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The Multidimensional Benefits of Low-Dose Naltrexone

Navigating the complex terrain of chronic pain and fatigue syndromes unveils a myriad of intertwined physiological and neurological pathways. Central to this exploration is Low-Dose Naltrexone (LDN), a versatile therapeutic agent. In this in-depth review, we unravel the multifaceted mechanisms of LDN's action, focusing on its unique interactions with microglial cells in the brain and its modulation of opioid receptors. We delve into the emerging scientific evidence illustrating LDN's efficacy in mitigating pain, alleviating fatigue, and improving mental well-being in conditions like Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), neuropathic pain, and Complex Regional Pain Syndrome (CRPS). Additionally, we explore LDN's potential in addressing mental health challenges, particularly in anxiety and depression, offering new insights into its broader role in enhancing overall health and quality of life.

Neurological Health

Cognitive Health

Multiple Sclerosis


16 mins

By: Shreshtha Jolly

Struggling with fatigue, irritation, or a general decrease in well-being can be frustrating, especially when standard methods like physical activities and refreshing routines don't seem to work. This challenge is one faced by many individuals as they navigate the complexities of modern life. Often, these issues are not just fleeting moments, but persistent conditions that require more than the usual health and wellness strategies.

In the search for effective remedies, one promising avenue is the exploration of Low-dose Naltrexone (LDN). This innovative approach involves using a reduced concentration of Naltrexone, a medication traditionally used in higher doses for opioid addiction treatment, but now gaining attention for its potential in managing chronic conditions related to well-being.

Recent scientific explorations have shed light on the potential benefits of LDN. Research suggests that LDN could effectively manage age-related inflammation, fatigue, and chronic pain if taken in the right dosages and frequencies. It is also believed to enhance endorphin release, which may improve mood and overall well-being.

Most discussions around LDN have historically centered on its anti-inflammatory properties. Our Research Review Team has written extensively about these benefits.

However, emerging studies are now revealing its impact on other aspects such as pain, fatigue, anxiety, and depression. In this review, Shreshtha Jolly of the Johns Hopkins Department of Molecular Biology focuses on these new findings, offering insights into how LDN could be a pivotal element in addressing these complex health issues.

Discovery and Functions of LDN

Naltrexone is a medication that has had a fascinating history of development. It was first synthesized in the early 1960s and was later discovered to be capable of blocking the effects of opioids in the 1970s. With these benefits, it took a relatively short time for the medication to be approved by the FDA (in 1984) for the treatment of opioid addiction. Once approved, the drug was primarily used in the management of opioid addiction.

To understand its benefits, let us first dive into its role in managing opioid addiction. As you may already know, opioids are a class of drugs that include prescription medications like oxycodone, hydrocodone, and morphine. They are often prescribed by healthcare professionals to relieve pain. However, without close monitoring by a medical professional, opioids can lead to addiction. Opioid use disorder (OUD) is a chronic medical condition characterized by a compulsive need to seek out and use opioids, even at the expense of personal, social, and occupational responsibilities.

Naltrexone works by blocking the effects of opioids. When opioids enter our bodies, they bind to specific receptors known as opioid receptors. Binding to these receptors activates biochemical and neurological responses that can produce euphoria or intense pleasure. This happens because opioid receptors are located in areas of the brain that regulate mood, emotion, and the perception of pleasure.

Naltrexone functions as an opioid antagonist. It binds to opioid receptors and hence blocks opioids from interacting with them. With opioid-receptor interactions halted, euphoric effects are attenuated to prevent the development of opiate addiction.

Another form of addiction Naltrexone battles against is alcohol addiction. Alcohol affects various parts of the brain. It impacts GABA and glutamate, two crucial neurotransmitters in the human brain, playing vital roles in regulating brain function and mental health. These neurotransmitters regulate feelings of stimulation, sedation, and intoxication, and also influence withdrawal symptoms when individuals stop drinking. Additionally, alcohol affects the dopamine and the opiate systems which play crucial roles in reinforcement, reward, craving, sustained alcohol use, and the risk of relapse after quitting.

When alcohol is consumed, it stimulates specific brain cells, leading to the release of dopamine (a neurochemical) in a region associated with pleasure and reward. This dopamine release contributes to the relaxation, pleasure, and euphoria experienced while drinking. However, chronic alcohol use can alter the brain's reward system over time. The brain adapts to alcohol, dulling the dopamine response. This adaptation can lead to tolerance, where more alcohol is needed for the same effects, and it can contribute to alcohol dependence or addiction.

Naltrexone addresses alcohol dependence by reducing the rewarding effects of alcohol, targeting the brain's reward system to help diminish the drive to drink excessively.

From the above, it becomes clear that Naltrexone is a vital tool in the battle against addiction. However, Naltrexone has other uses as well. Clinicians and researchers in the late 20th century began exploring the use of lower doses of Naltrexone for conditions beyond addiction. This off-label use, known as Low-Dose Naltrexone (LDN), gained attention for its potential benefits in managing pain, fatigue, and anxiety.

Role of LDN in Pain

Recent research has delved deeper into understanding the role of Low-dose Naltrexone (LDN) in pain management. This exploration has uncovered promising insights into how LDN may effectively alleviate various forms of pain, potentially offering a novel approach in the field of pain therapy.

When opioids, whether naturally produced in the body (like endorphins, enkephalins, or dynorphins) or synthetically created (such as morphine, oxycodone, and fentanyl), bind to opioid receptors, they initiate a cascade of physiological events. This process ultimately reduces the release of neurotransmitters such as Substance P, glutamate, and norepinephrine, which are crucial in transmitting pain signals. Therefore, the interaction between opioids and their receptors effectively diminishes pain by limiting the release of these pain-signaling neurotransmitters [1]

In the case of Low-dose Naltrexone (LDN), it interacts with opioid receptors in a unique way. LDN temporarily blocks these receptors, preventing both naturally occurring and synthetic opioids from binding to them. This blockage paradoxically triggers the body to increase its production of endogenous opioids, like endorphins, enkephalins, and dynorphins.

This surge in natural opioids may then interact with pain pathways, providing analgesic or pain-relieving effects. This phenomenon, often referred to as the "opioid rebound" hypothesis or "opioid-induced hyperalgesia," suggests that LDN's blocking action ironically results in increased pain relief [2].

A notable study investigated the effectiveness of Low-dose Naltrexone (LDN) in providing pain relief for patients with various pain disorder diagnoses. The study revealed that 64% of participants experienced some degree of pain relief following LDN treatment. Notably, the most significant relief was reported by patients with neuropathic pain and Complex Regional Pain Syndrome (CRPS).

Neuropathic pain, as defined in the study, refers to pain arising from damage or dysfunction in the nervous system. CRPS, on the other hand, is a chronic condition often affecting one limb, usually following an injury or trauma. This condition is thought to result from a malfunction in the nervous system and is characterized by persistent, severe pain that often exceeds the severity of the initial injury.

The research also included patients suffering from spondylosis, an age-related degeneration of the spinal column typically manifesting as neck and back pain. Interestingly, this group showed a lesser likelihood of responding positively to LDN treatment.

In conclusion, the study suggested that LDN could be a viable and safe alternative for managing certain types of pain, particularly neuropathic pain and CRPS. However, its effectiveness in conditions like spondylosis appears to be more limited [3].

The Dual Mechanism of Low-Dose Naltrexone (LDN) in Pain Management: Opioid Receptors and Glial Cell Modulation

Apart from affecting opioid receptors, LDN also reduces pain by acting on the glial cells of the central nervous system [4]. Glial cells, also known as neuroglia or gliocytes, constitute over half the volume of neural tissue in our body. They function as the caretakers of the nervous system, providing both physical and chemical support to neurons and maintaining their environment.

Our nervous system contains different types of glial cells, each with specific roles. Astrocytes, for example, act as janitors, cleaning up dead cells and regulating blood flow, while oligodendrocytes work like electricians, insulating neurons with a protective covering called myelin. We also have microglia, which function as the nervous system's defenders, constantly monitoring for signs of infection, injury, or abnormal cellular activities and providing defense against damage [5].

The role of LDN in pain management is gaining attention, particularly for its interaction with microglia in the brain. This interaction primarily involves Toll-like receptors (TLRs), especially TLR4, a critical component in the immune response.

Microglia are specialized immune cells in the brain, acting as vigilant guardians. They have TLRs on their surfaces, which are sophisticated sensors for detecting foreign invaders or signals of injury. TLR4 is notable for its role in identifying molecular patterns such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). When TLR4 recognizes these patterns, it triggers an inflammatory response, mobilizing the immune system to address potential threats or repair tissue damage [6].

Upon detecting these molecular patterns, TLR4 initiates a complex signaling cascade, leading to the activation of pro-inflammatory transcription factors. These factors increase the production of pro-inflammatory cytokines (like interleukin-1β, interleukin-6, and tumor necrosis factor-alpha), chemokines, and other agents that contribute to the inflammation process.

In chronic inflammation, continuous activation of TLR4 can lead to a relentless cycle of inflammation and tissue injury. Microglia, expressing TLR4, can initiate inflammation when activated. LDN, by binding to TLR4 on microglia, inhibits the microglia's activity. Normally, activated microglia produce inflammatory and excitatory factors that heighten pain sensitivity. However, LDN interrupts this process, dampening pain sensitivity and exerting its analgesic effects by blocking microglial activation through TLR4 binding. This mechanism highlights LDN's potential in reducing pain sensitivity and managing inflammation [7].

In summary, recent studies on LDN have opened new avenues in pain management. LDN's unique mechanism of temporarily blocking opioid receptors to increase the body's natural opioids, combined with its ability to modulate the activity of glial cells in the brain, particularly microglia, shows significant potential.

This dual action offers a promising approach for conditions like neuropathic pain and Complex Regional Pain Syndrome (CRPS), though its effectiveness varies across different pain disorders. The research underscores the complexity of pain treatment and the promise of LDN as a multifaceted therapeutic agent.

The Role of LDN in Treating Fatigue

The mechanism of LDN's effect on fatigue is not entirely understood but is believed to revolve around opioid receptors. When LDN temporarily blocks opioid receptors and increases endogenous endorphin production, it reduces pain and inflammation. Chronic inflammation is often associated with persistent fatigue. Hence, the anti-inflammatory effect of LDN could explain some potential benefits for individuals experiencing fatigue.

In one study, researchers investigated the potential of LDN in managing chronic fatigue syndrome (CFS) in patients. This syndrome is marked by persistent and severe fatigue, post-exertional malaise, pain, and disruptions in autonomic and neurocognitive functions [8]. In the study, case reports of three patients with CFS and varying dosages of LDN were collected.

The first case was of a white British female who was diagnosed with CFS in 1989. Since the onset of CFS, she experienced profound fatigue and cognitive impairments with only slight improvements over the years. She tried various treatments in response to these symptoms and showed slight improvement. In 2010, she started LDN, gradually increasing the dosage to 6 mg twice a day. By routinely administering LDN, she experienced increased energy, improved mood, and reduced pain. Hence, for the first case, LDN stabilized her condition.

The second case was of a white female living in the US who developed ill health at the age of 29 in 1989. Some of the symptoms she experienced included profound fatigue and weakness, flu-like symptoms, post-exertional malaise, nausea, widespread pain, and sleep disturbances. She was diagnosed with chronic fatigue immune dysfunction syndrome (CFIDS) after two years. CFIDS is similar to CFS in that both conditions are characterized by profound, chronic fatigue.

However, the critical difference between both conditions is the etiology of fatigue. In CFIDS, immune system abnormalities are believed to perpetuate and sustain chronic fatigue, while in CFS, the basis of fatigue is often unknown.

Returning to the case, in response to the symptoms of CFIDS, she was prescribed LDN in 2014 at 0.25 mg/day. The dosage was slowly increased to about 4 mg per day. The outcome of LDN administration was once again positive, with improved sleep and lowered pain levels.

The last case was of a white British male who sustained a head injury at the age of 7. In 1996, he developed severe tonsillitis, which eventually led to a diagnosis of CFS in 1997. Similar to the previous cases, the patient started LDN soon after his diagnosis (in 2018) and increased the dose to around 4.5 mg per day. He showed improved sleep patterns, fewer fatigue symptoms, improved mood, and decreased depression. All these studies underscore the benefits of LDN in reducing fatigue symptoms, especially for those diagnosed with CFS.

Besides case studies, literature has deeply explored the physiological basis of LDN's anti-fatigue capacities. In one study, researchers examined the effects of LDN in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

ME/CFS is a debilitating multi-systemic chronic condition that is characterized by impairments in both the immune and nervous systems. It is associated with feeling tired, taking a long time to recover from physical activity, problems having sustained restful sleep, and memory deficits. The pathophysiology of ME/CFS is intricately connected to a protein known as Transient Receptor Potential Melastatin 3 (TRMP3).

To comprehend the role of TRMP3, let's draw a parallel with electrical cables. Much like electrical cables transmit current (ions) from one point to another, TRMP3 channels the movement of calcium ions between the extracellular environment and the cell interior.

Natural Killer (NK) cells are crucial components of the innate immune system, playing a vital role in the body’s first line of defense against infections and tumors. The activity of NK cells depends significantly on the intracellular calcium concentration. The influx of calcium ions through channels like TRPM3 is essential for the activation and function of NK cells. Disruption in this calcium signaling can impair NK cell function, potentially contributing to the immune dysregulation seen in ME/CFS.

Interestingly, opioid receptors modulate the passage of calcium ions across TRMP3 and, hence, indirectly control NK activity. When endogenous or exogenous opioids bind the receptors, they activate and inhibit calcium ions' passing via TRMP3 for NK activity. This causes immune dysfunction, exacerbating the symptoms of ME/CFS.

Now, how does LDN fit into all this? As you already know, LDN deactivates opioid receptors by blocking their interaction with opioids. By inhibiting opioid receptors, it stops them from halting calcium ion flow across TRMP3 channels and hence triggers a resurgence of NK cell activity.

The study tested the theory by testing the flow of calcium ions in NK cells of ME/CFS patients prescribed varying dosages of LDN. Overall, the study did find a restoration of TRPM3-like ionic currents in NK cells in patients administered LDN. These patients also reported improved overall fatigue and related symptoms following LDN administration. Hence, the study lends insights into the physiological mechanisms by which LDN overrides fatigue [9].

Overall, LDN plays a vital role in alleviating feelings of tiredness. The anti-fatigue effects are well documented in the literature, demonstrating LDN as a promising therapeutic strategy for patients with fatigue symptoms.

Role of LDN in Anxiety and Depression

In addition to the role of LDN in pain relief, addiction, and fatigue, it turns out that LDN also appears effective in the sphere of mental health. This was demonstrated in a study conducted by McLaughlin et al. (2022). The study focused on understanding how LDN impacted the mental well-being of individuals with multiple sclerosis (MS) during the initial stages of the COVID-19 pandemic [13].

MS is a chronic and often disabling autoimmune disease that affects the brain and spinal cord. To understand the condition, let us delve into an analogy. In this analogy, you can think of the nervous system as an advanced computer network in a smart city. Nerves are like high-speed data cables transmitting messages between different parts of the town (representing the body). The nerves are covered by a fatty layer known as the myelin sheath, which ensures that electrical impulses run smoothly without being dispersed to peripheral regions. The myelin sheath is like the protective rubber sheath around the city cables, ensuring smooth and efficient communication.

In the case of MS, it is as if there is a glitch in the system. The immune system, which is supposed to protect the body, starts attacking and damaging the insulation around the cables (representing the myelin sheath around nerves). This attack disrupts the flow of information, causing signals to short-circuit or get lost. The glitches manifest as various issues in the city's functions: lights flicker (vision problems), traffic signals malfunction (coordination and balance issues), and messages get distorted or lost (numbness, tingling, or muscle weakness).

In McLaughlin’s study, the researchers examined patients with MS prescribed either LDN or standard disease-modifying therapy (DMT). DMT corresponds to a class of medications that are often used for the management of chronic diseases, particularly autoimmune conditions like MS and rheumatoid arthritis. In the context of MS, DMTs function by trying to 'calm down' the immune system by decreasing their overactive response to the myelin sheath. [10]

In the study, patients with MS who were prescribed LDN, either as a standalone treatment or in conjunction with standard DMT, reported significantly lower levels of anxiety and depression compared to those relying solely on oral DMTs. In essence, the study suggests that LDN could be a beneficial addition to the treatment regimen for MS, particularly in addressing the psychological impact of the disease and external factors.

In addition to anxiety, various trials have presented anecdotal evidence of the benefits of LDN against depression. In one study, a randomized, double-masked pilot trial was initiated. The trial was undertaken to evaluate whether the administration of LDN will improve depressive symptoms in patients diagnosed with recurrent major depressive disorder (MDD). MDD is a severe mental health condition characterized by persistent and overwhelming feelings of sadness, hopelessness, and a lack of interest or pleasure in once-enjoyable activities [11].

The study involved 12 MDD adults who were already on antidepressant regimens. Participants were randomly assigned to receive LDN (1 mg twice daily) or a placebo for three weeks. Results indicated that LDN augmentation led to a significant reduction in the severity of depression symptoms in individuals who had relapsed while on antidepressants. Hence, the study showed that for patients with depression, LDN supplementation could potentially alleviate depressive symptoms when used in conjunction with the original antidepressant [12].

The expanding scope of LDN's applications in mental health, as evidenced by recent research, highlights its potential as a versatile therapeutic agent. Its efficacy in improving mental well-being in conditions like multiple sclerosis and major depressive disorder opens up new possibilities for treatment strategies, suggesting a broader role for LDN in addressing complex mental health challenges beyond its known benefits in pain, addiction, and fatigue management.


Originating from Naltrexone's history in opioid addiction treatment, LDN has evolved into a multifaceted solution. It shows versatility in addressing age-related concerns like inflammation, fatigue, chronic pain, depression, and anxiety.

While recent research findings have highlighted LDN’s potential, individuals considering Low Dose Naltrexone should seek advice from healthcare professionals for personalized guidance. As research progresses, LDN's role in enhancing overall well-being unfolds as an intriguing and evolving narrative.


  • LDN’s Versatility: While much focus has been placed on LDN’s anti-inflammatory properties, recent research has provided clinicians with insights on additional off-label uses of the medication. 

  • Pain Management: LDN has shown promise in alleviating various forms of pain, especially neuropathic pain and Complex Regional Pain Syndrome (CRPS). Its mechanism involves temporarily blocking opioid receptors, which paradoxically triggers the body to increase production of natural opioids, thereby providing pain relief.

  • Impact on Glial Cells and Inflammation: Apart from its action on opioid receptors, LDN affects glial cells in the central nervous system, particularly microglia. By modulating the activity of these cells, LDN helps in managing inflammation and pain sensitivity, offering a novel approach to treating chronic pain and associated conditions.

  • Fatigue Reduction: LDN may play a vital role in reducing fatigue, particularly in conditions like Chronic Fatigue Syndrome (CFS). The mechanism is believed to involve LDN's impact on opioid receptors, reducing inflammation and thus, potentially alleviating persistent fatigue.

  • Mental Health Benefits: Emerging research indicates that LDN can positively impact mental health, specifically in reducing anxiety and depression. Studies, such as the one involving individuals with Multiple Sclerosis (MS), suggest that LDN can be an effective adjunct to standard treatments in improving psychological well-being.

  • Versatility in Application: The scope of LDN's applications extends beyond traditional pain and addiction management. Its potential benefits in treating a range of conditions, from neuropathic pain and fatigue to anxiety and depression, highlight its versatility as a therapeutic agent.


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  6. Watkins, L. R., Hutchinson, M. R., Ledeboer, A., Wieseler-Frank, J., Milligan, E. D., & Maier, S. F. (2007). Norman Cousins Lecture. Glia as the "bad guys": implications for improving clinical pain control and the clinical utility of opioids. Brain, behavior, and immunity, 21(2), 131–146.

  7. McCusker, R. H., & Kelley, K. W. (2013). Immune-neural connections: how the immune system's response to infectious agents influences behavior. The Journal of Experimental Biology, 216(Pt 1), 84–98.

  8. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. (2015). Military medicine, 180(7), 721–723.

  9. Cabanas, H., Muraki, K., Eaton-Fitch, N., Staines, D. R., & Marshall-Gradisnik, S. (2021). Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Role of Transient Receptor Potential Melastatin 3 Ion Channels in Pathophysiology and Treatment. Frontiers in immunology, 12, 687806.

  10. Robertson, D., & Moreo, N. (2016). Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations. Federal practitioner : for the health care professionals of the VA, DoD, and PHS, 33(6), 28–34.

  11. Hopkins, J. (2023, November 3). Major depression. Johns Hopkins Medicine.

  12. Mischoulon, D., Hylek, L., Yeung, A. S., Clain, A. J., Baer, L., Cusin, C., Ionescu, D. F., Alpert, J. E., Soskin, D. P., & Fava, M. (2017). Randomized, proof-of-concept trial of low-dose Naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. Journal of affective disorders, 208, 6–14.

  13. McLaughlin, P. J., Odom, L. B., Arnett, P. A., Orehek, S., Thomas, G. A., & Zagon, I. S. (2022). Low-dose naltrexone reduced anxiety in persons with multiple sclerosis during the COVID-19 pandemic. International Immunopharmacology, 113, Article 109438.


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