Acupuncture: an Ancient Practice in the Modern Era

       Acupuncture is a method of alternative medicine originating from traditional Chinese medicine where extremely thin needles are inserted into the skin to stimulate specific points of the body. Starting with some brief history, this practice dates back to ancient China where it was first documented in the Huangdi Neijing (The Yellow Emperor’s Classic of Internal Medicine) around 100 BCE (White & Ernst, 2004). This text was an influential reference for traditional Chinese medicine for centuries and most likely acted as the foundation for modern acupuncture (Curran, 2008). This text also describes the flow of Qi (vital energy) which was believed to maintain good health when in balance. A Qi deficiency could mean that you are lacking in sleep, nutrition, or social interaction while excess Qi could mean stress, overeating, or exposure to toxins (Acupuncture & Massage College, 2017). (This idea seemed a bit silly to me as I am always stressed and lacking sleep. So, what does that mean for my Qi levels?) Acupuncture was believed to treat people by improving Qi flow and restoring balance by poking certain acupuncture points (Johns Hopkins Medicine, N.d.).

Source

        Acupuncture is said to treat a wide variety of illnesses: musculoskeletal pain, headaches, addiction, and anxiety to name a few (Johns Hopkins Medicine, N.d.). Ok, but how does acupuncture really work? Well, the answer is, we don’t really know. Acupuncture is thought to stimulate the nervous system (and probably your peripheral nervous system if you have a fear of needles) to cause your body to release chemicals that activates its natural healing abilities (Johns Hopkins Medicine, N.d.). It is also believed that placebo effect may play an important role in the therapeutic effects of acupuncture.  However, very little is actually known about the mechanism, and we are just beginning to understand its effects on the brain and body. In fact, according to PubMed, in the recent years there has been an increase in research studying the clinical use of acupuncture.

         It seems that society now has become more open to alternative medicines, whether it is because medicinal treatments have failed or because people are simply seeking a more natural therapy. But the biggest question with alternative medicine is, does it work? After all, even China thought it was bogus enough to completely ban the practice in 1929 along with other forms of traditional Eastern medicine and it wasn’t until 1949 that the Communist government reinstated such practices (White & Ernst, 2004). Despite the stigma we Americans may have towards traditional Chinese medicine, there are actually significant amounts of evidence showing the benefits of acupuncture therapy.

    A recent study conducted in The General Hospital of Western Theater Command, Sichuan Province assessed the effects of acupuncture of chronic lower back pain (Luo et al. 2019). In this trial, participants were randomly assigned to one of three treatment groups: hand-ear acupuncture, standard acupuncture, and usual care, which involved restorative exercise, strength training, medications, etc. (Luo et al. 2019). Ear acupuncture, or auricular acupuncture, is thought to be similar to reflexology where the ear has regional organization centers that represent different parts of the body created by pluripotent cells. When a certain region is stimulated, it can relieve pathological symptoms from other parts of the body for a period of time (Gori & Firenzuolli, 2007). The hand-ear acupuncture group were acupunctured at yaotongdian (lower back pain points) EX-UE 7 on the hand every other day for 4 weeks followed by acupuncture at yaotongdian AH 9 on the ear twice a week for the remaining 3 weeks. The standard acupuncture group received routine needle treatment curated by experts to specifically treat chronic lower back pain every other day for 4 weeks and twice a week for the remaining 3. Finally, the usual care group received usual care for the 7 weeks (Luo et al. 2019). The outcomes of this study were assessed via a series of blind interviews and measured at baseline, at 2 months after treatment, and at 6 months after. A modified Roland-Morris Disability Questionnaire (RMDQ) was used to evaluate back dysfunction and the visual analogue scale (VAS) was used to assess the severity of pain (Luo et al. 2019) This study found that both acupuncture treatments were more effective than usual care; however, the hand-ear group improved notably better in back function and lower back pain than the standard acupuncture treatment. The hand-ear group also showed better improvement over time indicating better long-term efficacy (Luo et al. 2019). This shows that acupuncture itself may have therapeutic effects and it is not dependent on placebo, as if that were the case, both acupuncture groups would have similar results.

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        As an Asian-America, I find traditional Chinese medicine really fascinating and I think there is so much potential. However, there is still a lot of doubt surrounding the practice. Now that we have been conducting more research, I believe that we are on the road to unlocking new and effective methods for treating patients. In a 2012 breakthrough documentary, Escape Fire: The Fight to Rescue American Healthcare (a fantastic film, I highly recommend), acupuncture was used as an alternative to narcotics to reduce pain in military soldiers during long and turbulent flights (Froemke & Heineman, 2012). More research is still needed to understand the underlying effects of acupuncture and there is sill much to learn from ancient medicine.

 By Emily Xu, A Bachelor's of Science Student at the University of Kentucky

 References

 Acupuncture & Massage College. (2017, August 28). What is Qi? Definition of Qi in Traditional Chinese Medicine. https://www.amcollege.edu/blog/qi-in-traditional-chinese-medicine

 A. White, E. Ernst (2004). A brief history of acupuncture, Rheumatology, Volume 43, Issue 5, Pages 662– 663, https://doi.org/10.1093/rheumatology/keg005

 Curran, J. (2008). The Yellow Emperor’s Classic of Internal Medicine. BMJ : British Medical Journal, 336(7647), 777. https://doi.org/10.1136/bmj.39527.472303.4E

 Froemke, S. & Heineman, M. (Director). (2012). Escape Fire: The Fight to Rescue American Healthcare

[Film]. Aisle C & Our Time Projects.

Small Interfering RNAs: Gene Silencing and its Applications

   

PubMed trend for published papers on siRNA

           

    Gene therapy is a hot topic in both genetics and pharmacology. It involves exploiting genetic pathways to treat disease by replacing a mutated gene, integrating a new gene, knocking a gene out, or silencing a gene. "This allows for an entirely new platform of drug targets outside of traditional small molecule targets such as enzymes and receptors.  Among the most prominent of these methods is gene silencing, a field in research and medicine that has started to come into its own and show results clinically. The method I will be discussing here - gene silencing via the use of small interfering RNA (siRNA) - requires small pieces of RNA that complement the mRNA transcript of the targeted gene in order to disable or "silence" expression of the gene.

 

Figure 1: "Gene Silencing by Design" Chemical and Engeering News, November 18, 2013 https://cen.acs.org/articles/91/i46/Gene-Silencing-Design.html

    siRNAs are administered as double-stranded RNAs, and then cleaved by endonucleases into single-stranded RNAs (Fig. 1). One of these strands is simply a "passenger" strand that is released and plays no further role. The other strand is the siRNA itself, a fragment of 21-25 nucleotides engineered to be complimentary to the messenger RNA (mRNA) of the targeted gene (Gavrilov & Saltzman, 2012). The siRNA interacts with key proteins such as DICER (an RNA-cleaving endoribonuclease) and Ago-2 (an RNA-binding protein which can mediate RNA degradation) to form a complex called the RNA-Induced Silencing Complex (RISC). When the siRNA, as part of the RISC complex, binds the target mRNA, the mRNA is cleaved. The cleaved mRNA is thus incomplete and non-functional, and will not be translated into protein (Lam, Chow, Zhang, & Leung, 2015). The transcription of the gene, therefore, does not serve its biological purpose and is functionally "silenced".

 

Figure 2.  The growth of siRNA-based therapeutics: Updated clinical studies" Biochemical Pharmacology, July 2021 (https://www.sciencedirect.com/science/article/abs/pii/S0006295221000289?via%3Dihub)

  

    The clinical applications of siRNA-based treatments are extensive. As of July of 2021, there are three siRNA-based drugs which have been approved by FDA with several being tested in clinical trials (Fig. 2). The first to be approved was Patisiran, an siRNA drug approved to treat transthyretin-mediated amyloidosis (hATTR). hATTR is caused by mutations in the gene coding for the transthyretin protein, which causes amyloid deposition in the central nervous system (CNS), heart, kidneys, and GI tract, leading to severe neuropathy, heart disease, and ulimately death. The siRNA drug disrupts expression of this protein, and significantly alleviates symptoms. The second siRNA drug approved for clinical use by the FDA was Givosiran. Givosiran is used as a treatment for acute hepatic porphyria (AHP), which causes accumulation of neurotoxic metabolites, leading to symptoms such as seizures, muscle weakness, tachycardia, and paralysis. Givosiran disrupts expression of the ALAS1 gene, reducing AHP-related "attacks" by 74% in clinical trials. Finally, the most recent FDA-approved drug was Lumasiran, which hit the market in November of 2020. Lumasiran is used to treat primary hyperoxaluria type 1 (PH1), a disease associated with hepatic enzyme deficiency and toxic metabolite accumulation. The primary symptom of the disease is excessive calcium oxalate forming kidney stones, leading to severe damage of the renal system and potential death due to systemic accumulation of oxalate. Lumasiran targets the gene transcript associated with a protein which synthesizes the precursor to oxalate, providing a 53-65% reduction in oxalate levels. Several drugs are currently being tested in clinical trials for their potential to treat a variety of diseases, including other hepatic diseases, familial hypercholesterolemia, hemophilia, kidney disease, glaucoma, and others (Zhang, Bahal, Rasmussen, Manautou, & Zhong, 2021).

 

Figure 3.  RNA Therapy: Current Status and Future Potential" Chonnam Medical Journal, May 2020
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250668/

Clearly, siRNA therapeutics are a promising avenue in pharmacological research which have begun to realize their potential after gaining the interest of the biomedical research community in the late 1990's/early 2000's (Fig. 3). The results are impressive, and even more so is the fact that many of these treatments exhibit effects lasting months following a single treatment, due to the ability of the RISC to protect siRNAs from degradation (Kim, 2020). The merits of siRNA drugs are beginning to yield great advancements in gene therapy, and the number of siRNA- based products on the market is expected to grow significantly in the next decade. Clinical use of siRNA therapeutics is still in its infancy, but its role in the future of medicine is sure to be prominent.

By Henry Snider, A Master’s of Medical Science Student at the University of Kentucky

 

References

 Borman, S. (2013). Gene Silencing by Design. Chemical & Engineering News, 91(46).

Gavrilov, K., & Saltzman, W. M. (2012). Therapeutic siRNA: principles, challenges, and strategies. Yale J Biol Med, 85(2), 187-200.

 Kim, Y. K. (2020). RNA Therapy: Current Status and Future Potential. Chonnam Med J, 56(2), 87-93. doi:10.4068/cmj.2020.56.2.87

 Lam, J. K., Chow, M. Y., Zhang, Y., & Leung, S. W. (2015). siRNA Versus miRNA as Therapeutics for Gene Silencing. Mol Ther Nucleic Acids, 4, e252. doi:10.1038/mtna.2015.23

 Zhang, M. M., Bahal, R., Rasmussen, T. P., Manautou, J. E., & Zhong, X. B. (2021). The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol, 189, 114432. doi:10.1016/j.bcp.2021.114432

CBD: an effective therapeutic for seizures?

During the past few years, cannabis has become increasingly accepted from a societal standpoint. Contrary to the overall acceptance of the public, very little funding was gathered to explore therapeutics derived from cannabinoids. The lack of funding may be attributed to psychoactive effects produced by some of the products harvested from the plant such as THC. This has limited the potential benefits that patients may be able to receive due to limited research involving of the isolation of compounds derived from cannabis. Recently, a new isolated compound from hemp, cannabidiol (CBD), looks to have potential benefits but more research still needs to be completed to understand its therapeutic applications.

Figure 1: Minimal energy conformations (A) and 2D structures of CBD and THC (B)(Burstein, 2015).

Cannabis is comprised of two main compounds, which are tetrahydrocannabinol (THC) and CBD. CBD is the main compound of cannabis that has sparked research interest due to its similar structure and nature to THC, without producing the psychoactive high that THC produces (Figure 1). CBD is a cannabinoid, so its chemical targets are the CB1 and CB2 receptors. The CB1 receptor is found on neurons and glial cells, while the CB2 receptor is primarily found throughout the immune system (Volkow, 2015). The difference in structural conformation between CBD and THC allows THC to tightly bind to the CB1 receptor while CBD binds to the CB1 receptor with low affinity. The difference in binding affinities allows CBD to act on other pathways in the brain without eliciting a psychoactive effect (Volkow, 2015). The broad range of CBD’s therapeutic effects include exerting antioxidant, neuroprotectant, anti-tumor, antipsychotic, and anti-anxiety activities. These therapeutic uses have been tested through cell culture and animal models, however, in recent years a new therapeutic benefit of CBD emerged. Emerging research has indicated that CBD may also be used to reduce seizures and act as a mild anti-convulsant and is now an FDA approved therapeutic for treating seizures within genetic diseases.

            Research completed by Patel et al. (2019) emphasized a possible clinical application of CBD. Using the TMEV-induced model of epilepsy, researchers were able to observe the role CBD plays in epileptic seizures. Here, researchers administered two different doses of TMEV to the mice; one group was administered 180 mg/kg and the other group was administered 150 mg/kg and each dose was administered twice a day. These mice were analyzed based on the number and intensity of seizures experienced daily (graded by the Racine scale). When observing the outcomes between the two populations, they observed that the population administered with the 180mg/kg dose of CBD experienced a significant decrease in the frequency and severity of seizures due to TMEV infection. While the population administered with 150 mg/kg of CBD experienced decreased frequency of seizures, they did not experience a significant decrease in the severity of seizures. These results from Patel et al. (2019) suggest that CBD displays promising characteristics as an anti-seizure therapeutic for intractable epilepsies. This evidence of therapeutic success within the TMEV model suggests that further studies should be completed to further investigate the pharmacological effects and mechanisms behind CBD.

            Following the research done by Patel et al., Anderson et al. (2019) explored the pharmacokinetics of CBD and clobazam as a therapeutic to treat Dravet’s syndrome. Dravet’s syndrome, similarly to TMEV, is an intractable childhood epilepsy. The evidence of CBD’s effects as an anti-seizure medication sparked Anderson et al.’s interest to test CBD’s pharmacokinetics as an adjunct with clobazam. Anderson et al. (2019) utilized Scn1a^+/- mice to model the effects of Dravet’s syndrome. Utilizing this mice population, they administered clobazam with various concentrations of CBD, including concentrations that were above and below the anticonvulsant dosage for CBD. Anderson et al. (2019) then subjected the Scn1a^+/- mice to hyperthermia-induced seizure experiments and measured the drug-drug interactions and overall therapeutic efficacy of the treatment. When an anticonvulsant dose of CBD was paired with clobazam, Anderson et al. observed an increased efficacy of clobazam treatment on the mice. CBD acted by extending the half-life, increasing exposure time, and increasing interactions of clobazam and its target, N-CLB. Anderson et al. also discovered a pharmacokinetic mechanism between CBD and clobazam that enhanced inhibitory GABA_A receptor activation, further contributing to its efficacy in treating intractable epilepsy.

Figure 2: U.S. funding of the various cannabis research sectors (https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug)

The studies by Patel et al. and Anderson et al. displayed the therapeutic efficacy and the pharmacological interactions associated with the anti-seizure effects of CBD. Even with strong evidence supporting CBD’s therapeutic benefits, research is still slow to take off due in part, to cannabis being labeled as a Schedule I drug. This labelling has led to funding cannabis research that focuses on harm and abuse of cannabis, rather than the therapeutic benefits (O’Grady, 2021). This skewed distribution of funding has allowed for increased research on why cannabis is a dangerous and abusive substance, rather than the possible benefits of isolated compounds derived from cannabis. This has made introducing cannabis-derived therapeutics challenging, as it is illegal to produce so it is hard to obtain and further isolate its compounds. This negative stigma has been slowly chipped away by public opinion and cultural shifts, which can be observed by 36 states having legalized cannabis and their products for medicinal use. This rapid shifting of cultural norms and values has allowed further CBD and cannabinoid research to take place, allowing for further exploration of the therapeutic benefits that these compounds display. This increase in research has allowed the medical community to realize the therapeutic and clinical benefits of CBD use. The only question to be answered now is: when will society see CBD as a viable therapeutic, rather than simply another recreational substance?

           

By William Lathram, A Master's of Medical Science Student at the University of Kentucky            

References

Anderson, L. L., Absalom, N. L., Abelev, S. V., Low, I. K., Doohan, P. T., Martin, L. J., Chebib, M., McGregor, I. S., & Arnold, J. C. (2019). Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions. Epilepsia, 60(11), 2224–2234. https://doi.org/10.1111/epi.16355

Bissell, L. J. L., Balneaves, L. G., Oliffe, J. L., Capler, N. R., & Buxton, J. (2013). Perceptions of cannabis as a stigmatized medicine: A qualitative descriptive study. Harm Reduction Journal, 10(1), 2. https://doi.org/10.1186/1477-7517-10-2

Burstein, S. (2015). Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorganic & Medicinal Chemistry, 23(7), 1377–1385. https://doi.org/10.1016/j.bmc.2015.01.059

Commissioner, O. of the. (2020, July 31). FDA approves new indication for drug containing an active ingredient derived from cannabis to treat seizures in rare genetic disease. U.S. Food and Drug Administration. Retrieved October 27, 2021, from https://www.fda.gov/news-events/press-announcements/fda-approves-new-indication-drug-containing-active-ingredient-derived-cannabis-treat-seizures-rare.

O'Grady, C. (2020, August 27). Cannabis research database shows how U.S. funding focuses on harms of the drug. Science. Retrieved October 27, 2021, from https://www.science.org/content/article/cannabis-research-database-shows-how-us-funding-focuses-harms-drug.

Patel, D. C., Wallis, G., Fujinami, R. S., Wilcox, K. S., & Smith, M. D. (2019). Cannabidiol reduces seizures following CNS infection with Theiler's murine encephalomyelitis virus. Epilepsia Open, 4(3), 431–442. https://doi.org/10.1002/epi4.12351

Volkow, N. D. (2015, June 24). The biology and potential therapeutic effects of cannabidiol. NIDA Archives. Retrieved October 17, 2021, from https://archives.drugabuse.gov/testimonies/2015/biology-potential-therapeutic-effects-cannabidiol.

  

Micro-dosing as a Potential New Therapy for Various Psychiatric Disorders?

 

Source: Vanity Fair

In our culture today we tend to learn about new information via media whether that is movies, Instagram, or YouTube. Recently, one tv-show that has spurred some commotion is, Nine Perfect Strangers, which can be found on Hulu. In the beginning we are introduced to nine different people who have each gone through different perils throughout their life and have had a hard time overcoming them. Each of them decides to attend a retreat where they are promised healing and transformation. Towards the end of the show, it is uncovered that Masha the women who has been hosting this retreat has been micro dosing each of the guest. Each morning she was making a tea with a miniscule amount of psychedelics, which would help them deal with deeply rooted issues such as anxiety, depression, anger management issues and addiction. Interestingly, throughout the show we see the benefits of this micro dosing but also the drawbacks. If you are someone like me, you may be wondering whether this would work? Would this be a new treatment for patients in the future? No worries, these will all be questions that I will answer as I discuss more about micro-dosing in the upcoming paragraphs.

         There are pharmacological mechanisms of action for micro-dosing; however, it is possible that individual differences in metabolism, psychopathological diseases, personality, interpretation of signals may affect how micro-dosing outcomes manifest (Anderson et al., 2019). The receptor involved in micro-dosing is the serotonin 5HT-2A receptor. A variety of mutations of this receptor which may affect how the 5HT-2A agonists such as LSD and psilocybin are processed may be present in different individuals. This may be exemplified with an example of a healthy person in comparison to an individual who may be suffering with depression. In addition, the effect of these substances on 5HT-2A receptors has enhanced neural plasticity and neurogenesis along with neuroprotective effects, which are relevant to neurodegenerative diseases (Ona & Bouso, 2019). As we can see, micro-dosing will not have the same effect on everyone and there really isn’t a one dose fits all since there are genetic components involved in micro dosing that result in differential responses.

Source:  www.slashgear.com

So, you may be wondering if I begin micro-dosing what type of benefits could I possibly expect? Many personal accounts of micro-dosing have been uploaded on to YouTube and qualitative study was completed looking at some of these personal accounts. Anderson and Kjelleren (2019), classified their findings from these YouTube videos into four categories. The first category included enhanced state and heightened senses (more focus and energy, experiencing the present moment, improved mood and reductions in sadness, anger, and stress). The second category included insights and transformations (augmented self-reflection, thoughtful insights which led to deeper connections and changes in habits). The third category included improved abilities and optimal performance (increased creativity, enhanced productivity and effectiveness, and extraversion in social settings). In the final category was relief and cure for health conditions (benefits regarding depression, anxiety, and ADHD etc). These qualitative studies are informative, but survey studies are a little more helpful when potential benefits are emphasized. One survey study recruited 278 participants who had already been micro-dosing either with LSD or psilocybin. Anderson et al. (2019a) reported the major benefits of micro-dosing to be an improved mood (26.6%), improved focus (14.8%), creativity (12.9%). Some users even reported a reduction in caffeine (44.2%), alcohol (42.3%), cannabis (30.3%), and tobacco (21%). They also found that micro-dosing resulted in lower scores for dysfunctional attitudes and negative emotions, but higher scores for wisdom, creativity, and open mindedness (Anderson et al., 2019). It is easy to get caught up on all these positive results especially in an age when people want a quick fix to issues such as mental illness. I believe micro-dosing has very positive benefits, but it is important to consider the harmful effects as well before participating.

         There were some negative side effects reported by some of the participants from these previous studies. Anderson and Kjelleran (2019), mentioned how some users experienced increased anxiety, panic attacks, gastrointestinal cramps, restlessness, jitters, insomnia, decreased problem solving skills and cognitive function. In some instances, patients experienced a worsening of symptoms including mental health, over stimulations, or a bad trip when LSD was combined with cannabis. Honestly, the side effects continue from there and contradict the positive effects experienced in the paragraph above. To me, this emphasizes how little we still know about micro-dosing, and how studies are difficult to compare due to the difference in methods and variables which may or may not be confounding variables. I believe this may be a promising therapy for the future, but studies still need to be completed to have a firmer understanding of these positive and negative benefits.

         In my view this is an exciting field, in which more research needs to be completed before more of the public jumps on the micro-dosing bandwagon. As we have seen from other therapies such as cannabidiol (CBD), that micro-dosing will not be an end all therapy where it will fix each issue that you have but will be helpful in mitigating issues you may be experiencing. This therapy is gaining momentum in the medical community, but research is still being completed before it will be offered as a legal therapy. We have a lot to look forward to as the scientific community continues to discover more about micro-dosing.

 By Ashely Wahlman, A Master’s of Medical Science Student at the University of Kentucky College of Medicine

 Sources:

Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L. A., Hui, K., & Hapke, E. (2019). Psychedelic microdosing benefits and challenges: an empirical codebook. Harm reduction journal, 16(1), 43. https://doi.org/10.1186/s12954-019-0308-4

Anderson, M., and Kjellgren,A. (2019). Twenty Percent better with 20 micrograms?A qualitative study of psychedelic microdosing self-rapports and discussion on YouTube.Harm reduction Journal,16(1).

Ona,G., and Bouso, J.C.(2020).Psychedlic drugs as a long-needed innovation in psychiatry. Qeios, https://doi.org/10.32388/T3EM5E.2

 

Sleep and No-Sickness? The Preventative Impact of Melatonin on Covid-19 Patients

 

http://toonclips.com/600/cartoon-sleep-deprived-businessman-sleeping-standing-up-by-toonaday-66847.jpg

Being the hardworking students that we are, we tend to allow our sleep schedules to fall out of “circadian-rhythm” (haha get it?). We tend to give into the marketing of pretty Starbucks coffee drinks to keep us awake and the idea of studying for hours prioritizing good grades over getting a good night’s sleep. This contributes to the 50 to 70 million Americans who suffer from sleep disorders or sleep deprivation and more than 60 million Americans who take sleep medications every year. It is estimated that Americans spend more than $41 billion on sleep aids and remedies (Penn Medicine). But sleeping issues have been around since our earliest existence, so what did we do before?

 

When we think of sleep remedies, we can look back as early as early Egyptian and ancient Roman times. One of the most well-known ancient remedies is chamomile. Not only was it great for sleeping issues but has many other positive effects including its ability to act as a cold remedy (Wise Ape, 2021). Today we often use it as a common nighttime staple to help us sleep and relax. However, for some people it does not work, or they need something stronger to aid their sleep. This is where the understanding and pharmacological production of melatonin became a game changer to the sleep-deprived people of the world and now possibly Covid-19 patients? First, let’s understand where melatonin comes from.

 

Melatonin is a natural hormone that is produced by our pineal gland. It is a derivative of tryptophan, an important amino acid necessary for maintaining of many of bodily functions. It was first isolated by Aaron B Lerner in 1958 of Yale University School of Medicine when he was conducting vitiligo research on frogs. He isolated a hormone melatonin thinking it would lighten the skin of frogs, only it didn’t. Instead, he found that it was responsible for maintaining cycles of wakefulness and rest. With respect to its target, melatonin binds to two type of G-protein receptors, MT1 and MT2, in the suprachiasmatic nucleus, a tiny region of the hypothalamus in the brain. High levels of melatonin can induce sleep. When our sleep schedule is normal, darkness prompts our pineal gland to secrete melatonin. The lack of melatonin production during the day will elicit wakefulness. This is why if your sleep schedule is off because you are doing things like staring at your phone until 2am, you are exposing yourself to blue light which will not let you produce melatonin. Now you are a walking zombie at your 8am class because you got no sleep. However, as important as melatonin is to sleep, it has been found to have other amazing benefits, including helping in learning and memory, fertility and reproduction, and most-recently immune activity (Srinivasan et al., 2005). This finding has been used to explore its benefits to Covid-19 patients.

 

SARS-CoV-2 can cause severe inflammatory responses and oxidative stress; two biological events alleviated by melatonin. One way melatonin can act is by reducing oxidative stress through its ability to increase an antioxidant known as glutathione. Glutathione is an important antioxidant that combats damage within cells, such as free radicals. With respect to COVID-19, a common symptom resulting from viral infection is oxidative stress caused by an increase in free radicals. Thus, melatonin can increase glutathione levels and reduce conditions of oxidative stress in COVID-19 patients. In addition, melatonin has anti-inflammatory abilities which arise from its affinity to G-protein-coupled receptors which control the secondary signaling pathways that impact the immune response. With respect to COVID-19, the infecting SARS-CoV-2 virus binds with high affinity to angiotensin-converting enzyme 2 (ACE2) receptors on the epithelial lining of the lungs. This binding triggers a proinflammatory response. However, calmodulin, an important messenger protein in the G-protein-coupled secondary pathway, controls the amount of ACE2 receptors on the plasma membrane. Melatonin can inhibit the coupling of ACE2 receptors and SAR-COV2 during viral particle fusion through its inhibition of calmodulin as it is regulated by the secondary messenger pathway (Cross et al., 2021). But if you don’t believe me, just look at how complex melatonin’s target pathway is (Cecon et al., 2017).

Fig. 1. Melatonin receptor pathway. Graph from E Cecon et al., Melatonin receptors: molecular pharmacology and signaling in the context of system bias. British Journal of Pharmacology. (5 July 2017).

Complex, I know! There are so many other ways melatonin has proven to be a great drug for other disease use other than just sleep. But from those short explanations on how melatonin can work, you get the idea. This is an incredible new form of exploration that can truly help so many people fighting COVID-19. As incredible as these findings do sound, we are still exploring the full accuracy and positive effectiveness of this drug on COVID-19 patients. More importantly, it is imperative to stay on top of new research and findings as we are constantly at risk of COVID-19 as the world begins opening up again. So now we ask the big question, do we bring this idea further to light that COVID-19 is a potential drug market for COVID-19? Researchers have already explored melatonin’s benefits in viral disease similar to COVID-19 so why not to treat COVID-19 patients? One problem is that we could be risking another “Ivermectin” fiasco, with multiple people storming our local CVS and buying all of the over-the counter melatonin thinking it can completely fight COVID-19 (only this being a much safer and beneficial option if you are a struggling college student who never sleeps). What do you think?

By Sarah Mandviwala, A Master's of Medical Science Student at the University of Kentucky

 

Works Cited

Ape, T. W. (2018, April 17). The history of chamomile tea. Wise Ape. Retrieved October 12, 2021, from https://www.wiseapetea.com/blogs/knowledge/the-history-of-chamomile-tea.

Cecon, E., Oishi, A., & Jockers, R. (2017, August 17). BPS Publications. British Pharmacological Society | Journals. Retrieved October 12, 2021, from https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13950#:~:text=Melatonin%20receptor%20signalling%20pathways.,and%20increase%20in%20intracellular%20Ca2%2B.

Cross, K. M., Landis, D. M., Sehgal, L., & Payne, J. D. (2021, August). Melatonin for the early treatment of covid-19: A narrative review of current evidence and possible efficacy. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. Retrieved October 12, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190272/#bib38.

Melatonin and zolpidem: Do sleeping aids actually work? Penn Medicine. (n.d.). Retrieved October 12, 2021, from https://www.pennmedicine.org/updates/blogs/health-and-wellness/2018/july/sleeping-aids.

Srinivasan, V., Maestroni, G. J. M., Cardinali, D. P., Esquifino, A. I., Perumal, S. R. P., & Miller, S. C. (2005, November 29). Melatonin, Immune Function and aging. Immunity & ageing : I & A. Retrieved October 12, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1325257/.