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Low-Dose Naltrexone (LDN) in Psychiatry: A Comprehensive Guide

Low-dose naltrexone (LDN) is being explored as an investigational, off-label adjunct in psychiatry. This guide explains what LDN is, how it may work on endorphin and immune systems, where current evidence supports a careful trial, and the safety considerations every patient and prescriber should know.

Originally published November 14, 2025

Last reviewed June 3, 2026

Clinical review: Fady Boules, PMHNP-BC

What Is Low-Dose Naltrexone (LDN)?

Naltrexone, at its standard FDA-approved dose, has been used for decades to help treat alcohol and opioid use disorders. At that dose, naltrexone strongly and continuously blocks opioid receptors, which prevents substances like heroin or alcohol from producing their usual effects.

Low-dose naltrexone (LDN) is very different in both dose and intent:

  • Dose: A tiny fraction of the FDA-approved standard dose, prepared by a compounding pharmacy in milligram or fractional-milligram amounts
  • Use: Off-label for conditions linked to chronic pain, neuroinflammation, and mood dysregulation
  • Goal: Not to block all opioids, but to gently nudge the body’s own endorphin and immune systems toward a healthier balance

Because LDN uses such a small fraction of the standard dose, its side-effect profile, clinical effects, and proposed mechanisms differ from full-dose naltrexone.

How Does LDN Work?

LDN has two main proposed mechanisms that make it especially interesting for psychiatric and mind-body conditions.

1. Endorphin Rebound Effect

At low doses, naltrexone briefly blocks opioid receptors for only a few hours. The body senses this short-term blockade and responds by increasing production of its own endogenous opioids, including beta-endorphin.

When LDN wears off, this rebound effect can lead to:

  • Higher natural endorphin levels
  • Possible improvements in mood, motivation, pain tolerance, and sense of well-being

You can think of it like gently pressing down a spring for a short time. When the pressure is released, the spring bounces back a little higher than before.

2. Anti-Inflammatory Effect on Microglia

LDN also appears to affect the immune system in the brain and body, especially microglia — the brain’s resident immune cells.

LDN may:

  • Interact with Toll-like receptor 4 (TLR4) on microglia
  • Shift microglia from a pro-inflammatory state toward a more regulated, less inflammatory pattern

Chronic neuroinflammation is increasingly linked to conditions such as depression, anxiety, fatigue, and “brain fog.” By calming microglial activation, LDN may help stabilize mood, energy, and cognition.

How LDN Is Typically Prescribed

Because LDN is used off-label and the optimal dose is highly individual, every regimen is set by the prescriber for the specific patient and indication. The shared pattern across conditions looks like this:

  • LDN is started at a very low dose and increased slowly over weeks, based on response and tolerability.
  • The right target dose is highly individual — some patients do well at small daily amounts, others tolerate a somewhat higher dose, and a smaller group does best at lower-than-typical amounts.
  • Most regimens are evaluated after a sustained trial of several weeks at a steady dose before deciding whether to continue.
  • LDN must be prepared by a compounding pharmacy, since no FDA-approved low-dose formulation exists. Both capsules and liquid formulations are available.

This essay deliberately does not provide specific dosing guidance. If you are considering LDN, those numbers should come from a prescriber who will tailor them to you, your other medications, and the condition being treated.

Why Psychiatrists Are Interested in LDN

Psychiatrists and integrative clinicians are paying attention to LDN for several reasons:

  • It targets inflammation and immune imbalance, which fits emerging models of depression, anxiety, and post-viral syndromes.
  • At low doses, its safety profile appears generally favorable, with common side effects usually mild and short-lived.
  • It is not addictive and does not cause euphoria or withdrawal.
  • It is generic and relatively inexpensive when compounded.
  • It may improve several symptom clusters at once, including mood, sleep, pain, fatigue, and cognitive clarity.

At the same time, most psychiatric uses of LDN remain experimental, supported by a mix of small studies, observational data, and case reports rather than large randomized controlled trials.

LDN for Depression

LDN is not considered a first-line antidepressant. However, early findings suggest it may be useful as an add-on treatment in people with treatment-resistant major depressive disorder, especially when inflammation is suspected.

What Current Evidence Suggests

A small proof-of-concept randomized trial by Mischoulon and colleagues at Massachusetts General Hospital (Journal of Affective Disorders, 2017) studied 12 adults with recurrent depression who were already taking pro-dopaminergic antidepressants such as bupropion, dopamine agonists, or stimulants. Six received LDN augmentation, six received placebo, for three weeks.

The trial did not reach statistical significance on its primary outcome. The LDN group did show a numerical advantage over placebo on depression rating scales — a moderate effect size on the primary outcome and a larger effect size on a secondary outcome — but with only twelve participants, the sample was far too small to draw conclusions, and apparent effects of that magnitude could be due to chance. The authors framed the result as a preliminary signal worth confirming in larger trials, not as evidence of efficacy.

Larger confirmatory trials are now in progress. As of 2026, the depression evidence for LDN is best described as “promising but unproven.”

Who Might Be Considered?

LDN may be considered as an experimental adjunct in patients who have:

  • Depression alongside signs of inflammation, such as elevated CRP or autoimmune illness
  • Treatment-resistant depression despite adequate trials of standard antidepressants
  • Low motivation, reduced pleasure, or what some clinicians describe as “low endorphin tone”
  • Existing treatment with bupropion or other dopaminergic agents, where endorphin and dopamine systems may interact

For depression, LDN is best viewed as an experimental adjunct, not a replacement for established treatments. Overall evidence quality is low, and more research is needed before LDN can be considered a standard option.

LDN for Anxiety Disorders

There are currently no large randomized trials focused specifically on low-dose naltrexone for primary anxiety disorders such as generalized anxiety disorder or panic disorder.

However, indirect evidence and clinical experience suggest LDN may help in cases where anxiety is tightly linked to inflammation, chronic pain, or autoimmune conditions. For example, a study of people with multiple sclerosis (Ludwig and colleagues, International Immunopharmacology, 2022) found that those prescribed LDN — either alone or as an adjunct to standard disease-modifying therapies — reported significantly lower anxiety and depression scores than those on disease-modifying therapy alone.

When LDN Might Help Anxiety

LDN is not a fast-acting anti-anxiety medication. Any benefit tends to appear gradually as inflammation and nervous-system reactivity shift. It may be considered in situations such as:

  • Anxiety in the setting of autoimmune disease, chronic infections, or inflammatory conditions
  • Anxiety combined with chronic pain, fatigue, or post-viral syndromes like fibromyalgia and Long COVID
  • Treatment-resistant anxiety where standard medications and psychotherapy have been optimized but symptoms remain

Because evidence is still limited and low-quality, LDN should be used as a cautious experimental adjunct, not as a replacement for established anxiety treatments.

LDN and PTSD: Focus on Dissociation

One of the most intriguing psychiatric uses for LDN is in complex PTSD with significant dissociation — symptoms that include emotional numbing, feeling unreal, or feeling disconnected from one’s own body and surroundings.

Several small open-label case series in patients with severe, therapy-resistant complex PTSD have reported that LDN was associated with:

  • Reductions in depersonalization and derealization
  • Greater emotional presence and improved self-regulation
  • Better engagement in trauma-focused psychotherapy

For some patients, LDN appeared to reduce dissociation enough that they could feel emotions and memories more safely, without becoming overwhelmed or completely shut down.

It is important to be clear about the evidence quality here. These are small, open-label observations, not controlled trials. The broader literature on opioid antagonists in dissociative symptoms is mixed — including a higher-dose randomized trial that did not reach statistical significance. LDN for PTSD-related dissociation is a reasonable experimental option in carefully selected patients under specialist care, alongside trauma-informed psychotherapy, not a stand-alone treatment.

LDN for OCD and Compulsive Behaviors

Research on LDN for classic obsessive-compulsive disorder is extremely limited. There is also a small but interesting signal in body-focused repetitive behaviors, including:

  • Excoriation (skin-picking) disorder
  • Trichotillomania (hair-pulling)

The published low-dose evidence here is a single case report (Varghese, Yan, and Cao, Cureus, 2024): a 51-year-old woman who was prescribed LDN for fibromyalgia and incidentally reported substantial improvement in skin-picking after three months. When LDN was temporarily stopped for an elective procedure, her skin lesions worsened; when it was resumed, they improved again. To the authors’ knowledge, this was the first reported case of excoriation disorder improving with LDN specifically — earlier reports used the standard, much higher FDA-approved dose.

Because many compulsive and self-soothing behaviors are thought to involve opioid-mediated reward loops, gently modulating that system with LDN may, in theory, help weaken the cycle of urge and relief. But the current evidence base in body-focused repetitive behaviors is one case at the low dose. Anyone considering LDN for these conditions should view it as a thoughtful experimental option, always paired with behavioral therapies such as habit-reversal training and the standard OCD-spectrum treatments.

LDN in Neurodevelopmental Disorders

Autism Spectrum Disorder (ASD)

Naltrexone has been studied in autism since the late 1980s and 1990s. A systematic review by Roy and colleagues (Journal of Intellectual Disability Research, 2015) pooled ten small studies in 155 children and concluded that naltrexone produced a modest reduction in hyperactivity and restlessness but did not appear to improve the core features of autism such as social communication or stereotyped behaviors. Most of those studies used higher doses than what is now called LDN.

In modern clinical practice, some clinicians use truly low doses, targeting irritability, aggression, and self-injury as part of a broader integrative plan in selected children and adolescents. Evidence at these lower doses is largely anecdotal.

PANS and PANDAS

Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) involve sudden onset of OCD, tics, and severe anxiety, likely driven by autoimmune or inflammatory processes triggered by infection.

Because LDN appears to calm neuroinflammation and modulate immune activity, some PANS/PANDAS specialists include it as a potential adjunct. LDN should only be considered for these conditions under the care of clinicians experienced in pediatric neurodevelopmental and immune-mediated psychiatric care.

Pediatric Use in General

When LDN is used in children and adolescents, it should always be prescribed and monitored by clinicians experienced in pediatric care. Compounding pharmacies can prepare liquid formulations that allow very precise, child-friendly dosing.

LDN for Fibromyalgia, ME/CFS, and Long COVID

The strongest and most consistent clinical evidence for LDN comes from fibromyalgia. Two small placebo-controlled trials by Younger and colleagues at Stanford (Pain Medicine, 2009; Arthritis & Rheumatism, 2013) reported that LDN reduced fibromyalgia pain significantly more than placebo. In the 2013 trial, about a third of patients met strict criteria for response — meaningful reductions in pain plus improvements in fatigue or sleep — compared with roughly one in ten on placebo. Patients also reported improved mood and overall life satisfaction. Larger and more recent randomized trials are ongoing.

In Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Long COVID, evidence is more recent and largely observational, but growing. Tamariz and colleagues at the Miami VA Long COVID clinic (Clinical Therapeutics, 2024) reported that patients receiving LDN were significantly more likely to improve in both fatigue and pain than those receiving physical therapy alone. A separate pilot study by Bonilla and colleagues (Brain, Behavior, & Immunity — Health, 2024) found that about half of patients with persistent post-COVID fatigue showed meaningful improvement on quality-of-life and fatigue scales over twelve weeks of LDN.

These are observational and pre-post findings, not randomized controlled trials — there are no published RCTs of LDN in Long COVID yet, although several are underway. Clinical experience and emerging data suggest LDN may help with:

  • Fatigue and post-exertional malaise
  • Brain fog and concentration problems
  • Sleep quality and circadian rhythm

These conditions often blend neurologic, immune, and psychiatric features, and because LDN acts on both endorphin regulation and neuroinflammation, it is a logical candidate. In fibromyalgia, ME/CFS, and Long COVID, LDN is increasingly used as a third-line option once standard pain, mood, and sleep treatments have been tried.

It often takes several weeks at a steady dose to clearly see benefits, so trials of LDN in these conditions are evaluated over months, not days.

LDN, Addiction, and Borderline Personality Disorder

Addiction and Craving States

Standard FDA-approved naltrexone (at its full dose) is well-established in the treatment of alcohol and opioid use disorders. Low-dose naltrexone is being explored experimentally in early recovery for symptoms such as post-detox anhedonia, low mood, and persistent cravings — but this is not a replacement for evidence-based addiction protocols, which remain the foundation of care.

Important safety point: LDN must not be combined with ongoing daily opioid use. Patients currently taking any opioid medication, including buprenorphine or methadone, must complete a supervised washout before LDN can be started. This is covered in detail in the Safety section below.

Borderline Personality Disorder (BPD) and Self-Injury

Higher-dose naltrexone has been studied as a way to reduce non-suicidal self-injury behaviors and dissociation in BPD. Some clinicians have explored LDN in patients who cannot tolerate higher doses, hoping to reduce self-harm urges with fewer side effects. Evidence specific to LDN in BPD is limited, but the conceptual basis is similar to its use in dissociative PTSD. Any consideration of LDN in BPD should be coupled with evidence-based psychotherapy such as DBT.

Safety and Side Effects

Key Safety Issue: LDN and Opioids

The single most important safety issue with LDN is its interaction with opioid medications.

  • Patients currently taking any opioid medication on a daily basis — including buprenorphine (Suboxone, Subutex), methadone, oxycodone, hydrocodone, morphine, tramadol, or codeine-containing products — are absolutely contraindicated from starting LDN without first discontinuing the opioid and completing a full supervised washout. Starting LDN in someone still taking an opioid can trigger acute opioid withdrawal, which is a medically serious syndrome.
  • The standard washout period is generally about 7 to 10 days for short-acting opioids, and longer for methadone or other long-acting formulations. The exact window must be set by the prescriber based on the specific medication and patient.
  • A full medication reconciliation must occur before LDN is started, including over-the-counter and supplement use. Kratom contains opioid-active alkaloids and is sometimes overlooked in medication lists.
  • Patients already taking LDN should inform every surgical, dental, and anesthesia provider in advance. LDN should be stopped well before any procedure requiring opioid analgesia or anesthesia so that opioid receptor function can fully restore. The exact stop timing is set by the prescriber.
  • Tolerance and overdose risk: LDN reduces the body’s opioid tolerance over time. This means that if someone taking LDN — or someone who has recently stopped LDN — returns to a previous opioid dose, including in a relapse, they are at significantly higher risk of overdose, even at doses that were tolerated before. This point matters especially for anyone in recovery from opioid use disorder; the risk should be discussed in detail with the prescriber before LDN is started.

Liver and General Safety

At standard FDA-approved doses, naltrexone can affect the liver, especially in people with pre-existing liver disease. At low doses, this risk appears much smaller, but many clinicians still check baseline liver function and monitor periodically, particularly in patients with known liver concerns.

LDN is:

  • Not addictive
  • Not associated with withdrawal when stopped
  • Generally well-tolerated at the doses used in psychiatric and integrative care

The most frequently reported side effects at low doses are vivid or unusual dreams and initial sleep disruption. These usually settle within the first weeks; if they do not, the prescriber may adjust the timing of the dose or hold the dose at the last well-tolerated level.

As with any medication, individual responses vary, and all decisions should be made in partnership with a qualified clinician.

Key Takeaways

  • Low-dose naltrexone is a tiny-dose version of a long-standing medication that may gently boost natural endorphins and calm neuroinflammation.
  • The strongest research support currently comes from fibromyalgia and chronic pain, with growing observational evidence in Long COVID and ME/CFS.
  • In psychiatry, LDN is a promising experimental adjunct for treatment-resistant depression, complex PTSD with dissociation, body-focused repetitive behaviors, selected neurodevelopmental conditions, and complex mind-body syndromes where inflammation, pain, fatigue, and mood symptoms overlap.
  • Evidence quality varies by condition and is often limited. LDN is best used after standard therapies have been tried, not instead of them.
  • LDN is generally safe, inexpensive, and non-addictive — but it must not be combined with ongoing daily opioid use, and any patient on opioids must complete a supervised washout before starting LDN.

If you are a patient, the right step is to discuss with your psychiatrist, primary care provider, or integrative clinician whether LDN fits into your overall plan of care. If you are a clinician, LDN may offer a useful tool for carefully selected, treatment-resistant cases where standard approaches have not fully addressed the mix of mood, pain, fatigue, and cognitive symptoms.

References

  • Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Medicine. 2009;10(4):663–672.
  • Younger J, Noor N, McCue R, Mackey S. 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. 2013;65(2):529–538.
  • Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clinical Rheumatology. 2014;33(4):451–459.
  • Mischoulon D, Hylek L, Yeung AS, et al. Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants. Journal of Affective Disorders. 2017;208:6–14.
  • Ludwig MD, Turel AP, Zagon IS, McLaughlin PJ. Long-term treatment with low dose naltrexone maintains stable health in patients with multiple sclerosis. Multiple Sclerosis Journal — Experimental, Translational and Clinical. 2016;2:2055217316672242.
  • Ludwig MD, Zagon IS, McLaughlin PJ, et al. Low-dose naltrexone reduced anxiety in persons with multiple sclerosis during the COVID-19 pandemic. International Immunopharmacology. 2022;113(Pt A):109438.
  • Tamariz L, Bast E, Klimas N, Palacio A. Low-dose naltrexone improves post-COVID-19 condition symptoms. Clinical Therapeutics. 2024;46(3):e101–e106.
  • Bonilla H, Tian L, Marconi VC, et al. Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19. Brain, Behavior, & Immunity — Health. 2024;38:100796.
  • Varghese K, Yan X, Cao F. Low-dose naltrexone for excoriation disorder. Cureus. 2024;16(3):e55336.
  • Roy A, Roy M, Deb S, Unwin G, Roy A. Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review. Journal of Intellectual Disability Research. 2015;59(4):293–306.

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