Medical Options for Parkinson’s Disease

The conventional medical standard of care for Parkinson’s disease focuses on symptomatic relief using pharmaceutical agents. These drug treatments try to accomplish this by either increasing the levels of dopamine or mimicking its action. However, these approaches do not address the underlying causes of Parkinson’s disease that lead to neurodegeneration.

Levodopa (L-DOPA) / Carbidopa

Levodopa (L-DOPA) has been the standard of care for the management of Parkinson’s disease since its approval in 1970. L-DOPA is a direct precursor of dopamine and is made into dopamine in the body by and enzyme called aromatic L-amino acid decarboxylase (AADC). Although dopamine cannot pass through the blood-brain-barrier, L-DOPA can; when L-DOPA is taken orally, some of the L-DOPA crosses the blood-brain-barrier and is converted into dopamine by AADC. This temporary increase in dopamine levels provides relief of Parkinson’s disease symptoms if the dopamine levels are high enough.

Unfortunately, the dopamine levels needed to restore proper function for most people with Parkinson’s disease are higher than can be achieved with L-DOPA alone due to a number of unpleasant side effects from unopposed L-DOPA administration, including nausea, dystonia, involuntary movements, heart palpitations, paranoia, psychotic episodes, depression, suicidal ideation, dementia and urinary retention. Many of these side effects are thought to be due to the peripheral conversion of L-dopa into dopamine (i.e., conversion of L-dopa into dopamine outside of the brain). To counter the effects of this peripheral conversion of dopamine, L-DOPA is typically administered with a drug called carbidopa; carbidopa inhibits the peripheral conversion of L-DOPA into dopamine by inhibiting the peripheral AADC enzymes. This results in the need for less L-DOPA to obtain beneficial effects in the brain while reducing side effects, especially nausea and gastrointestinal complaints.

Unfortunately, unopposed L-DOPA and the use of carbidopa have a number of detrimental long-term effects.

The Downside of L-DOPA and Carbidopa

The unopposed use of L-DOPA (i.e., using L-DOPA without the proper balance of other amino acid precursors) has a number of detrimental effects in the body. As noted in the literature, administration of only L-dopa or improperly balanced L-dopa causes depletion of:

• L-tyrosine
• Serotonin
• L-tryptophan
• Sulfur amino acids (glutathione and S-adenosyl methionine)
• Epinephrine

The adverse effects due to these L-DOPA induced depletions are detailed below. The only known solution to these issues is to administer the proper balance of these other amino acids along with L-Dopa in order to prevent depletion.

In addition, the use of unopposed orally administered L-DOPA over time results in diminished production of endogenous L-dopa (i.e., L-DOPA that is naturally produced in the body). Once more, it is known that the use of unopposed L-DOPA results in the development of movement disorders called dyskinesias after 5-10 years of use in most cases. Dyskinesias are the result of permanent L-DOPA induced damage to the neurons, which causes inappropriate signaling between areas of the brain that coordinate movement. This inappropriate signaling results in uncontrollable, involuntary movements and can also lead to breathing irregularities. Over time (usually after about 5 years), responsiveness to L-DOPA as a therapy declines due to the L-DOPA induced damage to the neurons. This leads to increased dyskinesias and the rapid return of Parkinson’s symptoms.

Carbidopa also has a very long list of adverse effects in the body. As stated earlier, carbidopa acts by inhibiting and blocking the enzyme aromatic L-amino acid decarboxylase (AADC). This enzyme catalyzes the synthesis of both serotonin and dopamine in the periphery (i.e., outside the central nervous system). Therefore, carbidopa’s inhibition of AADC causes peripheral serotonin, dopamine, norepinephrine and epinephrine depletion due to AADC inhibition with a subsequent reduction in the synthesis of these neurotransmitters.

Administration of carbidopa/L-DOPA preparations thus lead to a “double depletion” of peripheral serotonin. One cause is due to carbidopa’s inhibition of AADC; the other is improperly balanced administration of L-DOPA, which leads to decreased serotonin synthesis through competitive inhibition along with increased metabolism (i.e., destruction) of serotonin.

Once more, recent research conducted by Marty Hinz, MD has found that carbidopa induces a system-wide and catastrophic depletion in vitamin B6 by irreversibly binding to vitamin B6 and vitamin B6-depdenent enzymes and permanently inactivating them (aromatic L-amino acid decarboxylase (AADC) is one of these enzymes). This induces a profound long-term vitamin B6 deficiency, resulting in an incredibly long list of side effects, as vitamin B6 impacts the function of over 300 enzymes and proteins in the body.

Table 1: Side effects and adverse reactions associated with carbidopa

Note: Data from Hinz et al.

Interestingly, this list of adverse effects encompasses all the symptoms associated with the progression of Parkinson’s disease. It has been postulated that carbidopa is in fact the reason for the progression of Parkinson’s disease as well as the reason for the dramatic 328.7% increase in the death rate due to Parkinson’s disease since the drug was first released.

Categorization of Side Effects and Adverse Reactions

The FDA-approved prescribing information for carbidopa/L-DOPA preparations lists many side effects, adverse reactions and problems associated with carbidopa/L-DOPA administration. Marty Hinz, et al. has placed each side effect in one or more of the following six categories of carbidopa/L-DOPA side effects:

• Category 1: Problems caused by depletion of serotonin by L-DOPA: Tachyphylaxis (i.e., the L-DOPA stops working).
• Category 2: Problems caused by imbalance of serotonin and dopamine: Nausea, vomiting, anorexia, weight loss, decreased mental acuity, depression, psychotic episodes including delusions, euphoria, pathologic gambling, impulse control, confusion, dream abnormalities including nightmares, anxiety, disorientation, dementia, nervousness, insomnia, sleep disorders, hallucinations and paranoid ideation, somnolence (sleepiness), memory impairment, and increased libido.
• Category 3: Problems caused by dopamine fluctuations due to inadequate tyrosine levels: On-off effect, motor fluctuations, dopamine fluctuations, implicated as an etiology of dyskinesia.
• Category 4: Problems caused by depletion of sulfur amino acids by L-DOPA: Bradykinesia (slowness of movement), akinesia (los of movement), dyskinesia (abnormal or impaired movement), dystonia (involuntary, sustained muscle contraction), chorea (involuntary jerky movements affecting especially the shoulders, hips and face), fatigue, abnormal involuntary movements, and depletion of glutathione potentiating further dopamine neuron damage by neurotoxins.
• Category 5: Problems caused by paradoxical amino acid reactions: Confusion, dizziness, headache, palpitations, difficult or labored breathing, anxiety, agitation, increased tremor, faintness, exacerbation of any disease related to the monoamine neurotransmitters (serotonin, dopamine, norepinephrine and epinephrine), and exacerbation of any central disease process associated with the serotonin and catecholamine systems.
• Category 6: Peripheral problems caused by peripheral depletion of serotonin and catecholamines by carbidopa: Glossitis, leg pain, ataxia, falling, gait abnormalities, blepharospasm, trismus, increased tremor, numbness, muscle twitching, peripheral neuropathy, myocardial infarction, flushing, oculogyric crises, diplopia, blurred vision, dilated pupils, urinary retention, urinary incontinency, dark urine, hoarseness, malaise, hot flashes, sense of stimulation, dyspepsia, constipation, palpitation, fatigue, upper respiratory infection, bruxism, hiccups, common cold, diarrhea, urinary tract infections, urinary frequency, flatulence, priapism, pharyngeal pain, abdominal pain, bizarre breathing patters, burning sensation of tongue, back pain, shoulder pain, chest pain (non-cardiac), muscle cramps, paresthesia, increased sweating, falling, syncope, orthostatic hypotension, asthenia (weakness), dysphagia, Horner’s syndrome, mydriasis, dry mouth, sialorrhea, neuroleptic malignant syndrome, phlebitis, agranulocytosis, hemolytic and nonhemolytic anemia, rash, gastrointestinal bleeding, duodenal ulcer, Henoch-Schonlein purpura, decreased hemoglobin and hematocrit, thrombocytopenia, leukopenia, angioedema, urticaria, pruritus, alopecia, dark sweat, abnormalities in alkaline phosphatase, abnormalities in SCOT/AST, SGPT/ALT, abnormal Coombs’ test, abnormal uric acid, hypokalemia, abnormalities in blood urea nitrogen (BUN), increased creatinine, increased serum LDH, and glycosuria.

Dopamine Agonists

Another medical approach that is sometimes used to try and restore dopaminergic signaling in Parkinson’s disease is taking a drug that acts as a dopamine agonist. A dopamine agonist is a drug containing a molecule that attempts to mimic dopamine and dock with the dopamine receptor in an attempt to trick the body into thinking there is more dopamine than there actually is. Dopamine agonists are usually only used in younger people or in the very early stages of Parkinson’s disease.

Research comparing the results of dopamine agonists or L-DOPA is conflicting and inconsistent. However, it is known that dopamine agonists pose a greater risk of series side effects than L-DOPA and are therefore not as tolerable for some people. Side effects of dopamine agonists include: hallucinations, psychosis, weight loss, nausea, insomnia, unusual tiredness or weakness, dizziness or fainting, orthostatic hypotension (low blood pressure upon standing), pathological addiction and compulsive behavior.

Monoamine Oxidase-B Inhibitors

Monoamine oxidase refers to a family of enzymes that are responsible for the oxidation (i.e., breakdown) of monoamine neurotransmitters, including serotonin, dopamine, norepinephrine, epinephrine and melatonin. Humans have two main subtypes of monoamine oxidase (MAO): MAO-A and MAO-B. Serotonin, norepinephrine, epinephrine and melatonin are mainly broken down by MAO-A. Both forms of MOA break down dopamine. Therefore, medications that block MAO-B are sometimes used to block the breakdown of dopamine in an attempt to compensate for the diminished production of dopamine that occurs in Parkinson’s disease.

Selegiline and Rasagiline are the two most common MAO-B inhibitors used for people with Parkinson’s disease. These drugs are commonly used in early-stage Parkinson’s, either alone or in combination with L-DOPA. Research has shown that these medications may slow the onset of symptoms associated with Parkinson’s disease if initiated within five years of diagnosis.

Side effects of these medications may include dizziness, dry mouth, sleepiness and an overall stimulating effect.

Deep-Brain Stimulation

A conventional medical therapy of last resort is deep-brain stimulation (also referred to as ablative therapy) where areas of the brain that are normally under the control of dopamine are destroyed. In some cases, this helps alleviate symptoms, but at a very high cost. Deep-brain stimulation involves boring small holes in the skull to implant electrodes into the brain and surgery to implant a signaling device that contains batteries in the chest. This surgery isn’t a one-time procedure, as the batteries that are implanted into the chest have a limited life span and must be replaced, which requires additional surgery.

Only a small percentage of people with Parkinson’s disease are candidates for deep-brain stimulation, and there are many risks, including: surgical risks: bleeding in the brain, stroke, infection, breathing problems, nausea and heart problems: side effects after surgery: seizure, infection, headache, insomnia, and memory problems; side effects of stimulation: numbness or tingling sensations, muscle tightness of the face or arm, speech problems, balance problems, lightheadedness and unwanted mood changes, such as mania and depression.