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Chapter 9: Levodopa, the Hard Stuff As longevists we have all been interested in reports of drugs prolonging lifespan and vigor. Of all of these reports, perhaps the most outstanding concerns L-Dopa, also called levodopa. In the 29 April 1977 issue of SCIENCE, p. 549-551, George Cotzias, Samuel Miller and others reported on their longterm experiment with rats fed L-Dopa. Cotzias and Miller fed L-Dopa to their experimental rats at a dose of 40 to 80mg per gram of food; prolonged treatment with L-Dopa increased mean lifespans by up to 50%. Since virtually all the other drugs proposed for aging have obtained publicly verifiable results of no more than 30% these figures should awaken a deep interest in L-Dopa among the longevist community. What is the evidence that L-Dopa will increase our own lifespan? What are the risks?
At present we have only one experiment, the one by Cotzias and Miller, proving that L-Dopa will increase lifespans. We have some corroborating evidence of a weak kind in reports by doctors treating Parkinsonism, the chief medical problem for which people now take L-Dopa. Several doctors treating Parkinsonism have reported that average lifespan of patients on L-Dopa exceeded that of controls (who also had Parkinsonism). All of these clinical reports are small, involving numbers of patients on the order of 10 and 20, so that little conclusions may follow on a statistical basis; much worse, of course, these patients suffered from a disease, and their lifespan may have to do much more with a mitigation of the effects of the disease than with any influence of L-Dopa on aging as such. Nevertheless, increases of 50% cannot be laughed at!
We have also some further corroborating evidence in the recent reports by Marshall and Berrios (SCIENCE 206(1979):477) and Jellinger et al (MECH AGING DEVEL 14 (1980) 253). Marshall and Berrios did not study lifespan at all; instead they studied the incidence of movement disorders among aged rats, and showed that L-Dopa almost totally reversed the slowness of motion and lack of coordination shown by aged rats. Their experiment involved a test of ability to swim. Aged rats, 24 to 27 months old, could not swim well for more than a few minutes; their swimming lacked coordination compared to control young rats, and after several minutes they would repeatedly sink. All of these problems disappeared after treatment with L-Dopa. Following up on previous and equivocal results, Jellinger et al showed that 6 months of levodopa treatment in people suffering from senile dementia would progressively improve their memory and coordination.
 We all recognize the way in which an older person moves compared to a younger one; Marshall and Berrios present strong evidence that regular treatment with L-Dopa will reverse this disability and therefore lead to greater vigor in the old, even if it does not lead to longer lifespan. Jellinger and his coworkers give us further evidence in support. Greater vigor should interest any longevist even without proof of lifespan increase; the sum of these reports therefore compells our serious attention.
Finally the theoretical interest of these results and some theoretical support for a claim that L-Dopa will increase lifespans comes from work on the dopamine content of the brain in aging. Unfortunately we don't really understand what's going on here, so that we would naturally weight an actual experimental increase in lifespan a lot more heavily than we would any theories on the matter; nevertheless the dopamine theories of aging rate a
mention. In brief, the suggestion is not only that dopamine content of the hindbrain or the hypothalamus declines with aging, but that this decline plays a large role in causing many of the deficits we associate with aging itself, particularly by its control of the hypothalamus, which in turn will control, through the pituitary, all the other glands in the body. Any derangement in the functioning of the hypothalamus and brain structures nearby, then, would imply quite profound degenerations virtually everywhere else. A statement of this theory may be found in Finch (QUARTERLY REVIEW BIOLOGY 51(1976):49-83) and a good, short general review on the whole range of such theories in Arthur Everitt's review paper in GERONTOLOGY (26(1980):108-119).
All of this is really very hopeful; however unlike some of the drugs against aging, such as calcium pantothenate, L-Dopa involves quite significant risks, and anyone taking it would have to use a good deal of caution. Perhaps the most fascinating thing about these risks, however, is that a real case exists that WITH CARE we might be able to avoid them.
Risks and Side Effects
The first observation to make about risks comes from a close reading of the paper by Cotzias and Miller. Cotzias and Miller do not report a 50% increase in lifespan for the whole of their experimental group; in fact, their experimental rats split into two groups: one group, about 13% of the total, had a greatly DECREASED lifespan, less than 130 days. The second group, the remaining 87%, are the ones whose lifespan increased by 50%. Furthermore, the initial period of drug dosage had quite apparent toxic effects among all experimental rats : experimental rats lost their hair and developed opacity in the corneas of their eye (put bluntly, their eyesight went bad). The signs are that the initial period of treatment at doses large enough to increase lifespan will cause significant risk of fatality. Further reading of the report by Cotzias and Miller suggests that all these toxic effects will disappear; after about five months of treatment the test animals actually appeared more youthful. Nevertheless if we want to prolong our lifespans with this drug, we'll want to know whether or not we're going to be among the unlucky 13%.
Clinical reports of L-Dopa as used in the treatment of Parkinsonism give us even more pause. All of the experiments in which L-Dopa was tried on human patients produced a very large number of side effects. In Parkinsonism patients, after prolonged treatment with L-Dopa, as many as 72% of patients will suffer from movement disorders. These disorders consist of uncontrollable facial movements: grimacing, tongue protrusion, chewing motions, and others; they can also include motion disorders of the limbs (twisting or curling of the fingers or toes, progressing to flinging movements of the arms or feet). Patients usually show these disorders at doses of about 4.5 grams, but there is a range in the dose, from 2 to 8 grams. The number of patients with this problem increases the longer the patients have been taking L-Dopa, with the highest rate at about 2 years. Younger patients show a lesser risk...but of course all younger people eventually become older. Often L-Dopa treatment must be discontinued because these uncontrollable motions become as severe in their way as Parkinsonism originally. A second frequent and serious side effect consists of nausea and vomiting. Unlike the reason for the movement disorders, we can say pretty definitely what the reason for the nausea is. What is happening is that the dopamine produced by the L-Dopa causes nausea. Unlike movement disorders, however, the incidence of nausea decreases the longer a patient has taken L-Dopa; in one series of patients, for instance, 36 out of 43 patients report nausea or vomiting in the first 3 months of treatment , while after 12 months the rate had fallen to only 7.
A third side effect is loss of blood pressure upon standing; about 33% of patients have shown this effect. This problem tends to disappear in patients receiving the drug for sufficiently long.
A fourth side effect is mental disturbance. L-Dopa causes the brain to create dopamine, one of the significant neurotransmitting hormones; we would therefore expect it to cause some mental problems. In two studies, L-Dopa in Parkinsonism patients showed some signs of mental instability with L-Dopa. The most common side effect appears to be insomnia; the most common serious side effect is delirium. Depression may be another side effect, although some patients have a lessened degree of depression. Mental disturbance, incoherence, and depression can of course become incapacitating or even dangerous. L-Dopa may also increase libido, although Barbeau reports that none of his patients showed increased libido beyond that which might be expected from their improved well-being, and no patients were cured of impotence (for instance) if it were present.
A fifth side effect, unimportant but alarming to those not forewarned, is that your urine will turn red, and later turn to black if left standing. This is caused by a metabolic product of L-Dopa (homovanillic acid) and means nothing.
Finally there may be increased susceptibility to a particularly rapid form of cancer, melanoma. This effect comes because our bodies convert L-Dopa into melanin, and L-Dopa may promote growth of melanoma. However L-Dopa associated cancers are very rare.
All of these side effects are at least bearable, and even if present will occur in a minority of patients. The most serious side effect of all with L-Dopa is the possibility of cardiac problems. In a group of 100 patients treated at Cornell Medical School, 12 developed disturbed heart rhythms; 10 of these patients showed frequent premature ventricular contractions, a sign of very much increased susceptibility to sudden stoppage of the heart: put bluntly, they had an increased risk of dropping dead. The number of patients showing heart arrhythmias differs from study to study. In at least one study, the incidence of arrhythmias was as high as 12%. Could such effects also account for the 13% of rats that died early from taking L-Dopa?
Although I give them in more detail than in standard references, all of these side effects, together with still more lesser effects, appear in standard reference works on L-Dopa, such as the PHYSICIANS DESK REFERENCE of the US. These problems are enough to deter even the most fanatical longevity drug fiend, and if the question stopped there, we might as well forget the matter. What is really interesting about L-Dopa is that it DOESN'T.
In the first place, some significant evidence exists that the movement disorders shown by Parkinsonism patients are quite special to Parkinsonism patients. In a very interesting paper, I. Mena, George Cotzias, and others report their experiments with L-Dopa in the treatment of chronic manganese poisoning (I.Mena, G.C.Cotzias NEW ENGLAND JOURNAL OF MEDICINE 282 (1070) 5-10). Miners working in manganese mines will sometimes develop neurological symptoms quite similar to those of Parkinsonism, even though they may only be in their twenties. Unlike Parkinsonism, chronic manganese poisoning does not become worse and worse as the patient ages, although their symptoms (tremor in the limbs, masklike face, loss of all coordination on walking) are already quite bad enough! Cotzias, Mena, et al. report in their paper that 5 out of 6 ex-miners of manganese in Chile improved quite markedly after chronic treatment with L-Dopa at doses of about 8 grams per day. Most interesting of all, these patients did not develop any of the movement disorders characteristic of Parkinsonism patients on L-Dopa. Mena and Cotzias report in this same paper that 8 normal people, acting as controls at doses of 1 gm/day showed no signs of the movement disorders either.
Some quite recent studies of chronic toxicity of L-Dopa in mice might give us some further indications on this problem. BJ Sahakian et al (COMM PSYCHOPHARM 4(2) (1980) 169), for instance, found that giving mice doses as high as 10 grams per kg per day for over nine months caused no detectable pathologies. HOWEVER it did cause mice of two strains to lose weight and mice of one strain to become much more active. Mice receiving L-Dopa will make chewing and sniffing motions perhaps similar to the dyskinesias humans show. Dopamine levels also increase in the brains of human beings in the manic stage of manic-depressive illenss.
As many longevists know, some people are already taking L-Dopa in the hope that it will extend their lifespans. I haven't been able to find any good clinical reports on this practice; however doses reported in longevist literature unfortunately come nowhere near the amounts which animal experiments would suggest we need to take if we want to significantly increase our lifespans. I discuss this question of dose below; we can all welcome the fact that some are taking this drug, but their experience tells us little about problems of side effects with chronic dosage.
Unfortunately I have been unable to find any careful report of treatment of normal human controls for periods of years, so that we still lack proof that we would not show these same movement disorders if dosage continued for sufficiently long. On the plus side of the ledger, however,I can also point out that the L-Dopa movement disorders in Parkinson patients DO disappear if the dose of L-Dopa is decreased; there appears to be no case on record in which this particular side effect did not disappear if dosage were discontinued. (Some psychiatric drugs will cause similar movement disorders, but irreversibly). Further on the plus side is the simple point that normal patients, or patients such as the miners treated for manganese poisoning, DID NOT develop any movement disorders at all; however if older people grow more susceptible to movement disorders, this fact might mean little simply because (for instance) the manganese miners were young.
Mental side effects, too, may be mitigated or eliminated by cautious treatment. In the first place, Barbeau reports that the majority of Parkinsonism patients actually improved: their depressions lessened or disappeared and they became more mentally alert; if it turns out that you are among those favorably affected by the drug, on balance it will be an extra benefit to add to your longevity. On the other hand, the mental effects are after all reversible if you stop L-Dopa.
It seems to me that the most cautious thing to do is to make very careful arrangements so that someone else who is NOT trying L-Dopa will be present at all times during the first 4 months of treatment to take you in hand if you start showing signs of confusion, delirium, or instability. The mental effects may be quite serious; Barbeau reports, for instance, that among his own patients a few cases attempted suicide. This fact tells me that attempting to take L-Dopa as an isolated individual would be a serious mistake. Suicidal depression is not good for longevity! In particular, the best thing would be to leave the decision to continue taking the drug or not up to someone else at the time you are on the drug: you might specify to him or her in detail exactly what you want done, before you begin, but don't depend on your judgement once you are actually taking L-Dopa. You cannot assume that your own judgement will be very good.
Again on the plus side, the mental effects of L-Dopa, even if they occur, should disappear completely if you go off the drug. Unfortunately, even this plus to L-Dopa may not cover everyone: it may have a priming effect on people predisposed to manic-depressive illness, throwing theminto that condition without recovery.
The most interesting and hopeful comment to make about both of the two side effects, nausea and cardiac problems, is that excellent evidence exists that one particular dose form marketed in the US and other countries will avoid them both! For cardiac problems, of course, this is a major advance, and over the last 5 years doctors have prescribed less and less L-Dopa and more of a mixture of L-Dopa and carbidopa or benserazide. The name for this combination is Sinemet.
To understand what's happening, I will review the metabolism of L-Dopa. As I mentioned before, our bodies turn L-Dopa into dopamine; to do this they use a special enzyme, dopa decarboxylase.
What is interesting here is that the brain cells, as distinct from body cells, will selectively restrict the drugs they take up from the bloodstream. This activity of the brain cells is often referred to as the "blood-brain barrier". What is even more interesting is that we know at least two drugs, benserazide and carbidopa, which can NOT be absorbed by the brain cells, and which will prevent the enzymes dopa decarboxylase from working anywhere else but in the brain.
When L-Dopa causes cardiac problems, it does so because dopa decarboxylase in the heart muscle and blood vessels produces dopamine from the L-Dopa, and this dopamine then disturbs rhythm of the heart. When it causes nausea and vomiting, a similar thing happens: the area postrema, the part of the brain controlling vomiting, is one of the few brain areas where the blood-brain barrier will let in carbidopa.
Since longevists are fortunately not the only people worried by cardiac problems caused by L-Dopa, considerable work has already gone on to show that carbidopa or benserazide, when given with L-Dopa, will prevent these two effects. A thorough review of this combination drug is available (C.D.Marsden "Combined treatment with selective decarboxylase inhibitors", in G. Stern (ed.) THE CLINICAL USES OF LEVODOPA). The prospect seems excellent that we can avoid significant danger from cardiac arrhythmias.
What about Dosage?
In addition to side effects, L-Dopa raises some additional problems. First, just how do we calculate dosage? Cotzias fed his mice doses of 164 to 220 mg/mouse/day; if we calculate that dose should increase as the 2/3rds power of body weight then we would conclude that a human being would need a dose of at least 29 GRAMS L-Dopa per day. This is far outside the normal therapeutic range, even for L-Dopa for human patients, who generally receive no more than about 8 grams a day. In fact, it is far enough outside the normal range that I'm not convinced that a 2/3rds power rule is applicable; however the best dosage of L-Dopa for longevity then sits completely up in the air!
Furthermore, the usual procedure with human patients is not to give them all a fixed amount of L-Dopa; clinical practice is to give the patient gradually increasing amounts of L-Dopa until Parkinsonism decreases. Cotzias in particular reported that he could control all the side effects best by giving increasing dosage in steps of only 50mg each step, until the final doses of 5 to 8 grams were reached (Cotzias, G. JAMA 218 (13) (1971) 1903). (The word for finding a dosage by this means is titration). This fact makes the choice of a proper dose for aging much harder.
What does seem clear to me from the animal experiments is that if we really want to increase our lifespans with L-Dopa or Sinemet then we'll have to try doses in the VERY HIGH range, at least 6 grams a day and probably more. My own suggestion about dosage would be to gradually increase dosage up to about 8 grams per day, or less if side effects became intolerable. I would not recommend doing this privately, either: your doctor should supervise you closely, and furthermore you should have someone you trust watching you in case you develop psychoses at the high doses.
A second problem with dosage of which any serious reader needs warning is COST. Several different preparations of L-Dopa are available, and all of them are expensive. Doses of 8 grams a day for a year will cost over $1000. All of these drugs, of course, are widely available in countries such as Mexico for very low prices, and widespread use of L-Dopa would produce an increase in supply and a fall in cost. I believe that opportunities exist for longevist entrepreneurs here; however the need to make your own L-Dopa, make regular foreign trips, or buy it on the US FDA regulated market at a cost of $1000 a year is going to be a barrier. For those willing to pay the cost, several different preparations are sold on the US market. The preparation we want, though, is the one which incorporates carbidopa with the L-Dopa, to eliminate cardiac side effects; Merck, Sharpe, and Dohme make the only preparation with carbidopa on the US market, SINEMET. In Europe you can buy a preparation called MADOPAR which uses benserazide.
Some comments for longevist entrepreneurs: carbidopa need not be incorporated into the same capsule as the levodopa; and vigorous work will probably uncover means to produce a preparation without violating existing licenses. Furthermore, levodopa is present in fava beans, from which it can be extracted, and might even qualify as a nutrient if properly handled.
A fourth point to keep in mind about these drugs is that of their compatibility with other drugs, both drugs for aging and therapeutic drugs. L-Dopa will probably work through the same metabolic pathways as Deanol and GH-3; both of these drugs appear to influence aging because of their effect on the central nervous system. If we take more than one of these drugs at a time they might cancel one another out, because of the possibility of competitive inhibition (see Appendix 1). Other drugs such as calcium pantothenate or BHT will probably not interfere with L-Dopa. Standard drug references specify that levodopa should not be taken in conjunction with MAO inhibitors (antidepressants) and if MAO inhibitors have been taken, they should be discontinued for at least two weeks before commencement of L-Dopa. GH-3 is a mild MAO inhibitor. It is also important to know that the vitamin Pyridoxine (Vitamin B6) will reverse all the effects of L-Dopa when it is taken without carbidopa; carbidopa, however, will prevent this effect. Because of side effects, L-Dopa may also prove unsuitable for asthmatics. Finally, very serious consequences may ensue if you suddenly stopped taking L-Dopa after a long period on the drug; the report by Toru et al listed below graphically describes what might happen.
Finally, the pattern among the experimental mice studied by Cotzias was that older mice benefited, while young mice did not and were even harmed. I would suggest that anyone seriously interested in L-Dopa should wait at least until they are over 40 before they begin to take it.
It should be clear from this article that L-Dopa has a lot of problems. I will have to say that I am not currently taking L-Dopa or any other dose form involving this drug. Yet look again: a 50% increase in lifespan means that if we take it successfully, we can expect to live to 100 years.... My own conclusion from my reading on levodopa is that this drug, among all the other candidates, is ripe for clinical use by a longevist doctor. The side effects and risks, at the high doses we are likely to need for aging, seem too great for anyone to try these doses privately; particularly with a risk of suicidal depression I feel that anyone trying HIGH DOSE L-Dopa would not be wise to do so alone. They would even do well to leave the decision about whether or not to stop taking the drug to SOMEONE ELSE trustworthy. Furthermore, anyone who tries L-Dopa will have to adjust emotionally to the possibility that dyskinesias MAY appear after several years of dosage and force him or her to give up the drug.
Of course, once enough people are taking L-Dopa at these high doses, everyone else will benefit from their experience; but pioneering is always dangerous !
TO LEARN MORE:
The major papers on L-Dopa in aging are:
Cotzias, GC et al, "Levodopa, fertility, and longevity", SCIENCE 196 (29 April 1977) 549-551
Marshall, JF; Berrios, N, "Movement disorders of aged rats: reversal by dopamine receptor stimulation" SCIENCE 206 (26 October l979) 477-479
Lewis, C et al. "Trial of levodopa in senile dementia" BRITISH MED J, 1 (1978) 550
Kristensen, V et al, "Levodopa treatment of presenile dementia", ACTA PSYCHIAT SCAND 55 (1977) 41-51
Jellinger K, et al, "Levodopa in the treatment of (pre)senile dementia", MECH AGING DEVEL 14 (1980) 253-264
Not all of these papers confirm the idea that levodopa will help senility. The paper by Kristensen et al reports failure in treating senility with L-dopa.
Two books which give a good overview of L-dopa in the treatment of Parkinsonism are:
Stern, G (ed) THE CLINICAL USES OF LEVODOPA, 1975
McDowell, FH; Markham, CH, (ed) RECENT ADVANCES IN PARKINSON'S DISEASE, 1971
A symposium on levodopa, its metabolism, side effects, and clinical use was held at the 119th Annual Meeting of the American Medical Association, papers printed in JAMA 218 (13) (1971) 1903-1927
A review article on L-Dopa:
Calne, DB; Reid, JL, "Antiparkinsonian drugs: pharmacological and therapeutic aspects DRUGS 4 (1972) 49-74
A review by a leading worker of his experience with L-Dopa:
Barbeau, A, "L-Dopa therapy in Parkinson's disease", CANAD MED ASS JOUR 101 (1969) 59-68
Two papers by Cotzias on his experience with L-Dopa:
Mena, I; Cotzias, GC, et al, "Modification of chronic manganese poisoning", NEW ENGL JOUR MED 282 (1970) 5-10
Cotzias, GC et al, "Modification of Parkinsonism", NEW ENGL JOUR MED 280 (1969) 337-345
A review paper on treatment with the combination of L-Dopa and carbidopa (Sinemet):
Boshes, B, "Sinemet and the treatment of Parkinsonism", ANNALS INTERNAL MED 94 (1981) 364-370
Some other papers on the side effects, cardiovascular and others, of L-Dopa treatment:
Goldberg, LI; Whitsett, TL, "Cardiovascular effects of L-Dopa", in the JAMA Symposium, pp. 1921-1923
Parks, LC et al, "Prevention and reversal of cardiac arrhythmias by decarboxylase inhibitors", LANCET 14 November 1970, 1014-1015
Toru, M et al, "Neuroleptic malignant syndrome-like state following a withdrawal of antiparkinsonian drugs", JOUR OF NERV MENTAL DIS 169 (3) (1981) 324
Bernstein, JE et al, "Levodopa administration and multiple primary cutaneous melanomas", ARCH DERMATOLOGY 116 (9) (1980) 1041-1044
Two recent longterm studies in animals which shed light on chronic toxicity of levodopa when those taking it have normal health:
Sahakian, BJ et al, "Functional and structural consequences of longterm dietary L-Dopa treatment in mice", COMM PSYCHOPHARMACOLOGY 4(2) (1980) 169-176
Bailey, R et al, "Chronic L-Dopa treatment of mice: a behavioral and biochemical study", JOUR NEURAL TRANSM 50(2-4) (1981) 209-224
| This article contains chapters from the book, A GUIDE TO ANTIAGING DRUGS, published by PERIASTRON.
Dr. Donaldson aimed to provide, in the GUIDE, a discussion of both the good points and the bad points, of every drug shown by experiment to prolong the healthy lifespan of some mammal. The mammals involved must normally reach at least the average lifespan of their species.
This Web Site provides only samples of only part of the GUIDE, which discusses other drugs also. | |