Parkinson's Disease

Enhancing Levodopa Therapy

Eventually, all patients who have Parkinson’s will need to take levodopa, which is converted into dopamine in the brain. As mentioned previously, while levodopa therapy is effective, after about 5 years, the drug begins to lose effectiveness. Eventually, higher doses are needed. The most commonly used levodopa drug is a drug that combines levodopa with carbidopa.

Dosage of the levodopa/carbidopa drug must be individualized based on previous drug treatments, making adjustments by adding or omitting ½ tablet to 1 tablet daily (Silverman HM 2000). Levodopa/carbidopa is also available in a controlled-release, slow-acting form, which is designed to give a smoother release of the drug. Often, somewhat more of the controlled-release form of the drug is required to obtain the same degree of relief obtained from the standard form. The controlled-release form of levodopa/carbidopa is started at a dosage equal to 10 percent more levodopa daily than the standard form of levodopa/carbidopa. The standard form should be taken with food, but the controlled-release form should be taken on an empty stomach (Silverman HM 2000). Food interactions, particularly protein, may impair the effectiveness of the controlled-release form because less of the drug may be absorbed and absorption may be more erratic (PDR 2002).

Another levodopa drug prescribed is a combination of levodopa and the decarboxylase inhibitor benserazide. Further improvement in availability of levodopa to the brain can be made by adding the generic drug entacapone. Entacapone is prescribed when the levodopa/carbidopa combo begins to wear off too soon. Entacapone extends the effect of each dose of levodopa/carbidopa, freeing the patient from stiffness and tremors for a longer period (PDR 2002).

Levodopa is sometimes prescribed in conjunction with a class of drugs called catechol-O-methyltransferase (COMT) inhibitors. These drugs prevent conversion of levodopa to 3-O-methyldopa, thereby increasing the available pool of dopamine. Two COMT inhibitors approved in the United States are entacapone and tolcapone. Both drugs are rarely used as monotherapy but instead enhance the effectiveness of levodopa by increasing the length of time between doses of levodopa (off-periods). A combination of levodopa, carbidopa, and entacapone is also available. Rasagiline can also be used in conjunction with levodopa.

After 5 years of continual use of levodopa, motor fluctuations and abnormal involuntary movements commonly begin to develop. If these involuntary movements are severe and difficult to control by other means, oral levodopa/carbidopa solutions may be beneficial (Kurth MC et al 1993). One study found an 80 percent improvement in severe dyskinesia in patients taking a solution of levodopa/carbidopa tablets combined with ascorbic acid. Ten tablets and 2 g of vitamin C were dissolved in 1 liter (L) of water. Each standard 5 milliliter (mL) teaspoon contained 5 mg of levodopa. An amount proportional to the usual daily intake was taken every hour and adjusted for optimal response. If one were to use this approach, it would be best to have the formulation prepared by a compounding pharmacist to avoid accidental levodopa overdose.

Long-term treatment with levodopa may also result in neurotic or psychotic symptoms (Chacon JR et al 2002; Garcia-Escrig M et al 1999). These symptoms are likely due to accumulation of the oxidation products of levodopa and dopamine in the brain. Similarly, the conditions of schizophrenics deteriorate when given levodopa. In schizophrenia, high doses of niacin/niacinamide and ascorbic acid can minimize or prevent hallucinogenic symptoms.

Levodopa competes with and ultimately reduces brain uptake of tyrosine and tryptophan, which may explain some of its adverse effects (Riederer P 1980), including depression, psychosis, and paranoid hallucinations. L-tryptophan supplementation (150 to 450 mg/day) may reduce visual hallucinations induced by levodopa (Rabey JM et al 1977; Gehlen WMJ 1974).

After about 10 years, another vicious cycle begins in which the drug becomes less effective, causing either spastic, uncontrolled movements or long periods of rigidity. Administering levodopa in different ways has the potential to avoid or reverse this negative spiral.

The consistent use of sufficient levodopa to prevent off-periods appears to overload the brain with potentially toxic or obstructive breakdown products. Because both the eventual loss of effectiveness and increased adverse effects seem to mainly result from the oxidation of dopamine and storage of the resulting toxic products in the brain cells, it is important to take regular “rest periods” from levodopa. Rest periods may be accomplished by withholding levodopa each day at bedtime and then reintroducing it the following morning when the body requires it. If you have low to moderate requirements for levodopa, this method works well (and many patients follow it).

• If you take high levels of levodopa and use frequent on-periods/off-periods, you have more difficulty than patients who have low to moderate requirements. You may find it helpful to take the final levodopa dose of the day so that withdrawal symptoms (or an off-period) are expected to start at about bedtime. To ease your symptoms, take the following relaxation supplements shortly before dinner and about 2 hours before withdrawal time. If the starting doses are not fully effective, try different timing, dosages, and combinations:
  • Magnesium citrate—320 milligrams (mg)
  • L-tryptophan—1000 mg
  • Melatonin—300 micrograms (mcg) to 10 mg
  • Vitamin C—1 to 3 grams (g)
  • Natural vitamin E—400 International Units (IU)
  • Gamma tocopherol—200 mg
  • Grape seed extract—200 mg
  • Any other desired antioxidant
  • Phosphatidylserine—100 mg
  • A good multivitamin mix

If you have advanced Parkinson’s disease, you may initially experience a period of uncontrolled movements followed by a period of rigidity. After an hour or two, you should be able to relax, making sleep possible. During the night and in the morning, full mobility without any disabling adverse effects may be possible. However, your energy level will be lower than when you are taking levodopa. Your energy level will progressively become lower during the morning. At this time, your body is operating on dopamine that is stored in the brain from excess levels of levodopa.

As an alternative method, try taking sufficient levodopa before bedtime so that withdrawal occurs while you are asleep. If you can fall asleep using this technique and not wake up during the night with withdrawal symptoms, this might be the preferred method.

Upon rising, the following supplements may help to stimulate natural dopamine production, allowing you to delay the start of daily levodopa therapy. As soon as possible after rising, drink strong coffee and take the following nutrients:

• L-tyrosine—1 g (take well before the protein drink described below)
• ALC—2 g
• NADH—5 to 10 mg
• A good antioxidant multi-nutrient mix

After taking these supplements, prepare a protein drink with a spoonful each of wheat or barley grass powder, spirulina, chlorella, and several spoonfuls of bee pollen. Stir or blend in a liquid (such as grape juice, black currant juice, or fresh vegetable juice) and drink before or with breakfast, 20 to 30 minutes after drinking coffee. Optionally, drink additional coffee. Take additional stimulating supplements, starting with small amounts and increasing them gradually. Try different combinations of the following:

• An antioxidant multi-nutrient mix
• Niacinamide—500 mg
• Vitamin C— 2 to 3 grams
• Vitamin E—400 IU
• CoQ10—1200 to 2400 mg/day
• Different stimulating herbs such as Ginkgo biloba, ginseng, or licorice root (avoid licorice root if you have elevated blood pressure)

The goal is to delay taking your first levodopa dose for as long as possible. Once daily levodopa therapy has started, however, take levodopa at sufficiently close intervals to prevent any unexpected off-periods before beginning the scheduled nightly withdrawal. If you start taking levodopa much later in the day, repeat most of the supplements listed above every 2 hours until about 2 hours before your first dose of levodopa.

With continued therapy, withdrawal symptoms will hopefully ease. Ideally, you will fall asleep without noticing distressing symptoms. Tremors that occur during the day and psychiatric or behavioral problems should also gradually ease or disappear. Taking sufficient amounts of magnesium and tryptophan helps overcome rigidity, tremors, constipation, and insomnia, while taking sufficient amounts of antioxidants (combined with nightly withdrawal of levodopa) helps overcome hallucinations and other psychiatric symptoms.

To keep the nightly withdrawal period as short as possible, let your levodopa level drop steeply after the last tablet. It appears there is a range of brain levodopa levels within which uncontrolled movements are most likely (not only when overdosing, but also when withdrawing). To move quickly through this range, do not take the last tablet after a longer time interval than previous tablets or at a lower dose or after a long-acting tablet in the late afternoon.

However, because experiences are different for everyone, experiment with the various techniques suggested. Increase the amount and variety of supplements gradually. After you notice improvement, stay with a comfortable maintenance dose, which may result in a reduction of some supplements. Also, remember that any emotional, nutritional, or chemical stress can increase your symptoms.

Taking Drug Holidays

The best way to improve the symptoms of advanced Parkinson’s disease, especially if levodopa therapy is no longer effective, is to take a “drug holiday” (in which you stop taking levodopa for a short time). A drug holiday should improve the response to levodopa and reduce adverse effects. Drug holidays, if they are attempted, should be done only under the direct supervision of a physician in a hospital setting. Withdrawal may lead to severe depression, immobility, and aspiration pneumonia.

Before taking a supervised drug holiday, it is best to wait until you have augmented levodopa therapy with the supplements recommended in this chapter and until you have been on an effective dietary program for several weeks or months. While under your physician’s guidance, try stopping all levodopa therapy for up to 1 week, while still continuing to take the recommended amounts of supplements.

The Importance of Diet

Levodopa intake must be adjusted based on diet. With a high-protein diet, levodopa absorption is delayed and less levodopa reaches the brain, which may worsen symptoms. High intake of amino acids significantly reduces the motor response to levodopa (Mizuta E et al 1993), and levodopa competes with and reduces brain uptake of tyrosine and tryptophan, which may contribute to some of its adverse effects (Riederer P 1980). With a high-carbohydrate diet, more levodopa reaches the brain, and dyskinesia may develop. It is best to eat only one protein meal daily, preferably in the evening after taking the final levodopa dose for the day.

Patients with Parkinson’s disease may not tolerate sharp cheeses, red wine, dark chocolate, nutmeg, smoked fish, or other foods containing tyramine, because they are more likely than the general population to have a genetic abnormality in the biochemical detoxification process by which sulfur reacts with cysteine to form sulfate (McFadden SA 1996). Patients with Parkinson’s should avoid these foods because tyramine can stimulate MAO-A, an enzyme that breaks down the neurotransmitters epinephrine and norepinephrine. Both epinephrine and norepinephrine are produced from dopamine, so stimulation of MAO-A by tyramine may further deplete dopamine levels.

It is best to choose organic chicken or low-mercury fish (both of which are good sources of protein) for your one protein meal a day. Red meat is rich in iron and should be avoided (Powers KM et al 2003). High intakes of sugar and animal fat, especially from junk food, increase body fat, reduce lean muscle mass, decrease delivery of brain fuel, and make brain cells more susceptible to toxins. Inactivity and inadequate exposure to sunlight may further exacerbate abnormalities in body composition (Petroni ML et al 2003). A high-fat diet may also predispose a person to coronary artery disease, reducing blood flow and oxygen delivery to the brain.

The benefits of coffee and tea may include the brain-stimulating effect of caffeine, the niacin found in coffee, and the polyphenols or other nutrients in both beverages (Checkoway H et al 2002).

For a person in the early stages of Parkinson’s disease, regular exercise, assistive devices in the home, and participation in support groups and organizations may improve morale and mobility. Physical therapy or muscle strengthening may improve function in daily activities. Depending on individual limitations, therapy may focus on mobility, range of motion, muscle tone, gait, or balance (Hirsch MA et al 2003; Van Vaerenbergh J et al 2003). Speech therapy may reduce difficulties in both speaking and swallowing.

Even without formal therapy, regular weight-bearing exercise (such as walking, jogging, or dancing), swimming, or gardening may be helpful. Stretching before and after exercise improves blood flow to the muscles, reduces stiffness, and improves flexibility and balance. Energy level should determine exercise intensity and duration (Sutoo D et al 2003).

In the early stages of Parkinson’s disease, the affected person tends to walk with a stooped, shuffling gait. If you have Parkinson’s, try to stand as upright as possible, with your head straight up and aligned over your hips. Your feet should be spaced 8 to 10 inches apart. A good exercise is to take long strides, lifting the legs and swinging the arms. Supportive walking shoes may improve stability. In the event of becoming stuck in place (“freezing”), rocking gently from side to side or pretending to step over an object on the floor may overcome immobility.

Practicing tai chi or performing other exercises that improve balance may help prevent falls. Remove area rugs, secure loose carpeting, install handrails and grab bars, stow electrical and telephone cords, and place the telephone within easy reach (or carry a cordless phone). For easier dressing, allow plenty of time, lay out your clothes nearby, and choose garments that slip on or fasten easily.

Other Supplements

Many additional supplements may enhance energy production, reduce oxidative stress, and/or improve cognitive function in patients with Parkinson’s disease. These supplements showed benefit in animal models, are generally well tolerated by patients, and show promise for further testing in Parkinson’s disease (Beal MF 2003).

Phosphatidylserine. Phosphatidylserine (PS), a naturally occurring component found in every cell membrane of the body, appears to reduce oxidative stress (Chong ZZ et al 2004). Brain levels of PS typically decline with age, suggesting that supplementation might improve neural function, help maintain cell membrane integrity, and protect brain cells. Lecithin, which contains all the phosphatides found naturally in cell membranes, helps to increase the cell membrane ratio of phosphatidylcholine/phosphatidylethanolamine to cholesterol. This maintains cell membrane structure while increasing cell membrane fluidity.

Essential fatty acids. Essential fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been shown to increase dopamine production in cultured brain cells of mice (Heller A et al 2005). This is an intriguing finding because fatty acids are known to reduce inflammation in many tissues, and inflammation has been implicated in the causation of Parkinson’s disease. DHA, in particular, is essential to brain health because it constitutes between 30 percent and 50 percent of the total fatty acid content of the human brain (Young G et al 2005). DHA has also been shown to increase PS (Akbar M et al 2005).

Scientists have recently developed a compound that takes DHA and binds it to a lecithin extract that has itself been shown to reduce the risk of cognitive dysfunction in the elderly. Laboratory studies have documented that this patented compound delivers higher DHA concentrations to brain cells.

Combining DHA with PS. Scientists have discovered that DHA attaches itself to PS molecules and acts as an important ally in the promotion of brain cell energy production. A number of brain researchers, including Dr. Norman Salem, head of the Laboratory of Membrane Biochemistry and Biophysics at the National Institutes of Health, are convinced that PS with attached DHA is among the most critically important molecules for healthy brain function. Scientists believe that PS supplementation works optimally if DHA levels are kept commensurately high (Kidd PM 2005).

In response to an increasing body of research showing the intricate relationship between DHA and PS, scientists have developed a PS-DHA compound that can be incorporated directly into the membranes of brain cells.

To evaluate the effects of PS-DHA on memory loss, a study was done on middle-aged rats that had laboratory-induced accelerated brain aging. Administering traditional sources of DHA did not have an effect on this experimental model, but the group receiving the PS-DHA compound was able to attain a great deal of protection against this neurological challenge. When the brains of these animals were analyzed, there was more DHA incorporated in the cells of the group receiving the PS-DHA than in those receiving other omega-3 agents.

Dehydroepiandrosterone (DHEA) improves neurological function and protects against age-related diseases (Cyr M et al 2000; Goncharova ND et al 2000; Azuma T et al 1999). The positive effects of DHEA on oxidative stress and on NMDA receptors suggest theoretical benefit in patients with Parkinson’s disease (Genedani S et al 2004).

Parkinsonism vs. Parkinson’s Disease

A multitude of disorders and conditions, from drug use to stroke to head injuries, may result in symptoms that are similar to Parkinson’s disease. People with these conditions have parkinsonism, or Parkinson’s disease–like symptoms. It is estimated that idiopathic Parkinson’s disease accounts for about 75 percent of cases of parkinsonism. The rest are associated with a multitude of risk factors, including head injury, exposure to pesticides, consumption of well water, and living in rural areas (Kasper DL et al 2004). Although these cases of parkinsonism have not been studied to the same extent as Parkinson’s disease, the condition is marked by the same underlying movement disorders and symptoms. Thus, it makes sense for people who have mild parkinsonism to follow the same approach as people in the early stages of Parkinson’s disease. The antioxidants (especially CoQ10) and other nutrients improve symptoms.