Focusing on serotonin and other approaches to long COVID

The virus SARS-CoV-2 causes a disease called COVID-19. Most people who develop acute COVID-19 recover. However, some people who recover from acute COVID-19 subsequently develop lingering symptoms commonly called long COVID.

Symptoms associated with long COVID can include the following (this list is not exhaustive):

• persistent and disabling fatigue
• loss of endurance
• difficulty breathing
• headache
• problems with sleep
• difficulty concentrating
• memory problems
• difficulty thinking clearly

Part of the difficulty of finding a treatment for long COVID is that researchers are uncertain why it occurs, why some people get it and others do not, and why it lasts for a few weeks or months in some people or even longer in others.

A team of researchers, including leading immunologists and infectious disease specialists, has been studying more than 1,500 people who developed COVID-19, some of whom subsequently developed long COVID.

The researchers undertook extensive analysis of tissues and samples from patients to understand what had happened to them. They also conducted experiments with laboratory animals to better understand the mechanisms that viruses can use to cause chronic problems. The researchers’ findings led them to explore serotonin.

About serotonin

Serotonin is a messenger molecule that is used to send signals from one cell to another. There are receptors for serotonin on nearly every major organ system in the body, including the following:

• cardiovascular system
• gastrointestinal system
• lungs
• genitourinary system
• nervous system

Serotonin and its receptors help to regulate energy, digestion, appetite and production of some hormones. They also affect mood, memory and libido.

Emerging research suggests that serotonin may play a role in regulating aspects of immunity.

Key findings

SARS-CoV-2 infection or fragments of the virus can persist at very low levels in the intestinal tract of some people with long COVID. This residual virus or fragments of the virus can incite inflammation and the production of interferon. These factors (residual virus, inflammation and interferon production) appear to reduce the absorption of the precursor used to make serotonin—an amino acid called tryptophan. This amino acid is also used to make melatonin, and reduced tryptophan could lead to reduced melatonin levels, which could affect sleep. Participants in the present study who had severe symptoms of long COVID had diminished serotonin levels.

Most of the body’s serotonin is made in the gastrointestinal tract. Serotonin is then stored in platelets, cells that are plentiful in the blood and help regulate blood clotting. Micro-clots form in both people with acute COVID and long COVID. As platelets may have insufficient serotonin caused by SARS-CoV-2 infection (and the resulting inflammation this virus causes), they may not be able to fully regulate the formation of blood clots, leading to excessive formation of micro-clots. Such clots could decrease the flow of blood to vital organs, degrading their function and in some cases, cause serious symptoms.

The vagus nerve sends signals from the brain to the heart, lungs and digestive tract (and vice versa). This nerve is involved in some of the automatic functions in the body, such as breathing, heart rate and so on. The researchers think that the inflammation in the gut and body caused by SARS-CoV-2 sends signals to the brain via the vagus nerve when serotonin levels in the gut and other places are low. These signals to the brain likely incite inflammation within this vital organ. Inflammation in the brain may play a role in chronic fatigue, sleeping problems, anxiety/depression and memory loss—all of which have been reported in people suffering from long COVID.

Further studies are needed to confirm the connection between reduced serotonin levels and long COVID found in the present study.

Experiments in animals suggest that focusing on serotonin may be a potential route to helping people with long COVID. Large randomized clinical trials are needed to safely assess the impact of drugs that affect serotonin—such as selective serotonin reuptake inhibitors (SSRIs) or precursors of serotonin (such as 5-hydroxytryptamine, or 5HTP)—in people with long COVID.

Noteworthy

Many of the mechanisms that could affect serotonin levels found in the present study can occur in other viral infections (such as dengue virus infection, which can cause long-term issues) and in non-viral infections such as multiple sclerosis and lupus.

Exploring low-dose naltrexone

A team of researchers in Dublin, Ireland, tried a different approach to long COVID. The researchers used low doses of the drug naltrexone—a treatment that can help some people overcome dependency on alcohol and opioids. At high doses (50 mg), naltrexone affects opioid receptors. However, a lower dose (between 1 to 4.5 mg/day) may have different and complex effects, such as reducing inflammation within the immune system and altering the behaviour of cells of the immune system. Some immune system cells patrol the brain to control infections in that organ. Low-dose naltrexone is thought to help these cells release signals that dampen inflammation in the brain.

The study from Ireland, which was small and uncontrolled, suggests that low-dose naltrexone may be useful in some people with long COVID. Other small and uncontrolled studies from the U.S. have also found similar promising results. However, large randomized clinical trials will be needed to confirm the effects of low-dose naltrexone in this population.

Another approach

An increasing number of studies suggest that repeated booster shots of COVID-19 vaccines could have a beneficial effect in reducing the risk for long COVID.

Long COVID and the brain

Headache, sleeping problems and cognitive issues (commonly called “brain fog”) are common in people who have long COVID. Another team of scientists in Dublin, Ireland, has found that some of the blood vessels in the brains of people with long COVID are “leaky.” The excess inflammation caused by COVID-19 may have an adverse impact on the health and integrity of blood vessels in the brain. In turn, this may play a role in the development of brain symptoms of long COVID-19.

This team of scientists needs to find ways to both prevent and treat the formation of leaky blood vessels to assess if such interventions can improve the health of people with long COVID.

—Sean R. Hosein

REFERENCES:

1. Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annual Review of Medicine. 2009; 60:355-66. 
2. Zhang Y, Bharathi V, Dokoshi T, et al. Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes. Proceedings of the National Academy of Sciences USA. 2024 Feb 6;121(6): e2300644120. 
3. Wong AC, Devason AS, Umana IC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023 Oct 26;186(22):4851-4867.e20. 
4. O’Kelly B, Vidal L, McHugh T, et al. Safety and efficacy of low-dose naltrexone in a long COVID cohort: an interventional pre-post study. Brain, Behavior and Immunity—Health. 2022 Oct; 24:100485. 
5. Isman A, Nyquist A, Strecker B, et al. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain, Behavior and Immunity—Health. 2024 Feb 1; 36:100733. 
6. Greene C, Connolly R, Brennan D, et al. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience. 2024; in press.
7. MacCallum-Bridges C, Hirschtick JL, Patel A, et al. The impact of COVID-19 vaccination prior to SARS-CoV-2 infection on prevalence of long COVID among a population-based probability sample of Michiganders, 2020-2022. Annals of Epidemiology. 2024; in press.
8. Maier HE, Kowalski-Dobson T, Eckard A, et al. Reduction in long COVID symptoms and symptom severity in vaccinated compared to unvaccinated adults. Open Forum Infectious Diseases. 2024 Jan 23;11(2): ofae039.