"Smart Drugs" & the Aging Brain:
A Superficial Review

by Ben Best

A life-extensionist is concerned with survival -- of the body, of the self -- and, in particular, of the brain. But beyond resisting the destruction & degeneration of the brain there looms also the possibility of regeneration & perhaps even augmentation. The "Smart Drug Movement" implies that this is possible -- and possible now.

I have several personal problems with "Smart Drug" people. Many of these individuals are the same people with whom I was arguing 20 years ago over the value of LSD, marijuana and other "recreational drugs" for enhanced creativity. I have seen several individuals devolve into intellectual dysfunction from brain-dissolving neurochemical pleasures. Even alcohol can promote a sense of one's own capabilities which is unrelated to reality. People who attempt to take a substance and try to judge it's effects must be aware that the substance may not only be influencing the experienced effects, but the very judgement of those experienced effects.

Here I review the subject of "Smart Drugs", referring to the most popular (to my knowledge) books on the subject: MIND FOOD & SMART PILLS by Ross Pelton (1989), SMART DRUGS & NUTRIENTS by Ward Dean & John Morgenthaler (1990) and SMART DRUGS II by Dean, Morgenthaler and Fowkes (1993) -- all paperback editions. What is presented here is mostly based on my remembered information and what is in these books, so readers should take what I say with a "grain of salt". I may write a more scientific analysis once I know more about neurochemistry.

The science of "Smart Drugs" is in an even more difficult position than that of anti-aging research. The brain is perhaps the most distinctive feature of human anatomy, and the results of animal studies may be more difficult to extrapolate. The anti-parkinsonian (and anti-aging) drug Deprenyl, for example, acts primarily in the brain, but has been studied in rats -- a species which does not demonstrate Parkinson's Disease. Many, if not most, of the experiments on human subjects using "Smart Drugs" have been performed on patients with Alzheimer's Disease and other forms of senile dementia. The applicability of these results to normal humans is questionable. Many of the so-called "Smart Drugs" are indeed valuable as anti-aging agents of specific value for the brain -- but to include these substances in a category of compounds intended to increase the intelligence of normal subjects is questionable.

The book by Pelton is the worst of the series. Samplings of the author's ignorance include statements like "acetylcholine is the major chemical transmitter for thoughts and memories" (p.69) and "the hippocampus is involved in working memory" (p.130). On page 55 he expresses the belief that glutathione is part of glutathione peroxidase (the enzyme that accepts glutathione as its substrate). On page 69 he tells readers that he will use the word "lecithin" to refer to phosphatidyl choline, but by the bottom of page 71 he has forgotten his convention (short-term memory loss?). As a role-model for "Smart Drugs" Pelton is a wash-out.

It does make intuitive sense that brains require certain neurochemicals to function in an optimum manner, and that diets don't always include optimum nutrients. In such a case, diet or supplements could rectify the situation. But the brain is an intricate signalling device, and flooding brains with neurotransmitter -- or even neurotransmitter precursors -- has the potential of disrupting communications. Page 30 of SMART DRUGS & NUTRIENTS shows an inverted "U" curve of improvement of short term memory in rats with increasing dosage levels of pramiracetam. The authors seem to support the view that such a relationship holds for all "Smart Drugs", suggesting that the use of these substances requires careful experimentation and self-assessment by each individual to determine the optimum dose.

SMART DRUGS II carries this principle even further with a remarkable study quoted on pages 114-117. School children given a multivitamin/mineral supplement of 100% RDA showed IQ improvement greater than those given 50% or 200% RDA. Even if megavitamins promote health and have anti-aging effects, if these results are true then those who take megavitamins may be gaining benefits at an IQ cost. The implications for "Orthomolecular Psychiatry" must also be re-examined in this light. At a recent conference I asked one of the authors about this (Ward Dean) and he seemed dumbfounded. He suggested that I subscribe to SMART DRUG NEWS and write a letter to the editor.

Hydergine is a mixture of alkaloids that come from a fungus (ergot) that grows on rye. Hydergine may have antioxidant and nerve growth factor (NGF)-like properties, but it's prime benefit is through increased blood circulation in the brain, possibly acting on the major vessels (since it is touted as opposing the vasoconstriction of nicotine). Hydergine is used medically to treat senile dementia, much of which is related to brain circulatory decline (and mini-strokes). Vincamine, Nimodipine and Vinpocetine (from periwinkle) can also promote brain blood circulation. Ginko biloba (from the oldest known species of tree) reputedly increases brain blood circulation, but by increased flow in the capillaries, rather than the arterioles.

L-Deprenyl has also been called a "Smart Drug", but again because it may protect against the effects of aging in the brain. The Japanese researcher Kenichi Kitani has shown that deprenyl can greatly increase the activity of SuperOxide Dismutase and Catalase in the striatum of rat brains, but above a certain dose level, deprenyl reduces the activity of these antioxidant enzymes. Deprenyl also binds to MonoAmine Oxidase B (MAO-B), opposing the increasing activity of that enzyme in aging brains & hearts. Deprenyl particularly reduces neuron loss in the rat frontal cortex and hippocampus.

Centrophenoxine (Lucidril) & DMAE (DiMethylAminoEthanol) function to protect against free-radical oxidation. DMAE (which is found in high concentrations in sardines & anchovies) is claimed to facilitate production of the neurotransmitter acetylcholine (as is phosphatidyl choline). Since acetylcholine (primarily from the nucleus of Meynert in the basal forebrain) acts as a neurotransmitter to stimulate the hippocampus, memory function can be improved somewhat by substances that facilitate acetylcholine production -- particularly in Alzheimer's patients. No cholinergic agonists have been successful in simulating this effect, but some acetylcholinesterase (acetylcholine-destroying enzyme) antagonists like tacrine have been.

DMAE is metabolized in the brain to form phosphatidyl-DMAE which becomes incorporated in nerve cell membranes where it is highly protective against hydroxyl (OH ) free-radical damage. Loss of permeability of cell membranes with aging is correlated with dehydration, declining enzyme activity and increasing lipofuscin accumulation. This is most serious in the brain & heart because the cells in these tissues are non-dividing.

Centrophenoxine is an ester (carboxyl-linked dimer, ie, two molecules linked to a C=O group by a -O- connection) of p-chlorophenoxyacetic acid and DMAE. Centrophenoxine crosses the blood-brain barrier (BBB) much more effectively than DMAE alone, and once across the BBB the DMAE can be released by hydrolysis. Centrophenoxine has actually been shown to reverse lipofuscin concentration in the frontal cortex and hippocampus in treated mice (lipofuscin concentration normally increases particularly dramatically in the CA3 cells of the hippocampus). Procaine (an ingredient of Gerovital, GH-3) is broken-down in the body into para-aminobenzoic acid (PABA, sometimes called a B-vitamin) and DEAE (DiEthylAminoEthanol), which may function similarly to DMAE. Acetyl-L-carnitine (an ester of the amino acid L-carnitine) has also been shown to reduce lipofuscin accumulation in neurons.

Diphenylhydantoin (Dilantin) decreases spontaneous electrical activity in neuronal cell membranes, and is therefore used in the treatment of epilepsy. It has also been touted as a "Smart Drug" that can improve concentration by reducing "distracting thoughts". But "distracting thoughts" may be the product of a more active mind and, indeed, epileptics taking excessive doses of Dilantin show decreased intelligence & reaction times. Dilantin also has an anti-thyroid effect and can result in gum overgrowth.

So far, most of the reputed "Smart Drugs" I have mentioned either oppose brain aging or serve to eliminate what I would call a nutrient deficiency. A few drugs remain which may increase intellectual performance in normal people. Vasopressin (Diapid) has some role as a neurotransmitter in the brain and it has been shown to improve learning ability. Piracetam in optimal concentrations can enhance memory & learning also, but the exact mechanism of its action is unknown. Piracetam is derived from Gamma-Amino Butyric Acid (GABA). GABA may have an inhibitory effect on memory & learning. Milacemide crosses the blood-brain barrier where it is converted to the amino acid glycine, a co-agonist with glutamic acid at NMDA receptors.

Although I am normally on the side of those who believe that everything in nature can ultimately be re-engineered, in such an exceedingly natural system as the human brain I am wary of tampering with the "ecology" when so little is known about it. I have even avoided the so-called "Smart Drug" caffeine, and I note with irony that SMART DRUGS & NUTRIENTS cites examples on page 83 of caffeine impairing intellectual performance.

So while I am skeptical of the ability of so-called "Smart Drugs" cause a long-term increase in intelligence (the current ones, anyway), I do believe that many of these substances are of value in an anti-aging plan with specific focus on reduction of the aging of the brain.

Urine tests?
Ginkgo biloba
Brain Doping?
Smarter brains?
New smart drugs
Smart and happy?
Cognitive enhancers?
Piracetam (Nootropil)
Nimodipine (Nimotop)
Vincamine (Oxicebral)
Vinpocetine (Cavinton)
Centrophenoxine (Lucidril)
Diphenylhydantoin (Dilantin)
Vasopressin (Diapid, Pressin)
DMAE (DiMethylAminoEthanol)
Hydergine (Ergoloid Mesylates)
Nootropics/Smart drugs: do they work?
Rasagiline (Agilect), ladostigil and VK-28
Personal identity and enhancement drugs
The quest for new smart drugs/nootropics
Cosmetic neurology? The future of smart drugs
UK Government considers ban on IQ-boosting Smart Drugs

Smart Drugs?
Future Opioids
BLTC Research
The Good Drug Guide