The Endocannabinoid System: A Master Regulator

Function of the Endocannabinoid System

The endocannabinoid system (ECS) was a mysterious being for quite some time, considering its recent discovery in only 1988. Although it is still in its infancy from a research standpoint, it is now known to be a major regulator with one primary goal: maintaining homeostasis. Many researchers consider the ECS to be the most important physiological system in establishing and maintaining human health. This is due in large part to the extensive network of cannabinoid receptors (CBR) located throughout the central nervous system (CNS), from neurons to immune cells to glands to organs. The ECS has been shown to be involved in many imperative processes:

  • Appetite and digestion

    Neuroprotective effects of CB1R activation through GSK-3 inhibition (Snitow, Bhansali, and Klein, 2021).
  • Immune function and inflammation
  • Mood
  • Sleep
  • Reproduction/fertility
  • Learning and memory
  • Pain
  • Motor control

Due to the wide range of ECS functions and receptor activation, the use of endocannabinoids, specifically cannabis, have been implicated in the treatment of a variety of diseases. Some of these diseases include multiple sclerosis (MS), Alzheimer’s disease (AD), and Huntington’s disease (HD). This is due to the fact that activation of CB1R by endocannabinoids have been shown to promote neuroprotective effects (Kendall and Yudowski, 2017). It has been found that administration of THC increases phosphorylation of Akt in the hippocampus, striatum, and cerebellum, mediated by CB1R (as phosphorylation was blocked with CB1R antagonist). Along with this, THC was also shown to increase inhibitory phosphorylation of GSK3ß (Ozaita, Puighermanal, and Maldonado, 2007). GSK3ß inhibition is involved in the activation of Wnt signaling and its target genes, one of these genes being BDNF which is heavily involved in neuroprotection. Inhibition of GSK3ß is also involved cell proliferation and survival (Snitow, Bhansali, and Klein, 2021). The molecular underlying of CB1R activation through THC has shown to provide neuroprotective effects in battling neurodegenerative disease. Along with maintaining homeostasis, the ECS may be necessary for much more.

How does the ECS Work?

The ECS utilizes endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and enzymes to break down endocannabinoids. The endocannabinoids, 2-AG and anandamide (AEA), are retrograde ‘neurotransmitters,’ meaning they work from post to pre-synapse, rather than pre to post-synapse. Also, rather than being synthesized prior to use and stored in vesicles such as traditional neurotransmitters, endocannabinoids are rapidly synthesized upon demand. They are then released into extracellular space where they bind to a CBR on the pre-synaptic terminal (Lu and Mackie, 2016). There are two main types of cannabinoid receptors:

Crystal structure of the human cannabinoid receptor (Hua et al., 2016).

 

  • Cannabinoid Receptor 1 (CBR1) – a G-protein coupled receptor (Gi/o) abundant in neurons of the CNS (cortex, basal ganglia, cerebellum, and hippocampus)
  • Cannabinoid Receptor 2 (CBR2) – a G-protein coupled receptor (Gi/o) abundant in the immune system and associated structures

Some researchers hypothesize that there may be a third cannabinoid receptor as well. Although, these are likely widespread with each receptor having a specific function (Sallaberry and Astern, 2018). Lastly, the ECS has specific enzymes used to break down the endocannabinoids. AEA is primarily degraded by the enzyme fatty acid amino hydrolase (FAAH). A second degradation process may be through oxidation via cyclooxygenase-2 (COX-2) to form prostamides. 2-AG may be degraded by three hydrolytic enzymes: monoacylglycerol lipase (MGL) and alpha/beta domain hydrolases 6 and 12 (ABHD6 and 12). It may also be oxidized by COX-2, or under rare conditions, hydrolyzed by FAAH. MGL is the primary degrading enzyme for 2-AG (Lu and Mackie, 2017).

The ECS and Cannabis Use

The ECS interacts with both delta-9-tetrahydracannabinol (THC) and cannabidiol (CBD) in the marijuana plant, but in differing ways. THC is most similar to AEA, as they are both low-efficacy agonists of the CB1R (Lu and Mackie, 2017). Although, THC produces a high while AEA does not. This is due to the enzyme, FAAH, which breaks down AEA but is not able to break down THC. Therefore, THC acts as competitive inhibitor for the body’s natural endocannabinoids which produces a dramatic effect due to its psychoactive properties. Although, AEA has been shown to produce calming effects. Researchers believe CBD works through inhibiting the FAAH enzyme from breaking down AEA to produce a calm sensation without psychoactive side effects.

References

Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294

Lu, H.-C., & Mackie, K. (2016). An introduction to the endogenous cannabinoid system. Biological Psychiatry, 79(7), 516–525. https://doi.org/10.1016/j.biopsych.2015.07.028

Ozaita, A., Puighermanal, E., & Maldonado, R. (2007). Regulation of PI3K/AKT/GSK-3 pathway by cannabinoids in the brain. Journal of Neurochemistry, 102(4), 1105–1114. https://doi.org/10.1111/j.1471-4159.2007.04642.x

Sallaberry, C., & Astern, L. (2018). The Endocannabinoid System, Our Universal Regulator. https://doi.org/10.22186/jyi.34.5.48-55

Snitow, M. E., Bhansali, R. S., & Klein, P. S. (2021). Lithium and therapeutic targeting of GSK-3. Cells, 10(2), 255. https://doi.org/10.3390/cells10020255

Perceptions of Obesity

Introduction to Obesity

Heart disease is the leading cause of death in the United States, with approximately 660,000 people dying of this condition every single year.[1] Heart disease is a very broad term that includes many different types of specific heart conditions. The most common type of heart disease is coronary artery disease, which is characterized by the build-up of plaque in your coronary arteries.[2] This cardiac disease is most commonly attributed to poor lifestyle habits including a lack of exercise, smoking, and a poor diet.[3] Obesity is also a major contributor to coronary artery disease (and is a potential consequence of the aforementioned lifestyle habits).[4] Obesity is a prevalent problem around the world, but it is considered an epidemic in the United States due to its prevalence. In 2018, 42.4% of adults were considered to be obese in the United States.[5]

Now that you have some basic information about obesity, I would like to use my social studies knowledge to compare and contrast obesity it two different countries: America and  Mauritania. I will compare how obesity is perceived in these two countries and the prevalence of the condition, just because I think it is interesting to analyze and learn about. After delving into the social science aspect of obesity, I will then dive into the neuroscience. We will dip our toes into the water of Lake Obesity before diving head-first into the deeper waters of said lake.

Obesity in America

I already discussed some of the statistics regarding obesity in the United States, so I will not rehash those. I will, instead, discuss the general perceptions and representation of obesity in America. As I stated previously, obesity in American society is pretty common. A little under half of the population is considered to be obese. Despite its prevalence, there are a lot of negative stereotypes that accompany the image of obese individuals. Individuals who are obese are often thought to be lazy, unintelligent, and weak-willed.[6] Many individuals believe that weight is something that should be in a person’s control, but those who are obese have simply failed at remaining in control of how much they eat and exercise.[7] As I will discuss in a later section, this belief is not entirely true (hint: neurochemistry is involved).

Many people are fighting the stigma of obesity by promoting “body positivity,” which is a movement that encourages people to love their own body, no matter their weight. It also encourages others in society to embrace those who have more weight, rather than ostracizing them. The movement is not meant to promote obesity, but it is more focused on people accepting their body and not letting others judge them based on their size.[8] There are also television shows that spread awareness of the obesity problem—showing the struggles of those individuals who are obese (the television programs tend to show the extreme cases of obesity). Though there are many stigmas surrounding individuals who are obese, our society is progressing (albeit, slowly) to see obesity as more of a societal issue, rather than an issue of an individual not being able to control their eating and exercising habits.

Obesity in Mauritania

I have discussed how obesity is generally viewed in America, but I now want to discuss how obesity is viewed in a country located in West Africa. I learned about this country and some of its traditional practices in eleventh grade when I took geography. In the country of Mauritania, obesity is seen in a completely different light, compared to America. Obesity has a lot of positive stereotypes in Mauritania. In fact, women purposely become obese because of what it means for them. Obesity is equivalent to wealth in Mauritania because being obese implies you have enough money to purchase an excess of food. Women are encouraged to become obese in Mauritania because it makes the more desirable and beautiful in the eyes of potential husbands. Obesity has many positive connotations in this West African country, and I think it is an important contrast to note. If you want to learn more about Mauritania’s “fat camp” (where girls are sent to gain weight), I HIGHLY recommend watching this video. Start the video at 10:09 to skip to the part about Mauritania. I have also included a drawing below of the stereotypes associated with obesity in both countries, just as a summary. 

Fig. 1. An image comparing perceptions of obesity in American and Mauritania. Drawn by H. Almlie. 

Neuroscience of Obesity[9]

Now that I have bored you to death by comparing how obesity is seen in two different countries, I want to give you whiplash and just talk a little bit about the neuroscience behind obesity. At the Thanksgiving dinner table, my dad asked a rhetorical question about why he feels full when he still wants to keep eating. Even though it was a rhetorical question, I answered his question. When you eat food, insulin and leptin receptors in your brain send signals to AgRP neurons and POMC neurons. AgRP neurons tell you to eat and POMC neurons tell you to not eat. So, when you are hungry, AgRP neurons are activated which encourages your body to intake food and limit energy expenditure. Meanwhile, the POMC neurons are inhibited, which means the signal to stop eating is not being sent. When you feel full, it is because the signals have switched so AgRP is being inhibited, while POMC is activated which is responsible for the “full” feeling you have after eating. In obesity, however, this signaling is altered. In obesity, the leptin and insulin receptors that are responsible for sending the signals to the AgRP and POMC neurons are resistant to their respective ligand. Because the receptors are resistant to their ligand, there is no regulation of the AgRP neuron, meaning your body is always receiving the signal to eat. This signaling cascade thus perpetuates the problem of obesity because you are not receiving the signal to stop eating. Jumping back to the section about obesity in America, this unregulated signaling is why obesity is not just simply a failure to control caloric intake—there are neurochemical changes going on in the brain that perpetuate the problem. The image below illustrates this neurochemical pathway and what is going on in obesity.

Fig. 2 An image that summarizes the neurochemical pathways of leptin/insulin signaling under normal conditions and obesity conditions. Image taken from https://moodle.cord.edu/pluginfile.php/1052912/mod_resource/content/2/inflammation%20and%20MD%202017.pdf 

[1] https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm

[2] https://www.mayoclinic.org/diseases-conditions/coronary-artery-disease/symptoms-causes/syc-20350613

[3] https://www.mayoclinic.org/diseases-conditions/heart-disease/symptoms-causes/syc-20353118

[4] https://www.mayoclinic.org/diseases-conditions/heart-disease/symptoms-causes/syc-20353118

[5] https://www.cdc.gov/obesity/data/adult.html

[6] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866597/

[7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866597/

[8] https://www.bbc.co.uk/bitesize/articles/z2w7dp3

[9] https://moodle.cord.edu/pluginfile.php/1052912/mod_resource/content/2/inflammation%20and%20MD%202017.pdf

Sleep. The Best Part of the Day

Sleep 

When sitting in class and finishing work many individuals look forward to a specific time of the day. This is the time in which we can snuggle into our beds and fall asleep. However, is sleep more important than we think? Sleep provides healing and restoration and promotes good health and recovery from illness. Sleep is a cyclical physiological process that alternates with long periods of wakefulness. It influences physiological function and behavioral responses. This is controlled by your internal clock called your circadian rhythm. The part of your brain that controls the circadian rhythm is the suprachiasmatic nucleus (SCN) nerve cells in the hypothalamus control the rhythm of the sleep-wake cycle and coordinate this cycle with other rhythms. 

Sleep Disturbance  

There are some symptoms of the sleep cycle that cause disturbances and result in lack of sleep. These include anxiety, restlessness, irritability, and impaired judgement. However, is lack of sleep really that big of a problem? Lack of sleep can have serious potential problems for one’s health including high blood pressure, diabetes, heart attacks, and heart failure. The previous list of health problems relates to that of physical health, but what about the physiological perspective of the brain? When making memories it is important to note that there are three types of ways in which something can become a memory. This includes acquisition-learning or experiencing something new, recall-having the ability to access the memory in the future, and consolidation-the memory becomes stable in the brain.  The first two are through to be done while an individual is awake, however, consolidation requires an individual to be asleep.  This is because adequate sleep aids in the health of your hippocamps and neocortex within the brain. These areas while sleeping are believed to replay the events of the day and review/process memories and move them into an area where they can be stored as long-term memories.  

Are there medical ways to help insomnia?  

GABA are inhibitory neurotransmitters of the central nervous system that aids in sleep. GABA inhibitors are broken down into three different generations of hypnotics based on the GABA receptor mediated inhibitory process. These include the first- and second-generation hypnotics being barbiturates and benzodiazepines, while the third generation of hypnotics being imidazopyridines and cyclopyrrolones. The first- and second-generation hypnotics decrease waking, increase slow-wave sleep and enhance paradoxical sleep. Slow-wave sleep is the third phase of sleep which is the deepest phase of non-rapid eye movement sleep. During this time dreaming and sleepwalking can occur. This stage is also important for memory consolidation, which is a process where recently learned experiences are transformed into long-term memory. When paradoxical sleep is reached intense brain activity in the forebrain and midbrain occur. It differs from slow wave sleep due to the absence of motor function except for eye muscles and the diaphragm. An individual is unable to sleepwalk but is still dreaming during this time. The third generation of hypnotics is like that of the first- and second-generation hypnotics on waking and slow wave sleep but has a decreased paradoxical sleep during the first few hours of sleep.  

How do benzodiazepines work?  

By Hannah P.

Benzodiazepines are a class of drugs named for their chemical structure that are commonly used to treat anxiety disorders and sleep-related disorders. They include well-known drugs like valium, Xanax, and klonopin. There are dozens of drugs in the benzodiazepine class, but the mechanism by which they all exert their effects is thought to be similar. The sedating and anxiety-reducing effects of benzodiazepines are believed to be attributable to the drugs’ actions at receptors for the neurotransmitter gamma-aminobutyric acid (GABA). In particular, benzodiazepines act at a subtype of GABA receptors called the GABAa receptor; GABAa receptors that also bind benzodiazepines are sometimes called benzodiazepine receptors. When benzodiazepines bind, or attach, to the GABA receptor, they bind at alocation separate from where GABA itself binds and exerts an influence over GABA binding. This type of action is called an allosteric effect, and in the case of benzodiazepines it results in increased action at the GABA receptor. There is not complete consensus on exactly how benzodiazepine binding affects activity at the GABA receptor but there is evidence to suggest that it increases the likelihood that GABA binding will activate the receptor and/or increases the effect that GABA has when it binds to the receptor. That effect is to open an ion channel and allow the passage of negatively charged chloride ions into the neuron. This influx of negatively charged ions pushes the membrane potential further from zero, or hyper polarizes it, and makes it less likely the neuron will fire an action potential.This type of neural inhibition is the basis for the effects of benzodiazepines, for by inhibiting the activity of neurons that make up networks involved with anxiety and arousal, the drugs are able to produce calming effects. 

Understanding Marijuana and Your Brain

Featured Image: The cycle a marijuana addicted brain will enter as the need for more and more weed is required to reach the same “high”. The mechanism is possibly mediated by an increase in go signals (as Glutamate) that increase the synthesis of dopamine (pleasure chemical). Dopamine is one of the chemicals produced that cause the pleasurable emotions associated with marijuana. Artstract by Alison Amundson.

Marijuana Use

18 states have legalized weed and has become the most commonly used federally illegal drug in the United States. Figure 1,  shows which states have legalized marijuana and the type of product that is legal. About 18% of Americans have used marijuana at least once. There has been a steady increase of marijuana use in

Figure 1: https://www.ncci.com/Articles/Pages/Insights-2021-Marijuana-Legalization-Update.aspx

young adults and adolescents since 2019. In 2017, 24% of 12th-graders had used marijuana in the past year and in 2019, the percentage increased to 35.7%.

With more and more people using marijuana the need to fully understand its mechanisms is becoming increasingly important.

Cannabinoids

Cannabis contains over 500 natural compounds, including cannabinoids, terpenoids, flavonoids, and alkaloids. The primary psychoactive agent is -tetrahydrocannabinol (THC). This ingredient is what has promoted the widespread recreational use of marijuana. THC is defined as a cannabinoid and acts on the endocannabinoid system (ECS) of the brain.

The brain produces its own cannabinoids known as endocannabinoids. Both cannabinoids and endocannabinoids act on cannabinoid (CB) receptors. The primary receptor in the brain is CB1, it is this receptor that mediates the effects of THC. CB2 receptors are predominantly found in peripheral systems of the body, as displayed in Figure 2.

Figure 2: https://www.drgreenrelief.com/blog/endocannabinoid-system-cb1-cb2-receptors/

CB1 is expressed in the cortical areas involved in higher cognitive functions, midbrain regions associated with motor control, and hindbrain regions that participate in control of motor and sensory functions of the autonomic nervous system. Therefore, marijuana has the potential to vastly affect the brain in a multiplicity of methods.

CB2 receptors are expressed in the midbrain ventral tegmental area on dopamine neurons. It is postulated this region is where the addictive properties of marijuana are modulated.

Figure 3: doi: 10.3389/fncel.2016.00294

THC and the Brain

Figure 3 is a proposed schematic of CB1 receptor activation at the synapse of a neuron. The depth this image provides to CB1 signaling is too vast for such a small blog post. However, it does show that an agonist of CB1, like an endocannabinoid (2-AG or AEA) or a cannabinoid (THC), decreases cAMP activity, inhibits Ca2+ channels, decreases the release of neurotransmitters (such as GABA), and opens K+ channels causing hyperactivity.

Consuming marijuana increases the amounts of agonists available to bind to CB1 receptors. An important note here is THC is only a partial agonist of CB1, thus the mechanism of THC on CB1 is more complicated. THC being a partial agonist lends to the complexity of THC’s effects on the brain and why scientists have not yet figured it out.

An interesting theory suggests that THC lasts longer and is present in greater amounts than our endocannabinoids, thus overwhelming the self-regulating system. THC inhibits the production of GABA, the ‘stop’ signal for dopamine synthesis. Therefore, the ‘go’ signal for dopamine synthesis (glutamate) becomes dominate and dopamine is over-synthesized. Dopamine is associated with pleasure and reward. This mechanism is suggesting that the effects of THC on the brain are due to an increase in dopamine synthesis and release.

Final Points

The precise mechanism of THC, the main psychoactive ingredient of marijuana, is not well defined. Thus, it cannot be definitively stated that marijuana is bad for you. Nevertheless, the widespread increase in marijuana use should not be encouraged until we have a full, clear view on this substance.

References:

https://www.cdc.gov/marijuana/data-statistics.htm

https://drugabusestatistics.org/marijuana-addiction/

https://www.drugabuse.gov/publications/research-reports/marijuana/what-scope-marijuana-use-in-united-states

https://www.frontiersin.org/articles/10.3389/fncel.2016.00294/full

doi: 10.1080/00952990.2019.1634086

Lights Out on Light Sleep

Night time light exposure is seemingly common. From working into the night hours to binge watching your favorite Netflix series, we are constantly bombarded with blue light exposure at night. The exposure to constant light does not come without a cost. Humans were made to function and follow an intelligent circadian rhythm. One that allows us to feel energized and ready to take on each day, and ready for a good night’s rest at night. Our circadian rhythm is highly regulated through the use of light. With light in the morning helping us to suppress melatonin and wake up, while in darkness in the evening to help us get tired before bed. What happens when we disrupt this natural rhythm? How does our sleep change and body respond?

What’s the Cost? 

During the night, humans undergo processes of REM and NREM sleep. However, if this is fragmented, daytime functioning is impaired and increased sleepiness occurs. This has further implications on human health including disruption of metabolism, cardiovascular function, mental health, and even cancer risks. In particular, artificial light at inappropriate times, specifically light at night and exposure to light from mobile devices like phones, computers, and tablets is known to cause this disruption in addition to poor performance, insomnia, emotional disturbances, and gastrointestinal issues.

It has been shown that short-wavelength light (470nm or lower) is associated with a decrease in melatonin, reduction in reaction times, and depression in sleepiness, as well as changes in EEG power in the delta-theta frequency range. The cognitive effect of light is increased in alertness. Disruptions in our natural circadian rhythm can cause disruptions in our ability to have REM sleep, which is needed for memory consolidation and learning abilities.

Dim Light at Night Impact

Studies have been done to test the impact dim light at night has on the ability to sleep and produce locomotor activity in rats and mice. Protocols in animals being exposed to dim light at night, during their normal dark phase, has shown to reduce locomotor activity levels, and in rats, studies show that there is a decreased amplitude of daily rhythms of REM and NREM sleep, in addition to specific changes in the NREM EEG spectra around 16-19Hz.

The figure below shows the impact of light (in different forms) on circadian rhythms, sleep, arousal, and cognitive function. As the figure shows, dim light at night results in a decrease in locomotor/ exploratory activity, a decrease in amplitude of activity rhythm, and a decrease in amplitude of mPER1/2 rhythms. There is also a decrease in the amplitude in REM and non-rapid eye movement rhythms. Likwise, there is also a decrease in spatial performance, and increase in both anxiety-related behavior, and depression-related behavior.

Likewise, another study found that while any light can suppress the secretion of melatonin, specifically blue light at night will cause more of a powerful effect. It was shown that blue light suppresses melatonin about twice as long as green light, while shifting circadian rhythms twice as much.

Overall, blue light impacts our ability to get a good night’s sleep, through REM sleep, which is vital for our health and wellness. Prioritizing restful sleep through avoiding light and following our natural circadian rhythm is important for human’s health.

Neurodegenerative Diseases: Is Cannabis the Answer?

Background:

Endocannabinoids are gaining media exposure as many states are legalizing the recreational and medicinal use of marijuana, which contains the numerous endocannabinoids, the two most commonly mentioned are CBD and THC. Endocannabinoids are signaling molecules that are naturally made throughout the body, including the brain, that act as signaling molecules for various processes: stress, cognition, immunity, pain, eating, anxiety, reproduction, growth, and metabolism. Endocannabinoids are synthesized from fatty acids in the phospholipid bilayer of the post-synaptic neuron when calcium concentrations rise due to too much excitatory signaling. The two main endocannabinoids synthesized in the brain are AEA (N-arachidonoylethanolamide) and 2-AG (2-arachidonoylglycerol). Once the endocannabinoids are synthesized, the molecules are then released and can bind to CB1 and CB2 (G-protein coupled receptors) receptors to set off various signaling cascades.

Endocannabinoid Receptors:

AEA and 2-AG readily bind to CB1 receptors, which are highly concentrated in the brain and even throughout the rest of the body. Most often, these ligands inhibit the release of neurotransmitters in the presynaptic cell to tell the neuron to stop releasing neurotransmitters as a retrograde signaling cascade. The neurotransmitters that AEA and 2-AG typically inhibit dopamine and glutamate from being released from the pre-synaptic neuron to stop excitatory signaling.

AEA and 2-AG can also bind to CB2 receptors, which are found in cells that have immune functions. CB2 receptors are often found on microglia, which are responsible for producing inflammatory and anti-inflammatory cytokines in the brain. One interesting finding is that CB2 receptors have been found to be downregulated or malfunctioning in some neurodegenerative diseases including Multiple Sclerosis and Alzheimer’s Disease.

Figure 1: Artstract by Lauryn L Hinckley

Signaling Pathway:

The CB1 and CB2 receptor activation via THC has shown great promise in activating the MAPK/PI3K, which ultimately activates BDNF or brain-derived neurotrophic factor, as seen in Figure 2. BDNF is responsible for promoting life-sustaining roles that include neurogenesis, synaptic plasticity, and neuroprotection. Neurogenesis slows down with aging and can also account for a more difficult time learning, as well as reduced synaptic plasticity due to decreased activation of BDNF. However, it is interesting to think about THC improving the synthesis of BDNFs to improve cognition and memory, as well as have neuroprotective factors. Thus, THC is currently being studied as a potential treatment for neurodegenerative diseases and traumatic brain injuries.

Figure 1: Endocannabinoid pathway.

THC is also an antioxidant, which could help to reduce amyloid beta plaques and hyperphosphorylation of tau. On the other hand, consuming a diet high in fruits and vegetables could also provide antioxidant properties as consuming THC to help manage age-related diseases and produce neuroprotective factors.

Side effects:

Consuming cannabis is not without side-effects. Some studies have demonstrated that marijuana can be addictive, approximately 9% of all people who use the substance will lead to a dependence. However, those who use cannabis in their teens can see a heightened dependence rate of 17%. Teenagers who use cannabis can also experience a decline in IQ and increased mental health issues.

Another alarming side effect of cannabis use is the interaction with other drugs, especially anesthetics. Users of cannabis require four times the amount of Propofol during surgery than those who do not use cannabis. Propofol can interact with both CB1 and CB2 receptors to reduce the release of dopamine, norepinephrine, and epinephrine and increase GABA release. THC has the exact opposite effects of Propofol. Increased amounts of anesthetics can increase the risk for adverse side effects. More research needs to be done to understand the negative impacts of THC exposure and anesthetic interactions.

So what?

More research needs to be done on cannabis and the endocannabinoids that it contains. Cannabis is a Schedule I Drug, so it is incredibly difficult and expensive to study. New research is hard to attain due to this classification, yet legalization of recreational and medicinal use is becoming more and more common in the United States. Thus, cannabis use for studies should also become more readily available to educate users and work to better understand how cannabis can be used to treat neurodegenerative illnesses.

Sources:

  1. https://www.frontiersin.org/articles/10.3389/fncel.2016.00294/full
  2. https://www.sciencedirect.com/science/article/pii/B9780128002131000158
  3. https://www.frontiersin.org/articles/10.3389/fncel.2019.00363/full 
  4. https://www.researchgate.net/publication/322146675_Functional_Foods_in_the_Management_of_Neurodegenerative_Diseases 
  5. https://www.drugabuse.gov/publications/research-reports/marijuana/marijuana-addictive 
  6.   https://www.anesthesiologynews.com/Clinical-Anesthesiology/Article/10-19/Regular-Marijuana-Use-Changes-Anesthesia-Needs/56086?sub=36F3CFDB6E5DCB6B427D1D3E23351E11EAEBB4459197186048A5C7FE69&enl=true&dgid=X3676465&utm_source=enl&utm_content=4&utm_campaign=20191031&utm_medium=title 
  7. https://www.aana.com/docs/default-source/aana-journal-web-documents-1/marijuana-use-in-the-anesthetized-patient-history-pharmacology-and-anesthetic-considerations-december-2019.pdf?sfvrsn=ce829198_4

Cannabinoid Use to Reduce Pain

By Hannah P.

How do we feel pain? 

When we feel pain sensory receptors in our skin send a message via nerve fibres, A-delta fibres and C fibres, to the spinal cord and brainstem and then onto the brain where the sensation of pain is registered, the information is processed and the pain is perceived. Fast pain is transported from A delta fibers while slow pain from C fibers.Examples of A delta fiber pain are sharp, prickling and acute pain and C fibers are slow, throbbing, aching chronic pain.

What is the pathway for pain? 

In short form pain starts at nociceptors –> Primary afferent sensory fibers –> Dorsal root ganglion –> Na channels allow depolarization through axons –> Dorsal Horn of spinal cord –> Second order neurons –> Brain.

The General Pain Pathway

Within the pain pathway there are 3 orders of neurons that carry action potentials, signalling pain. First-order neurons are pseudounipolar neurons which have cell bodies within the dorsal root ganglion. They have one axon which splits into two branches, a peripheral branch (which extends towards the periphery) and a central branch (which extends centrally into the spinal cord/brainstem). Second-order cell bodies of these neurons are found in the rexed laminae of the spinal cord, or in the nuclei of the cranial nerves within the brain stem. These neurons then decussate in the anterior white commissure of the spinal cord and ascend cranially in the spinothalamic tract to the ventral posterolateral (VPL) nucleus of the thalamus. Third-order the cell bodies of third-order neurons lie within the VPL of the thalamus. They project via the posterior limb of the internal capsule to terminate in the ipsilateral postcentral gyrus (primary somatosensory cortex). The postcentral gyrus is somatotopically organised. Therefore, pain signals initiated in the hand will terminate in the area of the cortex dedicated to sensations of the hand.

How do we react to pain? 

This can lead to two different responses, fight or flight. In response to the pain stimulus the brain overall increases in “fight or flight” arousal.

– increased sympathetic tone

– increased catecholamine release

– increased metabolism & oxygen consumption (via hypothalamus)

How can you treat pain? 

There are many ways an individual can help reduce pain and manage it. Some people will say to get plenty of rest, distract yourself, or participate in light exercise. However, what happens when these tips don’t help with the pain? Many people reach for pharmaceutical mechanisms to treat what they are experiencing from ibprohpen to different opioids. This occurs by inhibiting nociceptors and dorsal horn pain transmission. 

What are CB1 and CB2? 

CB1 are receptors found primarily on the presynaptic membrane of neurons, ubiquitous. It is coupled to G proteins, causing inhibition of adenylyl cyclase, influencing numerous transcription factors and potassium channels. While CB2 are receptors which are more localized, specifically to immune cells. Both CB2 and CB1 receptors on mast cells participate in the anti-inflammatory mechanism of action of cannabinoids.

How is CB1 involved in pain management? 

The CB1 receptor is distributed throughout the nervous system. It mediates psychoactivity, pain regulation, memory processing and motor control. CB1 is a presynaptic heteroreceptor that modulates neurotransmitter and neuropeptide release and inhibits synaptic transmission. Activation of CB1 results in the activation of inwardly rectifying potassium channels, which decrease presynaptic neuron firing, and in the inhibition of voltage-sensitive calcium channels that decrease neurotransmitter release. Allosteric modulators of the CB1 receptor bind to a distinct site apart from the orthosteric site and produce conformational changes in the receptor, thereby altering the potency of the ligand when it binds to the receptor. No effect in the absence of ligand binding. So, CB1 positive allosteric modulators would be expected to enhance the pain relieving effects of endocannabinoids, but with limited side effects. ZCZO11 reduced neuropathic pain and inflammatory pain without development of tolerance or occurrence of psychoactive side effects.

 

Endocannabinoids: The Modern Day Elixir of Life

NC medical marijuana: What might be allowed, rules for sales licenses

Figure 1: A generic picture of medicinal marijuana.

What are cannabinoid receptors?

Cannabinoid receptors CB1 and CB2 are receptors on the presynaptic side of a neural connection that function to inhibit adenylyl cyclase and subsequently decrease the presence of cyclic AMP. The ligands to these receptors (the endocannabinoids) are synthesized on the postsynaptic side because of the influx of calcium ions, which activate PLC, DAGL, and NAPE-PLD which are all enzymes important to the synthesis of the endocannabinoids 2-AG and AEA. However, there is also a noncanonical pathway which involves β-arrestin binding near the cannabinoid receptor and causing the membrane around it to be endocytosed into a intracellular vesicle,  effectively disabling the cannabinoid receptor temporarily. β-arrestin as part of this pathway also plays an important role in regulating other pathways such as ERK 1/2, JNK 1/2/3, CREB, and P38α. For more information about the cannabinoid receptors, see the article here. 

How CBD Blocks THC Euphoria Explained

Figure 2: The chemical difference between THC and CBD.

What benefits are seen from the activation of these pathways?

Both CBD and THC have been used in some medical practices to date, but the true capabilities of their use is often underrepresented. Below I include a list of many of the possible benefits of THC and/or CBD.

  • antioxidant properties lead to anti-aging effect
  • Can treat some skin diseases such as eczema and other inflammatory conditions
  • Decreased anxiety and depression in the short term
  • Potential to speed up recovery after a TBI sustained by an individual
  • Decreasing symptoms and effects of chronic pain
  • Proven effective cancer treatment on glaucomas

Those all sound like pretty great things, right? From anti-aging to cancer treatments, cannabinoid receptors do really seem like the modern day elixir of life. However, it would be irresponsible for me to mention all of these positives and not mention the possible negatives of THC and CBD as treatment strategies. So, below are a few of the possible negatives, however, it is important to note, there hasn’t been extensive studies done with either THC or CBD as it still remains a bit of a taboo subject in medicine. Subsequently, both the benefits list and the possible negatives list are working lists and are far from all-inclusive.

  • Potential to become addictive
  • Potential to build up a tolerance to effects
  • Decreased effectiveness of anesthetics in individuals with THC/CBD present in their body
  • Impaired judgment
  • Inconclusive data on memory
  • Paranoia
  • Increased potential for anxiety, mood, and bipolar disorders

Figure 3: A comparative table between THC and CBD coming from a website giving information about the production and sale of THC and CBD. Note, this table is not all-inclusive.

What this means for the future of treatment

The complexity of the cannabinoid receptor signaling and limited studies on THC and CBD have led to a tentative administration plan for treatments. As doctors begin to dip their toes into the possibilities of medical marijuana, there may begin to be more information about benefits and side effects that become present. However, from the current data, there seems to be a far greater potential for good that for harm when targeting the cannabinoid receptors. Also, as Figure 3 above starts to show, CBD offers a much greater medical potential because there are far less side effects and psychotropic effects than with THC. So perhaps with greater exposure in the future, there will begin to be more medical uses for marijuana or some of its isolated active ingredients.

Adenosine’s effect on sleep

Overview of the circadian rhythm

Circadian rhythm

The circadian rhythm regulation plays a crucial role in people’s healthy lives affected by factors consisting of cosmic events related to the universe and earth, environmental factors, and lifestyles. The circadian rhythm is affected by the circadian clock, which is an internal regulator in cells of organisms, coordinates physiological and behavioral activities with daily environmental variations within 24-hour cycles (Charrier et al., 2017). That’s just a quick explanation of the circadian rhythm but how does adenosine affect this.

 

 

Adenosine overview

 

Adenosine is linked to metabolism of cells. In the central nervous system, an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In the brain, adenosine antagonists affects A1 receptors which decreases neuronal activity which is why you have more energy (Porkka- Heiskanen et al., 2002).

 

 

Adenosine and sleep

Out of the many articles I have been reading it seems like the main area of adenosine activity is the cholinergic basal forebrain. It is important in this function because it is an essential area for mediating the sleep-inducing effects of adenosine by inhibition of wake-promoting neurons via the A1 receptor (Basheer et al., 2004). Their evidence finds that a cascade of signal transduction induced in A1 receptor activation in cholinergic neurons leads to increased transcription of the A1 receptor. They believe that this is the reason behind sleep-deprivation.

 

 

Coffee and sleep

caffeine’s affect on A1

The information I found on the effects of adenosine on sleep made me wonder if the time that one drinks caffeine has an effect on certain stages of sleep. A study monitored the effects of drinking caffeine at 0, 3, and 6 hours before going to sleep. The results of this study suggest that 400 mg of caffeine taken 0, 3, or even 6 hours prior to bedtime significantly disrupts sleep. Even at 6 hours, caffeine reduced sleep by more than 1 hour (Drake et al., 2013). This isn’t that crazy since 400 mg is a lot of caffeine but even 6 hours seems like it should be long enough. The caffeine however, only reduced the time between stage 1 and 2 sleep and had no effect on REM sleep. The results did conclude though that this degree of sleep loss, if experienced over multiple nights, may have detrimental effects on daytime function (although more research is needed).

 

 

 

 

Works cited

 

Basheer, R., Strecker, R. E., Thakkar, M. M., & McCarley, R. W. (2004). Adenosine and sleep–wake regulation. Progress in Neurobiology, 73(6), 379–396. https://doi.org/10.1016/j.pneurobio.2004.06.004

 

 

Charrier, A., Olliac, B., Roubertoux, P., & Tordjman, S. (2017, April 29). Clock genes and altered sleep-wake rhythms: Their role in the development of psychiatric disorders. International journal of molecular sciences. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454851/.

 

 

Drake, C., Roehrs, T., Shambroom, J., & Roth, T. (2013). Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. Journal of Clinical Sleep Medicine, 09(11), 1195–1200. https://doi.org/10.5664/jcsm.3170

 

Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A., & Stenberg, D. (2002). Adenosine and sleep. Sleep Medicine Reviews, 6(4), 321–332. https://doi.org/10.1053/smrv.2001.0201

Marijuana’s long-term effect on the brain

Cannabinoids in the brain

CB1 receptors in the presence of THC

Cannabinoids are popular in both recreational and medical use. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). Psychoactive cannabinoids cause enhancement of sensory perception, difficulties in concentration, impairment of memory, along with an extensive list of other symptoms. Recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus (Ameri et al., 1999). The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N and P-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. Interestingly, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system (Ameri et al., 1999). This might explain why people call it a ‘gateway drug.’

 

 

THC long-term effects studies

A study found that, cognitive impairments in adult rats exposed to THC during adolescence are associated with structural and functional changes in the hippocampus (NDA et al., 2021). They also found that when that animal is exposed to THC, there is an increased likelihood that the animal will target and self-administer other drugs that effect the same reward system. The studies referenced by the NDA found that some users developed altered connectivity within the brain leading to different cognitive impairments, while other studies found no significant structural differences in the brain. Basically, they have no idea if there is a negative long-term effect in general. However, they do believe that the age that you start using at is a determining factor.

 

 

Gateway drug?

dopaminergic receptor

So, if no conclusive results were found on the structure of the brain long-term, what about long term effects on usage. They found that, early exposure to cannabinoids in adolescent rodents decreases the reactivity of brain dopamine reward centers later in adulthood. Although this does not directly conclude the results of a human brain, this could help explain the increased vulnerability for addiction to other substances of misuse later in life. These findings naturally would suggest that marijuana is a gateway drug, however, most people who use marijuana do not go on to use other, “harder” substances. They found that there is also a cross sensational effect within alcohol and other drugs. This means that simply drinking alcohol also heightens your responses to other drugs (NDA et al., 2021).

 

 

What to draw out of this

 

To say that marijuana has no negative effect on the brain would be disingenuous. However, just because the evidence is inconclusive at this point does not mean that it is entirely safe to use. If you use marijuana, cool, but just know there could be risks of future cognitive development in store.

 

 

 

 

Works Cited

 

Ameri, A. (1999). The effects of cannabinoids on the brain. Progress in Neurobiology, 58(4), 315–348. https://doi.org/10.1016/s0301-0082(98)00087-2

 

National Institute on Drug Abuse. (2021, April 13). What are marijuana’s long-term effects on the brain? National Institute on Drug Abuse. Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana/what-are-marijuanas-long-term-effects-brain.

 

National Institute on Drug Abuse. (2021, May 24). Is marijuana a gateway drug? National Institute on Drug Abuse. Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana/marijuana-gateway-drug.

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