The original version of this article first appeared in the Lab Bench Science Column of the West Coast Leaf NewsPaper on June 4th 2010.
The Lab Bench
By Jahan Marcu
A research team from the School of Medicine at Temple University, Philadelphia, presented their preliminary cannabinoid and bone data at a scientific meeting in Anaheim, CA in April. Our results add to a growing body of scientific evidence, suggesting a prominent role for the endocannabinoid system in bone development. For the last year, researchers have been trying to reproduce and build upon previous work on cannabinoids and bone, specifically, by characterizing the effects of removing the CB1 and CB2 receptors from mice.
Few labs have published new discoveries regarding cannabis and bone. However, those that have are surprising so far. Some findings are so profound that the upcoming International Cannabinoid Research Society (ICRS) meeting will have a special symposium to discuss the bone data produced by just a few laboratories.
Research shows that bone cells have cannabinoid receptors and produce endocannabinoids. Bone cells express a lot of CB2 receptors and nerves that traverse our bones produce CB1 receptors. The `anti-cannabinoid’ receptor, GPR55, is also expressed in bone.
These receptors appear to work together to regulate bone health. Some clinical evidence supports the role of cannabinoids in various diseases. The Clinical Endocannabinoid Deficiency (Russo 2004) is thought to underlie many treatment- resistant conditions such as irritable bowel syndrome, fibromyalgia, and chronic pain. Recently, CB1 receptor mutations were linked to migraines, bi-polar disorder, and major depression (Monteleone 2010).
Now CB2 receptor mutations may be linked to lower human bone density and hand-bone strength. Research from Japan and France shows that mutations correlate to osteoporosis in post-menopausal women. The two studies looked at 2,626 elderly adults with and without osteoporosis. A study out in Russia analyzed the hand-bone strength of 574 adults and found that those with CB2 receptor muta- tions had weaker hand-bone strength (Yamada 2007, Karsak 2005, 2009). These all suggest that a less functional receptor is related to poor bone health.
Researchers have been studying how the body responds to traumatic brain injuries (TBI). When TBI occurs in a mouse, endocannabinoids are made and new bone is formed. Thus, cannabinoids may enhance the healing of bones in some instances such as fractures.
Genetically modified mice without the cannabinoid receptors have a deregulated skeleton. Depending on genetic makeup, the animals make too much or too little bone. So, research has shown that cannabinoids can both increase and decrease bone mass. However, all mice without cannabinoid receptors eventually develop severe osteoporosis (Bab 2008).
Plant cannabinoids such as CBDV, CBG, CBN, THC, and THCV may increase the number of bone stem cells in rats (Scutt 2007). Conversely, Anandamide has been shown to increase bone turnover by acti- vating osteoclasts, the cells that remodel or dissolve bone. CBD can inhibit osteoclasts. The infamous diet drug Rimonabandt, or SR141716A, is thought to prevent bone loss in mice by activating GPR55, not the CB1 receptor. Additionally, derivatives like WIN55,212 and some JWH compounds appear to severely inhibit osteoclasts from remodeling bone. Researchers have already speculated that cannabinoids represent a new generation of drugs that could treat a variety of bone diseases. For more information check out this recent review of the scientific literature, which discusses the role of the endocannabinoid system in bone disease and pathology.
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Disclaimer: These views are strictly the views of the author and not those of Temple University or its units.
This blog is not intended to diagnose or treat any disease.
The Los Angeles Times, Sacramento Bee, and the Associated press published articles on studies showing that Cannabis has therapeutic value. The studies were conducted through the Center for Medicinal Cannabis Research (CMCR) at the University of San Diego. The CMCR was created in 2000 to answer the question, “Does Marijuana have Therapeutic Value?”
The CMCR have submitted their report to the legislature and Governor of California, in which the authors claim to “have found reasonable evidence that cannabis is a promising treatment.”
The CMCR report is a summary of the clinical trials on smoked or vaporized cannabis that were conducted by the organization. Basically, the organization spent 10 million dollars and completed 6 clinical trials. These trials demonstrate that cannabis is an effective pain medicine for MS and HIV/AIDS patients. Notably, one study showed that ”low potency” cannabis may be effective at reducing pain with out inducing a “high”.
The CMCR had to overcome numerous setbacks. At least 5 clinical trials were canceled for various reasons. In one instance a clinical trial on chemotherapy induced nausea and vomiting had to be cancelled because not enough cancer patients could be recruited. Additionally, the approval of a study by the government typically took 18 months.
Elsewhere, the Iowa Pharmacy Board is already expecting cannabis to available as a medicine soon. As the board has recommended to legislators that cannabis be rescheduled to allow medical use. Could Iowa potentially distribute cannabis through a pharmacy? Not unless cannabis is removed from schedule I.
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A growing body of scientific research suggests that cannabinoid receptors or the endocannabinoid system may have a therapeutic role in major depression (MD) and/or bipolar disorder (BD). A paper published in “Pharmacological Research” demonstrated that certain variations or mutations associated with the Endocannabinoid system may make humans more susceptible to MD or BD. The current study found that specific mutations in both the CB1 receptor and FAAH enzyme, were found in human subjects suffering from MD and BP. Interestingly, only the CB1 receptor mutations were linked to Major Depression, while both CB1 receptor and FAAH mutations were found patients suffering from bipolar disorders
What is the Endocannabinoid system (ECS)? And why is it linked to emotion?
The ECS is comprised of two receptors, the CB1 and CB2 receptor. The CB1 receptor is perhaps one of the most abundant receptors in the human brain. It is found in high amounts in many areas of the human brain, including parts of the brain important for emotion. It is fairly common knowledge that THC, from the cannabis plant, can activate CB1 receptors. However, humans and many other animals also make a “natural THC” called Anandamide. Anandamide is synthesized by cells in our body, and can impact a variety of natural processes such as eating, sleeping, memory, energy, and mood. Once Anandamide is synthesized it will be degraded or destroyed by another protein FAAH. The enzyme activity or the rate at which FAAH destroys Anandamide will indirectly affect the level of CB1 activity.
Mutations in FAAH or cannabinoid receptors may underlie many diseases; in fact a “Clinical Endocannabinoid Deficiency” has already been proposed to explain some chronic diseases such as “migraines, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis“. A previous study has also linked variations in FAAH and CB1 rceptors to anorexia nervosa and bulimia nervosa.
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I was invited to write a blog for American’s for Safe Access. Here is a link to the ASA blog.
As a member of ASA’s Medical & Scientific Advisory Board, I’ve been actively engaged in pursuing further evidence of the medical efficacy of cannabis based medicine. Some of this work occurred while I was working at the California Pacific Medical Center Research Institute (CPMCRI), and yesterday the findings of that work were published by the peer-reviewed journal Molecular Cancer Therapeutics. With this study, we have shown that cannabis compounds can work together to inhibit glioblastoma (GBM), one of the nastiest and most aggressive of all brain cancers. GBM is the type of brain cancer that caused the recent death of Senator Ted Kennedy.
Tetrahydrocannabinol (THC) is the most prevalent compound found in the cannabis (marijuana) plant. Many studies have focused on THC and its therapeutic qualities, however other compounds in the plant should not be overlooked from a medical and scientific standpoint. In fact, the recently published study illustrates how THC and other compounds (known as Cannabinoids) found in the cannabis plant work synergistically to kill cancer cells and reduce tumor size. The anti-cancer effect, which is mediated through the activation of cannabinoid receptors on cancer cells, has been shown through both in vitro and in vivo experimentation.
The other most abundant compound in the cannabis plant is Cannabidiol (CBD). One of the main findings of our research was how THC and CBD act synergistically to inhibit GBM brain cancer cell proliferation and induce cell death. The research team at CPMCRI, lead by Dr. Sean McAllister, discovered that a ratio of about 4:1 of THC to CBD resulted in a synergistic or enhanced killing effect. We determined that CBD was the most active of 4 other natural cannabinoids, therefore, we tried it in combination with THC.
Interestingly, the individual doses of THC and CBD had little effect on the cancer cells or other proteins in the cells. However, when these two compounds were combined, the amount of cell death, or apoptosis, dramatically increased. And, as if this wasn’t enough, our research team discovered another potential breakthrough from the combined use of THC and CBD — a decrease in the protein known as ERK (extracellular signal-regulated kinase). The levels of ERK, often associated with cancer found in the body, were only affected by the combination of THC and CBD, suggesting that these compounds either converge on a shared pathway or together they activate a specific response in cancer cells.
Since these cannabinoids are relatively non-toxic and selectively kill cancer cells, large doses can be provided for in vivo studies. Hence, a direct injection to the site of the tumor or cancer, versus the more widely used methods of smoke or vapor inhalation, may be the most efficient for killing cancer cells. With more targeted applications, a much higher concentration of the active ingredients can be used without toxic side effects. We also speculate that other, non-cannabinoid components of the plant may also improve anti-cancer activity.
An improvement in the life expectancy of people with GBM has not occurred in 50 years, and because GBM is so aggressive and effective treatments have not yet been found, this study may represent a major breakthrough in the field. The next obvious step is further testing of how this combination of cannabinoids affects brain cancer and finding ways to put this important discovery to use.
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Jahan
Acetaminophen and cannabinoid receptor interactions were the focus of a research article published in the journal of Neuropharmacology in late December 2009. The research demonstrates that the effects of Acetaminophen on pain are mediated through the CB1 receptor. Acetaminophen has previously been shown to elevate the levels of endocannabinoids in the body. Thus increasing the amount of activated cannabinoid receptors, leading to pain relief and anti-inflammatory effects.
The study investigated the effects of acetaminophen in combination with different pain killers. The authors found that a combination of acetaminophen with gabapentin or morphine produced synergistic pain killing effects in rats. The results may have clinical significance because the effect was observed in rats that are a model of spinal cord injury. Interestingly, this synergistic pain relief disappeared when the rats were given AM251. AM251 blocks the Cannabinoid Type 1 Receptor (CB1R) thus inhibiting CB1R activation.
Given the notable toxicity of acetaminophen, cannabinoids might be a reasonable supplement to accompany current treatments for pain.
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Jahan
The Journal of Molecular Psychiatry recently published an LTE from a group of researchers who demonstrated that chronic low doses of the cannabinoid WIN55212, resulted in new brain cells or neurons in the hippocampus of old rats. As we age, our ability to make new cells decreases, this may be the cause of many age related disorders. A class of drugs that can restore neurons may be a potential cure for diseases such as Parkinson’s, depression, etc.
The data was simply amazing–3 weeks of treatment resulted in noticeable effects! So this blog includes the figures from the publication, see below. On the left hand side, Figure A shows brain cells stained with red and green. Green, spindle like, staining indicates neuron growth. Pictures A and B show the typical neuron growth in developing brains. As you can see in pictures E and F, chronic administration of a non-psychotropic dose of WIN55212 restores neuron production in older rats, indicated by the green wisps. Note that this green stain is very low in old rats that did not receive the cannabinoid, pictures C and D.
The authors speculate, “Cannabinoid receptor stimulation therapy may thus provide clinical benefit for humans with age-associated memory impairment.”
Lots of molecules can activate cannabinoid receptors, so take your pick. More research is needed to determine which cannabinoids are the best option. None of the plant cannabinoids have not been explored for this effect. This not the first time cannabinoids have been linked to neurogenesis; HU-210 has also demonstrated similar effects.
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Jahan
Scientists think the most abundant ingredients in tea may mediate activity of cannabinoid receptors. Polyphenols are the most abundant ingredient found in tea leaves. The average western diet usually includes at least 50mg of these polyphenols, the “mediterranean” diet contains at least twice this amount. Polyphenols such as catechins are known for their numerous health benefits including nueroprotection, anti-inflammatory properties, and appetite modulation. These health benefits manifest as reducing the chance of a stroke, slowing cognitive decline, and protecting against obesity. However, there is considerable disagreement on how these polyphenols cause these effects, for instance these researchers hypothesize that these compounds interact with cannabinoid receptor signalling.
Upon analysis the authors found that the compounds in tea actually bind both types of cannabinoid receptors, with notable higher affinity for the CB1 receptor. However, the receptor binding affinity of these polyphenols was relatively weak compared to a synthetic cannabinoid, CP55,940.
The authors speculate, “Signal strength may be amplified in vivo by non-receptor related mechanisms, i.e. Fatty acid amide hydrolase(FAAH)…” Meaning, the combination of polyphenols may activate many things at once in humans. FAAH would be an interesting target because the inhibition of this enzyme makes the levels of endocannabinoids rise.
Will Tea drinking or tea extracts be prohibited because of cannabinoid receptor activity? Does this mean Tea will become a schedule I drug like cannabis? Will 4:20 become the new tea time? Probably not. This is not the first evidence for cannabinoids as part of the human diet. Beta-caryophyllene can activate the CB2 receptor, and it is FDA approved.
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