Scientists Find New Sources of Plant Cannabinoids

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.

Posted in Cannabination, Contributing Author: Jahan Marcu | 1 Comment »

Preview of cannabis research for 2010

(The following post is from a Science Column which appears in the West Coast Leaf newspaper )

Each year thousands of articles are published about cannabis and cannabinoids.

Because of this promising research, scientists and doctors around the world are taking interest in cannabinoids. Part of the excitement comes from established data showing that cannabinoid receptors may be the most abundant protein in the human brain, and humans also produce a natural, THC-like compound, anandamide. In the first few months of 2010 a wide range of relevant research articles have already been published. Among the highlights: Researchers at the University of Leiden analyzed cannabis smoke and vapor by comparing their effects at the cannabinoid type 1 receptor (CB1R) (1). Both smoke and vapor activate the cannabinoid receptor equally, but vaporization is more efficient because fewer compounds are destroyed or degraded. However, what was shown for the first time was that terpenoids, the fragrant molecules such as myrcene, are a major component of the smoke and vapor.

The authors believe compounds such as myrcene may contribute to therapeutic benefits of medical cannabis.

Guinea pig studies suggest that the cannabinoid type 2 receptor (CB2R) may be helpful in preventing asthma (3). The development of asthma is linked to the activation of C-fibers, and researchers did find that CB2R activation, but not CB1R, could prevent the activation of C-fibers.Activating CB2R could be important in attenuating HIV-associated inflammation, which ultimately leads to destruction of parts of the body such as neurons, resulting in changes in cognitive and motor functions.

When HIV infects a cell, it releases viral proteins that create inflammation and attract healthy immune cells. One such viral protein called tat causes immune cells to arrive at the site of infection and usually become infected by HIV. Tat appears to be inhibited by cannabinods that activate the CB2R. THC and CP55,940 were both able to inhibit tat-mediated attraction and thus suppress this aspect of HIV/AIDS (4).

The cannabinoid receptors are also abundant in the gut. A lot of work has studied the therapeutic role of cannabinoids to treat diseases of the intestines such as infections, irritable bowel syndrome, abdominal pain, etc. Cannabinoids help control the two main functions of the gut: digestion and host defense. The collective research on this subject was reviewed and the authors suggest that academia and industry should fully develop cannabinoids as a treatment for diseases of the gastro- intestinal tract (2).

Nearly every week positive research on cannabis and cannabinoids is published by labs around the world. Despite the promising implications, the work of these pioneering scientists often goes unnoticed in media and the ‘science sections’ of national newspapers. Furthermore, medical schools do not provide any classes on cannabinoids, which forces patients to stay up-todate with the research on their own, in order to better inform their doctors of potential benefits of cannabis.

These examples offer a glimpse of a blossoming research field. By discussing cannabis research with doctors, other patients, friends and family you can prevent more studies from remaining unnoticed, underreported, or misunderstood.

Send your science questions to Jahan.Marcu@gmail.com

References:

 1) Fischedick et al. Cannabinoid Receptor 1 Binding Activity and Quantitative Analysis of Cannabis sativa L. Smoke and Vapor. Chem. Pharm. Bull. 58(2) 201—207 (2010) 2) Izzo et al. Cannabinoids and the gut: New developments and emerging concepts. Pharmacol Ther (2010). 3) Fukuda et al. The Cann. Receptor Agonist WIN 55,212-2 Inhibits Antigen-Induced Plasma Extravasation in Guinea Pig Airways. Int Arch Allergy Immunol 12;152(3):295-300 (2010) 4) Raborn et al. Cann. Inhibtion of Macrophage Migration To the TAT protein of HIV-1 is linked to the CB2 canabinoid receptor. JPET (2010).

Synthetic cannabinoids found in streets of Europe and Japan

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THC protects against MDMA Induced Brain Damage

Clara Tourino, Andreas Zimmer, and Olga Valverde published a provacative article demonstrating that THC can protect against MDMA (ecstasy) induced brain damage. The authors note that the negative effects of long term MDMA use  arise from it’s metabolism. High temperatures cause  “the formation and uptake of MDMA toxic metabolites that increase oxidative stress, causing nerve terminal damage…and eventually axonal degeneration.”

Basically current research suggests that taking MDMA (ecstasy) and going dancing may increase brain damage associated with long term use.

The authors also site evidence that MDMA is often consumed with cannabis (1) (2). They point out that THC has been widely reported to lower body temperature, decrease inflammation, and is a potent anti-oxidant. Interestingly, in animal models of drug abuse THC and MDMA appear to “counter balance” each other. THC is able to attenuate many effects of MDMA including hyperthermia (overheating), hyper-locomotion, and anxiety. However, these authors are the first to explore if THC can actually protect brain cells from MDMA’s toxic effects.

Below is a figure from the publication:

This image shows a vehicle or untreated brain compared to MDMA and THC treated brains. Notice the pale complexion of the MDMA brain slice? This decrease in staining indicates a reduction in important brain proteins, this unwanted protein reduction is prevented when THC is given to the mice.

They also discuss some of the implications of their findings:

“The frequent co-use of both drugs makes it particularly interesting to study the effects of their combination Indeed, previous studies describe the effects of THC and MDMA together in animal models of locomotor activity, temperature, anxiety, reward and THC-dependence. However, the neuroprotective effects of THC on MDMA neurotoxicity have never been reported. In addition, the dose of THC used in this  study (3 mg/kg, i.p.) could be considered a dose consumed by regular moderate cannabis users, and for that reason similar doses are used in the previously reported animal studies.”

So what does this mean to humans?

A few clinical studies on polydrug use have shown that use of cannabis and MDMA leads to deficits in brain function. Yet, the authors point to three studies which suggest that MDMA users that also consume THC have less ‘brain problems’ than “pure MDMA users.” (1) (2) (3)

MDMA also has a therapeutic role in diseases such as PTSD.  Given that THC may reduce possible negative effects associated with MDMA use, i.e., hyperthermia and listening to techno music. Future clinical studies that are examining a therapeutic role for MDMA, should consider including groups of patients that receive a measured dose of both drugs.

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U.C. Center for Medicinal Cannabis Research Submits Report to State of California

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.

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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 “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.

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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.

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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.

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