Philip Blair, MD
Inflammation is an integral part of the body’s natural defense mechanism, but when it becomes chronic, it can wreak havoc on our health and well-being. Recent research has illuminated the pivotal role chronic inflammation plays in autoimmune and neurodegenerative conditions. Scientists are only beginning to understand the connection between the Endocannabinoid System (ECS) and chronic inflammation and associated debilitating disorders.
Inflammation is the body’s natural, protective response to external threats like injuries, infections, and invaders such as bacteria and viruses. In acute cases, the immune system mobilizes inflammatory cells (M1 state) to combat these threats, followed by a transition to a healing phase (M2 state). However, when the immune system remains stuck in the M1 state, chronic inflammation can ensue, persisting long after the initial trigger has vanished.
Unlike acute inflammation, which is a normal and necessary response to injury or infection, chronic inflammation can cause damage to organs, tissues, and cells. It has been linked to a wide range of health problems, including autoimmune diseases, cardiovascular disease, diabetes, and even mental health disorders.
The underlying causes of chronic inflammation can vary, including lifestyle factors such as poor diet, lack of exercise, and chronic stress. Environmental factors, such as exposure to pollution or toxins, can also contribute to chronic inflammation. Understanding the root causes of chronic inflammation is crucial for developing effective treatment strategies.
Chronic inflammation is closely associated with various conditions, including:
- Autoimmune disorders — rheumatoid arthritis, systemic lupus
- Metabolic disorders — diabetes type 2 and metabolic syndrome; and
- Neuroinflammation-related disorders — ranging from mood disturbances like anxiety, PTSD, depression, addiction, to neurodegenerative conditions such as Alzheimer’s disease and CTE (Chronic Traumatic Encephalitis) from repeated concussions.
Inflammation: Conventional Therapies and Risks
Traditional treatments for these disorders often focus on suppressing the immune system, posing risks of adverse effects. Autoimmune disorders are managed by reducing inflammation and curbing immune system activity, which can often involve non-steroidal anti-inflammatory drugs (NSAIDs) or immunosuppressive therapies such as corticosteroids.
Similarly, metabolic disorders and obesity are tackled through lifestyle changes and medications that have potential side effects like headaches, nausea, and more. Neuroinflammatory disorders are often treated with medications, including antidepressants, anti-epileptic, antipsychotic and neurodegenerative disease drugs, which also have various side effects, including emotional numbness, memory, neuroinflammatory and metabolic issues.
The Function of the Endocannabinoid System (ECS)
Research is proving that the endocannabinoid system plays a critical role in regulating the body’s immune responses. This system is a master regulator of many core body systems and plays a vital role in maintaining balance and communication among the nervous, metabolic, endocrine, and immune systems. A key role of the ECS is to manage stress. It operates through cannabinoid receptors, ligands, enzymes, and transporters spread throughout the body. When activated, the ECS enables two-way communication between body systems, making it a critical system for maintaining homeostasis.
Since the ECS is present nearly everywhere in the human body and governs major body functions and systems, specifically regulating metabolism, inflammation, chronic pain, and neurological disorders. Multiple endocannabinoid molecules affect the ECS. All of them seem to have a purpose in anti-proliferative, anti-inflammatory, and anti-metastatic effects.[1]
In addition to the body’s own endocannabinoids, there are several drugs that impact the ECS such as Marinol (dronabinol), Cesamet (nabilone), and Epidiolex (cannabidiol). These are currently restricted in their use. Medicinal marijuana, legal in some states, provides blends of tetrahydrocannabinol (THC) and cannabidiol (CBD) as well as other minor cannabinoid substances. There are also many naturopathic herbs that favorably modulate the ECS, like echinacea, curcumin, and milk-thistle. But, perhaps the most comprehensive phyto-cannabinoid is ß-caryophyllene (BCP), a powerful plant-based cannabinoid with potent anti-inflammatory properties. BCP is a natural compound found in various plants, including certain spices like black pepper, cloves, and cinnamon. One of the most intriguing aspects of BCP is its ability to interact with the body’s endocannabinoid system.
What Is BCP?
β-caryophyllene (BCP) is a bicyclic sesquiterpene widely distributed in the plant kingdom and common foodstuffs like oregano, hops, and black pepper, where it provides a unique aroma to essential oils and plays a pivotal role in the survival and evolution of higher plants. Over 3,000 studies provided evidence for protective roles of BCP in animal cells, highlighting its possible use as a therapeutic anti-inflammatory tool. Experimental results proved BCP was able to reduce proinflammatory mediators, thus regulating chronic pathologies characterized by inflammation and oxidative stress.
BCP is a full-fledged phytocannabinoid acting adaptogenic within the endocannabinoid system to modulate pain, inflammation, metabolism, and vascular function. Although present in small amounts in cannabis its presence has long been considered as having only a minor “entourage” effect. BCP is a strong and selective agonist of CB2, found on all immune cells and organs, that regulates inflammation. CB2 receptors have been identified in every organ performing extensive regulatory functions, including throughout the brain in interneurons and synapses modulating memory, behavior, and mood.[2]
Included in this regulatory function is CB2 control of the blood-brain-barrier for vascular flow and permeability to extracerebral toxins and invasive monocytes key factors inducing CNS inflammation. In addition, BCP inhibits both enzymes that degrade ECS agonists anandamide and 2-AG thereby upregulating the system responses. BCP and CB2 endocannabinoid activators have been proven to be neuroprotective and do not trigger psychotropic adverse effects normally seen with activation of CB1 receptors.
The US Food and Drug Administration has classified β-caryophyllene as a generally safe food and cosmetic additive. And, the European Food Safety Authority has grandfathered BCP into oral and topical use as an exception to novel food regulations. LD50 of acute oral doses of BCP in rats and the LD50 of acute dermal doses in rabbits found more than 5000 mg/kg and intratracheal doses (12-48 mg/kg) was found non-toxic to the respiratory system, including lungs in rats. Also, BCP in ointments upon dermal exposure was not found to cause skin irritation or sensitization in humans at concentrations up to 4%.[3]
Furthermore, the Scientific Panel on Food Additives aimed at advising the European Commission on the human health of chemically defined flavoring substances determined that β-caryophyllene did not show any mutagenicity. [Ullah et al. Improvement of Oxidative Stress and Mitochondrial Dysfunction by β-Caryophyllene: A Focus on the Nervous System. Antioxidants (Basel). 2021 Apr 1;10(4):546. doi: 10.3390/antiox10040546]. And finally, BCP is metabolized to caryophyllene oxide and glucuronidase transformation excreted from the body without any significant inhibition of microsomal drug metabolism by CYP3A4.[4]
Because of its wide range of ECS modulation, BCP shows great potential in addressing conditions connected to the nervous, metabolic, endocrine, and immune systems mentioned previously. In vivo and vitro studies show BCP linkage to TRPV1, GPR55 and canonical CB2R. In addition, BCP inhibits ECS metabolizing enzymes thereby upregulating the whole family of endocannabinoids.[5]
How BCP Interacts with the ECS and the Body
Research has shown that ß-caryophyllene acts as a selective agonist for the CB2 receptors in the endocannabinoid system. When ß-caryophyllene binds to CB2 receptors, it provides a highly calming and soothing function, as well as inflammatory protection. In addition to activating CB2 receptors, BCP signals several other receptors to provide powerful therapeutic relief for chronic pain. Besides its analgesic effects, BCP influences levels of glucose and cholesterol. It has shown potent therapeutic promise in anxiety, depression, neuropathic pain, neuro-degenerative, and metabolic diseases, as well as having antibiotic, antifungal, and anti-cancer effects.
ß-caryophyllene acts by binding to multiple receptors that regulate immune cell behavior and the release of inflammatory substances, including endocannabinoid type 2 receptors (CB2), TRPV1, BDNF (Brain drive neurotrophic factor) and members of the family of peroxisome proliferator-activated nuclear receptors (PPARs).[6]
In preclinical studies, BCP shows beneficial effects on obesity, non-alcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) liver diseases, diabetes, cardiovascular diseases, pain, and other nervous system disorders.
BCP also controls reactive oxygen species (ROS) through multiple pathways. ROS are frequently products and causes of chronic inflammation inciting immune activation and mitochondrial dysfunction. β-caryophyllene has been shown to protect glioma cells from glutamate-induced cytotoxicity through alteration of antioxidant responses, mainly by inhibition of ROS production via CB2 receptor dependent nuclear factor erythroid 2–related factor 2 (Nrf2) activation.[7]
In fact, the underlying mechanism of BCP cholesterol-lowering action is scavenging ROS, leading to deactivation of HMG-CoA reductase and inhibition of endogenous cholesterol synthesis. In a head-to-head statin study BCP decreased in serum total cholesterol as well as LDL (31.6% and 39.1%) compared to atorvastatin (56.6% and 66.8%). In addition, BCP increased HDL level by 43.4% vs atorvastatin (47.1%) proving that BCP was comparable to statin drugs in its reduction in HMG-CoA reductase but in a more physiological manner by counteracting ROS.[8]
CB2 Receptors, Inflammation, and BCP Research
Researchers are exploring how BCP can be harnessed to provide relief for those suffering from chronic inflammation. Numerous scientific studies have shed light on the anti-inflammatory properties of ß-caryophyllene. Research shows that ß-caryophyllene exhibits a powerful protective role in multiple nervous system‐related disorders, including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer’s disease.
CB2 receptors, primarily found in the immune system, play a critical role in managing inflammation. Microglia, immune cells in the brain and central nervous system, are involved in chronic neuroinflammation. Experimental results show the ability of BCP to reduce pro-inflammatory mediators such as tumor necrosis factor alfa (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thus ameliorating chronic pathologies characterized by inflammation and oxidative stress, in particular metabolic and neurological diseases.[9]
In the classical arthritis of gout, BCP inhibited the expressions of the inflammasome NLRP3, Caspase-1, TLR4, and IL-1β in the synovial tissue reducing inflammation and protecting joint function.[10]
Another study investigated the effects of BCP on liver injury induced by chronic plus binge alcohol feeding in mice. BCP alleviated the alcohol-induced liver injury and inflammation by modulating the pro-inflammatory phenotypic `M1` switch to ‘M2’ of Kupffer cells and by decreasing the expression of vascular adhesion molecules as well as the neutrophil infiltration. It also regulated hepatic metabolism (steatosis, protein hyperacetylation and PPAR-α signaling). The authors concluded that given the safety of BCP in humans, this food additive has a high translational potential in treating or preventing hepatic injury associated with oxidative stress, inflammation, and steatosis.[11]
In a study of diabetic nephropathy (DN) oral β-caryophyllene was used to control complications of high glucose (HG) exposed glomerular mesangial renal cells. BCP inhibited HG-induced cell proliferation and ROS production. BCP exhibited decreased levels of these inflammatory markers TNF-α, IL-1β, IL-6 in HG-induced mesangial cells. Furthermore, this treatment suppressed fibronectin secretion and collagen IV synthesis in mesangial cells preventing fibrosis and renal impairment. In addition, BCP inhibited the nucleic factor NF-κB activation and enhanced the Nrf2 activation. NRF2 is a protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. NRF2 inhibits the NLRP3 inflammasome, which induces an inflammatory cascade, including IL-1β, induced IFN-γ and natural killer cell activation, DNA fragmentation and cell pore formation, and inhibition of glycolytic enzymes causing further elevations of glucose. BCP successfully provided nephro-protective effects by mitigating high glucose complication, which applies to all organ systems.[12]
Because ß-caryophyllene selectively activates the CB2 receptors, it is showing great potential in helping reduce and relieve chronic inflammation throughout the body. It can even cross the blood brain barrier to reach the CNS and act on the CB2 receptors of overactive microglia.
In a recent study β-caryophyllene was evaluated in rat models of dementia whose etiology mimicked neuro-inflammation and aging. BCP protected against drug-induced neuro-inflammation with no effect on neuronal aging associated with mitochondrial dysfunction.[13]
BCP switches the CNS immune system from reactive M1 state to resolution M2 state decreasing microglia, cytokines, and increasing Regulatory T cell to clean up debris. The overall effect is a powerful protective role without the unwanted side-effects commonly associated with other conventional therapies.
Conclusion: BCP and the Future of Inflammation Treatment
Because of its anti-inflammatory and pain management activity, “β-Caryophyllene is the foremost natural CB2 receptor and a potent phytocannabinoid.” BCP performs as a selective agonist for the CB2 receptor, the therapeutic target for the management of inflammation, atherosclerosis, pain, osteoporosis, etc. It is also proven to have antioxidant, anticarcinogenic, and antimicrobial properties and is an important oral nutraceutical. Similarly, BCP prevents inflammation and tissue damage in colitis and nephrotoxicity models.[14]
Chronic inflammation underlies the pathophysiology of numerous disorders, challenging the medical community to find effective and safe solutions. Beta-Caryophyllene, as a natural compound targeting the ECS’s CB2 receptors, holds immense therapeutic potential for addressing chronic inflammation and its associated debilitating conditions. As research continues to unveil the wonders of the ECS and BCP, we may be on the verge of a new era in the treatment of chronic inflammation, offering hope and relief to countless individuals suffering from these challenging disorders.
In future articles I hope to address the science of BCP mitigating the modern plagues of addiction, neurodegeneration, diabetes, mast cell activation, and cancer.
I am honored to be part of the medical professionals who are participating in Parkinson’s Solutions Summit Nov 13-19, 2023. Join me on Day 5 to learn how you can use natural compounds such as beta-caryophyllene to help reduce inflammation, boost brain health, protect and improve cognitive function and manage symptoms.
https://drtalks.com/natural-parkinsons-solutions-summit/?oid=58&ref=3617&uid=617
1. Maida V, Daeninck PJ. A user’s guide to cannabinoid therapies in oncology. Curr Oncol. 2016 Dec;23(6):398-406. doi: 10.3747/co.23.3487. PMID: 28050136.
2. Gertsch et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9099-104. doi: 10.1073/pnas.0803601105. PMID: 18574142.
3. Charu et al. Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise. Current Pharmaceutical Design 2016; 22(21). https://dx.doi.org/10.2174/1381612822666160311115226.
4. Špičáková et al. beta-caryophyllene oxide and trans-nerolidol affect enzyme activity of CYP3A4. Physiol Res. 2019 Nov 22;68(Suppl 1): S51-S58. doi: 10.33549/physiolres.934323. PMID: 31755290.
5. Sharma et al. Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise. Curr Pharm Des. 2016;22(21):3237-64. doi: 10.2174/1381612822666160311115226. PMID: 26965491.
6. Serra et al. Anti-Inflammatory Effect of Beta-Caryophyllene Mediated by the Involvement of TRPV1, BDNF and trkB in the Rat Cerebral Cortex after Hypoperfusion/Reperfusion. Int J Mol Sci. 2022 Mar 26;23(7):3633. doi: 10.3390/ijms23073633.
7. Assis et al. β-Caryophyllene protects the C6 glioma cells against glutamate-induced excitotoxicity through the Nrf2 pathway. Neuroscience. 2014 Oct 24;279:220-31. doi: 10.1016/j.neuroscience.2014.08.043. PMID: 25194788.
8. Harb et al. Hypocholesterolemic effect of β-caryophyllene in rats fed cholesterol and fat enriched diet. J Clin Biochem Nutr. 2018 May;62(3):230-237. doi: 10.3164/jcbn.17-3. PMID: 29892161
[9]. Scandiffio et al. Protective Effects of (E)-β-Caryophyllene (BCP) in Chronic Inflammation. Nutrients. 2020 Oct 26;12(11):3273. doi: 10.3390/nu12113273. PMID: 33114564.
[10]. Li et al. β-Caryophyllene Ameliorates MSU-Induced Gouty Arthritis and Inflammation Through Inhibiting NLRP3 and NF-κB Signal Pathway: In Silico and In Vivo. Front Pharmacol. 2021 Apr 23;12:651305. doi: 10.3389/fphar.2021.651305. PMID: 33967792.
[11]. Varga et al. β-Caryophyllene protects against alcoholic steatohepatitis by attenuating inflammation and metabolic dysregulation in mice. Br J Pharmacol. 2018 Jan;175(2):320-334. doi: 10.1111/bph.13722. PMID: 28107775.
[12]. Li et al. β-Caryophyllene inhibits high glucose-induced oxidative stress, inflammation and extracellular matrix accumulation in mesangial cells. Int Immunopharmacol. 2020 Jul;84:106556. doi: 10.1016/j.intimp.2020.106556. PMID: 32416450.
[13]. Kanojia et al. Beta-Caryophyllene, a CB2R Selective Agonist, Protects Against Cognitive Impairment Caused by Neuro-inflammation and Not in Dementia Due to Ageing Induced by Mitochondrial Dysfunction. CNS Neurol Disord Drug Targets. 2021;20(10):963-974. doi: 10.2174/1871527320666210202121103. PMID: 33530917.
[14]. Amalraj et al. ACS Omega 2020, 5, 24045−24056. https://dx.doi.org/10.1021/acsomega.0c03456.
Published November 4, 2023
About the Author
Retired Colonel (Dr.) Philip Blair is a board-certified family physician licensed in Washington state. He graduated from West Point in 1972 and attended University of Miami School of Medicine and trained as a family physician. He had assignments in Georgia, Louisiana, Washington, Oklahoma, Texas, Hawaii, Kansas, Italy, Korea, Germany, and the Gulf War.
In 2014 he was introduced to cannabidiol. Since then, he has treated several thousand patients with CBD in his clinical practice. Currently he is researching the terpene β-Caryophyllene as an alternative to medicinal cannabis. Blair Medical Group SPC provides physician-formulated BCP products that everyone can use to support, restore, and activate the endocannabinoid system as well as addressing chronic pain and inflammation-related conditions.
BCPlus products are available at blairmedicalgroup.shop. Dr. Blair is also available for private consultations and speaking engagements. Please contact him at DrBlairMD@icloud.com and (360) 991-4791. TOWNSEND E-LETTER READERS – USE CODE TOWNSEND TO GET 10% OFF YOUR PURCHASE! BCPLus Liposomal Blends (2 oz. size only) are buy one, get one free until December 31, 2023!!!