Pitolisant
FDA/EMA-approved histamine H3 inverse agonist (Wakix). Prescription wakefulness drug for excessive daytime sleepiness and cataplexy in adult narcolepsy, not a lifestyle nootropic.
Pharmacology
Contents
WHAT IS PITOLISANT?
Detailed overview
Pitolisant is a first-in-class histamine H3 receptor inverse agonist and antagonist developed in France by Jean-Charles Schwartz and colleagues. By blocking the presynaptic H3 autoreceptor it increases the firing of histaminergic neurons and boosts histamine release in the brain, which supports wakefulness and attention. The EMA approved it in 2016 and the FDA in 2019 (brand name Wakix) for excessive daytime sleepiness and cataplexy in adults with narcolepsy. It is a prescription medicine backed by randomized controlled trials, not a general-purpose cognitive enhancer, and in the United States it is not a DEA-scheduled controlled substance.
Mechanism
Histamine H3 inverse agonist
Half-life
10-12 hours
Onset
Morning dosing, titrated over ~3 weeks
Legal status
FDA/EMA Rx (Wakix), not scheduled in US
Safety note
Dose-dependent QT prolongation
Receptor profile
- Histamine H3 autoreceptor (inverse agonist)Strong
- Histamine release (downstream)Moderate
- Cortical acetylcholine / dopamine (downstream)Moderate
Safety
Side effects, stop signs, contraindications
Side effects · 6
- Insomnia, sleep disturbance (with late dosing)
- Headache (common)
- Nausea, abdominal pain, decreased appetite
- Anxiety, irritability
- QT interval prolongation (dose-dependent, ECG consideration)
- Increased heart rate
Contraindications · 6
- Severe hepatic impairment (Child-Pugh C): contraindicated (FDA/EMA label)
- Hormonal contraceptives: CYP3A4 induction reduces efficacy, backup contraception needed
- Known QT prolongation, congenital long QT syndrome, or concomitant QT-prolonging drugs: caution / avoid
- Breastfeeding: avoid (animal data suggest excretion in milk); pregnancy: limited data
- Strong CYP2D6 inhibitors (paroxetine, fluoxetine, quinidine) raise exposure (halve the dose); strong CYP3A4 inducers (rifampicin) lower it
- Severe renal impairment: dose adjustment required
Related Nootropics
Same therapeutic category
Studies
Related research and clinical findings
Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial
Dauvilliers Y, Bassetti C, Lammers GJ, et al.
Efficacy of pitolisant in patients with high burden of narcolepsy symptoms: pooled analysis of short-term, placebo-controlled studies
Davis CW, Kallweit U, Schwartz JC, et al.
Time to Onset of Response to Pitolisant for Excessive Daytime Sleepiness and Cataplexy in Narcolepsy: An Analysis of Randomized, Placebo-Controlled Trials
Watson NF, Davis CW, Zarycranski D, et al.
Pitolisant: A Review in Narcolepsy with or without Cataplexy
Lamb YN.
The histamine H3 receptor: from discovery to clinical trials with pitolisant
Schwartz JC.
FAQ
FAQ
FDA/EMA-approved histamine H3 inverse agonist (Wakix). Prescription wakefulness drug for excessive daytime sleepiness and cataplexy in adult narcolepsy, not a lifestyle nootropic.
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Structure & chemistry
The information here is strictly for educational and scientific purposes. It does not replace medical advice or clinical consultation, and it does not encourage illegal substance or pharmaceutical use. Data is sourced. When in doubt, consult your doctor.