Deprenyl - extending
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)
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.
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
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
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)
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)
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)
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
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.
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.
discovered that deprenyl (and its “cousin”, PEA) are “catecholamine
refers to the inter-related neurotransmitters dopamine, noradrenalin, and
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
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)
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
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
research also indicates that after sexual maturity the activity of the catecholamine
gradually declines, and that the rate of decline determines the rate at which a
person or animal ages. (10,20)
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.
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
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)
discovery of PEA’s catecholamine activity enhancer effect now explains this
PEA dopamine-enhancing effect.
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.
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
(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.
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)
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)
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)
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.
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)
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
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)
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).
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.
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)
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.
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)
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)
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
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)
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.”
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
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.”
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.
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.
with atypical depressives (33), treatment-resistant depressives (34), and major
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.
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.
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.
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
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)
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.
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)
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)
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.
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.
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)
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)
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.”
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)
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.
DOSAGE & SIDE-EFFECTS
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)
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)
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
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