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Viloxazine for ADHD


Viloxazine for ADHD

Viloxazine (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride; C13H20NO3Cl) (SPN-812) has been approved in the USA since April 2021 for the treatment of ADHD in children aged 6 to 17 and depression. It was approved as an antidepressant in Europe from 1976 to 2006 and was used off-label for enuresis and narcolepsy.1
Brand names: Viloxazin, Emovit, Viloxazina, Viloxazinum, Vivarint, Vicilan, Vivalan, Catatrol

Viloxazine modulates serotonin and noradrenaline activity.2 Viloxazine increases the serotonin level in the prefrontal cortex, but does not increase the release of noradrenaline. It has a weak effect on dopamine and shows a slight increase in drive compared to other ADHD medications.
Viloxazine is well tolerated and has side effects such as drowsiness, reduced appetite and headaches.
It should not be taken in the case of epilepsy, severe hepatic insufficiency or during pregnancy.

1. Mechanisms of action of viloxazine

Viloxazine acts as345

  • strong:
    • selective serotonin 5-HT2B receptor antagonist
    • Serotonin 5-HT2C receptor agonist
  • moderate:
    • selective noradrenaline reuptake inhibitor (Ki: 0.63 μM)
      • thereby increasing dopamine and noradrenaline in the PFC
      • no additional release of noradrenaline1
  • weak:
    • Serotonin 5-HT7 receptor antagonist
    • α1B-adrenoceptor antagonist
    • β2-adrenoceptor antagonist
  • very weak:
    • competitive and reversible inhibitor of monoamine oxidase A and B.1

Viloxazine has been shown to increase dopamine levels6, noradrenaline levels6 and serotonin levels in the PFC.76 However, it does not appear to act as a serotonin reuptake inhibitor.76
It does not increase the release of noradrenaline.

Viloxazine increases the dopamine level in the nucleus accumbens significantly less than stimulants.8 We consider the authors’ assertion that non-stimulants have fewer side effects to be misguided. Non-stimulants (atomoxetine, guanfacine) have significantly higher side effects with a significantly lower Effect size than stimulants.

Other in vitro studies found no dopamine release in the striatum and only a small effect on dopamine receptors or DAT. In rodents, viloxazine significantly increased dopamine in vivo in the PFC, moderately in the amygdala and minimally in the nucleus accumbens. The dopamine increase in the PFC is likely to be a consequence of NET reuptake inhibition. The minimal effect of viloxazine on dopamine in the nucleus accumbens could indicate a low susceptibility to abuse.1 We therefore suspect a lower increase in drive than stimulants.
Viloxazine significantly increases the plasma level of the adenosine A1 and A2 antagonist theophylline.910 It is conceivable that part of the effect of viloxazine in ADHD could be due to the dopamine-increasing effect of the adenosine antagonist theophylline.

Contrary to almost all widely used ADHD medications to date, viloxazine does not alter histamine levels. Viloxazine appears to exert a weak competitive inhibition at the histamine receptors H1 and H2 (< 25 %).1

Pharmacological data5

  • Bioavailability approx. 88 %
  • Tmax (time to maximum plasma concentration): approx. 5 hours at 200 mg
  • Active ingredient is highly protein-bound (76-82 %)
  • Average half-life of viloxazine ER is 7 hours (2.25 to 11.75 hours).

2. Viloxazine for ADHD

Viloxazine extended-release (viloxazine ER; SPN-812) has been shown to be an effective and well-tolerated alternative for some children with ADHD in several Phase 2 and Phase 3 studies at 200 to 400 mg/day. The mechanism of action of viloxazine is unique in that it modulates both serotonin and norepinephrine activity.115
The Effect size of viloxazine was determined to be between 0.46 and 0.63 in various studies12 and is thus considerably weaker than the Effect size of stimulants (1.1 to 1.5).13
Various phase II and phase III studies found a good effect of viloxazine on ADHD in

  • 100 and 200 mg / day14
  • 100, 200 and 400 mg / day15
  • 200 to 400 g / day161718
  • 400 or 600 mg / day19

The various publications on Phase III originate from an identical group of authors.

Symptom reduction after 2 weeks predicted treatment success after 6 weeks quite well.5
A comparative study found clear advantages of viloxazine ER over atomoxetine.20

Dosage 52

  • Age from 6 to 11 years
    • recommended starting dose 100 mg orally once daily
    • Up-dosing in steps of 100 mg per week
    • recommended maximum dose 400 mg once daily
  • Age from 12 to 17 years
    • recommended starting dose 200 mg orally once a day for the first week
    • Up-dosing to the maximum daily dose of 400 mg.

In adults with ADHD, one study found a symptom reduction of more than 50% compared to the AISRS baseline in 40.2% of subjects.21

A combination with methylphenidate is possible.22

3. Side effects and contraindications

3.1. Side effects of viloxazine

The most common adverse effects of viloxazine ER include2

  • Drowsiness
  • reduced appetite
    • The reduction in appetite caused by viloxazine appears to be significantly greater than that caused by atomoxetine (meta-analysis, k = 26)23
  • Headache
  • Tiredness
  • Upper abdominal pain
  • Nausea
  • Vomiting
  • Irritability

3.2. Contraindications for viloxazine

Viloxazine should not be taken if

  • Tendency to epilepsy
  • severe liver failure
  • during or if pregnancy is intended. Viloxazine can damage the fetus.
  • before the end of fourteen days after the last intake of a monoamine oxidase inhibitor (MAOI).

Increased suicidal tendencies were reported in a small proportion of child subjects.

4. Degradation of viloxazine

Viloxazine is metabolized by CYP2D6, UGT1A9 and UGT2B15, possibly also by CYP1A2 245

Viloxazine is a potent CYP1A2 inhibitor.
If drugs metabolized by CYP1A2 are taken at the same time, it may be necessary to reduce the dose of these drugs.

  1. Findling RL, Candler SA, Nasser AF, Schwabe S, Yu C, Garcia-Olivares J, O’Neal W, Newcorn JH (2021): Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status. CNS Drugs. 2021 Jun;35(6):643-653. doi: 10.1007/s40263-021-00825-w. PMID: 34003459; PMCID: PMC8219567.

  2. Raible H, D’Souza MS (2023): Extended-Release Viloxazine for the Treatment of Attention-Deficit Hyperactivity Disorder in School-Age Children and Adolescents. Ann Pharmacother. 2023 Dec;57(12):1436-1448. doi: 10.1177/10600280231163252. PMID: 37021356. REVIEW

  3. Viloxazin

  4. Wikipedia: Viloxazine

  5. Edinoff, Akuly, Wagner, Boudreaux, Kaplan, Yusuf, Neuchat, Cornett, Boyer, Kaye, Kaye (2021): Viloxazine in the Treatment of Attention Deficit Hyperactivity Disorder. Front Psychiatry. 2021 Dec 17;12:789982. doi: 10.3389/fpsyt.2021.789982. PMID: 34975586; PMCID: PMC8718796., REVIEW

  6. Garcia-Olivares J, Yegla B, Bymaster FP, Earnest J, Koch J, Yu C, Rubin J (2024): Viloxazine Increases Extracellular Concentrations of Norepinephrine, Dopamine, and Serotonin in the Rat Prefrontal Cortex at Doses Relevant for the Treatment of Attention-Deficit/Hyperactivity Disorder. J Exp Pharmacol. 2024 Jan 16;16:13-24. doi: 10.2147/JEP.S433524. PMID: 38249320; PMCID: PMC10799649.

  7. Mathew; Nguyen (2022). Viloxazine. In: StatPearls

  8. Robinson, Parker, Kataria, Downs, Supra, Kaye, Viswanath, Urits (2022): Viloxazine for the Treatment of Attention Deficit Hyperactivity Disorder. Health Psychol Res. 2022 Sep 23;10(3):38360. doi: 10.52965/001c.38360. PMID: 36168642; PMCID: PMC9501833.

  9. Perault, Griesemann, Bouquet, Lavoisy, Vandel (1989): A study of the interaction of viloxazine with theophylline. Ther Drug Monit. 1989 Sep;11(5):520-2. PMID: 2815226.

  10. Laaban, Dupeyron, Lafay, Sofeir, Rochemaure, Fabiani (1986): Theophylline intoxication following viloxazine induced decrease in clearance. Eur J Clin Pharmacol. 1986;30(3):351-3. doi: 10.1007/BF00541543. PMID: 3732375.

  11. Mather, Condren (2022): Extended-Release Viloxazine for Children and Adolescents With Attention Deficit Hyperactivity Disorder. J Pediatr Pharmacol Ther. 2022;27(5):409-414. doi: 10.5863/1551-6776-27.5.409. PMID: 35845566; PMCID: PMC9268104. REVIEW

  12. 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.)

  13. Childress A, Burton S (2022): Evaluating the pharmacokinetics of extended release viloxazine in the treatment of children with attention-deficit/hyperactivity disorder. Expert Opin Drug Metab Toxicol. 2022 Jun;18(6):357-366. doi: 10.1080/17425255.2022.2103406. PMID: 35848085.

  14. Nasser A, Liranso T, Adewole T, Fry N, Hull JT, Chowdhry F, Busse GD, Cutler AJ, Jones NJ, Findling RL, Schwabe S (2020): A Phase III, Randomized, Placebo-controlled Trial to Assess the Efficacy and Safety of Once-daily SPN-812 (Viloxazine Extended-release) in the Treatment of Attention-deficit/Hyperactivity Disorder in School-age Children. Clin Ther. 2020 Aug;42(8):1452-1466. doi: 10.1016/j.clinthera.2020.05.021. PMID: 32723670.

  15. Tan X, Xu Y, Wang S, Li J, Hu C, Chen Z, Cheng Q, Wang Z (2023): Efficacy and Safety of SPN-812 (Extended-Release Viloxazine) in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis. Brain Sci. 2023 Nov 24;13(12):1627. doi: 10.3390/brainsci13121627. PMID: 38137075; PMCID: PMC10742293. REVIEW

  16. Johnson JK, Liranso T, Saylor K, Tulloch G, Adewole T, Schwabe S, Nasser A, Findling RL, Newcorn JH (2020): A Phase II Double-Blind, Placebo-Controlled, Efficacy and Safety Study of SPN-812 (Extended-Release Viloxazine) in Children With ADHD. J Atten Disord. 2020 Jan;24(2):348-358. doi: 10.1177/1087054719836159. PMID: 30924702; PMCID: PMC6939319.

  17. Nasser A, Liranso T, Adewole T, Fry N, Hull JT, Chowdhry F, Busse GD, Melyan Z, Cutler AJ, Findling RL, Schwabe S (2021): Once-Daily SPN-812 200 and 400 mg in the treatment of ADHD in School-aged Children: A Phase III Randomized, Controlled Trial. Clin Ther. 2021 Apr;43(4):684-700. doi: 10.1016/j.clinthera.2021.01.027. PMID: 33750646.

  18. Nasser A, Liranso T, Adewole T, Fry N, Hull JT, Busse GD, Chowdhry F, Cutler AJ, Jones NJ, Findling RL, Schwabe S (2021): A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder. J Clin Psychopharmacol. 2021 Jul-Aug 01;41(4):370-380. doi: 10.1097/JCP.0000000000001404. PMID: 34181360; PMCID: PMC8244935.

  19. Nasser A, Liranso T, Adewole T, Fry N, Hull JT, Chowdhry F, Busse GD, Melyan Z, Cutler AJ, Findling RL, Schwabe S (2021): A Phase 3 Placebo-Controlled Trial of Once-Daily 400-mg and 600-mg SPN-812 (Viloxazine Extended-Release) in Adolescents with ADHD. Psychopharmacol Bull. 2021 Mar 16;51(2):43-64. PMID: 34092822; PMCID: PMC8146561.

  20. Price MZ, Price RL (2023): Extended-Release Viloxazine Compared with Atomoxetine for Attention Deficit Hyperactivity Disorder. CNS Drugs. 2023 Jul;37(7):655-660. doi: 10.1007/s40263-023-01023-6. PMID: 37430151; PMCID: PMC10374479.

  21. Faraone SV, Gomeni R, Hull JT, Chaturvedi SA, Busse GD, Melyan Z, O’Neal W, Rubin J, Nasser A (2022): Predicting efficacy of viloxazine extended-release treatment in adults with ADHD using an early change in ADHD symptoms: Machine learning Post Hoc analysis of a phase 3 clinical trial. Psychiatry Res. 2022 Oct 23;318:114922. doi: 10.1016/j.psychres.2022.114922. PMID: 36375329.

  22. Faison, Fry, Adewole, Odebo, Schwabe, Wang, Maletic, Nasser (2021): Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults. Clin Drug Investig. 2021 Feb;41(2):149-159. doi: 10.1007/s40261-020-00992-6. PMID: 33368026; PMCID: PMC7886742.

  23. Peterson BS, Trampush J, Maglione M, Bolshakova M, Brown M, Rozelle M, Motala A, Yagyu S, Miles J, Pakdaman S, Gastelum M, Nguyen BT, Tokutomi E, Lee E, Belay JZ, Schaefer C, Coughlin B, Celosse K, Molakalapalli S, Shaw B, Sazmin T, Onyekwuluje AN, Tolentino D, Hempel S (2024): ADHD Diagnosis and Treatment in Children and Adolescents [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2024 Mar. Report No.: 24-EHC003Report No.: 2023-SR-03. PMID: 38657097. METASTUDY

  24. Singh, Balasundaram, Singh (2022): Viloxazine for Attention-Deficit Hyperactivity Disorder: A Systematic Review and Meta-analysis of Randomized Clinical Trials. J Cent Nerv Syst Dis. 2022 May 20;14:11795735221092522. doi: 10.1177/11795735221092522. PMID: 35615643; PMCID: PMC9125110. REVIEW