What are nootropics?

Nootropics can be defined as “natural, semi-synthetic and synthetic molecules that claim to enhance cognitive function.” Often, they are consumed in the form of supplements. However, these supplements have yet to be approved by the FDA for the general population.

Intellectual Disability

Intellectual disability, or ID, affects 1 in 20 people in the United States. Those who suffer from ID also suffer from emotional and financial burdens along with “direct impairments on the individual and their ability to function in society.” [1] As such, there have been many attempts to improve the everyday lives of these people. However, all these therapies can be challenging because one size doesn’t fit all in this case. For example, a medication that targets gene defects may work for a person who develops ID because of a gene mutation, but it will not work for someone who develops ID because of disease. It’s clear that a one size fits all therapy would be the best outcome for everyone. Therapies that generalize to many types of disorders or conditions that are associated with cognitive dysfunction may be useful. There are a total of six neurocognitive domains, pictured below, that are assessed when addressing ID: perceptual and motor function, language and memory, social cognition, attention, and executive function. All these domains function together, and they do not and cannot operate in an isolated form. Knowing this, scientists have been working on multiple strategies that would help to enhance cognitive functioning. The two that will be addressed are environmental enrichment and pharmacological strategies that target signaling pathways.

Environmental Enrichment

   When talking about animals in this sense, it is easy to control their environment, but less so when talking about humans. Experimenting with rats, for example, researchers can control whether they are in an environment that enriches the rat or one that causes stress. Environmental enrichment is “the stimulation of the brain by its physical and social surroundings.” [2] It isn’t as easy to control our own environment, but we can avoid things that cause stress, as well as indulge ourselves in things that lead to happiness. Some examples that give us enrichment are mental stimulation, light, social partners, the birth of a baby, developing a hobby, etc. All these examples add value to our lives. [3]

Pharmacological Strategies

   Before addressing that pharmacological strategies that can be used to treat ID, we first need to address BDNF. Brain-derived neurotropic factor, BDNF, plays an important role in survival and growth of neurons. It also plays a role in neuroplasticity which aids in memory and learning. BDNF is released in response to neuronal activity and binds to specific receptors on neuron surfaces which promotes their survival and growth. Too much or too little BDNF in the brain causes problems, everything in moderation. Too much may cause seizures, while too little is associated with ID. For those of us who do not suffer from ID, there are natural remedies to increase BDNF: coffee, blueberries, omega-3, zinc, and so much more. [4] Although supplements may not be FDA-approved, there are plenty of safe, healthy, and natural ways to increase BDNF levels. On the other hand, for those who do suffer from ID, ampakines seem to be a very promising remedy. Ampakines are drugs that directly increase the levels of BDNF, and support neuronal survival and differentiation.

So, what?

BDNF levels are decreased in the brains of those diagnosed with ID. There are non-pharmacological and pharmacological strategies to address this, and combining both is the most promising. Do not use this information as a diagnosis, or treatment for yourself or someone you may know. It’s important to know that these strategies may not work for everyone. All this information is just the basis to ID and what is going on in the brain. There still needs to be more development and research to help improve the lives of those with ID. But the information that has known is a great start.

[1] Morè, L., Lauterborn, J. C., Papaleo, F., & Brambilla, R. (2020). Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders. Neuroscience & Biobehavioral Reviews, 110, 28–45. https://doi.org/10.1016/j.neubiorev.2019.02.003

[2] McDonald, M. W., Hayward, K. S., Rosbergen, I. C. M., Jeffers, M. S., & Corbett, D. (2018, June 14). Is environmental enrichment ready for clinical application in human post-stroke rehabilitation? Frontiers. Retrieved April 27, 2023, from https://www.frontiersin.org/articles/10.3389/fnbeh.2018.00135/full

[3] McDonald, M. W., Hayward, K. S., Rosbergen, I. C. M., Jeffers, M. S., & Corbett, D. (2018, June 14). Is environmental enrichment ready for clinical application in human post-stroke rehabilitation? Frontiers. Retrieved April 27, 2023, from https://www.frontiersin.org/articles/10.3389/fnbeh.2018.00135/full

[4] How to increase BDNF: 10 Ways To Rescue Your Brain. Strong Coffee Company. (n.d.). Retrieved April 27, 2023, from https://strongcoffeecompany.com/blogs/strong-words/how-to-increase-bdnf-10-ways-to-rescue-your-brain

Nootropics

Nootropics, also known as “smart drugs” or cognitive enhancers, are substances that are believed to enhance cognitive function, memory, creativity, and motivation. Nootropics can include natural substances such as herbs and botanicals, as well as synthetic substances like prescription drugs and supplements.

While the use of nootropics is not new, interest in them has grown in recent years as people look for ways to optimize their mental performance. However, it is important to note that the effectiveness and safety of nootropics can vary widely, and some are not well-researched or regulated.

Potential Benefits of Nootropics

The potential benefits of nootropics are varied and depend on the specific substance being used. Some of the most commonly reported benefits include:

1. Improved focus and concentration
2. Increased memory and learning capacity
3. Enhanced creativity and problem-solving abilities
4. Reduced anxiety and stress levels
5. Increased motivation and productivity

However, it is important to note that not all nootropics are created equal, and the effectiveness of these substances can vary widely based on individual factors like genetics, diet, and lifestyle.

BDNF

Brain-derived neurotrophic factor (BDNF) is a protein that plays a crucial role in the growth and survival of neurons in the brain. BDNF also plays an important role in the formation of new neural connections, which is key for learning and memory. Studies have shown that some nootropics may be able to increase BDNF levels in the brain, which could have potential benefits for cognitive function.

BDNF Signaling Pathway

BDNF activates the Ras-ERK pathway. The Ras-ERK pathway is involved in a variety of cellular processes that are important for cognitive function, including neuronal growth and differentiation, synaptic plasticity, and long-term potentiation (LTP), which is a cellular mechanism thought to underlie learning and memory. Studies have shown that inhibiting the Ras-ERK pathway can impair LTP and cognitive function, while activating this pathway can enhance LTP and cognitive function.

One of the most well-known nootropics that may increase BDNF levels is exercise. Regular physical activity has been shown to increase BDNF levels in the brain, which may help improve cognitive function and reduce the risk of age-related cognitive decline.

In addition to exercise, certain dietary supplements have also been shown to increase BDNF levels. For example, omega-3 fatty acids found in fish oil have been shown to increase BDNF levels in the brain, which may help improve cognitive function and reduce the risk of depression.

As the paper for this week mentioned, combining environmental enrichment therapies with those that promote neuronal activity and signaling, such as selective activation of the Ras-ERK pathway, and/or facilitate brain-derived neurotrophic factor (BDNF) through the use of ampakines, may be a promising strategy for improving learning and memory in various forms of cognitive impairment, including those that occur during early development and aging. However, more research is needed to determine the extent to which these therapies can improve cognitive/behavioral impairments in different disorders or conditions of impairment, as well as the most effective treatment regimens.

References:

https://www.sciencedirect.com/science/article/pii/S0149763418302926?via%3Dihub

https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.frontiersin.org%2Farticles%2F10.3389%2Ffnins.2019.00790%2Ffull&psig=AOvVaw0Y1JZ9hwMRf9An4uAusnT0&ust=1682616000287000&source=images&cd=vfe&ved=0CBIQjhxqFwoTCICP4JmHyP4CFQAAAAAdAAAAABAD

The Endocannabinoid System

The endocannabinoid system is a regulatory system in our bodies that has effects on many functions such as mood, pain, learning and memory, inflammatory response, and eating. There has also been evidence that the endocannabinoid system plays a neuroprotective role following injury (1).

There has been a lot of interest lately in the utilization of this system as a therapeutic target for many diseases. Drugs that act on the endocannabinoid system to increase appetite and to help treat seizures caused by epilepsy have been approved, and utilize both CBD and THC to do so.

Endocannabinoids

Our bodies naturally produce molecules that activate this system, called endocannabinoids. These molecules are produced on-demand in response to the state our body is in. The receptors endocannabinoids act on are two types of CB receptors.

1. 

   CB1 receptors are primarily found in the central nervous system, and are mainly on presynaptic neurons.

2. CB2 receptors are found commonly on cells and tissues in the immune system, and are mainly activated in response to inflammation.

There are also exogenous materials that will act on the endocannabinoid system. Most commonly known and used are cannabis and THC.

Cannabis and THC

While you may have heard the terms marijuana and cannabis used interchangeable there are different meanings to each. The word ‘cannabis’ refers to all products derived from the plant Cannabis sativa. ‘Marijuana” refers to parts or products from the Cannabis sativa plant that contain a significant amount of tetrahydrocannabinol (THC).

All natural (non-synthetic) marijuana is cannabis, but not all cannabis is marijuana. Hemp is the term used for cannabis compounds that contain less than .3% of THC or less (2).

• THC: the main psychoactive molecule found in cannabis plants. This is the molecule that produces the ‘high’ sensation.
• CBD: cannabidiol is a molecule found in cannabis and is an activator of the endocannabinoid system. This molecule however doesn’t give the high that THC does.

Throughout the 1900s it became illegal in most of the world to grow cannabis plants for sale or personal use. But why?

Drug Scheduling in the US

To talk about the illegality of cannabis and THC, we need to have some basic understanding of how drug classification works in the United States. Under the Controlled Substances Act the government allowed the Drug Enforcement Administration (DEA) to classify drugs into 5 categories depending on the drugs accepted medical uses and it’s potential for abuse and addiction.

The higher the schedule, the more potential for abuse and addiction. Schedule 1 drugs are substances or chemicals that are defined as “drugs with no currently accepted medical use and a high potential for abuse” (3). Examples include LSD, ecstasy, and marijuana.

Woah wait! Why is marijuana included in that list when we already mentioned drugs that use THC?  That’s where it gets tricky.

Medical Uses for CBD and THC

It’s commonly known that THC can induce hunger, or ‘the muchies’. Dronabinol is a capsule form of synthetic THC that is used as an appetite stimulant. It was approved in 1985 by the FDA, and was classified as a schedule 2 medication. However in 1991 it was rescheduled to schedule 3 based on evidence that it has low potential for abuse (4). So how is THC as dronabinol considered less addictive than the THC in marijuana? There has been lots of push to reschedule cannabis and marijuana down from schedule 1 based on this.

Benefits to Rescheduling Cannabis

THC is an approved an appetite stimulant medication and is often given to people undergoing chemotherapy to combat weight loss. However recently there has been research on the potential effects that THC can have for obstructive sleep apnea, chronic neuropathic pain, glaucoma, arthritis, and many others (5). CBD has recently been a topic of interest for the treatment of seizures, inflammation, migraines, and psychosis and other mental disorders (6).

Cannabis being a schedule 1 drug makes further research into the use of THC to treat these conditions rather difficult, requiring lengthy petitions and government approval. Rescheduling cannabis into a lower drug class would make researching and developing medications involving THC and CBD an easier process.

References:

1. https://www.health.harvard.edu/blog/the-endocannabinoid-system-essential-and-mysterious-202108112569

2. https://www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-need-to-know

3. https://www.dea.gov/drug-information/drug-scheduling

4. https://www.pharmacytimes.com/view/dea-denial-of-petition-to-reschedule-marijuana

5. https://www.ncbi.nlm.nih.gov/books/NBK563174/

6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966847/

Addiction is a significant issue in today’s society. Addiction is defined as a compulsive and persistent dependence on a substance or behavior that has negative consequences. Some of the most common types of addiction are substance addiction (addiction to drugs, alcohol, and tobacco), natural addiction (addiction to food, binge eating disorder) and behavioral addiction (addiction to gambling, video games, and social media).

Addiction can have a significant impact on an individual’s life as well as the lives of those close to them. It can result in physical and mental health issues, financial difficulties, social isolation, and legal complications. Addiction can also have a negative impact on the larger community by causing crime, violence, and other social problems.

Addiction is particularly problematic in today’s society due to a number of factors. For starters, addictive substances and behaviors are more widely available, thanks to the proliferation of online gaming and social media platforms. Second, there is less social stigma attached to addiction, which may make it easier for people to engage in addictive behaviors without fear of being judged. Finally, many people lack access to effective addiction treatment and support services, making it difficult for them to overcome their addiction and live a healthy life.

Drug abuse can activate several signaling pathways in the brain, leading to the development of addiction. The following are some of the most common signaling pathways involved in drug abuse:

1. Dopamine pathway:The mesolimbic dopamine pathway, which is a circuit of brain regions involved in reward and motivation, is one of the key pathways identified by Dr. Nestler and his colleagues. This pathway is activated when a person engages in rewarding behavior or takes an addictive drug, and dopamine is released in the nucleus accumbens, a key region of the brain’s reward circuitry. This dopamine release reinforces and motivates the individual to repeat the behavior.
2. Glutamate pathway: The glutamate pathway is responsible for learning and memory. Drugs of abuse can activate this pathway, leading to changes in synaptic plasticity, which can lead to drug cravings and addiction.
3. GABA pathway: The gamma-aminobutyric acid (GABA) pathway is responsible for the brain’s inhibitory system. Drugs of abuse can disrupt the balance of GABA signaling, leading to an increase in excitatory signaling, which can lead to drug cravings and addiction.
4. Endocannabinoid pathway: The endocannabinoid system is responsible for regulating appetite, pain, and mood. Drugs of abuse can activate the endocannabinoid pathway, leading to changes in appetite and mood.

Moreover, repeated drug use or addictive behavior causes the brain to adapt, resulting in long-term changes in gene expression and synaptic plasticity. Dr. Nestler has identified a number of specific molecular pathways involved in these adaptations, such as changes in gene expression of various transcription factors, epigenetic DNA modifications, and changes in synaptic plasticity and neuroplasticity.

While there may not be a single common molecular pathway for addiction, Dr. Nestler’s research has contributed to the identification of some of the key molecular and cellular mechanisms that underpin addictive behavior. This understanding is critical for the development of new treatments and interventions to assist individuals in overcoming addiction and leading healthy, fulfilling lives.

Artstract created by Kailee Vigen

The Obesity Crisis 

41.9 percent of American adults have obesity as of 2022. This obesity rate is due to many contributing factors such as race, genetics, environmental, and biological. Since 2021, nineteen states have announced a population obesity rate of 35% or higher. A decade ago, none of the fifty states were even near 35% obese. What has caused this increase, and what can be done to help the obesity crisis? With numbers as such, it is safe to say that this is not an individual problem – this is the nations, and even the world’s problem.

The only explanation for such an increase in obesity is, simply, increased caloric intake and decreased exercise causing weight gain. As treatment, it is advised to eat healthier and exercise more, which is attainable for some individuals, but not all. At such a large scale of obesity, our only hope for a “cure” is market changes and policy. One policy that has been proposed and is now implemented in Philadelphia, PA, Boulder, CO, and Berkeley, CA is a sweetened beverage tax. In Berkeley, this tax caused a 21% drop in sugary drink consumption. This is one promising example that such policies can help with the obesity crisis. It is discouraging seeing the healthy food priced at least two times more as the processed and fatty snack aisle in grocery stores. If healthier food costs were lowered and unhealthy foods were taxed, the obesity epidemic would see the end of its climb and plummet. 

The Science

Biologically, obesity is more than just a bigger waist and greater amounts of adipose tissue built up throughout the body, it actually affects brain function as well. Altered brain function also contributes to obesity in individuals, but it all begins with diet – a high fat diet.

What is a High Fat Diet (HFD)?

HFD is the consumption of 35% of total caloric intake coming from fats, both saturated and unsaturated. These high-fat foods include the beloved and cheap processed foods we all know and love, animal fats, chocolate, butter, and oils. To put this diet into perspective, if one consumes 2,000 calories in a day, and 700 calories of that came from fats, equivalent to half a normal sized bag of Doritos, then this would be considered a HFD. Unfortunately, just this one day of poor eating can cause detrimental change to the brain and thus the body as a whole. 

A HFD has been found to activate pathways causing leptin and insulin resistance – preventing individuals from feeling satiated and increasing blood sugar levels. This nutrient excess through overconsumption drives inflammation of the hypothalamus. This hypothalamic inflammation occurs even before weight gain. This inflammation alters the brain’s homeostatic and metabolic functions, contributing to obesity through such imbalanced energy and insulin resistance, as shown in the figure below. It has also been shown that HFD reduces synaptic plasticity, the body’s way of making new pathways for things learned and the formation of new memories. 

Conclusion

The obesity epidemic is one of the largest problems in the US and in the world. Obesity is not only gaining weight, it also alters brain function and creates different neuronal pathways from a HFD. Obesity effects an individual much more than one would think, and that is alarming. Taxes on unhealthy foods are a strong start to deterring individuals from buying such cheap, fat-filled  foods. Obesity is much more than an individual problem – the weight is truly in the country’s and world’s hands. 

References

Farberman, R. (2022). State of Obesity 2022: Better Policies for a Healthier America. Trust for America’s Help. Retrieved April 12, 2023, from https://www.tfah.org/report-details/state-of-obesity-2022/#:~:text=Nationally%2C%2041.9%20percent%20of%20adults,obesity%20rate%20of%2045.6%20percent.

Blumenthal, D.; Seervai, S. (2018). Rising Obesity in the United States Is a Public Health Crisis. The Commonwealth Fund. Retrieved April 13, 2023, from https://www.commonwealthfund.org/blog/2018/rising-obesity-united-states-public-health-crisis

Kristantis, B.; Turner, D. (2020). High-Fat Diet. Advances in Cancer Research. Retrieved April 11, 2023, from https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/high-fat-diet#:~:text=A%20high%2Dfat%20diet%20(HFD,%2C%20butter%2C%20and%20oily%20fish.

Jais, A., & Brüning, J. C. (2017). Hypothalamic inflammation in obesity and metabolic disease. The Journal of Clinical Investigation, 127(1), 24–32. https://doi.org/10.1172/JCI88878

What is Obesity?

Obesity is a condition characterized by excessive accumulation of body fat to the extent that it impairs health. It is commonly defined by body mass index (BMI), a measure of weight in relation to height, with a BMI of 30 or higher considered obese. Obesity and metabolic diseases such as type 2 diabetes are major public health challenges that have reached epidemic proportions globally. While the exact mechanisms underlying these diseases are complex, recent research has pointed to the role of hypothalamic inflammation in their development.

A paper titled “Hypothalamic inflammation in obesity and metabolic disease” by Alexander Jais and Jens C. Brüning provides an in-depth review of the current understanding of this phenomenon. The authors explain that the hypothalamus, a brain region that plays a crucial role in regulating energy balance and glucose homeostasis, is particularly vulnerable to inflammation due to its high sensitivity to changes in nutrient and hormonal signals.

One section of the paper discusses the mechanisms that contribute to hypothalamic inflammation in obesity and metabolic disease. It also discuss the role of the immune system and how chronic low-grade inflammation can lead to hypothalamic dysfunction.

Fatty Acids

Another interesting aspect of the paper is the discussion of how certain dietary components can influence hypothalamic inflammation. For example, saturated fatty acids, which are commonly found in animal products and many processed foods, can activate inflammatory pathways in the hypothalamus. On the other hand, consumption of omega-3 fatty acids, which are found in foods like fatty fish and flaxseed, has been shown to have anti-inflammatory effects in the hypothalamus.

Neural Networks

Inflammation can affect the neural circuits that regulate feeding behaviour and energy expenditure, leading to alterations in appetite, physical activity, and metabolic rate. Activation of pro-opiomelanocortin (POMC) neurons and inhibition of agouti-related peptide (AgRP) neurons by adipostatic signals leads to the activation of melanocortin 4 receptor (MC4R) expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus. This results in satiety and stimulation of energy expenditure. In contrast, during fasting, AgRP expression increases while POMC expression decreases, leading to decreased MC4R signaling.

Hypothalamic Inflammation

The figure above shows how the consumption of a high fat diet can lead to hypothalamic dysfunction, a condition associated with an increase in oxidative stress. When the hypothalamus becomes inflamed due to the consumption of a high-fat diet, it can lead to a disruption of insulin and Leptin hormones (appetite regulators) and contribute to the development of obesity. Insulin and leptin act directly on specific subsets of neurons in the arcuate nucleus (ARC) of the hypothalamus to control energy balance. The authors describe several approaches, including anti-inflammatory drugs, lifestyle interventions, and dietary modifications, that have shown promise in preclinical and clinical studies.

Overall, this blogpost highlights the importance of understanding the role of hypothalamic inflammation in the development of obesity and metabolic disease. By identifying the underlying mechanisms and consequences of this process, researchers may be able to develop more effective strategies for preventing and treating these conditions.