DL-Menthol primarily targets the GABAA receptor, where it acts as a positive allosteric modulator to enhance inhibitory neurotransmission. It also targets and activates the transient receptor potential melastatin 8 (TRPM8) channel, which is responsible for the sensation of coolness. Furthermore, it inhibits UDP-glucuronosyltransferase (UGT) enzymes and has been reported to target cholinesterase (ChE). Its agonistic activity at the TRPA1 receptor has also been documented.

In vitro, DL-Menthol demonstrates allosteric activation of the GABAA receptor, enhancing GABA-mediated chloride influx. It also acts as a UGT inhibitor. The compound triggers cold-sensitive TRPM8 receptors in skin neurons. At a concentration of 0.5 mM, it induces surgical anesthesia in fish models. It inhibits the metabolic detoxification of tobacco carcinogens by human liver and intestinal UGT enzymes, resulting in reduced NNAL-N-Gluc production.

In vivo, DL-Menthol induces surgical anesthesia in a dose-dependent manner in medaka, goldfish, and zebrafish at concentrations of 0.2-3.0 mM administered via water. At high concentrations (3.0 mM), it first induces rapid movement followed by anesthesia. Pretreatment with a GABAA receptor antagonist can prolong the anesthetic latency. These studies confirm its in vivo activity as a GABAA receptor modulator and anesthetic agent in aquatic models.

The GABAA receptor modulatory activity is assessed using electrophysiological or fluorescence-based assays. For example, the compound's ability to enhance GABA-mediated chloride influx can be measured in cells expressing GABAA receptors using patch-clamp techniques or fluorescent chloride-sensitive dyes. UGT inhibitory activity is evaluated using in vitro enzyme assays with human liver or intestinal microsomes and specific substrates, measuring the formation of glucuronidated metabolites by LC-MS/MS.

For in vitro cellular assays, DL-Menthol is typically dissolved in DMSO and diluted in culture media. Cells expressing GABAA receptors are treated with various concentrations of the compound (e.g., 0.1-100 μM) for a defined period, and receptor activation is measured by calcium flux or electrophysiology. For cytotoxicity or neuroactivity studies, neuronal cell lines are cultured in appropriate media and exposed to DL-Menthol, with cell viability assessed using MTT or similar assays.

In vivo studies for DL-Menthol are conducted in aquatic animal models such as medaka, goldfish, and zebrafish. Fish are placed in tanks containing water with varying concentrations of DL-Menthol (0.1-3.0 mM), and the time to induction of surgical anesthesia (loss of righting reflex and equilibrium) is recorded for up to 6 minutes. Recovery time is measured after transferring fish to fresh water. This model is used to study the anesthetic and neuroactive properties of the compound.

Absorption, Distribution and Excretion
In rabbits, the percentage of levonorgestrel excreted after binding with glucuronic acid depends on the dose; the higher the dose, the lower the binding rate. Metabolism/Metabolites Levomenthol readily binds with glucuronic acid in rabbits to form levonorgestrel-β-D-glucuronide. Approximately half of the levonorgestrel administered to rabbits is excreted as a glucuronide conjugate; the fate of the other half is unclear, but cyclic cleavage may occur, leading to significant degradation of the menthol molecule. In dogs, menthol undergoes extensive oxidation, with only about 5% of the dose being recovered in urine as glucuronide. /Menthol/ Levomenthol is rapidly but incompletely glucuroninated. Except for one subject, all subjects who pre-administered cimetidine (1 g/day for 1 week, an oxidative drug metabolism inhibitor) and all subjects who pre-administered the drug-metabolizing enzyme inducer phenobarbital (60 mg once nightly for 10 days) showed increased production of levmenthyl glucuronide. Corynebacterium RWM1 strain was able to grow using (-)-menthol, (-)-menthone, and other acyclic monoterpenes as the sole carbon source. Growth on menthol was very slow, with a doubling time exceeding 24 hours; growth on (-)-menthone was also slow (doubling time 12 hours). Growth was inhibited at carbon source concentrations exceeding 0.025%. Cells cultured in (-)-menthone medium transiently accumulate 3,7-dimethyl-6-hydroxyoctanoate during growth, while cells cultured in (-)-menthol medium oxidize (-)-menthol, (-)-menthone, 3,7-dimethyl-6-octanolactone, and 3,7-dimethyl-6-hydroxyoctanoate. Although menthol oxidase or menthol dehydrogenase was not detected in cell extracts from either (-)-menthol or (-)-menthone medium, an inducible NADPH-coupled monooxygenase active to (-)-menthone was readily detected. In the crude cell extract, only 3,7-dimethyl-6-hydroxyoctanoate was detected as a reaction product. When (-)-menthone monooxygenase was separated from the induced 3,7-dimethyl-6-octanolactone hydrolase by hydroxyapatite chromatography, the 3,7-dimethyl-6-octanolactone was found to be an oxidation product.
The known metabolites of (-)-menthol include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[(1R,2S,5R)-5-methyl-2-propyl-2-cyclohexyl]oxaoxane-2-carboxylic acid and p-menthane-3,8-diol.
L-menthol rapidly binds to glucuronic acid to form L-methyl-β-glucuronide. Approximately half of the absorbed menthol is excreted as glucuronic acid (A661).

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Pharmacokinetic data for DL-Menthol indicate it is orally active and can cross the blood-brain barrier. It is soluble in DMSO (100 mg/mL, 639.92 mM) and ethanol, but has poor water solubility (1 mg/mL, 6.40 mM). For in vivo formulations, it can be prepared using 10% DMSO and 90% (20% SBE-β-CD in saline) or corn oil. The compound is stored as a powder at -20°C for up to 3 years or in solvent at -80°C for up to 2 years.

DL-Menthol is generally recognized as safe for topical and oral use at low concentrations. However, as a GABAA receptor modulator and TRPM8 agonist, it can cause dose-dependent effects on the nervous system. In aquatic models, it induces anesthesia at high concentrations (3.0 mM). Comprehensive toxicology data for systemic administration at therapeutic doses are not detailed in the available literature. As with all research compounds, appropriate safety precautions should be taken during handling.

[1]. Menthol Induces Surgical Anesthesia and Rapid Movement in Fishes. The Open Neuroscience. 2014 Feb; 8(1):1-8.

D,l-Menthol is a white crystalline solid with a minty odor and taste. (NTP, 1992)
(-)-Menthol is a p-menthane-3-ol with a (1R,2S,5R) stereochemical configuration. It is the most common naturally occurring enantiomer. It is used as an antipruritic, antitussive, and antispasmodic. It is the enantiomer of (+)-menthol.
Menthol is a covalent organic compound that can be synthesized or extracted from peppermint or other peppermint oils. Menthol is usually solid at room temperature, forming transparent or white waxy crystals. (-)-Menthol is the main naturally occurring form of menthol with a (1R,2S,5R) configuration. Menthol has local anesthetic and antiirritant effects and is therefore widely used to relieve mild throat irritation.
L-menthol has been reported in citrus (Citrus reticulata), pomegranate (Punica granatum), and several other organisms with relevant data. Levomenthol, the levorotatory isomer of menthol, is an organic compound that can be synthesized or extracted from peppermint or peppermint oil. It has flavoring and local anesthetic effects. When added to pharmaceuticals and foods, menthol enhances the peppermint flavor. It also has a counter-irritant effect on the skin and mucous membranes, thus producing local analgesic or anesthetic effects. Menthol is an alcohol made from peppermint oil or prepared synthetically. Menthol is a covalent organic compound that can be synthesized or extracted from peppermint or other peppermint oils. It is a waxy crystalline substance, transparent or white, solid at room temperature and melting slightly above room temperature. The main form of menthol found in nature is (-)-menthol, with the molecular formula (1R,2S,5R). Menthol has local anesthetic and counter-irritant effects and is widely used to relieve mild throat irritation. See also: Menthol (note moved here).

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Drug Indications
For the treatment of occasional mild irritation, pain, oral ulcers, sore throat, and cough caused by colds or inhaled irritants.

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Mechanism of Action
Menthol primarily activates the cold-sensitive TRPM8 receptor in the skin. Upon topical application, menthol stimulates the "cold" receptors by inhibiting Ca++ currents on neuronal membranes, thereby producing a cooling sensation. It may also exert its analgesic effect by activating κ-opioid receptors.

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DL-Menthol is a widely used compound in pharmaceutical, cosmetic, and food industries for its cooling, analgesic, and anesthetic properties. As a research tool, it is valuable for studying GABAA receptor modulation, TRPM8 channel activation, and UGT enzyme inhibition. It is also used to induce surgical anesthesia in fish models. No clinical trials for new therapeutic indications are reported. It is for research use only and not for human therapeutic use.

C10H20O

156.2652

156.151

89-78-1

16666

White to off-white solid powder

0.9±0.1 g/cm3

215.4±8.0 °C at 760 mmHg

100 °F (NTP, 1992)

93.3±0.0 °C

0.0±0.9 mmHg at 25°C

1.457

3.2

1

1

1

11

120

3

C[C@@H]1CC[C@H]([C@@H](C1)O)C(C)C

NOOLISFMXDJSKH-KXUCPTDWSA-N

InChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3/t8-,9+,10-/m1/s1

(1R,2S,5R)-5-methyl-2-propan-2-ylcyclohexan-1-ol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~639.92 mM)
H2O : ~1 mg/mL (~6.40 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)