Alkaloids And Evolution

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.