Low-Dose Naltrexone for Dissociation and Feeling Unreal: What We Know

Feeling unreal, or cut off from your own body, is frightening. If you have read that low-dose naltrexone (LDN) might help, here is the short answer. There is a real but early signal. Small studies without a placebo group suggest that blocking opioid receptors can ease dissociation for some people, and one of those studies used truly low doses.5 No placebo-controlled trial of LDN has been done. The two placebo-controlled trials of standard-dose naltrexone did not reach statistical significance.4

For now, LDN is an experimental add-on for carefully chosen patients, alongside therapy. It is not a treatment to try on your own. No medicine has been proven to work for depersonalization-derealization disorder (DPDR).11

Key takeaways

• The only low-dose study followed 15 people with complex trauma and severe dissociation. Eleven felt a benefit right away, and seven had a lasting one. There was no placebo group.5
• The placebo-controlled trials used standard-dose naltrexone. Dissociation was a little lower on the drug, but the difference was too small to count as proven.4
• Dissociation can be protection. The study authors warn that lifting it can overwhelm a person who has relied on it.5 That is why a therapist belongs in the plan.
• Therapy comes first for DPDR and dissociation. No medicine has been proven to work.11

What do these words mean?

• Dissociation is a disconnect between you and your thoughts, feelings, body, or surroundings.
• Depersonalization is feeling detached from your own body, mind, or feelings. Some people say it is like watching their life from outside.11
• Derealization is when the world around you seems unreal, as if you were in a dream or a fog.11
• DPDR is the diagnosis when these feelings last or keep coming back and cause real distress.

Feeling unreal is not the same as losing touch with reality. People with DPDR stay aware that the detachment is a feeling and not a fact. That awareness is what separates it from psychosis.11 Our essay on PTSD and dissociative symptoms explains how dissociation shows up after trauma.

Why are opioids part of the story?

Your body makes its own opioids. Researchers have found some evidence that this system is out of balance in depersonalization.2 In lab studies, drugs that switch on one kind of opioid receptor, called the kappa receptor, caused feelings of depersonalization and a sense of being cut off from reality in volunteers.67

So the idea is simple. If too much opioid signaling can create distance and numbness, blocking opioid receptors might bring a person back. Naltrexone blocks those receptors. That makes it a reasonable medicine to test. A reasonable idea still has to pass the test.

What has been studied?

Here are the studies, from oldest to newest. Only the last one used a low dose.

• 1999, open-label. Thirteen women with borderline personality disorder took standard-dose naltrexone for at least two weeks. Dissociative symptoms became shorter and less intense. Six of nine women had fewer flashbacks per day. The authors called for a placebo-controlled study.3
• 2001, open-label. Fourteen people with depersonalization received naloxone, a related opioid blocker, by vein. Symptoms went away in three people and improved markedly in seven. There was no placebo group.1
• 2005, open-label. Fourteen adults with depersonalization disorder took naltrexone for six to ten weeks at standard to high doses. Symptoms dropped by about 30 percent on average. Four people were much or very much improved. The authors asked for a randomized trial.2
• 2012, placebo-controlled. Two small, double-blind crossover trials enrolled 29 people with borderline personality disorder. Each person took standard-dose naltrexone for three weeks and a placebo for three weeks. Dissociation was lower on naltrexone in both length and intensity, but the difference was too small to reach statistical significance.4
• 2015, the only low-dose study. Fifteen patients with complex trauma disorders and severe dissociation took a few milligrams of naltrexone a day. Eleven reported a benefit right away, and seven reported a lasting one. They described a clearer sense of their surroundings and inner life, better awareness of body and feelings, and more ability to steady themselves. Side effects were few. It was an open case series with no comparison group.5

Open-label studies often look better than the controlled trials that follow them. Hope, attention, and the natural ups and downs of symptoms all play a part. That pattern showed up here. When a placebo was added in 2012, the benefit shrank to a difference too small to prove.

What caution did the study authors give?

Dissociation is not only a symptom. For many people it began as protection, a way for the mind to get through something it could not escape. The authors of the low-dose study warn that reducing dissociation can be an overwhelming challenge for patients who have needed it as protection.5

In plain terms, feelings and memories can come back faster than a person is ready for. This is the main reason LDN for dissociation belongs inside a treatment relationship, with a therapist involved. It should never be a self-experiment.

What is still unknown?

• Whether LDN beats a placebo. No one has run that trial.
• Who is likely to respond, and how long any benefit lasts.
• Whether DPDR without trauma behaves like trauma-related dissociation. The low-dose study was in complex trauma disorders, not primary DPDR.5
• A 2026 review of all LDN research does not mention dissociation or DPDR at all.8

What helps DPDR and dissociation now?

Therapy first. Treatment for DPDR includes cognitive and behavioral techniques and grounding skills.11 In an open study of cognitive behavioral therapy adapted for DPDR, 21 patients improved on several measures. About three in ten no longer met criteria for the disorder at the end. The authors called for larger and stricter trials.9 When trauma drives the dissociation, trauma-focused therapy is the core of care. Our essay on complex PTSD explains the options.

Treat what feeds it. Poor sleep is a known trigger.11 Anxiety and depression often travel with DPDR, and treating them can lower the load.

Look at cannabis. Cannabis and hallucinogens are known triggers.11 In a survey of 394 adults with DPDR, about half said it began with drug use. Cannabis and hallucinogens were named most often.10

Medicines have thin evidence. A 2024 systematic review found 41 treatment studies with about 300 participants in total. Only four were randomized controlled trials.1213 Lamotrigine alone did no better than placebo in a nine-patient trial.14 A larger trial reported a benefit and was later retracted.13 Lamotrigine added to an antidepressant has support from a review of 32 past cases, not from a controlled trial.15

What if my prescriber and I consider LDN?

A careful trial looks like this, in words and not numbers:

• One change at a time. No other medicine changes during the trial, so you can tell what is doing what.
• A therapist in the loop. Your therapist knows the plan and the start date.
• A review date. You and your prescriber decide ahead of time when to judge whether it is helping.
• A plan for flooding. You agree on what to do if feelings or memories come back too fast.
• Opioid safety. LDN must never be combined with opioid medicines. Our full LDN guide explains why, and what to tell a surgeon or dentist.

Expect some sleep effects. In a 2026 trial of LDN for depression, about four in ten people taking it had nightmares or unusual dreams, and more than a third had sleep problems.16 For someone with trauma, that is worth planning for. There is no FDA-approved low-dose product. LDN is made by compounding pharmacies, is used off-label, and is usually not covered by insurance.

When should I get help now?

Get urgent help if feeling unreal comes with thoughts of harming yourself. Do the same if it is a sudden first episode that comes with confusion, a severe headache, weakness, or a seizure. Those signs need a medical check the same day. The crisis numbers are at the end of this page.

Bottom line

LDN for dissociation is a reasonable idea with early, uncontrolled support and no placebo-controlled proof. The one low-dose study was small and was done in complex trauma, not primary DPDR. If you and your prescriber try it, do it with a therapist involved, one change at a time, and with a date to review. Therapy remains the first treatment, and feeling unreal is something people recover from.

This article is for education, not personal medical advice. Do not start, stop, or change a medication without the clinician who manages it. Sources were checked on September 20, 2026.

Related reading on NP FADY

• Low-Dose Naltrexone (LDN) in Psychiatry: A Comprehensive Guide
• Understanding PTSD and Dissociative Symptoms
• Complex PTSD, Explained: How It Differs From PTSD and BPD
• Your Body Makes Its Own Opioids
• Cannabis and Mental Health

References

1. Nuller YL, Morozova MG, Kushnir ON, Hamper N. “Effect of naloxone therapy on depersonalization: a pilot study.” Journal of Psychopharmacology. 2001;15(2):93–95. 14 patients; open-label. SAGE.

2. Simeon D, Knutelska M. “An open trial of naltrexone in the treatment of depersonalization disorder.” Journal of Clinical Psychopharmacology. 2005;25(3):267–270. DOI: 10.1097/01.jcp.0000162803.61700.4f. 14 adults; open-label. Mount Sinai.

3. Bohus MJ, Landwehrmeyer GB, Stiglmayr CE, Limberger MF, Böhme R, Schmahl CG. “Naltrexone in the Treatment of Dissociative Symptoms in Patients With Borderline Personality Disorder: An Open-Label Trial.” Journal of Clinical Psychiatry. 1999;60(9):598–603. 13 women; open-label. JCP.

4. Schmahl C, Kleindienst N, Limberger MF, Lindauer P, et al. “Evaluation of naltrexone for dissociative symptoms in borderline personality disorder.” International Clinical Psychopharmacology. 2012;27(1):61–68. DOI: 10.1097/YIC.0b013e32834d0e50. Two double-blind, placebo-controlled crossover trials; 29 patients. DOI.

5. Pape W, Wöller W. “Niedrig dosiertes Naltrexon in der Behandlung dissoziativer Symptome” [Low dose naltrexone in the treatment of dissociative symptoms]. Der Nervenarzt. 2015;86(3):346–351. DOI: 10.1007/s00115-014-4015-9. 15 patients; open case series. Springer.

6. Walsh SL, Strain EC, Abreu ME, Bigelow GE. “Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans.” Psychopharmacology. 2001;157(2):151–162. Six volunteers in a controlled laboratory study. Springer.

7. Maqueda AE, Valle M, Addy PH, et al. “Salvinorin-A Induces Intense Dissociative Effects, Blocking External Sensory Perception and Modulating Interoception and Sense of Body Ownership in Humans.” International Journal of Neuropsychopharmacology. 2015;18(12):pyv065. Eight volunteers; placebo-controlled. Oxford Academic.

8. Gouda AHK, Aitcheson NEC, Steadman KJ. “Low-Dose Naltrexone: What is the Evidence? A Narrative Review.” Advances in Therapy. 2026;43(7):2852–2870. DOI: 10.1007/s12325-026-03612-5. Springer.

9. Hunter ECM, Baker D, Phillips ML, Sierra M, David AS. “Cognitive-behaviour therapy for depersonalisation disorder: an open study.” Behaviour Research and Therapy. 2005;43(9):1121–1130. DOI: 10.1016/j.brat.2004.08.003. 21 patients; open study. King’s College London.

10. Simeon D, Kozin DS, Segal K, Lerch B. “Is depersonalization disorder initiated by illicit drug use any different? A survey of 394 adults.” Journal of Clinical Psychiatry. 2009;70(10):1358–1364. DOI: 10.4088/JCP.08m04370. DOI.

11. Spiegel D. “Depersonalization/Derealization Disorder.” Merck Manual Consumer Version. Reviewed June 2025. Accessed September 20, 2026. Merck Manual.

12. Wang S, Zheng S, Zhang FX, Ma R, Feng S, Song M, Zhu H, Jia H. “The Treatment of Depersonalization-Derealization Disorder: A Systematic Review.” Journal of Trauma & Dissociation. 2024;25(1):6–29. DOI: 10.1080/15299732.2023.2231920. Taylor & Francis.

13. Soares M, Monteiro B, Barbosa J, et al. “Depersonalization and Derealization Disorder: A case report and literature review.” Psychiatry Research Case Reports. 2026;5(2):100333. Summarizes the 2024 systematic review and the lamotrigine trials, including the retraction. ScienceDirect.

14. Sierra M, Phillips ML, Ivin G, Krystal J, David AS. “A placebo-controlled, cross-over trial of lamotrigine in depersonalization disorder.” Journal of Psychopharmacology. 2003;17(1):103–105. Nine patients. SAGE.

15. Sierra M, Baker D, Medford N, Lawrence E, Patel M, Phillips ML, David AS. “Lamotrigine as an add-on treatment for depersonalization disorder: a retrospective study of 32 cases.” Clinical Neuropharmacology. 2006;29(5):253–258. King’s College London.

16. Moloney BD, Forsyth A, Sumner RL, et al. “Low-dose naltrexone as an adjunctive treatment for major depressive disorder: findings from a randomized, double-blind, placebo-controlled hybrid parallel-arm study.” Frontiers in Pharmacology. 2026;17:1767654. DOI: 10.3389/fphar.2026.1767654. Frontiers.

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