GABA Agonists to be Considered in the Treatment of Vestibular Migraine

The following medications up-regulate GABA activity in various ways and deserve consideration in the treatment of vestibular migraine patients who do not respond to general migraine preventive therapy:

Venlafaxine has been found to affect GABA levels in the brain. A study demonstrated that venlafaxine treatment was nonsignificantly associated with increased GABA levels compared to placebo[1]. This indicates that venlafaxine may have an impact on GABA activity in the brain that may explain it’s unique usefulness in vestibular migraine treatment compared to other serotonin active drugs.

Propranolol has been found to affect GABA. Research suggests that propranolol treatment can stimulate GABA-benzodiazepine receptor coupling, leading to an increase in GABA-stimulated diazepam binding[1][3]. Additionally, chronic administration of propranolol has been shown to increase GABA content, synthesis, and turnover rate in selected brain areas, indicating an influence on the functional state of the GABAergic system[4]. Therefore, there is evidence to support the notion that propranolol affects GABA activity in the brain. It, therefore, may have a specific role in the treatment of vestibular migraine.

Topiramate affects GABA. Research has shown that topiramate increases cerebral GABA concentrations acutely in healthy individuals and also raises brain GABA levels in epilepsy patients. This effect is thought to contribute to the drug's anticonvulsant properties[2][4]. Additionally, topiramate has been found to enhance GABA-mediated chloride flux and GABA-evoked chloride currents in the brain, which may contribute to its ability to increase seizure threshold[3]. Therefore, topiramate is known to modulate GABA levels in the brain, which is linked to its therapeutic effects. Topiramate is very effect in general management of chronic migraine and may exhibit its effect on vestibular migraine by this effect alone. Its specific usefulness in vestibular migraine specifically has not been demonstrated but deserves consideration even in patients without headache.

Gabapentin affects the GABA system in the brain. Although it does not directly bind to GABA receptors or act as a GABA agonist, it has been found to increase GABA synthesis and release. Gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), and increases non-synaptic GABA responses from neuronal tissues in vitro[2]. Glutamate decarboxylase is an enzyme involved in GABA synthesis, and increase GABA turnover in the brain[1]. Therefore, while gabapentin does not directly interact with GABA receptors, it exerts its effects by influencing GABA synthesis and release, which is relevant to its therapeutic use in conditions such as epilepsy and neuropathic pain[4]. The usefulness of gabapentin in vestibular migraine has not been demonstrated but deserves consideration.

Pregabalin, a structural analogue of GABA, does not directly bind to GABA receptors or acutely alter GABA uptake or degradation. However, prolonged application of pregabalin has been found to increase the density of GABA transporter protein as well as the rate of GABA transport, suggesting an indirect effect on the GABA system[2]. Additionally, pregabalin has been shown to modulate the action of GABA by reducing the release of excitatory neurotransmitters through its high-affinity binding to the α2-δ subunit on voltage-gated calcium channels[2]. Therefore, while pregabalin does not directly interact with GABA receptors, it exerts its effects by influencing GABAergic neurotransmission, which is relevant to its therapeutic use in conditions such as generalized anxiety disorder and neuropathic pain. Its usefulness in vestibular migraine has not been demonstrated but deserves consideration.

Valproic acid also affects the GABA system in the brain. It increases regional neuronal concentrations of GABA by inhibiting its metabolism and increasing its synthesis[2][3]. Additionally, valproic acid has been shown to enhance GABAergic transmission across synapses[4]. Furthermore, it stimulates GABA neurogenesis from rat forebrain stem cells, leading to an increase in GABAergic neuron numbers and phenotypic expression[5]. Therefore, valproic acid has a significant impact on the GABA system in the brain, which is relevant to its therapeutic effects in conditions such as bipolar disorder and epilepsy and possibly vestibular migraine. The use of valproic acid in VM deserves attention.

Clonazepam affects the brain by increasing the overall effects of GABA. It works by enhancing the neurotransmitter GABA at the GABA-A receptor, leading to sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties. Clonazepam strongly binds to the GABA-benzodiazepine receptor, which enhances the inhibitory effects of GABA, making the neuron less responsive to other neurotransmitters that would normally excite it[1][4][5]. This mechanism of action is responsible for its therapeutic effects in treating anxiety, panic disorders, epilepsy, and seizures, as well as vestibular migraine[3][5].