Terpenes

Caryophyllene (β-Caryophyllene or BCP)

β-Caryophyllene (BCP or just “caryophyllene”) is one of the most common terpenes found in cannabis and is frequently the predominant terpene overall in cannabis extracts, particularly if they have been processed under heat. Caryophyllene affects cellular and metabolic systems demonstrating antioxidant, anti-inflammatory, improved wound healing, neuroprotective, anti-cancer and analgesic properties. Additionally, caryophyllene decreases neuropathic pain associated with chemotherapy, diabetes, and chronic nerve damage.

B-Caryophyllene – Found in Black Pepper

Contents

 

Links to other Pertinent Educational Pages:

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Links to to Commercial Terpene-Based Products:

Products with beta-caryophylline (BCP):

 

Terpenes:

 

Terpenes  – Therapeutic Benefits:

 

Individual Terpenes:

 

Some β-Caryophyllene-dominant cannabis strains:

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Definitions and Terms Related to Pain

 

Terpenes – Brief Overview

Terpenes are mostly responsible for the aroma of cannabis but they are also responsible for many of the therapeutic benefits of different cannabis strains, especially in combination with the cannabinoids THC and CBD. Terpenes are quite potent when inhaled from ambient air and have been shown to affect human behavior at serum levels less than 10 ng/ml. In fact, although terpenes account for less than 1% in most cannabis plants, terpenes in concentrations above 0.05% are considered potentially pharmacological active.

See: Types of Terpenes and Terpenoids

 

 

Caryophyllene (β-Caryophyllene or BCP)

β-Caryophyllene (or just “caryophyllene”) is one of the most common terpenes found in cannabis and is frequently the predominant terpene found overall in cannabis extracts, particularly if they have been processed under heat for decarboxylation. In nature, β-caryophyllene is usually found together with small amount of its isomers, α-caryophyllene (α-humulene) and γ-caryophyllene or in a mixture with its oxidation product, β-caryophyllene oxide (BCPO).

Beta Caryophyllene is often known as a “dietary cannabinoid” because it is found in commonly ingested foods and is known for its analgesic, anti-anxiety, anti-inflammatory, and anti-bacterial properties. Beta caryophyllene can be ingested directly through the essential oils of cloves, in topical creams and carrier oils and through a terpene isolate of Beta Caryophyllene.

 

β-Caryophyllene in cannabis and other substances

Mainly synthesized by plants as a defense mechanism against insects and aphids while playing a role in pollination, BCP is found in more than two thousand plants including black pepper (Piper nigrum), Copaiba balsam (Copaifera officinalis), clove,  cinnamon, oregano, basil, thyme, coriander, sage, hops and rosemary.

Cannabis strains with prominent amounts of β-caryophyllene include:

    • Grease Monkey (0.23%)
    • Mandarin Cookies (0.24%)
    • Lumpy Space Princess (LSP) (0.12%)
    • Lilac Diesel (0.1%)
    • Planet of the Grapes (percentage not available, β-caryophyllene listed as dominant)
    • Mandarin Zkittles (percentage not available, β-caryophyllene listed as dominant)

 

Amount of Caryophyllene in the essential oils of other substances

Of naturally occurring sources, the essential oil of West African black pepper (Piper guineense) has the highest concentration of β-caryophyllene at 58%.

    • Cannabis, Hemp, Marijuana (Cannabis sativa): 3.8–37.5%
    • Cloves (Syzygium aromaticum): 1.7–19.5%
    • 
Hops (Humulus lupulus): 5.1–14.5%
    • 
Basil (O. micranthum): 4.0–19.8%
    • 
Oregano (Origanum vulgare): 4.9–15.7%
    • 
Black Pepper (Piper nigrum): 7%
    • 
Lavender (Lavandula angustifolia): 4.6–7.5%
    • 
Rosemary (Rosmarinus officinalis): 0.1–8.3%
    • 
True Cinnamon (Cinnamomum zeylanicum): 6.9–11.1%
    • Ylang-ylang (Cananga odorata) [3.1–10.7%]

 

 

How β-Caryophyllene Works

β-Caryophyllene’s multiple mechanisms of action are still being explored but its apparent dominant action is on the endocannabinoid system (ECS). The ECS is a naturally occurring neuro-endocrine network that is present throughout the body, including the brain, nervous system, heart and organs. The ECS regulates many physiologic functions including pain, inflammation, immunity, appetite and metabolism, gastrointestinal function, memory and movement.

The ECS is a network in which cannnabinoids bind with cannabinoid receptors that are on cells throughout the body. Cannabinoids are compounds that are either endogenous (“endocannabinoids” that are naturally manufactured in the body) or phytocannabinoids (found in cannabis plants such as THC and CBD).  When a cannabinoid binds with a receptor, it triggers a physio-chemical response particular to the type of receptor and the cell it is on. 

The dominant mechanism of action of β-Caryophyllene is as an agonist that binds to cannabinoid-2 receptors (CB2) which are present in the brain and nervous system but are predominantly found peripherally, outside the brain and nervous system. Some consider β-Caryophyllene to be a cannabinoid because it strongly binds to CB2 receptors as a functional agonist although it does not bind to CB1 receptors.  β-Caryophyllene oxide (BCPO) and α-humulene, isomers of BCP, do not bind with CB2 receptors and exert their pharmacologic effects through different mechanisms.

β-Caryophyllene as a CB2 Agonist

The CB2 receptor is the primary peripheral receptor for cannabinoids and is mainly expressed in immune tissues where it has been shown to regulate immune cell functions. The CB2 receptor is involved in many physiologic activities suggesting that BCP may offer potential for a multitude of therapeutic benefits. Of particular note, BCP inhibits inflammation and edema and also has analgesic effects.

In addition to its actions at CB2R, other BCP targets includes sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ, GABAergic signaling factors, transient receptor potential cation channel subfamily V (TRPV), fatty acid amide hydrolase (FAAH), and cyclooxygenase-2 (COX-2).

See: CB2-related mechanisms of action of BCP  (from: “A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid” Hebaallah Mamdouh Hashiesh et.al

 

Anti-inflammatory Properties of BCP

Growing research shows that BCP exerts potent anti-inflammatory properties in all body organs, including the liver, kidneys, brain, heart, pancreas, and blood. It suppresses systemic inflammation by inhibiting pro-inflammatory cytokines in macrophages and other inflammatory mediators.

BCP has been gaining attention for its benefit in reducing inflammation in the lungs via its action on macrophages, particularly as a means of reducing the cytokine storm, the massive inflammatory reaction which triggers fatal lung damage in COVID. It holds promise in other pulmonary inflammatory conditions as well. Additionally, due to its antiviral and antibacterial activities, BCP may be beneficial for secondary lung infections.

In the gastrointestinal tract, CB2 receptor agonists have been shown to reduce inflammation in colitis, suggesting a possible role for BCP in suoppressing flares of inflammatory bowel diseases including Crohns. The CB2 receptor is also a potential target for the treatment of atherosclerosis and osteoporosis.

 

Non-Alcoholic Fatty Liver Disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by hepatic steatosis (fatty liver), inflammation and cell damage. Conditions such as obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension, which make up metabolic syndrome, are one of the risk factors of NAFLD.  In preclinical animal studies, BCP has a cholesterol (LDL)-lowering effect and also increases high density lipoprotein (HDL), reducing liver injury and fibrosis, restoring liver function enzymes and improving antioxidants, thus suggesting a possible benefit for fatty liver disease.

Chronic and Binge Alcohol-induced Liver Disease

BCP also reduces chronic and binge alcohol-induced liver injury and inflammation in lab studies. Considering its liver protective roles, BCP could be promising in conditions of liver injury associated with drug toxicity and infection.

 

Kidney Diseases

 BCP reduces acute kidney injury in experimental models by lessening renal impairment and tubular injury, reducing kidney inflammation, oxidative stress  and preserving kidney cells via activation of CB2 receptors. BCP  has shown  protective effects against drug induced-acute kidney injury as well as diabetic and chronic kidney diseases by restoring function and suppressing oxidative stress and inflammation.  BCP also suppresses renal inflammation and oxidative stress by regulating NF-κB/Nrf2 signaling pathways in diabetic kidney diseases. This is the same mechanism by which curcumin, catechins (green tea) and other NRF2 activators act, suggesting a synergistic effect possible by combining curcmin with BCP.

 

COVID-19

Given the increased risk of pulmonary, liver and renal dysfunction in COVID-19 along with  the worsening of conditions in patients with chronic kidney or diabetic kidney disease, BCP may be a valuable supplement in preventing organ dysfunction in patients with COVID-19, especially the cytokine storm that contributes strongly to severe COVID disease and death. See:COVID CAM Treatment

Regarding long-term complications in some patients even after recovery from COVID-19, given the tissue protective effects, BCP could be a candidate to be investigated for possible use in improving prognosis and combating the long-term complications in COVID-19.

 

Oxidative Stress and the Antioxidant Properties of BCP

Besides the immune-inflammatory changes, macrophages and neutrophils produce many reactive oxygen species which further promotes oxidative stress.  Reactive oxygen species (ROS) is a generic term used for a variety of molecules derived from oxygen that react with biomolecules by oxidizing them, a destructive process.  ROS are widely believed to cause or aggravate many human pathologies such as neurodegenerative diseases, diabetes, high blood pressure, heart disease, cancer, stroke and many other ailments.  

“Oxidative stress” is an imbalance in the body of excessive “oxidants” (oxidizing or chemically active, agents, including free radicals obtained from the diet or produced by the body) and insufficient “antioxidants” (chemically active agents that are also obtained from the diet or produced by the body) and neutralize oxidants. This overabundance of oxidants causes damage to biomolecules, (lipids, proteins, DNA), cells and tissue, eventually contributing to aging and many chronic diseases including chronic inflammation, arthritis and pain, atherosclerosis, cancer, diabetes, heart diseases and stroke.

BCP builds tolerance against stress by improving antioxidant power. It reduces oxidative stress by counteracting ROS generation, inhibiting lipid peroxidation and glutathione depletion, free radical scavenging, and augmenting the endogenous antioxidant defense in the tissues of different organs, such as the heart, brain, intestine, stomach, pancreas and blood.

Both oxidative stress and mitochondrial dysfunction are essential hallmarks of the early pathological mechanisms of aging and neurodegenerative disorders, i.e., Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Findings from different experimental models of Parkinson’s disease and Alzheimer’s disease report the beneficial effects of BCP, suggesting that its use in treatments may be a promising strategy in the management of neurodegenerative diseases aimed at maintaining mitochondrial homeostasis and ameliorating glia-mediated neuroinflammation.

Research suggests that β-caryophyllene has the neuroprotective capability through decreasing oxidative stress and stabilizing mitochondria. BCP can readily cross the BBB and accumulate in brain regions, giving rise to neuroprotective effects by preventing mitochondrial dysfunction and inhibiting activated microglia, substantially through the activation of pro-survival signalling pathways, including regulation of apoptosis and autophagy, and molecular mechanisms related to mitochondrial quality control. Besides CB2 receptor agonism, β-caryophyllene has been found to positively regulate PPAR-γ, TLRs and neuroimmune pathways, as possible targets implicated in the protection against neuronal loss.

The available data is not sufficient to draw any clinical conclusion for the recommendation of β-caryophyllene in the management of neurodegenerative disorders, in particular regarding the most effective doses, or the potential benefits of β-caryophyllene in targeting mitochondria in neurodegenerative diseases.

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Other Mechanisms of Action of BCP

It is proposed that BCP also offers therapeutic effects by activating the nuclear receptors, peroxisome proliferator-activated receptors (PPARs). Additionally BCP also acts on other receptors in the skin including TRPM1, TRPM6, TRPV4, TRPV6 and TRP8. BCP modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Based on these pharmacological properties and molecular mechanisms, BCP may have therapeutic potential to modulate the immune system with anti-inflammatory, organ-protective, and anti-viral properties.

Bioavailability of β-Caryophyllene

Bioavailability refers to the proportion of a drug or other substance which enters the blood circulation when introduced into the body via inhalation, through the skin or through ingestion. Both BCP and BCPO are sesquiterpenes, a class of terpenes with more complex molecular formulas compared with the monoterpenoids (pinene, carene, myrcene and limonene) which contributes to a lower solubility in water and biological fluids which in turn limits BCP and BCPO absorption into cells. This may affect the therapeutic effectiveness of BCP and BCPO when ingested orally. This poor water solubility of BCP and BCPO may be overcome with use of liposomal drug delivery systems, which provide much higher bioavailability of these compounds to ensures obtaining desired therapeutic effects. Inhaled and topical applications of BCP and BCPO have high bioavailability and should allow for their effectiveness when administered in these ways.

 

Metabolism of BCP

The metabolism of BCP and BCPO is poorly understood.

 

Oral Use of BCP

Studies in humans are lacking regarding oral use of BCP for therapeutic purposes although it is “generally recognized as safe” by the FDA as a food additive. In preclinical studies with mice the chronic oral administration of BCP has been shown to reduce neuropathic pain, including thermal hyperalgesia (excessive pain perception) and mechanical allodynia (inappropriate perception of pain in response to a stimulis that should not be painful). BCP also reduces spinal neuroinflammation, the condition that is the basis of acute pain transitioning to chronic pain. No signs of tolerance to the anti-hyperalgesic effects of BCP over 2-weeks of treatment were identified in the mouse study but, on the contrary, the BCP effect became stronger during the treatment period. Given the potentially limited bioavailability of oral BCP and BCPO, studies are needed to determine effective oral dosing.

The question to be considered now is what dose is relevant to humans? Based on an effective dose in mice estimated for the human equivalent dose for a 132 lb adult, the average daily BCP intake would be in the range of 10–200 mg. This dose would be sufficient for significant CB2 cannabinoid receptor activation. It has also been estimated that BCP is commonly ingested with vegetable foods, including spinach and chard, at an estimated daily intake of 10–200 mg. This could be a dietary factor that potentially modulates inflammation. Human studies are needed.

Oral Bioavailability

β-caryophyllene is characterized by high lipophilicity and poor stability in hydrophilic media (biological fluids), which limit its bioavailability and absorption into cells. Bioavailability depends on the nature and chemical-physical properties of a molecule and is mainly due to water solubility (or dissolution rate) and membrane permeability. Drugs that are poorly water-soluble have low bioavailability which hinders their clinical application.

Liposomal and Micro-Emulsified β-caryophyllene

Various strategies that include the use of complex formulations such as micelles, liposomes, micro-emulsified polymeric nanoparticles and lipid nanoparticles have been approached. Among them, liposomes have been the most extensively adopted for natural compounds, such as terpenes including β-caryophyllene,  due to their excellent biocompatibility and biodegradability, low toxicity and lack of immunogenicity. Liposome structure allows the incorporation of different types of drugs: hydrophilic substances are encapsulated in the inner aqueous compartments, while lipophilic drugs are mainly entrapped within the lipid bilayer. Other natural compounds that incorporate liposomal formulations include PEA and curcumin.

Inhaled Use of BCP

Studies evaluating inhalation of BCP in mice determined that after inhalation volatile BCP is distributed into the brain via blood circulation. It is also possible that nasally inhaled BCP may also distribute directly into cerebrospinal fluid as well as blood. Inhaled BCP was also noted to distribute largely to the liver where it may increase the level of glutathione and thereby increase liver antioxidant capacity.  It was noted that upon entering the blood the half-life of BCP was 134 min.

Of interest it should also be noted that the olfactory nerve receptors believed to be involved in the therapeutic effects of nasally inhaled substances such as BCP are also found in the intestines, suggesting an alternative mechanism for therapeutic effect with ingested BCP and other terpenes. Additional pharmacokinetic studies need to be performed in humans but remain lacking.

Boiling Point of β-Caryophyllene: 266• (F), 130• (C)

When vaping a cannabis strain with BCP one would want to set the temperature of the vape device to about 280″ (F) to get the most benefit from this terpene. Temperatures achieved with smoking should be sufficient to allow full availability of the BCP. 

 

Topical Use of BCP

BCP applied topically reduces pain and inflammation and is proposed to improve wounds re-epithelialization and healing.

Pain receptors (nociceptor) terminate in the skin as sensory nerve endings that are stimulated by direct contact with injured tissue.  There is a great variety of receptors and inflammatory agents in the skin which play a role in pain reception (nociception). In the epidermis, sensory nerves interact with non-nerve cells found in the skin such as keratinocytes and mast cells. These non-nerve cells release substances which stimulate pain receptor nerve endings.

Cannabinoid-2 receptors (CB2) are present throughout the skin in nerve cells, immune tissue, hair follicles, sebaceous oil glands, the dermo-muscular layer in the dermis, vascular smooth muscle and are abundant in keratinocytes. BCP suppresses neuropathic pain through activation of CB2 receptors.

It is proposed that BCP activation of CB2 receptors reduces pain sensitization by suppressing the production of sensitizing factors released from neighboring mast and immune cells. Another proposed mechanism is that CB2 receptor stimulation triggers local release of β-endorphin from cells in the skin (keratinocytes). Endorphine are the natural opioids made in the body which suppress pain by activating local μ-opioid receptors.

Although it is not clear which receptors are most involved in BCP’s therapeutic benefits, BCP also acts on other receptors in the skin including TRPM1, TRPM6, TRPV4, TRPV6 and TRPM8 as well as adrenoceptors, voltage-gated sodium channels, temperature-sensitive transient receptor potential ion channels (TTRP), substance P and inflammatory markers such as caspase-1 and interleukin receptors. There is growing preclinical evidence to support the possibility that topically applied BCP may suppress the impact of cold-induced pain.

 

Topical BCP and Fascia

Topical application of CBD and BCP has been shown to be very effective in reducing muscle pain. Muscle pain can be generated from pain receptors located in muscle but also in fascia tissues which surround muscles.

Fascia is a dense connective tissue primarily composed of fibroblasts and collagen fibers. Although fascia tissue consists predominantly of an extracellular matrix of these fibrous tissues, there are also several other cells present: fat cells (adipocytes), endothelial cells of blood vessels, nerve terminals and various migrating white blood cells (i.e., mast cells).

Both CB1 and CB2 receptors have been identified in fascial tissue, suggesting a mechanism of analgesic benefit for muscle with BCP through its activation of CB2 receptors.

The activation of CB1 and CB2 receptors suppress pro-inflammatory cytokines such as TNF-alpha and to increase anti-inflammatory cytokines, and provide an anti-fibrotic activity. Consequently, the CB1 and CB2 receptors of fascial fibroblasts could represent a new target for drugs to care fascial fibrosis and inflammation.

Topical BCP Products commercialy available.

 

Therapeutic Properties of β-Caryophyllene

Our understanding of the therapeutic benefits offered by Carophyllene is based almost entirely “preclinical” research, which consists of studies performed in a laboratory (in vitro) and/or animal studies. Preclinical research indicates that BCP has anti-inflammatory, analgesic and anti-cancer properties and also facilitates wound healing. Early research suggests potential benefit for substance abuse of alcohol and cocaine. Unfortunately, clinical research with humans is still very limited in all these regards.

 

Pain and Inflammation & β-Caryophyllene

Anti-inflammatory activity

β-Caryophyllene’s anti-inflammatory activity is comparable in potency to phenylbutazone, etodolac and indomethacin. BCP is often used in topical anti-inflammatory ointments and salves. In contrast to NSAIDs, however, caryophyllene protects the stomach lining  and has been claimed to be effective in treating duodenal ulcers in the United Kingdom. Tissue inflammation enhances pain sensation through the sensitization of pain receptors (nociceptors) which are peripheral nerves that respond to painful stimuli, and also through sensitization of spinal nerves which leads to enhanced transmission of pain signals to the brain. The resulting allodynia and hyperalgesia of the inflamed tissue also contributes to the recuperative process in that pain sensation typically reverts to normal levels as the inflammatory response resolves.

The anti-inflammatory properties of BCP have been extensively shown in different mouse models of disease. A recent study shows that BCP synergizes with curcumin in exerting anti-inflammatory activity in an experimental in vitro model of osteoarthritis, strongly suggesting the potential benefit of a dual combination of these two compounds for the management of osteoarthritis. This curcumin synergy has also been found with the catechins found in green tea. Similar to curcumin, carophyllene suppresses inflammation by reducing levels of IL-1β, IL-6, through activity at  prostaglandin PGE-1 and at the NLRP3 inflammasome. 

Anti-oxidant activity and Oxidative Stress

Curcumin

Studies have also shown that both β-Caryophyllene and curcumin up-regulates Nrf2 activity to protect cells from oxidative damage. Nrf2 (nuclear factor erythroid 2) is a transcription factor that is involved in cellular responses to oxidative damage and inflammation.

See: Nrf2 Activators.

 

Neuroinflammation and Central Sensitization

Development of neuropathic pain is accompanied by the activation and proliferation of glia cells, immune cells in the spinal cord responsible for the development of neuroinflammation. Caryophyllene is thought to be effective against neuroinflammation by reducing activity of glial cells.

Central Sensitization

Central sensitization plays a pivotal role in the transition from acute to chronic pain. Hallmarks of central sensitization include the manifestation of altered pain responses, such as painful hypersensitivity (mechanical allodynia and hyperalgesia). Neuroinflammation involving spinal neuronal facilitation and the activation of spinal microglia and astrocytes plays a fundamental roles in these processes.

Pre-clinical evidence shows that activation of CB2 receptors inhibits central sensitization and its contribution to the manifestation of chronic arthritis pain. These findings suggest that targeting CB2 receptors may have therapeutic potential for treating arthritis pain.

 

 Inflammatory Bowel Disease

In the gastrointestinal tract, activation of CB2 receptors has been shown to prevent experimental colitis by reducing inflammation, suggesting the potential benefit of BCP for use in Crohn’s disease and ulcerative colitis.

 

 

Anti-Cancer Properties of β-Caryophyllene

Both sesquiterpenes BCP and BCPO have cytotoxic activities against several types of cancer cells including human cervical adenocarcinoma cells, leukemia cancer cells, lung cancer cells),  gastric cancer cells and stomach cancer cells. Aside from their direct anticancer activities, BCP and BCPO may also enhance the effectiveness of traditional anticancer drugs, such as paclitaxel and doxorubicin.

 

 

 

Conditions that may benefit from β-Caryophyllene:

Pain

Early animal research in rats/mice have identified β-caryophyllene (BCP) as a selective full agonist at the cannabinoid receptor type 2 (CB2). In inflammatory hyperalgesia, indirect pain inhibition through CB2 receptors on mast and immune cells is possibly achieved by the reduction of prostanoids or cytokines release, which are responsible for peripheral nociceptor sensitization. Additionally, BCP activation of CB2 receptors on keratinocytes (superficial skin cells) stimulates the release of endogenous opioids, the β-endorphins. When combined with morphine, this provides an increased synergistic analgesic benefit.

 

CB2 is critically involved in the modulation of inflammatory and neuropathic pain. Based on animal studies, orally administered BCP reduces inflammatory pain and neuropathic pain. It has been shown to exhibit analgesic effects in neuropathic pain associated with chemotherapy, diabetes, and chronic nerve damage.  Chronic oral administration of BCP may reduce thermal hyperalgesia, mechanical allodynia and spinal neuroinflammation. No signs of tolerance to these effects after prolonged treatment have been identified.  This suggests BCP may be highly effective in the treatment of long lasting, debilitating pain states although additional studies are needed in humans.

 

Muscle Pain and Soreness

Delayed onset muscle soreness (DOMS) and damage to muscles occurs as a result of intense exercise and activity. This muscle soreness is painful and also decreases power and performance capacity.

 

The oral consumption of BCP (Rephyll, see Nootropics Depot below) significantly reduced the pain scores in a study evaluating DOMS which demonstrated that Rephyll has potential for preventing DOMS. The improved recovery of pain intensity and muscle injury without any side effects showed that the product Rephyll may be an alternative supplement for pain management.

 

Osteoarthritis (OA)

Osteoarthritis (OA), otherwise known as degenerative arthritis, is the form of arthritis associated with aging. Until recently, OA had been considered solely a “wear and tear” disease, where cartilage degeneration caused by age and/or obesity cause the disease. However, recently the understanding of OA also emphasizes an inflammatory component that may develop early in the progression of the disease, not just in late stages. 

Joint inflammation is associated with influx of immune cells that produce inflammatory compounds (cytokines) that drive the production of enzymes such as matrix metalloproteinases (MMPs) that play key roles in the breakdown cartilage. Elevated levels of several pro-inflammatory factors can be found in OA patients in comparison to those of healthy individuals, however the levels are lower than those in Rheumatoid Arthritis (RA) patients.

The wear and tear breakdown of joint tissues enhanced by inflammatory influences damage the  cartilage as well as the bone underlying the cartilage and leads to inflammation of the synovium (synovitis), the soft tissue that lines the spaces of joints, tendon sheaths and bursae. The synovium produces synovial fluid that functions as a lubricant as well as a vehicle through which nutrients and regulatory substances bathe the cartilage.

 

The cannabinoid receptors CB1 and CB2 are located on sensory nerve terminals innervating synovial joints and their activation reduces nociceptor firing and pain. Cannabinoid receptor-mediated analgesia is achieved by a retrograde signaling process resulting in inhibition of pro-algesic neurotransmitter release from nociceptor terminals. Both cannabinoid receptors have also been located on immunocytes where they can induce both pro- and anti-inflammatory responses. In joints, cannabinoid receptor activation locally can alter synovial blood flow, leukocyte trafficking, and joint edema.

 

There is strong evidence for pain and inflammation reduction by CB2 receptor modulators in arthritis.  CB2 receptors are heavily distributed in the immune cells in joints that produce  inflammatory cytokines as well as having a large presence in joint cartilage and underlying bone. Activation of CB2 receptors by CB2 agonists have been shown to reduce pro-inflammatory cytokine and MMPs production in synovial fluid and reduce the breakdown of cartilage and bone. BCP, a CB2 agonist, has been shown in animals to protect against the breakdown of cartilage by reducing levels of MMPs and pro-inflammatory cytokines that contribute to OA as well as to increase anti-inflammatory cytokines to reduce inflammation and suppress pain.

If human studies substantiate these benefits,  BCP will be the first treatment for OA to actually slow the progression of the disease process (disease modification) as well as reduce pain. It stands to reason that BCP may be most beneficial when treatment is prolonged and begins in the early stages of OA. Of note also, BCP does not appear to develop tolerance related to the analgesic pain benefits with OA.

 

Rheumatoid Arthritis

Synovial tissues in joints with rheumatoid arthritis (RA) reportedly have more CB2 receptors than synovial tissues in joints with degenerative arthritis (osteoarthritis (OA), suggesting greater effectiveness and potency of CB2 activation with BCP in RA patients. Also, in RA, neutrophils are found in very high numbers in the joint synovium whereas neutrophils are absent in the synovial fluid in patients with OA. Elevated cytokine levels are thought to play a major role in the induction of neutrophil infiltration to the synovium in RA and BCP is known to inhibit migration of neutrophils.

Elevated cytokine levels are thought to play a major role in neutrophil infiltration to the synovium. Although neutrophils are absent in the synovial fluid in patients with OA, inflammatory cytokines, chemokines, and other inflammatory markers are found in pathogenic concentrations in the synovial fluids. While inflammation is a hallmark of OA, it is not its cause, unlike RA.

A 2020 placebo-controlled clinical study, patients with hand arthritis, both RA  and OA, applied BCP topically and BCP was found to be safe, well tolerated, and beneficial in reducing pain and inflammation.

 

 

β-Caryophyllene: Cold Weather and Wild Giant Pandas

The TRPM8 receptor on sensory nerves in the skin become activated upon exposure to cold, triggering the sensation of feeling cold.  This receptor may be triggered environmentally by exposure to cold or chemically by exposure to compounds such as menthol.  β-caryophyllene inhibits cold-activation of these receptors and suppresses the perception of feeling cold which helps to improve cold tolerance at low temperatures.

In fact, studies have shown that in cold weather, giant pandas roll in fresh horse manure which is rich in β-caryophyllene as a means of adapting to the cold!  As of yet, studies to assess how effective topical β-caryophyllene may be in humans for tolerating cold weather, or reducing the impact of cold weather on pain remain lacking. 

That being said, it has also been shown that functional impairment of the TRPM8 receptor will diminish the vascular response to cold weather. When environemental temperature drops below about 70 degrees F, the superficial blood vessels will normally begin to constrict as a means of preserving heat and body temperature.

For example, it has been shown that with advancing age, the elderly have an impaired vascular response to cold, making them less able to maintain their normal body temperature which in turn makes them more susceptible to cold weather injury. As such, with application of topical BCP one may perceive less discomfort in cold weather but additional care must be taken to preserve body heat in cold environments.

Ironically, stimulation of the TRPM8 receptor with application of menthol or ice provides an analgesic effect, thus the popularity of topical creams with menthol such as Biofreeze and Icy Hot.

While it is the TRPM8 receptor that is sensitive to environmental cold, it is not clear if activation of this receptor is also responsible for the downline experience of exacerbation of chronic pain during cold weather as is commonly. experienced by most individuals with chronic pain who almost uniformly complain of worsentngj joint and deep tissure pain.

 

Diabetic Neuropathy

BCP was administered as dietary supplement composed of a mixture of β- caryophyllene, myrrh, carnosic acid) and PEA to 25 diabetes patients with diabetes-related complications of painful distal symmetric polyneuropathy. It was found to relieve polyneuropathy  pain with good tolerance and no adverse effects (Semprini et al., 2018).

 

β-Caryophyllene: Paclitaxel-induced Peripheral Neuropathy (PINP)

Painful peripheral neuropathy is a common side effect of paclitaxel (PTX), a chemotherapy medication used to treat a number of types of cancer. However, currently employed analgesics have several side effects and are poorly effective. β-caryophyllene (BCP), a selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain is not yet known. A 2017 study in mice receiving PTX indicated that BCP reduced nerve pain sensitivity to mechanical stimulation (allodynia) induced by the PTX possibly through CB2-activation in the CNS and inhibition of inflammatory cytokines. These results suggest that BCP might be useful in treating the nerve pain associated with PINP.

 

Headaches

Anecdotal reports indicate Copaiba oil (55% BCP) can be used directly on the temples, back of the neck or other places involved in headaches. It also be used internally for headaches or migraines, using 3 drops about 3 times a day.

 

Insulin Resistance, Diet-induced Dyslipidemia and Vascular Inflammation

BCP has been shown to have selective agonistic activity to CB2 receptors and peroxisome proliferator-activated receptors, notably PPAR-α. A recent 2019 study found that BCP reduces also actss via PPAR-γ receptors. In rats fed a high-fat diet and 10% fructose for 12 weeks, BCP significantly improved blood sugar, dyslipidemia, and vascular oxidative stress and inflammation. It has been suggested that BCP may represent a more potent alternate with less side effects to pioglitazone, a diabetes drug (also called “glitazones”) used to control high blood sugar in patients with type 2 diabetes.

 

β-Caryophyllene: Wound Healing

β-caryophyllene may improve wound healing and reduce scarring, although it is not clear whether it does so via olfactory receptors or other receptors in the skin. Topical application of β-caryophyllene on cutaneous wounds can improve re-epithelialization, but β-caryophyllene activates several different types of receptors other than olfactory receptors, so this improved re-epithelialization may be mediated by activating other routes.  β-caryophyllene acts on the cannabinoid receptors 2 (CB2) in the skin but also on TRPM1, TRPM6, TRPV4, TRPV6 channel receptors, suggesting the possibility of the involvement of these channels in improving wound healing.

 

Peptic Ulcers

BCP given orally at a dose of 126 mg/day was evaluated in patients with peptic ulcer in a randomized double-blind, placebo-controlled trial (Shim et al., 2019). BCP improved dyspepsia symptoms by reducing Helicobacter pylori infections, improving nausea and epigastric pain, and inhibiting proinflammatory cytokines.

 

β-Caryophyllene: Depression and Stress

β-caryophyllene shows promise for treating depression and stress related mental illnesses due to its direct binding to CB2 receptors.

 

β-Caryophyllene: Diabetes and Associated Complications

Preclinical studies show underlying mechanisms of BCP in skeletal muscles, adipose tissues, liver, and pancreatic β-cells that suggest BCP has the capability to increase insulin secretion, insulin sensitivity, glucose uptake and reduce glucose absorption. Additionally it may reduce levels of triglycerides and cholesterol.

 

Based on the health benefits, low toxicity, relatively safety in humans use with plausible pharmacological activity and molecular mechanisms, BCP appears to be a promising candidate for use in insulin resistance, T2DM, obesity, hyperlipidemia, and diabetic complications. BCP has potential for use as an adjuvant to reduce the doses of the currently used medications and  synergistically enhance therapeutic effects. However, further studies are required to explore these preclinical studies towards offering therapeutic benefits in humans.

 

 

β-Caryophyllene: Multiple Sclerosis

Multiple sclerosis (MS) is a severe inflammatory demyelinating disease of the central nervous system (CNS). It affects over two million people worldwide although the cause of MS is  not completely understood. However, studies with MS patients suggest that the demyelination associated with MS in the CNS results from a T cell-mediated autoimmune response. Due to growing research indicating that some of the constituents found in cannabis possess anti-inflammatory properties and may suppress certain functions withing the immune response, research is focusing on cannabis use to treat MS.

In an investigation published in 2017 to evaluate the therapeutic potential of BCP in an experimental animal model of multiple sclerosis (MS),  it was found that BCP significantly reduces both the clinical and pathological features of the animal model. The mechanisms underlying BCPs immunomodulatory effect appears to be linked to its ability to inhibit microglial cells, CD4+ and CD8+ T lymphocytes and pro-inflammatory cytokines. Furthermore, it reduce axonal demyelination  through the activation of CB2 receptor. The study has important implications for clinical research and strongly supports the effectiveness of BCP as a possible molecule to target in the development of effective treatment for MS.

 

β-Caryophyllene: Alcohol and Cocaine Abuse

Research also suggest that CB2 receptors play a major role in alcohol reward and the CB2 receptor system may be involved in alcohol and cocaine dependence via modulation of dopamine reward pathways. In mice, β-caryophyllene has been shown to reduce voluntary alcohol intake as well as decrease cocaine self-administration. It may therefore represent a potential pharmacological target for the treatment of alcohol and cocaine abuse.

 

β-Caryophyllene: Other Potential Therapeutic Benefits

BCP is believed to be a neuroprotective,, antioxidant, and anticonvulsive agent with antiviral and antibacterial activities as well as being able to improve lipid profiles, alleviate endometriosis, and show promise for interstitial cystitis and protection against nonalcoholic fatty liver disease.

 

 

Caryophyllene: Products

Despite its promising biological activities, β-caryophyllene is characterized by high lipid solubility but poor solubility in water-based media such as biological fluids, which limits its bioavailability and absorption into cells. The poor solubility of this terpene in water-based fluids can hinder its uptake into cells, resulting in inconsistent therapeutic effects, thus limiting its application. BCP, upon exposure to air, is easily oxidized.

 

To overcome its low bioavailability, many novel drug delivery systems have been developed. Various kinds of formulations, such as liposomes, nanoemulsions, nanofibers, microemulsions, nanoparticles, micelles, phospholipid complexes, nanocarriers, nanocomposites, hydrogels, and matrix formulations using cyclodextrin, have been developed to enhance the solubility, stability, and release pattern of BCP.

β-caryophyllene’s absorption is improved when it is delivered in an oil-based medium but new products have been developed in which the β-caryophyllene is enveloped in a fatty layer (liposomal) and/or nanosized  to enhance its bioavailabity when delivered in aqueous media. Examples of BCP products offering these improved delivery systems includeNootropics Depot oral products (Rephyll) and CarolinaCannabinoidsCBD with terpenes products containing BCP (see below).

 

Over-the-Counter (OTC) Products

Topical BCP Products

Because β-caryophyllene is generally considered safe, it is available in over-the-counter (OTC) products. A particularly useful formulation for β-caryophyllene is in topical creams because there are many CB2 receptors as well as TRPM8 receptors in the skin allowing for potentially effective treatment of nerve pain and cold sensitivity respectively.

 

AliceCBD.com

AliceCBD.com offers multiple product with BCP, oral and topical. Of special note is a topical CBD/BCP salve with both CBD and BCP that is available in a trial size for only $2. Additional CBD and other cannabinoid-based products are available.

 

TullaBotanicals.com

TullaBotanicals.com offers multiple topical product with BCP. Of special note is “Soothe,” a topical cream which combines a high concentration BCP with PEA (palmitoylethanolamide) for pain relief. Additionally, a roll-on product is available for pain relief as well as “Mend,” a first aid balm to facilitate healing.

 

True Terpenes

True Terpenes is an excellent source of terpene isolates, both as individual isolates as well as mixed isolates formulated to mimic blends associated with specific cannabis strains.

 

doTERRA Copaiba essential oil (reportedly 55% BCP)

Direct Effects™ Topical β-Caryophyllene (? available)

As part of a patent process regarding topical therapy with β-Caryophyllene, it was reported that 30 mg of β-caryophyllene applied to the back of neck, spinal regions or at peripheral areas of neurological dysfunction provided relief and benefit for the following conditions within 10 to 15 minutes of topical application:

      • Muscle Tension & Spasm
      • Peripheral Neuropathic Pain
      • Post-Herpetic Neuralgia/Zoster

      • Tinnitus/Ringing in Ears

      • Trigeminal Neuralgia

      • Blepharospasm

It was reported that the duration of therapeutic effect ranged from a few hours to an entire day, depending on condition treated; and its severity and duration. The only side effects reported were occasional tingling and slight transient burning sensation following topical cream application. There was a rare headache. Rash or irritation at the site of application was experienced in less than 5% of patients treated. Because of its non-systemic nature, no systemic side effects or drug-drug interactions were observed.

 

Oral BCP-Only Products

Nootropics Depot  250 mg capsules with 6% BCP  (equal to 15 mg BCP)

Nootropics Depot powder with 6% BCP

doTERRA Copaiba Essential Oil 120 mg Softgels (?? % BCP)

 

Products combining CBD and β-Caryophyllene:

There is evidence that combining  CBD and β-Caryophyllene may have a synergistic benefit, called the “Entourage Effect” in which the two together will work better than either by themselves.  Selection of a CBD/terpene product can be challenging since identifying the terpenes and their amounts in a product is often difficult or impossible unless one can obtain a certificate of analysis of the product from the manufacturer. One recommended line of CBD products with terpenes is “CarolinaCannabinoids.”

 

Included in the CarolinaCannabinoids line of products are those that provide broad spectrum formulations (with no THC) and 30 mg CBD/ml, with a full profile of terpenes high in BCP and beneficial for pain, anxiety and sleep. In addition, they offer full spectrum formulations (with <0.3% THC) that contain 100-200 mg CBD/ml. Importantly, these stronger formulations also utilize a Self Micro Emulsifying Delivery System (SMEDS) that enhances the bio-availability of all the included cannabinoids and terpenes, including CBDA and β-caryophyllene.

 

Self-Emulsifying Delivery Systems (SMEDS)

Self Micro Emulsifying delivery systems (SMEDS) increase the oral bioavailability of poorly water-soluble drugs by multiple mechanisms in concert including:

      1. Improvement in drug’s solubility
      2. Reduced intra-enterocyte metabolism by CYP P450 enzymes
      3. Reduced P-glycoprotein (P-gp) efflux activity
      4. Reduced hepatic first-pass metabolism bypass via lymphatic absorption

 

 

Prescription BCP Products (Cannabis-based)

Topical

In addition to OTC products, prescription cannabis-based products that also contain THC are available in LA, including “Soothe” by Ilera.

 

Caryophyllene: In Food

β-caryophyllene is commonly ingested with vegetables, and an estimated daily intake of 10–200 mg of this terpene could be a dietary factor to benefit inflammation and other pathophysiological processes.

 

β-caryophyllene can be obtained in the diet by including fresh, aromatic herbs such as clove, black pepper, rosemary, cinnamon, and basil. Other source foods include carraway, hops, lavender, and sage. Chai, a spicy tea which usually blends tea with cinnamon, black peppercorns, clove, and ginger, is a good source of BCP.

 

β-Caryophyllene Oxide (BCPO)

This terpenoid is an oxidation metabolic byproduct of beta-caryophyllene and is found in dried hemp. Like BCP, β-caryophyllene oxide (BCPO) is also found in eucalyptus, lemon balm, cloves, basil, oregano, black pepper, rosemary, and hops. It has a characteristic herbal flavor and a woody aroma and it is said that this terpene is one that allows sniffing dogs to recognize cannabis because of its strong scent.

 

BCPO’s therapeutic benefits have not been well studied but it is purported to have anti-inflammatory and pain-relieving properties as well as anticancer activity by suppressing growth and proliferation of numerous cancer cells. β-caryophyllene oxide does not bind to CB1 or CB2 receptors.

While BCP binds to peripheral cannabinoid receptor type 2 (CB2) leading to β-endorphin release from keratinocytes and activation of opioid receptors, the analgesic benefits of BCPO may be obtained by inhibition of central pain receptors.

 

Caryophyllene: Synergy with Other Compounds

BCP Synergy – CBD

Topical cannabinoids have anti-inflammatory, anti-itching, analgesics, wound healing and anti-proliferative effects on the skin. Research has identified many skin conditions that benefit from topical application of CBD including aging skin, dry skin, eczema, psoriasis and wound healing.

Evidence supports that CBD and BCP work in combination via inflammatory mechanisms to produce safe therapeutic benefits superior to the individual effect of CBD and BCP. This is particualarly true for pain benfits.

Various potential mechanisms may contribute to the synergistic interaction between CBD and BCP. CBD acts on the TRPV1 receptor (transient receptor potential vanilloid 1) and the 5-HT1A receptor (serotonin 1A receptor) while BCP is a selective CB2 receptor agonist. A potential cross-talk between these receptors and, consequently, enhancement of their down-stream signaling may play a role in the synergistic analgesic effects of this combination. Pharmacokinetics interaction between CBD and BCP may also play a role.

In a study published in 2013 evaluating CBD combined with BCP in an animal model of spinal cord injury, (SCI) additive and synergistic pain benefits were identified. It is currently believed that SCI pain involves both neuropathic and inflammatory components, as anti-inflammatory mediators in spinal cord tissue and surrounding CSF are markedly increased following this injury. A reduction in a phantom limb pain model was noted by CBD/BCP along with reduced spinal inflammatory markers. However, these benefits were blocked by CB1 but not CB2 antagonists, implying that additional mechanisms are involved with this synergistic action of BCP combined with CBD.

The authors suggest the possibility that there are spinal cord injury-induced changes in cannabinoidergic pain processing leading to increased sensitivity to dorsal horn CB1 mediated effects that may, directly or indirectly via downstream effects, activate novel upregulated antinociceptive CB1 sites or induce changes in endocannabinoid levels. Upon further evaluation the authors determined that CBD alone produces little effect and BCP alone produces marginal effect on CB1 receptors but the combination of CBD and BCP appears to enhance CB1 activity. It was proposed that CBD/BCP may allosterically facilitate one another’s effect on CB1 receptors, supporting theoretical contribution of CB1 receptor activation, at least in part, to SCI antinociceptive effects. It was concluded that the combination of  CBD and BCP may be particularly effective in reducing neuropathic pain resulting from spinal cord injury.

See: Cannabidiol (CBD) Synergies

BCP Synergy – Curcumin

Studies have also shown that β-Caryophyllene and curcumin up-regulates Nrf2 activity to protect cells from oxidative damage. Nrf2 (nuclear factor erythroid 2) is a transcription factor that is involved in cellular responses to oxidative damage and inflammation. Again, the combination effects of these two compounds offer potential synergistic benefit.

See: Nrf2 Activators.

BCP Synergy – Opioids

A primary function of the endocannabionoid system is to moderate pain. Yet, few studies have evaluated whether opioids (mu opioid agonists) and CB2 agonists act synergistically to inhibit pain, particularly chronic pain, or reduce unwanted side effects including stimulating reward effects that contribute to addiction.

A 2017 study, “Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists,”  determined that combining opioids with CB2 agonists results in a significant synergistic inhibition of  pain while significantly reducing opioid-induced unwanted side effects. This study suggests that BCP, a CB2 receptor agonist, may have a synergistic effect in managing chronic pain. More clinical trials are needed.

 See: Cannabinoids and Opioids

 

BCP Synergy – PEA (Palmitoylethanolamide) and Pregabalin (Lyrica)

PEA (Palmitoylethanolamide) is a fatty acid commonly found in the diet and manufactured in the body that has anti-inflammatory, analgesic, and neuroprotective properties. It has been shown to also provide synergistic benefits for pain, especially nerve pain, with opioids as well as CB2 agonists such as BCP. 

PEA has multiple mechanisms of action that include inhibition of FAAH, an enzyme that breaks down endocannabinoids including anandamide, enhancing their analgesic benefits. It also interacts with the peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor, which is known to have an important role in pain relief.  In addition, PEA plays an important role in reducing inflammation by reducing the activity of the pro-inflammatory enzymes (cyclooxygenase (COX), endothelial Nitric Oxide Synthase (eNOS), and inducible nitric oxide synthase (iNOS) and by reducing immune cells activation.

 

In a 2018 retrospective study 46 elderly patients with chronic pain were provided a 6-week course of therapy with a fixed combination supplement (Noxiall®) twice a day (each tablet with PEA-600mg, BCP-10 mg, Commiphora Myrrha-50mg, Piper Nigrum-13.4mg, and Rosmarinus Officinalis-30.8 mg).

The participants showed a reduction in pain intensity both in mixed/nociceptive and in neuropathic pain as well as improvements in functional abilities and quality of life in all the domains assessed. Although only a preliminary study, results suggest an advantage of combining PEA and BCP, both very safe and inexpensive, for pain management.

In a pre-clinical 2019 animal study, the supplement (Noxiall®) demonstrated a synergy with pregabalin (Lyrica) for the treatment of the animal model of sciatic nerve pain.

 

Resources:

National Academy of Sciences

  1. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research

 

www.Healer.com

This website appears to be good resource for exploring medical marijuana.

 

References:

β-Caryophyllene (BCP)

BCP – Newly uploaded articles

  1. Cannabinoid Therapeutics in Chronic Neuropathic Pain – From Animal Research to Human Treatment – 2021
  2. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception – PubMed – 2013
  3. Mechanisms of Transmission and Processing of Pain- A Narrative Review – 2023
  4. Targeting nociceptive transient receptor potential channels to treat chronic pain- current state of the field – 2018
  5. β-caryophyllene, a dietary cannabinoid, complexed with β-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn – PubMed – 2016

 

 

BCP – Overviews

  1. Beta-caryophyllene-is-a-dietary-cannabinoid-2008
  2. The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application – 2020
  3. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid – 2021
  4. β‐caryophyllene and β‐caryophyllene oxide—natural compounds of anticancer and analgesic properties. – 2016

 

 

BCP – Aging/Geroprotection

  1. Terpenoids as Potential Geroprotectors – 2020

 

BCP – Anxiety

  1. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice – 2014
  2. β-Caryophyllene, the major constituent of copaiba oil, reduces systemic inflammation and oxidative stress in arthritic rats – PubMed – 2018
  3. The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice – 2012
  4. Anticonvulsant, Anxiolytic and Antidepressant Properties of the β-caryophyllene in Swiss Mice Involvement of Benzodiazepine-GABAAergic, Serotonergic and Nitrergic Systems – PubMed 2021
  5. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice – PubMed – 2014

 

BCP – Antioxidant/Oxidative Stress

  1. Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene – A Focus on the Nervous System – 2021
  2. β-Caryophyllene, the major constituent of copaiba oil, reduces systemic inflammation and oxidative stress in arthritic rats – PubMed – 2018
  3. A-systematic-review-on-the-neuroprotective-perspectives-of-beta-caryophyllene-PubMed-2018
  4. Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene – A Focus on the Nervous System – 2021
  5. Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration- From Oxidative Stress to Microglia-Mediated Neuroinflammation – 2022
  6. β-Caryophyllene inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells – PubMed-2020

 

BCP – Arthritis

  1. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
  2. β-Caryophyllene Ameliorates MSU-Induced Gouty Arthritis and Inflammation Through Inhibiting NLRP3 and NF-κB Signal Pathway – In Silico and In Vivo – 2021
  3. β-Caryophyllene, the major constituent of copaiba oil, reduces systemic inflammation and oxidative stress in arthritic rats – PubMed – 2018
  4. Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis – 2019
  5. Effects of a massage-like essential oil application procedure using Copaiba T and Deep Blue oils in individuals with hand arthritis – 2018
  6. Topical cannabidiol is well tolerated in individuals with a history of elite physical performance and chronic lower extremity pain – 2023
  7. Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation – 2020
  8. A Randomized Controlled Trial of Topical Cannabidiol for the Treatment of Thumb Basal Joint Arthritis – PubMed – 2022
  9. Myrtenal and β-caryophyllene oxide screened from Liquidambaris Fructus suppress NLRP3 inflammasome components in rheumatoid arthritis – 2021
  10. Antinociceptive and chondroprotective effects of prolonged β-caryophyllene treatment in the animal model of osteoarthritis Focus on tolerance development – 2021
  11. CB2 agonism controls pain and subchondral bone degeneration induced by mono-iodoacetate Implications GPCR functional bias and tolerance development – 2021
  12. Joint problems arising from lack of repair mechanisms can cannabinoids help – 2019
  13. Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain an updated review – 2021
  14. Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis – 2022

 

BCP – Pharmacology, Bioavailability & Pharmacokinetics

  1. Distribution of inhaled volatile β‐caryophyllene and dynamic changes of liver metabolites in mice – 2021
  2. β-caryophyllene Delivery Systems Enhancing the Oral Pharmacokinetic and Stability – PubMed – 2018
  3. SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene – 2018
  4. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid – 2021

 

BCP – Central Sensitization

  1. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
  2. A systematic review on the neuroprotective perspectives of beta-caryophyllene – PubMed – 2018

 

BCP – Colitis

  1. β-Caryophyllene Inhibits Dextran Sulfate Sodium-Induced Colitis in Mice through CB2 Receptor Activation and PPARγ Pathway – 2011

 

BCP – Copaiba

  1. Toxicological Effects of Copaiba Oil (Copaifera spp.) and Its Active Components – 2023
  2. Essential oils for treating anxiety- a systematic review of randomized controlled trials and network meta-analysis – 2023
  3. Effects of a massage-like essential oil application procedure using Copaiba T and Deep Blue oils in individuals with hand arthritis – 2018
  4. The Effect of Copaiba Oil Odor on Anxiety Relief in Adults under Mental Workload- A Randomized Controlled Trial – 2022

 

 BCP – Cold Pain / TPRM8 Receptor

  1. Why wild giant pandas frequently roll in horse manure – 2020
  2. Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. – 2006
  3. The menthol receptor TRPM8 is the principal detector of environmental cold – PubMed – 2007
  4. Molecular basis of peripheral innocuous cold sensitivity – 2018
  5. Dysfunctional TRPM8 signalling in the vascular response to environmental cold in ageing – 2021
  6. Characterization of New TRPM8 Modulators in Pain Perception – 2019
  7. Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine – 2017
  8. Discovery of a Selective TRPM8 Antagonist with Clinical Efficacy in Cold-Related Pain – 2015
  9. Evaluation by Survival Analysis of Cold Pain Tolerance in Patients with Fibromyalgia and Opioid Use – 2022
  10. Molecular mechanisms of cold pain 2020
  11. Targeting nociceptive transient receptor potential channels to treat chronic pain- current state of the field – 2018
  12. TRPM8 mechanism of cold allodynia after chronic nerve injury. – 2007
  13. Neuronal and non-neuronal TRPA1 as therapeutic targets for pain and headache relief – 2022 Therapeutic opportunities for targeting cold pain pathways – PubMed – 2014
  14. Transient Receptor Potential (TRP) Ion Channels in Orofacial Pain – 2021
  15. TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold – 2018

 

BCP – Dental

  1. β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors – 2020
  2. TRPM8 and TRPA1 do not contribute to dental pulp sensitivity to cold – 2018

 

BCP – Diabetes

  1. Therapeutic Potential of β-Caryophyllene – A Dietary Cannabinoid in Diabetes and Associated Complications – 2021
  2. Observational clinical and nerve conduction study on effects of a nutraceutical combination on painful diabetic distal symmetric sensory-motor neuropathy in patients with diabetes- PubMed – 2018
  3. β-Caryophyllene inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells – PubMed-2020

 

BCP – Diet

  1. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid – 2021
  2. Beta-caryophyllene is a dietary cannabinoid – 2008 
  3. β-caryophyllene Delivery Systems Enhancing the Oral Pharmacokinetic and Stability – PubMed – 2018
  4. Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation? – 2016
  5. Therapeutic Potential of β-Caryophyllene – A Dietary Cannabinoid in Diabetes and Associated Complications – 2021
  6. β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19 – 2021

 

 

BCP – Infection/COVID-19

  1. β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19 – 2021

 

BCP – Inflammation/Neuroinflammation

  1. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis – 2017
  2. β-Caryophyllene Ameliorates MSU-Induced Gouty Arthritis and Inflammation Through Inhibiting NLRP3 and NF-κB Signal Pathway – In Silico and In Vivo – 2021
  3. β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19 – 2021
  4. Role of β-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil – 2020
  5. β-Caryophyllene Reduces the Inflammatory Phenotype of Periodontal Cells by Targeting CB2 Receptors – 2020
  6. A systematic review on the neuroprotective perspectives of beta-caryophyllene – PubMed – 2018
  7. Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation – 2020
  8. Beta-caryophyllene protects against diet-induced dyslipidemia and vascular inflammation in rats Involvement of CB2 and PPAR-γ receptors – PubMed – 2019
  9. Myrtenal and β-caryophyllene oxide screened from Liquidambaris Fructus suppress NLRP3 inflammasome components in rheumatoid arthritis – 2021
  10. Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation – 2020
  11. The CB2 Agonist β-Caryophyllene in Male and Female Rats Exposed to a Model of Persistent Inflammatory Pain – 2020
  12. Cannabinoid CB2 Receptors in Neurodegenerative Proteinopathies- New Insights and Therapeutic Potential – 2022
  13. β-Caryophyllene inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells – PubMed-2020

 

BCP – Misc

  1. Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion – 2018
  2. Inhibitory Effects of β-Caryophyllene on Helicobacter pylori Infection In Vitro and In Vivo – 2020

 

BCP – Multiple Sclerosis

  1. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis – 2017
  2. Traditional Uses of Cannabinoids and New Perspectives in the Treatment of Multiple Sclerosis – 2018
  3. Low Doses of β-Caryophyllene Reduced Clinical and Paraclinical Parameters of an Autoimmune Animal Model of Multiple Sclerosis – 2023

 

BCP – Nephropathy

  1. β-Caryophyllene inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells – PubMed-2020

BCP – Pain

  1. β‐caryophyllene and β‐caryophyllene oxide—natural compounds of anticancer and analgesic properties – 2016
  2. Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice. – PubMed – NCBI
  3. The cannabinoid CB₂ receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic… – PubMed – NCBI – 2014
  4. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain – 2013
  5. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception – PubMed – 2013
  6. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
  7. Role of β-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil – 2020
  8. A systematic review on the neuroprotective perspectives of beta-caryophyllene – PubMed – 2018
  9. Efficacy of Essential Oils in Pain – A Systematic Review and Meta-Analysis of Preclinical Evidence – 2021
  10. Observational clinical and nerve conduction study on effects of a nutraceutical combination on painful diabetic distal symmetric sensory-motor neuropathy in patients with diabetes- PubMed – 2018
  11. Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction. 2022pdf
  12. Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice – PubMed 2017
  13. The cannabinoid CB 2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain 2014
  14. The Endocannabinoid System, Cannabinoids, and Pain – 2013
  15. β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain – 2019
  16. β-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice – PubMed – 2019
  17. Cannabinoid Therapeutics in Chronic Neuropathic Pain – From Animal Research to Human Treatment – 2021
  18. Mechanisms of Transmission and Processing of Pain- A Narrative Review – 2023
  19. Evaluation by Survival Analysis of Cold Pain Tolerance in Patients with Fibromyalgia and Opioid Use – 2022
  20. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception – PubMed – 2013
  21. Cannabinoids, the endocannabinoid system and pain- a review of preclinical studies – 2021
  22. The Endocannabinoid System as a Therapeutic Target in Diabetic Peripheral Neuropathic Pain- A Review – 2021

 

BCP – Products

  1. CarolinaCannabinoids.
  2. Nootropics Depot  250 mg capsules with 6% BCP  (equal to 15 mg BCP)
  3. Nootropics Depot powder with 6% BCP
  4. doTERRA Copaiba Essential Oil 120 mg Softgels (?? % BCP)
  5. Noxiall® (PEA 600 mg, Commiphora Myrrha 50 mg, Piper Nigrum 13.4 mg (10 mg β-cariofillene) and Rosmarinus Officinalis

 

Topical BCP/PEA – Tulla Botanicals, References

  1. Detailed Overview of Pharmacology of Active Ingredients in Tulla Botanicals Wellness Topicals 1.19.24

 

  1. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid – 2021
  2. Beta Caryophyllene-Loaded Nanostructured Lipid Carriers for Topical Management of Skin Disorders – 2023
  3. Beta-caryophyllene as an antioxidant, anti-inflammatory and re-epithelialization activities in a rat skin wound excision model – 2022
  4. Beta-caryophyllene enhances wound healing through multiple routes – 2019
  5. Beta-caryophyllene-is-a-dietary-cannabinoid-2008
  6. Efficacy of a Combination of N-Palmitoylethanolamide, Beta-Caryophyllene, Carnosic Acid, and Myrrh Extract on Chronic Neuropathic Pain – A Preclinical Study – 2019
  7. Hemp Seed Oil in Association with β-Caryophyllene, Myrcene and Ginger Extract as a Nutraceutical Integration in Knee Osteoarthritis – 2022
  8. Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene – A Focus on the Nervous System – 2021
  9. Multi-Target Effects of ß-Caryophyllene and Carnosic Acid at the Crossroads of Mitochondrial Dysfunction and Neurodegeneration- From Oxidative Stress to Microglia-Mediated Neuroinflammation – 2022
  10. Myrtenal and β-caryophyllene oxide screened from Liquidambaris Fructus suppress NLRP3 inflammasome components in rheumatoid arthritis – 2021
  11. Non-clinical toxicity of β-caryophyllene, a dietary cannabinoid Absence of adverse effects in female Swiss mice – PubMed – 2018
  12. Plant Natural Sources of the Endocannabinoid ( E)-β-Caryophyllene- A Systematic Quantitative Analysis of Published Literature – 2020
  13. Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation – 2020
  14. The CB2 Agonist β-Caryophyllene in Male and Female Rats Exposed to a Model of Persistent Inflammatory Pain – 2020
  15. The Endocannabinoid System, Cannabinoids, and Pain – 2013
  16. β-Caryophyllene inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells – PubMed-2020
  17. β-Caryophyllene-Loaded Microemulsion-Based Topical Hydrogel- A Promising Carrier to Enhance the Analgesic and Anti-Inflammatory Outcomes – 2023
  18. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice – PubMed – 2014
  19. (−)-β-Caryophyllene, a CB2 Receptor-Selective Phytocannabinoid, Suppresses Motor Paralysis and Neuroinflammation in a Murine Model of Multiple Sclerosis – 2017
  20. β-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain – 2019
  21. β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19 – 2021
  22. β-Caryophyllene, a Natural Sesquiterpene, Attenuates Neuropathic Pain and Depressive-Like Behavior in Experimental Diabetic Mice – PubMed – 2019

BCP – Product Formulations

  1. Preparation and Characterization of Liposomal β‐Caryophyllene (Rephyll) – 2020
  2. SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene – 2018
  3. Observational clinical and nerve conduction study on effects of a nutraceutical combination on painful diabetic distal symmetric sensory-motor neuropathy in patients with diabetes- PubMed – 2018

 

BCP – Safety

  1. Non-clinical toxicity of β-caryophyllene, a dietary cannabinoid Absence of adverse effects in female Swiss mice – PubMed – 2018

 

BCP – Sources

  1. Development of a Gas Chromatography Method for the Analysis of Copaiba Oil – 2017
  2. Fast-Acting_and_Receptor-Mediated_Regulation_of_Neuronal Signaling Pathways by Copaiba Essential Oil
  3. β-Caryophyllene, the major constituent of copaiba oil, reduces systemic inflammation and oxidative stress in arthritic rats – PubMed – 2018
  4. Role of β-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil – 2020
  5. The anxiolytic-like effect of an essential oil derived from Spiranthera odoratissima A. St. Hil. leaves and its major component, β-caryophyllene, in male mice – 2012
  6. Plant Natural Sources of the Endocannabinoid ( E)-β-Caryophyllene- A Systematic Quantitative Analysis of Published Literature – 2020

 

BCP – Synergy

BCP – CBD

  1. Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction. 2022.pdf
  2. Hemp Seed Oil in Association with β-Caryophyllene, Myrcene and Ginger Extract as a Nutraceutical Integration in Knee Osteoarthritis – 2022

 

 

BCP – Synergy: Curcumin & Echinacea

  1. Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis – 2019

BCP – Synergy: NSAIDs

  1. Dual-Acting Compounds Targeting Endocannabinoid and Endovanilloid Systems—A Novel Treatment Option for Chronic Pain Management – 2016
  2. Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat – 2022
  3. Combination Drug Therapy for the Management of Chronic Neuropathic Pain – 2023
  4. Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain – PubMed – 2006
  5. Involvement of Spinal CB1 Cannabinoid Receptors on the Antinociceptive Effect of Celecoxib in Rat Formalin Test – 2016

 

BCP – Synergy: Opioids

  1. Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists – 2016
  2. Effect of Pharmacological Modulation of the Endocannabinoid System on Opiate Withdrawal: A Review of the Preclinical Animal Literature – 2016

 

BCP – Synergy: Palmitoylethanolamide (PEA)

  1. Noxiall® (PEA 600 mg, Commiphora Myrrha 50 mg, Piper Nigrum 13.4 mg (10 mg β-cariofillene) and Rosmarinus Officinalis
  2. Efficacy of a Combination of N-Palmitoylethanolamide, Beta-Caryophyllene, Carnosic Acid, and Myrrh Extract on Chronic Neuropathic Pain – A Preclinical Study – 2019
  3. Short-term efficacy of a fixed association of Palmitoylethanolamide and other phytochemicals as add-on therapy in the management of chronic pain in elderly patients – 2018
  4. The Endocannabinoid System and PPARs – Focus on Their Signalling Crosstalk, Action and Transcriptional Regulation – 2021
  5. Observational clinical and nerve conduction study on effects of a nutraceutical combination on painful diabetic distal symmetric sensory-motor neuropathy in patients with diabetes- PubMed – 2018
  6. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs) – 2016

 

BCP – Topical

  1. NON-CANNABIS THERAPY – Cannabinoid Therapy Without Using Cannabis: Direct Effects™ Topical β-Caryophyllene
  2. Beta-caryophyllene enhances wound healing through multiple routes – 2019
  3. The fragrance chemical beta-caryophyllene-air oxidation and skin sensitization – PubMed – 2005
  4. Expression of the Endocannabinoid Receptors in Human Fascial Tissue – 2016
  5. Effects of a massage-like essential oil application procedure using Copaiba T and Deep Blue oils in individuals with hand arthritis – 2018
  6. Effects of a massage-like essential oil application procedure using Copaiba T and Deep Blue oils in individuals with hand arthritis – 2018
  7. The cannabinoid CB 2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain 2014
  8. Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction. 2022.pdf
  9. Antiallodynic effect of β-caryophyllene on paclitaxel-induced peripheral neuropathy in mice – PubMed 2017
  10. The Skin and Natural Cannabinoids–Topical and Transdermal Applications – 2023
  11. Topical cannabidiol (CBD) in skin pathology – A comprehensive review and prospects for new therapeutic opportunities – 2022
  12. Beta-caryophyllene as an antioxidant, anti-inflammatory and re-epithelialization activities in a rat skin wound excision model – 2022
  13. Beta-caryophyllene enhances wound healing through multiple routes – 2019
  14. β-Caryophyllene-Loaded Microemulsion-Based Topical Hydrogel- A Promising Carrier to Enhance the Analgesic and Anti-Inflammatory Outcomes – 2023

 

 

BCP – Toxicity

  1. The fragrance chemical beta-caryophyllene-air oxidation and skin sensitization – PubMed – 2005
  2. Toxicological Evaluation of β-Caryophyllene Oil: Subchronic Toxicity in Rats. – PubMed – NCBI 2016

 

BCP – Wound Healing

  1. Beta-caryophyllene enhances wound healing through multiple routes – 2019
  2. Beta-caryophyllene as an antioxidant, anti-inflammatory and re-epithelialization activities in a rat skin wound excision mode – 2022
  3. Cannabinoid Signaling in the Skin – Therapeutic Potential of the “C(ut)annabinoid” System – 2019

 

Terpenes

Terpenes – Overviews

  1. Therapeutic and Medicinal Uses of Terpenes – 2019
  2. Terpenes:Terpenoids in Cannabis – Are They Important? – 2020
  3. Advances in Pharmacological Activities of Terpenoids – 2020
  4. Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant – 2020
  5. The Cannabis Terpenes – 2020
  6. The “Entourage Effect” – Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders – 2020
  7. Cannabis Essential Oil – A Preliminary Study for the Evaluation of the Brain Effects – 2018
  8. A Systematic Review of Essential Oils and the Endocannabinoid System – A Connection Worthy of Further Exploration – 2020
  9. Efficacy of Essential Oils in Pain – A Systematic Review and Meta-Analysis of Preclinical Evidence – 2021
  10. The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application – 2020

 

Terpenes – Aromatherapy

  1. Aromatherapy and Aromatic Plants for the Treatment of Behavioural and Psychological Symptoms of Dementia in Patients with Alzheimer’s Disease Clinical Evidence and Possible Mechanisms – 2017
  2. Corrigendum – A question of scent – lavender aroma promotes interpersonal trust -2015
  3. Odors enhance slow-wave activity in non-rapid eye movement sleepOdors enhance slow-wave activity in non-rapid eye movement sleep
  4. Essential Oils and Animals – Which Essential Oils Are Toxic to Pets?
  5. Essential Oils and Pets
  6. Herbs and Their Uses for Animals – Patchouli and Pets
  7. Reactivating memories during sleep by odors – odor specificity and associated changes in sleep oscillations – 2014
  8. Increasing Explicit Sequence Knowledge by Odor Cueing during Sleep in Men but not Women – 2016
  9. Effects of odorant administration on objective and subjective measures of sleep quality, post-sleep mood and alertness, and cognitive performance – 2003
  10. An Olfactory Stimulus Modifies Nighttime Sleep in Young Men and Women – 2005
  11. Massage with or without aromatherapy for symptom relief in people with cancer. – PubMed – NCBI
  12. Aromatherapy hand massage for older adults with chronic pain living in long-term care. – PubMed – NCBI
  13. A Systematic Review of Essential Oils and the Endocannabinoid System – A Connection Worthy of Further Exploration – 2020
  14. Human olfactory receptors – novel cellular functions outside of the nose,” – 2017
  15. The diversified function and potential therapy of ectopic olfactory receptors in non-olfactory tissues – PubMed – 2017
  16. How does your kidney smell? Emerging roles for olfactory receptors in renal function,” – 2017
  17. The Effects of Essential Oils and Terpenes in Relation to Their Routes of Intake and Application – 2020

 

Terpenes – CB2 Receptor

  1. Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB2 receptor in the arthritis progression and pain – an updated review – 2021
  2. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice – 2014
  3. The CB2 receptor and its role as a regulator of inflammation – 2016
  4. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint
  5. Activation of Peripheral Cannabinoid Receptors Synergizes the Effect of Systemic Ibuprofen in a Pain Model in Rat – 2022
  6. Involvement of Spinal CB1 Cannabinoid Receptors on the Antinociceptive Effect of Celecoxib in Rat Formalin Test – 2016

 

Terpenes – Synergy with Cannabinoids:

  1. Taming THC – potential cannabis synergy and phytocannabinoid-terpenoid entourage effects – 2011
  2. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. – PubMed – NCBI
  3. Entourage Effect 2.0
  4. Cannabis and the Anxiety of Fragmentation—A Systems Approach for Finding an Anxiolytic Cannabis Chemotype – 2018
  5. Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity – 2019
  6. Absence of Entourage – Terpenoids Commonly Found in Cannabis sativa Do Not Modulate the Functional Activity of Δ9-THC at Human CB1 and CB2 Receptors – 2019
  7. Terpenoids From Cannabis Do Not Mediate an Entourage Effect by Acting at Cannabinoid Receptors – 2020
  8. The “Entourage Effect” – Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders – 2020

 

Terpenes – Marijuana Strains

  1. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  2. Terpenoid Chemoprofiles Distinguish Drug-type Cannabis sativa L. Cultivars in Nevada – 2018
  3. Terpenoids and Phytocannabinoids Co-Produced in Cannabis Sativa Strains Show Specific Interaction for Cell Cytotoxic Activity – 2019
  4. Identification of Terpenoid Chemotypes Among High (−)-trans-Δ9- Tetrahydrocannabinol-Producing Cannabis sativa L. Cultivars 0 2017
  5. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products – 2018

 

 

Terpenes – Bioavailability

  1. Bioavailability and Pharmacokinetics of Natural Volatile Terpenes in Animals and Humans – 2000
  2. Bioavailability of Bioactive Compounds
  3. SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene – 2018

Terpenes – Pain:

  1. Analgesic-like Activity of Essential Oils Constituents – 2011
  2. Analgesic-Like Activity of Essential Oil Constituents – An Update – 2017
  3. Medicinal Plants of the Family Lamiaceae in Pain Therapy – A Review – 2018
  4. Analgesic Potential of Essential Oils – 2016
  5. Medicinal Plants of the Family Lamiaceae in Pain Therapy – A Review – 2018
  6. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  7. Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant – 2020
  8.  The Molecular Mechanisms That Underpin the Biological Benefits of Full-Spectrum Cannabis Extract in the Treatment of Neuropathic Pain and Inflammation – PubMed – 2020
  9. Cannabis-based medicines and the perioperative physician – 2019
  10. Cannabis‐based medicines for chronic neuropathic pain in adults – 2018
  11. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain – An Update on Current Evidence and Cannabis Science – 2018
  12. Role of Cannabinoids and Terpenes in Cannabis-Mediated Analgesia in Rats – PubMed – 2019
  13. Antinociceptive effect of inhalation of the essential oil of bergamot in mice – 2018
  14. Analgesic Potential of Essential Oils – 2016
  15. Analgesic-Like Activity of Essential Oil Constituents – An Update – 2017

 

 

Terpenes – Inflammation:

  1. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015 
  2. Cannabis sativa L. and Nonpsychoactive Cannabinoids – Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer – 2018
  3. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort – 2018
  4. Therapeutic Potential of Volatile Terpenes and Terpenoids from Forests for Inflammatory Diseases – 2020
  5.  The Molecular Mechanisms That Underpin the Biological Benefits of Full-Spectrum Cannabis Extract in the Treatment of Neuropathic Pain and Inflammation – PubMed – 2020
  6. Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. – 2015
  7. Cannabis, Cannabinoids, and the Endocannabinoid System—Is there Therapeutic Potential for Inflammatory Bowel Disease? – 2019
  8. Therapeutic Applications of Terpenes on Inflammatory Diseases – 2021
  9. Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation – 2020

 

Terpenes – Wound Healing

  1. Beta-caryophyllene enhances wound healing through multiple routes – 2019

 

 

 Individual Sources of Terpenes

Terpenes – Bergamot

  1. The Anxiolytic Effect of Aromatherapy on Patients Awaiting Ambulatory Surgery – A Randomized Controlled Trial – 2013
  2. Antinociceptive effect of inhalation of the essential oil of bergamot in mice – 2018
  3. Anxiolytic-Like Effects of Bergamot Essential Oil Are Insensitive to Flumazenil in Rats – 2019
  4. Bergamot – Natural Medicines – Professional.pdf
  5. Citrus bergamia essential oil – from basic research to clinical application – 2015
  6. Role of 5-HT1A Receptor in the Anxiolytic-Relaxant Effects of Bergamot Essential Oil in Rodent – 2020 Neuropharmacological Properties of the Essential Oil of Bergamot for the Clinical Management of Pain-Related BPSDs – PubMed – 2019
  7. Possible involvement of the peripheral Mu-opioid system in antinociception induced by bergamot essential oil to allodynia after peripheral nerve injury – PubMed – 2018
  8. Peripherally injected linalool and bergamot essential oil attenuate mechanical allodynia via inhibiting spinal ERK phosphorylation – PubMed – 2013
  9. Neuropharmacology of the essential oil of bergamot – PubMed – 2010
  10. Effect of Harvesting Time on Volatile Compounds Composition of Bergamot (Citrus × Bergamia) Essential Oil – 2019
  11. Chemical Composition and Biological Activities of Essential Oils from Peels of Three Citrus Species – 2020
  12. Chemical_Composition_of_Bergamot_Citrus_Bergamia_Risso_Essential_Oil_Obtained_by_Hydrodistillation – 2010
  13. Cannabinoid Signaling in the Skin – Therapeutic Potential of the “C(ut)annabinoid” System – 2019
  14. Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain – PubMed – 2016

 

 

 

 

 

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

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Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

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