The Use of Cannabinoids in Treatment for Various Disorders

Cannabinoids have been widely taken to achieve a feeling of high and to reduce stress. Endogenous cannabinoids are naturally occurring substances in the brain that are involved in motivation, mood, pain, sleep, and neurological disorders. Research has more recently focused on the cannabinoid signaling pathway in the brain, the receptors being eCB ligands, and how cannabinoids can be utilized in treatment of various disorders. 

In the article by Patel et al., "Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment," the function of endocannabinoids is presented and how eCBs can be used to treat neuropsychiatric disease, epilepsy, developmental disorders, and obesity. The article discusses the physiological mechanisms underlying stress and how chronic stress can lead to depression and anxiety disorders as well as substance use disorders. It is described how endocannabinoids have an important role in the HPA axis, an area crucial for regulation of the stress response. ECBs regulate GABAergic and glutamatergic transmission in neurons of the PVN, which is part of the HPA axis. GABA is an inhibitory neurotransmitter while glutamate innervates excitatory responses in the brain. Signaling of these chemicals occurs in the amygdala, an area associated with assessment of valanced stimuli and managing stress and emotion. 2-AG (an endogenous cannabinoid ligand receptor) signaling in the basolateral amygdala increases expression of the neurotransmitters.

The therapeutic potential of cannabinoids is further debated in “Cannabinoids: Therapeutic Use in Clinical Practice”, by Pagano et al., mentioning implications in cancer and neurodegenerative diseases. Cannabinoids can reduce pain and inflammation, namely in cancer. The side effects of cancer or cancer treatment such as chemotherapy includes emesis, nausea, pain, and muscle spasms. Many patients are prescribed opioids, but cannabinoids can be used as analgesics acting through CB1 receptors, the main cannabinoid receptor. Another function is the anti-emetic properties of the drug. It can decrease activity of excitatory transmitters in areas involved in nausea and vomiting, limiting these responses. Furthermore, neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and multiple sclerosis have shown symptom improvements through the use of cannabinoids. AD is caused by accumulation of beta amyloid plaques and tau protein, leading to neuroinflammation. The concentration of CB1 receptors decreases with an increase in 2-AG in the hippocampus. Studies show neuroinflammation and beta amyloid could decrease with the use of cannabinoids. PD is characterized by changes in the endocannabinoid system, including an increase in activity of CB1 receptors in the basal ganglia. Patients of studies using cannabinoids reported improvements in motor control, tremors, sleep, pain, and even associated mood disorders. 

The two articles describe the emerging effects of cannabinoids and emphasize the importance of further studies to determine how various disorders could be improved with cannabinoid treatment. It could be concluded this treatment can be beneficial in people with muscular and movement disorders and show improvements in some anxiety and mood disorders; however, there is still much room for progression in science as many findings are inconclusive and contradictory. 

References:

1. Pagano, C., Navarra, G., Coppola, L., Avilia, G., Bifulco, M., & Laezza, C. (2022). Cannabinoids: Therapeutic use in clinical practice. International journal of molecular sciences, 23(6), 3344.

2. Sheyer, A., Yasmin, F., Naskar, S., Patel, S. Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment. Neuropsychopharmacology (2023) 48:37–53; https://doi.org/10.1038/s41386-022-01438-7

Can Sleep Deprivation Kill You?

 

Did you ever wonder why as a kid your parents emphasized your sleep so much? Why was bedtime always so early and why was this sleep so important? Do we really need that much sleep? 

Well, as it turns out, sleep is that important. Our sleep cycles are a part of the human circadian clock, or better known as our bodies 24-hour clock. Have you ever wondered how our body knows when it is time to go to bed, wake up, and even eat breakfast, lunch, or dinner? This is all due to circadian rhythms regulated in our bodies’. In the article Circadian disruption and human health written by Anna B. Fishbein, Kristen L. Knutson, and Phyllis C. Zee produced in 2021, “Circadian (circa, “about,” and diem, “day”) rhythms are endogenous oscillations with an approximately 24-hour cycle. Circadian rhythms in physiology and behavior are organized by a central “master” clock, the suprachiasmatic nucleus (SCN) located in the anterior hypothalamus…” The SCN is the structure in our brain that helps us manage the timing of our day-to-day lives. 

Well, what happens when our bodies’ experience disruptions from our typical wake-sleep cycle? Unfortunately, this does have consequences. “...[C]hanges in circadian function are often accompanied by sleep-wake disturbances, which also contribute to poor health outcomes,” (Fishbein et al., 2021). These “poor health outcomes'' range from a weakened immunity to an increased risk of neurological disorders, psychiatric disorders, and even metabolic disorders such as diabetes. For example, it has been demonstrated that autism spectrum disorders are not only pretty common but have been associated with misaligned cortisol rhythms and a lack of melatonin rhythm (which influences bodily responses to sleep), (Fishbein et al., 2021). 

In regard to respiratory infections, “...decades of scientific evidence show that sleep is a solid way to bolster the immune system against colds, influenza, and respiratory infections,” (Sohn, 2020). Interestingly enough, sleep deprived dogs and rats die in just a few weeks. For humans, a lack of sleep enhances risk for a multitude of things. “In a number of studies, people with sleep disorders, people who catch less than five or six hours of shut-eye per night, and people with low levels of sleep efficiency (the percentage of time spent snoozing during the night) report higher rates of respiratory illnesses, head colds, and related ills,” (Sohn, 2020). The reason behind higher risk of illness is due to the fact that when humans don’t sleep, their T cells, which are in charge of helping fight infection, remain in the bloodstream. Here they are less likely to interact with virus-infected cells (Sohn, 2020). In addition to that, “In one of the first such studies from 2002, one group of people slept about eight hours for four nights before getting a flu shot, then slept the same amount for the two nights after the shot. Ten days later, researchers reported the participants’ influenza antibody levels were more than twice as high as those in people in another group who had slept only four hours per night over the same period,” (Sohn, 2020). Thus, we can evidently see how and why sleeping is such an important task. 

In conclusion, Anna B. Fishbein, Kristen L. Knutson, and Phyllis C. Zee all emphasized the effects a lack of sleep has on a wide variety of levels in the body. In closer relevance to the COVID-19 pandemic that recently occurred, Emily Sohn goes into detail in her article on how a lack of sleep specifically influences the immune system and how that plays a role in our susceptibility to the SARS-CoV-2 virus. 

Sources: 

Sohn, Emily. (2020, October 1st). Want to reduce your COVID-19 risk? You need to sleep more. National Geographic. (https://www.nationalgeographic.com/science/article/sleep-more-reduce-coronavirus-risk)

Fishbein, A., Knutson, K. L., Zee, P. C. (2021). Circadian disruption and human health. The Journal of Clinical Investigation. (https://doi.org/10.1172/JCI148286)

Forming Memories and the Role of Sleep and Emotion

 Multiple studies have shown that sleep has a beneficial effect on memory and consolidation. Sleep can enhance the recall of declarative memories and has been seen to improve learning. Sleep is also linked to the circadian rhythm which is an internal sleep-wake cycle that is repeated over twenty-four hours. Poe et al. performed a study analyzing the development of the circadian rhythm in Drosophila melanogaster, the fruit fly, and how circadian rhythm development exhibits long-term memory. Sleep and memory have been investigated with neural processing and development before but the study by Carollo et al. investigated the possible contribution of emotion along with sleep and its impact on memory formation and retention. 

    Poe et al. demonstrated that the development of the circadian rhythm is what enabled complex cognitive processing which included the formation of long-term memories (Poe et al. 2022). Sleep rhythms and patterns appeared when analyzing the L3 stage of larvae, a further developed stage of larvae, and not the L2 stage. The L3 group showed deeper sleep at night compared to the L2 group. The L3 group also performed better on the long-term memory task. The duration and depth of sleep depend on the internal clock. Poe et al. demonstrated that disturbing the sleep cycle or producing stress showed a disturbance in long-term memory formation. Not only is the amount of sleep important but the quality of sleep in consideration of circadian rhythms is important as well for the retention of memories. 

Carollo et al. illustrated that emotions have a role in memory formation along with the period of wakefulness and sleep. The goal of this study was to investigate the effect of nocturnal sleep compared with daytime wakefulness and the subject of emotional reactivity and memory performance (Carollo et al. 2022). Two groups were compared for this study. Both groups slept after the learning task, the Sleep First group was asked to recall the information after sleeping, and the Wake first group was asked to recall the information before sleeping. Both were shown neutral and negative images to provoke emotion. This study demonstrated that negative images and information were remembered better over time than neutral information (Carollo et al. 2022) and that sleep did benefit the retention of memory. The Sleep First group performed better at memory recall than the Wake First group.

    Both of these studies demonstrate that sleep is a beneficial factor in setting long-term memories and the ability to recall information. The circadian rhythm is not only involved in the quality of sleep but also in establishing neural connections that improve cognitive processing and long-term memory retention. Emotion is also a factor at play in the retention of memories. Negative emotions attached to memory are better remembered than those that are not. The time at which one goes to sleep during memory recall is also an important factor. Overall, sleep improves cognitive processing, the formation of long-term memories, and recall. 

References:

Carollo, G., Degasperi, G., & Cellini, N. (2022). The role of sleep and wakefulness in the recognition of emotional pictures. Journal of Sleep Research, 31( 6), e13695. https://doi.org/10.1111/jsr.13695

Poe, A., Zhu. L., McClanahan, P., Szuperak, M., Anafi, R., Thum, A., Cavanaugh, D., Kayser, M.. (2022). Developmental emergence of sleep rhythms enables long-term memory capabilities in Drosophila

bioRxiv 2022.02.03.479025; doi: https://doi.org/10.1101/2022.02.03.479025

The Importance of Sleep's Role in the Formation and Maintenance of Long Term Memories

Sleep is absolutely vital in living organisms for various important bodily functions, especially in learning and the consolidation periods of this memory. How much sleep one is getting as well as the quality of the sleep in which they are getting alongside the inner neural mechanisms occurring during this sleep can severely impact cognitive function in relation to one’s memory.

Two neuroscientific research projects conducted in 2022 offer some clarity on this exact relationship between learning and memory capabilities and sleep. The first, published by Poe Et al. in February 2022, focuses on Drosophila while the second, published by Rebecca Sohn, focuses on the impact on humans. The study by Poe et al. was presented to my class by one of the researchers on the project, Dan Cavanaugh, providing us with insight into the sleep rhythms found in the formations of long term memory in fruit flies. Dan and the other researchers worked and found that, as Drosophila begin the pupal stage, they develop a circadian rhythm while sleeping. It is within the development of this rhythm that the ability to form long-term memories is gained. From there, they worked with sleep disruptions to see the impact on long term memory, finding that sleep disruptions did in fact disrupt the formation of long-term memories in this vulnerable state. With this, it was also found that manipulating the rhythms did enhance memory and improve cognitive capabilities in terms of long term memory maintenance. 

The secondary project, relating to the work Cavanaugh completed, published by Rebecca Sohn in the Scientific American journal in September 2022, worked with sleep spindles in the human brain and how they correlate to cognitive and memory functionality. These sleep spindles are defined as brief bursts of brain activity during non-REM sleep by which the brain consolidates memories, coordinating activity between different regions of the brain as the brain strengthens connections between neurons during memory formation. This work was conducted at the University of Chicago and used EEG to measure brain activity. It was found that these sleep spindles were directly associated with enhancing cognitive performance in visual memory tasks, suggesting that the strength of these spindles are strong predictors of memory performance, ultimately aiding in the encoding of memories and protecting them from interference. These bursts of energy can be increased in number and in strength with healthy habits, such as frequent exercise, healthy diets. calming activities such as meditation, etc., but their presence is ultimately mainly due to genetic reasons.

Together, these two studies are able to exhibit the importance of sleep in the cognitive processes of long term memories, both in terms of the development of circadian rhythms for formation and in the event of sleep spindles for consolidation and protection. By understanding the importance of the relationship between sleeping and memory, whether in fruit flies or in humans, can provide humans with insight in how to enhance learning down at the neurological level. 

References: 

Poe, A. R., Zhu, L., McClanahan, P. D., Szuperak, M., Anafi, R. C., Thum, A. S., Cavanaugh, D. J., & Kayser, M. S. (2022). Developmental emergence of sleep rhythms enables long-term memory capabilities in Drosophila. Neuroscience. https://doi.org/10.1101/2022.02.03.479025

Sohn, R. (2022, September 1). Spiky ‘sleep spindles’ linked to acts of learning. Scientific American. https://www.scientificamerican.com/article/spiky-lsquo-sleep-spindles-rsquo-linked-to-acts-of-learning/

Development of Circadian Regulation and its Implications in Future Health

The adult sleep-wake cycle is regulated by our circadian rhythms, which reflect physiological changes over a 24-hour period. In infants, however, sleep is not yet regulated by these rhythms and is scattered throughout the day (Poe et al., 2022). Poe et al. examined when the development of these rhythms occurred using the model organism Drosophila melanogaster by observing the sleep rhythms of flies at different stages of development. They found that sleep activity became circadian dependent between the L2 and L3 instar larvae stage and suggest that unchecked arousal is a ground state for state changes before this development. The major hypothesis that Poe et al. suggest for this delay in development is that metabolic and nutritional demands are more important in early life, therefore it might be advantageous for the sleep-wake cycle to be non-cyclical for the first stages of life. 

Recent studies have examined the implications of circadian rhythm development in human infants as well. In the article “Development of sleep–wake rhythms during the first year of age”, it was found that infants with slower development of sleep-wake cycles slept more hours during the day, had a later sleep-wake rhythm, took longer to get to sleep, and were awake longer during the night” (Paavonen et al., 2020). These findings are important because it indicates that proper development of the circadian system is crucial to infant sleep quality and quantity. Further, Paavonen et al. suggest that such developmental delays could be connected to sleeping problems which can lead to further sleep disorders later in life.  

Poe et al.’s study identifying the developmental timing of circadian regulation provides background information and identifies a hypothesis as to why circadian regulation doesn’t develop at birth. This information allows us to draw conclusions in regard to the human infant study. Paayonen et al.’s study has the potential to help identify criteria for circadian rhythm dysfunction problems later in life and suggests that a simple way to help improve infant sleep is to adjust to age-appropriate sleep-wake rhythms by paying attention to the timing of naps and maintaining consistent rhythms.

References 

Paavonen, E. J., Morales-Muñoz, I., Pölkki, P., Paunio, T., Porkka-Heiskanen, T., Kylliäinen, A., Partonen, T., & Saarenpää-Heikkilä, O. (2020). Development of sleep-wake rhythms during the first year of age. Journal of sleep research, 29(3), e12918. https://doi.org/10.1111/jsr.12918 

Poe, A. R., Zhu, L., McClanahan, P. D., Szuperak, M., Anafi, R. C., Thum, A. S., Cavanaugh, D. J., & Kayser, M. S. (2022). Developmental emergence of sleep rhythms enables long-term memory capabilities in Drosophila [Preprint]. Neuroscience. https://doi.org/10.1101/2022.02.03.479025 

Connecting Stress and Endocannabinoids with the Intake of Cannabis

 

 Stress and anxiety are common negative feelings that many people feel on a regular basis. While some have it worse than others, no one likes feeling anxious or stressed over something they do not have control over. Although there are several healthy ways to deal with stress, some people cope in an unhealthy manner. I.e., binge eating, drugs, not eating, and more. One major coping mechanism of stress that some people resort to is cannabis. This leads to changes in endocannabinoids within our system. Endocannabinoids control important functions in our body, including stress and anxiety. 

 

In the article "Endocannabinoids at the synapse and beyond: neuropsychiatric disease pathophysiology and treatment" by Sachin Patel, endocannabinoids and their effects on the human body are discussed. The article discussed how eCB could affect stress and anxiety levels. The researchers focused synaptic eCB can affect stress levels. They focused on two main regions that are highly involved with regulating stress levels: the ventricular hypothalamus and the amygdala. They also focused on the hypothalamic pituitary axis, which is highly involved in stress levels. To complete this study, they focused on the neurotransmitters GABA and glutamate. One of the findings from this study was that cells of the PVN mediate eCB release. This allowed the further determine that stress leads to an increased release of glutamate in the body. Although not correlated with stress in this study, Dr. Sachin went into minor details about what taking cannabis does to the human body. He explained how taking cannabis on a regular basis leads to changes in broadband neural oscillations. Furthermore, THC specifically can lead to a reduction in positive psychotic symptoms. 

 

Similarly, an article discusses the correlation between stress and intoxicating oneself with cannabis. In another article, “Enhancing Endocannabinoid Control of Stress with Cannabidiol,” researchers focused on the effects CBD has on our stress levels. Many people take CBD medicinally and/or recreationally. There have been several debates if it should be legal, and in some states it it officially legal. The article discusses how stress affects every person's life differently, and in some cases, it can cause harm. To prevent harm, the researchers found the effect of cannabis on stress. They found that of the two main components making cannabis (CBD and THC), CBD is what causes a decreased level of stress. They also found that compared to THC, CBD is the more effective and safer option to decreasing stress. 

Compared to Dr. Patel’s research, this article focused on how the endocannabinoid system and stress are related. It was determined that endocannabinoids are highly correlated with stress levels. The research also studied the effect of CBD on stress and found that over 90% of those taking CBD felt lower levels of stress. Both articles also discussed how an intake of THC at a moderate level could lead to a decreased level of psychotic symptoms. In conclusion, endocannabinoids are not only related to stress levels, but also other areas like psychosis. Treatments to these can involve medicinal THC, but only with a specific intake level. 

References

Henson, Jeremy D et al. “Enhancing Endocannabinoid Control of Stress with Cannabidiol.” Journal of clinical medicine vol. 10,24 5852. 14 Dec. 2021, doi:10.3390/jcm10245852

Scheyer, Andrew, et al. “Endocannabinoids at the Synapse and beyond: Implications for Neuropsychiatric Disease Pathophysiology and Treatment.” Neuropsychopharmacology, vol. 48, no. 1, 2022, pp. 37–53., https://doi.org/10.1038/s41386-022-01438-7.

The Secret of the Night Shift

    The circadian rhythm is commonly known as the body’s internal clock that runs in 24-hour cycles. This cycle is modulated by internal biological processes, behavioral activities, and environmental factors (Fishbein et al., 2021). Circadian disruption is the disturbance of this internal clock and has been correlated to numerous health disorders (Fishbein et al., 2021). In the US alone, 16% of nondaytime employees, 70% of indoor employees, 99% of the population affected by light pollution, and adults above 65 are at risk for circadian disruption (Fishbein et al., 2021). Therefore, circadian disruption poses a growing concern for the world. Fishbein, Knutson, and Zee emphasize circadian disruption's many psychological and physiological impacts. Pavanello et al. further this discussion by looking at the effects of night shift work on the health of 150 hospital workers. 

    Pavanello et al. used the work ability index (WAI) to determine how the employees perceived their abilities to handle the demands of their jobs and their coping ability with that work. Therefore, individuals with a high WAI perceive themselves to have higher work ability. The study found that the people with upper levels of work ability were young and healthy. These individuals were also more likely to do demanding tasks and work more night shifts (Pavanello et al., 2019). By analyzing urine samples and telomere length, the study found that the upper levels of workability correlated to higher oxidative damage and shorter telomere length (Pavanello et al., 2019). Oxidative damage is an important factor to consider because it has been correlated with many of the disorders that Fishbein, Knutson, and Zee emphasize to be caused by circadian disruption (Fishbein et al., 2021). Disorders associated with circadian disruption include neurodevelopmental, neurodegenerative, mood, metabolic (diabetes), and cardiovascular disorders (Fishbein et al., 2021). It has been hypothesized that the cause of this high oxidative damage is a reduction in antioxidative enzymes. Melatonin helps induce the production of these enzymes; however, when circadian rhythms are disrupted, melatonin production is also disrupted (Pavanello et al., 2019). Telomeres are repeated DNA sequences at the end of chromosomes that protect genes at the ends of chromosomes from being left unreplicated due to a limitation in the DNA polymerase enzyme (Pavanello et al., 2019). This region of the chromosome is susceptible to oxidative damage and can explain the shorter telomeric regions found in workers with high scores on the WAI. 

    The importance of the Pavanello et al. study is that it shows a clear correlation between night shift work and the damage it causes to the employee’s body. A more concerning discovery of the study is that it predicts future illnesses in healthy younger working employees. Healthier employees show a higher risk of future diseases due to oxidative damage and telomere shortening (Pavanello et al., 2019). In their review paper, Fishbein, Knutson, and Zee discussed methods to treat circadian disruption. One strategy is to use melatonin supplementation a few hours before bedtime, and a study has shown an improvement in sleep quality in children with autism (Fishbein et al., 2021). Light therapy has also increased sleep quality, reduced neuroinflammation, and reduced oxidative stress (Fishbein et al., 2021). Future therapies must test these therapies in night shift employees and help them engage in preventative measures for future illness. 

Citations: 

Fishbein, A. B., Knutson, K. L., & Zee, P. C. (2021). Circadian disruption and human health. Journal of Clinical Investigation, 131(19). https://doi.org/10.1172/jci148286 

Pavanello, S., Stendardo, M., Mastrangelo, G., Casillo, V., Nardini, M., Mutti, A., Campisi, M., Andreoli, R., & Boschetto, P. (2019). Higher number of night shifts associates with good perception of work capacity and optimal lung function but correlates with increased oxidative damage and telomere attrition. BioMed Research International, 2019, 1–10. https://doi.org/10.1155/2019/8327629