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Mazindol for ADHD


Mazindol for ADHD


Formel: 5-[p-Chlorphenyl]-2,5-dihydro-3H-imidazo-[2,1-a] isoindol-5-ol; 5-(4-Chlorphenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol; C16H13ClN2O
Brand names: Sanorex, Mazanor

1. Mechanisms of action of mazindol

Mechanisms of action:1

  • Norepinephrine reuptake inhibitor: Ki 3.2 nM
  • Dopamine reuptake inhibitor: Ki 27.8 nM
  • Serotonin reuptake inhibitors: Ki 153.0 nM
    (A lower Ki is stronger)

Mazindol reaches the highest blood level after 2 to 4 h. The bioavailability is 50%, the half-life is 33 to 55 h. It is excreted 25% renally and 75% biliterally.

Mazindol is a tricyclic imidazo-isoindole agent (not a tricyclic antidepressant).
In the USA, mazindol has been classified by the DEA as Schedule IV (low abuse and dependence potential). MPH and AMP, on the other hand, are Schedule II stimulants.

2. Indications for use of Mazindol

Mazindol was approved in the U.S. in 1973 and in the EU in the 1980s for the treatment of adult obesity. Due to low sales, it was voluntarily withdrawn from the market in 1999 in both the USA and the EU2

Mazindol was still approved in 2018 in:3

  • for the short-term treatment of obesity4
    • Mexico/Central America (IR = immediate release)
    • Japan (IR)
    • Argentina (IR and retarded)
  • for the treatment of narcolepsy and idiopathic hypersomnia56
    • EU (IR) in the context of compassionate use

Mazindol has a favorable risk-benefit ratio7

3. Mazindol for ADHD

Mazindol is an awakening substance with stimulant properties. Mazindol showed a high effect size of 1.09 on ADHD core symptoms in adults with ADHD in initial studies.8

A randomized, double-blind, placebo-controlled 6-week Phase II study of 85 adults with ADHD showed sustained-release 1-3 mg/day significantly improved ADHD symptom severity reduction in 42.9% of subjects, compared with 11.9% on placebo.3 The effect size was reported to be 1.09.
It is not officially approved for the treatment of ADHD.

Another phase 2 study in 21 children around 10 years of age with ADHD showed comparable results.9

4. Mazindol side effects

With mazindol, adverse events were found in 42% (1 mg), 38% (2 mg), and 57% (3 mg) of participants, compared with 21%, 12%, and 36%, respectively, with placebo. More common were: Dry mouth, nausea, fatigue, increased heart rate, decreased appetite, constipation, and weight loss (mean: -1.73 kg; -9.6 kg to +3.7 kg).
Mazindol showed a minimal average increase

  • of diastolic and systolic blood pressure (~3-6 mmHg)
  • the heart rate (7.5-11 bpm)

No significant changes were found in

  • QTcF
  • PR interval
  • QRS complex
  • Hematology
  • Serum Chemistry
  • Urinalysis

5. Contraindications of Mazindol

Mazindol must not be used in

  • Heart disease
  • Hypertension
  • Arteriosclerosis (hardening of the arteries)
  • Glaucoma

Taking a monoamine oxidase inhibitor (MAOI) in the last 14 days a

Caution is advised with

  • Thyroid problems
  • Anxiety disorders
  • Epilepsy or other seizure disorders
  • Diabetes.

It is not known if Mazindol can harm an unborn child or if Mazindol passes into breast milk. Do not take Mazindol if you are pregnant or planning to become pregnant, or if you are breastfeeding.

  1. Sigma-Aldrich: Mazindol (abgerufen 20.08.22).

  2. Konofal, Benzouid, Delclaux, Lecendreux, Hussey (2017): Mazindol: a risk factor for pulmonary arterial hypertension? Sleep Med. 2017 Jun;34:168-169. doi: 10.1016/j.sleep.2017.02.020. PMID: 28522087. REVIEW

  3. Wigal, Newcorn, Handal, Wigal, Mulligan, Schmith, Konofal (2018): A Double-Blind, Placebo-Controlled, Phase II Study to Determine the Efficacy, Safety, Tolerability and Pharmacokinetics of a Controlled Release (CR) Formulation of Mazindol in Adults with DSM-5 Attention-Deficit/Hyperactivity Disorder (ADHD). CNS Drugs. 2018 Mar;32(3):289-301. doi: 10.1007/s40263-018-0503-y. PMID: 29557078; PMCID: PMC5889769.

  4. Lucchetta, Riveros, Pontarolo, Radominski, Otuki, Fernandez-Llimos, Correr (2018): Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients. Clinics (Sao Paulo). 2017 May;72(5):317-324. doi: 10.6061/clinics/2017(05)10. Erratum in: Clinics (Sao Paulo). 2018 Mar 15;73:e1err. PMID: 28591345; PMCID: PMC5439101. REVIEW

  5. Lavault, Dauvilliers, Drouot, Leu-Semenescu, Golmard, Lecendreux, Franco, Arnulf (2011): Benefit and risk of modafinil in idiopathic hypersomnia vs. narcolepsy with cataplexy. Sleep Med. 2011 Jun;12(6):550-6. doi: 10.1016/j.sleep.2011.03.010. PMID: 21576035.

  6. Arnulf, Leu-Semenescu, Dodet (2019): Precision Medicine for Idiopathic Hypersomnia. Sleep Med Clin. 2019 Sep;14(3):333-350. doi: 10.1016/j.jsmc.2019.05.007. PMID: 31375202. REVIEW

  7. Nittur, Konofal, Dauvilliers, Franco, Leu-Semenescu, Cock, Inocente, Bayard, Scholtz, Lecendreux, Arnulf (2012): Mazindol in narcolepsy and idiopathic and symptomatic hypersomnia refractory to stimulants: a long-term chart review. Sleep Med. 2013 Jan;14(1):30-6. doi: 10.1016/j.sleep.2012.07.008. PMID: 23036267.

  8. Nageye, Cortese (2019): Beyond stimulants: a systematic review of randomised controlled trials assessing novel compounds for ADHD. Expert Rev Neurother. 2019 Jul;19(7):707-717. doi: 10.1080/14737175.2019.1628640. PMID: 31167583.)

  9. Konofal, Zhao, Laouénan, Lecendreux, Kaguelidou, Benadjaoud, Mentré, Jacqz-Aigrain (2014): Pilot Phase II study of mazindol in children with attention deficit/hyperactivity disorder. Drug Des Devel Ther. 2014 Dec 1;8:2321-32. doi: 10.2147/DDDT.S65495. PMID: 25525331; PMCID: PMC4266272. n = 21