Meta Information
ID:low-dose-naltrexone
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/opioid-agonists
Target name:
Opioid Agonist Medications (Analgesic Block)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
LDN is an opioid receptor antagonist. Taking it concurrently with opioid medications (e.g., morphine, oxycodone, hydrocodone, tramadol, methadone, buprenorphine) will block their effects and precipitate immediate, severe opioid withdrawal symptoms.
Actionable advice:
LDN should not be taken while using any opioid-containing medications for pain, cough, or substance use treatment.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
REVIA is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids.
Label source:
Naltrexone HCl (REVIA) FDA label, Clinical Pharmacology - Pharmacodynamic Actions.
Action type:
avoid
Target id:
/condition/opioid-dependence
Target name:
Opioid Dependence
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Initiating LDN in individuals who are physically dependent on opioids will trigger acute and potentially severe withdrawal symptoms, even if they have not recently taken an opioid.
Actionable advice:
You must be completely free of all opioids for at least 7-14 days before starting LDN.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
In subjects physically dependent on opioids, REVIA will precipitate withdrawal symptomatology.
Label source:
Naltrexone HCl (REVIA) FDA label, Clinical Pharmacology / Warnings - Precipitated Opioid Withdrawal. CONTRAINDICATIONS: patients currently dependent on opioids.
Action type:
informational_none
Target id:
/procedure/major-surgery
Target name:
Planned Major Surgery or Medical Procedure
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
72
Hours after target:
null
Description:
LDN blocks opioid receptors, which will render opioid-based anesthesia and post-operative pain medications ineffective. This can lead to inadequate pain control during and after the procedure.
Actionable advice:
LDN should be stopped at least 72 hours before any planned surgery or procedure requiring opioid analgesia.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
In a situation requiring opioid analgesia, the amount of opioid required may be greater than usual, and the resulting respiratory depression may be deeper and more prolonged.
Label source:
Naltrexone HCl (REVIA) FDA label, Precautions - When Reversal of REVIA Blockade is Required for Pain Management.
Action type:
separate
Target id:
/condition/hepatic-impairment
Target name:
Acute Hepatitis or Severe Liver Failure
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Standard-dose naltrexone can be toxic to the liver. While the risk is significantly lower with LDN, it is contraindicated in patients with acute hepatitis or decompensated liver disease.
Actionable advice:
LDN should be avoided with acute hepatitis or severe liver failure.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Hepatotoxicity Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone hydrochloride exposure during the clinical development program and in the postmarketing period.
Label source:
FDA label: Naltrexone
Action type:
avoid
Target id:
/condition/naltrexone-hypersensitivity
Target name:
Allergy to Naltrexone
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
A prior allergic reaction to naltrexone is an absolute contraindication to its use in any form, including low-dose.
Actionable advice:
LDN should not be taken with a known allergy to naltrexone.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
However, as mentioned above, among individuals using opioids, naltrexone hydrochloride may cause serious withdrawal reactions (see CONTRAINDICATIONS , WARNINGS , DOSAGE AND ADMINISTRATION ).
Label source:
Action type:
avoid
Target id:
/circadian/sleep
Target name:
Going to Sleep
Severity:
moderate
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
0.5
Hours after target:
null
Description:
Bedtime dosing is theorized to align the transient opioid blockade with the body's natural peak endorphin production cycle (2-4 AM), potentially maximizing the immunomodulatory rebound effect.
Actionable advice:
A daily dose of LDN is best taken within 30 minutes of bedtime for the most common and potentially effective protocol.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
LDN bedtime-dosing rationale (aligning a brief opioid-receptor blockade with the nocturnal endorphin peak) is a theoretical dosing strategy from the low-dose-naltrexone clinical literature (e.g., Younger 2014 review), not a demonstrated pharmacologic interaction.
Label source:
Class inference
Action type:
informational_none
Target id:
/class/immunosuppressants
Target name:
Immunosuppressants for Organ Transplant
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
LDN modulates the immune system, which could theoretically oppose the action of powerful immunosuppressant drugs (e.g., tacrolimus, cyclosporine) required to prevent organ transplant rejection. This combination is not well-studied and carries potential risk.
Actionable advice:
This is best used only with extreme caution and under the direct supervision of a transplant physician.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: LDN is proposed to modulate immune signalling (endorphin/TLR pathways), which could theoretically oppose pharmacologic immunosuppression; unstudied, and the brief blockade from low doses makes a major interaction unlikely. Caution-level only.
Label source:
Class inference
Action type:
informational_none
Target id:
/intervention/levothyroxine
Target name:
Levothyroxine (Thyroid Hormone)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
For individuals with autoimmune thyroid disease (Hashimoto's), LDN may reduce the autoimmune attack, potentially improving natural thyroid function over time. This can necessitate a reduction in the required dose of levothyroxine to avoid symptoms of hyperthyroidism.
Actionable advice:
Regularly monitor thyroid function tests (TSH, free T4/T3) when starting LDN, as your thyroid medication dose may need to be lowered.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Inform patients that agents such as iron and calcium supplements and antacids can decrease the absorption of levothyroxine.
Label source:
FDA label: Levothyroxine (Synthroid)
Action type:
adjust_with_prescriber
Target id:
/circadian/wake
Target name:
Waking Up
Severity:
minor
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
null
Hours after target:
0.5
Description:
A common side effect of bedtime LDN dosing is vivid dreams or insomnia. Switching to morning administration can alleviate these sleep disturbances while still providing therapeutic benefits for many users.
Actionable advice:
If bedtime dosing consistently disrupts your sleep, switch to taking your dose upon waking.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Sleep disturbance/vivid dreams are commonly reported with bedtime LDN; switching to morning dosing is a practical mitigation noted in the LDN literature. Practical/anecdotal dosing guidance, not a labeled effect.
Label source:
Class inference
Action type:
informational_none
Target id:
/dietary/alcohol-acute
Target name:
Alcohol (Acute Consumption)
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Naltrexone can blunt the rewarding, euphoric effects of alcohol by blocking opioid receptors involved in the pleasure response. This effect may be noticeable even at low doses.
Actionable advice:
Less pleasure or desire for alcohol may occur while taking LDN.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Subjects taking naltrexone reported significantly less alcohol craving and days in which any alcohol was consumed.
Label source:
Volpicelli JR et al., Arch Gen Psychiatry (1992), PMID 1345133. RCT at 50 mg/day; effect on alcohol reward/craving is the basis - LDN doses are lower, so magnitude at LDN is uncertain.
Action type:
informational_none
Target id:
/intervention/dextromethorphan
Target name:
Dextromethorphan (Cough Suppressant)
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Dextromethorphan (DXM) possesses weak opioid receptor activity. LDN may antagonize this action, potentially reducing the efficacy of DXM as a cough suppressant.
Actionable advice:
Cough medicines containing dextromethorphan may be less effective while taking LDN.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Monitor patients for adverse reactions potentially attributable
to dextromethorphan, such as somnolence and dizziness.
Label source:
Action type:
informational_none
Target id:
/biomarker/comprehensive-liver-function-panel
Target name:
Liver Function Panel (ALT, AST)
Severity:
minor
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Although the risk of liver injury is very low with LDN, naltrexone is metabolized by the liver. Establishing a baseline and performing periodic monitoring of liver enzymes is a prudent safety measure.
Actionable advice:
Obtain a baseline liver function panel before starting LDN and consider periodic re-testing as recommended by your healthcare provider.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Exact phrase from label:
Cases of hepatitis and clinically significant liver dysfunction were observed in association with REVIA exposure during the clinical development program and in the postmarketing period.
Label source:
Naltrexone HCl (REVIA) FDA label, Warnings - Hepatotoxicity. FLAG: dose-related hepatocellular injury was seen at up to 5x the receptor-blockade dose; risk at LDN doses (1.5-4.5 mg) is very low.
Action type:
monitor