Understanding the Role of Low-Dose Naltrexone in the Context of Long COVID

Introduction

In 2020, the COVID-19 pandemic proliferated across the globe with unprecedented health, economic, and psychosocial consequences on global society. However, since the pandemic's emergence, interventions including timely development of effective vaccines, routine syndromic surveillance, equipping of healthcare and other frontline workers with personal protective equipment, mandatory mask-wearing, periodic lockdowns, quarantining and other measures managed to contain the spread to a considerable extent.

But even if initial infections are resolved, many individuals are left with lingering symptoms, including dizziness, headaches, palpitations, chest pain, shortness of breath, fever, and concentration impairments. The persistence of these symptoms beyond the initial infection has now been famously dubbed 'long COVID.' Unfortunately, treatment choices for long COVID remain ambiguous, leaving patients and healthcare workers navigating a landscape of uncertainty.

In this review, Shreshtha Jolly of the Johns Hopkins Department of Molecular Biology will provide an in-depth exploration of the physiological and psychological underpinnings of long COVID. Additionally, she will shed light on the use of Low-Dose-Naltrexone as a novel treatment approach that has shown promise in the treatment of several long COVID symptoms.

What is long COVID?

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), corresponds to a condition where individuals experience persistent symptoms and health issues for weeks or months after the acute phase of a COVID-19 infection has resolved. [1]

While many people recover from COVID-19 within a few weeks, some individuals, even those with initially mild cases, continue to experience a range of symptoms that can significantly impact their quality of life. It is worth noting that a person's susceptibility to long-term COVID is independent of the intensity of their original COVID-19 infection [2]. Common symptoms of long-term COVID include fatigue, shortness of breath, chest pain, concentration impairments, joint pain, and persistent loss of taste or smell. Interestingly, long COVID can affect people of all ages, including those who had mild or asymptomatic cases of COVID-19 initially. [1]

Researchers have proposed several hypotheses to explain the physiological bases of long COVID. Based on a comprehensive review of these hypotheses, it becomes clear that long COVID is a condition that involves several, rather than a single part of the human body, working in tandem. In other words, it is a systemic rather than localized condition with physiological and psychological components playing a role in its severity.

The involvement of multiple body parts in the manifestation of the condition was confirmed by a study assessing organ impairment in individuals presenting persistent symptoms following recovery from acute SARS-CoV-2 infection.

Individuals were recruited from two U.K. centers between April 1st, 2020, and September 14th, 2020. Symptoms of COVID-19 were measured via standardized questionnaires. Organ dysfunction was evaluated via biochemical assays and quantitative magnetic resonance imaging (MRI).

Interestingly, the study showed that 70% of individuals at low risk of mortality from long COVID had impairments in one or more organs. Impairment was observed in the multiple organs (heart, lungs, kidneys, liver, pancreas, spleen) in 29% of the recruited cohort. [3]

This study showed that long COVID is a condition that cannot be taken lightly. It has a complex etiological basis and affects multiple organs in our body. To add to the already grim situation, treatment options for the condition remain limited, warranting further research and exploration.

Mechanisms underlying Long COVID

Viral Persistence

SARS-CoV-2, the virus causing COVID-19, typically enters the body by infecting cells in the respiratory system. These cells have special proteins on their surface called receptors. These receptors are like docking stations; they recognize and attach to specific molecules that fit them perfectly. When a receptor finds and binds to its matching molecule, it sets off certain processes and effects in the cell. What happens exactly depends on the type of receptor and the molecule it binds to.

In the case of COVID-19, the SARS-CoV-2 virus has a key feature on its surface known as the spike protein. This spike protein has a part called the receptor binding domain (RBD), which acts like a specific 'target molecule.' This RBD is designed to connect with a particular type of receptor known as ACE-2, found on many cells in our respiratory system, like in the nose and upper respiratory tract.

When the RBD of the virus's spike protein latches onto the ACE-2 receptor on a cell, it causes the structure of the spike protein to change. This change is like unlocking a door, allowing the virus to enter the cell. Once inside the cell, the virus can start to replicate, leading to infection.

Apart from the respiratory system, diverse cell types in different organ systems also express ACE-2 receptors, making them susceptible to SARS-CoV-2 infection. These include the kidney, gut, esophagus, liver, and brain cells.

Additionally, the genetic material of the COVID-19 virus, known as RNA, can stick around in the respiratory system for many weeks after someone has recovered clinically from COVID-19. Such viral RNA can persist for months post-infection and can be detected in different body parts including the respiratory tract, gastrointestinal tract, and blood.

A recent study by Cevik et al. (2021) found that the virus responsible for COVID-19 can continue to be released from various parts of the body, a process known as 'shedding,' for different durations.

On average, the virus was shed for up to 17 days from the upper respiratory tract (areas like the nose and throat), approximately 14.6 days from the lower respiratory tract (parts like the lungs), around 17.2 days from the gastrointestinal tract (the digestive system), and for about 1.6 days from the blood. This shedding refers to the release of the virus from these areas, which can be through actions like coughing (for the respiratory tract) or through waste (for the gastrointestinal tract). The persistence of viral RNA, which is the virus's genetic material, and the continuous shedding of the virus from multiple organs after the initial, acute phase of infection, are likely contributing factors to the symptoms associated with long COVID. [6]

Immunological Factors

Long COVID might also be explained by changes in how the immune system works, specifically regarding T cells, which are crucial defenders in our immune system. T cells help fight germs and protect us from diseases.

There are mainly two types of T cells:

• Cytotoxic T cells (CD8+ cells): These cells act like soldiers. They find and destroy our own cells that have been infected by the virus.

• Helper T cells (CD4+ cells): These cells are like the commanders. They don't fight directly but send signals to organize other immune cells to combat the infection.

When these T cells encounter a virus, like SARS-CoV-2 (the virus causing COVID-19), they multiply and create memory T cells. Memory T cells are special because they remember the virus. If the same virus tries to invade the body again, these memory T cells recognize it immediately. They then quickly turn into either helper or cytotoxic T cells and guide the immune system to the infection site to fight off the virus efficiently.

Several studies on long COVID have found that there are changes in the way T cells, especially these memory T cells, function. This alteration in the immune response could be a reason why some people experience long-term symptoms of COVID-19.

One study observed T cells in people who had recovered from COVID-19 with varying degrees of severity (mild, moderate, and severe cases). They checked these T cells at two different times: 3 and 6 months after infection. The researchers noticed that the T cell response varied based on how severe the COVID-19 case was and how much time had passed since recovery. In severe cases, there was a significant change towards a state of 'T cell exhaustion' in both CD4+ and CD8+ T cells.

To understand 'T cell exhaustion,' imagine a long-distance runner who starts energetically but gets tired and less efficient over time. Similarly, T cells initially respond vigorously to a virus but can become exhausted and less effective if the virus or its remnants, like RNA, linger for a long time, as in long COVID. In the study, the T cells in severe cases showed signs of this exhaustion, affecting their two main functions: activating other immune cells and directly killing infected cells.

Additionally, in severe cases, CD8+ T cells were found to produce more granzyme B and IFN-γ after six months. Granzyme B helps destroy virus-infected cells, while IFN-γ attracts other immune cells, like macrophages, to the infection site. Macrophages act like vacuums, engulfing and destroying virus-infected cells. This process is called phagocytosis. The increased production of these proteins in severe cases was linked to higher inflammation, which might be related to the prolonged symptoms of COVID-19.

On the other hand, mild cases showed an increase in CD4+ T regulatory cells. These cells help calm the immune system by suppressing the activity of other immune cells. An increase in these regulatory cells in mild cases could contribute to immune system dysregulation, leading to inflammation and the symptoms of long COVID. [7]

In summary, the varied and complex responses of T cells, ranging from their initial vigorous defense to eventual exhaustion and altered regulatory functions, highlight the intricate role of the immune system in the persistence of long COVID symptoms. This dynamic interplay between our body's defenders and the virus underscores the importance of understanding immune system behaviors for effective long-term COVID-19 management and treatment strategies.

Vascular and Microvascular Effects

Besides its effects on the immune system, the SARS-CoV-2 virus is also believed to affect the functioning of blood vessels in our circulatory system. By compromising their function, it can impede blood flow to vital organs and underlie multi-organ impairment during long COVID. To understand how it exerts these effects, we must first familiarize ourselves with how the virus enters our bodies.

The virus causing COVID-19 enters our body using a pathway involving the angiotensin-converting enzyme 2 (ACE2). ACE2 is a receptor found on the surface of various cells in parts of our body like the small intestine, blood vessels, and lungs [8]. The ACE2 receptor serves as an entry point for the virus, making these cells vulnerable to infection. The virus's interaction with ACE2 can cause inflammation and disturbances in small blood vessels, a condition known as microvascular dysfunction [9].

Another significant issue related to COVID-19 is coagulopathy, which affects how blood clots [10, 11]. Normally, blood clots form to seal wounds and prevent further bleeding. However, in coagulopathy, this process is disrupted, leading to either excessive bleeding or excessive clot formation.

Long COVID patients often experience a hypercoagulable state, where their blood is more prone to clotting. This can result in conditions like deep vein thrombosis (DVT), where clots form in deep veins (often in the legs), causing symptoms like swelling, pain, and redness. If a clot travels to the lungs, it can cause a pulmonary embolism, a serious condition that blocks blood flow to the lungs, leading to symptoms like shortness of breath, chest pain, and coughing up blood [12].

In a detailed study of long COVID, researchers tracked patients from hospital admission to discharge and then 3 and 6 months after discharge. They focused on measuring D-dimer levels, which are fragments produced when blood clots form and dissolve in the body. These levels can indicate recent or ongoing blood clot formation. The study found that D-dimer levels were higher in the recovery phase than at admission, suggesting a link between long COVID symptoms and ongoing abnormalities in blood clotting [12].

The multifaceted impact of the SARS-CoV-2 virus on blood vessel function and coagulation processes not only elucidates the complexities of its pathogenesis but also sheds light on the intricate mechanisms contributing to the persistent and diverse symptoms observed in long COVID cases.

Psychosocial Mechanisms Underlying Long COVID

Apart from physiological factors, psychosocial factors can also contribute to the persistence of symptoms tied to COVID-19. Anxiety, depression, and the overall stress of dealing with a chronic illness may exacerbate physical symptoms.

In one study, researchers were interested in investigating whether there was a link between psychological distress before SARS-CoV-2 infection and the development of persistent symptoms post-acute infection (or long COVID). The participant cohort was predominantly female and periodically surveyed to measure psychological distress levels characterized by depression, anxiety, worry, perceived stress, and loneliness.

Participants were included if they did not have current or prior SARS-CoV-2 infection at baseline (when the first survey was administered) and if they returned one or more follow-up questionnaires—of the 54,960 included participants, 6 % (3193 participants) reported positive for COVID-19 during the follow-up period. Among these, depression, anxiety, and worry about COVID-19 were each associated with post-COVID-19 infections.

Participants with two or more types of distress before infection were at nearly 50% increased risk for post–COVID–19 conditions. Hence, the study suggests that pre-infection psychological distress may be a risk factor for post-COVID-19 conditions in individuals with SARS-CoV-2 infection. [13]

As the medical community continues to unravel the basis of long COVID, this evidence emphasizes the need for a holistic approach that integrates physiological and psychosocial considerations. Recognizing and addressing psychological distress early on may not only enhance the overall well-being of individuals but also contribute to more effective strategies for the prevention and management of persistent symptoms post-COVID-19 infection.

LDN as a Novel Treatment for Long COVID

In the current realm of therapies, there are, unfortunately, no existing pharmacotherapy options that have been approved for the effective management of long-term COVID-19. This reality presents a significant challenge for both patients and healthcare providers. However, some medications have been prescribed off-label for the management of symptoms, offering a glimmer of hope in this complex situation.

Off-label use involves prescribing drugs for an unapproved condition or in an unapproved age group, dosage, or route of administration. In the context of long COVID, this approach is often adopted when standard treatments do not adequately address the wide range of persistent symptoms experienced by patients. These symptoms can include fatigue, shortness of breath, cognitive disturbances, and others.

For instance, drugs originally developed for other conditions, such as certain antidepressants, have been used to manage the neurological and mood-related symptoms of long COVID. Similarly, medications aimed at reducing inflammation or modulating the immune system are being explored to alleviate persistent inflammatory symptoms.

Low-dose Naltrexone (LDN) serves to be one seminal candidate that is gaining much support against long-term COVID-19 due to its potential to mitigate several long COVID symptoms.

As discussed in our previous Research Review Articles, LDN is a reduced formulation of Naltrexone, an otherwise FDA-approved medication primarily used to treat opioid and alcohol addiction.

When used in smaller doses, as in LDN, Naltrexone exerts many beneficial effects including lowering pain, fatigue, anxiety, and depression. The current scientific landscape is seeing a shift towards testing and validating the use of LDN as an anti-long COVID regimen.

In one study by O'Kelley et al. (2022), researchers investigated the safety and potential benefits of LDN in patients experiencing long COVID. Fifty-two participants were recruited from a post-COVID clinic. Long COVID was defined as a condition where the participants presented with lingering symptoms of COVID-19 for more than 12 weeks following initial SARS-CoV-2 infection.

The patients, mainly female healthcare workers, received LDN for two months (1 mg in the first month, 2 mg in the second). The participants also completed a quality of life questionnaire before and after the two months, and adverse events were monitored.

Overall, the results showed that LDN was well-tolerated, with only a tiny percentage experiencing side effects. Significant improvements were observed in various parameters, including recovery from COVID-19, daily activities, energy levels, pain, concentration, and sleep. The study suggests that LDN is safe for long-term COVID-19 and may enhance well-being, alleviating symptoms. [1]

The physiological mechanisms underlying the efficacy of LDN in the treatment of long-term COVID-19 are currently being actively explored. However, one proposed explanation for its beneficial effects is due to immune modulation. At low doses (1 mg – 4.5 mg), Naltrexone acts on various immune-related pathways. In particular, it inhibits the inflammatory activity of toll-like receptor 4 (TLR4).

As discussed in depth in our previous articles, TLR4 is a receptor found on the surface of many immune cells. Its job is to recognize specific proteins on germs like bacteria and viruses and start an inflammatory response to fight them off.

In long COVID, the virus or its remnants can cause TLR4 to become overactive, leading to ongoing inflammation. When TLR4 is activated, it also triggers the release of cytokines, which are proteins that help regulate the body's reaction to infection, inflammation, and injury.

Normally, cytokines are helpful in combating diseases, but in the case of a prolonged COVID-19 infection, this can lead to an excessive and prolonged release of cytokines. This overproduction of cytokines is what causes symptoms like fatigue and muscle aches commonly seen in long-term COVID-19 cases [14].

Now, how does LDN fit into all this? Fortunately, LDN can recognize these TLR4s on the surface of immune cells and suppress their activity. By keeping their activity levels in check, LDN likely exerts anti-inflammatory effects to improve the symptomology of long-term COVID-19. [15]

Apart from its effects on TLR4, another potential mechanism by which LDN exerts benefits against COVID-19 is through pain modulation. Interestingly, one study found that the most significant effect of LDN administration was improvement in pain for the patients.

LDN works to alleviate pain through a unique mechanism involving opioid receptors, which are proteins on certain cells that typically respond to opioid drugs like oxycodone, hydrocodone, and morphine.

Unlike typical opioids, LDN acts as an inhibitor at these receptors. It attaches to the opioid receptors, blocking them and preventing opioids from binding to these sites. This blockage triggers the body to slow down the removal of certain neurotransmitters, such as substance P, glutamate, and norepinephrine, which play a key role in transmitting pain signals. Consequently, by interfering with the normal opioid-receptor interaction, LDN effectively reduces the release of these neurotransmitters, thereby diminishing our sensitivity to pain [16].

LDN (Low Dose Naltrexone) not only affects opioid receptors but also influences glial cells in the nervous system, which play a crucial role in long COVID's anti-pain effects. Glial cells, often referred to as the nervous system's caretakers, provide support to brain cells. Among various glial cells, microglia are particularly important in this context.

Microglia are equipped with TLR4 receptors on their surfaces. When these TLR4 receptors are activated, microglia release substances that promote inflammation, thereby increasing our sensitivity to pain. LDN, as discussed earlier, can interact with these TLR4 receptors. By binding to TLR4 on microglia, LDN inhibits their activation, which in turn reduces the release of these proinflammatory substances. This action of LDN on microglia and their TLR4 receptors helps to decrease pain sensitivity, contributing to its pain-relieving effects in long COVID [17, 18].

Though more research is still needed to determine the full spectrum of benefits of LDN, it can be reasonably said that LDN exerts promising beneficial effects against long-term COVID-19. However, before widespread implementation, the dosage and type of patient likely to benefit from it must be defined. It is also worth noting that in the current state, long COVID is broadly classified into two syndromes based on the duration and etiology of the symptoms.

On-going symptomatic COVID-19 describes patients who experience persistent symptoms between 4 and 12 weeks post-acute infection. On the other hand, post-COVID-19 syndrome describes patients who experience persistent symptoms beyond 12 weeks. Hence, the overall efficacy of LDN also depends on the type of syndrome individuals are experiencing. More studies evaluating LDN in patients stratified based on their syndromic profile need to be considered.

Conclusion

As the world grapples with the aftermath of COVID-19 the emergence of long COVID, characterized by persistent symptoms beyond the acute infection phase, presents a complex and multifaceted challenge. This comprehensive review delves into long COVID's physiological and psychological underpinnings, shedding light on its intricate mechanisms. In particular, this chronic condition extends beyond the respiratory system, affecting multiple organs and presenting diverse symptoms. The persistence of symptoms in Long COVID is attributed to various mechanisms, including viral persistence, immunological factors, vascular and microvascular effects, and psychosocial factors.

In the therapeutic realm, LDN emerges as a promising candidate for the management of long-term COVID-19. The efficacy of the medication is attributed to immune modulation, particularly the inhibition of toll-like receptor 4 (TLR4) inflammatory activity and pain modulation through interactions with opioid receptors and glial cells.

Ongoing research is actively exploring the physiological mechanisms underlying the effectiveness of LDN in treating long COVID. While this review emphasizes the potential of LDN, it also underscores the need for further research to define optimal dosage, patient profiles, and the specific long COVID syndromes that may benefit most from LDN. The evolving understanding of long COVID necessitates continued scientific exploration to refine treatment approaches and enhance the overall management of this complex condition. As the medical community strives to address the challenges posed by long COVID, ongoing collaboration and research will play a crucial role in shaping effective strategies for the comprehensive care of individuals affected by this persistent condition.