CANNABINATION

Cannabinoid Receptors: A Link Between Genetic Variations and Depression

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 “Pharmaceuticl 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.

Tags: brain research, cannabinoids, cannabis, CB1, CB1 Receptor, depression, DNA mutation s, ECS, endocannabinoid system, genetic variations, Jahan Marcu, neuroscience, THC

“Published Study Shows How Cannabis Inhibits Brain Cancer”-ASA Blog

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 Synergizes Through the CB1 Receptor

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.

Tags: Acetaminophen, cannabis, cannabis research, CB1, CB1 Receptor, gabapentin, Morphine, Opiates, Pain killers, Pain Relief, science

Chronic Low Doses of a Cannabinoid Causes New Brain Cell Formation

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.

Tags: cannabis, cannabis research, endocannabinoid system, marijuana research, neurogenesis, NIH, research, science

The most abundant ingredients in Tea can activate cannabinoid receptors

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.

Gender’s emerging role in the Endocannabinoid System

Women and men percieve and respond to cannabis differently. Interesting gender differences are begining to be uncovered through animal studies, drug surveys, and clinical trials. Here are a few differences that have been published recently:

• Notably, estrogen can attenuate or inhibit various cannabinoid induced homeostatic changes such as appetite, body temperature, and brain activity.In other words, estrogen may allow women to be less susceptible to effects from cannabis or other cannabinoid medicines. Implying women can handle the effects of the drug better than men. Shel Silverstein’s “Smoke Off” provides a good analogy.
• In animal studies (Review, Original research Article) on mice without the type 1 cannabinoid receptor (CB1), there appears to be a gender dependent phenotype. Male mice develop “strange” bones earlier, resulting from the removal of the CB1 receptor. In the first few weeks of life ,male mice without this receptor have remarkably higher bone volume. However, both genders develop severe age related osteoporosis later in life. It is also interesting to note, that this gender disparity is not observed in all transgenic mice without cannabinoid receptors–only in mice missing the CB1 receptor. Mice without the CB2 receptor have equally bad bones; gender independent effects.
• The ‘putative’ cannabinoid receptor GPR55, also displays similar gender dependent effects. When knocked out or removed from mice, the males have higher bone mass or volume compared to females.
• Another study completed at Temple Medical School in Philadelphia also showed sex dependent differences in mice without CB1 receptors. These differences were in reward seeking behaviors when it comes to cocaine and food. Basically male mice without CB1 self administer less cocaine and and less sweet food (Ensure). This research suggests that the cannabinoid system modulates appetite differently between genders.
• Drug abuse surveys have shown that women and men endorse different issues when it comes to cannabis use and abuse

As new cannabinid drugs are brought to market, and cannabis is becoming available in pharmacies around the world; more research is needed which tracks potential gender differences in response to cannabinoids.

Don’t stress over a drug test–Hunger and stress elevate THC levels

A recent animal study out of Australia showed for the first time that food deprivation and stress hormones may enhance the release of THC stored in fat, thus increasing the amount of cannabinoids in the blood. The results may provide a mechanism for so called “Cannabis Flashbacks,” explaining instances where ex-cannabis users that were exposed to stress or under went weight loss, tested positive for THC.

THC is a lipophillic, fat loving or fat-like compound, that is rapidly absorbed or stored in fat. Interestingly, some researchers have discovered that THC accumulates in rodent gonadal fat tissue (epididymal) at higher levels than any other fatty tissue including the brain and liver (Ravitch 1979). In, humans it is still somewhat unclear where most of the THC gathers for its stay in the body. The precise mechanism whereby THC is released from fat is unknown but it appears THC is NOT metabolized in fat. THC is degraded by the liver to the excreted product: 11-Hydroxy-THC. Furthermore, THC has been found in fat 28 days since the last exposure. This long term storage of THC is consistent with observations that users can test positive after 77 days at levels >20ng/ml (Ellis et al 1985).

The authors suggest that it could be possible for THC to cause intoxication after being stored and released from fat. However,several things can cause THC release: stress,food deprivation, weight loss, exercise, physical or mental stress. However, MUCH MORE research is need in order to determine if it’s even possible to cause a measurable intoxication. Important questions remain like, “What’s the difference between a ‘perma-high‘ and a ‘cannabis flashback’? Will eating a lot of food and remaining sedentary help you test negative for THC? And if THC intoxication can occur from physical activity, then could Santonio Holmes have caught the winning pass in super bowl 43 while intoxicated?…similar analogies apply to Ricky Williams, Rob Van Dam, Michael Phelps, and other professional athletes.

Eating your way through a drug test is an attractive speculation. However, it would olny work if it was balanced with remaining abstinent from cannabis use.