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Viloxazine for ADHD


Viloxazine for ADHD

Viloxazine 1
Brand names: Viloxazine, Emovit, Viloxazina, Viloxazinum, Vivarint, Vicilan, Vivalan, Catatrol

1. Mechanisms of action of viloxazine

Viloxazine acts as a234

  • strong:
    • selective serotonin 5-HT2B receptor antagonist
    • Serotonin 5-HT2C receptor agonist
  • moderate:
    • selective norepinephrine reuptake inhibitor (Ki: 0.63 μM)
      • thereby increasing dopamine and norepinephrine in the PFC
      • no additional release of norepinephrine5
  • weak:
    • Serotonin 5-HT7 receptor antagonist
    • α1B-adrenoceptor antagonist
    • β2-adrenoceptor antagonist

Viloxazine has been shown to increase serotonin levels in the PFC.6 However, it does not appear to act as a serotonin reuptake inhibitor.
It does not increase the release of norepinephrine.

Viloxazine increases dopamine levels in the nucleus accumbens significantly less than stimulants.7 We consider the authors’ claim that non-stimulants would show lower side effects to be erroneous.

Other in vitro studies found no dopamine release in the striatum and little 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 a consequence of NET reuptake inhibition. The minimal effect of viloxazine on dopamine in the nucleus accumbens may indicate a low susceptibility to abuse.5 We therefore hypothesize a lower drive enhancement than stimulants.
Viloxazine markedly increases plasma levels of the adenosine A1 and A2 antagonist theophylline.89

It is conceivable that part of the effect of viloxazine in ADHD may be due to the dopamine-enhancing effect of the adenosine antagonist theophylline.

Viloxazine is a very weak, competitive, and reversible inhibitor of monoamine oxidase A and B.5

Contrary to almost all previously heavily used ADHD medications, viloxazine does not alter histamine levels. Viloxazine appears to exert weak competitive inhibition at histamine receptors H1 and H2 (< 25%).5

Pharmacological data4

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

2. Viloxazine for ADHD

Extended-release viloxazine (viloxazine ER; SPN-812) was shown to be an effective and well-tolerated alternative for some children with ADHD in multiple Phase 2 and Phase 3 studies at 200 to 400 mg/day. The mechanism of action of viloxazine is unique in that it modulates the activity of both serotonin and norepinephrine.104
The effect size of viloxazine was found to range from 0.46 to 0.63 in different studies.11
Several phase II and phase III studies found good effect of volixazine in ADHD at 200 to 400 g/day1213 14 , 400 or 600 mg/day15 and at 100 and 200 mg/day.16
The different publications on phase III are from an identical group of authors.

Symptom reduction at 2 weeks predicts treatment success at 6 weeks quite well.4


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

In adults with ADHD, one study found symptom reduction of greater than 50% from baseline AISRS in 40.2% of subjects.17

Combination with methylphenidate is possible.18

3. Side effects and contraindications

3.1. Viloxazine side effects

  • Drowsiness
  • reduced appetite
  • Headache
  • Fatigue
  • Upper abdominal pain
  • Nausea
  • Vomiting
  • Irritability

3.2. Contraindications for viloxazine

Viloxazine should not be taken in case of

  • Epilepsy predisposition
  • severe liver failure
  • during or if pregnancy is intended. Viloxazine may cause harm to the fetus.
  • before the expiry 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. Viloxazine degradation

Viloxazine is metabolized by CYP2D6, UGT1A9, and UGT2B15, and possibly by CYP1A2 194

Viloxazine is a potent CYP1A2 inhibitor.
Dose reduction may be required with concomitant use of drugs metabolized by CYP1A2.

  1. ±)-2-[(2-ethoxyphenoxy)methyl]morpholin Hydrochlorid; C13H20NO3Cl) (SPN-812) wird in den USA seit April 2021 zur Behandlung von AD(H)S bei Kindern von 6 bis 17 Jahren und von Depression zugelassen. Es wurde von 1976 bis 2006 in Europa als Antidepressivum sowie off-Label gegen Enuresis und Narkolepsie eingesetzt.((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. Viloxazin

  3. Wikipedia: Viloxazine

  4. 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

  5. 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.

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

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.)

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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