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00:02 This is lecture 14. And as explained we're actually going to cover the

00:07 system today. Instead of the taste smell that is listed on the

00:13 So this will be covering the endocannabinoid and this first slide actually doesn't show

00:19 the endocannabinoid system that shows you what talked about in the last couple of

00:25 . And what we really did is walked through one of the major sensory

00:32 in the C. N. It's a visual system and we understood

00:36 components in the retina and the components the lateral gene Nicollet nucleus All the

00:45 through the primary visual Cortex in the v. one. And we understood

00:51 in this area v. one is you we are capable of generating the

00:59 sketch of this visual world because of properties of certain properties of the cells

01:07 the primary visual cortex and receptive fuel . And so this shows you the

01:15 system would have system, it has components. There is a sensory photo

01:23 , it needs to be activated. information is conveyed by retinal ganglion cells

01:29 L. G. N. There's at the level of the thalamus and

01:33 ventricular nucleus. Before that information goes primary visual cortex and this is where

01:40 kind of a stop. But in the visual information is tied with other

01:46 And visual information further from area V divides into two mainstreams. The dorsal

01:56 pathway that targets the posterior parietal So this is would be area V

02:03 which is area 17 on broad most V Two. Area 18. Then

02:10 you get even further remember these are primary, secondary tertiary. And then

02:17 have to enter into the association So you have to start associating that

02:23 primal sketch with other things and other for example that are indicated by this

02:31 . So as you can see this , the posterior parietal cortex pathway through

02:37 area M. T. Is going be concerned about depth processing about motion

02:46 about four. And there is a pathway that is targeting the inferior temporal

02:55 . It's the ventral inferior temporal And if we follow through that

03:02 the bulk of what that pathway is about is the color in the

03:11 So as we always talked about there parallel streams there's redundancy that means that

03:17 level the color is primarily dominating in cortex. But if you're looking at

03:23 form which is more important than color basic rudimentary human survival, it's more

03:32 to process the form. And you see that the form processing and also

03:36 depth processing is is redundant and you find it along this two different bath

03:46 . So when you talk, when talk next lecture about the taste and

03:51 or faction uh and in particular we talk about another two sensory systems in

04:00 C. N. S. Now other thing to remind ourselves is that

04:09 of the components in the brain in C. N. S. Are

04:16 throughout the central nervous system. So as amino acids neurotransmitters, glutamate and

04:22 . They will be expressed throughout in parts of the cortex of cortical tissue

04:28 the cerebellum in the spinal cord. you'll find these neurotransmitters everywhere, the

04:36 much that synthesize those neurotransmitters, you find them everywhere and they are primarily

04:45 for the major excitation glutamate in the and inhibition Gaba in the brain.

04:54 we discussed these other modular tutorial neuromodulation substances and I've used this analogy that

05:02 excitation as plus an inhibition as minus black and white. Then these neuromodulation

05:09 molecules such as the means such as such as serotonin, they add the

05:16 the grayscale or color in general to activity of excitation and inhibition. They

05:22 localized the selma's that produced these neurotransmitters localized in the specific brainstem nuclei such

05:29 Locusts, Aurelius, for norepinephrine and nuclei for sartre ona and they will

05:36 this molecules throughout different parts of the so as in above the major information

05:45 the sensory system for example from the into L. G. And that's

05:50 be conveyed with glutamate with excitation. you recall in the L.

05:55 N. You have this sheet a of particular nucleus which is inhibitory.

06:00 there's excited or inhibitor circuits with them and then again these long range projections

06:07 are excited to our projections. The sauce from the thalamus will carry that

06:12 into the cortex. And of course of these areas will also be receiving

06:20 all of the cortical areas will be these other modular torrey inputs from the

06:27 systems if you recall, they're very and not only modulating the activity but

06:34 important and plasticity. And in particular looked at how spike timing dependent plasticity

06:43 can be changed and modulated by introducing amino neurotransmitters and neuro modulators. So

06:54 are different systems. There are chemical and there are neurotransmitters within these chemical

07:01 that are found throughout the cns are systems that are confined two nuclei in

07:08 brainstem but their projections are wide throughout cns. Okay. And then this

07:16 a summary of the neurotransmitters that we them, you know, assets and

07:22 mean neurotransmitters and today we're going to about the endocannabinoid system. An endocannabinoid

07:30 was discovered in the 1990s. It a group of Israeli scientists led by

07:37 national um that discovered different components of endocannabinoid system. But as we know

07:46 we know of the endocannabinoid system today that we have a reason to believe

07:53 it is one of the major homo and regulatory brain and body systems and

08:04 are different components of the endocannabinoid These are the major components of the

08:12 system. You have this synthesizing and enzymes. Again you have these small

08:20 that synthesize undo cannabinoids that are as here, the two major into cannabinoids

08:28 our bodies are to our aka donald , often abbreviated as to A

08:37 And and undermined anandamide and nanda and means a bliss. So it's a

08:48 molecule, that's what anandamide is named These and other cannabinoids that are synthesized

08:57 our bodies. They target cannabinoid receptors one And CB two and binding of

09:05 ominous to CB one and CB two in the brain and then the body

09:10 cause physiological and also psychological responses. just like with other molecules, glutamate

09:21 re synthesized reintroduced into the glutamate So you can adenoids, they get

09:28 and they get reintroduced back into the . Now, components of the endocannabinoid

09:36 are distributed widely throughout the brain and body And what this poster is showing

09:44 that CB one receptors, cannabinoid one are dominant in the brain.

09:53 the C. N. S. are CB two receptors and we will

09:58 at where those receptors are expressed on their function is But CB one is

10:05 the brain. CB one is also a lot of the digestive system

10:12 Okay. and high expression of CB receptors in the heart as well but

10:21 every cell in the body. And brain produces under cannabinoid molecules or has

10:30 of the endocannabinoid system which is the the molecules and the target receptors,

10:38 are cannabinoid molecules and CB one receptors important. Cannabinoid receptors in the brain

10:47 the most abundant G protein coupled receptors the brain. That's significant. If

10:56 told you that serotonin receptors five hT Ahmedabad tropic are the most predominant you'll

11:03 wow that must be important. Serotonin play important roles. So wow that

11:08 be important of CB one receptors cannabinoid in the brain that a G protein

11:15 and metabolic tropical signaling inducing receptors, the most dominant, the most prevalent

11:24 the expression levels in the cns CB receptors Are dominating in other organs over

11:34 brain. However, you will find two receptors in the brain as well

11:38 we'll discuss today with CB two receptors be dominant in the organs such as

11:47 . Find it in the bone marrow general, the organs that are responsible

11:54 amassing and regulating the immune response In brain. CB one receptors are distributed

12:07 . It's very abundant. The most but as you know different parts of

12:12 . n. s. serves different . So this is a really good

12:19 that actually tells you about some of major parts of the brain and what

12:25 parts of the brain are responsible for four effects of endocannabinoid molecules or cannabinoid

12:34 in different parts of the brain on receptors can affect and modulate all of

12:42 listed functions that you see here now is primarily focused on CB one

12:50 CB one receptor was always the first for neuroscientists and in fact it was

12:58 in the brain looking that discovered the of under cannabinoids because CL one receptors

13:06 the brain are responsible for inducing the effect and this high effect is what

13:12 reported with cannabis or marijuana plants that cannabinoids or phyto cannabinoids. So there

13:19 always an interest to figure out While one receptors are located especially in the

13:28 , the ones that have high expression are abundant here are the structures that

13:35 labeled in red. So you can that prefrontal cortex which is responsible for

13:42 function, basal ganglia which is involved cognition. Learning emotional response and motor

13:50 . Motor command controls cerebral cortex. cognitive functions also primary sensory functions in

13:59 ways hippocampus which is concerned with learning and stress and sarah balham which controls

14:09 are 12345 parts of the brain here are highlighted, They've contained high levels

14:18 CB one receptors therefore effects of endocannabinoid CB one receptors would be dominating in

14:26 particular areas of the brain. as you can see the other areas

14:32 the brain and amygdala which processes emotional of fair hypothalamus, temperature regulation.

14:39 balance, reproductive function, energy Perrier aqueduct alegre that is important involved

14:48 analgesia nucleus of solitary tract visceral nausea and vomiting brain stem which

15:00 arousal, temperature regulation motor control and the spinal cord of course, you

15:07 , it's peripheral sensations including pain but also motor commands through the spinal

15:13 So it's everywhere in the brain. a significance for the fact that you

15:19 CB receptors in the center in the stem the processes pain which is

15:27 And so these are some of the properties of endocannabinoid is there are involved

15:34 pain response and analgesia and also in control of the spain through the brainstem

15:43 . The other important thing to know that although cannabinoid receptors are expressed in

15:50 brain stem, the areas where they expressed in the brain stem are not

15:59 for vital body functions such as heart and breathing. And that's the difference

16:09 and the cannabinoids and opioid receptors. receptors actually are located in the brain

16:17 centers that control breathing and heart rate that's why opioids are so much more

16:26 . Then cannabinoids that are externally Okay, But this is an important

16:33 here. So again different parts of brain are responsible for different functions.

16:43 post rima that was mentioned is involved nausea and vomiting and this is also

16:50 known function of that cannabinoids, including and phyto cannabinoids, cannabinoids found in

16:59 , they control vomiting and nausea. in the brain circuits. If we

17:08 at the tripartite synapse between neurons and . We have the following information that

17:16 already familiar with. You have action which will de polarize external terminals.

17:22 is going to be an influx of through volt educated calcium channels. This

17:29 will allow for the fusion of the and the release of the neurotransmitter,

17:35 release of the neurotransmitter. For example it is glutamate will cause excitation post

17:43 aly by binding to glutamate receptors. it binds to the NMDA receptors is

17:48 to be a significant influx of calcium sodium there's gonna be significant deep polarization

17:55 optically and rises of calcium post synaptic and with very high levels of

18:02 Endocannabinoid molecules will be synthesized on demand synaptic lee. They're not going to

18:12 stored in the vesicles thereby they will diffuse through the plasma membranes. Travel

18:20 lee to the pre synaptic side where bind to the CB one receptors and

18:26 one receptors are G protein coupled receptors will actually close this calcium channel and

18:36 calcium influx. So through this neuronal and the cannabinoids can really regulate the

18:44 of glutamate release and that is very . So the endocannabinoid synthesizing enzymes that

18:51 shown here as possible. Title Anomie. Uh An NSL Foster

18:59 ethanol, amine, nape and I. Which is prospect title in

19:04 hospital and D. A. Which is diacetyl glycerol which are necessary

19:11 to produce to A. G. you remember something about the absolute

19:24 The divergent pathway and glutamate signaling formidable glutamate signaling. It diverges into

19:32 P. Three from P. P. Two and membrane bound

19:36 A. G. So glutamate activation metabolic tropic receptors would actually contribute to

19:44 levels of D. A. As well. What I'm saying is

19:48 there are mechanisms that will be induced up regulated calcium and phosphate synaptic deep

19:56 . There are mechanisms that are gonna induced through already measurable tropic receptor

20:03 And the inter cellular mechanisms cascade mechanisms as D. A. G.

20:07 can now serve as the necessary enzyme the synthesis of to A G.

20:13 raise the levels of that to A . On demand. Then this negative

20:18 loop can control the release of It's negative feedback because if there is

20:24 lot of glutamate, if there is lot of influx of calcium and a

20:28 of deep polarization, what happens is neurons can go through what is called

20:35 or calcium excited toxicity. They get up with so much calcium. There's

20:41 much active. There's so much glutamate neurons start dying slowly. They're

20:49 It's called hyper excitability and neurotoxic So by activating CB one receptors now

20:59 can regulate the levels of glutamate that being released. Glutamate is not the

21:05 neurotransmitter that is regulated by the end cannabinoids. Gaba can also be regulated

21:12 endo cannabinoids? So endocannabinoid through CB regulation pre synaptic Lee has a really

21:22 influence of being able to modulate and the amount of both excitation and inhibition

21:32 these neuronal communications. So now as can see glia cells and in particular

21:40 glial cells will be abundantly expressing CB receptors. And obviously the glial function

21:49 you're talking about astrocytes then they are in your restaurants that are cycling like

21:55 . But if you're talking about micro , what is the involvement of endocannabinoid

22:01 CB two receptors and micro glia CB receptor controls neural transmission and you can

22:08 about it as a faster system because having neurotransmitter release glutamate, post synaptic

22:14 polarization action potentials CB two receptors in in particular michael glia. They are

22:23 in regulating inflammation and immune response. glia, one of the functions is

22:32 , release their pro inflammatory molecules that called cytokines. So we've learned a

22:38 bit about micro glee and we said microglia are the scavengers and they're the

22:44 mobile glial elements of the brain that responsible for damage cleanup and repair in

22:50 of traumatic brain injury or chemical So but michael, we are also

22:59 for cytokine release and these cytokine molecules inflammatory molecules it's a normal response to

23:09 inflammation in case of injury in case toxicity in case of infection.

23:17 And it's important to have that inflammatory and start generating an immune response to

23:23 . For example infection, it can a covid infection in the brain.

23:29 if those cytokine levels are unchecked let's it was a very strong trauma,

23:35 was a very uh strong viral load infection in the brain. Then you

23:43 upset the side of kind balance and those upset cases there's too much of

23:50 release its uncontrolled and so CB two that cytokine release in the ways modulating

23:58 slower processes that are involved with inflammation are involved with immune response. Now

24:07 have the endocannabinoid system That can through one receptors can control the fast neural

24:16 And regulate the balance of excitation and plus and minus and through CB two

24:23 than the cannabinoids can control the slower that are involved in the inflammation immune

24:31 and as well as repair uh in cns. Yeah, so they know

24:44 gonna talk about the oh factory system because it's uh a cool system to

24:53 . And and it's also relevant for things. For example when you smell

25:03 that smell enters into your nasal cavity in that nasal cavity you have nerve

25:11 that are hanging out there like sort a little nerve endings hanging out that

25:16 uh shown here, these are the factory receptor cells and their nerve endings

25:24 actually hanging out through this what is all olfactory epithelium. Okay, so

25:32 are not the only cells that you'll the olfactory epithelium there's a whole collection

25:38 cells like supporting cells which will find too. But these are the receptor

25:45 just like we had the photo receptors the retina. These are the nasal

25:50 . So these are the olfactory receptors the structure of the skull in this

25:57 is weird because it has these very openings, very small cavities or administrations

26:07 the skull. It's called the crib plate. And these little administrations will

26:14 the site where you can see you the olfactory receptor cells that will have

26:20 peripheral nerve ending that's concerned with smelling and nasal cavity processing that information and

26:28 sending that information through the central axon the olfactory evolve. And more specifically

26:38 the glimmering realist in the olfactory bulb contacts onto the second order of factory

26:49 and the second order of factory neurons send their output to olfactory cortex.

27:01 , so this is how the information into the brain. So the smell

27:06 the odor molecules get detected that way they get processed eventually. The perception

27:13 smell through olfactory cortex. Part of pathway goes through thalamus part of the

27:19 goes directly into cortex. Now, are we talking about marijuana and munchies

27:28 ? When we're talking about the olfaction these circuits because you guys understand these

27:34 excited or inhibitory circuits. You understand CB-1 receptors how they can control excitation

27:40 inhibition. So a well known consequence marijuana intoxication or I guess getting high

27:51 of appetite and effect known by users the munchies. The active ingredients in

27:59 is Delta nine tetrahydrocannabinol THC, which neuronal functions by stimulating a receptor called

28:08 receptor CB one. So then the molecules that bind to CB one receptors

28:15 also the CB one receptors are also too. Exogenous molecules of phyto cannabinoid

28:25 . So the exogenous cannabinoid molecules can with the endogenous system. So there's

28:32 molecules like DELTA nine THC which comes cannabis plants, interacts with the cannabinoid

28:41 , it interacts with other systems and receptors but it interacts with cannabinoid

28:47 CB one receptors are abundant throughout the . So it is overly simplistic to

28:53 these receptors of serving only appetite regulation we just talked about. Nevertheless,

29:01 marijuana is often prescribed were legal as to stimulate appetite in patients with chronic

29:08 such as cancer and AIDS. So enough, When Cannabis was placed on

29:18 one which means it doesn't have any purpose and it is highly addictive and

29:25 . It was done in the 70's the same time. There was AIDS

29:35 problem that was happening and there was way of treating patients that had AIDS

29:45 these patients would go through what is the wasting syndrome, they wouldn't

29:51 There's no appetite a lot of times were subjected to very heavy doses of

29:58 or radiation therapy which caused a lot nausea lack of appetite, immobility,

30:07 and weakness of the patients would literally wasting away their bodies. And the

30:15 in California noticed that if they give patients marijuana or candidates, if they

30:22 that and boost their appetite, it their appetite and it also reduces the

30:29 at the same time. So those cancer patients and those with AIDS

30:35 And so in the 70s, about same time as cannabis by the federal

30:44 , FDA Food and Drug agency placed on this most severe schedule of drugs

30:51 you find heroin. Uh there was very significant movement, I would

31:00 And also facts that people are observing in legal states mostly, but also

31:07 illegal where cannabis was illegal. So compound that inhibits CB one receptors,

31:15 Bond was also developed as an appetite . So the idea was that if

31:23 stimulate CB one receptor CB one receptor mm Promotes appetite. So if you

31:32 CB one receptor with an antagonist, then you would reduce appetite and people

31:42 oh my God this is great because this is like you know, weight

31:46 pill, people just won't be We just need to block it.

31:52 , human drug trials had to be because of the psychiatric side effects.

31:59 goes to the same problem that we've discussed different things and different look functions

32:06 located in different parts of the although they have the same receptors,

32:09 responsible for different functions. So you're one problem but you're also causing another

32:18 . So like psychiatric problem. And drug was removed from the market very

32:22 actually it was causing suicide and some . So although this finding underscores that

32:30 that these receptors do much more than the munchies, it is still still

32:36 of interest to know where in the . CB one receptors act to stimulate

32:41 . Not surprisingly, CB one receptors with neurons in many regions of the

32:46 that controlled feeding such as the hypothalamus some of the direct psychogenic effects of

32:54 are related to changing these activities of neurons, appetite stimulating or exit

33:00 However, neuroscientists were surprised to learn 2014 that much of the appetite stimulation

33:06 from enhancing the sense of smell at in mice well, but you don't

33:14 to make that argument for mice. , you can say that it is

33:18 same for humans. Uh Covid has us that when you lose a sense

33:24 smile, you really don't want to that much and whatever you eat doesn't

33:28 that great. So you just do not because you're enjoying it just to

33:33 over and not to, you start. So we know that for

33:40 and part of what we taste is much about what we smell too.

33:47 collaborative research conducted by neuroscientist Frances spain incidentally known for the appreciation of good

33:54 and smells revealed that activation of CB receptors and olfactory bald increases odor detection

34:02 it's necessary for the increase in food , stimulated in hungry mice by

34:09 So in Chapter eight We didn't discuss how smells activating neurons. But let's

34:16 at the circuit here. The brain under cannabinoid are synthesized under fasting conditions

34:24 they inhibit glutamate released by acting on one receptors on cortical funeral axon terminals

34:33 granule cell activation by glutamate in the has the net effect of enhancing the

34:37 of smell. Let's look at the here. So what is happening in

34:42 circuit right here, the secondary order olfactory neurons, you can see that

34:47 have an inhibitory granule cell and from cortex which you get you get excited

34:54 glutamate release. So this is the when you smell something I guess it's

35:00 negative feedback to control that sense smell . So you release glutamate on the

35:05 cell. Okay. And that inhibitory then if not inhibits the smell modulates

35:12 amount of smell sculpts that smell the inhibition but you can say that

35:18 controls and it's very important especially if are surrounded by something that smells really

35:25 and imagine if your hands are tied you just have to smell something

35:30 really horrible. So this mechanism would basically like okay it's a lot of

35:35 now calm down calm down. You're gonna be processing the smell as much

35:40 the secondary neurons CB one receptors, just saw the CB one receptors will

35:46 glutamate release. So if you activate one with endocannabinoid you blog glutamate release

35:53 blocking calcium influx. So activation of one buy and sell cannabinoids or activation

36:03 CB one by phyto cannabinoids like delta THC. With them reduce glutamate reliefs

36:12 the inhibitory cells and will reduce the of the second order neurons. By

36:20 this inhibition. These secondary order neurons be enhanced so there would be smelling

36:27 . And that is I guess you make an argument then when there is

36:31 increased production of endocannabinoid, it stimulates smell and it stimulates the appetite.

36:41 just by stimulating the appetite centers but just by stimulating the smell. That's

36:48 important. One of the features of systems and the increased production of under

36:56 happens during early postnatal days when a child starts suckling and the mother increases

37:08 levels of the endocannabinoid and the breast . And if you think about these

37:13 basic rudimentary functions then that endocannabinoid will the child's sense of smell, Make

37:22 more hungry. Will make that child likely to survive. Okay, so

37:31 why not everything can be substituted with with powders with baby powders because there

37:39 certain physiological elements that potentially like I'm sure they're probably not present.

37:48 the milk. Baby powders potentially precursors the cannabinoids which are omega three and

37:57 six uh fatty assets are important and would be present and in child

38:08 So there you go. This is the munchies would happen within the

38:15 With exogenous use of cannabinoids, consumption THC would also reduce inhibition and promote

38:23 sense of smell um and make you hungry. So in the central nervous

38:34 you have neural transmission Controlled by CB , a faster response and the slow

38:44 . The cytokines, inflammation, Michael cell activity modulated by CB two receptors

38:54 the cannabinoid system can get engaged to more endocannabinoid wants. That means that

39:03 certain base level of under cannabidiol is our bodies but you can raise those

39:09 and other economic rewards. They get with stress. They also get raised

39:16 repeated exercise activity, repeated exercise activities as long distance running or hiking or

39:28 else is the low level of cellular stress, normal stress. Remember

39:38 stress that cannot be handled and stress is necessary to push our systems to

39:43 them more dynamic and to handle things . So for a long time there

39:49 a thought that runner's high this idea when long distance runners get this happy

40:00 , they just feel good after running sometimes during the middle of their

40:05 They get this overwhelming happy feeling. was always interpreted as endorphins or endogenous

40:15 like molecules but morphine is not a molecules. Exogenous molecule. And the

40:26 scientific research nurse scientific research shows that feeling of the runner's high is likely

40:34 of the increased levels of under Ananda the bliss molecule and activation of

40:41 one receptors and CB two receptors. chama traumatic brain injury, hypoxia lack

40:55 oxygen, death of neurons um hyper , calcium excitability, glutamate excitability which

41:08 everything into the favor of excitation. is when endocannabinoid system gets engaged.

41:18 inflammation. We're focusing on the brain you will see that these molecules and

41:26 they function and inflammation in the brain also they're involved. And as I

41:31 , CB two receptors are predominantly expressed the organs that are involved in the

41:36 response. Once you have this you , very fine balance of excitation and

41:46 of our brains that I really like image because it shows uh somebody standing

41:52 two chairs on top of a high in new york city, It looks

41:57 it's a turn of the 20th the middle of the 20th century and

42:02 can imagine that this is your brain this is the state of your

42:08 It's it's quite fragile. It's it's it's it's stable for most of our

42:16 but it constantly teeters between more more inhibition. Uh it is fragile

42:25 if you have a genetic mutation and of the chairs slips. You can

42:32 , you can fall to either Too much excitation or too much

42:40 So and the cannabinoids seemed to be of the molecules that is really well

42:47 to control this excitation and inhibition, this balance. They're responsible. They

42:54 produced is eat munchies, they make hungry, increase the sense of

43:01 They actually promote rest and sleep too and protected neural protection against excited

43:17 forgetting. Why is forgetting important because you remembered everything and especially if you

43:24 everything bad that happened to you. if you had no ability to clear

43:30 bad memories and bad emotions, you are reducing your your your capabilities or

43:40 , your lifespan potentially to. So an important mechanism for forgetting. What

43:46 that mean? That means that too much of CB one excitation can

43:53 short term memory. Delta nine THC affect short term memory if you have

44:01 levels of endogenous molecules. But then you're adding some something exogenous li like

44:07 nine THC. Oh I'm just can't things as well. I can't remember

44:12 as well because you're pushing the system the address of its dynamic range.

44:19 chemical system in the body. I the analogy of a rubber band.

44:26 has a dynamic range. You can it. It's meant to stretch,

44:31 can stretch it many times. But has it's finite dynamic range and once

44:42 reaches the boundaries of that range. rubber band may snap and then it

44:51 take your body two weeks, 3 , three months, 3 years to

45:00 the enzymes that are involved in the that synthesize molecules. So break down

45:08 to re express the receptors, reinsert receptors in the proper synopsis and the

45:16 neurons. And and believe this takes lot of time. Now, what's

45:22 about the endocannabinoid system and it has pretty vast dynamic range in contrast to

45:32 system and the brainstem that I already to. And that's the problem.

45:36 know, we're actually not even talking much about marijuana or cannabis or what

45:42 does. There's more information I would happy to share with you in the

45:46 lecture if you have questions. But fact of the matter is that there

45:54 negative effects and most of these negative is not from too much running.

46:02 runners can be addicted to the round much that they will prioritize that over

46:08 else. Which is a running use . Uh there is a cannabis use

46:16 , there is an effect on the system that can stretch it, that

46:22 affect the memory that can affect these . Now. The thing is that

46:27 not lethal. So if you're under system is or too much consumption of

46:35 nine THC, you may get intoxicated the point where you may end up

46:40 the hospital, there's a panic There's anxiety attack, heart racing because

46:46 one receptors are also present in the . For Children, it presents a

46:52 in the states where delta nine THC legal and it's an edibles that look

46:57 very colorful pretty gummies and they find on the parents table and consume

47:02 Those kids, they get their stomachs out, they usually sleep it off

47:07 they go to school the following day that's because the cannabinoid receptors are not

47:15 the vital body in the in the of the bracelet that control breathing and

47:22 rate and opioids are. So when hear about opioid epidemic going on,

47:30 many opioid deaths we get This is rubber band theory. Mr rubber band

47:37 , not theory or delta nine THC cannabinoids to have an effective dose,

47:47 say whatever that effective does, it's Gummi or if you're talking about consumption

47:52 cannabis flower, it's one joint, cigarette from marijuana from cannabis, it's

47:58 effective dose because it will intoxicate people . A deadly dose for Canada's is

48:05 1000 times of that in about 15 . So it's very, it's impossible

48:11 consume that high of a dose even you use very concentrated preparations, you

48:16 pass out or fall asleep before you and then you just sleep so you

48:24 die okay with opioids effective dose is treatment and that effective doses to treat

48:33 typically and the lethal dose is only or four times of the effective dose

48:41 is very easy to achieve. And problem is the opioid receptors are expressed

48:49 the brain stem areas and the centers control breathing and heart rate. And

48:57 the dynamic range of that system, rubber band is like you can't stretch

49:02 far, you stretch it just a bit, boom, that snaps.

49:05 when it snaps you don't fall he dies. Okay, will you

49:13 breathing? So that's that's that's the when we talk about effects of different

49:22 molecules, exogenous molecules. Uh and particular system then the cannabinoid system and

49:29 dynamic range. So this is a bit about cannabis and this is a

49:42 from 2017 which probably was one of very exciting times for the changes in

49:53 laws in this country and internationally. the fact that all of a sudden

49:58 saw marijuana companies on stock exchanges and trading the shares and the value of

50:10 company sort of like blown up out proportion. There was a big

50:14 Like with everything else in the there's a housing bubble, there's Bitcoin

50:21 . This was Canada's bubble butt, was so much excitement. Everybody thought

50:27 was gonna go legal everywhere in United States. Mexico Well it is

50:33 in Canada. We have very different and Canada is federally illegal for both

50:42 adult use and medical use. There medicines that are made from cannabis and

50:49 should actually, maybe I should have those here. Maybe I'll include a

50:55 more slides in there in Germany. have a federal illegal medical cannabis system

51:03 you obtain your cannabis flower or marijuana in a popular language. And the

51:12 where a pharmacist with a white lab explains to you Why you should get

51:19 product or the other one. And insurance covers your medical bills. So

51:25 very different systems in the United What we have is we have state

51:30 systems on a federal level. Canada's delta nine THC molecule remain on schedule

51:42 , which is basically the worst possible , Most addictive, no medicinal

51:50 That's what still the federal government Canada says now in 2017, when

51:56 of these changes were happening. people like me were already observing the

52:04 . And there's two realities. There a reality of not being able to

52:08 research on cannabis on the planet. could do research on synthetic cannabinoids and

52:14 could order one mg of THC pay to michigan came in pharmaceutical, $60

52:20 one mg, 20 mg, THC and texas costs. I think $10

52:27 something like that. So you can that synthetic drug. You could have

52:31 of the experiments in the dish you do. And in reality people were

52:37 all of these plant preparations and there's disconnect so there was a reality here

52:43 you can do this and then there's reality that you cannot do research on

52:47 plant. That still reality is is persistent. That the states just started

52:52 up to that. I mean the the feds just started opening up to

52:57 last year. That was the And at the same time Oregon decriminalized

53:08 in 1974, California legalized medical cannabis 1996. That's almost 30 years

53:20 D. C. I believe 1998 have most of the states in this

53:27 that have medical candidates. What is on and maybe I'll get into the

53:34 between what's happening in the state and state level, What's happening in the

53:39 world and the pharmaceutical level. But as this culture was emerging, the

53:45 , the big business was emerging and of people were using cannabis for various

53:52 reasons. Well it was no longer you know, an a grandma's tale

54:00 could be ignored. Oh it just so and sell, oh just the

54:05 you know, I went to the epilepsy meetings around that time, 2000

54:10 15, 16 17, I was Dravet syndrome and the drive a syndrome

54:16 . It's an intractable form of epilepsy talk about it. Which means these

54:20 don't lend themselves to available pharmaceutical Over 20% of them die in their

54:28 because of the medications not working. was going to epilepsy meetings. I

54:34 listening to the to the parents of patients of kids saying they're using cannabis

54:40 . So they're using marijuana, they're their Children even inhale marijuana smoke even

54:46 the pumps and stuff just to stop seizures. And the scientific community didn't

54:56 want to listen to those parents and found it very frustrating and found that

55:02 can we work with synthetic drugs with molecules? Yet we have thousands of

55:09 that are using these plant derived oils preparations that have been around actually for

55:16 of years. Nobody's dying from And what is the disconnect here?

55:25 In 2016, 2017, it was difficult to even speak about this.

55:32 in in in the pharmaceutical scientific It was very frustrating. These people

55:39 together from the National Academy of Sciences and Medicine and you can look up

55:43 article I can post for you and reviewed all of the available data on

55:49 and Cannabinoids. So when they say of the available data, you have

55:54 keep in mind what I've just told the systematic suppression of no data on

55:58 plant. And despite all of there's still some studies and they published

56:05 following this conclusive or substantial evidence that or cannabinoids are affected for the treatment

56:10 chronic pain and adults candidates as anti in the treatment of chemotherapy induced nausea

56:19 vomiting for improving patient reported multiple spasticity symptoms. Oral cannabinoids. There's

56:28 evidence that cannabis or cannabinoids are effective improving short term sleep outcomes and individuals

56:33 sleep disturbance associated with obstructive sleep apnea , Fibromyalgia, chronic pain, multiple

56:39 , cannabinoids primarily in the big So while you have the brightest minds

56:48 the sciences, engineering and medicine telling this is medicine, the federal law

56:57 says this is not medicine. This an addictive drug does not have

57:04 Where is the truth? The truth lies. Somewhere in between? I

57:11 will prepare maybe three or four more for you for our next meeting so

57:15 we can look up and see what acceptable for 95% of medical doctors at

57:23 medical center. As a recommendation of approved cannabis pharmaceuticals, What is acceptable

57:32 5% of medical doctors that are open openly prescribing medical cannabis. You can

57:43 that there's pain here, anti anti nausea spasticity, maybe sleep When

57:53 come back. We'll see that Texas medical candidates in the state for about

57:58 different conditions. Why who determines How does a regular individual? Who

58:08 not an analytical lab themselves, understand whole world and discrepancy between federal state

58:17 also, I think we should look Delta eight because Delta eight THC is

58:22 advertised a lot of gas stations and shops. And I just wanted to

58:28 you some very basic thing that delta not produced by a plant. That's

58:32 a synthetic molecule. And then it's out there for the consumers and

58:38 of them have difficult time understanding what is most actually, because even for

58:45 and people that are interested in it takes time to figure things

58:50 Okay, so we'll end here. think I'll tag on another three or

58:53 slides onto this lecture when we meet on Wednesday and we'll see how our

59:03 proceeds. Um, most likely I'll into the olfactory and taste systems.

59:09 I'll just do olfactory instead of both . It's most closely related to what

59:14 talked about today. Okay, thank for being

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