Last month, Dr. Sean McAllister traveled from California to talk in Philadelphia on a potential new breast cancer treatment. Dr. McAllister has been studying the anti-cancer effects of cannabinoids for years and he has discovered that the cannabinoid, CBD (Cannabidiol) is a very potent inhibitor of breast cancer. Usually, his research draws a lot of media interest and then some. His research sparks an interest in the general public, as CBD is also the second most abundant compound on the Cannabis plant.
Dr.McAllister shared his results of his recently published study on CBD and breast cancer. This is not the first paper on the anti-cancer activity of CBD, the McAllister lab also published other articles on cannabinoids and cancer: CBD and Breast Cancer and THC&CBD kill brain cancer cells. The current study is an in depth look at how CBD kills breast cancer cells in an animal model. Specifically, CBD affects a protein called ID-1. ID-1 appears to be a major conductor of cancer cells and thus is an excellent target for a cancer treatment.
There are a variety of ways for a scientist to measure how effective an anticancer drug is. For instance in the image below is an experiment testing how CBD can stop the invasion of cancer cells. When cancer spreads it can eat through tissue, and CBD appears to be able to inhibit this aspect of breast cancer cells. The cancer cells are placed on a gel which contain small holes. The cells are dosed with a drug and after a few days you can count the number of cells that have made it through. This simulates what a tumor does as it eats its way through human tissues. The little black triangles are the cells, you can see that only a half-dozen or so made it through the gel when dosed with CBD (on the right). Without CBD, the control on the left, the cancer cells easily move through the gel.
The therapeutic potential of CBD or a synthetic version thereof, is of interest to pharmaceutical companies. During his presentation, Dr. McAllister mentioned that work may soon start on a CBD and breast cancer clinical trial with STI pharmaceuticals.
However CBD is a scheduled drug in this country, but it doesn’t get you high and has virtually no toxicity! Furthermore, CBD also inhibits the negative effects of THC! Why is this safe and useful compound a scheduled drug of abuse!? Luckily, the government’s view on CBD hasn’t deterred researchers from developing this into a medicine.
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Articles like this and more are also available at www.examiner.com
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There are numerous references in popular Cannabis literature which claim that Cannabis strains can smell like mango, melon, and even grapes. Well, it might not be their imagination. The odor of cannabis comes from over 120 terpenes (a.k.a. terpenoids fragrance molecules) that are made by the plant(1).
The main ingredients in Cannabis Fragrance
Terpenes have some interesting effects on humans, including modulating the effects of THC (2) and decreasing memory loss(3). Terpenes are non-toxic and other types of plants have a unique mixture as well. One terpene is unique to Cannabis (m-mentha-1,8(9)-dien-5-ol). All others occur in fruits, vegetables, and flowers. Many of the beneficial terpenes on Cannabis also occur in tropical fruits. So, maybe it isn’t your imagination when something smells like mango, melon, or even grapes.
Cannabis’ odor molecules may offer benefits to patients, as these molecules have medical applications of their own. At a recent cannabinoid science meeting Ethan Russo M.D. highlighted some of the most interesting aspects of terpenes; the fragrant component of Cannabis(4):
Linolool has anti-anxiety and sedative properties (also in lavender).
Beta-Caryophyllene is a potent activator of CB2 Receptors and is found in nearly all plants.
Myrcene has analgesic, anti-inflammatory, and muscle relaxing properties (also in Mangos).
Nerolidol has sedative and anti-malarial properties (Also in citrus rind). Limonene is also found in citrus rinds and is very abundant in Cannabis.
Limonene is available through retailers by the bottle or barrel
Terpenoids can also alter the effects of THC and other cannabinoids. It’s probably best to think of these skunky molecules as enhancing the positive effects of cannabis and reducing the negative effects of cannabis. For instance, terpenes are also wonderful antioxidants. ‘Skunky’ molecules should not be confused with ‘funky’ odors, from contamination such as fungus or, bacteria, a smell that resembles musk or moldy bread.
Unfortunately and ironically, the smell of this plant causes a lot of trouble. Since THC does not have a smell, drug dogs are trained to find one, very smelly molecule called -caryophyllene-epoxide. It’s an unfortunate catch 22 for Cannabis patients; that the odor molecules in Cannabis are probable cause for police. Yet, smell does not necessarily have anything to do with potency. Even the smelliest Cannabis could, in theory, not have THC in its trichomes.
Non-cannabinoid parts, such as terpenes, are of medical importance and possibly central to understanding the diverse benefits and varieties of Cannabis reported by patients-over 700 varieties of cannabis have been reported.
GW pharmaceutical’s Cannabis extract, Sativex maintains a strict ratio of THC and CBD but also maintains a strict ratio of certain terpenes. The data on the cannabinoid content is widely available on the web and in cannabis scientific literature, yet the company doesn’t mentions what the actual concentrations of terpenoids might be.
You could try to sniff out the culprits but even the most well trained perfumist may not be able to pick out an individual terpene from Cannabis.
Attempting to sniff out the terpene content of Sativex or Cannabis is tempting and it’s hard not to speculate: is it linalool? Is it eugenol? Or is it 1,8-cineole? Only time (and our perhaps our noses) will tell.
Due to concerns over the use of Spice and similar herbal products sprayed with cannabinoids, government officials have been advising that these substances become controlled drugs. The United States has become concerned with this issue…so much so that even I was recently contacted by the Dr. Phil show for information on ‘Spice’ or “K2″. The current Dr. Phil episode was centered around the issue of the safety of these drugs. With limited scientific information fear and fantasy have started to run rampant, overshadowing other important issues surrounding this synthetic phenomena. There is a lot to discuss and learn about these popular drugs, as other countries are starting to deal with the issue. However, there are no studies on the prevalence of use and we are just starting to understand why people are using this stuff.
Here are some links to background info on ‘Spice’:
The UK attempted to deal with the problem but it was soon realized that the reality of the situation would not yield a politically palatable solution. As the scientific community, at least in the UK, basically suggested regulating these herbal preparation or legalizing cannabis would be the responsible thing todo. Let’s review some of this global discussion and we may see what happens when science and politics collide.
To set the stage for the discussion we should start in late 2009 in the UK. The Gordon Brown government had began to reschedule cannabis from a less harmful drug to a more harmful drug, carrying with it immense penalties for use. While this anti-cannabis legislation was being worked out, Spice use seemingly appeared and took off quickly. The reclassification of cannabis may have given the synthetic cannabis industry a push. The government then moved to criminalize all cannabinoids, including natural and synthetic compounds. Scientists began to speak out but the discussion quickly ended when the Chairman of the Advisory Council on the Misuse of drugs, Professor Nutt “was sacked after he said that cannabis is less harmful than nicotine or alcohol and there was no evidence to back the government’s decision to reclassify the drug. “It seems unlikely that any ‘true’ scientist — one who can only speak the truth — will be able to work for this, or future, home secretaries,” Nutt wrote in the Times. The firing of Dr.Nutt sent a message to medical and scientific advisers, that science must fit the governments views or prejudice on the issue. Since then only a handful of scientists have dared published their opinions in scientific and medical journals such as the Lancet and Addiction.
Here is a link to an article on Cannabis by Dr.Nutt : Guardian UK
More links to News Article on UK’s Cannabis reclassification:
As discussions of cannabis and cannabinoid regulations continue, more and more prominent scientists are speaking out. Recently a renowned cannabinoid researcher spoke out at a UK science festival. Here’s an exert from the IACM bulletin and links to News Articles:
“Professor Pertwee, who is an eminent expert on cannabis and
cannabinoids for 40 years, is a former President of the
International Cannabinoid Research Society and a former
Chairman of the International Association for Cannabinoid
Medicines. He says that a group should be set up with expert
pharmacologists, lawyers and police, amongst others, to thrash out
the issue. He wants the “social, ethical, legal and economic
factors in addition to current medical and pharmacological” factors
to be taken into account: “We need a better solution than we have
now.” “You need to avoid younger people taking it: perhaps have
a minimum age of 21. You might have to have it licensed so that
you can only take it if it’s considered medically safe for you to do
so. We have car licences, so why not cannabis licences?” he said.”
As these herbal mixtures are explored they appear to be a complex mixture of synthetic and natural compounds. A team in Japan found 7 sources of these herbal designer drugs contained Oleamide. A generic ban on spice products could lead to banning an endogenous cannabinoid that humans and animals make. It appears to be important for regulating sleep and is being developed as a therapeutic agent. Synthetic variations of Oleamide appear to have anti-cancer activity. If such generic bans continue, Will Oleamide then become the “illegal neurotransmitter?”
In the journal of Addiction Richard Hammersley discusses the dangers of banning spice and related compounds. Hammersley discusses the origin of the politics around synthetic cannabinoids. As Hammersley says a” generic ban may not make criminological sense, and there is a risk that it will make this herbal market more dangerous.”
In online discussions and retailer’s websites, the effects of these herbal preparations are said to mimic cannabis (cannabimimetic). If a ban were to take effect, Hammersley points out, it would turn the users to an illegal market, which would inevitably harm otherwise law abiding citizens, who have chosen not to be involved with an illegal market. These herbal products also pose a difficult problem for law enforcement to identify as these compounds do not have a characteristic appearance or smell. Furthermore, Hammersley also asks, “what other legal products have ever been banned without industry consultation?” This is a unique opportunity to handle ‘herbal highs’ in a responsible manner; rather than give control of their strength, purity, and safety to criminal elements.
Hammerlsey goes on to argue that there is a clear demand for legal ‘highs’ and this may continue to be supplied by other cannabinoids that are not yet banned. The manufactures may have tried to produce a relatively safe product with the desired effect. Perhaps their own market research or self-experimentation has excluded chemicals that have obvious bad effects. Interestingly, some samples contain high levels Vitamin E; perhaps it’s added for it’s antioxidant properties?
Following a ban, these drugs may be replaced with others, leading to the use of truly dangerous ‘highs.’ Without further research there is a serious risk of banning a relatively less dangerous class of chemicals, which will be replaced by more dangerous ones.
In the Lancet, two letters were published regarding the reclassification of synthetic cannabinoids ( 1 & 2). The authors disagree that synthetic cannabinoids “do not have a recognized medical value.” For instance, Nabilone ( a synthetic derivative of THC) is available by prescription in the United States. Originally, these synthetic cannabinoids were developed as therapeutic derivatives of the cannabis plant. The medical use of cannabis and its derivatives has been described in the scientific literature, as well as in the U.S. governments I.O.M. report, and “British Medical Association book Therapeutic Uses of Cannabis.”
They also are concerned that a ban would severely inhibit our ability to respond effectively to potential adverse health effects. Our hospitals have virtually no information that can be used to base advice, provide information, and interventions.
We need more information from laboratory work and cross sectional studies, as there is virtually no medical information on prevalence of use and adverse effects. Presently, the media relies on self-experimentation reports and websites of Internet retailers. The necessary information is unlikely to be forthcoming following a change in the legal status of synthetic cannabinoids.
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Jahan
In order to present research at the ICRS, the data must be unpublished. So the presentations consist of new ideas and cutting edge research. Furthermore, most of the findings are conducted and presented by students. The combination of new research and youthful energy makes the ICRS meetings different from most other research societies.
The research topics range from the treatment of diseases to the evolution of THC synthase in Sativas and Indicas. A few highlights from the meeting were:
THCV delayed the progression of Parkinson’s disease
CB2 receptor activation inhibited cocaine self administration in mice
The CB1 and CB2 receptors in appear to have a therapeutic role in bone health and metabolism
Cannabinoid Acids from the cannabis plant inhibit breast cancer cells
The characterization of endocannabinoids in stem cells
The entire program with summaries of all the research can be downloaded here:
“CB or not CB”
The meeting also held a debate, followed by a vote, to determine if the term “cannabinoid” should be changed to something “politically neutral” which would better describe all the components of the Endocannabinoid System. A move like this would change the name of the ICRS and the terms used in research publications.
Two teams were assembled to have the debate. Raphael Mechoulam led the debate team in favor of changing the term “cannabinoid.” For instance, he suggested that the cannabinoid Type 1 receptor could be changed to something like Human Receptor 184. Another member of Dr.Mechoulam’s team argued that we should change the term, because among the 100 some odd plant cannabinoids only THC is known to bind the CB1 receptor efficiently.
The other team rallied to keep “cannabinoid,” making arguments that changing the term would cause confusion and headaches for decades to come. One scientist argued comically, that we are lucky we call these molecules cannabinoids, because the CB1 receptor gene could have easily been dubbed the “pothead” gene. It was also stated that the term cannabinoid tells a beautiful story about how this receptor system was discovered. In the end, the attendees voted overwhelmingly to keep “cannabiniod” as the official term.
Also of note, Ric Musty retired as the ED of the ICRS and received the lifetime achievement award.
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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.
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The practice of smoking cannabis has probably been around since pre-historic times. There is strong evidence that the plant was extensively cultivated about 6,000 years ago in North Eastern Asia, primarily used for its fiber. Records of medicinal use and physiological effects are found in the earliest pharmacopoeia in existence, attributed to Emperor Shen Nung (2,000 BC). Cannabis most likely diffused from Asia to Persia, India, and other parts of the Middle East before entering Africa and Western Europe. Muslim and Persian trade routes probably introduced cannabis or dagga to Africa during the first few centuries AD. Interestingly, cannabis smoking wasn’t documented in Jamaica until about 1807, after the British empire brought in slaves from India and Africa.
Researchers recently found the 2,700 year-old grave of a shaman that contained about 789 grams of cannabis flower tops. They speculate that the cannabis was used for ritual or medicinal properties. This was a rare find, but archaeologists also have found other evidence of ancient cannabis smoking. Ornate “smoking bowls” have been found at other sites. These vary greatly in design, intricacy, and often contain ancient cannabis resin. Such bowls have been found throughout Africa. It is also thought that tobacco smoking spread quickly in Europe because humans were already familiar with smoking cannabis.
Methods for smoking cannabis have been developed over thousands of years. Early implements worked similarly to the so called Persian “hubble bubble” or hookah. Ancient societies made waterpipes from gourds, animal horns, earthernwares, and even straight out of the ground using a “smoking bowl” and a tube or reed. The modern age offers something new: vaporizer technology. Vaporizers are the result of thousands of years of humans exploring new and better methods for the use of cannabis.
Since the advent of vaporizers the inadequacies of smoking have become more apparent. Vaporizers basically pass ‘hot air’ over the plant material to make a mist or steam. In addition to reducing the exposure to smoke, vaporizers are a more efficient delivery system for cannabinoids.
Take the example of a cannabis cigarette or joint which contains 1 gram (1,000mg) of cannabis with 5 percent CBD (cannabidiol) by weight, or about 50mg of CBD. Upon lighting the cigarette, cannabinoids begin to be destroyed by burning and lost through side stream smoke. Vaporizers can reduce much of this flame-related cannabinoid loss. From that 50mg, some 11.5mg will be delivered to the body through smoking. Research has shown that vaporizers can recover up to 99.5 percent of cannabinoids. However, some loss cannot be prevented, as only some of the CBD is absorbed by the lungs and the rest is exhaled. It is unlikely that cigarettes, vaporizers, or hookahs can change the amount absorbed through the lungs. Scientists aren’t sure how much is exhaled but some estimate it at 30 to 80 percent.
As cannabis re-enters mainstream medicine, vaporizers are beginning to be accepted in hospitals and have been used in recent clinical trials exploring the medical benefits of cannabis. Finding efficient non-smoking alternatives to deliver cannabinoids may be key to gaining widespread acceptance in modern medicine.
Sources: Li, Hui-Lin. The Origin and use of cannabis in Eastern Asia: Their linguistic-cultural implications. Cannabis and Culture, 1975, pgs 51-62.
Jones, Lovinger. The Marijuana Question. 1985, Supplement A pg 463.
Pomahacova et al. Cannabis Smoke Condensate III: The cannabinoid content of vaporised Cannabis Sativa. Inhalation Toxicology 2009, 1-5, iFirst.
Russo et al. Phytochemical and genetic analysis of ancient cannabis from central Asia. Journal of Experimental Botany, Vol. 59, No. 15, pp. 4171–4182, 2008
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.
Invasion assay pic control vs CBD
