I didn’t know what to expect going into neurochemistry this semester. I had no experience in the neurosciences and had never taken a chemistry class without a lab. To say the least, what expectations I did have for this class were blown out of the water and this became one of the most enjoyable classes I have taken at Concordia.
In a short time, I went from knowing nothing about neurosciences to craving more of the specifics about neurochemical pathways. The neat thing is that everyone in our class was the same way. We were all genuinely curious which fostered a unique learning environment. On Wednesdays we would have speed dating rounds where we would each share something regarding the weekly topic that we had researched further. As a group there was so much energy in the room as we shared information and learned more together, it was invigorating. Neurochemistry definitely heightened my love of learning as I always wanted to know more.
Image from https://themindblower96.wordpress.com/2015/05/21/54/.
Each week we read an article outlining the pathology and neurochemistry surrounding a neurological disease or other neurological functions. We would try to understand what we could individually and then discussed the article in class to learn about areas in the paper that were more difficult. Scientific literacy is a transferable skill that will be important in my future endeavors. I might even go as far to include scientific literacy on my resume. My future goal currently is to study plant biology, in which understanding research in the field is critical as it is in all the sciences.
On Fridays, we would sit in a large circle and discuss the topic that our paper covered and other social implications that surround the topic. This was a great way to observe other perspectives in the class but also gave us the opportunity to move away from the microscopic neurochemistry to the macroscopic implications a neurological disorder, substance abuse, or obesity has on society. We were given the opportunity to share our own experiences and biases in an open, accepting zone. I think these discussions were really a time to draw from other disciplines as we analyzed what we knew about the topic. Discussions often included political, ethical, cultural, and social concerns showing that this class provided a wholesome learning experience.
Lastly, a project that we mostly did outside of class was the Community Action Project. In this project we teamed up with social work students to tackle a societal issue with components of neurochemistry. We were each assigned a topic. My group was addiction and we decided to tackle youth vaping. We held four sessions with middle school students who had been cited for vaping. Not only was the project interdisciplinary, as we worked with social work students, but it also allowed us to contribute to the community in one way or another. I’m not sure the middle school students will quit vaping tomorrow but maybe we gave them some things to think about when they do vape. I consider this as the BREW component of our class. We were engaged in an issue that is a part of our world and hopefully were able to contribute to fixing the problem. The addiction counselor at the school will be implementing a similar program in the future with students which makes it feel like we really did contribute.
Neurochemistry was a class that I think embodies the liberal arts education. The course provided a wholesome learning experience through the discussions we had and the Community Action Project. Overall, the class is very creatively administered which is refreshing when most courses in the sciences are lecture based. I thoroughly enjoyed this class and cannot praise the applicability of this class to liberal learning enough. This is liberal learning at its finest!!
That is the question that often comes to mind when we see that all-too-distinct 7-point leaf. The use of marijuana, or cannabis, has remained a controversial topic in the States over the past years. Whereas some see legalizing cannabis as a stinkingly massive, scary issue, others see it as a sort of “Miracle Drug” – one that has potentially beneficial, yet often overlooked uses. With a nation that’s become keen on broadcasting the dangers of the drug war and “gateway” substances whilst preaching “Pugs Not Drugs” to children (starting as early as elementary school), it becomes quite easy to see how stigmas grow and understand why many often jump to believe the former argument. But without getting lost in the ‘weeds’ – that is, outside of the social stigma, the politics, and the stereotypical associations that come with any type of cannabis use – does cannabis have physiological benefits that would warrant it as the Miracle Drug that many claim it is?
Without further ado, let’s delve into some of the recently researched science behind this Miracle Drug and see if it really does hold up to its controversial nickname.
Weeding Out The Fluff – Endocannabinoids and the Body
Down to core, cannabis is a drug – a chemical that has affects on the body. Claims that cannabis can be used to treat seizures, cancer symptoms, and even neurodegenerative disorders stems from the particular effects it causes. Throughout the body, there is widespread distribution of a special type cell receptor, called an endocannabinoid receptor (CB1 and CB2, two subtypes of CBRs, for short), and CB1 receptors are especially common in the brain. Normally, the body produces lipid-based, endogenous, cannabinoid-like substances called endocannabinoids, which help regulate some processes that occur in the brain via interactions with these receptors (yes, your body synthesizes biological CBD). Thus, plant-derived cannabinoids and synthetic cannabinoids can also interact with these CBRs and produce similar effects. But to understand these, it’s first important to look at what the effects of endocannabinoids.
What are these effects? Because CB1 is so widely dispersed, it can be hard to pinpoint just one. To the right are a few of the many affects cannabinoids can have throughout the body:
Zou, S., & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. International journal of molecular sciences, 19(3), 833.
But let’s talk about the brain. Normally, CB1 receptors are found on the surfaces of neurons, in especially high concentrations within portions of the brain dedicated to memory, such as the hippocampus. Now for some basic neuroscience. Many types of neurons can be divided into two basic classes: excitatory and inhibitory. Excitatory neurons release communicating molecules, neurotransmitters, to the next neuron. These neurotransmitters are (you guessed it) excitatory, in that they excite the next neuron so it can fire a signal off to whatever its target is – another neuron, a cell, a muscle, you name it. Inhibitory neurons also release neurotransmitters, but in contrast these prevent, or ‘inhibit’ the next neuron from firing or cell from acting, living up to its name. For a basic rundown of excitatory and inhibitory neurotransmitters, check out this video:
Cannabinoids enter the scene in synapses, the space between two neurons where the previous neuron releases its neurotransmitters into, in order for the second to receive and respond to them. From there, they can perform two different feedback processes, depending on the type of neuron (excitatory or inhibitory) – Depolarization Induced Suppression of Inhibition (DSI) or Depolarization Induced Suppression of Excitation (DSE). Though these might sound complicated, their names basically give away their action. Here’s a simplified rundown of DSI:
After being activated (in neuroscience terms, ‘depolarized’) the first neuron, an inhibitory neuron, releases inhibitory neurotransmitter (such as GABA), into the synapse.
The inhibitory neurotransmitter prevents the downstream neuron from firing by binding to its respective receptors on this neuron. This binding induces a series of biochemical events that makes the neuron much less likely to fire.
Still with me? Up to this point, the first neuron has quite literally inhibited the second neuron. But we don’t want this to last too long – neurons have to fire at various levels in order to carry out their function, form memories, and communicate! So what happens next?
Over time, high-frequency inhibitory firing from the first neuron activates regulatory calcium channels on the second neuron, so calcium enters the second neuron.
Increased calcium concentration activates an enzyme in the downstream neuron, called phospholipase C (PLC).
PLC takes phospholipids from the cell membrane and creates diacylglycerol (DAG)
Another enzyme, DAG Lipase, acts on DAG to create whoolah…
2-AG. The name is so long I won’t even bother spelling it out here
A substance called 2-AG. This is that biological endocannabinoid. What does it do next?
2-AG is released back into the synapse, from the downstream neuron, as a “retrograde” (backwards communicating) signaling molecule.
The endocannabinoid reacts with our friends, the CB receptors, on the first neuron.
This can set off a variety of chemical cascades, but ultimately it results in less inhibitory neurotransmitter being released. So what happens when you stop inhibiting the second neuron? It is allowed to fire. Thus, the process lives quite literally up to its name – a “Depolarization (Firing) – Induced Suppression of Inhibition.” If you could guess, a DSE does practically the same thing, except the first neuron is excitatory, so suppressing it would lead to more inhibition and less firing of the second neuron (although DSI is more relevant when talking about CBD). These processes are important in making sure signals don’t run too rampant, or the brain isn’t inhibited for too long, but they are relatively short-lived and thus don’t cause any significant changes in the brain. If you’re more of a visual learner, here’s the entire process in one lovely diagram:
Outline comparing retrograde signalling (DSE, DSI) to regular plasticity in the brain (the process by which synapses, neuronal ‘connections’ change
Putting the ‘Can’ in Cannabis – Beneficial Uses for CBD
Cannabis kept for medical research
So back to cannabis – when you put more endocannabinoid analogs into the synapse for longer periods of time, what happens? Well, depending on whether the process is DSE or DSI, there could be too much or too little excitation or inhibition in various parts of the brain, which could have various effects. Sounds very vague, and it is, but then again it’s nearly impossible to pinpoint what specific part of the brain CBD acts in at one moment in time, and thus what downstream effects are attributed to it (in part due to the widespread nature of CB receptors). Some of the effects are pictured above, but because of the neuro-basis mechanism of cannabis, it’s come into the light of neurodegenerative disease treatments.
Wait a minute, isn’t cannabis psychoactive? How can it be used to treat some of the most vulnerable patient population? In reality, synthetically created CBD is often contaminated with other chemicals and does NOT contain THC, making it a full agonist (interacts fully) with CB receptors and to some extent producing unpredictable and more intense effects. On the other hand, what is often considered “medical marijuana” is plant-derived and exists in the more pure phytochemical state. This form contains THC, making it only a partial agonist for CB receptors, thus producing milder, more natural effects that would normally happen when the body produces endocannabinoids. Here are some potential benefits CBD CAN hold for specific patients:
Parkinson’s Disease: In this degenerative disease, neurons that release regulatory neurotransmitter dopamine are damaged over time. Dopamine is largely excitatory, and is important in maintaining smooth motor movement. Thus, using CBD to induce DSI (allow for more excitation in the brain) can make up for some of the excitation lost from losing dopaminergic neurons.
Alzheimer’s and Cognitive Decline: A disease marked by slowing memory and mental ability, neurons in areas of the brain relevant to memory are damaged over time in Alzheimer’s. Because they are damaged, they cannot fire the usually excitatory neurotransmitters (such as glutamate) needed for learning and forming new neuronal ‘connections’ (synapses!). Using CBD can again induce DSI and increase excitation in these parts of the brain, potentially improving cognitive ability.
Seizures and Epilepsy: Though not directly CBD, a similar derivative of CBD called cannabidiol with lower affinity for CB1 and CB2 receptors has been found to be effective in reducing seizure activity. It is suspected that this derivative “counteracts” DSI, producing less neuronal activity and activation, which could play into reduction of the overactivity seen in many seizure cases. The research can be found here.
And that is definitely not all. Patient cases where CBD has been used to treat anything from pain to cancer-related appetite loss have shown increased quality of life for the users. Nonetheless there is still much research to be done in order to fully discover the mechanisms and reasons behind the beneficial findings detailed in the papers above. However, as marijuana is currently a Schedule 1 drug in the US (a completely different issue I won’t get into today), conducting adequate research on CBD is extremely difficult, and with that the “Miracle” remains unknown for much of society.
On its own, marijuana doesn’t sound so bad – research exists that shows its pure derivative can treat anything from general pain to ultimately fatal neurodegenerative disorders. What’s standing in the way? It’s a complicated, multi-faceted issue that brings into play politics, social stigma, elementary education, and the policies of our current drug industry, and I can say that we are a long way from changing. Who knows, maybe a future with cannabis isn’t such a bad thing. But until word on the street starts welcoming discussion of this Miracle Drug, I guess ‘weed’ never know.
Enrichment. I associate this word with study hall because the teachers of Absarokee Highschool thought it was a clever way to get students to actually study. Really enrichment is improving or enhancing the value of something. Now, whether calling study hall “enrichment” improved the quality of my education is debatable but, recent research has found that enriching experiences modify the structure of the brain. This is called brain plasticity. Experiences change the nervous system structurally and functionally, and effectively produce a protective reserve that sustains brain function with aging and the onset of diseases.
There are two kinds of protective reserves, brain and cognitive. Brain reserve is the physiological qualities of the brain such as the number of neurons and synapses and the molecular processes maintained by the brain. Cognitive reserve, on the other hand, is the psychological ability to make use of the brain reserve. Building and preserving these reserves protects the brain from deterioration or malfunction of neurochemical processes.
Cognitive reserve is preserved through social, mental, and physical engagement. Research on social interactions such as marital status, living arrangement, parenthood, and friendship have shown to have protective effects on the cognitive reserve. Similarly, activities that are mentally demanding, high education, and complex work are protective of the cognitive reserve as well. Physically, regular exercise and a healthy diet rich in antioxidants and unsaturated fatty acids has been associated with the decreased risk for dementia.
Brain reserve is primarily tested in animal models, as it encompasses the actual anatomy of the brain. In many studies, environmental enrichment induced brain plasticity through cellular and molecular changes. Cellularly, enrichment fosters neurogenesis, gliogenesis, angiogenesis, and synaptogenesis.
Neurogenesis: The generation of new, functional neurons
Gliogenesis: The generation of astrocytes, which provide structural and functional support to neurons, oligodendrites that facilitate neurotransmission, and microglia that dispose of waste material creating space for neurogenesis.
Angiogenesis: The formation of blood vessels
Synaptogenesis: The formation of synapses for neurotransmission
At the molecular level, enrichment changes gene expression of certain proteins. These changes facilitate changes in concentrations of neurotransmitters and neurotrophins. Neurotransmitters are involved in the neurotransmission across synapses. Neurotrophins are central to growth and proliferation. Interestingly, there has been some variability in the location in the brain and how neurotransmitters and neurotrophins increase. For the most part, neurotrophins increase; however, neurtransmitters and the receptors there of are not as definitive.
Now that we know what enrichment does, what is enrichment? As mentioned in the cognitive reserve section, neuroprotection is based on social, mental, and physical factors. These three areas are considered the components of enrichment. For testing animal models, treatment groups are afforded social interaction through placing multiple organisms in one confinement. Mental enrichment is applied by allowing the animals access to objects that the organisms can forage for or use in one form or another. Finally, the physical component of enrichment is applied by the type of diet afforded the animals and the access to exercise, such as the size of the confinement and exercise machines.
Increased enrichment resulted in increased neuroprotection through the cellular and molecular processes discussed up above. Enrichment occurs through social, mental, and physical engagement. Neuroprotection can decrease cognitive decline with age and as a result of a degenerative brain disease. Therefore, enrichment is GOOD!
Maybe my teachers were on to something, in calling study hall enrichment. Although, I think all my classmates can attest that high school “enrichment” lacked social interaction as we were not allowed to talk, mental engagement unless you worked on homework, and physical enriching as food and moving was not allowed. So maybe anti-enrichment is a better word?
The terms brain reserve and cognitive reserve are often used interchangeably, however, there is a difference between the two. They are sometimes categorized as passive and active models. Brain reserve is a passive model. It is the size of the brain and its neural components. Individuals have different capacities of brain reserve. These differences lead to differences in how different degrees of brain damage is expressed. Cognitive reserve, on the other hand, is an active model. Cognitive reserve suggests that the brain actively tries to adapt or cope with damage by utilizing pre-existing cognitive processes or by using compensatory processes. With this idea, someone who has more cognitive reserve may be able to tolerate more damage before showing any impairment than someone with less cognitive reserve, even if they have the same amount of brain reserve capacity.
Exposure to environmental enrichment can be beneficial to brain reserve. Enriching factors may include high educational level, complex work, and large amounts of mentally demanding activities. Environmental enrichment has been shown to increase neurogenesis, gliogenesis, angiogenesis, and synaptogenesis in hippocampal and neocortex regions.
Cognitive Reserve and Alzheimer’s Disease
Cognitive reserve has been shown to mediate the clinical manifestations of Alzheimer’s disease (AD). One study looked at AD patients with higher education levels and lower education levels and the differences in different abilities. They saw no difference between groups with the preservation of verbal abilities. They did notice, however, that higher education patients had better preserved visuo-spatial abilities, logical deductive reasoning, constructional praxis, and executive functions. Lower education patients had reduced grey matter volume when compared to higher education patients.
Bilingualism can also increase cognitive reserve. Studies indicate that bilinguals can compensate for more severe changes from early phases of AD than monolinguals.
Cognitive Reserve and Parkinson’s Disease
There has been a greater interest in research regarding cognitive reserve and Parkinson’s disease (PD). Again, like as in Alzheimer’s disease, studies suggest that higher levels of education as a proxy for cognitive reserve has significant associations with the performance of cognitive tests in PD.
Though bilingualism has been shown to delay clinical manifestations in AD, it has not been well studied with PD. The first study to look at this found no significant difference between monolinguals and bilinguals with PD in the performance of executive function tests.
Research between cognitive reserve and neurodegenerative diseases like AD or PD is limited. Further studies need to be conducted to come to any further conclusions on how cognitive reserve impacts brains of these patients.
Marijuana or cannabis. Some say it is bad, others say its good. Lets dive down deep to discover the ins and outs of the endocannabinoid system.
Cannabis is a plant that is grown and yields CBD and THC. THC activates cannabinoid receptors and leads to the common high due to the psychoactive component. More is still being learned about CBD, and it is known that it is use as a treatment option for pain. THC uses two different receptors to bind, CB1R and CB2R. CB1R is dominant in brain and skeletal muscle whereas CB1Rb has higher expression within the liver and pancreatic cells due to its involvement in metabolism. CB2R are found in the testes and lower levels in brain reward regions. Endogenous agonist (AEA) and 2-AG are important endocannabinoids that bind to both receptors. AEA has a high-affinity and partial agonist of CB1R and inactive to CB2R. 2-AG is a full agonist against both receptors, but has a low affinity. CB1R can inhibit GABA and glutamate release from presynaptic terminals meaning it can modulate neurotransmission. This is important because CB1R plays a neuroprotective role against excitotoxicity, inhibits nitric oxide, and increases brain derived neurotrophic factors (BDNF). So how is this all beneficial or hurtful to the body?
CB1R has been observed in a variety of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. In Parkinson’s, there is an upregulation of CB1R and the endocannabinoid system. In Huntington’s, there is a progressive loss of CB1Rs and worsens over time. Currently, CB1R is being looked at as a way to control appetite. The most common use of cannabinoids however is for pain. In cancer patients who are undergoing chemotherapy or radiation, they typically experience a loss of appetite. Cannabinoids are being used to help increase their appetite to maintain a healthy weight to continue treatment and increase their well being. Along with stimulating appetite, it also reduces nausea, vomiting, and alleviates pain. As mentioned above, one property of endocannabinoids is the neuroprotective effects against excitotoxicity. This is commonly associated with seizures due to the over active firing. Endocannabinoids can reduce this, resulting in dramatic decreases for those that have epilepsy. In fact, some families who have young children with severe epilepsy will move to a state that has legalized medical marijuana. In moving to these places, these families have had children or family members go from hundreds of small seizures and frequent gran mal seizures to less than a quarter of that. This shows that the endocannabinoid system can drastically reduce neurological diseases and their symptoms to increase the way of life of these people. However, there are some fears that are associated with endocannabinoids such as the addictive or gate way drug tendencies. However, cannabis does not actually have an addictive chemical like nicotine. Cannabis is considered a gateway drug but not a lot of research has been done, in fact, alcohol a frequently consumed item is considered a gateway drug.
The endocannabinoid is a complex system that is still being studied for pros and cons. A lot of the research that is now available is leaning towards more benefits than harms, especially for neurodegenerative diseases in which this system can help improve the quality of life.
What causes obesity? The popular idea is that obesity is caused by over-eating and not exercising. But why does this happen? Why do people over-eat? The exact answer to that question is unknown.
To understand why people over-eat we must first understand how normal eating works. Two important factors involved in mediating appetite are insulin and leptin. In normal metabolic homeostasis, insulin and leptin activate POMC neurons and inhibit AgRP neurons. POMC neurons are involved in satiety, while AgRP neurons are involved in eating. This leads to a balance in energy expenditure and food intake.
There are several other peptides released by the gastrointestinal system that are involved in satiety. The first factor identified was cholecystokinin (CCK). This peptide is responsible for decreasing meal size. Glucagon-like peptide (GLP) is another peptide released from this intestine in response to meals. In rodent models, GLP-1 was shown to be involved in decreasing food intake. Peptide YY (PYY) is secreted along side GLP-1 and has similar affects. One peptide, Ghrelin, is released from the stomach and is involved in stimulating appetite.
In obesity and metabolic syndrome, there is a resistance to anorexigenic signals from insulin and leptin. This means there is no activation of POMC neurons and no inhibition of AgRP neurons. This causes a decrease in energy expenditure and an increase in food intake.
A deeper question to ask is what causes resistance to leptin and insulin?
Several mechanisms for leptin resistance have been identified including gene mutation, altered transportation across the blood brain barrier (BBB), and inflammation. Though it is extremely rare, it is possible to inherit leptin resistance. This is caused by mutations in the OB and DBU genes. However, these mutations are very rare and cause hyperphagia, obesity soon after birth, and hypothalamic hypogonadism. Because it is so rare to find these mutations in the leptin gene or its receptor, this is not the main factor for the development of leptin resistance. A factor that does play a role is altered transport of leptin across the blood brain barrier. Leptin resistance at the BBB allows for unregulated transport of leptin from the blood to the brain. Excessive levels of leptin in the blood cause a decrease in BBB permeability. Another factor that plays a part in leptin resistance is inflammation. High-fat diets can induce low-grade inflammation in tissues such as adipose tissue and the liver, which can lead to an increase in inflammatory cytokines such as IL-6 and TNF-α. Leptin is also a proinflammatory cytokine in a family similar to IL-6.
Insulin resistance is also due to many factors including genetics, aging, and ethnicity. However, the biggest factors behind insulin resistance include excess body weight and lack of exercise. With insulin resistance, cells in muscles, fat, and liver can’t respond to insulin and therefore can’t allow glucose to enter the cells.
In conclusion, insulin and leptin resistance can lead to a variety of problems. One of those problems is the inability to activate POMC neurons and inhibit AgRP neurons. This leads to no feelings of satiety, decreased energy expenditure, and an increase in food intake. Eventually, this can lead to problems such as obesity and metabolic syndrome.
The debate of whether or not cannabis should be used for recreation has been raging for well over a decade now, and there are strong arguments on both sides. People in favor of recreational marijuana point to research that shows the extensive benefits of the plant, while those opposed call cannabis a “gateway drug” and point to the conflicting data in the scientific community surrounding the substance. With the topic being so prominent, the fact that the sciences can display cannabis as a cure and poison is extremely interesting.
This is conflicting representation is most likely due the lack of scientific research regarding the substance. Cannabis interacts with receptors of the endocannabinoid system which has several important functions in the body. The most widely studied receptors of this system are the CB1 receptor and CB2 receptors, which can be found both in the brain and in peripheral nervous tissues and cells.
The abundance of these receptors throughout the body are one of the major obstacles when determining the effect of Cannabis on the human body. For example the CB1 receptor has been found in the brain, cardiovascular system, liver, GI tract, and reproductive systems. Therefore administration of cannabis affects the body in several ways simultaneously making it difficult to study. Recent studies have attempted to demonstrate the effects of marijuana on several diseases.
Zou, S., & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. International journal of molecular sciences, 19(3), 833.
The CB1 receptor has been found to inhibit GABA and Glutamate release in which directly impacts neurotransmission. This is proposed as a plausible underlying mechanism of CB1-mediated neuroprotection against excitotoxicity, a prominent pathological process of many disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease.
In Parkinson’s disease the up regulation of the CB1R and endocannabinoid system activity which could be a mechanism to compensate the degenerated dopaminergic neurons, or a pathological process that contributes to the worsening of the disease. In addition, the activation of the CB1 receptor has been shown to be beneficial in Alzheimer disorder animal models with memory deficits and cognitive disorders. However, results from these models are still debated in the scientific community.
The conflicting data is not the only problem however. Marijuana is currently considered a schedule 1 drug. This means that in the eyes of the law and the government, cannabis is in the same class as heroin, LSD, and ecstasy. This classification has several impacts on the scientific communities ability to research the effects of the drug. For instance, in order to perform research on a schedule 1 drug, there are mountains of paperwork and regulations which must be addressed. This makes the already expensive research even more expensive and time consuming. This leads to limited research on a drug that has the several possibilities in regards to several crippling diseases.
The effects of cannabis on the human body is still uncertain. Several studies have shown remarkable effects of the drug , while other studies have shown the drugs potential to exacerbate several diseases. This uncertainty is a product of conflicting experiments as well as limited research. In order to determine whether or not cannabis is a miracle drug or a potent poison, further research is needed.
Marijuana has long been used recreationally and medicinally. While its recreational use is still of debate, its medicinal properties have also come under great study, especially in recent years. The active components in marijuana act on the bodies endocannabinoid system, comprised of the receptors cannabinoid receptor 1 and 2 (CBR1 and CBR2). There are around 70 phytocannabinoids that have been identified in the marijuana plant, but ∆9-tetrahydrocannabinol (THC) is the main psychoactive component. THC has long been the barrier to effective medicinal use of marijuana, although deeper research suggests there are additional hurdles.
Endocannabinoids
Endocannabinoids, or the endogenous agonists of the CBRs, in the human body are anandamide (AEA) and 2-arachnidonoylglycerol (2-AG). These are the chemicals that are synthesized inside the brain and act on the CBRs in response to various signaling events. CBR1 is the dominant receptor in the brain and muscle, with other isoforms in tissue like the liver and pancreas. CBR2 is present in brain reward regions, the testis, and spleen, depending on the isoform. Because there are multiple forms of both receptors and they are expressed at significant levels in many different tissues, it becomes more difficult to target a specific response from the endocannabinoid system. Depending on the endocannabinoid, they also act and target the receptors differently. AEA has been shown to be a high-affinity partial agonist of CBR1, meaning it binds at low concentrations but only has a partial effect; it is also almost entirely inactive at the CBR2. 2-AG, however, acts as a full agonist of both receptors but at moderately low affinity. Both endocannabinoids are produced on demand in response to increased intracellular Ca+2 concentrations, which means this system can be activated from a variety of upstream effects. The full paper that reviews these topics and more can be found here.
Medicinal Use of Endocannabinoids
The effects of the endocannabinoid system based on single cell activation is extremely varied, as is demonstrated in this graphic.
Zou, S., & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. International journal of molecular sciences, 19(3), 833.
Not only can these receptors be activated by a ligand binding on the extracellular side, but there has also been activity shown on internally localized receptors, whether those were taken in through endosome processes or if they were intrinsically localized on a lysosome or mitochondria. This is another reason why targeting the CBRs for medical use is difficult.
Zou, S., & Kumar, U. (2018). Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. International journal of molecular sciences, 19(3), 833ys
Cell signaling pathways through β-arrestin and other methods result in different cellular effects that might be off of the intended process. In addition to their highly distinct roles and locations in the cell, they are also found around the body with different affects, depending on the location and cell type.
What does it mean?
In the end, while medical marijuana is currently being marketed as a miracle for conditions from multiple sclerosis, to seizures, to palliative cancer care, the science is less clear. Our understanding of the signaling processes, especially the non-GPCR alternate pathways, is limited. Until we are able to elucidate the pathways more succinctly and understand the downstream effects, positive development of cannabinoid pharmaceuticals will be limited.
If someone had advocated for the legalization of recreational marijuana a few decades ago, he or she would have laughed at. After all, marijuana is a drug and drugs are bad. Yet, over the years research has appeared that contradicts this. Suddenly, there is debate on whether marijuana has any medical uses and whether or not it should be legalized, both recreational or medically.
Recent studies and testimonials from patients discuss how marijuana may be useful in treating epilepsy, cancer, AIDS, and other disorders. There is also a growing body of evidence that marijuana may not be as harmful as previously thought. But yet, there is still a strong stigma against marijuana. Is the drug really deserving of all this controversy?
Endocannabinoids
In general, most chemicals and neurons in the brain can be classified as excitatory or inhibitory. Excitatory means that it increases the likelihood of a signal firing. Inhibitory decreases the likelihood. Depending on the context, marijuana is capable of both.
The two main chemicals in marijuana: THC and CBD act on a little-known signaling system in the nervous system. They act on the endocannabinoid system. Now, THC and CBD are obviously not something that is naturally produced by the human body. Rather, neurons in the cannabinoid system produce 2-AG and AEA. These chemicals act on the two receptors: CBR1 and CBR2. AEA causes a response at CBR1, but does not too much when bound to CBR2. 2-Ag acts strongly on both receptors. Of these two chemicals, AEA is the more well-studied, yet 2-Ag is more prevalent in the brain.
Imagine two neurons in the brain. Normally, the signal flows from the upstream neuron to the downstream neuron. Sometimes the upstream neuron sends a signal to the downstream neuron to get it to stop firing. However, this causes calcium to build up in the second neuron, which really wants to fire. The second neuron than releases 2-AG to the upstream neuron that shuts off the inhibition. This happens because 2-AG binds to CBR1 and closes the calcium channels. This can lead to excitation or inhibition, depending on what the upstream neuron was doing. If the upstream neuron was inhibiting the downstream neuron, then the signal is now excitatory. If the upstream neuron was excitatory, the signal is now inhibited.
That all seems fairly simple. However, the exact nature of the individual receptors complicates things. CBR1 can actually increase cAMP in some cases. (cAMP is typically inhibited if calcium is inhibited). In most cases, the CBR1 receptor inhibits calcium channels and is involved in inhibiting GABA, the primary inhibitory neurotransmitter in the brain. Additionally, CBR1 is heavily involved in cell proliferation and death. The receptor regulates MAPK signaling pathways including ERK and JNK. (For a summary of these pathways, click here). Essentially, activation of these pathways increase brain -derived neurotrophic factor (BDNF) which aids in cell survival.
Treatment of Various Disorders
Marijuana has come to attention today partially because of its possible medicinal properities. Indeed, drugs that act on the CBR1 receptors have been helpful in treating disorders like Huntington’s disease and Parkinson’s, which arise from an imbalance of glutamate and GABA in the brain. Drugs like marijuana are able to reset this balance.
Additionally, marijuana may aid in treating pain, lack of appetite, and seizures. Some research indicates that overeating and seizures may be linked to dysfunctions in the endocannabinoid system. The appetite stimulating effects come from the CBR1’s ability to activate the POMC neurons and release several hormones involved in eating. Little is known about how exactly CBR1 drugs are able to stop pain, but it likely involves CBR2 and the receptor TRPV1. CBD is mainly responsible for this effect, as it indirectly inhibits the CBRs. Normally, this regulates the effects of THC, controlling the potency of marijuana.
Why the stigma matters
Even with all that science, there is still a lot unknown about marijuana. The effects of chronic usage are still debated. However, there may very well be some benefits to it.
Marijuana is currently classified as a Schedule I drug. This classification is often cited for the main reason that marijuana research is hard to come by in the United States. However, heroin is also a Schedule I drug and it is more well-studied. It is possible to study Schedule I drugs. Marijuana simply gets more heavily stigmatized.
Like all stereotypes and stigmas, this one causes harm. There are a lot of people who could benefit from medical marijuana. The drug is by no means a magical solution to these disorders, but it may help those suffering from them.
It is human nature to fear the unknown and there is certainly a lot unknown about marijuana. It is often people’s gut instinct. But, doing so often causes people to make hasty, often harmful generalizations. Marijuana is not deserving of all this controversy, but rather curiosity. Instead of following the gut instinct to fear the unknown, we should use our heads to study it.
Many of us wonder where we will be in ten, maybe twenty years from now regarding our health. What will the health care system look like? Will it be improved? What advancements will be made that prolong life as well as improve quality of life?
Let’s take a look through the crystal ball to see what the future has in store…
Congrats! I see cannabis in your future!
That’s right. Cannabis. You might be surprised, maybe even unhappy with these results, but the truth is that there are some pretty neat findings involving cannabis and the endocannabinoid system that may be beneficial to your health.
Cannabidiol (CBD) is an essential component of medical marijuana/cannabis. The CBD industry is growing at exponential rates and will continue to grow. It is your choice if you are going to jump on board with these products that are rapidly growing in popularity.
Cannabis has been used throughout history and has been used for a diverse range of medical purposes. However, although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice.
Understanding the Crystal Ball
The science described below will help explain the reason for the wide range of effects associated with the endocannabinoid system.
The Cannabinoid Receptor (CB1): CB1 receptors are members of the Gi/Go – linked GPCR family. This means they inhibit voltage sensitive calcium channels and adenylyl cyclase. On the other hand, CB1 receptors regulate the activity of G-protein coupled inwardly rectifying potassium channels and stimulate the MAPK signaling pathway. The figure below shows the activating and inhibiting roles of the CB1 receptor.
Fig. 1
Inhibition: adenylyl cyclase (AC), formation of cyclic adenosine monophosphate (cAMP), activity of protein kinase A (PKA), calcium influx via voltage-gated calcium channels (VGCC).
Activation: MAPK signaling pathway and PI3K/Akt pathway
The CB1 receptors are widely spread throughout the body, thus giving reason to the broad spectrum of physiological roles these receptors can play. With this being said, research has shown the endocannabinoid system to be largely involved in various central neural activities and disorders including appetite, learning and memory, anxiety, depression, schizophrenia, stroke, multiple sclerosis, neurodegeneration, epilepsy, and addiction. The figure below shows the different regions the CB1 receptor is involved in throughout the human body.
Fig. 2
The widespread expression and versatile functions of CB1 receptors support its potential as a drug target for various diseases. However, the undesired effects that arise immediately or later on in life should not be ignored.
The Future is in Your Hands
Nobody can know for sure what the future will bring from these findings, but we can always be optimistic. Ultimately, if individuals are using cannabis for health related reasons and it is improving their quality of life, then there is no point in judgement.
With the growing CBD industry, there are many questions that arise. There are so many different directions to go with the endocannabinoid system that can potentially lead to finding drugs that benefit human health and, of course, improving human health is the ultimate goal. I hope we all go on to live healthy lives. If that life involves drugs targeting the endocannabinoid system, then so be it. The future is in your hands!
For more information on the research presented on the endocannabinoid system follow this link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877694/
inst both receptors, but has a low affinity. CB1R can inhibit GABA and glutamate release from presynaptic terminals meaning it can modulate neurotransmission. This is important because CB1R plays a neuroprotective role against excitotoxicity, inhibits nitric oxide, and increases brain derived neurotrophic factors (BDNF). So how is this all beneficial or hurtful to the body?
