Safinamide mesylate

Safinamide mesylate (available under the brand name Xadago®), originally developed as PNU-151774E is a highly selective and reversible monoamine oxidase B (MAO-B) inhibitor, recently introduced to the market and currently approved as an adjunct to levodopa / carbidopa for Parkinson’s disease. Given that its mechanisms of action reach beyond straightforward MAO inhibition, it has the potential to offer substantial benefits in various neuropsychiatric conditions, and as such is very likely to be repurposed in the future. As a truly modern MAO inhibitor, it increases synaptic dopamine with impressive selectivity (ca. thousand times more selective for MAO-B than MAO-A at therapeutic doses).

Interestingly enough, while safinamide mesylate was never targeted specifically as a potential anti-epileptic drug, it turns out to possess potent anti-convulsant properties, enacted through glutamate modulation via voltage-gated sodium channels and N-type calcium channel blockage. Additionally, it has been found to bind to the Σ-receptors, displaying high affinity for Sig1R, which broadens its spectrum as an anticonvulsant. While selegiline is known to lower GABA by inhibiting the enzyme involved in its metabolism (particularly in astrocytes), which might result in problematic insomnia in some individuals, thanks to its unique pharmacological profile, safinamide actually prevents excessive glutamate release, which, in the light of recent research might offer not only neuroprotection but also cognitive and affective advantages. Via dopamine D2/D3 receptor modulation, it could potentially increase dopaminergic tone without overstimulation. Safinamide’s dual dopaminergic (mood-enhancing) and glutamatergic (anxiolytic) effects may help PD-related depression. Clinical trials show improved mood independent of motor symptoms. Certain case studies suggest that combined safinamide mesylate as an adjunct to SSRIs might be effective in the management of treatment-resistant depression.

In fact, it could even be said that safinamide happens to be a MAO-B inhibitor and CNS stimulant in one, as it has been observed to inhibit dopamine and noradrenaline reuptake at around a concentration of 10μM. It appears to act in a similar, albeit weaker, manner on serotonin. Its glutamatergic modulation is also speculated to support executive function in PD patients with “on-off” cognitive swings, and one could make an educated guess that its unique dual action might be particularly beneficial for individuals with neurodivergent (and often comorbid) conditions. Dopamine enhancement could improve focus and executive function in ADHD and Autism Spectrum Disorder, while glutamate modulation might reduce hyperactivity, hyperarousal, and irritability and prevent sensory overload. According to some animal studies, its glutamate-modulating effects might improve prefrontal cortex function; it has also been demonstrated to reduce oxidative stress and excitotoxicity, potentially slowing neurodegeneration (relevant to early dementia).

It could be said that safinamide possesses a wide range of potential applications that are yet to be explored and fully understood. Let’s take the example of its anti-epileptic properties; after a preliminary screening, safinamide was chosen for its impressive potency, wide-ranging effects, and commendable safety profile, paving the way for its efficacy to be tested in a pilot phase 2 clinical study. A twelve-week study on thirty-eight patients with refractory epilepsy began at a modest 50 mg/day, gradually ramping up to 300 mg/day. With 41% of subjects noting their seizure count by at least half, it is a slight understatement to call its results promising. Nevertheless, given that safinamide was primarily concocted to tackle Parkinson’s disease, no further research has been conducted to chase after its potential for clinical use in this particular realm.

Benefits of taking safinamide mesylate

• prevents excitotoxicity;

• boost in mood;

• decreased anxiety;

• reduced oxidative stress;

• might enhance executive function;

• likely to address the symptoms of “long” COVID-19;

• possible aid in the treatment of neurodivergent conditions;

• protection against neurodegeneration;

• potent anti-convulsant properties.

Side effects

• nausea;

• insomnia;

• dizziness;

• hypersexuality;

• dyskinesias (PD);

• hallucinations (rare);

• confusion (rare).

Interactions & contraindications

While it can be argued that used in conjunction with high-dose SSRIs/SNRIs, safinamide could potentially cause serotonin syndrome, the risk of such an occurrence is mostly theoretical at safinamide’s MAO-B-selective doses. Still, caution is advised.

No tyramine-related dietary restrictions are necessary within its standard therapeutic dose range (not exceeding 100 mg / day).

Dosage

In clinical practice, it is initially dosed at 50 mg (single oral dose taken in the morning). If necessary, it could be increased to 100 mg / day past the second week mark.

As mentioned before, early clinical trials evaluating safinamide’s efficacy as a possible anti-seizure drug utilized more radical approach, with maximum dose established at 300 mg / day, meeting a favorable outcome.

On the other hand, safinamide seems to have a wide therapeutic margin, in that lower doses have also been used off-label for mood and cognition enhancement, and in the absence of official protocols or guidelines, it is generally assumed that 25-50 mg should be adequate for such purposes.