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Caryophyllene
Caryophyllene
Caryophyllene
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Caryophyllene
Names
Preferred IUPAC name
(1R,4E,9S)-4,11,11-Trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene
Other names
β-Caryophyllene
trans-(1R,9S)-8-Methylene-4,11,11-trimethylbicyclo[7.2.0]undec-4-ene
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.001.588 Edit this at Wikidata
EC Number
  • 201-746-1
KEGG
UNII
  • InChI=1S/C15H24/c1-11-6-5-7-12(2)13-10-15(3,4)14(13)9-8-11/h6,13-14H,2,5,7-10H2,1,3-4H3/b11-6+/t13-,14-/m1/s1 checkY
    Key: NPNUFJAVOOONJE-GFUGXAQUSA-N checkY
  • InChI=1/C15H24/c1-11-6-5-7-12(2)13-10-15(3,4)14(13)9-8-11/h6,13-14H,2,5,7-10H2,1,3-4H3/b11-6+/t13-,14-/m1/s1
    Key: NPNUFJAVOOONJE-GFUGXAQUBC
  • C1(=C)\CC/C=C(/CC[C@@H]2[C@@H]1CC2(C)C)C
Properties
C15H24
Molar mass 204.357 g·mol−1
Density 0.9052 g/cm3 (17 °C)[1]
Boiling point 262–264 °C (504–507 °F; 535–537 K)[2]
Hazards
GHS labelling:[1]
GHS07: Exclamation markGHS08: Health hazard
Warning
H304, H317
P261, P272, P280, P301+P316, P302+P352, P321, P331, P333+P317, P362+P364, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)

Caryophyllene (/ˌkærioʊˈfɪliːn/), more formally (−)-β-caryophyllene (BCP), is a natural bicyclic sesquiterpene that occurs widely in nature. Caryophyllene is notable for having a cyclobutane ring, as well as a trans-double bond in a 9-membered ring, both rarities in nature.[3]

Production

[edit]

Caryophyllene can be produced synthetically,[4] but it is invariably obtained from natural sources because it is widespread. It is a constituent of many essential oils, especially clove oil, the oil from the stems and flowers of Syzygium aromaticum (cloves), the essential oil of Cannabis sativa, copaiba, rosemary, and hops.[3] It is usually found as a mixture with isocaryophyllene (the cis double bond isomer) and α-humulene (obsolete name: α-caryophyllene), a ring-opened isomer.

Caryophyllene is one of the chemical compounds that contributes to the aroma of black pepper.[5]

Basic research

[edit]

β-Caryophyllene is under basic research for its potential action as an agonist of the cannabinoid receptor type 2 (CB2 receptor).[6] In other basic studies, β-caryophyllene has a binding affinity of Ki = 155 nM at the CB2 receptors.[7]

β-Caryophyllene has the highest cannabinoid activity compared to the ring opened isomer α-caryophyllene humulene which may modulate CB2 activity.[8] To compare binding, cannabinol binds to the CB2 receptors as a partial agonist with an affinity of Ki = 126.4 nM,[9] while delta-9-tetrahydrocannabinol binds to the CB2 receptors as a partial agonist with an affinity of Ki = 36 nM.[10]

Safety

[edit]

Caryophyllene has been given generally recognized as safe (GRAS) designation by the FDA and is approved by the FDA for use as a food additive, typically for flavoring.[11][12] Rats given up to 700 mg/kg daily for 90 days did not produce any significant toxic effects.[13] Caryophyllene has an LD50 of 5,000 mg/kg in mice.[14][15]

Metabolism and derivatives

[edit]

14-Hydroxycaryophyllene oxide (C15H24O2) was isolated from the urine of rabbits treated with (−)-caryophyllene (C15H24). The X-ray crystal structure of 14-hydroxycaryophyllene (as its acetate derivative) has been reported.[16]

The metabolism of caryophyllene progresses through (−)-caryophyllene oxide (C15H24O) since the latter compound also afforded 14-hydroxycaryophyllene (C15H24O) as a metabolite.[17]

Caryophyllene (C15H24) → caryophyllene oxide (C15H24O) → 14-hydroxycaryophyllene (C15H24O) → 14-hydroxycaryophyllene oxide (C15H24O2).

Caryophyllene oxide,[18] in which the alkene group of caryophyllene has become an epoxide, is the component responsible for cannabis identification by drug-sniffing dogs[19][20] and is also an approved food additive, often as flavoring.[12] Caryophyllene oxide may have negligible cannabinoid activity.[21]

Natural sources

[edit]

The approximate quantity of caryophyllene in the essential oil of each source is given in square brackets ([ ]):

Biosynthesis

[edit]

Caryophyllene is a common sesquiterpene among plant species. It is biosynthesized from the common terpene precursors dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). First, single units of DMAPP and IPP are reacted via an SN1-type reaction with the loss of pyrophosphate, catalyzed by the enzyme GPPS2, to form geranyl pyrophosphate (GPP). This further reacts with a second unit of IPP, also via an SN1-type reaction catalyzed by the enzyme IspA, to form farnesyl pyrophosphate (FPP). Finally, FPP undergoes QHS1 enzyme-catalyzed intramolecular cyclization to form caryophyllene.[39]

Biosynthesis of caryophyllene

Compendial status

[edit]

Further reading

[edit]

Notes and references

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Caryophyllene

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from Grokipedia
β-Caryophyllene is a naturally occurring bicyclic with the molecular formula C₁₅H₂₄, widely present in the essential oils of plants such as cloves (Syzygium aromaticum), (Piper nigrum), (Origanum vulgare), and (). This compound, the most common among α-, β-, and γ-caryophyllene variants, exhibits a spicy, woody, and clove-like aroma that contributes to the olfactory profiles of these botanicals. Distinguished by its selective agonism of the type 2 (CB₂), β-caryophyllene elicits , , and potentially neuroprotective effects without activating the psychoactive CB₁ receptor, marking it as a unique dietary phytocannabinoid. Research highlights its role in modulating inflammatory responses through CB₂-dependent pathways, with preclinical studies demonstrating efficacy in models of , , and neurological disorders. As a (GRAS) substance by regulatory bodies, β-caryophyllene's natural abundance and pharmacological profile underscore its potential in functional foods and therapeutics, though human clinical data remain limited.

Chemical Characteristics

Structure and Isomers

β-Caryophyllene, the most common and naturally abundant of caryophyllene, possesses the molecular C₁₅H₂₄. It features a bicyclic with a nine-membered ring fused to a cyclobutane ring, including a trans (E) in the larger ring, an exocyclic at position 8, a methyl at position 4, and geminal dimethyl groups at the position 11. The systematic IUPAC name for the naturally occurring (-)-β-caryophyllene is (1R,4E,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene. Caryophyllene exhibits geometric isomerism, with β-caryophyllene representing the thermodynamically stable trans () configuration at the endocyclic , while the cis () isomer is termed isocaryophyllene or δ-caryophyllene. Structural isomers include α-caryophyllene, which corresponds to (a monocyclic with a 11-membered ring), and γ-caryophyllene, featuring an alternative ring arrangement. Enantiomeric forms exist, but the levorotatory (-)- predominates in natural sources. These isomers often co-occur in essential oils, influencing separation and identification challenges in .

Physical and Organoleptic Properties

β-Caryophyllene appears as a colorless to pale yellow oily liquid at room temperature. Its molecular formula is C₁₅H₂₄, with a molecular weight of 204.35 g/mol. The compound exhibits a density ranging from 0.899 to 0.912 g/cm³ at 20°C, a refractive index of 1.498 to 1.504, and low water solubility, being insoluble in aqueous media but soluble in ethanol and other organic solvents. It boils at approximately 256–260°C under standard atmospheric pressure, though reported values vary slightly with measurement conditions, and remains liquid below 25°C with no distinct melting point in typical ranges.
PropertyValue
Density (20°C)0.899–0.912 g/cm³
1.498–1.504
256–260°C (atmospheric)
Insoluble in ; soluble in , oils
Organoleptically, β-caryophyllene imparts a medium-strength spicy characterized by woody, clove-like, and dry notes with subtle sweet undertones, persisting for up to 44 hours in sensory evaluations. In flavor applications, it contributes peppery, earthy, and warm sensations reminiscent of or cloves, enhancing profiles in spices and essential oils. These sensory attributes stem from its volatile sesquiterpenoid structure, making it valuable in perfumery and flavoring as a GRAS-listed substance per FDA evaluations.

Natural Occurrence and Biosynthesis

Primary Natural Sources

β-Caryophyllene, primarily in its (E)-β form, is a bicyclic ubiquitous in the essential oils, oleoresins, and other volatile fractions of from over 50 families worldwide. A systematic analysis of published literature documented nearly 300 instances of plant-derived essential oils containing more than 10% β-caryophyllene, extracted from diverse parts such as leaves, flowers, barks, and resins across 56 countries. This compound contributes to the aroma and potential defensive properties of these plants, with concentrations varying by species, environmental factors, and extraction methods. Notable high-concentration sources include species from the and families, which dominate the records. For instance, Scutellaria havanensis leaves yield up to 75.6% β-caryophyllene in , while Pentadesma butyracea bark contains 74.0%. Oleoresins from Copaifera langsdorffii () register 72.0% β-caryophyllene with a high overall yield of 28%, and Bursera microphylla () oleo-gum-resin reaches 72.9%. Tagetes patula () flowers provide 53.5%.
Plant SpeciesFamilyPlant Partβ-Caryophyllene Content (%)Reference
Scutellaria havanensisLeaves75.6
Pentadesma butyraceaBark74.0
Copaifera langsdorffiiOleoresin72.0
Bursera microphyllaOleo-gum-resin72.9
Tagetes patulaFlowers53.5
Dietary and spice plants also serve as primary sources, often with substantial fractions in their essential oils. Black pepper (Piper nigrum) fruits, cloves (Syzygium aromaticum) buds, cinnamon (Cinnamomum spp.) bark, oregano (Origanum vulgare), basil (Ocimum spp.), rosemary (Rosmarinus officinalis), and hops (Humulus lupulus) contain notable levels, contributing to their characteristic spicy or herbal profiles. Cannabis (Cannabis sativa) flowers can reach up to 37% β-caryophyllene in essential oil, varying by chemotype and cultivation conditions, contributing to the spicy and peppery aroma of certain strains. In the context of cannabis use, β-caryophyllene is associated with potential anti-stress and mood-brightening effects through its selective agonism of the cannabinoid receptor type 2 (CB2). These sources underscore β-caryophyllene's role in both wild and cultivated flora, with abundance linked to sesquiterpene biosynthetic pathways.

Biosynthetic Mechanisms

Beta-caryophyllene, the predominant isomer of caryophyllene, is synthesized in plant cytosol via the mevalonate (MVA) pathway, where undergoes sequential phosphorylation and decarboxylation to yield isopentenyl pyrophosphate (IPP) and its isomer (DMAPP). These C5 units condense head-to-tail via prenyltransferases to form (GPP, C10), which further extends to (FPP, C15), the universal precursor for sesquiterpenes. The committed step involves class I terpene synthases, specifically beta-caryophyllene synthases (EC 4.2.3.89), which catalyze the Mg²⁺-dependent of FPP's diphosphate group, initiating electrophilic 1,10-cyclization. This proceeds via a germacrenyl intermediate that rearranges through a 1,11-closure to the caryophyllenyl cation, followed by to yield the bicyclic (E)-beta-caryophyllene with its characteristic 9-membered ring fused to a 4-membered ring and an exocyclic methylene. Minor coproducts like alpha-humulene arise from alternative pathways. These synthases, encoded by terpene synthase (TPS) genes such as TPS23 in maize (Zea mays) or TPS7 in tobacco (Nicotiana tabacum), exhibit substrate specificity for (E,E)-FPP and are upregulated in response to herbivory or environmental cues, facilitating volatile emission for indirect defense. Expression varies across species; for instance, in Artemisia annua, AaCPS1 produces beta-caryophyllene alongside other sesquiterpenes. Biosynthetic flux is modulated by transcription factors like MYC2 or PIF4, linking light signaling to enhanced production under red light conditions. While the core mechanism is conserved, variants differ in and product profiles; tobacco TPS7, for example, achieves over 90% beta-caryophyllene selectivity in systems, outperforming homologs from hop or lavender. Pathway crosstalk with the plastidial methylerythritol phosphate (MEP) route is minimal for sesquiterpenes, though IPP exchange via transporters can occur under stress.

Production Methods

Extraction from Plant Materials

Steam distillation represents the conventional approach for obtaining caryophyllene-rich essential oils from plant sources such as cloves (Syzygium aromaticum) and (Piper nigrum), where beta-caryophyllene constitutes 5-40% of the oil composition depending on the part and conditions. The process involves passing through comminuted material at around 100°C under for 4-6 hours, causing volatile compounds to vaporize, condense, and separate from the aqueous phase due to density differences. Yields from clove buds typically reach 6.5% essential oil by weight, with beta-caryophyllene comprising 5-10% thereof. Solvent extraction using non-polar solvents like n- or polar ones like provides an alternative for higher yields in certain matrices, avoiding thermal degradation risks. For powder, hexane extraction delivers 16.87 mg/g beta-caryophyllene, outperforming aqueous methods in raw yield but requiring subsequent removal and purification steps such as or . Supercritical fluid extraction (SFE) with offers a solvent-free, tunable method for enriched, pigment-free extracts, particularly from leaves or resins. Applied to Copaifera reticulata leaves at 35°C and 27.5 MPa, SFE yields extracts containing 13-109 mg/g beta-caryophyllene, surpassing commercial oleoresins by up to 70% while minimizing environmental impact compared to traditional or hydrodistillation techniques. Subcritical water extraction (SWE) utilizes pressurized hot water (170°C, 10 minutes) to extract beta-caryophyllene from at 1.19 mg/g, though yields decline at higher temperatures due to and oxidation products like caryophyllene oxide; this method uniquely accesses oxygenated derivatives absent in organic solvent extractions. Emerging techniques, including ultrasound-assisted extraction, enhance efficiency by disrupting plant cell walls, enabling shorter extraction times and higher recoveries from diverse sources like sea buckthorn or verbenacea, often combined with hydrodistillation for caryophyllene contents up to 37% in the resulting oil.

Chemical and Biotechnological Synthesis

Chemical synthesis of β-caryophyllene, the predominant , has been achieved through multi-step organic transformations, but remains complex due to the molecule's featuring a nine-membered ring and a cyclobutane moiety. A of racemic (d,l-)caryophyllene and isocaryophyllene was reported in 1964, involving photochemical [2+2] followed by ring-opening and functional group manipulations to construct the framework. Earlier attempts, such as those by et al., highlighted the challenges of multistep processes that are expensive, environmentally burdensome, and yield low quantities, rendering chemical routes economically unfeasible for large-scale production. Biotechnological production has emerged as a sustainable alternative, leveraging to express β-caryophyllene enzymes that cyclize (FPP), an intermediate from the mevalonate (MVA) or methylerythritol phosphate (MEP) pathways. In Escherichia coli, integration of a heterologous MVA pathway with tobacco-derived TPS7 yielded 100.3 mg/L in shake flasks and up to 5.142 g/L in fed-batch with n-dodecane extraction to mitigate volatilization losses. Engineered Saccharomyces cerevisiae strains, optimized with of like QHS1 from Artemisia annua (e.g., E353D mutant increasing activity by 35%) and MVA pathway enhancements (e.g., tHMG1 overexpression), achieved titers of 2.949 g/L in fed-batch cultures over 140 hours. Recent advancements include engineering Yarrowia lipolytica, where overexpression of S. cerevisiae tHMG1 and A. annua QHS1 in wild-type strains produced 798.1 mg/L in batch fermentation, outperforming lipid-accumulating variants due to reduced competition for precursors; glucose-erythritol carbon mixes further boosted output. Other hosts like cyanobacteria (Synechocystis sp. at 46.4 ng/mL/week) and purple bacteria (Rhodobacter capsulatus at 139 mg/L) demonstrate photosynthetic or alternative pathways, though yields lag behind yeast and bacterial systems. Challenges persist, including FPP toxicity, enzyme specificity, and product extraction, but strategies like chromosomal integration and fed-batch processes have improved scalability and purity (>99% via specialized resins).

Pharmacological Actions

CB2 Receptor Selectivity and Mechanisms

β-Caryophyllene, particularly its β-isomer (BCP), functions as a selective at the type 2 (CB2), a predominantly expressed on immune cells and peripheral tissues. This selectivity arises from its high binding affinity for CB2 (Ki = 155 ± 4 nM) with negligible interaction at CB1 receptors, avoiding central psychoactive effects associated with CB1 activation. Early characterization in 2008 demonstrated that BCP competitively binds to the orthosteric site of CB2, mimicking endocannabinoids like but without affinity for CB1 even at concentrations up to 30 μM. Upon binding, BCP activates CB2 through Gi/o protein coupling, leading to inhibition of and reduced cyclic AMP levels, which modulates downstream signaling pathways including MAPK/ERK and calcium mobilization in immune cells. This agonism promotes anti-inflammatory responses, such as decreased production of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and enhanced recruitment of regulatory T cells, as evidenced in models of where BCP effects were abolished by CB2 antagonists like AM630. Functional studies confirm BCP's in reducing neuropathic and inflammatory via CB2-dependent mechanisms, with oral doses (e.g., 100-200 mg/kg in mice) eliciting analgesia comparable to synthetic CB2 agonists without tolerance development over repeated administration. The receptor selectivity of BCP is further supported by its structural bicyclic scaffold, which aligns with CB2's binding pocket preferences over CB1's, as revealed by docking simulations and studies identifying key residues like Ser2.60 and Phe7.36 in CB2 for interaction. Unlike non-selective cannabinoids, BCP exhibits biased at CB2, preferentially signaling through β-arrestin pathways in some cellular contexts, potentially contributing to its immunomodulatory profile without desensitization. These mechanisms underpin BCP's therapeutic promise in conditions involving peripheral , though human receptor binding data remain limited compared to preclinical models.

Interactions with Other Targets

β-Caryophyllene (BCP) interacts with proliferator-activated receptors (PPARs), notably PPARγ, contributing to its and metabolic regulatory effects. Activation of PPARγ by BCP has been observed in models of dextran sulfate sodium-induced , where it suppressed pathways independently of CB2 receptor involvement, as evidenced by persistent effects in CB2 knockout mice. Similarly, in diet-induced and vascular in rats, BCP's protective actions involved PPARγ upregulation alongside CB2 , with antagonists blocking these benefits. PPARα modulation has also been reported, enhancing oxidation and mitochondrial function in metabolic stress contexts. BCP modulates transient receptor potential vanilloid 1 () channels, primarily through regulation of expression rather than direct agonism, influencing and . In cerebral ischemia-reperfusion models, a single dose of BCP altered , BDNF, and TrkB levels in the brain cortex, correlating with reduced . This interaction may underlie BCP's properties in peripheral , as intraplantar administration alleviated in a manner suggestive of TRPV1 desensitization or downstream signaling interference. As an enzyme modulator, BCP inhibits (MAGL), elevating (2-AG) levels and amplifying endocannabinoid tone. administration increased brain 2-AG concentrations dose-dependently, with values around 12.5 μM in enzymatic assays, providing an indirect mechanism for enhanced CB2 signaling without direct receptor binding. These polypharmacological actions distinguish BCP from strict CB2-selective ligands, potentially explaining its broad preclinical efficacy in and neurodegeneration, though human binding affinities for non-CB2 targets remain less characterized.

Biological Research and Effects

Preclinical Evidence

Preclinical studies have demonstrated that β-caryophyllene (BCP), a selective of the type 2 (CB2) receptor, exerts effects in models of inflammatory and , with efficacy mediated through CB2 activation as evidenced by reversal with selective antagonists such as AM630. In formalin-induced and complete (CFA)-evoked inflammatory models in mice, systemic administration of BCP at doses of 10–50 mg/kg reduced paw edema and , comparable to non-steroidal drugs like indomethacin, without inducing tolerance or motor impairment upon repeated dosing. Similarly, intraplantar BCP injection alleviated mechanical and thermal in CFA-treated rats, with effects persisting up to 7 days post-administration, attributed to suppression of pro-inflammatory cytokines like TNF-α and IL-1β. In models of chronic , such as dextran sodium (DSS)-induced in mice, oral BCP at 200 mg/kg daily for 7 days reduced colonic , histopathological damage scores, and activity while modulating CB2-dependent pathways to inhibit signaling. BCP also exhibited chondroprotective effects in monosodium iodoacetate (MIA)-induced in rats, where intra-articular doses of 1–10 μg/joint over 28 days decreased degradation, synovial , and behaviors, with benefits linked to downregulation of matrix metalloproteinases (MMPs) and upregulation of type II expression. In vitro assays using lipopolysaccharide (LPS)-stimulated macrophages confirmed BCP's anti-inflammatory mechanism, showing dose-dependent (5–50 μM) inhibition of production and iNOS expression via CB2 and PPARγ receptor interactions. Neuroprotective and other effects have been observed in preclinical paradigms. In methamphetamine-induced models in mice, BCP pretreatment at 50–200 mg/kg attenuated striatal depletion and markers like , effects blocked by CB2 antagonists, suggesting modulation of glial activation and activity. For , topical BCP application (10–100 mg/kg equivalent) in excisional wounds on mice accelerated closure rates by 20–30% compared to controls, reducing infiltration and enhancing proliferation through decreased TNF-α and increased TGF-β1 levels. In seizure models using in mice, BCP at 100–200 mg/kg intraperitoneally raised the and shortened duration, independent of CB1 but reliant on CB2 and channels. These findings, primarily from and cell-based assays, indicate broad therapeutic potential but require validation against species-specific and long-term safety. Although most preclinical evidence for β-caryophyllene derives from rodent models, limited studies have been conducted in dogs, with none identified in cats. A 2016 in vitro and in vivo study demonstrated antimicrobial activity against bacteria isolated from canine dental plaque and significant reduction in plaque formation in mongrel dogs when applied topically, with results comparable or superior to chlorhexidine in certain metrics. Additionally, a 2025 in vitro study found β-caryophyllene non-cytotoxic to peripheral blood mononuclear cells from healthy and atopic dogs but showed no direct anti-inflammatory effects on cytokine secretion under the tested conditions. No direct veterinary clinical trials in companion animals have been identified.

Clinical and Human Data

A 2022 pharmacokinetic study in 12 healthy human volunteers demonstrated that β-caryophyllene exhibits poor oral in standard oil form, with plasma concentrations often below detection limits, but achieves significantly enhanced absorption—reaching peak levels of 10-25 ng/mL within 2-4 hours—when delivered via a self-emulsifying system, with elimination around 3-5 hours and no serious adverse effects observed. In a randomized, double-blind, -controlled involving 60 adults with traits, daily oral administration of 30 mg β-caryophyllene for 8 weeks resulted in significant reductions in Yale Food Addiction Scale symptom scores (mean change: -1.5 ± 0.9 versus -0.7 ± 1.4 for ), indicating potential modulation of addictive eating behaviors, though no notable impacts on , anthropometric measures, , or dietary intake were found. A small 2022 pilot study in 25 habitual smokers showed that inhaling β-caryophyllene (approximately 10-20 mg per session) concurrently with cigarette smoke over 4 weeks decreased brachial-ankle pulse wave velocity—a measure of arterial stiffness—by 10-15% compared to smoking alone, without altering blood pressure or lipid profiles, and with no reported adverse respiratory or systemic events. Human safety data derive mainly from its use as an FDA-approved food additive (GRAS status) and fragrance ingredient, where exposure levels up to 1-2% in products show no evidence of genotoxicity, reproductive toxicity, or skin sensitization in predictive assays and limited patch testing; subchronic rodent studies support no-observed-adverse-effect levels exceeding human dietary intakes by factors of 100-500, though long-term clinical tolerability remains understudied. Proposed clinical evaluations for analgesic effects, such as a 2021 single-dose oral trial (NCT04794205) assessing thermal pain thresholds in healthy subjects, were withdrawn before enrollment, leaving human pain efficacy data reliant on preclinical extrapolation rather than direct evidence. Overall, while these preliminary human investigations suggest tolerability and niche physiological influences, the absence of large-scale, long-term randomized trials precludes firm conclusions on therapeutic efficacy or broader safety margins for pharmacological dosing.

Therapeutic Potentials and Limitations

Beta-caryophyllene (BCP), a selective agonist of the cannabinoid type 2 (CB2) receptor, exhibits preclinical evidence of anti-inflammatory effects across multiple tissues, including reductions in pro-inflammatory cytokines such as TNF-α and IL-6 in models of hepatic, renal, and neurological inflammation. These properties stem from CB2 receptor-dependent modulation of immune responses, without activating the psychoactive CB1 receptor, positioning BCP as a potential non-psychoactive alternative for managing chronic inflammatory conditions like osteoarthritis and diabetic neuropathy. Analgesic effects have been demonstrated in rodent models of inflammatory and neuropathic pain, where oral or intraplantar administration reduced thermal hyperalgesia and mechanical allodynia via CB2 agonism and inhibition of monoacylglycerol lipase, enhancing endocannabinoid tone. Additional therapeutic potentials include neuroprotective and antidepressant-like activities, with studies showing BCP supplementation mitigating and hippocampal damage in maternal separation stress models, improving in aged , and exerting effects in neurological disease models. In the context of cannabis, beta-caryophyllene has been associated with anti-stress and mood-brightening effects, potentially contributing to focused states and mild euphoric sensations in certain strains, though these psychological benefits are primarily supported by preclinical evidence and limited human reports rather than definitive clinical trials. In , BCP has shown promise as an adjunct to chemotherapeutics like and , enhancing efficacy against cancer cell proliferation while potentially reducing toxicity, though these findings are limited to and animal studies. Antiviral mechanisms against pathogens like have been observed in cell cultures, involving inhibition of viral entry and replication, but require validation beyond preclinical stages. Despite these potentials, clinical evidence remains sparse, with human trials primarily small-scale or exploratory, such as a 2021 study on acute thermal response showing preliminary effects but lacking large cohorts or long-term data. A 2021 pilot on cognitive improvement in elderly subjects reported benefits but was constrained by the absence of a control, limiting causal attribution. challenges, including rapid metabolism and low oral absorption, hinder systemic efficacy, though formulations like nanoemulsions have improved in healthy volunteers without adverse events. Overall limitations include reliance on preclinical models, which may not translate to humans due to species differences in CB2 signaling; potential for tolerance in prolonged use despite a favorable profile; and insufficient randomized controlled trials to establish dosing, safety in vulnerable populations, or superiority over standard therapies. Regulatory hurdles persist, as BCP lacks approval for specific indications beyond its status as a , underscoring the need for rigorous phase II/III trials to confirm therapeutic utility.

Safety and Toxicology

Acute and Subchronic Toxicity Profiles

β-Caryophyllene exhibits low . The acute oral LD50 in rats exceeds 5 g/kg body weight, while the acute dermal LD50 in rabbits similarly exceeds 5 g/kg. Subchronic toxicity studies confirm a favorable safety profile. In a 90-day oral gavage study compliant with guidelines, β-caryophyllene oil was administered to Wistar rats at doses of 0, 150, 450, or 700 mg/kg/day, with a subset undergoing a 21-day recovery period and interim sacrifices at 28 days. No treatment-related mortality, clinical signs, neurobehavioral changes, body weight reductions, food or water intake alterations, ophthalmoscopic abnormalities, hematological shifts, deviations, anomalies, organ weight differences, or histopathological findings were observed; incidental deaths in two high-dose animals were attributed to gavage aspiration. The (NOAEL) was 700 mg/kg/day for both sexes. Supporting evidence from a 28-day repeated-dose study in female Swiss mice, following OECD guideline 407, involved doses of 300 or 2000 mg/kg body weight. No clinical signs, mortality, body weight changes, food or water intake variations, organ weight alterations, , , neurobehavioral effects, hematological abnormalities, biochemical perturbations, or indicators were noted, indicating absence of up to the highest dose tested.

Regulatory Status and Approved Uses

Beta-caryophyllene holds (GRAS) status from the Flavor and Extract Manufacturers Association (FEMA) and is approved by the (FDA) for use as a agent in and beverages at specified concentrations, typically up to 0.01% in final products. This approval stems from its natural occurrence in spices like and cloves, supporting its role as a synthetic or isolated additive without established safety concerns for dietary exposure at these levels. It is also permitted in non-alcoholic beverages and other categories under FDA regulations for indirect additives, but not as a color additive requiring specific listing in 21 CFR Parts 73, 74, or 82. In the European Union, beta-caryophyllene is authorized as a flavoring substance under Regulation (EC) No 1334/2008, with evaluations by the European Food Safety Authority (EFSA) confirming its safety for use in food at levels up to 5 mg/kg in certain categories, based on toxicity data including 90-day studies showing no adverse effects at relevant doses. It appears in the EU Register of Feed Additives under category 2b (sensory additives) for use in animal nutrition, often as part of essential oil blends from sources like clove or black pepper, with EFSA opinions supporting efficacy as a flavorant without genotoxicity or carcinogenicity risks. However, novel food applications involving higher concentrations from hemp-derived sources may require additional authorization under EU novel food regulations, as GRAS-equivalent status applies primarily to traditional flavoring uses. Beta-caryophyllene lacks approval as a pharmaceutical drug by the FDA, (EMA), or equivalent bodies worldwide, remaining investigational for therapeutic applications such as or CB2 receptor modulation despite preclinical promise. As of 2025, its highest development stage is Phase 1 clinical trials for select indications like , with no marketed drug formulations; any medical claims rely on contexts, which are unregulated for efficacy by the FDA.

Metabolism and Derivatives

Pharmacokinetic Pathways

β-Caryophyllene, a lipophilic with a log P value of approximately 4.24, demonstrates limited oral in its unmodified form, estimated at less than 10% in s, primarily due to poor aqueous leading to dissolution-limited absorption and extensive first-pass hepatic . Formulations such as self-emulsifying systems (SEDDS), including VESIsorb technology, significantly enhance oral absorption; in a randomized, double-blind crossover study of 24 healthy subjects receiving a single 100 mg dose under conditions, SEDDS-formulated β-caryophyllene achieved a 2.2-fold increase in AUC_{0-12h} (549.5 ng/mL×h versus 260.7 ng/mL×h for neat oil) and a 3.6-fold higher C_{max} (204.6 ng/mL versus 58.22 ng/mL), with a reduced T_{max} of 1.43 hours compared to 3.07 hours for neat oil. Similarly, in rats administered 50 mg/kg orally, a β-cyclodextrin inclusion complex improved , yielding a 2.6-fold higher AUC_{0-12h} and elevated C_{max} relative to free β-caryophyllene. Following absorption, β-caryophyllene distributes widely to tissues owing to its high lipophilicity. In mice exposed to inhaled volatile β-caryophyllene, the compound was detectable in serum, lungs, olfactory bulb, brain, heart, liver, kidney, epididymal fat, and brown adipose tissue, with the highest concentrations in brown adipose tissue and persistence up to 24 hours in brain, liver, and adipose tissues; serum half-life was approximately 134 minutes. Oral administration in rodents results in relatively higher liver accumulation compared to other routes, potentially facilitating processing for excretion. Metabolism occurs rapidly via hepatic P450-mediated oxidation, progressing through intermediates such as β-caryophyllene oxide to hydroxylated products like 14-hydroxycaryophyllene, followed by phase II conjugation. studies using human liver microsomes show a short of 9.6 minutes and high intrinsic clearance (194.9 mL/min/kg), with near-complete depletion within 30 minutes; S9 fractions indicate slower phase II metabolism with a of 44.4 minutes. Inhaled exposure in mice alters liver metabolite dynamics, elevating and cystathionine levels while reducing and , suggesting influence on and energy pathways. Plasma concentrations return to baseline within 10-12 hours post-oral dosing, reflecting efficient clearance. Excretion data remain sparse, but the compound's implies predominant biliary/fecal elimination following hepatic , consistent with observed liver accumulation after oral dosing. ADME predictions support favorable overall pharmacokinetic properties with low toxicity risk, though empirical studies emphasize the need for route-specific investigations.

Key Derivatives and Their Properties

Beta-caryophyllene , formed via epoxidation of beta-caryophyllene, represents a primary natural derivative with distinct pharmacological profiles. This sesquiterpenoid , present in plants such as and , demonstrates nontoxic and nonsensitizing characteristics, making it suitable for potential topical applications. It exhibits significant anticancer effects by inhibiting proliferation and inducing in various lines, including those resistant to conventional therapies, through mechanisms involving (ROS) modulation and disruption of mitochondrial function. Synthetic derivatives of beta-caryophyllene, such as difluoroalkylated analogs, have been engineered to enhance specific bioactivities. These compounds display local anesthetic properties comparable to lidocaine in preclinical models, alongside effects mediated by selective modulation of receptors and ion channels. Recent advancements include novel derivatives designed to target , potentially mitigating in conditions like , with inhibitory potencies influenced by structural features such as exocyclic methylene groups. Functionalized beta-caryophyllene derivatives also show polypharmacological potential within the , acting as agonists at CB2 receptors while exhibiting cytotoxic and activities against bacterial strains. For instance, derivatives from plant sources like Pulicaria vulgaris demonstrate broad biological properties, including inhibition and action, positioning them as candidates for bioactive alternatives in therapeutic development. These modifications generally preserve the core scaffold but alter and receptor affinity, influencing and target specificity.

Recent Developments

Biosynthesis and Application Advances (2023–2025)

In 2024, engineers optimized β-caryophyllene production in Saccharomyces cerevisiae by fusing the ERG20 gene with a β-caryophyllene synthase from Artemisia argyi using a linker, alongside enhancements to the mevalonate pathway via overexpression of HMGR and UPC2-1, yielding 15.6 g/L in fed-batch fermentation—the highest reported titer in yeast to date. This approach leverages farnesyl pyrophosphate as a precursor, addressing limitations in synthase efficiency and precursor flux for scalable microbial synthesis. Parallel efforts in non-conventional yeasts advanced yields in Yarrowia lipolytica, where integration of tHMG1 and QHS1 genes under strong promoters, combined with multi-copy strategies and optimized fermentation on glucose/, produced up to 318.5 mg/L in flasks and 798.1 mg/L in batch fermentation by early 2025. These strains utilized the strain's for improved flux, highlighting Y. lipolytica's potential over traditional yeasts for industrial production. Novel photosynthetic biosynthesis emerged in 2024 with the first successful expression of β-caryophyllene synthase in the eukaryotic microalga Chlamydomonas reinhardtii, augmented by overexpression of DXS and IDI enzymes in the methylerythritol phosphate pathway, achieving 854.7 μg/L under photoautotrophic conditions and 1,016.8 μg/L photomixotrophically without impairing growth or photosynthesis. This light-driven method positions β-caryophyllene as a sustainable aviation fuel precursor, bypassing heterotrophic carbon needs and enabling CO₂ fixation-based production. Application advances capitalized on these biosynthetic gains for biofuels and therapeutics; the algal platform directly supports high-density development, while microbial routes enable cost-effective supply for and uses via CB2 . In therapeutics, 2025 research demonstrated β-caryophyllene's role as a chemosensitizer enhancing and in cancers by inhibiting and multidrug resistance, with preclinical reducing tumor viability. Antiviral mechanisms were elucidated, showing broad against enveloped viruses through disruption and low , outperforming some herbal extracts. Neuroprotective applications advanced with evidence of β-caryophyllene mitigating and in neurodegeneration models, often synergizing with . These developments underscore biosynthetic scalability enabling expanded pharmaceutical testing, though human trials remain limited.

Unresolved Claims and Skeptical Perspectives

Despite promising preclinical data suggesting β-caryophyllene's selective at CB2 receptors contributes to and effects, studies have questioned the functional potency and specificity of this interaction, with binding affinities described as weak and lacking significant downstream signaling in isolation or combination with other cannabinoids. This challenges claims of a robust "entourage effect" wherein like β-caryophyllene amplify THC's therapeutic benefits via modulation, as empirical tests in cell-based assays failed to demonstrate additive or synergistic receptor activation beyond marginal CB2 engagement. Human clinical evidence remains sparse and inconclusive, with most therapeutic assertions—such as for pain relief, , or metabolic disorders—derived from rodent models or experiments that may not translate due to species differences in receptor expression and . For instance, while report reduced cocaine-seeking behavior via PPARα/γ pathways, no large-scale randomized controlled trials confirm or in humans for or related indications. Bioavailability challenges, including poor water and volatility, further complicate oral or topical delivery, potentially undermining purported benefits in supplement forms where product purity and dosing variability raise additional doubts about consistency. Skeptics highlight risks of overextrapolation from industry-funded or cannabis-adjacent research, where preliminary findings on induction or chemosensitization in cancer cells lack validation in human cohorts, and occasional retractions underscore methodological vulnerabilities in models. Regulatory bodies have not approved β-caryophyllene for specific medical uses beyond its GRAS status as a , reflecting unresolved gaps in long-term data and causal links to clinical outcomes amid hype-driven marketing. Future resolution demands standardized human trials to disentangle genuine mechanisms from or off-target effects.

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