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 extended-release capsules: Qelbree®, Supernus

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
• 2. Viloxazine for ADHD
• 3. Side effects and contraindications
  • 3.1. Side effects of viloxazine
  • 3.2. Contraindications for viloxazine
• 4. Degradation of viloxazine

1. Mechanisms of action of viloxazine¶

Viloxazine differs from other ADHD medications that target the reuptake of norepinephrine and is better described as a serotonin and norepinephrine modulating agent. It has antagonistic activity at 5-HT-2B and agonistic activity at 5-HT-2C receptors and increases serotonin levels in the PFC. It has a moderate inhibitory effect on the noradrenaline transporter and a moderate effect on the noradrenergic and dopaminergic systems. This finding is consistent with the low rate of cardiac effects in clinical practice.

Viloxazine has no binding affinity for the dopamine transporter (DAT) and does not interact directly with the dopamine receptors D1 and D2. Due to its minimal effect on dopamine in the nucleus accumbens, it is thought to pose a low risk of substance abuse. The immediate-release viloxazine formulation was initially marketed as an antidepressant in Europe and later discontinued for reasons unrelated to safety or efficacy. Data from more than two decades of research in adults have shown viloxazine to be safe and tolerable compared to the TCAs, with fewer cardiovascular effects and minimal effects on blood pressure.

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 does not interact with the DAT or dopamine receptors.⁶

Viloxazine has been shown to increase dopamine levels⁷, noradrenaline levels⁷ and serotonin levels^{89 6} in the PFC. However, it does not appear to act as a serotonin reuptake inhibitor.⁸⁷
It does not increase the release of noradrenaline.

Viloxazine increases the dopamine level in the nucleus accumbens significantly less than stimulants.¹⁰ We consider the authors’ assertion that non-stimulants have fewer side effects to be incorrect. Non-stimulants (atomoxetine, guanfacine) have significantly higher side effects compared to stimulants with a significantly lower Effect size.

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.¹¹¹² 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 data:

• Bioavailability approx. 88 %⁵
• Tmax (time to maximum plasma concentration): approx. 5 hours at 200 mg⁵; 6 to 9 hours⁶
• Active ingredient is highly protein-bound (76-82 %)⁵
• Average half-life of viloxazine ER is 7 hours (2.25 to 11.75 hours)⁵⁶
• Degradation mainly by the enzymes CYP2D6, UGT1A9 and UGT2B15⁶
• 90 % of the drug is excreted via the kidneys. Of this, 12-15% is in unchanged form, the rest as inactive metabolites⁶

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.¹³⁵
The Effect size of viloxazine was determined to be between 0.46 and 0.63 in various studies¹⁴ and is thus considerably weaker than the Effect size of stimulants (1.1 to 1.5).¹⁵
Various phase II and phase III studies found a good effect of viloxazine on ADHD in

• 100 and 200 mg / day¹⁶
• 100, 200 and 400 mg / day¹⁷
• 200 to 400 g / day^18192021
• 400 or 600 mg / day²²

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.²³

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 in the first week
  • Up-dosing up to the maximum daily dose of 400 mg
    • 73 % of the subjects in one study used 400 mg²⁴

In adults with ADHD, one study found a symptom reduction of more than 50% compared to the AISRS baseline in 40.2% of subjects.²⁵

A combination of viloxazine is possible with

• Methylphenidate²⁶⁶
• Lisdexamphetamine⁶.

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)²⁷
• Headache
• Tiredness
• Upper abdominal pain
• Nausea
• Vomiting
• Irritability
• increased heart rate²⁸
  • by more than 20 beats/minute in 30% of the children, compared to 15% of those treated with placebo
  • Increase was dose-dependent
• increased blood pressure²⁸
  • below 400 mg/day, 25% of adolescents showed an increase in diastolic blood pressure of ≥ 15 mmHg at any time during the clinical trial, compared with 13% in the placebo group

Another placebo-controlled study in n = 384 adults with a free dose titration resulted in an average dose of 500 mg. The most common treatment-related adverse events were:²⁹

• Insomnia (14.8 %)
• Tiredness (11.6 %)
• Nausea (10.1 %)
• Loss of appetite (10.1 %)
• Dry mouth (9.0 %)
• Headaches (9.0 %).

The discontinuation rate due to side effects was 9.0% compared to 4.9% in the placebo group.

3.2. Contraindications for viloxazine¶

Viloxazine should not be taken in the case of

• 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 ³⁰⁵

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.