Endocannabinoids and Mental Health

Foreign. The 2021 Wellness Retreat is an opportunity for clinicians and non clinicians to enjoy fall in Tennessee and maybe even a leaf change while you take a deep dive into learning about the mind, body connection and strategies for improving your overall well being. Up to 21 CEUs will be available for clinicians, but again, you don't need to be a clinician to attend. The retreat is being held October 20th through 23rd at Cumberland Mountain State park and is limited to 60 people to allow me to have plenty of time to interact with everyone. Go to allce.comwellness to see the detailed schedule and download the registration form. I look forward to seeing you there. I'd like to welcome everybody to today's presentation on endocannabinoids and mental health. I'm your host, Dr. Dr. Donnelly Snipes. Today we're going to explore the roles of the endocannabinoid system in mood disorders, cognitive disorders, autoimmune and inflammatory disorders, pain and stress. But we're going to start out by learning a little bit about the endocannabinoid system. That's just one of those fun things to say. When I took anatomy and physiology, sternocleidomastoid, which is one of your neck muscles, was one of my favorite words. And now endocannabinoid. It doesn't take much to humor me, I guess. But your endocannabinoid system are your natural cannabinoids and your cannabinoid receptors. Your CB1 and CB2 receptors are the ones that are activated by cannabis and cannabidiol, which is CBD oil. Excuse me. So what we're talking about is the body's natural cannabinoids. The ECB or endocannabinoid system targets both monoamines, which are your neurotransmitters, and the HPA axis. For those of you who are new, the HPA axis is your threat response system or your stress response system. It kicks off when your body believes that there is a threat, either physically or cognitively, and causes your body to dump cortisol and a bunch of excitatory neurotransmitters and hormones in order to give you the energy to fight or flee. So the ECB system targets and and again, I'm I know I'm repeating myself, but it targets both neurotransmitters and the HPA axis. But it's one of those interesting systems that is not one direction or the other. It's one of your regulating systems. It can downregulate, it can help upregulate just depending on which neurons are triggered. Both monoamines and the HPA axis are disregulated during the stress induced psychiatric disorders. And they found recently at the, as they've started to investigate the endocannabinoid system, that it also may become dysfunctional. All right, so let's let that sink in. Sometimes the causes of the neurotransmitter imbalances or the HPA axis dysregulation could be due to a dysfunctional endocannabinoid system. So your underlying pathology that is causing the dysfunction may, may require a different approach in order to fix it than SSRIs, for example, because SSRIs in, in terms of depression are going to increase the amount of serotonin. But if there's an underlying pathology that's causing low cell serotonin, then people, I, if they want to fully heal their bodies, may need to ask themselves, you know, why is it that my serotonin or my norepinephrine or my GABA or whatever it is that's causing their depression is actually of whack. Hyperactivity of the endocannabinoid signaling in, in. The endocannabinoid system contributes to excessive intake and storage of high calorie foods. All right, well, that makes sense. And I will tie it back to exogenous cannabinoids. You know, your marijuana, where people get the munchies. So when people are excessively signaling, triggering those endocannabinoid receptors, it may trigger a desire for high calorie foods. While endocannabinoid hypoactivity is a risk factor for the development of depression, anxiety, and even ptsd. The endocannabinoid system is comprised of your endogenous, your natural cannabinoids, your cannabinoid receptors, and the enzymes responsible for the synthesis and degradation of the endocannabinoids. In our other presentations on hormones and neurotransmitters, we've talked about how there are multiple different ways that a hormone or neurotransmitter can be imbalanced. The body may not make enough of it because it doesn't have the building blocks it needs. So it may not make enough. The body may make enough, but it doesn't secrete enough. The body may secrete enough, but it doesn't stay in the synaptic space for long enough. But because it either gets taken up too quickly, or the enzymes responsible for breaking it down break it down too quickly. Or the fifth option is that it makes enough, it secretes enough, it stays in the space for long enough. But then once it is sucked up by those receptors, for some reason, the transmission does not continue. So there are five ways basically that the neurotransmitter system can break down. Endogenous cannabinoids are endogenous lipids that engage the cannabinoid receptors. Now this is important especially for people who are on ultra low fat diets or who don't have a good balance of omega 3s and 6s. Because your body needs a certain amount of fat to function. It needs a certain amount of fat to process fat soluble, soluble vitamins. It needs a certain amount of fat and cholesterol to make your gonadal hormones. And it needs a certain amount of fat, which lipids is another word for fat, in order to create the endogenous cannabinoids, to create those chemicals that people are so often trying to supplement. The first discovered and best characterized endocannabinoids are anandamide. I always have a hard time pronouncing that 1 and 2 AG. Not even gonna try on that one. So the endocannabinoids that we most know are anand, anandamide, anandamide and 2Ag. Both 2Ag and anandamide are agonists. That means they upregulate the CB1 and CB2 receptors. Those are our two primary cannabinoid receptors. Now, CB1 is more prevalent in the CNS, in the nervous system. CB2 is more prevalent in the, in the body and in the immune system. So you, you start to see that this cannabinoid system is not just about mood, it's not just about cognition. It actually has its little fingers in all kinds of pies, so to speak. In systems with low receptor expression, anandamide can antagonize the effects of more efficacious agonists. So in, in systems where there aren't a lot of receptors, other agonists can actually be slowed down. It can slow down the uptake and slow down the excitation. So it actually slows things down, which is kind of interesting, not something you really need to know for the test, Just kind of an interesting thing that normally it's an agonist. But if there's something else out there that's activating the cannabinoid receptors, then it's possible that anandamide can actually act as sort of an antagonist or a slowing or reversing on demand. Endocannabinoids are liberated and released into, into the extracellular space. This contrasts with classical neurotransmitters that are Synthesized ahead of time and stored in synaptic vesicles. So what does this mean? Why do we care basically? Well, if somebody is, you know, doing well, eat, living healthfully, eating a good diet, they are probably making and storing plenty of neurotransmitters. So if they go through a period where they don't have access to good nutrition or, you know, the, the system gets out of whack because they're, they don't get enough sleep or they have surgery or something else, whatever happens, there's still that reserve of neurotransmitters. But endocannabinoids don't act that way. Endocannabinoids are made on demand. So if the body for some reason does not have the supplies at the ready, then the endocannabinoid system is going to take a hit. Which is another reason why consistent good nutrition, hydration, sleep, all of those things is important. CB1 receptors are abundant in the central nervous system, particularly in the cortex, basil, ganglia, hippocampus and cerebellum. So in a lot of the areas of the brain that are responsible for our daily motor function, our thinking, our emotions, CB2 receptors are expressed at a much lower, lower level in the cns and as I said, they're more prominent in the immune system and throughout the rest of the body. Physical exercise mobilizes endocannabinoids, which could contribute to the refilling of energy stores and also the analgesic and mood elevating effects of exercise. So when you exercise, endocannabinoids are released. Endocannabinoids upregulate those cannabinoid receptors which make you want to seek out good quality food. So by mobilizing the endocannabinoids, the body is refilling its energy stores, which is a great survival mechanism. It also can help prevent pain. You know, if you work out, you're probably familiar that right after you work out, you may feel kind of tired, you may feel kind of jelly legged or something if it's been a good leg day. But it usually doesn't start hurting until later, little bit that evening, the next day you're really sore. And the day after, the day after you really feel it. And your endocannabinoids are present right when you're working out, they're present right after you're working out. So it helps with the anti inflammatory effect, it helps with the analgesic effect, it helps with mood elevating, because remember, exercise increases serotonin and they speculate that part of that may be due to increased endogenous endo or endocannabinoids. So there are a lot of benefits to exercise, and exercise doesn't have to be running a marathon. You know, people overestimate a lot of times how hard they have to work out in order to get the benefits. A second important role for the endocannabinoid signaling system is to restore homeostasis following stress. Endocannabinoids generally help the body relax, go recognize that there's no longer a threat, and help trigger the rest and digest reaction, which is the opposite or antagonistic to the fight or flea. All right, And I know the print on this is a little small, but I tried to create it myself and it still was had to be really small to get all this in here. But there's a lot of information in this, in this slide. So I encourage you to, you know, download it from the classroom and look at the slide at your on your own time. But interestingly, interesting to note, things that can increase the endocannabinoids in people's system. Stress, glucocorticoids like cortisol, obesity, food presentation, time of day. Interestingly, your endocannabinoids peak in the middle of the day. They are affected by your circadian rhythms. Your circadian rhythms are affected by your sleep, and your sleep is affected by your circadian rhythms. You start to see how all these things start to intertwine. Exercise, inflammation and tissue injury, all of these things can increase endocannabinoids in the system. So I said earlier that endocannabinoids help restore homeostasis after stress. Well, they're also involved in the stress response. So at the beginning of the presentation, I wanted you to conceptualize the endocannabinoids as a regulator. They're sort of like the traffic cop for some of the systems of the body. They're, you know, when they're letting traffic go in one direction, and then they decide, okay, now it's time to make it go in the other direction. Now, what are some of the effects of the cannabinoids? When we have increased levels of cannabinoids, we see a lot of effects that are very similar to effects that we've talked about with increased levels of serotonin and dopamine. And you're going to find out why in in the next slide. But as cannabinoid receptors get activated, it affects the whole body. And your HPA axis and your monoamines, your neurotransmitters, results in elevated mood and reduced anxiety, increased food consumption. Consumption, it promotes lipogenesis it promotes, unfortunately, cirrhosis, it can decrease satiety, satiety signals and it can decrease pro inflammatory cytokines. So there are some good things and some bad things with cannabinoid effects and part of it is whether CB1 or CB2 are being activated. And that's just way too much to get into today. But it does have positive mood effects. It can lead to increased consumption of high fat, high sugar foods, which can be not so good. It can decrease satiety. So increased or a dysfunctional endocannabinoid system that's ramped up can contribute to binge eating, can contribute to some eating issues and obesity. But as I said earlier, it also can contribute to reduced anxiety, elevated mood and decreased inflammation. We want to examine with each individual, why is it you're eating, for example, are you hungry? Are you eating because you know you're in pain and you're trying to distract yourself what's going on? In order to try to figure out more about what's going on with their over 10,000 people come to BetterHelp every day looking for a counselor. BetterHelp makes it easy for you to move your practice online and focus on what you love most, helping others. Better Help's easy to use platform, takes care of referrals and billing and provides a secured platform to communicate with your clients. Join more than 18, 000 therapists at BetterHelp, helping to improve people's mental health and lives. Changes in the endocannabinoid system are involved in several psychiatric disorders, most of them actually, and we're not going to go through all of them here because we don't have enough time. But serotonin is one of our monoamines, is one of our neurotransmitters. The endocannabinoids reduce serotonin release in the CNS via the activation of the CB1 receptors. So if the CB1 receptors are activated, then you're actually going to see less serotonin and you might be scratching your head going, that sounds like a problem there. Well, not necessarily because too much serotonin is associated with anxiety. So if people have anxiety because of excess serotonin, this can help them feel more relaxed and happier, have an elevated mood and reduced anxiety. Early evidence for a role of endocannabinoid signaling in the regulation of the serotonin system 5ht is the chemical representation of serotonin suggest that a high level of functional overlap between the serotonin and endocannabinoid systems. Both serotonin and endocannabinoid systems regulate body temperature, feeding sleep, arousal, or energy and emotional processes. So they are. Both of these systems are involved in most bodily and cognitive functions. That's important to recognize. So if either one of them goes wonky, it's going to affect the other one. And if either one of them goes wonky or both go wonky, I know clinical term there, it's likely going to lead to certain physical and or psychiatric issues. Dopamine is another neurotransmitter. CB1 receptors tightly regulate dopamine activity. They're expressed at presynaptic inputs to the dopamine neurons and either facilitate or suppress dopamine, depending on their location. So dopamine is one of those neurotransmitters that gives us motivation, it gives us energy, it helps us stay focused. When dopamine goes up, a lot of times, not always, but a lot of times, endorphins also go up. So it's important to recognize that dopamine or low dopamine can also contribute to depression. If the endocannabinoid system is not working correctly and it's suppressing dopamine, then that can be a problem. If the activation of the CB1 receptors is calibrated, for lack of a better word, then the body is going to be getting enough dopamine. So if there's a breakdown in the end, in the endocannabinoid system, then we may see insufficient dopamine. Sometimes you can see excessive dopamine, depending on, you know, again, whether the receptors that are wonky are the ones that are antagonistic or agonistic. But the point remains the same. Endocannabinoid system can impact dopamine levels. GABA is our natural valium. It's our endogenous volume, if you want to think about it that way. CB1 receptors upregulate GABA neurotransmitters, thereby reducing pain signals throughout the body. CB1 receptors have been shown to be localized presynaptically on the GABAergic interneurons and glutamatergic neurons. So GABA is made from glutamate, and glutamate is our main excitatory neurotransmitter. GABA is when glutamate's broken down and the body says, okay, we can relax, then GABA is made. So it's interesting to note that the door to where the GABA and glutamate are hanging out is regulated by the endocannabinoid receptors, the CB1 receptors that are there. So if that bouncer, if you want to think about it that way, if that bouncer is not doing his job correctly, then there may be a breakdown and not enough GABA will be made or too much. There will be too much activation of glutamate. So the endocannabinoid system helps tell your body, what are we supposed to do? Are we supposed to release glutamate, you know, that comes from the HPA axis, or are we supposed to trigger rest and digest and break down glutamate to make gaba? Norepinephrine is yet another neurotransmitter involved in psychiatric issues. The endocannabinoids are capable of attenuating the neur norepinephrine excitability. So endocan endocannabinoids can actually slow down or tamp down the excitability of the norepinephrine receptors. Overexpression of endocannabinoids have also been shown to increase basal norepinephrine activity. So overexpression of endocannabinoid can also lead to the opposite where you have excess nor norepinephrine activity. The pattern and time course of endocannabinoid release in the prefrontal cortex will be influenced by the controllability of the stress. And I wasn't exactly sure where to put that because a lot of stuff is dumped into the body when people are under stress. You have your glut mate, your norepinephrine, your adrenaline, your thyroxin, you know, a ton of stuff, cortisol. But they did do a bunch of studies and they found out that when people believed the stress to be more controllable, it altered the release, it altered the pattern as well as the amount of endocannabinoids that were released into the system. Obviously, when they perceived the stress to be more controllable, there was less of a surge and there was quicker return to baseline. There was quicker downregulation. And if you remember, in people who are prone to emotional dysregulation, including those that eventually go on to develop diagnosable borderline personality disorder, when they become dysregulated, they stay upregulated for longer, and it takes them longer to down regulate. It's not that they perseverate, but they. It actually takes them physiologically longer to down regulate, which indicates that there may be something going on in that endocannabinoid system. But it, you know, there's a lot of different places it could come from. But people with borderline personality disorder and those who tend to habitually disregulate and exist in what they perceive as invalidating and unsafe environments, perceive stressors as much more uncontrollable as those who live, who are not highly sensitive, who don't dysregulate, and who live in a safe environment. So it is interesting that one way that we can help people regulate their endocannabinoid system and by virtue of that regulate to a certain extent their HPA axis, is by helping them feel a sense of safety and empowerment in the face of stress. Evidence suggests a link between a CB2 receptor dysfunction and an increased risk for schizophrenia. Well, that's interesting because CB2, as I've mentioned multiple times, is not nearly as prevalent in the central nervous system in the brain as CB1. But they have found that there are links between CB2 dysfunction and schizophrenia. Dopamine receptor stimulation increases anandamide levels. So as dopamine goes up, anandamide goes up. Remember, there are multiple endogenous opioids. I'm sorry, not opioids. There are multiple endocannabinoids that exist. We've really only begun to study two of them so far. Likewise, when you talk about the cannabis plant, there are multiple cannabinoids, exogenous cannabinoids in each in the cannabis plant. And we only know about some of them and we only are super familiar with two of those. So we have a lot to learn about the cannabinoids and the endocannabinoid system. CB1 receptor antagonists. So. Substances that people use that will suppress CB1 receptor, kind of turn it off, suppress the increased locomotion seen with excessive dopamine. So when you see people who have excessive dopamine, remember, we see that in schizophrenia. That's what a lot of your antipsychotics do, is reduce dopamine levels. But you can also see dopamine alterations in Parkinson's disease and when. So CP, CB1 receptor antagonists can help reduce some of that agitation. CBD. Now that's not an endogenous opioid. That is an exogenous. I'm sorry, I keep saying opioids. I'm so used to that. That is not an endocannabinoid. CBD is an exogenous cannabinoid. That is a cannabinoid that is gotten from the cannabis plant. They found that CBD is protective against acute psychotic effects of THC or ketamine in healthy volunteers. So it's interesting that they found that. They've also found, as a little aside, again, in an exogenous cannabinoid. That CBD seems to counter the effects of THC when. So a lot of the Nabix malls, which are the prescription cannabinoid medications that are out there, a lot of them are in a one to one ratio of CBD to THC or higher levels of CBD and lower levels of thc because the CBD tends to be more neuroprotective and provide more anxiety reduction in a lot of people. Cannabinoid receptor agonists such as AEA have been shown to provide protection against neurotoxicity. So when we increase the cannabinoid levels in the brain like CBD as, as an exogenous cannabinoid has shown to do, but when we increase endogenous cannabinoids, that can also be protective against the excitatory neurotoxicity that occurs when people are under chronic stress. Chronic stress amps up, ramps up that HPA axis. So you've got a lot of excitatory neurochemicals just flowing through the body, flowing through the brain. And for lack of a better analogy, your body is running really hot and it runs too hot at a certain point and it becomes neurotoxic, it becomes too hot and the neurons start to die off, they start to get pruned back, as they say. But they found that increasing the activity of the cannabinoid system provides protection. Activation of CB1 and CB2 attenu attenuates the beta amyloid induced neuroinflammation. Now, if you're familiar at all with Alzheimer's disease, you know that this is one of the main issues that is associated with the development of Alzheimer's disease is the beta amyloid plaques. And activation of the CB1 and CB2 receptors has been found to reduce that neuroinflammation, neuro degeneration, and spatial memory impairment. So there's a lot to be said for figuring out how to help people make sure that their endocannabinoid system is healthy. And there's a lot of research going into looking at exogenous cannabinoids in the treatment of certain neurodegenerative disorders. And it doesn't stop there. We've talked about anxiety, we've talked about depression, we've talked about schizophrenia and Alzheimer's and dementia. But gut health is also impacted by the endocannabinoid system. Your gut microbiota modulate the endocannabinoid system to regulate energy metabolism and gastrointestinal function. So the two of them work together to figure out what needs to happen. If the gut and the brain. In the gut brain axis that is connected by the vagus nerve, if that axis is saying bad stuff is happening, fight or flee, then the endocannabinoid system will alter energy metabolism in order to make sure that the body has sufficient resources to fight or flee. Then once the threat has passed, it alters our hormones, our, our gin and our leptin in order to promote hunger and so we can refill those energy stores. The endocannabinoid system is a key modulator of gastrointestinal physiology. It influences our hunger and sat satiety, which is our gin and our leptin. Our immune function function, our mucosal integrity, motility, secretion and visceral sensation. So it affects how our tummy feels, how quickly stuff moves through. Remember, when it's time to fight or flee, then the body tries to clear out as much stuff as possible because it doesn't have time to focus on, on digestion at that point in time. When we're resting, we're resting and digesting, then things are going to sl down a little bit more. And the endocannabinoid system is responsible in part for helping to regulate the speed of gut motility. We've talked about leaky gut and in the leak in your gut, serotonin is made. 90% of your serotonin is made in your gut. And 5ht mucosa is, helps line the intestinal systems and that keeps some of the toxins from the digestion of food and breakdown and all that other stuff. You know, some of the ickies from your, from your intestines, from leaking out through the porous membranes that are your intestines when the mucosa, because our gut microbiota is not healthy, because we're not making enough serotonin to support that system for whatever reason reason. And this often happens under stress. When your mucosa becomes thin, then bad things can permeate into the body which promote systemic inflammation, including in the brain, which, and we know that systemic inflammation is associated with depression. Mucosal integrity is important. So we want to make sure for, for mood, not just for immune system functioning. In terms of immune system functioning, autoimmune disorders are basically the body attacking itself or a rogue immune system, a hyperactive immune system. And in autoimmune disorders, one of the key features, or the key feature is inflammation. Back to what I just said. We know that systemic inflammation is associated not only with depression, but with autoimmune disorders and one of the causes or contributors, not causes, contributors to a dysfunctional immune system or lack of mucosal integrity or even poor nutrient absorption can be a breakdown of the endocannabinoid system. Increasing evidence shows that the levels of endocannabinoids and or cannabinoid receptors are altered in patients with intestinal dysfunction. So there's direct evidence pointing to the fact that people who have intestinal dysfunction have altered, have a wonky endocannabinoid system. And the, the body has tried to adjust, it's tried to alter, it wants to maintain homeostasis, but it may not be able to figure out how to fix the machine. So, so they're ultimately the person ends up experiencing problems. People with diverticulitis, inflammation of the diverticula, celiac disease, irritable bowel syndrome, inflammatory bowel disease and even colon cancer have been shown to have a dysfunctional or alterations in their endocannabinoid system. That's important to look at, you know, with the exception of colon cancer. That's, it's a whole other thing. All of these diverticulitis, celiac disease, irritable bowel syndrome and inflammatory bowel disease are all associated with increased inflammation and with problems within the gut system. Denise asked for someone with IBD or other diseases who may need a bowel resection during their lifetime. What would that resection contribute to their endocannabinoid system? My guess would be, and I am not a gastric surgeon, that taking out the diseased portion of the bowel that is not able to repair itself may contribute to healing of that endocannabinoid system. Because it the body quits having that hyperactivation of the HPA axis from the signals coming from the gut going, there's a problem here. So if you want to think of it this way, people who have I irritable bowel syndrome or some sort of intestinal dysfunction that is perpetual, they are in pain a lot and it ends up causing, you know, ulcers and things like that. But basically that's like having practice online. Alarm bells going off, helping 247 better. So there's easy to use a signal takes care of going on from somewhere in your body, telling your brain platform 24 hours a day, hey, there's a break down clean up on aisle three helping. So my guess is mental health again, and it's only a guess, would be that if it gets to that point where that tissue is just done that it probably would help the body regain homeostasis through that resection. But that's a really good question. Activation of the CB2 and adenosine receptors leads to a decrease in oxidative stress and inflammation. CB2 is that one that's involved in your immune system mainly. And oxidative stress, remember, happens when you go through the day, through the breakdown of nutrients and everything you do. There are toxic byproducts that are created. Those toxic, toxic byproducts are referred to as free radicals. And normally your body can handle those. And the janitor comes in and cleans everything out and it's all good. And you know, obviously I'm speaking hypothetically here, but when you have too much stress, when you are anxious a lot, when you're running hot, think about driving a car. And instead of driving easy, you know, you're cruising along at 60 miles an hour on the interstate. Interstate or something. You've just got that puppy floored and you're going as hard and fast as it can. And the temperature of the engine is pegging out. You're going through gas like nobody's business. Well, that's kind of what your body does when it's in a perpetual state of stress. And just like the engine starts having difficulty cooling itself off after a while, your body has difficulty clearing out all of those free radicals. And the buildup of those free radicals is referred to as oxidative stress. And when our body can't get rid of all of those toxins, then it starts causing problems in our, in our system. However, CB2 and adenosine both help clear those things out. CBD is one of the main pharmacologically active phytocannabinoids. It's an exogenous, that means it's made from outside of the body. But phyto means it's made from a plant. Obviously it comes from the cannabis plant, but it is one of the main pharmacologically active phytocannabinoids. THC is the other one. CBD is not psychoactive, but it has many beneficial pharmacological effects. Now psychoactive in terms of it doesn't make you feel high, it doesn't make you feel loopy or whatever word you want to use. However, it does have anti inflammatory effects. You know, it helps activates the CB2 receptors. That helps get rid of some of those inflammatory cytokines through in the, throughout the body it acts as an antioxidant. It goes around and helps your body clear out those free radicals. It just, you know, goes on, grabs one of those free radicals and says Come with me. We're going out through the, through the kidneys or whatever. It's anxiolytic. It actually helps people reduce their scent, their anxiety, and they expect that that's because it can actually reduce serotonin levels, but they're not exactly sure why. They do know that it does tend to reduce anx anxiety. We also know that when people are in less pain, they tend to be less anxious. So that may be another byproduct of the pain management. It has antidepressant effects a lot of times because it helps regulate. It's not altering in any major fashion the dopamine, the neuro, norepinephrine, the serotonin. But it's helping the body find homeostasis. That's what it's designed to do, is help everybody. It's kind of like a family counselor, if you want to think about it that way. It's kind of like a family counselor for, for all your neurotransmitters. It's trying to help everybody find their, find their balance in the body machine or body factory. It has antipsychotic effects and anticonvulsant properties. GABA tends to be your main neurotransmitter that's involved in anti convulsant types of medications. And so by virtue of the fact that your endo endocannabinoid system does alter the levels of gaba, increasing can help reduce convulsions, chronic stress and steroid treatments, which steroids ramp up that HPA axis and amp up the system. Chronic stress and steroid treatments are both known to impair the endocannabinoid signaling at multiple levels. So as clinicians, we can help people address their chronic stress to the best of their ability. Stress related downregulation or antagonism of the CB1 receptor leads to greater changes in glutamatergic signaling and excitotoxicity within the prefrontal cortex following chronic stress. So when the endocannabinoid system is antagonized by stress, then there, there's more glutamate being secreted. The body's going, oh, there's more to be worried about. We need more energy. So there's more glutamate being secreted and there's more excitotoxicity because more glutamate means more heat, so to speak. So it becomes more excitotoxic in the brain, specifically the prefrontal cortex, which is where we do our higher order thinking and we have our impulse control and all those other things. So it's important to be aware of that interconnection that chronic stress hampers the functioning of, of this system. It's been repeatedly shown that CBD and THC concurrently, remember I said they work together, decrease anxiety and depression. Now CBD and THC can be altered in their proportion to one another. In most medical cannabis the CBD is much higher than the THC because they're going for the reduction of inflammation, they're going for the anti anxiety and those sorts of things. But as I said, a lot of the, what they call them, they call them nabix mals have a one to one CBD THC ratio. In studies they've shown that the use of these two things together can decrease anxiety and depression, which leads us to believe that in those people for which this is effective, they may have a breakdown in their endocannabinoid system. Essential oils, and specifically terpenes or the aromas in essential oils can Also activate your CB1 and CB2 receptors, your cannabinoid receptors, and are associated with cognitive and mood effects. They found, interestingly enough, it's called the entourage effect, that when you have for example, CBD alone or THC alone or the terpenes alone, they have certain effects. But when you start combining them, their effects are exponentially additive. So together they are far more powerful than each one of them independently, which is, which is really kind of cool to think about. And, and when we consider the impact of, for example, people, some of your clients may be taking exogenous CBD oil right now, obviously exogenous. So for them, they are getting cbd. Now if you combine that with chronic stress management to help them naturally try to help regulate that HPA axis with health related behaviors and cognitive behavioral therapy, but then pair that also with terpenes from essential oils, there's a potential that it could have an exponential, exponentially positive effect. They've shown the same thing, and I know I'm off on a little tangent here, but they've shown the same thing in nature therapy, forest bathing, whatever you want to call it, that people who are exposed to the terpenes or the aromas from plants experience reductions and anxiety and reductions in pain. And they're, they don't exactly understand why, but it is interesting if you're into essential oils at all, to look at the different terpenes. I actually have a video on the YouTube channel. I went through some of the different terpenes that are present in cannabis, the plant, to examine some of the information about the entourage effect and why Whole cannabis in some ways may be more beneficial to people than extracts. Not that I'm. Not that I'm promoting it. I'm just saying it may have different effects from a medicinal, clinical standpoint. Interventions. What can people do in order to maintain the health of their endocannabinoid system? If they have anxiety, depression, dementia, Alzheimer's disease, there's a lot of things where nutritional interventions can play a big role. Interestingly enough, a lot of the endocannabinoids are actually made from omega sixes. And they are sort of the bad guys of the Omega 3s. When you hear about them, generally, you should have. I believe it's a 1 to 25 ratio. I can't remember right now what the ratio is of omega 3s to omega sixes. Americans have way blown out that ratio. We tend to have a very, very minimal level of omega 3s to omega sixes. So omega 6s are still important. But omega threes are also important in regulating inflammation and keeping the endocannabinoid system healthy. So you don't want to eliminate omega 6s? I don't know that that's even possible to do. You don't want to eliminate them, but it's important to try to get that ratio back in balance. Flavonoids, those are the substances that are in those really colorful flavors, fruits and vegetables. Flavonoids can inhibit endocannabinoid degradation. So eating a diet that's colorful, three colors on your plate at every meal, that's a rule we have in, in our family. They can inhibit the breakdown of those endocannabinoids when they're in that synaptic space, so they stay there a little bit longer so more of them can get absorbed. Meditation can increase your endocannabinoids. When you are starting to relax, your endocannabinoids typically go up. Endocannabinoids also promote relaxation. So anything you do that promotes relaxation is also going to cause increases in endocannabinoids, which can further promote relaxation, strengthening of the immune system, and reduction of inflammation. Exercise. We've already talked about how exercise increases the endocannabinoids that can help with pain relief. But also, you know, right after you work out, the endocannabinoids are part of the reason that you may be hungry. And sex, you know, I threw that in here because whenever I can find literature that actually supports that as a, you know, positive intervention, I always try to give people the benefit. But sex can also cause a confluence of release of different neurochemicals that promotes increases in the endocannabinoids in your body, which promotes neuro, neurogenesis, neuroprotection, reduced inflammation, improved, improved immunity. There's lots of good things that happen. So the endocannabinoid system interacts with most other bodily functions and neurotransmitters, including your circadian rhythms. So if your circadian rhythms are out of whack, your endocannabinoids may be out of whack. And when you're hungry and when you're satiated may be out of whack. Problems in the endocannabinoid system are associated with chronic pain and inflammation, GI disorders, gastrointestinal disorders, mood disorders, neurodegenerative disorders like Alzheimer's or Parkinson's disease, and even metabolic disorders. When you're, when you've got more inflammation and, or when your circadian rhythms are out of whack, it is more difficult to regulate your blood sugar. So people who have problems with their endocannabinoid system are often also going to have more Difficulty maintaining their A1C levels or their blood sugar levels. Now that's not that, that is a, you know, down the road consequence. There are a lot of people who have dysfunction in their endocannabinoid system that don't go on to develop metabolic disorders. So you don't want to use that as a rule out factor. It's also interesting to note, as long as I'm here and we've got a little more time, that up to 25% of the population in America is pre diabetic and doesn't even know it. Just let that sink in for a minute. People who are pre diabetic, their body is already having difficulty managing their blood sugar levels. They're already insulin resistant. As they say. Endocannabinoids are created partially from lipids, particularly those omega 3s and 6s. So eating a diet that is has some of the healthy fats, obviously moderation is the key everywhere and reducing HPA axis activation and increasing serotonin and dopamine will all increase endocannabinoid levels. So some of the ways, if you go back to any of my presentations on aromatherapy, there are a lot of essential oils that actually have been shown and you can go into PubMed and, and read the journal articles or you can just click on the links and the presentations but there are a lot of essential oils, the terpenes and the essential oils that actually do increase levels of serotonin and dopamine. So that's another one of those non pharmacological you know, for people who don't want to be taking a bunch of medications, it's something they can talk about with their doctor. I know we went through a lot. Are there questions, any other questions about the endocannabinoid system or the endocannabinoids and mood or cognitive disorders?