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Selective Signaling in the endocannabinoid System : The ECS’s Secret to Keeping You Balanced

Posted on by smtesa / 0 Comment

The human body is a finely tuned machine, constantly regulating pain, mood, metabolism, and more to maintain balance. One important system responsible for this regulation is the endocannabinoid system (ECS), a network of cannabinoid receptors(CB1 and CB2) , endocannabinoids (Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) ) , and enzymes (FAAH and MAGL) that work together to keep everything running smoothly. This means that the ECS helps regulate things like pain perception, mood, immune function, and metabolism. It’s constantly monitoring the body’s needs and adjusting accordingly, ensuring that everything stays in balance. [1]

  • Endocannabinoids (AEA and 2-AG) are produced when needed and act locally to help regulate these functions.
  • Cannabinoid Receptors (CB1 and CB2) are activated by these endocannabinoids to trigger specific responses.
  • Enzymes (FAAH and MAGL) break down these molecules once they’ve done their job, ensuring the ECS doesn’t overdo it.

But maintaining balance isn’t as simple as turning functions on and off. If the ECS activated all its pathways randomly or continuously, it could lead to dysfunction instead of stability. That’s why it relies on selective signaling, only activating specific pathways when needed to ensure precise control.

Therefore, understanding how the ECS’s selective signaling works is essential for improving health. By learning how to support this system, we can regulate vital functions more effectively while avoiding unwanted side effects, helping the body stay in perfect balance.

So, how does the ECS know when and where to act? It carefully monitors the body’s needs and responds accordingly. Without selective signaling, ECS pathways would activate constantly and unpredictably, disrupting balance rather than maintaining it.

What Is Selective Signaling and Why Does It Matter?

Selective signaling is the ability of the ECS to target specific pathways or receptors at just the right time and place [2]. It’s like a light switch, when you need light in a room, you flip the switch, and it turns on just the right amount. If the light was on everywhere, all at once, it would be too bright and overwhelming. 

The ECS uses selective signaling to activate only the receptors that are needed in specific tissues, reducing unnecessary effects elsewhere. This process is achieved through factors such as GPCR signalling and β-Arrestin Pathway.

The GPCR Pathway in the Endocannabinoid System (ECS)

CB1 and CB2 receptors are G-protein coupled receptors (GPCRs) that help control pain, mood, and immune function [3]. When endocannabinoids like  AEA or 2-AG attach to these receptors, they start a Gi/o protein signaling process, which leads to:

  • Blocking adenylate cyclase (AC) → Lowers cAMP levels, slowing down cell activity.
  • Reducing protein kinase A (PKA) activation → Less activation of other proteins inside the cell.
  • Decreasing neurotransmitter release → Less glutamate, GABA, and dopamine are sent between brain cells.

But the effects of CB1 and CB2 activation depend on where they are located in the body. CB1 receptors in the brain and nervous system help regulate pain, mood, and neurotransmission by:

  • Reducing glutamate & GABA release, altering pain perception and mood (leading to relaxation or, in some cases, anxiety).[4]
  • Changing dopamine levels, which influences pleasure, motivation, and addiction.
  • Activating potassium (K+) channels and blocking calcium (Ca2+) channels, making neurons less excitable—reducing pain but sometimes causing drowsiness.

Meanwhile, CB2 receptors in the immune system and peripheral tissues focus on reducing inflammation and regulating immune responses by:

  • Lowering immune cell activity, which helps control inflammation.
  • Modulating chronic pain and autoimmune diseases, calming an overactive immune system.

Therefore, selective signaling is essential for ensuring these processes remain controlled and beneficial. Without it, the ECS could become overactive or unbalanced. 

β-Arrestin Pathway and CB1 Receptor Regulation

When CB1 receptors are overstimulated, such as with excessive THC use, the β-arrestin pathway helps regulate their activity to prevent overstimulation and build-up of tolerance. [5] This happens through three key processes:

  1. Desensitization: β-arrestin attaches to the CB1 receptor, blocking it from sending signals and reducing its activity.
  2. Internalization: The receptor is pulled inside the cell through clathrin-coated vesicles, making it temporarily inactive.
  3. Downregulation and Tolerance: If CB1 receptors stay internalized for too long, they may be broken down instead of recycled, leading to fewer receptors available for activation. This makes the body less responsive to THC over time, requiring higher doses to achieve the same effects.


Figure 1: Shows how GPCR signaling is regulated and how β-arrestin affects CB1 receptors. (a) When an agonist binds, GPCRs activate G proteins. (b) GRK phosphorylates the receptor, allowing β-arrestin to bind and stop signaling (desensitization). (c) β-arrestin helps remove the receptor through clathrin-coated vesicles for recycling or breakdown. With too much THC, CB1 receptors may be broken down instead of reused, reducing their numbers and leading to tolerance. [6]

But, if CB1 receptors are overstimulated too often, this desensitization can lead to tolerance, meaning the user will need more of the substance to experience the same effect. Over time, this could increase the risk of dependence. Since excessive β-arrestin activation plays an important role in this process, researchers are looking for ways to fine-tune CB1 receptor signaling.

This is where ligand bias comes in. Instead of activating all pathways equally, ligand bias allows for more accurate control, favoring beneficial signaling while minimizing unwanted effects.

Ligand Bias: Activating the Right Pathway

CB1 receptors don’t always respond the same way to different molecules. Some activate the G-protein pathway, which helps with pain relief, while others activate the β-arrestin pathway as shown in figure 2, which can lead to tolerance and side effects.

  • G-protein signaling → Helps with pain & inflammation
  • β-arrestin pathway → Leads to tolerance & side effects

This idea, called ligand bias (biased agonism), is helping scientists develop better treatments. By creating drugs that only activate the helpful G-protein pathway while avoiding too much β-arrestin activation, we can improve pain relief and neuroprotection without causing tolerance or unwanted effects.


Figure 2. Ligand-Biased Signaling in CB1 and CB2 Receptors. This figure shows ligand-biased signaling in CB1 and CB2 receptors, where ligands primarily activate either the G protein pathway or the β-arrestin pathway, leading to different cellular responses. Antagonists block both pathways by preventing ligand binding.[7]

Selective Signaling in Neurodegenerative Diseases 

Neurodegenerative diseases like multiple sclerosis (MS), Huntington’s disease (HD), and Alzheimer’s disease (AD)are linked to problems in the endocannabinoid system (ECS). The CB1 receptor plays an important role in protecting the brain, but if it is overused, the body can build tolerance, making treatments less effective.

Multiple Sclerosis (MS)

✔ CB1 activation helps reduce brain inflammation, muscle stiffness, and pain.
✔ Sativex (a THC-CBD spray) improves movement and reduces symptoms in MS patients.[8]
✔ According to the paper “Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease” studies on CB1-deficient mice show increased brain damage, proving that CB1 protects neurons. [9]

Huntington’s Disease (HD)

✔ CB1 receptors start disappearing early in the disease, even before symptoms appear.
✔ Losing CB1 receptors makes movement problems worse and leads to faster brain cell damage.
✔ CB1 activation increases BDNF (Brain-Derived Neurotrophic Factor), which helps protect brain cells and supports neuron survival. [9]

Alzheimer’s Disease (AD) 

✔ CB1 activation helps clear harmful β-amyloid buildup, which is linked to memory loss in AD.
✔ Mice without CB1 receptors have worse memory problems, showing that CB1 is needed for brain function.
✔ CBD helps protect the brain by reducing tau buildup, which contributes to neuron damage. [9]

In diseases like MS, HD, and AD, selective CB1 activation can help protect brain cells and improve symptoms. However, too much activation can lead to tolerance, making treatments less effective over time.Therefore, Selective signaling plays an important role in ensuring that CB1 receptors are activated only when and where needed, allowing scientists to develop more effective therapies with fewer side effects.

What Happens When Selective Signaling Fails?

Without selective signaling, the body could suffer from several issues:

  • Increased side effects: If CB1 receptors are overstimulated in the brain, it could lead to memory loss, confusion, and impaired motor function. Overstimulation of CB2 receptors might suppress the immune system too much, making us vulnerable to infections.
  • Uncontrolled pain and inflammation: Without selective signaling, the body could either feel too much pain in some areas or too little in others. Pain relief might not be targeted properly, leaving some areas of the body still suffering.
  • Tolerance and receptor burnout: With constant activation of CB1 receptors, they can become desensitized. This means a person may need higher doses to achieve the same effect, which increases the risk of addiction and worsens the overall response.
  • Mood disruptions: Overactivation of the ECS could lead to psychological side effects like anxiety, paranoia, or depression.

Therefore, without selective signaling, the ECS would lose its ability to finely tune processes, and the body would suffer from overactivation or underactivation of critical pathways.

The Bottom Line: Balance Is Key

And the endocannabinoid system (ECS) plays a vital role in regulating key functions like pain, mood, and immune response. It’s like the body’s internal balancing act, making sure everything runs smoothly. But here’s the catch: when the ECS doesn’t work properly, it can lead to serious issues, from chronic pain to mood swings and even disorders like anxiety or inflammation. Without proper regulation, things can get out of control fast!

Therefore, by understanding how selective signaling works in the ECS, we can create better treatments that target exactly what’s needed without all the side effects. So, why should you care? Because the ECS affects everyone! Whether you’re dealing with pain, stress, or just want to stay healthy as you age, learning more about how the ECS works could lead to safer, smarter treatments for a better life. And who wouldn’t want that?







 

 

 

 

 

 

Footnotes

[1] Lu, H. C., & Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological psychiatry, 79(7), 516–525. https://doi.org/10.1016/j.biopsych.2015.07.028

[2] Bosier, B., Muccioli, G. G., Hermans, E., & Lambert, D. M. (2010). Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. Biochemical pharmacology, 80(1), 1–12. https://doi.org/10.1016/j.bcp.2010.02.013

[3] Howlett, A. C., & Abood, M. E. (2017). CB1 and CB2 Receptor Pharmacology. Advances in pharmacology (San Diego, Calif.), 80, 169–206. https://doi.org/10.1016/bs.apha.2017.03.007

[4] Patel, S., & Hillard, C. J. (2009). Role of endocannabinoid signaling in anxiety and depression. Current topics in behavioral neurosciences, 1, 347–371. https://doi.org/10.1007/978-3-540-88955-7_14

[5] Nguyen, P. T., Schmid, C. L., Raehal, K. M., Selley, D. E., Bohn, L. M., & Sim-Selley, L. J. (2012). β-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biological psychiatry, 71(8), 714–724. https://doi.org/10.1016/j.biopsych.2011.11.027

[6] Whalen, E. J., Rajagopal, S., & Lefkowitz, R. J. (2011). Therapeutic potential of β-arrestin- and G protein-biased agonists. Trends in Molecular Medicine, 17(3), 126-139. https://doi.org/10.1016/j.molmed.2010.11.004

[7] Ye, L., Cao, Z., Wang, W., & Zhou, N. (2019). New Insights in Cannabinoid Receptor Structure and Signaling. Current Molecular Pharmacology, 12(3), 239–248. https://doi.org/10.2174/1874467212666190215112036

[8] Russo, M., Calabrò, R. S., Naro, A., Sessa, E., Rifici, C., D’Aleo, G., Leo, A., De Luca, R., Quartarone, A., & Bramanti, P. (2015). Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation. Neural plasticity, 2015, 656582. https://doi.org/10.1155/2015/656582

[9] Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience, 10(294). https://doi.org/10.3389/fncel.2016.00294



 

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CB1 Receptor Trafficking in Cannabinoid Signaling in the CNS: Why It Matters

Posted on by tchilala / 0 Comment

The human brain is a sophisticated network of impulses that continually adapts to its surroundings.  Among its various functions, the endocannabinoid system (ECS) regulates mood, memory, and neurological health.  But what happens if the system is disrupted?  More significantly, how does the trafficking of CB1 receptors within our cells affect neurological disorders?  Kendall and Yudowski (2017)[1] investigate the complicated mechanics of CB1 receptor signaling, offer insight on how these receptors travel throughout neurons, and discuss the potential for illness treatment.

Understanding the CB1 Receptor

CB1 receptors are a type of G protein-coupled receptor (GPCR) that is widely distributed throughout the central nervous system.  They are triggered by cannabinoids, which include both endogenous substances like anandamide and plant-derived molecules like tetrahydrocannabinol.  When activated, CB1 receptors alter neurotransmitter release, which influences mood, cognition, and pain perception.  However, these receptors do not remain stationary within cells; instead, they move about in a process known as receptor trafficking (Figure 1)

Figure adapted from Kendall and Yudowski, 2017[1]

www.frontiersin.org

Figure 1. Differential cannabinoid (CB) receptor signaling modalities can impact neuromodulation in health and disease in specific ways. (A)Endogenous ligands arachidonylethanolamine (AEA) and 2-arachidonylglycerol (2-AG) are produced by key enzymes, including diacylglycerol lipase(DGLα) and phospholipase D.  These activate the CB1 receptor in the central nervous system (CNS).  The outcome may include modification of adenylate cyclase activity to decrease cAMP buildup, voltage-gated calcium channels (VGCC), K+ channels, and neurotransmitter release in presynaptic excitatory and inhibitory synapses. After ligand binding activates the CB1 receptor, signaling through G protein and/or β-arrestin might occur at the plasma membrane, endocytic pits, or endosomes.  G proteins typically bind unphosphorylated receptors, whereas β-arrestin binds phosphorylated receptors via G protein receptor kinases[1].

CB1 Receptor Trafficking: A Key to Understanding Disease

When CB1 receptors are activated, they can undergo endocytosis, which is the process by which they move from the cell surface to intracellular compartments.  This movement is critical for controlling the strength and duration of cannabinoid signaling.  CB1 receptor trafficking is governed by interactions with proteins such β-arrestins, which can either encourage receptor recycling back to the surface or target receptors for destruction [2].

Why does this matter? Research suggests that dysregulation in CB1 receptor trafficking is linked to several neurological disorders, including:

  • Alzheimer’s Disease (AD): Impaired CB1 receptor signaling may contribute to memory deficits, as CB1 receptors are involved in synaptic plasticity[3].
  • Multiple Sclerosis (MS): Modulating CB1 receptor activity has been explored as a therapeutic approach for reducing neuroinflammation and spasticity[4].
  • Huntington’s Disease (HD): A decline in CB1 receptor expression correlates with disease progression, suggesting that preserving receptor function could be neuroprotective[5].

    Therapeutic Implications: The Future of CB1 Receptor Research

  • The ability to modulate CB1 receptor trafficking presents exciting therapeutic possibilities. By designing drugs that influence receptor movement and signaling bias, researchers aim to create targeted treatments with fewer side effects. For instance, ‘biased ligands’—molecules that preferentially activate either G-protein or β-arrestin pathways—could lead to more selective therapeutic outcomes (Figure 2).

    Figure 2. Adapted from Hua et al., “Crystal structure of the human cannabinoid

  • 1-s2.0-S009286741631385X-gr2.jpg

    Figure 2. Synthesis and Characterization of AM6538

    (A) Synthetic processes for AM6538[6].
    (B) Saturation [3H]-CP55,940 binding assays in the absence (control) or presence of rimonabant (100 nM) or AM6538 (50 nM) show that both antagonists cause displacement of the radioligand’s specific binding when present concurrently in the 1 hr binding assay[6].

    (C) Membranes were pretreated with buffer (none), rimonabant (100 nM), or AM6538 (50 nM) at 37°C for 6 hours. Membranes were rinsed with buffer 3× before [3H]-CP55,940 binding as described in (B)[6].
    (D) The percentage of residual binding (Bmax) was determined using the conditions specified in (B) (concurrent) and (C) (pretreat and wash).  When both antagonists were incubated together during the 1 hour binding assay, they reduced [3H]-CP55,940 binding by approximately 30%.  Rimonabant has no effect on future radioligand binding under pretreatment or washout conditions, but AM6538 competes even after membrane washing[6].

    Moreover, understanding the structure of CB1 receptors at the molecular level, as revealed in recent crystallography studies[6], opens doors to designing precise drugs that either enhance or suppress specific receptor functions

    Why Should the Public Care?

    The public’s interest in the ECS is expanding as cannabis-based medicines become more common.  However, without a more sophisticated knowledge of CB1 receptor dynamics, the effects of cannabinoids risk being oversimplified.  What’s the takeaway?  While cannabinoids show promise, their effects are heavily dependent on receptor signaling and trafficking.  Future treatments must account for these complications in order to realize the full potential of cannabinoid-based therapy.

     As research progresses, we get closer to understanding the entire therapeutic potential of CB1 receptor regulation.  This could open the path for new medicines that benefit millions of people suffering from neurological illnesses.

    References:

    1. Kendall DA, Yudowski GA. “Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.” Front. Cell. Neurosci. 2017;10:294. DOI:10.3389/fncel.2016.00294
    2. Delgado-Peraza et al., “Mechanisms of biased β-arrestin-mediated signaling downstream from the cannabinoid 1 receptor.” Molecular Pharmacology. 2016;89(6):618-629. DOI: 10.1124/mol.115.103176.
    3. Mulder et al., “Molecular reorganization of endocannabinoid signalling in Alzheimer’s disease.” Brain. 2011;134(4):1041-1060. DOI:10.1093/brain/awr046.
    4. Pryce et al., “Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.” Brain. 2003;126(10):2191-2202. DOI: 10.1093/brain/awg224.
    5. Mievis et al., “Worsening of Huntington disease phenotype in CB1 receptor knockout mice.” Neurobiology of Disease. 2011;42(3):524-529. DOI: 10.1016/j.nbd.2011.03.006.
    6. Hua et al., “Crystal structure of the human cannabinoid receptor CB1.” Cell. 2016;167(3):750-762.e14. DOI: 10.1016/j.cell.2016.10.004.
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Endocannabinoid

Posted on by rhurley1 / 0 Comment

The article we have covered in a previous week, “Cannabinoid Receptors in the Central
Nervous System: Their Signaling
and Roles in Disease” by Debra A. Kendall
and Guillermo A. Yudowski was an article about the purpose of Cannabinoid Receptors in the Central Nervous System. Basically, it can be summarized as the following; the endocannabinoid system has been connected to various essential roles in the synaptic ability to neurologically adapt and maintaining proper homeostasis in the brain. However, must those processes fail a myriad of things can go wrong to cause a tragedies in the subject.The topic today is why people should care about this topic and what the people must know, so without further ado let’s get to reading and clarifying!

The article informs us that certain kinds of unfortunate scenarios involving the endocannabinoid system are connected to various neurological diseases such as, Multiple Sclerosis, Huntington’s, Type Three Diabetes (Alzheimer’s Disease), and brain trauma.^1 Though, the article unfortunately leaves these tragic consequences at the article. As a result of these connection, we can now understand the essential nature of this information before us.

Figure one from the article mentioned is specifically excellent at explaining the essential nature of endocannabinoids. That piece is a diagram which explains the roles through the context of the membrane of neurons. Although, it could feel a tad bit overwhelming if you’re unfamiliar with the professional acronyms mentioned in figure one from the Neuroscience field. This was an excellent piece to me for it is maximized simplicity because, for clear reasons, that kind of thing strongly helps at a mere glance. The figure may also benefit people uninvolved in Neuroscience as well because figure one works similarly with the textbooks we grew up with in school with all the brief, yet descriptive, labeling and artistic style, and I find all of that effective myself in general because it’s easy on the eyes to track and logicate.

Now, at this point, one, such as yourself, may wonder why people really should care about all the above information. Well, let’s answer with essential basics to answer ourselves by quickly asking ourselves something simpler first; what really is so bad about what I considered consequences during a dysfunctional cannabinoid system? Well, Alzheimer’s disease for example is not very nice at all and looks even worse when examined scientifically. According to the NIH, Alzheimer’s disease has a wide spectrum of symptoms from memory loss and brain literal deterioration. Considering that we know the brain to be the most vital organ of all in the body, it’s no shock that such a scenario is serious and even severe. The severity of both mentioned examples of the consequences of Alzheimer’s disease in the last paragraph is clear and concerning when thought of this way in the clinical lens rather than “just another syndrome/disease” I personally notice in the general public awareness. I recommend reading the articles yourself to truly understand as I can only summarize so much of what we know!

Footnotes:
1: “Cannabinoid Receptors in the Central
Nervous System: Their Signaling
and Roles in Disease” by Debra A. Kendall
and Guillermo A. Yudowski

2: https://www.nia.nih.gov/health/alzheimers-causes-and-risk-factors/what-happens-brain-alzheimers-disease

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From Treatment to Tolerance: Understanding Marijuana’s Long-Term Effects

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Cannabis

Cannabis is a generic term used for the variety of products derived from the cannabis sativa plant. Cannabis goes by many names including marijuana which describes parts of the plant high in THC[1]. Delta 9 tetrahydrocannabinol (THC)  and Cannabidiol (CBD) are the most investigated[1]. Marijuana is one of the most used drugs in the United States, particularly among individuals aged 18-25.[1] In 2021, 35.4% of people aged 18 to 25 reported using marijuana in the past year[1]. The drug is surrounded by a significant amount of controversy and stigma as it is slowly being legalized for recreational use across the nation.

It is important to note that not all uses of marijuana are recreational. Before the drug was legalized for recreational use, it was legalized for medical use. Cannabis has been used in medicine to treat chronic pain, opioid withdrawals, seizures, multiple sclerosis, and decreased appetite[2].  The two main cannabis-derived medications available are Cannabidiol and Dronabinol[2].

Epidiolex

Epidolex (cannabiniol) is used in the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome. The medication is approved for individuals 2 years and older. it contains a purified form of CBD derived from marijuana without any THC.  Epidiolex is administered orally with strawberry flavoring. Common side effects include drowsiness, diarrhea, decreased appetite, lack of energy, sleep problems, increased liver enzymes, and infections

Dronabinol

Dronabinol is commonly used to treat weight loss in individuals with AIDs. It is also used to treat nausea and vomiting associated with chemotherapy. Dronabinol is a synthetic form of THC. The medication can be taken as a pill ranging from 2.5-5mg of THC per dose. It can also be administered orally as a spray with a 2.7 mg/100ul dose. Common side effects include dizziness, euphoria, nausea, vomiting, stomach pain, paranoia, sleepiness, and abnormal thinking[4].

Cannabis use disorder

Cannabis use disorder is a mental health condition where cannabis use causes distress or impairments in day-to-day tasks and functioning. In more severe cases the diagnosis can be classified as cannabis addiction [5].

Symptoms

  • Strong urge to consume cannabis
  • Unsuccessful attempts to limit cannabis use
  • Disruptions in social, occupational, or recreational activities because of cannabis use
  • Developing a tolerance
  • Confusion
  • Delusions
  • Memory issues

Forceps minor | Radiology Reference Article | Radiopaedia.org
Figure 3 Forceps minor [6]
Figure 4 orbitofrontal cortex  [7]
 

 

 

 

 

 

 

Long term effects

In the study Long-term effects of marijuana use on the brain, researchers found that long-term marijuana use had significant impacts on cognition and brain anatomy. Cannabis users exhibited significantly lower gray matter volume in the right and left middle orbitofrontal cortex (Figure 3) than controls. The marijuana groups also displayed increased white matter growth in the Forceps minor (Figure 4). Marijuana users also displayed significantly lower IQ scores compared to the control group.

 

[1] WHO. (2024, October 24). Cannabis. World Health Organization. https://www.who.int/teams/mental-health-and-substance-use/alcohol-drugs-and-addictive-behaviours/drugs-psychoactive/cannabis

[2] Cleveland Clinic medical. (2025, February 21). Marijuana. Cleveland Clinic. https://my.clevelandclinic.org/health/articles/4392-marijuana-cannabis

[3] Abu-Sawwa, R., & Stehling, C. (2020). Epidiolex (Cannabidiol) Primer: Frequently Asked Questions for Patients and Caregivers. The Journal of Pediatric Pharmacology and Therapeutics : JPPT, 25(1), 75. https://doi.org/10.5863/1551-6776-25.1.75

[4] Drugbank. (2025, February 16). Dronabinol: Uses, interactions, mechanism of action | drugbank online. https://go.drugbank.com/drugs/DB00470

[5] Cleveland Clinic medical. (2025a, February 21). Cannabis use disorder. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/cannabis-use-disorder

[6] Filbey, F. M., Aslan, S., Calhoun, V. D., Spence, J. S., Damaraju, E., Caprihan, A., & Segall, J. (2014). Long-term effects of marijuana use on the brain. Proceedings of the National Academy of Sciences of the United States of America, 111(47), 16913–16918. https://doi.org/10.1073/pnas.1415297111

[7] https://en.wikipedia.org/wiki/Orbitofrontal_cortex

[8]Gaillard F, Murphy A, Hacking C, et al. Forceps minor. Reference article, Radiopaedia.org (Accessed on 25 Feb 2025) https://doi.org/10.53347/rID-4705

 

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Targeting Weed: Therapeutic possibilities

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Targeting Weed: Therapeutic Possibilities

Cannabis has a complicated relationship with society. The perception of the widely used recreational drug has attracted scientific attention and ignited ideas of research. However accessibility has changed throughout the previous years with legalization of the drug. In turn, the availability of the drug increases along with tolerance.

Marijuana is a schedule 1 drug, meaning there is plenty of red tape when it comes to researching the affects of the drug within human disease; despite this, cannabinoids have the ability to provide pain relief on such chronic conditions and neuro-degeneration.

No matter the public perception, scientific studies are showing therapeutic possibilities with marijuana and its link to the endocannabinoid system. Potential therapies could be used in remarkable ways if used with intentionality and knowledge.

Understanding Cannabis

The active compound in marijuana is delta-9 tetrahydrocannabinol (THC)  and cannabidol (CBD). These compounds are not present in your body unlike the cannabinoid system. THC is responsible for the psychoactive experience that occurs when using marijuana,  the feeling of being ‘high’.

CBD on the other hand is non-psychoactive. CBD has anti-inflammatory, anxiolytic affects–reducing anxiety, and neuro-protective properties.

The Endocannabinoid System (ECS)

What is the Endocannabinoid System? - Siam Herbal Health CBD
Figure 1: image of location of CB1 and CB2

 

CB1 and CB2 regulate the release of neurotransmitters. Cannabinoids react with cannabinoid receptors in the endocannabinoid system. The endocannabinoid system already exist in your body believe it or not. The job of ECS is to regulate a multitude of processing in the CNS central nervous system. This include things such as pain perception, memory and learning, emotional processing, sleeping and eating, and immune and inflammatory response. ECS is diverse with chemical signals and receptors. Our bodies produces cannabinoids, CB1 receptors are more abundant than CB2 receptors and are posed at at different areas in the body. The two primary cannabinoids however are, endocannibinoids 2-archidonoyl glycerol (2AG) and arachidonoyl ethanolamide (AEA) / anandamide. These molecules are synthesized and released as needed.

Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke
Figure 2: cannabinoids CB1 and CB2, showing the beneficial outcomes and detrimental outcomes.

 

CB1 has the ability to decrease excitotoxicity which is the process where nerve cells are damaged from excess stimulation resulting in neurodegenerative diseases, strokes, or traumatic brain injury. By decreasing excitotoxicity, CB1 reduces the amount of glutamate release at synapses, therefore inhibiting excitotoxic damage.

CB1 also plays a role in temperature regulation by preserving stability and circulation. CB1 activation causes hyper-activation of microglia which releases pro inflammatory cytokines. This is the microglial phenotype shifting from M1 phenotype (pro-inflammatory) to M2 phenotype  (Anti-inflammatory and neuro-protection). With reduction of inflammatory molecules, CB2 helps create a neuro-protective environment. improving the outcome of pain management and slowing progression of diseases like Alzheimers disease or Parkinson’s disease.

Future Research

Medical marijuana is known to help in treatment to alleviate pain, but the question is can this drug have potentially curing possibilities that are lasting, and how are we able to target that? There is far enough evidence that the drug has therapeutic properties. Where it is most commonly used to alleviate pain. Cannabis can be used as an anti-inflammatory and anti-hypertensive which lowers blood glucose levels.

This issue with trying to flip the script with a schedule-1 drug is that, cannabis has been used as a recreational drug for as long as it has been around. The real question  and research is long-term safety and the side affects that may occur with long-term and short-term use of cannabis.

Footnotes:

D’Amico, E. J., Miles, J. N. V., & Tucker, J. S. (2015, September). Gateway to curiosity: Medical marijuana ads and intention and use during Middle School. Psychology of addictive behaviors : journal of the Society of Psychologists in Addictive Behaviors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587352/

Kendall, D. A., & Yudowski, G. A. (2017, January 4). Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Frontiers in cellular neuroscience. https://pmc.ncbi.nlm.nih.gov/articles/PMC5209363/

Leinen ZJ;Mohan R;Premadasa LS;Acharya A;Mohan M;Byrareddy SN; (2025). Therapeutic potential of cannabis: A comprehensive review of current and future applications. Biomedicines. https://pubmed.ncbi.nlm.nih.gov/37893004/

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The Healing Power of Endocannabinoids: The Brain’s Secret Weapon

Posted on by Nessa Angau / 0 Comment

Grand Rounds: The Endocannabinoid System & Cannabis Therapeutics: An Integrative Approach to Peripheral Neuropathy - Osher Center For Integrative Medicine

Have you ever wondered if your brain has its own version of cannabis? Well it does! Your body naturally produces chemicals that work like the active ingredients in cannabis, and they’re part of a powerful system known as the Endocannabinoid System (ECS). This system influences everything from your mood to memory, pain perception, and even how you recover from injuries.

BUT here’s the twist: while scientists have learned a lot about the ECS, unlocking its full therapeutic potential is proving to be a challenge. The ECS is like a complex network, and its signaling pathways are like intricate mazes. Researchers believe the ECS could revolutionize treatments for conditions like Alzheimer’s disease, multiple sclerosis, and Huntington’s disease – AND it might hold the key to managing pain, anxiety, and brain injuries. [1]

THEREFORE, understanding how to harness this system safely and effectively could transform medicine as we know it. Let’s read and dive more into the science and the promise it holds!

The Science Behind Endocannabinoids

Figure 1. Diagram showing the Endocannabinoid System
Figure 1. Diagram consisting of the endocannabinoids and the cannabinoid receptors – regulates nerve cell communication at the synapse, thereby playing a role in a variety of bodily functions.  [2]

 

 

According to the paper “Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease” by Kendall and Yudowski (2017), the ECS primarily involves two major receptors: CB1 and CB2. CB1 receptors are found in the brain, where they control how neurons communicate, affecting memory, mood, and motor control. CB2 receptors, on the other hand, are mostly located in immune cells and are crucial in controlling inflammation. [1]

The ECS works through natural chemicals called endocannabinoids like anandamide (AEA) and 2-AG, which are produced on demand by the body. These endocannabinoids help the brain maintain balance, regulate pain, and protect itself from damage. [3] This system also plays a role in synaptic plasticity – the brain’s ability to adapt and reorganize itself, which is essential for learning and memory.

The Therapeutic Promise: Can the Endocannabinoid System Save the Day?

The ECS isn’t just fascinating – it could be life-changing. For example, in multiple sclerosis (MS), cannabinoids have shown promise in reducing muscle spasms and pain. The cannabis-based medicine Sativex is already being used to treat some MS symptoms! [4] In Alzheimer’s Disease, eCBs may reduce harmful brain plaques and protect neurons, potentially slowing memory loss.

Huntington’s disease also shows hope. Loss of CB1 receptors worsens the disease, while activating these receptors could help protect brain cells. And after a traumatic brain injury (TBI), the body boosts eCB production to reduce swelling and protect brain tissue.

 

But… There’s a Catch

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases
Figure 2. The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases [5]

The biggest challenge? Cannabis contains over 60 different compounds, and figuring out which ones help – without unwanted side effects – is complicated. Plus, the ECS’s signaling pathways are highly complex, making it tough to target treatments without hitting unwanted effects. Scientists are now looking at biased ligands, compounds that could selectively trigger only the beneficial parts ECS signaling. [6]

The Future Looks Bright

While there’s still much to learn, one thing’s clear: the ECS holds incredible potential for treating neurological diseases, managing pain, and improving mental health. With more research and better drug development, we may soon unlock the full therapeutic potential of endocannabinoids. So, the next time you hear about cannabinoids, remember – your brain might already be using them to keep you healthy and happy!

 

Resources

[1] Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Frontiers in Cellular Neuroscience, 10(294). https://doi.org/10.3389/fncel.2016.00294

[2] Nagarkatti, M., & Nagarkatti, P. (2023, February 22). People produce endocannabinoids – similar to compounds found in marijuana – that are critical to many bodily functions. The Conversation. https://theconversation.com/people-produce-endocannabinoids-similar-to-compounds-found-in-marijuana-that-are-critical-to-many-bodily-functions-198220

[3] Woodcock, S. (2023, October 24). Everything You Need to Know About the Endocannabinoid System. GoodRx. https://www.goodrx.com/classes/cannabinoids/what-is-the-endocannabinoid-system

[4] Russo, M., Calabrò, R. S., Naro, A., Sessa, E., Rifici, C., D’Aleo, G., Leo, A., De Luca, R., Quartarone, A., & Bramanti, P. (2015). Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation. Neural Plasticity, 2015, 656582. https://doi.org/10.1155/2015/656582

[5] Tudorancea, I. M., Ciorpac, M., Stanciu, G. D., Caratașu, C., Săcărescu, A., Ignat, B., Burlui, A., Rezuș, E., Creangă, I., Alexa-Stratulat, T., Tudorancea, I., & Tamba, B. I. (2022). The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases. Biomedicines, 10(10), 2492. https://doi.org/10.3390/biomedicines10102492

[6] Tian, L., Qiang, T., Liu, S., Zhang, B., Zhang, Y., Zhang, B., Hu, J., Zhang, J., Lu, Q., Ke, C., Xia, J., & Liang, C. (2025). Cannabinoid receptor 1 ligands: Biased signaling mechanisms driving functionally selective drug discovery. Pharmacology & Therapeutics, 267, 108795. https://doi.org/10.1016/j.pharmthera.2025.108795

 

Disease/Health

The Silent Link Between Insulin and Alzheimer’s: What You Need to Know

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Imagine this: You walk into a room, but suddenly, you forget why you’re there. You struggle to recall a familiar name or misplace your keys more often than usual. While occasional forgetfulness is normal, when memory loss starts to interfere with daily life, it could be a sign of something more serious: Alzheimer’s disease (AD).

Alzheimer’s is the most common cause of dementia, affecting millions of people worldwide. It slowly erodes memory, thinking skills, and even the ability to carry out simple tasks. Scientists have spent decades unraveling its causes, and one surprising factor keeps showing up insulin resistance in the brain.[1]

Alzheimer’s and the Brain: A Metabolic Disaster

We often associate insulin with diabetes, and it also plays a crucial role in brain function. Normally, insulin helps regulate glucose levels, providing energy to brain cells.

But in Alzheimer’s patients, the brain stops responding to insulin properly, leading to what some researchers call “Type 3 Diabetes”. [2]  This insulin resistance makes it difficult for neurons to get the energy they need to function.

Therefore, neurons experience oxidative stress and inflammation, while harmful plaques like amyloid-β build up in the brain. Insulin resistance also contributes to tau protein tangles, which disrupt communication between brain cells, further impairing cognitive function.[3]

Insulin in the Brain: More Than Just Sugar Control

For years, people believed that insulin was only relevant to the body’s metabolism. But groundbreaking research has shown that insulin in the brain does so much more. It helps with:

  • Memory formation – Insulin receptors are abundant in the hippocampus, the brain’s memory center.
  • Neuroprotection – It shields brain cells from damage and prevents cognitive decline.
  • Synaptic plasticity – Insulin supports the connections between neurons, keeping thinking sharp and learning intact.

But when insulin signaling is disrupted, all these functions begin to fail—setting the stage for Alzheimer’s disease.

Insulin Growth Factor (IGF): The Brain’s Unsung Hero

Insulin-like growth factors (IGFs) are proteins with a molecular structure similar to insulin. They bind to insulin receptors as well as IGF receptors. There are two subtypes, IGF-1 and IGF-2, which play crucial roles in metabolism, growth, and the proliferation of peripheral and central cells.

  • Neuronal survival and repair – IGF-1 helps brain cells recover from damage.
    • IGF-1 binds to its receptor (IGF-1R), activating the PI3K/Akt signaling pathway.
    • Akt promotes neuron survival by inhibiting apoptosis (cell death) and stimulating neurogenesis and synaptic plasticity. [4]
  • Clearing amyloid-β plaques – It prevents toxic proteins from accumulating in the brain.
    • IGF-1 boosts microglial and astrocyte activity, enhancing their ability to clear amyloid-β through phagocytosis. [4]
  • Regulating tau proteins – Keeping tau from forming deadly tangles inside neurons.
    • IGF-1 activates Akt, which inhibits GSK-3β (Glycogen Synthase Kinase-3β), a key enzyme that phosphorylates tau.
    • By reducing tau phosphorylation, IGF-1 prevents the formation of neurofibrillary tangles that disrupt neuron function. [4]

Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies | Molecular Neurobiology

Figure 3. This figure demonstrates how decrease of IGF-1 levels contribute to AD.

In Alzheimer’s, IGF-1 levels decline, and the brain loses this protective mechanism. Without enough IGF-1, toxic proteins build up, neurons die, and the disease progresses faster. [5]

Can You Prevent Alzheimer’s? Here’s What Science Says

The good news? You CAN take steps to protect your brain. While there’s no guaranteed cure for Alzheimer’s, research strongly suggests that lifestyle changes can significantly lower your risk.

1. Healthy eating 

Diets rich in healthy fats, lean proteins, and fiber can help reduce insulin resistance. The Mediterranean diet, full of fish, olive oil, nuts, and leafy greens, is linked to a lower risk of Alzheimer’s.

MIND Diet May Help Lower Alzheimer's Risk: Food List and Sample Menu

Figure 4. A Mediterranean diet with fish, olive oil, nuts, and greens reduces insulin resistance, supports weight management, and lowers Alzheimer’s risk.

2. Stay Physically Active

Exercise boosts insulin sensitivity, increases blood flow to the brain, and reduces inflammation. Aim for at least 30 minutes of movement a day—whether it’s walking, dancing, or yoga.

How to Cope When Your Spouse Has Dementia: 14 Keys

Figure 5. Walking, dancing, or yoga boosts insulin sensitivity, improves brain blood flow, and reduces inflammation.

3. Keep Your Blood Sugar in Check

High blood sugar contributes to insulin resistance and Alzheimer’s progression. Avoid processed sugars, refined carbs, and sugary drinks to keep your glucose levels stable. [4]

4. Engage Your Brain

Keeping your mind active is just as important as exercising your body! Try:

  • Reading books
  • Learning a new skill
  • Solving puzzles
  • Engaging in social activities
5. Sleep Like Your Brain Depends on It (Because It Does!)

During deep sleep, the brain clears out toxins, including amyloid-β plaques. Adults should aim for 7–9 hours of quality sleep per night.

Treatment Approaches:

While there’s no cure yet, scientists are exploring treatments targeting insulin resistance in the brain:

  • Intranasal Insulin Therapy – Delivers insulin directly to the brain to enhance cognitive function.[6]
  •  Anti-Diabetic Drugs – Medications like Metformin and Pioglitazone show promise in reducing Alzheimer’s risk.
  • IGF-1 Therapy – Boosting IGF-1 levels may help clear toxic proteins and protect neurons.
  • GSK-3β Inhibitors – These drugs prevent tau tangles, slowing down neurodegeneration.

Footnotes

[1] Kumar, V., Kim, S. H., & Bishayee, K. (2022). Dysfunctional Glucose Metabolism in Alzheimer’s Disease Onset and Potential Pharmacological Interventions. International journal of molecular sciences, 23(17), 9540. https://doi.org/10.3390/ijms23179540

[2] de la Monte, S. M., & Wands, J. R. (2008). Alzheimer’s disease is type 3 diabetes-evidence reviewed. Journal of diabetes science and technology, 2(6), 1101–1113. https://doi.org/10.1177/193229680800200619

[3],[5] Sędzikowska, A., & Szablewski, L. (2021). Insulin and Insulin Resistance in Alzheimer’s Disease. International journal of molecular sciences, 22(18), 9987. https://doi.org/10.3390/ijms22189987

[4] Al-Samerria, S., & Radovick, S. (2021). The Role of Insulin-like Growth Factor-1 (IGF-1) in the Control of Neuroendocrine Regulation of Growth. Cells, 10(10), 2664. https://doi.org/10.3390/cells10102664

[6] Hallschmid M. (2021). Intranasal Insulin for Alzheimer’s Disease. CNS drugs, 35(1), 21–37. https://doi.org/10.1007/s40263-020-00781-x

Health

The Science of Sports Recovery: Is Cannabis the Missing Piece?

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Athletes push their bodies to the limit, and injuries are an inevitable part of the game. Concussions have become a major concern in contact sports due to their long-term effects on brain health. The search for better treatments is more urgent than ever. Could cannabis be the unexpected game-changer in sports medicine?

Understanding the Science

The endocannabinoid system (ECS) plays a crucial role in brain function, regulating pain, inflammation, and recovery after injury. It primarily functions through two naturally occurring ligands, 2-arachidonoylglycerol (2-AG) and anandamide (AEA).1 While these endocannabinoids are produced by the body, other compounds such as Δ9-THC from cannabis an also interact with the ECS.

A key feature of the ECS is its retrograde signaling. This means that ligands travel backwards from the postsynaptic neuron to the presynaptic neuron to help regulate neurotransmitter release. The system relies on two main receptors, CB1 and CB2, which both are G protein-coupled receptors (GPCRs).1

  • CB1 receptors are found in high concentrations in the brain and help regulate neurotransmitter release, pain perception, and neuroprotection.
  • CB2 receptors are primarily located in immune cells and play a role in inflammation and immune response.

When endocannabinoids or other cannabinoids bind to these receptors, they trigger a cascade of intracellular events. For example, CB1 receptor activation can lead to a decrease in cAMP accumulation which can inhibit certain signaling pathways. Another example includes how it can block calcium channels while promoting potassium efflux which will ultimately reduce neurotransmitter release and dampen excessive neural activity. Figure 1 can help give a visual representation of some of effects of the ECS.1

Figure 1. Basic overview of some of the pathways affected through the ECS.

The Ongoing Debate

But the science is still unclear. While early research suggests that cannabinoids may help reduce brain inflammation, protect neurons, and ease concussion symptoms, most findings come from animal studies or small-scale trials.2 There is no concrete evidence that cannabis speeds up brain healing rather than just masking symptoms like pain and headaches.

Sports leagues remain divided on cannabis use. While the UFC and MLB have loosened restrictions, organizations like the NFL and Olympic committees still enforce strict regulations.3 Without true patient centered clinical trials is cannabis a legitimate treatment or just another unproven trend?

Recently, athletes have started to share their personal experiences with cannabis use. Former Seattle Seahawks running back Marshawn Lynch recently appeared on a podcast hosted by Shannon Sharpe, where he shared his experiences and discussed the benefits of cannabis use for NFL players. Here is a link to a small clip from the podcast: Link.

The Path Forward

Researchers are working to bridge the gap between promising early findings and real-world applications. Studies suggest cannabinoids interact with the ECS to reduce inflammation, regulate neurotransmitters, and promote cell survival.1 Some evidence indicates that CBD and THC may help reduce brain swelling, protect neurons, and ease post-concussion symptoms.2

However, more rigorous trials are needed to determine safe and effective dosages and their interactions with existing treatments for traumatic brain injuries (TBI). Sports regulations also raise important questions about how cannabis should be integrated into medical care.

Beyond Sports: A Bigger Conversation

This conversation goes beyond athletes. Millions of people suffer concussions each year, from youth sports to military personnel to everyday accidents. If cannabinoids prove effective, they could revolutionize how we treat brain injuries across all levels of society.

But some critical questions remain: Are we on the verge of a medical breakthrough, or is the hype moving faster than the science?

Final Thoughts

The potential for cannabis in concussion recovery is exciting, but the science isn’t settled yet. While early findings suggest benefits, more research is needed to fully understand the risks and rewards. As discussions on cannabis in sports continue, athletes, doctors, and policymakers must prioritize science over speculation.

References 

(1)      Kendall, D. A.; Yudowski, G. A. Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front Cell Neurosci 2017, 10. https://doi.org/10.3389/fncel.2016.00294.

(2)      Hergert, D. C.; Robertson-Benta, C.; Sicard, V.; Schwotzer, D.; Hutchison, K.; Covey, D. P.; Quinn, D. K.; Sadek, J. R.; McDonald, J.; Mayer, A. R. Use of Medical Cannabis to Treat Traumatic Brain Injury. Journal of Neurotrauma. Mary Ann Liebert Inc. July 15, 2021, pp 1904–1917. https://doi.org/10.1089/neu.2020.7148.

(3)      Docter, S.; Khan, M.; Gohal, C.; Ravi, B.; Bhandari, M.; Gandhi, R.; Leroux, T. Cannabis Use and Sport: A Systematic Review. Sports Health. SAGE Publications Inc. March 1, 2020, pp 189–199. https://doi.org/10.1177/1941738120901670.

 

Health

Beyond THC: The Endocannabinoid System

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The endocannabinoid system (ECS) is a key modulatory signaling pathway [1]. Which, I’ve heard, is a very common phrase in the scientific community, and is simply a fancy way of saying it does a whole lot of stuff. So what exactly does it modulate, and what does that mean?

The ECS is made up of two major receptors, called CB1 and CB2. CB1 receptors are found primarily in the central nervous system, and CB2 receptors are found in the immune system.

Activation of ECS receptors [1]
These receptors are actually found on the presynaptic cell (normally receptors are found on the postsynaptic cell), making them a part of retrograde signalling [1]. 

The ligands of this system are endogenous cannabinoids, which are produced on demand. An increase of intracellular calcium triggers arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) to be synthesized from the phospholipid bilayer [1]. 

  • Starting at the phospholipid bilayer, the enzymes NAPE and PLD are used to make AEA. The enzyme FAAH is used to degrade AEA into AA. 
  • From the phospholipid bilayer, the enzyme PLC is used to make DAG, then the enzyme DAGL is used to make 2-AG. The enzyme MAGL is used to degrade 2-AG into AA.

Once synthesized, these eCB bind to CB1 and CB2 (GPCR receptors), and inhibit adenylyl cyclase. This decreases levels of cyclic-AMP, inhibits calcium channels, and inhibits neurotransmitter release. Overall, when the receptors are activated, they decrease signaling in other pathways [1].

Roles

As we said earlier, the ECS modulates a whole bunch of stuff. Another way of saying that, is the ECS regulates a lot of cellular processes. This means it has a lot of roles, and can change cellular communication and processes in relation to them all. These are some of the processes the ECS modulates:

Benefits & Risks

Endocannabinoids, such as THC, are often used to treat central nervous system diseases including multiple sclerosis, Huntington’s disease, Alzheimer’s disease, epilepsy, anxiety, and depression. THC can be helpful with reducing pain and inflammation, regulating mood, and providing a neuroprotective role against neurodegeneration [1]. However, the ECS is an incredibly complicated system, and long term use of THC does have potential side effects and risks. This can include:

  • Apathy and passivity, as well as a decrease in motivation and goal-oriented behaviors. This may be due to altered neurocognitive functioning and reward salience [2].
  • Alterations in learning and memory, and disruptions of long-term potentiation. This is due to changes in glutamatergic neurotransmission signaling [3].
  • Excitotoxicity due to increased glutamate receptor expression [3].
  • Neurodegeneration due to too much calcium [3].
  • Inflammatory cytokine production and inflammation
    Desensitization [4].
    due to activation of microglia and astrocytes [3].
  • Downregulation, receptors permanently being removed, and desensitization, the uncoupling of the G-protein from the receptor. These processes are related to tolerance [4]. 

Research and Regulations

The gist of it is we do not know enough about the ECS and endocannabinoids work. We need more research in order to be prepared with a more complete explanation of risks and benefits. However, marijuana (the cannabis plant that contains more than 60 active synthetic ligands for CB1 and CB2, including THC), is a schedule 1 drug. This classification is defined with “no currently accepted medical use and a high potential for abuse” despite proven therapeutic benefits [5]. This means in order to study cannabis, there are a lot of regulations and paperwork involved, restricting the amount of research that can be done [6]. 

With this lack of understanding of the risks, there needs to be more regulations on marijuana. Regulations, not criminalization. For example, making sure kids and their developing brains don’t have access without a medical prescription. Or regulating the marketing and packaging, so colorful bags of gummy bears don’t catch the eyes of an eight year old, who then ends up ingesting 100mg of THC. 

People need to be able to make informed decisions, taking into consideration the short-term and long-term impacts on their health. The scientific community needs to be able to do more research, then communicate the results to the public in a way that educates them, but doesn’t tell them what to do. People who rely on endocannabinoids for their medical purposes have a right to understand all the benefits as well as risks. And the general public has the right to be informed to aid in their decision making as well.

References

[1] Kendall, D. A., & Yudowski, G. A. (2017). Cannabinoid receptors in the central nervous system: Their signaling and roles in disease. Frontiers in Cellular Neuroscience, 10. https://doi.org/10.3389/fncel.2016.00294 

[2] Rovai, L., Maremmani, A. G. I., Pacini, M., Pani, P. P., Rugani, F., Lamanna, F., Schiavi, E., Mautone, S., Dell’Osso, L., & Maremmani, I. (2013). Negative dimension in psychiatry. Amotivational syndrome as a paradigm of negative symptoms in substance abuse. Rivista Di Psichiatria, 48(1), 1–9. https://doi.org/10.1708/1228.13610 

[3] Chowdhury, K. U., Holden, M. E., Wiley, M. T., Suppiramaniam, V., & Reed, M. N. (2024). Effects of Cannabis on Glutamatergic Neurotransmission: The Interplay between Cannabinoids and Glutamate. Cells, 13(13), 1130. https://doi.org/10.3390/cells13131130 ‌

[4] Piscura, M. K., Henderson-Redmond, A. N., Barnes, R. C., Mitra, S., Guindon, J., & Morgan, D. J. (2023). Mechanisms of cannabinoid tolerance. Biochemical Pharmacology, 214, 115665. https://doi.org/10.1016/j.bcp.2023.115665

[5] U.S. Department of Justice. (n.d.). Drug scheduling. United States Drug Enforcement Administration. https://www.dea.gov/drug-information/drug-scheduling

[6] Medications: Research on schedule I drugs. National Alliance on Mental Illness. (2024, July 23). https://www.nami.org/advocacy/policy-priorities/improving-health/medications-research-on-schedule-i-drugs/#:~:text=Federal%20law%20prohibits%20the%20manufacture,studying%20any%20Schedule%20I%20drugs.

Uncategorized

The Potential Protective Impact of Cannabis on Your Neurons

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Artstract created by C. Geraci

Have you ever smoked weed? If you haven’t, recent research has shown that you may want to consider it, as it may have neuroprotective roles on our body’s neurons.

The Endocannabinoid System (ECS)

The system in the brain that cannabis targets is the endocannabinoid system (ECS). Delta-9-tetrahydrocannabinol, better known as delta-9-THC, is the main ligand, out of around 60 ligands, within marijuana that binds to the ECS’s two receptors: cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 receptors are concentrated with the brain and spinal cord, while CB2 receptors are more localized in the peripheral nervous system and more directly associated with regulating microglia and inflammation.1

CB1 receptors are G-protein coupled receptors (GPCRs) localized on pre-synaptic membranes of neurons that are activated in the absence of agonists like delta-9-THC. The binding of such agonists to CB1 receptors inhibits Ca2+ outflow from the presynaptic neuron while triggering a temporary increase of intracellular Ca2+ in the post-synaptic neuron. This triggers enzymes NAPE-PLD and DAGL to make arachidonylethanolamine (AEA) and 2-arachidononylglycerol (2-AG), respectively. AEA and 2-AG are the main endocannabinoids that bind to the CB1 receptors, further inhibiting the outflow of calcium and potassium, neurotransmitters release, and production of cAMP by inhibiting adenylyl cyclase. 1 This cycle can be seen in the upper portion of Figure 1.

Figure 1. This shows the pathway that occurs after a ligand, such as delta-9-THC, binds to a CB1 receptor. 1

The lower portion of Figure 1 shows how a protein called B-arrestin is involved in the internalization of CB receptors, which may occur after prolonged exposure to CB1 receptor agonists. The binding of B-arrestins uncouples the G-proteins of the CB1 receptor and stimulates internalization, leading to a tolerance to endocannabinoids.1 For more information on the pathways of the ECS, click here.

And that tolerance may be what you think of when you think of people becoming addicted to smoking weed. But what positive effects can occur when you consume cannabis or delta-9-THC?

How Endocannabinoids Are Protective

Well, the endocannabinoid lipid molecules similar to AEA, such as palmitoylethanolamide (PEA) and N-oleoylethanolamide (SEA), have been shown to anti-inflammatory and neuroprotective actions. PEA and SEA do this by inhibiting fatty acid amid hydrolase (FAAH) and monoacylglycerol (MAGL), the enzymes that degrade AEA and 2-AG, respectively. With increased levels of AEA and 2-AG, neurodegeneration is prevented. Considering a mouse study where mice were treated with SEA, 2-AG levels were increased before an increase of CB receptor expression, confirming that SEA interferes with the ECS system.2

But what makes the increase of 2-AG and AEA neuroprotective? One role to consider is that of microglia, which play a large role in neuroprotection. Microglia have CB2 receptors on them, and chronic activation is generally considered detrimental for neuronal health. Since 2-AG and AEA are inverse agonists of the ECS in microglia, they inhibit their activation, decreasing prolonged microglial immunoreactivity, therefore protecting neurons from being unnecessarily degraded. 2 For more information regarding what PEA and SEA do, look at Figure 2 or click here.

Figure 2: This illustrated the neuroprotective effects that AEA, PEA, and SEA have on neurons. 1

Aside from microglia, astrocytes also play a large role in neuroprotection. Similar to microglia, astroglial CB1 and CB2 receptors play critical roles in inflammatory responses, with activation of these receptors protecting neurons against oxidative stress, apoptosis, and nitric oxide. 2

Endocannabinoids & Neurodegenerative Diseases

Looking at neurodegenerative diseases, is has been shown that CB2 receptors and FAAH are overexpressed during Alzheimer’s disease, leading to neurotic plaque buildup in astrocytes and microglia. Administration of MAGL and FAAH inhibitors led had anti-inflammatory effect on these glial cells, reducing amyloid-beta deposition. The ECS system has also been shown to have positive effects on dopaminergic neurons in Parkinson’s disease and neuronal regeneration in multiple sclerosis. Therefore, the ECS, cannabis, and delta-9-THC have the potential to treat neurogenerative disease and stimulate neuroprotection within the brain. 2 For more information on that, click here.

Conclusion

In conclusion, microglia and astrocytes are coupled to functions related to inflammatory production, pro-survival changes, resolution of neuroinflammation, and protection from toxic metabolites. The contribution of eCB signaling is relevant to protection of neurons, and further research should be done to determine whether the use of medical marijuana can effectively target neurodegenerative diseases without significant negative side effects. If that research is promising, it may suggest that cannabis be used as a preventative treatment for such diseases, promoting its use by the general population.

Footnotes

1Kendall, D., Yudowski, G. “Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease.” Frontiers in Cellular Neuroscience, vol. 10, no. 294, 2017, pp. 1-10, doi: 10.3389/fncel.2016.00294.

2Kasatkina, L.A., et. al. “Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation.” International Journal of Molecular Sciences, vol. 22, 2021, pp. 1-35,  https://doi.org/10.3390/ijms22115431.

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