Cobbers on the Brain

What’s your favorite song? Can you picture a specific time or place that makes that song so special? Music has been incorporated into the lives of humans for hundreds of years. We know how it can make us feel, whether it’s screaming in your ears as you push up on the bench press for your new personal record at the gym or as it’s gently swaying back and forth in the background as you are studying for an upcoming exam, music seems to be used in everyday life, and for good reason! Recent studies are beginning to specifically explore just why our brain likes music so much, so that is what we will find out below along with a brief analysis of if playing an instrument or listening to music seems to be more beneficial to your brain!

The Neurochemistry of Music

If someone has ever told you “music is medicine”, they might not be completely wrong! In recent years, there has continued to be additional amounts of information regarding the positive impacts that music has through neurochemical changes in the brain. One way music affects us is through reward, motivation and pleasure. Certain songs and/or noises can instantly evoke powerful emotions ranging from happiness to sadness to even a state of reminiscence. This has been stated as one of the main reasons as to why people even listen to music. Inside the brain, it has been shown that during this process, there is a dump off of dopamine at places such as the VTA and NAc that provide us with that pleasurable feeling that medication such as opioids do. This in part is why music has been shown to be capable of triggering short-term behavioral changes while also temporarily inhibiting feelings such as stress and/or anxiety. In fact, music that is non-lyrical with a low pitch and/or slow tempo (types that I personal enjoy listening to while studying) have been shown to be most effective at reducing stress and anxiety!

A few other areas that music has been shown in improve are immunity and social interactions. Having the ability to partake in creating music or simply just listening have both shown to decrease inflammation within the body as well as boosting the immune system overall! Social health has also seen an increase in those who listen to or create music together. Neurochemicals such as oxytocin and vasopressin are presented in the body which seems to establish and maintain positive feelings and reduce stress– so keep up with those weekly group-garage band sessions with your friends! There is still currently ongoing research in each of these areas, as we still cannot be certain that it is solely music alone causing these impacts on our emotions and body, so hold off on telling your mom that you only have to listen to music in order to feel better the next time you catch the flu!

Playing versus Listening

Okay, so whether you skipped down to this section of the post immediately after reading the final line of the introduction or have read the blog to its entirety up to this point, it is now time to see what benefits our brain the most: playing an instrument or listening to music. So, what do you think? Ultimately: playing an instrument has generally shown to be more beneficial to your brain than listening to music. Of course, there will be a select number of individuals who have more benefits through listening, but this is what covers the majority of individuals. There are two factors that this largely comes down to. The first being that playing an instrument is normally far more of an active process than is listening to music. Your fingers and hands are usually both doing different things at the same time while your eyes dart across the sheet music. Most of the time when music is on, the only “active” thing we do is sing along and that can be thought of as more of a pleasurable aspect versus “testing” your brain to see how accurate you can be on wording and pitch. Researchers have been quoted as saying how this process “engages every major part of your central nervous system”. It has also been shown to relieve stress and bring people together even more than just listening to music does. A short video description of the two can be found here!

The second factor is how playing an instrument can be thought of as engaging all parts of your brain versus listening to music only engaging specific areas. I like to think of this in reference as to going to the gym. Listening to music can be thought of as just working a specific area of your body, let’s say your arms, while playing an instrument compares to doing a full-body workout! This in turn demonstrates an increase in the fine motor skills, specific to playing an instrument, that results in both hemispheres of your brain working on a task simultaneously. This has your corpus callosum constantly bringing signals back and forth between the two hemispheres to communicate with one another and in turn both strengthens and increases the speed at which this is done. This ultimately results in an individual being more effective and efficient at other tasks that require both hemispheres of the brain to be working simultaneously!

The Coda

Over the last few years, much has been discovered with regards to just how beneficial music is to our brains, not only emotional or behavioral, but also through our interactions and abilities to perform other tasks. There are still many questions left to be answered, however, so future research is still necessary to explore specifically how music is impacting our body so much and if it will one day be able to compete with modern medicine through uses more than we have ever initially intended or imagined.

Music, a universally understood and appreciated artistic form of expression. We use it to amplify or suppress emotions, share in creativity, empathize with others, and even to wreak havoc. Music is so important we find our own identity in many of the countless forms and genres. Music has the power to ignite rebellions, spark innovation, establish peace, and inspire love. So, let’s take a look at current research in an attempt to understand the neurochemistry of music and how music is so influential.

Reward, Motivation, Pleasure

Music is associated with countless emotions but is most commonly associated with sensations of joy, accomplishment, and determination. Because of this, initially, we will focus on music’s implications on the reward pathway. Music can trigger short-term behavioral changes and temporarily inhibit feelings such as stress and/or anxiety. While listening, music serves as a reward stimulus which ultimately amplifies the reward pathway triggering dopaminergic transmissions and the release of endogenous opioids (naturally produced within the organism). Dopamine in this case serves as a regulator of motivation and goal-directed behaviors in the reward system. The feelings that are associated with musical reward are mediated by a region of the brain called the mesocorticolimbic system. The actions of motivation, learning, and goal-directed behavior are mediated by the dopaminergic neurons in the specific brain region called the ventral tegmentum (VTA), which projects to another region called the Nucleus accumbens (NAc) and the prefrontal cortex (PFC). The endogenous opioids released during musical reward in the NAc are what provide the reward feeling of pleasure. The involved neurochemicals interact with receptors at different sites of action, so dopamine and opioid release can each affect various actions/behaviors.

Stress and Immune function

Many environmental triggers can stimulate stress responses in the body and when these responses are activated, they prompt short-term adaptive behaviors, physiological changes, and inhibit non-essential functions (sympathetic nervous system). It has been found that slow tempo, low pitch, non-lyrical music can reduce stress and anxiety in healthy subjects ultimately protecting against the neurotoxic effects of long-term stress. Listening to music or participating in music-making has been shown to decrease inflammation and have positive effects on the immune system. However, it remains uncertain if these effects are due to the mood-regulating function of music, the camaraderie of making music in a group atmosphere, or some other factor. What data has shown is that group music increased Natural killer cell (NK) activity, increased 5-DHA-to-cortisol ratio (reduces level of stress), enhanced immune functioning, decreased stress-induced cytokines (important factors in inflammation), counteracted age-related decline in immune function, and significantly increased the total number of lymphocytes (defensive cells of the immune system). Passively listening to music and group singing had similar effects.

Social Affiliations

Music has also been found to influence the neurochemicals oxytocin and vasopressin. Oxytocin is a vital neuropeptide involved in the establishment and maintenance of social health but can have contradicting effects. Oxytocin can facilitate increased social health and development of connections, but its levels also increase during periods of separation and social isolation. This facet demonstrates oxytocin’s additional role as a distress signal in social or nonsocial situations indicating that context matters. Vasopressin is a molecule that closely regulates social behavior (affiliative, social, & romantic behaviors) and whose gene regulates oxytocin activity. Endogenous opioids (b-endorphin) may also play a role in pain signaling in response to social isolation. Low levels of endogenous opioids or opioid antagonists promote separation distress behaviors and lead animals to seek out contact, while increased opioid levels reduce these behaviors. Music could potentially increase opioid production, leading to a sense of comfort. Through the increased actions of neurochemicals like oxytocin, vasopressin, and endogenous opioids stimulated by music, there is a potential link between music and the establishment and maintenance of social bonds in a variety of social and nonsocial contexts.

Conclusion

We understand music to have a significant impact on our lives, visible through our emotions, behaviors, and interactions. However, there remains much to learn about the exact mechanisms by which music influences our neurochemistry as many of the current studies exhibit significant limitations, therefore, continued future study is necessary to fully elucidate the profound influences of the phenomenon we call music.

Legalizing marijuana has been a pressing debate throughout the past decade. Our generation has been able to be front and center on this hot topic. Slowly, we are witnessing states legalize it both medically and recreationally. The legalization allows for many benefits along with consequences. In a recent class discussion, we were able to discuss the endocannabinoid system (ECS) and the possibility of using marijuana-based products to activate this system. Activation of ECS is useful because the system “plays key modulatory roles during synaptic plasticity and homeostatic processes in the brain.”

Within the ECS, there are cannabinoid receptors. The two receptors discussed in our research article were the CB1 and CB2 receptors. Throughout the rest of the blog, I will be mainly focusing on relationships dealing with the CB1 receptor. The CB1 receptor is found in the central nervous system and provides as a binding site to a marijuana most active ingredient which is delta-9 tetrahydrocannabinol (delta-9 THC). The binding of Delta-9 THC to the CB1 receptor allows for activation of the ECS. This allows in feelings that have been described as relaxing and pain reducing. Due to these effects, therapeutic conversations have been aroused. One use of therapy that has been discussed is using marijuana derivatives as a pain killer. The thought is to be used similarly to opioids. However, just like opioids, marijuana can have negative impacts as well. Addiction can still be present but said to be at a lesser extent in marijuana than opioids. Recreational use is used in many of the same reasons that opioids are used for which is a large part of the hold up on legalization. Delta-9 THC also provides users with paranoia and euphoria. This gives them anxious feelings along with sickness and not being able to function. Research continues to create products that will not being on these consequential feelings yet provide the consumer with beneficial effects.

Barstool Sports is a multi-media sports company and provides a podcast. On their podcast they heavily advertise for a different derivative of cannabis. They advertise 3-chi which is a delta-8 THC company. After discussing delta-9 THC in class I wanted to do more research on delta-8 THC and see what the differences are. On their website, 3-chi has a biochemist explain why the use of delta-8 THC is much more beneficial than delta-9 THC. Although this podcast and company advertises on the recreational side of things, relating this to potential medical use is relevant.

Delta-8 THC is also an ingredient in a cannabis plant but comes off as the least abundant. Through chemical reactions, scientist can make delta-8 THC out of delta-9 THC. The reaction process is what turns some researchers away due to safety concerns. When researchers get past the point of the chemical process of the THC derivative, they noticed that delta-8 does not bind as well to the CB1 receptor as the delta-9 receptor. The slight difference in the double bond as you can see below is the reason the binding is not as strong. The lower binding ability is what makes delta-8 THC a more effective product. When the CB1 does not get the perfect binding, activation is not as strong within the ECS. This has proven to provide similar benefits to delta-9 THC such as relaxation and pain reducer but does not give off the negative effects. Delta-8 users report that they do not need to use as much, and they don’t get the paranoia or the euphoria.

Whether or not recreational use of marijuana becomes legal, there is still a lot of research to be done with cannabis. Research has shown that the use of marijuana can provide medical benefits, but negative effects can come with it. The ability to derive delta-9 THC to delta-8 THC can be very significant if in further research does show the medical benefits. There is still a long ways to go, but it makes me more comfortable knowing that certain derivatives could possibly provide medical use without the negative impacts.

Your family might not be like my family. At Thanksgiving, In between the catching up on how school and work is, an interesting conversation came up between us. My Aunt and Uncle began talking about CBD, and how it’s helped them for a variety of ailments, including one specific issue they’d been having. Turns out their dog has an intense fear of storms, and CBD lotion seems to alleviate that fear. I personally couldn’t imagine giving my dog CBD, but this example does speak to just how wide a range for use the general public see for CBD. Indeed, it has been suggested that CBD and medical marijuana can offer help in a variety of conditions, all the way from anxiety to pain.

Neurochemical Mechanisms

As it turns out, there is specific neurochemical evidence to support that the human endocannabinoid system, which is stimulated by things like medical marijuana and CBD, can be leveraged to alleviate all types of distressing symptoms. This is due, in part, to the fact that the endocannabinoid system is self-regulating. As a certain signal increases, pain for example, a neuron that receiving excessive pain signals, can signal to the neuron that sent the initial signal to just chill just a bit. This method of self-regulation can be extremely helpful, especially in situation where excessive cell signaling is taking place such as in anxiety and pain. The way this retroactive signaling takes place is only somewhat understood. We know the endocannabinoid systems activates a vast array of downstream signaling cascades within cells, but not all their functions are fully understood. Considering both the function and widespread availability of endocannabinoids, the science supports the proposed healing effects put forth by an abundance of experimental and anecdotal evidence. In fact, the CB1 endocannabinoid receptor is one of the most largely expressed in the entire central nervous system! It makes sense that it could help a variety of ailments, even those that seem they couldn’t possibly be related.

Miracle Drug?

When considering CBD and medical marijuana, I have even heard the term “miracle drug” thrown around due to both it’s efficacy, and range in use. Now, for the rest of this blog, I will make no attempt to hide my own biases and opinions. I’m a psych guy. I tend to view issues through a psychological perspective, one which involves avoiding the use of pharmacological options until it is absolutely clear their benefit outweighs their risk. Indeed, every intervention, in my opinion, should be viewed in this way. A provider should only pull out the pen to write the script when the dangers/discomfort of an ailment clearly less of a risk than the condition itself. Any pill or injection is an unnatural means for chemical agents to enter the body. Regarding taking Ibuprofen for a headache, the risk is low and the benefit can be great, so taking it makes all the sense in the world. When issuing chemotherapy for cancer, the risk of cancer far outweighs that of chemo in nearly all scenarios, despite the brutal side effects.  Now, the water begins to get murky when thinking of diseases typically associated with the treatment of medical marijuana and CBD. For the sake of this blog, I am going to focus on chronic pain and anxiety.

Artstract by Ben Swanson

As a society, we tend to look for the next drug to alleviate suffering, almost as if it is the only option. Alleviating suffering is indeed a positive thing, and every opportunity to research CBD and medical marijuana should be taken because the opportunities for replacing opioids and benzodiazepines for treatments are impressive. However, as with chronic pain and anxiety, and other disorders CBD and medical marijuana is typically used for, these things usually aren’t going to do serious bodily harm. Cause distress? Absolutely. Impact quality of life? Certainly. These things should certainly be addressed, but they should be done so when looking at the risks and benefits of taking CBD and weed. Now I can guess what you’re thinking…

”Come on Ben, this is a natural substance that comes from plants. This is a lot safer than other stuff we put in our bodies that get prescribed. You’re fear mongering about a relatively harmless drug that millions have found helpful.”

Word of Caution

What I would say is this; we don’t really know that. On initial inspection, it sure seems that way when CBD and marijuana is less harmful compared to other drugs used to treat anxiety and pain. However, the reality is that we do not have the scientific data to support that assumption. The exact mechanisms for CBD are not well understood, and because it is so widespread in the CNS, I fear we have jumped the gun on CBD and medical marijuana. What is someone going to look like after 20 years of taking CBD? What kind of effects will this have in the CNS and it’s ability to regulate itself? Could CBD be addictive long term? The fact is, there are no answers to these questions because the research does not yet exist. Should it exist? Absolutely. There will be a flood of research in coming years examining these very questions. But without this research, I hope providers and consumers alike are weighing the risk benefit of CBD and medical marijuana. I hope people ask themselves, is this something I really NEED? Or is this something that I think I need. Do the risks of not fully understanding this drug, truly outweigh the treatment benefits? The possibilities behind medical marijuana and CBD are exciting, and I’m going to be thrilled if they truly are a less harmful substituted for some common ailments. However, right now I am cautiously optimistic, and believe more research is needed before we can coin this the “miracle drug”.

The first thing many people think of when someone starts talking about cannabinoid signaling likely isn’t how cannabinoid exposure can change how your brain processes signals by directly modulating the number of receptors on neurons but likely has something to do with how recreational marijuana has been talked about in media or in pop culture. While there’s certainly nothing wrong with thinking of marijuana’s recreational uses first, cannabinoids do so much more for the human brain than create the ‘high’ associated with recreational marijuana use. Cannabinoids, a wide family of molecules, have been used to treat pain, muscle aches, anxiety, and even reduce the risks of addiction development when used in place of opiate pain medications. However, I’m most fascinated by how they directly change the number of receptors present on individual axons, leading to the formation of drug tolerance.

This is where beta-arrestin comes in. Let’s dive inside the brain.

Inside the brain: How beta-arrestin alters receptor concentration on post-synaptic neurons

Figure 1. Graphic showing GPCR activation and eventual endocytosis via beta-arrestin signaling. (Ma L, Pei G. 2007. β-arrestin signaling and regulation of transcription. Journal of Cell Science. doi:10.1242/jcs.03338.)

Let’s break it down. First, a ligand (a small signaling molecule) will bind to the GPCR on the extracellular (outside) part of the neuron. This is what tells the GPCR to activate. Once the ligand binds, the g protein dissociates from the GPCR and its alpha subunit, an effector protein, goes off to trigger the response. After the alpha subunit leaves the GPCR, GRK2 binds to the beta-gamma subunits of the GPCR and removes them, phosphorylating the GPCR’s tail in the process. This leaves the phosphorylated tail open for beta-arrestin to bind to it. Once beta-arrestin binds to the tail of the GPCR, it triggers endocytosis, bringing the entire GPCR into the cell in a small bubble of the cell membrane. This leads to desensitization by reducing the number of receptors available to respond to a given signal.

“That’s great,” you might say, “I now understand beta arrestin’s impacts on GPCRs, but how do endocannabinoids activate beta-arrestin?”

Great question. I’m glad you asked it. Let’s talk about it.

It’s actually pretty simple. Repeated exposure to cannabinoids that function as ligands for CB1 receptors increases GRK2 activity, thereby also increasing both beta-arrestin signaling, and GPCR endocytosis. This helps explain why some individuals who use cannabinoids repeatedly build up a tolerance, requiring more of the cannabinoid to achieve the same feeling. For example, THC, the cannabinoid found in recreational marijuana responsible for the “high” associated with its use, is likely the most well-known example of this effect.

Conclusion

In closing, there are two things I think you should take from this.

• Endocannabinoid signaling can be complicated. Beta arrestin’s role in changing receptor concentrations was only discovered in the last 20 years and its stimulation by endocannabinoids is still being understood.
• There’s still so much that science does not understand about how the brain works. It’s both a daunting and highly exciting prospect.