L-dopa, also known as Levodopa and L-3, 4-dihydroxyphenylalanine (1), is best known to the world as a treatment for Parkinson’s disease (PD), a neurological disorder. Indeed, as Hauser and Zesiewicz remark: “L-dopa and peripheral decarboxylase inhibitor (PDI) (Sinemet) therapy remains the gold standard for symptomatic treatment for PD. It provides the greatest anti-Parkinsonian benefit with the fewest side effects” (2). Yet even though it is used to treat a disease, L-dopa is not an artificial human-created drug. It is a natural amino acid derivative that occurs in food, (making up 13% of the velvet bean) (1) and is normally present in the human brain (3). L-dopa is the precursor for the neurotransmitter dopamine (DA) (3), and is produced by the action of the enzyme tyrosine hydroxylase on the amino acid tyrosine (3). DA is the precursor of the brain neurotransmitter noradrenalin (NA), yet administration of L-dopa preferentially increases brain DA, while giving tyrosine increases NA more than it increases DA (3).
If L-dopa were useful only as a PD treatment, it would be of little interest to most people. Yet L-dopa has uses beyond PD. It has been known for over 30 years that it is an effective stimulant of human growth hormone (HGH) release. In 1970, Boyd and colleagues found that a 500mg oral dose …”caused a significant rise in plasma growth hormone in PD patients, initially starting therapy or on chronic L-dopa therapy for as long as 11 months. The rise in plasma growth hormone persisted for 120 minutes after the administration of the drug.” (4). Boden and his co-workers gave 500mg of the drug orally to four male and five female volunteers. “HGH levels rose sharply at 45 minutes from the basal value of 0.8mg/ml, to a maximum of 10.0mg/ml at 90 minutes (p<0.001) and declined thereafter. This rise occurred in eight of the nine subjects.” (5). Hayek and Crawford reported that six out of seven “constitutionally short children” responded to oral L-dopa (200-500mg), “…with elevations in HGH concentration above 7mg/ml, peak levels occurring between 30 and 120 minutes after drug administration..”. (6).
In 1975, Ajlouni and colleagues reported the effects of 500mg of oral L-dopa on eight normal and 8 non-obese insulin-dependent diabetic subjects. The normal subjects increased their plasma HGH from 1.5mg/ml before L-dopa, to an average 21mg/ml at 90 minutes post L-dopa, with all subjects showing at least a 10 mg/ml increase. The diabetics increased from 2.5mg/ml to 20mg/ml from 60-90 minutes post L-dopa. Giving 100 grams (3 _ ounces) of glucose with, or 30 minutes after the drug totally suppressed the expected HGH increase (7).
Obesity has been shown to blunt HGH release after oral L-dopa. Laurian and his co-workers tested 17 obese, non-diabetic and six normal weight volunteers. All 17 obese subjects failed to respond to L-dopa, while the normal weight subjects had HGH increases of 10-11mg/ml at 90 and 120 minutes after the drug was administered. The 17 obese men and women subsequently lost 12-50kg. After weight loss, 8 people secreted HGH in response to L-dopa, but at levels only 50-60% of the normal weight people. 9 formerly obese people still failed to respond to it (8).
Barbarino and colleagues gave 500mg orally to 12 obese people, with no significant HGH increases. When some of the subjects were given 40mg oral Propranolol, two hours before L-dopa, they then showed HGH response, although at only 50-75% of the level shown by 12 normal weight subjects given L-dopa, whose serum HGH levels reached 7 to 32mg/ml 60-120 minutes after L-dopa (9).
Greenspan et al. compared HGH response to L-dopa in 44 young patients (31-44 years of age) and 42 older patients (64-88 years of age). All were considered “healthy participants”. Plasma HGH increased by 221% in the young patients and 167% in the older patients. The post L-dopa HGH levels were similar in young and old (4.5 and 4.8mg/ml) (10).
The preceding studies illustrate some of the studies showing that 500mg oral L-dopa is an effective stimulator of HGH release. Whether a person is male or female, young or old, diabetic or not, thin or obese (possibly with Propranolol), a PD patient or not, L-dopa is a natural HGH-releasing agent when taken on an empty stomach. For those who can’t afford HGH injections, or just don’t like self-injecting,L-dopa may provide a reasonable alternative.
It is common knowledge that bodily movement becomes more difficult with age. Elderly people move at a slower pace, often walking with a shuffling or stooped gait. Hand-eye co-ordination deteriorates and it can become more difficult to get out of a chair. Joints stiffen, muscles weaken and hands tremble. In many ways, the dyskinesia (difficulty performing voluntary movements) of old age resembles a mild form of Parkinson’s disease. Marshall and Berrios believe there is a connection. They point out that “The dopamine-containing neurons of the brain have long been known to be essential for normal movement and sensori-motor integration. The movement disturbances of Parkinson’s disease, for example, are attributable to a loss of dopamine-containing neurons that innervate forebrain structures, particularly the neostriatum. Damage to these neurons of young adult mammals results in sensorimotor disturbances similar to Parkinsonism. The symptoms of this clinical disorder and its analog in animals are frequently controlled by administration of L-dopa, apomorphine or similar compounds. Our findings suggest that advanced age may represent another link between movement disturbances and the deterioration of dopaminergic neurotransmission.
This conclusion is supported by recent clinical investigations that have noted similarities between the movement disturbances of Parkinsonian and those of non-diseased elderly individuals.” (11).
Marshall and Berrios noted that aged rats swim very poorly compared to young rats. In a 15 minute swimming test, young rats swim with vigour for most of the test, with their performance declining gradually. Old rats are significantly impaired after 6 minutes, unable to sustain a horizontal position in the water, frequently sinking below the water. Young rats, whose dopamine neurons are damaged, swim just like the old rats. Giving old rats intraperitoneal L-dopa injections 15 minutes before the test restores their ability to swim just like the healthy young rats (11).
Papavbasiliou and co-workers compared old mice who were fed L-dopa-enriched, with regular mice chow since youth. They noted a profound decrease in motor activity with aging in the regular, chow-fed old mice, but no loss of motor activity in the L-dopa-fed old mice. They concluded: “…motor impairment is an age-related phenomenon in mice associated with selective alterations in brain dopaminergic systems, which may be prevented by dietary Levodopa.” (12)
Thus, the animal evidence combined with the effectiveness of L-dopa in PD, and the similarity of the neuromuscular degeneration typical of “normal” aging to PD, all suggest that it may provide a remedy for maintaining more normal “motor activity” throughout middle age into old age. On an anecdotal basis, I have confirmed with various friends and colleagues during the past 20 years that modest L-dopa supplementation (typically 100mg Sinemet ®/day) has increased their sense of neuromuscular co-ordination, strength, vigour and greater “drive to action”.
In their recent book “Balance Your Brain, Balance Your Life”, neurologist, Dr. Jay Lombard and preventative medicine specialist Dr. Christian Renna have provided evidence that our health, energy and happiness are significantly affected by our personal brain balance of “warming” and “cooling” neurotransmitters (13). Dopamine, noradrenalin (norepinephrine), acetylcholine and glutamate are the major “warming” neurotransmitters (NTs), while serotonin and GABA are the chief “cooling” NTs (13). They note that “warming” NTs are dominant in the daytime, while the “cooling” counterparts predominate at night, and that “….dopamine is our principal warming neurotransmitter…”(13). A broad array of symptoms may indicate possible warming NT/DA deficiency, including weight gain, drop in energy level, apathy, difficulty concentrating, loss of interest in things that were formerly pleasurable, irritability, not wanting to get out of bed, decreased testosterone in men, depression, spaciness or forgetfulness, reduced speed of information processing and capacity for abstract thought, to name just a few (13). Lombard and Renna provide a 150 question self-test to help assess if one might be suffering a warming or cooling NT deficiency, a modest (100mg Sinemet ®) L-dopa supplement taken at breakfast might reasonably be part of a plan to restore neurological balance to the brain, since L-dopa is more specific to increasing brain DA than the L-dopa precursors phenyl-alanine and tyrosine (3).
It was announced in the American media in early 2004 that actor, Michael J Fox, who has suffered early onset PD for over a decade, recently began a “new” (for him) therapy that brought virtually miraculous relief from his ever-worsening PD. The drug was Sinemet ®. The obvious question is, why had his doctors delayed giving him the “gold standard” PD treatment (2) for so many years? The answer involves some extremely complex biochemistry and brain physiology, and is relevant to L-dopa use by those not suffering the disease.
If one looks at the vast literature on L-dopa, one finds two completely different views about L-dopa and DA. One body of scientific literature says L-dopa and DA are highly toxic to DA – using neurons, while another body of evidence pronounces L-dopa to be not only non-toxic, but claims that it will “….increase reduced glutathione (a critical intra-cellular antioxidant), protect dopamine neurons from oxidants, increase cell survival, and promote neuritic extension, or nerve growth.” (2)
What could make L-dopa/DA toxic to dopaminergic neurons? L-dopa/DA both can oxidise to generate toxic free radicals, quinines, hydrogen peroxide and lipid peroxides (14). L-dopa may create excito-toxic metabolites (14). Chronic L-dopa administration may inhibit complex 1 of the mitochondrial electron transport chain, simultaneously reducing mitochondrial ATP energy production and increasing free radical/oxidant levels (15). Indeed, Parris Kidd has argued that PD is the result of “multifactorial oxidative neurodegeneration”, brought about by known and unknown environmental insults (such as heavy metal or pesticide poisoning) and metabolic derangements (such as poor antioxidant status). He also argues that the naturally high levels of DA in the substantia nigra (the brain region that “melts down” in PD) plays a key role in promoting such oxidative neurodegeneration (16). It should be noted, however, that “Evidence supporting a toxic action of levodopa or DA on dopaminergic neurons arises largely from in vitro, or test-tube studies.” (14).
As mentioned previously, a large body of evidence finds L-dopa harmless or even beneficial to DA neurons. Thus, Mean et al remark: “The effects of L-dopa on dopamine (DA) neurons are quite different in vivo (living organisms) and in vitro. Whereas, relatively low levels of L-dopa are toxic in culture…, the drug has not been seen to damage DA neurons in healthy animals….or humans…” (17). “It has not been possible to demonstrate a toxic effect of chronic levodopa treatment on dopaminergic neurons of healthy rats and mice.” (14) “Treatment for 120 days, (equivalent to roughly 10 human years) with maximally tolerated doses of L-dopa and carbidopa (Sinemet ®)…failed to produce biochemical, histological, or behavioural evidence of damage to the nigrostriatal dopaminergic tract in rats.” (18) A 1986 case report found that a 76 year old man who was treated with Sinemet ® L-dopa over 4 years, equivalent to 8-10kg of plain L-dopa. (19). The authors concluded: “Nevertheless, this case report emphasises that the burden of proof for a cytotoxic effect of levodopa in man remains with its proponents.” (19).
Many studies have actually found L-dopa to have a “neurotrophic”, or health-promoting effect on DA neurons. Thus Murer and colleagues report: “Our results clearly indicate the absence of toxicity of a pharmacologically effective chronic levodopa treatment on remaining dopaminergic neurons of rats with moderate and severe 6-OHDA-induced lesions. In addition, they clearly suggest that chronic levodopa administration induced a partial recovery of remaining dopaminergic neurons in moderately lesioned rats.” (14). Mena et al cultured DA neurons with cortical astrocytes (glial cells), then fed them L-dopa. “This study demonstrates that L-dopa has neurotrophic effects on DA neurons, stimulates elaboration of neuritis, and protects DA neurons from cell death.” (17). Han and colleagues found that giving L-dopa or rat mesencephalon (DA neurons) cultures increased levels of the critical antioxidant glutathione. They note: “When mixed mesencephalic cultures were exposed to strong oxidant stress….a loss of viability was seen. Cultures pre-treated with L-dopa….were protected from loss of viability.” (20). Uitti and co-workers studies survival data for all Olmsted county PD patients seen at the Mayo Clinic from 1964 to 1978. 61% of the 179 patients were levodopa-treated. They found that the treatment significantly lengthened life of PD patients compared to those not receiving the drug. “We believe our study provides compelling evidence in support of decreased mortality associated with the treatment in PD patients….Levodopa therapy improved survival unconditionally, in that it did not require early institution. We found no evidence for increased mortality in patients treated with levodopa, as one might expect hypothetically, on the basis of levodopa-related oxidative stress mechanisms.” (21).
As Murer and colleagues note, “Evidence supporting a toxic action of levodopa or DA on dopaminergic neurons arises largely from in vitro studies.” (14). More precisely, L-dopa toxicity evidence arises from one type of in vitro study – those wherein L-dopa is added to cultures containing DA neurons, but which are without glial/astrocyte cells (17, 20, 23-25). Glial/astrocyte cells are non-nerve cells that support, structurally and nutritionally, the nerve cells of the brain, retina and spinal cord (22). It is generally estimated that there are 10 times the number of glial cells than neurons in the brain. They surround nerve cells, providing mechanical support and nutritional/ antioxidant/ detoxicative/ neurotrophic services to neurons (17, 20, 26).
Mena et al. found that “In……embryonically derived glia-free (DA) neurons, …L-dopa is toxic.” (17). Han and colleagues reported that “…pure neuronal cultures (without glia) were exquisitely sensitive to the toxic effects of L-dopa.” (20). Michel and Hefti found both DA (formed from L-dopa in DA neurons) and 6-hydroxy DA (potentially formed through oxidation of DA) were potent neurotoxins to DA neurons (23). They also noted that “…our cultures contain a relatively small percentage of non-neuronal (glial) cells, and neurons are not embedded in a matrix of glial cells as in the living brain….” (23). Pardo and co-workers found that “…DA neurons are affected by L-dopa more severely, earlier, and with a lower concentration than non-DA cells.” (24). They also reported that “…our cultures….are enriched in neurons and almost (completely) lack glia (1-2% of the total population).” (24). Walkinshaw and Waters found “…that L-dopa induced death of catecholaminergic cells in vitro with an active programme of apoptosis.” (25). They also used “pure” neuronal cultures without glial cells.
In contrast, many studies have used L-dopa with DA neurons combined with (“co cultured with”) glial/astrocyte cells. They have uniformly found different (and positive!) effects when L-dopa is given to DA neuron/glial combinations, which is the way neurons naturally occur in the living brain (23). Thus, Mena and co-workers found that when L-dopa was added to “dopamine neuron/cortical astrocyte (glia) cultures,” “L-dopa…protected against dopamine neuronal cell death and increased the number and branching of (neurite) processes.” (17). Mean and colleagues reported elsewhere that “L-dopa kills dopamine neurons in culture but is the most effective drug for the treatment of Parkinson’s disease, where it exhibits no clear toxicity. While glial cells surround and protect neurons in vivo, neurons are usually cultured in vitro in the absence of glia. We treated fetal mid brain rat neurons with L-dopa mesencephalic glia conditioned medium ….Mesencephalic glia therefore produced soluble factors which are neurotrophic for dopamine neurons, and which protect these neurons from the toxic effects of L-dopa.” (27). Han et al. found that “…a mild oxidative stress (generated by L-dopa) is tolerated by primary cultures of rat fetal mesencephalon (which contain both DA neurons and glial cells)….Therefore, it appears that (pure) neuronal cultures do not respond (to L-dopa) in the same way as mixed cultures, which are comprised of both neuronal and glial cells.” (20). Desagher and co-workers observed that the “…neurotoxic effect of H2O2 (Hydrogen peroxide) on neurons co-cultured with astrocytes was strongly attenuated compared with that observed on a pure population of neurons…” (26). H2O2 is a neurotoxin generated from L-dopa/DA metabolism, which may be primarily responsible for the L-dopa toxicity observed in pure (without glial cells) neuronal cultures (17, 20).
Thus, the L-dopa controversy is clearly resolved. L-dopa (and its products, DA and 6-Hydroxy DA) toxicity is an artefact. An “artefact” is an artificially produced result, “…any structure of feature produced by the technique used and not occurring naturally.” (28). The studies showing L-dopa toxicity required a specific technique: adding L-dopa (or DA/6-hydroxy DA) to neurons without glial cells. Yet in the living brain, DA neurons are naturally surrounded by glial cells, and the number of glial cells surrounding DA neurons actually increases in Parkinson’s disease, in an effort to protect the remaining neurons (17). The L-dopa toxicity studies are classic artefacts, and thus of little or no “real world” significance.
The reader is also referred back to the various studies of L-dopa in living animals and humans summarised in the section headed “L-dopa : not harmful” earlier in this article. These in vivo studies, where L-dopa interacts with DA neurons in living brains naturally “conditioned by glia”, also found not only no harm, but clear evidence of benefits to DA neurons from L-dopa.
Although the “pure culture” L-dopa toxicity studies do not have direct application to what does on in the brain, they still have produced some interesting and potentially useful information. Although L-dopa was found toxic to DA neurons without glial protectors in these studies, it was typically found that various nutrients and pharmaceuticals could provide partial or even total protection against “L-dopa toxicity”. Thus, Han and co-workers observed that pure DA neuronal cultures were protected from L-dopa toxicity by ascorbate (Vitamin C) (20). Pardo and colleagues also reported, “In the human neuroblastoma cell line NB69, we have previously shown that co-treatment with AA (ascorbic acid) and Deprenyl, totally protected against L-dopa toxicity”. (24). Walkinshaw and Waters found that catecholaminergic PC12 cell death induced by L-dopa in glial-free culture was reduced 67% by co-treatment with vitamin E, 99% by vitamin C and 99.5% by reduced glutathione (25). Mena et al. found that both reduced glutathione, and NAC (N-Acetylcysteine), which induces intracellular glutathione production and is a direct antioxidant as well, provided major protection against L-dopa toxicity in glial free DA neuron cultures (17). Levites and colleagues discovered that the green tea polyphenol epigallocatechin-3-gallate (EGCG) provided almost total neuroprotection from 6-hydroxyDA toxicity in neuroblastoma cells (29). What these reports indicate is that any potential toxicity that might, in a worst-case scenario, somehow occur from use of L-dopa, can be prevented by appropriate nutrients and pharmaceuticals.
One problem that has been shown to be triggered by L-dopa in living rat brain is a diminution of complex 1 activity in the cerebral mitochondrial electron transport chain. This mitochondrial activity involves transferring electrons from complex 1 enzymes through complex 5 enzymes sequentially, to generate ATP energy (15). Przedborski and co-workers did find a drop in complex 1 enzyme activity after feeding test rats L-dopa at doses equivalent to human Parkinson patient doses (15). However, they also found that “Reduced glutathione, ascorbate, superoxide dismutase, and catalase prevented the effect of levodopa and dopamine on complex 1”. (15). They also observed that “Various inhibitors of monoamine oxidase also prevented the effect of dopamine”. (15). Of course, deprenyl is a well-known inhibitor of monoamine oxidase metabolism of dopamine (30). Shults and colleagues reported that “The activities of complex 1 and complex 2/3 in platelet mitochondria are reduced in patients with early, untreated Parkinson’s disease. Co-enzyme Q10 is the electron acceptor for complex 1 and complex 2. We found that the level of Co-enzyme Q10 was significantly lower in mitochondria from Parkinsonian patients that in mitochondria from age and set-matched control subjects and that the activities of complex 1 and complex 2/3 were significantly correlated”. (31) In a later clinical study, Shults and colleagues discovered that CoQ10 supplements could successfully “slow the progressive deterioration of function” in Parkinson’s disease compared to placebo, with the greatest benefit coming from the highest dose (1200mg/day) (32). Thus, supplements of Vitamin C, deprenyl and CoQ10 can presumably combat any potential diminution of complex 1 mitochondrial activity that L-dopa might otherwise induce.
Because L-deprenyl was known to reduce MAO-B activity, and MAO-B creates various toxins from metabolising dopamine, deprenyl was routinely combined with L-dopa in treating Parkinson’s disease (PD) patients during the 1980’s up to 1995. Then in 1995, A.J. Lees et al. on behalf of the UK-PD Research Group published a “bombshell” paper on L-dopa/deprenyl use in PD patients (33). The Research Group followed 520 PD patients for 5-6 years. Several hundred patients initially received 375mg L-dopa plus a peripheral decarboxylase inhibitor (PDI) daily, while several hundred others received 375mg L-dopa plus PDI along with 10 mg L-deprenyl daily. After 5-6 years, the mortality rate in the L-dopa/deprenyl group was 60% higher than in the L-dopa only group. The study authors therefore recommended that deprenyl not be used in PD treatment, with an implication being drawn by many life extension/deprenyl “enthusiasts” that L-dopa and deprenyl should not be combined in any context, not just in PD treatment.
The UK-PD study is the only one ever to find increased mortality with deprenyl use in PD, and the study has been severely criticised on various methodological grounds by various PD experts. In response to the study, the British Medical Journal published 7 letters in 1996 criticising the study on various methodological, statistical and comparative grounds (34). A 1996 Annals of Neurology article by 4 PD experts provided a detailed analysis of the Lees’ UK-PD Group study, raising many questions and criticisms. One key criticism is that the UK-PD study was open label (not blinded), and patients could be withdrawn from their treatment group and changed to other treatments (e.g. Parlodel) during the study. 52% of the L-dopa group and 45% of the L-dopa/deprenyl group changed treatment during the study, yet the allocation of end points (death) was based on patients’ original drug assignment, regardless of which drugs the patient was actually taking at the time of death! (This is called an “intent to treat” analysis). When the death rate was compared by Olanow and colleagues only between those remaining on their original drug assignment, there was no statistically significant difference in mortality between the L-dopa and L-dopa/deprenyl groups (35).
Another criticism raised was that a large number of other studies using deprenyl in PD, many combined with L-dopa, failed to find any difference in mortality between deprenyl groups and control groups (36). Olanow and colleagues also pointed out a glaring difference between the Lees study and other L-dopa with or without L-deprenyl PD studies. The death rate was 200-400% higher in both L-dopa only and L-dopa/deprenyl patients in the Lees study compared to that found in a meta-analysis of 5 previous studies, indicating that something odd was going on in the Lees study, irrespective of deprenyluse or not (35). Clinicians D. MacMahon and R. Bland also pointed out that the deprenyl therapy dose needs to be individually titrated, not just given at one (somewhat high) uniform dose, for maximum benefit and safety. They recounted that a quarter of their patients took less than the 10mg dose, with one elderly gentleman finding a mere 1.25mg deprenyl average daily dose (from taking one half 5mg tablet every other day) as his optimal dose (37). A further “refutation” of the Lees UK-PD study occurred in 2000. Donnan and co-workers published a study showing the results of comparing PD patients treated with L-dopa for seven years, to matched control (“comparators”). They concluded that “subjects with PD had twice the rate of mortality relative to age, and sex-matched comparators. However, those subjects who received selegiline (deprenyl) at any time in combination with co-careldopa or co-beneldopa (i.e. L-dopa plus a peripheral decarboxylase inhibitor) showed no significant difference in mortality compared with comparators”. (38). This study thus indicated that the combination of L-dopa plus deprenyl cut the death rate of PD patients dramatically, equalizing (lowering) it to the death rate of age and sex-matched controls without PD and taking neither drug! That is hardly evidence of the toxicity of combined L-dopa/deprenyl treatment.
Already in 1996, Olanow and colleagues had concluded their paper reviewing the UK-PD study with the statement: “It is our opinion that the evidence in support of discontinuing selegiline (deprenyl) in levodopa treated patients, because of fears of early mortality, is not persuasive. Accordingly, we do not recommend that selegiline be withheld in PD patients based solely on the results of the UK study”. (35). Given the data cited in this section, and the further detail contained in references 34-38, I can only conclude there is no good reason to avoid combining L-dopa with deprenyl. Indeed, there is positive reason to do so, given Pardo and co-workers success in completely reversing L-dopa toxicity in pure (with protective glial cells) neuroblastoma cell cultures with ascorbate plus deprenyl, in case one’s own glial cells should somehow “fall down on the job” in protecting one’s own DA neurons when taking supplementary L-dopa.
[Ed.- A report in the British Medical Journal, August 14, 2004 stated that “deprenyl can slow Parkinson’s disease safely.” They further reported that deprenyl can reduce disability and the need for L-dopa, and that the drugs were not associated with increased mortality. In 17 trials involving 3525 patients wit early Parkinson’s disease, the analysis showed no significant differences in mortality, but did find that patients using deprenyl along with L-dopa had better total scores and activity of daily living. In conclusion Professor Keith Wheatley and his colleagues from the University of Birmingham concluded; “Our review provides no evidence that mortality is increased by selegiline (deprenyl) and suggests that this inexpensive drug could be one of the most clinically effective and cost-effective treatments available for early Parkinson’s disease.” They also believe that the 1995 study that suggested there was increased mortality was a chance finding].
From the data summarised in this paper, it is clear that L-dopa has a safe and useful place in the nutrition/pharmaceutical “life enhancement” strategy. Increasing growth hormone output, preserving healthy, vigorous and well-coordinated movement ability into old age, and gaining anti-depressant/ assertiveness/ increased goal-oriented drive benefits from the chief “warming” neurotransmitter dopamine, whose immediate precursor is L-dopa, are sound reasons for L-dopa use outside a PD content. It should be pointed out, however, that the L-dopa used in the human growth hormone studies was “plain” L-dopa, while the “gold standard” L-dopa (Sinemet ®) used in PD, and which is the most widely used form of L-dopa worldwide, is a combination of L-dopa with a peripheral decarboxylase inhibitor (PDI). The PDI prevents L-dopa from being converted to dopamine outside the brain, thereby reducing side effects (such as nausea) while simultaneously getting more L-dopa to the brain (where the PDI cannot enter). It is generally accepted that 100mg Sinemet ® L-dopa is equal to 400-500mg L-dopa alone (19). Thus 100mg Sinemet ® will approximately provide the typical 500mg L-dopa alone dose used in the human growth hormone studies. However, if the Sinemet ® used is a sustained release variety, it will need to be carefully chewed up (sublingualised) to mimic the fast release L-dopa used in the growth hormone studies. For the movement regulation benefits, as well as for the “warming” neurotransmitter benefits, the sustained-release form is preferable. To maximise the benefit/risk ratio, anyone using L-dopa/ Sinemet ® without medical supervision/monitoring, should probably restrict the dosage to 100mg daily. It is also important to note that dopamine is a stimulating neurotransmitter: Coffee works in part through stimulating dopamine release. Some people will be more sensitive to L-dopa than others. Such effects might look like those from drinking too much coffee, and may include irritability, insomnia, agitation, restlessness, etc. If this occurs, reduce dose to 50mg daily, or take it every other day. If an extreme overreaction occurs, you’re dopamine hypersensitive, and its use should be discontinued.
In addition to taking the 100mg Sinemet ® dose daily (or less if needed), prudence suggests taking one or more of the previously mentioned L-dopa neuro-protectors: vitamin C (ascorbate), vitamin E (d-alpha plus d-gamma tocopherols), glutathione, N-acetylcysteine, CoQ10, EGCG from green tea extract, and L-deprenyl. Two recent studies have shown that a 1.25mg sublingual (buccal) form of deprenyl (selegiline) provides superior results to 10mg of swallowed “conventional” deprenyl (29, 40). There was less of a problem with the so-called “cheese effect” (intestinal MOA-A inhibition) with the 1.25mg sublingual form. There were significantly reduced levels (80% or more reduction) of the toxic deprenyl metabolites amphetamine and methamphetamine with the sublingual form. Blood levels were more stable and uniform. Patients who compared the 1.25mg buccal form to the 10mg conventional dose generally preferred the 1.25mg conventional dose generally preferred the 1.25mg form. A similar degree of MAO-B inhibition occurred with either form. Those wishing to emulate this dosing method can simply take one drop (1mg) of liquid deprenyl citrate under their tongue, (and don’t wash it down the liquid immediately afterwards).
This would actually equate to an approximate 8mg conventional dosage. Taking one drop every other day would approximate 4mg conventional dose per day. Taking one drop every third day would approximately be equivale