Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics


Albert Leng, Manuj Shah, Syed Ameen Ahmad, Lavienraj Premraj, Karin Wildi, Gianluigi Li Bassi, Carlos A. Pardo, Alex Choi and Sung-Min Cho


March 6, 2023

“In addition to the specific use of antivirals, other agents, such as cannabidiol, may have some antiviral efficacy as a therapy for long COVID. It is known that the active metabolite in cannabidiol, 7-OH-CBD, can block SARS-CoV-2 replication by inhibiting viral gene expression, upregulating interferon expression, and promoting antiviral signaling pathways [76]. Notably, cannabidiol has been reported to downregulate ACE2 and TMPRSS2 [77]—key enzymes involved in the SARS-CoV-2 virus invasion process and the potential evolution to long COVID. A phase 2 clinical trial (NCT04997395) has begun looking into the feasibility of using cannabidiol as a treatment for long COVID (Table 2). Additionally, Cannabidiol has been shown to induce neuroprotective effects [78,79]. Taken together, this suggests that cannabidiol can help ameliorate the neurological symptoms of long COVID, although future clinical trials are needed to provide further evidence.”


The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, we sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.


DOI: 10.3390/cells12050816


Leng, A., Shah, M., Ahmad, S. A., Premraj, L., Wildi, K., Li Bassi, G., … & Cho, S. M. (2023). Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics. Cells, 12(5), 816.