Medical Disclaimer: This article is for educational purposes only and does not constitute medical advice. Low-dose naltrexone should be prescribed and monitored by a qualified healthcare provider. Do not adjust your medication without consulting your physician.

By Yoon Hang Kim, MD, MPH

Board-Certified in Preventive Medicine and Integrative & Holistic Medicine

www.directintegrativecare.com

Introduction

Low-dose naltrexone (LDN) has become an increasingly popular therapy for chronic pain, autoimmune disease, and inflammatory conditions.^1,2 While many patients benefit from LDN, dosing errors can lead to unexpected and sometimes alarming symptoms. One of the most common pitfalls I encounter in clinical practice is starting at too high a dose, which can trigger a phenomenon I refer to as endorphin depletion.

This article explains how endorphin depletion develops, what symptoms to watch for, and how to manage dosing safely when it occurs.

Can LDN Cause Emotional Side Effects?

A question that arises regularly in my practice and in the LDN Support Group involves patients who experience emotional reactions or shakiness shortly after starting LDN—even at very low doses.

Consider a representative scenario: a patient with twenty-five years of chronic illness and pain, previously stable, begins LDN at 0.1 mg (100 micrograms). The first two doses are tolerated without difficulty. After the third dose, however, the patient develops persistent shakiness, emotional dysregulation, and sudden mood instability. Blood glucose levels are normal. There are no other medication changes or new life stressors.

This pattern—tolerating the initial doses and then developing significant emotional symptoms—is highly suggestive of endorphin depletion.

The Role of Endorphins in Mood Regulation

Endorphins are most commonly understood as the body’s natural painkillers, but their role extends well beyond analgesia. Endorphin signaling contributes to emotional stability, stress resilience, reward processing, and overall mood regulation.^3,4 In many ways, endorphins function somewhere between serotonin and dopamine in the brain’s emotional circuitry.

When LDN dosing disrupts endorphin balance—either by starting too high or escalating too quickly—the result can be emotional instability, anxiety, or depression-like symptoms that may be alarming to both the patient and the prescriber.

What Is Endorphin Depletion?

Endorphin depletion occurs when the body temporarily loses its capacity to maintain normal endorphin signaling. In the context of LDN, this typically happens when the degree of opioid receptor blockade exceeds what the system can compensate for. The net effect is a transient deficit in endorphin-mediated function.⁵

Common triggers include starting at a dose that is too high for the individual patient, increasing doses too rapidly during titration, or the presence of high biological sensitivity—which is particularly prevalent in patients with conditions such as mast cell activation syndrome (MCAS), fibromyalgia, or Ehlers-Danlos syndrome.^6,7

Symptoms of endorphin depletion may include anxiety, mood swings, emotional reactivity, body aches, sleep disruption, and fatigue. These symptoms can overlap with the underlying chronic illness, which makes recognition of the pattern especially important.

A Screening-Based Approach to Starting Dose

In my practice, I use a set of three screening questions before initiating LDN. The number of positive responses determines my starting dose:

If one screening question is positive, I begin at 10⁻¹ mg (approximately 0.1 mg). If two are positive, I begin at 10⁻² mg (approximately 0.01 mg). If all three are positive, I begin at 10⁻³ mg—approximately one microgram.

This approach does not guarantee that problems will not occur, but in my clinical experience it substantially reduces the incidence of endorphin depletion.

Managing Endorphin Depletion

When endorphin depletion occurs, the most effective intervention is straightforward: stop LDN temporarily. In most cases, a washout period of approximately seven days allows the body’s endorphin system to recover.

After recovery, LDN can be restarted at a significantly lower dose. Some patients require doses as low as one microgram; in rare cases, I have had patients dilute further into the nanogram range before they could tolerate the medication.

A common clinical scenario illustrates this well: a patient starts at 1.5 mg, experiences mild side effects that resolve, then increases to 3 mg. Severe anxiety develops at the higher dose. Even after dropping back to 1.5 mg, the anxiety persists. Stopping for several days and restarting at 0.5 mg improves the anxiety but introduces new symptoms such as body aches. This cascade pattern is classic for endorphin depletion and signals the need for a full washout before resuming at a much lower dose.

Adjusting LDN Timing

Another issue that arises is sleep disruption. Some patients—particularly children and adolescents—notice that LDN causes a progressive delay in sleep onset. For example, a child being titrated slowly to approximately 1 mg may experience improvements in fatigue, brain fog, and focus but begin sleeping later and later each night.

In these cases, adjusting the timing of the dose can be helpful. Strategies include taking LDN earlier in the evening, shifting it to the morning, or splitting the dose. Because LDN responses vary widely across individuals, careful experimentation under medical supervision is the safest approach.⁸

Why LDN Dosing Must Be Individualized

LDN is not a one-size-fits-all therapy. Two patients with the same diagnosis may require dramatically different doses. Factors that influence optimal dosing include the duration and severity of chronic illness, hormonal status (particularly perimenopause and hypothyroidism), nervous system sensitivity, and baseline endorphin function.⁹

For this reason, I believe it is essential for patients to work with a clinician who understands LDN titration and can serve as a thinking partner throughout the process. While LDN is increasingly available through online services and quick-prescribing platforms, the dosing guidance that accompanies these prescriptions is often inadequate. When complications arise, patients may find themselves without meaningful clinical support.

Conclusion

Low-dose naltrexone remains a powerful therapeutic tool for a wide range of chronic conditions. However, dosing errors are common, and the consequences—particularly endorphin depletion syndrome—are frequently misunderstood or misattributed to the underlying disease.

The core principles are simple: start low, increase slowly, pause treatment if symptoms appear, and restart at a lower dose when necessary. When used with care and clinical attentiveness, LDN can be both safe and profoundly effective.

For additional reading on endorphin depletion and LDN dosing, visit my blog at www.ifmsynergy.com.

References

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2. Toljan K, Vrooman B. Low-dose naltrexone (LDN)—review of therapeutic utilization. Med Sci (Basel). 2018;6(4):82.
3. Sprouse-Blum AS, Smith G, Sugai D, Parsa FD. Understanding endorphins and their importance in pain management. Hawaii Med J. 2010;69(3):70–71.
4. Dishman RK, O’Connor PJ. Lessons in exercise neurobiology: the case of endorphins. Ment Health Phys Act. 2009;2(1):4–9.
5. Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response in mice with neuroblastoma. Science. 1983;221(4611):671–673.
6. Kim YH. 2025 LDN Therapy: LDN Plus Other Tools for Healing. Amazon; 2025. See also: Kim YH, Ely KB. Low Dose Naltrexone (LDN) Therapy: An Evidence Based Review and Case Histories. Independently published; 2018.
7. Weinstock LB, Brook JB, Walters AS, et al. Mast cell activation symptoms are prevalent in long-COVID. Int J Infect Dis. 2021;112:217–226.
8. Raknes G, Simonsen P, Småbrekke L. The effect of low-dose naltrexone on medication in inflammatory bowel disease: a quasi-experimental before-and-after prescription database study. J Crohns Colitis. 2018;12(6):677–686.
9. Patten DK, Schultz BG, Berlau DJ. The safety and efficacy of low-dose naltrexone in the management of chronic pain and inflammation in multiple sclerosis, fibromyalgia, Crohn’s disease, and other chronic pain disorders. Pharmacotherapy. 2018;38(3):382–389.