Thursday, October 17, 2002
James L. McGaugh, Ph.D.,
Director, Center for the Neurobiology of Learning and Memory,
University of California-Irvine
Session 3: Remembering and Forgetting: Physiological and
CHAIRMAN KASS: Let me just remind Council
members that we are in the midst of a three month inquiry
into various uses of biomedical technology, present and projected,
for purposes that go beyond the treatment of individuals with
known diseases and disorders or that have uses that could
go beyond those purposes, and we are doing so because we were,
by executive order, encouraged to undertake some fundamental
inquiry into the human and ethical significance of developments
in biomedical technology and to contribute to the public understanding
of these questions.
And that meant at least that we have the opportunity, but
also the liberty to step back from some hot button topics
and to try to take a look at the field as a whole and to discover
whether there are certain kinds of questions that cut across
the uses of this or that technology.
And as I suggested in the memo that was circulated to you
before, the prospect of these kinds of uses of biomedical
technology really do raise for us some of the weightiest questions
in bioethics, as we saw this morning, already touching on
not just the means that are to be used, but also the ends
that we wish to pursue and touching very often on certain
fundamental features of human life.
We've been looking at technologies that affect the body,
whether in terms of muscle enhancement or blood doping for
athletics. We will be talking in December about research
on aging and the human life span, and we have been looking
now — this will be the second of three sessions in which
we will be looking at technologies that offer the possibility
of influencing certain features of the human psyche, mood
and affect the last time; next time, attention and conduct
and the discussions of Ritalin and the use of stimulants;
and this time things that affect memory and cognition.
And we are very, very fortunate to have with us today two
of the leading researchers in the field of human memory.
Dr. James McGaugh, since the 1950s, has been a pioneer in
the neurobiology of learning and memory. He's Professor
in the Departments of Neurology and Behavioral Science, Psychiatry,
Pharmacology, the School of Social Sciences, and the Director
of the Center for Neurobiology of Learning and Memory at the
University of California at Irvine.
And we have PROF. Daniel Schacter, who has written very widely
and for a broad, nonspecialist audience wonderful books on
the psychology of memory. He's the William R. Keenan
PROF. and Chair of the Department of Psychology at Harvard.
We're delighted to have both of you with us, and by prior
arrangement Dr. McGaugh will go first. We'll then take
our break after about an hour and a half, and then we'll
have PROF. Schacter's presentation.
But the conversation can flow with all of you present.
Please, Dr. McGaugh, thank you for being with us.
DR. MCGAUGH: Well, thank you very much
for inviting me. It's nice to come here and speak about
a topic that I have been interested in for over four decades
and which serves as my current interest, deep current interest,
at the present time.
I'm going to talk about memory, and I think we can all
agree that memory is a good thing to have. You'll hear
later on this afternoon that it comes in different forms and
provides different advantages and different disadvantages.
But I'm going to focus on only one aspect of it, and
that is the experimental or other treatments that will make
long lasting memories longer lasting and stronger, and the
general assumption underlying this, which certainly can be
questioned, is that if it's good for us to have memories
that enable us to get along during the day, to remember where
we parked our car, to remember our motor skills, and so on,
then maybe it's a good idea to have a little bit more
of that. That's an underlying assumption that's been
made. I'm even going to question that assumption.
Now, there are several reasons for investigating memory
enhancement which I'll start with later. I'll talk
about memory blocking and start with memory enhancement.
First is just the basic research on brain memory, and that's
what drives my research. I use drugs and other treatments
to enhance memory in order to understand how the brain ordinarily
works when memories are made. That's the purpose of it.
If we take drugs, in particular, if we know something about
the mechanism of actions of drugs, let's suppose we give
a drug which is a GABA receptor antagonist, and we find that
this drug does something to memory in a very precise way.
Then we can conclude that GABA receptors located in some places
of the brain are very important in the making of the memory
Beyond that, if we focus on those places in the brain, we
can learn much more about not only the receptors of a particular
kind, but a receptor in a particular location.
And out of this is unraveling little by little more and more
understanding of the key neurochemical systems and the key
anatomical systems that are involved in making and preserving
memory. So that's a fundamental line of inquiry that
drives this research, where memory enhancement is a way of
inducing the brain to behave in a different way so that you
can learn something about it.
Another more obvious reason is the question for finding treatments
for memory disorders, such as Alzheimer's disease. I
probably shouldn't say "such as Alzheimer's disease"
because the research is almost restricted to that.
There isn't any research on the drug effects for the
mentally retarded or it's just minuscule research. There
isn't any research for drug effects on people who have
brain damage that prevent them from learning and remembering.
That's a nascent field. It really doesn't exist.
The focus has been on progressive disorders of learning and
memory and cognition that are progressive, such as Alzheimer's
disease, because as you know, the incidence is estimated to
be at least 25 percent, if not 30 percent, in people over
the age of 85.
So we're all looking at something that can happen to
us. So it drives our attention.
Now, there are other interests of the pharmaceutical companies
and the biotech companies that overlap, but differ somewhat
from the two categories that I've given you, and one is
looking for treatments for a new disease, which is age related
Now, that's a new disease because drugs can be found
to treat it. It was new to me that it was a disease. I thought
normal aging was normal aging, and we have known for at least
a couple of decades that there is, on average, a slow decline
over the decades starting at the age of 30 in cognitive processing
on memory tasks, in particular, memory tasks that use speed
as a criterion.
For example, if you ever watch "Jeopardy," you
don't see many 80 year old people on "Jeopardy"
because of speed of response is such a high priority, but
those of us who are over 50 or well over 50 know that we curse
the television because we know, but we can't respond as
quickly as the folks that are there.
I'm also concerned about that because while there is
age related memory decline, without question, on average there
are plenty of people who show absolutely no age related memory
decline, and there are others who show rapid age related memory
And underlying all of that, by the way, is a countervailing
influence which is an increase in knowledge and wisdom and
ability to deal with the environment, which readily compensates
for the speed driven responses. But that is a new target
for drug development.
Another target for drug development which sometimes is said
explicitly, but most of the time it's implicitly, is just
drug improvement for everybody else, and why not? And why
If you look at the health stores or even your drugstores
or your supermarkets, you can find dozens, if not hundreds,
of bottles and packages on the shelf which are entitled something
like "memory boosters" or "brain busters"
or something of that kind, and they're not on the shelves
because people want to fill up the shelves and make them look
pretty. They're on the shelves because they're being
Ginkgo biloba, which is now the latest study shows has no
effect at all in age related memory decline, still sells,
makes millions and millions of euros in Germany and, I suppose,
somewhat less than that here, but nonetheless, I get more
questions about ginkgo biloba than anything else appearing
on my E-mail screen.
But that's a target you can see. That is, as soon as
you see there is a market, you can see that there's a
target for it, and so there is a slippery slide from disorders
of memory to the new disease of age related memory decline,
which is in normals, to just having a drug to improve memory
in normal subjects.
Now, I have done a nonscientific sample of this by just
asking lots of people I know. I've asked if there were
a drug that was safe and effective and would improve your
memory for such things as where I parked my car yesterday
or, you know, things of that kind. I have yet to find anyone
who said, "No, I wouldn't be interested in it."
And I would have thought that most people would say, "No,
you'd have to convince me to take it." But even
people whose judgment I trust and have trusted and maybe no
longer trust have said, yes, they would take it.
And then I had another question. I said, "Well, let's
ask how eager you are. Would you do it if it was free? How
about a penny a day? How about ten dollars a day? How about
a hundred dollars a day?"
Well, they drop off, of course. Now, the drop-off doesn't
occur for family members of people who have memory disorders.
The drop-off is not really quite so steep because they will
do anything to try to keep their family members more cognitively
competent for a longer period of time.
But what this nonscientific study tells me is that this is
almost a frivolous kind of thing for most people. Yes, if
we're there, and, yes, if it were cheap, and if it would
give me a slight edge, yes, I would do it.
And don't misunderstand. The pharmaceutical companies
and biotech companies are listening to that by looking at
the sales of ginkgo biloba and other ones.
ow, there are other reasons you have to come that are implicit,
unstated. One of them is memory enhancement in children,
that is, school children, just regular school children. I'm
not talking about children with disorders.
I was driving to a concert with a neighbor, and our families
went, and she said, "Oh, Jim, I'd like to have a
drug for my daughter to make her more competitive in school.
Could you give me the name of one?"
It wasn't "do you know anything about it,"
"are there any things that are safe and effective."
It was "can you give me the name of one," and the
model that she had in mind was Ritalin because some of her
children friends take Ritalin. So there must be something
else that her child could take so that she wouldn't have
to study very hard, you know, just to make up the difference.
But I think that that's coming down the road, and it's
something I think appropriate for this group because that's
part of the slippery slope. If there is a drug which is safe
and effective and not too expensive for enhancing memory in
normal adults, why not normal children? After all, they're
going to school, and what's more important than education
of the young? And what would be more important then than
to give them a little chemical edge in getting a better education
if it didn't do damage, and so on?
So I see that that's there.
Now, we also have genetic manipulation, which I'll talk
about perhaps a little bit more later down the line. Many
of you, I'm sure, saw the cover of Time magazine and read
the article after the report of a genetic manipulation which
increased the number of a certain kind of receptors, glutamate
receptors in the brain, and the mice that had that genetic
manipulation, those mice were better at a couple of memory
tasks than were other mice.
And so all of a sudden Time magazine began talking about
designer babies, I think, which would fit in with your topic
of discussion this morning. If you think selecting for sex
is a problem, think about selecting for learning or selecting
for intelligence using genetic manipulation, gene transfer
or knockouts or something of that kind. I think that is an
Now, as we consider these latter, however, in children and
even for adults, there's an important confusion to clear
up that was not cleared up by Time magazine, on the contrary,
and that is the distinction between intelligence and memory.
All these things do — all of these things do, including
all of the drugs that I work with, is make animals and humans
remember a little better information that they have been presented.
That's all they do.
Now, intelligence is quite another matter, whether you think
of it conceptually or whether you think of it the way it's
tested in an intelligence test. Memory is a very small component
and memory tests are small components of intelligence tests.
They have to do with reasoning. They have to do with judgment.
They have to do with all kind of things, and there's no
evidence that inserting a gene or taking a gene away from
a mouse imparts it with greater ability to make better judgment,
better reasoning or anything of that kind.
So I think that these experiments, however interesting, do
not lead to the conclusions that were jumped on by Time magazine,
that all of a sudden we can do genetic engineering, and we
have to be worried about intelligence.
If that is something of concern, then I think those people
who are interested in it have to be better educated about
what it is that memory is and what can be expected from such
And finally on this, there's a huge caveat. I'm
now going to question the assumption that I made at the very
beginning, that if memory is good, then more is better.
Well, more is not better. At the extreme more is worse.
There are two famous cases, one a fictional case of "Funes
de Memorias" by Borges, a short story in which Funes
was capable of memorizing everything that was presented to
him, and he remembered everything that he encountered such
that towards the end of it he said, "Sir, my mind is
like a garbage heap. It's all there."
And over 100 years ago the famous psychologist William James,
in whose hall Dr. Schacter lives, said that to remember everything
is as valuable as to remember nothing because it's all
there and needs to be sorted out.
Now, there's also the case written in Luria's book,
The Mind of a Mnemonist, which you can get at your local Border's
bookstore, a subject that he studied for many, many years.
This was a subject who could memorize very well. He memorized
by using synesthesia, by mixing the senses which enabled him
to remember better, and he could remember very detailed information
for 15 years, very precise knowledge of what numbers were
given to him in what order over a 15 year period of time.
He had a very unhappy life and ended up a failure.
I also had a subject. Up popped on my E-mail one day as
the Director of the center, "I have a memory problem.
Would you talk with me?"
And I sent back, "This is not a memory disorders clinic.
I can direct you to one."
"No, I have a kind of a problem you might be interested
in. Would you at least talk with me?"
And this was a young woman who claimed that she had such
a powerful memory that it interfered with her daily life,
and could I at least listen to her and direct her to someone
who might help her, and I had trouble at first understanding
what she meant by that.
So I got out the two books that were published at the millennia
about all of the things that happened in the last hundred
years and just randomly opened pages, and I couldn't stump
her. I just randomly opened pages, and several times she
said, "Well, you have the date wrong."
And I said, "No, no, it's written right here. It's
a date line out of a newspaper."
"No, no. That's the date in which they wrote it.
The date of the occurrence was three days before that,"
and so on.
And I said, "Well, how did you do in college?"
She was a C student in college, barely made it through, and
I said, "Well, why couldn't you put this extraordinary
capacity of being able to remember to good use?"
She said she never could because it's disorganizing.
"I'd begin to do something and somebody would say,
'Well, it's Thursday,' and I'd begin to go
backwards, Thursday last week, the week before, the month
before, the month — five years before, and it's just
like going through a Rollodex, flip, flip, flip, flip, flip,
flip, like that," and she was distracted from what she
was to do because she had such a powerful memory.
Now, lest you think I'm making this up, we also have
her diaries, which she kept over all these years, and with
the help of an assistant, we are able to check information
that she said that she has by going through her diaries, and
we have yet failed to find any error or any mistake.
Here's a failed person in life who has an extraordinarily
strong memory for events that occurred in her life. She's
unable to use that, and the only way she used it productively
was she worked for a while with a very well known trial attorney,
and she was the assistant standing there or sitting there
so that when some claim was made about something happening
on a certain day and it rained that day and so on, this trial
attorney could turn to her and say, "Did it rain on that
day?" And she could say yes or no without having to
go to the records and see. That's all that she was good
So a little, maybe a little is good, but I don't think
any of us would want to have the memory of Mr. S, Mr. Luria's
patient, or Funes, the Memorias, the fictional character,
or the subject that I've worked with.
Now, let me turn a little bit to the research on drug enhancement
of memory, which is my special interest. This was all started
in 1917 by a study by Karl Lashley, a very famous neuropsychologist,
in which he gave a drug, strychnine sulfate, which many of
you know to be a rat poison, to rats each day shortly before
they were trained on a simple, little maze, and he found that
they learned the maze faster.
Now, this was of interest to me many years ago because we
thought we knew something about the mechanisms of strychnine.
So in the mid-'50s, with a colleague I replicated and
extended this study and found that, yes, strychnine did what
Lashley said it did.
But we couldn't draw the conclusions that we'd like
to draw, which has to do with the drug making memory stronger,
because we're confronted immediately with what we know
is a classic learning performance problem. The animals learn
better. The drug influenced the learning, but did it influence
the learning because the animals could smell better, because
they were more attentive, because they were more reluctant
to enter alleys and so they were more selective? All kinds
of performance factors.
Now, if one is only interested in having human performance
better, then one doesn't care about this distinction.
That is, if you just want to get humans to perform better,
you don't care whether they remember better, whether they're
more attentive, or whether they're more highly motivated
But if you're interested in mechanism, it's very
important. So I introduced the procedure of injecting drugs
not before learning, but immediately after learning, and the
reason I did that is because it had already been established
or already been suggested that when you make a new memory,
there's a period of consolidation in which the formation
of the memory is susceptible to influence.
This was first seen with electroconvulsive shock so that
humans and animals that are given electroconvulsive shock
treatments remember less well those things that happened just
before the treatment, and this and other things led to the
view that memories consolidate over time.
Now, if that's the case, I said it should be possible
to give a drug after the animals are trained and find the
same effect, and, lo and behold, I did.
Now, that led me and many others down a path of using this
post training drug injection procedure to find out which drugs
would enhance memory, which would not, where they acted in
the brain, and what mechanisms they used in acting in the
brain to produce these effects.
And I won't bore you with all of the details. Suffice
to say that we know that there are several brain regions that
are very important, and for those of you who are interested
in neuroanatomy, they include primarily the basolateral amygdala.
They include the hippocampus, the entorhinal cortex, and the
medial part of the prefrontal cortex, in particular, but there
are some other regions as well.
We can enhance memory in laboratory animals by microinfusing
microquantities of the same drugs that we would inject peripherally
into specific regions of the brain and get exactly the same
results or we can put antagonists of those drugs directly
into those brain regions and completely block the memory enhancing
effects induced by peripheral drug injections. So this is
a way of learning about the anatomy of memory, the pharmacology
of memory, and the neuromodulatory systems that are involved
Now, interestingly many of these drugs converge on promoting
the release of noradrenalin, norepinephrine or acting on the
receptors that adrenalin and noradrenalin use because if we
use blockers of those compounds or of those neuromodulatory
influences, we can prevent the memory enhancing effects.
Now, we asked then a number of years ago why is it that we
have a brain that's organized in such a way as to be labile
to influences that happen after learning. Why is it your
and my brain is made that way?
Because I can skip ahead and say some of the same drugs have
been studied in humans. Amphetamine, for example, given post
training to humans will enhance memory just as it does in
laboratory animals. Well, why are our organs organized this
We came up with the idea that this might be part of the
selection process that enables us to keep things that are
important to us and not clog up our brain like Mr. S in Funes,
the Memorias with things that don't happen. It's
a way of allowing a period of time for selection.
So you have an experience, and a decision has to be made.
Is this memory to be kept or not?
Well, we ask what is it that ordinarily would act in the
body that does the same things that drugs do? Well, what
happens when you get excited? You release stress hormones
to yourself. We all do that.
When you are aroused, when you are insulted, when you're
frightened, you release adrenalin into the blood stream from
the middle part of the adrenal gland, and you release cortisol
from the outer part of the adrenal gland. They go into the
blood stream. Both of these stress hormones are released.
So we ask the question then: do the stress hormones do
the same things as the drugs? And the short answer is, yes,
they do exactly the same thing, and they work exactly in the
same places in the brain, and they use the same mechanisms
that I describe for the other drugs that work on GABA systems
and noradrenurgic systems, and so on.
So here's a built in system that does the job, and our
conclusion is that what happens with this release is that
a correlation is then created between the significance of
an event and the subsequent remembrance of the event, and
I'll come back to that a little bit later.
Finally, there's a caveat in all of this research, which
is very important to think about whether it's drug manipulation
or whether it's genetic manipulation, and that is if there
is simply a tradeoff between a drug and additional training.
We have found nothing that a drug can do that additional training
So it's not as though the drugs turn the animals into
super animals. It just means that they get there a little
faster. That is, it gives them a little edge in how they
get to that point. That's very important to think about
because if you're thinking about outcome, then there's
lots of ways to get that outcome. You don't have to give
a drug to get the outcome.
If you have a child that's not learning well, you don't
need to give it a drug. Give it more training to get to the
same outcome. Now, if you want to use a drug as an aid to
get to that outcome, then that's a decision that you have
to make, but it's not going to get you someplace that
you otherwise wouldn't get.
For example, Mr. S could do all of these marvelous feats
of memorizing. Well, we know perfectly ordinary people who
have been trained to memorize a telephone book. You can do
that. I mean if you want to spend your time learning a telephone
book, you can do that. I wouldn't particularly advise
that unless you had some special reason for doing so.
All right. Let me turn now more specifically for a moment
to the effects of drugs used in the treatment of memory disorders,
and here we have a sad story.
Despite many millions and millions and millions of dollars
that have been spent by pharmaceutical companies and biotech
companies, and despite a lot of academic research, we only
have one class of drugs that is useful in treating Alzheimer's
disease. It's all the same class. They're all acetylcholinesterase
inhibitors, which means that they inhibit the enzyme that
destroys acetylcholine when it's released. If you inhibit
that enzyme, then this neurotransmitter, neuromodulator is
around at the synapse for a longer period of time.
And the drug such as Tacrine, Aricept, Exelon, and so on,
they're all "me, too" drugs. They're all
acetylcholinesterase inhibitors, and the further development
is to try to get rid of the gastric distress, all of the cholinergic
side effects that one would not want to have, and they are
more or less effective in doing that, but they are not horrendously
As a matter of fact, they're modestly effective. The
underlying problem is that Alzheimer's disease is a progressive
disease. Subjects are going to get worse and worse and worse
no matter what you do, and all you can do is squeeze a little
bit more effectiveness out of a patient for some period of
time. It is no cure.
And — and this is a tough one — no new or novel drugs
have been produced. So there isn't any drug out there
which is a novel drug, which has been found to be effective,
and there have been a lot of them that were this close to
being effective and didn't make it all the way through
for one reason or another.
There are lots of them that have been developed by pharmaceutical
companies that are very effective in animal models, and then
they drop out along the way because of side effects. I'll
just give you one odd ball side effect. There was a company
that I was consulting with that had a very powerful memory
enhancing drug in laboratory animals, which means they could
learn much faster, not ever better, but much faster, and it
was yanked out because in Phase 1 it caused nosebleeds in
humans. So it was kicked out because of that, and others
have liver damage and they have other things.
They just haven't made it through for whatever variety
of reasons. And I was wrong because a dozen or so years ago
because so much money was being put into it, I bet that we'd
have three or four by this time working on different classes,
that are different classes of drugs working on different systems,
but they don't exist.
What's really needed when you look at it carefully in
disorders such as Alzheimer's disease is not the palliative
types of drugs we're talking about that squeeze a little
bit more out of a deteriorating brain, but we need drugs that
will or some treatments which will prevent the disorder from
occurring in the first place or restoring cellular function
through some other means if that's possible to do so.
And there is an awful lot of effort going on at the present
time, and now I switched my bet, and my bet is that these
are going to pay off. Let's say, in the next ten to 15
years we'll have some treatments which might — particularly
because so much more is known about the etiology of Alzheimer's
disease that it's a good bet that something will happen
in that area.
All right. Now, let me say a few words about blocking memory
formation. Can we block the formation of memory? The answer
is, yes, we can do that.
I already mentioned that electroconvulsive shock will do
that. That's been known since 1949 approximately, and
it's known both for humans and animals that if you give
such a treatment, there will be a selective forgetting of
things that have just been learned.
But there are also a lot of drugs that are in common use
that are antagonists of memory that impair or block memory,
and I'll mention some of them. Anti-cholinergic drugs
will do that, drugs like atropine and scopolamine will prevent
memory formation. There's not much danger of that happening
because these drugs are not used in high doses ordinarily,
and they're not anything that's subject to abuse,
by the way. These drugs have such unpleasant side effects
that you wouldn't find many people abusing them.
But there are others that are abused. Benzodiazepines are
memory impairing drugs, drugs like Valium, Halcyon, clonazopam.
All of these drugs induce anterograde amnesia, in both humans
and in animals, if these drugs are taken in high doses. Performance
can be reasonably normal without registering the information
acquired while under the drug. This is anterograde amnesia.
And these drugs certainly will weaken the formation of memory,
and in some cases they will have very powerful effects, and
these are drugs that are commonly taken by many of us. They
were anti-anxiety drugs originally, but we apparently have
lots of anxiety because they are sold in vast amounts throughout
the world, much vaster, I think, than the extent of anxiety.
So benzodiazepines are there, and interestingly they work
in the same place in the brain that I talked about. They
induced their amnesia by acting specifically in the basolateral
amygdala. So there's something about that region of the
brain that's integrating an awful lot of neuromodulatory
influences coming in, including those for the benzodiazepines.
In the last category are the beta blockers, which are commonly
used for the treatment of heart disease, and I'll say
a little bit more about those.
This work came out of the work in my laboratory with laboratory
animals in which we found that a common effect of many drugs
that enhance memory had to do with the activation of the noradrenergic
system within the brain and then this particular region of
the brain and some other regions as well.
So it looked as though with that information and the information
that we had from the stress hormones that it might be that
ordinary emotionally aroused memory, the memory of emotionally
arousing experiences might involve the systems in humans.
So Larry Cahill, a colleague of mine in the laboratory, set
out to do this. We did the following study, which is now
well known in the literature.
He told human subjects a story about a boy, and it had two
versions. One is an emotionally arousing story, and the other
is a boring story. And then he measured the memory in a surprise
memory test three weeks later, and the subjects selectively
remembered better the information presented to them during
the exciting part of the story.
So let me run through it for you. A boy and a mother leave
home and they cross the street and there's a slide. There
are 12 slide that are shown. Cross the street. They see
a damaged — I'm giving you the boring story — they see
a damaged automobile. They visit father who works in the
hospital. They're having disaster prepared in the demonstration
They see people with make-up on to make them look like they've
been injured. The mother makes a telephone call and goes
to the bus and goes home, and that's the story.
And you can divide it into three parts. Early stages, leaving
home, in the hospital, and then the denouement at the end.
On the surprise memory test three weeks later, the subjects
remembered all three parts equally well.
Now, other subjects, exactly like those, were told a different
story, same 12 slides, and the test is on what's in the
slide. Told the same story.
The boy and a mother leave home. They cross the street.
The boy is hit by the car. He's seriously injured. They
rush him to the hospital.
Surgeons work frantically to save his life and reattach his
severed legs. A distraught mother makes a telephone call,
goes to the bus and goes home.
So here it is. Same pictures, and then the surprise memory
test is: tell us what you saw in the picture. Don't
tell us about the story. What was in the pictures?
And there is a significant increase in the information remembered
in the pictures in this subjects that had the exciting story
So then Larry and I did the same experiment, except we gave
the subjects a beta blocker, Propranolol or Endurol, in clinically
used dose, in a clinically used dose, and told them the story,
and then tested them three weeks later, and those subjects
were — their memory was just like that of subjects that had
received the boring story.
So here's a blocking of emotionally influenced memory
by Propranolol. Now, this turns out to be important, we think
because it has some implications for the etiology of post
traumatic stress disorder, and as you may know, about 25 percent
of the Vietnam veterans had or have post traumatic stress
disorder, and any time there is crisis, traumatic event,
there can be a significant amount of this disorder, which
in many cases will never go away.
In some cases it will go away in a few months, and what Roger
Pitman did was to get hold of human subjects that had been
traumatized in an accident or in some way and put them on
beta blockers as quickly as possible afterwards and maintained
them on for several weeks and then looked to see symptoms
of PTSD several months down the line.
And a first study that was just published showed that there
is a significant decrease in the expression of PTSD several
months down the line, and subjects were put on the beta blockers.
Well, what is the logic of this? After all, the exciting
event is over.
The logic is based on the evidence from studies of post traumatic
patients, that the events will flash into the mind after
they're over the next day and the day afterward, and you
consider each one of these as a rehearsal.
So every time they relive the experience of being mugged
or being raped or being almost killed in a car or whatever,
every time that comes up again, there's the same emotional
reaction again. It's like a rehearsal with the autonomic
concomitance of this, and the effect of the propranolol is
to allow this inadvertent rehearsal, but without the stress
hormone consequences of that, which would lead to a strengthening
of the memory.
There's another study in press that shows the same results.
So there now will soon be two studies showing the effects
on PTSD. Whether this will hold up in the long run we don't
know. This is very early in this research.
Now, let me bring up very quickly some issues. You asked
me to, some issues that might be worth discussing, and one
is the blocking memory. I'll start with that because
that's where we just finished discussing, and there is
some concern that it might be a bad thing to reduce the strength
of memory for people who have had a traumatic event for lots
Maybe we need to remember trauma in order to deal with life
or maybe we need to remember the trauma in order to testify
in court, and so on.
So one could make an argument that it is certainly a judgment
to be made as to whether if this really does work, as it appears
to, but we're not sure at this point; if it really does
work, then one would have to make a judgment. Is it better
to reduce the probability of development of PTSD and forego
a strong memory, or is it better to save strong memories,
complete with the suffering, and forego the opportunity to
decrease the suffering?
That's a judgment call that each individual would have
to make if what I have told you turns out to be validated
Here's another one that's of deep concern to me,
and this is, by the way — we've had several conferences
on this topic, including one at the Ciba Foundation in London
a few years ago, and so we've discussed these issues many
times in small conferences.
This one concerns me. Arresting neurodegeneration, I said
that there were likely to be such drugs. I'm worried
about that because I could anticipate a situation in which
Alzheimer's disease was identified, let's say, because
a person is becoming demented. Now there's a drug which
will prevent any further deterioration, and now you have an
arrested dementia, which means that people will be in this
arrested state for a longer period of time.
It is not necessarily the case that you would want to stop
deterioration if the deterioration is far along. Once, again,
that would be a judgment call.
The next one I touched on, drugs for children. If we go
down that slippery slope from Alzheimer's disease to age
related declines in memory to drugs for normal people who
would like to have an edge, well, children can be normal people
who would like to have the edge. They would be on that slope,
and so the question would, in the subjunctive, or will, if
things have a certain way, come up; should drugs be given
to children as an ancillary treatment for learning? Why?
Which children? Is this going to be another economic divide?
The rich kids get the pill in the lunch box and the poor kids
don't, if it's readily available.
I mean, I can certainly foresee that happening. I can't
predict that it would happen, but I can foresee that happening.
And is this yet another cost that we're going to have
to bear in society in treating the walking well?
We already spent a lot of money on treating the walking
well. Here's yet another example of it.
And finally, the worst one of this is the designer baby
and what I call the Time magazine issue. Time magazine, based
on this study that was published in a very reputable journal
took unfortunately a word that was used in the paper, both
in the abstract and in the introduction of the paper, "intelligence."
That PET study did not study intelligence. That study asked
does a mouse freeze when you put it in a place where it had
received a shock. Does a mouse swim more rapidly to a platform
where it could escape from cold water?
The genetic manipulation produced mice that both of those
did better than their controls. That's what they did.
Now, there's nothing in there that 100 other people
haven't already done with drugs. Those are the same studies
that have been done literally hundreds of times with drugs,
enhancing memory of this kind. So there's nothing conceptually
What's new is the permanence of it and the use of molecular
genetics to produce it, which leads people to think, and Time
magazine certainly thought that and the author of the paper
implicitly suggested that by using the word "intelligence"
rather than "memory" or "performance,"
that it might be possible with right consultation of the right
people to have designer babies in which you insert particular
genes which are guaranteed to make them learn better.
Well, there's no guarantee, but my guess is that we
would have, if they worked, we'd have more Mr. Ses and
more Mr. Funes de Memoriases and not necessarily more thoughtful,
intelligent human beings that will help to make this place
a better world.
CHAIRMAN KASS: Thank you very much.
We should just open the floor for discussion. Mike Gazzaniga,
DR. GAZZANIGA:: Thanks, Jim. That's
It might be helpful though for us to have you distinguish
between memory as sort of a unitary event and memory as you
and I know it to be, which is this complex system of information
and coding, retrieval and all of the rest.
The reason I say that is that one of the benchmark observations
in the clinical and neuropsychology is that the memory quotient
score correlates perfectly with the IQ score. And so when
we have these enhancing devices that allow for, quote, increased
memory, probably what we mean by that is increased sort of
lexical entries or something. It isn't enhancing the
entire memory system that allows the intelligent encoding
and retrieval of all that information for use.
And if that pill came along there might well be an impact,
it would seem to me, on these matters. What do you think?
DR. MCGAUGH: Well, starting way back when
I first began working on the drug enhancement, I tried to
ask the question are there limits to the kind of information
that, let's say, post training drug injections will influence.
And the answer so far is no. That is, I found memory enhancement
with post training administration of a variety of drugs in
every task that I could think of that would tap different
kinds of information that the animals were acquiring.
So it appeared to be general over a very broad range. Now,
we're going to hear more about different forms of memory
in the human this afternoon, but as far as different kinds
of things that animals are capable of being taught, I haven't
found any constraint on that, nor has anyone else.
Now, with respect to the memory and the IQ, however, wouldn't
you agree that if the memory test was a perfect predictor,
then you wouldn't need the IQ test, and the IQ test covers
things besides just the memory subtest, correct?
DR. GAZZANIGA:: Oh, yes, yes. The fact
is though that if you take a look of somebody with an IQ of
100 versus an IQ of 125, the memory subtest goes right up
DR. MCGAUGH: Sure, sure, and it would
have to because that's the way it was built.
DR. GAZZANIGA:: Well, no, in separate,
totally different, independent memory tests, too. But anyway,
you know my point.
But one final point. Beta blockers and Baghdad. So let's
say you're going to send troops into harm's way.
Is in some sense modern neuropharmacology suggesting in order
to prevent post traumatic syndrome you ought to give them
a beta blocker before they go in for their dirty work?
DR. MCGAUGH: Well, first let's assume
that what has been found will be replicated. Let's make
that case. I don't want to make that too strongly because
this is an early stage in the human application.
But once again, that's your tradeoff question,
isn't it. Let's suppose they really were to prevent
or to attenuate the development of post traumatic stress syndrome,
and actually the number from Vietnam, I think was 29 percent
of the veterans of the Vietnam War had post traumatic stress
syndrome, from which many never recovered, and then they filled
up the veterans hospitals. That's just a fact of life.
Would it be worth using pharmacology to prevent that from
happening, if it didn't do anything which would harm the
person? That's the judgment to be made. Somebody would
have to make that.
DR. GAZZANIGA:: That's right.
DR. MCGAUGH: Now, stimulants have been
given to soldiers for years to make them implicitly, and I
think explicitly in some cases, to make them better soldiers.
Nicotine is a memory enhancing compound in laboratory animals.
Post training injections of nicotine enhance memory. It just
does. It's been known for many years.
One doesn't do those studies in humans because of the
taint from the tobacco industry so that one just wouldn't
do that research. You don't want to be tagged as somebody
who's going to increase tobacco sales, but my guess is
it's probably is memory enhancing in humans as well, and
caffeine as well.
Soldiers are routinely given cigarettes, and that came in
with their K rations. Amphetamines were used by the Germans,
given all the time to their soldiers.
So the use of pharmacological enhancement of human performance
is not new to the military. So the question is if you think
that they're going to survive and they have a quarter
percent, a 25 percent chance of being debilitated even if
they win, would you want to do something to prevent that from
happening? That's a judgment that would have to be made.
CHAIRMAN KASS: Gil and then Dan.
PROF. MEILAENDER: I don't know I even
know enough to know how to ask my questions here, but I have
two sorts of questions. One is — and this is really a naive
layman's question — but in some of the things you talked
about with respect to — actually it was particularly with
respect to sort of blocking memory formation, which it seemed
to involve controlling various kinds of emotional responses
that one might have in various ways.
In what sense is that — in what sense were you doing something
that specifically touches memory when you do that?
I mean, I don't know. As I say, this may just be too
naive, but is it really memory that one's dealing with
at that point? That's my one question.
Let me just ask my other and you can do what you want with
both of them.
Is it conceivable just in terms of the mechanisms one's
working on that one could go to work on Alzheimer's, on
trying to find ways to stop that kind of degeneration, that
would not also be applicable to, you know, possible memory
enhancement in school children, say, or something like that?
Are these separable categories?
So those are my two questions.
DR. MCGAUGH: Well, those are both very
good questions, but I do think they are completely separable
from my perspective. Let me take the first one.
The answer is no. We're not only affecting memory.
The question is are we affecting memory, and the answer to
that is yes. We can show that it's not due to some other
side effect of it.
We are affecting memory, but we're also affecting —
I mean, after all, these beta blockers are going to affect
the action of the heart. I mean, that's what — think
of all the things that adrenalin are required for. They're
required for releasing glucose from the liver and so on.
So that when we give a beta blocker, lots of systems are
going to be affected. The body is going to be changed in
lots of different ways, but we've been able to sort out
with our experiments the question is it specifically, no matter
what else it's doing, is it working on memory, and the
answer is, yes, it's working on memory while it's
doing all of these other things.
Does that answer that part of it?
All right. The second one is that I think that they're
really quite different questions. Let's take the Alzheimer's
disease, and let's assume for the moment that the cause
of it is the anatomical sequelae that lead to these plaques
and tangles in the brain. Let's just assume that for
a moment, and that's still a little contentious in the
The kinds of drugs that one would use for that would be the
ones that would interfere with the cellular processes that
lead to that kind of neuronal damage, and they may have no
other effects. They may have no other effects at all. They
just may prevent that sequelae from taking place.
Whereas the drugs that are currently given for Alzheimer's
disease, the acetylcholinesterase inhibitors, make better
use of a declining brain system that uses acetylcholine as
part of its communication mechanism, makes better use of that,
but it doesn't do anything that we know of to stop the
So the degeneration is continuing, and it's sort of like
trying to squeeze a little bit more lemon juice out of the
lemon juice that's been squeezed. You can always find
a little bit more.
It's like the economists who say that we are never going
to run out of oil, and their reason is because there will
always be some oil. Now, we'll never run out of coal
because there will always be some coal.
Well, there will always be some acetylcholine. Can you make
it work better with a declining brain?
But the drugs that are used to make the acetylcholine work
better or whatever neurotransmitter may do nothing at all
to deal with the underlying cause of the disease, whatever
that may be.
So I see them as going in different mechanisms. To put it
in another way, I don't think that there's any danger
that normal human beings will run out and buy Exelon or Cylert
or one of the other Alzheimer's disease to try to make
them a better sales manager. That's not going to happen,
and those drugs are not going to be given to children. I
mean, nobody in their even quasi right mind would think of
doing that, nor if there were drugs that would prevent neurodegeneration
would a normal person take them unless they thought they were
at risk for the degeneration, which brings up another question.
If we were able to make those predictions, would there be
drugs to deal with that?
CHAIRMAN KASS: Dan Foster.
DR. FOSTER: Just a comment and then my
Of course, the Alzheimer syndrome or disease is sad, but
the sadness and pity is not so much for the patient, who doesn't
remember anything, but for the caregivers. The caregivers
are continually stressed and presumably releasing epinephrine
and norepinephrine all the time. Maybe that is what keeps
them going. It is not a bad disease for the patient when fully
developed because memory is gone, but one wants to prevent
it if at all possible.
Now, you just made a statement which I was going to follow
up. You said that even if you knew that there was a drug
that was going to be preventive, let's say, of the Alzheimer's
dementia, as an example, would I take it or would you take
it, and the answer might be if that were solely an effect
of the drug that you would not. You don't have a family
history of Alzheimer and so forth.
But one of the things that there's an increasing interest
in in medicine, I believe, is where a drug which is used for
one reason has powerful effects in others. For example, probably
the cheapest and safest chemopreventive drug that you can
take with the rare exception that you're going to bleed
is an aspirin. It's going to cut colon cancer 50 percent,
probably going to diminish, slow down Alzheimer dementia.
You know, it's got a variety of things that are additional.
Now, one of the drugs, and I'd be interested in your
comments, that's been very much of interest lately in
terms of chemoprevention of the Alzheimer dementia are the
statins, the drugs that are used to lower blood cholesterol.
I mean, at least in terms of retrospective studies, if you've
ever taken them, you may be as much as 70 percent in large
populations. The veterans population study is the one I know
It also is very helpful, it turns out in odd ways of preventing
osteopenia in women, bone loss, and of course, the people
who really work on cholesterol, we have two guys that are
Nobel Laureates for cholesterol at our place. They believe
that, you know, to take a target of a cholesterol of 100,
let's say, even if you've got diabetes and so forth.
The NIH says 130 LDL, the bad cholesterol.
They clearly show a linear progression back to the 60s and
so forth. In other words, if your LDL is 100, that's
great, but if it's 60, it's better if you want to
prevent atherosclerosis and so forth.
So the question would be: would you have the same anxiety
about a single prevention for something like dementia if at
the same time you could handle — and this is before they
get a disease. So you're in prevention and not treatment.
Would that change your thought about the approach to this
fairly common problem?
I guess I don't know whether I'm saying this very
well, but if you get several effects from a drug that's
relatively cheap and seems to be — and I don't want to
confirm that it's really stopped. It's not due to
the cholesterol. That's clear. It's not due to the
cholesterol even though E4 — I mean apolipoprotein, E4, E4
is one of the genetic risks for early Alzheimer's and
so forth, and that also gives you lipid disease, as well.
But if you could do that, would you have the same concern
DR. MCGAUGH: Well, let me shift diseases
DR. FOSTER: Okay.
DR. MCGAUGH: There it's clear. If
there was neuroprotection for Huntington's disease or
for multiplesclerosis, I don't think there would be any
question at all because they're well understood or pretty
DR. FOSTER: Sure.
DR. MCGAUGH: But at the present time, in
the case of Alzheimer's disease, it's etiology is
not well understood even though we know that there are genetic
predictors of it, and so it's not clear what one should
You know, take ten times the amount of Vitamin E and take
more aspirin and all the rest, statins, whatever. If I had
three of the genetic markers for Alzheimer's disease,
I probably would look for all of the above in order to keep
that from happening, just as I would if I were destined to
have Huntington's disease do everything I could to find
out how I could be neuroprotected.
Now, let's think about it more broadly, about the general
public where they're not going to have genetic information
about this. Already people are taking Vitamin E. People
are taking aspirin, I mean, much more than they used to.
So there are people who are trying to be neuroprotective just
to cover the odds.
Now, let's suppose it costs $100 a day to be neuroprotected.
What do you think would happen to the Vitamin E sales and
the aspirin sales and so on? They'd go down to the floor
because people would say getting that new car today is more
important than what happens to me when I'm 70 years old
or 80 or whatever.
So there are huge economic consequences that have to be factored
into this, just as there are economic factors for dealing
with AIDS, for example, or the cost of the medication influences
how well it's point to be accepted and used in different
countries and so on.
So the same thing would apply in the United States. The
cost of these things, even if you knew their effectiveness,
would have a big influence.
DR. FOSTER: I was just really trying to
get to the issue that sometimes there are surfaces, and we've
heard a little bit of it today, that if you do anything to
alter the natural development of nature, that is to say if
you — I'm not talking about acute disease or, you know,
a kid who gets zapped by a sniper or something like that —
but if you alter it, that that is both — it should not be
done. The playing God syndrome.
And I just want to be sure that your worry about the issue
of the side effects and so forth of dementia did not imply
in some sense that if scientific investigation could give
us prevention against some of these major things and at a
reasonable cost, which also has to be taken that you — I
just wanted to be sure I understood your philosophy about
that, and you've just answered it, but I wanted to bring
that to the floor.
DR. MCGAUGH: And I think in the case of
neuroprotection that that's likely to happen. I mean,
that's the greatest effort that's being made at the
present time on finding neuroprotection, even some thinking
that it might be possible to make the cells behave better
and behave the way they're supposed to after they have
started to degenerate.
So not only protection, but recovery are two targets that
are being actively pursued at the present time.
What I was trying to say though is that this is quite apart
from the other reasons for having drug enhancement of memory,
CHAIRMAN KASS: Could I clarify? I was
in the queue. I've also got Janet and Paul.
I would like to clarify just the bottom line on what is currently
available or likely to be available in terms of interventions
both for enhancement and for blockage.
I think I heard you say that notwithstanding the huge amount
of effort, we have nothing really available with respect to
the already existing degenerations of Alzheimer's disease.
Nevertheless we do have in animal models various kinds of
things that can enhance memory at least as testified, the
performance of certain kinds of tests, but that the attempt
to use these things in human beings have run afoul because
of side effects in most cases.
Let me add one additional fact that you alluded to at the
beginning, but stayed away from. As I understand it, the
main interest in the biotech companies or the others who are
pursuing this is less Alzheimer's disease, but much more
the memory enhancement —
DR. MCGAUGH: Yes.
CHAIRMAN KASS: — of — I can't find
DR. MCGAUGH: That's where the market
CHAIRMAN KASS: That's where the market
is and enhanced probably further by the market of the people
who want their kids to do better on the SATs or as you have
With respect to those things, is there likely to be something
— if you leave aside the treatment of the degenerations,
but talk about possible things that would be coming in the
area of the potentiation of more or less normal memory or
this new age related; is this 20 years, 30 years or —
DR. MCGAUGH: Well, we always think it's
right around the corner because so much money is being spent
doing exactly that.
I did send in a tape [to the Council Staff] of a BBC program
that is about ten years old. It's available from somebody
here, and in it I was interviewed, and I said that my belief
was that the real target of this drug development was not
for the memory impaired, but it was for the normal because
that's where the market is, but nobody will say that.
I'll be damned if they didn't find the Director of
Marketing of a major pharmaceutical company that they put
right after my statement who said, "Yeah, that's
what we're going after. That's where the market is."
I mean, he just said what I said that nobody would say in
public. I mean just opening.
Well, their compound failed. They put a lot of money into
a compound, and it just didn't work.
Now, let me back up here and say there are things that work,
but they have no interest because there's no money in
them. Paul Gold has shown that glucose enhances memory, not
only in normal people, but in elderly people and in Alzheimer's
patients. You get a little improvement with glucose, but
there's no money to be made in that.
Amphetamine is a very potent memory enhancing drug, as I
mentioned, both in humans and in animals, and it works even
when injected in humans or given to humans after they've
learned something. It strengthens consolidation.
But there's no money to be made in amphetamine, and besides
that, it's a nasty drug, and people get dependent on it
and they get addicted to amphetamines.
So there are things right now that people could take that
will enhance memory, but pharmaceutical companies are not
Now, one major company, Abbott Laboratories, certainly knew
about nicotine. So they decided to modify the nicotine molecule
and, once again, the count was millions of dollars to make
a drug that is like nicotine, but for which they could get
a patent, and it didn't work all the way through Phase
3. So that was a big loss of financial investment.
Now, nicotine probably works, but it's also addicting.
So there are these side things, the things that might do something
for memory that we know of or that companies have tried to
develop. All have some kind of a restriction. They just
— there's no free memory enhancement that isn't going
to do something else.
It's sort of like looking for a nonaddicting opiate.
You remember in the early part of this — well, right at the
turn of the last century when heroin was introduced by Bayer.
It was called Heroin because it was heroic. That's why
they called it that, as the nonaddicting opiate for children,
and it was in children's cough medicine for probably 20
And after the discovery of the opiate receptor, there was
a huge increase in looking for nonaddicting opiates. If we
could only take that drug which is analgesic and modify it,
you know, pull off a methyl group here, add another group
over there; we'll find an opiate that is nonaddicting.
Well, the less analgesic it is, the less addicting it is.
So memory enhancing compounds, let's say, our own memory
enhancing compounds are adrenalin and cortisol, and they do
all kinds of things. I mean, you wouldn't want to give
adrenalin to a heart patient, for example, but we know that
if we give adrenalin to a rat or a mouse, we can make it learn
a lot faster or if we give a drug that will activate those
receptors it will happen.
But there are always going to be these side effects, and
I don't see them disappearing, but that's what the
pharmaceutical companies are looking for. They're looking
for the pure memory enhancing drug that doesn't do these
other nasty things.
And is that around the corner? Maybe it will be in the paper
tomorrow. I don't know.
CHAIRMAN KASS: On the parallel side now
on the memory blocking, the same answer?
DR. MCGAUGH: Well, that can be done right
now. I don't think —
CHAIRMAN KASS: But also with drugs that
have systemic effects, right?
DR. MCGAUGH: Yes.
CHAIRMAN KASS: I mean blockers are also
not innocent —
DR. MCGAUGH: You pay for it, but let's
put the emphasis. You want to reduce the anxiety, and so
you take a benzodiazepine. Well, the sufferance there is
that you are also likely to induce anterograde amnesia. It
was discovered after it was approved for anxiolytic effect.
So now you take, let's say, benzodiazepine to produce
anterograde amnesia. The payoff is you're going to be
less anxious. I mean, you don't have to remember.
DR. MCGAUGH: I mean, the way this — many
of you here probably know that it was discovered by psychiatrists
and psychologists after the benzodiazepines were introduced.
People would come back after having been on a trip, and they
were very anxious about going, and they would come back in
the report, "I don't remember what happened on this trip,"
and so that's what stimulated the research on it.
And then it was discovered in animal models as well as in
humans it's a very strong anterograde amnesia, which of
course is dose dependent. So that you can certainly take
a benzodiazepine and get an anxiolytic effect without having
severe anterograde amnesia, but you can also take a high dose,
and you think you're okay, and then have anterograde amnesia.
CHAIRMAN KASS: Thank you.
I have Janet and then Paul.
DR. ROWLEY: Well, I want to follow up.
My question is in a sense related to what you just said because
many, many individuals are taking beta blockers, particularly
older individuals, and the question then is — and I don't
even know what doses are generally used for beta blockers,
but what is the relationship of the dose that would be used
clinically and that which causes retrograde amnesia?
DR. MCGAUGH: The clinically used doses,
let's say, propranolol, 20 milligrams, is not going to
induce any retrograde amnesia. What it does in a study so
far is simply prevent the added memory that is induced by
emotional arousal. So we have not found in human subjects
any memory impairment in these doses, but we have found complete
blockage of the effect of this emotional arousal on subsequent
memory. So in that sense I don't think there's any
This, by the way, independently in the same year, an experiment
was done in a very different way by Rob Jenson and his colleagues
in southern Illinois, but in place of emotional arousal what
they — these were now with elderly people who are on beta
blockers or on other drugs for controlling heart disease,
and they taught them standard psychological verbal material.
And then after that they had them squeeze what's called
the hand dynamometer in which you squeeze it, and you can
see how much pressure is induced by squeezing it, and this
is well known to release catecholamines, including adrenalin.
You do this.
And they found that the memory, squeezing this thing, enhanced
memory in the elderly subjects who were on other drugs for
treatment of heart disease, but did not enhance memory in
subjects who were taking beta blockers.
In normal subjects now, Larry Cahill has used another technique
which is standard procedure in cardiology studies, and that
is just thrusting one's hand into a bucket of ice water.
I know that doesn't sound very sophisticated, but it will
certainly get the heart going, and it releases adrenalin massively
right at that time, and Larry Cahill has now found that memory
for ordinary verbal material is significantly enhanced. Subjects
learn something and put their hand in this tub of ice water.
So it doesn't have to be an emotionally arousing response,
but we think in our nature that's probably what ordinarily
controls it because we don't go around putting our hands
in buckets of ice water to release catacholamines. We get
catacholamines release when people say, "You're dumb,
you're ugly, you're stupid. You did a good job.
You won the lottery. You got a Nobel Prize. You're going
to be executed. Things like that tend to get epinephrine
or adrenalin released.
CHAIRMAN KASS: Paul McHugh.
DR. MCHUGH: Well, we could talk all afternoon
after that wonderful talk, Dr. McGaugh. I had two comments
and then one question.
The first comment was in your deep wisdom you reinforced
what my father told me when I first went off and recognized
that there were a lot of people in schools that were smarter
than I was. He said, "Don't worry. You can out
DR. MCGAUGH: That's right.
DR. MCHUGH: And it's the truth. You're
backing that up.
DR. MCGAUGH: That's a missed point.
My neighbor, who wanted the drug for her child, I don't
think had asked the child to work a little harder. I think
she was just saying she's not doing well. Let's make
up for that..
DR. MCHUGH: That's right. That was
my father's idea. Just work harder. You can do it.
DR. MCGAUGH: Well, he was right.
DR. MCHUGH: He was right in many things.
The other thing was, of course, in relationship to treatments
for the conditions, the deteriorating conditions like Huntington's
disease or Alzheimer's disease and the like, which are
devastating when they occur and which have their beginnings
before, if we understood not just the risk factors, but the
mechanisms, it probably would be that everybody who had those
mechanisms in play would probably take the treatments even
no matter what they cost.
The real problem now is not for Huntington's, but something
like Alzheimer's disease. We only know that there are
risk factors that are tied to it.
DR. MCGAUGH: Think of all the people who
are taking Vitamin E and aspirin at the present time.
DR. MCHUGH: Oh, I'm well aware of that.
DR. MCGAUGH: So that there is at least
among people who pay attention to these things — we try to
reduce our risk. I mean, if we knew more about it, we could
do more selective things to reduce that risk.
DR. MCHUGH: That's right. So the mechanisms
would help us to know more things.
DR. MCGAUGH: Absolutely.
DR. MCHUGH: I had one real question I wanted
because it was very interesting what you were saying about
the effects of beta blockers on consolidation of memory.
But as you know, lots of people use beta blockers who are
performers, particularly artistic performers.
DR. MCGAUGH: Absolutely.
DR. MCHUGH: Stringed instrument players
and the like, and they discovered in their performance that
they can do much better if their hands aren't trembling
and the like.
And I wondered about you making the point that beta blockers
inhibit consolidation. Do they have any effect on retrieval,
on memory retrieval, which would both affect the piano player
who was following the Schuman approach of doing it by memory,
but also might affect us otherwise negatively?
DR. MCGAUGH: I had a whole section on that
that I didn't include because of lack of time, but may
I just say something about that?
First of all, it is the case that beta blockers are the drug
of choice for stage fright, speech fright, and also for controlling
trembling and things of that kind.
But in the case of the violin player who is up there performing,
that is so over rehearsed that the memory is not going to
be affected for that. That's on automatic drive at that
point. So that's not an issue.
But these same hormones that I told you enhance memory consolidation
on other circumstances, on other conditions, will impair the
retrieval of memory, and we have studied that fairly carefully
using cortisol in the human or corticosterone in the rat,
and the experiments are as follows, and we try to make them
as parallel as we could for the two.
The subjects learned something on one day to some criterion,
and then the next day they are tested on it, and then we check
to make sure it's not interfering with their performance
or anything of that kind.
And it turns out that a glucocorticoid, a cortisol, has an
impairing effect for about one hour after it is either released
or after it is injected, and we know that it is the cortisol
because if we give a drug that blocks the release of cortisol,
then there is no memory impairing effect of the treatment
or in a rats it can be a shock, an electric shock to its
And this is an effect that lasts for about an hour, an impaired
retrieval selectively induced by that. So we think that all
of the things that we have learned from our undergraduates
over the year about how they knew the information very well
and they just panicked on a test and couldn't remember
it. We now think that at least some of that may have been
honest, that there was an over excitement and there was a
temporary depression of selectivity of memory retrieval lasting
for about an hour, and this we found both in rats and in human
And we are now doing experiments at the moment to find out
the involvement of beta receptors, beta adrenergic receptors
in that mechanism. We had experiments in place right now
doing that. So I can't answer the question.
But in everything else I said it had to do with getting information
in and getting it stored. It all had to do with making a
memory, and now we're shifting it. That's why I left
it out of my main talk here. We're shifting to something
else and saying are there things that affect our ability to
utilize information that we have, and stress hormones do affect
DR. FOSTER: Just one quick question. Does
epi/norepi also do the same thing, that one hour impairment
DR. MCGAUGH: No, we haven't examined
DR. FOSTER: Because oftentimes they're
almost always up together.
DR. MCGAUGH: Yes.
DR. FOSTER: And you know that cortisol
has a permissive effect on that.
DR. MCGAUGH: And we're looking specifically
once again in the basolateral nucleus of the amygdala because
that was critical for our consolidation effect, and I can
say our first experiments indicate that activation of beta
adrenergic receptors within this same region of the brain
plays a role in this memory retrieval effect that I just described.
But that's not published. That's the only thing
I've told you that's not published yet.
CHAIRMAN KASS: Frank Fukuyama.
PROF. FUKUYAMA: Are you born with a certain
natural memory capacity?
And when you talk about memory enhancement, you're talking
about the ability to move information in and out of that fixed
capacity or can the capacity itself be affected by environmental
DR. MCGAUGH: You're probably going
to hear a lot of that, something about that from Dan Schacter,
but let me just touch it briefly.
The answer is no because there are lots of ways in which
as we go through life we improve our memory capacities. Let's
say in areas that are your hobbies or things that you deal
with an awful lot, you just get better and better because
you have more information that's related to other information,
and it's not stored as an isolated packet, but it becomes
So that I have two hobbies. I play jazz clarinet and saxophone,
and I do woodworking. So I have lots of things that are very
easy for me to learn because they are related to that, but
if somebody starts talking to me about their hobby which is
something I don't know anything about, I would have trouble
remembering it just because I don't have the contextual
connections formed to do that.
Now, also, if you take very specific domains, memory can
be trained. So that if you want to be able to memorize digits,
let's say for some reason you have a zip code which is
2,000 numbers long. You could do that. You could do that.
And you would be better then for a while in memorizing of
digits. So that this specific domain can actually be improved.
So you're not born with a capacity. What we're born
with is without any extra effort to get seven digits plus
or minus one, and that's one reason we had seven digit
telephone numbers and the area code was kept separate, because
you can remember seven digits at least long enough to write
That's probably the native thing that most people have,
but you can have a digit span of 15 if you'd like to
have it for some reason. You can get special training to
CHAIRMAN KASS: Bill and then —
DR. MCGAUGH: And, Dan, I hope that you'll
elaborate on that because that's more in your domain.
CHAIRMAN KASS: Bill.
DR. HURLBUT: I want to ask you about something
you touched on briefly, the engagement of possible memory
enhancing agents in education. If you say that, as you more
or less said or at least implied strongly, that memories related
to life significant issues because the body itself produces
through at least the adrenal gland, and probably in many other
ways, agents that modulate memory retention. It then implies
from that that if you enhance one component of that system
artificially that you might be disrupting the psychophysical
unity of your identity or your normal life processes.
In other words, you'd be forcing on your system memory
of things that your other normal process wasn't encoding.
DR. MCGAUGH: Absolutely.
DR. HURLBUT: So in other words, we have
a therapeutic model of memory enhancement where we think there's
a deficit. That makes sense, and just as it's easier
to fix a broken link in a chain than it is to strengthen the
whole chain, we can comprehend how that might work where there
was a problem.
But would you really improve life overall is a large question
I hear going on in the background of what you said. In fact,
you started at the beginning in saying if memory enhancement
were a simple good, then evolution probably would have done
it. Didn't you say something like that?
strong>DR. MCGAUGH: Somebody.
DR. HURLBUT: Okay. Here's my question.
The work that Mike Merzenich is doing with enhancing Ó- going
back to basic neural processing, things like dyslexia and
reworking very fundamental things in the way a person takes
information where they have a learning deficit or, for that
matter, any strategy of approaching life tasks.
He suggests that maybe you could combine what he's doing
now with computers with drug enhancement to reinforce or make
more powerful that basic neural revision. You're familiar
DR. MCGAUGH: Sure.
DR. HURLBUT: Do you think this is something
that is coming? Is it realistic? Would it be profoundly
And what do you see as the ethical questions associated with
DR. MCGAUGH: Well, I hope it's not
coming because I think that the ramifications are really very
The reason I hope it's not coming is because you picked
a particular case, but I could pick many others. Let's
just say the school teacher who is teaching the number facts
to the children, and number facts are not very exciting, but
you need to know how to multiply at least 12 times 12 and
how to do the division, and that's not any different than
dealing with dyslexics. You're trying to correct here
The disorder is that they don't know the number facts,
and they have to know them or that they have to know the grammar.
And so why not a little chemical aid to do that?
So if you start with something as narrow as that and say:
folks, this is a very special case. We're going to do
this for the dyslexics under this condition because we think
we can give a drug to enhance this particular thing. All
right? Then we'll expand it. What about English literature?
You know, how about the sonnet? You know, memorization of
the sonnet is due tomorrow, or how about language? I have
to learn German, as I did in graduate school in four months
in order to pass the exam. Wouldn't that have been nice?
Well, we did have amphetamine in those days. So that was
helpful. Amphetamine and caffeine, as you know, were not
— amphetamine was not controlled when I was a graduate student,
and it was commonly taken. Would keep you awake, but probably
helped a little bit.
No, I think that you've given a very special case, but
it's easy to make an argument for a large number of cases.
I don't know how you would constrain it after that. I
mean, that just happens to be his interest in what he's
doing, but other people are interested in other things, and
they say, "Fine. What we need is a little pharmacological
And now remember the basic thing I said is that whether it's
hormones, our own pharmacological agents or the ones that
we manipulate, we have never been able to do anything that
we can't do by just more training, never.
Now, in the case of Alzheimer's patient, that isn't
the case. With some subjects, particularly with Exelon, which
appears to be a little bit better than some of the others,
they can get them to do some things that they couldn't
otherwise do. So there's some help for a degenerating
brain to make it work a little better so that it can finally
do something that it couldn't do. That data on that are
weak, but that's another case.
So I guess what I was trying to do is present things here,
which were tailor made for this group, and so in this context
I would say this is not immune from my criticism. It falls
into, let's say, my concern. It falls into my bag of
concerns because it is a very short step from there to giving
the drug to my neighbor to give her child because she's
not going to tall the child to work harder, but it's just
a little bit easier to do.
It's sort of like taking a valium when you're anxious
rather than to use the anxiety to help cope with the problem.
DR. HURLBUT: I hear a strong preference,
if not prejudice, for the natural in what you're saying
because one could argue, well, so what if it enhances one
thing even at the expense of the other.
DR. MCGAUGH: No. I'm neutral. I'm
bringing it to your attention. I'm neutral on this.
What I was trying to say is that I don't think that that
special case solves the problem for us. If that works, then
I don't see any reason not to do it for any learning condition.
I do favor the natural circumstance. I think I would go
back and say how can you become a better teacher to use the
naturally occurring devices that children have rather than
to use some ancillary treatment, which we know we're probably
going to have to do for the deteriorating brain, but that
kid has all of the machinery. The machinery is there. How
can you make that machinery work better would be the first
approach that I think should be taken.
DR. HURLBUT: Well, you've convinced
me that I should be scaring my students more. A little more
adrenalin would help them learn better, but really —
DR. MCGAUGH: Let me — let me — I don't
think you're entirely wrong in the statement that you
just made. It's nice to be nice to people, but I just
had to write something about my earlier experiences recently,
and the two teachers that I singled out as having the biggest
impact on my life were two of the sternest teachers that I
I mean it just didn't dawn on me that until I've
thought about it pretty systematically. These were not touchy-feely
people. These were the most demanding teachers I ever had
in my life. One of them was my band and orchestra instructor
whose aim was to embarrass you in front of everybody else.
And so we knew that at any moment during rehearsal he would
stop it and point at somebody and say, "Play the next
16 bars. Stand up and play the next 16 bars." At any
moment. Now, that kept our attention. It really did.
So if you want to get learning to take place and have an
impact, I don't think that roughness is necessarily bad.
I mean, it's better if they could do it in a nice way
and say, "Gee, Jim, would you do the next 16 bars? We'd
sure love to hear you do it in a nice way for the group."
You know, that would be helpful, but that's not the way
CHAIRMAN KASS: Rebecca and then we'll
take a break.
PROF. DRESSER: This is in line with some
of the other comments. I think at one point you said there
is no memory enhancing free lunch or something like that.
I mean, the tone of your presentation seems to me to be a
good corrective to the media, kind of public image about a
lot of these prospects, which is there are always going to
be costs, financial costs, adverse effect costs, as well as
your great problem of what if we could arrest neurodegeneration
in the early stages of Alzheimer's disease. Would that
be a good thing or not?
I mean that's a very complicated question socially.
So thank you for the really, I think, balanced point of view
DR. MCGAUGH: Well, let me comment on that.
I do memory enhancement as a living, and that's what I
do for a living. So that's what my research is all about.
So I wouldn't want you to let me get out of here saying
that I have dissed memory enhancement.
But I think there is a role for it, and I think it has been
excessively over-hyped by pharmaceutical companies, biotech
companies, and by the press because it requires the kind of
thoughtful thinking that you people as a group have as your
mission in order to evaluate these things and find out what
is the proper place.
I think that there may well be — just as I believe some
children need Ritalin, all hyperactive children do not need
Ritalin. All right? I think there may be some children who
need memory enhancing drugs because they can't do it.
They don't have the machinery to do it in the same way
that the deeply disturbed hyperactive child does not have
the machinery which enables normal behavior.
So some children's brains will need this, but once again,
I come back to the slippery slope. Which ones do and which
ones don't and under what conditions and so on? And
that's a tough one. That's a tough one.
CHAIRMAN KASS: Let's take a break.
the conversation will continue. Let's take 15 minutes.
(Whereupon, the foregoing matter went off the record
at 3:24 p.m. and went back on the record at 3:44 p.m.)