Interactions Between Low-Dose Naltrexone and Selective Serotonin Reuptake Inhibitors: Clinical Considerations

Edited by Yoon Hang Kim MD MPH

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Introduction

Low-dose naltrexone (LDN), administered at doses ranging from 1–5 mg daily, has gained attention as an off-label therapy for chronic pain, autoimmune conditions, and major depressive disorder (MDD). Unlike standard 50 mg naltrexone, LDN works by briefly antagonizing mu-opioid receptors, which paradoxically stimulates endogenous opioid production (endorphins, enkephalins) and reduces neuroinflammation by modulating glial cells and cytokines.

In contrast, selective serotonin reuptake inhibitors (SSRIs)—such as sertraline, fluoxetine, and escitalopram—remain first-line treatments for MDD and anxiety disorders. They increase serotonin availability in the synaptic cleft, enhancing mood regulation and reducing anxiety.

With polypharmacy becoming more common, clinicians and patients alike are asking: Can LDN be safely combined with SSRIs? This article explores pharmacological mechanisms, available evidence, and clinical recommendations for co-administration.

Pharmacological Mechanisms and Theoretical Interactions

Both the opioid and serotonergic systems play central roles in mood regulation, pain perception, and immune signaling.

• LDN effects: By briefly blocking opioid receptors, LDN triggers a rebound increase in endogenous opioids, potentially enhancing dopamine activity and improving mood.

• SSRI effects: By increasing serotonin levels, SSRIs may also influence opioid tone indirectly, as serotonin modulates hypothalamic beta-endorphin release.

Potential Concerns

• Endorphin suppression: Certain SSRIs (e.g., fluoxetine, sertraline) may blunt endorphin production, possibly reducing LDN’s effectiveness.

• Serotonin syndrome (theoretical): While naltrexone may alter monoamine signaling, no published cases link LDN with serotonin syndrome when used alongside SSRIs.

• Drug interaction data: Major databases report no significant pharmacokinetic interactions between naltrexone and SSRIs.

Empirical Evidence from Clinical Studies

LDN as an Add-On in Depression

• Proof-of-concept trial (Mischoulon et al., 2017): In 12 patients with MDD relapse, 1 mg LDN added to antidepressants significantly reduced Hamilton Depression Rating Scale scores.

• Registry study (Morken et al., 2019): Norwegian data showed patients starting LDN had reduced use of psychotropic drugs, including antidepressants.

• Ongoing trial (Parkitny et al., 2022): A 48-patient study is assessing LDN (4.5 mg) alongside antidepressants, stratified by inflammatory biomarkers. Safety is a key endpoint.

Comorbid Conditions

• Fibromyalgia: Case reports and small studies suggest LDN can improve both pain and depressive symptoms when added to SSRIs.

• Alcohol dependence (Weerts et al., 2009): Higher-dose naltrexone (50 mg) with sertraline showed synergy, though mechanisms differ from low-dose use.

Safety Profile

Across studies, LDN has been well tolerated with SSRIs. Starting at lower doses (e.g., 0.5–1 mg) is recommended to monitor for tolerability. Adverse events are mild (GI upset, sleep changes) and typically resolve.

Clinical Implications and Recommendations

• When to consider LDN + SSRI:

  • Treatment-resistant depression

  • Inflammatory-driven depression subtypes

  • Chronic pain or autoimmune comorbidities

• Monitoring:

  • Track subtle mood shifts or GI side effects

  • Educate patients about gradual titration (0.5–1 mg start, up to 4.5 mg)

  • Reassure regarding low serotonin syndrome risk

• Clinical takeaway: LDN may provide a safe, low-cost augmentation strategy for patients who have not fully responded to SSRIs.

Conclusion

The evidence to date suggests that low-dose naltrexone can be safely co-administered with SSRIs, with minimal interaction risk and potential synergistic benefits. While larger randomized trials are still needed, early data support cautious optimism. For clinicians, LDN represents an intriguing adjunctive tool in precision psychiatry—especially for patients with inflammatory or treatment-resistant depression.

References

Mischoulon, D., Fava, M., Laird, N. M., Fogelman, S. M., IsHak, W. W., Rosenbaum, J. F., & Papakostas, G. I. (2017). A randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder. Journal of Affective Disorders, 208, 294–300. https://doi.org/10.1016/j.jad.2016.10.018

Morken, G., Waal, H., Bakken, I. J., & Bramness, J. G. (2019). Changes in the consumption of antiepileptics and psychotropic medicines after starting low dose naltrexone: A nationwide study. Scientific Reports, 9(1), 15065. https://doi.org/10.1038/s41598-019-51569-z

Parkitny, L., Vollset, S. E., Ystrom, E., Surén, P., Stoltenberg, C., Magnus, P., & Magnus, M. C. (2022). A randomized, double-blind, placebo-controlled, hybrid parallel-arm study of low-dose naltrexone as an adjunctive anti-inflammatory treatment for major depressive disorder. Trials, 23(1), 803. https://doi.org/10.1186/s13063-022-06707-8

Tolliver, B. K., Wells, E. A., Basinski, J., & McCarty, D. (2010). A double-blind, placebo-controlled trial combining sertraline and naltrexone for compulsive sexual behavior. American Journal of Psychiatry, 167(6), 668–674. https://doi.org/10.1176/appi.ajp.2009.09030394

Weerts, E. M., Kim, Y. K., Wand, G. S., Dannals, R. F., Lee, J. S., Frost, J. J., McCaul, M. E., & Levin, K. H. (2009). Naltrexone alone and with sertraline for the treatment of alcohol dependence in dual-diagnosis patients. Alcoholism: Clinical and Experimental Research, 33(10), 1646–1654. https://doi.org/10.1111/j.1530-0277.2009.01003.x

Younger, J., Noor, N., McCue, R., & Mackey, S. (2013). Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis & Rheumatism, 65(2), 356–364. https://doi.org/10.1002/art.37734

Girgenti, A., Di Sabato, F., & Conte, A. (2022). Depression in fibromyalgia patients may require low-dose naltrexone in addition to standard antidepressants. Cureus, 14(2), e22703. https://doi.org/10.7759/cureus.22703

References (Weblink)

1. Tolliver BK, et al. Am J Psychiatry. 2010

2. Mischoulon D, et al. J Affect Disord. 2017

3. Morken G, et al. Sci Rep. 2019

4. Parkitny L, et al. Trials. 2022

5. Weerts EM, et al. Alcohol Clin Exp Res. 2009

6. Girgenti A, et al. Cureus. 2022

7. Younger J, et al. Arthritis Rheum. 2013

Guiding patients toward optimal wellness is Dr. Yoon Hang Kim, MD, a dedicated practitioner in the field of integrative and functional medicine. Through his virtual practice, Dr. Kim provides personalized, root-cause analysis to help individuals uncover the underlying factors contributing to their health concerns. He partners with patients to develop tailored, holistic treatment plans that integrate evidence-based strategies for sustainable well-being. His supportive and methodical approach is accessible to residents across several states, including Illinois (IL), Missouri (MO), Iowa (IA), Florida (FL), Georgia (GA), and Texas (TX), offering a clear path to improved health. www.directintegrativecare.com