[Ed.- Deprenyl is one of the mainstays and still one of the most important drugs used in Antiaging Medicine today. It has been shown to have a wide diversity of uses, including slowing and treating the prevalence of dementia (in particular Parkinson’s and Alzheimer’s Disease), and is also a potent anti-depressive, as well as a libido enhancing agent. Furthermore, it has significantly increased the life span of animals. How can one substance have such a wide diversity of effects? This article attempts to highlight the actions and issues surrounding deprenyl and detail some of its uses].

Deprenyl is a drug that was discovered around 1964 by Dr. Joseph Knoll and colleagues, and was originally developed as a “psychic energizer.” Also known as L-deprenyl and selegiline, it has been intensively researched over the past 40 years with many hundreds of research papers having been published. When reviewing them, it becomes apparent that deprenyl has a unique and exciting profile. It is the only potent, selective MAO-B inhibitor in medical use, plus it is a “catecholamine activity enhancer.”

In addition, deprenyl has been shown to protect nerve cells against a wide range of neurotoxins, and to act as a “neuroprotection agent” when nerve cells are exposed to damaging or stressful conditions.

Today, deprenyl is a recognised treatment for Parkinson’s disease, but it is also useful in treating depression. Furthermore, in aged animals, deprenyl has proven to be a highly effective “sexual rejuvenator” and also shows promise as a cognitive enhancement agent.

Deprenyl has been proven, in four different rodent studies, and one dog study, to be a remarkable life-extension agent.

Unique Activity

It was in 1971 when Dr. Knoll showed that deprenyl was a unique kind of MAO inhibitor– specifically a selective MAO-B inhibitor, without any “cheese effect.” Effectively by inhibiting this enzyme, deprenyl can increase the brain’s levels of dopamine, and while some authors have questioned deprenyl’s ability to increase dopamine levels by this method alone, it wasn’t until the 1990s that Dr. Knoll discovered the “main basis” of deprenyl’s action.

Jozeph Knoll, M.D., PharmD., is the Professor of Pharmacology at the University of Semmelweiss, in Hungary. His long career has seen him achieve numerous innovative medical and pharmaceutical breakthroughs, including the development of tests for pharmacological analysis of tranquillizers and psychostimulants. Plus his analysis of the physiological basis of drive-motivated behavior created new analgesic anti-inflammatory drug groups. In the 1960s he was a key-player in the development of deprenyl. His experiments have shown it to slow the age-related decline of sexual and learning performance and prolong life. He is also a recipient of the Monte Carlo Award for Excellence in Anti-Aging Medicine.

Attention, Depression, Life Span and the Catecholamines

During the 1990s Dr. Knoll uncovered a new mode of action of deprenyl that he believes explains its widespread clinical utility. He discovered that deprenyl (and its “cousin”- phenylethylamine) are “catecholamine activity enhancers.”

Catecholamines refer to the inter-related neurotransmitters of dopamine, noradrenaline and adrenaline. These transmitters activate key brain circuits helping to maintain focus, concentration, alertness and attention. Dopamine is also the transmitter for a brainstem circuit that connects the substantia nigra and the striatum, helping control bodily movement and which partially dies off and malfunctions with Parkinson’s disease.

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 Dr. Knoll and colleagues discovered through their highly technical experiments, is that deprenyl and phenylethylamine act more efficiently to couple the release of neurotransmitters.

Deprenyl causes a larger release of transmitters in response to a given electrical impulse. It’s like “turning up the volume” on catecholamine nerve cell activity. This may be clinically very useful in various contexts such as Parkinson’s and Alzheimer’s disease, where the nigrostriatal tract and neural circuits under-function. It can also be useful in depression, where there may be under-activity of both dopamine and noradrenalin neurons.

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

Therefore, Dr. Knoll believes that deprenyl’s positive catecholamine effect explains its antiaging benefit. In addition, his work indicates that phenylethylamine is also a catecholamine substance. Phenylethylamine is a trace amine made in the brain that modulates (enhances) the activity of dopamine and noradrenaline neurons. Autopsy studies have shown that while deprenyl increases dopamine levels in a Parkinson’s patient brain by 40% to 70%, deprenyl increases phenylethylamine levels by 1300% to 3500%. Phenylethylamine is the preferred substrate for MAO-B, the MAO that deprenyl inhibits. Paterson and colleagues have shown that phenylethylamine has an extremely rapid turnover due to its rapid and continuous breakdown by MAO-B. Thus deprenyl’s catecholamine activity has a dual mode of action. At low, non MAO-B inhibiting doses, deprenyl has direct catecholamine enhancing activity.

At higher, MAO-B inhibiting doses, deprenyl creates an additional catecholamine effect, due to the huge increases in brain phenylethylamine levels that deprenyl causes, (phenylethylamine also being a catecholamine substance). Many authors have pointed out the probable dopamine neuron activity enhancing effect of phenylethylamine in Parkinson’s patients taking deprenyl. Therefore, Dr. Knoll’s discovery of phenylethylamine’s catecholamine effect now explains this phenylethylamine/ dopamine-enhancing effect.

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. Some of these neurotoxins are noted below:

• MPTP is a contaminant in synthetic heroin, however compounds with a chemical structure similar to MPTP, include both natural and synthetic products, (e.g. paraquat), and are used in agriculture!

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

• DSP-4 is a synthetic noradrenaline nerve toxin. In rodents, deprenyl has been shown to prevent the depletion of noradrenaline that DSP-4 causes.

• AF64A is a cholinergic toxin- it damages brain cells that use acetylcholine, (the neurotransmitter primarily affected in Alzheimer’s disease). Deprenyl has been shown to protect cholinergic neurons from AF64A toxicity.

• Deprenyl has also protected human nerve cells from peroxynitrite and nitric oxide toxicity.

• Methyl-salsolinol is another MAO-B produced endogenous neurotoxin. Salsolinol is produced from the interaction of dopamine and acetaldehyde, (the first-stage breakdown product of alcohol). By inhibiting MAO-B, deprenyl reduces the toxic load on the brain that is routinely produced through the normal operation of MAO-B. MAO-B digests not just dopamine and phenylethylamine, but also tryptamine, tyramine and various other secondary and tertiary amines.

• The above are just some of the many reports in the scientific literature on deprenyl’s versatile neuroprotection.

Parkinson’s Disease

Parkinson’s disease is one of the two major neurodegenerative diseases of the modern world, (Alzheimer’s disease is the other). Parkinson’s affects approximately 1% of those over 70, a lesser percent of those 40 to 70, and rarely anyone below 40. 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.

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

However A. Barbeau, after analyzing results of 1052 Parkinson’s patients treated over 12 years, wrote of levodopa 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.”

Deprenyl became a standard therapy to treat Parkinson’s by the late 1970s. In 1985 Birkmayer, Knoll and colleagues published a paper summarizing the results of a 9-year study with levodopa alone, or combined with deprenyl in Parkinson’s patients. They found a typical 1 to 2 year life-extension over the average 10-years from levodopa onset until death in the combined levodopa/ 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 in the early stages of Parkinson’s.” 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 [deprenyl] is beneficial.” Thus, by the 1990s, deprenyl had become a standard Parkinson’s therapy, used either to delay levodopa use, or used in combination with it. However, in 1995, a report published in the British Medical Journal seriously questioned the use of deprenyl in combination with levodopa to treat Parkinson’s. This study stood alone as being detrimental, but since then, it has been recognised that this particular study was deeply flawed, and consequently it can virtually be ignored.

Alzheimer’s Disease

Alzheimer’s disease is the most widespread neurodenerative disease of modern times, affecting several million people in the U.S. alone. Alzheimer’s is characterized not only by severe memory loss, but also 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 addition to the reduction of acetylcholine, alterations have been observed in the activities of other neurotransmitters. In particular, cerebral depletion of dopamine can lead to memory and attention deficits, plus in Alzheimer’s there is significant increase in MAO-B.

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

Tolbert and Fuller reviewed 4 single-blind and 2 open label deprenyl trials in Alzheimer’s, as well as 11 double-blind deprenyl/Alzheimer’s studies. They noted that all 6 of the single-blind/open label studies reported positive results, while 8 of the 11 double-blind studies reported favorable results, typically utilizing 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 deprenyl was superior to all 3. Tolbert and Fuller were so impressed with deprenyl that they concluded; “...in our opinion, [deprenyl] 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, [deprenyl’s] efficacy has not been adequately assessed. However, given the lack of standard treatment, selegiline should be considered among the various treatment options.”

Depression

Deprenyl has been used experimentally as a treatment for depression since the late 1970s. While the causes of depression are diverse, it is by now accepted that dysfunction of dopamine and noradrenaline neural systems is a frequent biochemical cause of depression.

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

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

In 1978, Mendelwicz and Youdim treated 14 depressed patients with 5 mg deprenyl plus 300 mg 5-HTP three times daily for 32 days. Deprenyl potentiated the antidepressant effect of 5-HTP in 10 of the 14 patients. 5-HTP enhances brain serotonin metabolism, which is frequently a problem in depression, while deprenyl enhances the dopamine/ noradrenaline activity. Under-activity of brain dopamine, noradrenaline and serotonin neural systems are the most frequently cited biochemical causes of depression, 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. Approximately 70% of their patients given 5 mg to 10 mg of deprenyl plus 250 mg of phenylalanine daily, achieved full remission, typically within 1-3 weeks. Some patients were continued for up to 2 years on treatment without loss of antidepressant action. The combination of deprenyl plus phenylalanine enhances brain phenylethylamine activity, while both deprenyl and phenylethylamine enhance brain catecholamine activity. Thus, deprenyl plus phenylalanine is also a natural antidepressant combination.

In 1991 H. Sabelli reported successful results treating 6 out of 10 drug-resistant major depressive disorder patients. Sabelli used 5 mg of deprenyl daily, 100 mg of vitamin B6 daily, and 1-3 grams of phenylalanine twice daily as treatment. 6 out of 10 patients considered that 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 phenylethylamine, so the combination of low-dose deprenyl, B6, and phenylalanine is another biological way to enhance both phenylethylamine and catecholamine brain function, and thus diminish depression.

The Antiaging Drug

Four 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! Dr. Knoll reported that 132 Wistar-Logan rats were treated from the end of their second year of life with either placebo (saline injections) or 0.25 mg/kg deprenyl injected 3 times weekly.

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 treated group, the average lifespan was increased by 30% to 192 weeks, with the shortest-living rat dying at 171 weeks and the longest-lived rat reaching 226 weeks, (a 38% increase).

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

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

Ruehl and colleagues performed an experiment with beagle dogs and deprenyl, administered at 1 mg/kg orally per day, for up to 2 years and 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. Ruehl noted that; “dogs provide an excellent model of human aging.” So this study takes on an added significance.

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

This fact literally sets the human technical lifespan (maximum obtainable by a member of a species) at approximately 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 was healthy).

Based on the sum total of the animal deprenyl literature, and the 1985 study showing life extension in deprenyl-treated Parkinson’s patients, Dr. Knoll has suggested the following: If deprenyl were used from the age of 40 something onward, and even if it only modestly lowered the nigrostriatal neuron death rate, i.e. from 13% to 10% per decade, then the average human lifespan might increase by 15 years, and the human technical lifespan would increase to roughly 145 years.

After 45 years of research, Dr. Knoll has concluded that; “the regulation of lifespan must be located in the brain.” 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.” Dr. Knoll’s research has shown that catecholaminergic nerve activity reaches a maximum at sexual maturity, and then begins a long, gradual downhill slide thereafter. His animal research has shown catecholaminergic activity, learning ability, sexual activity and longevity to be inextricably linked.

Dr. Knoll argues that the quality and duration of life is a function of the inborn efficiency of the catecholaminergic brain machinery. In other words, a high performing, longer living individual has a more active, more slowly deteriorating catecholaminergic system than their low performing, shorter living peer.” 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.”

Dosage and Side Effects

Both Dr. Jozeph Knoll and the Life Extension Foundation recommend a 10 mg to 15 mg weekly (i.e. 1.5 mg to 2 mg a day) oral deprenyl dosage for humans, starting around age 40, possibly even in the 30s. 10 mg a 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. It is also noted that at 10mg plus a day, MAO-A inhibition is also noted. Some deprenyl experts believe this dosage is excessive, and that with long term deprenyl use, lower doses may still be effective and safer, particularly when combined with occasional breaks.

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

Deprenyl is reported in most human studies to be well tolerated. Typically, no abnormalities are noted in blood pressure, laboratory values, ECG or EEG. The most common side effects reported for deprenyl are gastrointestinal symptoms, nausea, heartburn, upset stomach, etc. Some studies have found side effects such as irritability, hyper-excitability, psychomotor agitation and insomnia. These effects are probably due to deprenyl’s catecholamine-enhancing effect, over-activating the dopamine/noradrenaline neural systems at the expense of the calming/sleep-inducing serotonergic systems. Thus, taking magnesium and L-Tryptophan (or 5-HTP) may suffice to counter these “psychic” effects.

Dr. Knoll consistently, throughout his deprenyl papers, recommends the use of 10 mg to 15 mg of oral deprenyl per week, starting in the 40s. Dr. 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 is undoubtedly an important antiaging drug. Plus, it is safe and effective, well validated (theoretically and experimentally), inexpensive (especially given the need for very low dosages) and what’s more, it’s available now.

Adapted from; “deprenyl- extending life span” by James South, MA. To read the original complete article along with all clinical references, please go to:
http://www.antiaging-systems.com/extract/depren.htm