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.
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.
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.
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)
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.
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.
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.
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|REFERENCES www.deprenyl.net1. 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.
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