Cobbers on the Brain

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.

Rates of Autism Spectrum Disorder (ASD) are rising in the U.S., and as a result, scientists are scrambling to figure out what is behind this increase and what we should do about it. A neurological disorder that varies widely in presentation and severity, Autism is broadly defined by the CDC as a disability “that can cause significant social, communication and behavioral challenges.” Since the 1990’s, autism prevalence has shifted from 1 in 150 children to 1 in 69. This may be caused by changes in diagnostic practices, such as the inclusion of Asperger’s into the Autism spectrum and looser diagnostic criteria, but a variety of other factors have been proposed as well.

Neurochemically, there are many proposed mechanisms that lead to the development of ASD. One of the most prominent hypotheses of pathophysiology involves abnormal neuroconnectivity, where neurons are overconnected within local circuits but underconnected across brain regions further apart, possibly due to an initial misplacement and impaired removal of unneccesary neurons during development. An imbalance of glutamate and GABA may also be involved, resulting in a net overexcitation of certain brain areas that would help explain the repetitive behaviors, seizures, sensory processing difficulties and social impairments commonly seen in Autism. Genetics, environmental factors and neuroinflammation, along with  components, are additional aspects of autism development that have been demonstrated through research.

People with Autism often experience life differently from neurotypical individuals, but to what degree does this warrant treatment or interventions? A fairly convincing argument has even been made by some that the occurrence of ASD within a population provides evolutionary benefits, with common autistic qualities such as enhanced memory and heightened perception contributing to the specialization of roles that further society. However, I have worked with several dozen teens and adults with Autism at a therapeutic recreation program, many of whom on the more severe end of the spectrum are unable to independently care for themselves or communicate verbally. Especially without the right type of support system, challenges like these can make it difficult to connect with others.

I am by no means an expert on ASD treatment, but my view is this: we should help individuals with ASD foster skills that will directly improve their quality of life, such as communicating their needs and thoughts they want to express to others. However, we should spend just as much energy toward creating an environment where they feel free to be authentically themselves. This is both by helping those around them learn how to best support their needs, but also by teaching society to accept and integrate individuals with ASD into their community. 

When it comes down to actual treatment decisions, things can get tricky. Do therapies such as Applied Behavior Analysis (ABA) help children with Autism “overcome” their symptoms? Or are there aspects of ABA that force children with Autism to assimilate to societal expectations in ways they may not need to? Different medications/therapies may pose similar ethical dilemmas. Given the wide range of symptom presentation and severity, it may be best to have a variety of treatment routes and options as well. I don’t have the answers to questions like these, but I hope that someday we will. In the meantime, we each play a part in creating a world where anyone can thrive.

When the endocannabinoid system is mentioned, most people generally infer that it has something to do with cannabis, more commonly known as marijuana. What most don’t realize is that the endocannabinoid system is a natural occurring system within the body and has cannabinoid receptors to bind with endogenous ligands (endocannabinoids (eCB)). This system plays a prominent role in synaptic plasticity and homeostatic processes and has garnered quite a bit of research in the therapeutics department. CBD and THC, which can both be extracted from cannabis, are chemically similar to the body’s natural endocannabinoids. Using forms of CBD, THC, and arachidonic acid-derived endocannabinoids, Anandamide (AEA) and 2-Arachidonylglycerol (2-AG) have shown to have neuroprotective effects and pain reduction. So how exactly does the endocannabinoid system do this?

What is the Endocannabinoid System?

As previously stated, AEA and 2-AG are two of the major endocannabinoids expressed within the body. These, along with CBD and THC, bind to the cannabinoid 1 receptor (CB₁) receptor. The CB₁ receptor is a G protein-coupled receptor located on presynaptic neurons and mediates the CNS effects of the endocannabinoids. AEA and 2-AG are produced by the enzymes diacylglycerol lipase (DAGL) and phospholipase D (PLD) and then activate the CB₁ receptor, which regulates adenylate cyclase activity and inhibits cAMP, voltage-gated calcium channels, potassium channels, and neurotransmitter release. There is also the CB₂ receptor, which is more concerned with the immune system as it is largely associated with inflammation and localized to microglia. AEA and 2-AG are agonists for the cannabinoid receptors and are triggered by an influx of calcium at postsynaptic sites after synaptic activity. The endocannabinoid system works to regulate a variety of events including pain perception, neuroprotection, learning, memory, and mood.

The Endocannabinoid System’s Role in Therapeutics

The use of endocannabinoids in therapeutics has increased greatly in the past few years with CBD pop-up stores and the legalization of marijuana in a handful of states. To read more on CBD for pain relief, read here: https://www.healthline.com/health/cbd-oil-for-pain#arthritis-pain-relief. The endocannabinoid system though has garnered quite a bit of attention in research by being linked to a variety of CNS diseases like Multiple Sclerosis, Alzheimer’s Disease, Huntington’s Disease, and Traumatic Brain Injuries (TBIs). In TBIs specifically, it’s been found that the endocannabinoid 2-AG and endothelin (ET-1) induced vasoconstriction, which constricts blood vessels and lessens blood flow) both form after a TBI. The balance of the two is what determines how bad in jury may be.

2-AG activates the CB1, CB2, and TRPV1 receptors to counteract the ET-1 response and dilates the blood vessels, decreasing the injury severity. This means that the endocannabinoid system is exerting a neuroprotective effect and has also been shown to lower the expression of proinflammatory cytokines in the early stages of a TBI, lowering the severity of the injury in the long haul. You can read more on the effects of the endocannabinoid system and TBI here: https://link.springer.com/article/10.1007/s12035-007-8008-6

Increasing endocannabinoids by injecting synthetic 2-AG or AEA to relieve pain and decrease disease/injury severity still requires more research but is looking to be a promising avenue in therapeutics. Currently, use of CBD and THC derivatives in different treatment forms, whether it be gummies, pills, or smoking, all seem to be beneficial ways to relieve pain, especially chronic forms. Hopefully research will continue on the use of endocannabinoid system’s role in neuroprotection and pain perception to increase the therapy for these disorders and pain management options.