Long COVID and Brain Fog: Is Serotonin the Culprit?
Introduction
Long COVID is an often-incapacitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus infections. Over 200 symptoms that affect many organ systems have been found. Global estimates place the number of people with COVID at about 65 million. While all age groups have been diagnosed with Long COVID, the age group between 36 and 50 years old has the largest percentage of diagnoses. The majority of Long COVID occur in patients who are not hospitalized and who have a mild acute illness.
Although theories abound, there is still no clear explanation for how infection with SARS-CoV-2 leads to lingering problems with attention and memory, difficulties concentrating, and other, debilitating symptoms. However, new research from Pennsylvania University proposes the intriguing and surprising possibility that a drop in serotonin may be responsible for the inflammation response which in turn causes cognitive problems. The reason that this may be a significant discovery is that we already have drugs that can increase serotonin levels in our bodies. The so-called SSRIs, the serum serotonin reuptake inhibitors, like Prozac.
Brain Fog
Neurological and cognitive symptoms are a major feature of long COVID, including sleep disturbances, changes in mood,, pain perception, memory loss, cognitive impairment, paresthesia, dizziness and balance issues, sensitivity to light and noise, loss of (or phantom) smell or taste, often impacting activities of daily living. Audio-vestibular manifestations of long COVID include tinnitus, hearing loss and vertigo. Moreover, serotonin is intricately linked to the regulation of other neurotransmitters such as dopamine and norepinephrine. Imbalances in these neurotransmitter systems might contribute to the development of conditions like brain fog, fatigue, and depression, frequently reported in individuals with Long Covid.
In one study, fatigue was found in 32% and cognitive impairment was in 22% of patients with COVID-19 at 12 weeks after infection. Cognitive impairments in long COVID are debilitating, at the same magnitude as intoxication ageing and may increase over time.
A report on more than 1.3 million people who had COVID-19 showed mental health conditions such as anxiety and depression returned to normal over time, but increased risks of cognitive impairment (brain fog), seizures, dementia, psychosis and other neurocognitive conditions persisted for at least 2 years.
Prof. Wong and his team at Penn U, found that viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
Serotonin
Serotonin is a chemical messenger involved in regulating mood and digestion, among myriad other functions. Serotonin is found in all animals, plants, and most unicellular organisms. Serotonin has the evolutionary and anatomical properties to serve as a global regulator unifying the whole brain into a cohesive biological system. Approximately 80% of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons in the CNS. In the human brain, serotonin neurons are more numerous (>250,000) than in other species and form a tight, small cluster along the midline of the brainstem.
In the CNS serotonin has various functions:
the regulation of mood
acts to reduce anxiety
may buffer aversive events
modulates
§ appetite
§ sleep
§ breathing
§ heart rate
§ cognitive functions including memory and learning
§ resilience to stress
Increasing the availability of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants particularly the SSRIs like Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Paroxetine (Paxil, Pexeva) or Sertraline (Zoloft).
SSRIs may not be suitable if you have any of the following conditions: bipolar disorder, and you’re in a manic phase (a period of extremely excitable mood), although they can be useful for depressive phases, a bleeding disorder, diabetes, narrow angle glaucoma, serious kidney, liver or heart problems and epilepsy.
Serotonin has an important function in prenatal development where serotonin from maternal blood begins to bathe the developing fetus from conception, providing a very early start to its functioning as a homeostatic regulator in the dynamic emerging connections of the brain.
Serotonin is manufactured from the essential amino acid tryptophan which is found in foods such as bananas, pineapples, plums, turkey and milk.
Treatment Implications
Understanding the connection between Long Covid and serotonin opens avenues for potential treatments and interventions. Targeting serotonin pathways or utilizing medications that modulate serotonin function might offer therapeutic benefits in managing Long Covid symptoms. However, the complexity of serotonin's role in the body and the variability of Long Covid symptoms necessitates a tailored and multidisciplinary approach to treatment.
Therapeutic interventions may include medications that target serotonin receptors, such as SSRIs commonly used in treating mood disorders. These medications could potentially address both the mood-related symptoms and some of the cognitive impairments associated with Long Covid.
Additionally, non-pharmacological approaches such as cognitive behavioral therapy, exercise, and dietary modifications that support serotonin production could play a complementary role in managing Long Covid symptoms.
Finally, it's important to note that research in this field is ongoing, and the mechanisms through which Covid-19 affects serotonin and contributes to Long Covid symptoms are not yet fully elucidated.
Key Takeaways
Long COVID is associated with reduced circulating serotonin levels.
Peripheral serotonin deficiency impairs cognition via reduced vagal signaling.
SSRIs may prove helpful in the treatment of Long Covid.
Tryptophan rich foods should be added to the diet of people suffering of Long COVID.
References
Ceban, F. et al. (2022). Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav. Immun. 101, 93–135.
Holdsworth, D. A. et al.(2022). Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID. PLoS ONE 17, e0267392.
Offord, Catherine (2023). Low serotonin levels might explain some Long Covid symptoms, study proposes. Science. Proal, A. D. & VanElzakker, M. B. Long COVID or post-acute sequelae of COVID-19 (PASC): an overview of biological factors that may contribute to persistent symptoms. Front. Microbiol. 12, 698169 (2021).
Sadlier, C., Albrich, W. C, . . . & O’Mahony, L. (2022). Metabolic rewiring and serotonin depletion in patients with postacute sequelae of COVID‐19. Allergy, 77(5), 1623.
Taquet, M. et al.(2022). Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients. Lancet Psychiatry 9, 815–827.
Wong, A. C., Devason, A. S., . . . & Levy, M. (2023). Serotonin reduction in post-acute sequelae of viral infection. Cell.
