GABA-ergic System

Most-studied kavalactone; positive allosteric modulation of GABA-A at a site distinct from the benzodiazepine binding site, plus sodium and calcium channel modulation. Rapid brain uptake (peaks at 5 min after IP administration in mouse models). One of the six major lactones (kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, demethoxyyangonin) accounting for ~96% of the lipid resin.

Reduced form of kavain — rapid brain uptake (peak ~5 min after IP). Sedative-leaning profile. Hepatically metabolized via hydroxylation and ring-opening pathways (Rasmussen 1979).

Anxiolytic kavalactone with sodium and calcium channel modulation in addition to GABA-A activity. The methylenedioxyphenyl ring contributes to slower hepatic metabolism vs simpler kavalactones.

Reduced form of methysticin; sedative-leaning. One of the six major lactones in the resin.

CB1 receptor binding has been reported in vitro — adds an unexpected cannabinoid-system overlap to kava's profile. Slow brain elimination and dose-related accumulation when administered as crude resin (vs isolated compound).

Negative in Ames mutagenicity assay (Hsu 1994). One of the six major lactones; slow brain elimination similar to yangonin.

5,6-dehydromethysticin, 5,6-dihydroyangonin, 5,6,7,8-tetrahydroyangonin, 7,8-dihydroyangonin, 10/11-methoxyyangonin, 11-hydroxyyangonin, hydroxykavain, 11-methoxy-12-hydroxydehydrokavain — fifteen kavalactones total identified in the rootstock; together they make up the remaining ~4% of the lipid resin.

Primary anxiolytic flavone; GABA-A binding and weak MAO-A inhibition.

Auxiliary GABA-A binding site activity.

Flavone glycoside; also abundant in hawthorn.

Primary anxiolytic/hypnotic constituent; positive allosteric modulator at GABA-A β3 subunits.

Secondary sedative sesquiterpene.

Unstable iridoids (degrade with storage) — contribute to fresh-extract activity.

Primary anxiolytic constituent; 5-HT1A modulation and indirect GABAergic activity. The mechanism behind Silexan's clinical effect.

Aromatic ester; sedative contribution.

Hop bitter acids — sedative properties partly mediated through GABA-A binding. The compounds responsible for traditional hop-pillow sleep use.

Aromatic terpenes contributing to mild sedative profile. Myrcene is also abundant in cannabis (terpene-profile overlap).

Multi-target polyphenol; GABA-A modulation, anti-inflammatory, and direct anti-HSV activity in vitro. Shared with rosemary, sage, holy basil — plants with parallel anxiolytic / antimicrobial profiles.

Volatile aroma compounds; mild GABAergic / anxiolytic activity.

Positive allosteric modulator of GABA-A at a binding site distinct from benzodiazepines. Anxiolytic and pro-sleep without classical benzo binding.

Sister compound to honokiol; combined GABAergic and HPA-modulating activity. Also has CB1 / CB2 binding reported in vitro.

Primary bioactive flavones (S. baicalensis); well-characterized positive allosteric modulators of GABA-A receptors and broad anti-inflammatory activity.

Selective benzodiazepine-receptor-site flavone — anxiolytic activity in animal models without sedation.

Modulates the HPA axis (cortisol-lowering during stress) and exerts mild GABA-A modulation centrally. Together these underlie the documented anxiolytic and sleep-promoting effects.

Negative allosteric modulator at CB1; agonist at 5-HT1A, TRPV1; modulates GABA-A. Potent CYP3A4/2C9/2C19 inhibitor — major source of pharmacokinetic interactions.

Glutamate-related amino acid unique to green tea (also Camellia japonica). Modulates GABA, glutamate, and dopamine; the 'calm focus' counterbalance to caffeine.

Kavalactones are reported to modulate GABAergic transmission and have been investigated for interactions with 5-HT2A and serotonin reuptake pathways; MAO-B inhibitory activity has been proposed in preclinical models. Clinical anxiolytic signals reported in one RCT (Sarris et al. 2009).

Apigenin binds GABA-A at the benzodiazepine site (its anxiolytic mechanism) and has separately been investigated for cyclin-dependent-kinase-mediated cell-cycle arrest in preclinical cancer models. Research only — not a treatment claim.

Preclinical studies indicate apigenin binds benzodiazepine-site of GABA-A receptors and may modulate serotonergic signaling; proposed as a contributor to anxiolytic-relevant activity observed in clinical chamomile trials

Preclinical studies report modulation of GABAergic neurotransmission and upregulation of BDNF/NGF expression; proposed to underlie the observed sedative and neuroprotective signals in animal models

Animal and limited human data suggest possible GABAergic modulation contributing to observed anxiolytic-like signals; mechanism not confirmed in clinical studies.

Flavone class compounds are investigated as modulators of GABAergic tone and HPA-axis activity; class-level mechanistic inference — not specifically demonstrated for this plant extract in human trials.

GABA-A receptor antagonist at meaningful exposure — toxic at high doses, lowering seizure threshold and contributing to the safety ceiling of high-dose oral sage.

Preclinical data suggest linalool may modulate GABAergic signalling; proposed as a contributor to reported sedative-adjacent effects in vitro and in animal models. Clinical relevance in humans has not been established.

Animal studies (MES and PTZ seizure models) report dose-dependent anticonvulsant and sedative activity attributed to the essential oil; GABAergic modulation is proposed but not confirmed at the molecular level in the cited literature.

GABA-A potentiator (mild anxiolytic and antispasmodic effects), modest estrogen-receptor modulator activity (basis for use in PCOS hyperandrogenism in the TJ-68 / Shakuyaku-kanzo-to formulation), and direct smooth muscle relaxant on uterine and skeletal muscle.

Preclinical studies report GABAergic modulation and serotonergic activity attributed in part to linalool; investigated as a major anxiolytic-relevant constituent of ylang-ylang essential oil.

Preclinical studies report linalool may modulate GABAergic neurotransmission; proposed as a contributor to observed anxiolytic-like effects in animal models (Emamghoreishi et al., 2005). Mechanism not confirmed in human studies.

Partial agonist at the central benzodiazepine site of GABA-A; the principal mechanism for the mild anxiolytic and sleep-promoting effects shared with German chamomile.

**GABA-A antagonist at high doses** — proconvulsant; basis for thujone toxicity at chronic high intakes. Different stereochemistry than the GABAergic positive allosteric modulators (kava, valerian) — opposite pharmacology.

Free GABA is present in the aerial parts; proposed CNS-calming / anxiolytic contribution in preclinical models.