Cobbers on the Brain

Each day in the United States, about 15 individuals are diagnosed with a fatal motor neuron disease called ALS. This diagnosis is not one that can be lifted: ALS has no known cure. And after the physician mutters the three words “You have ALS,” the individual’s life is changed forever, their days become numbered, and they begin to ask themselves: What is going to happen to me?

What these individuals find out is terrifying, absolute, and unstoppable: ALS will lead to the death of voluntary muscles, and will take away:

• Their ability to move
• Their ability to speak
• Their ability to eat
   and finally…
• Their ability to breathe

But perhaps the most terrifying part about ALS is what it doesn’t take away: your brain.

Individuals diagnosed with ALS retain cognitive function. They are still there mentally, even if their bodies aren’t there physically. And with that information, I will leave you with some food for thought:

Could you imagine watching your body fade away? The effect that this would have on your loved ones? Being constantly aware that you have an expiration date, and that that date is quickly approaching?

I can’t even begin to fathom these feelings, but for over 20,000 individuals in America, these thoughts have become reality.

The Science behind ALS:

• ALS can be divided into two categories
  • Familial (fALS)
    • This form of ALS has an inheritable, or genetic, component.
    • It is likely the result of gene mutations that are inherited in an autosomal dominant fashion.
  • Sporadic (sALS)
    • This form of ALS has no known causes and occurs randomly.
      • Although not inherited, sporadic forms of ALS have also been linked to mutated genes

In addition to two main categories, there are also two main theories as to what is happening within the bodies of individuals living with ALS:

• oxidative stress → mitochondrial abnormalities → protein aggregation
  • This oxidative stress is likely the result of a mutation in the gene

    

    

    SOD1

    • SOD1 is needed to remove dangerous, unstable superoxide radicals that form in the body
    • When this gene is mutated, SOD1 is not able to remove these radicals, and they begin to accumulate within the cell, specifically within mitochondria
      • Soon after their formation, the SOD1 mutants will  get engulfed by healthy motor neurons and will:
        • build up within the cell, or aggregate together
        • cause the aggregation and improper folding of other necessary proteins within the body
        • lead to hyperactivation of the motor neuron, also known as excitotoxicity
          • induce motor neuron death
• RNA dysmetabolism
  • This is believed to be the result of an expanded GGGGCC (G4C2) repeat in the C9orf72 gene
    • This repeat is likely the cause of something known as an RNA gain-of-function mutation in which RNA post-transcriptional modifications are flawed and proper translation of RNA into proteins is unable to occur
    • As a result, RNA transcripts will begin to aggregate together, preventing the translation of proteins needed for the proper functioning of the voluntary muscles in the body.

      

      • • In ALS, specifically, these proteins will aggregate within motor neurons, leading to their death, subsequent muscle atrophy, and thus loss of motor function.

So what can you do to help?

• Raise Awareness
  • The link below is a calendar that was released during ALS awareness month in May that depicts 31 different ways that you can help raise awareness on ALS.
    • Just because it isn’t May doesn’t mean you can’t help raise awareness!
    • http://web.alsa.org/site/PageServer?pagename=AAM_calendar_PA
• Help Fund Research
  • This is a direct link to make donations to the ALS Foundation
    • Read about current research, and how your donation will be used
    • Learn how you can help support current and future ALS research
      • http://www.alsa.org/donate/
• Be kind, be understanding, and help those who can’t help themselves
  • Below is a link to an article giving helpful and meaningful tips to those who have recently been diagnosed with ALS
    • http://www.alsa.org/als-care/resources/publications-videos/factsheets/tips-for-newly-diagnosed.html

http://www.alsa.org/about-als/facts-you-should-know.html

https://www.ncbi.nlm.nih.gov/pubmed/27150074

https://journals.sagepub.com/doi/pdf/10.1177/1073858414561795

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923493/

Stages of ALS

Overview of the ALS

Amyotrophic Lateral Sclerosis or ALS is a fatal disease that affects motor neurons. It is defined by the degeneration of upper and lower motor neurons, but the severity, symptoms, age of onset and cognitive deficits vary from case to case. Ultimately, respiratory failure due to the degeneration of the motor neurons is what causes the death of ALS patients.

What causes the development of ALS?

ALS is classified into two different sub-types: familial ALS (fALS) and sporadic ALS (sALS). The familial forms of ALS account for 10% of total ALS diagnoses and stems from inheritable, autosomal genetic mutations. It is usually characterized by having a family member with ALS as well. Sporadic ALS cases make up the remaining 90% of ALS diagnoses. These patients have no family history of ALS and there is no direct inheritance of a genetic mutation. The average age of onset for sporadic ALS is 56 which is about 10 years later than for familial ALS which is 45.7. These two sub-types of ALS are clinically the same but differ in how the genetic mutations develop. There are genetic mutations found in fALS that are also found in sALS which cause the motor neuron degeneration. However, the difference is the family history of the patient. 

For example, a mutation of the SOD1 gene is found in both fALS and sALS. SOD1 is an antioxidant enzyme that helps defend against Reactive Oxygen Species (ROS) that the cell produces. When there is a mutation in this enzyme, it leads to the oxidative stress that is found in the pathology of ALS. Oxidative stress also can cause  the unfolded protein aggregation that are found in the motor neurons of ALS patients.

The development of this disease can happen two different ways that are linked by common factors. Either oxidative stress and mitochondrial dysfunction cause changes in RNA metabolism leading to the motor neuron degeneration, or mutations in the proteins that bind RNA cause oxidative stress and mitochondrial dysfunction which also leads to motor neuron degeneration. The common links of these two different ways ALS can develop are the oxidative stress, RNA metabolism alteration and mitochondrial dysfunction. These ultimately cause the degeneration of the motor neurons by either protein aggregation, energy deficit or RNA dysfunction.

Caring for those with ALS

There are currently no treatments for ALS that can reverse the neurological damage that it causes. However, current medications aim at slowing the damage the disease causes and managing the pain the patient experiences. Breathing care is used to help patients breathe as their muscles become weaker. Physical therapy is also used to help with pain, walking and mobility to help the patient remain independent for as long as possible. Low-impact exercise is also used to maintain fitness and physical abilities. Other therapies used to manage the disease include occupational and speech therapy, nutritional support and psychological support.

In the late stage of ALS, most voluntary muscles are paralyzed (including those for breathing and swallowing). Patients in this stage usually require a ventilator for breathing and feeding tubes. The ALS association suggests hospice care for patients in the late stage of the disease. When patients received hospice care they were more likely to die in their preferred location (usually outside the hospital) and receive morphine. The final stage of ALS is the most physically and mentally distressing for the patient so it is important that their comfort level and desires are recognized.

What is ALS:

Amyotrophic lateral sclerosis, more commonly known as ALS, is a progressive neurogenerative disease that affects nerve cells in the brain and spinal cord that control your muscles. With ALS, motor neurons in your brain and spinal cord begin to break down and die. When this occurs, your brain is no longer able to send messages to your muscles. This lack of muscle movements causes your muscles to become very weak and muscle atrophy ensues. ALS is particularly difficult for the individual as though ones body may physically be deteriorating, they individual remains mentally sound.

Onset:

In the onset of ALS, the symptoms are often overlook or misread due to them being so subtle in the beginning. The earliest symptoms may include:

• Muscle weakness
• Muscle twitches (fasciculations)
• Cramps and/or tight and stiff muscles (spasticity)
• Muscle loss and/or atrophy
• Slurred and nasal speech
• Difficulty chewing and swallowing
• Excessive choking
• Excessive shortness of breath
• Unintended weight loss
• Hand or leg weakness
• Problems with balance or walking
• Fatigue
• Diminished musculature between forefinger and thumb.

These complaints develop into a more obvious weakness, atrophy, or rigidity that may cause a physician to suspect ALS. The part of the body that shows the earliest symptoms depends on which muscles are affected in that particular individual. Many first see the first effects in the hands or arms and experience difficulty with basic tasks that require manual dexterity (buttoning a shirt, writing, turning a key in a lock). In other people symptoms can initially affect the legs. This can lead to awkwardness when walking or running or notice more frequent tripping to stumbling. When these symptoms first occur in the arms or legs, this is referred to as “limb onset” ALS. Other individual can notice their first changes in their voice and speech, spasms in muscle of the face, jaw, voice box, throat, tongue, and inappropriate, excessive laughing or crying. This is referred to as “bulbar onset” ALS.

Most people that develop ALS are between the ages of 40 and 70, with an average of age 55 with a diagnosis. ALS is 20% more common in men and your risk becomes higher as you age.

Treatment:

Like in neurological diseases, treatment cannot reverse damages that had already occurred, however, we can treat symptoms in an attempt to make lives for comfortable for those affected. Various drugs such as Riluzole, Edaravone, can help to slow the progression of the diseases. Individuals can also partake in various therapies such as breathing care, physical therapy, occupational therapy, speech therapy, and nutritional support.

End of Life Care:

End of life care becomes a relevant topic during late stage of this disease. Late stage is characterized by most voluntary muscles becoming paralyzed, including those used for breathing and swallowing. During this stage, a feeding tube or a ventilator are often necessary. Hospice is often recommended during this final stage of progression. This stage of life can be very painful causing many to be prescribed morphine. This is where the idea of physician assisted suicide becomes a very relevant topic of conversation.

http://alsworldwide.org/care-and-support/article/early-symptoms-of-als-mnd
http://www.alsa.org/about-als/facts-you-should-know.html

ALS, or amyotrophic lateral sclerosis, is a neurodegenerative disease that affects neurons in the brain and spinal cord. This disease is characterized by muscle atrophy, as the neurons that signal and control the muscles are targeted for degeneration. This causes sclerosis, which is scarring or hardening of tissue. The disease is typically diagnosed between ages 40 and 70. There are two types of ALS: sporadic and familial.

• • • • Sporadic: most common form of ALS; can affect anyone
      • Familial: accounts for 5-10% of all cases of ALS; inherited disease

Symptoms of ALS get worse over time and there is currently no cure for the disease. Most people diagnosed with ALS die about 3-5 years after diagnosis, often from respiratory failure. Common symptoms of ALS include:

• • • • Fasciculations, or muscle twitches
      • Muscle cramps
      • Tight/stiff muscles, or spasticity
      • Muscle weakness
      • Slurred speech
      • Difficulty chewing and swallowing

As the disease progresses, individuals may experience difficulty moving, speaking or forming words, and breathing, as well as difficulty with some mental processes. As there is no cure for ALS currently, it is treated mostly to control and slow down symptoms. Treatment is mostly provided by supportive care to keep individuals as mobile and comfortable as possible. Medication, physical therapy, speech therapy, nutritional support, and breathing support are some of the specific treatments available. Despite all of these treatments, the disease can only be slowed down so much.

Due to the fast progression of the disease, much of the focus of ALS is on end-of-life care. There is a large controversy about how to handle this disease toward the end of someone’s life, what treatments should be done, and who should be able to make final decisions during that time. Some of the biggest questions surrounding this topic include:

• • • • Hospice
      • Physician-assisted suicide
      • Decisions at end-of-life

The discussion surrounding hospice is whether or not it is right to stop curing/treating the illness, as well as who decides whether or not the individual should enter hospice care. Hospice is meant for when the illness can no longer be cured and the individual has 6 months or less to live. Hospice is meant to keep the patient comfortable and only provide relief for the symptoms. It is difficult for many individuals to accept that there is no further treatment, that they have less than 6 months to live, and that they will have to spend the rest of their life without any control until they die. This leads to the controversy with physician-assisted suicide. Many people believe that a person diagnosed with ALS should be able to choose this option toward the end of their life in order to stop them uncontrollably watching themselves losing motor control and slowly dying. The main reason for supporting this decision is to avoid pain and suffering, leave the world with dignity and peace, and reduce health care costs. However, others believe that there should be no reason for anyone to choose to die and that it is selfish to choose this option when they have a family or other people in their lives. It is also an argument that people near death should not be responsible for making the decision to take their own life. Many people see physician-assisted suicide as breaking the oath a doctor takes to preserve lives and increasing the value of human life. Finally, the question about who is expected to make the decisions toward an individual’s end of life is often controversial. It is based on a thin line between whether or not the diagnosed individual is able to make their own decision or if the family must make final decisions for them. 

All of these issues create difficult conversations when dealing with ALS and causes struggles when deciding treatment plans for individuals after diagnosis. In order to provide the best care for patients, it is important to keep the patient’s wants and needs as a priority and make decisions based off of what is best for the patient and the remainder of their life.

http://www.alsa.org/about-als/what-is-als.html

https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Amyotrophic-Lateral-Sclerosis-ALS-Fact-Sheet

https://www.lawteacher.net/free-law-essays/medical-law/physician-assisted-suicide-one-of-the-most-controversial-topics-law-medical-essay.php

Marijuana is found in many cultures around the world. People in India used it in ancient times for its medicinal properties. The Rastafari religion in Jamaica promotes cannabis for religious uses. In the United States it has been used illegally for recreational purposes for years and now it is being used at an increasing rate as a medical treatment to some health problems. What is going on in marijuana?

CBD vs. THC

The two main active chemicals in marijuana are Cannabidiol (CBD) and Tetrahydrocannabinol (THC). They are nearly identical to each other in chemical structure with each having 21 carbons, 30 hydrogens, and 2 oxygens. As you can see in the picture below, the only difference is how an oxygen is bound. So if they are so similar in structure, shouldn’t they do the same things?

https://medium.com/cbd-origin/cbd-vs-thc-the-difference-explained-b3cfc1da52f0

That answer is no. These two molecules are different in the ways that they bind to Cannabinoid Receptors. There are two different types of Cannabinoid Receptors: CB1 and CB2. CB1 is primarily found in the brain and in the central nervous system whereas CB2 is mostly found in peripheral organs and the immune system. CBD and THC both bind to the CB2 receptor enabling them to make changes to the immune system and these peripheral organs. But, THC binds to CB1 in the brain causing psychoactive effects like “getting high”. CBD does not bind to CB1 and can actually negate the bond between CB1 and THC, neutralizing the psychoactive effects.

So many companies and states have started using CBD oil as a beneficial product to help boost the immune system of individuals. This also keeps large concentrations of THC out of the brains of these people. That being said, medical marijuana with both THC and CBD are still in use.

Medical Usage states

Medical marijuana has been legalized in 33 States and recreational marijuana has been legalized in 10 states, below is a map of these “green states”. Marijuana has been used to treat migraines, anxiety, cancer, obesity, and general pain.

https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881

Reasons for Hesitation

So if using marijuana as a medical drug can be so helpful to our society, what makes people not want this to happen everywhere?

THC that binds to the CB1 receptors in the brain causes psychoactive effects. One part of the brain that these receptors are very prevalent in is the hippocampus, the hub for memory. With chronic use of marijuana, there is a possibility for long-term effects on the memories of those using.

Another reason is the lack of parameters to police usage. With alcohol, we have a clear limit of how much can be in your blood before you are impaired to drive. With THC it is harder to test, and THC can stay in the body for much longer making the test less accurate.

Conclusion

As I am writing this blog, marijuana is still classified as a Schedule I drug by federal law. This makes it very difficult to obtain marijuana to do research to find scientific evidence of more uses of marijuana. Many people think that we could more easily find a middle ground for marijuana if it were lowered to a Schedule II or Schedule III drug. Along with this we could do more research to possibly make it even better as a medicine and potentially less dangerous.

“I use CBD oil with my dog to calm his separation anxiety when I’m gone or when we travel.”

“I use CBD oil for muscle pain when my neck is sore instead of ibuprofen.”

“I know of many pet owners that give CBD in some form to their pets to help with arthritis.”

These are just a few quotes from people in my life who have had positive outcomes from using CBD oil as a therapeutic technique for various pain, illness, etc. CBD in many forms, but especially oil, has become very popular as a therapeutic way of treating a variety of aches, pains, diseases, and more.

What’s the difference?

CBD (cannabidiol) and THC (tetrahydrocannabinol) are the same compound besides one simple atom. But that one atom has a big impact on the difference between these two compounds.

As shown above, there a tons of cannabinoids in cannabis, but CBD and THC are the most prominent. These cannabinoids interact with the endocannabinoid System (ECS) which basically is a big network of receptors that interact with cannabinoids to maintain vital functions throughout our body (find out more about cannabinoids here https://medium.com/cbd-origin/cbd-vs-thc-the-difference-explained-b3cfc1da52f0). The difference between the two cannabinoids is how it binds to certain receptors in the ECS. These bindings can produce different effects like a psychoactive effect on your brain or not. Another difference between the two is the legality. Hemp-derived CBD is legal in all 50 states, but ‘marijuana’-derived CBD is not legal federally. So if you were to go to a health product store in your town, you will be buying CBD oil from hemp. This is not only because of legality but also because the hemp plant has far more CBD than marijuana plants, which have much more THC.

Possible effects of CBD

For the purpose of discussing CBD, we can use CBD oil as the therapy of choice. For years, many research articles have shown how cannabinoids can help ease anxiety and pain through many ways. Below are some benefits of CBD oil.

1. Reduce anxiety/depressive symptoms
2. Alleviate cancer-related symptoms
3. Relieve pain
4. Benefit heart health
5. May reduce acne
6. Have neuropcrotecive properties (benefit neurological disorder symptoms like spasms, seizures, denigration of neurons)

You can read more on the scientific research behind each of these benefits here: https://www.healthline.com/nutrition/cbd-oil-benefits#section5

As discussed above, CBD oil has several great benefits to it’s use. As with any pharmacological drug that may be prescribed by a physician, the outcomes and side effects will vary from person to person. There can be many factors that impact CBD oil’s effect such as other prescription drugs or over-the-counter medications you take, the dosage and frequency you use CBD oil, and how severe your symptoms of pain. For these reasons and more, it is important to remember that CBD oil will most likely work differently for each person who tries it.

I believe that CBD oil is a great alternative medicine to other drugs. It can be used for such a wide variety of pain and illnesses that when possible, CBD should be studied more in order to further our knowledge of how therapeutic this drug can be.

What are endocannabinoids anyways?

Endocannabinoids are lipid-based molecules that bind to cannabinoid receptors which are from the G-protein-coupled receptor (GPCR) family. These components make up the endocannabinoid system. Endocannabinoids are made in the the body and activate these receptors. The most common endocannabinoids found in the body are Anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These molecules are fatty-acid based molecules that are derived from arachidonic acid and therefore have similar structures. These molecules activate the CB1 or CB2 receptors. The CB1 receptors are typically found in the brain and can influence behavior, memory, cognition and movement.  These receptors modulate adenylyl cyclase and therefore the the intracellular cAMP levels which regulates regulates protein kinase A (PKA) phosphorylation. This causes changes in the cellular activity. The CB2 receptors are predominantly associated with immune cells and modulating the immune system. Activation of these receptors can promote neuro-protection

CBD oil vs. Cannabis

The use of cannabis and cannabidiol oil (CBD oil) to treat various diseases and illnesses is increasing in popularity. However, the differences between the two substances are not very well known. Cannabis is a schedule I drug and is only legal in a few states, whereas CBD oil is legal in all 50 states. THC is the psychoactive component found in cannabis that is not in the CBD oil. The THS is the component that causes the undesirable side effects  and produces the ‘high’ feeling. The CBD oil, however, is non-psychoactive and can yield the same benefits of activating the endocannabinoid receptors without the psychoactive component. CBD can help inhibit adenosine re-uptake. This leads to an increase of adenosine in the brain which can help alleviate anxiety symptoms and improve anti-inflammatory effects.

These substances can be used therapeutically to treat anxiety, Parkinson’s Disease and cancer. Anxiety is reduced due to the activation of the CB1 receptors by THC which is known to have relaxing and mood enhancing effects. However regular use of Cannabis has been shown to worsen symptoms of anxiety.

Endocannabinoids can differentiate between healthy cells and cancerous cells when carrying out apoptosis. There are more CB1 receptors in cancerous cells which lead to more endocannabinoids binding and therefore more apoptosis occurring in cancerous cells. By this mechanism, endocannabinoids can help shrink tumors and prevent metastasis.

The endocannabinoid system is also affected in Parkinson’s Disease. The CB1 receptors are predominantly expressed in sensory motor neurons. The loss of dopaminergic neurons in Parkinson’s Disease causes an overactive inhibitory pathway on the motor thalamus which is why motor issues are displayed in Parkinson’s disease. Using agonists for the CB1 receptors here would regulate the neurotransmitter balance in this area and help restore motor function.

There are still lots of unanswered questions… 

The main issue faced with the therapeutic use of cannabis or endocannabinoid agonist is that these drugs can be hard to access. Due to the fact that cannabis is a Schedule I drug, it is illegal to have possession of this substance. Since it is so difficult to gain access to this substance- even for research purposes- there still is a lot of research to be done to completely understand the drug and all of its benefits as well as side-effects and drawbacks.

Due to its classification as a schedule one drug, not enough research has been done on cannabis. Although we don’t understand everything about cannabis, we do know that the endocannabinoid system is present across the human body, not just in the brain. This is one reason why medical marijuana use can aid in pain control, over/under eating, and cancer.

As a current hot topic in mainstream media, the legalization of medical and recreational marijuana can be compared to the legality of alcoholism. In the case of cannabis, we understand that there are positive health benefits to the drug. In contrast, alcohol possesses no medically beneficial properties and it purely legal for recreational purposes. I wanted to further understand the comparisons between marijuana use and alcohol use. Even former President Barack Obama has shared his opinion regarding marijuana in multiple interviews, stating, “I don’t think it is more dangerous than alcohol.”

To compare marijuana and alcohol, cases of overdose and life-threatening side-effects should be considered first. The CDC has stated that approximately 88,000 alcohol-related deaths occur every year, many having to do with alcohol poisoning/overdose. In contrast, it has been determined by previous research that a fatal dose of marijuana is between 15-70 grams, meaning that an individual would have to smoke between 238-1,113 joints over the span of 24 hours in order to overdose. This makes the annual number of marijuana-related deaths around zero. When it comes to automobile-related dangers, driving under the influence of marijuana is still safer than driving drunk. Although it is still unsafe to drive while high, marijuana increases the likelihood of car accidents by 83% while the consumption of alcohol increases the odds by 2,200%. Likewise, both alcohol and marijuana can lead to addiction or dependence. Since both drugs utilize the reward pathway in the brain, releasing ample amounts of dopamine, both can be addictive and affect an individual’s neurochemistry when used chronically–with alcohol use, this is called alcoholism, and in marijuana use, this is labeled as marijuana use disorder. Although it is common among young consumers and popular media to believe that marijuana is non-addictive, this is a false assumption. The National Institute of Health found that in 2016, nearly 6 million people had experienced marijuana use disorder within the past year–approximately 2.5% of adults. The study also reported that 6.3% of individuals had, at some point in their lives, met the diagnostic criteria for marijuana use disorder.

Most commonly, cannabis binds to the CB1 receptors in the brain. Once bound, endocannabinoid activity usually leads to cell apoptosis or cell death. Previous research studies have identified that this action is why marijuana aids in cases of cancer, attacking the cancer cells. We understand that for unknown reasons, cancer cells possess more CB1 receptors, allowing for more binding, and therefore more cell death than other cells with less CB1 receptors. In regards to the reward pathway, the THC in marijuana binds to the nucleus accumbens, activating the pathway. Likewise, alcohol also leads to the activation of the reward pathway, but in a different way. Alcohol promotes GABA, a common inhibitory neurotransmitter, leading to the activation of the ventral tegmental area and release of dopamine. Although some researchers contemplate the ability of alcohol to activate endogenous cannabinoid pathways, the way in which we currently understand alcohol and marijuana to act in the body remains incredibly different–even if they both lead to the activation of the reward pathway. For these reasons, more research needs to be done to compare the two, especially when considering the legalization of both drugs.

Little research has been done to understand the long-term effects of marijuana use. Before it can be determined whether alcohol or marijuana is worse for humans to consume, more research needs to be done. Although our current understanding of both drugs tends to promote the safety of marijuana over alcohol, too many pieces of the story are still unknown. Likewise, the stigma against marijuana use continues to affect our current understanding of the drug.

https://pubs.niaaa.nih.gov/publications/arh313/185-195.htm

https://www.psychologytoday.com/us/blog/your-brain-food/201012/alcohol-vs-marijuana-in-the-brain

https://www.nih.gov/news-events/news-releases/marijuana-use-disorder-common-often-untreated

https://drugabuse.com/marijuana-vs-alcohol/