The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has emerged as one of the most significant global health crises of the 21st century.
But, beyond its immediate health implications, the COVID-19 pandemic has had far-reaching consequences on various facets of human life, in particular its psychological toll on from to social distancing and isolation. Moreover, the economic fallout resulting from the pandemic, including job losses, business closures, and financial instability, has induced considerable stress and anxiety for many. Chronic stress coupled with social isolation, hardship, loss and microbial threats created a perfect storm for the emergence of depression and anxiety, and may also precipitate the development of neurological conditions. Studies have estimated that about 1 in 3 people with COVID-19 will subsequently be diagnosed with a neurological or psychiatric condition.
While COVID-19 initially presented as an infection of the respiratory system, multiorgan complications were rapidly observed including neurocognitive symptoms that are informally referred to as “COVID-brain”.
How does COVID affect brain function?
As the pandemic unfolded, scientists discovered that the SARS-CoV-2 virus could infiltrate into the nervous system causing neurological symptoms – ranging from headaches and brain fog to, albeit rarer in incidence, strokes and paralysis. One notable effect being the loss of taste and smell experienced by many following infection. Sudden sensory losses or changes are an indicator of a neurological disturbance. Moreover, studies found viral particles in the brain tissue of individuals who have died from COVID-19, however the exact mechanisms of whether the virus affects neurons directly is still unknown1.
While a small percentage of cases experience major neurological events like strokes and seizures, and severity of symptoms are associated with poorer long-term outcomes, neurological complications can impact people that have mild covid, and there is an elevated risk of developing neurological issues for up to two years after infection1.
Beyond directly infecting brain tissue, COVID-19 can lead to an exaggerated immune response throughout the body via increases in cytokines (immune signalling molecules). An excessive release of these molecules can lead to system-wide inflammation, which can infiltrate into the brain and contribute to the development or exacerbation of neurological symptoms. The body's immune response to the virus itself may also contribute to neurological symptoms. Autoimmune reactions, where the immune system mistakenly attacks the body's own tissues are seen in a number of neurological conditions.
The cardiovascular and respiratory effect of COVID-19 can have a knock-on effect on brain function due to increased risk of blood clotting. Clots in the blood vessels of the brain can lead to ischemic strokes. Severe respiratory complications from COVID-19 can lead to decreased oxygen levels in the blood (hypoxia), which may negatively impact the brain and other organs. Prolonged periods of low oxygen can cause damage to brain tissue causing permanent neurological deficits.
What is Long-Covid?
While most individuals recover fully from COVID-19 within a few weeks, a significant portion continue to experience symptoms that can significantly impact their quality of life. Long-COVID (also referred to as post-acute sequelae of COVID-19, PASC) is an umbrella term for the wide range of physical and mental health consequences experienced by some patients that are present four or more weeks after SARS-CoV-2 infection, including by patients who had initial mild or asymptomatic acute infection. It is a complex condition that can manifest in a wide range of ongoing health problems, lasting for weeks, months, or even years after the initial infection.
Prevalence of Long-Covid
As of 2022, estimates suggest a minimum of 65 million people globally are dealing with Long-COVID2. However, the actual figure could be significantly higher due to a large number of unreported cases. The estimated prevalence ranges from 10-30% in non-hospitalized cases, 50-70% in hospitalized cases3,4, and 10-12% in vaccinated individuals5,6. The majority of Long-COVID cases occur in non-hospitalized patients with initial symptoms that were mild, as this demographic makes up the bulk of overall COVID-19 cases.
Long-COVID can produce an array of symptoms
The symptoms of Long-COVID can vary widely from person to person. Some individuals may experience fatigue or tiredness that interferes with their daily life, while others may have symptoms that worsen after physical or mental exertion, known as "post-exertional malaise." Fever, respiratory and heart symptoms such as difficulty breathing, cough, chest pain, and heart palpitations, are also commonly reported.
Importantly, neurological symptoms, including difficulties with thinking or concentration - often referred to as "brain fog", headaches, sleep problems, dizziness, and changes in smell or taste, are frequently observed in individuals with Long-COVID. It is important to note that these symptoms may fluctuate or relapse over time.
Long-COVID and Mental and Neurological Health
Recent studies suggest that COVID-19 survivors may experience long-term mental and neurological health consequences7. For example, 6-months after testing positive for COVID-19, the estimated incidence rate of a neurological or psychiatric diagnoses was 33%, while 13% were receiving a first-time diagnosis. Psychiatric conditions ranged from mood and anxiety disorders to neurological disorders, including Guillain-Barre syndrome and nerve disorders. Other symptoms commonly reported were fatigue, weakness, olfactory dysfunction, tremor, postural instability and sleep disturbance.
Long-COVID and Cognitive Dysfunction
One of the most prevalent neurological symptoms observed in COVID-19 survivors is cognitive dysfunction, which encompasses various mental processes, including learning, memory, attention, and executive function. This dysfunction has been linked to a decreased quality of life and increased disability in survivors. In fact, it has been shown that individuals with Long-COVID may experience deficits in these cognitive domains, leading to difficulties in daily functioning. For example, some individuals may struggle with memory recall, have trouble concentrating, or experience a decline in problem-solving abilities4. These cognitive impairments can significantly impact quality of life and may contribute to the development of mental health disorders. Indeed, one study found that up to 80% of COVID-19 survivors experience some form of neurological symptoms, with cognitive dysfunction being one of the most commonly reported issues. The cognitive deficits observed in patients recovering from COVID-19 may be due to the virus's direct effect on the brain and/or secondary effects from the body's immune response.
Serotonin, Cognitive Function, and Long-COVID
Serotonin, a neurotransmitter involved in mood regulation, is also implicated in cognitive function. In the brain, serotonin (5-HT) receptors are found in regions known to be involved in learning and memory, such as the amygdala, hippocampus and cortex. Activation of a subgroup receptors called 5-HT2A receptors, have been shown to facilitate learning in rodent models and humans. It is believed that COVID-19 may decrease serotonin levels in the brain, which can contribute to cognitive dysfunction and mental health symptoms8. Thus, understanding the role of serotonin in cognitive function and mental health will be instrumental in developing therapeutic interventions to combat the cognitive deficits experience by those with Long-COVID.
The connection between Long-COVID and serotonin is complex. The virus may decrease serotonin levels in the brain, contributing to cognitive dysfunction and mental health symptoms. Additionally, because the COVID-19 virus is able to enter the brain by passing through its protective barrier, pro-inflammatory cytokines, such as (TNFa, IL-6, IL-1b) can enter the brain, possibly contributing to a decrease in serotonin production and functioning as well as neuronal damage.
Could Psychedelics provide a Potential Therapeutic Intervention for Long-COVID?
Psychedelics, such as psilocybin (derived from magic mushrooms), LSD, DMT and 5-MeO-DMT have shown promise in clinical trials as potential treatments for mental health disorders9. These substances work by acting as ‘psychoplastogens’, enhancing the nervous systems ability to reorganize its structure and function to adapt to changing environments. This occurs through their ability to catalyze accelerated dendritic and neuronal growth throughout the brain. In addition, psychedelics have also been shown to increase neurogenesis, a unique process in which new neurons are born in the hippocampus, a region well known for its role in learning and memory. Importantly, psychedelics are believed to exert their psychoplastogenic effects by interacting with the serotonin receptors in regions such as the neocortex, hippocampus, and other subcortical regions. Moreover, psychedelics have been shown to exert anti-inflammatory properties, effectively decreasing pro-inflammatory cytokines found in individuals suffering from Long-COVID, including TNFa, IL-6, IL-1b.
The Future of Psychedelic Therapy
Understanding the cellular mechanisms behind psychedelics' potential therapeutic effects could help scientists develop safer and more effective treatments for mental and neurological disorders. As we continue to grapple with the long-term effects of COVID-19 on cognitive function and mental health, psychedelic therapy could become an integral part of the solution.
Disclaimer: The information provided in this article is for educational purposes only and should not be substituted for professional medical advice. Always consult with a qualified healthcare provider before making any changes to your healthcare regimen or treatment plan.
1. Maree Williams L. How covid-19 affects the brain. Neurology. Published online 2021:14-15.
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3. Bull-Otterson L, Baca S, Saydah S, et al. MMWR, Post–COVID-19 Conditions Among Adult COVID-19 Survivors Aged 18–64 and ≥65 Years — United States, March 2020–November 2021. https://stacks.cdc.gov/view/cdc/117411
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