Low-dose naltrexone (LDN) is an unusual contender in multiple sclerosis: a well-known medicine at standard doses, but used off-label in much smaller amounts for very different proposed effects. With MS symptoms and inflammation often persist despite disease-modifying treatment, it’s no surprise people are curious about safe, low-cost options that might support day-to-day quality of life.
In this review, we break down what the science actually says so far. It will include how LDN may work (including effects on endorphins and microglial signalling), what animal and human studies have found, and where the evidence is still thin.
Table of contents
- Introduction
- Mechanism of action and pharmacology
- Immunomodulatory effects and animal models
- EAE evidence: OGF/LDN suppress peripheral T- and B-cell proliferation after MOG immunisation
- Serum biomarkers and opioid system dysregulation
- Clinical trial evidence in multiple sclerosis
- Relapsing-remitting MS and quality of life
- Long-term safety and efficacy
- Symptom management
- Cytokine modulation
- Medication utilisation patterns
- Safety concerns and rare complications
- Limitations of current evidence
- Future research directions
- Conclusion
- References:
Introduction
Low-dose naltrexone (LDN) has become a topic of sustained interest in multiple sclerosis (MS). However, it sits at an unusual crossroads. it is an established medicine at standard doses, yet it is used “off-label” at much lower doses with a different proposed set of effects. In MS, inflammation, immune dysregulation, and symptom burden can persist despite disease-modifying therapy. Hence, it is no surprise there is an understandable appetite for treatments that may be safe, affordable, and potentially helpful for quality of life.
This review summarises what is currently known about LDN in MS across three key areas. First, it outlines the pharmacology and biological rationale for the use of low-dose naltrexone. This will include discussing transient opioid receptor blockade, potential enhancement of endogenous opioid signalling, and modulation of glial and microglial inflammatory pathways (including TLR4-related mechanisms). Second, it evaluates evidence from animal models and human studies, with attention to outcomes that matter in practice—spasticity, pain, fatigue, mood, and broader quality of life—alongside any signals of disease activity.
Finally, it highlights the limitations of the existing literature, including small sample sizes, variable study designs, and uncertainty around optimal dosing and duration. It sets out priorities for future research to clarify whether LDN’s role in MS is best understood as symptom support, adjunctive therapy, or something more.
Mechanism of action and pharmacology
Low-dose naltrexone, typically administered at doses of 1.5 to 4.5 mg daily, represents a fundamentally different therapeutic approach compared to naltrexone’s standard approved doses of 50-150 mg used for opioid and alcohol dependence [1].
At these low doses, LDN operates through distinct mechanisms that are largely independent of traditional opioid receptor antagonism.
The primary mechanism involves transient opioid receptor blockade, which induces a rebound effect that enhances endorphin release and compensatory upregulation of endogenous opioids [2].
Importantly, low-dose naltrexone also modulates Toll-like receptor 4 (TLR4) signalling pathways, reducing glial cell inflammatory responses and microglial activation [3]. This glial cell modulation represents a novel anti-inflammatory mechanism distinct from opioid receptor effects, making LDN a potentially useful first-in-class glial cell modulator for the management of chronic inflammatory conditions [1].
Immunomodulatory effects and animal models
Research utilising experimental autoimmune encephalomyelitis (EAE), the primary animal model of multiple sclerosis, has provided crucial insights into LDN’s immunomodulatory properties.
Studies demonstrate that both prophylactic and traditional low-dose naltrexone treatment regimens modulate disease progression, with timing of treatment initiation proving critical for outcomes [4].
Prophylactic LDN treatment delayed disease onset, suppressed neutrophil replication, and curtailed lymphocyte proliferation, resulting in improved behavioural outcomes [4].
Traditional therapy initiated at disease presentation reversed behavioural deficits within 8 days, restored serum opioid growth factor (OGF) levels, and inhibited microglial activation [4].
Both treatment regimens reduced activated microglia, though only prophylactic treatment prevented CNS macrophage aggregation [4].
At the cellular level, low-dose naltrexone induces a shift in microglial phenotype from a pro-inflammatory (iNOShigh CD206low) state to an anti-inflammatory M2 phenotype (iNOSlow CD206high) [5]. This phenotypic shift is accompanied by metabolic reprogramming, with cells transitioning from high glycolysis to mitochondrial oxidative phosphorylation [5].
EAE evidence: OGF/LDN suppress peripheral T- and B-cell proliferation after MOG immunisation
Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of multiple sclerosis. In this model, EAE is induced by immunising mice with myelin oligodendrocytic glycoprotein (MOG35–55), and behavioural signs of chronic, progressive disease typically appear around nine days later [6].
The immune response includes activation and proliferation of T and B lymphocytes in peripheral lymphoid tissues such as the spleen and inguinal lymph nodes. Previous work suggests the opioid growth factor–opioid growth factor receptor (OGF–OGFr) axis can limit EAE progression when treatment begins at induction or after disease is established, with OGF or low-dose naltrexone (LDN) also linked to improved behavioural outcomes and reduced spinal cord pathology. However, there has been relatively limited detail on how these treatments affect peripheral lymphocyte dynamics following MOG immunisation [6].
In one study, six-week-old female mice were immunised with MOG35–55 and treated intraperitoneally with either OGF or LDN from the time of immunisation, with saline-treated immunised mice serving as controls. Over two weeks, spleens and inguinal lymph nodes were collected to quantify total lymphocytes and assess CD4+ and CD8+ T-cell and B-lymphocyte subpopulations by flow cytometry; lumbar spinal cord tissue was also analysed on day 15 to assess Th1, Th2, and Th17 markers [6].
Treatment with OGF (or increased endogenous OGF following LDN) suppressed proliferation of CD4+ and CD8+ T cells and B220+ B lymphocytes in peripheral tissues, and reduced peripheral T-cell proliferation at days 5 and 12 was associated with improved clinical behaviour. After 15 days of OGF treatment, Th1 and Th17 populations were elevated, while Th2-associated subpopulations were not detected, supporting a potential immunomodulatory mechanism relevant to MS [6].
Serum biomarkers and opioid system dysregulation
A significant finding in MS research is that serum met-enkephalin levels, an endogenous opioid, are markedly reduced in patients with multiple sclerosis compared to healthy controls and individuals with other neurological disorders [7].
This reduction appears to be a characteristic feature of MS pathophysiology. Importantly, LDN treatment restores these depressed enkephalin levels to normal ranges prior to the appearance of clinical improvement, suggesting that restoration of the endogenous opioid system may be crucial for therapeutic efficacy [7].
Opioid growth factor (OGF), which is chemically identical to met-enkephalin, is similarly decreased in MS patients and in EAE animal models, suggesting dysregulation of this inhibitory neuropeptide system in MS [7].
Modulation of the OGF-OGFr pathway by LDN alters multiple cytokine profiles, with studies showing reductions in pro-inflammatory cytokines, including IL-6 and TNF-?, while maintaining appropriate anti-inflammatory responses [8].
Clinical trial evidence in multiple sclerosis
Primary progressive multiple sclerosis
A pivotal six-month, multicentre, phase II pilot trial examined the safety and efficacy of LDN in 40 patients with primary progressive multiple sclerosis [9]. The primary endpoints were safety and tolerability, with secondary outcomes measuring effects on spasticity, pain, fatigue, depression, and quality of life.
The trial demonstrated that LDN was safe and well-tolerated, with 5 dropouts and 2 major adverse events that did not interfere with daily activities. Importantly, neurological disability progressed in only one patient throughout the trial [9]. Significant reduction in spasticity was measured during the trial, and beta-endorphin levels increased, though no significant association was found between OPRM1 (opioid receptor gene) allelic variants and improvement in spasticity [9].
Relapsing-remitting MS and quality of life
A significant randomised, double-blind, placebo-controlled trial evaluated the efficacy of nightly 4.5 mg naltrexone on quality of life in 80 patients with clinically definite MS, of whom 60 completed the trial [10].
Despite substantial dropout rates that reduced statistical power, LDN was well tolerated with no serious adverse events. The medication showed significant improvement in several mental health measures, including a 3.3-point increase in the Mental Component Summary score of the Short Form-36 General Health Survey, a 6-point increase in the Inventory of Depressive Symptomatology, a 1.6-point increase in the Pain Effects Scale, and a 2.4-point increase in the Perceived Deficits Questionnaire [10].
Another 17-week, randomised, double-blind, placebo-controlled trial involving 96 adults with relapsing-remitting or secondary progressive MS assessed quality of life using the MSQoL-54 questionnaire [11].
Results showed that while various quality of life variables, including pain, energy, emotional well-being, social function, cognitive function, and sexual function, did not show statistically significant differences between LDN and placebo groups, the study concluded that LDN represents a relatively safe therapeutic option for both RRMS and SPMS. However, its efficacy remains questionable, with longer-term follow-up studies deemed necessary [11].
Long-term safety and efficacy
Long-term retrospective data from Penn State Hershey Medical Center followed patients with relapsing-remitting MS receiving either low-dose naltrexone alone or LDN as adjunctive therapy to glatiramer acetate [12].
One cohort of 23 patients received LDN at their initial visit due to fatigue symptoms or refusal of available disease-modifying therapy. In contrast, a second cohort of 31 patients received glatiramer acetate with LDN offered as adjunctive therapy. Data from visits after 150 months post-diagnosis showed no significant differences in clinical laboratory values, timed walking, or MRI changes between groups, suggesting that LDN, when taken alone, did not result in disease exacerbation and appeared to be non-toxic and inexpensive, supporting its safety profile [12].
Symptom management
LDN has demonstrated utility in managing multiple MS-related symptoms beyond those typically targeted by disease-modifying therapies. A case study documented the use of LDN (4.5 mg nightly) in conjunction with the Wahls Protocol in reducing the frequency and severity of chronic migraines in a 62-year-old female with multiple sclerosis, with significant improvement in her quality of life by reducing migraine severity and duration [13]. The anti-inflammatory effects of LDN appear to extend across multiple domains of MS symptomatology, contributing to pain relief, fatigue reduction, and improved mood [2].
Cytokine modulation
Studies examining the effects of the OGF-OGFr pathway on cytokine profiles in EAE and MS have revealed that LDN and OGF treatment modulate the expression of several key cytokines [8].
In experimental autoimmune encephalomyelitis, LDN resulted in reduced IL-6 expression and a significant reduction in IL-10 levels relative to saline-treated mice. In contrast, TNF-? values that were elevated in untreated EAE mice returned to normal with LDN treatment [8].
While observations in human MS patients, markedly reduced IL-6 levels were observed among those receiving standard disease-modifying therapy, and LDN similarly modulated the expression patterns of cytokines critical to the inflammatory cascade [8].
Medication utilisation patterns
A quasi-experimental Norwegian study examined whether the sudden increase in LDN use in 2013 was followed by changes in the dispensing of other MS medications [14].
Data from 341 MS patients showed that initiation of LDN was not followed by reductions in cumulative dispensed doses or number of prevalent users of MS-specific medications over a two-year observation period [14].
This finding suggests that, although patients in clinical practice adopted low-dose naltrexone extensively, there was no corresponding reduction in the use of other disease-modifying therapies, raising questions about the complementary versus substitutive roles of LDN.
Safety concerns and rare complications
While low-dose naltrexone is generally considered safe, isolated case reports have documented rare but serious complications. A notable case describes treatment-resistant immune thrombocytopenic purpura (ITP) developing after LDN use in an MS patient [15]. This unusual association highlights the need for vigilant monitoring during LDN therapy, as some patients may develop immune complications despite the generally favourable safety profile [15].
Limitations of current evidence
Despite promising preclinical and some clinical evidence, several significant limitations characterise the current LDN literature in MS. Most published trials have small sample sizes, with few replications performed [3].
The evidence base remains highly experimental, with questions persisting about optimal dosing, treatment duration, patient selection criteria, and long-term efficacy [3].
The high degree of variation in study designs, outcome measures, and patient populations makes direct comparison and meta-analysis challenging. Furthermore, while LDN appears safe and potentially beneficial for symptom management, its role as a primary disease-modifying therapy remains uncertain, with efficacy demonstrated primarily for specific symptoms like pain and fatigue rather than for halting overall disease progression [11].
Future research directions
The immunomodulatory and neuroprotective properties of low-dose naltrexone warrant continued investigation through rigorously designed, adequately powered randomised controlled trials.
Research should focus on defining optimal dosing regimens, identifying patient populations most likely to benefit, clarifying the relationship between enkephalin restoration and clinical improvement, and determining whether LDN has disease-modifying potential beyond symptom management.
Additionally, mechanistic studies exploring the interplay between LDN effects on the endogenous opioid system, glial cell modulation, and specific MS pathogenic pathways would advance understanding of this potentially paradigm-shifting therapeutic approach [3].
Conclusion
Low-dose naltrexone represents a novel therapeutic approach to multiple sclerosis with multiple lines of evidence supporting immunomodulatory and anti-inflammatory mechanisms.
While preclinical studies demonstrate clear effects on microglial activation, cytokine modulation, and immune cell proliferation, clinical evidence remains limited to small trials that show promise in symptom management, particularly for pain, fatigue, and quality-of-life measures.
LDN appears to be a safe and inexpensive option for symptom management in MS patients, particularly those experiencing pain or fatigue. However, its role as a disease-modifying therapy has not been established, and larger, well-designed clinical trials are essential before definitive therapeutic recommendations can be made.
The dysregulation of endogenous opioid systems in MS patients, characterised by reduced met-enkephalin and OGF levels, provides a compelling biological rationale for LDN therapy that deserves continued investigation.
References:
Mechanism of action and pharmacology
Immunomodulatory effects and animal models
[5] N. Kui, V. Raki, R. Verko, T. Vidovi, I. Grahovac, and J. MriPeli, “Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells,” Multidisciplinary Digital Publishing Institute, Aug. 2021,https://www.mdpi.com/1422-0067/22/16/8429
[6] P. J. McLaughlin, D. P. McHugh, M. J. Magister, and I. S. Zagon, “Endogenous opioid inhibition of proliferation of T and B cell subpopulations in response to immunization for experimental autoimmune encephalomyelitis,” BioMed Central, Apr. 2015, doi: https://doi.org/10.1186/s12865-015-0093-0.
Serum biomarkers and opioid system dysregulation
[8] M. D. Ludwig, I. S. Zagon, and P. J. McLaughlin, “Featured Article: Modulation of the OGFOGFr pathway alters cytokine profiles in experimental autoimmune encephalomyelitis and multiple sclerosis,” SAGE Publishing, Jan. 2018, https://journals.sagepub.com/doi/abs/10.1177/1535370217749830
Primary progressive multiple sclerosis
[9] M. Gironi et al., “A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis,” SAGE Publishing, Jul. 2008. https://journals.sagepub.com/doi/abs/10.1177/1352458508095828?casa_token=HVc7n3VYWP8AAAAA:mdYUTJlg3T3WH8i04qbhY86vbn2QT28wOk0krIZF-N_koug-nP7J42SkCmKy_ym0zV0SDdfoovE
Relapsing-remitting MS and quality of life
[10] B. Cree, E. Kornyeyeva, and D. S. Goodin, “Pilot trial of lowdose naltrexone and quality of life in multiple sclerosis,” Wiley, Feb. 2010, doi: https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.22006
[11] N. Sharafaddinzadeh, A. Moghtaderi, D. Kashipazha, N. Majdinasab, and B. Shalbafan, “The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial,” SAGE Publishing, Jun. 2010, doi: https://journals.sagepub.com/doi/abs/10.1177/1352458510366857?casa_token=LPi_VNRCuXwAAAAA:bESJdjAWioKf02t2R-4DHw56yPi0AdgE_IY5x1qMSnLJI00sPLbbAx-rHYY_fSsnTVHFCvQDmek
Long-term safety and efficacy
Symptom management
Safety concerns and rare complications
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