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Evidence-Based Supplements for Long COVID

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), refers to a range of symptoms that continue for weeks or months after the acute phase of the infection has passed. The prevalence of Long COVID can vary widely based on different studies and populations.

Common symptoms of Long COVID include fatigue, shortness of breath, cognitive disturbances (often referred to as “brain fog”), joint pain, chest pain, poor exercise recovery, loss of taste and smell, insomnia, mood disorders and others. The symptom profile can vary greatly among individuals.

Most of the studies on treatment for Long COVID use a single drug, but there are some excellent studies and natural compounds for Long COVID.

The full research review includes meta-analysis of:

  • Alpha Lipoic Acid
  • CoQ10
  • Ginkgo biloba
  • Luteolin
  • PEA

The full review written by Dr. Hedberg is below, and if you’d like to explore this subject in more detail, join us on March 16th at Grand Rounds.

Palmitoylethanolamide, Luteolin and Long COVID

Palmitoylethanolamide (PEA) is a naturally occurring endocannabinoid-like lipid mediator naturally found in many plants. PEA is analgesic, immunomodulatory, neuroprotective, antipyretic, antiepileptic, anti-inflammatory, anticonvulsant, antibacterial and antiviral. PEA also increases endocannabinoids and it downregulates mast cell activation.

PEA can improve immune system function without increasing inflammation. PEA also regulates fatty acid metabolism, reduces oxidation of fats, and inhibits excessive nitric oxide.

PEA may contribute to enhanced muscle recovery and improved cognition, mood and sleep. PEA may be indicated for anti-aging, immunoenhancement, brain health, allergies, and joint health.

These properties make PEA a perfect compound for managing the difficult symptoms of Long COVID.

Studies on PEA and Long COVID

A recent study entitled, “The Use of Palmitoylethanolamide in the Treatment of Long COVID: A Real-Life Retrospective Cohort Study” looked at the potential benefits of PEA for Long COVID symptoms. Some of the most common Long COVID symptoms include fatigue, brain fog, headache, exercise intolerance, trouble breathing, memory lapse, anosmia, dysgeusia, depression, anxiety, psychosis, nervous asthenia, PTSD, insomnia, delirium and anhedonia.

33 (10 male and 23 female) patients were given 600 mg PEA twice a day for 3 months. All patients were administered the post-COVID-19 Functional Status (PCFS) scale, to assess meaningful function, before (T0) and at the end of the treatment (T1). None of the patients had any side effects from the PEA.

All of the patients experienced improvement in their Long COVID symptoms as measured by the Post-COVID-19 Functional Status scale.

PEA, Luteolin, and Long COVID Studies

The combination of PEA and Luteolin has been studied extensively with multiple published papers showing the synergistic benefits of these two compounds. PEA and luteolin have been shown to reduce neuroinflammation by modulating microglia and reducing reactive oxygen species (ROS).

Luteolin is a flavonoid, specifically a flavone, found naturally in fruits, vegetables, and herbs such as celery, parsley, lettuce, spinach, peppers, broccoli, cabbage, carrots, onions (leaves), and apples (skins). Luteolin is similar in structure to quercetin, but luteolin is more potent and is sometimes referred to as a “supercharged” quercetin.

Luteolin has the following properties:

Anti-neurodegenerative (neuroprotective)
Mast cell stabilizer

Another study entitled, “What Is the Role of Palmitoylethanolamide Co-Ultramicronized with Luteolin on the Symptomatology Reported by Patients Suffering from Long COVID? A Retrospective Analysis Performed by a Group of General Practitioners in a Real-Life Setting” looked at the medical charts of 49 patients with Long COVID who were treated by one of nine doctors in Rome, Italy.

The patients were treated with 700 mg of PEA and 70 mg of luteolin twice a day for 90 days.

No side-effects were reported during treatment, nor any drug interactions with their medications.

The authors conclude, “Supplementation with PEALUT (PEA and Luteolin) helped to improve all patient-reported symptoms, especially pain, anxiety and depression, fatigue, brain fog, anosmia and dysgeusia, leading to an overall improvement in patients’ health status.”

PEA and luteolin have been found to be effective for post-COVID loss of smell (anosmia) and memory loss.

The first study entitled, “Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo- Controlled Clinical Trial” was done for 90 days on subjects who took 700 mg of PEA and 70 mg of luteolin once a day combined with olfactory training.

The results of this study found that those supplementing with PEA and luteolin had significant improvements and even resolution of their loss of smell compared to the placebo group who only did olfactory training.

The second study entitled, “Parosmia COVID-19 Related Treated by a Combination of Olfactory Training and Ultramicronized PEA-LUT: A Prospective Randomized Controlled Trial” was virtually identical to the first study. Subjects took 700 mg of PEA and 70 mg of luteolin along with olfactory training for 90 days and they achieved significant results compared to the control group.

The third study entitled, “Treatment of COVID-19 olfactory dysfunction with olfactory training, palmitoylethanolamide with luteolin, or combined therapy: a blinded controlled multicenter randomized trial” set out to see if doubling the dose of PEA and luteolin to 700 mg of PEA and 70 mg of luteolin taken twice a day was superior to just once a day dosing.

The results were surprising because there was no difference between the single dose or doubling the dose. This is good news for patients because this results in a significant cost-savings.

The fourth study entitled, “Effect of Ultra-Micronized Palmitoylethanolamide and Luteolin on Olfaction and Memory in Patients with Long COVID: Results of a Longitudinal Study” used the same dose as the above studies of 700 mg of PEA and 70 mg of luteolin combined with olfactory training and found significant improvements in olfaction and improved memory/brain fog.

The one common thread among all the above studies was the importance of olfactory training along with the PEA and luteolin supplement.

PEA is not well absorbed so it must be delivered in a specific form called Levagen+. Levagen+ PEA uses LipiSperse technology to enhance the absorption of PEA.

Most of the studies on Levagen+ PEA used 300 mg twice a day with excellent results. For more complex cases, 600 mg twice a day of Levagen+ PEA may provide better results.

The therapeutic dose of luteolin is 100-200 mg a day since it is a potent flavonoid.

I use a product that combines 300 mg of Levagen+ PEA combined with 50 mg of luteolin per capsule.

Long COVID and Ginkgo biloba

5 case reports were reported in an excellent paper on ginkgo biloba and Long COVID symptoms.

Patients with Long COVID were given 80 mg of ginkgo biloba extract (EGb 761) twice a day.

Patient 1 took ginkgo biloba for 11 weeks, and he had a substantial improvement in cognitive concerns, decreased perception of fatigue and an improvement in olfaction. He completely regained his sense of smell.

Patient 2 took ginkgo biloba for 13 weeks and reported improvement in concentration and fatigue.

Patient 3 took ginkgo biloba for 4 months and reported significant improvement in cognitive deficits.

Patient 4 took ginkgo biloba for 7 weeks and reported improved concentration and fatigue.

Patient 5 took ginkgo biloba for 6 weeks and reported improvement in depression, fatigue, irritability, and hyposmia.

Two of these patients reported complete remission of their cognitive symptoms.

None of the patients had any adverse effects.

SARS-CoV-2, the virus that causes COVID-19, has been shown to damage the microcirculation blood vessels resulting in decreased blood flow to vital tissues such as the heart, kidney, muscle tissue, ear, eyes, liver, brain and nervous system.

Ginkgo biloba has been shown to protect and repair large and small blood vessels, as well as a host of other body tissues. Ginkgo biloba has antioxidant properties, improves circulation, repairs and protects the brain, nervous system, eye, ear, kidney, intestine, heart, and cardiovascular system.

This makes ginkgo biloba a perfect herbal medicine for Long COVID, and the results of these case reports are not surprising.

Ginkgo biloba is usually dosed 120-240 mg a day in one or two doses with or without food. It can disrupt sleep, so some people may need to take it in the morning and no later than the early afternoon.

The dose used in this study was 80 mg twice a day totaling 160 mg a day. But the author’s point out that a higher dose may have yielded even better results.

I normally use 120 mg twice a day with my patients. Ginkgo biloba side effects such as headache only occur in 2% of people who take it.

It can take up to six weeks to notice the full effects of ginkgo biloba so give it some time to work.

Ginkgo biloba should be standardized to 24% flavonol glycosides and 6% terpenes for maximum effectiveness. I prefer to use ginkgo biloba combined with grape seed extract and mango fruit powder for enhanced microcirculation support.

CoQ10, Alpha Lipoic Acid and Long COVID

A study entitled, “Coenzyme Q10 + alpha lipoic acid for chronic COVID syndrome” has been published in the journal Clinical and Experimental Medicine which found that supplementation with Coenzyme Q10 (CoQ10) and alpha lipoic acid (ALA) may be helpful in Long COVID.

COVID-19 can deplete CoQ10 levels and damage the mitochondria which are important for energy production and immune system function. CoQ10 and alpha lipoic acid can both be helpful in protecting and supporting mitochondrial function by reducing oxidative stress.

CoQ10 deficiency can lead to decreased energy production resulting in fatigue and increased free radical production. Fatigue is by far the most common symptom reported in Long COVID so CoQ10 is at the top of the list of supplements to try with this condition.

Alpha lipoic acid is a powerful antioxidant and it is involved in mitochondrial energy production. ALA also has immunomodulatory properties and may actually be an anti-viral as well.

The properties of both nutrients in theory make them a promising combination in the treatment of Long COVID.

174 patients (51% male and 49% female) aged 18-81 (mean of 51) who had COVID-19 previously and met the 2015 National Academy of Medicine diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

52% had comorbidities including chronic lung disease (16%, 28/174), diabetes mellitus (13%,23/174), psychiatric diseases (7.5%, 13/174), and rheumatic diseases (9.8%, 17/174).

17.8% (31) of patients had been previously hospitalized for severe respiratory SARS-CoV-2 pneumonia.

82.2% had mild/moderate symptoms during the acute phase.

The mean duration of Long COVID symptoms was 5.9 months.

The most common symptoms were fatigue (80%), impaired concentration (68%), sleep disorders (85%) disturbed smell and/or taste (60%), memory loss (45%), dyspnea (21%) and arthromyalgias (64%).

Patients were divided into two groups. The first one (116 patients) received coenzyme Q10 (ubiquinone form) and alpha lipoic acid taken every day for two months at a dose of 100 mg of CoQ10 and 100 mg of alpha lipoic acid twice a day. The control group of 58 patients did not take either supplement.

The characteristics of the patients in the two groups were similar at baseline.

Patients in both groups also received a variety of medications including paracetamol, codeine, NSAIDS, antidepressants (duloxetine), anticonvulsants and analgesics (pregabalin and gabapentin). They also undertook psychological and psychiatric counseling, physio-kinesiotherapy, yoga, and pilates.

“The primary end-point was to evaluate the effectiveness of the association of coenzyme Q10 and alpha lipoic acid in reducing fatigue, expressed as a reduction in Fatigue Severity Scale (FSS), at the second month (T1), of at least 50% (complete response) from the baseline (T0) or at least 20% (partial response) from the baseline (T0). A reduction in FSS < 20% from baseline at T1 was considered as a non-response.

A complete FSS response was reached most frequently in the treatment group compared to the control group. A FSS complete response was reached in 62 (53.5%) patients in treatment group and in two (3.5%) patients in control group. A reduction in FSS score < 20% from baseline at T1 (non-response) was observed in 11 patients in the treatment group (9.5%) and in 15 patients in the control group (25.9%) (p < 0.0001).”

Author’s Conclusion

“Despite the short follow-up period, we demonstrated a clinical benefit, suggesting the rapid effect of this therapy. On the other hand, because of the short follow-up duration, we do not know if this clinical benefit persists over time. Our results, all based on subjective indices, were definitely in favor of the treatment group.”

The form of CoQ10 used in this study was ubiquinone instead of the more active ubiquinol. 100 mg of CoQ10 (ubiquinol) twice a day is the dose I use in practice.

The dose of alpha lipoic acid was only 100 mg twice a day but I use 300 mg twice a day with meals.

The mitochondria are vital for energy production and immune system function so they need support in patients with Long COVID and ME/CFS. These two compounds have a long history of use in ME/CFS and in patients who have fatigue.

This study provides supporting evidence that CoQ10 and ALA may be helpful to your patients with Long COVID who suffer from ongoing fatigue.

All the above supplements are readily available to patients with Long COVID with minimal to no side effects. I have been using these successfully with my Long COVID patients to improve their symptoms and help heal from this complex illness.

NCIMS Member Blogger: Dr. Nikolas Hedberg, DC, DABCI, DACBN is the founder of the Hedberg Institute, an online functional medicine education platform for practitioners of all types. He is also the Chief Medical Officer of Moss Nutrition Products. His work can be found at https://hedberginstitute.com.

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  1. Want to learn more and get the latest update? Attend the March 16th Grand Rounds, where Dr. Hedberg will speak in detail on this subject!

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