Thursday, August 25, 2016

puppets brookline

>> okay, - good afternoon. i think we'll--can you hear me? so i see a lot of new faces. i hope you'll keep coming back, at any rate, because there are new faces, to explain what this is, is there anyone in the audience who doesn't know what it is.

we will try that. huh? okay, what is it? right. that's the brooklyn bridge so why would we be showing a picture of the brooklyn bridge and a session on demystifying medicine and it's simple and of

course in this facts in research in general, it's the to bridge the gap between brooklyn and manhattan but as represented by basic science, whatever you will, and call it human health on the other side problem is one of communication, we don't speak the same

languages. this is of course in linguistics, and even though you may be a molecular biologist or structural biologist, or something else, the other person's language and and your experience and knowledge that you may bring up in the

discussion or maybe even influence the direction of your research. so this is truly outstanding science at the forefront of this issue of cannabinoids or in the popular lingo of marijuana. the bridge is a little bit different from some of the

issues that we've considered before because these days we have this tremendous that emerges in the public, so there's enormous public interest in this from various perspectives which we're not going to dwell on today. but we are going to did dwell on

is more scientific basis, for endocannabinoids what they do and how they act. and that's what our two speakers will focus on. now if you get off the plane as we did if den virnot so long ago, you see big signs saying welcome to denver, colorado and

all the green dots are places that have one crazy sign after another where you can buy marijuana in whatever forms you wish. including ice cream, candy, all kinds of stuff and this is serious business because it legalized of course and whoops

what did i do? oh no, help. so from the sort of--socio logical economic political point of view there are lots of ups and a lot of downs and if you just read the newspaper and listen to various people talk, sometimes you get the idea that

with these events listed here, that the ups in favor of legalization and so forth are having the lions share of the action. you know there's increased legal use in several states and it make its rolely incredible to read about the prices in one

week in washington state plunged by 40% when there was competition. the banks can't handle money from drug use and they run around with suitcases and they don't know what to do with it so it's really the wild west, they have to have guards and

everything. native americans can legally grow, sell and profit from marijuana on reservations so we may have a new form of casino operation which may be good i hope for the native americans who need all the help they can get and marijuana tourism is big

time f. you want to really get chacken just google marijuana tours and it includes everything so this raises the important question of course, how save is all of this, what are the risks of marijuana which is a topic that's going to be discussed today both from a neuroscience

perspective and from a metabolic stance. now the science is incredible loamacy to read about and i hope that alla of of you will look at references posted on the web site because of the history of all this and some of the interesting questions, you know?

a first discovery of an actual endogenous receptor, the representor came before the ligand did, the discovery in 1992, of the first receptor, i believe, so now there's the question how many receptors are there for cannabinoids as structures?

well the one we're emphasizing at least in the first slide comes from a plant, but why are there receptors in mammalian tissues to something that's in a plant? well it turns out there are endogenous ligands and the first was identified by

[indiscernible] and was driverred a bliss, and so now there are a whole bunch of others where are the receptorses are either they work, where are they there? why are the indodgeious ligands? and if there are receptors and there are antagonist and there

will be blocks, selectively, are they therapeutically useful for anything and most importantly is how does all this work? so these are things that will be discussed. now i will briefly introduce, people who i'm sure you--hopefully all know are know

of. so the first speaker will be george kunos, who is the director of the niaaa. george is originally from hungary and got his ph.d. at the college of mc gill where he was a proeases fessor, came to the nih as the chief of the

laboratory, physiological and pharmacology studies and niaaa, and since 2000 has been the scientific director. george has received all kinds of medals and honors and recognition for his remarkable work on basic biochemistry, pharmacology, physiology and

disease related aspect of cannabinoids. and our second speaker nora volkov well known to you, nora was born and graduate friday medical school, not the same time but they could have because her record is so stellar that anything could happen at a fast

pace. she graduated from the university of mexico where she received a word as the best medical student of her generation. that's really something. and then she trained in psychiatry in new york

university and was one of the outstanding psychiatric residents in the united states. she then spent most of her career as the department of energies laboratory at brook haven, long island. where she was director of nuclear medicine and really did

her salient work demonstrate a drug addiction was real lye a disease of the brain. this was largely by imaging technology and this ultimately led to her coming here as director of nida in 2003. and since then, all curves as been up, i suspect--i know this

with my own family when they hear it here at the nih and say a oh, do you know nora volkov, it's not that she's a rock star or anything like that. she may be or anything like that,--she may be. but it's just that her impact on the public at all levels visit

been so profound with influ expense understanding and policy as well as science and as head of nida, remarkable things have happened since she's been at the helm. now she may not like this, but i have to add this because i always thought that my wife was

one of the 100 most powerful women in the united states but it turns out, at least according to time magazine in 2009 and 2011 nora you were, she's been recognized widely as a member of the institute of medicine and has received all kinds of awards.

one of which was amongst the top people who shape our world from time magazine. at any rate, we welcome both of you and really look forward to your presentations and we will have questions after each session and at the end and i encourage all of you to

please--anything i would ask is a lot of people watch these sessions online if they don't hear the question, they send me e-mails. so if you wait a minute we'll get a microphone to you and you will have an opportunity to be heard around the world.

george? >> each though i work at the institute and i speaking on the subject of marijuana my talk will not talk about alcohol or [indiscernible] and today's topic and when you get into a project and find something interesting, one question leads

to another, and you don't be where you will end up but you will find out where you ended up and many years ago, my lab and my self got interested in endocannabinoids and as they pointed out, they discovered this and a sebaticle in the department where i was chair of

the pharmacology department of medical college of virginia and vcu and that's where my interest was in endocan a--bitsoids. so what are endocannabinoids? so receptors are discovered and mediate the effect as happened at first with opiates, the longical question is why are

these receptors in mammalian including human cells in the body and the answer as it turned out, that there are endogenous ligands, so these are these own marijuana like or morphine like substances. so in the case of the cannabinoids, the discovery in

the 80s when specific g-protein receptors were discovered that mediated the psychoaxis of ph.d., and two such receptors were ididn'tified by molecular cloning, the receptors which are present at very high levels in the brain, that's first demonstrated by [indiscernible]

on who is here in the audience about a generation ago. --now the discovery--whoops what's that. i got it. the discovery of these receptors as i mentioned led to the question, what are the endogenous ligands and we had

the insight that going after peptides, by analogy of the one recently discovered endogenous opiate peptide, they had the lipid substances based on the fact that ph.d. is a highly lymphfeelic substance and it was a metabolite arachikonoyl and these produced a represent

setter semesterular to marijuana and here again this group in jeopardy an adentified the second metabolite to the two ag, now there were analogues of these compounds but these are the two most widely studied endocan a--bitsoid which have been ashes rouped for about 20

years and during this there were over 5000 papers in the pubmed database and the epped o kacct nabboids effects and the large number of biological functions, mediated both centrally in the central nervous system but also in increasing numbers, and the mechanisms that are regulated or

modulated by these endokacct nabboids. now for today's part i highlighted a few effects in red and when you look at these like marijuana or endogenous counterpart to help us relax, eat, drink, more, rest, sleep, conserve energy, these are the

whole of what we call the three singles are the significant survival values during human evolution during the starvation but in the last 80 year when is we have the food supply and increasing with the lifestyle, it has become the main culprit of what we call the metabolic

syndrome or in other words obesity in the metabolic complication which is include the resistance, diabetes, study liver and dislipodemias that could lead to heart disease. now we could speculate or maybe formute two hypothesis, based on what i show here.

these effects, if all of these effects are promoted by endocan a--bitsoids and if this is so, then blocking these receptors by cb-one receptor antagonist may have therapeutic value and visceral obesity it's complication. in fact, the stimulus that led

to the development of these compounds was the observation that the first cb-one antagonist which was introduced by the company in town, were able to reduce food intake and this led to the idea that it may be effected with this obesity. and of course this effect on

food intake reflected the fact that endogenous compound similar to marijuana which causes the murphys, theend--and the got to the clinical trials and it turned out not only that it matched the expectation and effective as an introducing agent but first ending obesity

with the drug, it was able to improve all of the important complications of obesity chai is insulin sensitivity, dislip deania and reduced fatty liver and unfortunately and not unexpectedly i have to say it also had very important side effects.

so for that you have to know that the endocan a--bitsoid system pathway and obligatory component so if you drop that have rop that have a very wide [indiscernible]--in a very risk aversive drug rate and regulatory environment that led to the [indiscernible] from the

pharmaceutical market in 50 different countries, the u.s. was more cautious to introduce it and more over it talked about further research in the therapeutic in the research and therapeutic application of cb-one blockers, interestingly at about the same time

laboratorys including our own have demonstrated that cb-one receptors in various issues all of which are important in metabolic regulation, mediates important effects and the issue and the increase glike o genesis and the observation that result in increase obesity, the liver,

the increase glucose production, the inn surveys lynn resistance, also increase hepato genesis that is the atopic generation and that's the position of that and the stress in the muscle and they inhibit glucose uptake and so on. now this led up and the few

[indiscernible] companies for the idea that maybe the c b-1 antagonism, the therapeutec potential of this could be salvaged, could be developed second generation compound that have greatly reduced ability to penetrate the blood-brain barrier and this way we could

minimize or eliminate the neuropsyche treat [indiscernible] and side effect but we've seen some or even most of the therapeutec benefits. and further more, what also led to this idea that we as well as others found that in these metabolic disorders, there's a

significant increase for excavation of the system which was reflected in the major upregulation increased expression of cb-1 receptors and post tissue in liver and in the muscle, the animals which had a normal [indiscernible] became obese mice for the high fat diet

have a greatly increased amount of cb-receptors which is normally very low, same in the eddie post tissue, and in the mouse, lean verses obese mice. and the amount that increase which is [indiscernible]. so at this time, we were approached and these also

recognize this possibility and develop modified cb-1 antagonist with the penetrants and ask if we could collaborate because they're interested in this problem. so the part of what i talk will be the jb compound the structurally modified derivative

of the base penetrants and which was developed by the company and up to clinical testing because by the it was [indiscernible] so sort of research with all the other like substance. now in modification of the penetrants iltraited on the other side, luckily however, it

didn't effect--actually didn't reduce but strangely even increase the affint of the compound for the cdone receptor about a 10 fold increase from about eight--or 20 fold increase in potency and the same activity to cb-1 and much less effect for the receptors and similar to the

compound, it acted as an inverse agonist which means not only it blocks the effects of an agonist but in the upstream of agonist it produces an effect opposite to the agonist and that is in this case, decreasing gat gamma slate. i won't about about the other

initiation about the properties, that illustrates that. so to establish how well or poorly in the brain, the first step was measuring the compound after either acute or chronic oralla administration to mice, that was the model of the mice that we use in these early

studies. and measure the level of the compound in the plasma and brain and found that the compound as significant levels in the brain which as i mentioned causes significant receptor occupancy where the j. v. compound vs greatly reduced penetrants and

only about five or six% of the total, sorry in this case, about three% of the total and even after chronic administration where the brain compound has high levels in the brain, the amount of the jb compound compared to the plasma jonitration is very low.

both compound significant in the liver and explain very high rate efficiency in the liver and today i will not get to that but that's one of the interesting factors. now even though the amount in the brain is very low and most of it specifically bound to

proteins, we still wanted to be sure that the very small amount of free drug is not whether it can or cannot occupy receptors in the brain and the state-of-the-art approach to do that realtime is cb-one pet studies for this tomography studies but here at the nih was

among the first to develop a very good cb-one receptor antagonist peptide ligand and we collaborate with him in the study for what we see here is a mouse brain showing the uptake of the radial labeled pet ligand in an animal that just received vehicle about an hour before the

injection was a pep ligand and another animal was injebted with the base and the doses here for both compounds were selected as the maximal effective dose for various metabolic parameters and then you see that there's a very significant oppression of the uptake of the label compound

because the compound its occupy the receptor and prevents the radial ligand to do that. whera i similar dose of the jv compound causes low displacement indicating that a dose which produces metabolic benefits, it doesn't occupy a significant section of the cb one receptors

in the brain and the full occupants could be demonstrate indeed animals that were treated for four weeks, daily with oral doses of the compound with from the vehicle. so as expected this lack of occupants, resulted in the absence of the side effects in

these animals that can be attributed to blockade of cb-one receptors in the brain. we use two sets, one is that if an animal, a mouse is injected to the highly potent cb-one agonist compound, it develops catalepsy which is measured and the mouse is [indiscernible]

front paws on the butt and the normal mouse has to be hung up like that immediately releases the bar and runs away, so the amount of time that the mouse spends on the bar is indicated here. the mouse [indiscernible] dispotent agonist, it hangs on

for over 10 seconds before he's able to really let go. if these creatures with the nonbrain penetrant with the cb-onan taganist, the animal is able to cause almost the same deagree of catalepsy in the animal. otherwise if it's with the same

brain compound, the ability of the agonist, is completely flat, the effect similar to what happens if the animal gets [indiscernible]. another become difficult to handle and relevant for hours in the cage which could be quantified by the infrared and

the prevention compound of single injection in these case causes a huge increase and it's hired and background after two hours, and there's no significant effect with the similar dose of the jv compound. so, about five years ago, i was talking the same session, on

demystifying medicine and i told you about our first study with an earlier analogue of the cb-one antagonist and the mouse model of obesity. and this is a model that that c67 black six mice, that if they're exposed to food high in fat, all of these are effective

in the antagonist however, these mice only develop insulin resistance which means that plasma insulin levels increase very high level to maintain blood glucose at normal or slightly elevated level, but they never develop full strength type two diabetes for the source

of insulin are able to compensate for these and histones by proliferation and putting out increase levels of insulin throughout the life of the mouse. so we were wondering, what happens if the--if the role of cb-one receptors is only in a

model of two type two diabetes, and there is such a model, it's called the glucose diabetic study wrap, a bit of background on this. the glucose study is obviously from the name, it's an obese that the reason for the obesity is the serious mutation in the

leptin receptor, leptin is the peptide hormone for the tissue that suppresses food intake and reduces [indiscernible]. and it's unable to pro duce the effect because of the receptor has been inactive in the mutation, the animal becomes hyper frag and i can eats more

and becomes obese. these animals become insulin resistant but don't develop diabetes. many years ago someone undertook a project where they studied a few animals and selective breeding developed a line of this strain, the diabetic study,

which actually very nicely replicates the natural history of human type two diabetes. as you see here in this, when the animallas were born they're normal glycemic, insulin is normal, diet is normal but the age of two weeks, the insulin sky rockets, and within four or

five weeks, they come out and event extend hyperglycemia and for the first time is shown yellow, the plasma influence appears to be normal level but this is actually due to the fact that the beta styles, in the pancreatic eyelet which is the source of insulin are dying off

so there's no more source of enyou surveys lynn at this point. there's a pair of dropin peptides which is a marker for insulin secretion so that indicates that the drop is that the secretion of insulin is reduces, not that it's

elimination is increased. what happen fist we take these animals and treat them daily with the cb-one antagonist for about three months? as you see are the treatment prevents it, the appearance of hyperglycemia for about four weeks so there's significant

delay in the onset of this process, and even then, hyperglycemia, started to develop. the level remains significant for the vehicle throughout this series of treatments and at the same time the treatment also largely presented this loss of

insulin and c-peptide use of the deamination of the beta cells that you see here. the post plasma remains high. so this then suggested that the cb-1 antagonist treatment somehow is able to preserve the beta cells. at first we want to have

functional evidence, what is the function of beta cells and how do you test them? and this--the first test is very similar in the way that the patients are sometimes specific for the function of their own data sets and that is glucose stimulated insulin, so beta

cells produce insulin and then blood glucose rises and the most powerful stimulus for the increase production released from the beta cell. you can test it by giving a single bowl of glucose for people who drink a bottle of juice and the animals we give it

similarly and then measure within five menutes, we increase plasma insulin and side level. which is measurable and significant. the obese animal vs a greatly elevated but become almost completely unresponsive to the glucose stimulus, there's no

significant further increase in sin insulin or c-peptides. the animals that were treated with the cb-one antagonist, even though they're based on insulin and the peptide, it increased further, now you see that the glucose stimulous causes a insulin and c-peptide and this

is even more clearly and quantitatively demonstrated and the insulin in vivo, an in vivo model. the isolated pancreatic for which we added increasing dose of the concentration, and increase the concentration of glucose and you see the normal

wrap, very low amount of insulin release and then as you increase glucose, there is a very nice dose dependent progressive about four to five fold increase in insulin release from the eyelet that you can measure in the median. the vehicle treated diabetic

wrap at very high basal release of insulin which is not responding at all to the increase in the glucose concentration as in vivo model and again that's happened in in vivo, it is isolated from the levels but now you see a very nice doze depentine regimen end

progressive increase, here is the drug so it actually is remarkable it's about a three fold increase from the lower to the maximal level. so that means that the loss of data of the either cell functions by the treatment of the jd compound.

so what happens in the islets, what we found here is that this is an islet from lean mouse and the immunostaining on insulin antibody and the color is brown and surely that's normal islets are very rich and have high ensurveys lincoln septorss but diabetic ask large and the

organized and the insulin is dramatically used, and similarly and also showing @ same time we notice thad there's a large number of the styles in the islet, for the staining which are not present in the lean animal but also absent in the jv treated animal.

at the same time, the expression in the islet which is lowering the animal become significantly increase in the diabetic animal and that's also reversed by the antagonist treatment. now one of the other things we noticed that the large concentration that we're in the

vehicle treated diabetic animals turned out to be pro inflammaatory macrophages with an antibody against the macrophage marker cd-58 molecule, we see a significant increase in the positive macrophages and this increases reverse larger by the peripheral

antagonist treatment at the same time the analogue and inflammasome and i will decide what it is is also causes a increase and reverse by the treatment. now inflammasomes were discovered about 15 years ago and they are a protein that the

file produces and that they're rolling the cell is that they serve [indiscernible]y proinflammaatory protein that allows 12 or 13 inflammasome, this inflammasome is known to be known to the metabolic dangers and the machinery that is assembled in

both nf-kappab, the proteins enzyme tested is one which whose main role is in that or preilone beta and il18, these are proinflammatory cytokines, from an inactive precursor to the active cytokine. next slide shows that these macrophages that not only that

they produce them the same but they represent the m-one as a oppose to the n-two pen o type and m-one markers are increased and two markers are decreased in the diabetic compared to normal and the changes are reversed in the islets from the jd-treated diabetic animal.

and this just shows thatot only the [indiscernible] but the [indiscernible] the protein machinery that is assembled on these is also increased and nf-kappab goes up and the activity here as much as activity goes up and the amount of actual active il-one beta and

ilone beta and il18 proteins are also increased on all of these changes are normalized or nearly normalized by the antagonist so at this point, we consider that one of the possibilities that the cb-one taganist treatment may be on the on themselves have, i will show you

a number of federal lines of evidence that suggest that sort of this unexpected conclusion from our experiment and this cb-one antagonist and this beneficial is the effect there's macrofadges and the endocannabinoids for the transfectors into the issue in

this state into the pan kre tinsatec hour and also the expression of the inflammasome of il-one betaa and eight and the cytokines are released from the data from the mack wophages and offot neighboring data cells to kill the cells by a pull system this way in the diabetes

to the lack of insulin. so the first evidence is--ooh. the first evidence is that cbloan receptors are not really co legalized to insulin producing beta cells as you see here, the beta cells are visualized by antibody, the cb-one antibody shown in red,

it's mostly localized in the perimeter and then you over lay them and the colocalidessation is minimal less than 15% and on the other hand, the cb-one receptor show a nearly perfect colocalization with a cd68 macrophages in the eyelet, shows the overlay and there's also

colocalization of the inflammasome for the proinflammatory macrofadges shown here. the second line of evidence from the tool will be used which is a compounded called quadramate and it's set up by macrophages and causes apoptosis.

so the way that we--and this can actually lead to a depletion of macrophages, designated such as liaison so studies of multiple endocrine and diabetic rats are treated with the liposomes which could continue [indiscernible] or just the lysosomes, if you treat the lysosomes they show

the typical gradual increase during an early life period in the lysosomes that--well, anyway, as it progressive increase in blood glucose is treatment throughout this period and result in increase influence and the level experience of data function and probably operate in

collaborative study with monica from the diabetes institute we collected monocytes from 28 normal [indiscernible] and isolated them based on cultural and differentiation and then you expose the cells for the endocannabinoid and it causes a decrease in the cellular

contents of the inflammasome, associated protein and also in the level of cb-one receptors and also causes a significant increase of immune reactive ilone beta and il18 and all these will be blocked by the antagonist which is called the aning itanist alone and the

endomights together. however the strongest evidence we've seen is the effect of selective knock down of cb-one receptors only in these macrophages. so the approach you take is the approach that there introduced several years ago and interested

in nature, and the approach is that if you have the low rnas and you package these in the beta glue can particles, beta glue can is the ligand for the ductive receptor and the ductin receptor is uniquely assessedot surface of the phagocytic macrophages, so if you have

these particles these are selectively taken up in macrofadges where the content is released from the lysosomes and then the sirna can target the gene against the gene developed and knock it out. so the approach first you have to develop the right sirna and

then thal case we show the one which we finally selected which causes a robust dose dependent near complete knock down of the cdone receptor which no effect on cbc receptor showing selectivity and also the scramble sirna which doesn't recognize and has no effect and

selectivity. then you treat animals for the sirna, or the sirna and after 10 days treatment, isolate the elicited cells and the glue can capsule labeled with fitc to facilitate those and then we also immunologically label the either the macrofadge cd68

antibody or cdthree which is a lymphocyte marker and then what she show here is that the great enrichment about 10 times more in the cb68 positive macrofadges in cdthree positive lymphocytes and then you isolate them and enrich population of these cells by class sorting and then

measure the level of cb-one and sirna, we found the macrophages that other than 70% of the cb-one receptor with no change in cb-two, where in the lymphocytes isolated there's no change in either receptor. and treat the animals for 10 days we found that during the

treme, the progressive rise in blood glucose is presented and at the same time, insulin of the five levels are sieving 95 cant indicating preservation which is illustrated care in histology. so these now are unpublished resulting in a unpublished cb-one receptor knock out mouse

so on the irigeinal diabetic exam, we elevated the cb-one receptors if you see here, you have to geno type these animals because they are generated by the heterogeneous row zygous breeding both for the leptin receptor mutation and the animals illustrated here and all

positive for are this mutation, so they're vbs positive animals, some of them had normal levels of cb-one receptors and some receptors and the functional assay confirmed that the cb-one receptor stimulated cb-one binding and they had no such effect and what we found is i

will focus on this slide by dramatic these animals were wide for normal levels of cb-one receptors as many times before, and gradually develop extreme hyperglycemia, and the ones which are heterozygotes for the receptor, and a similar for the binds however, which left

complete the glycemic up to 26, even more dramatic than with the antagonist and this is parallelled by the insulin receptor. and this is the islet in the old vbs wild-type animals there is nearly complete destruction or atrophy of the islet, slowly

reduced insulin comes down and the knock out house and it has an enlarged and close to normal and then and the macrophage of the atrophy shows significant, nothing or in the knock out animals and the few islegalitys which are larger are actually very highly populated for the

macrophages so this suggests that this model will be very interesting for the role of cb one receptors. and then human diabetics these animals also develop severe diabetic neuroectodermal cropathy which means kidney disease and just a few words of

cropathy, it's a disease effecting the glomeule, it's end stage for people, maj or pathogenic factor is veesular cells that in a apparatus and also regulate filtration rates and finally, that it is recognize thad the angio tensein and hyperglycemia are the two

main drivers of diabetec glomerulopathy. --and very dramatically reduce limited filtration rates all of these were normalized by the however, in this case, the mechanism is that in the islet, we got a similar reverse of the hyperglycemia, than we did the

completion by [indiscernible], however the microfadge did not do anything to the nephropathy and from this, there's significant filtration that we could find in the kidney in the glomuro of the animals or the changes and however there is another pattern fully with the

cytogins with the alpha and the this marker for these decrease and these effects were reversed by the blockade. so the mechanism is somewhat different which is and there's animals that a marked increase why mr.'s immunostaining and it's preserved for the

antagonist shown here with the podicin, and it's important for the neff rin that are important and at the same time, the only expression increased and as you see here, and and that's just the cost and effect relationship. yeah, i'm finishing.

and in conclusion, the increased cb-one signaling in the mack row zygous phages are the most and it's responsible for the beta cell loss due to a pericrip mechanism and cb-one blockage that delays the diabetes and protects the beta cells. and nephropathy can develop in

the absence of hyperglycemia and macrophages situation about and just induce photosight image and the effect of both wasinhibitedg!p by blockade suggesting that cb-one receptors and represent the common pathway through which both high and angio sense cause renal damage and the final

group, and this restricted antagonist and do have potential in type two diabetes complications. with the lab and thank you very much! [ applause ] >> we have time for a few questions.

>> cb-one are antagonist now index but the studies are moving to clinical evaluation. >> several year ago, i applied for a grant and fortunate to get one and collaborating with this company and these in the toxicology in these studies program, so there are a lot of

thens you have to get through but hopefully the idea to get an ind and collaborators who are interest indeed participating. so interested in the effects of endo can a--bitsoids and what the tested? snshes -- >> the jb wasn't tested and a

colleague what passed away tested that there were recept ons in a class and they have a very important role and may even participate, may have some pathogenic role in osteoporosis. my former post doc, you see, was there in a second from israel, that was his ph.d. thesis and

his back up to the university and it continuing the work and the bone related work. >> george is there any evidence in increase in endoor exocan a--bitsoids can accelerate? >> endo can a--bitsoids i was trying to show, is for the disease and this is the

interesting that [indiscernible] use. you might conclude that based on this that marijuana use will lead to obisity, diabetes and so on but this is not the case even or old collaborators didn't find an significant effect on glycemic controlling heavy users

and the [indiscernible] first suggested by [indiscernible] the term metaboleec syndrome is that chronic heavy marijuana smoke suggest leds to rapid desensitization of the receptors so the endocannabinoids do not desensitize shown in nature or science.

>> thank you very much a we will have time for more discussion [indiscernible]. >> it's a pleasure to be here this, is our third time to be together, in this special session in linking with brookline with manat an i was trying to figure out if the

science is manhattan or brooklyn. i will be jumping and doing a very different presentation from the wonderful one that you heard from george but it's--i mean i think that it's a very good segue, because you see from his work where he's focusing onthe

pan kre tins asnow, on the kidney and before on the liver and those kacct nabboids are extraordinary and result of that for many year vs been interested on developing either agonist,an taganist, of potential for protein targets and it's very likely that these process of

these receptors of the properties why we're starting to have these normal things are wide spread, i call it like a dilution in the whole world about the potential benefits of marijuana for treating everything [indiscernible]. and you know the thing i was

thinking george when you were presenting this study with the rats is also, why it is true that you do not have greater range of obesity among people that [indiscernible] marijuana smokers and there was no evidence of the path of damage, we do know that from source of

the group in fnce that if you already have liver damage, then, smoking marijuana exacerbates the apoptosis so my question as i was sitting down and listening to it, so a lot of it is obese and you're actually smoking marijuana whether in that case, that may increase your risk for

diabetes, but i think that the source of questions that we need to pose within the [indiscernible] and certainly very interesting. so here i am and i'm actually criticized and gotten mad at interfering with the research of the [indiscernible] blah, blah,

blah, and it's an interesting petressable national library of medicine nabecause it's really over the past five years we've seen a dramatic change in the articles of people of marijuana, so five years ago, more than the majority of people in the united states would say the use of

marijuana on a regular base sis harmful, in five years that has changed to being the minority of individuals and during that five year period, it's not like there has been a massive amount of people that have shown that marijuana is no time for, there's really none.

so it's against--our brain or polarizing things that they are either good or bad without recognizing that there is an intermediate state that needs to be taken into the extent to which undercertain conditions marijuana can be [indiscernible] and the other conditions it

might not. and in this diaa log which has been polarized now, that level of discourse has been eliminated so what i want to try to do to you is present you worthy evidence is worth where the evidence is lacking and focusing on the main issue as it relates

to the brain because now i'm going to jump to thenot that i don't care about the i like them very much but i like the brain more. we all know that marijuana is the most frequently illicit drug use in the world and in the united states it's estimated

that 140 million people have tried it at least once. and every year, they are like 2.3 or 2.5 or 2.4, initiate into marijuana take it and the question is that arguably the merger and the harmful to you or not. now again if you ask about

whether to sample or not, i will show nucleotides most of my presentation, but all of it you will be talking into the stage of adolescence and [indiscernible] because what is the stage at which it's much more plast and i can what they do is basically they trigger the

activate the molecular targets of neuroplastickity by which the brain actually strengthening the connections where they're synaptic by that's actually the lab of another, so those neuroplastic changes appear much faster and your brain and able to learn faster but the main

side of that is you get exposed to the drug that transition into the strengthening of those synapses at least with a drug with everywhere are actually appearing faster and long lasting and therefore you can become much more rapidly. and for more severe way, you

start early in the adolescence and all of the drug, for marijuana all of them. so younger you are initiating the drug use and the outcomes of the addiction. now what is the directly the status of my marijuana among teenagers and what you've seen

what i'm seeing here is a result from the survey that was done in the university of michigan that every single year close to 46,000 kids at school throughout the whole us. and we ask them questions about why is the exposed to different drugs, did they take them and

also about their perception of crick what i'm showing you here is the prevalence of 17-18 years of age reportingot cigarettes marijuana and alcohol and we are going to [indiscernible] and take the race of the united states in terms of adolescence and you can see that we're doing

very well with respect to alcohol, everything is relative, we have high rates of alcohol, but they are going at least and going into the right direction, and we're seeing less kids of using alcohol and we're also seeing less kids binge drinking. we also gradually grow and for

the cigarette smoking and we see more signet smoking over 10 years and in contrast we see increase in the consusmgdz of mar juan and for one, two, three, four years in a row, and we have higher rates of use than of cigarette smoking as indicates the use of this drug

and this is something we have never, ever seen in this survey that was 1979. this is the first time that we're seeing use nothing the mas ma report, that you're using this and this was a phenomena, that was leading by the increase and the other one the very significant programs

that we're doing with smoking. so should we be concerned about it or not, with the pattern of the use of marijuana. so let's start--go backwards and try to sort offed [indiscernible] why are people taking marijuana. they are taking marijuana

because of the receptors that george was speaking about which have high [indiscernible] and activate with the pathways and there's very much like dopamine and we know that these pharmacologically, dopamine in the nuclear succumb succumb bents and these are different

molecular targets in the case of nicotine, the representor in the case of cocaine and this is extraordinary relevant for the survival of the individual because the biology have create the system that incentivized our behaviors on the base estimate thad of [indiscernible] or

punerbment and this is extraordinary powerful system that is evolutionary conserved so maybe you want to leave behaviors that necessary for survival, you want to insure the creatures will use them and leave with them wide what. approximate you want to insure

the creatures avoid things that are harmful you link them with the system. and so that's why, no surprise, food and sex are linked with the system, why? because it was [indiscernible] or have sex, we don't prokre tins ate, we don't if we eat, we

die. so they do it with different potency, so in terms of the ability to hijack the system and the answer is no, there's some drugs that are more adaative than others, they just pharmacological properties so i'm choosing here, and the

importance of this in activating this and on the other hand and it has been activating and this again would explain why in general terms are you exposed to amphetamines there are many higher than you're supposed to [indiscernible], however this marijuana is not [indiscernible]

and it's actually to smoke marijuana as an adolescent. now, many of you actually were discussing in the terms ofa&ã· we have an extremely complex endogenous can a--bitsoid system which is actually by permission is proliferating and we're taking advantage of this and

marijuana targeting those molecular systems that are effected by endogenous cannabinoids except that when you're taking marijuana you're actually smoking these leaves that contain a wide variety of can a--bitsoids and have different properties and these

cannabinoids and this is the one that has the properties. so discussion in terms of potential for example, these--the ability of some of these, the potential treatments and antipsychotics then we're looking at this compound here. and interestingly i'm not going

into the depth of this one but it illustrate what is we're doing and while we identify the cb-one and the representor as being the target it's increasing recementors that are directly offered by the cannabinoid, and this is made evident by the fact that these cannabinoids in the

receptors indicating these are pharmacologically for another target that why may know or we may not. but further targets that we're have well studied that was we were thinking that the receptor particularly in the brain. they are v, very [indiscerniblea

all over the place and it's high concentrations so some of the area are higher than other and like certains, this really incredible paper that open our eyes about how widely we do it and how the high concentration of this particular receptors, and if you look at it, of the

role, you see high concentration in the cerebellum and i know it's high concentration to the hippocampus and that immediately gave an explanation about why you see one of the main things to do wednesday about the cannabinoid, and it's hypothat will mic or humans it's effects

coordination. and the first thing that happened with memory where it's marijuana is that is serves memory and learn and while this may be acute and maybe have an akronic or acute effect ask if you're [indiscernible]. what we're observing with

cannabinoids and michael observed that is the effect of the aganist will be dependent on the dose, so when you get for example, marijuana people smoke marijuana they want to relax and [indiscernible] if they get marijuana with high contents and they take all of those cabbedies

and chocolates you can buy in colorado, you done know how much they can end up psychotic increased anxiety so we have this u-shaped curve that characterizes a lot of things that we're observing with the cannabinoids in medical complications so it's not very

much flexions when you get to psychotic and you will get psychotic if you have those of [indiscernible] in your brain. an a--bitsinoids and that's late and wonderful but if you get into the high doses, of the competition and these in the [indiscernible] system generate

a lot of interest because these individuals come in with myocardial influx with a use of marijuana. the same thing that one of the reason yes the cannabinoid for the therapy and you can take the cannabinoid agonist, that is [indiscernible] but if you get

this high doses of cannabinoids there is a hyper mass that, merges that [indiscernible]. so we're discussing the black and white and the have to be understood and the basis and in the brain, the same for the phenomena that were going to be the high level all over the

place are going to [indiscernible] and a wide variety of the set of of these, and interfere with the agents and learning and you can also effect sensational sense of [indiscernible] a also now is marijuana, i told you, there's [indiscernible] but

everybody says how, well this is one of the ways we quantify our addiction and the morph logical way and not a methlogical way, it's [indiscernible] approximate who-fic you compare the number of people that become the percent of them, that are exposed to the drop and as can

you see that indeed these theological side for analysis, this is most of this is all of the drugs of the tobacco but what's interesting is if do you this an animal model you find out that the tobacco nickee teen is not the most addictive, it's hard to make animals administer

nicotine,ot other hand you have drugs like i was saying that similar in an animal model are highly [indiscernible] of the obvious will be highly addictive so when you look at this, it's important factor of contributing to the emdeemio logical data which is [indiscernible] you

have a drug that's legal and the dins tinks of a drug that's illegal, having a drug that's legal make its more available but those changes the norms for doing [indiscernible] that would take an illegal drug if it's able to take this and that's one of the issues why we do respond

to social norms, the path of making marijuanaa legal, we will actually make an individual take it but otherwise have [indiscernible] for legality issue. so in general with the epidemiological data, nine% of users may become dependent, but

then it goes to 16% and if you are actually a regular dacey use, then that comes to close to 50% of individuals will become [indiscernible] so it's not the number, but it has to recognize that with these properties with the data is one of the ones that [indiscernible] and that field

is that marijuana providing the way as a gateway drug and the most and taking drugs by taking marijuana if you are honest about it and you look at data carefully you realize that most of those are spoking tobacco or alcohol, so speaking the gateway drug, you can consider the fact

of the legal drug saying a gateway drug phenomena, but has the data shown. the data have and these have shown us that if you actually this, is what the real le elegant story was doing so you were controlling for genetic patterns because have you no

ability for addictions has a genetic component and what they showed that the [indiscernible] for the initiation, so one before a17 and the other is a70, so they show that the increasing use or abuse in dependents were much higher for those that had [indiscernible] and this

sequence is international classification indicating that alcohol and nickee teen that the earlier you take the drugs, greater likelihood of becoming addicted to them. asked what. and i don't know that that's the specific for marijuana.

they're still something that happening with the now, one of the big question marks we have and actually very important because if you want to send messages, people also ask you, is it bad for to you take marijuana when you're a teenager and the question is overall the

evidence, right, can i tell you black and white, yes, no? and [indiscernible] etched that shows that smoking marijuana is harmful to the adolescent brain but there are also studies that have basically identify thad there's negative results and there's also studies that

criticize the design of these stories ba united states they have no control for [indiscernible] for the perhaps if you function and your brain was not funking properly that may put you at greater risk for smoking marijuana so that when they tell you later on, they're

not functioning very well because of marijuana because your brain was not functioning to start well with. so that has been a constant before a lot of the [indiscernible] on marijuana. however, one of the things that come again with the

epidemiological systems and replicated by a laboratory which i believe is very, very telling, is and i'll show you in 2008, but i will show you the new version, the newest version of this time again and as replicated by a lot of people in 2014, this is a rate of use in

the last time during adolescents and now, and i would say 14-21 and the can a--bits educationals and indicator of performance and what's replicated consistently is that if you smoke marijuana in a dose related way, that will interfere with your capacity to finish school and to obtain a

degree, again, very, very consistent finding, so when people say is marijuana bad for your brain, i said bottom line it's not going to be good for your brain. it employ result in the decrease of the ability of these kids to finish university.

and it goes all of the--this could be underlie why they have a lodger percent of [indiscernible] and dependent if you don't finish your education and i'm focus on the going into the complexits of whether [indiscernible] or not. if you're going to finish school

that,'s not going to help you very much. this is the actual--the newer version of 2014 of a completely different group, it's actually a pretty large cohort of individuals and you see australia and they're actually the same thing, and so high

school completions don't get much lower, the degree obtainment, those don't get much lower, there's no such depression and increase in the welfare dependence but let what's also interesting, is that in this side here, they actually [indiscernible] the same thing

what i was telling you, the alteration is much greater, no surprise there, the increased use of further drug, much greater, no surprise but was a surprise and have never seen these in a study and have seen an increasing suicide event so it was very significant, just

adjusting the ratio of more than six if you're regular user, like anything else, we're all very sensitive about the rep laicability, it's reproducible or whether it's not. but we can not ignore it, we have to start to pay attention of whether in this comsumption

of the marijuana may increase lethality and again as i say this, is not something for which there is evidence from pass past so this another important study for dwelve, publishing cnas. again this is a study that this study followed 1037 kids also from age 13 they measure iqand

during adolescence and thigh arks doll 30 years of age, they said it was very important because it was not the first one but control for premorbiddize and take the marijuana, but there was one with the largest sample size and what they showed is that in those kids that smoke

consistently dog adolescence, marijuana, are controlling for their i. q. for what's on average the iq associate wide the muse of ma mar juan and that use with the marijuana and baskly smoked much mar juan and smoking it in [indiscernible] that was not associated with the

decrease in intelligence quotient indicate as one would expect that they are related to the aslessens and again these are studies that the way i view that that are focusing on in terms of this previous [indiscernible] this was another paper that was published very,

very shortly after the paper on tnas, but it's imaging technology, and these are imaging that allows to you look at the structural connectivity of the brain, the brain is the network and the it is worked by creating interacademiess with different areas of the brain and

with the technology we can measure the density of these connections and what this investigator showed in a study and again imaging studies, relatively well relatively sized one but with the ability to come to realize that we need to again--there are things we can

no longer ignore, these were the ones we were comparing with thor impletaging and those have been exposed to marijuana in adolescence ask those that have not been exposed during adolescence and they showed interestingly that the connectsivity path that were

deranged between them, were very localized in the brain which to me was first a big surprise. and but what's also very much interesting was the location of where these were observed, one of them was the main connection into the hippocampus which made a lot of sense because the

hypocampus has a very high density of cb-one receptors. but the other one was actually the [indiscernible] and again most people don't know what the [indiscernible] is, and the slightest idea of what the [indiscernible] and and [indiscernible] now it's

everywhere. but and and and that have actually not connected and with [indiscernible] and 80-90% lower connectsivity and and very lightly but disruption of this connectivity and not just and emotional reactivity and the destruction of this very

important nose of the brain and horrible of the brain, and you have to and that one that's first abnormal limitations in this particular study, it showed the age of the younger you are, the worst? you bring these together and by inferring the connectivity of

brain and sees one of the mechanisms by whichy repeated use of marijuana during adolescence and persists after this drug and again these are questions that are really out there for doing the investigations and see this is the case or not.

co transactivator aspects about marijuana in the aspect and going to the medical textbook and that's the use of marijuana generates in a multi--andr link electronics, inc. model number: pdr-885 software version: 3.0a >> are going to be decreased and

your own endogenous production will also be--the terms of those for the effect that are acute and what--it may trigger and no other patients that may exacerbate that. so coming to that psychotic effect, that again is i think it will be obsessed by it.

but the first study was that in large actually that alerted the attention of the field because it was multiple clinical reports with schizophrenia when the trigger was there by smoking marijuana but when the fund became of the last cohort, of 1987, the cb-one construct that

established the number of cases that are basically associated with psychosis and the functional of the funds taken that alerted the field. it alerted it because shea showed dose effect that could not be ignored into the ability to detect and inspect sides.

--for developing schizophrenia at age 26 indicating that those were from from consuming cannabinoids before the age 18. but the new state of emergencys. what do they show, the study in 2012 it identifies the whole concept we were saying, can you get--you can smoke all your life

and be a hundred years old and you never get lung cancer. andoose not because cigarette smoke suggest not increasing the risk of lung cancer alternates because there's an interaction between the ability but what you're consume sec employee or guard what's fascinating about

this is that they were looking at it, the akt one which has been associated with the risk of schizophrenia, so this is one of the genes that has been by independent investigators associate wide concerning a risk of schizophrenia, and the high risk allele, which is the 51 is

the one that you see here, you can--about what's interesting is that smoking marijuana so they compare on the function of your allele whether you the risk allele, the one that you have both risk in both sides, and the ones without the risk alleles. if you smoke and you don't have

that risk allele, nothing happens to you. you smoke marijuana and you just have one of them, nothing happens to you, but if you do have both of them, the risk of developing schizophrenia is seven fold higher identifying one of the largest factors

associated with developing schizophrenia. from the susmgz of regular marijuana when you have the increase and end up with skits frania, and at least of which the paper made it up into the [indiscernible] that generated a lot of potential because they

actually look the style longer but and you can get very, very high highitration mar juan and they're available at hyper [indiscernible] rates. so, they survey these from a hospital in the emergency room with diagnosis of schizophrenia and they were actually then

looking at the extent to which they had been exposed to mar juan and what's interesting by them, again is that those individuals that have been exposed to skunk, skunk is marijuana chd, it's like 12,-16% and actually's about the circulating in our country,

those have a regular five-fold increase for risk of developing chronic syicoseis, indicating this risk is not really--in this particular story what's unclear to me is that i do not know that these numbers how long they follow them to kroneisity because it is--and again, i know

because i've actually worked with cannabinoids and we were giving high doses and i do consider [indiscernible] psychotic episodes and what these stories do not tell is that what percent of those vo voweds are going into a chronic estate which will be the

increase it is risk and the one that's most concerned about so the use of marijuana is not as benign as we would like to compare it to nicotine, we like to compare it to control, they have very different behavior and we need to actually look at them.

and in my presentation for the chd of the today, because that's the other thing we have a very large baby boomer that consumer, a lot of marijuana when they were young and they said oh my god, i smoke marijuana all my life and look how well i'm doing and they basically using

marijuana and because of the potency of ph.d., these are 1995, so i'm not looking at the ones that were growing up and it was 2 percent, but 1995 was 12%, we currently have it at 13%, 13 prt, thc and look at very dramatic increase from 209 to 2012, increasing the content of

chd, this marijuana with high content thc will be associated with much more likelihood of that, and if you look for example at these data here that actually so the drug related emergency department of the united states, you have marijuana look at thatta very

significant increases that are basically a 50% increase in 2004 over a seven year period in [indiscernible] where we're not seeing increase in emergency room, either from cocaine or heroine. even hero win which is antag fliesed in the united states, so

this indicates these very sharp increase is not--not be explained just on the basis of these very sort of increases in the population because they're not so large. this very significant increase in emergency room and one of the treatment programs allowed us to

reflect the fact we still have access to potent mar juans and that indeed that example that are taken, this is from a group where they actually get the blog content of drivers, can you seelet ideas are going up and up and up, and a lot of people when you hear and you make the

disease, hello and they're exaggerating, blah, blah, blah, hay say there's a thc content because it doesn't matter because you [indiscernible] and so you set yourself at the same level, well, guy's not what's not exactly what the data shows so you if you measure and

quantify what you see, that the amount of thc is going up and this is to account for the higher problems we're seeing with the drug. and this is my last slide and it's important because it shows monitoring, but now the positive one, for the complication of use, first the

risk of things that are smoking marijuana [indiscernible]. and then of course, the five near you and what can you see is that [indiscernible] the greater risk of marijuana the less the number of kids that are smoking indicating that actually, messages, prevention operate

information to adolescence is extraordinary importance in motivating this behavior, adolescence, the notion of these success and even though the use of the slide, the risk of the part of the excitement, it's also a group adolescence sensitive to norms.

so, one of the things that we need to proscried adolescence is as well as a policy maker is very good information about what it is st. that marijuana is doing with the brain. so one of these priorities of this institute of nida, and also in partnership with the alcohol

with many other institutes and to do that and empowers sufficiently, and do the most sophisticated to evaluate the last cohort, what are the effects of dose exposure in this rate, so that we can answer that question, is exposure to marijuana effects the brain, the

way my brain is connected, the way my brain is functioning. it's interesting, my rates for mental illnesses, and it was a cognitive capacity and we owe it now that the policy changes are happening whether we like themmer not and that in turn is making the use of marijuana much

more acceptable and available, not just for adults but for adolescences and with that i want to thank you for giving me an opportunity to speak to you all about the ups and downs of marijuana and the in betweens. >> well we have another full hour to entertain all your

questions, so please. >> you sowed in the monitoring of user study that high school, alcohol and cigarette use consistently decreased over the last 15 years with all of use of marijuana has remained relatively stable and you said it was increasing, i think it's

stable. anyway, do you think this is evidence that legalization with strict regulation and sound education can effectively reduce adolescent drug use? >> it'll be fantastic and in fact, this is the argument that a lot of these policy makers

with the states will say they're not promoting the legalize ages of marijuana, but we're going to control it but if you actuallyac the number of kids that are exposed to alcohol r there's control, i would say 80% is not much more in the united states where they have been exposed to

alcohol. so we don't do a very good job of controlling and regulatg the sale of alcohol to teenagers. so while theoretically sounds very nice, is actually there's no evidence that we have been able to do isht ventions that

perfect the exposure and in fact, it would be--i think that the [indiscernible] would be very different if it could create a system that actually was shown to work and protected. and colorado where you could see start hopping for example, you see the 30% increase in number

of those and basically letting them out because i'm use of marijuana 5o concept, we are not doing a very good job of controlling these. >> fantastic lecture, i have a question about result in amsterdam, where a legalize marijuanaa for many years, do

you think from a societal level for example, has the iq. levels psychosis rate, et cetera has that been changchanged you know as a society as a whole, having legalized marijuana over many years. >> normally one of the things i did learn was the author of nida

[indiscernible] that actually the rate of use of marijuana among teenagers in amsterdam and very low. most of the marijuana use goes for [indiscernible]. the problem they're having actually right now where there's really an attempt to try to

regulate it, the [indiscernible] has had a lot of trouble because the producers are are porting so they cannot control it and i mean i bring this up because one of the arguments of people make is you will be able to make [indiscernible] revenue without recognizing they are costs

associated with that legalization that in this case is associated with the controlling the exparliamentation of marijuana h. of-exportation of marijuana. so why is it that we have social pat other than of drug use in a country like amsterdam or in a

city leak amster dam like in the united states of canada, with the continued high rates of drug so understanding what it is that they're doing differently would be very important because so they use the frequency. [indiscernible] >> yes i'm paula goredoon i have

a web site on--called gordon drug abuse, i know we talked about this earlier but i want to mention the exchange that you had with the dalai lama in 2013, fall, was extraordinary and you're showing him in a two hour 20 presentation a brain scan of

those who were addicted. i wonder if you could tell us what you're possible action might be with respect to making sure that message that you conveyed to the dalai lama and exchange that you had could reach as many as [indiscernible] for the help of the people who

are addicts tar the help of those who are trying to treat and help them because i finished a hopeful message. >> yeah, i being i was fascinated by the concept of the dale's llama so don't say no, just go, go, go and i was happy, it was [indiscernible] the dalai

lama but the issues are increasing very much was the concept that here you have a man that the lifestyle have optimal ability to control his study, ways that are extraordinary, and very few people can and with therapist is exactly the opposite of what happen when is

someone is is dicked and they lose the control over their own behave. so i was very increeinged about how would we learn from those [indiscernible] that they use in the--like to call it a religion of science on the whole discipline that we coul

implement to and it's a devastating disease and there's the interveks and that's why i went there and there was a fantastic exchange and felt that because it was the web and anybody can look at it. but i tell you it's maybe too long and we may need to make it

short, so i'll ask my staff and see if there's a way of making it show up there so people don't have to spend so much time happening. >> i guess i just had a question on cause and effect. so the had the statistickics on adients using marijuana and then

a decreased likelihood of decreasing college ask suicides but are there statistical studies on whether dollar are pele that may be like a type of people, like had they propense etics maybe not to go to college, like started using marijuana and that's why these

statistics increase or decrease? absolutely that's one of the problem where is i start to say, this whole from the science. >> --can family influence may in tern have determined whether you have strived and improve your i. q. ordinance numberinal so if my brain, i say all of these

stories are actually highlighting that there may be a signal there, but there are not black and white. and that we need to do a study that can [indiscernible] those questions in an objective way and not exaggerating and it's the first thing that people say,

well, why don't you come up and say this is terrible, blah, blah, blah. but we need to host a context, understand what the signal is and what are the errors and we are really pushing for where we're doing this study on 10,000, very well control so

that we can--unequivocally answer these questions and then base on those findings, can you do stories to look at lethality but where the real world basically cannot question. >> i wonder nora you meet with a lot of youngsters, what are the kinds of questions that they ask

you about drugs [indiscernible]. >> well every year actually we get scientists from all over the place and different different institutes and we all sit there and try to answer questions from adolescents from high schools all over the place, and it's actually interesting because

over the years it hashanged some. so these are--these past two years, you know there's been a lot of questions of marijuana clearly driven by this phenomena butee also see a lot of questions for example, which we have not seen in the past about

the electronic cigarettes which is a new device that's permeating in the young people, adolescence that we know--what we want to know is these drugs are harmful, they want to do for a relative drug, they want to know how one of these friends is taken drug what is they should

do? >> do you know why plants secrete a substance like a cannabinoid, does it have value to the species? >> well, george [indiscernible] gave me this fantastic book on plants and it goes into those phenomena and we do know for

nickee teen for cocaine, they have--they protect against inspects for cannabinoids i don't know exactly but we have a cannabinoid expert here. >> does it make the insects woozy going somewhere else? >> for cocaine it's extremely [indcernible] and it's and and

that would mean that some insect smut have these--must have these. >> and you show a bigger increase about emergency departments increase wide cana bus use and i'm sure you know that the thc metabolites stay in the blood for aa long time

because they're lip ophilic and so, how are those now on and related events defined and you think it's really the cannabis that's leading to these events or is it an underlying signal that these people may have used in the past couple of wee. >> that is one of the things

that makes [indiscernible] very difficult with marijuana. now, this is one of the questions how proximal was the event of the concopings and recent mechanism on jama or lung cancer, one of them that's specificspecifically the cardiovascular one and the

proximity of the event and they come through them, the database of these meta-analysis that the evidence is quite strong to suggest that these were associated. because they have not been as rigorous meta-analysis so those are more i clinical reports of

a more much higher risk of individuals that are [indiscernible] with those that have smoked marijuana. where you could say lyou know and i suspect we're going what's going to happen is that the association if you have a risk for popular pathology, the

cannabinoid that may put you over so that the [indiscernible] of high risk. but then [indiscernible]. do have you a quick question? >> [indiscernible]. >> the question is very important because obviously it relates to the fact that you

were speaking about medical marijuana [indiscernible] we need to provide the that evidence it works so the dose is evidence of marijuana having the [indiscernible] potential tdoesn't mean that you can have the [indiscernible] discussing being shown and [indiscernible]

to improve appetite in patients for example with hiv, and there is evidence flaw coma and there's some evidence that it may have antiinflammatory effects but the evidence is not @ a lower level, but then you are proposing the use of marijuana per se, my argument is

that we have technology and science inner tore identify the active ingredients in a plan that are likely to have the most apt maleffect and minimal risk effect and actually know so we're going to use the plan, we don't really know which are the constituents and what are the

concentration but that is the problem that needs to be dressed that someone for example, there's a local thing there right now on the potential use of cannabinoids for kids that have this issue that cannot be controlled with regular [indiscernible] and there are

curnotly three large clinical trials ongoing and nida pro proparticit but this is marijuana that has extremely high content of the [indiscernible] and it's extracting tracting[indiscernible] to give to the children. that's the way.

you have to do it with specific control and regulation or that the ndiscernible] and the content that you're giving. and that's--i would--i would hope that--that research will start to answer those questions and there's currently work ongoing as i mentioned post

traumatec stress disorder and there's work in for alzheimers and it may have antiflammatory effect, but what's interesting to actually hear the presentation of groarnlg because he actually showing that if fact, it's activating microbial and pro inflammation in this

organ but i wouldn't have expected it. i valid expected exactly the opposite but that's how we do science because we can have beliefs and prejudices and we need to find out and if was, great. and if doesn't work then if you

don't want to be prescribing to someone instead of prescribing them something that could help >> bindiscernible]--different parts of the brain? you also mentioned a extraction when the neurons die, we have some [indiscernible] >> well we don't know

specifically but what we know from the cannabinoid system in development, this is very important in forming axonal so if you interrupt that pathway, the connections between neurons do not form properly so again, just purely, purely speculative because the dat is

taking it from rab to bringing it into humans. so the way i was interpreting it, is if do u have the system involving the information of connections and you are actually exaggerating them that may have interfer wide that normal orchesterated and very if i'mly

precise pathways by which the inform each other so i wasn't--i don't think there was any evidence that i know of that cannabind pruce apoptosis of neurons in the brine at the doses that are going to be i don't think there's any evidence but i don't know, i

mean i don't know of anything, if there were because they have a you have polarized my wonderful of everything and the other ones marijuana and you see it and your brain dissolves, those people have been [indiscernible] about the marijuana [indiscernible] i

don't think there's any evidence. >> exactly inspired by can the what of that story. >> we can start it. >> the last question. >> so in ibs, which has any of the mediated factors that are trying to describe this for the

rat model of diabetes cannabinoids appear in the literature as being beneficial, they reduce all sorts of sort of things, do you think that your studies provide a clue as to a possible mechanism where something like that, may actually be occurring?

are you investigating other inflammatory immune diseases? >> cb-two receptors do have inflammatory activity and [indiscernible] has cb-two activities so the net effect depends on the circumstances but that may explain some of the controversy for the cb-one that

[indiscernible] mack wofadges and micro glue mariousa but ph.d. is a [indiscernible] agonist but that may be and there's some, and published evident, and we actually survive the common [indiscernible] ofinate and you are medicine on the paper on that as beneficial

effect on animal model of inflammatory bowels and antiinflammar tow. >> well i have one question for nora is that you very nicely pointed out in the early part of the discussion of the ph.d., is that [indiscernible] low level addiction model citizen

tential relative to nickee teen or other other substances other statistics merges or [indiscernible] designer drugs that sometime vs synthetic drugs that have analogues that are hundred times more potent than thc, and the cardio [indiscernible] dangerous for

cardiovascular events at, thc itself so that could be a danger emerging that these designer drugs start to [indiscernible] for heroine is much more harmful than [indiscernible] from the is there any statistic >> we start to look at it actually for the first time in

[indiscernible] 2012 or monitoring the rate of this and this the cannabinoid, this it was very high, something like 11%, so--okay rapidly it was the first time we research evaluating it so woe were surprise high level in the surprise use of [indiscernible].

--11% but in the media, if you follow the media there's been a serious and many reports of many, many adverse reactions and if you have a myocardial infarct that can you go into a keep and you can die and i think that's interesting because [indiscernible] media attention

showing it can be very harmful but it makes people not want to take it. and what we see, very rapidly following all of this then which is 2012 on the [indiscernible] past two years or [indiscernible] it's been a significant decline in the use

of the cannabinoids machining them so i suspect that what happen system the effects are so potent that they become so one thing that i'm curious know to is that because the idea of the [indiscernible] is going high and high, but that may start to become adverse to

people the first time they take and i come again this, is anecdota that they say, nora i used to smoke when i was a teen agent and are i try today and i didn't like it, it was the effects were very adverse, very anxious provoking, it's a different effect, the concept

and for someone that is used to it may be okay, if you are a first time user consume thanksgiving drug tmakes you feel very avers and may perfect you against [indiscernible]. for the can a--bits nighs, it appears to be controlcontrolled they are very potent and

obviously, it's an issue of concern. >> okay, well, listen i want to thank both of you for a really very talk. thank you all so much.

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