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Welcome, everybody. It's so nice to see so many

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of you here this morning. So I'm gonna be talking about GABA.

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What's GABA got to do with it? R.

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I. P. My name is Dr Scott.

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Sure. I'm the chief operating officer of Health

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Optimization, Medicine and Practice. Our nonprofit organization training

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doctors like you and practitioners

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like you how to optimize health rather than treat disease and treatment.

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I have a lot of fun with this talk.

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I've, this is something that actually Dr.

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Ted and I, but mostly Dr. Ted developed as a strategy for

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our overall understanding that

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nobody remembers the most important neurotransmitter in our opinion, GABA.

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Everybody remembers serotonin and dopamine and norepinephrine.

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These, these are the fancy ones. Everybody knows about these, but

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everybody forgets about GABA.

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So this is going to be a talk on how GABA is made, what GABA

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is and why we should care. Let's talk about top

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symptoms of GABA deficiency.

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So if you have a clinical practice, you probably have some of your

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patients with these symptoms. Anxiety, fear, depression, a short temper,

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phobias, impulsiveness, disorganization,

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addictions, schizophrenia, obsessive compulsive disorder.

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Any of your patients have any of these? Probably, right?

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But you're not thinking about GABA deficiency most of the time.

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And then systemic symptoms, these are also associated with GABA deficiency.

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IBS, diarrhea, high blood pressure,

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tinnitus, chronic pain, migraines,

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allergies, frequent urination, flushing,

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sweating, salt cravings, muscle tension.

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So all of these, could potentially

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be showing you that your patients and clients may have a GABA deficiency.

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It's not the first thing on many of our radars, of course, but maybe

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it should be part of that initial understanding of what might be going on.

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GABA is really important, and now even

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the drug industries are getting the idea.

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So this is the first drug Approved just recently.

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This is a New York Times article. The first pill for postpartum depression.

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And it's called, Zuranolone, I think is how you say it.

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And it is a positive allosteric

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modulator of the GABA receptor. We'll talk about what that is.

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But it's supposed to be used for the first 14 days.

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Only for two weeks. Supposedly, while you're taking another

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drug like an SSRI for that to work, but these work right away because

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it's affecting the GABA receptors s directly and improving depression almost

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immediately, too, which is pretty awesome. You don't have to go directly to drugs, of

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course, but sometimes they're necessary. So, let's talk about GABA synthesis.

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GABA is only made in the brain. Okay, you have to have glutamine,

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which is an amino acid, it's converted into glutamate.

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in the brain. And then glutamate is our

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excitatory neurotransmitter. And you have GABA, which is our

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inhibitory neurotransmitter. So 20 percent of the brain's

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neurotransmission is actually GABA.

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So it's a huge amount. And glutamate in GABA combined

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is about 80 percent actually. So it's the combination of the two is the

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majority of your neurotransmitter system.

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And to make glutamine into GABA, you need.

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You need this enzyme called glutamine synthesase. And then from glutamate to GABA itself,

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you have to convert this, you need vitamin B6, and you need magnesium.

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So you need cofactors along the way to make this conversion happen.

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Some people are really great at converting GABA into GABA.

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Some people are not very good at it. And a lot of times it's related to these

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cofactors, but there's other reasons, too. And see, here are some of those reasons.

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So, If you have a high copper level

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and a low zinc level, you're not going to be able to actually have the

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GABA receptor work as effectively. If you're vitamin B6 deficient, you're

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also not going to convert well from glutamate to GABA, as I mentioned.

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If you have chronic stress, if you have chronic hypercortisolemia, if

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you're always stressed, you're going to deplete your GABA system, and then

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your GABA levels are going to go down. If you're magnesium deficient, and

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most of our clients and patients are magnesium deficient, they're

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not going to convert well either. If you have infection, this

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is going to stress the system and also decrease GABA levels.

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Now, GABA supplementation may help your

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GABA levels, but actually under most circumstances it's not going to because

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GABA itself is a big molecule and doesn't

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go across the blood-brain barrier. Under , certain circumstances, it

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may, and we'll talk about that. And then probiotics can also help with

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this conversion, help with this enzyme. So, you can actually measure, and

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you saw some of these slides with Dr. Ted, you can actually measure

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people's vitamin B6 level, and if

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it's low, it's very likely they're not converting well from glutamate to GABA.

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So this is something to be thinking about, and this is why we do

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metabolomics testing as well.

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You can check their magnesium level. In this patient, in this client, it

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was a normal magnesium level, this is red blood cell magnesium, but a lot

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of our clients, it's going to be low. So if you have a low magnesium

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level, if you have low B6 levels.

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You're not going to convert well from glutamate to GABA. This is the GABA receptor.

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You don't have to worry about this too much. Just to know that it's a pentameric structure.

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It's got five subunits. And these subunits change depending on

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where the GABA receptor is in the brain.

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Sometimes they'll look one way and

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they'll have various combinations depending on what they're doing. GABA is everywhere in the brain.

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These GABA receptors, the subunits change depending on what's required and

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what's going on in that particular area. So this is the mechanism of the

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GABA receptor, so we're going to start with GABA A here.

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So you have activation of the receptor, you have opening of the central pore,

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you have influx of chloride, you have hyperpolarization, you have decreased

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occurrence of the action potential. So this all is saying that you're

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inhibiting the actual firing

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of this particular neuron that has the GABA receptor.

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So you're inhibiting the action potential. So you're stopping things, you're

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calming things down in general. Chloride goes through,

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and it hyperpolarizes. This is the GABA B receptor.

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It's called a G protein couple receptor. It's a little bit different, and it's

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called a metabotropic receptor, and I'll show you what this means in a minute.

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This is GABA B. So, GABA B itself, what it does,

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it's a presynaptic and postsynaptic.

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So, presynaptically, it's preventing, here, the release of an excitatory

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neurotransmitter, glutamate, which is what we've been talking about before,

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is the conversion of glutamate to GABA. And then you have the postsynaptic, here,

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which is increasing potassium outflux,

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which causes the hyperpolarization. It's a little bit different, and

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there's a different distribution of the GABA B receptors in the brain.

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So here's a quick summary. So GABA A is, it's called an ionotropic,

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or it's a ligand gated channel opening, and it's a pentamer structure.

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It's widespread as post synaptic influx.

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It's endogenous agonist is GABA.

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You have other drugs acting on it, which we'll talk about in a minute.

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Pharmacological actions here and then

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GABA B is, as you see here, it's

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also widespread, it's metabotropic, it's presynaptic and postsynaptic,

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and it has these particular, pharmacological actions as well,

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all right. So. There's a couple definitions here.

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So orthosteric ligands, these are chemicals that interact with

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the same binding site as the natural endogenous chemical.

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In this case, we're talking about GABA itself.

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So an allosteric ligand or allosteric

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modulator is something that works by

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modifying how the receptors behave when it's bound to the orthosteric ligand.

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So in this case, we're talking about a separate site.

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away from GABA that binds this

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particular modulator and then makes

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GABA work better or helps the binding or

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improves the chloride channel opening. And then a positive allosteric modulator

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is something that binds and it causes this positive response where you have

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an increased affinity of GABA to bind, you have more chloride going through,

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and you have more hyperpolarization. So this is a picture of the

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GABA receptor and ligand. So here's a couple, examples of

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what it looks like to have where GABA is binding and where some of

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these other drugs will bind to.

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So you have alcohol everybody used

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to love or maybe still loves alcohol. It's got a very high affinity

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for the GABA receptor. Very, very high affinity.

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Benzodiazepines here, very

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high affinity as well. Has anybody ever used Flamazenil before?

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I used it a couple of times in residency, I don't recommend it.

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It causes seizures because it has the opposite effect.

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GABA antagonist, so it prevents the chloride channel from opening.

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Zolpidem, which is the Z drugs, Ambien and others, they bind and bind

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very tightly to the GABA receptor. Quaaludes, anybody ever tried a Quaalude?

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I don't know how everybody, yeah. Dr. Ted, no, no.

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This is back in the 70s. So, but they also were, , A GABA

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binding here, an allosteric site, barbiturates, which we use sometimes

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for alcohol withdrawal, actually. Sometimes we'll still use those,

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but for pretty much not used otherwise, general anesthetics.

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And then finally, the GABA is where it's GABA binding itself.

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So that's where GABA is binding. And so all these other sites on the

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GABA receptor are places where other

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molecules can bind, increase or decrease

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the affinity of GABA binding and increase or decrease chloride channel opening.

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It's on the right side of your screen over there.

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You can see just a top view of the same thing happening.

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Benzos are probably the most common positive allosteric modulator of

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the GABA receptor that we use. Unfortunately, Benzos

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have a very high affinity. We're talking about Ativan,

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Xanax, Valium, those kinds of

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drugs have a very high affinity. affinity for the GABA receptor.

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So when somebody is taking these

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medications for long periods of time, they cause tolerance, they cause withdrawal,

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they can actually cause hallucinations

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and death and all those fun things too. So, but you can see here that what I

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wanted to point out is that there's different subunits of the Alpha

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1 subunit of the GABA receptor is

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associated with sedation hypnosis. So this is actually a lot of

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your Z drugs, like your Ambien's

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and Lunesta's of the world. And then your Alpha 2 subunit is.

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It's more of your anxiolytic and muscle relaxer.

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So this is where your benzo is going to mostly bind.

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So in general, positive allosteric modulators are less addictive overall.

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However, that's not the case obviously for benzos and barbiturates and alcohol.

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And some of the natural equivalents that we'll talk about do have less of affinity,

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but still have significant impact. So drugs that act on the GABA

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B receptor, the most famous being, GHB gamma hydroxybutyrate.

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GHB is well known as the , date rape drug. But it's actually a fantastic drug

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for muscle relaxation, sleep, and

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has lots of great other indications,

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including narcolepsy actually. If anybody lives, listens to our podcast,

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the Smarter Not Harder podcast, I had a

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really great conversation with a guy named Dan Party, who was involved in getting

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GHB to market for pharmaceutical reasons

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with very interesting talk with him. So we're going to switch over here.

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So GABA cell GABA in general.

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The cells that have GABA receptors are mostly what we call inter neurons.

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These are neurons that are between neurons, inter neurons,

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and they're really important for learning, for memory, for behavior.

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They're kind of like the way stations between sensory and motor

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processing, and even though they're

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really small, like if you can't really see here, but it's a tiny one.

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Like, the GABA here, but this is the big dopamine receptor, , neuron, the big

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5 HTP, the big serotonin neuron here. But you have, like, the small GABA.

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This is doing a lot of the processing between them.

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So they're extremely important, and they're actually in these locations

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to make sure that they can actually be those wave stations to prevent signaling.

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Oftentimes, in our brain, it's actually preventing signaling

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that's most important, not propagating, interestingly enough.

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Okay. So we're going to talk about how

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you can dim your GABA switches without a prescription required.

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And, but the first thing to say is that most GABA supplements don't work.

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And we, and I was mentioning that earlier, it's because GABA is such

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a big molecule, it doesn't get across the blood brain barrier.

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If you do have patients that are taking GABA and they are getting an effect,

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it could mean that they have a leaky brain, leaky gut axis, potentially.

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There are some formulations, maybe nanoliposomal, for example, that may work.

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But in general, if they're getting a significant impact from GABA itself,

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at least clinically, I've seen that they often have a leaky gut, and that

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usually means they have a leaky brain. I don't like telling patients

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they have a leaky brain because that doesn't sound that great. I usually say that your

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blood brain barrier may not be as great as it should be.

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But anyway, so you can also, of course, give glutamine and glutamates.

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So glutamine is an amino acid, it's

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in various types of foods, meat,

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Spinach, and fish as well, of course.

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And so you can get glutamine from a lot of different sources, but what we do in

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health optimization medicine and practice, we test for these kinds of things.

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We test vitamin B6, we test for magnesium, we test their

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glutamine levels, and we can tell. And if they have a certain symptomatology

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and they have certain co factor

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deficiencies, well, you know, we know that they're probably GABA deficient too.

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MSG. Everybody loves MSG. Everybody actually doesn't love MSG.

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It's monosodium glutamate, right? This is what you can get

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in Chinese restaurants. They make the food nice and sweet

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for you, but you get a headache. That's because you get all of a sudden

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this huge rise in glutamate, and you have

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to get that conversion over to glutamate, to GABA, and that can take some time.

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And nicotinyl GABA. So this is a really cool form of

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GABA that's attached to a vitamin B3. And when you do this, you actually

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allow this molecule, nicotinyl GABA, to get through the blood

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brain barrier very easily. And then it hydrolyzes

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to vitamin B3 and GABA. And when that happens, you get this

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nice vitamin B3 effect, which is mild vasodilation and mild energy

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production, , At the same time, your

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GABA itself, getting into the brain, increasing, your GABA ability and

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increasing GABA binding to its receptor. So relaxation.

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What's nice about this is it's not very sedating for most people.

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So if you have anxiety and stress during the day, you can take nicotinyl

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GABA and you don't feel tired. You just don't feel stressed, anybody use

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valerian root before for patients, right?

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So very common. This is actually a valerian

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root, something that actually binds to the benzo site.

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So it's a positive allosteric

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modulator of the GABA receptor. Doesn't bind as tightly, but it does work

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really well for some people for sleep. Covain, which is the

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active ingredient in Kava. It's actually a similar binding site.

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Also a positive allosteric modulator of the GABA receptor.

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Honokyl. Anybody used Honokyl as well?

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So this is from Magnolia Bark. Also binds as a positive allosteric

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modulator to the GABA receptor.

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Works really well, for a lot of people. Does anybody know what this is?

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It's a mushroom it's a very famous mushroom. It's called Flyagaric, or

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Amanita muscaria is the other name for it, of Christmas lore.

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Does anybody know about the Christmas tales of Amanita?

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Amanita has two compounds in it, mostly.

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It's got a lot of other things, but two major ones. One is called agarin, otherwise

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named muscimol, and another one is called ibotenic acid.

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Ibotenic acid is neurotoxic. This is the one that mostly causes

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the psychedelic experiences of

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taking this particular mushroom. But, you don't mostly take

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this mushroom directly. The stories were that shamans would

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drink the urine of reindeers, because

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reindeers would be able to tolerate this.

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Okay. And then the shaman would actually then urinate.

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And then other people would drink the urine. This is in Northern.

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You can, this is actually a great New York times article on this with some

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great videos as well, but that's mostly because the toxicity is because of

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ibotenic acid, but agarin or muscimol

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is a fantastic orthosteric ligand of

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the GABA receptor, which means That it

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directly enhances GABA in the system,

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and it does it very effectively. But the key is to have

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it at very low doses. So it's a GABA receptor agonist.

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It easily crosses the blood-brain barrier. It's got a high potency, it's long-acting.

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It's about 6 to 10 hours overall for a half-life.

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It's naturally occurring, or you can make it synthetically, in low doses.

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It's safe and effective. And at high doses it can be

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hallucinogenic, but usually in, in combination with the Ibotenic

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acid and the actual musher. Non pharmacologic, of course, yoga,

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meditation, breathwork, anything that's going to make you more

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parasympathetic is also going to increase GABA tone in the brain.

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Physical activity also helps reset the system and the balance between glutamate

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and GABA, so also being physically

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active is also really important. And then, finally, it's really

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important, and this is kind of the ethos of health optimization medicine

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and practice, is we're detecting and correcting at the metabolomic level.

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And so, you really want to be keeping the GABA deficiency aspect

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of things on your clinical radar. So we test for the nutrients.

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We test for magnesium. We test for vitamin B6. We ensure optimized GABA production.

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And you want to do that as sort of your baseline for everybody.

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So when somebody comes to see me, I'm not looking for GABA deficiency exactly.

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What I'm doing is doing a full metabolic, metabolomic profile,

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correcting as I see, and then you often

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will see these improvements in mood and depression and anxiety because

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you're actually working on that. neurotransmitter system.

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Sometimes you can give herbals and you can give supplements and

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things like that to help right now. That's what the company, the

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transcriptions company is all about. But the key for the long term is to really

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work on that foundation and optimize it. Of course, you want to implement dietary

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and lifestyle measures to boost GABA production, considering herbal and fungal

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GABA agonists and orthosteric ligands to support GABA production as well.

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And then you want to really want to avoid your benzos and your barbiturates,

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obviously, and drugs that are going to

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cause dependence, withdrawal, intolerance. I mean, that's just important

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for us to think about. Sometimes it's unavoidable and I use

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these in my patients when they really need it, but oftentimes we can get

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away with not using them because we have a lot of great options here from

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an herbal and fungal perspective. Thank you guys very much for listening.

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I really appreciate your time.