Well, first of all, I don't know if we'll be able to see the slides.
The lighting situation isn't the best, but we'll do what we can.
I can tell you it may be boring with the slides, but it would certainly be boring without them.
I was telling Jonathan, he probably gave a two-hour slot this afternoon for this talk,
which seems to be kind of a mistake, because I can possibly take that and more from being someone who's able to ramble on at some length about these things.
But hopefully this will be of interest to some of you.
Those of you that were at the Seeds of Change conference last year can be excused,
because this talk is essentially the same as that that I gave.
At that time, and with a few other elaborations.
So if you don't want to sit through it again, I fully understand.
I urge you to leave now while the leaving is good.
The name of this talk on the program is Alkaloids and Evolution,
which is kind of a truncated real title,
because we're going to be talking...
about a lot more than alkaloids,
but alkaloids and evolution was easy to get on the limited space.
What it really should be called is plant allelochemicals and plant-human coevolution.
But that seemed like somewhat more of a mouthful.
And some of what I'm going to talk about today is kind of more established.
There's not a whole lot of controversy.
The understanding may be limited,
but most scientists and people that study these things are in general agreement.
And other aspects that I'm going to be talking about are definitely in the realm of speculation.
And I'll try to kind of give you notice when we step off into the hypothetical realm
and away from the more established areas,
just to let you know if nothing else,
that I...
sort of have a grip on what the difference is.
I guess so.
The reason I started out with this illustration,
which is from the book Parallel Botany,
if any of you know that book.
It's a charming little book,
and it talks about a completely hypothetical,
completely fictitious plant kingdom.
It's basically a book of anatomy for a bunch of plants that never existed.
At least not on this planet.
But I put this up here to illustrate the point that
even though plants and animals
have an extreme relationship of interdependence with each other,
plants are not at all like people.
And they're not at all really like the animals.
Even though we, as part of the animal kingdom and the rest of the biosphere,
really depends on plants.
For one thing, plants, by and large, don't move around.
They are stuck in one place.
And so, in order to develop evolutionary strategies
for protecting themselves, getting along in the world,
they have tended to evolve biosynthetic strategies
as opposed to behavioral strategies.
In fact, one person, a few years ago, said,
in fact, one famous botanist, Tony Swain, put it very succinctly.
He said, plants have substituted biosynthesis for behavior.
And if you think about it, that's an interesting concept.
Plants are chemical virtuosos.
A greater variety and a greater number of complex organic molecules
are found in the plant kingdom
than have ever been synthesized by all the organic chemists
since the beginning of time.
Plants outstrip them in terms of varieties of different types of compounds.
And the reason that plants are able to do this,
one of the main contributing factors
and a kind of neat trick that plants can do
that's unique to the plant kingdom
is that plants are photosynthetic.
I put this up here.
This is a rendering of the cosmic ayahuasca vine
by a Brazilian artist.
I put it up here to suggest the idea of photosynthesis, actually.
I guess I could have put an electron micrograph
with a chloroplastic or something.
But this seemed more appropriate.
Plants have this ability to take simple elements,
carbon dioxide, water, sunlight,
and transform them through the process of photosynthesis
into complex organic molecules.
The molecules of life, sugars, lipids, amino acids,
nucleic acids, all these things
basically proceed through the process of photosynthesis.
All other organisms in the biosphere
are essentially parasites on the plant kingdom.
Because, well, not all.
I mean, you want to be careful about using those kinds of terms.
Most organisms in the biosphere are heterotrophs.
That means they don't make their own nutrients.
They don't make their own sustenance.
Plants are autotrophs.
They can, out of sunlight and water and carbon dioxide,
manufacture their own food.
And that's what the process of photosynthesis is.
As energy impinges on this biosphere from outer space,
the plants, through chlorophyll,
are the first to grab that energy and do something with it.
And then from that point,
as this electromagnetic energy
becomes transformed into chemical energy,
it basically cascades through the entire biosphere.
Everything else feeds off the plants.
But the plants are what is able to
fix that energy into the simple sugars.
Now, this is a busy slide,
and it's probably not visible to most of you,
but that's probably just as well.
You won't know.
But this is one of the things that plants can do
as a result of their photosynthetic ability.
Not only can they make the major molecules of life
that we talked about,
the sugars, the proteins, the amino acids,
all these things that are basically universally distributed
in all organisms on which we depend for life.
These we call primary metabolites.
Primary because they're universally distributed
and they're pretty much essential for life.
But plants, in addition to that,
can make a vast array
of what is sometimes kind of pejoratively called secondary metabolites.
And these are the chemical compounds
that make plants interesting,
that make them these chemical virtuosos.
Plants have energy to burn,
because of their photosynthetic ability.
So there are no constraints on their energy.
They can use that energy and they can seemingly waste it.
And for a long time it was thought
that these secondary plant metabolites,
which are things like alkaloids, terpenoids,
your essential oils, your tannins,
these sorts of things,
are all these plant secondary metabolites.
And it was thought that they were secondary
because it wasn't really understood
what their purpose was.
It was thought that they were some kind of
metabolic waste product, basically.
Just a physiological garbage
that the plant made and sequestered
in its different parts.
And what has come to be understood,
probably in the last 10 to 15 years,
maybe the last 20 years,
is that these so-called secondary metabolites,
this vast array of structural diversity
that plants have evolved,
are not really secondary at all.
The purpose that they serve the plant
is to mediate the relationship
between the plant and the rest of its environment,
between the other organisms in its environment.
From other plants, to microorganisms,
to fungi, to grazing animals,
and also humans,
because we're also organisms in the environment
that interact with plants
on this molecular level,
via this molecular language, if you will,
that plants have evolved.
What this slide illustrates
is basically two things.
It shows the primary gateway
for energy and simple compounds
to get into primary metabolism in the plant.
That's CO2, water, plus light energy.
And that feeds first into the pentose phosphate cycle,
where you get your simple sugars being created,
ribulose, diphosphate,
and then these are black boxes, you understand.
There's a lot more going on here than is implied.
But you get first your simple sugars.
That leads eventually down the spine
of primary metabolism
into your tricarboxylic acid cycle.
And that's on into your amino acids,
which lead eventually to proteins,
and also your liquids come out
of the tricarboxylic acid cycle.
This is sort of the spine of primary metabolism.
What's perhaps more interesting
is that at different branches along the spine,
you get things coming out
that lead into the major classes
of secondary metabolites.
For example, coming off the pentose phosphate cycle,
from the simple sugars,
is a compound called shikimic acid.
And that's your first aromatic compound.
Aromatic in the sense, not that it smells good,
but aromatic in the sense that chemists use it.
It's the precursor to compounds
that contain benzene ring, aromatic ring.
And from shikimic,
you get the aromatic amino acids
for the three essential amino acids,
phenylalanine, tyrosine, and tryptophan.
And from those, you get a vast array
of secondary compounds.
The ones that tend to be most,
that we tend to be most interested in
as psychothermicologists
are the aromatic alkaloids.
An alkaloid, by the way,
for those of you that don't already know,
is a plant secondary compound
if you will,
that has already occurred again.
But a plant metabolite
that's not part of a primary metabolism
that contains nitrogen.
And you can sort of define an alkaloid
more easily by what it is than what it is.
But one of the essential requirements
is that they,
that alkaloids contain nitrogen.
So the aromatic amino acids
lead to the aromatic alkaloids,
which include things like EOTs,
OCDs, psilocybin,
multiple of these things,
multiple things like morphine.
Many of the drugs of use and abuse
that are so economically important
are these aromatic compounds.
In addition to the shikinic,
the shikinic acid also gives rise
to phenolic compounds,
such as cinnamogastin, capsaic acid,
where these tend to be
flavorings and essential oils,
flavorings and literally aromatic compounds
in the sense of fragrances.
This is one of the main branches
of primary metabolism
that leads to aromatic compounds.
Further down the chain from the Krebs cycle,
you get,
branching out of the Krebs cycle,
you get aliphatic amino acids,
things like valine and lysine
that lead to another class of alkaloids,
the aliphatic alkaloids.
Which include things like nicotine.
Some of the trophates are also aliphatic.
Pyralisidine alkaloids are aliphatic.
That is, they don't incorporate
an aromatic ingredient.
They're not derived from one of these
three aromatic amino acids
that are so important in metabolites.
But also, coming off of the Krebs cycle,
is a two-carbon fragment
called STL-CoA.
And this two-carbon,
fragment,
feeds into a number of secondary product
biosynthetic pathways.
For one thing, it leads to
both fatty acids and lipids,
and a class of compounds
called the acetogenomes,
which are just many of these
acetyl-CoA units joined together.
And you get things like eugenome
along with a class of acetogenomes.
But acetyl acetyl,
acetyl-CoA,
can also lead to
metalonic acid.
And metalonic acid is basically
a five-carbon unit
that leads to the terpenides.
And the terpenides are down here.
You have the simple terpenes
like menthol,
which basically are five or ten carbon units.
You have the sesquiterpenes.
One example is picrotoxin.
And the diterpenes,
you've heard this morning
a lot of talk about salvinorin,
and that's a classic example of a diterpene.
And even more complex terpenes
such as digitonin
and other steroid-related compounds.
So these are all basically built up
of many units of metalonic acid
joined usually in a head-to-tail fashion.
So you have basically four main classes
of plant secondary compounds.
You have your aromatic,
shinginic acid derivatives.
You've got your aliphatic alkaloids,
your acetogenes,
and your terpenes.
I mean, there are other classes
of plant secondary compounds.
Those are the four biggies.
This is just an example of some alkaloids
derived from these different sources.
These are aliphatic alkaloids,
and these are the aromatic alkaloids.
This is quinidine,
which is,
for the quinine tree,
centrona,
an important medicine
in treating heart arrhythmias.
Tubocurarine,
from curarate,
that's used in abdominal surgery
and other muscle relaxants
in certain kinds of surgery.
Your beta-carbolines,
also aromatic alkaloids
derived from diterpenes.
They are,
alkaloids are one of the largest classes
of secondary compounds
and also one of the most structurally
diverse classes
of secondary compounds.
And also,
because we get so many important medicines
from them,
drugs both of use and abuse,
and the distinction is really
in how they're used,
alkaloids are one of the classes
that have the greatest
economic importance for us.
One of the things that we get from plants
that is most important.
This is a slide I haven't put up before
and I'm not sure how much
I'm going to go into it.
I don't know exactly how to say this.
One of the things that's always been,
that's always struck me as curious
about the biosynthesis
of these aromatic compounds,
these things that branch off
the shikimate pathway,
is what you might call
curious parallelism
in biosynthesis.
It's either something important
or it's so what,
ho hum,
I'm not sure which.
I think it's kind of neat.
You know how sometimes
people on DOT
or sometimes on mushrooms
report having the experience
that you can kind of
turn the circuit board of reality over
and see how it's wired
and you realize that
it's not at all what it appears to be.
This is sort of
on that level.
I don't know if that really makes any sense.
This particular slide here shows
how these three aromatic amino acids arise.
This is your CO2 plus H2O plus light.
Photosynthesis leads eventually
to these two simple sugars
which are coordinated to shikimate acid
and then chorismic acid
and out of that
you get your aromatic amino acids
ranging up here.
Phenylalanine, tyrosine, and tryptophan.
And then also other important
metabolites,
folic acids and so on
which were not really great to introduce.
But then if you look at the classes
of secondary compounds
that come off of each one,
there's something that I always thought
was kind of interesting.
You have phenylalanine here
and tyrosine here
and phenylalanine and tyrosine
can basically go two ways.
You can get decarboxylation
to form the amines
beta-phenethylamine and phenylalanine
and tyramine coming from tyrosine.
So basically you've removed an acid group
and you've left the amine intact.
And then from these simple amines
you get things like mescaline
which interestingly enough
is the only hallucinogenic phenethylamine in nature.
Although it's given synthetic chemists
such as Sascha Schopen
many ideas or many analogs
but they're not found in nature.
You get neurotransmitters
such as dopamine, norepinephrine
or epinephrine and norepinephrine.
Epidrine, another plant compound
that has some of the stimulatory properties
of amphetamines.
And then even further down the chain
you get complex alkaloids
in which these amines
these simple amines
are precursors.
They're incorporated into more complex rings
morphine, triple curare and so on.
The other thing that can happen
to these simple aromatic amino acids
is instead of losing a carboxyl group
instead of losing an acid group
you can lose the amine.
And then you have your
your phenylacetic acid derivatives.
Things like cinnamic acid
caffeic acid.
They can lead
these are widespread in coffee
and a lot of spices.
They contribute to the flavor of coffee.
Spices, this sort of thing.
Things like saprole and nutmeg
saprole, which is a concession of nutmeg oil
dilapial and dill oil
they're also basic.
Simple derivatives of these cinnamic acid derivatives.
They are fragrant.
Their biological activity
is basically that they're volatile.
And then these can further join
into dimers.
They can form dimers
and form a class that's sometimes called lignans.
Which are things like glutaphylatoxin.
It's an anti-cancer drug.
There are many interesting lignans
and they have a whole range of biological activities
ranging from some are antimicrobial
some are antiviral
and some have activity on the central nervous system.
And then if they polymerize even further
you get lignans
which are polymers of these C6C3 units.
The C6 in the ring and the 3 carbon units sticking out from it.
When it becomes polymerized you get lignan.
And lignan is the major structural constituent of wood.
Lignan is what gives trees its strength.
And interestingly enough
when I was a graduate student at the University of Hawaii
my professor was interested in stress physiology.
And he showed that by growing seedlings
under conditions of increased gravity
he was interested in gravity
as a biochemical determinant.
And he showed that he would put seedlings in a centrifuge
and germinate them there.
And show that the levels of lignans
were increased.
And not only were they increased
but he did anatomy.
If he took sections of these seedlings
he showed that the distribution
was corresponded with the points of maximum stress in the plant.
So this is lignification.
The lignans are deposited on the cell walls.
This is basically a gravity determined property
that governs the distribution of these lignans.
If you make an engineering diagram of a tree
where the major points of stress are
that will match exactly
where the maximum depositions of lignans are.
So, you know, whatever.
So that's kind of the story
with the aromatic amino acids
phenylalanine and tyrosine.
The precursor of the phenethylamines
and the complex alkaloids that come off that.
And then this class of compounds
the essential oils
and the lignans.
And then lignans itself.
Well if you look at the same thing
with respect to tryptophan
it's kind of the opposite.
Tryptophan can be decarboxylated
or deaminated.
It can remove the amine group of tryptophan.
What you're left with is indoleacetic acid.
Indoleacetic acid, it turns out
is one of the major plant growth hormones.
It's the plant hormone
that's universally distributed in plants
and it governs the elongation
of the plant stem and cell division.
So this is basically a very important
plant growth hormone.
But it doesn't seem to go
there's not a vast array
unlike with the
with the deamination products
of phenylalanine and tyrosine
with the indole
there's not a vast array of secondary compounds
based on indole acetic acid.
I mean there are variations.
But it hasn't amphloresced into
a great variety.
Where you see the variety in the indole
is when you lose the carboxyl group
you get the simple tryptamine.
You get tryptamine.
And then leading to that
you get your other compounds
like bimethoxy DMT,
dimethyltryptamine
by adding methyl groups.
When you add a hydroxyl group
in this position you get
bifhydroxytryptamine which is a major
neurotransmitter as you all know
also known as serotonin.
Again, I don't know if this is neat
but it's always struck me as interesting
that dimethyltryptamine
is basically two steps
of a tryptophan.
I mean tryptophan is universally
distributed in nature.
Here two enzymatic steps away
is dimethyltryptamine.
The curious thing about
dimethyltryptamine as you all know
is it's not orally active.
So it could be widely distributed
in a lot of foods that we eat
and we never know it unless we happen to
fortuitously also eat
a plant containing an MAO inhibitor
at the same time.
Then you know.
You might be happily dining on a plant's
cereals for example high in
dimethyltryptamine for a long time
and you've never been invited
with an MAO inhibitor
you wouldn't know.
But these tryptamines
there's quite a structural variety
within the tryptamines
of these simple things.
And then even more complex
you get the next step is beta carbamines
and then there's a whole
vast array of more or less
complex indole opioids
things like Evogaine
and even more complex
enormous things like vitristine
which is one of the more
complex indole opioids.
This of course is an anti-cancer drug
it's used to treat leukemia
in children.
Rumor has it that it's also psychedelic
or not psychedelic,
psychoactive.
People undergoing cancer chemotherapy
have reported interesting experiences
of being treated with vitristine.
I don't recommend it.
It's not something
that I would care to try.
But another interesting thing
when we saw that
in the phenylalanine and tyrosine
class when you get polymerization
into the lignans
it becomes the structural component
of the trees.
What happens when the indoles polymerize?
You get melanin.
Melanin is the black pigment
that makes
many mushrooms turn black.
It's the black pigment
when bananas
begin to turn black on the outside.
That is melanin.
Melanin is an indole polymer
basically.
The curious thing is that in nature
it doesn't really usually come from
indoles at all.
It comes from tyrosine and dopamine
and these phenylamine type compounds.
So, you know, go figure.
I guess the point
that I'm trying to bring out
from all this is that
depending on which way it goes
these aromatic amino acids
can lead into major
secondary product pathways
into large categories
of compounds
that are basically
derived from these things.
If you go decarboxylation
you lead into one category.
If you go deamination,
you lead into nitrogen.
You lead into the other category.
And there's a kind of a symmetry here.
I haven't got it completely figured out
but it's interesting
that it exists.
This is another example.
Sasha Shulgin has talked
about the essential amphetamines.
Interesting thing.
You know, in nature
the only CNS active phenethylamine
the only hallucinogenic phenethylamine
is methadone.
That's 3, 4, 5-trimethoxyzinephrine.
But some of these essential oils
alamycin from nutmeg,
acerone from, of course,
calamus, sweet flag
these sorts of things
if you make it
you know, they themselves
are not psychoactive
but if you make a trivial
synthetic modification
if you introduce a molecule
of ammonia into this
at the right position
then you get your essential amphetamines
the simplest
or probably the most obvious one
which is 3, 4, 5-trimethoxyamphetamine.
You can think of it
as a mescaline analog
which it certainly is
but it's also
and it can be made directly
from alamycin
by simply adding an ammonia
at this position.
Similarly, if you take acerone
and do the same type of
ammonia substitution
you get TMA2
and the potential difference
between these two
is the position of the epoxy groups
where they are located on the ring.
This is 3, 4, 5
this is 2, 4, 5
One of the most interesting
discoveries Dr. Shogun made
when he was working on this
early on back in the late 50s
was that this simple trivial
rearrangement movement
moving this one from here to here
from the three positions
to the two positions
is called a forges effect.
Sasha's here
correct me if I misrepresented him a bit
but then he found that
by making various substitutes
so that the 2, 4, 5
configuration was important
and then various substitutes
on this core position
basically he could hang
just about anything he wanted off that
and still get some kind of activity.
So he started hanging
things like halogens off it
or metal groups.
He first came up with DOM
which was known a few years ago
as STP
but then perhaps the most potent ones
where this R group becomes things like
bromine or iodine
and DOB and DOI
and these are very potent phenethylamines
they are not quite as potent
as LSD
but they are in that magnitude
one milligram or less
is an above threshold dose
they are also
extremely selective
for the 5HT2 receptors
which is this class of receptors
serotonin receptors
that they now believe
is intimately involved in the action
of these solutions.
So
it's just interesting
that nature invented
compounds like these
and these are widespread in nature
but somehow she never bothered
to add an ammonia to these
and come up with these
synthetic chemists that come along
and do that.
I don't know.
Maybe nature just never thought of it
or there was some other reason.
Maybe he was part of the alien.
Well yes
that also
this controversy about
synthetic versus natural
is really
attempts at a teapot in my opinion
because as someone said
nature did synthesize
the aforementioned
amino acids
we shouldn't lose sight of that.
So anyway
that just illustrates
the kind of the variety
from the standpoint of the
aromatic amino acids
kind of the structural varieties
and types of compounds
that you get just within that class
just coming off the
the shikimic acid derivatives
and you could basically say the same thing
for any of these other classes
the terpenes or the acetogenins
you know these other classes.
So one of the
the understanding now
is that these are not secondary compounds
but these actually do function
in the day to day economy
of the plant in terms of modifying
the plants relationship
to its external environment
is this biosynthesis
for behavior paradigm
that we're talking about.
And the functions of these plant
chemicals are
defenses and or symbiosis
or semiosis
in other words a signaling function
stay away
or come closer
or symbiosis
really these functions overlap
for example
an example of both
the semiotic function
and the symbiotic function
is found in plants relationship
to insects
where the fragrance
of the flower
and the color of the flower
acts as an attractive to the insect
you know so the plant basically
sends out a signal
come closer and become involved
but also it enables the
insect to play a role in
completing the plants life cycle
the plant cannot pollinate itself
it needs the insect to help it
at least these particular
flowering plants.
So this is you know
it's by virtue of the chemicals
that the plant produces
which is the symbiotic
and semiotic relationship
to the insects.
This is an example
of a defensive chemical
this is DeRoya Pursuitif
that Dr. Schultes has written about
quite interestingly
this plant causes
in Peru
a phenomenon called
the Supai Chakra
the Devil's Clearing
where this plant grows
about twenty to forty feet
around it
nothing grows
actually Solaginella grows
but nothing else
and the thinking is that
this plant probably secretes
a compound into the soil
either from the leaves
or from the roots
that inhibits the growth
of other plants
inhibits germination
so this is a defensive function
the plant is basically
a potential competing plant
for moving in on its space
so it's basically saying
stay away
I'm toxic
this plant is chemically unstudied
as far as I know
at least it was a few years ago
it's never been examined chemically
but it's in a
the Rubiaceae
which is a family that's very well known
for its biodynamic compounds
so there's potentially
some interesting chemistry
uncovered here
this is another example
of a symbiotic
a neurosymbiotic relationship
sorry for the quality of this slide
but the butterfly
pollinates certain plants
and actually
certain types of butterflies
that develop on its wide spread
probably the best studied example
are butterflies of a monarch type
which feed on milkweeds
milkweeds are full of
a variety of
class of compounds
called cardiac glycosides
they're steroids
so they belong to
the class of terpenoids
but they're highly toxic
the butterfly has evolved
enzymatic defenses against it
the butterfly
or actually the caterpillar
is able to feed on this plant
with impunity
not only does it feed on it
but it takes the cardiac toxins
into its body
and itself is not poisoned by them
but when it transforms itself
into a butterfly
it puts the plant toxin
to use as a chemical defense
it becomes unpalatable
to potential predators
and they can see these butterflies
they have learned that
certain butterflies of this class
don't taste good
because they're full of
these cardiac glycosides
so this is an example
of an even more baroque
difference between
the plants and the animals
where the consumer of the plant
has evolved a biochemical defense
against the toxin
and then goes one step further
and uses the toxin
for its own defensive purposes
well the tryptamines
and beta-carbolines
provide
a good illustration
there are a class of compounds
that we're very interested in
here
but they also provide
a very good illustration
of what you might call
the parsimony of nature
these compounds
tend to have multiple activities
depending on
what biological targets
they interact with
it's not just
that they're hallucinogens
and they're hallucinogens
given that nervous systems
are the biological targets
they interact with
at different levels
these are the tryptamines
of the earth
and beta-carbolines
down here
and for example
these beta-carboline alkaloids
are in the presence of UV light
many of them are photoactive
and that's what's shown here
if you take something like
six-boxy carmelan or harmine
put a little bit on a
filter paper disk
and put that on a petri plate
that's a whole lot of bacteria
and incubate it in the dark
nothing happens
the bacteria grows just fine
but if you expose it
to UVA I believe
or UVB
I forget which
for about ten minutes
and then incubate it in the dark
you get a nice clear zone
around the filter paper disk
where the bacteria's been killed
it hasn't grown
due to the photoactive
of these beta-carbolines
and you can do
reasonably nice
structure activity relationships
and that sort of thing
but
so this explains possibly
one of the
allelochemical functions
of beta-carbolines
for the plant
in the presence of sunlight
it might help to defend it
against bacteria or fungi
that might otherwise invade
the leaves
or the roots
another example
with the tryptamines
indoleacetic acids remember
we talked about
is a major plant growth hormone
as you can see
it bears a pretty close
structural resemblance
to our favorite
dimethyltryptamine
phytoxybmt
and bifopamine
these psychoactive methylated tryptamines
are found in plants
with them
these are found in plants
like desmanthus illinoiensis
in the roots
and where they were first discovered
in why they were discovered in there
is they were looking at plant growth inhibitors
this is a good plant growth inhibitor
and they isolated
the fraction responsible
and found that it was dimethyltryptamine
and other related tryptamines
so at this level
these compounds function
as their target
that is their ecological function
probably for the
for the weed
desmanthus illinoiensis
probably didn't evolve it
so that we could go out and gather it
and extract it
the same tryptamines
in other plants
such as varrolis
when the organism being interacted
with are human
such as these yatalonga indians
then the target for the tryptamine
is the central nervous system
and you get the activity
that we're familiar with
the hallucinogenic activity
so I guess the point of this
is that the compounds
can have multiple activities
depending on what molecular
or biological target
they actually interact with
it's not that they have
only one kind of activity
so nature makes good use of these things
they are multipurpose compounds
and the reason
that these allelochemicals
have these multiple activities
can target multiple biological
can mediate
multiple biological
relationships in nature
is because of the variety
of molecular targets
that they interact with
for instance the photoactivity
of the baby cartilagins
that we saw with the bacterias
due to the fact that they are
able to insert themselves
between the base pairs of DNA
they do that and then
in the presence of UV light
they form covalent crosslinks
with the base pairs of the DNA
which is basically like throwing
a big monkey wrench in DNA
so they pretty well inactivate
the cellular processes at that point
in the presence of
in the absence of light
they don't do this
but in the presence of
the right wavelength of light
this can happen
so the beta carbolines do this
under certain circumstances
another class of compounds
that do the same thing
are also derived from plants
they are called the soralines
and I don't know if you've heard
of PUVA therapy
but it's a kind of treatment
for psoriasis
where you take soraline pills
for several days
it accumulates in your body
and in your skin
and you go into a tanning salon
and you get an all over tan
and you take the DNA
in the outer surface of your skin
and it causes that to fluff up
so you come out of it
looking all pink and healthy
and then gradually
the psoriasis comes back
and you have to do it again
it was for a while
a promising treatment for psoriasis
a heartbreak of psoriasis
I don't know if it's still being used
and it really is a heartbreak
it's a serious condition
in advanced cases
another example of photo-plexicity
I mean the example there
is the target
in the case of beta-carbolines
is DNA
that basically throws a monkey ranch into DNA
but cell membranes
are another important biological target
for these
active plant allelochemicals
this is an example
this used to be a red blood cell
before it was exposed
to a compound called
alkyl thionyl
which is a photoactive
sulfur derivative
found in marigolds
and in the presence of UV light
alkyl thionyl
sequesters itself in the membrane
it's highly lipophilic
it's highly fat soluble
it literally blows holes
in the membrane
so that's what you're seeing here
these craters are literally
riddled with holes
and of course it's lost
its osmotic tone
another photoactive compound
but a completely different mechanism
of action
it works on membranes
instead of DNA
another example of biological targets
are enzymes
of different kinds
and again we can illustrate
from the beta-carbolines
the beta-carbolines
are potent monoamine oxidase inhibitors
they inhibit the enzyme
that deaminates neurotransmitters
such as phylogenesis
block that enzyme
so at that level
they're working on
I mean that becomes the target
for them
this of course is the
underlies the pharmacological
mechanism behind ayahuasca
ayahuasca is
I'm sure all of you know
is a combination of two plants
at least two
one of which contains beta-carbolines
the banisteriopsis
contains dimethyltryptamine
dimethyltryptamine taken orally
by itself is not active
because it's inactivated
by monoamine oxidase
which is present in peripherally
in your stomach in your liver
and so on
but if you take it in the presence
of a beta-carboline
the beta-carboline inhibits MAO
and protects the DMT
from peripheral breakdown
allowing it to be absorbed
into the nervous system
this particular action
of beta-carbolines
the ability to inhibit monoamine oxidase
becomes important in the human interaction
with these two plants
that have led to ayahuasca
and all the ayahuasca analogues
that people are now experimenting with
another example
of an important biological target
are second messenger systems
second messengers
are enzymes usually
such as protein kinase
and adenylates
or cyclase
they're enzymes that are
usually bound to membranes
that mediate
what you can call
kind of generically
post-binding events
they are second messengers
they govern intracellular processes
usually that follow on
the binding
of a drug or a neurotransmitter
to a receptor
and one of the classes of compounds
that are one of the most potent inhibitors
are second messengers
that are called 4-vol esters
found in the family Leucorbiaceae
they are very important
activators
of a protein
called protein kinase C
protein kinase C is involved in
and one of the reasons
that 4-vol esters are highly carcinogenic
is because of their action
on protein kinase C
ok so
sort of the point of that
is that
these biochemicals
these biologically active secondary compounds
have these activities
because they interact with some kind of receptor
they have to get in and bind
with something
in order to do what they do
now you can take the term receptor
in a sort of broad sense
where a receptor
is anything
that a drug binds to
to exert its effect
it might be an enzyme
it might be a membrane carrier molecule
it might be a nucleic acid
all of these
are in some sense receptors
in the sense that
these biodynamic molecules
can bind to them
and affect them by doing so
um
but
receptors and their ligands
that's what we call the molecules
that bind to the receptors
are a complex
chemical communication system
that regulates the internal
kinostasis of the organism
by governing this signaling
between cells
systems of cells and even other organisms
and it may
the speculation is
I mean how did we
end up with all these internal receptors
the speculation is
that these receptors originally
served an ecological function
that they originally
were found on the outsides of organisms
and that the
biosynthetic diversity we observe
in the natural world
is the evolutionary consequence
of billions of years
of this biochemical
or chemical ecological warfare
part of one component
is the elaboration of these
defensive or aggressive
or symbiotic allelochemicals
on the part of the plants
the organisms that they're targeted to
in turn evolve adaptations
adaptive responses
to neutralize them
detoxify them or counter attack
and then the plants respond
with biosynthesis
of even more novel
even more complex molecules
with even more complex modes
of biological activity
and as multicellular organisms
became more complex
this interchange
between organisms
which is basically organisms
synthesizing and excreting
these compounds into the environment
they travel to other organisms
we're talking about
largely one-celled organisms
and interacting with receptors
on the outside of the cells
but as organisms became more complex
and multicellular
these receptor systems
gradually became internalized
and the signaling functions
instead of transmitting between organisms
then became adapted to transmitting
signals between populations
of cells within an organism
so you get hormones
and neurotransmitters
which are basically our own
biological chemicals
that have been adapted
to this internal function
but they were originally there
to mediate relations between organisms
in an ecosystem
that's how they arose
and then as they became adapted
to this internalized function
they became specialized
to that kind of activity
this is a typical
neurotransmitter receptor
which is sort of more the
what we think of conventionally
when we think of a receptor
this is sort of a narrow definition
of a receptor
and this happens to be
a seroclomin receptor
but any neurotransmitter receptor
incorporates much the same
processes
in this case you've got tryptophan
which is the essential amino acid
right off the shiitake pathway
and that is transformed
within the presynaptic membrane
into pyhidroxycryptamine
or seroclomin
that is stored
in membrane bound vesicles
until it's used
and when it's used
these vesicles migrate
to the membrane of the cell
and the neurotransmitter
is released into the
synaptic cleft
then various things happen to it
it travels across to the
postsynaptic membrane
and it interacts with the
one or more different types
of serotonin receptors
on the postsynaptic membrane
the 5-HT2 receptors
the 5-HT1 receptors
are just shown
but now I think there is
enough to be at least
8 different subtypes
of serotonin receptors alone
and every neurotransmitter
dopamine, gaba
all these things have their own
receptor subtypes
so it's quite a complex picture really
once they bound to these
membrane
these receptors
these specific receptors
located on the membrane
it activates second messengers
and subsequent events take place
once the neurotransmitter
has done its work
it's taken back up
into the presynaptic membrane
through a carrier molecule
this is yet another kind of receptor
and recycled
it's either recycled
the membrane found vesicles
and reused
or at that point it may also be
degraded by monoamine oxidase
and turned into 5-HT2
in this case
now psychoactive drugs
those that work on a central nervous system
tend to do their job
by affecting one or more
of these processes
that are taking place
at the receptor site
and in the vicinity of the synapse
they either select
the synthesis
the storage
the release
the receptor binding
or the re-uptake
or the degradation
of the neurotransmitter
that's how they do their job
for instance Recipe
the aqua-lactamidium snake root
basically disrupts these vesicles
and causes the 5-HT2
to be released into the cytoplasm
and sort of leak out of the cells
actually it's not selected for
all your
monoamine type neurotransmitters
but it depletes
the presynaptic cell
of its neurotransmitters
that's what the surfine does
your hallucinogens
the so-called true hallucinogens
LSD, psilocybin
these ones
is now thought to interact primarily
with the 5-HT2 receptor
in other words they substitute
the serotonin at the 5-HT2 receptor
they also affect some of the
B1 receptors
but that's not quite so well understood
anti-depressant drugs
such as Prozac
is a very
likely blocker of the
serotonin re-uptake molecule
it gets in here, prevents the
serotonin from binding
to this and being taken back up
into the cell with the result being
that there's a higher amount
a higher availability of serotonin
in the synaptic cleft
Prozac is
a typical anti-depressant
in that respect
in a marvel of
I guess structure activity engineering
because it is so selective
for serotonin
so this is
this table is
undoubtedly hard to read
but this just shows
some of the natural products
that affect the nervous system
the compound, its chemical flaps
its pharmacological action
and its therapeutic application
basically I think the point of this slide
is that you can't think of an
activity, a pharmacological activity
for which there is
not a natural product
that shows that somehow
affects those receptors or those
mechanisms involved in that activity
you could put
the same kind of slide up for any
type of, any class of activity
if you're interested in liver
functions you could start to sit
along with the liver
antimicrobial activity
you could start to sit
along with the antimicrobial activity
notice in the case of
the central nervous system complex
how many of these are alkaloids
alkaloids are disproportionately
represented when it comes to
the central nervous system activity
something about the presence
of that nitrogen
that gives them the ability to
interact with these
receptor systems that are so important
in the functioning of the nervous system
but any
class of activity that you can name
as a natural product
that displays the activity
this is, you know,
recipe
THC
says it's cycle acting
but one of the exceptions
it's not an alkaloid
it doesn't have nitrogen
so it's kind of interesting
nature has evolved these
chemicals that interact with receptors
that we haven't discovered yet
which is kind of interesting
I mean we've seen the classical example of this
in Salvinorum
I mean the work that's been described here is very interesting
the compound has been identified
it has definite cycle activity
and we at the moment don't have a clue
what receptor system
it might interact with except
we're pretty sure it's probably not 5-HT2
you know
I mean there's speculation
that's partly the
importance of natural products
because of
the importance of natural products
in drug discovery is that
this molecular diversity
out of looking at the molecular diversity
of natural products
you get new chemical entities come out
and they point the way to
new modes of pharmacological activity
I mean you can
make, you know
many phenethylamine derivatives
many tryptamine derivatives
and that's all very well
but you're looking basically
with subtle differences
you're looking basically at a
characterized mode of activity
you know pretty much
that it involves the 5-HT2 receptors
some of these new molecules
that are coming out of the natural world
point the way
may open the door to completely new
pharmacologies
Dr. Schultes
a few years ago wrote a book
or wrote an article
not widespread at all
it was called
Phytochemical Gaps
in our Knowledge of Hallucinogens
and I think it was
published in a very
obscure journal
Journal of Plant Science
or something like that
and I always thought that it was
I mean of his many very significant papers
I always thought it was
one of the most significant
because he pointed out in there
it was a description of about
phytochemical plants
for which the ethnobotanical documentation
was clear
no doubt that there was
probably activity there
because people were using it
and they were experiencing effects from it
in different traditional societies
but there was no information
on the chemistry
and I always
I sort of wished
I wish that he had called it
phytochemical gaps in our knowledge
of CNS acting plants
and it might have
induced some of these drug companies
to look into these plants more
by calling it phytochemical gaps
in our knowledge of hallucinogens
they said oh wow
who needs another hallucinogen
but as we show with salvinorin
and these sorts of things
you never know what these things
may end up being
you can't dismiss these
this is another example
just another
out of focus
this is another example
of the varieties of CNS activity
that you get in the natural world
this is a table that I put together
from Napalert
some of you have heard me talk about Napalert
it's a natural products database
created by Norman Farnsworth
at the University of Illinois
and among the things that it talks about
are different classes
of pharmacological activity
I went into Napalert
and I asked it
if I specify these types
for system activity
analgesic, anesthetic
local and general
anorexic, drug addiction
inhibition, learning enhancement
hallucinogenic
I say in Napalert
how many hits are there
for each of these types of activity
how many plants are reported
to have these different types of activity
so it's just a number
analgesic
3710 citations
for plants with analgesic
activity
hallucinogenic activity
not bad 88 citations
anesthetic activity
226 citations
tranquilizing
effects 260
citations
and I guess what the point of this is
that
there are indications
of activity far
more
extensive than have been looked at
the world needs a good
non-addictive effective analgesic
you know
chances are
you'll find it in the natural world
if you look hard enough
the world needs a better tranquilizer
you know if you went through
and you collected all 260 plants
that this referred to
and started screening
you'd probably come up with a pretty good tranquilizer
after a while
so the point is that this information is out there
what's not happening is
there needs to be a systematic
follow up to these things
I mean we talk a lot
in the drug discovery game
about hit rates
when I was at Shaman Pharmaceuticals
they were always saying well what's our hit rate
and what's the correlation
to the ethnobotanical data that we're collecting
and I always said
it's a completely ridiculous argument
the hit rate is 100%
right
because every plant
contains allelochemicals
that have biological activity
do they hit a target
that's of therapeutic interest to us
that's a more interesting question
I mean often they don't
often they hit a known target
or something we're not interested in
but the point is
they all have biological activity
you can take any plant at random
if you screen it against enough receptors
sooner or later you're going to get a hit
so the hit rate is 100%
the other thing is
that these natural products
these molecular templates
in the natural world
one of their main things
as far as drug discovery
is they give synthetic chemists like Sasha
ideas
synthetic chemists
Sasha accepted
tend to be kind of an unimaginative group
you know
they really can't come up with very many ideas
but they can look at the natural compounds
and they can say oh well
we'll tweak it here and tweak it there
and maybe modify its activity
come up with something a little better
for a given receptor
maybe less toxic
or maybe longer lasting
or something like that
and that's what's going on here
this is just an example
and you have the natural compound here
morphine
which is a non-selecting opiate agonist
very good stuff
very important in medicine
very important in analgesia
but then the synthetic chemist comes along
and turns it into now Trindell
or that is the
modified
so it incorporates the basic morphine
and this becomes a
delta opiate selective
antagonist
so morphine is a non-selecting
opiate agonist
it's all the opiate receptors more or less
this is a blocker of one of the
opiate receptors
very important to be able to
introduce that selectivity
another example cocaine
a central stimulant
a local anesthetic
being used to label
the dopamine uptake carrier
because mine is very selective
with that important drug again
of use and abuse
but some very chemists
come up with CFT
it's an even better
label of the dopamine uptake
than
cocaine itself
and it's 3 to 10 times more potent
than cocaine as a cyclone
or stimulant
just what the world needs
iotinic acid from a mushroom
is an
an NMBA agonist
the NMBA is
it has the aspartate
one of the excitatory amino acid receptors
and this is an agonist
of that receptor
so it has among other things
anesthesia potentiation
and it gives it's tremor
and it can give it's anesis
but synthetic chemists come up with
AMPHA
which is a structural analog of this
and this becomes a potent glutamate
which is called an agonist
so basically the take home lesson
here is that by making
relatively trivial patients
in natural compounds
synthetic chemists can tweak their activity
to make them selective for certain substrates
or even turn agonists
into antagonists
so they have the opposite effects
and this is part of the game again
of coming up with
new drugs new therapeutic compounds
but natural products lead
the way because they give the chemists
the ideas for things to work with
well on a more intimate level
you know you could say that humans
really value plants
in some sense if you want to be reductions
about it humans value plants
for the chemicals that they produce
which we find useful
for some reason because we either
put them into our bodies
or we put them on our bodies
and we find them useful
spices fragrances cosmetics
drugs
and of course food
also has to be included in this category
we depend on
the biochemical diversity of plants
and the biochemical versatility
to
give us these products which
we find indispensable
in our economy in our
health maintenance and in our lifestyle
for example
plants contain
flavorful compounds
these terpenoids and
polyketides that give spices
such as nutmeg and ginger
their flavor
drugs as we've said
opium poppy
is probably the primary
example and in other cases
they yield pigments they yield dyes
which we use to dye our clothes
or put in cosmetics to
put on our own
body
well I've always thought
that
one useful way to look at
the array of
these biological activities and the array
of
allelochemicals when it comes to
to
thinking about human interaction
with plants secondary compounds
in other words I'm talking not so much about
other organisms I'm talking specifically
about the human
relationship with plants and how that's
chemically mediated
via this molecular language
that plants
speak and a
concept that seems to me to be useful
is you can class all
these things as
sensorotropic chemicals
I don't know if you'll find the term
sensorotropic in any dictionary
probably not because I coined it
but what I mean there is
all these allelochemicals
from plants interact
impact on our senses
in some way
sensorotropic chemicals are chemical
messengers which are produced by
plants which transmit their message
by interacting with sensory
functions in some manner
and this includes pigments aromatic
compounds spices flavoring
agents and
pharmacologically active compounds such as
drugs
and one useful way to think
about these sensorotropic chemicals is
to picture them arranged along a spectrum
I don't have a slide but if you
over on this side
you have your
sensorotropic chemicals that are
utilized primarily as food
in this case
their impact is primarily on the
taste receptors and to some degree
on the olfactory receptors
and also visual I mean that's
that's the level on which we interact
with food if it looks good smells
good and tastes good
you know it's food but
what gives it those properties is largely
the plant secondary compounds
that's in the food
toward the middle of the spectrum
you get compounds
which you know you get things that
sort of I mean they're definitely
foods things like chocolate
which as shown here one of my
and Jonathan Ott's favorites
in sensorotropic chemicals
is are the
flavoring agent that gives chocolate
its unique
qualities well but chocolate also
contains alkaloids which are
drugs is chocolate a food
or a drug I don't
really know it's actually both it's
a moot point the point is
they fade into each other
you can't really separate
foods on this side and
drugs and flavors
somewhere in the middle and drugs over
there but there is a tendency
along the spectrum
for pharmacological
activity to become more
prominent as you get
into the more drug like
things for example herbs
you go into any herb stall
in a third world country this happens
to be in Florencia Colombia
and there will be any variety
of aromatic plants
that you can buy from the herb lady
and they'll say
put it in your bath
you know it's good for this it's good for that
put it in your bath or make a tea and rub it on
your body you know and if you want
you can also put it in your salad
I mean it's definitely a food
but it's also a drug these
herbs are drugs
as well as are their medicines
so where is the distinction
and then finally on
the far side of the spectrum you get
an even greater elaboration
you get plants that are more
unambiguously drug like
I mean they tend to be more toxic
their active principles
tend to target
specific receptors
they tend to be
a higher molecular weight
than the aromatic compounds you find
in herbs and you know
they're medicinal plants definitely
but they're still on the spectrum
of centrotropic plants
so you know
on the spectrum the foods
and the aromatic and fragrant plants
the flavoring plants and the spices
and the drugs all sort of
really fade into each other
and so you know it's
it's not really a valid
question to say these things are drugs
or foods or flavorings they're really
both and they're all centrotropic
chemicals
this is supposed to be opium
I don't know if you can see it
this is a Chinese fellow
I mean it's
but another aspect
of the use of these
pharmacologically active plants
when humans
this is different
folk remedies
in the marketplace of the ketones
you can go into the marketplace
and they have these bags of
dry plant material set out
they're common names of what each one is for
and you can just buy your medicines
you don't go to the pharmacy
particularly if you're
if you're poor if you're in that economy
you just go to the local
herbalist and buy the medicines
that you need
and what this is
illustrative of in a way
is that when it comes to the
human interaction with plant
allelochemicals we take
the plant chemicals which the plants
evolved as defenses
or symbiotic chemicals
or fragrances or whatever
for its own purposes and we put
those chemicals to our purposes
we make a deliberate
implementation
of an allelochemical interaction
to achieve some
desired therapeutic effect
now the plant didn't evolve
these things so that we could use them
we happen to find these chemicals
useful for our purposes
so there's an element here
of human intervention
of human adaptation of an allelochemical
to serve a purpose that may be
very different from the reason that the plant
originally evolved that particular compound
but this
can have profound influences
both on the
humans that utilize the plant
and on the plants themselves
for example this is diastoria
which is
the source of complex
plant steroids
and in the plant
the steroid compounds that are found in this
probably
serve a defensive
function because they can interfere
with insect
molting and they can interfere
with the development of the insect life cycle
and essentially protect the plant
against being
decimated by insects
by interfering in the molting process
the insect eats the steroid
and that basically throws a whole
monkey wrench in its life cycle
however if humans come along
and take the same plant
and extract the steroids out of it
and turn it into an effective
oral contraceptive
this is far removed from the
ecological function and served in
protecting the plant
but the human use of the steroid
has greater evolutionary consequences
for the plant
greater long term consequences
because it leads us to domesticate
the diastoria to cultivate it
to install plantations of it
so that we can get this
valuable chemical out of it
and that affects the
future evolution of the plant
what's happened to the plant is
it's become domesticated
and that is going to affect it for as long
as the species exists
as long as we still find it
useful
the development of these
agricultural techniques
which was kind of an enhancement
of this
allelochemically mediated
interaction or relationship
between humans and plants
led us to evolve from a
nomadic foraging lifestyle
to a sedentary lifestyle
and cultivated plants
instead of primary plants
of our basic necessities
and it's literally this rooting
of formerly nomadic populations
to permanently inhabited sites
where crop cultivation took place
season after season
and year after year
led first to the establishment of villages
eventually city states
with larger populations
division of labor
complex political organizations
systems of law, science, technology
based largely on the storage
and transmission of written information
but it was the invention of agriculture
the first real formalization
of the plant human symbiosis
which defined the relationship
between humans as plants
and plants as something
qualitatively different
from simple foraging of herbivores
on plant populations
it was this formalization
of the relationship
the creation of domesticated plants
that made possible
the milieu in which civilization
arose and could flourish
and if this process
had a profound impact
on human culture
it also had an equally profound impact
on the food and medicinal plants
which were the basis
of this agricultural revolution
this establishment of sedentary agriculture
set the stage for the process
of plant domestication
of selective breeding
initially this was an empirical process
an empirical human activity
based largely on observation
trial and error
farmers would unwittingly select
for those specimens
which displayed an enhancement
of some desirable property
a sweeter or larger fruit
an unusual pigmentation
a pungent fragrance
a less bitter taste
a more bitter taste
indicating high levels of alkaloids
who knows
basically this process
is a process of modifying
the plant for other purposes
to increase the biosynthesis
of those secondary compounds
we consider important
or to lessen them
to get rid of the bitter ones
and that sort of thing
so this led to the development
of cultivars
plant cultivars are basically
genetic monstrosities
as shown here
they don't occur in nature
they couldn't survive in nature
they're entirely dependent
they exist
and most of our major food plants
are cultivars
and most of our major medicinal plants
as well
cannabis sativa is a good example
it probably doesn't even exist
in the wild state
there are many different strains
many different cultigens
that we have bred
over thousands of years
for different purposes
oil, fiber and resin
but the cannabis is a good illustration
of a plant
that is basically
almost entirely exists
as a cultivar now
salvia divinorum
may be a similar example
tobacco is another one
actually that wasn't tobacco
that was belladonna
in fact one ethnobiologist
even suggested
that the pharmacological
utilization of plants
could not appear
as a specialized branch
but that the process
of plant domestication
had led to the development
of cultivars
with reduced levels
of allelochemicals
compared to the wild types
and this happened
as centers of civilization grew up
and people began living
in more concentrated areas
you had sanitation problems
and transmission of disease problems
his theory was
that as long as you were eating
plants that were not
immune to the immune system
this was protecting you
from infection
when these people started
eating domesticated plants
they became more susceptible
to disease
their immune systems
were not as stimulated
by these allelochemicals
so it then became necessary
to go out and gather
medicinal plants
now we hear about people
who said this
Timothy Johns
do you know his work
he wrote a book called
with bitter herbs they shall eat it
which is a very interesting
quote from the bible
a very interesting study
of the importance
of allelochemicals
and the way that allelochemicals
have mediated
plant domestication
he started out doing his work
in cultivars believe it or not
in the Andes
and then from that
looking at how these less toxic
varieties of potato became
domesticated and integrated
into cultivation
came up with these ideas
very interesting book
well now they are talking
about using plants
to carry this one step further
not just breeding plants
to modify their chemical properties
but actually breeding
through engineering
through genetic engineering
they are talking about breeding plants
to produce things like plastics
within the plant
and I've even heard it said
that maybe we can get them
to produce manufactured products
so instead of buying your VCR
in the store you just go
pluck it off the tree
we are a bit far from that
but this is in principle
just a further extension
I don't see anything unnatural about it
we can do it
ok we and the plant
it's a reciprocal
give and take relationship
well I think the argument
now I'm sort of speculating
moving more into the area of speculation
I think the notion that
humans have influenced
the evolution of plants profoundly
we can all sort of accept that
because clearly we have
domesticated plants
and in the process of
domesticating them we have
modified them and their chemistry
and modified them in ways
that are desirable to us
that enhances their usefulness
or appeal to us in some way
the other side of the coin
is not so clear
and this is the part
that I want to kind of speculate on
but
we know that
we have influenced the plants
the question is how much
have the plants influenced us
in our evolution
in the sense that
they have been
certainly in the iconography
of artists
we get the suggestions
that there
the feeling that there is
a more intimate association
between plants and humans
that we might like to acknowledge
this is a plant man
I'm not sure
Archimoldo
yeah
Archimoldo
or a pandrake
sorry it's not
a mushroom shaman
it's a solid plane
I mean we've all seen this
I'm not sure many times
what these images basically suggest
is you know maybe humans and plants
are not that far apart
maybe there is an even more intimate
symbiosis than we realize
and could these
could this symbiosis
and perhaps even evolution of humans
into what we are
somehow by plant allelochemicals
in some way
the interesting thing is
that humans have been
humans and the precursors to humans
have been interacting with these
plant allelochemicals
they've been chewing them
snorting them
smoking them
brewing them
and otherwise ingesting them
for 65 million years or so
give or take a few
which is basically when the angiosperms
started
not that the
the gymnosperms and seedless plants
don't have secondary chemicals
but the angiosperms really carried it to
sort of its level of complexity
that we see now
so is it possible that this long association
between mammals
between herbivores
and physiologically active allelochemicals
might have evolutionary consequences
for primates
and us
I mean we evolved from the primates
certainly this is well known in insects
it's known that
chemically mediated
coevolution between plants
and insects
profoundly affected the chemistry
and physiology of both
so similar processes of biochemical
adaptation may have gone on
between plants
and plant consuming mammals
including primates
the evolution of complex secondary compounds
particularly alkaloids
in the angiosperms and the concomitants
may have been related
it seems likely that early in the evolution
of mammals
tens of millions of years before anything
even resembling humans
appeared in the evolutionary scene
the process of biochemical and genetic
adaptations to plant toxins
was working subtle changes
in mammalian physiology
creating selection pressure
for toxin resistance
biochemical adaptations involving
the evolution of multiple
substrate highly
efficient inducible enzyme systems
such as the amine oxidases
and the cytochrome P450
microsomal enzyme systems
these are essentially mammalian
adaptations to
metabolizing these
plant allelochemicals
to neutralizing these allelochemicals
this is part of the biochemical warfare
that we were talking about
constant low levels
of these allelotropic
and psychotropic plant chemicals
in the diet of foraging primates
or early humans
could certainly have affected
their phenotypic biochemical adaptations
they could also have affected
their immune genetic and sensory
and cognitive functions
for example many plant toxins
are mutagens
and they can impact on inheritance
on the inheritance process directly
if they should cause mutations
in the germ cells in the egg or the sperm
unfortunately
as far as we understand evolution
the majority of mutations
are detrimental
but from these some are favored by selection
and result in evolutionary adaptations
and those flourish
so it's possible that over
many generations
constant
exposure to low levels of mutagens
in the diet might have contributed
to enhanced mutation rates
or enhanced genetic drift
of a population so that perhaps
over time the mutation rate
was actually accelerated
and so the overall rate of evolution
was accelerated
another area where plant allelochemicals
could have had an effect
is in the modulation of our immune systems
these dietary allelochemicals
could have
directly affected the immune response
of primates
there's been some recent work published in Germany
in which the effects of extremely
small doses of toxic
alkaloids and other allelochemicals
on immune functions
was investigated
these were a thousand
to a thousand times less
than what we consider the
pharmacologically active dose
much less than any dose
thought to cause any toxicity
or really any kind of response at all
but what these people found was
that if these vanishingly small doses
10 to the minus 12 molar
and lower
so down in the picomolar
and femtomolar ranges
many of these compounds caused
a very strong activation
of the nonspecific immune system
when these doses were increased
to putatively therapeutic doses
the level of
cytotoxicity or whatever
they caused, they became
immune suppressants
they became strong immune suppressants
so these investigators
their rationale, their interest was
to explain the mechanism of action
of homeopathic medicines
and they felt that this perhaps
explained it, that these extremely
dilute homeopathic medicines
working at, you know,
minus 12 molar and lower
concentrations cause the
stimulation of the nonspecific
immune system
but the relevance of this finding
for the present argument is that these
chronic low levels of these
dietary allelochemicals
could have functioned to potentiate
the immune functions of certain individuals
thus conferring a greater resistance
to disease, longer life
enhanced reproductive potential
and all the evolutionary consequences
all the evolutionary advantages
for those that foraged on these
immunostimulating allelochemicals
again
it's probably hard to test this
but it's a reasonable note
one of the puzzles of evolution
certainly in the evolution of primate
is the explosive evolution
of the human neural hardware
the size of the human brain
tripled in a mere 3 million years
during which time we went from
language-less, tool-less
four-legged primates
to two-legged, tool-wielding
verbally expressive and deity
worshipping human beings
all this happened while the invention
of writing was still 100,000 years
in the future
of course
everyone knows that the fossil record
is full of gaps
but it still is the most
tangible physical evidence
we have that something very peculiar
was going on in hominid evolution
since about 3 million years ago
that date
more or less, give or take half a million years
marks the appearance of Homo habilis
the first unmistakably human primate
the first proto-human
probably walked upright
may have used simple tools
and displays a dramatic increase
in cranial capacity and brain size
relative to its close cousin
Australopithecus bocei
the most remarkable fossil
this one here
ER 1470
has been dated somewhere
between 2 and 2.8 million years
ER 1470
has a cranial capacity
of 780 cubic centimeters
nearly twice that
of the contemporary
Australopithecus africanus
which is shown here
and even larger
than other Homo habilis species
this guy essentially
is like us
but he lived 3 million years ago
um
so it shows that
something
some evolutionary pressure
was going on
about that time
out on the Serengeti plain in Africa
where all this stuff was taking place
what caused this explosive expansion
of the human
neural capacity
of the complexity of the human brain
well one of the anomalies of our existence
is that we are very much unlike
any other species
that inhabits this planet
we're the only species with a complex language
technology utilizing species
we're the only species
able to store accumulated knowledge
in a symbolic form
external to ourselves
we're the only species for whom
symbols
which are ideas of abstractions
have as great a reality
as physical objects
this preoccupation with symbols
with abstractions
is the cause and the result of human culture
and it is culture
this abstract edifice
of symbols
composed of art, science, medicine
artifice, myth, folklore
all of these things are symbolic structures
that truly sets us apart
from biological species
so yes
I mean we're part of nature
but we're also quite anomalous
our species is unique
in having these symbolic functions
it's clear
this symbolic underpinning
that carries our civilization forward
and that makes us what we are
is derived from
or perhaps the inevitable result
of the extraordinary complexity
of the human brain
the complexity of our nervous system
our neuro-linguistic
portions of the brain
combined with our associated capacities
our acute eyesight
our tactile sensitivity
and fine motor control
all of which
are reflected on the neural level
by complex systems of organization
that govern all these functions
these essentially give us
the neural hardware
the wetware if you will
that is needed to run the software
of cultural programs
the symbolic capacity
so
I'm really sticking my neck out here
I want to suggest that perhaps
one explanation for this
is that some of these psychotropic
allelochemicals specifically
some of these hallucinogens
which were probably widespread
in the environment
that these primates evolved in
in the forms of mushrooms
like psilocybe cubensis
may have directly or indirectly
affected the evolutionary development
of human neuro-linguistic adaptations
our large size
and complex neural organization
of the brain is directly related
to our linguistic and symbolic abilities
the neurons that control the lips
the tongue
the muscles involved in speech
are disproportionately
hypertrophied in the human brain
the brain also has large
specialized internal structures
devoted to language
understanding and processing language
well if you think about
what language is
and it's really language
that distinguishes
languages that
both written and spoken
is the vehicle
on which we erect these symbolic structures
is the intimate association
of sounds and images
language is literally
imagination
in the truest sense
having agreed upon meaning
I can say table
and you think of a table
or you visualize a table
in your head
so you have certain
I make certain sounds
and that triggers certain pictures
in your imagination
that's why you can understand me
reading written words
is another extension of this
my eyes see the words
I can hear the words
in my imagination
and that interior speech evokes
the same pictures
that speech evokes
if heard
well it seems to me that
what underlies this process
of linguistic understanding
what mediates this symbolic process
is in a way
a process of synesthesia
synesthesia
is the
is experiencing one
sensory modality
in terms of another
it's like you can see sounds
or hear colors
well
hallucinogens are one of the few
chemicals
one of the few drugs we know of
that can reliably induce
the process of synesthesia
it's very commonly
experienced under the influence of
hallucinogens
it's one of the few instances
except that we routinely engage
in this process of language
which is a synesthetic process
but we don't think about it very much
but then when we take a hallucinogen
and experience synesthesia
it seems remarkable
we say well I heard the
I saw the sounds
or I heard the colors
or whatever and this seems remarkable to us
but there may have been a time
in human evolution
where the association
between the spoken word
or meaningless sounds
and meaningful images
was not so obvious
and could it have been a synesthesia
induced by a plant hallucinogen
which provided this triggering event
that led to the realization
of the equivalence of sound and image
and hence gave rise to the first human language
this is
clearly speculation
but this is one possibility
where these plant hallucinogens
are in human evolution
and into the evolution of the language
and symbol using species that we are
obviously
it's hard to check this
I mean nobody can prove me wrong
but I can't prove myself right either
so at that point
I think we have to leave it there
this is a painting by Pablo Amarrico
the Peruvian painter
that shows in his paintings
he represents synesthesia
synesthesia is a common
experience under the influence of
ayahuasca
and he represents it
by these wavy lines
that surround everything
this is how he shows synesthesia
in his paintings
so that's
quite enough I think
and that's all I was going to say
so long-winded
do you have any questions
good
um
I guess probably everybody has
or maybe not
but everybody has heard
of some evolutionary example
that seems to
not quite fit into what we normally
think of evolution
I like the example of the hammer orchid
and the wasp
which is required to pollinate it
the hammer orchid
smells like the female wasp
the male wasps
are hatched out
or
I think earlier than the female wasps
and
the hammer orchid flowers
at the same time that the male wasps
are coming out
so there's lots of male wasps around
and no female wasps
so they all happily pollinate the hammer orchids
and
the evolutionary
idea that
there was a trial and error
um
narrowing in on this particular scent
such that
it now works
but in that case
the mist is as good as a mile
and it seems like
many of the examples here
also it doesn't seem like
you would hunt around in this absolute
myriad molecules
universe of molecules
by trial and error
and find out the right one
so in other words
how could it have taken place
through random selection
yeah
like non-local mind and
what have you
or morphogenetic fields or whatever
I mean it's hard to
rationalize some of this
I think it's clear that
you know
natural selection is
one of the processes that operates
in evolution
but clearly not the only process
I think they're now beginning to
realize well we were speaking
the artificial life specialist
says you know there are other
boundary conditions on this process
that put constraints
on natural selection
that's only one of the things
there are other determinants
that uh
which are not fully understood yet
which I think
must explain why
these things seem sometimes more directed
you know
it's not exactly design
but it's
there's more to it than just random
throwing up of molecules
in particular templates
and selecting out
the one which seems to fit it
I don't know
I mean yeah
you might have
actually I have a question
yeah
have you talked to Lindmark
at all about
external chemical agents
coming
incorporated into
mobile cellular organs
now being adapted to internal functions
I have not talked with her about it
but I think it's a notion she would
be sympathetic to
right right right
and there's been interesting work
you know if you look at
I mean there's been work looking at different receptors
certain bacteria for example
have endorphin receptors
on the surface of their outside
well you know what does endorphins
do for bacteria
who knows but it's not what they
you know that was probably the original function
of endorphins and then we
you know our complex organisms
you know they became
adapted to internal functions
and it's true for
just about all our neurotransmitters
you know you can find these
things in microorganisms
as well
so yeah
now we were looking at the
synaptic cleft and the
something like serotonin being released
and then getting a
receptor type
it might take a certain amount of
a certain amount of time back
causing a certain amount of cycle time
these psychoactive
hallucinogenic drugs
do they have
different kinds of time
or is it just a slight variation
that turns into
what's that
what really happens in the cleft
you asked the 64,000
dollar question
it may be variations in
transit time it may be
the I mean another
factor is that the
exogenously introduced hallucinogen
tends to you know essentially
massively flood the system
with an excess of these
chemicals whereas internally
they're released in small amounts
in specific places
in specific times I mean it may be
that you know it's
more when they're exogenously
introduced in your all your
receptors are flooded
immediately with something like
dimethyltryptamine for example you get
the acute
you know overwhelming hallucinogenic
response well dimethyltryptamine is in
the brain you know itself
but it may never it may
only be released
in small amounts under certain
you know at certain specific sites
so you never get a you know
an internal
effect like a DMT
flash because
it doesn't work that way
it's probably also a problem of
turnability it's also
because the blood brain barrier
is always in between you and
that's right but many
of these things readily cross the
blood and
yeah I mean transit time is
one of the things the other thing is maybe they
don't you know maybe they
fit into the receptor in a different
way and
you know they don't evoke quite the same
type of response I mean I don't
think it's well
understood why they're
different you know
yeah
there is an endogenous mechanism
definitely in fact
your comment
I
remember seeing an article about
a woman
a doctor in England who was studying
a person who
what was it she was able
to reliably
see
colors or rather see
sounds that he could give certain
tones and she
could she had a genetic
it was two sisters that was the thing that
was interesting they both had this ability
they weren't identical twins
but I believe they were twins
and they
you know had they
both had very specific synesthetic
responses to certain tones
but they weren't the same
right person A saw
blue at the key of C
and the other one saw yellow
or something but they could both
consistently see it so they're beginning
to find out there is
definitely an internal mechanism for
synesthesia at least to some people
and you know as I say
when we engage in a symbolic
activity we do it routinely
we don't even think about it
but that's really what's happening
so
not
not that I'm aware of
yeah
it's clear that some
psychedelic chemicals are
defensive chemicals are there
to slow down stop
so
what helps me is
that since DMT is so
widespread in the plant world
and maybe it's serving other functions
that you mentioned in the plant world
but it's also
you know
the
this
as a defensive chemical
well
I guess I don't know
the short answer is I don't know
they do they're very close
biosynthetically
and you often get plants that have both
but usually
one or the other usually predominates
like in varroa for example you get
triptamines and only traces of beta-carbolines. In certain malpighiasis plants, such as Banisteriopsis
argentina, or now a different species, I understand, but you get primarily beta-carbolines and
also traces of DMT. Why it doesn't happen more often, I don't know. It may be that what these
tryptamines generally, the function they generally subserve in the plant is more of a plant growth
inhibitor than being targeted at herbivores. And in that case, you know, there's no need for the
MAO inhibitor. If they're biosynthesized as a defense against herbivores, then you're right,
it would make sense to have beta-carbolines to render
that.
Also, it's possible that it's just, in the case of the herbivores, it could simply be the bitterness
that's involved as a defensive function, not the psychoactivity, although we tend to see it in terms
of...
But we can, you know, again, that sets us apart in terms of our behavior, and we can perceive a
chemical quality of a plant, such as bitterness, which would drive, you know, any sensible herbivore
away, it wouldn't want to eat it, and we say, oh, great, it's bitter, you know, it must make a good drug.
So, you know, then we go for it even more.
It's known, for example, in the case of secondary compounds in nectars, that different classes of animals that are
pollinating species, since we have birds, bats, which are mammals, and then insects, react differently to different
categories of secondary compounds.
And mammals seem to be bats who are deterred by alkaloids.
And so, you know, we can see that in nectars, but bees aren't, and so it's another subtle interaction.
Right.
Again, probably because the bees, they probably aren't bitter.
I mean, they probably have a whole different set of receptors and probably perceive these things differently.
This is the result of this biochemical coevolution, the evolution of these receptors, and how the animals,
the interactants of plants, perceive these chemical qualities.
Do you have a simple thought?
Do things like manatomes also have MAO, or would DMT affect them more strongly?
They certainly have MAO.
You mean, would DMT be orally active, for instance, in them?
Or in manatomes, yeah.
Something similar to cellulose.
A lot of times it's found in moot bars, so it makes me wonder.
Right.
It's very possible.
One speculation, for instance, psilocybin is, you know, a serotonin, affects the serotonin system.
Snails and those sorts of things love to feast on mushrooms.
So perhaps what psilocybin really is, is a snail poison, a snail defense.
I mean, it certainly is, you know, might protect the mushroom from being consumed by snails in that respect.
But then, you know, since it's valuable to us, or since we're interested in it,
it affects that whole relationship as well.
So I don't know.
I mean, it's speculation.
A lot of this, but good enough.
Thanks for bearing with me.
Sorry.