Betahistine mesylate

Betahistine is a histamine-like drug primarily used to treat Ménière’s disease and other vestibular disorders by improving blood flow in the inner ear and modulating histaminergic neurotransmission. It has also been prescribed in tinnitus, migraine, and cluster headaches. As a weak H₁ receptor agonist, it improves vasodilation, yet, its particularly interesting effects are linked to its action as a strong H₃ receptor antagonist. While H₃ receptors act as autoreceptors in presynaptic histaminergic neurons and control histamine turnover by feedback inhibition of histamine synthesis and release, their scope of action is anything but limited to histamine. It has also been demonstrated to presynaptically inhibit the release of a number of other neurotransmitters including, but probably not limited to dopamine, GABA, acetylcholine, noradrenaline, histamine and serotonin. Conversely, as its antagonist, betahistine contributes to their increased release, most notably histamine, acetylcholine, dopamine, and norepinephrine, which amounts to its nootropic potential.

Preclinical studies suggest that histamine enhances long-term potentiation (LTP) and neuroplasticity. H₃ knockout mice perform better than controls at tasks engaging working memory. Furthermore, betahistine was found to enhance cholinergic neurotransmission in rats.

Moreover, some data indicates that it may reduce cortical spreading depression (CSD), a wave of electrophysiological hyperactivity followed by a wave of inhibition (disrupting neuronal activity and leading to a period of reduced electrical activity), associated with conditions such as migraine with aura, traumatic brain injury, and stroke.

It is currently believed that betahistine might counteract the cognitive decline in Alzheimer’s, and possibly other dementias of cortical etiology, as preliminary research implicates the pro-cognitive role of histaminergic system and its modulation — further investigation and human trials, are, however, essential to corroborate this hypothesis. Betahistine has also been studied as adjunctive treatment for Parkinson’s, for its potential to address balance and cognitive symptoms.

Evidence suggests that H₃ antagonists improve sustained attention in rodent models. Given their ability to raise dopamine and norepinephrine levels in prefrontal cortex, potentially improving attention, memory, and executive function, betahistine would also make a natural candidate drug for the treatment of ADHD. While this area remains to be researched, anecdotal reports generally support this theoretical premise. It is definitely worth mentioning that betahistine would have a major advantage over stimulant medication, as it is unlikely to cause anxiety or insomnia at typical doses.

A potent H₃ antagonist might also succeed at alleviating the cognitive symptoms of schizophrenia; a more speculative line of thought posits that histaminergic modulation may influence mood, outlining novel avenues of research to be explored to assess the impact of drugs like betahistine on the symptoms of major depressive disorder.

A 2018 small study found that betahistine improved reaction time in healthy adults, a result that could be attributed to H₃ effects.

Benefits of taking betahistine

• improved attention and focus;

• increased task persistence;

• enhanced memory and learning;

• increased alertness;

• higher energy levels;

• enhanced neuroplasticity;

• boost in mood;

• decrease in anhedonia.

Side effects

• gastrointestinal discomfort;

• headache;

• nausea;

• hypersensitivity and allergic reactions (rashes, swelling, paraesthesia);

• mild sedation (dose-dependent).

Contraindications

• asthma;

• peptic ulcers;

• pheochromocytoma;

• histamine intolerance (medical consultation recommended).

Dosage

Betahistine is available in two forms: HCl (dihydrochloride) vs. mesylate, with the former being more common and well-studied. It is taken orally, typically dosed at 16–48 mg/day, divided in two or three doses. The starting dose is 8–16 mg twice daily, taken in the morning and early afternoon. For the purpose of cognitive enhancement, it is suggested to stay within the 24–48 mg range, as higher doses would be more likely to produce side effects than added benefit.

As the more stable form of the two, with longer shelf life, betahistine dihydrochloride is generally more common. It is typically available at higher doses, possibly more effective for some patients.

Betahistine mesylate, on the other hand, is less common — with slightly higher molecular weight. According to some sources, it might require dose adjustment (~120% HCl dose for achieving equivalent effect). That said, mesilate salts are an alternative to conventional hydrochloride salts, typically superior in terms of solubility and bioavailability. Some research pharmacists claim that a lower dose of betahistine mesilate may be actually needed to achieve the same therapeutic effect as betahistine dihydrochloride, and indeed, it is sold as 6 and 12 mg tablets.

As mentioned in a review article published in International Journal of Basic & Clinical Pharmacology, there are certain differences in pharmacokinetic behavior that could potentially be influenced ethnically. While both formulations are available by prescription in numerous countries around the world, only one form of betahistine may be registered and marketed in some regions.

Certain mesilate esters that could be formed during the preparation of mesilate drug formulations, have been found to be potentially genotoxic and carcinogenic by virtue of DNA alkylation. Therefore, the established techological process of betahistine mesilate synhesis needs to be followed meticulously and rigorously to ensure that alkyl mesilates are not detectable in the final product.