"Anti-Aging" drugs/therapies

[LR3]

Is there anyone here on any sort of anti-aging regimen? I've been using antioxidants since I was in my late teens, and started using the 'anti-agining' drug deprenyl about 10 years ago. I've also experimented with various other 'smart drugs' such as hydergine, pyritinol, piracetam (and relatives), etc. I've always experimented with this sort of thing, and along the way I've found some things that actually work, while others I've gotten get no noticeable effect from. I wanted to see if anyone else has experience with these things, or others as I'd like to hear about it.

[Lat-eralus]

Are you interested in items that can be purchased in a health food shop? or other therapies?

I am currently on a doctor prescribed hormone replacement therapy. I was feeling exhausted every day, so I went to the doc and had blood work done. Fould that I had a test level under 250. Since then I have been on test, with support supplements. It is still early (third week), but it seems to be helping.

[Mark1T]

Those drugs I am assuming you imported in from the UK? I have read a lot about such drugs/anti-aging in Durk Pearson's Life Extension, but have never tried any. I would be afraid some customs guys might knock on my door.

It is very interesting subject, trying to slow down or reverse the aging process, but I am not sure which sources to trust, and I wouldn't really want to experiment too much with powerful drugs. So, I just do my normal regimine of multi, Bs, fish and flax oils, melatonin, and aspirin.

[BurritoMan]

Interesting. Never seen anyone mention hydergine before. Did you read Life Extension back in 1982 or something?

I did and have been messing around with anti-aging techniques since about then, 1982, when I was about 19.

Don't know if it's that or just genetics but I look pretty young esp considering all the beer I drank in the past.

Always tried to make sure to not have insulin in my blood when I went to bed.

Currently I've been using l-arginine, l-ornithine, l-lysine for the last 5 years or so. However, the technique conflicts with going to bed with cassein so now not sure how to proceed.

[LR3]

Are you interested in items that can be purchased in a health food shop? or other therapies?

I am currently on a doctor prescribed hormone replacement therapy. I was feeling exhausted every day, so I went to the doc and had blood work done. Fould that I had a test level under 250. Since then I have been on test, with support supplements. It is still early (third week), but it seems to be helping.

anything you want to discuss is fine with me. Rx or non Rx treatments, or off-label uses for Rx medications for "life extension" or improving quality of life by restoring body chemistry to where it was when you were younger--or things that slow the aging process (such as deprenyl, which acts as a very strong anti-oxidant in the mitchondria--where ATPs are cracked into ADP and energy is formed--also where most free-radicals are formed).

[LR3]

Those drugs I am assuming you imported in from the UK? I have read a lot about such drugs/anti-aging in Durk Pearson's Life Extension, but have never tried any. I would be afraid some customs guys might knock on my door.

It is very interesting subject, trying to slow down or reverse the aging process, but I am not sure which sources to trust, and I wouldn't really want to experiment too much with powerful drugs. So, I just do my normal regimine of multi, Bs, fish and flax oils, melatonin, and aspirin.

most are not controlled substances and are able to be imported legally.

[LR3]

Interesting. Never seen anyone mention hydergine before. Did you read Life Extension back in 1982 or something?

I did and have been messing around with anti-aging techniques since about then, 1982, when I was about 19.

Don't know if it's that or just genetics but I look pretty young esp considering all the beer I drank in the past.

Always tried to make sure to not have insulin in my blood when I went to bed.

Currently I've been using l-arginine, l-ornithine, l-lysine for the last 5 years or so. However, the technique conflicts with going to bed with cassein so now not sure how to proceed.

i was using hyergine, but then switched to pyritinol, after reading that it produced better results (mental function continued to improve, never leveled off), and when discontinued the pyritinol patients (was given for dementia in eldery patients) did not go back to baseline but continued to function at a higher level, whereas the hydergine benefit leveled off after a while and was reversed after discontinuing the medication. i have not taken it in a few years, and i don't think i had any blood-flow issues to my brain at the time, but as i age, i am thinking about getting a supply of it again. i used to buy it at pharmacies in china really cheap when i was over there on business a few years back.

[BurritoMan]

I would be interested to hear more about those LR3.

For me avoiding rancid fats and oils has been a big thing since I read Life Extension. I'm almost phobic about it and have barely eaten deep fried food since I read it.

I've also done about 800 I.U. of E every day for about 25 years. Vitamin E that is.

[asuguy]

Is there anyone here on any sort of anti-aging regimen? I've been using antioxidants since I was in my late teens, and started using the 'anti-agining' drug deprenyl about 10 years ago. I've also experimented with various other 'smart drugs' such as hydergine, pyritinol, piracetam (and relatives), etc. I've always experimented with this sort of thing, and along the way I've found some things that actually work, while others I've gotten get no noticeable effect from. I wanted to see if anyone else has experience with these things, or others as I'd like to hear about it.

oh jigga u be lookin youngster than 41 so i me thinks what shizzle you be takin is working you hear?

[LR3]

Deprenyl - extending lifespan by James South MA

Deprenyl is a drug that was discovered around 1964-65 by Dr. Joseph Knoll and colleagues. It was originally developed as a “psychic energizer,” designed to integrate some amphetamine-like brain effects with antidepressant effects. (1) Also known as L-deprenyl, (-)-deprenyl, and selegiline, deprenyl has been intensively researched over the past 36 years - many hundreds of research papers on deprenyl have been published. Knoll has stated that deprenyl “...is an exceptionally lucky modification of PEA [phenylethylamine], an endogenous ... member of the family to which also the transmitters noradrenaline and dopamine belong.” (13) Deprenyl has shown a unique and exciting pharmacologic/clinical profile. It is the only potent, selective MAO-B inhibitor in medical use.(1) Deprenyl is a “catecholamine activity enhancer.” (2) Deprenyl has been shown to protect nerve cells against a wide (and growing) number of neurotoxins. (3,4) Deprenyl has also been shown to be a “neuroprotection/ neurorescue agent” when nerve cells are exposed to damaging or stressful conditions. (5)

Deprenyl has become a standard treatment for Parkinson’s disease. (6) Deprenyl is also useful in treating drug-resistant depression. (8,9) In aged rats, deprenyl has proven to be a highly effective “sexual rejuvenator.” (10) Deprenyl also shows promise as a cognitive enhancement agent. (10) Deprenyl has also proven in four different rat studies and one dog study to be an effective life-extension agent, even increasing the “technical lifespan” in Knoll’s rat experiments. (11,12) and these are just some of deprenyl's reported benefits.

DEPRENYL: MAO-B INHIBITOR EXTRAORDINAIRE
By 1971 Knoll had shown that deprenyl was a unique kind of MAO inhibitor - a selective MAO-B inhibitor, without the “cheese effect.” To fully appreciate what this means, some technical background is necessary.

Some of the most important neurotransmitters in the brain are the monoamine transmitters: serotonin, dopamine and noradrenalin. After being secreted into the synaptic gap, where one neuron connects to another, many to the transmitter molecules are reabsorbed by the secreting neuron and then disposed of by enzymes called “monoamine oxidases” (MAO). This prevents excessive levels of transmitters from accumulating in the synaptic gap and “over-amping” the brain. However, with aging MAO activity significantly increases in the human brain, often to the point of severely depressing necessary levels of monoamine transmitters. (1) In the 1950s the first antidepressant drugs to be developed were MAO inhibitors. By the 1960s however, MAO inhibitors began to drop out of medical use due to a dangerous side-effect - the so-called “cheese effect.” When most MAO inhibitors are used in people consuming a diet rich in a substance called “tyramine,” a dangerous, even fatal, high blood pressure crisis can be triggered. Tyramine is found in many foods, including aged cheeses, some wines, beans, yeast products, chicken liver and pickled herring, to name just a few. (23)

By 1968, further research had shown that there were two types of MAO-A and B. It is primarily intestinal MAO-A that digests incoming tyramine. Most of the MAO inhibitors that have been used clinically inhibit both MAO-A and MAO-B, thus setting up the danger of the cheese effect by inhibiting intestinal and brain MAO-A, allowing “toxic” tyramine levels to accumulate. Deprenyl is unique among clinically used MAO-Is. At normally used clinical dosages (10-15 mg/day), deprenyl is a selective MAO-B inhibitor, so it doesn’t prevent intestinal MAO-A from digesting dietary tyramine. (1) In addition, deprenyl has the unique ability to prevent tyramine from getting into noradrenalin-using nerve calls, and it’s only when tyramine enters noradrenalin nerve cells that control arterial blood pressure that it triggers the “cheese effect.” (1) Deprenyl thus has a dual “safety lock” in preventing the “cheese effect,” making it far safer than other MAO inhibitors. At doses over 20-30 mg/day, however, deprenyl does start to significantly inhibit MAO-A , so there is some risk of the “cheese effect” at these higher (rarely clinically used) doses. (1)

MAO-A enzymes break down serotonin (5-HT) and noradrenalin, and to a lesser extent dopamine. MAO-B breaks down dopamine and the “traceamine” phenylethylamine (PEA). At doses of 5-10 mg per day deprenyl will inhibit MAO-B about 90%. (1) It was initially presumed that deprenyl would increase synaptic levels of dopamine in dopamine-using neurons, and this lead to its use to treat Parkinson’s disease in the late 1970s, Alzheimer’s disease in the 1980s-90s, and depression starting in the late 1970s. In his 1983 paper on the history of deprenyl's clinical benefits to its unique MAO-B effects. (1)

Yet many experts have questioned whether deprenyl's MAO-B inhibition can significantly increase synaptic dopamine levels. (14, 15) This is due to the fact that MAO-B is found only in glial cells in the human brain, non-nerve cells that support, surround and feed the brain’s billions of neurons. (1) And whether there is any exchange of dopamine between these glial cells and the dopamine-using neurons is still an unanswered question. It is commonly believed that it is MAO-A in dopamine neurons that breaks dopamine down. By the 1990s Knoll believed he had discovered the “real basis” of deprenyl's being a MAO-B inhibitor. (2)

Yet as will be made clear shortly, even if deprenyl's originally hypothesized mode of action - directly increasing synaptic dopamine levels through MAO-B inhibition - is false, deprenyl's MAO-B inhibition still provides part of its benefit.

DEPRENYL: CATECHOLAMINE ACTIVITY ENHANCER
During the 1990s Knoll’s deprenyl research took a new direction. Working with rat brain stems, rabbit pulmonary and ear arteries, frog hearts and rats in shuttle boxes, Knoll discovered a new mode of action of deprenyl that he believes explains its widespread clinical utility. (2, 16) Knoll discovered that deprenyl (and its “cousin”, PEA) are “catecholamine activity enhancers”.

Catecholamines refers to the inter-related neurotransmitters dopamine, noradrenalin, and adrenalin. Catecholamines are the transmitters for key activating brain circuits - the mesolimbic-cortical circuit and the locus coeruleus. The neurons of the mesolimbic-cortical circuit and locus coeruleus project from the brain stem, through the mid-brain, to the cerebral cortex. They help to maintain focus, concentration, alertness and effortful attention. (17) Dopamine is also the transmitter for a brainstem circuit - the nigrostriatal tract - which connects the substantia nigra and the striatum, a nerve tract that helps control bodily movement and which partially dies off and malfunctions in Parkinson’s disease. (1)

When an electrical impulse travels down the length of a neuron - from the receiving dendrite, through the cell body, and down the transmitting axon - it triggers the release of packets of neurotransmitters into the synaptic gap. These transmitters hook onto receptors of the next neuron, triggering an electrical impulse which then travels down that neuron, causing yet another transmitter release. What Knoll and colleagues discovered through their highly technical experiments is that deprenyl and PEA act to more efficiently couple the release of neurotransmitters to the electrical impulse that triggers their release. (2, 16)

In other words, deprenyl (and PEA) cause a larger release of transmitters in response to a given electrical impulse. It’s like “turning up the volume” on catecholamine nerve cell activity. And this may be clinically very useful in various contexts - such as Parkinson’s disease and Alzheimer’s disease, where the nigrostriatal tract and mesolimbic-cortical circuits under-function (1, 17), as well as in depression, where they may be under-activity of both dopamine and noradrenalin neurons. (18,19)

Knoll’s research also indicates that after sexual maturity the activity of the catecholamine nervous system gradually declines, and that the rate of decline determines the rate at which a person or animal ages. (10,20)

Knoll therefore believes that deprenyl's catecholamine activity enhancers effect explains its anti-aging benefit. (10, 20) Knoll also believes that deprenyl's catecholamine activity enhancer activity is independent of its MAO-B inhibition effect, because in rats he has shown catecholamine activity enhancer effect at doses considerably lower than that needed to achieve MAO-B inhibition.

Knoll’s work indicates that PEA is also a catecholamine activity enhancer substance. (16) PEA is a trace amine made in the brain that modulates (enhances) the activity of dopamine/noradrenalin neurons. (16, 21) Autopsy studies have shown that while deprenyl increases dopamine levels in Parkinson patient brains by only 40-70%, deprenyl increases PEA levels 1300 - 3500%! (14, 22) PEA is the preferred substrate for MAO-B, the MAO that deprenyl inhibits. Paterson and colleagues have shown that PEA has an extremely rapid turnover due to its rapid and continuous breakdown by MAO-B. (21) Thus deprenyl's catecholamine activity enhancer activity has a dual mode of action. At low, non-MAO-B inhibiting doses, deprenyl has a direct catecholamine activity enhancer activity.

At higher, MAO-B inhibiting doses, deprenyl creates an additional catecholamine activity enhancer effect, due to the huge increases in brain PEA levels that deprenyl causes, PEA also being a catecholamine activity enhancer substance. Many authors have pointed out the probable dopamine neuron activity enhancing effect of PEA in Parkinson patients taking deprenyl. (14, 15, 22)

Knoll’s discovery of PEA’s catecholamine activity enhancer effect now explains this PEA dopamine-enhancing effect.

[LR3]

DEPRENYL: THE NEUROPROTECTOR

Deprenyl has been shown to protect nerve cells from an ever-growing list of neurotoxins. Some of these neurotoxins can actually be produced within the brain under certain conditions, while others come from the environment or diet.

MPTP is a chemical first identified as a contaminant in synthetic heroin. In the 1980s young men using synthetic heroin suddenly developed a Parkinson-like disease. It was then discovered that the MPTP was taken up by glial cells surrounding nigrostriatal neurons, where it was converted by glial MAO-B enzymes into the real toxin, MPP+. The nigral neurons then absorbed MPP+ into their mitochondria, where MPP+ poisoned the mitochondria, killing the dopamine-using neurons.(15) The MAO-B inhibiting dose of deprenyl (10 mg/day) has been shown to prevent MPTP from being converted to the neurotoxin MPP+.(4) And as Lange and colleagues note, “Compounds with a chemical structure similar to MPTP include both natural and synthetic products (e.g. paraquat) that are used in agriculture!” (15)

6-hydroxydopamine (6-OHDA) is a potent neurotoxin that can spontaneously form from dopamine in dopamine-using neurons. (11, 13) 6-OHDA may then further auto-oxidize to generate toxic superoxide and hydroxyl free radicals and hydrogen peroxide. (11, 13) Knoll’s research has shown that pre-treatment of striatal dopamine-neurons with deprenyl can completely protect them from 6-OHDA toxicity. (4, 11, 13) Even in those not suffering from Parkinson’s disease, the nigrostriatal neurons are the fastest aging neuron population in the human brain - an average 13% loss every decade from the 40s on. (1, 13) Knoll and others believe that 6-OHDA neurotoxicity is a key cause of this “normal” nigral death, and that deprenyl may be “just what the doctor ordered” to retard this debilitating downhill neural slide.

DSP-4 is a synthetic noradrenalin nerve toxin. In rodents deprenyl has been shown to prevent the depletion of noradrenalin in noradrenalin-using neurons and noradrenalin-nerve degeneration that DSP-4 causes. (4) AF64A is a cholinergic toxin - it damages brain cells that use acetylcholine. Deprenyl pre-treatment has been shown to protect cholinergic neurons from AF64A toxicity. (4)

Deprenyl has also protected human nerve cells from peroxynitrite and nitric oxide toxicity. Peroxynitrite is formed naturally in the brain when nitric oxide reacts with superoxide radical. Peroxynitrite causes “apoptosis”, a programmed “suicide” cell death that can be triggered in neurons by various agents. deprenyl was found to inhibit peroxynitrite-caused apoptosis, even after the deprenyl was washed from deprenyl pre-treated cells. (3)

Methyl-salsolinol is another MAO-B produced endogenous neurotoxin. Salsolinol is a tetra-hydroisoquinoline produced from the interaction of dopamine and acetaldehyde, the first-stage breakdown product of alcohol.

Once formed, salsolinol can then be further modified by MAO-B to generate methyl-salsolinol. deprenyl's MAO-B inhibiting activity can prevent the DNA damage caused by this toxin. (3, 4)

By inhibiting MAO-B, deprenyl reduces the toxic load on the brain that is routinely produced through the normal operation of MAO-B. MAO-B digests not just dopamine and PEA, but also tryptamine, tyramine and various other secondary and tertiary amines. (15)

As noted earlier, PEA is the substance MAO-B is most efficient at digesting, so that the half-life of PEA is estimated at only 0.4 minutes. (21)

This continuous high level breakdown of PEA (and other amines) produces aldehydes, hydrogen peroxide and ammonia as automatic MAO-B reaction products, and they are all toxins. (4) Thus by reducing age-elevated MAO-B activity, deprenyl reduces the toxin burden on dopamine/noradrenalin neurons (where PEA is primarily produced).

“...L-deprenyl provides neuroprotection against growth factor withdrawal in PC12 cells, oxidative stress in mesencepahalic neurons, and the genotoxic compound, Ara C, in cerebellar granule neurons, and against axotomy-induced motoneuronal degeneration and delayed neuronal death in hippocampus after global ischaemia.” (24) And these are just some of the many reports in the scientific literature on deprenyl's versatile neuroprotection.

[LR3]

DEPRENYL: PARKINSON’S DISEASE
Parkinson’s disease is one of the two major neurodegenerative diseases of the modern world - Alzheimer’s disease is the other. Parkinson’s affects up to 1% of those over 70, a lesser percent of those 40-70, and rarely anyone below 40. (23) Parkinson’s is caused by a severe loss of dopamine-using nigrostriatal neurons, with symptoms manifesting after 70% neuronal loss, and death usually ensuing after 90% loss. (23)

The physiologic role of the nigral neurons is the continuous inhibition of the firing rate of the cholinergic interneurons in the striatum. (13) When the nigral neurons fail in this negative feedback control, voluntary movement and motor control is “scrambled,” leading to the typical Parkinson’s symptoms: shuffling gait, stooped posture, difficulty initiating movement, freezing in mid-movement, and the “shaking palsy.” By the late 1960’s the standard treatment for Parkinson’s was the amino-acid precursor of dopamine, L-dopa. The L-dopa increased the dopamine levels in the few remaining nigrostriatal neurons in Parkinson’s patients (80% of brain dopamine is normally located in nigral neurons (11), thus at least partially restoring normal movement and motor control.

However by 1980 A. Barbeau, after analyzing results of 1052 Parkinson’s patients treated over 12 years, wrote that “long-term side effects are numerous.... although we recognize that levodopa is still the best available therapy, we prefer to delay its onset until absolutely necessary.” (1)

Deprenyl became a standard therapy to treat Parkinson’s by the late 1970’s. In 1985 Birkmayer, Knoll and colleagues published a paper summarizing the results of long term (9 years) treatment with L-dopa alone or combined with deprenyl in Parkinson’s. (25) They found a typical 1 to 2 year life extension over the average 10 years from L-dopa onset until death in the L-Dopa/deprenyl group. The 1996 DATATOP study found that “To the extent that it is desirable to delay levodopa therapy, deprenyl remains a rational therapeutic option for patients with early Parkinson’s.” (26) In a 1992 paper Lieberman cited 17 studies supporting the claim that “... with levodopa-treated patients with moderate or advanced Parkinson’s... the addition of selegiline [deprenyl] is beneficial.” (6) Thus by the 1980s-1990s deprenyl had become a standard Parkinson’s therapy, used either to delay L-dopa use, or in combination with L-dopa. Yet in 1995 a report published in the British Medical Journal seriously questioned the use of deprenyl in combination with L-dopa to treat Parkinson’s. (27)

The UK-Parkinson’s Research Group study followed 520 Parkinson’s patients for 5-6 years. Several hundred patients initially received 375 mg L-dopa, while several hundred others received 375 mg L-dopa plus 10 mg deprenyl daily. After 5-6 years, the mortality rate in the L-Dopa/deprenyl group was almost 60% higher than in the L-dopa only group. The study authors therefore recommended deprenyl not be used in Parkinson’s treatment. Yet the UK-Parkinson’s study is the only one ever to find increased mortality with deprenyl use in Parkinson’s, and the study has been severely criticized on multiple grounds by various Parkinson’s experts. In response to the study, the British Medical Journal published 8 letters in 1996 criticizing the study on various methodological and statistical grounds. (28) And a 1996 Annals of Neurology article by 4 Parkinson’s experts provided an exhaustive analysis of the British Medical Journal study, raising many questions and criticisms. (29) One key criticism is that the UK-Parkinson’s study was open label and patients could be reassigned to treatment groups during the study. 52% of the L-dopa group and 45% of the L-Dopa/deprenyl group changed treatment groups, yet the allocation of end points (deaths) was based on patients’ original drug assignment, regardless of which drugs the patient was actually taking at time of death! When the death rate was compared only between those remaining on their original drug assignment, there was no statistically significant difference in mortality between the L-dopa and deprenyl/L-Dopa groups.

Another criticism leveled against the UK study is based on the dosage of L-dopa. It is generally accepted that deprenyl reduces L-dopa need by about 40%. (14) Thus, to achieve bio-equivalent L-dopa doses, the deprenyl/L-Dopa group should have only received 225 mg L-dopa, compared to 375 mg in the L-dopa only group. As evidence that the initial L-dopa dose was too high in the deprenyl/L-Dopa group, after 4-5 years the median L-dopa dose remained at 375 mg in the deprenyl group, while it had increased to 625 mg in the L-dopa only group. And a growing body of evidence has shown L-dopa to be neurotoxic in Parkinson’s patients. In a 1996 review paper, S. Fahn briefly reviews 20 in vitro and 17 in vivo studies showing L-dopa to be toxic, especially in neurologically compromised, oxidant-stressed individuals, such as Parkinson’s patients. (30) Thus if there were any real increased mortality in the deprenyl/L-Dopa group in the UK study, it is more likely due to L-dopa toxicity than deprenyl. This is further borne out by a 1991 study by Rinne and colleagues, who studied 25 autopsied Parkinson’s brains. (31) When they compared the substantia nigra of 10 patients who had received L-dopa plus deprenyl with 15 patients who had received L-dopa only, they discovered that there were significantly more nigral neurons remaining in the deprenyl/L-Dopa brains, i.e. the deprenyl had actually acted to preserve nigral neurons from L-dopa toxicity. Olanow and co-authors conclude their paper reviewing the UK study: “It is our opinion that the evidence in support of discontinuing selegiline [deprenyl] in levodopa-treated patients, because of fears of early mortality, is not persuasive. Accordingly, we do not recommend that selegiline be withheld in Parkinson’s patients based solely on the results of the UK study.” (29)

DEPRENYL: ALZHEIMER'S DISEASE
Alzheimer’s disease is the most widespread neurodenerative disease of modern times, affecting several million people in the U.S. alone. Alzheimer’s is characterized not only by severe memory loss, but by verbal dysfunction, learning disability and behavioral difficulties - even hallucinations. Alzheimer’s is known to involve damage to the cholinergic neurons of the hippocampus, but “In [Alzheimer’s], in addition to the reduction of acetylcholine, alterations have been observed in the activities of other neurotransmitters. More specifically, the deterioration of the dopaminergic and noradrenergic [NA] systems... seems particularly relevant to the cognitive manifestations.... cerebral depletion of dopamine can easily lead to memory and attention deficits. In [Alzheimer’s] there is significant increase in type-B cerebral and platelet monoamine oxidases (MAO-Bs).... [Therefore] pharmacological inhibition of MAO-B could result in an improvement in the cognitive functions normally mediated by the catecholaminergic systems.” (17)

Thus, with its combined MAO-B inhibition effects and catecholamine activity enhancing effects, deprenyl would seem “tailor-made” to treat Alzheimer’s. And indeed that is the conclusion of a 1996 review paper on Alzheimer’s and deprenyl.

Tolbert and Fuller reviewed 4 single-blind and 2 open label deprenyl trials in Alzheimer’s, as well as 11 double-blind deprenyl/Alzheimer’s studies. (7) They noted that all 6 single-blind/open label studies reported positive results, while 8 of the 11 double-blind studies reported favorable results, typically with a 10 mg deprenyl/day dosage. In 3 of the single-blind studies deprenyl was compared to 3 “nootropics” - oxiracetam, phosphatidylserine and acetyl L-carnitine - and was superior to all three nootropics. Tolbert and Fuller were so impressed with deprenyl that they concluded “...in our opinion, selegiline is useful as initial therapy in patients with mild-to-moderate Alzheimer disease to manage cognitive behavioral symptoms. In patients with moderate-to-severe Alzheimer disease, selegiline’s efficacy has not been adequately assessed; however, given the lack of standard treatment, selegiline should be considered among the various treatment options.” (7)

[LR3]

DEPRENYL: DEPRESSION
Deprenyl has been used experimentally as a treatment for depression since the late 1970s. While the causes of depression are diverse and still under investigation, it is by now accepted that dysfunction of dopamine and noradrenalin neural systems is a frequent biochemical cause of depression. (18,19)

In addition the research of A. Sabelli and colleagues has established that a brain PEA deficiency also seems to be strongly implicated in many cases of depression. (32) Given that deprenyl is a catecholamine (dopamine and noradrenalin) activity enhancer, and that deprenyl strongly increases brain PEA through MAO-B inhibition, deprenyl would seem a rational treatment for depression.

Studies with atypical depressives (33), treatment-resistant depressives (34), and major depressives (35) have shown deprenyl to be an effective, low side-effect depression treatment. However, such studies have often required deprenyl dosages in the 20-30, even 60 mg range. While these dosages caused little problem in short-term studies, it is dubious to consider using such high, non-selective MAO-B inhibition doses for long term (months - years) treatment. Three studies have shown antidepressant promise at selective, MAO-B inhibiting doses.

In 1978 Mendelwicz and Youdim treated 14 depressed patients with 5 mg deprenyl plus 300 mg 5-HTP 3 times daily for 32 days. (1) Deprenyl potentiated the antidepressant effect of 5-HTP in 10/14 patients. 5-HTP enhances brain serotonin metabolism, which is frequently a problem in depression (37), while deprenyl enhances dopamine/noradrenalin activity. Under-activity of brain dopamine, noradrenalin and serotonin neural systems are the most frequently cited biochemical causes of depression (18,19,37), so deprenyl plus 5-HTP would seem a natural antidepressant combination.

In 1984 Birkmayer, Knoll and colleagues published their successful results in 155 unipolar depressed patients who were extremely treatment-resistant. (8) Patients were given 5-10 mg deprenyl plus 250 mg phenylalanine daily. Approximately 70% of their patients achieved full remission, typically within 1-3 weeks. Some patients were continued up to 2 years on treatment without loss of antidepressant action. The combination of deprenyl plus phenylalanine enhances brain PEA activity, while both deprenyl and PEA enhance brain catecholamine activity. Thus deprenyl plus phenylalanine is also a natural antidepressant combination.

In 1991 H. Sabelli reported successful results treating 6 of 10 drug-resistant major depressive disorder patients. (9) Sabelli used 5 mg deprenyl daily, 100 mg vitamin B6 daily, and 1-3 grams phenylalanine twice daily as treatment. 6 of 10 patients viewed their depressive episodes terminated within 2-3 days! Global Assessment Scale scores confirmed the patients’ subjective experiences. Vitamin B6 activates the enzyme that converts phenylalanine to PEA, so the combination of low-dose deprenyl, B6, and phenylalanine is a bio-logical way to enhance both PEA and catecholamine brain function, and thus to diminish depression.

DEPRENYL: THE ANTI-AGING DRUG
4 series of rat experiments, as well as an experiment with beagle dogs, have shown that deprenyl can extend lifespan significantly, even beyond the “technical lifespan” of a species. Knoll reported that 132 Wistar-Logan rats were treated from the end of their second year of life with either saline injections or 0.25 mg/kg deprenyl injection 3 times weekly until death. (11)

In the saline-treated group the oldest rat reached 164 weeks of age, and the average lifespan of the group was 147 weeks. In the deprenyl group, the average lifespan was 192 weeks, with the shortest-living rat dying at 171 weeks, and the longest-lived rat reaching 226 weeks.

In a second series of experiments Knoll treated a group of 94 “low-performing” (LP) sexually inactive male rats with either saline or deprenyl injections (0.25 mg/kg) from their eighth month of life until death. (11) Knoll had already established a general correlation between sexual activity status and longevity in the rats. The saline-treated LP rats lived an average 135 weeks, while the deprenyl-treated LP rats averaged 153 weeks of life. The saline treated HP rats lived an average 151 weeks of life, while the deprenyl -treated HP rats averaged 185 weeks of life, with 17/50 HP-deprenyl rats exceeding their estimated technical lifespan of 182 weeks. (20)

Knoll’s experiments were partially replicated by Milgram and co-workers and Kitani and colleagues. (11) Milgram’s group used shorter-living Fischer 344 rats, while still starting deprenyl treatment at 2 years of age - in effect later in their lives - and found a marginally significant 16% lifespan extension. The Kitani group, also using the shorter-lived Fischer rats, started their deprenyl treatment at 1.5 years of age, and found a 34% life increase. (11)

Ruehl and colleagues performed an experiment with beagle dogs and deprenyl, administered at 1 mg/kg orally per day, for up to 2 years 10 weeks. In a subset of the oldest dogs tested (10-15 years of age), 12 of 15 deprenyl-treated dogs survived to the conclusion of the study, while only 7 of 18 placebo-treated dogs survived. By the time the first deprenyl-treated dog died on day 427 of the study, 5 placebo-treated dogs had already died, the first at day 295. (12) Ruehl et al note that “dogs provide an excellent model of human aging,” so their study takes on added significance.

Knoll has repeatedly emphasized that the nigrostriatal tract, the tiny dopamine-using nerve cluster in the basal ganglia (“old brain”), typically dies off at an average rate of 13% per decade starting around age 45 in humans.

This fact literally sets the human technical lifespan (maximum obtainable by a member of a species) at about 115 years, since by that age the nigral neuron population would have dropped below 10% of its original number, at which time death ensues even if in all other respects the organism were healthy. (23) Based on the sum total of the animal deprenyl literature, as well as the 1985 study showing life-extension in deprenyl-treated Parkinson’s patients (25) Knoll has suggested that if deprenyl were used from the 40s on, and only modestly lowered the nigrostriatal neuron death rate - i.e. from 13% to 10% per decade - then the average human lifespan might increase 15 years, and the human technical lifespan would increase to roughly 145 years. (23)

After 45 years of research, Knoll has concluded that “...the regulation of lifespan must be located in the brain,” (20) His research has further convinced him that “... it is the role of the catecholaminergic neurones to keep the higher brain centers in a continually active state, the intensity of which is dynamically changed within broad limits according to need.” (20) Knoll’s research has shown that catecholaminergic nerve activity reaches a maximum at sexual maturity, and then begins a long, gradual downhill slide thereafter. Knoll’s animal research has shown catecholaminergic activity, learning ability, sexual activity and longevity to be inextricably interlinked. (11, 20)

Knoll argues that the quality and duration of life is a function of the inborn efficiency of the catecholaminergic brain machinery, “i.e. a high performing longer living individual has a more active, more slowly deteriorating catecholaminergic system than [his/her] low performing, shorter living peer.” (20) And his key conclusion is that “... as the activity of the catecholaminergic system can be improved at any time during life, it must be essentially feasible to ... [transform] a lower performing, shorter living individual to a better performing, longer living one.” (20)

It is on this basis that Knoll consistently, throughout his deprenyl papers (11,20, 23), recommends the use of 10 - 15 mg oral deprenyl/week, starting in the 40s, to help achieve this goal in humans. Knoll’s research clearly convinces him that deprenyl is both a safe and effective preserver of the nigrostriatal tract, as well as a catecholamine activity enhancer. deprenyl may not be the ultimate anti-aging drug, but it is one that is safe and effective, well validated theoretically and experimentally, and it’s available now.

[LR3]

DEPRENYL: DOSAGE & SIDE-EFFECTS
Both Dr. Joseph Knoll and the Life Extension Foundation (37) recommend a 10-15 mg weekly (i.e. 1.5 - 2 mg/day) oral deprenyl dosage for humans, starting around age 40, possibly even in the 30s. 10 mg/day is a relatively standard deprenyl dose for treatment of Parkinson’s and Alzheimer’s, but this higher dose should only be used with medical supervision. Some deprenyl experts believe this dosage is excessive, and that with long term deprenyl use lower doses may still be effective and safer. (22)

Knoll has noted that the human MAO-B inhibiting deprenyl dose ranges from 0.05 to 0.20 mg/kg of bodyweight. (1) Thus, even in those wishing to use deprenyl at an effective MAO-B inhibiting dose, it should not be necessary to use more than 3-5 mg/day. Because deprenyl is a potent and irreversible MAO-B inhibitor, it may even turn out in many individuals that the suggested 1.5-2 mg/day “life extension” deprenyl dose may achieve MAO-B inhibition with long term use.

Deprenyl is reported in most human studies to be well tolerated. (7) Typically, no abnormalities are noted in blood pressure, laboratory valves, ECG or EEG. (7)

The most common side effects reported for deprenyl are gastrointestinal symptoms, such as nausea, heartburn, upset stomach, etc. (7) Some studies have found side effects such as irritability, hyper-excitability, psychomotor agitation, and insomnia, (7, 8) These effects are probably due to deprenyl's catecholamine-enhancing effect, over-activating dopamine/noradrenalin neural systems at the expense of calming/sleep-inducing serotonergic systems, so taking magnesium and tryptophan or 5-HTP may suffice to counter these “psychic” effects.

REFERENCES

1. Knoll, J. (1983) “Deprenyl (selegeline): the history of its development and pharmacological action” Acta Neurol Scand (Suppl) 95, 57-80.

2. Knoll, J. et al (1996) “Deprenyl and (-) -1-phenyl-2-propylaminopentane [(-)PPAP], act primarily as potent stimulants of action-potential-transmitter release coupling in the catecholaminergic neurons” Life Sci 58, S17-27.

3. Maruyama, W. et al (1998) “Deprenyl protects human dopaminergic neuroblastma SH-SY5Y cells from apoptosis induced by peroxynitrite and nitric oxide” J Neurochem 70,2510-15.

4. Magyar, K. et al (1996) “The pharmacology of B-type selective monoamine oxidase inhibitors; milestones in deprenyl research” J Neural Transm (Suppl) 48, 29-43.

5. Tatton, W.G. et al (1996) “Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase” J Neural Transm (Suppl) 48, 45-59.

6. Lieberman, A. (1992) “Long-term experience with selegeline and levodopa in Parkinson’s disease” Neurol (Suppl) 42, 32-36.

7. Tolbert, S. & Fuller, M. (1996) “Selegeline in treatment of behavioral and cognitive symptoms of Alzheimer disease” Ann Pharmacother 30, 1122-29.

8. Birkmayer, W. et al (1984) “L-deprenyl plus L-phenylalanine in the treatment of depression” J Neural Transm 59, 81-87.

9. Sabelli, H. (1991) “Rapid treatment of depression with selegeline-phenylalanine combination” J Clin Psychiat 52,3.

10. Knoll, J. (1997) “Sexual performance and longevity” Exp Gerontal 32, 539-52.

11. Knoll, J. (1995) “Rationale for (-)-deprenyl (selegeline) medication in Parkinson’s disease and in prevention of age-related nigral changes” Biomed Pharmacother 49, 187-95.

12. Ruehl, W. et al (1997) “Treatment with L-deprenyl prolongs life in elderly dogs” Life Sci 61, 1037-44.

13. Knoll, J. (1992) “The pharmacological profile of (-)-deprenyl (selegeline) and its relevance for humans: a personal view” Parmacol Toxicol 70, 317-21.

14. Youdim, M. & Finberg, J. (1994) “Pharmacological actions of L-deprenyl (selegeline) and other selective monoamine oxidase B inhibitors” Clin Pharmacol Ther 56, 725-33.

15. Lange, K. et al (1994) “Biochemical actions of L-deprenyl (selegeline)” Clin Pharmacol Ther 56, 734-41.

16. Knoll, J. et al (1996) “Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain” Life Sci 58, 2101-14.

17. Finali, G. et al (1991) “L-deprenyl therapy improves verbal memory in amnesic Alzheimer patients” Clin Neuropharmacol 14, 523-36.

18. Leonard, B. (1997) “The role of noradrenaline in depression: a review” J Psychopharmacol 11(Suppl), S39-S47.

19. Brown, A & Gershon, S. (1993) “Dopamine and depression” J Neural Transm 91, 75-109.

20. Knoll, J. (1994) “Memories of my 45 years in research” Pharmacol Toxicol 75, 65-72.

21. Paterson, I. et al (1990) “2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system?” J Neurochem. 55, 1827-37.

22. Gerlach, M. et al (1996) “Pharmacology of selegiline” Neurol 47 (Suppl), S137-S145.

23. Knoll, J (1992) “Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system” J Am Geriat Soc 40, 839-47.

24. Suuronen, T. et al (2000) “Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells” Biochem Pharmacol 59, 1589-95.

25. Birkmayer, W. et al (1985) “Increased life expectancy resulting from addition of L-deprenyl to Madopar® treatment in Parkinson’s disease: a long term study: J Neural Transm 64, 113-27.

26. Parkinson Study Group (1996) “Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa” Ann Neurol 39, 29-30.

27. Lees, A (1995) “Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegeline in patients with early, mild Parkinson’s disease” Br Med J 311, 1602 - 07.

28. Maki-Ikola, O. et al (1996) 8 letters criticizing Lee’s 1995 study Br Med J 312, 702-04.

29. Olanwo, C. et al (1996) “ Selegiline and mortality in Parkinson’s disease” Ann Neurol 40, 841-45.

30. Fahn, S. (1996) “ is L-dopa toxic?” Neurol 47 (Suppl) S184-S193

31. Rinne, J. et al (1991) “Selegiline (deprenyl) treatment and death of migral neurons in Parkinson’s disease” Neurol 41, 859-61.

32. Sabelli, H. et al (1986) “Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements” J Clin Psychiat 47,777-81.

34. Sunderland, T. et al (1994) “High-dose selegiline in treatment-resistant older depressive patients” Arch Gen Psychiat 51, 607-15.

35. Mann, J. et al (1989) “A controlled study of the antidepressant efficacy and side effects of deprenyl” Arch Gen Psychiat 46, 45-50.

36. Life Extension Foundation. The Physician’s Guide to Life Extension Drugs. Hollywood, FL: Life Extension Foundation n.d. Pp 67-107.

37. Passwater, R & South J. 5-HTP: The Natural Serotonin Solution. New Canaan, CT: Keats Pub., 1998

[LR3]

Pyritinol - the Immune-Enhancing Nootropic
by James South MA

Pyritinol is perhaps the oldest nootropic drug which is still in use - it has been continuously used and researched in Europe since it was patented by Merck in 1961. Surprisingly for a drug whose patent expired in the late 1970’s

Pyritinol has generated as much published research in the 1980’s and 1990’s as was generated in the early years of Pyritinol studies. This seems to be due to the wide range of uses, safety, and efficacy of Pyritinol. Most of the research on Pyritinol has been published in British, French, German, Czech, and Swiss journals. Thus the drug is virtually unknown in America, not to mention ignored by the AMA and FDA.

Pyritinol has been used clinically in a wide range of disorders. A 1981 report states: "Pyritinol... is widely used throughout Europe for the treatment of organic psychosyndromes..., cerebral circulatory disorders..., alcoholism..., dyslexic factors..., behavior and intellect disorders in children... and post-cerebral infarction [stroke] states....

In patients suffering from cerebral trauma it has been reported to be of therapeutic benefit in influencing the immediate post-operative recovery state and as an aid in rehabilitation...." (1).

Pyritinol has also shown excellent benefit on the clinical course of victims of traumatic coma (caused by head injury). Pyritinol has both reduced the normal high death rate in such cases, and has rapidly returned coma patients to more or less normal waking consciousness, even when the brain injuries were so severe the patient ultimately died. (2). Pyritinol has also been used successfully to treat rheumatoid arthritis patients. (3) Pioneer nootropic researcher I.Hindmarch has also noted that "The clinical properties of Pyritinol have also been demonstrated using experimentally induced hypoxia [low brain oxygen] where a 68% [decrease] on psychometric assessments was reduced to 21% by 600 mg and to 12% by 1000 mg of the drug." (4)

Pyritinol is also known as pyrithioxine, and pyridoxine disulfide. In the Pyritinol molecule, two pyridoxine sulfide molecules are linked together by their two sulfur atoms.

One of the keys to understanding Pyritinol’s wide mode of action was first revealed in 1989. Two Czech scientists performed sophisticated experiments on 6 nootropic drugs to determine their free radical-quenching power. Pyritinol proved to be far superior to the acknowledged antioxidant nootropics, centrophenoxine (Lucidril) and DMAE, while piracetam and oxiracetam showed no antioxidant effect. Pavlik and Pilar state: "There is growing evidence that free-radical interactions are implicated in the pathogenesis of many diseases including radiation injury, atherosclerosis, arthritis, cancer and aging.... The most dangerous [kind] of oxygen radicals is the hydroxyl radical that can attack proteins, lipids, nucleic acids and, actually, almost any molecule of a living cell. If the production of hydroxyl radical escapes the control mechanisms, then … substantial damage to cell functions [and structure] may occur.... It was found that Pyritinol exerted a pronounced scavenger action against hydroxyl radicals which was confirmed by the electron spin resonance spectroscopic technique in spin trapping experiments". (5) It is interesting to note that brain proteins were protected from hydroxyl radical damage by Pyritinol in these experiments. As will now be explained, the superior hydroxyl radical antioxidant effect of Pyritinol is what provides much of the immune, arthritis, and neuroprotective benefits of Pyritinol.

Three of the most common ‘free radicals’ that are continuously being produced in human cells are superoxide radical, hydrogen peroxide (H2O2), and hydroxyl radical (HR). Superoxide radicals are normally produced through white blood cell germ-killing activities, energy metabolism, and in many disease states. "It is believed that the activity of superoxide is at least partly.... responsible for aging and most if not all degenerative diseases". (6A)

Fortunately the body has two different enzymes - copper-zinc SOD and manganese SOD - to neutralise superoxide radicals. Unfortunately, SOD production drops with age: "Lowered levels of SOD... have been found in elderly persons.... Decreases in all human tissues examined have found in humans, progressing from ages 1 to 89" (6B). SOD converts neutralise superoxide radicals into oxygen and hydrogen peroxide. Hydrogen peroxide is less cell-damaging than neutralise superoxide radicals, but it is still injurious if it accumulates in cells.

Although hydrogen peroxide has some uses in the body (e.g. white blood cells secrete it to kill germs), the body’s need to continuously rid itself of hydrogen peroxide is shown by the fact that our cells possess two completely different enzymes - catalase and glutathione peroxidase - to ensure neutralization of hydrogen peroxide. Hydrogen peroxide uncontrolled can damage cell membranes and structures, as well as promote inflammation.

The brain is particularly vulnerable to damage by hydrogen peroxide. (6C) Unfortunately, under conditions all too common in our cells, neutralise superoxide radicals and hydrogen peroxide "will react with each other in what is known as the Haber-Weiss reaction. The product of this reaction is a free radical even more damaging than superoxide known as the hydroxyl radical...." (6D). And to make matters worse, human cells have no enzymatic defense against HR. HR is normally quenched primarily by cholesterol, Vitamin C or proanthocyanidins, (6E). (Thus, the elevated cholesterol levels found in most modern humans may actually be a defensive tactic used by the body to quench the excesses of HR induced by our toxic modern diet, environment and lifestyles). HR’s are so injurious to cells that when huge uncontrollable numbers of them are generated in a person exposed to massive levels of X-ray or gamma radiation, the flesh may literally melt from the bones within hours!

As Pavlik and Pilar note: "There are some clinical reports that may be viewed as supporting the opinion that Pyritinol may also have a [hydroxyl] scavenger effect in vivo. Camus [et al] (1978) and Berry (1986) used Pyritinol successfully, instead of the … more toxic scavenger penacillamine, for the treatment of some cases of rheumatoid arthritis. [So did Lemmel et al, reporting in 1993. (3)] The protection of cartilage and synovial protein against free-radical -induced degradation … may be an important factor in the treatment of rheumatoid arthritis. The same line of reasoning may be applied to some cases of stroke or brain trauma ..., where the generation of hydroxyl free-radicals … is abundant … and where Pyritinol was successfully used for treatment .... Finally, the potency of Pyritinol to protect proteins in brain against radical induced polymerization, in conjunction with recent reports that Pyritinol enhanced cholinergic transmission in brain ..., substantiates its use for the treatment of cognitive disorders". (5).

Increased brain cell energy

Another key benefit of Pyritinol has been known since the 1960’s: its ability to enhance or normalize glucose transport through the blood-brain barrier and to increase brain cell energy production from glucose. (7). In a placebo-controlled, double-blind study, Hoyer and colleagues examined 87 patients suffering from various brain disorders. Careful measurements of cerebral blood flow, oxygen uptake, glucose uptake, and cerebral metabolic rate were taken. Of the 45 patients receiving Pyritinol, 27 (60%) suffered from disturbed glucose uptake/cerebral energy metabolism. "Cerebral uptake of glucose, … which … was reduced to approximately 50% of the normal value, increased significantly during Pyritinol treatment … and returned to normal.... The clinical disturbances generally also improved to the same extent as did the disturbed glucose metabolism". (7).

Enhanced Glucose Transport

Pyritinol’s ability to enhance glucose transport through the blood-brain barrier when it is low is a highly significant benefit of Pyritinol. Although the brain is usually less than 2% of total bodyweight, the brain must produce and use about 20% - 500 calories per day - of the body’s total energy production. And under normal, non-fasting conditions, the brain can only ‘burn’ glucose (sugar) for fuel. Unlike virtually all other body cells, nerve cells cannot use fat as an energy fuel. Brain cells also cannot store any significant amount of glucose - they are completely dependent upon a continuous delivery of glucose from the blood, through the blood-brain barrier. Thus, brain glucose uptake is a major rate-limiting factor for crucial brain energy production. Low cerebral glucose uptake necessarily translates into low brain carbohydrate energy metabolism.

And brain energy metabolism is so important to optimal, healthy brain function that "... brain carbohydrate metabolism is impaired in a variety of dementias [e.g. Alzheimer’s, stroke, metabolic, or drug toxicity dementias] and … the degree of reduction in brain carbohydrate metabolism is correlated with the severity of the dementias ...." (8) Pyritinol is good for optimal brain carbohydrate metabolism , and what is good for brain carbohydrate metabolism is good for the brain and the mind!

[LR3]

Effective Immune Enhancer

A surprising effect of Pyritinol was first reported in 1993: Pyritinol may be an effective immune enhancer through its stimulation of neutrophil migration. (9). Neutrophils are a major type of white blood cell (WBC) - they typically constitute about 60% of the total number of white blood cells in the blood. Wherever there is a wound, cut, sore, abrasion etc., neutrophils are attracted to leave the bloodstream and travel to the site of injury/infection - the process of chemotaxis. Once at the site of injury, neutrophils proceed to engulf germs - especially bacteria - that may now be growing at the injury site. Neutrophils then secrete a powerful mix of free radicals and oxidants, such as hydrogen peroxide and hypochlorous acid, which destroy the germs before they can seriously multiply and overwhelm the body. However, neutrophils sooner or later die "in the line of duty" from their own germ-killing free radical barrage.

One neutrophil averages 5 to 20 germ kills before succumbing. The free radicals neutrophils release also typically promote inflammation at the site of injury, a process that all too easily gets out of control and proceeds to excess. Excessive inflammation promotes excessive swelling, tenderness, redness, heat and pain at the injury site. The pus that forms with cuts and wounds is in large part made up of dead neutrophils.

In a study with rabbit neutrophils, Elferink and De Koster found that Pyritinol, at levels likely to be achieved in tissue, through oral doses, strongly promoted neutrophil chemotaxis (migration to injury site), but did not increase free radical levels or inflammation. (9). Given the earlier discussion on Pyritinol’s antioxidant effects, this differential effect of Pyritinol on neutrophil activity (increases migration, but not free radicals or inflammation) becomes comprehensible. When large numbers of neutrophils release huge amounts of hydrogen peroxide and hydrogen peroxide, this generates huge quantities of inflammatory, tissue-damaging hydroxyl radicals. Yet Pyritinol is a powerful quencher of hydroxyl radicals. Thus Pyritinol is able to reduce hydroxyl radical-induced inflammation and tissue damage - the unpleasant side effect that usually accompanies successful germ-killing by neutrophils.

Immune Defense

Neutrophils comprise the body’s first line of white blood cell immune defense - they are normally first to arrive at wound/injury sites. Yet our modern sugar-rich diet has been shown in multiple studies to significantly impair neutrophil activity.

When human volunteers were given various forms and levels of sugar in drinks, the number of germs a neutrophil could kill before dying from its own free radical release typically dropped 50 - 80%! The effect began within one hour of sugar intake, peaked at two hours, and was still significant five hours after sugar ingestion. (10) Thus a sugar-rich diet literally enhances neutrophil self-destruction as neutrophils kill germs, yet Pyritinol enhances neutrophil survival through reducing the hydroxyl radical excesses that normally lead to neutrophil death.

Another key property of Pyritinol is its vigilance-enhancing effect. Pyritinol increases nerve activity in the locus coeruleus. (11) "In humans, the number of neurons in the locus coeruleus declines with advancing age. Degeneration appears to advance slightly faster in males than females. The locus coeruleus is a brain area that … is particularly susceptible to neuronal degeneration in Alzheimer’s disease.... [There are many] studies indicating a role of this system in control of attention and … learning and memory". (11)

EEG Power

"Pyritinol has also been shown to produce a vigilance response, both behaviorally and electrophysiologically (EEG recordings) in animals and in healthy human volunteers. More recently, using topographic brain mapping of EEG, it has been shown that 600 mg Pyritinol resulted in an increase in total (EEG) power and … other changes indicative of improved vigilance.... Specific studies of the effects of Pyritinol on … memory using a battery of seven tests … showed that repeated daily doses of Pyritinol 300mg improved memory performance [which is in part a function of locus coeruleus - regulated vigilance] over a wide range of measures in volunteers aged from 16 to 66 years". (4)

Who might benefit?

1. Pyritinol may be useful in various forms of dementia, organic brain syndrome, head injury, stroke aftermath, coma, and cerebral circulatory disorders. Vinpocetine, piracetam, oxiracetam, and phosphatidyl serine may be useful synergists with Pyritinol.

2. Pyritinol may be useful as an anti-brain aging nootropic drug.

3. Pyritinol may be useful as an aid to increased focus and concentration, memory, alertness and information processing in both young and old, normal or mildly brain dysfunctional persons.

4. Pyritinol may be useful in Attention Deficit Disorder (ADD), hyperkinetic, or mildly retarded children to increase drive, alertness, concentration and learning ability. (12, 13)

5. Pyritinol may be useful as part of a health-optimizing antioxidant program, along with vitamins C and E, selenium, zinc and lipoic acid.

6. Pyritinol may be useful in the treatment of rheumatoid arthritis. In a large, double blind yearlong trial comparing Pyritinol to a standard anti-rheumatoid drug (Auranofin), the response rate was superior for Pyritinol (78% vs. 59%, at one year). "Every individual efficacy parameter showed a numerical trend for better results in the Pyritinol group...." (3)

Pyritinol Side-Effects

Most published studies on Pyritinol report few if any side effects, with skin rashes and/or gastric upset occasionally noted. E.g. "In general, the tolerability of the drug was good. Practically no problems occurred during the trial.... None of the reported symptoms were rated as serious or persisted over a long period of time". (14) "No undesirable side-effects were observed". (13) "With the exception of cutaneous [skin] symptoms ... there were no significant differences in the incidence of adverse reactions in the drug and placebo group.... No significant changes were observed in [clinical laboratory] parameters". (1)

The one major exception to Pyritinol’s low side-effect profile occurred in the large-scale rheumatoid arthritis trial. The authors note that Pyritinol side effects "were mostly nuisance events, which led to stopping therapy [in some cases], but did not constitute a health risk for the patient and were fully and rapidly reversible." (3) However, they also note a general trend in the Pyritinol-arthritis literature of about 2% potentially serious adverse effects involving blood, kidney or liver, which makes it important for regular monitoring of liver enzymes, urine status and blood cell status when using Pyritinol to treat rheumatoid arthritis. Therefore, Pyritinol should be used in rheumatoid arthritis treatment only with the knowledge and supervision of a physician.

Pyritinol Doses

A wide range of doses have been used in Pyritinol studies. These have ranged from as low as 100 mg twice daily (12) to 200 mg three time’s daily (14) or 200 mg four times daily. (15) For anti-aging, cognition-enhancing or antioxidant purposes, 100 mg Pyritinol two or three times daily is generally safe and adequate. Higher doses (400 - 1000 mg daily) should probably be used only with physician supervision, just to err on the safe side. Pyritinol may be taken either on empty stomach or after food, as desired. Persons only prone to insomnia should probably only take Pyritinol morning and early afternoon. There may be a mutual enhancement of action between Pyritinol and other nootropic drugs, allowing/requiring lower doses of some or all the drugs in order to avoid an over-excitation effect.

[LR3]

REFERENCES

1. K.Kitamura (1981) "Therapeutic Effect of Pyritinol on Sequelae of Head Injuries" J Int Med Res 9, 215-21.

2. G. Dalle Ore et al (1980) "The Influence of the Administration of Pyritinol on the Clinical Course of Traumatic Coma", J Neuroserg Sci 24, 1-8.

3. E.-M. Lemmel (1993) "Comparison of Pyritinol and Auranofin in the Treatment of Rheumatoid Arthritis" Br J Rheumatol 32, 375-82.

4. I. Hindmarch et al (1990) "Psychpharmacalogical Effects of Pyritinol in Normal Volunteers" Neuropsychobiol 24, 159-64.

5. A. Pavlik & J. Pilar (1989) "Protection of Cell Proteins Against Free-Radical Attack by Nootropic Drugs: Scavenger Effects of Pyritinol Confirmed by Electron Spin Resonance Spectroscopy" Nueropharmacol 28, 557-61.

6. R. Bradford & H. Allen, Oxidology, Chula Vista, CA: R.W. Bradford Foundation, 1997. A.65 B323 C.142 D.66 E.175.

7. S. Hoyer et al (1977) "Effect of Pyritinol-HCL on Blood Flow and Oxidative Metabolism of the Brain in Patients with Dementia" Arzneim Forsch/Drug Res 27, 671-74.

8. R. Branconnier (1983) "The Efficacy of the Cerebral Metabolic Enhancers in the Treatment of Senile Dementia" Psychopharmacol Bull 1983 Spring;19(2):212-9.

9. J. Elferink & B. de Koster (1993) "Differential Stimulation of Neutrophil Functions by Pyrithioxine" Int J Immunopharmac 15, 641-46.

10. R. Huemer & J. Challem, "The Natural Health Guide to Beating the Supergerms", NY: PocketBooks, 1997. Pp.124-27.

11. H.-R. Olpe et al (1985) "Locus Coeruleus as a Target for Psychogeriatric Agents" Ann NY Acad Sci 444, 394-405.

12. G. Logue et al (1974) "The Effects of Pyrithioxine on the Behavior and Intellectual Functioning of Learning-Disabled Children" S.Afr Med J 48, 2245-46.

13. D. Lane O’Kelly (1975) "Pyritinol in the Treatment of Chronic Alcoholics" J Int Med Res 3, 323-27.

14. K. Fischhof et al (1992) "Therapeutic Efficacy of Pyritinol in Patients with Senile Dementia of the Alzheimer Type (SDAT) and Multi-Infarct Dementia (MID)" Neuropsychobiol 26, 65-70.

15. A. Cooper & R. Magnus (1980) "A Placebo-Controlled Study of Pyritinol in Dementia" Pharmatherapeutica 2, 317-22.

ALL INFORMATION IS EDUCATIONAL AND PROVIDED UNDER IAS TERMS AND CONDITIONS. IT DOES NOT AND SHOULD NOT REPLACE THE ADVICE OF YOUR PHYSICIAN.

Efficacy of Pyritinol versus Hydergine upon cognitive performance in patients with senile dementia of the Alzheimer's type: A double-blind multi-center trial

Alzheimer's Research (United Kingdom) , 1996, 2/3 (79-84)

In this multi-center trial, 100 patients with the diagnosis of Senile Dementia of the Alzheimer's type (SDAT) of mild to moderate severity were randomly divided into two treatment groups and, following a placebo wash-out phase, were administered either pyritinol or Hydergine for 12 weeks in a double-blind, randomized parallel comparison. Two measures of cognitive functioning were employed to assess treatment effects. The results indicated that treatment with Pyritinol was associated with a significant and continuous improvement in cognitive functioning over the course of the study while treatment with Hydergine was associated with a more modest improvement that tended to plateau early in the treatment phase.

[LR3]

Below are two other compounds i've used. I take 45mg of idebenone daily, and I'll use Piracetam before meetings or when I have a lot of mentally taxing work to do.

http://www.piracetam.com/

http://www.idebenone.info/

Theses were just a few of what is out there. I'd love to hear people's experiences with these or others.

[Baldsnake]

Yipes!! Now I forgot what I was gonna say. Do I need Deprawhatever??

[LR3]

it is one "anti-aging" drug that has shown to actually increase lifespan across different species (canine, rodent, insect)--as it's mode of action appears to be twofold. one is that it is a super antioxidant that gets into your mitochondria and cleans up free radicals there, where most are produced--and it protects dopamine stem-cells which degrade over time as each decade after 35 you lose about 13% of your dompamine producing cells, which are needed for proper neuro function.

[Lat-eralus]

Is there anyone here on any sort of anti-aging regimen? I've been using antioxidants since I was in my late teens, and started using the 'anti-agining' drug deprenyl about 10 years ago. I've also experimented with various other 'smart drugs' such as hydergine, pyritinol, piracetam (and relatives), etc. I've always experimented with this sort of thing, and along the way I've found some things that actually work, while others I've gotten get no noticeable effect from. I wanted to see if anyone else has experience with these things, or others as I'd like to hear about it.

LR3 - Very interesting info

Of the compounds you have listed, which ones have had the greatest effect?

Which compounds are you currently taking

[LR3]

LR3 - Very interesting info

Of the compounds you have listed, which ones have had the greatest effect?

Which compounds are you currently taking

currently taking deprenyl, and idebenone on a daily basis, and piracetam as needed (i have a meeting in 12 minutes and i am going to take some now to ensure i am at the top of my game). i also take 25mg dhea, and a handfull of vitamins/supplments, fish oil, etc. on a daily basis.

piracetam increases oxygen levels in the brain, as well as the neurotransmitter acetylcholine, and increases communication between the left and right sides of the brain (measured by activity across the corpus corpus callosum, which is the bridge between the left and right hemispheres of the brain). i find it makes a noticable difference.

deprenyl can have a slight stimulatory effect as it can increase dopamine levels, and a lot of people find that it improves mood in general, sexual function, etc.

i've been considering low dose hGH, which in life extension doses, doesn't have any negative side effects and improves lots of things, such as kidney function, healing/recovery time, and produces a general sense of well-being. basically the idea is to bring your hormone levels back to where they were when you were younger (aka, as in hormone replacement therapy)--not to hit levels that your body was never capable of producing (not high doses such as in extreme body building).

[grapemaster]

www.imminst.org

lots of good information and forums, though I'm just a lurker.

most of the good stuff is expensive

I only mess with nootropics right now.

I know I'm not over 35 but saw this post, oh well.

The future looks promising though.

Piracetam is great, sometimes it makes me not as friendly though... not really in a bad way, I just don't bull**** around as much I guess and straight to the point.

[LR3]

there is plenty of information on the internet about these compounds as well as others that have proven track records. i started this thread for two reasons, first to see what others have used and what kind of results they've had. second, for bring a lot of these things to peoples attenion.

some of these kinds of things are not terribly expensive. i've seen them online as bulk powders (some US, some overseas). piracetam is available domestically for $20 for 700gm, aniracetam (a longer acting piracetam, more or less) and idebenone is available from the same place (oops, didn't realise that might be seen as posting a source--feel free to PM me about domestic source for some of these).

basically, hydergine and pyritinol act similar to gingko, but the pharmaceuticals are probably more effective (though i've never seen a side-by-side comparison to gingko).

deprenyl is harder to come by, at least cheaply. since idebenone also gets into the mitochondria and cleans up free-radicals, so it might be a less costly (and easier to obtain) substitute for deprenyl (though I suspect deprenyl is more benefitial and has years of studies to back its safety and effectiveness). i bought my l-selegiline (deprenyl) as a bulk pharmaceutical in the late 90's from a domestic company that is no longer in business--in that form it was pretty cheap (basically a lifetime supply for somewhere around $200). i have seen it offered as a bulk parmaceutical overseas. one thing to look-out for is that it is actually l-selegeline and not just selegiline (a mixture of both the d and the l isormers) as it is only the isolated l-isomer that has been thuroughly researched.

[Ironized]

Interesting. Never seen anyone mention hydergine before. Did you read Life Extension back in 1982 or something?

I did and have been messing around with anti-aging techniques since about then, 1982, when I was about 19.

Don't know if it's that or just genetics but I look pretty young esp considering all the beer I drank in the past.

Always tried to make sure to not have insulin in my blood when I went to bed.

Currently I've been using l-arginine, l-ornithine, l-lysine for the last 5 years or so. However, the technique conflicts with going to bed with cassein so now not sure how to proceed.

Since you were 19? Wow! most 19 year old I know are more interested in getting laid then growing old.

But hey! Why not try to stretch out our LUCKY years..

[LR3]

I would be interested to hear more about those LR3.

For me avoiding rancid fats and oils has been a big thing since I read Life Extension. I'm almost phobic about it and have barely eaten deep fried food since I read it.

I've also done about 800 I.U. of E every day for about 25 years. Vitamin E that is.

i avoid trans fats like the plague. i learned about them about 10 years ago from a talk by dr. weil.

i'd hope you haven't been doing E (ecstasy) every day for 25 years i've used beta carotene pretty regularly since i was in my late teens. i've always been into things that are good for me--i've tried just about everything from asprin, ginseng, bee-pollen, ginko to nootropics.

[BurritoMan]

Since you were 19? Wow! most 19 year old I know are more interested in getting laid then growing old.

But hey! Why not try to stretch out our LUCKY years..

Slight correction: at 19 I was interested in getting laid and NOT growing old. Mentally I'm still about 19, I still think farting is top humour. And I still feel pretty lucky so all in all it's all worked very well!

[BurritoMan]

i avoid trans fats like the plague. i learned about them about 10 years ago from a talk by dr. weil.

Personally I would much rather have trans fats than rancid unsaturated fats and oils. Rancid fats/oils are much more harmful, in my opinion, due to the amount of crosslinking they cause. I would also rather eat something fried in butter or lard than in rancid unsaturated fat.

i'd hope you haven't been doing E (ecstasy) every day for 25 years

No LOL although I did do a lot of LSD and shroomies in my 20s. MDMA is damaging.

i've used beta carotene pretty regularly since i was in my late teens. i've always been into things that are good for me--i've tried just about everything from asprin, ginseng, bee-pollen, ginko to nootropics.

I'm a big fan of beta carotene.

[LR3]

No LOL although I did do a lot of LSD and shroomies in my 20s. MDMA is damaging.

not too bad if you use deprenyl, it has been shown to prevent the damage from MDMA. do a google search, there are a few studies on its use as a neuroprotective agent.

[Lat-eralus]

i've been considering low dose hGH, which in life extension doses, doesn't have any negative side effects and improves lots of things, such as kidney function, healing/recovery time, and produces a general sense of well-being. basically the idea is to bring your hormone levels back to where they were when you were younger (aka, as in hormone replacement therapy)--not to hit levels that your body was never capable of producing (not high doses such as in extreme body building).

I have been looking into the same thing. I am currently on TRT for low test (237), but am also considering HGH.