COVID-19 as a polymorphic inflammatory spectrum of diseases: a review with focus on the brain.

There appear to be huge variations and aberrations in the reported data in COVID-19 2 years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases, and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host's inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19.

Long COVID, neuropsychiatric disorders, psychotropics, present and future.

Long COVID refers to the lingering symptoms which persist or appear after the acute illness. The dominant long COVID symptoms in the two years since the pandemic began (2020-2021) have been depression, anxiety, fatigue, concentration and cognitive impairments with few reports of psychosis. Whether other symptoms will appear later on is not yet known. For example, dopamine-dependent movement disorders generally take many years before first symptoms are seen. Post-stroke depression and anxiety may explain many of the early long COVID cases. Hemorrhagic, hypoxic and inflammatory damages of the central nervous system, unresolved systematic inflammation, metabolic impairment, cerebral vascular accidents such as stroke, hypoxia from pulmonary damages and fibrotic changes are among the major causes of long COVID. Glucose metabolic and hypoxic brain issues likely predispose subjects with pre-existing diabetes, cardiovascular or lung problems to long COVID as well. Preliminary data suggest that psychotropic medications may not be a danger but could instead be beneficial in combating COVID-19 infection. The same is true for diabetes medications such as metformin. Thus, a focus on sigma-1 receptor ligands and glucose metabolism is expected to be useful for new drug development as well as the repurposing of current drugs. The reported protective effects of psychotropics and antihistamines against COVID-19, the earlier reports of reduced number of sigma-1 receptors in post-mortem schizophrenic brains, with many antidepressant and antipsychotic drugs being antihistamines with significant affinity for the sigma-1 receptor, support the role of sigma and histamine receptors in neuroinflammation and viral infections. Literature and data in all these areas are accumulating at a fast rate. We reviewed and discussed the relevant and important literature.

CANNABINOIDS AND NEUROINFLAMMATION: THERAPEUTIC IMPLICATIONS

This review summarizes the pharmacological properties of tetrahydrocannabinol (THC) and cannabidiol (CBD), cannabinoid components of several species of herbal cannabis. The pharmacological effects of the phytocannabinoids have been extensively investigated and the importance of the cannabinoid receptors (CB1 and CB2) on immune cells has provided important information on the intracellular targets for these molecules. In addition to the phytocannabinoids, endogenous cannabinoids also exist in the form of anadramide and 2-srodolylglycerol (2-AG). These, together with their synthesizing and metabolizing enzymes, form the cannabinoid system. Since the discovery of the endocannabinoid system and the role that neuroinflammation plays in neurological and psychiatric illness, the potential therapeutic importance of this system has been of growing interest. In addition, the need to develop drugs which specifically target the CB1 and CB2 receptors has been stimulated by the pharmacological complexity of both THC and CBD. This review briefly summarizes the therapeutic potential of the naturally occurring and the synthetic cannabinoids which will need to be developed, if such drugs are to fulfill the therapeutic promise which the cannabinoids offer.