IngredientsMonoterpenes belong to a large and diverse group of chemical compounds named terpenes. They represent a group of naturally occurring organic compounds whose basic structure consists of two linked isoprene units, each of which is formed by a 5-carbon base. They are classified as monoterpenes (2 C-5 units), sesquiterpenes (3 C-5 units), diterpenes (4 C-5 units), triterpenes (6 C-5 units), and so forth. Monoterpenes consist of two isoprene units, with a molecular formula C10H16.
The most widespread terpenes are monoterpenes, consisting of two isoprene fragments. Monoterpenes that incorporate heteroatoms, such as oxygen, are categorized as monoterpenoids. Monoterpenes, comprising hydrocarbons, are the largest class of plant secondary metabolites and are commonly found in essential oils.
Monoterpenes are conventionally subdivided according to carbon skeleton geometry:
A review in the field focuses on selected aliphatic, monocyclic, and bicyclic monoterpenes like geraniol, thymol, myrtenal, pinene, camphor, borneol, and their modified structures. Monoterpenes and sesquiterpenes with acyclic (C10 and C15), p-menthane, pinane, bisabolane, germacrane, caryophyllane, cadinane, and aromadendrane skeleton-types are the primary constituents found in essential oils across many plant families.
Monoterpenes are widely occurring, likely ubiquitous natural products found in the plant kingdom and are the primary contributors to the organoleptic properties associated with various herbs, spices, citrus, conifers, and most flowers and fruits. Monoterpenes are light molecules that evaporate quickly and are called "top notes" by the perfume industry. Citrus oils, with the exception of bergamot, contain a high proportion of monoterpenes, in particular the optical isomer d-limonene, a cyclic form.
Key botanical sources and their characteristic monoterpenes include:
The precursors of all different types of terpenes are the five carbon isoprene units, isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). In plants, they are synthesized from two different pathways localized in different subcellular compartments.
The methyl erythritol-4-phosphate (MEP) pathway located in plastids, which produces monoterpenes (linalool, myrcene, and limonene), diterpenes (geranyl linalool), and their derivatives, while the mevaleric acid (MVA) pathway produces sesquiterpenes and their derivatives. The mevalonate pathway (MVA pathway) in yeast and animal cells utilizes acetyl-CoA as the starting substrate, while the methylerythritol 4-phosphate pathway (MEP pathway) in gram-negative bacteria and eukaryotic organelles uses 3-phosphoglycerate (G3P) and pyruvate as the starting substrates.
Monoterpenes are commercially available and studied in several forms:
Mentha × piperita L. is a textbook example, having been used for centuries in traditional medicine to reduce numerous ailments such as infections, insomnia, irritable bowel syndrome, and also pain. Plant products have been employed in medicine for centuries.
Thyme (Thymus vulgaris) offered powerful antimicrobial action through its phenolic monoterpenes, particularly thymol and carvacrol, which remain therapeutic standards in modern respiratory medicine. Monoterpene-containing preparations were a cornerstone of Greek and Roman medicine. Lavender, thyme, sage, and rosemary were routinely used as antiseptics, analgesics, and respiratory aids in the ancient Mediterranean world.
In China's and India's traditional medicine, borneol has long since been used as a remedy against gastrointestinal diseases. Paeoniflorin and cornuside, two natural monoterpenoids, are used in traditional oriental herbal medicine.
Chew sticks, such as miswak, are thought to have been used in Babylonia as early as 3500 B.C. A screening of medicinal plants occurring on the Isle of Arran in Scotland, based on Meddygion Myddvai (a 14th-century Welsh manuscript used to treat conditions related to microbial infections), found that juniper berries exhibited antibacterial activity against Staphylococcus aureus and Escherichia coli.
As natural products, monoterpenes and monoterpenoids are the subject of increased attention from the world scientific community in the search for new pharmacological agents. They have many biological properties, including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, and vasodilating effects.
Across traditions, monoterpene-rich plants were employed for:
It is important to note that these traditional uses predate controlled clinical investigation and should be distinguished from the evidence standards of modern research reviewed below.
The following are among the most pharmacologically characterized individual monoterpenes:
Monoterpenes have shown a promising profile as agents which reduce the inflammatory process and also modulate the key chemical mediators of inflammation, such as pro- and anti-inflammatory cytokines.
NF-κB and MAPK signaling are important pathways for the anti-inflammatory action of monoterpenes. Twenty-four monoterpenes have been found that modulate the production of cytokines, which appears to be the major pharmacological mechanism these compounds possess in relation to the attenuation of inflammatory response.
P-cymene, a prominent thyme monoterpene, shows anti-inflammatory activity, being able to modulate cytokine production (TNF-α, IL-1β, IL-6) in vitro and in vivo by inhibiting nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways involved in synthesis of pro-inflammatory cytokines.
Monoterpenes promote vasodilation and vascular protection through multiple mechanisms: they increase the expression and activation of eNOS via Akt/PKB phosphorylation. Monoterpenes also act on TRPV3, increasing Ca²⁺, which activates eNOS in endothelial cells. NO production activates GCs, increasing cGMP formation and, consequently, leading to VSMC relaxation. Furthermore, monoterpenes reduce ROS formation, which culminates in increased NO bioavailability.
Monoterpenes also activate KCa2.3 and KCa3.1 channels, inducing hyperpolarization in endothelial cells. Monoterpene-mediated endothelial hyperpolarization propagates to VSMC through gap junctions, causing relaxation. Furthermore, monoterpenes modulate channels such as Cav1.2, ROC, and SOCE in VSMC, reducing Ca²⁺ entry and inducing relaxation.
Numerous studies have demonstrated the antimicrobial potency of monoterpenes and monoterpenoids. Monoterpenoids are modified monoterpenes containing different functional groups such as alcohols, carboxylic acids, ketones, aldehydes, and phenols. Some of these compounds exhibit a broad-spectrum antimicrobial effect.
P-cymene is the main antimicrobial compound in thyme, and a large body of evidence suggests that this monoterpene possesses antibacterial, antiviral, and antifungal activities.
The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. Multiple monoterpenes interact with TRP channels — most notably, menthol activates TRPM8 (the "cold" receptor), producing the characteristic cooling sensation and contributing to analgesia. This review suggests that monoterpene solutions, based on composition from traditional healing herbs, offer an interesting avenue for the development of new phytotherapeutic treatments to alleviate chronic inflammatory pain conditions.
In vitro research shows peppermint oil to be effective in relaxing GI smooth muscle, possibly through an antagonistic effect on calcium channels in the gut. Peppermint oil also has been shown to relax the lower esophageal sphincter, which can result in gastroesophageal reflux.
Some monoterpenes, notably linalool and α-pinene, have been shown to act as positive allosteric modulators of GABAA receptors. Electrophysiological studies reveal that linalool potentiates GABA-evoked currents at GABAA receptors, enhancing inhibitory neurotransmission and contributing to its antinociceptive and anxiolytic action.
Limonene has been shown to exert anxiolytic effects, regulatory effects on neurotransmitters, and antinociceptive effects. It has been shown that limonene increased the metabolic conversion of dopamine and serotonin in the hippocampus and prefrontal cortex and striatum, respectively, suggesting that anxiolytic and antidepressant-like effects can include suppression of dopamine activity associated with increased serotonergic neurons through 5-HT1A.
The blocking chemopreventive effects of limonene and other monoterpenes during the initiation phase of mammary carcinogenesis are likely due to the induction of Phase II carcinogen-metabolizing enzymes, resulting in carcinogen detoxification. The post-initiation phase, tumor suppressive chemopreventive activity of monoterpenes may be due to the induction of apoptosis and/or to inhibition of the post-translational isoprenylation of cell growth-regulating proteins.
The action mechanisms of these natural products are wildly varied, with apoptosis being the most prevalent, followed by cell cycle impairment, ROS production, autophagy, necroptosis, and others.
Monoterpenes with p-menthane structure (perillyl series) can inhibit Ras-proteins prenylation involved in carcinogenesis processes.
Evidence strength: Moderate–Strong for peppermint oil (menthol) in IBS; preliminary for other monoterpenes.
Nine studies that evaluated 726 patients were identified in a systematic review and meta-analysis. The risk of bias was low for most of the factors assessed. Peppermint oil was found to be significantly superior to placebo for global improvement of IBS symptoms (5 studies, 392 patients, relative risk 2.23; 95% confidence interval, 1.78–2.81) and improvement in abdominal pain (5 studies, 357 patients, relative risk 2.14; 95% confidence interval, 1.64–2.79). The conclusion of this meta-analysis was that peppermint oil is a safe and effective short-term treatment for IBS.
The studies overall showed a number needed to treat of three for global symptoms and four for abdominal pain. Given the minimal risks and overall positive results in the RCTs, the ACG conditionally suggests the use of peppermint oil, with emphasis to be placed on further trials focusing on optimal formulation and benefits for the different IBS subgroups.
Because of the potential for peppermint oil to relax the lower esophageal sphincter and result in heartburn symptoms, most trials have tested enteric-coated preparations. Although results of studies on the use of this herb for the treatment of IBS symptoms have been mixed, there seems to be a trend indicating mild effectiveness in the reduction of some IBS symptoms, especially flatulence and abdominal pain and distension.
The therapeutic dosage range studied in most IBS trials was 0.2 to 0.4 mL of peppermint oil taken three times daily in enteric-coated capsules.
Evidence strength: Moderate; multiple RCTs in humans, but largely for the proprietary preparation Silexan™ rather than isolated monoterpenes.
Oral intake of linalool, in the form of lavender essential oil (Silexan™) capsules, was demonstrated to be effective for anxiety in a meta-analysis published in 2019. Five studies with a total of 524 participants evaluated oral treatment with Silexan™ at 80 mg and 160 mg dosing. Silexan™ contains primarily linalool (36.8%) and linalyl acetate (34.2%).
The effectiveness of Silexan™ for anxiety was found to be equivalent to that of paroxetine (Paxil), a prescription SSRI. Overall, the 160 mg dose of Silexan™ was well tolerated and found to be more effective than the 80 mg dose.
These findings require the important caveat that Silexan™ is a complex multi-component essential oil and that attributing the effects specifically to linalool as an isolated monoterpene is not established by these human clinical data. Mechanistically, monoterpenes are responsible for the hypnotic, sedative, and anxiolytic activities noted in several plant-based extracts and essential oils.
Evidence strength: Weak to preliminary in humans; promising preclinical data; clinical trials found limited efficacy at safe doses.
Monoterpenes prevent the carcinogenesis process at both the initiation and promotion/progression stages. In addition, monoterpenes are effective in treating early and advanced cancers in animal models. Monoterpenes such as limonene and perillyl alcohol have been shown to prevent mammary, liver, lung, and other cancers in animal studies.
In human studies, the picture is more mixed. Studies conducted between 1998 and 2013 included clinical evaluation of d-limonene (n = 2 studies) and perillyl alcohol (n = 3 studies) on breast cancer–specific outcomes. One hundred and thirty-three participants were included across the two d-limonene and three perillyl alcohol studies meeting eligibility for review.
Multiple early phase trials have been conducted with perillyl alcohol in advanced cancer patients, with a few reported cases of disease stabilization. It was concluded that clinical antitumor activity of perillyl alcohol is not likely to occur at safe doses. Perillyl alcohol undergoes extensive first-pass metabolism and is converted almost completely to two active but polar metabolites, perillic acid and dihydroperillic acid, in humans. Due to their polarity, the tissue distribution of these metabolites may be limited, thus limiting their in vivo tissue activity.
There is one reported Phase I/II trial with limonene in cancer patients with locally advanced or metastatic disease. The study reported a partial response in one breast cancer patient and stabilization of the disease in three colon cancer patients.
Perillyl alcohol and limonene were studied in phase II of clinical trials evaluating their safety and efficacy in patients with advanced melanoma. Both terpenes were well-tolerated, with no dose-limiting toxicities observed, but no objective responses were observed, with a median time to progression of 2 months.
After screening titles, abstracts, and full texts, one study on limonene (oral) and 19 on perillyl alcohol administered by oral (13 studies), dermal (2 studies), or intranasal-instillation routes (4 studies), comprising Phase I or I/II trials, were included in the systematic review. Overall, human oncology trials of these monoterpenes have remained at early phases, and no Phase III evidence is currently available to support their use as anticancer treatments.
Evidence strength: Preliminary — mostly animal models; no definitive human RCTs as of current literature.
Monoterpenes are a large class of naturally occurring compounds commonly found in many aromatic and medicinal plants. Emerging evidence has shown that monoterpenes have many biological properties, including cardioprotective effects. Remarkably, an increasing number of studies have demonstrated the therapeutic potential of natural monoterpenes to protect against the pathogenesis of atherosclerosis.
Studies using monoterpenes to assess their cardiovascular effects have increased over the years. A systematic review aimed to summarize the use of monoterpenes in animal models of cardiovascular diseases, using PubMed, SCOPUS, LILACS, and Web of Science databases. Thirty-three articles were selected for the systematic review. The variability of cardiovascular effects demonstrated by the monoterpenes highlighted them as promising candidates for treatment or prevention of CVDs. Nevertheless, studies that investigate their biological sites of action need to be further encouraged.
Evidence strength: Strong in vitro; limited in vivo human clinical data for most pathogens. Menthol/thymol in oral care products represent the best-established applied use.
Essential oils containing monoterpenes have shown various biological activities, including antioxidant, antifungal, antibacterial, phytotoxic, larvicidal, anti-inflammatory, and cytotoxic properties. With an increasing prevalence of multi-drug-resistant pathogens, these compounds have drawn attention as alternative therapeutic agents.
In the specific context of oral health, although there are insufficient appropriate data to substantiate the health benefits of herbal components in oral health care products, monoterpenes are commonly added to everyday care products in the form of volatile oils.
Evidence strength: Preliminary; primarily animal and in vitro data. Limited human data available.
The class of monoterpenes that have been recognized as having analgesic and anti-inflammatory properties stands out. Monoterpenes also exhibit anti-ulcer, healing, and antimicrobial activities and are a pharmacological alternative for the treatment of peptic ulcers. Table 1 also presents the healing capacities of some important monoterpenes, including substances able to heal gastric wounds induced by acetic acid, an experimental model that simulates chronic gastric ulcers in humans.
Evidence strength: Moderate — small trials exist for a specific terpene mixture.
A combination of seven naturally occurring terpenes (31% α- and β-pinene, 15% camphene, 10% borneol, 4% anethole, 4% fenchone, and 3% 1,8-cineole) was introduced in Europe in the early 1960s. Due to the antibacterial effects related mostly to pinenes, diuretic, anti-inflammatory, and analgesic properties, the drug has been considered effective in conservative stone management and reducing symptomatology during spontaneous stone passage. Several trials have been carried out to confirm the efficacy — after 4 weeks of treatment, significantly higher expulsion rates of urinary stones were noticed (81% vs. 59% of control group with placebo).
Evidence strength: Preliminary — mostly in vitro, animal, and preclinical data; no definitive human RCTs for cognitive outcomes as yet.
Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes — low-molecular compounds with anti-inflammatory, antioxidant, enzyme inhibitory, analgesic, and sedative, as well as other biological properties.
The monoterpene-rich essential oil obtained from Artemisia santonicum L. provides a neuroprotective effect by targeting the pathological mechanisms of Alzheimer's disease in preclinical in vitro models, though this finding has not yet been replicated in human clinical trials.
Evidence strength: Moderate for mechanism; predominantly preclinical studies; selected human data for topical menthol.
A review of the anti-inflammatory activity of 32 bioactive monoterpenes found in essential oils demonstrates the pharmacological potential of this group of natural chemicals to act as anti-inflammatory drugs. The evidence base is predominantly preclinical. However, menthol in topical analgesic formulations represents one area where human evidence does exist. Menthol possesses a specific receptor on the cell membrane and raises the cell stimulation threshold. Furthermore, menthol could block the flow and transfer of pain signaling pathways and alleviate the pain by affecting the kappa opioid receptor.
The class of monoterpenes discusses anti-inflammatory, antimicrobial, anticonvulsant, analgesic, antiviral, anticancer, antituberculosis, and antioxidant biological activities. The primary body systems associated with monoterpene research are:
Dosages vary considerably by monoterpene, indication, and route of administration. The following represent dosages documented in peer-reviewed sources, not recommendations:
The therapeutic dosage range studied in most IBS trials was 0.2 to 0.4 mL of peppermint oil taken three times daily in enteric-coated capsules. Peppermint oil is best taken in the form of enteric-coated capsules (containing 0.2 mL of oil), which reduces the risk of heartburn, and the recommended dosage for adults is 1 to 2 capsules 3 times per day.
Five studies with a total of 524 participants evaluated oral treatment with Silexan™ at 80 mg and 160 mg dosing. Silexan™ contains primarily linalool (36.8%) and linalyl acetate (34.2%). Overall, the 160 mg dose of Silexan™ was well tolerated and found to be more effective than the 80 mg dose.
A combination of seven naturally occurring terpenes including α- and β-pinene, camphene, borneol, anethole, fenchone, and 1,8-cineole, administered over 4 weeks of treatment, showed significantly higher expulsion rates of urinary stones.
Perillyl alcohol (POH) was administered by oral (13 studies), dermal (2 studies), or intranasal-instillation routes (4 studies) in Phase I or I/II trials. Specific oral dose levels varied across trials; details are available in individual Phase I/II publications cited in systematic reviews.
In a clinical trial, the supplement containing peppermint oil (40% menthol, 1.5% limonene) at 240 mg and ginger oil at 50 mg, in a 730 mg capsule taken once per day, was used for 30 days.
Monoterpenes demonstrate antioxidative, antibacterial, sedative, and anti-inflammatory activity; hence, they are often employed in medicine and pharmaceuticals. Additionally, their fragrant character is often made use of, notably in the food and cosmetic industries. Although most are safe for human food and medical applications, there are monoterpene compounds that, in certain amounts or under particular circumstances (e.g., pregnancy), can cause serious disorders.
Computational analysis emphasizes that the investigated acyclic monoterpenes are usually safe for humans; they do not lead to hepatotoxicity, cardiotoxicity, mutagenicity, carcinogenicity, and endocrine disruption, and usually do not have an inhibitory potential against the cytochromes involved in the metabolism of xenobiotics, excepting CYP2B6. The inhibition of CYP2B6 should be further analyzed as this enzyme is involved in both the metabolism of several common drugs and in the activation of some procarcinogens.
A review characterizes the toxic properties of selected monoterpenes including α-terpinene, camphor, citral, limonene, pulegone, and thujone, as well as their original plant sources and essential oils. The selected monoterpenes reveal various toxic properties, among which are embryotoxic, neurotoxic, allergenic, and genotoxic effects.
Exposure to elevated concentrations of monoterpenes, particularly in occupational environments like the flavor, fragrance, and cleaning industries, presents health hazards. Inhaling or coming into contact with certain monoterpenes could result in respiratory irritation, skin sensitization, and other adverse health outcomes.
The oxidation byproducts of monoterpenes, generated through reactions with indoor ozone, could exhibit greater toxicity than the original compounds, prompting concerns about indoor air quality.
Peppermint oil has been reported to raise serum levels of simvastatin (Zocor) and felodipine (Plendil) in at least one case report. This is consistent with potential inhibitory effects on cytochrome P450 enzymes involved in drug metabolism.
Computational predictions suggest acyclic monoterpenes do not have an inhibitory potential for CYP1A2, CYP2C9, CYP2C19, but do show potential CYP2B6 inhibition. The outcomes of the study emphasize that the investigated compounds are usually safe for humans, they do not lead to hepatotoxicity, cardiotoxicity, mutagenicity, carcinogenicity, and endocrine disruption, and usually do not have an inhibitory potential against the cytochromes involved in the metabolism of xenobiotics, excepting CYP2B6.
Although peppermint oil patients were significantly more likely to experience an adverse event in IBS trials, such events were mild and transient in nature. The most commonly reported adverse event was heartburn. Single-unit, liquid-filled, enteric-coated peppermint oil capsules can rupture in the stomach and have been associated with heartburn and nausea. Additionally, delayed release of l-menthol has been associated with anal burning.
Studies based on female Wistar rats treated with α-terpinene via gavage between 6–15 days of gestation revealed a reduction in maternal body weight at the highest doses (250 mg/kg bw/day). Lower doses (30 and 60 mg/kg bw/d) did not affect maternal body weight gain. Additionally, delayed ossification at 60, 125, and 250 mg/kg bw/d of the monoterpene was observed. These developmental findings from animal studies raise caution regarding use of concentrated monoterpene preparations during pregnancy, though human data are limited.
Despite the compelling evidence supporting the anti-inflammatory effect of monoterpenes, further studies are necessary to fully explore their potential as anti-inflammatory compounds. All these data indicate the necessity to perform in vivo studies to understand the pharmacokinetic and toxicological characteristics of the acyclic monoterpenes in order to better establish the clinical relevance of their use.
Future studies should assess the long-term efficacy and safety of peppermint oil and its efficacy relative to other IBS treatments including antidepressants and antispasmodic drugs.
Health conditions that Monoterpenes may help support.
Body systems that Monoterpenes may help support.
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