© 1991-2014 Jerry Emanuelson
Deprenyl was developed by Dr. Joseph Knoll of Semmelweis University in Budapest, Hungary during the early 1960's for possible use as an anti-depressant. The medicine initially showed limited usefulness as a treatment for depression; but more than a decade after its initial development, deprenyl was found to be an effective treatment for Parkinson's Disease. (See the note at the end of this chapter, however, about the use of a deprenyl skin patch shown to be effective for depression.)
In April, 1989, the FDA approved deprenyl for use against Parkinson's Disease, a disease that usually strikes people between the ages of 50 and 70. Parkinson's Disease is an incurable disorder that begins with a characteristic tremor and causes progressive disability, ultimately resulting in death.
Deprenyl acts on an important chemical in the brain called dopamine. Dopamine is manufactured in the brain from two amino acids that occur naturally in foods: phenylalanine and tyrosine.
To function properly, the human body requires a multitude of chemicals in well-regulated quantities. For most of these necessary chemicals, the human body has one biological process to manufacture the chemical and another process to break it down. Dopamine is broken down in the brain by a chemical called MAO-B. It is important for good health that the manufacture of dopamine from amino acids and the destruction of dopamine by MAO-B is kept in balance. If the destruction of dopamine by MAO-B occurs at a faster rate than its production from the amino acids, the brain cells that use dopamine will die. The loss of dopamine and the resulting brain damage can cause tremors, rigid muscles, loss of coordination, weakness and death.
Beginning at about age 45, the destruction of dopamine in the brain by MAO-B begins increasing. The amount of dopamine in the typical about human brain begins decreasing by 13 percent every decade.
In about 0.5 percent of the population, the decrease in dopamine takes place much more rapidly than the usual 13 percent every ten years. When the dopamine content drops to about 30 percent of normal, these individuals develop the tremors and rigid muscles that are typical of Parkinson's Disease. Parkinson's patients typically experience a decrease in dopamine levels of 30 percent to 90 percent every ten years. Death usually occurs in Parkinson's patients about the time their brain dopamine content falls to 10 percent of normal.
In the past, the most popular treatment for Parkinson's Disease has been L-Dopa. L-Dopa is an amino acid that is not present in the ordinary human diet. The brain can make dopamine much more easily from L-Dopa than from the tyrosine and phenylalanine usually obtained from the human diet.
Deprenyl attacks the other end of the dopamine-preservation process by inhibiting the action of the MAO-B.
During the 1980's, deprenyl, either alone or in combination with L-Dopa, was the most effective known drug treatment for Parkinson's Disease. Researchers complained that few physicians are using deprenyl for Parkinson's Disease. Several months after its approval by the FDA, many physicians still hadn't even heard of the medicine, which is marketed by Somerset Pharmaceuticals under the brand name Eldepryl.
The Sept. 5, 1990 issue of the Journal of the American Medical Association (JAMA) contained an article titled "Many Researchers, Few Clinicians, Using Drug That May Slow, Even Prevent, Parkinson's." The article re-emphasized the dramatic results of deprenyl as shown in several large-scale human studies. In the JAMA article, Dr. Christopher Goetz, a neurologist, said he is "surprised by how few" physicians are prescribing deprenyl. "They don't understand the implications" of the studies, Goetz said.
Some of the enthusiasm for using deprenyl in Parkinson's Disease has been dampened after it was discovered that the dosage levels used were often too large, and that determining and maintaining the proper dosage in a clinical setting was more difficult that was first thought.
Dr. Knoll claims that deprenyl is also effective in preventing Parkinson's Disease. Most other scientists working with deprenyl take this claim seriously but are much more cautious about recommending deprenyl in healthy persons.
A review article in Clinical Neuropharmacology by Dr. Patricia Sonsalla and Dr. Lawrence Golbe typifies the most prevalent thinking on this subject. Sonsalla and Golbe discuss reasons for believing that deprenyl may be a useful preventive therapy for Parkinson's Disease (PD), warning that in autopsies of elderly persons who had no Parkinson's symptoms during life, eight to 10 percent show pathological indications of Parkinson's Disease.
Sonsalla and Golbe wrote that "clinically evident PD may then be merely the top of a pathologic iceberg comprising 10 percent of the population over 60 in Western countries. If deprenyl is shown to even modestly delay or attenuate the development of clinical PD, or is widely suspected of doing so, large numbers of people may seek the drug. The still distant prospect of a valid pre-symptomatic test may lend a more rational basis to this practice. In any case, frightened patients and their physicians must understand that there are no data on the safety of deprenyl over a span of several decades."
According to Dr. Knoll, deprenyl has "proved to be a safe drug in man. Neither hypertensive reactions nor the need for special dietary care were ever encountered during long-term (2-8 years) daily administration of the drug." Knoll said that the lethal dose of the drug is more than 1000 times its effective daily dose. Knoll called this safety margin "remarkable."
Dr. Knoll also said that deprenyl is an effective treatment for aging. Knoll wrote a lengthy report on his study of the age-retarding effects of deprenyl which was published in a European medical journal in 1989.
In that study, Dr. Knoll divided 132 male rats of the same age into two groups. One group of 66 rats received an injection of salt solution three times a week. The other group of 66 rats each received a similar injection containing deprenyl three times a week. The treatments began when the rats were 104 weeks-old. The rats that did not receive deprenyl died at an average age of 147 weeks. After 164 weeks, all of the untreated (salt-water injected) rats had died; but all of the deprenyl-treated rats were still alive and healthy. It was not until seven weeks later that the first deprenyl-treated rat died. The last deprenyl-treated rat lived to 226 weeks.
The average life span of the deprenyl-treated rats was 192 weeks. The researchers considered this to be particularly remarkable since the maximum life span of that strain of laboratory rats is considered to be 182 weeks.
According to Dr. Knoll, similar life-extending results could be expected in humans. The biological processes deprenyl acts upon to cause its life span extending effects in rats are well-known; and there is general agreement among scientists that deprenyl acts on the same processes in humans.
Dr. Knoll points to the normal decrease in dopamine in the aging brain as an indication of how deprenyl works to increase life span. He said that it is no coincidence that even the healthiest humans die at about the time the dopamine content of their brain drops below the critical 30 percent level. According to our present knowledge, the neurons (brain cells) that use dopamine are the most rapidly aging neurons in the human brain.
| AGE
45 55 65 75 85 95 105 115 125 |
DOPAMINE CONTENT 100 percent
87 percent
74 percent
61 percent
48 percent
35 percent
22 percent
11 percent
0
|
Dr. Knoll's advocacy of deprenyl use to extend the human lifespan is controversial. Claims of enhanced longevity in humans without conclusive proof have often caused drug companies to have problems with government regulatory agencies. At one symposium on deprenyl, the organizer of the event, Dr. John Mann, was careful to emphasize that Dr. Knoll's statements about the anti-aging effects of deprenyl have "nothing to do with the claims of any pharmaceutical company."
If the animal experiments translate directly into the same slowing of the aging process in humans, this would result in a 24 percent increase in the maximum life span of humans along with a stretching of the healthy middle years of human life by 25 to 30 years. Since the natural life span of humans is much longer than laboratory animals, whether deprenyl actually has this effect in humans won't be known for at least another three decades.
In a report in the August 1992 Journal of the American Geriatric Society, Dr. Knoll concluded his report on deprenyl by saying, "We propose that the healthy population be maintained on 10-15 mg deprenyl weekly starting at age 45 to combat the age-related decline of the nigrostriatal dopaminergic neurons. Prophylactic deprenyl medication seems to offer a reasonable prospect of improving the quality of life in the later decades, delaying the time of natural death and decreasing the susceptibility of age-related neurological diseases."
The editor of the Journal of the American Geriatric Society appended a note to Dr. Knoll's report stating that "The proposal in this final paragraph is the author's opinion and does not reflect mainstream opinion at the present time." Nevertheless, it is remarkable, and probably unprecedented, for a report in a serious medical journal to propose that all healthy persons above a certain age take a prescription drug on a regular basis.
Since deprenyl is a prescription medicine, those using it for personal life extension experiments are either scientists or physicians or are persons whom physicians trust to have the knowledge and responsibility to be able to use wisely a medicine such as deprenyl on a long-term basis.
One of the greatest problems that the healthy individuals using deprenyl face is not a medical problem, but a social one. Deprenyl is broken down in the body to amphetamine and methamphetamine. London researcher G. P. Reynolds and his associates reported in a British medical journal that even in the larger doses used in Parkinson's Disease, deprenyl is "unlikely to produce any marked degree of central amphetamine-like action."
The amphetamine and the methamphetamine breakdown products of deprenyl can show up in urine, though. Some scientists have warned that this may cause problems for those individuals who must undergo employer required drug testing.
Methamphetamine is a common illegal "street drug" with the potential for producing addiction. The scientists who work with deprenyl are not concerned that any harm will be caused by the tiny amounts of amphetamine and methamphetamine produced by deprenyl, but concern has been expressed about the dangers to a person's job and reputation from positive results on drug tests.
The Marketing of Deprenyl
Deprenyl Research Ltd., the company that markets deprenyl in Canada, is researching the use of deprenyl in controlling the symptoms of Alzheimer's disease and in reducing fatigue in multiple sclerosis. The company hopes eventually to secure approval from government regulatory agencies to market deprenyl for these uses. (In mid-1994, Deprenyl Research changed its name to Draxis Health, Inc, reflecting its intention to become involved in other products besides deprenyl.)
A number of entrepreneurs have been involved in efforts to gain approval to sell deprenyl for extending the lives of dogs, cats and other pets. The first such effort was by Dr. Morton Shulman of Toronto. In 1987, Dr. Shulman was 62 years-old and so severely afflicted with Parkinson's Disease that he was hardly able to move without help. He obtained some deprenyl from Europe after hearing about the drug from a neurologist.
In Longevity magazine, Dr. Shulman is quoted as saying that "within 24 hours of taking the drug, I stopped shaking and shuffling, returned to normal, and went back to work."
According to a report in the Oct. 3, 1988 issue of Business Week, after deprenyl halted the course of his disease, Dr. Shulman began stirring up a considerable amount of controversy with his efforts market the drug as a life span extender for pets.
Shulman made efforts to induce pet food companies to secure official approval for deprenyl for animal lifespan extension from U.S. and Canadian regulators. At that time, deprenyl had yet to be approved by the U.S. FDA for any use; and many people feared that Shulman's claims about life span extension in animals would cause the FDA to slow the approval process in the U.S. This problem was complicated by the fact that Shulman had a financial interest in the company that was applying for FDA approval for human use in Parkinson's Disease.
According to a report in the Jan. 7, 1991 issue of Barron's, a weekly financial newspaper, a new company, Deprenyl Animal Health, Inc. was formed for the purpose of marketing deprenyl for veterinary use. Barron's quoted company officials as saying that they believe that deprenyl "when chronically administered in low doses, may extend the healthy period of small companion animal's lives by retarding the 'normal' decline of certain physiological functions, particularly in dogs and cats, during the senescent period of such animals lives."
Deprenyl Animal Health, Inc. later signed agreements with Chinoin of Hungary, the world's primary producer of deprenyl, for exclusive rights to market deprenyl for "veterinary prescription applications" in the U.S. and Canada. In 1992, they established headquarters in Overland Park, Kansas, and began implementing plans to sell a veterinary form of deprenyl under the brand name Anipryl.
By 1999, television ads for Anipryl, the veterinary form of deprenyl, were commonplace.
The basic U.S. and Canadian patents on deprenyl that were held by Chinoin of Hungary have expired. However, Chinoin holds patents in both countries on the process used for making deprenyl. Those patents did not expire until Dec. 20, 2003.
Competing companies were searching for alternative processes for manufacturing the drug that are not covered by the Chinoin patents. One company, Discovery Experimental and Development, Inc., apparently succeeded in using a completely different process to make a liquid form of deprenyl. The company claimed that it was more bioavailable than the Chinoin product. At one time, it was submitted for FDA approval. Subsequently, competitors conspired with rogue agents of the FDA to put Discovery out of business.
Dangers of Deprenyl
In spite of the impressive safety record of deprenyl, any substance that affects a system as critical as the brain's dopaminergic system is destined to have adverse effects under some circumstances. The first adverse effects of low-dose deprenyl were discovered by long-time practitioners of life extension who had been using l-dopa for life extension purposes. L-dopa had been shown to increase life expectancy in animals by helping to replace the dopamine normally lost by aging. (L-dopa is also a potent growth hormone releaser.) The addition of low-dose deprenyl to low-dose l-dopa usually results in a rather alarming adverse reaction, often after a delay of a week or two after the combination is begun. The symptoms are usually those of a dopamine overload, including involuntary muscle movements, nausea, headache, or just plain feeling lousy.
About five years after life extensionists discovered the results of the deprenyl/l-dopa interaction, reports in the scientific literature began to appear showing the long-term adverse effects of the deprenyl/l-dopa combination on Parkinson's patients. A study in the Dec. 16, 1995 British Medical Journal reported the worst long-term effects, with a sharp increase in deaths occurring in the period between 29 months and 41 months after beginning the deprenyl/l-dopa combination, with an overall death rate nearly 60 percent above that of patients using l-dopa alone.
More recent reports on the DATATOP study have shown that the early benefits of deprenyl vanished when it became necessary to add l-dopa to the patient's therapy.
Deprenyl is known to multiply some of the effects of l-dopa. It is likely that the deprenyl/l-dopa combination produces what is effectively an l-dopa overdose. Until more is known about the deprenyl/l-dopa combination, healthy people (and probably even those with mild Parkinson's disease) should avoid the deprenyl/l-dopa combination.
There are also possible long-term adverse effects of low-dose deprenyl without l-dopa. Deprenyl greatly increases the activity of superoxide dismutase (SOD), one of the body's natural antioxidants. On the surface, this appears to be a good thing. For years, people have been trying to find ways to increase natural antioxidant activity, especially SOD. In the process of destroying some free radicals, though, SOD, like most antioxidants, produces other free radicals. This is why complementary antioxidant systems must be kept in balance.
This is true whether the antioxidants are vitamin supplements or the natural antioxidant systems of the body. (See Appendix A: Notes on Antioxidants)
This is one reason why it is wise to avoid whatever is the latest antioxidant fad. Just because a substance is an antioxidant doesn't mean it is good for you.
One of several causes of impaired mental development in Down's syndrome is the excess production of SOD. The excess SOD destroys some types of free radicals but, in the process, SOD produces more of the dangerous hydroxyl radical than the other antioxidant systems can handle. There is a possibility that deprenyl, even at low doses, could produce some of the same kind of damage.
Obviously, if we could re-balance the antioxidant systems, the excess SOD activity could be turned from a problem to an advantage. It will be years before we know the effect of long-term low-dose deprenyl in humans. In the meantime, here are some things for anyone contemplating low-dose deprenyl for life extension to consider:
- The three major natural antioxidant systems in the body are SOD, catalase, and glutathione peroxidase. Deprenyl raises SOD activity markedly, catalase activity slightly, and glutathione peroxidase activity none at all. The nutritional supplement N-Acetyl-Cysteine (NAC) raises glutathione peroxidase levels and should help to re-balance the body's natural antioxidant system in those using deprenyl.
- It is probably unwise for anyone to use deprenyl without rather large doses of supplementary antioxidant vitamins, especially vitamins C and E.
- The increased SOD activity induced by deprenyl is greater in females than males. The lifespan studies with deprenyl that produced positive results in animals were always done with male animals. Female animals did not have positive results in lifespan studies. The ideal dose of deprenyl in women appears to be less than the ideal dose for men. The use of supplementary antioxidants in women taking deprenyl is correspondingly more important than for men taking deprenyl.
Dosage for Life Extension.
The optimum dose of deprenyl for life extension purposes is unknown. Extrapolation from animal experiments would indicate that it is about 5 mg. every other day. Some scientists, though, have suggested that people in their forties begin with 5 mg. per week and gradually increase to about 5 mg. per day by the time they reach their seventies. Another complicating factor is that the early deprenyl experiments were done only with male animals. A recent study using male and female rats indicated that the optimal dose for females is much smaller than the optimal dose for males. Until more research is done, it may be prudent for healthy women under 70 to limit their dosage to 5 mg. per week.
The half-life of deprenyl in the body is only a few hours; but once it enters the brain, its effects are very long-lasting. The half-life of MAO-B inhibition in humans has been measured to be about 40 days, therefore, deprenyl probably need not be taken daily by persons who do not have a neurological disease.
The successful life extension experiments with deprenyl have been done in rodents, where the half-life of MAO-B inhibition due to deprenyl is 8 to 11 days, as opposed to 40 days in humans. This indicates that life extension doses extrapolated from rat studies may be 4 to 5 times too high for humans.
(In the study where the half-life of MAO-B inhibition was measured in humans, it was about 38 days in the normal subjects and 43 days for patients with early Parkinson's disease. The normal subjects were four non-smoking males ages 62 to 69. The Parkinson's patients were 2 males and 2 females ages 62-70.)
[A personal note: After all this, sometimes confusing, information about deprenyl, you are probably wondering how much, if any, deprenyl I take. In 1989, I began taking 15 mg. a week. I soon reduced the dosage to 5 to 10 mg. of deprenyl weekly. In 1996, I reduced my dose to 5 mg. a week and started using liquid deprenyl citrate. Since the most well-tested brand of liquid deprenyl citrate became unavailable, I began using 5 mg. per week in the tablet form. I also take 1000 mg. of NAC per day and at least 400 I.U. of vitamin E and 1000 mg. of vitamin C per day. I also take a lot of lipoic acid.]
(I should also note that some of the information in this chapter may be somewhat out-of-date since the last really major update to this particular chapter was made in 1999. In the subsequent ten years, I only made some minor changes until 2009, when another significant update was made.)
In the United States, the FDA has approved a deprenyl skin patch that is sold under the brand name Emsam for depression. It is not known whether this might be a better form of deprenyl for preventive and life extension purposes. Since the skin patch releases deprenyl at a steady rate over a 24 hour period, there is some reason to believe that using the 6 mg. Emsam patch every other day might be a good approach to the preventive medicine uses of deprenyl. The big downside, for now, to the use of Emsam is its extremely high price tag. As of this writing, the price of Emsam is more than 500 dollars for a box of 30 of the 6 mg. patches. This is more than 30 times the price of deprenyl tablets.)
About Joseph Knoll
Dr. Knoll began taking deprenyl in 1988, more than two decades after he developed it. Dr. Knoll is Past Chairman of the Department of Pharmacology and Professor Emeritus at Semmelweis University. He has developed many other new medicines in addition to deprenyl and has published 852 scientific papers and holds 53 patents.
Dr. Knoll is a survivor of the Nazi concentration camps during World War II. According to an interview with Knoll in the December, 1992 issue of Longevity magazine, his weight was down to just 81 pounds during one point in his captivity. He was in a group of 65 people, of which only two survived.
"The body is a servant to the brain," according to Knoll. This belief has driven much of his professional life.
- INFORMATION SOURCES ON DEPRENYL:
Carrillo, M.C. and others. "Long Term Treatment with (-)Deprenyl Reduces the Optimal Dose as well as the Effective Dose Range for Increasing Antioxidant Enzyme Activities in Old Mouse Brain." Life Science. 1996: Vol.59, No.13. pp.1047-1057.
Cochran, Thomas N. "Offerings in the Offing (Deprenyl Animal Health, Inc.)" Barron's. Jan 7, 1991. p. 61
Cotton, Paul. "Many Researchers, Few Clinicians, Using Drug That May Slow, Even Prevent, Parkinson's" Journal of the American Medical Association. Vol. 264, No. 9. Sept. 5, 1990. pp. 1083-1084.
Crowell-Davis, S.L. Cognitive dysfunction in senior pets. Compendium: Continuing Education For Veterinarians. Vol. 30. No. 2. February, 2008. pp. 106-8, 110.
Fowler, J.S and others. "Slow Recovery of Human Brain MAO-B After L-Deprenyl (Selegiline) Withdrawal" Synapse. (1994) Vol.18. pp.86-93.
Hawkins, C., "The Dogfight Over a New Drug for Parkinson's Disease" Business Week. Oct. 3, 1988. p. 36.
Heinonen, E.H., and others. "Pharmokinetics and Metabolism of Selegiline" Acta Neurol. Scand. 1989:126 pp.93-99.
Kahn, Carol. "An Anti-Aging Aphrodisiac" Longevity. Dec., 1990. pp.42-48.
Knoll, J. "The Pharmacology of Selegiline ((-)Deprenyl): New Aspects" Acta Neurol. Scand. 1989:126 pp. 83-91.
Knoll, J. "Deprenyl (selegiline): The History of Its Development and Pharmacological Action" Acta. Neurol. Scand. Supp.95:1983. pp. 57-80.
Knoll, J. "Deprenyl Medication: A Strategy To Modulate the Age-Related Decline of the Striatal Dopaminergic System" Journal of the American Geriatric Society. V.40., No.8, August, 1992, pp. 839-847.
Kushleika, J. and others. "Selegiline and Lymphocyte Superoxide Dismutase Activities in Parkinson's Disease." V. 39, No.3, March, 1996. pp.378-381.
Lees, A.J. "Comparison of Therapeutic Effects and Mortality Data of Levodopa and Levodopa combined with Selegiline in Patients with Early, Mild Parkinson's Disease" British Medical Journal. 311, Dec. 16, 1995, pp. 1602-1607.
McGrath, P.J. and others. "A Placebo-Controlled Trial of l-Deprenyl in Atypical Depression" Psychopharmacology Bulletin. 1989, Vol. 25, No. 1, pp. 63-67.
Parkinson Study Group [DATATOP]. "Effect of Deprenyl on the Progression of Disability in Early Parkinson's Disease" New England Journal of Medicine. Nov. 16, 1989. pp.1364-1371.
Parkinson Study Group. "Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism" Acta Neurol. Scand. 1989:126 pp. 171-175.
Parkinson Study Group. "Impact of Deprenyl and Tocopherol Treatment on Parkinson's Disease in DATATOP Patients Not Requiring Levodopa." Annals of Neurology. Vol. 39. No.1, January, 1996. pp. 29-36.
Parkinson Study Group. "Impact of Deprenyl and Tocopherol Treatment on Parkinson's Disease in DATATOP Patients Requiring Levodopa." Annals of Neurology. Vol. 39. No.1, January, 1996. pp. 37-43.
Reynolds, G.P. and others. "Deprenyl is Metabolized to Methamphetamine and Amphetamine in Man" British Journal of Clinical Pharmacology. 1978:6, pp. 542-544.
Shoulson, "I. Neuroprotective Clinical Strategies for Parkinson's Disease." Annals of Neurology, 1992, Supplement 32, pp. 143-145.
Sonsalla, P.K. and Golbe L.I. "Deprenyl as Prophylaxis Against Parkinson's Disease?" Clinical Neuropharmacology. Vol. 11, No. 6., pp. 500-511.
Thomas, Patricia. "Anti-Aging Ploy Evokes Doubts" Medical World News. June 11, 1990. p. 16.
Yahr, M.D. and others. "Selegiline in the Treatment of Parkinson's Disease - Long Term Experience" Acta Neurol. Scand. 1989:126 pp. 157-161.
[Book] Dow, Alastair. The Deprenyl Story. Publisher: Stoddard, Toronto. ISBN: 0-7737-2406-0. [This book was only available in Canada. It is now out of print.]
A revised version of the above book was available in the U.S. under the title Deprenyl: The Inside Story by Alastair Dow (220 pages). Publisher: Easton Publishers. It is now out of print, but can often be found from used bookstores.