Gamma-aminobutyric acid (GABA) is the principal inhibitory or ‘calming’ neurotransmitter in the central nervous system (CNS). It is opposed by its main counterpart, the excitatory neurotransmitter glutamate which is also the most abundant neurotransmitter and a precursor to GABA.^1-3

Maintaining a well-coordinated balance between GABA and glutamate (or ‘inhibition and excitation’) is essential for normal brain function. Glutamate excess on the other hand, coupled with low brain levels of GABA or decreased GABA function, can lead to various neurological, psychological and other disorders, including anxiety. In these instances, GABA (receptor) agonists can be employed as a “break” to counteract excessive excitation and re-establish balance.³

Pharmaceuticals such as benzodiazepines (’benzos’) typically exert their anxiolytic, sedating and anticonvulsant effects by targeting GABA receptors.⁴ However, where non-pharmacological treatment is warranted (i.e. in milder forms of anxiety), GABA-modulating herbal medicines may provide a novel treatment option with fewer side effects, either as an adjunct or an alternative to existing conventional GABA-agonists.

Plant Sources of GABA

GABA is widely present in plants, including in foods (i.e. cruciferous vegetables, various beans, potatoes, tomatoes, mushrooms),⁵ functional foods (i.e. fermented cheeses and yoghurts using GABA-producing micro-organisms such as lactic acid bacteria),^6,7 and herbal medicines.

Plants primarily synthesise GABA from glutamic acid via the enzyme glutamic acid decarboxylase (also known as glutamate decarboxylase or GAD) (see diagram below⁸). Generally, plant levels of GABA are fairly low, but can increase substantially after exposure to a range of stressors (i.e. oxygen deficiency, drought, salt, wounds, infection, soaking and germination).^5,9 As such, plants are a valuable source of GABA. However, because isolated supplemental GABA is not believed to pass the blood–brain barrier (BBB), botanical and dietary sources are thought to act on the peripheral GABA systems via their many active plant constituents (i.e. alkaloids, saponins, polyphenols and flavonoids).¹⁰ 

Pharmaceutical Properties of GABA

GABA is a powerful bioactive compound with numerous pharmaceutical properties which affect both neuronal and non-neuronal peripheral tissues and organs. Therapeutic applications of GABA therefore include not only anxiety, but many other conditions such as pain, neuromuscular spasticity and cognition (see diagram below).

Diagram 1 | Pharmacological effects of GABA and Glutamate.^1,2,11-13

 

GABA‐Modulating Herbal Medicines

GABA-modulating herbal medicines exert their actions in various ways, i.e. by binding with GABA‐receptors; particularly with the ionotropic receptors GABA-A and GABA-C which are responsible for fast synaptic transmission via ligand-gated ion channels.¹⁰ Active plant constituents, in particular flavonoids (i.e. apigenin, hispidulin and luteolin), have many and varied effects, particularly on ionotropic GABA receptors, including dual actions (i.e. they may potentiate GABA actions at low concentrations and inhibit GABA at high concentrations). They may also act by modulating enzymatic processes associated with GABA,¹¹ or act as agonists on certain GABA receptors by directly gating the receptor in the absence of GABA (as is the case with flavonoids).^10,14,15

In summary, GABA-ergic activities involve the following mechanisms of action:¹¹

• Binding to novel allosteric binding sites on GABA-A receptors, thereby reducing neural activity (excitation)
• Inhibiting GABA reuptake, which results in more GABA being available, as well as improved transmission of messages between neurons
• Targeting GABA transporters (type 1 or 2) in order to up- or down-regulate GABA transport
• Inhibiting GABA transaminase (GABA‐T), the enzyme that degrades GABA, thereby sparing GABA
• Promoting the activity of GAD, the enzyme that converts glutamate to GABA, thus increasing GABA levels

The table below itemises 15 herbal medicines and their confirmed GABA-ergic mechanisms in the CNS, based on the available evidence from in vitro studies, animal studies and human clinical trials.

Table 1 | GABA-ergic Herbal Medicines and their Pharmacological Targets in the CNS

Herbal Medicines	Active Constituents & GABA-ergic Mechanisms
Brahmi (Bacopa monnieri)	Over 50 active constituents from Bacopa have been identified,16  with the main ones classed as saponins (bacosides A, B, C), bacosaponins (A to H), bacopasides (I-VIII, XII), alkaloids (brahmine, herpestine), flavonoids (luteolin-7-glucoside, glucuronyl-7-apigenin, glucuronyl-7-luteolin), phytosterols (β-sitosterol) and triterpenes.16-19 Bacopa has been shown to increase the concentration of GABA-ergic neurons in the brain.19,20
Green tea (Camellia sinensis)	Green tea mainly consists of polyphenols (catechins such as epigallocatechin gallate [EGCG] and flavonols, including myricetin, kaempferol, quercetin, chlorogenic acid), amino acids, theanine, proanthocyanidins and caffeine.21 The processing of tea leaves, which involves anoxic stress and mechanical damage, results in high accumulation of GABA.22 Moreover, EGCG has been shown to activate GABA-A receptors.18
Gotu kola (Centella asiatica)	Gotu kola contains triterpene saponins, including asiatic acid, monoterpenoids and flavonoids (i.e. quercetin and kaempferol glucosides).11,23 The plant significantly increases GAD activity in vitro by more than 50%,24  as well as whole brain levels of GABA.25 Anxiolytic effects of asiatic acid are thought to be due to GABA‐ergic benzodiazepine (BDZ) receptor activity.26
Chamomile (Matricaria chamomilla, M. recutita)	Chamomile contains numerous active constituents including flavonoids (i.e. apigenin, luteolin, rutin), coumarins (herniarin, umbelliferone), and phenolic acids.11,27,28 GABA-ergic activity in Chamomile is expressed via the flavonoid apigenin,4 which modulates the function of GABA receptors via ligand effects on the central BDZ site, thereby acting as a BDZ agonist.14
Ginkgo (Ginkgo biloba)	Some of the active components in Ginkgo are flavonoids (kaempferol, quercetin, myricetin), flavones (apigenin, luteolin), and terpenoids (bilobalides, gingkolides A, B, and C).11,29 Ginkgo flavonoids are thought to have GABA-ergic activity and might directly affect BDZ receptors.30 However, why bilobalide and ginkgolide B negatively modulate the action of GABA-A receptors has not been established.31
Hops (Humulus lupulus)	Hops contain several flavonoids including the isoprenylated chalcone xanthohumol, the isoprenylated flavanone isoxanthohumol, 6-prenylnaringenin (6-PN), 8-prenylnaringenin (8-PN), quercetin, and kaempferol.27,28 Myrcenol appears to potentiate the GABA‐A receptor response,32 while humulone (alpha acid) and 6-prenylnaringenin (prenylflavonoid) are potent modulators of GABA-A receptors at low concentration. 33 Hops also ops Hops exerts GAD inhibition.24
St. John’s wort (Hypericum perforatum)	St. John’s wort contains phloroglucinol derivatives (mostly hyperforin), naphthodianthrones (i.e. hypericin and pseudohypericin), flavonoids (i.e. hyperoside, rutin, isoquercetrin, kaempferol), tannins, trace amounts of xanthoses, as well as volatile oil.18,29 Hyperforin inhibits synaptosomal uptake of GABA and L-glutamate, while hypericin acts as a receptor antagonist at adenosine, BDZ, GABA-A, and GABA-B receptors.34
Kava (Piper methysticum)	Kava contains kavalactones (kavapyrones), chalcones (flavokawains), alkaloids and flavonoids (flavokavains).18,23,29 Kava facilitates GABA transmission and exerts GABA agonist activity.35 Many GABA-ergic mechanisms appear to be due to kavalactones, which rapidly upregulate GABA-A receptor function,10,11 block voltage‐gated sodium ion channels, enhance ligand binding across GABA‐A receptor subtypes, and reduce excitatory neurotransmitter release via blockade of calcium ion channels.11 Their effects may also be due to an increase in the number of GABA binding sites or a dopamine antagonist action.35
Lemon balm (Melissa officinalis)	Some of the main active constituents of Lemon balm include flavonoids (i.e. glycosides of luteolin, apigenin, kaempferol, quercetin), volatile oils, triterpenes (ursolic acid, oleanolic acids) and hydroxycinnamic acid derivatives (i.e. rosmarinic acid).11,28,29 Lemon balm constituents elevate GABA levels by inhibiting GABA‐T. Moreover, ursolic acid was shown to have a moderate affinity for the GABA-A BDZ receptor site,36 while terpenes contained in the volatile oil are thought to possess cholinergic activity or act on GABA receptors.37
Passionflower (Passiflora incarnata)	Passionflower contains flavonoids (glycosides of apigenin and luteolin), maltol, chlorogenic acid, and traces of volatile oil and alkaloids.11,27,28 GABA‐ergic modulation is thought to occur via an affinity with GABA‐A and GABA‐B receptor subtypes, GABA reuptake inhibition, as well as via positive allosteric modulation of the GABA‐A receptor complex through BDZ sites.11,38
Saffron (Crocus sativus)	Saffron contains more than 150 volatile and non-volatile constituents. The most important ones include the carotenoids (crocetin, crocins, lycopene, zeaxanthin), monoterpene aldehydes (picrocrocin and safranal), monoterpenoids and flavonoids.18,39 Safranal has been shown to interact with the GABA-A complex.40
Skullcap (Scutellaria lateriflora)	Skullcap contains numerous flavonoids (i.e. baicalin, baicalein, oroxylin,wogonin), as well as diterpenes, amino acids and volatile oils.11,29 Baicalin, wogonin and apigenin are thought to act as GABA agonists;11,41 they act at the BDZ site of GABA‐A receptor via positive allosteric modulation.11
Valerian (Valeriana officinalis)	The chief active constituents of Valerian are volatile oils containing monoterpenes, sesquiterpenes and sequiterpenic acids (i.e. valerenic acid), as well as GABA, glutamine, arginine, and traces of flavonoids (6-methylapigenin and hesperidin).42 Valerenic acid and other constituents of Valerian are GABA agonists, which may bind directly to GABA-A receptors. They potentiate GABA release and inhibit reuptake or degradation by inhibiting GABA‐T activity in brain tissue, thereby increasing GABA concentrations and decreasing CNS activity.11,43
Withania (Withania somnifera)	The main active constituents of Withania are steroidal lactones (about 40 withanolides) and alkaloids. Smaller amounts of flavonoids, saponins, coumarins and triterpenes are also present.18,23 Withania acts as a GABA mimetic agent by binding to ionotropic GABA‐A receptors; it is also a GABAρ1 receptor agonist.11,44

Conclusion

Many herbal medicines traditionally described as ‘anxiolytics’, ‘sedatives’ and ‘nervine tonics’ have been proven to exert their calming effects on the CNS via a range of different neurobiological mechanisms involving the inhibitory neurotransmitter GABA. This phenomenon is due to their many naturally occurring active constituents, which synergistically, give rise to direct and indirect mechanisms in which they work. Hence, GABA-ergic herbal medicines present potential and novel treatment option for hyper-excitatory states such as anxiety - either as an adjunctive or an alternative treatment to conventional GABA agonists.

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