Long COVID is defined as symptoms that persist for at least two months after an initial SARS-CoV-2 infection and for which there is no other clear medical explanation. An estimated 65 million people worldwide are currently affected, but there are still no approved, evidence-based treatments. Researchers are working to better understand the causes of this disease and to test a variety of potential therapies, including structured rehabilitation programs, antiviral drugs, blood thinners, anti-inflammatory drugs, nutritional supplements and new biological treatments.
How Does Long Covid Develop?
Scientists believe that Long COVID is caused by several overlapping biological issues. These include remaining viruses in the body, persistent mild inflammation characterized by elevated IL-1β, IL-6 and TNF-α levels, and the formation of tiny blood clots caused by interactions between the viral spike protein and fibrinogen. Other factors include autoimmunity, intestinal flora disorders and impaired mitochondrial function. Together, these processes can damage multiple organs and lead to vascular dysfunction, cardiac inflammation, neuroinflammation, small fiber neuropathy, ME/CFS-like fatigue, menstrual irregularities, problems with blood sugar regulation and kidney or liver damage.
Rehabilitation and Non-Drug Approaches
For people with mild symptoms in the early stages, non-drug treatments remain the first choice. Clinical studies show that online-based, group-oriented physical and mental rehabilitation programs can improve quality of life. Breathing exercises and inhalation muscle training have been shown to improve heart and lung function.
Other strategies may include adapting daily activities, cognitive and speech therapy, olfactory retraining and nutritional counseling. However, exercise that is not carefully monitored can exacerbate inflammation. For this reason, activity programs must be built up gradually and adapted to the symptoms.
Medication and Early Treatment
Antiviral drugs taken during the first COVID-19 infection appear to slightly reduce the risk of developing Long COVID. In Japan, Ensitrelvir reduced the Long COVID rate in outpatients by 25%. In high-risk patients, nirmatrelvir/ritonavir and molnupiravir were associated with a risk reduction of about 25%, while favipiravir showed little benefit. Researchers are also investigating monoclonal antibodies targeting the spike protein for potential effects on neurotoxicity, although the results of the phase 3 trial are not yet available.
Some treatments focus on specific complications such as clotting disorders, autonomic nervous system problems and immune imbalances. Low-dose naltrexone has been shown to reduce fatigue and lower platelet aggregation. Apheresis can be used to remove microclots and autoantibodies from the blood, but this method is expensive and its benefits are usually short-lived.
Other medications are being tested to relieve symptoms. β-blockers are used to treat postural tachycardia syndrome. Famotidine, intravenous immunoglobulin, SGLT-2 inhibitors and GLP-1 agonists are currently being investigated for neurological, immunological, cardiac and renal symptoms.
Fighting Inflammation at its Source
Early reduction of inflammation appears to be one of the most active areas of research. When started within seven days of infection, metformin reduced the risk of Long COVID by 41%, likely by reducing mTOR signaling. Herbal supplements containing quercetin, curcumin and piperine improved fatigue compared to placebo.
Other approaches include inhalation of sulfur-containing thermal water and enzyme-released salmon oil, both of which lowered CRP levels and helped restore the lung’s protective barrier. Baricitinib and rapamycin, which act on the JAK and mTOR signaling pathways, are currently being tested in multicenter trials aimed at interrupting the inflammation caused by STAT3.
Gut Health, Dietary Supplements and Energy Metabolism
Adjusting the gut microbiome can also be helpful. The gut microbiome refers to the entirety of all microorganisms that live in the human gut. This mainly includes bacteria, but also viruses, fungi and other microbes. These tiny creatures form a complex ecosystem that plays an important role in health. The synbiotic SIM01 alleviated the overall symptoms after six months. Small randomized trials suggest that high doses of vitamins C and D, coenzyme Q10, magnesium and creatine-glucose mixtures can improve cellular energy production and blood vessel function. Early studies also reported benefits of N-acetylcysteine and the amino acid blend AXA1125, both of which improved mitochondrial respiration and reduced fatigue.
Experimental Biologics and New Therapies
New biologic treatments are investigating the role of neuroinflammation caused by fibrin. A humanized antibody that blocks the inflammatory domain of fibrinogen is currently in Phase 1 trials after animal studies showed protection against neuronal loss. Another experimental therapy, the DNA aptamer BC007, removes G protein-coupled receptor autoantibodies and reversed fatigue and poor capillary blood circulation in a single patient, but larger studies are still needed.
Other non-drug approaches have shown potential. Hyperbaric oxygen therapy improved cognitive ability, sleep and pain in a six-month randomized trial. Case series on acupuncture reported a reduction in brain fog and joint pain.
Vaccinations provide limited protection against Long COVID after breakthrough infections and reduce the risk by about 15 to 41%. In people who already had Long COVID symptoms, results after a booster vaccination were mixed. Around 17% saw an improvement, 21% saw a worsening and 62% saw no change.
The Current State of Science
Although many potential treatments show promising initial results, most evidence still comes from small or open studies that rely on indirect outcome measures. There is an urgent need for large, adaptive randomized trials with consistent definitions and biomarker-based patient grouping. Until clearer answers are available, experts advocate a flexible, team-based approach that includes early use of antivirals, carefully graded exercise, targeted antithrombotic and anti-inflammatory treatments, gut microbiome support, and personalized rehabilitation. This strategy reflects the multifaceted, multisystemic nature of Long COVID as researchers continue to search for definitive, mechanism-based cures.