The Endocannabinoid System Fighting Cabin Fever, Aging and Depression
Nrf2 and Its Role in Attacking Inflammation and Depression
81 years of scientific suppression and now the truth be told. No, I am not talking about global warming, but there are some intersecting historical points where politics and ideology were selected for the few over the masses. Let’s look back at what happened to the electric car from 1890 which could go 14 mph and hold 6 people. Today, the electric car is in its renaissance and is being promoted to address the global warming caused by the gasoline car first introduced in 1893. Funny, history repeating itself. The subject of this article has a similar story that needs to be told. This is a story about the rise, fall and renaissance of hemp. I will review where we are today with hemp as we head toward the shortest day of the year and Cabin Fever!
Hemp was a major agricultural crop at the turn of the 20th century in the United States. The hemp harvest imprinted on the back of the $10 bill in 1920 showed (photo)that hemp was King. By 1937, the hemp kingdom was politically made a bad actor by legal statute. Passage of the1937 Marijuana Tax Act was designed to keep this hemp crop suppressed for the few and it did.
Now we have 7 billion people on a warming planet, and hemp could help. Both global warming and hemp suppression have created these two Black Swans. This article will be talking about hemp’s renaissance and the love affair with the Endocannabinoid System (ECS). I will show why we need to learn about this biological system as we await for the shortest day of the year and how hemp can play a major role in fighting the druthers of winter and Cabin Fever!
I am talking about our mammal biological system, the ECS. The ECS has been the victim of willful blindness which was predictably irrational which started a Black Swan for Hemp in 1937. This suppression continued to 1970 when this botanical became a Schedule 1 drug and criminalized for the masses. Hemp was released from statutory prison in 2018 with passage of the 2018 Farm Bill. Hemp was made legal again after 81 years of political incarceration.
Mood swings and the weather
With the sky dark by 4:30 pm in the afternoon and snow on the roof and the dooryard yet to be plowed, trouble is brewing. There is nowhere to go because everything is closed, which interrupts our socialization and helps to create Cabin Fever. These climate conditions have similar effects around the world when the “sun don’t shine”. These environmental conditions increase the number of people that may take one of 95 different medications for depression. Yes, I said there are at least 95 pharmacological medications that are allocated and directed for the treatment of depression. Why?
Depression is a mood condition characterized by persistent and overwhelming feelings of sadness that can affect your day-to-day activities and how you think, feel, and behave. Sometimes it can affect your outlook on life and make you feel that life isn’t worth living. Depression may also be called major depressive disorder or clinical depression.
Experts aren’t exactly sure what causes depression but believe it is due to a combination of different factors, such as genetic vulnerability, faulty mood regulation by the brain, stress, chemicals in the brain, medications, or medical problems, that all interact together to bring on depression.
The risk of developing depression is higher in women and older people:
● Aged 45 to 64 years of age or the elderly
● People with chronic or acute health conditions
● Who are undergoing a major life event, such as a job loss, divorce, workplace stress, or physical or mental abuse
and yes Cabin Fever!
The ECS is an important molecular system responsible for controlling our bodies homeostasis and is becoming an increasingly popular target of pharmacotherapy in the treatment of depression. Endocannabinoids which our bodies make are: Ester, ether, and amide derivatives of long chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid, and they act mainly as cannabinoid receptor ligands, like the CB1 and CB2 receptors in our body’s.
Endocannabinoids belong to a large group of compounds with a similar structure and biological activity called Cannabinoids. These Cannabinoids now number about 140 known ligands that are found in the Cannabis sativa L plant. The top four are an important external supply of THC, CBD, CBC and CBG are our top four cannabinoids now all the rage. This quartet of cannabinoids will not be the end all to what ails us. However, you and I need to know what they do and can do in supporting the prevention and treatment from depression to cancer!
First Things First
The first thing the government must do, is take THC, the number one most studied cannabinoid off the Controlled Substances Act (CSA) Schedule as a Schedule 1 drug. The pharmaceutical companies have spent millions of dollars and many years of time to replicate these botanical cannabinoids into a pharmaceutical analog. Many of these efforts have failed because mother nature continues to be the dominant force for mankind. The botanical phenomena known as the “Entourage Effect“ is achieved when THC and the other Cannabinoids can work together to give a more potent and targeted effect against diseases. This means these cannabinoids are moving from an adjunctive addition to therapy, to a main therapeutic index to help to suppress the disease and work toward a cure of a disease state.
Cannabidiol (CBD)
Cannabidiol (CBD) is the second most common Cannabinoid studied and is one of the main pharmacologically active phytocannabinoids (plant based) of Cannabis sativa L, and no it does not cure everything! CBD is the non-psychoactive Cannabinoid unlike THC, the deemed bad boy, but does exert a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties working through the ECS.
The chemistry and pharmacology of CBD, as well as various molecular targets, include CB1 and CB2 cannabinoid receptors which serve as a target opportunity for treatment in our homeostatic ECS system. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential that CBD has for many diseases, including diseases associated with oxidative stress, free radicals, and chronic inflammation, all of which are related to aging and plays a part in depression.
Flip the Switch
Inflammation is a stereotypical response to tissue damage. Our most powerful detoxification from chronic inflammation lies deep within, a master antioxidant switch that is inside every cell of our body. It is called Nrf2 (pronounced Nurf-2, and short for nuclear factor [erythroid-2]–related factor 2) and it is so important that it is found in all mammalian species. Nrf2 is an exquisitely sensitive cellular switch that when turned on regulates the activity of over 200 genes, almost all of them involved in either antioxidant defense or detoxification of our cellular makeup!
Because Nrf2 participates in inflammation ablation, it is hypothesized that Nrf2 could play a role in mitigating depressive disorders. Side note, a causative relationship between inflammation and depression is gradually gaining consistency. Nrf2 is capable of activating powerful protective genes and signaling molecules that are critical for our processing of drugs and toxins, for dampening inflammation, removing damaged proteins, and helping repair our DNA.
Measure It to Understand It
Monitoring inflammation is now possible with techniques such as microdialysis and has been extensively documented in experimental and clinical traumatic brain injury (TBI). Altering of the acute inflammatory response may be neuroprotective. Nrf2 is an essential transcription factor that regulates an array of detoxifying important antioxidant defense genes that are expressed in the liver. It is activated in response to oxidative stress and induces the expression of its target genes by binding to the Antioxidant Response Element (ARE).
When you are sitting in the cabin stressing, inflammation occurs, and a number of biochemical mediators, including prostaglandins, cytokines, chemokines, neuropeptides, and nerve growth factor (NGF), are released. In conditions related to chronic musculoskeletal pain, such as osteoarthritis (OA), rheumatoid arthritis (RA), tendinitis, and chronic low back pain (CLBP), these mediators have been identified as key drivers for chronic pain. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf2 can lead to a depressive-like phenotype while induction of Nrf2 could become a new and interesting target to develop novel anti-depressive drugs.
Chronic diseases in the elderly are most likely characterized by the loss of homeostasis during aging or as a result of environmental factors, all of them leading to low-grade stress by pathologic formation of reactive oxygen species (ROS), chronic inflammation, and metabolic imbalance. A review of recent science shows evidence indicating that Nrf2, as the master regulator of multiple cytoprotective responses and a key molecular node within a particular cluster of diseases, provides a new strategy for drug development and repurposing, the antioxidant activity of CBD through Nrf2 activation.
Reactive Oxygen Species (ROS)
Oxidative stress resulting from overproduction of ROS is a key element of the immune system’s response to combat pathogens and initiate tissue repair. However, metabolic modifications resulting from overproduction of ROS also have many negative aspects and lead to the development and/or exacerbation of many diseases. It is believed that the ECS, which includes G-protein coupled receptors and their endogenous lipid ligands, may be responsible for the therapeutic modulation of oxidative stress in various diseases. In this context, the phytocannabinoid cannabidiol (CBD), which was identified several decades ago and may interact with the cannabinoid system, is a promising molecule for pharmacotherapy.
During post‐traumatic inflammation, metabolic products of arachidonic acid, known as prostanoids (prostaglandins and thromboxanes) are released and aggravate the injury process. Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegenerative diseases like dementia, Alzheimer’s, Parkinson’s, and Traumatic Brain injury (TBI).
Prostanoid synthesis is regulated by the enzyme cyclooxygenase (COX), which is present in at least two isoforms, COX‐1 (the constitutive form) and COX‐2 (the inducible form). These two isoforms have been shown to have an adverse effect on brain tissue from several days to several weeks after TBI. Animal studies have been done to show by blocking the COX reactions then recovery to the TBI brain is faster and with better motor outcomes. The acid form of CBD known as CBD-A works to block the COX-1 and COX-2 inhibitors. Because TBI is a leading killer of both men and women, I will plan to make this, “Ask the Expert”, an article in the near future. But right now, let’s get back to depression.
The therapeutic potential of CBD has been evaluated in cardiovascular, neurodegenerative, cancer, and metabolic diseases, which are usually accompanied by oxidative stress and inflammation. The production of many antioxidant enzymes is regulated at the transcriptional level by the transcription factor nuclear factor (Nrf2). Although evidence is accumulating that activation of the Nrf2 pathway represents a promising therapeutic approach to restore the CNS redox balance by reducing ROS-mediated neuronal damage in experimental models of neurodegenerative disorders, only a few Nrf2-activating compounds have been tested in a clinical setting so far, with a lot more to come! How can we fight back?
Vitamins by Funk 1919
Originally, Vitamins were called “accessory substances” which later changed to the term “vitamine” on scientific papers, which then again changed to the word we all know today, the vitamin. Casimir Funk, credited for discovering vitamins, proposed the idea that various diseases could be cured if these nutrients were present in foods.
This initial vitamin discovery spawned various products to enter the market. Names such as Vitamine, Double Strength Yeast and Super Vitamins arrived on shelves and generally contained vitamin B from yeast and included various other ingredients. Mastin’s Yeast Vitamin Tablets, created in 1916, were a leading product of the day and likely most like today’s multivitamins, with vitamins A, B, and C, iron, calcium, and Nux-vomica, a homoeopathic remedy for heartburn. Its label claimed: “This preparation contains vitamines together with other ingredients which should prove of value in helping to improve the appetite, aid digestion, correct constipation, clear the skin, increase energy, and, as a tonic, to assist in putting on weight in weakened, run down conditions due to malnutrition.” It sounds like snake oil, doesn’t it!
By the way, the immune system plays an integral part in executing and creating these factors so that we can stay in balance through the ECS. When we get out of balance, we’re going have a rough ride on the road to good health. So, I believe a “Daily Dose of Wellness” is important to incorporate in your daily taking of CBD. CBD was not included in your daily vitamin regimen when the One-A-Day Vitamin was introduced in 1943 during WWII.
I, the author, like Funk in 1919, consider that cannabinoid, CBD, is another fundamental dietary supplement that keeps the ECS in balance. In 2018, I named and filed a Trademark application for VitaminCBD™ as the very first vitamin of the ECS. VitaminCBD has all the criteria that each and every other vitamin falls under. The DEA and FDA have yet to address my Trademark request. Keep your fingers crossed and get your www.DailyVitaminCBD.com and think about ice fishing, snow shoeing and skiing. By the time you read this article, the days will be getting longer.
Please and thank you.
Authored by:
Eric I. Mitchell, MD MA FACPE CPE
Nrf2 and Its Role in Attacking Inflammation and Depression
81 years of scientific suppression and now the truth be told. No, I am not talking about global warming, but there are some intersecting historical points where politics and ideology were selected for the few over the masses. Let’s look back at what happened to the electric car from 1890 which could go 14 mph and hold 6 people. Today, the electric car is in its renaissance and is being promoted to address the global warming caused by the gasoline car first introduced in 1893. Funny, history repeating itself. The subject of this article has a similar story that needs to be told. This is a story about the rise, fall and renaissance of hemp. I will review where we are today with hemp as we head toward the shortest day of the year and Cabin Fever!
Hemp was a major agricultural crop at the turn of the 20th century in the United States. The hemp harvest imprinted on the back of the $10 bill in 1920 showed (photo)that hemp was King. By 1937, the hemp kingdom was politically made a bad actor by legal statute. Passage of the1937 Marijuana Tax Act was designed to keep this hemp crop suppressed for the few and it did.
Now we have 7 billion people on a warming planet, and hemp could help. Both global warming and hemp suppression have created these two Black Swans. This article will be talking about hemp’s renaissance and the love affair with the Endocannabinoid System (ECS). I will show why we need to learn about this biological system as we await for the shortest day of the year and how hemp can play a major role in fighting the druthers of winter and Cabin Fever!
I am talking about our mammal biological system, the ECS. The ECS has been the victim of willful blindness which was predictably irrational which started a Black Swan for Hemp in 1937. This suppression continued to 1970 when this botanical became a Schedule 1 drug and criminalized for the masses. Hemp was released from statutory prison in 2018 with passage of the 2018 Farm Bill. Hemp was made legal again after 81 years of political incarceration.
Mood swings and the weather
With the sky dark by 4:30 pm in the afternoon and snow on the roof and the dooryard yet to be plowed, trouble is brewing. There is nowhere to go because everything is closed, which interrupts our socialization and helps to create Cabin Fever. These climate conditions have similar effects around the world when the “sun don’t shine”. These environmental conditions increase the number of people that may take one of 95 different medications for depression. Yes, I said there are at least 95 pharmacological medications that are allocated and directed for the treatment of depression. Why?
Depression is a mood condition characterized by persistent and overwhelming feelings of sadness that can affect your day-to-day activities and how you think, feel, and behave. Sometimes it can affect your outlook on life and make you feel that life isn’t worth living. Depression may also be called major depressive disorder or clinical depression.
Experts aren’t exactly sure what causes depression but believe it is due to a combination of different factors, such as genetic vulnerability, faulty mood regulation by the brain, stress, chemicals in the brain, medications, or medical problems, that all interact together to bring on depression.
The risk of developing depression is higher in women and older people:
● Aged 45 to 64 years of age or the elderly
● People with chronic or acute health conditions
● Who are undergoing a major life event, such as a job loss, divorce, workplace stress, or physical or mental abuse
and yes Cabin Fever!
The ECS is an important molecular system responsible for controlling our bodies homeostasis and is becoming an increasingly popular target of pharmacotherapy in the treatment of depression. Endocannabinoids which our bodies make are: Ester, ether, and amide derivatives of long chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid, and they act mainly as cannabinoid receptor ligands, like the CB1 and CB2 receptors in our body’s.
Endocannabinoids belong to a large group of compounds with a similar structure and biological activity called Cannabinoids. These Cannabinoids now number about 140 known ligands that are found in the Cannabis sativa L plant. The top four are an important external supply of THC, CBD, CBC and CBG are our top four cannabinoids now all the rage. This quartet of cannabinoids will not be the end all to what ails us. However, you and I need to know what they do and can do in supporting the prevention and treatment from depression to cancer!
First Things First
The first thing the government must do, is take THC, the number one most studied cannabinoid off the Controlled Substances Act (CSA) Schedule as a Schedule 1 drug. The pharmaceutical companies have spent millions of dollars and many years of time to replicate these botanical cannabinoids into a pharmaceutical analog. Many of these efforts have failed because mother nature continues to be the dominant force for mankind. The botanical phenomena known as the “Entourage Effect“ is achieved when THC and the other Cannabinoids can work together to give a more potent and targeted effect against diseases. This means these cannabinoids are moving from an adjunctive addition to therapy, to a main therapeutic index to help to suppress the disease and work toward a cure of a disease state.
Cannabidiol (CBD)
Cannabidiol (CBD) is the second most common Cannabinoid studied and is one of the main pharmacologically active phytocannabinoids (plant based) of Cannabis sativa L, and no it does not cure everything! CBD is the non-psychoactive Cannabinoid unlike THC, the deemed bad boy, but does exert a number of beneficial pharmacological effects, including anti-inflammatory and antioxidant properties working through the ECS.
The chemistry and pharmacology of CBD, as well as various molecular targets, include CB1 and CB2 cannabinoid receptors which serve as a target opportunity for treatment in our homeostatic ECS system. In addition, preclinical and clinical studies have contributed to our understanding of the therapeutic potential that CBD has for many diseases, including diseases associated with oxidative stress, free radicals, and chronic inflammation, all of which are related to aging and plays a part in depression.
Flip the Switch
Inflammation is a stereotypical response to tissue damage. Our most powerful detoxification from chronic inflammation lies deep within, a master antioxidant switch that is inside every cell of our body. It is called Nrf2 (pronounced Nurf-2, and short for nuclear factor [erythroid-2]–related factor 2) and it is so important that it is found in all mammalian species. Nrf2 is an exquisitely sensitive cellular switch that when turned on regulates the activity of over 200 genes, almost all of them involved in either antioxidant defense or detoxification of our cellular makeup!
Because Nrf2 participates in inflammation ablation, it is hypothesized that Nrf2 could play a role in mitigating depressive disorders. Side note, a causative relationship between inflammation and depression is gradually gaining consistency. Nrf2 is capable of activating powerful protective genes and signaling molecules that are critical for our processing of drugs and toxins, for dampening inflammation, removing damaged proteins, and helping repair our DNA.
Measure It to Understand It
Monitoring inflammation is now possible with techniques such as microdialysis and has been extensively documented in experimental and clinical traumatic brain injury (TBI). Altering of the acute inflammatory response may be neuroprotective. Nrf2 is an essential transcription factor that regulates an array of detoxifying important antioxidant defense genes that are expressed in the liver. It is activated in response to oxidative stress and induces the expression of its target genes by binding to the Antioxidant Response Element (ARE).
When you are sitting in the cabin stressing, inflammation occurs, and a number of biochemical mediators, including prostaglandins, cytokines, chemokines, neuropeptides, and nerve growth factor (NGF), are released. In conditions related to chronic musculoskeletal pain, such as osteoarthritis (OA), rheumatoid arthritis (RA), tendinitis, and chronic low back pain (CLBP), these mediators have been identified as key drivers for chronic pain. In conclusion, our results indicate that chronic inflammation due to a deletion of Nrf2 can lead to a depressive-like phenotype while induction of Nrf2 could become a new and interesting target to develop novel anti-depressive drugs.
Chronic diseases in the elderly are most likely characterized by the loss of homeostasis during aging or as a result of environmental factors, all of them leading to low-grade stress by pathologic formation of reactive oxygen species (ROS), chronic inflammation, and metabolic imbalance. A review of recent science shows evidence indicating that Nrf2, as the master regulator of multiple cytoprotective responses and a key molecular node within a particular cluster of diseases, provides a new strategy for drug development and repurposing, the antioxidant activity of CBD through Nrf2 activation.
Reactive Oxygen Species (ROS)
Oxidative stress resulting from overproduction of ROS is a key element of the immune system’s response to combat pathogens and initiate tissue repair. However, metabolic modifications resulting from overproduction of ROS also have many negative aspects and lead to the development and/or exacerbation of many diseases. It is believed that the ECS, which includes G-protein coupled receptors and their endogenous lipid ligands, may be responsible for the therapeutic modulation of oxidative stress in various diseases. In this context, the phytocannabinoid cannabidiol (CBD), which was identified several decades ago and may interact with the cannabinoid system, is a promising molecule for pharmacotherapy.
During post‐traumatic inflammation, metabolic products of arachidonic acid, known as prostanoids (prostaglandins and thromboxanes) are released and aggravate the injury process. Neural injury leads to inflammation and activation of microglia that in turn may participate in progression of neurodegenerative diseases like dementia, Alzheimer’s, Parkinson’s, and Traumatic Brain injury (TBI).
Prostanoid synthesis is regulated by the enzyme cyclooxygenase (COX), which is present in at least two isoforms, COX‐1 (the constitutive form) and COX‐2 (the inducible form). These two isoforms have been shown to have an adverse effect on brain tissue from several days to several weeks after TBI. Animal studies have been done to show by blocking the COX reactions then recovery to the TBI brain is faster and with better motor outcomes. The acid form of CBD known as CBD-A works to block the COX-1 and COX-2 inhibitors. Because TBI is a leading killer of both men and women, I will plan to make this, “Ask the Expert”, an article in the near future. But right now, let’s get back to depression.
The therapeutic potential of CBD has been evaluated in cardiovascular, neurodegenerative, cancer, and metabolic diseases, which are usually accompanied by oxidative stress and inflammation. The production of many antioxidant enzymes is regulated at the transcriptional level by the transcription factor nuclear factor (Nrf2). Although evidence is accumulating that activation of the Nrf2 pathway represents a promising therapeutic approach to restore the CNS redox balance by reducing ROS-mediated neuronal damage in experimental models of neurodegenerative disorders, only a few Nrf2-activating compounds have been tested in a clinical setting so far, with a lot more to come! How can we fight back?
Vitamins by Funk 1919
Originally, Vitamins were called “accessory substances” which later changed to the term “vitamine” on scientific papers, which then again changed to the word we all know today, the vitamin. Casimir Funk, credited for discovering vitamins, proposed the idea that various diseases could be cured if these nutrients were present in foods.
This initial vitamin discovery spawned various products to enter the market. Names such as Vitamine, Double Strength Yeast and Super Vitamins arrived on shelves and generally contained vitamin B from yeast and included various other ingredients. Mastin’s Yeast Vitamin Tablets, created in 1916, were a leading product of the day and likely most like today’s multivitamins, with vitamins A, B, and C, iron, calcium, and Nux-vomica, a homoeopathic remedy for heartburn. Its label claimed: “This preparation contains vitamines together with other ingredients which should prove of value in helping to improve the appetite, aid digestion, correct constipation, clear the skin, increase energy, and, as a tonic, to assist in putting on weight in weakened, run down conditions due to malnutrition.” It sounds like snake oil, doesn’t it!
By the way, the immune system plays an integral part in executing and creating these factors so that we can stay in balance through the ECS. When we get out of balance, we’re going have a rough ride on the road to good health. So, I believe a “Daily Dose of Wellness” is important to incorporate in your daily taking of CBD. CBD was not included in your daily vitamin regimen when the One-A-Day Vitamin was introduced in 1943 during WWII.
I, the author, like Funk in 1919, consider that cannabinoid, CBD, is another fundamental dietary supplement that keeps the ECS in balance. In 2018, I named and filed a Trademark application for VitaminCBD™ as the very first vitamin of the ECS. VitaminCBD has all the criteria that each and every other vitamin falls under. The DEA and FDA have yet to address my Trademark request. Keep your fingers crossed and get your www.DailyVitaminCBD.com and think about ice fishing, snow shoeing and skiing. By the time you read this article, the days will be getting longer.
Please and thank you.
Authored by:
Eric I. Mitchell, MD MA FACPE CPE
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