IngredientsSesquiterpenes are a class of organic compounds composed of three isoprene units, resulting in a total of 15 carbon atoms. Sesquiterpenoids are a class of enormously diverse natural products derived from the 15-carbon precursor, farnesyl pyrophosphate (FPP). The terms "sesquiterpene" and "sesquiterpenoid" are often used interchangeably in the scientific literature; strictly speaking, sesquiterpenes refers to the pure hydrocarbon skeleton, while sesquiterpenoids encompasses oxygenated and otherwise functionalized derivatives. The name derives from the Latin sesqui (one and a half) combined with terpene, reflecting that these molecules are one and a half times the size of a monoterpene (C10).
The number and arrangement of isoprene units determine the subclass of terpenoids: monoterpenes (2 isoprene units, C10), sesquiterpenes (3 isoprene units, C15), diterpenes (4 isoprene units, C20), and triterpenes (6 isoprene units, C30). Terpene synthases catalyze the synthesis of these compounds from the common precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP).
Sesquiterpenoids are the largest class of natural terpenoids, with a structural diversity that includes thousands of compounds and more than 100 skeletal types. Many of them show "drug-like" chemical properties, including alkylating center reactivity, lipophilicity, and favorable molecular geometry and electronic features, and have attracted considerable interest due to their pronounced biological activities.
Sesquiterpenoids are natural products derived from three isoprene units. These compounds exist in several forms such as linear, monocyclic, bicyclic, and tricyclic frameworks. The chemical diversity of sesquiterpenoids starts from the diverse sesquiterpene hydrocarbon backbones, which are created by carbocation cascade reactions programmed in sesquiterpene synthases (STSs). The C15 sesquiterpene skeletons are then often oxygenated by regio- and stereo-selective cytochrome P450 monooxygenases (P450s).
Among the most toxicologically, pharmacologically, and nutritionally relevant structural subclasses are:
Based on skeleton type, sesquiterpenes can be classified as acyclic-type, guaiane-type, cadinane-type, eudesmane-type, germacrane-type, and others. Sesquiterpene lactone subtypes include germacranolides, eudesmanolides, elemanolides, and guaianolides.
Sesquiterpenes, 15-carbon compounds formed from 3 isoprenoid units, are secondary metabolites produced mainly in higher plants but also in fungi and invertebrates. Fungi are rich in sesquiterpenoid natural products, many of which have good biological activities, including antibacterial, antifungal, anti-inflammatory, antitumor, vascular-relaxing, immunosuppressant, and cytotoxic activities.
Key botanical and fungal sources include:
Sesquiterpenes occur in human food, but they are principally taken as components of many folk medicines and dietary supplements. Preparations in which sesquiterpenes are significant active constituents include:
Some of these plants have been used for centuries in indigenous medical practices in various cultures worldwide. For millennia, numerous cultures and civilizations have relied on traditional remedies derived from plants to treat a wide range of conditions and ailments. The use of medicinal plants to treat myriad indications can be traced back thousands of years across a wide variety of geographical regions, cultures, and civilizations.
Based on the traditional application of the fresh plant juice in the treatment of malaria as documented in the Zhou Hou Jiu Zu Fang (A Handbook of Formulas for Emergencies), written in 340 AD by the Chinese physician and Daoist philosopher Ge Hong, Tu Youyou et al. isolated the active sesquiterpene lactone artemisinin, that has since been marketed worldwide as a treatment for malaria (Plasmodium falciparum). This research was later honoured with the 2015 Nobel Prize in Physiology or Medicine. The Qinghao plant (Artemisia annua) thus constitutes one of the most consequential intersections of traditional ethnomedicine and modern pharmacology in history.
One example of the transfer of medicinal knowledge involves Vernonia amygdalina Del. Chimpanzees (Pan troglodytes) have been observed on numerous occasions to chew on the bitter pith of this plant as self-medication in case of parasitic nematode infections. Traditional healers of the WaTongwe people of the Mahale Mountains in Tanzania use this plant for intestinal parasites, diarrhoea, and stomach upset. Phytochemical research has demonstrated that sesquiterpene lactones in V. amygdalina are among the compounds likely responsible for these effects.
Valerian has been used as a sedative for the treatment of insomnia and restlessness since the second century. Valerian (Valeriana officinalis) is a perennial flowering plant native to Europe and Asia that has a long history of use as a sedative and anxiolytic in traditional medicine. The valerenic acid sesquiterpene class is the primary constituent regarded as responsible for this traditional application.
Feverfew (Tanacetum parthenium), rich in the sesquiterpene lactone parthenolide, has been used in European herbal medicine for centuries for headaches, fever, and inflammatory conditions. Parthenolide is a germacrane sesquiterpene lactone with a unique structure. It has been isolated from several different species in the Asteraceae (Compositae) family, feverfew (Tanacetum parthenium) being one of them.
Plants from the Asteraceae family with sesquiterpene lactone content, including chamomile, yarrow (Achillea millefolium), and elecampane (Inula helenium), were widely used across European traditions for treating fever, digestive complaints, wounds, and inflammatory conditions.
The primary sesquiterpene lactone sources are numerous plant species, many of which have been historically utilized in traditional medicine systems worldwide. Prominent examples include plants from the Asteraceae family, such as Tanacetum parthenium (feverfew), known for parthenolide; Cichorium intybus (chicory), containing lactucin and lactucopicrin; and Artemisia annua (sweet wormwood), the source of artemisinin. These plants synthesize sesquiterpene lactones as part of their natural defense mechanisms against herbivores, pathogens, and environmental stressors.
Sesquiterpene lactones (STLs) are widely present in numerous genera of the family Asteraceae (Compositae). They are described as the active constituents used in traditional medicine for the treatment of various diseases.
Artemisinin (ART), a sesquiterpene lactone, was first isolated from Artemisia annua by Youyou Tu, contributing significantly to antimalarial therapy. Artemisinin is a sesquiterpene lactone compound with a peroxy group and is composed of carbon, hydrogen, and oxygen. Its molecular formula is C₁₅H₂₂O₅. A lactone ring in artemisinin's molecular structure is formed by connecting two carbon atoms via a peroxy bond. This peroxy bond is key to the antimalarial action of artemisinin molecules. The compound's unique endoperoxide bridge plays a crucial role in generating reactive oxygen species for therapeutic effects.
Parthenolide is a germacrane-type sesquiterpene lactone and the primary bioactive constituent of feverfew. With new sesquiterpene lactones discovered in recent years, new biological activities have been tested, along with different action mechanisms (synergistic and/or antagonistic effects), as well as molecular structure–activity relationships. A key mechanism attributed to parthenolide and related sesquiterpene lactones is the inhibition of the NF-κB signaling pathway. In RAW264.7 cells, the mechanism of action of ergolide (a related sesquiterpene lactone) involves the degradation of IκB proteins and inhibition of translocation of the NF-κB complex into the nucleus. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells.
β-Caryophyllene (BCP), a dietary sesquiterpene and highly selective CB2 agonist with favorable safety and pharmacokinetic attributes, has attracted attention as a promising topical candidate. BCP selectively binds to the CP55,940 binding site (i.e., THC binding site) in the CB2 receptor, leading to cellular activation and an anti-inflammatory effect. The endocannabinoid system has two classical receptors: the cannabinoid receptor of type 1 (CB1) and the cannabinoid receptor of type 2 (CB2). While the CB1 mediates the classical psychotropic effects, the CB2 is expressed in the immune system and exerts anti-inflammatory effects. Crucially, BCP's action through CB2 does not produce the psychoactive effects associated with CB1 agonism.
BCP penetrates the stratum corneum, suppresses NF-κB/MAPK and IL-4/TSLP pathways, enhances Nrf2-driven antioxidant defenses, and accelerates re-epithelialization and collagen remodeling. β-Caryophyllene (BCP) is a Food and Drug Administration (FDA) approved natural compound that engages cannabinoid CB2 receptors and causes anti-inflammatory and analgesic effects.
Valepotriates and valerenic acid found in valerian root are responsible for the plant's sedative and anxiolytic effects. The valerenic acid contained in valerian inhibits the enzyme system responsible for the catabolism of GABA. Valerian and its constituents (e.g., valerenic acid) serve as GABA agonists, and the effect of the plant on GABAA receptors is similar to the effect of benzodiazepines.
Valerenic acid has been reported to enhance GABA-evoked currents in cultured hippocampal neurons at 10 μM and recombinant GABAA receptors at 1–30 μM, indicating a positive modulatory action. Reported plasma levels of valerenic acid in humans were in a range that corresponds to its minimum effective concentration (1 µM).
Valerenic acid and pinoresinol, key constituents of valerian extract Ze 911, were identified as positive allosteric modulators (PAMs) of adenosine A1 receptors (A1ARs). This finding suggests that valerenic acid may act through multiple receptor systems simultaneously.
Farnesol and nerolidol are acyclic sesquiterpene alcohols found in many plant essential oils. Both acyclic sesquiterpenes have interesting biological activities, and their use in human therapy might be considered. Moreover, the popularity of herbal products and essential oils containing these sesquiterpenes in folk medicines increases. In spite of these facts, farnesol, and particularly nerolidol isomers, have not been properly studied for their possible herb–drug interactions.
Caryophyllane sesquiterpenes are unique natural compounds widely occurring in nature, especially in plant essential oils, that are characterized by multiple properties of pharmacological interest. Although β-caryophyllene is the most investigated compound, its metabolite β-caryophyllene oxide and the analogues α-humulene and isocaryophyllene have been evaluated, too.
Previous studies showed a polypharmacological profile of these compounds and a possible interest in cancer research; however, emerging evidence has highlighted a complex pool of healing properties, including a block of carcinogen-mediated DNA damage and cytoprotection against anticancer drug toxicity in noncancerous cells, along with antiproliferative and chemosensitizing activities in cancer cells, thus suggesting their promising role as chemopreventive agents.
Many sesquiterpenes' biological activities are based on antioxidant or pro-oxidant actions. Structure, concentration, metabolism, as well as type of cells determine if a sesquiterpene acts as antioxidant or pro-oxidant. This dual character is pharmacologically significant: pro-oxidant activity may underlie anticancer and antimicrobial effects (by damaging pathogen or tumor cells), while antioxidant activity is relevant to anti-inflammatory and cytoprotective roles in normal tissues. Recent efforts in the research and development of new drugs derived from natural products have led to the identification of a variety of sesquiterpenes that possess promising anti-inflammatory, antiparasitic, and anti-carcinogenic activities. On the other hand, some sesquiterpenes can cause serious toxicity and other adverse effects.
The therapeutic potential of essential oil sesquiterpenes with anti-inflammatory activity has been extensively reviewed. The data provide a basis for seeking new anti-inflammatory drugs from natural products that do not exhibit the undesirable side effects often displayed by anti-inflammatory drugs.
In this context, the sesquiterpenes appear as potential anti-inflammatory agents. In vivo and in vitro experimental protocols were able to indicate possible mechanisms of action involved in the modulation or suppression of elements that play a direct role in the inflammatory response. Thus, the sesquiterpenes could provide a promising approach against the development of inflammatory conditions and be considered for further evaluations to ensure their therapeutic action.
Reviews identify the main sesquiterpene lactones with interconnections between immune responses and anti-inflammatory actions, within different cellular models as well as in in vivo studies. Bioaccessibility and bioavailability, as well as molecular structure–activity relationships are addressed.
Systematic review evidence indicated that sesquiterpenes are potential novel, bioactive compounds for rheumatoid arthritis (RA) prevention and treatment strategies. Sesquiterpenes have been scrutinized in the context of RA through classification as acyclic-type, guaiane-type, cadinane-type, eudesmane-type, germacrane-type, and others, examining their role and mechanism in RA. However, the overwhelming majority of this evidence derives from in vitro cell studies and animal models; robust human clinical trials in inflammatory diseases remain limited.
Evidence strength: Predominantly preclinical (in vitro and animal). Mechanistic data on NF-κB inhibition are compelling. Human clinical data are limited.
The most clinically validated application of any sesquiterpene is artemisinin's antimalarial activity. Artemisinin and its derivatives (ARTs) are known as conventional antimalarial drugs with clinical safety and efficacy. Youyou Tu was awarded a Nobel Prize in Physiology and Medicine due to her discovery of artemisinin and its therapeutic effects on malaria. Artemisinin-based combination therapies (ACTs) have become standard treatment worldwide for P. falciparum malaria as well as malaria due to other species of Plasmodium.
Artemisinin's clinical value was initially limited by various deficiencies, such as its poor solubility, poor stability, low oral bioavailability, and short plasma half-life. These pharmacokinetic limitations drove the development of semi-synthetic derivatives such as artesunate, artemether, and dihydroartemisinin. Some artemisinin-based derivatives with better bioactivity or solubility have been synthesized, including dihydroartemisinin, artesunate, artemether, SM934, DC32, and ADART.
Beyond artemisinin, other sesquiterpene lactones have demonstrated antiparasitic activity in laboratory settings. Parthenin and parthenolide are natural products that are closely related in structure to artemisinin, which is also a sesquiterpene lactone (SQL) and one of the most important antimalarial drugs available. Parthenolide demonstrated activity nearly identical to that of parthenin against P. falciparum, highlighting its potential as a possible transmission-blocking drug scaffold.
Evidence strength: For artemisinin — high; multiple large-scale clinical trials and WHO guideline endorsement. For other sesquiterpene lactones as antiparasitic agents — preclinical only; no established clinical evidence.
Apart from antimalarial effects, mounting evidence has demonstrated that ARTs exert therapeutic effects on inflammation and autoimmune disorders because of their anti-inflammatory and immunoregulatory properties. Tremendous progress has been made in this area during the past five to seven years. Naturally produced in the plant Artemisia annua, artemisinin has broad therapeutic efficacy against a variety of parasites, viruses, and neoplasms with a diverse effect on the immune system. The molecule has a variety of therapeutic mechanisms, some still under debate.
A total of 233 relevant clinical studies have investigated artemisinin, many of which have focused on its application in the treatment of malaria. Its effect on schizophrenia induced by Toxoplasma gondii infection has been studied. Notably, artemisinin has been evaluated in the treatment of hospitalized patients with severe COVID-19. The results from such investigations, however, remain preliminary and have not established clinical standards of care outside of malaria.
Evidence strength: Mechanistic and preclinical data are strong. Clinical evidence for immunoregulatory indications (outside of malaria) is preliminary and exploratory.
Sesquiterpene lactones exhibited a wide range of biological activities with impacts on human health, ranging from antitumor, antimicrobial, antioxidant, hepatoprotective, among many others. Sesquiterpene lactones represent an interesting group of plant-derived compounds that are currently being tested as lead drugs in cancer clinical trials.
In the domain of β-caryophyllene, β-caryophyllene exhibited selective anti-proliferative effects against colorectal cancer cells (IC₅₀ 19 µM). The results showed that β-caryophyllene induces apoptosis via nuclear condensation and fragmentation pathways including disruption of mitochondrial membrane potential. Further, β-caryophyllene demonstrated potent inhibition against clonogenicity, migration, invasion, and spheroid formation in colon cancer cells. These are in vitro results, however, and have not been replicated in human trials.
Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. The scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved has been collected and discussed, with possible structure–activity relationships highlighted.
Sesquiterpene lactones have been described for their potent anticancer activities such as modulating nuclear factor kappa (NF-κB) activity, inhibitory action against lipid peroxidation, and retarding the production of reactive oxygen and nitrogen species (ROS and RNS).
Evidence strength: Primarily in vitro and animal models. No approved cancer therapies are based on isolated dietary sesquiterpenes (excluding the pharmaceutical use of artesunate in certain jurisdictions). Human clinical trial data remain sparse and exploratory.
Approximately 15 controlled clinical trials have assessed the efficacy of various valerian extracts, and the German Commission E has approved its use for the treatment of restlessness and sleeping disorders. Numerous clinical trials support the use of valerian and have demonstrated an improvement in sleep latency and quality in both healthy volunteers and patients with sleep disorder. The primary active sesquiterpene is valerenic acid.
There is no scientific agreement on the mechanism of action of valerian's sedating activity or the compounds responsible. Many potential mechanisms for the pharmacological activity of valerian have been proposed, including agonistic activities on the GABA, adenosine, barbiturate, and benzodiazepine receptors.
Valerian extracts allosterically modulate GABA-A receptors and induce anxiolytic activity. This activity is closely related to valerenic acid. Valerenic acid and pinoresinol, key constituents of valerian extract Ze 911, were identified as positive allosteric modulators (PAMs) of adenosine A1 receptors (A1ARs).
A randomized, double-blind, crossover clinical trial in hemodialysis patients examined the effects of valerian on sleep quality. The mixture significantly increased the non-rapid eye movement sleep time, while rapid eye movement sleeping time was decreased. Electroencephalography investigation indicated decreased awakening and increased total sleep time.
Evidence strength: Moderate. The German Commission E endorsement is based on a meaningful body of controlled trials. However, clinical studies are heterogeneous in design, extract preparation, and dosage, limiting meta-analytic power.
(−)-β-Caryophyllene (BCP), a cannabinoid receptor type 2 (CB2)-selective phytocannabinoid, has been shown to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain.
In a murine model of antiretroviral drug-induced neuropathic pain: β-Caryophyllene prevented the ddC-induced increase in cytokine transcripts (interleukin 1 beta, tumor necrosis factor alpha, and interferon gamma) in the paw skin and brain. BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation.
In a murine model of multiple sclerosis (EAE): BCP significantly ameliorated both the clinical and pathological parameters of EAE. Data indicate that mechanisms underlying BCP's immunomodulatory effect are linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes, as well as protein expression of pro-inflammatory cytokines. Furthermore, it diminished axonal demyelination and modulated Th1/Treg immune balance through the activation of CB2 receptor.
Evidence strength: Primarily preclinical (animal models). No published human clinical trials on BCP for pain or neurological conditions had been completed at the time of this writing.
Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and their metabolic enzymes, regulates inflammation, pruritus, barrier integrity, and tissue repair; cannabinoid receptor type 2 (CB2) has emerged as a particularly relevant target.
A systematic review of PubMed, Embase, and Web of Science found that across in vitro, in vivo, and formulation studies, BCP produced consistent anti-inflammatory and barrier-restorative effects. CB2 antagonism attenuated these responses, confirming receptor specificity.
Evidence strength: Preclinical evidence is mechanistically consistent. Human clinical trials are lacking. Evidence for topical BCP in dermatology remains preliminary.
Sesquiterpenoid natural products in fungi have good biological activities, including antibacterial, antifungal, anti-inflammatory, antitumor, vascular-relaxing, immunosuppressant, and cytotoxic activities. Laboratory studies have shown that β-caryophyllene demonstrated selective antibacterial activity against S. aureus (MIC 3 ± 1.0 µM) and more pronounced anti-fungal activity than kanamycin in in vitro assays.
Evidence strength: In vitro. No human clinical trials have established antimicrobial clinical efficacy for isolated dietary sesquiterpenes.
Parthenolide shows in vitro activity against adult worms of S. mansoni, opening the route to further schistosomicidal studies with this compound. This constitutes a preliminary finding only; no human clinical data exist.
Evidence strength: In vitro only. No human data.
The following dosages are reported strictly as described in peer-reviewed sources and do not represent clinical recommendations.
Sesquiterpene lactones are a large, diverse group of chemicals found in several plant families that cause allergic contact dermatitis. This is among the most clinically well-documented adverse effects of sesquiterpene lactone exposure.
Compositae allergy is diagnosed by patch tests performed on a patient with contact allergic dermatitis. The baseline series of patch test allergens usually contains sesquiterpene lactone mix (alantolactone, dehydroxosus lactone, costunolide), and may also contain compositae mix. Related plant allergens include parthenolide and specific extracts prepared from individual plants such as dandelion, tansy, yarrow, feverfew, chamomile, arnica, and chrysanthemum.
In one study, sesquiterpene mix detected 65% and compositae mix detected 87% of compositae-allergic patients, but individual plant extracts were necessary to confirm the diagnosis in all patients. Parthenolide detects 75% of sesquiterpene lactone-allergic patients.
Patients with Compositae sensitization are routinely warned against the ingestion of vegetables, spices, teas, and herbal remedies from this family of plants. The evidence for the occurrence of systemic allergic dermatitis caused by sesquiterpene lactone-containing plants is mostly anecdotal and based on statements from patients rather than scientific data. However, a few clinical reports on accidental sensitization and exposure and oral challenge prove the existence of this kind of reaction, most convincingly for strong contact allergens such as costunolide in bay leaves.
Other Compositae species suspected of causing systemic reactions are artichoke, mugwort, yarrow, dandelion, feverfew, and elecampane. Some Compositae vegetables and teas, such as lettuce and chamomile tea, may induce systemic reactions through both humoral and cell-mediated mechanisms.
Results showed significant inhibition of cytochromes P450 (namely CYP1A, CYP2B, and CYP3A subfamilies) activities by all tested sesquiterpenes (trans-nerolidol, cis-nerolidol, and farnesol) in rat as well as in human hepatic microsomes. These interactions, based on the ability to modulate activities of important drug-metabolizing enzymes such as cytochromes P450 (CYP), carbonyl reductase 1 (CBR1), NADPH-quinone oxidoreductase 1 (NQO1), aldo-keto reductases (AKR), UDP-glucuronosyltransferases (UGT), sulfotransferases (SULT), and glutathione S-transferases (GST), may cause serious adverse effects on human health. Inhibition of CYP3A4 in particular has implications for the metabolism of numerous pharmaceutical drugs, and this warrants investigation in human subjects.
Many sesquiterpenes' biological activities are based on antioxidant or pro-oxidant actions. Structure, concentration, metabolism, as well as type of cells determine if a sesquiterpene acts as anti-oxidant or pro-oxidant. Therefore, detailed research of sesquiterpenes is very important for evaluation of their efficacy and for their safe use.
Patients allergic to sesquiterpene lactone mix may react to the plant or pollen, as well as cosmetics, ointments, creams, lotions, and topical medicaments that use these plant extracts. Cross-sensitization between structurally related sesquiterpene lactones across different plant families is a recognized clinical phenomenon.
Artemisia absinthium L. is one of the most famous Artemisia spp. due to its use in the production of the absinthe drink, which is restricted in most countries because of neurotoxicity. The analyzed studies confirmed that Artemisia plants have many traditional and pharmacological applications. However, scientific data are limited to clinical and toxicological research. Therefore, further research is needed on these aspects to understand the full therapeutic potential and molecular pharmacological mechanisms of this medicinal species.
β-Caryophyllene (BCP) is an FDA-approved natural compound recognized as safe as a food flavoring agent by the FDA. Its selective CB2 (versus CB1) activity means it lacks psychotropic effects associated with CB1 agonism. BCP has favorable safety and pharmacokinetic attributes, though systematic human toxicological studies specifically on BCP as a dietary supplement are limited.
Across the sesquiterpene class, several significant limitations characterize the current body of evidence:
Health conditions that Sesquiterpenes may help support.
Body systems that Sesquiterpenes may help support.
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