CBD Clues for ALS Treatment

Yet another study shows the potential usefulness of marijuana’s cannabinoids to treat ALS.

Cannabidiol Modulates Genes Linked with Amyotrophic Lateral Sclerosis is the partial title of a new article accepted for publication by the Journal of Cellular Biology.  ALS, amyotrophic lateral sclerosis, aka Lou Gehrig’s disease, is a miserable neuromuscular condition, terribly disabling and nearly always fatal. Like other degenerative, inflammatory diseases, ALS is associated with a demon’s brew of “oxidative stress, mitochondrial dysfunction, and excitotoxicity.”

Perhaps this century’s best know sufferer of ALS is physicist and cosmologist Steven Hawking. Defying the odds, Hawking has lived with this disease for nearly half a century. The ALS pathology has destroyed nerves controlling his muscles. As the nerves wasted, so did the muscles, confining Hawking to a wheelchair and robbing him of speech. But while these motor neurons have decayed, the cerebral neurons in his brain have soared into realms of thought few other humans have attained. He ponders, and rigorously researches, the biggest questions of space and time, black holes, and possible alien life. He cannot stand, yet he stands on the shoulders of Einstein, Copernicus, and Galileo.

A desire to conquer this cruel disease recently inspired many a Facebook video of a volunteer enduring drenching in the ALS Bucket Challenge. Perhaps they may find another glimmer of hope in this research.

Intriguingly, this in vitro study shows that CBD, or cannabidiol, modulates gene expression in stem cells (human gingiva-derived mesenchymal stromal cells (hGMSCs)) “connected with ALS pathology.”

The researchers gave reason for their research choice of CBD in their abstract:

Cannabidiol, a non-psychotrophic cannabinoid, has been demonstrated as a potent anti-inflammatory and neuroprotective agent in neurological preclinical models.

The research demonstrates yet another way CBD and other molecules from cannabis deliver innovative new tools for medical researchers and hope for those suffering neurodegenerative disorders.

 

Your brain on exercise: rewarded with dopamine by cannabinoid receptors.

Lack of enough physical activity is a huge problem in the obesity-plagued modern world. With much of physical activity removed from work and daily life, to be fit and not obese, we have to exercise for extended periods of time, in activities like jogging, fast walking, bike riding and other aerobic exercise. Our willingness to exercise in this way is really a cornerstone of our health, and our society’s health. Probably more than anything single factor, our health care system would benefit from people getting more exercise. New research now reports the crucial role of cannabinoid receptors and our endocannabinoid regulatory system in our motivation to keep moving.

Research out of France, reported in Biological Psychiatry shows how small protein cannabinoid receptors operating in the walls of nerve cells in the  brain reward exercise. This unlocks a key to voluntary exercise, and perhaps ways to promote it.  Also reported in ScienceDaily, the research reported that the endocannabinoid system, especially CB1 receptors in certain parts of the brain, reward our bodies and minds with pleasurable sensations. This research was with mice, not humans, but the physiology and responses are very similar. Lack (or blockage) of these receptors caused a sharp drop in the amount of exercise control mice were willing to do.

For us to continue to exercise, rather than stopping, depends a lot on how we feel. If tired and uncomfortable we might well stop; if exhilarated and “in the zone,” we continue. How we feel during exercise, it turns out, depends much on how much of the feel-good substance, dopamine, our brains produce and receive.  Our dopamine levels, this research shows, are controlled in part by our endocannabinoid systems and CB1 receptors in certain parts of the brain. CB1 receptors are activated by our natural endocannabinoids such as anandamide. They also fit like lock and key and are activated by plant cannabinoids, especially THC, from cannabis.

Dopamine is an organic chemical produced in several areas of the brain. Many brain functions involve dopamine, especially learning, voluntary movement, reward and motivation. We feel higher dopamine levels as enjoyment and are rewarded by the experience, making us want to continue or repeat. Drugs like cocaine increase and prolong dopamine levels. The Bordeaux, France researchers studied dopamine producing nerve cells in the brain’s ventral tegmental area (VTA) known to play an important role in motivation. By working with mice with CB1 receptors present or absent or blocked, they found marked difference in how much running wheel time the rodents would spend.

The researchers had previously found “that the endogenous stimulation of cannabinoid type-1 (CB1) receptors is a prerequisite for voluntary running in mice,” but did not understand the mechanisms. In experiments involving “in vivo electrophysiology, the consequences of wheel running on VTA dopamine (DA) neuronal activity” on mice with combinations of CB1 blockage and GABA blockage. GABA is an inhibitory neurotransmitter that reduces levels of dopamine produced by other neurons. Cannabinoid receptor activation in GABA neurons inhibits this inhibitory effect on dopamine. This “inhibition of inhibition” results in an increased level of dopamine produced in this motivation area of the brain.

Exercise promotes endocannabinoid activation of CB1 receptors and this activation encourages continued exercise. If we exercise enough to allow them, our bodies reward us for the physical activities that are so good for us.

Not mentioned in this research, the “runner’s high” is likely a function of endocannabinoids, along with the endorphins. For earlier evidence of the runner’s high association with the endocannabinoid system check Runner’s high – your body rewarding exercise.

Protecting the brain with cannabinoid receptor activation.

Cannabinoid receptors, small protein structures in the cell walls of neurons (and other cells) have been shown positive effects in protecting the brain from degeneration. Now, new research out of Bonn, Germany confirms how important CB1 receptors and the activation of these receptors, are to the well-being of our aging brains. Science Daily‘s write up of the research was entitled, Bodyguard for the Brain: Researchers Identify Mechanism That Seems to Protect Brain from Aging. The bodyguard mentioned is none other than the CB1 receptor, which is activated by endocannabinoids such as anandamide and also by the plant cannabinoid, THC.  Activation of the CB1 receptors helped protect the brain from inflammation, memory loss, and learning deficiency. It prevented nerve cell loss in the critical hippocampus structure. These were mouse studies but with strong correlation to human learning, aging, memory and dementia.

Seemingly, this research would have important implications for medical cannabis. One of the main effects of  cannabis and its cannabinoids such as THC is the activation of these CB receptors in the brain. This research would imply that such activation provides a neuroprotective, anti-aging effect.

Another implication would include caution towards the use of CB1 receptor antagonists and/or CB1 receptor inverse agonist. Rimonabant, is just such a compound, acting as a blocker and perhaps inverse activator of CB1 receptors. Five years ago there was great hope that this “anti-marijuana” would make an effective weight loss drug, by causing the “anti-munchies.” But just as cannabis provides a mild uplifting “high,” this drug predictably caused the opposite effect, that is depression. It failed approval by the FDA and was later removed in some European markets for its depressive (and sometimes nauseating) effects. The new German research should spur caution about the possible brain degenerative effects of blocking CB receptors.

Regarding the importance of the identification of the CB1 receptor in brain neuroprotection, one of the lead German researchers noted: “The root cause of aging is one of the secrets of life. This study has begun to open the door to solving this enigma.”

Cinnamon, spices and cannabis for anti-inflammation.

Cinnamon

Cinnamon

Both the spice, cinnamon and the medicinal herb, cannabis, provide beneficial anti-inflammatory effects. At least some of these healthy effects are from stimulation of the same receptors in your endocannabinoid receptor system.

Although useful and beneficial when protecting the body against bacterial intruders and other perils, inflammation becomes a medical problem if it becomes chronic. Diseases ending in “itis,” such as arthritis and gingivitis are just two of dozens of such maladies, laden with toxic effects to the tissues affected and destructive to the body in general. Indeed, chronic inflammation has become a key medical villain in the degenerative diseases that bedevil modern society. Such inflammation is now seen as a generator of atherosclerosis and is a potent cardiovascular risk factor.

Cinnamon has long been recognized for health-enhancing properties, including providing anti-inflammatory effects. The spice’s component coumarin, in cinnamomum aromaticum thins the blood. Increasingly, cinnamon appears to be very useful in addressing insulin resistance and diabetes.

At least some of the spice’s anti-inflammatory properties come from its another component shared with other spices, beta-caryophyllene. Cloves, black pepper, rosemary, hops and other spices all provide this component of essential oils.

The plant cannabis also provides anti-inflammatory properties. Cannabinoids such as THC and CBD provide anti-inflammatory effects, but at least some of the anti-inflammatory properties of cannabis also come from the plant terpene, beta-caryophyllene.

Research published in 2008 by The National Academy of Sciences of the USA, an international team of researchers show that beta-caryophyllene is a dietary cannabinoid. A cannabinoid is a substance that activates (or otherwise modulates) our endocannabinoid receptor system. This newly discovered and ubiquitous system has been shown be be a key regulatory system for many of our body’s functions. Activation of the key components of this system, cannabinoid receptors, has been shown to provide health benefits. These receptors come in at least two types, CB1, found mainly on neurons but also elsewhere and CB2, found mainly on immune cells. Activation of CB1 receptors, primarily by THC, provides cannabis its psychotropic effect.

Activation of CB2 receptors, on the other hand, provokes no psychotropic response but does seem to provide useful modulation of the immune response. CB2 receptors are activated by THC, CBD (cannabidiol) and other cannabinoids, and the terpene beta-caryophyllene. CB2 receptor activation triggers an anti-inflammatory, neuron protecting response. The NSA research concludes it abstract with, “These results identify (E)-BCP (beta-caryophyllene) as a functional nonpsychoactive CB2 receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.

As a general anti-inflammatory tactic, consider adding or increasing cinnamon in your diet. Few foods are more nutritious and heart healthy than say, oatmeal flavored with natural cinnamon. Those battling insulin resistance and diabetes might find special benefit. A great move is to replace reduced salt in food with additional beta-caryophyllene bearing spices of several types.

Just be sure to eat your spices, not smoke them.

Your brain on anti-matter. Positron/gamma ray images of cannabinoid receptors in the human brain.

Those interested in medical cannabis will remember that the CB1 receptors, discovered less than 20 years ago, are activated by THC and other cannabinoids in cannabis. This activation provides the psychoactive effects of cannabis and also some of its other health enhancing properties. CB receptors also respond to endocannabinoids produced by own bodies, primarily in our nerve cells. The receptors are part of the endocannabinoid receptor (or regulatory) system, now seen as a major physiological system, with important roles in pain relief, neuroprotection and anti-inflammation, even digestion and vision.

Such CB1 activation by THC from the plant world or anandamide from our own cells, along with other cannabinoids produced by the cannabis plant or our own bodies, can provide profound health benefits. Cannabinoids also work by activating CB2 receptors (primarily found on immune cells). Independent of their actions on receptors, cannabinoids are anti-oxidants, protecting nerve cells and other tissue from oxidation stress.

In the photo below, the CB1 receptors are being marked by the inverse agonist, 18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Inverse agonists tend to cause receptors to respond in ways opposite their response to agonists such as THC and anandamide. In the case of cannabinoid receptors, hope that inverse agonists might serve as obesity control agents has faded with problems from nausea and mood disturbances.

The physics of what goes on during such as PET scan it astounding. The process would appear to be highly hazardous to health, yet the procedure is commonplace and apparently without risk. Markers with affinities for certain cell types, such as the compounds used above, MK-9470, emit anti-matter. A positron is the anti-matter equivalent of an electron. When it is emitted from the source, in this case on a CB1 receptor in the brain, it travels only a short distance, a millimeter or so, before encountering its matter equivalent, an electron.

When matter electron and antimatter positron meet, the result is annihilation. Such an encounter releases a short burst of highly energetic photons in the form of gamma rays. Why matter/antimatter annihilation with accompanying gamma ray burst inside the brain is not fatal is not exactly clear. Perhaps a high-energy physicist could comment. Or even a low-energy physicist after coffee.

During this positron emission tomography, sensors detect where the gamma rays are coming from and map these in a 3D representation of brain anatomy and activity.  In the images above the patterns of gamma rays being emitted from this matter/antimatter annihilation show the relative distributions of CB1 receptors in various parts of the human brain. See the original research for more detail. Although they are most highly concentrated in the brain, CB1 receptors are also found throughout the entire human body, mainly on nerve cell membranes.

Bliss out (and pump up) your brain with exercise.

Just as doing push-ups pumps up the size of your triceps, so does aerobic exercise appear to increase the volume of your brain! American researchers reporting in the British Journal of Sports Medicine show that physical exercise, especially aerobic activity, improves the functioning and structure of the brains of older people.

Improvements in brain size, with increased volumes of grey and white matter, and better brain function were found in both those with and without dementia. The so called functions of “executive control,” that help us carry on our lives planning, remembering and changing tasks are those first attacked by dementia. But study co-author Art Kramer of the University of Illinois notes that these functions are those most helped with exercise. Dementia is not only forestalled, but in some ways actually reversed with 6 months of aerobic activity. Brains benefiting from the exercise exertions of their owners maintained plasticity, essentially the capabilities to continue growing, developing and learning.

Although huge rewards accrue to both brain and body from simply walking, these researchers point out the increased benefit from more rigorous aerobic activities, such as jogging, that cause increases in heart rate and rate of breathing. So by all means walk your 10,000 steps a day, at least 5 miles, but also pick up the pace for some of those steps.  Jogging one of those five miles and moving your heart rate up into your age-appropriate training zone will yield great benefits, toning your body and growing your brain. Professor Kramer summarized, “We can safely argue that an active lifestyle with moderate amounts of aerobic activity will likely improve cognitive and brain function, and reverse the neural decay frequently observed in older adults.”

If you bliss out your brain with exercise, there is now good evidence your brain will return the favor. “Runner’s high,” is a flowing, blissful, pain-free experience associated with aerobic exercise. Formerly, the enjoyable mental and physical state was associated solely with endorphins, the body’s natural opiates. With the discovery of the endocannabinoid receptor system and endogenous cannabinoids produced by our own bodies, such as anandamide and 2-AG, this explanation is taking a new turn. After you begin exercising, your level of natural bliss cannabinoid anandamide elevates, and more of these bliss molecules float in your bloodstream, ready to jump the blood-brain barrier and activate CB1receptors on your nerve cells. The result is pain reduction and mood elevation.  So, in addition to endorphins, endocannabinoids such as anandamide reward you for your exercise efforts.

Better adaptive functioning and increased brain volumes are, at least in part, due to neurogenesis, the birth of new brain cells. Both exercise and cannabinoids promote neurogenesis. So, to gain huge health rewards, second-by-second, year-by-year, for your entire life, bliss out your brain with exercise. Walk every day, run some too, lift some weights, and every cell in your brain and body benefits.