FROM MEGABRAIN REPORT VOL. 2 NO. 1
Edited by Michael Hutchison




              SMART PILLS:  THE SECOND GENERATION
                               by
                  Ross Pelton and Lee Overholser

From the moment we enter life we are limited by our
genetic potential, the genome.  But do we realize, either
individually or as a species, all of our genetic
potential?

Pharmacology participates, very modestly, in one of the
great efforts of humanity, that of answering Plato's
question: "Who are we?"  The aim is "to know oneself,"
but toward what end?  It seems to us that the deeper
sense of this socratic imperative is to know oneself
neither in a narcissistic nor timid fashion,
but in order to create oneself.  Humankind will not wait
passively for millions of years so that evolution can
offer a better brain.  Mankind must refashion itself by
realizing its highest genetic potential in the direction
that evolution is taking, that is to say, by increasing
the integrative capacity of the forebrain.  All things
considered, developing a pharmacology of the brain's
integrative activity has a place in this great
human undertaking.
				Dr. Corneliu Giurgea, tr. by Lee
					Overholser.


As readers of Megabrain, you are doubtless familiar with the first
generation of cognitive enhancing drugs--smart pills--that have
been publicized and popularized over the past decade.  Since the
publication of Mind Food and Smart Pills in 1986 and the appearance
of the expanded version in 1989, there has been an exponential
growth in research in this area.

The first generation of intelligence enhancing drugs
generated a great deal of excitement.  Not only was there the
potential for treating cognitive decline in the elderly, research
also indicated that normal healthy individuals could improve
memory and learning capabilities.  According to Fortune magazine
the pharmaceutical industry foresees the probability of a $1-
billion-plus per year market for cognitive enhancing drugs.

Following the development of piracetam, many pharmaceutical
companies began to develop structurally similar nootropics.
There is significant ongoing research in three very important
areas:  A) enhancement of intelligence and the ability to think,
B) improvement of memory and learning and C) prevention of brain
aging and the loss of cognitive capabilities so that senility
doesn't develop or develops at a much later age.

This article and the three to follow in future issues of Megabrain
Report will bring you up to date on the explosion of activity
in this field of research.  The development of the second
generation of smart pills is now well under way.

                  THE NEED FOR A BETTER BRAIN
In a world that demands the integration of ever greater
masses of information from a multitude of sources, we cannot get
by with a stone age brain.  During the course of evolution the
mammalian brain has devoted more and more of its cortex to the
task of integrating and interpreting sensory information.  The
forward third of the human brain, the frontal lobes, is devoted
entirely to processing information.  This area makes plans for
the future and handles complex social interactions.  In rats the
frontal lobes are dedicated to analyzing olfactory input.

This human capacity to plan for the future is both a
blessing and a curse.  Technology has freed us from having to
hunt for our food and conquered most infectious diseases.  On the
other hand the pollution, environmental destruction and the
population explosion threaten the existence of all forms of life
on the planet.  To survive we must enlarge our capacity to handle
and integrate information.  If ecology is the integrated
functioning of life systems, the brain is a similar integrated
system that must be enhanced if we are to survive.

Dr. Giurgea, the developer of Piracetam, the first nootropic or
intelligence-enhancing drug, is a leader in the effort to
transcend our genetic limitations.  He realized that the real
breakthrough represented by Piracetam was that it increased the
functioning of the integrative areas of the cortex.

The accompanying illustration compares the rat and human
brains with the primary sensory and motor areas in black and the
associative or integrative areas in white.  The difference is
obvious.  Most of the rat brain is occupied with receiving
information and giving orders to the muscles.  Most of the human
brain is devoted to complex analysis of incoming information.

[INSERT ILLUSTRATION HERE]

The promise of smart pills is that they will enable us to
deal with the incredibly complex problems that are pressing in on
us both individually and as a society.  Unfortunately, the
pharmaceutical industry has not shown a major interest in
developing "smart pills" or in preventing brain aging in healthy
individuals.  Instead, economic forces and FDA policy necessitate
a focus on treating diseases.  Much of the current research
effort concentrates on developing drugs that can treat cognitive
impairment due to aging.  Nevertheless, many of these drugs show
considerable promise for helping healthy people stay smart and
think smarter.

                   CATEGORIES OF SMART PILLS

Drs. Merlini and Pinza divide cognitive enhancing agents
into six categories:  nootropics, brain metabolism activators,
neuropeptides, cholinergic drugs, cerebral vasodilators and
miscellaneous compounds.  They reserve the term nootropic for
piracetam and its analogs which have a primary influence on
intelligence.

We will look at each of these categories under three
headings:  Future Brain, Memory, and Keeping Your Brain Young,
according to the major effect of each category of cognitive
enhancing agents.

                          FUTURE BRAIN

The current situation in the development of smart pills is
much like the early years of the space program.  The first
rockets weren't very impressive, but eventually the benefits from
that exploration filtered down to the general public in the form
of products like teflon, new and stronger metal alloys, improved
computers and other advances.  (OK, there was Tang, too.  Not
every new development was a great leap forward.)

Dr. Giurgea's development of piracetam opened the door to a
completely unexpected realm.  Before then it was inconceivable
that there was any drug that could actually make a normal person
smarter or improve mental functioning.  One of the fascinating
features of these new drugs, the nootropics, is that they affect
the integrative areas of the brain.

Drugs like amphetamines and caffeine speed up most of the
neuronal functions.  A person feels more alert, but high doses
can cause shaking, nervousness and even paranoia.  Other
psychoactive drugs strongly influence emotional behavior.
Alcohol would fall in this category.  It not only alters
emotions, it also powerfully degrades motor and sensory
abilities, as the scene of an angry or euphoric drunk falling
downstairs demonstrates.

Smart pills have very little influence on areas of the brain other
than those that process and integrate information.  For
this reason they lack the distressing side effects of other mind
altering drugs and are among the safest drugs that have ever been
developed.  They are much safer, in fact, than that most common
of drugs--aspirin.

                           Nootropics

Piracetam was the first nootropic drug to be discovered.    The
term "nootropic" literally means "acting upon the mind."
Nootropics are a unique class of drugs whose common features
include:  a) enhancing learning, b) alleviation of impaired
learning and memory, c) protection against brain insults,
especially oxygen deprivation and d) low toxicity.

Much of the excitement driving current research is the
possibility that new variants of piracetam and other drugs will
have even greater cognitive improving effects.  UCB-
Pharmaceutical, the Belgian company that originally discovered
piracetam, has now developed a new second generation nootropic
called ucb L059 which is structurally similar to piracetam, yet
possesses considerably more pharmacological activity.

Other drugs with a structure somewhat similar to piracteam's
2-pyrrolidinone ring structure are oxiracetam, pramiracetam,
etiracetam, aniracetam, propaniracetam, D-pyroglutamic acid,
hopantenate, eburnamonine,  WEB 1881, ubc L059 and BMY 21502.
Aniracetam was effective on nine different tests of learning and
memory, whereas piracetam was only effective on six tests.
Aniracetam also proved to be ten times more potent in improving
test scores than piracetam.

In the last few years several compounds have been developed which
differed structurally from piracetam, but which showed
interesting cognition enhancing effects.  This new group includes
tenilsetam, rolziracetam, minaprine, bifemelane, indeloxazine,
and idebenone.

Many of the nootropic drugs are also able to increase the
transcallosal flow of electrical information between the left and
right hemisphere of the brain.  This has been called
"Superconnecting" both halves of the brain.  When both
hemispheres are interacting, creativity is enhanced and the
ability to integrate artistic abilities with reasoning is
increased.

Poor integration between the halves of the brain is
implicated in some learning disorders.  It has been estimated
that up to 10% of school-age children suffer from some type of
learning disability.  Nootropics man eventually become the
treatment of choice for dyslexia and other learning disorders.

                  Brain Metabolism Activators

Agents that enhance the metabolism of brain cells are
classified as brain metabolism activators or enhancers.  They are
placed in the Future Brain section because their primary effect
is on cognitive abilities.  Hydergine is the most famous drug in
this category.

Newer drugs in this category include acetyl-L-carnitine,
phosphatidylserine, derivatives of griseolic acid and
naftidrofuryl, to name a few.  An interesting effect of
phosphatidylserine is that postnatal administration to laboratory
animals led to improved memory in adulthood.

                      MEMORY AND LEARNING

The TV show Jeopardy is taken by many as a measure of
intelligence.  Those who remember the most trivial pieces of
information are the smartest.  This is an idea that has its roots
in the way our educational system rewards those with the best
memories with good grades since most courses emphasize the
acquisition of information in place of creativity and reasoning
skills.

A good memory can boost overall intelligence since facts and
figures are the raw stuff of reasoning.  But those with
photographic or eidetic memories are rarely able to do much with
all the little bits and pieces of information that they fill
their brains with.  What we forget can be as important as what we
remember when it comes to making new discoveries.  A little
forgetting sorts out the unimportant material so the things that
really make a difference stand out.

Current evidence points to the synapse as the main storage
unit of memory.  Previously it was theorized that memories were
stored in coded RNA or in specific patterns of synaptic intercon-
nections.  When animals or people have to learn more, the neurons
involved develop more RNA and grow larger dendritic trees with
more synapses.  However, it now appears that this increased
activity supports memory formation by providing more of the
medium needed for laying down memories.

The actual memories are stored in networks of synapses by
changing the sensitivity of groups of synapses to firing when
stimulated.  Those drugs which favor the facilitation of changes
in synaptic sensitivity and supply more neurotransmitter to the
synapses will increase the ability to form memories.

                       The Neuropeptides

Neuropeptides have multiple functions.  They act as
neurotransmitters and they also act as modulators or regulators
at other sites.  Vasopressin is a neuropeptide that is well
established as a facilitator of memory.

Several analogs of vasopressin have been developed.
Interestingly, the vasopressin analog DDAVP has been shown to
facilitate memory in men but not in women.  Another vasopressin
analog, DGAVP has produced improvements in various types of
learning.  Some of the other neuropeptides that are currently
under investigation are the ACTH analogs, thyrotropin releasing
hormone (TRH) and its analogs, cholecystokinin-8 (CCK-8) and
neuropeptide Y.

                    KEEPING YOUR BRAIN YOUNG

The search for drugs that can treat the aging brain is
concentrated on those that can reverse the damage that has
already occurred.  However, when it comes to brain health, an
ounce of prevention is definitely worth a pound of cure.  Some of
the drugs that have a little effect in reducing the effects of
Alzheimer's disease and senility are proving more effective in
preventing brain aging.

Increasing cognitive abilities is useful, but the long term
implications of being able to prevent brain aging may ultimately
be much more important.  Whatever controversy there might be
about the value of becoming smarter, there is no debate about the
value of not becoming dumber.  Much of the damage in the aging
brain centers around the synapses.  As the number of synapses in
the cortex decreases along with the quantity of neurotransmitter
for carrying messages, both memory and reasoning abilities enter
a slow decline.  Maintaining healthy synaptic functioning is the
key to keeping your brain young.

                       Cholinergic Drugs

Acetylcholine is the neurotransmitter used by about 90% of
the brain's cells.  Acetylcholine precursors such as choline or
lecithin have been somewhat disappointing in the treatment of
cognitive decline.  Perhaps this is because there has already
been too much destruction of brain cells by the time the problem
is recognized.  Deanol and Lucidril (centrophenoxine) are
structurally related to choline and have shown positive memory
improving effects in human trials.

Lucidril is a particularly exciting drug because it has been shown
to produce significant life extension in laboratory
animals, restore the synaptic contact zones between brain cells
and actually reverse one of the primary processes of brain aging,
the build-up of lipofuscin, a form of cellular garbage, in brain
cells.

An analog of Lucidril, initially named BCE-001, has
reportedly shown twice the activity level of Lucidril.

                          Vasodilators

Some cognitive decline in the elderly may be due to a
decrease in the blood supply to the brain due to arteriosclerosis
of "hardening of the arteries" which results in a narrowing of
the cerebral blood vessels.  So far these drugs have not been
very effective, which may indicate that the circulatory problem
is not a major cause of the decrease in mental sharpness.  Some
of the new drugs in this group include vinpocetine, bromvincamine
and vincamine.

                    Miscellaneous Compounds

There are a few compounds with structures and mechanisms of action
that are different from the preceding groups which seem to be able
to reverse induced amnesia in laboratory animals or to
protect other cerebral functions.  Pyritinol is an exciting new
drug that has been shown to produce an increase in the regional
blood flow within the grey matter of the brain.  In elderly
patients with diminished mental capacity it activated the
dominant frontal lobe and enhanced cerebral electrical activity.
In healthy volunteers it improved both psychomotor performance
and short-term memory.

Deprenyl is another drug that appears to slow the damage
caused by Parkinson's and Alzheimer's disease.  A substance
called MAO-B (monamine oxidase type B) seems to be the culprit in
the destruction of nerve cells that causes Parkinson's disease
and Deprenyl is an MAO-B inhibitor.

At about age 45 the nerve cells that use dopamine as a
neurotransmitter enter a period of slow decline.  When the
dopamine level reaches about 30% of normal,the shaking and other
symptoms of Parkinson's show up.  The rate of change varies from
person to person and those who have a very slow loss of these
nerve cells never develop the disease.  Dr. Jozef Knoll, the
world's most prominent deprenyl researcher recommends the long-
term use of deprenyl to prevent the inevitable aging of dopamine
producing brain cells.

Nerve cells that use dopamine are also involved in producing many
of the drives that motivate people.  As age lowers the
brain's dopamine levels, there is a gradual decline in drives,
particularly the male sex drive.  This is why patients who take
L-dopa for Parkinson's disease often experience a sudden increase
in sex drive.

This drug is particularly useful because it does not produce the
"cheese effect."  Other MAO-B inhibitors cause high blood
pressure as the neurons begin to take in tyramine from foods such
as aged cheese, yeast, beans, chicken liver, herring and certain
wines.  Not only is deprenyl safe in this regard, but, since the
drug was discovered over 30 years ago, no reports of significant
side effects have appeared.

Dr. Knoll has developed even more selective MAO-B
inhibitors, J-508 and U-1424, that do not interfere with other
processes such as the normal uptake of MAO-A by nerve cells.
These are currently being tested for therapeutic effect.

                    EVOLUTION OR DEVOLUTION?

As the demands on our mental capacities increase, we are
gaining the capacity to meet the challenge.  Scientific advances
and technological innovations are creating the communication and
information glut that is overwhelming us.  At the same time
science and technology are giving us ways of speeding up
evolution to develop the brain power we need.

As the baby boomers enter maturity and life span continues
to increase, there will soon be a crisis in dealing with the
aging brain.  Drugs like deprenyl hold out the promise of
preventing brain aging.  Other strategies to prevent brain aging
include good nutrition and using sound and light technology to
exercise and focus the brain.

We face a clear choice.  Will we use drugs, brain enhancing devices
and good nutrition to move forward on the evolutionary
ladder or will we be overwhelmed by the information explosion and
be forced backwards?  This isn't just a question of individual
improvement.  Our entire society needs all the brain power it can
get and the sooner the knowledge of how to increase brain power
and prevent brain aging is disseminated, the better.

                            ********

Ross Pelton R.Ph. Ph.D. is a pharmacist, a nutritionist and an
educator in the areas of anti-aging and life extension.  He is the
author of Mind Food and Smart Pills, which is a sourcebook for the
vitamins, herbs and drugs that can increase intelligence improve
memory and prevent brian aging.  He has just finished a new book,
Revolution in Cnncer Therapy, which will be published by Simon &
Schuster.	

Lee Overholzer received his Doctorate in Linguistics from the
University of Michigan and went on to receive a Masters in
Counseling Psychology. He worked with Ross Pelton on his book Mind
Food and Smart Pills, and has published his own book on hypnosis.



                           BIBLIOGRAPHY
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60. New York: Academic Press, 1981.

Beckwith, B.E., et.al. "Vasopressin Analog (DDAVP) Improves
Memory in Human Males." Peptides. 1984, Vol. 5, pp. 819-822.

Brandeis, R., et al. "Improvement of Cognitive Function by MAO-B
Inhibitor L-Deprenyl in Aged Rats." Pharmacology, Biochemistry
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Bylinsky, G. "Medicine's Next Marvel: The Memory Pill." Fortune.
January 20, 1986, pp. 68-72.

Cumin, R., et.al. "Effects of the Novel Compound Aniracetam (Ro
13-5057) Upon Impaired Learning and Memory in Rodents."
Psychopharmacology. 1982, Vol. 78, pp.104-111.

Fagioli, S., et. al. "Phosphatidylserine administration during
postnatal development improves memory in adult mice."
Neuroscience Letters. 1989, Vol. 101, pp. 229-233.

Giuli, D., et. al. "Morphometric Studies on Synapses of the
Cerebellar Glomerulus: The Effect of Centrophenoxine Treatment in
Old Rats." Mechanisms of Aging and Development. 1980, Vol. 14,
pp. 265-71.

Giurgea, C. "Vers une Pharmacologie de l'Activite Integrative du
Cerveau.  Tentative du Concept Nootrope en Psychopharmacologie."
Actualities Pharmacologique. 1972, Vol. 25, pp. 115-117.

Herrmann, W.M., et. al. "On the Effects of Pyritinol on
Functional Deficits of Patients with Organic Mental Disorders."
Pharmacological Psychiatry. 1986, Vol. 19, pp. 378-385.

Hochschild, R. "Effect of Eimethylamionethyl p-Chlorophenocy-
acetate on the Life Span of Male Swiss Webster Albino Mice."
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Knoll, J. "The Possible Mechanisms of Action of Deprenyl in
Parkinson's Disease." Journal of Neural Transmission. Vol. 43,
1978, pp. 177-198.

Merlini, L., and M. Pinza. "Trends In Searching For New Cognition
Enhancing Drugs."  Progress in Neuro-Psychopharmacology &
Biological Psychiatry. 1989, Vol. 13, pp. S61-S75.

Nagy, Zs., et al. "Effect of Centrophenoxine and BCE-001
Treatment on Lateral Diffuciton of Proteins in the Hepatocyte
Plasma Membrane as Revealed by Fluorescence Revocery after
Photobleaching in Rat Liver Smears." Experimental Gerontology.
1989, Vol. 24. pp. 317-330.

Nandy, K. and Bourne, G.H. "Effects of Centrophenoxine on the
Lipofuscin Pigments of the Neurones of Senile Guinea Pigs."
Nature. 1966, Vol. 210, pp. 313-14.

Peabody, C.A., et.al. "Desgylcinamide-9-Arginine-8-Vasopressin
(DGAVP, Organon 5667) in Patients with Dementia." Neurobiology of
Aging. 1985, Vol. 6, pp. 95-100.

Pelton, R., and Pelton, T. Mind Food and Smart Pills: A
Sourcebook for the Vitamins, Herbs, and Drugs that can Increase
Intelligence, Improve memory, and Prevent Brain Aging.  New York:
Doubleday, 1989.

Salo, P.T., and Tatton, W.G. "Deprenyl Reduces the Death of
Notoneurons Caused by Axotomy." Journal of Neuroscience Research.
1992, Vol. 31, pp. 394-400.

Schindler, U. "Pre-Clinical Evaluation of Cognition Enhancing
Drugs."  Progress in Neuro-Psychopharmacology & Biological
Psychiatry. 1989, Vol. 13, pp. S99-S115.

Till, R.E., and Beckwith, B.E. "Sentence Memory Affected by
Vasopressin Analog (DDAVP) in Cross-Over Experiment." Peptides.
1985, Vol. 6, pp. 397-402.

Wulfert, R., et.al. "Facilitation of Calcium-Dependent
Cholinergic Function by ucb L059, a New 'Second Generation'
Nootropic Agent."  Psychopharmacology Bulletin. 1989, Vol. 25,
No. 3, pp. 498-502.






          HOW TO OBTAIN MEGABRAIN DRUGS BY MAIL ORDER
	
Many of the substances described by Dr. Pelton (and those explored
in "Cognition-Enhancement Drugs and Peak Performance Pills," by
John Morgenthaler and Michael Hutchison, in Megabrain Report #1)
are not available in the U.S., or are available only by
prescription. However, it is legal to obtain these substances by
mail order. One reason some of these substances are not available
in the U.S. is that they have not yet gone through the
extraordinarily expensive and lengthy process required to obtain
FDA approval.  This does not mean however that it is not quite
legal to use these substances. And some of the substances have been
approved by the FDA for limited medical applications. This does not
mean that it is not quite proper to use these substances for
"unapproved" or "off-label" purposes.

In the April, 1982 issue of the FDA Drug Bulletin, the agency
included a policy statement clarifying the question of "unapproved"
uses for drugs, clearly stating that "'unapproved' uses may be
appropriate and rational in certain circumstances, and may, in
fact, reflect approaches to drug therapy that have been extensively
reported in medical literature. . . . Valid new uses for drugs
already on the market are often first discovered through
serendipitous observations and therapeutic innovations."  In sum,
the FDA clearly approves of the "unapproved" uses as an important
means for innovation and discovery.

Also, though it is not widely known, a July, 1989 FDA ruling now
makes it quite legal to import effective drugs used elsewhere but
not available in the U.S. The FDA now allows the importation and
mail shipment of a three month supply of drugs, for personal use,
as long as they are regarded as safe in other countries. The new
ruling, FDA pilot guidelines chapter 971, was made as a result of
heavy pressure from AIDS political action groups, which insisted
AIDS sufferers were denied access to potentially life-saving
substances that were widely used abroad but were still unapproved
for use in the U.S.

The drugs discussed here, as well as the many other cognition
enhancing nutrients described in MBR #1 can be purchased without
a prescription. When you write to place an order, we recommend you
send a signed letter, so that it can be returned with your
shipment. This letter should include your name, address and phone
number, and your doctor's name, address and phone number.
Cognition Enhancement Research Institute (CERI) suggests that the
letter "should also state the following: 1) that the drug is for
personal use only, 2) that the amount is within the personal-use
guideline (3 months' supply), 3) that the drug is not approved in
the United States, 4) that you were responsible for requesting the
drug, 5) that the company shipping it to you did not engage in
promotional activities related to the drug or you, 6) that your
doctor will be supervising your use of the drug (provide a
photocopy of the prescription, if you have one), and 7) that the
drug is for treating a life-threatening or debilitating condition
(you may or may not want to detail your medical condition. . . .
The FDA regulations specify that the drug must be for a life-
threatening or debilitating condition.  If you are basically
healthy, you might want to avoid the details of your medical reason
for ordering the drug.  If they insist, you can always argue that
you are suffering from age-related mental decline (a debilitating
illness) or from aging (a life-threatening illness)."

A sample letter suggested by CERI is:

To whom it may concern:

This letter is to confirm that the enclosed medication has been
obtained for my personal use under the FDA personal importation
policy for life-threatening or debilitating illnesses.  My
physician, Dr. [name], will be providing medical supervision for
my use of the drug.  I have purchased the drug from [company] on
my own initiative; no promotional activities on their part were
involved in this transaction.  If you have further questions,
please call at your earliest opportunity.  I appreciate any efforts
you can make to expedite arrival of this important medical
treatment.
[Your name, address, phone number]
[Your doctor's name, address, phone number]

Such a letter will in all probability never be necessary.  I have
heard of only a few cases in which shipments were detained.
However, as this is written, the FDA's future policy on the
importation of of smart drugs from abroad cannot be predicted.



For information about smart nutrients in various formulations
available in the U.S., write:

Michael Hutchison
MEGABRAIN
PO BOX 2744
Sausalito, CA 94966

                       DISCLAIMER/WARNING
The information in the accompanying articles about smart drugs is
not intended to provide medical advice.  It is intended to be
educational and informational only.  Please consult with a health
professional for medical advice. The author and editor are not
recommending that anyone use any of the substances described, but
rather are presenting and seeking information. Adequate studies of
both long and short term effects of some of these substances have
not been performed, some of them can have adverse side effects, and
all humans have different biochemical natures and sensitivities,
so that safe dosages of some of these substances may vary
enormously from individual to individual. Also, some of these
substances may be dangerous for individuals not in sound mental and
physical health.  As a result, we recommend that anyone interested
in experimenting with these substances do so with caution and under
the supervision of a medical professional. We strongly recommend
that children and pregnant or lactating women should not experiment
with these substances under any circumstances.