Chronic pain afflicts millions of people around the world and represents a healthcare expense that cannot be effectively mitigated. The use of NSAIDs and opioids is not always effective in all its forms; this is why research has turned to other molecular pathways different from those affected by these two categories of drugs. Neuropathic pain, for example, is a debilitating condition that results from the activation of peripheral nociceptors (a type of neuron), the chemistry of which cannot always be controlled with opioids or regular painkillers. Among other things, the clinic is well aware of the often serious side effects associated with their use. In light of this, research is focusing on alternative molecules, often of natural origin. Among these, the latest discovery is beta-caryophyllene.
This natural organic compound is present in the essential oil of many plants and spices, to which it often gives aroma. It is present in black pepper, oregano, basil, cinnamon and even cannabis, to name a few. In the latter it is an analgesic component but does not have the psychotropic effects of THC. Together with eugenol, beta-caryophyllene is responsible for the analgesic effect of cloves, much appreciated (even today) by dentists to relieve the pain of tooth decay. A very recent discovery is that it is able to modulate the cannabinoid receptors involved in pain regulation. These receptors are studied as mediators of analgesia, as their interaction with exogenous and endogenous ligands (anandamide, PEA and virodhamine are well known) leads to a reduction of pain.
Of the two cannabinoid receptors, CB1 is expressed more in the central nervous system (although it has also been detected in the liver, spleen, heart and skeletal muscle), while CB2 is expressed at a peripheral level and in the immune system. The latter is important for energy regulation, neurotransmission and immune response, phenomena that underlie processes such as neurodegeneration, diabetic neuropathy and neuropathic pain of various kinds. The activation of CB2 receptors is pain-relieving both directly (action on primary neurons, which thus release endorphins), and indirectly (action on immune cells, with blocking the secretion of inflammatory cytokines). This information is of particular relevance, because beta-caryophyllene binds and activates the CB2 receptor.
The molecular pathways activated by this interaction are multiple (protein kinases, ion channels, lipid mediators), and have the aim of attenuating pain by promoting the release of endorphins by somatosensory neurons, but also of suppressing inflammatory pathways (p38, NF-kB, COX2, iNOS) of immune origin which can contribute to exacerbating pain. The molecular synergy favors the reduction of the inflammatory state, but also of cellular oxidative stress through induction of antioxidant enzymes (GSR, SOD1, CAT). More recent experiments have also proven how it inhibits the enzyme monoacyl-glycerol lipase (MAGL) which is used for the synthesis of arachidonyl-glycerol (AraG), a brain endocannabinoid. Aside from these actions, beta-caryophyllene is antimicrobial and may also have a certain anxiolytic effect.
This makes it useful in conditions in which the pain has an infectious component (e.g. osteomyelitis, herpes neuralgia, etc.) or psychological component (e.g. chronic back pain, fibromyalgia and similar). Very recent data indicate that the most promising indication for this substance is the treatment of neuroinflammation (search for this keyword on the site for further information). In fact, various in vitro studies, in laboratory animals and on humans have demonstrated the effectiveness of this substance in the treatment of various forms of neuropathy. In animal models of neuropathic pain, beta-caryophyllene is more effective than a synthetic CB2 agonist that acts on spinal cord neurons. Therefore it could be effective in treating debilitating and long-lasting pain conditions.
Apart from diabetes, beta-caryophyllene can improve neuropathy induced by anticancer drugs (especially taxanes such as paclitaxel and docetaxel) used for breast, stomach, prostate and lung cancer. A 2021 study found it experimentally effective also in the pain of rheumatoid arthritis, a very debilitating condition that afflicts almost 1.5 million people in U.S. alone. In this context, in the form of oxide, the substance interfered with the activation of the NRLP3 inflammasome, producing active cytokines (IL-1 beta and TNF-alpha), responsible for inflammation and part of the painful process in the disease. RA is an autoimmune condition for which the participation of the emotional state as a recrudescence factor has been demonstrated (e.g. repeated states of psychological and depressive stress).
As previously mentioned, beta-caryophyllene is also found in cannabis and is a cannabinoid CB2 type agonist. But unlike THC, it is not psychoactive, that is, it does not alter the state of consciousness; indeed, it is slightly anxiolytic and this has its impact on the intensity of the pain. This is because the compound does not activate the CB1 receptor, which is instead activated by THC. Medicine knows well that the anxious and psychosomatic component can amplify the pain threshold. Adding an anxiolytic effect can better manage chronic pain with a central component (also dictated by the emotional state). This makes beta-caryophyllene a medically safe molecule, adding the fact that it is approved by both the American FDA and the European Food Safety Authority (EFSA).
- edited Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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