Welcome, everybody.
It's so nice to see so many
of you here this morning.
So I'm gonna be talking about GABA.
What's GABA got to do with it?
R.
I.
P.
My name is Dr Scott.
Sure.
I'm the chief operating officer of Health
Optimization, Medicine and Practice.
Our nonprofit organization training
doctors like you and practitioners
like you how to optimize health rather
than treat disease and treatment.
I have a lot of fun with this talk.
I've, this is something that actually Dr.
Ted and I, but mostly Dr.
Ted developed as a strategy for
our overall understanding that
nobody remembers the most important
neurotransmitter in our opinion, GABA.
Everybody remembers serotonin
and dopamine and norepinephrine.
These, these are the fancy ones.
Everybody knows about these, but
everybody forgets about GABA.
So this is going to be a talk
on how GABA is made, what GABA
is and why we should care.
Let's talk about top
symptoms of GABA deficiency.
So if you have a clinical practice,
you probably have some of your
patients with these symptoms.
Anxiety, fear, depression, a short temper,
phobias, impulsiveness, disorganization,
addictions, schizophrenia,
obsessive compulsive disorder.
Any of your patients have any of these?
Probably, right?
But you're not thinking about
GABA deficiency most of the time.
And then systemic symptoms, these are
also associated with GABA deficiency.
IBS, diarrhea, high blood pressure,
tinnitus, chronic pain, migraines,
allergies, frequent urination, flushing,
sweating, salt cravings, muscle tension.
So all of these, could potentially
be showing you that your patients and
clients may have a GABA deficiency.
It's not the first thing on many
of our radars, of course, but maybe
it should be part of that initial
understanding of what might be going on.
GABA is really important, and now even
the drug industries are getting the idea.
So this is the first drug
Approved just recently.
This is a New York Times article.
The first pill for postpartum depression.
And it's called, Zuranolone,
I think is how you say it.
And it is a positive allosteric
modulator of the GABA receptor.
We'll talk about what that is.
But it's supposed to be
used for the first 14 days.
Only for two weeks.
Supposedly, while you're taking another
drug like an SSRI for that to work,
but these work right away because
it's affecting the GABA receptors s
directly and improving depression almost
immediately, too, which is pretty awesome.
You don't have to go directly to drugs, of
course, but sometimes they're necessary.
So, let's talk about GABA synthesis.
GABA is only made in the brain.
Okay, you have to have glutamine,
which is an amino acid, it's
converted into glutamate.
in the brain.
And then glutamate is our
excitatory neurotransmitter.
And you have GABA, which is our
inhibitory neurotransmitter.
So 20 percent of the brain's
neurotransmission is actually GABA.
So it's a huge amount.
And glutamate in GABA combined
is about 80 percent actually.
So it's the combination of the two is the
majority of your neurotransmitter system.
And to make glutamine into GABA, you need.
You need this enzyme called
glutamine synthesase.
And then from glutamate to GABA itself,
you have to convert this, you need
vitamin B6, and you need magnesium.
So you need cofactors along the
way to make this conversion happen.
Some people are really great
at converting GABA into GABA.
Some people are not very good at it.
And a lot of times it's related to these
cofactors, but there's other reasons, too.
And see, here are some of those reasons.
So, If you have a high copper level
and a low zinc level, you're not
going to be able to actually have the
GABA receptor work as effectively.
If you're vitamin B6 deficient, you're
also not going to convert well from
glutamate to GABA, as I mentioned.
If you have chronic stress, if you
have chronic hypercortisolemia, if
you're always stressed, you're going
to deplete your GABA system, and then
your GABA levels are going to go down.
If you're magnesium deficient, and
most of our clients and patients
are magnesium deficient, they're
not going to convert well either.
If you have infection, this
is going to stress the system
and also decrease GABA levels.
Now, GABA supplementation may help your
GABA levels, but actually under most
circumstances it's not going to because
GABA itself is a big molecule and doesn't
go across the blood-brain barrier.
Under , certain circumstances, it
may, and we'll talk about that.
And then probiotics can also help with
this conversion, help with this enzyme.
So, you can actually measure, and
you saw some of these slides with Dr.
Ted, you can actually measure
people's vitamin B6 level, and if
it's low, it's very likely they're not
converting well from glutamate to GABA.
So this is something to be thinking
about, and this is why we do
metabolomics testing as well.
You can check their magnesium level.
In this patient, in this client, it
was a normal magnesium level, this is
red blood cell magnesium, but a lot
of our clients, it's going to be low.
So if you have a low magnesium
level, if you have low B6 levels.
You're not going to convert
well from glutamate to GABA.
This is the GABA receptor.
You don't have to worry
about this too much.
Just to know that it's
a pentameric structure.
It's got five subunits.
And these subunits change depending on
where the GABA receptor is in the brain.
Sometimes they'll look one way and
they'll have various combinations
depending on what they're doing.
GABA is everywhere in the brain.
These GABA receptors, the subunits
change depending on what's required and
what's going on in that particular area.
So this is the mechanism of the
GABA receptor, so we're going
to start with GABA A here.
So you have activation of the receptor,
you have opening of the central pore,
you have influx of chloride, you have
hyperpolarization, you have decreased
occurrence of the action potential.
So this all is saying that you're
inhibiting the actual firing
of this particular neuron
that has the GABA receptor.
So you're inhibiting the action potential.
So you're stopping things, you're
calming things down in general.
Chloride goes through,
and it hyperpolarizes.
This is the GABA B receptor.
It's called a G protein couple receptor.
It's a little bit different, and it's
called a metabotropic receptor, and I'll
show you what this means in a minute.
This is GABA B.
So, GABA B itself, what it does,
it's a presynaptic and postsynaptic.
So, presynaptically, it's preventing,
here, the release of an excitatory
neurotransmitter, glutamate, which is
what we've been talking about before,
is the conversion of glutamate to GABA.
And then you have the postsynaptic, here,
which is increasing potassium outflux,
which causes the hyperpolarization.
It's a little bit different, and
there's a different distribution of
the GABA B receptors in the brain.
So here's a quick summary.
So GABA A is, it's called an ionotropic,
or it's a ligand gated channel
opening, and it's a pentamer structure.
It's widespread as post synaptic influx.
It's endogenous agonist is GABA.
You have other drugs acting on it,
which we'll talk about in a minute.
Pharmacological actions here and then
GABA B is, as you see here, it's
also widespread, it's metabotropic,
it's presynaptic and postsynaptic,
and it has these particular,
pharmacological actions as well,
all right.
So.
There's a couple definitions here.
So orthosteric ligands, these
are chemicals that interact with
the same binding site as the
natural endogenous chemical.
In this case, we're
talking about GABA itself.
So an allosteric ligand or allosteric
modulator is something that works by
modifying how the receptors behave when
it's bound to the orthosteric ligand.
So in this case, we're
talking about a separate site.
away from GABA that binds this
particular modulator and then makes
GABA work better or helps the binding or
improves the chloride channel opening.
And then a positive allosteric modulator
is something that binds and it causes
this positive response where you have
an increased affinity of GABA to bind,
you have more chloride going through,
and you have more hyperpolarization.
So this is a picture of the
GABA receptor and ligand.
So here's a couple, examples of
what it looks like to have where
GABA is binding and where some of
these other drugs will bind to.
So you have alcohol everybody used
to love or maybe still loves alcohol.
It's got a very high affinity
for the GABA receptor.
Very, very high affinity.
Benzodiazepines here, very
high affinity as well.
Has anybody ever used Flamazenil before?
I used it a couple of times in
residency, I don't recommend it.
It causes seizures because
it has the opposite effect.
GABA antagonist, so it prevents
the chloride channel from opening.
Zolpidem, which is the Z drugs,
Ambien and others, they bind and bind
very tightly to the GABA receptor.
Quaaludes, anybody ever tried a Quaalude?
I don't know how everybody, yeah.
Dr.
Ted, no, no.
This is back in the 70s.
So, but they also were, , A GABA
binding here, an allosteric site,
barbiturates, which we use sometimes
for alcohol withdrawal, actually.
Sometimes we'll still use those,
but for pretty much not used
otherwise, general anesthetics.
And then finally, the GABA is
where it's GABA binding itself.
So that's where GABA is binding.
And so all these other sites on the
GABA receptor are places where other
molecules can bind, increase or decrease
the affinity of GABA binding and increase
or decrease chloride channel opening.
It's on the right side
of your screen over there.
You can see just a top view
of the same thing happening.
Benzos are probably the most common
positive allosteric modulator of
the GABA receptor that we use.
Unfortunately, Benzos
have a very high affinity.
We're talking about Ativan,
Xanax, Valium, those kinds of
drugs have a very high affinity.
affinity for the GABA receptor.
So when somebody is taking these
medications for long periods of time, they
cause tolerance, they cause withdrawal,
they can actually cause hallucinations
and death and all those fun things too.
So, but you can see here that what I
wanted to point out is that there's
different subunits of the Alpha
1 subunit of the GABA receptor is
associated with sedation hypnosis.
So this is actually a lot of
your Z drugs, like your Ambien's
and Lunesta's of the world.
And then your Alpha 2 subunit is.
It's more of your anxiolytic
and muscle relaxer.
So this is where your benzo
is going to mostly bind.
So in general, positive allosteric
modulators are less addictive overall.
However, that's not the case obviously
for benzos and barbiturates and alcohol.
And some of the natural equivalents that
we'll talk about do have less of affinity,
but still have significant impact.
So drugs that act on the GABA
B receptor, the most famous
being, GHB gamma hydroxybutyrate.
GHB is well known as the , date rape drug.
But it's actually a fantastic drug
for muscle relaxation, sleep, and
has lots of great other indications,
including narcolepsy actually.
If anybody lives, listens to our podcast,
the Smarter Not Harder podcast, I had a
really great conversation with a guy named
Dan Party, who was involved in getting
GHB to market for pharmaceutical reasons
with very interesting talk with him.
So we're going to switch over here.
So GABA cell GABA in general.
The cells that have GABA receptors
are mostly what we call inter neurons.
These are neurons that are
between neurons, inter neurons,
and they're really important for
learning, for memory, for behavior.
They're kind of like the way
stations between sensory and motor
processing, and even though they're
really small, like if you can't
really see here, but it's a tiny one.
Like, the GABA here, but this is the
big dopamine receptor, , neuron, the big
5 HTP, the big serotonin neuron here.
But you have, like, the small GABA.
This is doing a lot of the
processing between them.
So they're extremely important, and
they're actually in these locations
to make sure that they can actually be
those wave stations to prevent signaling.
Oftentimes, in our brain, it's
actually preventing signaling
that's most important, not
propagating, interestingly enough.
Okay.
So we're going to talk about how
you can dim your GABA switches
without a prescription required.
And, but the first thing to say is
that most GABA supplements don't work.
And we, and I was mentioning that
earlier, it's because GABA is such
a big molecule, it doesn't get
across the blood brain barrier.
If you do have patients that are taking
GABA and they are getting an effect,
it could mean that they have a leaky
brain, leaky gut axis, potentially.
There are some formulations, maybe
nanoliposomal, for example, that may work.
But in general, if they're getting a
significant impact from GABA itself,
at least clinically, I've seen that
they often have a leaky gut, and that
usually means they have a leaky brain.
I don't like telling patients
they have a leaky brain because
that doesn't sound that great.
I usually say that your
blood brain barrier may not
be as great as it should be.
But anyway, so you can also, of
course, give glutamine and glutamates.
So glutamine is an amino acid, it's
in various types of foods, meat,
Spinach, and fish as well, of course.
And so you can get glutamine from a lot
of different sources, but what we do in
health optimization medicine and practice,
we test for these kinds of things.
We test vitamin B6, we test
for magnesium, we test their
glutamine levels, and we can tell.
And if they have a certain symptomatology
and they have certain co factor
deficiencies, well, you know, we know
that they're probably GABA deficient too.
MSG.
Everybody loves MSG.
Everybody actually doesn't love MSG.
It's monosodium glutamate, right?
This is what you can get
in Chinese restaurants.
They make the food nice and sweet
for you, but you get a headache.
That's because you get all of a sudden
this huge rise in glutamate, and you have
to get that conversion over to glutamate,
to GABA, and that can take some time.
And nicotinyl GABA.
So this is a really cool form of
GABA that's attached to a vitamin B3.
And when you do this, you actually
allow this molecule, nicotinyl
GABA, to get through the blood
brain barrier very easily.
And then it hydrolyzes
to vitamin B3 and GABA.
And when that happens, you get this
nice vitamin B3 effect, which is
mild vasodilation and mild energy
production, , At the same time, your
GABA itself, getting into the brain,
increasing, your GABA ability and
increasing GABA binding to its receptor.
So relaxation.
What's nice about this is it's
not very sedating for most people.
So if you have anxiety and stress
during the day, you can take nicotinyl
GABA and you don't feel tired.
You just don't feel stressed, anybody use
valerian root before for patients, right?
So very common.
This is actually a valerian
root, something that actually
binds to the benzo site.
So it's a positive allosteric
modulator of the GABA receptor.
Doesn't bind as tightly, but it does work
really well for some people for sleep.
Covain, which is the
active ingredient in Kava.
It's actually a similar binding site.
Also a positive allosteric
modulator of the GABA receptor.
Honokyl.
Anybody used Honokyl as well?
So this is from Magnolia Bark.
Also binds as a positive allosteric
modulator to the GABA receptor.
Works really well, for a lot of people.
Does anybody know what this is?
It's a mushroom it's a
very famous mushroom.
It's called Flyagaric, or
Amanita muscaria is the other
name for it, of Christmas lore.
Does anybody know about the
Christmas tales of Amanita?
Amanita has two compounds in it, mostly.
It's got a lot of other
things, but two major ones.
One is called agarin, otherwise
named muscimol, and another
one is called ibotenic acid.
Ibotenic acid is neurotoxic.
This is the one that mostly causes
the psychedelic experiences of
taking this particular mushroom.
But, you don't mostly take
this mushroom directly.
The stories were that shamans would
drink the urine of reindeers, because
reindeers would be able to tolerate this.
Okay.
And then the shaman would
actually then urinate.
And then other people
would drink the urine.
This is in Northern.
You can, this is actually a great New
York times article on this with some
great videos as well, but that's mostly
because the toxicity is because of
ibotenic acid, but agarin or muscimol
is a fantastic orthosteric ligand of
the GABA receptor, which means That it
directly enhances GABA in the system,
and it does it very effectively.
But the key is to have
it at very low doses.
So it's a GABA receptor agonist.
It easily crosses the blood-brain barrier.
It's got a high potency, it's long-acting.
It's about 6 to 10 hours
overall for a half-life.
It's naturally occurring, or you can
make it synthetically, in low doses.
It's safe and effective.
And at high doses it can be
hallucinogenic, but usually in,
in combination with the Ibotenic
acid and the actual musher.
Non pharmacologic, of course, yoga,
meditation, breathwork, anything
that's going to make you more
parasympathetic is also going to
increase GABA tone in the brain.
Physical activity also helps reset the
system and the balance between glutamate
and GABA, so also being physically
active is also really important.
And then, finally, it's really
important, and this is kind of the
ethos of health optimization medicine
and practice, is we're detecting and
correcting at the metabolomic level.
And so, you really want to be
keeping the GABA deficiency aspect
of things on your clinical radar.
So we test for the nutrients.
We test for magnesium.
We test for vitamin B6.
We ensure optimized GABA production.
And you want to do that as sort
of your baseline for everybody.
So when somebody comes to see me, I'm
not looking for GABA deficiency exactly.
What I'm doing is doing a full
metabolic, metabolomic profile,
correcting as I see, and then you often
will see these improvements in mood
and depression and anxiety because
you're actually working on that.
neurotransmitter system.
Sometimes you can give herbals
and you can give supplements and
things like that to help right now.
That's what the company, the
transcriptions company is all about.
But the key for the long term is to really
work on that foundation and optimize it.
Of course, you want to implement dietary
and lifestyle measures to boost GABA
production, considering herbal and fungal
GABA agonists and orthosteric ligands
to support GABA production as well.
And then you want to really want to
avoid your benzos and your barbiturates,
obviously, and drugs that are going to
cause dependence, withdrawal, intolerance.
I mean, that's just important
for us to think about.
Sometimes it's unavoidable and I use
these in my patients when they really
need it, but oftentimes we can get
away with not using them because we
have a lot of great options here from
an herbal and fungal perspective.
Thank you guys very much for listening.
I really appreciate your time.