Lex Pelger's Endocannabinoid System & Cannabinoids #4: The CB2 Receptor
Lex Pelger's Endocannabinoid System & Cannabinoids #4: The CB2 Receptor
Big Pharma’s certainly aware of the CB2 receptor’s ability to modulate the immune system but as Dr. Appendino poetically commented, “If drug discovery is a sea, then CB2 is a rock that is surrounded by shipwrecked-projects.”
In his paper ‘Is lipid signaling through cannabinoid 2 receptors part of a protective system?’, Dr. Mechoulam comments, “The CB2 receptor has recently been bestowed the title of a ‘cannabinoid receptor with an identity crisis’ [50]. Initially it was presumed to be absent in the central nervous system… However, more recently it was found in microglia, particularly during neuroinflammation, which causes activation of the microglia and enhancement of CB2 levels [13,50]. Its presence in neurons [51] is still controversial – hence the ‘identity crisis’.”
Indeed, the second endocannabinoid receptor identified in vertebrates appears to be ubiquitous to every type of cell circulating in the bloodstream. CB2 receptors are vital players in the body’s response to inflammatory stimuli, help macrophages kill invader cells marked for death, and perform a key role in a number of other advanced immune system functions. They’re even shown to be involved in the rallying of stem cells in the blood that may assist bone marrow transplantation.
Outside the low levels found in various parts of the brain, the CB2 receptor has been found on the surface of the colon, various cell types of the heart, the hepatic stellate cells of the liver that respond to damage, the hormonal nexus of the pancreas, the depths of the bone marrow, the outer layer of endothelial cells across many organs, and are pervasive across the organs of reproduction and on many human tumors. The range of the CB2 receptor is sweeping and far-flung in tissues, from the retina of a mouse’s eye to the tips of its vas deferens in its wee testicles.
However, as Pertwee points out in his excellent review of receptor agonists, one looming problem dogs the research looking into the downstream effect of triggering these CB2 receptors that are nearly global across the body’s tissues and cell types: none of the CB2-selective agonists that have been developed to-date are completely CB2-specific.
In a recent review of selective CB2 receptors, Nevalainen says that despite the potential therapeutic value for “pain relief, cancer therapy, control of nausea and vomiting, and appetite stimulation… their therapeutic benefits are limited by unwanted central nervous system (CNS) side-effects.”
The science of synthetics is as fascinating as it is ignored by the wider cannabis community. They often see natural molecules from the plant as the only valid way to manipulate the human endocannabinoid system. But it’s clear to any historian of science that the widespread nature of the system will obviously necessitate more focused drugs.
The molecules already created in the lab would probably already be under investigation if their original structure didn’t come from the cannabinoid family. There are hundreds of synthetic cannabinoids created by academic labs trying to explore the endocannabinoid system and created molecules that showed effectiveness for diseases often treated by cannabis. JWH-133, one of the many creations by Clemson’s Dr. John W. Huffman, has been found to prevent the amyloid plaques of Alzheimers and to abolish neurotoxicity by preventing microglia activation. The HU-308 molecule created by the research team at Mechoulam’s Hebrew University has been shown to help with pain and the proliferation of neuronal stem cells. Finally, the AM-1241 molecule synthesized by Dr. Alexandros Makriyannis of Northeastern works as analgesic for atypical pain, a strengthener of the body’s own painkillers and an effective treatment in mice for both ALS and bone cancer. However, none of these molecules bind cleanly to CB2 alone. For the pharmaceutical companies looking to use synthetic compounds in the absence of Central Nervous System side-effects, these CB2 agonists are too unruly, too unpredictable.
Despite the limitations of study with the natural as well as the synthetically made cannabinoids, the fruitful avenues of research are as obvious as they are varied.
In Alzheimer’s disease, activating the CB2 receptor with JWH-015 improves macrophage capacity to better remove the buildup of beta-amyloid plaques. The possibilities don’t stop at the neuronal level but rise to mental effects as well. When researchers addicted mice to cocaine, and allowed the rodents to access cocaine supply at the press of a lever, infusing the rodent systems with JHW-133 resulted in the mice pressing the level with less frequency.
For pain, as one paper noted in the review section of its report on the novel synthetic painkiller MDA7, “Several studies have demonstrated that CB2-selective ligands have a significant function in the modulation of pain perception but do not produce the adverse psychoactive effects associated with CB1 receptor activation.” Even the terpenes that give the plant its characteristic aromas help to mitigate pain. Beta-caryophyllene (BCP) - usually known for being a backbone molecule that contributes spiciness to black pepper - is present in many varieties of cannabis and also acts as a CB2 agonist that helps lower pain sensation. The means by which scientists test for painkilling properties in mice is one of the reasons that we should erect a gigantic statue to the many experimental animals who gave their lives to advance the translational knowledge of human biochemistry.
The clinical uses of activating the CB2 system can be seen in the number of diseases in Pacher’s review that initiate an increase of CB2 receptors and activation: “preclinical disease models and pathological conditions [4], ranging from cardiovascular disorders [11], various forms of ischaemic-reperfusion injury [90], gastrointestinal and liver inflammation [13, 150, 151], autoimmune and neurodegenerative disorders [7, 152-154], kidney disorders [4], bone disorders [143, 144], cancer [149, 155-157], and pain [17, 95].” What we learn from the knockout mice with no CB2 receptors is that they have fewer immune cells, lower liver repair ability, more allergies and more bone loss.
And to end on a high note, one of the most widespread and noted effects of CB2 activation and endocannabinoid system in general is the lessening of inflammation. At the conclusion of this Journal of Immunology review of the long list of immune cells with heavy levels of CB2 receptors, the authors list some of the major diseases with documented potential for cannabinoid treatment:
Multiple Sclerosis - the neurodegenerative autoimmune disorder with more clinical evidence on the efficacy of the cannabinoids than any other disease...
Cannabinoids have an inhibitory effect on the immune cells that are primarily involved in the pathogenesis of MS. Studies suggest that the beneficial effect of cannabinoids is due to its effects on both Central Nervous System cells and on the peripheral immune system.
Rheumatoid Arthritis - a disease of the body attacking itself where both topical and orally ingested cannabinoids seem to help greatly...
Diabetes Type 1 (Juvenile Diabetes) - also an autoimmune disorder wherein the immune system attacks the pancreatic cells that make insulin, with an incidence that’s increasing at a rate of 4% per year...
Cannabinoids are shown to suppress insulin-producing islet cell destruction as well as inhibit diabetic neuropathic pain via a CB2-mediated pathway.
Allergic Asthma - if I’ve heard one story on the road, it’s the one about a teenager or young adult smoking their first joint and being able to throw their inhaler away.