Long Covid – The Evidence For and Use of Low Dose Naltrexone
Oyungerel Byambasuren, MD, PhD
Institute for Evidence-Based Healthcare
Bond University
14 University Dr, Robina QLD 4226 Australia
Tel: 61 7 5595 4182
obyambas@bond.edu.au
“Effect of Low-Dose Naltrexone for Long COVID:
Systematic Review”, medRxiv 2025 (3/2026)
Kirk Hamilton: Can you please share with me your educational background and current position?
Oyuka Byambasuren: I am an Assistant Professor at the Institute for Evidence-Based Healthcare, Bond University, Australia. I am a medical doctor and general practitioner by background. My current work focuses on Long COVID (LC), clinical trial methodology, and improving the evidence base for primary care interventions. I recently led a systematic review examining the effectiveness of low-dose naltrexone for Long COVID.KH: What do you mean by Long Haul COVID?
OB: Long Haul COVID (also known as Long COVID or post-COVID-19 condition) refers to persistent or new symptoms that continue beyond 12 weeks after acute SARS-CoV-2 infection and cannot be explained by another diagnosis. It is a highly heterogeneous condition. The most disabling symptoms typically include fatigue, post-exertional malaise or symptom exacerbation, cognitive dysfunction (brain fog”), pain, sleep disturbance, and dyspnea.
KH: What systems or pathophysiology are hypothesized in LC?
OB: The pathophysiology remains uncertain. Multiple non-exclusive mechanisms are under investigation:
- Immune dysregulation and persistent inflammation
- Neuroinflammation and microglial activation
- Endothelial dysfunction
- Autonomic dysfunction
- Microvascular abnormalities and hypercoagulability
- Mitochondrial dysfunction and altered cellular energy metabolism
- TRPM3 ion channel impairment
- Possible viral persistence or antigen reservoirs
Clinically speaking, there is a big overlap between ME/CSF and LC and both conditions have been associated with impairment of TRPM3 ion channel shown by another Australian team. It’s highly likely that multiple mechanisms play at the same time and therefore these conditions would require combination treatments to be treated successfully.
KH: What is Low Dose Naltrexone (LDN)? Why does it act differently than normal doses of Naltrexone?
OB: Naltrexone at standard doses (50–100 mg/day) is approved for opioid and alcohol use disorders. Low Dose Naltrexone (LDN) refers to doses typically between 1–10 mg/day and at these lower doses, proposed mechanisms of action include:
- Transient opioid receptor antagonism with possible rebound endogenous opioid upregulation
- Modulation of microglial activation
- Antagonism of Toll-like receptor 4
- Potential restoration of TRPM3 ion channel function (based on mechanistic studies)
KH: What illnesses have LDN been used for? What are common doses used and timing?
OB: LDN has been studied in small trials or observational studies in fibromyalgia, multiple sclerosis, Crohn’s disease, and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In the Long COVID studies included in our review, doses ranged from 0.5 mg/day to 6 mg/day, with various titration schedules. There is no standardized regimen.
KH: What are common side effects of LDN if any? Same as full-dose naltrexone?
OB: In the four observational studies included in our review (n=155 total participants), no serious adverse events were reported. Reported side effects were mild and included vivid dreams, insomnia, gastrointestinal upset, mild mood changes, and skin irritation (in the study that combined LDN with NAD+ patches).
KH: Why did you want to do this study?
OB: LDN was increasingly being prescribed off label for Long COVID despite the absence of high-quality evidence. Given the scale of disability and patient desperation for treatment, it was important to systematically assess all available evidence regarding its effectiveness for Long COVID. The goal was to move the conversation from anecdote to evidence.
KH: Can you summarize your study and the basic results?
OB: We conducted a systematic review of published and registered studies up to May 2025.
Key findings:
- No randomized controlled trials were identified.
- Four pre–post observational studies (n=155 participants) met inclusion criteria.
- Doses ranged from 1–6 mg/day.
- Pooled analyses showed:
- Moderate improvement in fatigue (Hedges’ g −0.74)
- Moderate improvement in brain fog (−0.53)
- Moderate improvement in sleep (−0.60)
- Large improvement in pain (−0.93)
- Large improvement in daily functioning (−0.93)
However, all studies were uncontrolled, and all outcomes were self-reported. Therefore, regression to the mean, placebo effects, natural recovery, and other bias cannot be excluded. Certainty of evidence remains low. Three registered trials are ongoing and will be critical for determining true efficacy.
KH: Is the mechanism for brain fog and fatigue the same as for pain and sleep?
OB: Unfortunately, the current evidence does not allow us to distinguish these mechanisms yet.
KH: Do you have any comments on the SarsCov2 spike protein being a triggering agent in the etiology of Long Covid?
OB: The spike protein is one of several hypotheses under investigation, but there is currently no definitive evidence establishing it as the cause of Long COVID. A monoclonal antibody trial targeting the spike protein is underway at Nova Southeastern University in Florida. That study, together with ongoing basic science research, may contribute useful data, although it is unlikely to resolve the broader question of causation on its own (See Spike Protein Guide by The Wellness Company below).
KH: I realize RCT are needed to make a definitive statement about LDN’s efficacy but people currently living with Long Covid don’t have years to wait. If you or a family member had severe Long Covid disrupting your quality of life significantly, would you consider a therapeutic trial as being reasonable and safe? If so, for how long? 1 month, 2 months, etc. before saying this therapy was having no benefit?
OB: I completely understand why people don’t want to wait years for definitive trials. Living with severe Long COVID can be devastating. If it were me or a close family member, I would consider a therapeutic trial of LDN. I would probably give it around 2–3 months to see if there was any meaningful improvement, and if not, I would stop. It’s important to be hopeful, but also realistic about the uncertainty.
KH: Any final comments?
OB: LDN is a biologically plausible, inexpensive, and accessible candidate for repurposing. The preliminary signal is encouraging. However, the history of medicine is full of promising uncontrolled findings that did not survive randomized testing. So, the most important next step is rigorous, adequately powered randomized trials. Until then, LDN should be framed as investigational therapy.
Kirk Hamilton PA’s Clinical Pearls: Dr. Oyuka Byambasuren and colleagues’ paper and this interview came at a perfect time. I was discussing with a compounding pharmacist just yesterday what compounded agent she liked the most. Hands down she stated Low Dose Naltrexone (LDN)! She says it is excellent for many pain patients, those with autoimmune illness like Hashimoto’s Thyroiditis and she sees it used for Long Covid quite frequently and successfully. She reemphasized LDNs distinct, sometimes dramatic benefit in chronic pain patients like fibromyalgia and just the improvement in quality of life in those who take LDN.
I have been practicing integrative medicine for 43 years. In this type of medicine there maybe 5-10 agents that show some benefit in a condition and have some reasonable biological rationale. Sometimes I lose track of a therapy that I may have used in the past because I started using other treatment (s). It is easy in this medicine to think of 10-20 things you can give someone for a condition that make biological sense (aside from lifestyle change which is the most important) but really 5 or less things to take for a problem is ideal.
So LDN is going to be “bumped” up on my list to try again in LC patients which I have used in the past.
Quick Treatment Thoughts on Long Covid…
1) Low glycemic diet (no processed carbs, added sugars or alcohol), Prolon – Fasting Mimicking Diet once per month for 6 months.
2) Minimize caffeine intake initially.
3) Vitamins C, D, B1, B12, methyl folate, Zinc, magnesium, free form amino acids, CoQ10, probiotic/bifidobacter, colostrum product, N-acetylcystiene 500-600 mg twice daily, Ultimate Spike Detox 4/d or an empty stomach (or at least 400 mg / 8000 FU nattokinase, bromelain 1000 mg, Curcumin 1000-2000 mg and N-Acetylcysteine 500-600 mg/d) Read/Watch “SPIKE PROTEIN EFFECT” – Guide to Understanding the Spike Protein Effect. Dr McCullough reviews public educational brochure with Dr Michael Gaeta. Peter A. McCullough, MD, MPH, Focal Points, Feb 27, 2026. ”Spike Protein Guide” by The Wellness Company .
4) Adrenal Glandular Support or low dose cortisone acetate (Safe Uses of Cortisol by William McK. Jefferies, MD) especially between 12-2 p.m.
5) LDN 1.5-4.5 mg at bedtime 2-3 month.
6) Ivermectin ½ mg/kg 1 month trial.
7) IV vitamin C (vits/mins), NAD SQ injections and/or B1B12folic acid home injections.
8) Exercise daily 30-60 minutes of gentle aerobics and then strength training 20 minutes 3 x week (circuit training) ***Note if your are tired after exercising but recover by the next day keep at the same intensity or gently increase it. If you feel “wiped out” the next day you have to cut back on the duration and intensity of the exercise. But always keep trying. Any movement is better than no movement. People who move get well faster. Try to get to an intensity where you sweat.
9) Meditation daily (www.drjoedispenza.com Dr. Hemal Patel Interviews 1. 2. / Falun Dafa Practice )
10) Far-infared saunas. ( I have one. Reasonable price and mobile. Definitely makes you sweat).
There are more possible treatments for Covid Long Haul but this is a good start…The key is you keep “tightening spokes” on the persons “wheel of health”. If you keep tightening and adjusting with the therapies you are skilled at good things many times eventually happen.
Be Well Kirk
Kirk Hamilton PA-C
Health Associates Medical Group
3301 Alta Arden, Suite 3
Sacramento, CA 95825
(916) 489-4400 (w)
krhammer@surewest.net
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