Thymol as a Potential Natural Antiemetic: Insights From In Vivo and In Silico Studies

Abstract

Nausea and vomiting are common and distressing responses to toxins, chemotherapy, and gastrointestinal disturbances. Although antiemetic medications are available, their adverse effects make safer substitutes necessary. In our study, Thymol (THY), a phenolic monoterpene from essential oils, was evaluated for its antiemetic potential using in vivo and in silico methods. In the in vivo study, emesis was induced in 2-day-old chicks by oral administration of copper sulfate pentahydrate (50 mg/kg). THY was administered orally at doses of 10, 20, and 40 mg/kg, alone or in combination with standard antiemetics ondansetron (ODN), domperidone (DPD), hyoscine butyl bromide (HYS), and promethazine hydrochloride (PRO). The 20 mg/kg dose (THY-20) showed the highest efficacy, significantly (p < 0.0001) reducing the number of retches (24.6 ± 2.7; 67.2% reduction) and increasing latency to first retch (52.6 ± 4.2 s; 77.18% increase) compared to the negative control (NC). The THY + ODN combination further enhanced effects (68.53% retch reduction). Molecular docking showed strong binding of THY to 5-HT_3A (-6.4 kcal/mol), D₂ (-7.1 kcal/mol), M₃ (-6.2 kcal/mol), and H₁ (-7.1 kcal/mol) receptors, comparable to standard drugs. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling revealed THY's compliance with Lipinski's Rule, high gastrointestinal absorption, blood-brain barrier permeability, and low toxicity risk. The multi-target binding profile and synergistic potential of THY suggest its promise as a natural, broad-spectrum antiemetic. Further receptor-specific studies and trials in chemotherapy-induced emesis models are recommended to validate its clinical potential.

Keywords: 5‐HT3 antagonist; GABAB agonist; calcium channel; nausea and vomiting; thymol.

FIGURE 1

Mechanisms that can trigger nausea and vomiting.

FIGURE 2

The two‐dimensional chemical structures of test sample and standard drugs.

FIGURE 3

The three‐dimensional crystal structure of emetic receptors (A) 5‐HT_3A, (B) D₂, (C) M₃, and (D) H₁.

FIGURE 4

(A) Retching latency was noticed in single‐dose test samples and controls. (B) Retching latency was noticed in controls and combinations. Values are presented as mean ± SD (n = 5); data normality was confirmed using the Shapiro–Wilk test (p > 0.05). Statistical analysis was performed using one‐way ANOVA followed by Tukey's post hoc test for multiple comparisons. p < 0.05 compared to the ^aNC (Vehicle); ^bODN; ^cDPD; ^dHYS; ^ePRO; ^fTHY + ODN; ^gTHY + DPD; ^hTHY + HYS; ⁱTHY + PRO; NC: Vehicle (distilled water containing 0.9% NaCl and 0.5% tween 80); DPD, domperidone; HYS, hyoscine butyl bromide; ODN, ondansetron; PRO, promethazine hydrochloride.

FIGURE 5

(A) Number of retching noticed in single doses test samples, and controls. (B) Retching latency was noticed in controls, and combinations. Values are presented as mean ± SD (n = 5); data normality was confirmed using the Shapiro–Wilk test (p > 0.05). Statistical analysis was performed using one‐way ANOVA followed by Tukey's post hoc test for multiple comparisons. p < 0.05 compared to the ^aNC (Vehicle); ^bODN; ^cDPD; ^dHYS; ^ePRO; ^fTHY + ODN; ^gTHY + DPD; ^hTHY + HYS; ⁱTHY + PRO; NC: Vehicle (distilled water containing 0.9% NaCl and 0.5% tween 80); DPD, domperidone; HYS, hyoscine butyl bromide; ODN, ondansetron; PRO, promethazine hydrochloride.

FIGURE 6

Ramachandran plot of (A) 5‐HT_3A, (B) D₂, (C) M₃, and (D) H₁.

FIGURE 7

Three‐dimensional and two‐dimensional structures of molecular docking interaction of emetic receptors with THY. (A) 5‐HT_3A and THY, (B) D₂ and THY, (C) M₃ and THY, and (D) H₁ and THY.

FIGURE 8

Three‐dimensional (3D) and two‐dimensional (2D) structures of molecular docking interaction between emetic receptors (A) 5‐HT_3A with ODN, (B) D₂ with DPD, (C) M₃ with HYS, and (D) H₁ with PRO.

FIGURE 9

General mechanism of the antiemetic drugs.

FIGURE 10

Possible antiemetic mechanism of thymol. Thymol inhibits the release of key emetogenic neurotransmitters, histamine, serotonin, and acetylcholine by blocking intracellular calcium release and vesicular exocytosis. It also acts as an antagonist of dopamine D₂ and serotonin 5‐HT₃ receptors, preventing their activation in the chemoreceptor trigger zone (CTZ). Together, these actions inhibit signal transmission to the vomiting center, thereby suppressing the emetic response.