Low Dose Naltrexone (LDN) — Consent (Off‑label Neuroimmune/Inflammatory Use)

INFORMED CONSENT FOR LOW DOSE NALTREXONE (LDN) — OFF‑LABEL USE

§1 PURPOSE, CONTEXT, AND SCOPE

§1.1 This document constitutes an informed consent agreement between the Patient identified herein (the "Patient") and the Prescribing Physician acting on behalf of the Clinic. It is intended to document that the Patient has received, understood, and accepted comprehensive information regarding the proposed pharmacological use of Low Dose Naltrexone (LDN) for off‑label neuroimmune/inflammatory conditions.

§1.3 Health optimization context: The Patient understands that the Clinic operates as a proactive health optimization / longevity practice. The Clinic is not an emergency provider. The Patient is responsible for maintaining an appropriate relationship with a primary care physician and/or relevant specialist(s) for diagnosis and management of disease, acute care, and emergencies.

§1.4 This consent is governed by the laws of Denmark and the European Union, including but not limited to the Danish Health Act (Sundhedsloven) and Regulation (EU) 2016/679 (General Data Protection Regulation).

§1.5 By signing this document, the Patient confirms they have had adequate time to read, consider, and ask questions, and that their questions have been answered to their satisfaction.

§3 MEDICATION, CLASS, AND DESCRIPTION OF TREATMENT

§3.1 Naltrexone is a medication that acts as an opioid receptor antagonist. At standard doses (typically 50–100 mg/day), naltrexone is EMA‑authorised for the treatment of opioid dependence and alcohol dependence.

§3.3 Low Dose Naltrexone (LDN): At much lower doses (commonly 0.25–4.5 mg/day), naltrexone is referred to as Low Dose Naltrexone (LDN) and is used by some clinicians off‑label for immune‑mediated, inflammatory, pain, fatigue, and neuroinflammatory conditions.

§3.4 Intended use in this Clinic: The Patient understands that LDN is being prescribed for the purpose of reducing inflammatory and histamine‑mediated symptoms consistent with mast cell mediator excess and related neuroimmune and gut‑immune activation. The Patient understands that this intended use is off‑label and is not an EMA‑authorised indication.

§3.5 Compounded formulation: LDN may be prescribed as:

  • A compounded low‑dose capsule or liquid prepared by a compounding pharmacy
  • An accurately measured solution derived from standard naltrexone tablets

The Patient understands that if LDN is supplied as a compounded preparation, it is prepared by a pharmacy to the clinician's specification and may have variability compared with industrially manufactured, EMA‑authorised products.

§3.6 The treatment will be administered orally, typically once daily (often in the morning), at a dose and titration schedule determined by the Prescribing Physician based on the Patient's clinical status and treatment goals.

§4 REGULATORY STATUS AND APPROVED INDICATIONS

§4.1 Naltrexone has been authorised by the European Medicines Agency (EMA) for the treatment of:

  • Opioid dependence (at standard doses, typically 50 mg/day)
  • Alcohol dependence (at standard doses, typically 50 mg/day)

§4.2 Off‑label use: The Patient understands that prescribing LDN (low doses, typically 0.25–4.5 mg/day) for suspected mast cell activation, neuroimmune inflammation, chronic inflammatory conditions, or related symptoms is off‑label and is not an EMA‑approved indication.

§4.3 The Patient understands that evidence supporting off‑label LDN use is derived from:

  • Mechanistic research suggesting potential effects on TLR4 signaling, microglial activation, and opioid growth factor receptors
  • Clinical experience and case reports
  • Limited small clinical studies
  • Large randomised controlled trials specific to mast cell activation syndromes or the Patient's specific condition are limited or not available

§4.4 The Patient understands that benefits are not guaranteed and that clinical evidence is limited/emerging.

§4.5 The Patient has been informed that the intended use in this Clinic is off‑label and accepts this information.

§5 PROPOSED BENEFITS OF TREATMENT

§5.1 The Patient understands that the potential benefits of LDN in the context of off‑label use for neuroimmune/inflammatory conditions may include, but are not limited to:

§5.1.1 Symptom improvement: Potential improvement in one or more of the following:

  • Flushing, itching, hives, or skin reactivity
  • Gastrointestinal symptoms such as bloating, abdominal discomfort, diarrhoea, or food‑related reactions
  • Fatigue and cognitive "brain fog"
  • Headaches or migraine tendency
  • Dysautonomia symptoms (e.g., lightheadedness, palpitations, temperature dysregulation)
  • General inflammatory reactivity and reduced flare frequency
  • Pain and neuroinflammatory symptoms

§5.1.2 Mechanistic rationale: The Patient understands that LDN is not a direct antihistamine. Proposed mechanisms include:

  • TLR4 and microglial modulation: TLR4 is involved in innate immune sensing and inflammatory signaling. Overactivation may contribute to systemic inflammation and activation of brain immune cells (microglia), potentially amplifying fatigue, brain fog, pain sensitization, headache, and autonomic instability.
  • Opioid growth factor receptor (OGFr) modulation: Temporary receptor blockade may shift immune signaling in a time‑limited, pulsatile manner that some clinicians consider potentially useful in chronic inflammatory immune dysregulation states.

§5.2 No guarantee of benefit: The Patient acknowledges that:

  • Clinical evidence specific to mast cell activation syndromes and related conditions is limited/emerging
  • Large randomised controlled trials are not available
  • Benefits are not guaranteed
  • Individual responses vary, and some patients may not experience any benefit

§6 MATERIAL RISKS AND ADVERSE EFFECTS

§6.1 The Patient has been informed of the following risks and adverse effects associated with LDN therapy. The Patient understands that this list is not exhaustive and that other adverse effects may occur.

§6.2 Common adverse effects (occurring in ≥1% of patients):

  • Sleep disturbance or vivid dreams (especially if taken late in the day)
  • Headache
  • Nausea or mild gastrointestinal upset
  • Temporary increase in anxiety, restlessness, or irritability
  • Transient worsening of symptoms during early titration (paradoxical reaction)

§6.3 Uncommon adverse effects (occurring in 0.1–1% of patients):

  • Dizziness
  • Fatigue
  • Insomnia
  • Mood changes

§6.4 Rare but serious adverse effects (occurring in <0.1% of patients or reported post‑marketing):

§6.4.1 Elevation of liver enzymes: Rare elevation of liver enzymes has been reported, although this is very uncommon at low doses. The Patient understands that liver function monitoring may be recommended.

§6.4.2 Allergic reactions: Rare allergic reactions can occur. The Patient must seek urgent care for swelling of face/tongue/throat, difficulty breathing, or widespread rash.

§6.4.3 Paradoxical reactions: Some patients may experience transient worsening of symptoms during early titration. The Patient understands that dose reduction or slower titration may be necessary.

§6.5 Generally well tolerated: LDN is generally well tolerated at low doses. Most side effects are mild and improve with dose reduction or slower titration.

§7 CONTRAINDICATIONS AND PRECAUTIONS

§7.1 The Patient confirms that they have disclosed all relevant medical history and current medications to the Prescribing Physician.

§7.2 ABSOLUTE CONTRAINDICATION — OPIOIDS (CRITICAL):

§7.2.1 Naltrexone blocks opioid receptors and must not be used with opioid medications. This is an absolute contraindication.

§7.2.2 The Patient must inform the Clinic if they are using any opioid‑containing drugs, including:

  • Prescription pain medications such as morphine, oxycodone, hydrocodone, tramadol, codeine, fentanyl, methadone, buprenorphine
  • Over‑the‑counter medications containing codeine or other opioids
  • Certain cough syrups containing codeine or dextromethorphan (in some formulations)
  • Kratom or other opioid‑like substances
  • Any medication or substance with opioid activity

§7.2.3 Consequences of using opioids with LDN:

  • LDN will block the effects of opioids, preventing pain relief
  • In opioid‑dependent individuals, LDN may trigger acute withdrawal, which can be severe and potentially life‑threatening
  • This combination can create a medical emergency

§7.2.4 The Patient agrees to:

  • Disclose all opioid use (current and past) to the Clinic
  • Not start any opioid medications while taking LDN without first consulting the Clinic
  • Inform other healthcare providers that they are taking LDN before receiving any opioid medications
  • Seek emergency care if they accidentally take opioids while on LDN

§7.3 Other contraindications and precautions:

  • Known hypersensitivity or allergy to naltrexone or any excipients
  • Acute hepatitis or liver failure
  • Use in children or adolescents (except under specialist supervision)

§8 DRUG INTERACTIONS

§8.1 The Patient has disclosed all current medications, including prescription drugs, over‑the‑counter medications, supplements, and herbal products.

§8.2 Opioids: As stated in §7.2, opioids are absolutely contraindicated with LDN.

§8.3 Other medications: The Patient understands that LDN may interact with other medications, and agrees to inform the Clinic before starting any new medication.

§8.4 The Patient agrees to inform the Clinic before starting any new medication, supplement, or herbal product.

§9 MONITORING REQUIREMENTS

§9.1 The Patient agrees to undergo monitoring as recommended by the Prescribing Physician, which may include:

§9.2 Baseline assessments (before starting LDN):

  • Clinical assessment of symptoms and baseline function
  • Liver function tests (if indicated)
  • Assessment of current medications (especially opioids)

§9.3 Ongoing monitoring:

  • Clinical assessment of symptoms, adverse effects, and treatment response
  • Patient self‑tracking of symptoms and flares during titration
  • Follow‑up typically occurs ~4 weeks after initiation and then as clinically indicated
  • Liver function tests (if indicated, especially with long‑term use)

§9.4 Dosing and titration: The Patient understands that:

  • Because medication sensitivity is common in mast‑cell/neuroimmune presentations, a slow titration is planned
  • Typical titration plan (individualised):
  • Start: 0.5 mg once daily (often in the morning)
  • Increase by 0.5 mg every 1–2 weeks as tolerated
  • Typical target range: up to ~4.5 mg once daily (some patients remain at lower doses)
  • A fair therapeutic trial is usually 6–12 weeks at a stable dose
  • Dosing may be adjusted based on response and tolerability

§9.5 The Patient agrees to follow dosing instructions and not to self‑adjust the dose.

§9.6 The Patient agrees to report significant adverse effects promptly.

§10 ALTERNATIVE TREATMENTS

§10.1 The Patient has been informed of the following alternatives to LDN:

§10.2 Other pharmacological interventions:

  • Continuing H1/H2 histamine blockade alone
  • Mast‑cell stabilisers (e.g., cromolyn, ketotifen)
  • Leukotriene pathway inhibitors
  • Anti‑IgE therapy (in selected cases)
  • Other anti‑inflammatory or immunomodulatory agents

§10.3 Non‑pharmacological interventions:

  • Dietary modifications (e.g., low histamine diet)
  • Stress management
  • Sleep optimization
  • Further work‑up and treatment of upstream triggers

§10.4 No treatment: The Patient may choose not to receive LDN, understanding that symptoms may persist.

§10.5 The Patient confirms that these alternatives have been discussed and that they have chosen to proceed with LDN.

§12 LIMITATION OF LIABILITY / NO GUARANTEE

§12.1 The Patient understands that medicine is not an exact science and no outcomes can be guaranteed.

§12.2 The Patient understands that:

  • Clinical evidence for LDN in mast cell activation syndromes and related conditions is limited/emerging
  • Benefits are not guaranteed
  • Individual responses vary

§12.3 The Patient understands that adverse effects may occur despite appropriate prescribing and monitoring.

§12.4 Compounding variability: If LDN is supplied as a compounded preparation, the Patient understands that compounded medicines may have variability compared with industrially manufactured, EMA‑authorised products, and accepts this risk.

§12.5 Nothing in this consent excludes liability that cannot be excluded under applicable Danish law.

§13 WITHDRAWAL OF CONSENT

§13.1 The Patient may withdraw consent at any time by contacting the Clinic. The Prescribing Physician will provide guidance on safe discontinuation where applicable.

§14 DATA PROTECTION AND RECORDKEEPING

§14.1 The Patient's personal data and health information will be processed in accordance with GDPR and applicable Danish law.

§14.2 This consent may be retained as part of the Patient's medical record.

§15 ACKNOWLEDGMENTS AND DECLARATIONS

By consenting, the Patient confirms the following:

  • I have read this consent document in its entirety, or it has been read to me, and I understand its contents.
  • I understand that LDN is being used off‑label for suspected mast cell mediator‑related inflammation/neuroimmune dysregulation.
  • I understand that clinical evidence specific to MCAS and related conditions is limited/emerging and that benefit is not guaranteed.
  • I understand the medication prescribed (the prescribed medication) and the purpose of LDN therapy.
  • I understand the dosing and titration plan may be adjusted based on response and tolerability.
  • I understand potential side effects and risks.
  • I understand that LDN must not be taken with opioids and I agree to inform my clinician about any opioid use (current or planned).
  • I understand that using opioids with LDN may block pain relief, trigger withdrawal, and create a medical emergency.
  • I understand alternative treatment options.
  • I understand that if LDN is compounded, it may have variability compared with industrially manufactured products.
  • I have disclosed all relevant medical history and current medications (especially opioids) to the Clinic.
  • I understand I must seek urgent/emergency care for severe symptoms and that the Clinic is not an emergency service.
  • I have had the opportunity to ask questions and my questions were answered.
  • I voluntarily consent to commence or continue treatment with the prescribed medication under the regimen agreed with my clinician.