A review conducted by Wilson and colleagues, published in Nature Reviews Disease Primers, defines long COVID as a condition[1] in which symptoms persist for at least three months following acute SARS-CoV-2 infection. It is estimated that between 5% and 20% of people infected in the community experience these complications, and among hospitalized patients this proportion rises to 50%. The most common neurological symptoms include memory deficits, executive dysfunction, anxiety, depression, recurrent headaches, sleep disturbances, and problems with taste and smell.
Scope and Neurological Symptoms of Long COVID
The review also highlights other symptoms such as neuropathies, dizziness, irregular heartbeat, and severe post-exertional malaise. The global burden of these symptoms is enormous[4]—it is estimated that between 80 and 400 million people worldwide struggle with the neurological consequences of long COVID. This wide range of health problems affects patients’ daily functioning and poses challenges for healthcare systems.
Pathophysiological Mechanisms and Research
The authors of the review identify several pathophysiological mechanisms responsible for the persistent symptoms. These include SARS-CoV-2 viral persistence, herpesvirus reactivation, gut microbiota dysbiosis, autoimmunity, coagulation disorders, endothelial abnormalities, and chronic immune activation. Studies published in Nature Immunology confirmed that patients with long COVID show elevated levels of inflammatory markers[2] such as IL-6 and activation of JAK-STAT pathways even more than six months after infection.
Additionally, research has detected viral RNA in the tissues of patients with long COVID[5] along with altered gut microbiome composition. The more frequent detection of herpes simplex virus type 1 and other viruses in these individuals suggests a possible role of latent infection reactivation in disease progression.
New Therapies and Treatment Challenges
In response to the growing need for effective therapies, the company Bio. Vie launched the ADDRESS-LC clinical trial in May 2025[7], testing the drug besisterim in 200 adult patients with cognitive impairments and fatigue related to long COVID. Besisterim increases insulin sensitivity and crosses the blood-brain barrier[8]. The trial is randomized and placebo-controlled[9], funded by the United States Department of Defense, with preliminary results expected in the first half of 2026.
The National Institutes of Health are conducting a series of studies as part of the RECOVER initiative[11] on drugs such as low-dose naltrexone and baricitinib aimed at counteracting long COVID symptoms. The review in Nature emphasizes that due to the heterogeneous clinical presentation, treatment must be individually tailored to each patient’s symptoms[12], reflecting the complexity of this disease affecting multiple organ systems.