Deprenyl:
The Anti-Aging Smart Drug

Deprenyl (trade names Eldepryl, Jumex) was developed by Professor J�zsef Knoll, of Semmelweis University in Hungary. It has been extensively researched since the 1950s and has been used by millions as a treatment for Parkinson's disease. Recently, deprenyl has been recognized as one of the most promising (and safe) drugs for treating Alzheimer's disease. Deprenyl is also one of the first drugs proven to extend maximum lifespan in animals, and it has been found to act as a cognition-enhancer in normal, healthy animals. As a bonus, deprenyl also acts as an aphrodisiac in male animals and some men. Because it corrects so many of the typical problems associated with aging we can justifiably call it an anti-aging drug.

Sex Enhancement

We have received a steady stream of reports from men (usually over age 50) who note increased libido after taking deprenyl. This is not surprising, considering the number of animal studies that have consistently shown dramatic increases in the sexual activity of old male rats (see the graph on page 37 [Knoll, et., 1983]). As far as we know, there have been no studies of deprenyl's aphrodisiac effects on normal, healthy humans, although our anecdotal reports would seem to indicate that human experimental results would parallel those of animal studies.

Life Extension Effects of Deprenyl

The oldest living humans live to about 110-120 years. This is the maximum lifespan for humans under normal conditions. However, the average human lives to be only about 70 or 80.

The maximum lifespan in rats is about 140 weeks (approximately three years), but the average life expectancy is, of course, considerably less than that. To extend the average lifespan means to increase the number of rats living to be older than the average. Many substances have been shown to extend the average lifespan of laboratory animals (for example, vitamin E and BHT). Some scientists think these substances may also increase the odds of humans reaching closer to the maximum lifespan of 110-120 years. Deprenyl, on the other hand, has been shown to extend maximum lifespan in rats by about 40%! This would be like a human living to 150 years of age! And if the animal research holds true for humans, a hundred-year-old would look and feel 60.

The graph above illustrates a normal survival curve and how that curve changes with life-extension techniques that increase average lifespans. As the average lifespan is increased, death is postponed to later ages and the survival curve (white arrows) becomes progressively squarer, approaching the dashed-line maximum. With average-lifespan increases, the maximum lifespan is not increased, but a greater percentage of the population approaches the maximum age.

The bottom graph (facing page) illustrates the effect of a generalized slowing of the aging process itself, where both average and maximum lifespan are increased. Deprenyl has extended both average and maximum lifespan in animal studies.

The figure below depicts the dramatic lifespan increase in old rats treated with deprenyl, compared to placebo-treated controls. Note that all of the control animals had died well before the first of the deprenyl-treated rats had died. Data from three groups of rats are displayed. The broken line represents the rats no longer exhibiting any sexual activity, the thin line represents the rats still exhibiting some sexual activity, and the bold line represents rats still able to sexually function (although not necessarily well). The higher sexed rats generally lived longer, in both the deprenyl and control groups.

Some conservative people will want to wait until deprenyl's life-extending effects are proven on humans before they take it themselves. If such studies are initiated, everyone waiting for the results will be long dead before the study is ever completed. Our guess (and the guess of most people familiar with the research) is that deprenyl will do exactly the same thing to humans that it does to animals slow down aging . This is why many people we know (including the authors) are taking deprenyl.

Deprenyl for Alzheimer's Disease

Deprenyl has become a powerful new weapon against Alzheimer's disease. In a study in Italy, 10 Alzheimer's patients were given either a placebo or 5 mg of deprenyl twice a day for two months. The results showed that deprenyl improved memory, attention, and language abilities among those who received the drug, while those who received placebo became worse [Agnoli, et al. , 1992]. Another study of 20 Alzheimer's patients treated with deprenyl for six months also showed significant improvements in memory and attention [Piccinin, et al., 1990].

Verbal memory was tested in patients with Alzheimer's disease in yet another double-blind randomized crossover trial which also lasted 6 months. Each subject was tested before, during, and after the study with the Rey-Auditory-Verbal Learning Test. Deprenyl brought about a significant improvement in verbal memory, and improved information processing abilities and learning strategies at the moment of acquisition [Finali, et al. , 1992].

Numerous other studies have shown similar positive results in people with Alzheimer's disease [Goad, et al. , 1991; Finali, et al., 1991; Sloane, 1991; Mangoni, et al. , 1991; Martini, et al. , 1987]. Dr. Knoll [1992] states bluntly that Alzheimer's disease patients need to be treated daily with 10 mg deprenyl from diagnosis until death. See our Suggested Treatment Protocols chapter for specifics on the use of deprenyl for people with Alzheimer's disease.

Deprenyl Versus Other Drugs for Alzheimer's Disease

Oxiracetam (a nootropic drug similar to piracetam see the chapter on oxiracetam in Smart Drugs & Nutrients) was tested against deprenyl in a trial involving 22 men and 18 women with mild-to-moderate Alzheimer's disease. Ten milligrams per day of deprenyl were given to one group and 800 mg per day of oxiracetam were given to the other group. The results showed that at these doses, deprenyl was more effective than oxira- cetam in improving higher cognitive functions and reducing impairment in daily living. Deprenyl helped more with short- and long-term memory, sustained concentration, attention, verbal fluency, and visuospatial abilities. Both drugs were well tolerated with few or no side effects [Falsaperla, et al. , 1990].

In another study, deprenyl was compared to phosphatidylserine in forty people with Alzheimer's disease. The dosage of deprenyl was 10 mg per day and that of phosphatidylserine was 200 mg per day. Both treatments lasted three months. For most measures of cognition, the deprenyl group did better [Monteverde, et al. , 1990]. (See the Phosphatidylserine chapter in this book.)

Deprenyl was also compared to acetyl-L-carnitine (ALC) in forty people with mild-to-moderate Alzheimer's disease. Deprenyl (10 mg per day) was slightly more effective than ALC (500 mg twice daily), but we believe that the dosage of ALC may have been too low. However, it is interesting that both drugs were effective [Campi, et al. , 1990]. (See the Acetyl- L-Carnitine Update chapter.)

Deprenyl Improves Cognition in Parkinson's Disease

Deprenyl is becoming recognized as the treatment of choice for people with Parkinson's disease. Although it is well known that deprenyl dramatically slows down the progression of the disease, it is not so widely recognized that deprenyl also improves cognition in people with Parkinsonism. Several studies show that deprenyl improves attention, memory, and reaction times in Parkinson's patients. It also brings about subjective feelings of increased vitality, euphoria, and increased energy [Lees, 1991].

Deprenyl significantly delays the progression of Parkinson's disease under many conditions. Newly-diagnosed patients treated with deprenyl take far longer for their symptoms to become bad enough to require L-dopa (L-dopa used to be the drug of choice for Parkinson's disease). Many patients on deprenyl never require L-dopa . In addition, advanced Parkinson's patients treated with deprenyl plus L-dopa live longer than those treated with L-dopa alone.

Better Than Chocolate

Deprenyl is chemically related to phenylethylamine (PEA), a substance found in chocolate and produced in higher-than- normal amounts in the brains of people who are in love. Deprenyl's chemical structure is also closely related to amphetamine which, like PEA, is able to cross into brain neurons and trigger the release of the neurotransmitter's norepinephrine, epinephrine and dopamine. The release of these neurotransmitters causes mental stimulation and increased alertness.

Deprenyl, however, does not trigger neurotransmitter release. In this respect, deprenyl is unique among PEA derivatives. Deprenyl is a member of a class of drugs called monoamine oxidase (MAO) inhibitors. MAO is an enzyme responsible for breaking down used neurotransmitters so that they can be excreted. MAO levels tend to rise with age, and as a result, brain levels of monoamine neurotransmitters like dopamine tend to fall with age.

MAO inhibition can correct this age-related decrease in neuro- transmitters. However, when MAO is over-inhibited, neuro- transmitters can build up to excessive levels causing neuronal hyperstimulation hence the `speediness' effect of amphetamines. Deprenyl manages to avoid this side effect by inhibiting only a selected form of MAO.

Forms of Monoamine Oxidase

MAO enzymes are found throughout the body and come in two known types: type A (found in most body tissues), and type B (found predominantly in brain glial cells). Glial cells are small brain cells which surround and metabolically support the neurons which conduct the electrical signals throughout the brain.

Most MAO inhibitors are unselective, inhibiting both MAO-A and MAO-B to a similar degree. When MAO-A is inhibited (as with amphetamines, for example), a dangerous high-blood- pressure reaction can occur in patients who eat certain foods like aged cheeses, chianti wines, and chicken liver pat*, which contain a chemical called tyramine. Tyramine is usually metabolized by MAO, and inhibition of MAO causes tyramine to dangerously accumulate. This same high-blood-pressure reaction can occur in patients taking L-dopa disease. Unlike other MAO inhibitors, however, deprenyl inhibits only MAO-B. It does not cause the cheese reaction and it can be safely administered with L-dopa.

Deprenyl was the first selective MAO-B inhibitor to be described in the scientific literature. Over the last 30 years, it has become the reference standard for MAO-B inhibition. It is still the only one in widespread clinical use today.

How Does it Work?

Deprenyl is the only drug known to selectively enhance the activity of a tiny region of the brain called the substantia nigra. The substantia nigra is exceptionally rich in dopaminergic (dopamine -using) neurons. Dopamine is the neurotransmitter that regulates such primitive functions as motor control and sex drive. Deficiencies of dopamine result in Parkinson's disease symptoms.

Degeneration of the neurons in the substantia nigra is implicated not only in the development of Parkinson's disease, but also in the aging process itself. Deprenyl protects against the age-related degeneration of the substantia nigra and dopaminergic nervous system. It also protects sensitive dopamine -containing neurons from age-associated increases in glial cells and the MAO-B that they contain.

Deprenyl also inhibits the degrading of neurotransmitters and boosts the release of dopamine. Deprenyl-induced enhancement of brain function manifests in several dramatic ways. Dopamine is crucial to sex-drive, fine motor control, immune function and motivation. The steep decline of dopamine -containing neurons in the human brain after age 45 is a universal characteristic of the aging process. The tiny substantia nigra region of the brain is richest in dopamine and undergoes the most rapid aging of any brain area. It is the premature aging of this region which causes Parkinson's disease. On the other hand, normal age-associated depletion of dopamine accounts for many other symptoms most notably the gradual decline of male (and, possibly, female) sex drive.

Variable Aging in the Brain

The rate at which the dopamine neurons age is quite variable. Prior to age 40-45, dopamine levels remain fairly stable. Starting at age 40-45, average dopamine content in healthy individuals decreases by about 13% per decade (see illustration below). When it reaches approximately 30% of youthful levels (gray area), Parkinson's symptoms result. Below 10%, death results.

Those with average or slow decline die of other causes before Parkinson's symptoms become apparent. In fact, it has been suggested that if we all lived long enough, we would all even- tually develop Parkinson's disease. As average and maximum lifespan is increased, the use of deprenyl will become even more critical for the prevention of dopamine -deficiency degenerative diseases. Treatment with deprenyl may come to be a central strategy in geriatrics.

Dopamine activity in the brain is also increased by acetyl- L-carnitine (see the Acetyl-L-carnitine Update chapter).

Deprenyl for Depression

Deprenyl alone, or combined with phenylalanine, is often very effective at relieving depression. Phenylalanine is an amino acid that acts as a precursor (a chemical building block) to neurotransmitters such as norepinephrine.

In 1984, in Vienna, Dr. Birkmayer and colleagues treated 155 patients (102 outpatients and 53 inpatients) who were suffering from unipolar depression. The patients were given 5-10 mg of deprenyl and 250 mg of L- phenylalanine per day. The outpatients were treated orally, and 68.5% achieved full remission. Of the remaining patients, 21.5% achieved moderate improvement, 6% were unchanged, and 4% dropped out.

The inpatients were treated intravenously.Of these, 69.5% achieved full remission, 11% exhibited mild to moderate improvement, 12% showed no improvement and 7.5% dropped out. The therapeutic effect started one to three weeks into the treatment.

The beneficial effect of the daily intravenous infusion was maintained when the dose was reduced to twice a week, and also when switched to oral dosing. The authors noted that the outstanding clinical efficacy of deprenyl-plus- phenylalanine for depression was equaled only by electroconvulsive treatments (ECT) without the memory-loss side effect of ECT. The side effects of the deprenyl-plus- phenylalanine were primarily sleep lessness, anxiety , and tension (these could probably be eliminated by decreasing the dose of phenylalanine, or adding a serotonergic precursor like tryptophan). The treatment was well tolerated in 90% of the patients, and no withdrawal symptoms were noted in any of the patients.

In another study conducted in Chicago, 6 out of ten patients suffering from drug-resistant major depressive disorders considered their depression totally relieved after only 2-3 days treatment with 5 mg of deprenyl, 100 mg of vitamin B6, and 1-6 grams of phenylalanine per day. Their Global Assessment Scale scores dropped by 33% and stayed down over the remaining 6 weeks of the study [Sabelli, 1991]. The patients had been suffering from numerous depressions including manic depression, bipolar type II depression, schizoaffective disorder, seasonal affective disorder, and unipolar recurrent depression. Further double-blind research is underway. The relatively slow response in the first study and fast response in the later study is probably due to the difference in phenyl- alanine dosage (250 mg vs. 1000-6000 mg respectively).

Conclusion

Deprenyl's low level of toxicity, few side effects, and uniquely broad spectrum of pharmacological activities make it ideal for protection against brain aging and the age-related decline of the dopargic nervous system. Deprenyl is the drug of choice for Parkinson's disease and is currently being established as a treatment for Alzheimer's disease. Eventually, deprenyl may become recognized as a general preventive treatment for aging and age-related degenerative diseases in the above-45-year-old population.

Precautions

Deprenyl is very safe. No mutation-causing or birth defect-causing effects have been observed with deprenyl . In animal experiments, the LD-50 (lethal) dose is approximately 300-500 times greater than the dose required for complete MAO-B inhibition. Human patients have tolerated up to 60 mg of deprenyl per day for over three weeks without difficulty. The hypertensive reaction that occurs with MAO-A inhibitors following ingestion of tyramine-containing foods (like cheese, chianti wine, beans, chicken liver) has not been observed in patients taking the standard 5-10 mg dose of deprenyl. This response is observed to some degree at the 60 mg dose.

Dosage

For Parkinsonism, the recommended dosage of deprenyl is 5-10 mg daily. For the healthy population 45 and older, Dr. Knoll recommends 10-15 mg per week. For 45-year-olds, we think this dose may be high. For younger people, much smaller doses may suffice. Some people take only tablet (1.25-2.5 mg) once a week. One manufacturer of deprenyl, Discovery Experimental and Development, recommends a more gradual, age- related dosing schedule which takes full advantage of their 1-mg-per-drop liquid deprenyl.

Deprenyl causes a general stimulation of mental function that is distinctly different from that of other nutrients and drugs ( phenylalanine, tyrosine, L-dopa , and amphetamine). Most people report a mild-to-moderate anti- depressant effect, increased energy, improved feelings of well-being, substantially increased sex drive, and more assertiveness . The effect is mild in low doses and can last for several days.

As the dose of deprenyl is increased, symptoms of overstimula- tion can result. People have reported feeling over-amped, sexually overstimulated, nauseous, irritable, emotionally hyper-reactive, and even detached from their surroundings. When too much deprenyl is taken, the stimulation that it produces becomes L-dopa-like or amphetamine-like which can become tiresome because it lasts so long. At high doses, many people report such sleeping disturbances as vivid dreams, nightmares and insomnia. With deprenyl, more is not necessarily better. As with most smart drugs, starting with low doses and increasing gradually is the best policy. When combining smart drugs you may need to reduce the dosages.

Sources

Also called l-deprenyl, L-deprenyl, (-)deprenyl, selegiline, Jumex, or Eldepryl, deprenyl is available throughout the world. As Eldepryl, deprenyl is available from any pharmacy in the U.S. or Canada with a physician's prescription. It is also available from a number of overseas mail-order pharmacies. You can obtain a list of such sources by mailing the tearout card at the front of this book to CERI (the Cognitive Enhancement Research Institute). CERI also publishes Smart Drug News which frequently includes information of interest to people who are using (or want to use) deprenyl. A high purity liquid deprenyl manufactured by the Discovery Experimental and Development company (Wesley Chapel, Florida) has been submitted for approval by the FDA . It is already approved and available in Mexico. Discovery's liquid deprenyl has the added convenience of being dispensable in single milligram doses (1 mg per drop) as opposed to the standard 5 mg tablet. This makes it easier for healthy 40-50 year olds to take the correct amount (see the Dosage section in this chapter.)

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