Caryophyllene

Beta-Caryophyllene (BCP): A Comprehensive Reference

1. Identity and Chemical Characterization

Nomenclature and Molecular Structure

Caryophyllene, more formally (−)-β-caryophyllene (BCP), is a natural bicyclic sesquiterpene that occurs widely in nature. Its molecular formula is C₁₅H₂₄, and its IUPAC name is (1R,4E,9S)-4,11,11-trimethyl-8-methylidenebicyclo[7.2.0]undec-4-ene. Caryophyllene is notable for having a cyclobutane ring, as well as a trans-double bond in a 9-membered ring, both rarities in nature.

Beta-caryophyllene is a pale yellow oily liquid with an odor midway between the odor of cloves and turpentine. (-)-beta-caryophyllene is a beta-caryophyllene in which the stereocentre adjacent to the exocyclic double bond has S configuration while the remaining stereocentre has R configuration. It is the most commonly occurring form of beta-caryophyllene, occurring in many essential oils, particularly oil of cloves.

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. 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. Shown are the chemical structures of the bicyclic sesquiterpenes (E)-β-caryophyllene, (Z)-β-caryophyllene, caryophyllene oxide, and the ring-opened isomer.

Natural Sources and Distribution

BCP is a natural sesquiterpene hydrocarbon present in hundreds of plant species. A systematic analysis of plant species with essential oils containing a BCP percentage greater than 10% provided almost 300 entries with species belonging to 51 families. The essential oils were found to be extracted from 13 plant parts and samples originated from 56 countries worldwide.

Caryophyllene is one of the chemical compounds that contributes to the aroma of black pepper. β-Caryophyllene is the primary sesquiterpene contributing to the spiciness of black pepper, and is widely found in more than 1,000 types of plants, including the essential oils of cinnamon, oregano, black pepper, basil, and cloves. Other notable botanical sources include clove, black pepper, melissa, rosemary, basil, lavender, oregano, hops, and hemp (Cannabis sativa L.).

β-caryophyllene is a sesquiterpene found in large amounts in the essential oils of various spice and food plants such as oregano, cinnamon, and black pepper. The copaiba tree (Copaifera spp.) is a particularly concentrated botanical source; there are over 50 species of the tropical Copaifera genus, with three in particular being exploited for their oleoresin on a large scale. The main country of origin for the oleoresin and essential oil is Brazil (in particular the Amazon region), but Copaifera species distribution is wide across South America as well as West Africa.

Regulatory Status and Common Forms

β-Caryophyllene has the distinction of being the first known "dietary cannabinoid," a common component of food that has GRAS (Generally Recognized as Safe) status and is approved by the FDA for food use. BCP is approved by the United States Food and Drug Administration and European agencies as a food additive, taste enhancer, and flavoring agent.

Caryophyllene can be produced synthetically, but it is invariably obtained from natural sources because it is widespread. Common commercial preparations include purified BCP neat oils, softgel capsules, self-emulsifying formulations, cyclodextrin inclusion complexes, and topical preparations such as essential oil blends and oleoresins. Due to its woody and spicy odour, BCP has been commonly used as a fragrance and flavouring agent since the 1930s.

2. Traditional and Historical Use

Spices and Culinary Traditions

In ancient Ayurvedic and Chinese medicine, black pepper and cloves were used not only as flavor enhancers but also for their therapeutic properties. Remedies involving these spices were commonly prepared to aid digestion, relieve pain, and reduce inflammation. These plants are among the most significant dietary sources of BCP, though the compound was not isolated and identified by name in ancient texts.

Historically, plants containing caryophyllene have been utilized in traditional medicine for their purported anti-inflammatory and analgesic properties. The use of caryophyllene-rich botanicals, particularly cloves and black pepper, spans multiple continents and millennia of recorded herbal practice. In north Africa, particularly Egypt, basil has been used for centuries for both culinary and medicinal purposes, with archaeological evidence indicating its cultural significance.

Copaiba in Amazonian Tradition

Copaiba resin and essential oil are extremely high in BCP and have been used in traditional South American medicine for centuries. The name copaiba originates from an indigenous Amazonian language (Tupi), cupa-yba, to denote reservoir or vessel, with reference to its store of oleoresin in the trunk. The oleoresin of these trees is extracted through tapping, and the oleoresin is used therapeutically in its raw state or distilled to yield copaiba essential oil.

Traditional Chinese Medicine

Both caryophyllene and humulene are used in traditional Chinese medicine to relieve inflammation. Caryophyllene-rich plants such as cloves and pepper have been integral to classical Chinese formulary, where they have historically been employed in preparations targeting pain and digestive complaints.

3. Key Constituents, Active Compounds, and Mechanisms of Action

Primary Mechanism: CB2 Receptor Agonism

These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic anti-inflammatory cannabinoid in Cannabis. This landmark finding, published in the Proceedings of the National Academy of Sciences in 2008 by Gertsch and colleagues, established BCP as the first known dietary cannabinoid that directly and selectively activates a cannabinoid receptor.

β-Caryophyllene is under basic research for its potential action as an agonist of the cannabinoid receptor type 2 (CB2 receptor). In other basic studies, β-caryophyllene has a binding affinity of Ki = 155 nM at the CB2 receptors. Critically, BCP possesses several important pharmacological activities, ranging from pain treatment to neurological and metabolic disorders. These are mainly due to its ability to interact with the cannabinoid receptor 2 (CB2) and the complete lack of interaction with the brain CB1.

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. CB2 receptor ligands have been shown to inhibit inflammation and edema formation and thus to have an analgesic effect.

Downstream Molecular Signaling

In parallel, CB2 signaling modulates mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK), and converges on nuclear factor kappa B (NF-κB), reducing the expression of cyclooxygenase-2 (COX-2), TNF-α, IL-1β, and IL-6. This pathway is central to BCP's broad anti-inflammatory profile across multiple body systems.

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. Additionally, by influencing the PGC-1α and AMPK/CREB signaling pathways, BCP enhances hippocampal BDNF levels while reducing hippocampal COX-2 expression, ultimately promoting neuroprotection.

Endocannabinoid System Interaction

CB2R has been recently identified as a potential immunomodulatory agent in neuroinflammation associated with psychiatric disorders. When activated, CB2R inhibits the release of pro-inflammatory mediators by microglia, resulting in a neuroprotective effect in different neuropsychiatric conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), depression, anxiety and addiction.

BCP has been identified as a fully selective agonist of CB2R (pKi value = 155 nM), making its putative clinical application free from the psychotropic effects mediated by brain CB1R activation. This selectivity distinguishes BCP from classical phytocannabinoids such as THC, which are non-selective across both CB1 and CB2 receptors.

PPAR Pathway Activation

Through the binding to CB2 cannabinoid receptors and peroxisome proliferator-activated receptors (PPARs), BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH), liver diseases, diabetes, and cardiovascular diseases. PPAR-γ is a nuclear receptor that plays a key role in the regulation of glucose metabolism and adipogenesis, and its activation by BCP may underlie several of the compound's metabolic effects.

Related Compounds: Caryophyllene Oxide and α-Humulene

BCP's volatility and autoxidation to β-caryophyllene oxide (BCPO) necessitate stability-by-design strategies using antioxidants, low-oxygen processing, and protective packaging. Caryophyllene oxide, the oxidized metabolite, retains biological activity including analgesic, anticancer, antifungal, and anti-inflammatory properties. α-Humulene (α-caryophyllene), the ring-opened isomer with an identical molecular formula, exhibits synergistic anticancer activity with humulene and isocaryophyllene, as shown by studies on MCF-7, DLD-1, and L-929 cell lines.

4. Scientific Evidence by Area of Use

4.1 Inflammation

Preclinical evidence (animal and in vitro): The 2008 PNAS study by Gertsch et al. demonstrated that (E)-BCP at 500 nM inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo.

BCP exerts its potent anti-inflammatory effect by multimodal mechanisms including inhibition of COX-2 enzyme, a target for newer anti-inflammatory drugs, coxibs.

Evidence strength: Robust preclinical (in vitro and animal) evidence. Human clinical data on isolated BCP as an anti-inflammatory intervention are limited; extrapolation from animal models to human disease requires caution.

4.2 Pain (Inflammatory and Neuropathic)

Preclinical evidence: The widespread plant volatile beta-caryophyllene was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB2). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB2 is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, analgesic effects of BCP were investigated in animal models of inflammatory and neuropathic pain. The investigators demonstrated that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB2 receptor-dependent manner, while it had no effect on acute (early phase) responses.

Female BALB/c mice treated with the nucleoside reverse transcriptase inhibitor ddC for 5 days developed mechanical allodynia, which was prevented by co-treatment with BCP. A CB2 receptor antagonist (AM 630), but not a CB1 receptor antagonist (AM 251), antagonized BCP attenuation of established ddC-induced mechanical allodynia. β-Caryophyllene prevented the ddC-induced increase in cytokine (interleukin 1 beta, tumor necrosis factor alpha, and interferon gamma) transcripts in the paw skin and brain. In conclusion, BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation.

Sex differences: Sex differences in the BCP-induced analgesic effect were studied by exposing male and female rats to a persistent/repeated painful stimulation. To simulate treatment of a repeated inflammatory condition, after the first formalin injection, rats received BCP per os for 7 days at two dosages: 5 and 10 mg/kg dissolved in olive oil.

Evidence strength: Strong and consistent preclinical evidence across multiple pain models. There are no published randomized controlled trials (RCTs) evaluating isolated BCP specifically for pain endpoints in humans as of the available literature. Human evidence is inferred from traditional use of BCP-containing plants and the single RCT on food addiction (see section 4.7).

4.3 Neurology and Neuroprotection

Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect.

Some studies have proposed that BCP may be efficacious for the treatment of several neurologic diseases and disorders, such as cerebral ischemia, brain lesions, neuroinflammation, and problems in cortical, hippocampal, and cerebellar neurons and glial cells.

In a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis / EAE): BCP treatment was able to extinguish clinical EAE signs, including motor impairment. BCP, a CB2-selective phytocannabinoid, has been shown to exhibit both anti-inflammatory and analgesic effects in mouse models of inflammatory and neuropathic pain. Researchers endeavored to investigate the therapeutic potential of BCP on experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, and sought to demonstrate mechanisms that underlie BCP's modulation of autoimmune activated T cells, the pro-inflammatory scenery of the CNS, and demyelination. Findings demonstrate that BCP significantly ameliorates both the clinical and pathological parameters of EAE.

Regarding Alzheimer's disease, BCP significantly protected human microglial HMC3 cells from Aβ₂₅₋₃₅-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action.

Evidence strength: Predominantly preclinical (animal and in vitro). Although early animal research indicates that BCP may be effective in treating a large variety of neurological diseases and disorders, there is a need for a more extensive evaluation of the pharmacokinetic profile of BCP and its long-term effects, optimal dosing, alternative routes of administration, and safety in humans, and future trials are required.

4.4 Anxiety and Mood

The bicyclic sesquiterpene β-caryophyllene has diverse biological activities, including antioxidant, anti-inflammatory, antidiabetic, and analgesic effects. One study evaluates anxiolytic, toxicity, and antioxidant effects of BCP using in vitro and in vivo test models. The anxiolytic effects were tested in Swiss albino mice by applying the elevated plus-maze, rota-rod, light and dark, and hiding sphere models, while the toxicity was evaluated by brine shrimp lethality bioassay. The results suggest that BCP exerted a dose-dependent anxiolytic-like effect on the experimental animals. It did not show toxicity in the model used.

When activated, CB2R inhibits the release of pro-inflammatory mediators by microglia, resulting in a neuroprotective effect in different neuropsychiatric conditions, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, depression, anxiety, and addiction.

Evidence strength: Preclinical (animal) only. No published human RCTs have specifically assessed BCP's anxiolytic or antidepressant effects in isolation.

4.5 Metabolic Disorders: Obesity, Type 2 Diabetes, and NAFLD

The available data indicate that BCP and its derivatives have the potential to inhibit the activity of α-glucosidase, α-amylase, lipase, and PTP1B, suggestive of underlying mechanisms of usefulness of BCP in diabetes. BCP appears to be more potent than acarbose, which further demonstrates its use as an adjuvant with other agents in type 2 diabetes mellitus and obesity. BCP and congeners could be developed as potent antihyperglycemic agents particularly useful in T2DM and obesity due to polypharmacological properties on fat- and carbohydrate-metabolizing enzymes.

In a 16-week diet-induced obesity mouse study, male mice were randomly assigned to groups over a 16-week period: standard diet as lean control, high-fat diet (HFD) as obese control, and HFD + β-caryophyllene at 50 mg/kg. Treatment with β-caryophyllene improved various metabolic parameters including increased total body weight, fasting glucose levels, oral-glucose tolerance, insulin tolerance, fasting triglycerides, adipocyte hypertrophy, and liver macrovesicular steatosis. β-caryophyllene also modulated the levels and expression of immune response factors including adiponectin, leptin, insulin, interleukin-6, tumor necrosis factor-α, and Toll-like receptor-4. Data indicate that chronic supplementation with β-caryophyllene can improve relevant metabolic and immunological processes in obese mice.

In a separate rat study with type 2 diabetes induced by high-fat diet and fructose, a dose of β-caryophyllene at 200 mg/kg body weight orally for 30 days was given to type-2 diabetic rats. The treatment restored the altered levels of blood glucose, serum insulin, lipid parameters, oxidative stress markers, and antioxidant enzymes. Findings show that β-caryophyllene improves glycemia control by enhancing glucose absorption and oxidation in the skeletal muscle of type-2 diabetic rats.

Evidence strength: Promising preclinical (animal and in vitro) data. No large human RCTs in metabolic disease have been published using isolated BCP.

4.6 Dermatology and Skin

Preclinical evidence supports BCP as a pro-regenerative and anti-inflammatory agent, with additional antioxidant and analgesic properties. The cutaneous endocannabinoid system, 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. β-Caryophyllene, a dietary sesquiterpene and highly selective CB2 agonist with favorable safety and pharmacokinetic attributes, has attracted attention as a promising topical candidate.

Human evidence, limited to BCP-rich botanicals such as Copaifera oleoresins, suggests benefits for scars, wounds, and acne but lacks compound-specific validation.

Importantly, a dose-dependent effect has been noted: studies suggest an exposure-dependent therapeutic window: BCP is anti-inflammatory at treatment-range doses but sensitizing with high-dose, repeated exposure, highlighting the importance of formulation control, oxidation monitoring, and CB2 verification.

BCP exhibits coherent CB2-mediated anti-inflammatory, antipruritic, antioxidant, and reparative actions with a favorable safety profile. Dose-defined, oxidation-controlled clinical trials of purified BCP are warranted to establish its potential as a steroid-sparing topical therapy.

Evidence strength: Preclinical and in vitro. Human evidence for isolated BCP topically is indirect (via BCP-rich botanical preparations). Controlled human trials are absent as of available published literature.

4.7 Food Addiction and Appetite Regulation

One published human RCT is noteworthy: this study explored the impacts of β-caryophyllene supplementation on eating behavior, appetite, mental health, anthropometric parameters, body composition, and some hormones related to appetite in women with obesity diagnosed with food addiction (FA). Women with obesity and FA, diagnosed by the Yale Food Addiction Scale Score (YFAS-S) ≥3, were randomly allocated to receive a β-caryophyllene softgel (n = 26) at 100 mg/daily with meal or placebo (n = 26) for 8 weeks. Anthropometric measurements, body composition, eating behavior, biochemical markers, dietary intake, appetite, stress, anxiety, and depression were evaluated during the study period.

β-caryophyllene administration significantly reduced YFAS-S compared to the placebo group (changes in FA score: 1.5 ± 0.9 vs. −0.7 ± 1.4; corrected P = 0.05). Serum levels of orexin-A significantly decreased in the β-caryophyllene group (p = 0.02); however, no significant difference was observed compared to the placebo group (corrected P = 0.09). β-caryophyllene supplementation had no significant effect on body composition, anthropometric indices, appetite, eating behavior, dietary intake, physical activity level, mental health, and levels of oxytocin and neuropeptide Y (NPY), compared to the placebo. β-caryophyllene supplementation may have beneficial effects on improving YFAS-S in women with obesity diagnosed with FA.

Evidence strength: Single small RCT (n = 52) showing a trend on food addiction score. Results are preliminary; the primary outcome met borderline statistical significance. Larger, adequately powered trials are needed.

4.8 Antimicrobial Activity

Results showed that β-caryophyllene demonstrated selective antibacterial activity against S. aureus (MIC 3 ± 1.0 µM) and more pronounced anti-fungal activity than kanamycin. β-Caryophyllene also displayed strong antioxidant effects.

Evidence strength: In vitro only. No clinical trials have evaluated BCP as a stand-alone antimicrobial or antifungal agent in human populations.

4.9 Anticancer Activity

β-caryophyllene exhibited selective anti-proliferative effects against colorectal cancer cells (IC₅₀ 19 µM). The results also 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.

Despite the low cytotoxicity, BCP can potentiate the efficacy of classical cancer drugs by augmenting their concentrations inside the cells. Furthermore, it exhibits a synergistic anticancer activity with humulene and isocaryophyllene, as shown by studies on MCF-7, DLD-1, and L-929 cell lines. 10 µg/mL BCP was able to potentiate the activity of paclitaxel by a 10-fold increase.

Evidence strength: In vitro and early animal data only. No human oncology trials have been conducted evaluating BCP as a primary or adjunct anticancer agent. These findings are hypothesis-generating.

4.10 Gastroprotection

The gastroprotective properties of BCP are an added advantage in encouraging it for anti-inflammatory properties without the appearance of gastrointestinal issues signaling. Preclinical studies have reported cytoprotective effects on gastric mucosa. BCP is also reported to display important pharmacological activities, such as anticancer, cardioprotective, hepatoprotective, gastroprotective, antioxidant, anti-inflammatory, antimicrobial, immune-modulatory, and neuroprotective effects.

Evidence strength: Preclinical only. Human trials for gastroprotective endpoints are lacking.

5. Body Systems Associated with BCP

• Immune system: CB2 receptors are heavily expressed on immune cells; BCP modulates cytokine release, microglial activity, and T-lymphocyte responses.
• Central and peripheral nervous system: CB2R activation inhibits the release of pro-inflammatory mediators by microglia, resulting in a neuroprotective effect in different neuropsychiatric conditions.
• Musculoskeletal / pain pathways: CB2-mediated reduction of inflammatory and neuropathic pain via peripheral and spinal mechanisms.
• Metabolic / endocrine system: Through the binding to CB2 cannabinoid receptors and PPARs, BCP shows beneficial effects on obesity, NAFLD/NASH liver diseases, and diabetes.
• Gastrointestinal system: Gastroprotective effects observed preclinically; potential modulation of gut microbiota observed in animal studies.
• Integumentary system (skin): Anti-inflammatory, barrier-restoring, and wound-healing actions at therapeutic doses via CB2 and Nrf2 pathways.
• Cardiovascular system: Preliminary cardioprotective and hepatoprotective preclinical data documented in review literature.

6. Pharmacokinetics, Dosage Forms, and Dosages Reported in Research

Pharmacokinetics and Bioavailability

β-Caryophyllene, a common constituent of many spice and food plants, is gaining increased attention due to recent research identifying numerous potential health benefits. Due to limited oral bioavailability observed in preclinical models, the described benefits of BCP may be maximized by using a suitable delivery system. Additionally, human pharmacokinetics remain unknown beyond what is described in delivery system comparison studies.

The most informative human pharmacokinetic study to date: a randomized, double-blind, cross-over design, single oral dose study using 100 mg BCP in 24 healthy subjects (12 men/12 women) was performed under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves. The data show that BCP in a self-emulsifying drug delivery system (BCP-SEDDS) resulted in a 2.2/2.0-fold increase in AUC₀–₁₂h/AUC₀–₂₄h and a 3.6-fold increase in Cmax compared to BCP neat oil. Moreover, BCP was absorbed faster from BCP-SEDDS (Tmax: 1.43 h) compared to BCP neat oil (Tmax: 3.07 h). Gender analysis revealed that there is no significant difference between men and women for both the investigated formulations and all investigated pharmacokinetic endpoints. In conclusion, BCP-SEDDS offers a well-tolerated and effective oral delivery system to significantly enhance the oral bioavailability of BCP in humans.

Thanks to its lipophilicity, BCP is highly bioavailable upon oral consumption, and thus, the fruits, florescences, seeds, leaves, oils, and plant extracts rich in BCP could be used as useful nutritional or dietary supplements in day-to-day life, promoting health and curbing a large amount of inflammatory diseases.

β-Caryophyllene, a natural sesquiterpene existing in the essential oil of many plants, has exhibited a wide range of biological activities. However, its volatility and poor water-solubility limit its application in the pharmaceutical field. β-Cyclodextrin (β-CD) has intrinsic ability to form specific inclusion complexes with different drugs to enhance their stability, solubility, and bioavailability. Results demonstrated that BCP/β-CD inclusion complex has significantly increased the oral bioavailability of the drug in rats compared to free BCP.

In terms of metabolic fate, 14-hydroxycaryophyllene oxide was isolated from the urine of rabbits treated with (−)-caryophyllene. The X-ray crystal structure of 14-hydroxycaryophyllene (as its acetate derivative) has been reported. The metabolism of caryophyllene progresses through (−)-caryophyllene oxide since the latter compound also afforded 14-hydroxycaryophyllene as a metabolite.

Dosages Reported in Studies

• Peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice.
• Rats received BCP per os for 7 days at two dosages: 5 and 10 mg/kg dissolved in olive oil.
• Treatment with BCP at 50 mg/kg, orally, twice per day, notably attenuated mechanical hyperalgesia induced by EAE immunization in mice.
• In the diet-induced obesity mouse model, β-caryophyllene was administered at 50 mg/kg over a 16-week period.
• A dose of β-caryophyllene at 200 mg/kg body weight was given orally for 30 days to type-2 diabetic rats fed a high-fat diet.
• In the single published human RCT, women with obesity and food addiction were allocated to receive a β-caryophyllene softgel at 100 mg/daily with a meal or placebo for 8 weeks.
• In the human bioavailability crossover study, a single oral dose of 100 mg BCP was administered to 24 healthy subjects under fasting conditions.

Dosage Forms

BCP is available commercially in several formulation types, each with different bioavailability characteristics:

• Neat oil / liquid extract: BCP dissolved in a carrier oil (e.g., olive oil); lower and slower absorption per pharmacokinetic data.
• Softgel capsules: Used in the published human RCT at 100 mg/day.
• Self-emulsifying drug delivery systems (SEDDS): Demonstrated substantially higher bioavailability in the human crossover study.
• Cyclodextrin inclusion complexes: Shown to increase oral bioavailability in animal studies by addressing poor water solubility.
• Topical preparations: Used in dermatological studies, including copaiba oleoresin and formulated BCP in emollients.
• Essential oils: BCP-rich essential oils (clove, black pepper, copaiba) used aromatically and in traditional medicine; not directly equivalent to isolated BCP supplementation.

7. Safety Considerations and Notable Interactions

Regulatory Safety Status

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. Rats given up to 700 mg/kg daily for 90 days did not produce any significant toxic effects. Caryophyllene has an LD₅₀ of 5,000 mg/kg in mice.

β-Caryophyllene was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that β-caryophyllene is not genotoxic. Data on β-caryophyllene provided a calculated Margin of Exposure (MOE) greater than 100 for the repeated dose toxicity and fertility endpoints.

Skin Sensitization: A Dose-Dependent Consideration

Data show that there are no safety concerns for β-caryophyllene for skin sensitization under the current declared levels of use. However, high-dose or repeated topical exposure warrants caution. Higher concentrations (0.1–10 mg/mL, repeated epicutaneous dosing) induced dose-dependent pruritic dermatitis with scratching, mast cell recruitment, reduced FLG, and elevated serum IgE in murine models. Tisserand and Young (2013) state that β-caryophyllene is a weak skin allergen, non-toxic, non-mutagenic, and antitumoral.

Researchers examined whether β-caryophyllene acts as a contact sensitizer. The repeated topical application of mice skin with β-CP at 10 mg/mL induced an itch response and dermatitis at 2 weeks in mice, which was sustained for the period of study. Histopathological analysis of skin tissues revealed significant edema and desquamation for β-CP at 10 mg/mL. These findings indicate that skin sensitization risk increases substantially with concentrated, repeated topical exposure—conditions differing substantially from normal dietary intake or standard supplement use.

Copaiba Oil: A Source-Specific Caution

Copaiba resin and essential oil are extremely high in BCP and have been used in traditional South American medicine for centuries. However, copaiba also contains diterpene compounds that research has identified as toxic to the liver. This finding is important for consumers seeking to use copaiba oil as a BCP supplement, as the purified sesquiterpene fraction and the whole oleoresin have differing toxicological profiles.

Oxidation and Stability

BCP's volatility and autoxidation to β-caryophyllene oxide (BCPO) necessitate stability-by-design strategies using antioxidants, low-oxygen processing, and protective packaging. The oxidation product, caryophyllene oxide, is pharmacologically active but represents a chemically distinct entity from BCP itself, and proper storage conditions are necessary to maintain product integrity.

Drug Interactions

BCP's high lipophilicity and low stability in hydrophilic environments limit its therapeutic application. Possible mechanisms of BCP action include the capability to alter levels of mitogen-activated protein kinase (MAPK) and PI3K/AKT/mTOR/S6K1 and STAT3 pathways, which are relevant to oncological drug interactions in the preclinical setting. Formal human drug interaction pharmacokinetic studies have not been published for isolated BCP. Drug: essential oil interactions for BCP are noted as none known in available safety literature, though this reflects a general absence of documented interaction data rather than a confirmed clean interaction profile.

Psychoactivity

BCP is identified as a functional nonpsychoactive CB(2) receptor ligand in foodstuff. Its complete lack of binding to CB1 receptors—the receptor primarily responsible for the psychotropic effects of THC—means BCP does not produce intoxication, cognitive impairment, or dependency associated with classical cannabinoids.

Overall Safety Summary

BCP exhibits coherent CB2-mediated anti-inflammatory, antipruritic, antioxidant, and reparative actions with a favorable safety profile. The preponderance of toxicological data from both regulatory assessment and preclinical studies supports its safety at dietary and low-supplemental doses. The primary documented safety concern relates to high-dose, repeated topical application inducing contact sensitization, and the potential hepatotoxicity of whole copaiba preparations (attributable to their diterpene content, not to BCP per se). Long-term human safety data for supplemental, isolated BCP at therapeutic doses remain sparse, as robust clinical trial data are still limited.

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