Monoterpenes and sesquiterpenes are constituents of essential oils, and they have properties plausible for a potential application. Their low molecular weight and high lipophilicity allow them to penetrate membranes and interact with epilepsy-related proteins [51]. Thymoquinone, the dominant compound in black seed oil (Nigella sativa), has shown the most notable activity of all the monoterpenes found in this search, inhibiting convulsions in male BALB/c mice at the relatively low dose of 40 mg/kg [52]. Preclinical findings led to a pilot study in children with refractory epilepsy. The results demonstrated that thymoquinone was effective and well-tolerated [53]. Moreover, thymoquinone potentiated the antiepileptic properties of VPA [50] and phenytoin [54]. It also displayed a neuroprotective effect in Sprague Dawley rats by phosphorylating cAMP response element-binding protein (CREB) [55] and downregulating TNF-α and COX-2 [56]. Unfortunately, thymoquinone inhibits the activity of cytochrome P450 2C9 (CYP2C9), and this must be taken into account when thymoquinone is co-administered with phenytoin [57]. To sum up, its anticonvulsant and neuroprotective properties make thymoquinone a very promising substance that deserves further investigation with emphasis on an in-depth exploration of its pharmacokinetics and potential interactions.

Iridoids seem to be effective in the inhibition of convulsions as well, and especially the reports of the anticonvulsant activity of the extracts of Valeriana species are increasingly frequent. Pretreatment with valepotriate (5, 10, 20 mg/kg/day, i.p.) protected mice against MES and PTZ-induced convulsions, but it was far less effective than diazepam (4 mg/kg/day, i.p.) [58]. Significant anticonvulsant activity has also been reported for paederosidic acid, a rare sulfur-containing iridoid [59], but such compounds are, unfortunately, very unstable under acidic conditions, which makes their peroral administration difficult [60].

Bilobalide, the main sesquiterpene trilactone found in the leaves of Ginkgo biloba, must be included. Bilobalide (30 mg/kg, p.o., once a day for 4 days) elevated GABA levels in the hippocampus, cerebral cortex, and striatum of male ddY mice, possibly through the potentiation of the activity of GAD [61]. Also considering its neuroprotective effect [62], makes bilobalide seems very promising, although Ng et al. point out that bilobalide negatively modulated the action of GABA at α₁β₂γ_2L GABA_A receptors [63].

An even more promising natural product affecting GABA transmission has been found in huperzine A (HupA), a dietary supplement used in the USA as a memory enhancer. HupA is an acetylcholinesterase inhibitor isolated from the Chinese club moss Huperzia serrata. It also exerts anti-inflammatory and neuroprotective effects by activating nicotinic cholinergic receptors [64]. In addition, HupA has delivered seizure relief in a 6 Hz model, with an ED₅₀ value of 0.34 mg/kg in the 32 mA paradigm, being 57 times more potent than levetiracetam and 301 times more potent than VPA [65]. It also suppressed PTZ-induced seizures in rats by activating the cortical transmission of GABA [66]. These findings, together with the favorable pharmacokinetic properties of HupA in humans [67], have led to clinical testing.

Recently, several coumarins have been reported to effectively inhibit PTZ-induced seizures in the zebrafish larvae model of epilepsy at doses lower than those of the positive controls diazepam (10 mM) and VPA (1 mM), respectively [68,69]. Based on the seizure-inducing agent used (PTZ), it was postulated that the test coumarins interfered with the GABA transmission. Coumarins have previously been shown to inhibit the activity of GABA transaminase (GABA-T), the main degradative enzyme of GABA [70]. This hypothesis was supported by a molecular docking study of oxypeucedanin hydrate, the most active furanocoumarin, to the structural model of GABA-T. The results indicated that a bulky substituent at the C5 position is crucial for antiseizure activity, whereas an analogous bulky moiety substituted at the C8 position diminishes the activity [69]. Similar results have been reported by Singhuber et al. [71] in a study dealing with the modulation of GABA-induced chloride currents by selected coumarin derivatives on recombinant α₁β₂γ_2S GABA_A receptors expressed in Xenopus laevis oocytes [71]. On the other hand, exactly the opposite results were found for the mice MES test. C5-substituted furanocoumarins were inactive, whereas C8-substituted furanocoumarins exerted strong anticonvulsant activity [72]. Hence, more studies are needed to clarify the structure–activity relationship with respect to the model of epilepsy used as well as to find out more about bioavailability. However, as coumarins are simple molecules, they are ideal for chemical synthesis and modifications to improve their pharmacodynamic and pharmacokinetic properties.

Glutamate is the principal excitatory neurotransmitter in the brain, and therefore, glutamate receptor agonists, such as α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), N-methyl-D-aspartate (NMDA), and kainate, act as elicitors of seizures. Glutamate receptors can be divided into ionotropic glutamate receptors (ligand-gated ion channels) and metabotropic glutamate receptors (G-protein-coupled receptors) [91]. Among the ionotropic glutamate receptors, the AMPA-type and NMDA-type glutamate receptors are the most important, as certain AEDs affect these ionotropic receptors (e.g., perampanel and topiramate).

Interestingly, no reports of natural products interacting with AMPA receptors have been found during our search, except for one recent study describing the potent anticonvulsant activity of magnolol and honokiol in a model of therapy-resistant epilepsy. However, the authors postulate the involvement of not only AMPA receptors but also GABA_A and cannabinoid receptors [92]. Magnolol and honokiol, the main bioactive substances in the bark of Magnolia officinalis, are known for antioxidant, anti-inflammatory, and neuroprotective properties that make them promising for further research in the field of epilepsy, especially at a time when knowledge of their toxicity and bioavailability is accumulating [93].

Panax ginseng is well-known for its neuroprotective properties with ginsenosides as the main active constituents. Among the test ginsenosides, 20(S)-Rg₃ and 20(S)-Rh₂ inhibited NMDA receptors. However, 20(S)-Rg₃ interacted with the glycine site, while 20(S)-Rh₂ likely did so with the polyamine-binding site of NMDA receptors. (R)-isomers were inactive and the mono-glycosylated moiety at C-3 was found to be essential for binding to polyamine sites [94]. Further assays showed that 20(S)-Rg₃ regulated GABA_A receptor activity by interacting with the γ₂ subunit [76], demonstrating its multitarget mechanism of action. Nevertheless, the bioavailability of ginsenosides after oral administration is relatively poor. Low water solubility and easy degradation by gastric acid and gut microbiota are the crucial disadvantages. Therefore, their absorption needs to be enhanced by sophisticated formulation strategies [95].

Cannabis sativa contains more than 100 compounds (lipophilic phytocannabinoids) with different therapeutic potentials and because phytocannabinoids affect diverse epilepsy-related targets [104], they have been given a separate section. Medicinal marijuana is applicable as a treatment option mainly for patients with chronic, autoimmune, inflammatory, degenerative, or oncological illnesses, and also for palliative care [105]. Multiple in vitro and in vivo preclinical trials have reported antiepileptic effects for several constituents of medical marijuana. Compounds of interest include psychoactive ∆⁹-tetrahydrocannabinol (∆⁹-THC) and structurally similar cannabidiol (CBD), along with non-psychoactive ∆⁹-tetrahydrocannabivarin (∆⁹-THCV), cannabidivarin (CBDV), and ∆⁹-tetrahydrocannabinolic acid (Δ⁹-THCA). ∆⁹-THC acts as a potent partial agonist on endocannabinoid receptor CB₁, influencing both GABAergic and glutamatergic synaptic transmission. The clinical use of medical marijuana is limited because the anticonvulsant effect of ∆⁹-THC is relatively unpredictable. It acts simultaneously on several receptor targets, such as the transient receptor potential (TRP) cation channels TRPA1, TRPV2, and TRPM8; the orphan G-coupled protein receptor GPR55; the 5-HT_3A receptor; the peroxisome proliferator-activated receptor gamma (PPARγ); the μ- and δ-opioid receptors, the β-adrenoreceptors; and some subtypes of Ca²⁺, K⁺, and Na⁺ channels. Interestingly, some experiments have shown medical marijuana to have no or even a pro-convulsant effect [104]. Δ⁹-THCA is used to prevent seizures, e.g., in the USA. This metabolic precursor of Δ⁹-THC is more affordable and should have only minor psychoactive properties [106]. Experimental observations have demonstrated that it has anticonvulsant effects via the modulation of ion channels and enzymes crucial for the biosynthesis of the endocannabinoid 2-arachidonoylglycerol [104]. The mechanisms of anticonvulsant activity of Δ⁹-THCV and CBDV are not well understood. Both compounds probably exert their anticonvulsant effects via non-CB₁/CB₂ mechanisms. TRPV1, TRPV2, TRPA1, and TRPM8 channels are the likely molecular targets of Δ⁹-THCV and CBDV [107].

CBD is the most promising of these agents, with effects proved by several clinical trials, especially for the treatment of drug-resistant epilepsies. Recent studies have proposed that its anticonvulsant effect may involve agonistic activity at the TRPV1 channel, the blockade of human T-type VGCCs, the modulation of various receptors such as 5-HT_1A, 5-HT_2A, GPR55, adenosine A1 and A2, voltage-dependent anion-selective channel protein 1 (VDAC1), or an influence on the release of TNF-α [104].

 Smoked, inhaled, or vaporized Δ⁹-THC has a bioavailability in the range from ~10–35% in contrast to (~6%) by oral administration. CBD and CBDV are hardly soluble in water, and their bioavailability after oral administration is poor, but many trials have evaluated cannabinoids suspended in sesame oil or mixed with glycocholate to increase their bioavailability, and intranasal, sublingual, and transdermal applications are common. Unfortunately, because of their lipophilic properties, large amounts of cannabinoids accumulate in adipose and other tissues, especially with repeated administration. Negative interactions with other drugs metabolized by the cytochrome P450 system or isoenzymes CYP3A4, CYP2C19, CYP2C9, and CYP2D6 should be taken into account, especially in Europe, where the co-administration of CBD and clobazam has been approved as adjunctive treatment of Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS). The strong inhibition of CYP2C19 by CBD leads to a remarkable rise in clobazam concentration, which may contribute to side effects, including somnolence and sedation. Finally, potenti