Low-Dose Naltrexone (LDN)

At sub-therapeutic doses (1-4.5mg versus the standard 50mg), naltrexone produces transient opioid receptor blockade lasting 4-6 hours, triggering a compensatory upregulation of endogenous opioid production (beta-endorphin, met-enkephalin) and opioid receptor sensitivity. Additionally modulates TLR4 signaling on microglia, reducing neuroinflammatory cytokine production. The combination produces immunomodulatory and analgesic effects distinct from full-dose naltrexone.

Half-life

4 hours

Bioavailability

5-40% (oral, extensive first-pass)

Route

oral

Evidence tier

T2 — Single-RCT or mechanistic

Optimization pillars

recovery · cellular-health

References

3 peer-reviewed

Dose ranges

Three tiers ordered by aggressiveness. Tier chips on every OPTIMIZE intervention let you filter the catalog by your evidence tolerance.

conservative

0.5–1.5 mg/day

Initial titration

moderate

1.5–3 mg/day

Standard LDN dosing

aggressive

3–4.5 mg/day

Full LDN protocol

Monitoring

hs-crp
wbc
alt
ast
thyroid-panel

Contraindications

current-opioid-use
opioid-dependence
acute-hepatitis
liver-failure

References

PMID:17959715Low-dose naltrexone therapy improves active Crohn disease — Am J Gastroenterol, 2007
PMID:23415783Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial — Arthritis Rheum, 2013
PMID:24930711The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain — Clin Rheumatol, 2014

Notes

Low-dose naltrexone is the most counterintuitive compound in this database. Full-dose naltrexone blocks opioid receptors to treat addiction. LDN blocks them for 4 hours, then gets out of the way so the body overshoots with endogenous opioid production. The transient blockade becomes a stimulus for upregulation. This is not a paradox. It is pharmacological hormesis. The TLR4 mechanism adds a separate anti-inflammatory pathway that has nothing to do with opioid receptors. Tier 2 because the RCT evidence is growing but still underpowered for most indications. The mechanistic rationale is strong. The clinical validation is catching up.

This is not medical advice

Discuss with a licensed clinician before starting, stopping, or changing any compound. This page documents what the research literature describes — it is not a prescription.

See Low-Dose Naltrexone (LDN) in a protocol matched to you