What is β-Caryophyllene?

β-Caryophyllene (BCP) is a member of a class of organic molecules called terpenes. Terpenes are small hydrocarbon-based molecules called isoprenes produced by nearly all plants. The possible combinations of 3 carbon atoms and 8 hydrogen atoms of which all isoprenes are comprised yields a vast array of compounds including terpenoids or terpenes, which are combinations of isoprenes. As such, terpenes are sometimes referred to as isoprenoids.

Such a vast array of combinations enables plants to create identifying characteristics much like fingerprints, such as flavor and aroma. Limonene provides the fresh, lemony scent associated with lemons. Humulene imparts the sharp and bitter taste characteristic of hops. Linalool is the primary terpenoid giving plants in the lavender family their familiar scent regardless of species. At least 30,000 terpenes have been found in nature to date. 

Cannabis sativa is a particularly rich and diverse source of terpenes. Up to 140 terpenes have been found among some 470 cannabis chemovars with the 40 being the largest number of terpenes found in a single cannabis plant. 

Many in the cannabis industry claim that terpenes and other molecules in the cannabis plant can interact or synergize with the main cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) to provide unique therapeutic benefits. This hypothesis has been described as the “Entourage Effect” [1-4]. While there is, as yet, no definitive evidence substantiating the entourage effect, what is clear is that terpenes themselves have their own unique therapeutic benefits. 

Numerous terpenes, including BCP, have been described to have analgesic, anti-inflammatory, anti-anxiety, sedative, and other beneficial effects in both animal and human studies [5]. This has focused intense interest on terpenes as potential natural, non-opioid therapies to improve human health.

The most intense interest has focused on BCP. Early studies suggest that BCP specifically binds to the non-psychoactive cannabinoid receptor (CB2), suggesting it could have benefits without psychoactive side effects [6] that cause feelings of euphoria or intoxication. Since that time, the picture of how BCP works has become more complex, but its therapeutic promise remains.

BCP in Pain

Many studies now show that BCP can relieve different types of pain, including acute pain [7] and neuropathic pain [8, 9]. In my own studies, we showed that BCP could relieve neuropathic pain to roughly the same extent as THC or morphine [8]. The same studies also showed that BCP could relieve this pain with no addictive side effects, strongly suggesting it could be a powerful approach to treating pain without the dangerous, negative side effects associated with the commonly-used medications. 

While a number of studies have shown that BCP can relieve pain, the mechanism by which it does so is far less clear. A few studies have suggested that BCP can alleviate pain through the cannabinoid receptors in your body [9]. My own work suggested that BCP relieves pain by activating Adenosine A2a receptors in the spinal cord, the very same receptors that are blocked by the drug caffeine [8]. This work is ongoing, and will further support and refine and understanding of the use of BCP in pain management.

So, what is missing? What stands between where we are and using BCP as a pain treatment in the clinic? 

One vital next step is a comprehensive analysis of BCP side effects and tolerability. It is a Generally Recognized as Safe (GRAS) by the Food and Drug Administration, so BCP is broadly considered to be safe for consumption by humans and animals and is therefore commonly used in food products we consume daily. As noted above, studies conducted by my teams found the drug had no addictive liability. 

However, much remains to be learned through further scientific and clinical investigation. Does the drug have unwanted sedative or other side effects? What is the true therapeutic profile? Are there interactions with other drugs commonly used among certain patient populations? 

We are committed to finding answers to these questions and striving to make pharmaceutical-grade products that are rigorously evaluated through clinical research this humble molecule from ordinary plants we eat every day—cloves, black pepper, hops, sage and more—is a true and effective alternative for treating many types of pain.

BCP in Treating Addiction

Recent evidence has shown that BCP could potentially be effective in blocking opioid reward and treating opioid and other drug addictions. Animal experiments have shown that BCP can prevent rats from self-administering methamphetamine [10] and cocaine [11]. My own unpublished research has shown that BCP can block the rewarding effects of opioids like morphine. In addition, my previous work showed that combining low doses of opioid and BCP made the resulting pain relief more effective than either alone [8]. This raises the intriguing possibility of co-formulating BCP with a drug like morphine to provide better pain relief with substantially reduced or no addiction liability. These findings also suggest that BCP might be used to treat active addiction.

Although the research is still in the early stages, we are steadfastly committed to exploring these and other possibilities with cutting-edge research and by expanding our network of collaborators and partners in this effort.

The future for the therapeutic potential of BCP is bright. With sound scientific research and high-quality product development, BCP may have a role in blunting the scourge of the opioid epidemic by creating new, non-addictive therapies that are equally effective and safe for long-term use.

References

[1] Ferber SG, Namdar D, Hen-Shoval D, Eger G, Koltai H, Shoval G, et al. The "Entourage Effect": Terpenes Coupled with Cannabinoids for the Treatment of Mood Disorders and Anxiety Disorders. Curr Neuropharmacol. 2020;18:87-96.

[2] Russo EB. The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No "Strain," No Gain. Front Plant Sci. 2018;9:1969.

[3] Pamplona FA, da Silva LR, Coan AC. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Front Neurol. 2018;9:759.

[4] Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344-64.

[5] Liktor-Busa E, Keresztes A, LaVigne J, Streicher JM, Largent-Milnes TM. Analgesic Potential of Terpenes Derived from Cannabis sativa. Pharmacol Rev. 2021;73:98-126.

[6] Gertsch J, Leonti M, Raduner S, Racz I, Chen JZ, Xie XQ, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008;105:9099-104.

[7] LaVigne JE, Hecksel R, Keresztes A, Streicher JM. Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific reports. 2021;11:8232.

[8] Schwarz AM, Keresztes A, Bui T, Hecksel R, Pena A, Lent B, et al. Terpenes from Cannabis sativa induce antinociception in a mouse model of chronic neuropathic pain via activation of adenosine A2A receptors. Pain. 2024.

[9] Aly E, Khajah MA, Masocha W. beta-Caryophyllene, a CB2-Receptor-Selective Phytocannabinoid, Suppresses Mechanical Allodynia in a Mouse Model of Antiretroviral-Induced Neuropathic Pain. Molecules (Basel, Switzerland). 2019;25.

[10] He XH, Galaj E, Bi GH, He Y, Hempel B, Wang YL, et al. beta-caryophyllene, an FDA-Approved Food Additive, Inhibits Methamphetamine-Taking and Methamphetamine-Seeking Behaviors Possibly via CB2 and Non-CB2 Receptor Mechanisms. Frontiers in pharmacology. 2021;12:722476.

[11] Galaj E, Bi GH, Moore A, Chen K, He Y, Gardner E, et al. Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARalpha and PPARgamma: repurposing a FDA-approved food additive for cocaine use disorder. Neuropsychopharmacology. 2021;46:860-70.