LSD Neuroscience - David E. Nichols
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Not Syncedso i'm gonna give a tiny bit of pharmacology because i don't know how many people here are pharmacologists
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Not Syncedmaybe a lot maybe not a lot
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Not Syncedhow did we study psychedelics without using humans
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Not Syncedwhen I was in a purude university
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Not Syncedworked with receptor targets, most of you know that, but I talk about it briefly
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Not Syncedand when I was doing this talk I had my talk finished
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Not Syncedi thought, you know there is nobody in this conference that talk about research chemicals
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Not Syncedand large number of people these days are getting their first exposure to a psychedelic or an enctatogen
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Not Syncedthrough a research chemical
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Not Syncedso what I did was I changed the whole back in my presentation to talk a little bit about research chemicals
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Not Syncedbecause lot of people don't know what they are
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Not Syncedsadly a large number of them was pilfered from my publications
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Not Syncedso i feel a little responsible for the fact they're out there
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Not Syncedand then I should talk a little bit about if you want to be a researcher, what should you do and that's part of the CME requirement
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Not Syncedso inform patients about new research, refer patients to clinical studies, develop strategies for conducting research and evaluating research
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Not SyncedI'm gonna touch on some of these, but obviously this talk like that would be a 2 hour talk in depth
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Not Syncedso I won't spend a lot of time, i do want to point out that the sort of revolution in neuroscience
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Not Syncedwas catalysed by the discovery of LSD and then few years later the finding that serotonin was in the brain]
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Not Syncedand I think somebody earlier pointed that out, maybe it was Rick, that
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Not Syncedprior to discovery of LSD and serotonin in the brain, psychiatric disorders were thought to be due to poor parenting
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Not Syncedso we had mothers that were called refrigerator mothers, because they had a child with schizophrenia and they would say that's the mothers fault she didn't nurture the child properly
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Not Syncedso there's no connection, so whe they discovered that
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Not SyncedLSD had effects and serotonin was in the brain and the recognition that
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Not Syncedthere was a similarity in the skeletal fragment of LSD and serotonin
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Not Synceda number of people put together the idea well maybe behaviour and mental function is somehow related to neurochemistry
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Not Syncedand that seem sort of silly today because it's obvious thing but back then they thought that brain was sort of an electrical box
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Not Syncednothing about neurochemistry had anything to do with behaviour
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Not Syncedkind of weird thinking, but that's the way it was
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Not Syncedand another thing to point out about psychedelics, and I used to used this definition a lot
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Not Syncedbecause you try to tell people what psychedelics were
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Not Syncedand Jaffe wrote a chapter in Goodman and Gilman which was a pharmacologist Bible
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Not Syncedand I like this definition because it says that psychedelic
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Not Syncedthe feature that distinguishes them from other classes of drugs is their capacity reliably to induce or compel
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Not Syncedstates of altered perception thought and feeling that are not or can not
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Not Syncedbe experienced otherwise except in dreams or at times of religious exultation
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Not SyncedI often give the seminar to pharmacology departments at medical schools
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Not Syncedwhere i give this definition and I say
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Not Synceddo you know of any other pharmacological class that has a definition like that?
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Not Synceda drug that produces religious experience? and so, very unique class
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Not Syncedand i'm preaching to the choir you all know that but just to mention that
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Not Syncedbefore we start
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Not Syncedthis is a list of what I'll call recently published
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Not Syncedclinical studies, that have come out, and i probably dont have everything
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Not Syncedlisted here that's been published but the point
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Not Syncedof the slide is, what i want you to notice is the colouring
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Not Syncedso these purple ones ate the 1990s
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Not Syncedthese red ones are 2000-2010
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Not Syncedand then after 2010, what you see is exponential explosion
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Not Syncedof published studies that relate to clinical research
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Not Syncedon psychedelics. And i think this trend is likely to continue
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Not Syncedso this is really exciting trend and it really obvious when you look at these numbers
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Not Syncedthe literature in this field is exploding, so we're having an impact
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Not Syncedthe key brain receptors
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Not Syncedfor psychedelic are the serotonin 2a and serotonin 2c receptors
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Not Syncedand for tryptamines they also activate the 1a receptor
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Not SyncedLSD is a little bit different
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Not Syncedsomebody have a question?
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Not SyncedLSDis a little bit different because it hits lots of different receptors
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Not Syncedand people used to say that LSD was a promiscuous drug pharmacologicaly
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Not Syncedand then they switched over
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Not Syncedand they started sayin it had rich pharmacology
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Not Syncedbutfrom the point of view of understanding how they work if all these drugs
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Not Syncedthese types of compounds are considered to have a similar action in the brain
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Not Syncedit pretty obvious that the serotonin 2a and 2c
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Not Syncedreceptors are probably the ones that are the most important
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Not Syncedthings like DOM, DOB, 2C-B, the kind of things you hear about
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Not Synceda lot on the streetm activate principally the serotonin
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Not Synced2a receptor, they may not fully activate it but they have a high
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Not Syncedefficacy so they produce a good activation of the receptor
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Not Syncedwe dont know much about the serotonin 1a receptor
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Not Syncedit may be important in distinguishing the effects of the tryptamines from phenethylamines
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Not Syncedand with lsd its uniquely potent so its doing more than just activating these 2 receptots
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Not Syncedand that's the quest i've been on for a long time
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Not Syncedand will continue work on, to try to understand why LSDhas such profound effects
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Not Syncedwhen if you look at its receptor effects at the 2a 2c or even 1a receptor
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Not Syncedthere is no evidence that it should be as potent in humans as it actually is
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Not Syncedso it has unique pharmacology
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Not Syncedso what happens inside the brain cell when we activate these receptors?
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Not Syncedthis is just a model of a brain synapse
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Not Syncedbut principaly these serotonin 2a receptors are located postsynaptically
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Not Syncedso we have release of serotonin in a normal brain
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Not Syncedit comes out of these vesicles and interacts with these receptors
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Not Syncedso LSD or the other psychedelics will bind to these receptors and will induce a signalling in this receptor
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Not Syncedor within the cell
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Not Syncedand they can induce signalling in number of ways
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Not Syncedthey can either fully activate the receptor
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Not Syncedthat what serotonin does, lsd doesn't fully activate it
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Not Syncedits actually fairly weak agonist, so if we look at LSD on this scheme it would probably be over here
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Not Syncedabout 30% of full activation
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Not Syncedso not only does LSD not have the kind of receptor affinity or stick-to-it-iveness
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Not Syncedwe might expect from such a potent compound but it also doesn't activate the receptor fully
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Not Syncedso its maybe related to its mechanism of action
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Not Syncedand an antagonist which dont do anything, BOL as you just heard in a previous talk
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Not Syncedits currently thought to be either antagonist or inverse agonist, an inverse agonist
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Not Syncedactually drops the basal level below this
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Not Syncedso BOL would fit into the scheme there
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Not Syncedwhat happends when a psychedelic binds to the receptor?
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Not Syncedthese receptors are bundles of alpha-helical protein pieces
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Not Syncedthat are fit together in the membrane of the cell
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Not Syncedand when the drug interacts with the exterior part of this receptor,
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Not Syncedit binds inside inside an area that's in between what is called helices 3, 4, 5, 6 and 7 to some extend
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Not Syncedit causes the shape of this protein bundle to change
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Not Syncedand when the shape of that bundle changes, there are pieces of the protein that stick down into the cell
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Not Syncedand they also change, so as the receptor changes, the interor pieces of the protein of the receptor also change
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Not Syncedand when those pieces change they allow it to couple to signalling molecules within the cell
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Not SyncedNow years ago pharmacologists used to talk about a drug that was an agonist
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Not Syncedthat would activate the receptor
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Not Syncedor not activate it. And its alwas thought that the receptor
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Not Syncedwas sort of like a switch, you turn it on and turn it off and signal is produced.
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Not SyncedNow today there is a concept in pharmacology that is called functional selectivity
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Not Syncedwhich means that all drugs don't do the same thing to the receptor
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Not Syncedso imagine serotonin, which is the natural transmitter
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Not Syncedbinding down inside the receptor
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Not Syncedit causes the shape of the receptor to change in a specific way
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Not Syncedand now we have an ensemble, the serotonin inside the receptor
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Not Syncedand that ensemble produces a change in a pieces of the receptor that are inside the cell that allow it to couple
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Not Syncedto some set of signalling molecules
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Not Syncedif we put LSD in there
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Not Syncedor 2C-B or you name your favourite drug
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Not Syncedwhen the receptor binds it doesn't go to the same shape
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Not Syncedthat it had when the serotonin bound, because it's a different molecule
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Not Syncedthis new receptor shape induces new changes
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Not Syncedin the interior part of the receptor and it no longer binds
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Not Syncedthe same way to the same set of signalling molecules that serotonin bound to
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Not SyncedSo we have a possibility of coupling to a lot of different things
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Not Syncedso we have what we call G proteins, those are what
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Not Syncednormally couple to G protein coupled receptors (GCR)
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Not SyncedG alpha I which generally inhibits cellular activity
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Not SyncedG alpha s which typically stimulates cellular activity
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Not Syncedtheres another series of G proteins called G alpha q that I dont have shown here
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Not Syncedthat typically also activate the cell
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Not Syncedit can also be phosphorylated with an enzyme
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Not Syncedthat put phosphate groups on to serines inside these pieces of the receptor
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Not Syncedand that can allow them to interact with another signalling molecule
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Not Syncedcalled beta arrestin, so there are number
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Not Syncedof these signalling pathways that can be activated
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Not Syncedso when a drug binds to the receptor and activates it, it just doesn't turn it on and off, like light switch
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Not Syncedit turns it on and it induces certain amount of signals inside the cell
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Not Synceda different drug produces a different set of signals
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Not Syncedand yet a third drug will produce even a different set of signals
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Not Syncedso we have the complexity of understanding how psychedelics work, because
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Not Syncedthey don't just turn the receptor on and off
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Not Syncedthey induce a whole bunch of different kinds of changes
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Not Syncedand these changes are related to
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Not Syncedthe structure of the drug itself
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Not SyncedSo how does receptor signal change consciousness?
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Not Syncedso this is when the hand-waving comes in
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Not SyncedFranz Vollenvaider will give a talk i think tomorrow
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Not Syncedand Robin Carhart-Harris will also talk about
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Not Syncedsome of the newer technologies involved in looking at how the brain
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Not Syncedactually responds to psilocybin or to other psychoactive drugs
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Not Syncedthe kinds of electrical changes as measured by EEG
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Not Syncedor glucose utilization as measure by PET
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Not Syncedand a number of other techniques
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Not Syncedso what happens?
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Not Syncedwell basically, we don't know clearly
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Not Syncedbut one of the things we know that the serotonin
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Not Synced2a receptor, which is the esential receptor
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Not Syncedfor producing the effects of psychedelics, is highly expresed in
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Not Syncedall of the structures in the brain that are involved in perception
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Not Syncedand counsciousness.
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Not SyncedSo if we look at the top of the brainstem lower midbrain we have a locus coeruleus
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Not Syncedwhich sends norepinephrine projections to the whole forebrain
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Not Syncedwe have the raphe nuclei, the dorsal rapahe is also in the same area as the brain stem
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Not Syncedthat sends serotonin projections to the whole forebrain,
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Not Syncedwe have the ventral tegmental area which also have serotonin 2a receptors
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Not Syncedwe have serotonin 2a receptors both in thalamus
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Not Syncedbut particularly in the reticular nucleus and the reticular nucleus wraps around the thalamus
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Not Syncedso the thalamus has the nuclei that are involved in processing all the senses
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Not Syncedso auditory, vision, sensing, touch
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Not Syncedall of that is processed through the thalamus
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Not Syncedand those signals are sent onto the cortex for final sort of procesing and integration
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Not Syncedwhile the reticular nucleus wraps around the thalamus as a single layer
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Not Syncedand sends inhibitory projections down into the thalamus
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Not Syncedand tells the thalamus what kind of information it should let through
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Not Syncedso we serotoning 2a receptors there, and we have serotonin 2a receptors located on the apical dendrites
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Not Syncedof these cortical cells which are the main processing units in cortex
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Not Syncedthe cortex is where we put together our picture of the world
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Not Syncedits where we make our executive decisions, where we do abstract thinking
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Not Syncedso the cortex is critical to the funtion of higher conciousness
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Not Syncedit's critical to defining who we are
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Not Syncedit's critical to defining whether we're conscious, unconscious
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Not Syncedand its activity is determined by all these other areas
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Not Syncedso any sensory information that comes in, is filtered through
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Not Syncedthe thalamus, that's regulated by reticular nucleus
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Not Syncedwe have the Raphe sending signals to the cortex
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Not Syncedto the apical dendrites, we have a locus corelueus producing norepinephrine
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Not Syncedthere are alpha receptors responding to norepinephine located on these pyramidal cells
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Not Syncedand the ventral tegmental area produces dopamine and also produces activation
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Not Syncedso the confluence of all these things onto these senitive processing units
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Not Syncedwill change the way we perceive things
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Not Syncedchanges the whole process of sensory, perception, and consciousness
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Not Syncedso it's not surprising that something that activate serotonin 2a receptors
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Not Syncedor interacts with 2a receptors will change the way we see
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Not Syncedand experience, because thats a fundamental receptor in the brain in all these areas
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Not Syncedthe serotonin 2a receptors and serotonin 2 receptor, its progenitor
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Not Syncedis probably one of the oldest receptors
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Not Syncedthere's known. Serotonin as a transmitter is thought to be phylogenetically
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Not Syncedprobably the oldest of the monoamine transmitters
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Not Syncedwe consider serotonin, dopamine and epinephrine
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Not Syncedbecause you find serotonin 2 receptors even in single cell organisms like
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Not Syncedparamecium, where is responsible for the movement of the cells
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Not Syncedso you know when nature finds something that works, like serotonin 2 receptor
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Not Syncedit continues to use it and exploit it in ways, and as it turns out exploited it in modulating our perception and conciousness
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Not Syncedone of the problems I had in Purdue university
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Not Syncedworking in the pharmacy school in the midwest
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Not Syncedi had a lot of students who would come and volunteer to be a subject in my experiments
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Not Syncedand i would say well i can't really do that
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Not Syncedi can't even talk about anything i may or may not have done
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Not Syncedi plead the 5th amendment
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Not Syncedso how did we actually do our studies?
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Not Syncedwe spend a lot of time looking at animal models
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Not Syncedtrying to find something that would parallel the activity in animals that we saw in humans
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Not Syncedno animal can model what happens is humans though
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Not Syncedtheres no animal model that can tell you i had a mystical experience
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Not Syncedor i remembered my childhood
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Not Syncedor anything like that, it's a real problem.
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Not Syncedturns out that in pharmacology
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Not Syncedthe whole subject of pharmacology is the study of the action of drugs
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Not Syncedand if you want to understand how the system in the body works
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Not Syncedyou apply the drug that modifies that system
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Not Syncedso for example we know that they are beta 1 adrenergic receptors in the heart
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Not Syncedso if we want to know what beta 1 receptors are doing
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Not Syncedwe can give the organism a drug that stimulates beta 1 receptors
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Not Syncedand if we do we find out that beta 1 receptors control the heart rate
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Not Syncedgive a beta 1 agonist to human their heart will start beating faster
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Not Syncedin a fight or flight response if you hear
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Not Synceda noise at night,
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Not Syncedyou walking down a dark street
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Not Syncedand you hear someone say: Hey hippie, what are you doing down here?
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Not Syncedwhat happens: your heart start beating, you start going [quick breathing]; that's epinephrine produced by adrenals
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Not Syncedand it stimulates beta 1 receptors in the heart
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Not Syncedso similarly we can argue to study consciousnesses
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Not Syncedwe can use agents that perturbs consciousnesses, so, psychedelics
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Not Syncedthey're the best drugs to look at consciousness and how we can perturb it
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Not SyncedI like to use this slide, but I don't hear the sound that goes with it
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Not Syncedso if you could hear this you would hear Grace Slick singing The White Rabbit, right
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Not Syncedanyway, the ones that mother gives you don't do anything at all, but the ones Sasha gives you would probably have some effect
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Not Syncedwe use the techinque called drug discrimination, the two-lever drug discrimination
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Not Syncedand it's actually a pretty good model for what these drugs do
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Not Syncedwe have an operant chamber that has two levers in the front
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Not Syncedand we can train the rats to press one lever or another
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Not Syncedso if we give a rat a drug, LSD in this case, what we can do is turn on the right lever
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Not Syncedand this is a trough that delivers 50mg sucrose pellets, so it's rat candy
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Not Syncedso we put the rat in the box, we turn this level on, and he'll explore the box, and learn that if he presses this lever he gets a food pellet
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Not Syncedif he presses the left lever, nothing happens, we turn if off
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Not Syncedthe next day we put the rat in, we turn on the left lever, and we give him nothing, placebo
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Not Syncedand he presses the right lever, nothing happens, he presses the left lever he gets food pellets
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Not Syncedthe next day we give him LSD, we put him back in, we turn on the right lever, we give him food pellets if he presses the right lever
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Not Syncedit takes 2-3 months to train rats to do this, but once you do, the rat will recognise very reliably the effects of a drug like LSD
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Not Syncedand when you train rats and they're really well trained they'll press to get a good pellet anywhere from 1500 to 2500 times in a 15 minute training session
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Not Syncedso they're really pressing that lever
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Not Syncedand the way it works is, there's something unique about this called the third state hypothesis
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Not Syncedif you now give the rat some other drug, like amphetamine or MDMA, and he's been trained with LSD, he won't respond on the LSD lever, he'll respond on the non-drug lever
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Not Syncedso they uniquely recognise the drug they were trained with
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Not Syncedso if we give this rat a drug that we've made that we think might have activity like LSD, and we've trained them on the right lever
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Not Syncedhe presses the right lever, he's telling us "I think you gave me LSD"
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Not Syncedand if he doesn't press it, he presses the left lever, "I don't think you gave it to me"
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Not Syncedso we always tested our compounds after we started using this in about 1984
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Not Syncedwe've tested our compounds with drug discrimination, and it actually is a fairly good assay
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Not Syncedthis is just a correlation that I put together some years ago where we look at the relative potency compared with LSD in rats
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Not Syncedand relative potency compared to LSD in humans
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Not Syncedand the numbers aren't exact but you see here the ETH-LAD compound we made which is more potent than LSD in humans
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Not Syncedit's also more potent in rats
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Not Syncedwe have a relative potency of about 185 which is exaggerated compared to its actualy potency which is around 140 times LSD
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Not SyncedLSD is 100, DOB 2.37, DOI 9.26, psilocin 2.61, MDMA 2.4, mescaline .06
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Not Syncedso there's a good general correlation
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Not Syncedthis assay works well, but will sometimes give you false positive, so it will sometimes tell you something is active when in humans it may not be active
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Not Syncedbut it was a mainstay of all the biological work in animals that we did and it served us well
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Not Syncednow I'm gonna talk about a compound that we worked with some time ago that some of you may of heard of called 25I-NBOMe
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Not Syncedthat's an extremely potent compound, there have actually been a couple of deaths from overdose
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Not Syncedthis stuff the dose of it is about 500 micrograms, 200-500 micrograms
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Not Syncedpeople have gotten hold of a pure powder, they insufflate it up their nose and die
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Not Syncedand I'm just going to tell you how we did a little bit of work with this before it actually came out as a so-called research chemical
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Not Synceda German fellow called Rolf Heim (?) had published that these compounds with an N-benzyl were very potent
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Not Syncedand we were interested into whether they would actually have psychedelic-type effects
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Not Syncedso here's a compound called 2,5-dimethoxy phenethylamine, it's basically inactive in humans but we used it as a model for early studies
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Not Syncedthis is the affinity, which is how tightly it sticks to the receptor, so 300nM is not a particularly potent compound
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Not Syncedif you put an N-methyl on this compound, you see it gets even worse, you see it gets up to 1900
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Not Syncedit's even less effective in binding
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Not Syncedadd an N-propyl, which is even larger, there's about comparable decreased affinity
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Not Syncedso if you put something onto the nitrogen of these phenethylamines, generally it ruins their activity
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Not Syncedif you take DOB and you put a methyl on it, almost kills the activity
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Not Synced2C-B, you put a methyl on it, almost kills the activity
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Not Syncedby contrast, when you put an N-benzyl on, the affinity goes from 380 to 68 nM
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Not Syncedand if you put a methoxy over here, it goes to 2.8nM
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Not Syncedso this is really curious; you put stuff onto the nitrogen, the activity goes down, way down
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Not Syncedbut if you put on a benzyl or a methoxy-benzyl, it goes up
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Not Syncedand this compound with an iodo is the 25-I-NBOME, and the affinity in this case 0.04 nM, so it's a super potent compound
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Not Syncedso we did a lot of work trying to model the receptor, and our earliest work with an activated model of rhodopsin
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Not Syncedwhich we converted into a serotonin 2a receptor
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Not Syncedand this is something in March of 2013, the crystal structure of the human serotonin 2b receptor was published
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Not Syncedthis shows it with ergotamine bound, which is the way it was crystallised
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Not Syncedand we've now converted that into a homology model, this is now the serotonin 2a receptor
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Not Syncedand this is LSD bound
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Not Syncedso we now have a very good receptor model to go in and look at what these things actually do
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Not Syncedso early on, after doing some virtual computer docking with this N-benzyl compound, it appeared to us that the N-benzyl, which is right here
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Not Syncedthis thing that's in spheres is the N-benzyl compound
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Not Syncedand these things that are labelled here are the residues that are in the active site, the binding site of the serotonin 2a receptor
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Not Syncedand we docked it in virtually, we saw that this N-benzyl groups appeared to be interacting with phenylalanine 339
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Not Syncedas a kind of edge-to-face interaction
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Not Syncedso we thought, let's mutate all these residues and see if that assumption if that assumption or that hypothesis is true
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Not Syncedso we mutated that phenylalanine to leucine
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Not Syncedso phenylalanine is like a benzene ring, it's aromatic
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Not Syncedleucine is just a series of aliphatic carbon atoms, you lose the aromatic character which is necessary for these rings to stack if it binds in the receptor
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Not Syncedbut it still keeps some hydrophobicity
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Not Syncedso when we looked at the mutated receptor, where that phenylalanine was mutated, now we put those compounds in, we saw the affinity drop from 380 to 4200
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Not Syncedso about a tenfold drop in affinity, about a fivefold drop in affinity and in this case a sixfold drop in affinity
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Not Syncedso that didn't tell us anything, but when we looked at the N-benzyl, you see when we did the same mutation we got a 40-fold drop in affinity, and a 500-fold loss in affinity with the methoxy-phenyl
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Not Syncedso this was strong was strong evidence that that residue, phenylalanine 339, was interacting with the N-benzyl group
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Not Syncednow with our new model now, we're trying to dock these compounds in and get a better idea of how exactly they're fitting into the receptor
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Not Syncedone of the other things we did though was to try to discover what shape that molecule might have when it bound to the serotonin 2a receptor
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Not Syncedso we made a whole series of compounds, so here's a compound 2C-B, its affinity is about 6nM in a series of experiments, and here's the N-methoxy-benzyl-2C-B, about .2nM
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Not Syncedso you can see the increase in potency, 6 down to .2
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Not Syncedso we use this is a model because the bromine atom was easier to get on than the iodine, so we made most of our compounds with bromine
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Not Syncedand I had a fairly large group of students so I assigned each student one of these molecules
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Not SyncedI said let's make all the possible combinations of 2C-B with the N-benzyl group attached
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Not Syncedso in each one of these although it's not immediately obvious, they all have the equivalent of an N-benzyl
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Not Syncedso here's the 2C-B nitrogen, and here's the N-bencyl
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Not Syncedhere's the 2C-B nitrogen with the N-benzyl
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Not Syncedhere's the 2C-B nitrogen and the N-benzyl is over here
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Not Syncedhere's the N-benzyl down here
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Not Syncedthis one is a little harder to see, 2C-B is here, here's the N-benzyl
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Not Synced2C-B is here with the N-benzyl
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Not Syncedand then this one substituted, this is this so they're on the same side of the ring, and this is trans on the opposite side of the ring
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Not Syncedand the affinities for this compound is 2.6nM
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Not Syncedwe actually crysallised this into its stereoisomers, this is a pure stereoisomer, and this is the one that's most active
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Not Syncedso though we don't strike the .2nM affinity, if you look at these, 70, 2000, 160, 170, 300, 800, 800, 2.8
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Not Syncedwe're pretty sure that that represents the shape that these N-benzyl compounds mainatin when they bind to the receptor
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Not Syncedso we're doing docking studies now to see how that fits into the receptor
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Not Syncedwe get a better understanding of how this super potent compound can activate the receptor
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Not Syncedso what I did when I changed my talk was to cut out the back end and talk about research chemicals
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Not Syncedand I don't think anybody here at this conference is talking about research chemicals
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Not Syncedso I thought that this we should really spend some time on because a lot of people are taking these
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Not Syncedthey don't know what they are , they don't know where they came from
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Not Syncedand a lot of young people their first experience with a psychedelic-type compound is one of these research chemicals
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Not Syncedand there are several kinds of research chemicals that we could talk about
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Not Syncedthe psychedelics, the entheogens, the psychostimulants that are like amphetamine, or entactogens or empathogens
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Not Synceddepending on what you prefer
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Not Syncedsynthetic cannabinoids, and I'll briefly talk about those
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Not Syncedand ketamine analogues, there are one or two of those out there, I'm not going to spend time on those
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Not Syncedbut there is a methoxy-substituted ketamine analogue out there that people seem to be using quite a bit
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Not Syncedalso I'd point out that this paper just came out, I just got it for review a week ago, showing that lifetime use of psychedelics in the US population in 2010 is over 30 million people
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Not Syncedand that includes LSD, psilocybin, mescaline and a lot of other things were not classified
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Not Syncedso there's a large number of people that are using these
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Not Syncedso psychedlics, or hallucinogens, we know they're characterised by changes in perception, thought, feeling, distortion of space
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Not Syncedfeelings of portentiousness, something important is about to happen
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Not Syncedhigh doses can elicit anxiety, or psychotic behaviour
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Not Syncedgenerally they have low toxicity and non-addictive
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Not Syncednow the peculiar thing about the 25I-NBOMe compounds is they have killed people
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Not Syncedthere are no overdose deaths from LSD, mescaline, psilocybin
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Not Syncedsome of these newer so-called research chemicals do have toxic properties that are not fully appreciated
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Not Syncedthe psychostimulants are related to amphetamine, they produce elation and euphoria, give you energy,
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Not Syncedbut their chronic use or high doses can produce depression and fatigue, dependence and continued can produce acute psychosis, amphetamine psychosis
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Not Syncedand most psychostimulants have cardiovascular effects
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Not Syncedthey release norepinephrine into the circulation and that causes blood vessel constriction, and that's a major toxic problem of some of the research chemicals
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Not Syncedand entactogens also produce elation and euphoria, depending on the dose and the pharmacology
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Not Syncedlarge doses or chronic use can produce depression and fatigue
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Not Syncedand high doses can also produce psychotic behaviour
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Not Syncedpeople who repeatedly take large doses over short periods of time most these also have cardiovascular side effects because they release norepinephrine
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Not Syncedthey cause vasoconstriction
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Not Syncedthese are different from psychostimulants, the pure amphetamine, and in the beginning when MDMA was brought out and there was a lot of publicity
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Not Syncedthere were drug abuse experts who said well, MDMA is just another methamphetamine
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Not Syncedwe all know today that MDMA is not just another methamphetamine
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Not Syncedwe did a number of experiments in the early days to prove that MDMA was not just another amphetamine or methamphetamine
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Not Syncedwe also proved it wasn't another psychedelic amphetamine, that it had a specific category
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Not Syncedand many of you know that I created this name entactogens so set them off as a specific class of drugs
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Not Syncedso they wouldn't be lumped into the hallucinogenic amphetamine class
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Not Syncedthey are dfferent; I collaborated with a fellow in Germany named Wilfred Dimpfel who planted electrodes in the brains of rats
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Not Syncedgive them different drugs and then we'd characterise the power spectra
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Not Syncedso frontal cortex, hippocampus, striatum and reticular formation
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Not Syncedand then separated these into six frequency bins, and could do pattern recognition
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Not Syncednow clearly here's amphetamine, LSD and MDA, and although there's some similarities, each one is unique
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Not Syncedand so it's possible to show that electically in the rat brain they also were distinct and that ... psychostimulants were different from entactogens and also psychedelics
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Not Syncedso most of the research chemicals target receptors or reuptake sites for monoamines
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Not Syncedwe talk about the phenethylamine type, typically they're interacting with targets for serotonin, dopamine or norepinephrine
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Not Syncedand depends on the substituents on the aromatic ring what kind of pharmacology you will actually get
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Not Syncedso we had the G-protein coupled recptor and this would include the serotonin 2a receptor showed you earlier
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Not Syncedthese seven transmembrane helices bound together, they couple to intracellular signalling
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Not Synceddopamine, serotonin, norepinephrine, cannabinoid receptors that are all members of this GPCR family
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Not Syncedwe have things that interact with reuptake transporters
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Not Syncedso after transmitters are released from the nerve terminal, there are specific protein that pump the transmitter back in to conserve it, reuse it
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Not Syncedwe have reuptake transporters for dopamine, norepinephrine, and serotonin
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Not Syncedand things like cocaine block these transporters so they can't transport at all
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Not SyncedMDMA and amphetamine actually get inside the substrates for the transporter
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Not Syncedonce they get inside, they displace the stored dopamine, serotonin, norepinephrine
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Not Syncedand it spills out in the reverse direction through the transporter
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Not Syncedketamine and some of the others interact with what is called an ionotropic receptor, a glutamate receptor
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Not Syncedand I'm not going to spend any time on those but that's a third kind of target
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Not Syncedso the reserch chemicals typically they hit either this or this
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Not Syncedthe psychostimulants and entactogens they're principally interacting with the reuptake transporters
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Not Syncedand the psychedelics and cannabinoids they're principally interacting with a GPCR
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Not Synceda G-protein coupled receptor
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Not Syncedin terms of preclinical characterisation, we work with a lot of these in the lab
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Not Syncedhallucinogens have affinity for serotonin 2a receptors, and in drug discrimination in LSD-trained rats we get generalisation
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Not Synced
- Title:
- LSD Neuroscience - David E. Nichols
- Description:
-
http://psychedelicscience.org
Help us caption and translate this video on Amara.org:
LSD Neuroscience
David E. Nichols, PhD
Abstract: This talk will provide a foundation for understanding the importance of 5-HT2A receptors in the brain, now widely believed to be the key brain target for psychedelics. The study of this G protein-coupled receptor (GPCR) has required research efforts across several disciplines. Although it was initially thought to couple only to Gq, leading to activation of phospholipase C, it is now known to couple to multiple intracellular signaling pathways. The unique psychopharmacological properties of psychedelics clearly demonstrate that this receptor has special importance as a critical component of sensory perception in humans, and by extension, may be a key player in mediating consciousness. This presentation will focus on current understanding of the structure-activity relationships of psychedelics at the 5-HT2A receptor from a molecular perspective that has included synthesis of libraries of compounds, in vitro effects on cloned wild-type and mutated receptors, in vivo studies in rats, and computational chemistry.
Until his retirement in June 2012, David E. Nichols, PhD, was the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology, and a Distinguished Professor of Medicinal Chemistry and Molecular Pharmacology at Purdue University. He also was an Adjunct Professor of Pharmacology and Toxicology at the Indiana University School of Medicine. He currently is an Adjunct Professor of Medicinal Chemistry at the University of North Carolina, Chapel Hill.
Nichols received his PhD from the University of Iowa in 1973, followed by a postdoctoral stint in Pharmacology. From his time as a graduate student, Nichols focused his research on the relationship between molecular structure and the action of substances that modify behavior. His research took him to Purdue University in 1974, where he remained until his retirement this year.
His research was funded by government agencies for more than three decades. Internationally recognized for his research on centrally active drugs, he is one of the world's foremost authorities on psychedelic agents, and founded the nonprofit Heffter Research Institute in 1993. He also was a pioneer in the study of the medicinal chemistry of dopamine D1 receptor agonists, and in 1991 he and his colleagues first showed that dopamine D1 agonists had remarkable efficacy in a primate model of Parkinson's disease. He consults for the pharmaceutical industry and has served on numerous committees and government review groups.
More videos available at http://psychedelicscience.org
At Psychedelic Science 2013, over 100 of the world's leading researchers and more than 1,900 international attendees gathered to share recent findings on the benefits and risks of LSD, psilocybin, MDMA, ayahuasca, ibogaine, 2C-B, ketamine, DMT, marijuana, and more, over three days of conference presentations, and two days of pre- and post-conference workshops.
- Video Language:
- English
- Duration:
- 01:11:15
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