neurological MCAS symptoms improvement

our brilliant naturopath Tobias Eisenkolb has several significantly improved patients with neurological symptoms that can be identified as neurological MCAS by their response:

In mast cell activation syndrome (MCAS), it is indeed not uncommon that the standard dose of Levocetirizine (5 mg/day) is insufficient to control symptoms permanently — especially when central (CNS-related) symptoms such as restlessness, anxiety, sleep disturbances, or cognitive overstimulation occur, often caused in part by histamine in the brain.

Here are some medically sound notes you can discuss with your treating physician:

• 1. Dose escalation in MCAS
  The medical literature and MCAS guidelines often state that higher doses of H1-antihistamines may be required.
  Levocetirizine can be used in adults up to 10 mg/day, in some cases even 20 mg/day (divided twice daily) — under medical supervision.
  Advantage: the compound has a favorable side-effect profile and low hepatic metabolism, making it well tolerated for long-term use.
• 2. Combination with other antihistamines
  The regimen you are using — DAO enzyme supplements with meals plus H1-blocker (Levocetirizine) and H2-blocker (e.g. Famotidine or Ranitidine, if tolerated) — is a classic therapeutic approach in MCAS.
  Atarax (Hydroxyzine) has stronger central sedative effects, which can be helpful in acute phases but limiting in daily life.
  Some patients tolerate a small evening dose of Atarax (5–10 mg) or alternatively a non-sedating antihistamine (e.g. Cetirizine or Fexofenadine) in addition to Levocetirizine.
• 3. Seasonality and DAO
  DAO activity measurably decreases in winter — due to less sunlight, vitamin D deficiency, altered gut microbiota, and lower metabolic activity.
  This can lower the histamine tolerance threshold → more CNS symptoms.
• 4. Practical recommendation (to discuss with your doctor)
  5 mg Levocetirizine in the morning + 5 mg in the evening is a reasonable next step.
  If drowsiness becomes an issue: take the second dose 1–2 h before bedtime.
  If restlessness persists despite doubling the dose, one can consider adding an H2-blocker or Ketotifen (prescription only, mast-cell stabilizing).

Ketotifen and CNS effect

Ketotifen is indeed an effective H1-antihistamine and mast-cell stabilizer, but its penetration into the CNS is relatively limited.

This is due to its chemical structure and polarity:

• Ketotifen is a highly polar molecule and crosses the blood-brain barrier only to a limited extent.
• It acts primarily peripherally (mast cells in tissues, gut, skin, etc.), less so centrally (in the brain).

This explains why it is often insufficient in MCAS with pronounced neurological symptoms (restlessness, panic, brain fog, mood swings) — although it is very useful for skin- or gut-dominant symptoms.

Comparison: CNS activity of different antihistamines

Patient with central CNS symptomatology

For a patient with CNS histamine symptoms (restlessness, panic, dysautonomia), it is logical to focus on CNS-penetrant antihistamines such as Levocetirizine.
Splitting the dose 5 mg morning + 5 mg evening can help maintain stable levels and avoid rebounds.
DAO supplementation complements this by reducing peripheral histamine load.

CNS penetration and pharmacokinetics of common H1-antihistamines (relevant for MCAS)

• Hydroxyzine: Highly lipophilic, not a P-gp substrate, strongly CNS-active; sedating, anxiolytic.
• Cetirizine / Levocetirizine: Moderately lipophilic, low P-gp activity, CNS-active, well tolerated.
• Loratadine / Desloratadine: Strong P-gp efflux, barely CNS-active, good for peripheral mast-cell activation.
• Fexofenadine / Bilastine: Very low CNS penetration, purely peripheral.
• Rupatadine: Peripheral + mast-cell stabilizing through anti-PAF action.
• Ketotifen: Peripheral + mast-cell stabilizer, low CNS activity, good for GI and skin dominance.
• Ebastine / Carebastine: Minimal CNS activity, negligible sedation.

Pharmacodynamic parameters

• P-gp (P-glycoprotein): Efflux transporter at the blood-brain barrier; strong P-gp efflux means low CNS effect (e.g. Fexofenadine, Bilastine).
• Lipophilicity (logP): Higher logP facilitates CNS diffusion; Cetirizine/Levocetirizine: logP ≈ –2.
• Protein binding: About 90 % → influences half-life (8–10 h).
• Half-life: Levocetirizine approx. 8–10 h, Hydroxyzine 20–25 h.

MCAS-specific recommendations

1. CNS-dominant symptomatology (restlessness, anxiety, dysautonomia)
   → Levocetirizine 5 mg 2×/day, possibly Hydroxyzine 5–10 mg in the evening.
   → Add DAO supplementation, optimize vitamin D.
2. Peripheral forms (skin, GI, vascular)
   → Fexofenadine, Loratadine, Bilastine, or Rupatadine.
3. Chronically unstable courses
   → Combination of H1 + H2-blocker (Famotidine) + Ketotifen.

Practical notes

• CNS-dominant → prefer Levocetirizine
• Peripheral → Fexofenadine, Loratadine, Bilastine, Rupatadine
• Chronic → H1 + H2 + Ketotifen
• DAO supplementation lowers histamine load and improves CNS symptoms