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 (DPR) has been intensively researched over the past 36 years – many hundreds of research papers on DPR have been published. Knoll has stated that DPR …is an exceptionally lucky modification of PEA [phenylethylamine], an endogenous … member of the family to which also the transmitters noradrenaline and dopamine belong. (13) [See diagram.] DPR has shown a unique and exciting pharmacologic/clinical profile. It is the only potent, selective MAO-B inhibitor in medical use. (1) DPR is a catecholamine activity enhancer. (2) DPR has been shown to protect nerve cells against a wide (and growing) number of neurotoxins. (3,4) DPR has also been shown to be a neuroprotection/ neurorescue agent when nerve cells are exposed to damaging or stressful conditions. (5)
DPR has become a standard treatment for Parkinsons disease. (6) DPR is also useful in treating drug-resistant depression. (8,9) In aged rats, DPR has proven to be a highly effective sexual rejuvenator. (10) DPR also shows promise as a cognitive enhancement agent. (10) DPR has also proven in four different rat studies and one dog study to be an effective life-extension agent, even increasing the technical life span in Knolls rat experiments. (11,12) and these are just some of DPRs reported benefits.
DEPRENYL: MAO-B INHIBITOR EXTRAORDINAIRE
By 1971 Knoll had shown that DPR 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 (MA) 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 MA transmitters. (1) In the 1950s the first antidepressant drugs to be developed were MAO inhibitors (MAOI). By the 1960s however, MAOIs began to drop out of medical use due to a dangerous side-effect – the so-called cheese effect. When most MOIs 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 MAOIs 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. DPR is unique among clinically used MAO-Is. At normally used clinical dosages (10-15 mg/day), DPR is a selective MAO-B inhibitor, so it doesnt prevent intestinal MAO-A from digesting dietary tyramine.(1) In addition, DPR has the unique ability to prevent tyramine from getting into noradrenalin-using nerve calls, and its only when tyramine enters noradrenalin nerve cells that control arterial blood pressure that it triggers the cheese effect. (1) DPR thus has a dual safety lock in preventing the cheese effect, making it far safer than other MAOIs. At doses over 20-30 mg/day, however, DPR 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 (NA), and to a lesser extent dopamine (DA). MAO-B breaks down DA and the traceamine phenylethylamine (PEA). At doses of 5-10 mg per day DPR will inhibit MAO-B about 90%. (1) It was initially presumed that DPR would increase synaptic levels of DA in DA-using neurons, and this lead to its use to treat Parkinsons disease in the late 1970s, Alzheimers disease in the 1980s-90s, and depression starting in the late 1970s. In his 1983 paper on the history of DPRs clinical benefits to its unique MAO-B effects. (1)
Yet many experts have questioned whether DPRs MAO-B inhibition can significantly increase synaptic DA 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 brains billions of neurons. (1) And whether there is any exchange of DA between these glial cells and the DA-using neurons is still an unanswered question. It is commonly believed that it is MAO-A in DA neurons that breaks DA down. By the 1990s Knoll believed he had discovered the real basis of DPRs being a MAO-B inhibitor. (2)
Yet as will be made clear shortly, even if DPRs originally hypothesized mode of action – directly increasing synaptic DA levels through MAO-B inhibition – is false, DPRs MAO-B inhibition still provides part of its benefit.
DEPRENYL: CATECHOLAMINE ACTIVITY ENHANCER
During the 1990s Knolls DPR 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 DPR that he believes explains its widespread clinical utility. (2,16) Knoll discovered that DPR (and its cousin, PEA) are catecholamine activity enhancers (CAE). (Ed. – Dr. Knoll explains this on his 2000 Monte Carlo Antiaging Conference ™ Audio Cassette).
Catecholamines (CA) refers to the inter-related neurotransmitters dopamine (DA), noradrenalin (NA) and adrenalin. CAs are the transmitters for key activating brain circuits – the mesolimbic-cortical circuit (MLC) and the locus coeruleus (LC). The neurons of the MLC and LC project from the brain stem, through the mid-brain, to the cerebral cortex. They help to maintain focus, concentration, alertness and effortful attention. (17) DA 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 Parkinsons 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 DPR and PEA act to more efficiently couple the release of neurotransmitters to the electrical impulse that triggers their release. (2,16)
In other words, DPR (and PEA) cause a larger release of transmitters in response to a given electrical impulse. Its like turning up the volume on CA nerve cell activity. And this may be clinically very useful in various contexts – such as Parkinsons disease and Alzheimers disease, where the nigrostriatal tract (PD) and MLC circuits (AD) under-function (1,17), as well as in depression, where they may be under-activity of both DA and NA neurons. (18,19)
Knolls research also indicates that after sexual maturity the activity of the CA 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 DPRs CAE effect explains its anti-aging benefit. (10,20) Knoll also believes that DPRs CAE activity is independent of its MAO-B inhibition effect, because in rats he has shown CAE effect at doses considerably lower than that needed to achieve MAO-B inhibition.
Knolls work indicates that PEA is also a CAE substance. (16) PEA is a trace amine made in the brain that modulates (enhances) the activity of DA/NA neurons. (16,21) Autopsy studies have shown that while DPR increases DA levels in Parkinson patient brains by only 40-70%, DPR increases PEA levels 1300 – 3500%! (14,22) PEA is the preferred substrate for MAO-B, the MAO that DPR 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 DPRs CAE activity has a dual mode of action. At low, non-MAO-B inhibiting doses, DPR has a direct CAE activity.
At higher, MAO-B inhibiting doses, DPR creates an additional CAE effect, due to the huge increases in brain PEA levels that DPR causes, PEA also being a CAE substance. Many authors have pointed out the probable DA neuron activity enhancing effect of PEA in Parkinson patients taking DPR. (14, 15, 22)
Knolls discovery of PEAs CAE effect now explains this PEA DA-enhancing effect.
DEPRENYL: THE NEUROPROTECTOR
DPR 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 DA-using neurons.(15) The MAO-B inhibiting dose of DPR (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 DA in DA-using neurons. (11,13) 6-OHDA may then further auto-oxidize to generate toxic superoxide and hydroxyl free radicals and hydrogen peroxide. (11,13) Knolls research has shown that pre-treatment of striatal DA-neurons with DPR can completely protect them from 6-OHDA toxicity. (4,11,13) Even in those not suffering from Parkinsons 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 DPR may be just what the doctor ordered to retard this debilitating downhill neural slide.
DSP-4 is a synthetic NA-nerve toxin. In rodents DPR has been shown to prevent the depletion of NA in NA-using neurons and NA-nerve degeneration that DSP-4 causes. (4) AF64A is a cholinergic toxin – it damages brain cells that use acetylcholine. DPR pre-treatment has been shown to protect cholinergic neurons from AF64A toxicity. (4)
DPR 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. DPR was found to inhibit peroxynitrite-caused apoptosis, even after the DPR was washed from DPR pre-treated cells. (3)
Methyl-salsolinol is another MAO-B produced endogenous neurotoxin. Salsolinol is a tetra-hydroisoquinoline produced from the interaction of DA and acetaldehyde, the first-stage breakdown product of alcohol.
Once formed, salsolinol can then be further modified by MAO-B to generate methyl-salsolinol. DPRs MAO-B inhibiting activity can prevent the DNA damage caused by this toxin. (3,4)
By inhibiting MAO-B, DPR reduces the toxic load on the brain that is routinely produced through the normal operation of MAO-B. MAO-B digests not just DA 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, DPR reduces the toxin burden on DA/NA 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 DPRs versatile neuroprotection.
DEPRENYL: PARKINSONS DISEASE
Parkinsons disease (PD) is one of the two major neurodegenerative diseases of the modern world – Alzheimers disease is the other. PD affects up to 1% of those over 70, a lesser percent of those 40-70, and rarely anyone below 40. (23) PD is caused by a severe loss of DA-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 PD symptoms: shuffling gait, stooped posture, difficulty initiating movement, freezing in mid-movement, and the shaking palsy. By the late 1960s the standard treatment for PD was the amino-acid precursor of DA, L-dopa. The L-dopa increased the DA levels in the few remaining nigrostriatal neurons in PD patients (80% of brain DA 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 PD 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)
DPR became a standard therapy to treat PD by the late 1970s. 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 DPR in PD. (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/DPR 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 PD. (26) In a 1992 paper Lieberman cited 17 studies supporting the claim that … with levodopa-treated patients with moderate or advanced PD… the addition of selegiline [DPR] is beneficial. (6) Thus by the 1980s-1990s DPR had become a standard PD 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 DPR in combination with L-dopa to treat PD. (27)
The UK-PD Research Group study followed 520 PD 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 DPR daily. After 5-6 years, the mortality rate in the L-Dopa/DPR group was almost 60% higher than in the L-dopa only group. The study authors therefore recommended DPR not be used in PD treatment. Yet the UK-PD study is the only one ever to find increased mortality with DPR use in PD, and the study has been severely criticized on multiple grounds by various PD experts. In response to the study, the BMJ published 8 letters in 1996 criticizing the study on various methodological and statistical grounds. (28) And a 1996 Annals of Neurology article by 4 PD experts provided an exhaustive analysis of the BMJ study, raising many questions and criticisms. (29) One key criticism is that the UK-PD 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/DPR 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 DPR/L-Dopa groups.
Another criticism levelled against the UK study is based on the dosage of L-dopa. It is generally accepted that DPR reduces L-dopa need by about 40%. (14) Thus, to achieve bio-equivalent L-dopa doses, the DPR/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 DPR/L-Dopa group, after 4-5 years the median L-dopa dose remained at 375 mg in the DPR 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 PD 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 PD patients. (30) Thus if there were any real increased mortality in the DPR/L-Dopa group in the UK study, it is more likely due to L-dopa toxicity than DPR. This is further borne out by a 1991 study by Rinne and colleagues, who studied 25 autopsied PD brains. (31) When they compared the substantia nigra of 10 patients who had received L-dopa plus DPR with 15 patients who had received L-dopa only, they discovered that there were significantly more nigral neurons remaining in the DPR/L-Dopa brains, i.e. the DPR 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 [DPR] in levodopa-treated patients, because of fears of early mortality, is not persuasive. Accordingly, we do not recommend that selegiline be withheld in PD patients based solely on the results of the UK study. (29)
DEPRENYL: ALZHEIMERS DISEASE
Alzheimers disease (AD) is the most widespread neurodenerative disease of modern times, affecting several million people in the U.S. alone. AD is characterized not only by severe memory loss, but by verbal dysfunction, learning disability and behavioral difficulties – even hallucinations. AD is known to involve damage to the cholinergic neurons of the hippocampus, but In [AD], in addition to the reduction of acetylcholine, alterations have been observed in the activities of other neurotransmitters. More specifically, the deterioration of the dopaminergic [DA] and noradrenergic [NA] systems… seems particularly relevant to the cognitive manifestations…. cerebral depletion of dopamine (DA) can easily lead to memory and attention deficits. In [AD] 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, DPR would seem tailor-made to treat AD. And indeed that is the conclusion of a 1996 review paper on AD and DPR.
Tolbert and Fuller reviewed 4 single-blind and 2 open label DPR trials in AD, as well as 11 double-blind DPR/AD 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 DPR/day dosage. In 3 of the single-blind studies DPR was compared to 3 nootropics – oxiracetam, phosphatidylserine and acetyl-l-carnitine – and was superior to all 3. Tolbert and Fuller were so impressed with DPR 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, selegilines efficacy has not been adequately assessed; however, given the lack of standard treatment, selegiline should be considered among the various treatment options. (7)
DPR 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 DA and NA 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 DPR is a catecholamine (DA and NA) activity enhancer, and that DPR strongly increases brain PEA through MAO-B inhibition, DPR would seem a rational treatment for depression.
Studies with atypical depressives (33), treatment-resistant depressives (34), and major depressives (35) have shown DPR to be an effective, low side-effect depression treatment. However, such studies have often required DPR 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 DPR plus 300 mg 5-HTP 3 times daily for 32 days. (1) DPR 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 DPR enhances DA/NA activity. Under-activity of brain DA, NA and serotonin neural systems are the most frequently cited biochemical causes of depression (18,19,37), so DPR 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 DPR 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 DPR plus phenylalanine enhances brain PEA activity, while both DPR and PEA enhance brain catecholamine activity. Thus DPR 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 DPR 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 DPR, 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 DPR can extend life span significantly, even beyond the technical life span 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 DPR injection 3 times weekly until death. (11)
In the saline-treated group the oldest rat reached 164 weeks of age, and the average life span of the group was 147 weeks. In the DPR group, the average life span 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 DPR 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 DPR-treated LP rats averaged 153 weeks of life. The saline treated HP rats lived an average 151 weeks of life, while the DPR -treated HP rats averaged 185 weeks of life, with 17/50 HP-DPR rats exceeding their estimated technical life span of 182 weeks. (20)
Knolls experiments were partially replicated by Milgram and co-workers and Kitani and colleagues. (11) Milgrams group used shorter-living Fischer 344 rats, while still starting DPR treatment at 2 years of age – in effect later in their lives – and found a marginally significant 16% life span extension. The Kitani group, also using the shorter-lived Fischer rats, started their DPR treatment at 1.5 years of age, and found a 34% life increase.(11)
Ruehl and colleagues performed an experiment with beagle dogs and DPR, 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 DPR-treated dogs survived to the conclusion of the study, while only 7 of 18 placebo-treated dogs survived. By the time the first DPR-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 DA-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 life span (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 DPR literature, as well as the 1985 study showing life-extension in DPR-treated PD patients (25) Knoll has suggested that if DPR 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 life span might increase 15 years, and the human technical life span would increase to roughly 145 years. (23)
After 45 years of research, Knoll has concluded that …the regulation of life span 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 centres in a continually active state, the intensity of which is dynamically changed within broad limits according to need. (20) Knolls research has shown that catecholaminergic nerve activity reaches a maximum at sexual maturity, and then begins a long, gradual downhill slide thereafter. Knolls 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 DPR papers (11,20,23), recommends the use of 10 – 15 mg oral DPR/week, starting in the 40s, to help achieve this goal in humans. Knolls research clearly convinces him that DPR is both a safe and effective preserver of the nigrostriatal tract, as well as a catecholamine activity enhancer. DPR may not be the ultimate anti-aging drug, but it is one that is safe and effective, well validated theoretically and experimentally, and its 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 DPR dosage for humans, starting around age 40, possibly even in the 30s. 10 mg/day is a relatively standard DPR dose for treatment of PD and AD, but this higher dose should only be used with medical supervision. Some DPR experts believe this dosage is excessive, and that with long term DPR use lower doses may still be effective and safer. (22)
Knoll has noted that the human MAO-B inhibiting DPR dose ranges from 0.05 to 0.20 mg/kg of body weight. (1) Thus, even in those wishing to use DPR at an effective MAO-B inhibiting dose, it should not be necessary to use more than 3-5 mg/day. Because DPR 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 DPR dose may achieve MAO-B inhibition with long term use.
DPR 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 DPR 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 DPRs catecholamine-enhancing effect, over-activating DA/NA 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.
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. Maroyama, 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.
5. Lieberman, A. (1992) Long-term experience with selegeline and levodopa in Parkinsons 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 depresion with selegeline-phenylalamine 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 (-)-depreny