Over the last decade there have been numerous publications demonstrating the anti-cancer effects of plant and synthetic cannabinoids. Notably, the main ingredient of Cannabis, THC (tetrahydrocannabinol), has demonstrated the ability to kill multiple types of cancers in a variety of cancer research models. CBD (cannabidiol), another common plant component, has also shown the ability to kill cancer cells, recently it has been used to successfully treat breast cancer in a mouse research model of the disease.

Certain types of brain cancer appear to be vulnerable to cannabinoids such as THC and CBD. Scientific research has demonstrated that THC and other cannabinoids can kill extremely aggressive brain cancers known as glioblastoma multiforme (GBM) or grade IV astrocytomas. Researchers have also experimented with combining different cananbinoids for the treatment of aggressive brain cancers. So far, the results have been extremely promising. There is a need for new treatments for GBMs, as current  treatments for these cancers can extend life for up to 15 months, if you’re lucky.

Last year, the journal of Molecular Cancer Therapeutics published research demonstrating that combination’s of THC and CBD, the two most abundant cannabinoids on the plant, can lead to a greater-than-additive or synergistic inhibition of cancer growth. Now, nearly a year to the date, the journal has published another article studying the anti-cancer effects of THC and CBD. The new article takes the next steps towards getting this therapy in to the clinic by testing THC and CBD in animals along side a common brain tumor drug TMZ (temozolomide).

The study was conducted in Spain, and the experiments analyzing the effects of cannabinoids were conducted with tumors or brain cancer cells from human samples and a tumor xenograft mouse model. A tumor xenograft model is basically a cancer that is induced into an animal that has a compromised immune system. This allows researchers to give a mouse a tumor consisting of human cells, thus a promising anti-cancer treatment can be tested on a human tumor in a more natural environment, than a petri dish.

The plant cannabinoids used for this study were “kindly provided by GW pharmaceuticals.”  THC and CBD were also provided as plant extracts or “botanical drug substances,” meaning they contained small amounts of other cannabinoids. Allowing these researchers to construct a custom anti-cancer, Sativex-like substance.  Other synthetic cannabinoids such as SR141716A and SR144528 were donated by Sonafi-Aventis.

The figure below shows that THC and TMZ can drastically inhibit the size of tumor.

In the following figure, the authors also examined combinations of THC,CBD, TMZ , and SAT-L (a “botonical drug substance” or extract containing a 1:1 ratio of THC and CBD, 7.5mg each). Interestingly their results also showed that TMZ resistant cells, can be killed by cannabinoids or in combination with cannabinoids.

The researchers conclude that:

“Taken together, our observations support that the administration of cannabinoids, and in particular of Sativex, which is currently used for palliative applications in patients with cancer and multiple sclerosis, alone or in combination with TMZ, could be of potential interest for the management of GBM.”

Cannabis-based medicines are most often prescribed to increase quality of life or treat symptoms of disease. As research continues on this ancient medicine, scientific data suggests that cannabinoids are not only promising treatments but represent potential cures.

Links to Cannabinoid & Cancer Studies:

Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition

Cannabidiol enhances the inhibitory effects of Delta⁹-tetrahydrocannabinol on human glioblastoma cell proliferation and survival

Cannabinoids for Cancer Treatments: Progress and Promise

Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum stress-related genes

Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines

Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma

Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation

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Recently, a Doctor came out against using Cannabis for the treatment of HIV/AIDS. Among oncologists, his opinion is probably in the minority. This Doctor claims that no HIV patients he knows, would benefit from Cannabis. Unfortunately, the Doctor only discussed his opinion and did not site any current research from controlled studies to support his stance. Current research  in HIV/AIDS and cannabinoids has been promising– practically every clinical trial that has looked at HIV/AIDS and THC has shown that cannabinoids may help patients.

Some of the first patients that were infected with HIV were treated at San Francisco General Hospital.  It was probably there, that the medical staff first noticed patients who used Cannabis seemed to be doing better. Notably, cannabis became known as an effective treatment for HIV/AIDS wasting syndrome.  Among the medical staff, was Dr. Donald Abrams who recorded his observations and would later go on to conduct some of the most important clinical trials in the history of cannabinoid research. Dr. Abrams demonstrated that smoked Cannabis could effectively alleviate neuropathic pain in HIV/AIDS patients. Videos of Dr.Abrams presenting his results can be viewed here: Cannabis & Neuropathic Pain, Dr. Abrams, pt 1 and Cannabis & Neuropathic Pain, Dr. Abrams, pt 2

Later, other researchers would show, in a similar group of HIV patients, that smoked Cannabis can modulate pain where conventional opiates were ineffective. The beneficial effect of cannabis on HIV/AIDS symptoms in humans has inspired other researches to take a closer look at the mechanisms behind these effects.

A research team from Virginia Commonweatlh University showed that natural Delta9- THC and synthetic CP-55,940 could inhibit the HIV inflammatory response through the Cannabinoid Type II (CB2) Receptor. Once HIV invades a cell, the virus makes the cell secrete many proteins to attract other immune cells and this leads to the ongoing infection of other cells. One such protein called Tat is important for viral replication and gene expression; the effects of this protein on cell migration appear to be inhibited by both synthetic and natural cannabinoids. The main finding of these researchers is that cannabinoids can slow the migration of uninfected cells towards the Tat protein and thus could inhibit the HIV infection process and the associated inflammation.

Another research group also thought that the previous worked on HIV and cannabinoids was unbelievable. So, they sought to see if THC made the disease worse in monkeys. The researchers infected monkeys with SIV and studied them for 1 year. SIV is the equivalent of HIV in humans. Their research was published in September 2010 and the entire article can be found here:Molina Article on THC attenuates SIV.

Note that each monkey costs around $8,000.00 for the research study.

The researcher demonstrated that THC slows the progression of HIV in primates. See  Figure 4 below from the Article by Molina et al.

SIV THC Figure 4

In Figure 4, there are two groups of monkeys. The solid line is the THC group and the dotted line is the control group (no drug). Within 11 months, 80% of the control group died (dotted line). In the group that received the drug THC, no deaths were reported.

The authors conclude :”this study is the first to report in vivo experimental data demonstrating that chronic THC initiated prior to, and continued throughout the asymptomatic phase of SIV infection, does not impair the host’s ability to control viral load, and does not increase morbidity and mortality from the infection… THC treatment clearly did not increase disease progression, and indeed resulted in generalized attenuation of the classic markers of SIV disease (set point viral load/viral level in general)…based on our results and reports in the literature, we speculate that retention of body mass,attenuation of viral replication, and an overall immunosuppressant effect of cannabinoids may contribute to the amelioration of SIV disease progression seen in our study.”

However, THC is only part of the story. There are over 500 compounds on the Cannabis plant and some of these compounds may contain powerful medical properties which could treat a variety of diseases including Cancer and HIV/AIDS. For instance researchers have found that Cannabis extracts which contain Denbinobin can inhibit HIV replication in a petri dish. Denbinobin is found on the Cannabis and other plants as well.

The therapeutic promise of this plant remains high and some states have medical laws allowing the use of Cannabis for HIV. Furthermore, Marinol or synthetic THC in a capsule remains available by prescription in the U.S. GW pharmaceuticals has an extract available for the treatment of HIV symptoms but it is not allowed in the United States. It is available in Canada, UK, Spain, and soon to be available in South America.

Disclaimer: The information is not intended to treat and diagnose any illness. The views expressed are those of the author and do not reflect those of any University or its affiliates.

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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.

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.

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.

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In the journal of Clincal Pyschopharmacology, a research team reports on the improvement of schizophrenic symptoms in a small group of patients who were treated with pure Delta9-THC (Marinol AKA Dronabinol). The doctors sought out patients who had chronic refractory schizophrenia and had a documented history of cannabis use. After going through about 200 patients, the doctors found a total of 6 that met the criteria.

Generally, cannabinoids are associated with the worsening of psychotic symptoms. So, why did Doctors give THC, the main ingredient in cannabis, to a group of patients who had severe cases of mental illness?

The authors write, “The idea for our use of dronabinol in this population came from the surprisingly good response of 1 patient. He was grossly psychotic, assaultive, disorganized, and highly refractory to multiple medication trials. However, in reviewing his history, we noted that he had a history of several years of calm behavior when he was using marijuana.”

After treatment with pure THC the authors note, ” Remarkably, he became calm, logical, nonviolent, and cooperative within days and was discharged within weeks. This prompted us to try dronabinol on other patients who fit this profile: having a diagnosis of chronic refractory schizophrenia, together with a history of marijuana use during which they reported some improvement.”

In regards to the safety profile of synthetic THC, the author’s comment that it “does not seem to have significant addictive potential or withdrawal in clinical practice.”

These results are remarkable patients with refractory schizophrenia because current interventions and treatments rarely succeed. These patients were also unresponsive to standard dopamine blockers, thus the abnormalities could lay in a non-dopamine system, i.e, the endocannabiod system. Perhaps the abnormalities may be related to the endocannabinoid deficiency theory.  Since there is no viable treatment–there us an urgent need to find and develop medications for this patient population.

Additionally, these results go against the current accepted theory that activating the cannabinoid receptors (CB1) should worsen psychotic symptoms and blocking the receptor should improve it. Another piece of supporting evidence against this theory, comes from a clinical trial with Rimonabant, a CB1 Receptor Blocker. CB1 Blockers prevent other compunds from activating the receptor, thus limiting the activity of the receptor. The Cb1 receptor blocker did not improve symptoms.

The Doctors also site current research (1,2,3) which shows that not all cases of schizophrenia become worse after using Cannabis. It is also now being considered that vulnerability to the side effects of cannabis comes from a genetic predisposition.

The take home message is that the main ingredient of cannabis may become an effective treatment for patients with a severe mental illness. And that the Endocannabinoid system might be more important and complex than previously thought.
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