Mast Cell Activation Syndrome


Philip Blair, MD

Mast cells are derived from hematopoietic stem cell precursors and are essential to the typical allergic response. Activation of these cells by allergens leads to degranulation and release of inflammatory mediators, responsible for regulating the acute inflammatory symptomatology. Mast cells have also been implicated in malignancy, arthritis, coronary artery disease, and osteoporosis health conditions.

Mast cell activation syndrome (MCAS) is an immune disease with an estimated prevalence in 17% (around 57 million) of the US population, disproportionately affecting women at the rate of 80% (roughly 46 million). This syndrome is associated with various neurologic and psychiatric disorders, including chronic pain, headache, depression, generalized anxiety disorder, skin rashes and hives outbreaks, and can be a secondary symptom of several other women’s health conditions, including menstrual pain, vulvodynia, and endometriosis.

Current research suggests mast cells are largely controlled by the endocannabinoid system. The endocannabinoid system is integrated into all systems and organs through CB1 and CB2 receptors. CB2 receptors are found on all immune cells, such as white blood cells, keratinocytes, astrocytes, glial cells, and mast cells. Research suggests that the mast cell CB2 receptors control mast cell activation syndrome.[1] When the CB2 receptors on mast cells and immune cells are activated by non-cannabis dietary endocannabinoid compounds, such as b-caryophyllene (BCP), the mast cell’s release of histamine and other mediators is shut down, which immediately prevents the episode of cascading inflammatory symptoms, and allows the body to shift the immune system from inflammatory overload to resolution/healing phase.[2],[3],[4],[5] Here I report on clinical case studies of BCP impacting MCAS.

Case Study 1: A 51-year-old woman with complex medical issues stemming from MCAS which include a vertebral compression fracture and incomplete spinal cord injury, gastroparesis, allergies, asthma, and dermatographia. She was depressed with impaired motivation and cognitive focusing. Many conventional medications including antihistamines and albuterol inhalers failed to provide significant relief. b-caryophyllene (BCPlus®)[6], a clove extract with CB2R agonist properties, was recommended at 15 mg twice daily sublingual. Ten minutes after her first dose of BCP her wheezing lessened and dermatographia completely resolved. She also experienced reduced pain in her back and legs. BCP also eliminated her gut pain, reduced her bloating, and normalized her eliminations. In addition, she noted that her anxiety, depression, and PTSD symptoms nearly resolved with increased energy, focus and motivation. At one point she ran out of BCP and noticed a gradual return of pain, gastrointestinal issues, and allergies symptoms. Now, after two years of usage she can go days or weeks without critical need for BCP on a regular basis.

Case Study #2: 65-year-old woman with MCAS for 5 years and the full range of mast cell disorders. After first dose of BCP (BCPLus®) within ten minutes she had improvements in anxiety, depression, GI pain, pelvic spasm, energy, nasally, breathing, wheezing, near & far vision, back pain, skin-dermatographia, and mood with feelings of wellbeing. Her dose was 15 mg of BCP twice daily. She also used topical BCP (BCPLUS Gel®)[7] on her bunion providing immediate relief of chronic pain and increased range of motion. Benefits lasted 12 hours, including improved sleep, clear headed and coordinated with no additional medications.

Case study #3: 60-year-old man with 30 years of increasing food intolerances and 12 years of chronic hives was diagnosed with MCAS five years ago based on DNA findings. He has managed his symptoms with antihistamines, cannabis and 80 different medications and supplements over the years. Within 5 minutes after taking 1/2mL (15mg) of BCP, he felt tingling over his upper body, relief of pain in legs, back, neck, wrist, damaged Achilles tendon and foot. All itching has been resolved. He also noted feelings of wellbeing and energy. He then applied a topical form of BCP (BCPLUS Gel®) to a neuroma on his foot and within minutes it seemed to shrink, and irritation was controlled. He has continued treatment at least twice daily and gradually eliminated all narcotics, antidepressant, and benzodiazepines from his regimen after two years of BCP use.

MCAS is a condition that occurs when mast cells are overactive or easily triggered, releasing inappropriate amounts of histamine mediators. The body eventually experiences a state of continual inflammation and mast cell hyperactivation, causing multiple serious symptoms. MCAS was only recognized as a condition in 1999 and given a name in 2007. Many people (including physicians) mistakenly refer to these symptoms as histamine intolerance, making diagnosis and treatment of the correct condition very difficult. People often suffer with MCAS symptoms for multiple years.[8] Currently, many Long COVID patients are also being diagnosed with MCAS. However, it is unknown if the SARS-CoV-2 virus triggers mast cell dysfunction or if an underlying mast cell dysfunction contributes to the development of Long COVID. Researchers believe that the virus increases activation of the mast cells, resulting in the symptoms many experience with Long COVID. If this is the case, possible MCAS treatments may prove to be an effective therapy for both MCAS and Long COVID.[9]

Many people (including physicians) mistakenly refer to these symptoms as histamine intolerance, when MCAS is the probable cause. It is clinically difficult to diagnose for the reasons further outlined below.[10] The International Mast Cell Disorder Working Conference established diagnostic criteria for mast cell disorders in 2010. They established three (3) required co-criterion for a systemic mast cell activation diagnosis:

  1. Patients exhibit symptoms involving two or more organ systems in parallel.
  2. Documentation that mast cell mediators are directly involved in symptoms such as elevated serum tryptase, histamine and/or prostaglandin lab tests.
  3. Proven response to medications that inhibit histamine or another mediator release.

Laboratory testing of MCAS requires detecting abnormal levels of mediators, such as histamines and prostaglandins. Testing and validating MCAS can be an arduous and complex process.

 The most important MCAS tests to consider are:[11]

  • Histamine – plasma
  • N-Methylhistamine 24-hour urine test. Measures levels of histamine, prostaglandins, and leukotrienes.
  • Prostaglandin D2 – plasma and 24-hour urine
  • Chromogranin A
  • Serum Tryptase Test – measures degranulation in mast cells.
  • Complete Blood Count – to rule out mastocytosis, an unrelated condition.
  • Bone Marrow Biopsy
  • Taking NSAIDs, aspirin or antihistamines can throw-off test results, resulting in false negatives. Lab samples also need to be chilled immediately to avoid deterioration. With these challenges, it is very common to get a false negative for tests.

Common Approaches to Managing MCAS

Today, most of the medications used to treat MCAS have severe and unpleasant side effects, especially over long-term use. Many of these side effects are the same as the symptoms of mast cell activation syndrome: joint pain, chronic fatigue, loss of appetite, weight gain, tingling, swelling, numbness, sensitivity to cold, hives, and flushing. Due to the symptom/side effects similarities, people often discontinue using the medication.[12]

Drugs used in treating MCAS are commonly used to treat allergic diseases and inflammation, such as steroids, non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, and immunosuppressants. Medications that stabilize mast cell include cromolyn sodium and ketotifen. However, long-term use of these may lead to serious long-term side effects such as immune system deterioration, osteoporosis, renal or liver disorders, and addictions. While immunosuppressants can help mitigate symptoms, they can make the immune system less able to detect and destroy cancer cells or fight off infections, putting the whole body at risk.

Mast cells are derived from hematopoietic stem cell precursors and are essential to the typical allergic response. Activation of these cells by allergens leads to degranulation and release of inflammatory mediators, responsible for regulating the acute inflammatory symptomatology. Mast cells have also been involved in malignancy, arthritis, coronary artery disease, and osteoporosis.  Some genetic mutations are known to cause clonal disease. Such disorders include mastocytosis and clonal (or monoclonal) mast cell activation disorders or mast cell activation can also occur secondary to allergic, inflammatory, or neoplastic disease. Most mast cell disorders have unexplained molecular pathogenesis.

Mast cell activation can occur following many triggers and cell surface receptors, including receptors for IgE, IgG, complement, cytokines, growth factors, stem cell factor, and neuropeptides.[13] Typically, IgE is bound by an allergen and interacts with the high affinity receptor for immunoglobulin E (FcεR1) leading to the activation of tyrosine protein kinase-stimulated degranulation surfaces.[14]  This results in the extravasation of preformed mediators from mast cells and basophils that set off an inflammatory sequence that, in severe cases can manifest in anaphylaxis in the form of angioedema, asthma, urticaria or vascular instability. Genetic factors, again, may modulate the severity of such reactions.[15]

Mast cells can initiate typical allergic manifestations from food, hymenoptera (insect species including bees, wasps, hornets, sawflies, and ants) venom, latex, antibiotics, and pollen, leading to degranulation and elaboration of inflammatory signals that include angiogenesis, tissue inflammation and repair, innate and adaptive immune responses, immune tolerance, and host defense.[16] Mast cells have also been incriminated in many diverse disorders such as Crohn’s disease, malignancy, autoimmunity (including Guillain–Barré syndrome, Sjögren syndrome, vasculitis, and inflammatory arthritis), multiple sclerosis, coronary artery disease, arterial aneurysms, and osteoporosis.[17],[18],[19],[20]  Expansion of mast cell populations also occurs in chronic infections as well chronic renal and hepatic disease. 12

  • Common correlations and triggers of MCAS include Fibromyalgia, Complex Regional Pain Syndrome (CRPS), Irritable Bowel Disease (IBD), Postural Orthostatic Tachycardia Syndrome (POTS), chronic fatigue syndrome(s), Ehlers-Danlos Syndrome (EDS) and autoimmune diseases.
  • Emerging research suggests that the mast cell response correlated with Long COVID is having severe effects on women’s reproductive health.

Endometriosis is an estrogen dependent, chronic inflammatory disease characterized by the growth of endometrial lining outside of the uterus. Mast cells have emerged as key players in regulating not only allergic responses but also other mechanisms such as angiogenesis, fibrosis, and pain. Compared to normal endometrium, endometriosis lesions had significantly higher levels of stem cell factor (SCF), a potent growth factor critical for mast cell expansion, differentiation, and survival for tissue resident mast cells. Endometriosis lesions provide a microenvironment necessary for recruitment and differentiation of mast cells. In turn, mast cells potentially release pro-inflammatory mediators that contribute to chronic pelvic pain and endometriosis disease progression.[21]

Even men are not excluded. Men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) were recruited and evaluated in an open-label, interventional uncontrolled trial after therapy with cromolyn sodium and cetirizine hydrochloride. The primary endpoint was a change in mast cell tryptase concentrations after treatment while secondary endpoints were symptom changes. Isolated cells from post-prostatic massage urine were evaluated for immune changes using mRNA expression analysis. 20/31 men with a diagnosis of CP/CPPS had active tryptase in expressed prostatic secretions. After treatment with cromolyn sodium and cetirizine dihydrochloride for 3-week, active tryptase concentrations were significantly reduced by half along with reduction in the pain, urinary pattern, and quality of life improvements. In addition, there was a downregulation of immune-related pathways involving Th1 and Th17 T and TLR (Toll Like Receptors) signaling along with a marked reduction in macrophages and neutrophils.

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are usually expressed as macrophages, dendritic and mast cells that recognize characteristic microbe compounds, like lipopolysaccharides (LPS). Once these compounds are recognized by TLRs, they activate inflammatory immune cell responses. Mast cell-directed therapy in this targeted subgroup may be effective in reducing symptoms and modulating the immune inflammatory environment.[22]

In sickle cell anemia, caused by a single point genetic mutation in hemoglobin, mast cell activation contributes to the neurogenic inflammation and pain that are the hallmarks of this disease. One study showed that both cannabinoid receptors 1 and 2, specifically found in mast cells, mitigate mast cell activation, inflammation, and neurogenic inflammation in sickle mice.[23]

Mast cell activation strongly contributes to sickle inflammation and pain. Inflammatory mediators, proteases including tryptase and pro-inflammatory cytokines are released from mast cells enhancing inflammation in sickle cell anemia. Tryptase, in addition to enhancing inflammation and neurogenic inflammation, activates protease and promotes nociception.[24]  The sickle microenvironment induces persistent mast cell activation causing hyper-sensitization pain consistent with central nervous system exacerbating roll.[25] Activation of CB1/2 receptors could halt the entire cascade of release of mediators, inflammatory signaling, and control pain.

BCP as Intervention Solution for MCAS

β-caryophyllene is a bicyclic sesquiterpene is found in large amount in essential oils of many food and spice plants such as clove (Syzygium aromaticum), cinnamon (Cinnamomum spp.), black pepper (Piper nigrum L.), and oregano (Origanum vulgare L.). BCP elicits full agonist action on CB2R representing important therapeutic targets in several diseases. Activation of CB2R appears devoid of psychotropic effect of cannabinoids contrary to the CB1 receptors.[26] In addition to CB2R, BCP exhibits potent anti-inflammatory, antioxidant, anti-mutagenic, anti-cancer properties and inhibiting key endocannabinoid degradation enzymes FAAH and MAGL. In a study of the antiallergic potential on mast cells, BCP was investigated using the systemic allergic and immunoglobulin E-induced cutaneous allergic reaction in murine models. Mast cell degranulation occurred, as well as pro-inflammatory gene expression and production. BCP attenuated the allergic reaction and inhibited the mast cell degranulation and histamine release. Furthermore, a decreased expression of TNF, IL 6, and NF kB in mast cells compared favorably with ketotifen fumarate, a standard mast cell stabilizer. These benefits suggest BCP to be a possible therapeutic agent for a broad range of inflammatory and allergic conditions.[27]

In 1995 a study identified mast cell connections to the endocannabinoid system. Mast cells were found to express both the gene and a functional CB2 receptor protein with negative regulatory effects on mast cell activation. Two endocannabinoids were identified as modulating mast cells with palmitoylethanolamide (PEA) and anandamide (arachidonoylethanolamide; AEA), commonly referred to as the Bliss Molecule, binding to the CB2 receptor, but only the former down-modulates mast cell activation in vitro.

This suggests that CB2 receptors control mast cell activation and therefore inflammation. PEA appeared to act as an endogenous agonist for the CB2 receptor on mast cells modulating their inflammatory cascade. Interestingly, PEA is a pleiotropic endogenous lipid mediator used as a “dietary food for special medical purposes cited against neuropathic pain, neuro-inflammatory conditions and down-regulation of mast cell degranulation. Thus, PEA working through the CB2 mechanism offers another alternative approach to controlling MCAS.[28],[29]

In 2008 β-caryophyllene (BCP) was identified as a strong and selective CB2 receptor activator with a broad range of anti-inflammatory effects on standard Lipopolysaccharide-Stimulated (LPS) induced cytokines and nuclear receptors. As a commonly ingested vegetable food, it was postulated that an estimated daily intake of 10–200 mg of this lipophilic sesquiterpene could be a dietary factor that potentially modulates inflammation and other pathophysiological processes via the endocannabinoid system.

In addition, BCP was found to inhibit histamine-triggered edema and inflammation equal to oral dexamethasone, the powerful glucocorticoid steroid.[30] Recent studies demonstrated the ability of β-caryophyllene to reduce pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thereby regulating chronic pathologies of inflammation and oxidative stress. These conditions involved the analgesic, anesthetic, and anti-tumoral effects of BCP on metabolic and neurological diseases in vitro and in vivo.[31]

Mast cells are clearly involved with anaphylactic shock syndrome. Recently it was learned that there are two distinct pathways for this reaction: IGE dependent and IGE independent. The independent pathway goes through adiponectin receptors, type 1 and 2, which are G-protein dependent activators of the mast cell as opposed to the antigen antibody interaction from IGE.

In an anaphylactic study, researchers used BCP to activate the adiponectin signaling pathway that controls the vascular bed. After inducing systemic and cutaneous anaphylaxis in mice, BCP dose dependently, inhibited mast cell degranulation and consequently histamine release. The BCP reversed the drop in blood pressure and stabilized all membranes from excessive permeability. Thus, it not only curtailed the vascular abnormalities, but the numerous cytokines and inflammatory molecules as well as histamine release from mast cells protecting the body and the organism from complications.[32]

In endometriosis, endogenous cells propagate, migrate to abnormal locations outside of the uterus, and form cystic structures. Characteristically, active mast cells and eosinophils are found in the endometrial cyst. In one study BCP suppressed the growth of the implants and produced apoptosis in the endothelium of the cyst and endothelial cells of the associated blood vessels. In addition, BCP exerted a potent anti-inflammatory effect and caused regression of the endometrial implants in a rat model. In fact, low doses of BCP, 10 mg per kilogram, suppress the growth of endometrial implants by 52% compared with controls. Ultra-structural studies showed the presence of active mast cells in the cyst. In contrast with this strong regulatory influence, BCP showed no ill effect on ovulation, pregnancy, and normal delivery. In this case, BCP strictly regulated mast cell activity, probably by preventing cytokine release.[33]

Typically associated with endometriosis is menstrual pain or dysmenorrhea. In one of the few human studies of BCP, forty-eight outpatients diagnosed with primary dysmenorrhea used the topical oils containing BCP in a randomized, double-blind clinical trial.  The oils were a blend containing lavender, sage, and marjoram containing BCP in a 3% concentration. The women massaged the oils into the low abdomen from the end of their last menstruation until the beginning of their next. Both the numeric rating scale and the verbal rating scale significantly decreased (P < 0.001) after one menstrual cycle intervention. The duration of pain was significantly reduced from 2.4 to 1.8 days after aromatherapy intervention in the essential oil group. This formulation showed significant primary dysmenorrhea relief, reducing the duration and the intensity of menstrual pain.[34]

CB2 receptor expression appears to be significantly augmented in ovaries with endometriotic lesions compared to normal ovaries, suggesting that CB2 may be a potential target for immunotherapies against ovarian endometriosis. CB2 receptors appear to be useful for the treatment of inflammation and pain that does not respond well to conventional treatments. Neuropathic pain is characteristic. CB2 receptors modulate cellular functions in immune cells by regulating the levels of cyclic AMP. Promotion of this molecule results in reduced immune regulatory genes leading to immune-suppression and reduced cytokine release. For neuropathic spinal pain, cyclic AMP and A2A receptors activated by BCP seem to be closely involved.[35] Evidence shows that CB2 receptors inhibit MAPK/NF-κB activate μ-opioid, benzodiazepine, and 5-HT1A serotonin receptors along with nitric oxide regulation.[36] Thus, CB2 agonists like BCP, may also be useful for treatment of inflammation and pain.[37]

In conclusion, BCP is a pleiotropic (producing more than one effect) dietary supplement widely available in nutritious foods generally regarded as safe by the FDA. BCP has a firmly established anti-inflammatory, antioxidant, anti-anxiety, anti-depressant, and anti-mutation profile in preclinical studies. β-caryophyllene has unique properties of analgesia that offers a possible solution for a rampant mast cell activation phenomenon now epidemic affecting literally millions of women and men. BCP has been shown to prevent the release of inflammatory molecules and histamines from mast cells and, even, to prevent anaphylactic reactions. By acting at the CB2 receptor and ignoring the CB1 receptors, BCP avoids the complications related to cannabis-THC stimulation. The case studies listed appear to show that Β-caryophyllene is associated with a wide range of resolving symptoms without adverse effects suggesting a potential mitigation of many types of mast cell conditions, including common allergies, anaphylaxis, MCAS, and endometriosis.

  • Townsend newsletter readers can get 10% off their purchase of BCPlus Immunity Blend capsules. Use code TOWNSEND at blairmedicalgroup.shop

References

[1]. Endocannabinoid modulation of allergic responses: Focus on the control of FcεRI-mediated mast cell activation. European Journal of Cell Biology, Version of Record 24 May 2023. https://doi.org/10.1016/j.ejcb.2023.151324.

[2]. Crosstalk between AdipoR1/AdipoR2 and Nrf2/HO-1 signal pathways activated by β-caryophyllene suppressed the compound 48/80 induced pseudo-allergic reactions. https://pubmed.ncbi.nlm.nih.gov/34314522/

[3]. Low Doses of β-Caryophyllene Reduced Clinical and Paraclinical Parameters of an Autoimmune Animal Model of Multiple Sclerosis: Investigating the Role of CB2 Receptors in Inflammation by Lymphocytes and Microglial. International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran. Published online 2023 Jul 19. doi: 10.3390/brainsci13071092

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[5]. Gertsch J. Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action? Commun Integr Biol. 2008;1(1):26-28. doi:10.4161/cib.1.1.6568

[6]. BCPlus liposomal https://www.blairmedicalgroup.com/post/amazing-magic-of-liposomes-for-better-health

[7]. BCPlus Gel https://www.blairmedicalgroup.com/post/transforming-your-skincare-routine-with-bcplus-dmae-topical-gel

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[9]. Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence.  Department of Biophysics Physiology & Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland. 2022 Jun 22. doi: 10.1155/2022/9534163

[10]. Crosstalk between AdipoR1/AdipoR2 and Nrf2/HO-1 signal pathways activated by β-caryophyllene suppressed the compound 48/80 induced pseudo-allergic reactions. Division of Pharmaceutical Technology, Defense Research Laboratory, Tezpur, India https://pubmed.ncbi.nlm.nih.gov/34314522/

[11]. Low Doses of β-Caryophyllene Reduced Clinical and Paraclinical Parameters of an Autoimmune Animal Model of Multiple Sclerosis: Investigating the Role of CB2 Receptors in Inflammation by Lymphocytes and Microglial. International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran. Published online 2023 Jul 19. doi: 10.3390/brainsci13071092

[12]. Jackson et al. Mastocytosis and Mast Cell Activation Disorders: Clearing the Air. Int J Mol Sci. 2021 Oct 19;22(20):11270. doi: 10.3390/ijms222011270. PMID: 34681933

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[14]. Ando, T.; Kitaura, J. Tuning IgE: IgE-Associating Molecules and Their Effects on IgE-Dependent Mast Cell Reactions. Cells 2021, 10, 1697.

[15]. Jackson et al. Mastocytosis and Mast Cell Activation Disorders: Clearing the Air. Int J Mol Sci. 2021 Oct 19;22(20):11270. doi: 10.3390/ijms222011270. PMID: 34681933

[16]. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.  Researchlife, Castelfranco Veneto (TV), Italy. doi: 10.1073/pnas.92.8.3376

[17]. Mast Cell Activation Syndrome in COVID-19 and Female Reproductive Function: Theoretical Background vs. Accumulating Clinical Evidence.  Department of Biophysics Physiology & Pathophysiology, Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland.   Published online 2022 Jun 22. doi: 10.1155/2022/9534163

[18]. National Library of Medicine National Center for Biotechnology Information: Corticosteroids 1 Lake Erie College, 2 Southern Ohio Medical Center https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10672129/

[19]. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide.  Researchlife, Castelfranco Veneto (TV), Italy. doi: 10.1073/pnas.92.8.3376

[20]. Gertsch J. Anti-inflammatory cannabinoids in diet: Towards a better understanding of CB(2) receptor action? Commun Integr Biol. 2008;1(1):26-28. doi:10.4161/cib.1.1.6568

[21]. Lingegowda et al. Role of the endocannabinoid system in the pathophysiology of endometriosis and therapeutic implications. 2022 PMID: 36207747

[22]. Pattabiraman et al. Efficacy of Targeted Mast Cell Inhibition Therapy in Chronic Prostatitis/Chronic Pelvic Pain Syndrome. 2023 PMID: 37442295

[23]. Stander S, Schmelz M, Metze D, Luger T, Rukwied R. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci. 2005;38(3):177- 188

[24]. Vincent L, Vang D, Nguyen J, et al. Mast cell activation contributes to sickle cell pathobiology and pain in mice. Blood. 2013;122 (11):1853-1862.

[25]. Cataldo G, Rajput S, Gupta K, Simone DA. Sensitization of nociceptive spinal neurons contributes to pain in a transgenic model of sickle cell disease. Pain. 2015;156(4):722-730.

[26]. Sharma et al. Polypharmacological Properties and Therapeutic Potential of β-Caryophyllene: A Dietary Phytocannabinoid of Pharmaceutical Promise. 2016 PMID: 26965491.

[27]. Pathak et al. Beta caryophyllene exerts its anti-allergic potency by inhibiting histamine release and pro-inflammatory markers in mast cells. 2018 Proceedings for Annual Meeting of The Japanese Pharmacological Society DOI:10.1254/jpssuppl.WCP2018.0_PO1-4-21

[28]. Facci et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-80. doi: 10.1073/pnas.92.8.3376. PMID: 7724569

[29]. Cerrato et al. Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells. 2010 PMID: 19625089

[30]. Gertsch et al. Beta-caryophyllene is a dietary cannabinoid.  2008 PMID: 18574142

[31]. Viveiros et al. Anti-inflammatory effects of α-humulene and β-caryophyllene on pterygium fibroblasts. Int J Ophthalmol. 2022 Dec 18;15(12):1903-1907. doi: 10.18240/ijo.2022.12.02. PMID: 36536965

[32]. Pathak et al. Crosstalk between AdipoR1/AdipoR2 and Nrf2/HO-1 signal pathways activated by β-caryophyllene suppressed the compound 48/80 induced pseudo-allergic reactions. Clin Exp Pharmacol Physiol. 2021 Nov;48(11):1523-1536. doi: 10.1111/1440-1681.13555. PMID: 34314522

[33]. Abbas et al. Caryophyllene causes regression of endometrial implants in a rat model of endometriosis without affecting fertility. 2013. DOI: 10.1016/j.ejphar.2013.01.011. PMID: 23353590

[34]. Ou et al. Pain relief assessment by aromatic essential oil massage on outpatients with primary dysmenorrhea: a randomized, double-blind clinical trial. J Obstet Gynaecol Res. 2012 May;38(5):817-22. doi: 10.1111/j.1447-0756.2011.01802.x. PMID: 22435409

[35]. Schwarz et al. Terpenes from Cannabis sativa Induce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A2A Receptors. 2023 Mar 29:2023.03.28.534594. doi: 10.1101/2023.03.28.534594. PMID: 37034662.

[36]. Hernandez-Leon et al. Role of β-Caryophyllene in the Antinociceptive and Anti-Inflammatory Effects of Tagetes lucida Cav. Essential Oil. Molecules. 2020 Feb 5;25(3):675. doi: 10.3390/molecules25030675. PMID: 32033302.

[37]. Allam et al. Detection of Cannabinoid Receptor Expression by Endometriotic Lesions in Women with Endometriosis as an Alternative to Opioid-Based Pain Medication. J Immunol Res. 2022 Jun 2;2022:4323259. doi: 10.1155/2022/4323259. PMID: 35692500.

Published May 18, 2024

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.com. Dr. Blair is also available for private consultations and speaking engagements. Please contact him at DrBlairMD@icloud.com and (360) 991-4791.