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 Parkinsons 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 Knolls 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 doesnt 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 its 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 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 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 brains 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 Knolls 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 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 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. Its like turning up the volume
on catecholamine nerve cell activity. And this may be clinically very useful
in various contexts - such as Parkinsons disease and Alzheimers 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)
Knolls 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.
Knolls 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)
Knolls discovery of PEAs 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) Knolls 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 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 deprenyl
may be just what the doctor ordered to retard this debilitating downhill
neural slide.
DSP-4 is a synthetic noradrenalin nerve toxin. In rodents deprenyl has
been shown to prevent the depletion of noradrenalin in noradrenalin-using
neurons and noradrenalin-nerve degeneration that DSP-4 causes. (4)
AF64A is a cholinergic toxin - it damages brain cells that use acetylcholine.
Deprenyl pre-treatment has been shown to protect cholinergic neurons
from AF64A toxicity. (4)
Deprenyl has also protected human nerve cells from peroxynitrite and nitric
oxide toxicity. Peroxynitrite is formed naturally in the brain when nitric
oxide reacts with superoxide radical. Peroxynitrite causes apoptosis, a
programmed suicide cell death that can be triggered in neurons by
various agents. deprenyl was found to inhibit peroxynitrite-caused
apoptosis, even after the deprenyl was washed from deprenyl pre-treated
cells. (3)
Methyl-salsolinol is another MAO-B produced endogenous neurotoxin.
Salsolinol is a tetra-hydroisoquinoline produced from the interaction of
dopamine and acetaldehyde, the first-stage breakdown product of alcohol.
Once formed, salsolinol can then be further modified by MAO-B to
generate methyl-salsolinol. deprenyl's MAO-B inhibiting activity can
prevent the DNA damage caused by this toxin. (3, 4)
By inhibiting MAO-B, deprenyl reduces the toxic load on the brain that is
routinely produced through the normal operation of MAO-B. MAO-B digests
not just dopamine and PEA, but also tryptamine, tyramine and various
other secondary and tertiary amines. (15)
As noted earlier, PEA is the substance MAO-B is most efficient at
digesting, so that the half-life of PEA is estimated at only 0.4 minutes. (21)
This continuous high level breakdown of PEA (and other amines) produces
aldehydes, hydrogen peroxide and ammonia as automatic MAO-B reaction
products, and they are all toxins. (4) Thus by reducing age-elevated
MAO-B activity, deprenyl reduces the toxin burden on
dopamine/noradrenalin neurons (where PEA is primarily produced).
...L-deprenyl provides neuroprotection against growth factor withdrawal in
PC12 cells, oxidative stress in mesencepahalic neurons, and the genotoxic
compound, Ara C, in cerebellar granule neurons, and against
axotomy-induced motoneuronal degeneration and delayed neuronal death
in hippocampus after global ischaemia. (24) And these are just some of the
many reports in the scientific literature on deprenyl's versatile
neuroprotection.
DEPRENYL: PARKINSONS DISEASE
Parkinsons disease is one of the two major neurodegenerative diseases of
the modern world - Alzheimers disease is the other. Parkinsons affects up
to 1% of those over 70, a lesser percent of those 40-70, and rarely anyone
below 40. (23) Parkinsons 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 Parkinsons
symptoms: shuffling gait, stooped posture, difficulty initiating movement,
freezing in mid-movement, and the shaking palsy. By the late 1960s the
standard treatment for Parkinsons was the amino-acid precursor of
dopamine, L-dopa. The L-dopa increased the dopamine levels in the few
remaining nigrostriatal neurons in Parkinsons 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 Parkinsons
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 Parkinsons 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 deprenyl in Parkinsons. (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 Parkinsons. (26) In a
1992 paper Lieberman cited 17 studies supporting the claim that ... with
levodopa-treated patients with moderate or advanced Parkinsons... the
addition of selegiline [deprenyl] is beneficial. (6) Thus by the 1980s-1990s
deprenyl had become a standard Parkinsons 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 Parkinsons. (27)
The UK-Parkinsons Research Group study followed 520 Parkinsons
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 Parkinsons
treatment. Yet the UK-Parkinsons study is the only one ever to find
increased mortality with deprenyl use in Parkinsons, and the study has
been severely criticized on multiple grounds by various Parkinsons
experts. In response to the study, the British Medical Journal published 8
letters in 1996 criticizing the study on various methodological and statistical
grounds. (2
And a 1996 Annals of Neurology article by 4 Parkinsons
experts provided an exhaustive analysis of the British Medical Journal
study, raising many questions and criticisms. (29) One key criticism is that
the UK-Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons patients based solely on the results of the UK study. (29)
DEPRENYL: ALZHEIMER'S DISEASE
Alzheimers disease is the most widespread neurodenerative disease of
modern times, affecting several million people in the U.S. alone.
Alzheimers is characterized not only by severe memory loss, but by verbal
dysfunction, learning disability and behavioral difficulties - even
hallucinations. Alzheimers is known to involve damage to the cholinergic
neurons of the hippocampus, but In [Alzheimers], 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 [Alzheimers] 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
Alzheimers. And indeed that is the conclusion of a 1996 review paper on
Alzheimers and deprenyl.
Tolbert and Fuller reviewed 4 single-blind and 2 open label deprenyl trials
in Alzheimers, as well as 11 double-blind deprenyl/Alzheimers 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,
selegilines efficacy has not been adequately assessed; however, given
the lack of standard treatment, selegiline should be considered among the
various treatment options. (7)
DEPRENYL: DEPRESSION
Deprenyl has been used experimentally as a treatment for depression
since the late 1970s. While the causes of depression are diverse and still
under investigation, it is by now accepted that dysfunction of dopamine
and noradrenalin neural systems is a frequent biochemical cause of
depression. (18,19)
In addition the research of A. Sabelli and colleagues has established that a
brain PEA deficiency also seems to be strongly implicated in many cases
of depression. (32) Given that deprenyl is a catecholamine (dopamine and
noradrenalin) activity enhancer, and that deprenyl strongly increases brain
PEA through MAO-B inhibition, deprenyl would seem a rational treatment
for depression.
Studies with atypical depressives (33), treatment-resistant depressives (34),
and major depressives (35) have shown deprenyl to be an effective, low
side-effect depression treatment. However, such studies have often
required deprenyl dosages in the 20-30, even 60 mg range. While these
dosages caused little problem in short-term studies, it is dubious to
consider using such high, non-selective MAO-B inhibition doses for long
term (months - years) treatment. Three studies have shown
antidepressant promise at selective, MAO-B inhibiting doses.
In 1978 Mendelwicz and Youdim treated 14 depressed patients with 5 mg
deprenyl plus 300 mg 5-HTP 3 times daily for 32 days. (1) Deprenyl
potentiated the antidepressant effect of 5-HTP in 10/14 patients. 5-HTP
enhances brain serotonin metabolism, which is frequently a problem in
depression (37), while deprenyl enhances dopamine/noradrenalin activity.
Under-activity of brain dopamine, noradrenalin and serotonin neural
systems are the most frequently cited biochemical causes of depression
(18,19,37), so deprenyl plus 5-HTP would seem a natural antidepressant
combination.
In 1984 Birkmayer, Knoll and colleagues published their successful results
in 155 unipolar depressed patients who were extremely
treatment-resistant. ( 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)
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 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
Parkinsons 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 huma
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 Parkinsons 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 Knolls 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 doesnt 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 its 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 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 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 brains 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 Knolls 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 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 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. Its like turning up the volume
on catecholamine nerve cell activity. And this may be clinically very useful
in various contexts - such as Parkinsons disease and Alzheimers 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)
Knolls 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.
Knolls 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)
Knolls discovery of PEAs 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) Knolls 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 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 deprenyl
may be just what the doctor ordered to retard this debilitating downhill
neural slide.
DSP-4 is a synthetic noradrenalin nerve toxin. In rodents deprenyl has
been shown to prevent the depletion of noradrenalin in noradrenalin-using
neurons and noradrenalin-nerve degeneration that DSP-4 causes. (4)
AF64A is a cholinergic toxin - it damages brain cells that use acetylcholine.
Deprenyl pre-treatment has been shown to protect cholinergic neurons
from AF64A toxicity. (4)
Deprenyl has also protected human nerve cells from peroxynitrite and nitric
oxide toxicity. Peroxynitrite is formed naturally in the brain when nitric
oxide reacts with superoxide radical. Peroxynitrite causes apoptosis, a
programmed suicide cell death that can be triggered in neurons by
various agents. deprenyl was found to inhibit peroxynitrite-caused
apoptosis, even after the deprenyl was washed from deprenyl pre-treated
cells. (3)
Methyl-salsolinol is another MAO-B produced endogenous neurotoxin.
Salsolinol is a tetra-hydroisoquinoline produced from the interaction of
dopamine and acetaldehyde, the first-stage breakdown product of alcohol.
Once formed, salsolinol can then be further modified by MAO-B to
generate methyl-salsolinol. deprenyl's MAO-B inhibiting activity can
prevent the DNA damage caused by this toxin. (3, 4)
By inhibiting MAO-B, deprenyl reduces the toxic load on the brain that is
routinely produced through the normal operation of MAO-B. MAO-B digests
not just dopamine and PEA, but also tryptamine, tyramine and various
other secondary and tertiary amines. (15)
As noted earlier, PEA is the substance MAO-B is most efficient at
digesting, so that the half-life of PEA is estimated at only 0.4 minutes. (21)
This continuous high level breakdown of PEA (and other amines) produces
aldehydes, hydrogen peroxide and ammonia as automatic MAO-B reaction
products, and they are all toxins. (4) Thus by reducing age-elevated
MAO-B activity, deprenyl reduces the toxin burden on
dopamine/noradrenalin neurons (where PEA is primarily produced).
...L-deprenyl provides neuroprotection against growth factor withdrawal in
PC12 cells, oxidative stress in mesencepahalic neurons, and the genotoxic
compound, Ara C, in cerebellar granule neurons, and against
axotomy-induced motoneuronal degeneration and delayed neuronal death
in hippocampus after global ischaemia. (24) And these are just some of the
many reports in the scientific literature on deprenyl's versatile
neuroprotection.
DEPRENYL: PARKINSONS DISEASE
Parkinsons disease is one of the two major neurodegenerative diseases of
the modern world - Alzheimers disease is the other. Parkinsons affects up
to 1% of those over 70, a lesser percent of those 40-70, and rarely anyone
below 40. (23) Parkinsons 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 Parkinsons
symptoms: shuffling gait, stooped posture, difficulty initiating movement,
freezing in mid-movement, and the shaking palsy. By the late 1960s the
standard treatment for Parkinsons was the amino-acid precursor of
dopamine, L-dopa. The L-dopa increased the dopamine levels in the few
remaining nigrostriatal neurons in Parkinsons 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 Parkinsons
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 Parkinsons 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 deprenyl in Parkinsons. (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 Parkinsons. (26) In a
1992 paper Lieberman cited 17 studies supporting the claim that ... with
levodopa-treated patients with moderate or advanced Parkinsons... the
addition of selegiline [deprenyl] is beneficial. (6) Thus by the 1980s-1990s
deprenyl had become a standard Parkinsons 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 Parkinsons. (27)
The UK-Parkinsons Research Group study followed 520 Parkinsons
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 Parkinsons
treatment. Yet the UK-Parkinsons study is the only one ever to find
increased mortality with deprenyl use in Parkinsons, and the study has
been severely criticized on multiple grounds by various Parkinsons
experts. In response to the study, the British Medical Journal published 8
letters in 1996 criticizing the study on various methodological and statistical
grounds. (2
And a 1996 Annals of Neurology article by 4 Parkinsonsexperts provided an exhaustive analysis of the British Medical Journal
study, raising many questions and criticisms. (29) One key criticism is that
the UK-Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons patients based solely on the results of the UK study. (29)
DEPRENYL: ALZHEIMER'S DISEASE
Alzheimers disease is the most widespread neurodenerative disease of
modern times, affecting several million people in the U.S. alone.
Alzheimers is characterized not only by severe memory loss, but by verbal
dysfunction, learning disability and behavioral difficulties - even
hallucinations. Alzheimers is known to involve damage to the cholinergic
neurons of the hippocampus, but In [Alzheimers], 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 [Alzheimers] 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
Alzheimers. And indeed that is the conclusion of a 1996 review paper on
Alzheimers and deprenyl.
Tolbert and Fuller reviewed 4 single-blind and 2 open label deprenyl trials
in Alzheimers, as well as 11 double-blind deprenyl/Alzheimers 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,
selegilines efficacy has not been adequately assessed; however, given
the lack of standard treatment, selegiline should be considered among the
various treatment options. (7)
DEPRENYL: DEPRESSION
Deprenyl has been used experimentally as a treatment for depression
since the late 1970s. While the causes of depression are diverse and still
under investigation, it is by now accepted that dysfunction of dopamine
and noradrenalin neural systems is a frequent biochemical cause of
depression. (18,19)
In addition the research of A. Sabelli and colleagues has established that a
brain PEA deficiency also seems to be strongly implicated in many cases
of depression. (32) Given that deprenyl is a catecholamine (dopamine and
noradrenalin) activity enhancer, and that deprenyl strongly increases brain
PEA through MAO-B inhibition, deprenyl would seem a rational treatment
for depression.
Studies with atypical depressives (33), treatment-resistant depressives (34),
and major depressives (35) have shown deprenyl to be an effective, low
side-effect depression treatment. However, such studies have often
required deprenyl dosages in the 20-30, even 60 mg range. While these
dosages caused little problem in short-term studies, it is dubious to
consider using such high, non-selective MAO-B inhibition doses for long
term (months - years) treatment. Three studies have shown
antidepressant promise at selective, MAO-B inhibiting doses.
In 1978 Mendelwicz and Youdim treated 14 depressed patients with 5 mg
deprenyl plus 300 mg 5-HTP 3 times daily for 32 days. (1) Deprenyl
potentiated the antidepressant effect of 5-HTP in 10/14 patients. 5-HTP
enhances brain serotonin metabolism, which is frequently a problem in
depression (37), while deprenyl enhances dopamine/noradrenalin activity.
Under-activity of brain dopamine, noradrenalin and serotonin neural
systems are the most frequently cited biochemical causes of depression
(18,19,37), so deprenyl plus 5-HTP would seem a natural antidepressant
combination.
In 1984 Birkmayer, Knoll and colleagues published their successful results
in 155 unipolar depressed patients who were extremely
treatment-resistant. (
Patients were given 5-10 mg deprenyl plus 250 mgphenylalanine 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)
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 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
Parkinsons 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 huma
