The British Journal of Pharmacology (link to article: BJP) has devoted another issue to the theme of cannabinoids. This issue contains numerous intriguing articles that you would be hard pressed to find discussed among media and science outlets.  In a recent NPR Science Friday show on medical cannabis, Ira Flatow and guests suggested that there is a suppression of cannabis and cannabinoid research findings due to politics. This causes some journals to reject cannabinoid research without even reading the manuscript.  Research journals are hesitant to publish research on cannabinoids, and many researchers often have to squander valuable funds re-submitting articles until they find a journal that will allow their research to be peer reviewed.  The BJP deserves our attention for the great service it is doing for cannabinoid researchers—allowing our findings to be shared and discussed. One particular article in the BJP captured the imagination and wonder of cannabinoid science. The authors speculate on additional sources of plant cannabinoids, beyond the cannabis plant.

It appears that other plants produce things that directly and indirectly affect the Endocannabinoid system (ECS). The ECS is a system in our body which produces compounds or ligands that activate specific receptors. This system regulates important functions of mammals. If you have ever slept, eaten, forgot, or relaxed then you have used your ECS.

The receptors for cannabinoids are one of the most abundant receptors in the human brain and are expressed in nearly every tissue and cell. The two main receptors are the CB1 and CB2 receptor. CB1 is located in the brain and on neurons throughout the body, while the CB2 is mostly found in the immune system. Given the abundance of these receptors, it’s not hard to imagine that these receptors are important for something.   However, THC and other cannabis parts are not the only plant compounds which can affect the ECS. Other plants produce compounds which can change the production and breakdown of Anandamide. Anandamide activates the same receptor as THC and is one of many endogenous cannabinoids produced by our body.

The recent discovery of different plants with compounds that can modulate this system means we can no longer simply define plant cannabinoids as merely a product of cannabis. The authors propose that the term phytocannabinoid is more appropriate now that scientists have discovered that Beta-Caryophyllene activates the CB2 receptor and is “among the most abundant plant essential oil component.” Beta-caryophyllene in found in nearly all plants, in fact it was proposed years ago that it is a “dietary cannabinoid.”

So, what else have you been eating that mimics the effects of molecules from cannabis?

Echinacea, Ruta graveolens (Citrus Family), and the Brassica genus (Mustard family, i.e. Broccoli) all contain compounds which may bind the CB2 receptor, some with an affinity or strength similar to THC. Note that unlike the CB1 receptor, the CB2 receptor does not cause psychotropic effects.

Even the Apiaceae family contains a compound which interacts with the CB1 receptor.  Why should you care about the Apiacea family? Carrots.

Carrots and its relatives contain the compound falcarinol.  This appears to interact with both cannabinoid receptors, undergoing a mysterious alkylation reaction at the CB1 receptor. The questions of how and what this compound is doing to the CB1 receptor still needs to be investigated before we can draw any conclusions about the similarities between cannabis and carrots.

Polyphenols are common components of tea and were speculated to interact with cannabinoid receptors. However, according to this article, Gertsch and collegues think that these may be non-specific interactions.  The smelly molecular class of compounds known as terpenoids represents another potential group that can modulate the effects of cannabis and may affect the ECS. Terpenoids are abundant in vegetables and fruit.

One misconception or urban legend regarding cannabis is the presence of cannabinoids in chocolate. Sorry to disappoint some of you but that infamous research has never been duplicated… However what is true about chocolate and cannabinoids is far more fascinating and beautifully complex.  There are fatty acid derivatives in chocolate and many other plants which inhibit the FAAH enzyme. The FAAH enzyme destroys or eats Anandamide. The blocking of this FAAH enzyme leads to an increase or elevation of the levels of Anandamide. That’s right chocolate, like aspirin, elevates the so called “natural THC” in your body. No wonder chocolate is so popular. Halloween will never be the same for this scientist.

It is obvious that phytocannabinoids are found in abundance in nature, is our next step to regulate these plants like cannabis, since large doses of the active ingredients may have some cannabis-like effects?  Maybe less drastic actions should be taken.

A lot of work remains for scientists to determine the effectiveness of these phytocannabinoids and related compounds.  If you want to engage in cannabis research, a great place to start would be looking at other ingredients of a healthy diet for new members of the phytocannabinoid family.

Nature has provided a single plant which produces THC-acid. THC-acid readily becomes THC, the most potent phytocannabinoid known to man. Why does nature not provide a single other plant that produces this compound? When all around us, we can find molecular messengers from plants that influence subtle components of the endcannabinoid system.

The take home message is that fatty acid derivatives, terpenes, and polyphenols are found in numerous plants. Fruits and veggies represent another source, if not treasure troves, of compounds which may interact with the endocannabinoid system.

I don’t know about you but I am certainly looking forward to having my next snack; maybe some fruit, a cup of tea, and just a few bites of chocolate.

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.

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.

The Full Report may be downloaded here: http://www.cmcr.ucsd.edu/CMCR_REPORT_FEB17.pdf

The Press Release can be viewed here:  http://health.ucsd.edu/news/2010/2-17-medical-marijuana.htm

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.

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 “Pharmaceutic 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.

So, if FAAH is over active there will be fewer signals in the brain telling you to eat and sleep, among other things.  If there is not enough FAAH, it will make a person hungry.

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.

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.

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.

Most prescription narcotics such as percocet and vicodin are cut with acetaminophen by pharmaceutical companies. This gives the pain killers more of a “kick.” Without acetaminophen, some pain killers are not nearly as effective. Researchers have been investigating the molecular mechanism for this interaction and the Endocannabinoid System appears to be a big player. Previous research has also shown that there is some “cross talk” between opiate receptors and cannabinoid receptors.

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.