptoms and talk to doctors about targeted options. Genetics (e.g., mutations making inflammation worse) may explain why it varies. Untreated, risks include brain changes or higher cancer odds—early action matters.

Early Phase: The Inflammation Storm

What's Happening: Virus activates immune sensors (TLRs), releasing chemicals (cytokines like IL-6) and histamine from mast cells, causing leaks and brain swelling. Early symptoms: Fatigue, fog.

Treatment Ideas:

• Antivirals (e.g., Paxlovid) if caught early.

• Add-ons:

  • Metformin: Lowers Long COVID risk by ~40% if started soon; fights virus and inflammation.

  • H1 antihistamines (e.g., cetirizine): Calms mast cells, may block virus.

  • Famotidine (H2 antihistamine): Reduces signals.

  • Low-dose naltrexone (LDN): Blocks inflammation, eases glial (brain support cell) overactivity.

Patient Tip: Best for mild cases in first weeks. If post-COVID, mention to your doctor at 4-week check. Combine with rest, hydration—don't push.  Combined H1 and H2 are best when Magnesium supplementation is added.  Doses are higher than normally used.

Transition Phase: Ongoing Stress and Energy Drain

What's Happening: Inflammation lingers (IL-6, CCL2), tiring mitochondria (cell powerhouses), starting brain drainage issues. Shift to tougher stage with hypoxia hints.

Treatment Ideas (Target Hubs like STAT3/CCL2/RAGE):

• Nicotinamide riboside (NR): Boosts energy molecule (NAD+), improves mitochondrial functioning.

• Magnesium: Helps energy, calms overexcited nerves.

• Alpha-lipoic acid (ALA): Antioxidant, restores energy.

• Fenofibrate: Manages lipids/inflammation; not for early phase. (may be replaced by Omega 3)

• Dapagliflozin: Reduces fluid buildup, improves drainage/energy; good if you have metabolic issues but not routine use.

Patient Tip: For 1-3 months post-infection with stuck fatigue. Track blood sugar/lipids—discuss if diabetes overlaps. Supplements like NR may be over-the-counter, but check interactions.

Chronic Phase: Hypoxia and Scarring Take Over

What's Happening: Low oxygen stabilizes HIF-1α, boosting RAGE/TLR4, shifting to wasteful energy (glycolysis), lactate pileup, fibrosis. NLRP3 inflammasome key (releases more inflammation); others like AIM2/NLRC4 may play in. Loops cause PEM, scarring, risks.

Amplifiers: Damage signals, stress, mould.

Treatment Ideas:

• Tirzepatide: Resets metabolism, cuts inflammation/scarring; may help fatigue/fog.

• Telmisartan: Boosts brain blood flow, anti-inflammatory; crosses brain barrier.

Add-ons:

• Fenofibrate: Fights scarring, helps clots; pair with nattokinase or nigella sativa if clots suspected.

• High-purity omega-3s (EPA/DHA with polyphenols/vitamin D): Balances fats, reduces inflammation; safer ongoing option, replacing Fenofibrate

• Manual lymphatic therapy (MLT): Improves brain/body drainage, clears waste.

• Hyperbaric oxygen therapy (HBOT): Adds oxygen, calms HIF-1α; eases fatigue/fog.

• Plasmapheresis: Filters out bad chemicals; early promise.

• Keep H1/H2, LDN going.

Patient Tip: For symptoms >3 months. Ask for brain scans (SPECT) to check flow. Peptides (e.g., BPC-157) for repair—experimental, and very dependent on mode of use (oral ineffective), need doctor oversight and may not be available except in research testing.

Key Treatment Anchors and Personalization

Mainstays: Tirzepatide (metabolism), telmisartan (flow), peptides (repair). Add-ons based on phase. Genetics (e.g., ApoE4 for brain risk) may tailor—ask about testing.

Table: Phase Guide for Patients

Phase	Common Symptoms	Main Ideas	Potential Add-Ons to Try
Acute	Early fatigue, fog	Antivirals, metformin, antihistamines	LDN
Transition	Lingering tiredness, energy dips	NR, magnesium, ALA	Fenofibrate, dapagliflozin
Chronic	PEM, stiffness, pressure	Tirzepatide, telmisartan	HBOT, MLT, omega-3s, plasmapheresis (experimental)

What This Means for You

These ideas aim to break cycles, not just mask symptoms. Research-stage, so evidence varies—trials needed.

Your Role: Track symptoms (journal phases), share this with doctors. Lifestyle helps: Pace activities, eat anti-inflammatory, stay hydrated. Join patient groups for support.

Discuss off-label uses carefully—get informed consent. Monitor progress; if no improvement, reassess phase.

This empowers you—Long COVID is biological and potentially fixable. Work with your team.