What is Parkinson's Disease?

Parkinson’s disease is a degenerative disease of the central nervous system resulting from depletion of dopamine-producing cells in the brain. While the underlying cause of the disease is not clearly understood, depletion of dopamine-producing cells may be exacerbated by oxidative stress, inflammation, and mitochondrial dysfunction. Parkinson’s patients generally experience decline in motor function and eventually cognitive decline and dementia.

Parkinson’s may manifest as a primary condition or secondary to another condition, such as a brain tumor, exposure to toxins, or after a viral infection.

Existing conventional treatments do not slow or reverse the course of the disease. However, natural interventions such as coenzyme Q10 and creatine may support neuronal health and promote mitochondrial function.

What are the Risk Factors for Parkinson’s Disease?

• Family history/genetic predisposition
• Exposure to pesticides or other toxins like carbon monoxide
• Brain tumor
• Viral encephalitis
• AIDS
• Chronic constipation
• Repeated blows to the head (eg, professional fighters or football players)
• Certain medications
• Stroke

What are the Signs and Symptoms of Parkinson’s Disease?

Note: Symptoms of Parkinson’s generally progress slowly. Tremors are often the first sign.

• Tremors, often in the hand
• Muscle cramping or rigidity
• Pain throughout the body
• Slow movements
• Incontinence or constipation
• Difficulty swallowing and/or controlling saliva
• Dizziness
• Sleepiness
• Depression and/or anxiety
• Hallucinations or frightening dreams
• Cognitive decline and/or dementia

What are Conventional Medical Treatments for Parkinson’s Disease?

• Levodopa, or L-DOPA
• Monoamine oxidase-B inhibitors (eg, selegiline and rasagiline)
• Catechol-O-methyltransferase inhibitors
• Dopamine agonists
• In extreme cases, ablative surgery or deep brain stimulation

What are Emerging Therapies for Parkinson’s Disease?

• Amantadine, an antiviral drug, may help reduce the side effects of L-DOPA
• Nicotine
• Granulocyte colony-stimulating factor (G-CSF), a growth factor that promotes creation of new neurons, has shown promising results in animal models.
• Stem cell replacement therapy
• Cognitive-behavioral therapy

What Dietary and Lifestyle Changes Can Be Beneficial for Parkinson’s Disease?

• Physical therapy and exercise
• For patients on L-DOPA, protein meal distribution may be recommended (ie, eating dietary protein separate from dosing with L-DOPA)

What Natural Interventions May Be Beneficial for Parkinson’s Disease?

• Coenzyme Q10 (CoQ10). Patients with Parkinson’s appear to be deficient in CoQ10. Supplementation may slow the progressive deterioration of function in Parkinson's disease (Shults 2002) and have a neuroprotective effect.
• Creatine. Creatine deficiency is associated with neurological damage. Some studies indicate supplementation may slow disease progression.
• Omega-3 fatty acids. Levels of omega-3 fatty acids in nerve cell membranes decrease with age, oxidative stress, and in neurodegenerative disorders such as Parkinson's disease. Supplementation may favorably modify brain function and protect brain health.
• Coffee. Coffee consumption is linked to a reduced risk of developing Parkinson’s disease. Coffee extracts have been shown to act via mechanisms similar to some pharmaceutical Parkinson's therapies.
• Nicotinamide riboside. Decline in NAD+, a cofactor critical for regulating cellular energy balance, is associated with Parkinson’s disease. Administering nicotinamide riboside, an NAD+ precursor, may offer benefits in Parkinson’s patients.
• B vitamins. B vitamins (eg, folate, B12, B6, etc.) lower homocysteine levels. Many studies have shown B vitamins to have beneficial effects in Parkinson’s patients, and supplementation may be recommended in patients taking L-DOPA.
• Vitamin D. Parkinson’s patients tend to have lower serum vitamin D levels than those without the disease. Several studies have shown that higher levels of vitamin D protect against the onset of Parkinson's disease symptoms.
• Other natural interventions that may benefit Parkinson’s patients include carnitine, green tea, resveratrol, wild green oat extract, pyrroloquinoline quinone (PQQ), and others.

Parkinson's disease is a degenerative disease of the central nervous system resulting from depletion of dopamine-producing cells in a region of the brain called the substantia nigra. A variety of genetic and environmental factors underlie this loss of brain cells. However, emergent research implicates oxidative stress, inflammation, and dysfunctional mitochondria as major contributors to neurodegeneration in Parkinson's disease.

Up to one million Americans live with Parkinson's disease, with 60,000 new cases being diagnosed each year. Men are more likely to be affected than women, and the risk increases substantially after age 50–60; however, one in 20 patients is diagnosed under the age of 40.^1,2

Progression of the disease usually leads to characteristic symptoms such as tremors, muscle rigidity, bradykinesia (slowness and difficulty with movements), poor balance, sleep disturbances, and loss of coordination; eventually, cognitive decline occurs, and, in advanced disease, dementia arises.

Conventional medical approaches to treating Parkinson's disease aim to replace the lost dopamine, but fall short of addressing the ongoing destruction of dopaminergic neurons. Over time, the ability of medications to replenish dopamine levels becomes overwhelmed by further loss of dopaminergic cells. Moreover, the pharmaceutical drugs typically used to alleviate symptoms of Parkinson's disease are laden with debilitating side effects and often worsen affection over time. Thus, the prognosis for Parkinson's disease patients relying on conventional treatment remains limited.

The mainstream medical establishment has failed to recognize the urgent need to address the multiple, interrelated pathological features of Parkinson's disease in order to prevent further neuronal loss and slow disease progression.

Scientific innovation has led to the realization that natural compounds and some underappreciated pharmaceutical compounds can synergize to support mitochondrial function, suppress inflammation, ease oxidative stress and may improve outlook for Parkinson's disease patients.

Life Extension's approach encompasses a regimen combining conventional therapeutics to ease symptoms and innovative natural ingredients along with state-of-the-art pharmaceuticals to reduce the destruction of dopaminergic neurons. This approach offers Parkinson's disease patients a chance for symptomatic improvement and enhanced quality of life.

Dr. James Parkinson first described the motor system disorder known today as Parkinson's disease in an 1817 paper entitled "An Essay on the Shaking Palsy."³ In his report, Dr. Parkinson described several characteristic traits, including an abnormal posture and gait, and partial paralysis with muscle weakness; he also described the progression of the disease. The contribution of more clearly defining the condition, theretofore known as paralysis agitans, led to the adoption of Dr. Parkinson's last name as the moniker that remains with us today.

Since 1817, medical advancements have helped us establish a much greater understanding of Parkinson's disease. Today, clustered symptoms like tremor at rest, stiffness, slowed movement, and postural instability are classified, based upon their cause, into different categories.

Parkinson's Disease (Primary Parkinson's)

This is the most common form of the disease; what most of us think of when we hear the term "Parkinson's." Primary Parkinson's disease has no clear external cause, and is therefore classified as idiopathic or without cause (arising spontaneously). Recently, however, several genes directly tied with the development of Parkinson's disease have been identified. This has led to the classification of heritable Parkinson's disease of genetic origin as familial Parkinson's disease, while Parkinson's disease that arises independently of genetic predisposition is referred to as sporadic Parkinson's disease.

Despite the fact that conventional medical dogma holds tightly to the notion that primary Parkinson's disease truly lacks an identifiable cause (other than genetics in familial Parkinson's disease), metabolic phenomena, such as oxidative stress, mitochondrial fatigue, and other age-related abnormalities are linked with the death of dopamine-producing neurons.⁴

Exposure to pesticides may substantially increase risk for Parkinson's disease.^5-10 In one study, higher pesticide exposure increased Parkinson's disease risk three-fold.¹⁰ Numerous epidemiological studies have confirmed the association.^6,11 Toxin-induced Parkinson's symptoms may be classified as secondary, rather than primary Parkinson's.^4,12

Interestingly, pesticides seem to accumulate in the dopaminergic tract, where they inhibit mitochondrial function and lead to neuronal death.^7,13 Dopaminergic neurons are particularly susceptible to the pesticide dieldrin, which is no longer in use in the United States, but remains ubiquitous due to environmental contamination.¹⁴ In addition to acting as neuronal and mitochondrial toxins, some pesticides also impair the breakdown of protein aggregates, like Lewy bodies.¹⁵

Several lines of evidence suggest that a genetic inability to properly detoxify environmental toxicants may predispose some individuals to Parkinson's disease.^16,17

In addition, those who experience constipation throughout their lives appear to be at increased risk.¹⁸ In one study, constipation documented in medical records as much as 20 years before disease onset was associated with a significantly increased risk.¹⁹ Some researchers believe that this may be related to intake of drinking water—lower water intake appears to be a risk factor as well.²⁰ This may be linked to reduced elimination of water-soluble toxins.

Due to the strong association between pesticides, and other environmental toxins, with Parkinson's disease, readers are strongly encouraged to review Life Extension's “Metabolic Detoxification” protocol.

Parkinsonian Syndrome (Secondary Parkinson's)

Other forms of Parkinsonism can occur as a secondary effect of brain tumor, drugs, toxins (eg, carbon monoxide poisoning), post encephalitis (viral infectious disease, "sleeping sickness"). For example, another cause of Parkinsonism is brain damage sustained by repeated blows to the head such as suffered by professional prize fighters and athletes in high-impact sports like football. Traumatic events, infections, use of certain medications, etc. can all damage the dopaminergic cells within the midbrain and lead to the same symptoms as primary Parkinson's disease.

For example, the defining basis for Parkinsonism due to encephalitis (brain inflammation) was a worldwide influenza pandemic in 1917. After recovering from this illness, many patients developed Parkinson's disease years later.²¹ Acquired immunodeficiency syndrome (AIDS) may also lead to Parkinsonism.²² Resuscitation from cardiac arrest (due to temporary lack of oxygen supply to the brain), and stroke can lead to Parkinsonism as well.²³

Several centrally acting drugs, especially those that exert an effect on the dopamine system within the brain, such as antipsychotics, frequently induce secondary Parkinsonism after sustained chronic use. In fact, drug-induced Parkinsonism is a well-documented phenomenon.^24-26 Some antidepressants and calcium channel blockers, and the antiarrhythmic drug amiodarone, can lead to Parkinsonian tremors as well.²⁶ Several illicit drugs can cause Parkinsonism as well.

Some diseases or disorders considered to cause Parkinsonian syndromes include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBGD), and Pick's disease.

Dopamine is a neurotransmitter that, among other functions, allows messages to be sent to regions of the brain responsible for coordinating movement. When dopamine levels decline, due to the death of dopaminergic cells, these messages no longer reach their destination, and so the regions of the brain that control movement no longer function properly. This results in loss of conscious control of movement, and, in advanced Parkinson's disease, loss of control over several other bodily functions.

The onset and course of Parkinson's disease may be different for each patient. For example, while tremor is evident in most patients, some may not experience movement complications until the disease has advanced considerably.

Initial symptoms of primary Parkinson's disease typically develop slowly and randomly as the supply of dopamine dwindles over time. In some cases, symptoms do not appear until approximately 70% of the dopaminergic cells in the substantia nigra are already destroyed.²

Motor Symptoms

The onset of a slight tremor, usually in the hand, which increases in intensity over time, is often the initial sign of Parkinson's. However, roughly 30% of patients do not develop a tremor. Parkinson's patients often experience muscle rigidity or cramping that can be painful—movements as simple as turning over in bed or buttoning a shirt can become arduous, and as the disease advances, nearly impossible. Progression of Parkinson's disease leads to slowness of movements, which can cause a great deal of frustration for patients who cannot move as quickly as they would like.

"Freezing" is a frequently reported motor symptom in advancing Parkinson's. This involves the sudden onset of the inability to move at all; patients sometimes describe freezing as feeling as if their feet are stuck to the floor. Freezing is temporary and usually lasts from a few seconds to a few minutes.

Non-Motor Symptoms

Dopamine is involved in a number of functions beyond control of movement, so loss of dopaminergic neurons (and other neurons in late-stage Parkinson's) can cause several non-motor symptoms as well. However, non-motor symptoms usually develop at later stages of disease progression; nonetheless, they can be equally as debilitating as motor symptoms for many patients.

Patients with advanced Parkinson's disease may experience a variety of non-motor symptoms. These can include incontinence, constipation, difficulty swallowing, inability to control saliva, dizziness, which can lead to falls, excessive daytime sleepiness, intense frightening dreams, depression and/or anxiety, and hallucinations.² In addition, Parkinson's disease can cause perceptible pain throughout the body, which is sometimes severe.

Dementia

Dementia and related cognitive decline is a major concern among those with advanced Parkinson's disease; up to 75‒80% of those with Parkinson's develop dementia near the end of their life.^27,28 In addition to loss of dopaminergic neurons, cholinergic neurons are also at risk. Cholinergic neurons produce a neurotransmitter called acetylcholine, which is important for cognitive function. The accumulation of protein aggregates (clumps of dysfunctional proteins) known as Lewy bodies within cholinergic neurons is a common characteristic of Parkinson's disease.

As Lewy bodies accumulate inside neurons, the cells can no longer function, and eventually die. Loss of acetylcholine leads to diminished attention span, blunted sensory perceptions, loss of arousal and structural changes in the synaptic junctions (the connections between neurons through which they communicate using chemical and electrical signals). Loss of acetylcholinergic signaling is thought to be associated with memory deficits in Alzheimer's disease as well, though the exact mechanisms are complex.²⁹

Two subsets of dementia exist in the context of Parkinson's disease, Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB). The distinction of the two is quite subjective and largely based upon the time of dementia diagnosis in relation to onset of motor symptoms. Whether or not the two dementias are truly separate entities, or simply manifestations of different points along the "Lewy body spectrum," is a hotly debated topic.³⁰

Diagnosis

Clinicians must rely on clinical experience, interpretation of symptoms, and evaluation of medical history in order to tentatively diagnose a patient as having Parkinson's disease. This is because there are no lab tests available that definitively diagnose Parkinson's disease. Parkinson's disease is a diagnosis of exclusion; in other words, the physician will first rule out other possible diagnoses before assuming Parkinson's.

If Parkinson's is suspected because the patient is exhibiting signs such as a tremor on one side of their body, or rigidity with loss of postural reflexes, oftentimes L-DOPA, a drug used to treat Parkinson's symptoms, is administered. If L-DOPA causes the symptoms to subside, the diagnosis of Parkinson's disease can be made more confidently, yet still not definitively.

Due to the elusive nature of a definitive Parkinson's disease diagnosis, patients should be reevaluated regularly to make sure that their symptoms are not due to another neurological disorder that causes similar symptoms.

Genetics—Familial Parkinson's

Roughly 15% of Parkinson's disease patients have a first-degree relative who also has/had Parkinson's disease; this suggests that genetics play a consequential role in the development of familial Parkinson's disease.³¹ Roughly nine genetic mutations have been associated with Parkinson's disease; of these, six have been particularly well characterized.^31,32 Mutations in these genes are generally associated with early onset Parkinson's disease, which is diagnosed before age 40; Parkinson's disease of genetic origin is sometimes diagnosed in childhood.

Mutations in the following genes are associated with an increased risk of Parkinson's disease:

• SNCA^33-36
• LRRK2³⁷
• PARK2³⁸
• PINK1^39-42
• PARK7^43-47
• ATP13A2^48-51

Additional research is required to fully elucidate the role of genetics in Parkinson's etiology; it is likely that several additional genes involved in the pathology will be identified in the coming years. Treatments based upon genetic therapy are likely to become more widespread and therapeutic as scientific knowledge progresses.

Mitochondrial Dysfunction

A flurry of emergent research has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease. Mitochondrial dysfunction results in impaired ATP generation, loss of cellular repair mechanisms, and cellular inefficiency.

As mitochondria become dysfunctional they generate large quantities of free radicals, which contribute to oxidative stress that, in turn, causes further mitochondrial dysfunction. Concurrently, loss of mitochondria to oxidative damage means fewer mitochondria are available to meet the energy demands of the cell to repair damaged components. The cascade of mitochondrial dysfunction, oxidative stress, and loss of mitochondria form a continuity that ultimately leads to cell death.^52,53

Numerous studies have clearly identified mitochondrial dysfunction as a central pathological feature of both genetic and sporadic Parkinson's disease.^54,55 Moreover, many of the genes that confer predisposition to familial Parkinson's are intimately related to mitochondrial function; much of the neuronal death in Parkinson's of genetic origin is due to mitochondrial dysfunction, and impaired mitophagy.^56-58 While several factors, including exposure to environmental toxins,^56,59,60 also contribute to mitochondrial dysfunction in the substantia nigra, age-related mutations in mitochondrial DNA are thought to be a primary culprit.^60,61 Alarmingly, dopamine itself, and L-DOPA, may contribute to mitochondrial toxicity in dopaminergic neurons.^62-64

Mitophagy, Lewy Bodies, and alpha-Synuclein

Damaged mitochondria are continually being cleared from within the cell through a process calledmitophagy. Mitophagy, a type of autophagy, is a kind of cellular recycling system that clears damaged mitochondria before they can accumulate and cause cellular dysfunction. However, age-related mutations in mitochondrial DNA, which cause mitophagy to become less efficient, coupled with an ever-intensifying propensity for endogenous and environmentally mediated mitochondrial damage cause the neuronal mitophagic system to become overwhelmed.^57,65 Over time, damaged mitochondria build up inside the neuron, leading to cell death. Not surprisingly, several of the genetic mutations linked to familial Parkinson's disease cause disturbances in mitophagy.^57,58

Another toxic byproduct of mitochondrial dysfunction and impaired mitophagy is the formation of Lewy bodies. Lewy bodies form as reactive oxygen species derived from dysfunctional mitochondria damage structural components of the cell called microtubules. As microtubules are damaged, they release a protein called alpha-synuclein. The loose alpha-synuclein proteins then group together, or aggregate, and form a toxic mass (a Lewy body) that further damages the cell. Moreover, alpha-synuclein has been shown to directly interfere with mitochondrial function and inhibit ATP synthesis, furthering the spread of mitochondrial dysfunction in the brains of Parkinson's disease patients.^66-68 Over time, Lewy bodies spread to neighboring cells, damaging neurons within the vicinity of a dead or dying neuron.⁶⁹

Lewy bodies share some characteristics with toxic proteins that develop in the brains of patients with Alzheimer's disease and other neurodegenerative diseases, primarily in that they cannot be broken down and cleared from the cell by normal autophagic (cellular house cleaning) actions.

The Role of Inflammation in Parkinson's Disease

Inflammatory responses contribute to the perpetuation of neurodegeneration in Parkinson's disease. The brain contains immune cells called microglia, which are known to be activated in Parkinson's disease.^70,71 Upon activation, microglia release inflammatory cytokines that can spread to nearby healthy neurons and cause degeneration. Dopaminergic neurons in the substantia nigra, the brain region most affected by Parkinson's disease, express receptors for an inflammatory cytokine called tumor necrosis factor-alpha (TNF-α), which suggests that excess TNF-α released by nearby activated microglia may damage nigral dopaminergic cells.

Elevated cytokines in the brain of those with Parkinson's disease is a consequence of neurodegeneration.⁷² In experimental models, exposure to the neurotoxin MPTP (a chemical used to induce Parkinson's disease in experiments) leads to death of dopaminergic neurons. Interestingly, in monkeys, inflammation is increased even years after initial exposure to MPTP.⁷¹ This suggests inflammation, once initiated, has long-term consequences in Parkinson's disease.

As dopaminergic cells succumb to either environmentally or genetically induced mitochondrial dysfunction, they release free radicals. These free radicals then activate nearby microglial cells, which in turn, excrete inflammatory cytokines that bind to and damage nearby dopaminergic neurons. This positive feedback loop may continue over years or even decades and slowly contribute to the loss of dopaminergic neurons that leads to Parkinson symptoms.^72,73

Epidemiological studies on the use of anti-inflammatory drugs and the risk of Parkinson's onset are conflicting. Some studies suggest a protective role of ibuprofen, but not other anti-inflammatory drugs.⁷⁴ However, a large study published in the British Medical Journal involving over 22,000 subjects found no association between use of any NSAID reduced risk.⁷⁵ These findings reinforce the notion that, rather than initiating dopaminergic cell death, inflammation may perpetuate it, thus contributing to Parkinson's disease progression. Life Extension believes that suppressing inflammation may slow disease progression in Parkinson's disease patients.

For decades, the conventional standard of care for Parkinson's disease has focused on symptomatic relief. Pharmaceutical treatments for Parkinson's accomplish this by either increasing dopamine levels or mimicking its action. While conventional therapeutics are indispensable for improving quality of life in Parkinson's patients, they do not provide fundamental neuroprotection or support for neuronal mitochondria. Thus, mainstream pharmaceutical treatments cannot be expected to address the underlying cause of disease progression—neurodegeneration.

Treatment with L-DOPA causes patients to be less responsive to the medication over time and can evoke a number of adverse side effects. However, careful dosing strategies, and utilization of ancillary medications may help limit side effects and maintain the effectiveness of conventional pharmaceutical therapies.

Pharmaceutical treatment of Parkinson's disease symptoms is usually initiated when the patient has already developed some disability for which he/she needs to be treated. This is typically referred to as the initial stage of therapy. The primary goal of treatment during the initial stage is to limit symptoms arising from progression of the disease. However, with time, adverse side effects of the medications arise, which leads into the secondary treatment stage. The aim of the secondary treatment stage is to reduce Parkinson's symptoms, as well as counterbalance the adverse side effects of levodopa.

Levodopa (L-DOPA)/Carbidopa

Since its FDA approval in 1970, Levodopa (L-DOPA) has been a staple for the management of Parkinson's disease symptoms.

L-DOPA (the precursor to dopamine) is metabolized into dopamine in the body by an enzyme called aromatic L-amino acid decarboxylase (AADC). Dopamine itself cannot pass through the protective blood-brain barrier, but L-DOPA can. When L-DOPA is administered orally, a small percentage passes into the brain and is converted into dopamine. This temporary increase in dopamine levels within the brain offers relief of Parkinson's disease symptoms for a short period.

However, the body presents many obstacles that limit the efficiency of oral L-DOPA therapy. First, AADC exists outside the brain as well, which means that the majority of orally administered L-DOPA will be converted into dopamine peripherally (not in the central nervous system). Therefore, L-DOPA is typically administered with an inhibitor of peripheral AADC, called carbidopa. Carbidopa (or another AADC inhibitor) helps preserve orally administered L-DOPA for conversion to dopamine in the brain.

Regrettably, the use of orally administered L-DOPA over time results in diminished production of endogenous (naturally occurring within the body) L-DOPA. L-DOPA therapy is further complicated by the development of movement disorders called dyskinesias after 5–10 years of use in most cases.

Dyskinesias are movement disorders in which neurological discoordination results in uncontrollable, involuntary movements. This discoordination can also affect the autonomic nervous system, resulting in, for example, respiratory irregularities.⁸² Dyskinesia is the result of L-DOPA-induced synaptic dysfunction and inappropriate signaling between areas of the brain that normally coordinate movement, namely the motor cortex and the striatum.⁸³

With long-term L-DOPA use (usually after about five years), responsiveness declines and dose adjustment is often necessary. This phenomenon leads to fluctuations in the effectiveness of L-DOPA therapy that cause the patient to experience dyskinesia as the post-dose concentration of L-DOPA peaks, and rapid reversion to severe Parkinsonism towards the end of the dosing period.

Several strategies exist for enhancing L-DOPA effectiveness. Some of these include varying combinations of L-DOPA and other medications discussed in this section as well as altering dose timing and amount. Other strategies can involve "rest periods" or "drug holidays" during which the patient abstains from L-DOPA for a short time; as little as skipping a single dose each day may help lessen the damage caused by oxidation products of L-DOPA metabolism and maintain dopamine receptor sensitivity. A patient should never adjust their L-DOPA dose without close supervision by their physician.

Other strategies for stabilizing dopamine levels include combining L-DOPA with inhibitors of enzymes that breakdown dopamine. Medications of this type include monoamine oxidase-B (MAO-B) inhibitors, and catechol-O-methyltransferase (COMT) inhibitors. By combining L-DOPA with COMT and/or MAO-B inhibitors, a physician may be able to reduce the dose of L-DOPA required to relieve symptoms, and widen dose intervals, which is more convenient for the patient.

There are a variety of ways that pharmaceuticals can be combined to deliver optimal effects in each Parkinson's case, but the needs of each patient may vary widely. Therefore, patients should always consult an experienced physician to discuss medication combinations that may be ideal for their unique situation.

L-DOPA can produce several adverse side effects, including:

• Arrhythmia
• Gastrointestinal discomfort (taking L-DOPA with low protein snacks may help avoid stomach upset)
• Breathing disturbances
• Hair loss
• Confusion
• Extreme emotional variability with prevalent anxiety
• Vivid dreams
• Hallucinations
• Impaired social behavior
• Sleepiness
• Excessive libido
• Compulsive behavior (ie, reckless gambling)

L-DOPA-induced elevations in homocysteine, a potentially harmful amino-acid derivative, are another major concern for Parkinson's patients. High levels of homocysteine have been implicated in various cardiovascular diseases, including cerebral small vessel disease, as well as brain atrophy.^84,85 A comprehensive review of 16 studies found that elevated homocysteine was associated with dementia and markers of neurodegeneration in patients with Parkinson's patients.⁸⁶

Parkinson's disease patients taking L-DOPA should read Life Extension's “Homocysteine Reduction” protocol and strive to maintain homocysteine levels of less than 7–8 µmol/L.

Dopamine Agonists

Another method used to restore dopaminergic signaling in Parkinson's disease is medicating with a dopamine agonist. A dopamine agonist is a drug containing a molecule that binds to and activates dopamine receptors, similar to dopamine itself, thus compensating for low dopamine levels. Dopamine agonists are often used in younger patients, or in very early Parkinson's disease.

Research comparing the results of initial therapy with a dopamine agonists or L-DOPA is conflicting. Some studies suggest that initiating therapy with a dopamine agonist may delay the onset of dyskinesias as the disease progresses, while some seem to indicate that this may not be the case. Other studies suggest initial dopamine agonist therapy delivers results similar to those seen in L-DOPA plus COMT inhibitor therapy.⁸⁹ Results from a 14-year follow up study found that initial therapy with a dopamine agonist offered no greater benefit over standard L-DOPA therapy in the long term.⁹⁰

Dopamine agonists pose a greater risk of serious side effects than L-DOPA and are therefore not as tolerable for some patients. Some side effects of dopamine agonists include:

• Euphoria
• Hallucinations
• Psychosis
• Orthostatic hypotension (low blood pressure upon standing)
• Increased orgasmic intensity
• Weight loss
• Nausea
• Insomnia
• Unusual tiredness or weakness
• Dizziness or fainting
• Twitching, twisting, or other unusual body movements
• Pathological addiction and compulsive behavior (ie, hyper-sexuality, gambling)

Selegiline and Rasagiline

Selegiline is a MAO-B inhibitor that, due to its unique chemical structure, also exerts other neuropharmacological actions via its metabolites. By blocking the breakdown of dopamine, selegiline helps compensate for the diminished production of dopamine in Parkinson's disease. This can lead to symptomatic improvement, especially in early-stage Parkinson's.

Numerous clinical trials have confirmed the efficacy of selegiline alone and in combination with L-DOPA in early Parkinson's disease.^91-93 One study showed that selegiline was highly effective if initiated within five years of Parkinson's disease diagnosis, but less effective if initiated 10 years or more after diagnosis.⁹¹

Selegiline exerts a number of other benefits as well, including maintenance of whole-brain blood flow in depressed Parkinson's disease patients.⁹⁴ Moreover, selegiline may reduce the formation and toxicity of alpha-synuclein aggregates.⁹⁵

Rasagiline is a newer generation medication based upon selegiline. Laboratory studies suggest that, in addition to functioning very similarly to selegiline, rasagiline may exert a greater neuroprotective effect.⁹⁶

Rasagiline was superior to placebo in slowing progression of Parkinson's disease in a cohort of 1,176 early-stage patients. In this study, subjects receiving rasagiline were less likely than those taking placebo to need additional anti-Parkinson drugs to manage symptoms.⁹⁷ More trials need to be conducted to determine if rasagiline is significantly more effective than selegiline for treating Parkinson's disease.

Selegiline is available via prescription in a clinically studied transdermal patch called Emsam. Selegiline and rasagiline may cause dizziness, dry mouth, sleeplessness, and an overall stimulating effect.

In addition to the conventional standard of care, which relies heavily on L-DOPA therapy, physicians may sometimes implement other pharmaceutical agents that complement the effects of L-DOPA therapy, or limit its side effects.

Amantadine

Amantadine is an antiviral drug that exerts a number of actions in the brain. Amantadine has been shown in some studies to benefit Parkinson's patients, primarily by reducing the side effects of L-DOPA, or as an adjuvant during L-DOPA drug holidays as mentioned above, though the mechanisms are largely unclear.

In clinical studies, amantadine has been shown to temporarily reduce L-DOPA induced dyskinesia; an effect which dissipates after about eight months.^98,99 However, in some patients, discontinuation of amantadine appears to cause a rebound worsening of dyskinesias to an even higher intensity than before its introduction.⁹⁹

As mentioned earlier in this protocol, at least one study suggests amantadine may suppress side effects of L-DOPA abstinence during a drug holiday.⁸⁸

Amantadine may ease Parkinson's symptoms in some patients, but should only be initiated under physician supervision.

Nicotine

Within the brain, there exists a grand diversity of neurotransmitter interaction and overlap. One such relationship is that existing between the dopaminergic and cholinergic systems. For example, acetylcholine modulates dopaminergic signaling in the striatum, an area considerably impacted in Parkinson's disease.

Nicotine interacts with the cholinergic system by binding to sites known as nicotinic acetylcholinergic receptors (nAChRs), which influence several functions relevant in Parkinson's disease, including dopamine signaling.¹⁰⁰ Moreover, loss of nAChRs accompanies many neurodegenerative diseases, including Parkinson's disease, suggesting that declining cholinergic signaling may be a key etiological feature.¹⁰¹ Several studies indicate that nicotine exerts neuroprotective effects via activation of nAChRs.¹⁰² Some data indicates that among the neuroprotective effects of nicotine is the ability to reduce alpha-synuclein aggregation, which may suppress the formation of Lewy bodies.¹⁰³

Epidemiological evidence suggests that smoking tobacco is associated with a reduced risk of developing Parkinson's disease.^104,105 Moreover, transdermal nicotine patches have been shown to improve cognitive functioning in patients with Parkinson's disease.¹⁰⁶ Other evidence suggests a therapeutic effect of nicotine in reducing L-DOPA-induced dyskinesias.¹⁰⁷

However, the ability of nicotine to improve symptoms and slow progression of Parkinson’s disease is inconclusive. A double-blind, randomized, controlled trial randomly assigned 163 therapy-naïve patients with early Parkinson’s disease, diagnosed within 18 months and in Hoehn and Yahr stage ≤2, to receive transdermal nicotine (7–28 mg/day, titrated to the maximum tolerated dose) or placebo for 52 weeks followed by an 8-week washout period. Patients did not require dopaminergic therapy at the initiation of the trial. The primary endpoint was change in Unified Parkinson’s Disease Rating Scale (UPDRS) at 60 weeks; the secondary endpoint was change in UPDRS at 52 weeks. The primary outcome worsened by 3.5 points in the placebo group and 6.0 points in the nicotine group. The secondary endpoint showed similar results, with a worsening of 5.4 in the placebo group and 9.1 in the nicotine group.³²⁵ A separate study examining 40 patients with Parkinson’s disease receiving 90 mg/day (titrated over the course of 11 weeks) of transdermal nicotine for 28 weeks found no significant difference in UPDRS motor scores between treated and non-treated groups after six weeks of washout.³²⁶ Other studies have reported a worsening or no improvement in Parkinson’s symptoms for patients administered transdermal nicotine compared with placebo.^327,328

In summary, while there is experimental evidence supporting nicotine's neuroprotective effect on dopaminergic neurons, clinical trials have yet to provide convincing evidence of its efficacy in slowing Parkinson’s disease progression. The intriguing epidemiological observations and some promising preclinical data suggest further research, with a focus on dosing and delivery systems, may be warranted to fully understand nicotine's potential role in Parkinson’s disease prevention or treatment.

Granulocyte Colony-Stimulating Factor (G-CSF)

G-CSF is a signaling glycoprotein (produced in several tissues) that stimulates the production and differentiation of white blood cells, thereby playing a significant role in immune system function. Recombinant G-CSF is frequently given to chemotherapy patients to restore levels of white blood cells that have been suppressed by treatment.

The interaction of G-CSF with the immune system is very complex. However, current evidence suggests that besides stimulating white blood cell generation, it pushes the immune system towards a less autoreactive, anti-inflammatory TH2 phenotype rich in T-regulatory cells.¹⁰⁸ Due to this unique action, G-CSF may be of benefit in diseases in which inflammation contributes to the pathology.

Interestingly, receptors for G-CSF are expressed in neurons throughout the central nervous system and activation of those receptors (by G-CSF) stimulates neurogenesis and protects neurons from damage.^108,109

In animal models of both Alzheimer 's disease and Parkinson 's disease, subcutaneous injections of recombinant human G-CSF suppressed inflammation in brain regions centrally involved in the pathology of each disease and stimulated the formation of new synapses.^110-112 In these studies, mice treated with G-CSF performed much better on cognitive tests than those not treated with G-CSF. These findings are very exciting and hold promise for future research.

Stem Cells and Cell Replacement Therapy

The hallmark of Parkinson's disease is loss of dopaminergic neurons in the substantia nigra. Therefore, many therapeutic approaches have aimed at replacing lost neurons in this region using cell replacement therapy, or stem cell therapy. These therapies are largely experimental as of the current time and no large-scale clinical trials have been conducted as of yet. In fact, small-scale clinical trials have shown that benefit of replacing dopamine neurons may be questionable, and that the therapy caused severe dyskinesias in some subjects.¹¹³

Another major challenge associated with cell replacement therapy is ensuring survival of transplanted neurons. So far, this has proven extremely difficult.¹¹⁴ However, further studies are underway, and advancements in research may allow for widespread use of these therapies in the not-too-distant future.

Focused Ultrasound and Parkinson's Disease

Focused ultrasound (FUS) is an FDA-approved noninvasive, therapeutic technology with the potential to improve quality of life in Parkinson’s Disease patients that experience severe tremors, especially among those for whom medications do not work well. FUS uses ultrasound waves, which carry energy through tissue and can be focused precisely to ablate tissue and cells contributing to tremors.³⁰⁰ FUS is also capable of temporarily disrupting the blood-brain barrier, allowing therapeutics to enter the brain and undesired materials to depart from the brain.³⁰¹

FUS has the potential to achieve symptomatic relief by causing lesions in the brain to disrupt circuits associated with tremor. Some targets include the thalamus, subthalamic nucleus, globus pallidus, and pallidothalamic tract, which have been implicated in parkinsonian tremor, dyskinesia, and akinesia.³⁰² A 2020 clinical trial randomized 40 participants with Parkinson's disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation in a 2:1 ratio to receive FUS of subthalamic nuclei or a sham procedure as control. This trial found that FUS in one hemisphere improved motor features of Parkinson’s disease as evidenced by a decrease in Unified Parkinson’s Disease Rating Scale (UPDRS) scores, although some adverse events were reported including speech and gait disturbances and weakness on the treated side.³⁰³ The clinical benefits of FUS have been corroborated in multiple clinical trials in which the majority of treated patients reported significant improvements in their tremor, dyskinesia, or akinesia.³⁰⁴

Currently, FUS is limited to being used to treat only one side of the brain, which results in unilateral effects.³⁰⁰ Despite this limitation, FUS is gaining popularity as a therapy since it is a single noninvasive technique that does not require subsequent procedures.

Deep Brain Stimulation and Parkinson's Disease

Deep brain stimulation (DBS) is a surgical procedure in which electrodes are inserted into a target area of the brain to modulate abnormal electrical activity of cells.³⁰⁵ In fact, some consider it to be the most important therapeutic advance in treating Parkinson’s disease symptoms since the development of levodopa. DBS was approved to treat Parkinson’s disease tremor in 1997, then in 2002 for treatment of advanced Parkinson’s disease syndromes, and finally in 2016 for the treatment of early stages of Parkinson’s disease. DBS is capable of providing relief from symptomatic Parkinson’s disease, but it does not slow disease progression.³⁰⁶ Further, its benefits are mostly limited to tremor, dyskinesia, and akinesia; it has not been reliably demonstrated to ameliorate non-motor issues (eg, speech or cognitive problems) that may significantly impact patient’s quality of life.^307,308

Various clinical trials have demonstrated the efficacy of DBS in lessening motor symptoms associated with Parkinson’s disease.³⁰⁹ Particularly, DBS as a combination therapy with traditional medications, such as levodopa, may result in an additive effect while also helping lessen side effects associated with dopaminergic medications.³¹⁰ A five-year, randomized, single-blind trial of patients with early-stage Parkinson’s disease examined the effect of bilateral DBS of the subthalamic nucleus (STN) in combination with levodopa compared with levodopa alone. Patients treated with combination therapy required lower daily dosages of levodopa and had significantly reduced odds of worsening rest tremor compared with levodopa alone.³¹¹ A systematic review and meta-analysis of eight randomized controlled trials found DBS led to significant improvements in UPDRS for patients and a reduction in medication dose, although this was accompanied by a significantly higher risk of serious adverse events.³⁰⁹ Further, a meta-analysis of 13 studies found that although the motor benefits achieved via DBS of the globus pallidus internal (GPi) and STN were similar, DBS of the STN allowed for a greater reduction in medication.³¹² 

Potential risks arising from electrode implantation for DBS include surgical complications such as bleeding, stroke, and infection. The benefits of DBS, such as improvements in motor function and dyskinesia, are thought to last for 5‒10 years, although the magnitude of these improvements tends to decline over time.³¹³

Cognitive-Behavioral Therapy

Parkinson's disease is often accompanied by comorbid psychological disturbances such as depression and/or anxiety, and psychosis (a potential side effect of anti-Parkinson medications). Treatment of psychological disturbances is limited, to some degree, due to potential interactions between pharmaceuticals used to treat Parkinson's and those used to treat other psychological conditions.

Cognitive-behavioral therapy offers a highly effective drug free alternative for relieving psychological disturbances in Parkinson's disease patients. In one study, depressed Parkinson's patients were either clinically monitored or engaged in cognitive-behavioral therapy for just over three years. While a mere 8% of patients undergoing clinical monitoring experienced improvements in their depressive symptoms, significant improvement was noted in 56% of those engaged in cognitive-behavioral therapy.¹¹⁶

In addition to the psychological benefits, cognitive-behavioral therapy may be effective for the treatment of some physical symptoms of Parkinson's disease. A 2011 study found that in patients older than 50 years, cognitive-behavioral therapy led to a significant reduction in the incidence of urinary incontinence.¹¹⁷

Several different types of cognitive-behavioral therapy are available and different styles may be appropriate in some cases while inappropriate in others. Patients with Parkinson's disease may benefit from cognitive-behavioral therapy and therefore, should discuss this option with their physicians.

Physical Therapy and Exercise

Parkinson's patients are prone to motor disturbances, such as poor balance and a greater chance of falling, which can lead to decreased mobility. As the disease progresses, engaging in structured physical therapy or exercise may be an effective way of maintaining balance and avoiding falls.¹¹⁸

Moreover, an array of studies has shown that exercise and physical activity in general exert substantial supportive effects upon brain structure and function. In fact, physical activity is associated with a decreased propensity for aging adults to develop dementia, a common problem in Parkinson's disease.¹¹⁹ Experimental Parkinson's disease models demonstrate that physical activity provides neuroprotection and promotes mitochondrial integrity.¹²⁰

Staying active is very important for Parkinson's disease patients. Those not engaged in regular physical activity are encouraged to speak with their healthcare provider about initiating a structured exercise or physical therapy regimen. A target goal of 75% maximum age adjusted heart rate for a minimum of 20 minutes at least three times per week is ideal. However, this may not be possible for advanced Parkinson's disease patients.

Low-Protein Diet/Protein Meal Redistribution

L-DOPA therapy is hindered by many obstacles, one of which is excess protein (specifically, aromatic amino acids) competing with L-DOPA for transport into the brain. Therefore, some studies have evaluated the effects of engaging in protein meal redistribution, involving eating dietary protein separate from dosing with L-DOPA.

Current research indicates that protein meal redistribution may be favorable with a low protein diet. It appears that protein meal redistribution reduces fluctuations, or "on-off periods" in response to L-DOPA therapy.¹²¹ Taking L-DOPA at least 30 minutes before consuming protein and/or having your highest protein meal at a time when L-DOPA is not needed may be an effective strategy. However, patients should speak with their physician to determine which dieting approach is appropriate for them.

Coffee Consumption

Coffee contains a multitude of pharmacologically active compounds, some of which have been shown to suppress oxidative stress and protect against diabetes, cancer, cognitive decline, and so on.¹²² Additionally, several epidemiological studies have found that those who consume large amounts of coffee are much less likely to develop Parkinson's disease.^105,123,124

Coffee constituents (compounds) protect brain cells which can be extremely beneficial for Parkinson's disease patients. Coffee extracts have been shown to inhibit MAO-A and -B enzymes, a mechanism similar to that of some pharmaceutical Parkinson's therapies.¹²⁵ Experimental models suggest that coffee constituents promote neuronal development and increase antioxidant defense systems in the brain.^126,127

Green coffee extract contains more of the active antioxidant compounds than brewed coffee, and may be a promising option for Parkinson's disease patients.¹²⁸ However, clinical trials have yet to confirm this potential benefit.

Intriguing research suggests that caffeine itself may be a potent anti-Parkinson agent. Upon ingestion, caffeine readily crosses the blood-brain barrier and blocks adenosine receptors, an effect responsible for many of its pharmacologic actions. The adenosine receptor system interacts with the dopaminergic system in several ways.¹²⁹ Experimental studies have shown that caffeine binds to presynaptic adenosine receptors causing an increase in dopamine release, thereby temporarily ameliorating some symptoms of Parkinson's disease.¹³⁰ In fact, some data from non-human primate studies indicate that adenosine receptor antagonists, like caffeine, may allow for a reduced dosage of L-DOPA. Data in mice also supports this notion, but more studies need to be done.^131,132

In a clinical trial, a daily caffeine dose of 100 mg was shown to reduce "freezing." However, it appeared the subjects developed a tolerance after a few months. The researchers went on to suggest that caffeine might have therapeutic potential, but a periodic 2-week abstinence period may be required to maintain long term effectiveness.¹³³

Current evidence suggests that coffee consumption may provide some neuroprotection and pharmacologic support, with very little potential downside for Parkinson's patients.

Flavonoid-Rich Diet

A healthy, well-balanced diet that provides adequate fruits and vegetables may be protective against Parkinson’s disease.³¹⁴ A population-based study of 9,414 participants found that those who adhered to a Mediterranean diet, which emphasizes vegetables, fruits, olive oil, and whole grains, were less likely to develop Parkinson’s disease than those who had “unhealthy” diets.³¹⁵ Plant foods provide numerous bioactive compounds, such as flavonoids, that may be beneficial in the context of Parkinson’s disease due to their neuroprotective activity.³¹⁶ Various flavonoids have been shown to reduce the loss of dopaminergic neurons and improve behavioral symptoms in preclinical models of Parkinson’s disease.^317-320 In addition, flavonoids may exert anti-inflammatory effects, improve mitochondrial function, and induce neurotrophic factors.^321,322

A large cohort study that included 599 women from the Nurses’ Health Study and 652 men from the Health Professionals Follow-up Study who were diagnosed with Parkinson’s disease examined the relationship between flavonoid intake and mortality. Over 34 years of follow-up, the researchers found that risk of mortality was reduced by 47% for men in the highest quartile of flavonoid intake pre-diagnosis compared with men in the lowest quartile. In addition, greater flavonoid consumption post-diagnosis was associated with a 22% lower risk of mortality. The specific flavonoid subclasses anthocyanins, flavones, and flavan-3-ols, as well as flavonoid-rich foods like berries and red wine, were also protective when analyzed individually, with anthocyanins showing the greatest inverse association (37% and 47% risk reduction pre- and post-diagnosis, respectively).³²³

Conventional treatment of Parkinson's disease relies heavily on targeting amelioration of symptoms, without providing neuroprotection against continual cell death in the substantia nigra. On the other hand, a variety of natural ingredients have been shown to support neuronal health and promote mitochondrial function in a variety of ways, including suppressing oxidative stress and limiting inflammation. Many natural ingredients may have a complementary effect in combination with conventional therapies.

Coenzyme Q10 (CoQ10)

The connection between defects in mitochondrial energy management, oxidative stress, and neurodegeneration has led neuroscientists to explore several mitochondria-targeted supplemental compounds in the context of Parkinson’s disease. Coenzyme Q10 (CoQ10), also known as ubiquinone or ubiquinol because of its omnipresence in living cells, has garnered considerable interest in this area.^134,135

CoQ10 is used in many biological reactions to facilitate the transport of electrons from energy-supplying nutrients and their metabolism within cells. Importantly, CoQ10 is essential for the generation of ATP, the most important source of energy in the body. CoQ10 deficiencies disrupt these reactions and may contribute to many age-related neurodegenerative conditions.²⁹⁰

Low plasma and platelet levels of CoQ10 have been observed in people with Parkinson's, suggesting a systemic deficiency state may be common in people with this disease. A 2008 study conducted in England observed, for the first time, reduced CoQ10 levels in cortical regions of the brain of Parkinson's disease patients.¹³⁶ This deficiency, along with the role of oxidative stress in degeneration of dopaminergic neurons,²⁹¹ supports the concept of utilizing CoQ10 supplementation to protect against oxidative stress and neurodegeneration in Parkinson’s disease. Moreover, several preclinical studies provided evidence that CoQ10 supplementation might mitigate the dopaminergic neurodegeneration characteristic of Parkinson’s disease.^140,141,292 However, the protective effects observed in these preclinical studies were generally mild.²⁹³

Results from early clinical trials of CoQ10 in Parkinson’s disease were promising. In a multicenter clinical trial published in 2002, 80 treatment-naïve individuals with early Parkinson's disease were randomly assigned to receive either placebo or CoQ10 at daily doses of 300, 600, or 1,200 mg for 16 months or until disability required drug treatment. All subjects were scored using the standard Unified Parkinson Disease Rating Scale (UPDRS), for which higher scores indicate a progressively worsening disease state. The results were compelling with a mean change of 11.99 with placebo, 8.81 with the 300 mg dose, 10.82 with the 600 mg dose, and 6.69 with the 1,200 mg CoQ10 dose—a significant difference. All dosages were well tolerated. The authors concluded that "coenzyme Q10 appears to slow the progressive deterioration of function in Parkinson's disease."¹³⁷ Two years later, the same researchers showed that dosages up to 3,000 mg/day of ubiquinone were safe and well tolerated, though plasma levels reached a plateau at 2,400 mg/day.¹³⁸

Although these early clinical studies supported CoQ10 as a potential treatment for Parkinson’s disease, trial data obtained over recent years suggest less benefit than previously thought.

German researchers undertook a randomized controlled trial that was published in 2007. Unfortunately, their results were discouraging, showing no change in UPDRS scores. However, the subjects received a lower dose of CoQ10 (100 mg three times daily) over just three months. Unlike the previous trial, they also studied patients with "mid-range" Parkinson's disease, already requiring L-DOPA. Therefore, they would have been unable to detect meaningful neuroprotective effects that may be evident when CoQ10 supplementation is initiated preventively or in the very early stages of Parkinson’s disease. They did conclude, however, that CoQ10 was safe and well tolerated.¹³⁹

Trial results published more recently have cast significant doubt on the potential of CoQ10 supplementation in providing clinical benefits in the context of Parkinson’s disease. A phase III, randomized, placebo-controlled, double-blind clinical trial conducted across 67 North American sites enrolled 600 participants 30 years of age or older who had been diagnosed with Parkinson’s disease within the previous five years. This study examined the effect of CoQ10 supplementation (1,200 mg or 2,400 mg daily) versus placebo on Parkinson’s disease severity over 16 months; results were published in 2014. The change in UPDRS score from baseline to final visit was used as the primary outcome to assess improvements following supplementation. CoQ10 supplementation was safe and well tolerated by participants, but the trial was halted as it showed no evidence of clinical benefit.²⁹⁴

These results showing lack of CoQ10 efficacy were affirmed in a 2016 meta-analysis of five randomized controlled trials totaling almost 1,000 participants. CoQ10 supplementation was compared with placebo in terms of motor functions and quality of life, as measured by UPDRS scores. UPDRS scores were not significantly different between CoQ10 and placebo, suggesting a lack of efficacy in providing symptomatic benefits for patients with Parkinson’s disease.²⁹⁵ A separate meta-analysis of eight randomized controlled trials totaling 899 patients with Parkinson’s disease further supported these findings. CoQ10 supplementation did not lead to significant differences in UPDRS scores compared with placebo but was well-tolerated by patients.²⁹⁶

Despite positive results from early clinical trials, supportive preclinical research, and strong biological plausibility for benefit, the totality of the clinical evidence available as of late 2021 suggests that CoQ10 supplementation may not provide as much benefit on the progression of Parkinson’s disease as previously hoped. Nevertheless, given the demonstrated tolerability of CoQ10 and the numerous benefits it has been shown to provide in clinical trials of other conditions, supplementation may still be reasonable for some people with Parkinson’s disease, or even those at a higher risk for developing the disease.^297-299

Creatine

Creatine, an important amino acid-like compound, is vital to cellular energy management. Creatine deficiency is associated with neurological damage.¹⁴² Several animal studies have shown creatine, because of its "pro-mitochondrial" effect, to be effective in preventing or slowing the progression of Parkinson's disease.^54,143,144 Influential Harvard neurologists noted that "creatine is a critical component in maintaining cellular energy homeostasis, and its administration has been reported to be neuroprotective in a wide number of both acute and chronic experimental models of neurological disease."¹⁴⁵ Studies have shown that creatine is safe and well tolerated by patients with Parkinson's disease.¹⁴⁶

In 2006, the Neuroprotective Exploratory Trials in Parkinson’s Disease (NET-PD) group at the National Institute of Neurological Disorders and Stroke (NINDS) studied 200 treatment-naïve subjects who had been diagnosed with Parkinson’s disease within the past five years. Subjects were randomly assigned to receive creatine 10 grams/day, the antibiotic drug minocycline (a proposed neuroprotectant) 200 mg/day, or placebo for 12 months while their scores on a standard Parkinson's disease rating scale were monitored. Both creatine and minocycline performed well, yet creatine showed a substantial edge in performance over minocycline. Tolerability of the treatment was 91% in the creatine group and 77% in the minocycline group.¹⁴⁷ However, a follow-up study published by this same research group in 2015 failed to show a benefit associated with creatine supplementation (10 grams daily) for a minimum of five years.¹⁴⁸

While it is unclear why the latter study did not identify a benefit with creatine supplementation, small differences in inclusion criteria and patient characteristics between the two studies may have contributed. Also, some evidence suggests that perhaps creatine in combination with other neuroprotective nutrients (as opposed to alone, as in the NET-PD studies) might be of benefit: a recent animal study found that creatine, in combination with CoQ10, conferred significant neuroprotection by reducing the accumulation of alpha-synuclein and suppressing lipid oxidation. In addition, animals being treated with the nutrient combination survived longer than those not being treated.¹⁴⁹ Clinical trials are needed to assess the effects of creatine in combination with other neuroprotective nutrients in Parkinson’s patients.

Omega-3 Fatty Acids

These natural components of omega-3 fats, obtained chiefly from fish and some plant sources, exert significant anti-inflammatory action. Their concentration in nerve cell membranes decrease with age, oxidant stress, and in neurodegenerative disorders such as Parkinson's disease.^150,151 In fact, researchers in Norway have presented convincing evidence of a systematic omega-3 deficit in Parkinson's disease, Alzheimer's disease, and autism, suggesting a fundamental neurological role for these vital fat molecules.^152,153 Supplementation with the omega-3 DHA can favorably modify brain functions and has been proposed as a nutraceutical tool in Parkinson's and Alzheimer's disease.¹⁵⁴

A study from Japan found that treatment of nerve cells with omega-3 prevents apoptosis, the programmed cell death that occurs in part as the result of inflammatory stimuli in the brain. Interestingly, results were a lot better when treatment was introduced before the chemical stresses that induced apoptosis were imposed, leading them to conclude that "dietary supplementation with [omega-3s] may be beneficial as a potential means to delay the onset of the diseases and/or their rate of progression."¹⁵⁵

Canadian researchers took this study to the next level when they supplemented mice with omega-3 before injecting them with a Parkinson's inducing chemical.¹⁵⁶ The mice were fed either a control or a high omega-3 diet for 10 months prior to injection. Control mice demonstrated a rapid loss of the dopamine producing cells in their substantia nigra accompanied by profound drops of dopamine levels in brain tissue. These effects were prevented in the mice receiving the high omega-3 diet.

A study of primates at the same institution demonstrated actual changes in Parkinson's symptoms, providing further compelling evidence for omega-3's protective and therapeutic effects. In this study, one group of animals was first treated for several months with L-DOPA before being given omega-3 DHA, while a second group was pre-treated with omega-3 DHA before starting on L-DOPA. The study was designed this way because L-DOPA, though effective in treating Parkinson's symptoms, as stated earlier in the protocol is also known to damage dopamine producing cells and induce dyskinesias. Omega-3 DHA reduced the occurrence of dyskinesias in both groups of monkeys, without altering the beneficial effects of L-DOPA. The researchers concluded that "DHA may represent a new approach to improve the quality of life of Parkinson's disease patients."¹⁵⁷

B Vitamins

B vitamin deficiencies have long been implicated in many neurological disorders, including Parkinson's disease. Studies as early as the 1970's directed at demonstrating the effects of supplementation yielded discouraging results^158-160 However, as our understanding of the close link between the toxic amino acid homocysteine and B vitamins grew, more targeted and mechanism-based studies became possible. Homocysteine levels are closely linked to folate, vitamins B6 and B12 status. Elevated homocysteine levels are found in cardiovascular disease as well as a variety of neurological and psychiatric disturbances.^161-163 Also, L-DOPA treatment can itself lead to elevated homocysteine levels. As a result, more recent studies have led researchers to recommend B complex supplementation in those utilizing L-DOPA therapy.¹⁶⁴

Definitive evidence supporting the benefit of this approach came from Singapore where Parkinson's disease patients, already on a stable dose of L-DOPA, were supplemented with pyridoxine (a common form of vitamin B6).¹⁶⁵ Mean motor and activities of daily living scores improved significantly following supplementation, and worsened again when the supplements were stopped. Low serum folate is also found in Parkinson's disease patients, especially those taking L-DOPA.¹⁶³ Canadian researchers demonstrated that a supplement containing folate and B12 could decrease plasma homocysteine levels in patients taking L-DOPA.¹⁶⁶

A systematic review paper concluded that B vitamin supplementation may be of value for neurocognitive function.¹⁶⁷ A similar review points to recent work with the active form of vitamin B6, pyridoxal-5' phosphate (P5P), noting that a number of neurological disorders including Parkinson's disease offer attractive therapeutic targets for this substance.¹⁶⁸ The consensus among experts is that due to the deleterious effect that elevated homocysteine levels has on both Parkinson's itself and L-DOPA therapy, supplementation with folate, B6, and B12 is warranted.^169-172

Thiamine, also known as vitamin B1, may benefit Parkinson’s patients. In 1999, low levels of free thiamine were detected in the cerebrospinal fluid of Parkinson’s disease patients.¹⁷³ In 2013, researchers treated three newly diagnosed Parkinson’s patients with high-dose thiamine injections. Remarkably, the injections considerably improved the patients’ motor symptom deficits.¹⁷⁴ Although only three subjects participated in this uncontrolled, informal clinical trial, the results corroborated very similar findings from another small trial in 2012.¹⁷⁵

More recently, in 2015, an open-label clinical trial on 50 Parkinson’s disease patients showed that intramuscular injections of 100 mg of thiamine twice weekly led to significant and lasting improvements on a standardized Parkinson’s disease rating scale. Some participants—those with mild symptoms—had a complete clinical recovery. The benefits persisted throughout the follow-up period of up to about 2.2 years.¹⁷⁶ In another open-label study, published in 2016, researchers treated 10 consecutive Parkinson’s patients with intramuscular 100 mg thiamine injections twice weekly without changing their medication regimens. Several measures of Parkinson’s disease symptoms improved significantly, and when the investigators increased the dosage of thiamine into the second month of treatment, the benefits became even more pronounced. Researchers speculated that the benefits of thiamine may arise from improvements in energy metabolism in surviving dopaminergic neurons in the substantia nigra.¹⁷⁷ Additional clinical trials are needed to test whether oral thiamine, or thiamine derivatives such as benfotiamine, may have similarly beneficial effects.

Vitamin D

Vitamin D functions more like a hormone than a vitamin. Vitamin D receptors are expressed ubiquitously throughout the body, including on microglial cells.¹⁷⁸ Upon activation by vitamin D, vitamin D receptors signal for increased or decreased expression of numerous genes, many of which are immunomodulatory.¹⁷⁹

Several studies have shown that higher levels of vitamin D protect against the onset of Parkinson's disease symptoms. Also, that patients diagnosed with Parkinson's have lower serum vitamin D levels than those without the disease.^180,181

Since many of the actions of vitamin D are anti-inflammatory, Life Extension believes that maintaining optimal vitamin D blood levels (50–80 ng/mL) may quell some of the inflammatory aspects of Parkinson's disease neurodegeneration. It is likely that having optimal vitamin D levels might decrease the activation of microglial cells and reduce the release of inflammatory cytokines.

Carnitine

Carnitine is a vital nutrient that serves as a co-factor in fatty acid metabolism. It helps to "ferry" large fat molecules into the mitochondrial "furnaces" where they are burned for energy, making it an important component of brain energy management and mitochondrial function.¹⁸² There is a growing body of literature suggesting that carnitine supplementation, through its support of brain energy management, protects against Parkinson's disease.

Mount Sinai researchers were able to prevent chemically induced Parkinson's disease in monkeys by pre-treating them with acetyl-l-carnitine, a readily absorbed form of the nutrient.¹⁸³ Moreover, Italian researchers have studied carnitine as a neuroprotectant in the brains of methamphetamine users. Methamphetamines cause the same basic mitochondrial destruction and free radical brain damage as that seen in Parkinson's patients.^182,184 This work has been extended in similar studies at the U.S. National Center for Toxicological Research.¹⁸⁵

In an intriguing study, Chinese nutritional scientists in Shanghai explored in culture both acetyl-L-carnitine and lipoic acid (each alone and in combination with the other) in preventing Parkinson's disease-like changes in human neural cells. They found that both nutrients either alone or in combination, applied for four weeks prior to a Parkinson's disease-inducing chemical, protected the cells from mitochondrial dysfunction, oxidative damage, and an accumulation of the dangerous alpha-synuclein proteins. Notably, the combination of supplements was effective at 100- to 1000-fold lower concentrations than were required for either acting alone—powerful evidence that led the researchers to state that "this study provides important evidence that combining mitochondrial antioxidant/nutrients at optimal doses might be an effective and safe prevention strategy for Parkinson's disease."¹⁸⁶

Green Tea

Increased tea consumption is correlated with reduced incidence of dementia, Alzheimer's and Parkinson's disease.¹⁸⁷ Green tea contains valuable antioxidant polyphenols known to be protective against a host of chronic age-related conditions. There is tremendous scientific interest in green tea and its active compound epigallocatechin gallate (EGCG) as a neuroprotectant in Parkinson's disease; especially since when compared to many drugs, EGCG is extremely effective at penetrating brain tissue.^188,189

Israeli researchers showed that they could prevent the cellular changes associated with Parkinson's by pre-treating mice with either green tea extracts or EGCG ahead of inducing the disease by chemical injection.^188,190 This research has subsequently been repeated and extended in laboratories around the world.^191-195 Utilizing the brain cell cultures pretreated to develop Parkinson's-like changes, the Israeli group also showed that green tea extracts prevented activation of the inflammation producing NF-kappaB system.¹⁹⁰ EGCG's specific anti-inflammatory properties have been demonstrated to protect cultured brain tissue from the loss of dopaminergic cells as well.¹⁹⁶ L-theanine, a component of green and black tea, was shown by Korean scientists to prevent dopaminergic cell death such as that seen in Parkinson's disease.¹⁹⁷

Another potential benefit of green tea extract is its ability to inhibit the dopamine degrading enzyme COMT.⁷⁴ This may help to sustain dopamine levels in ailing brain tissue thereby reducing the severity of symptoms.

Just as we use multiple combinations of prescription drugs to capitalize on their synergistic effects, we can capitalize on green tea's neuroprotective effects in Parkinson's and other neurodegenerative diseases.¹⁹⁸ While more human studies are yet to be completed, green tea polyphenols have proven to exert powerful protection for dopaminergic neurons making them a key component in the prevention and treatment of Parkinson's disease.^195,199-202

Resveratrol

Resveratrol is a polyphenolic antioxidant compound that has shown stunning potential in preventing cardiovascular disease and prolonging life.^203-205 Not surprisingly, scientists interested in protecting brain tissue and enhancing the quality of life in aging individuals have directed their attention towards this remarkable compound.

Since dopamine itself is an oxidant compound which can contribute to the early destruction of neurons, Korean scientists studied the impact of resveratrol at preventing this paradoxical effect.²⁰⁶ They found that through the loss of mitochondrial function, human neural tissue treated with dopamine underwent rapid cell death. However, exposing the cells to resveratrol for one hour prior to dopamine treatment prevented cell loss and preserved mitochondrial function. In addition, Canadian scientists used resveratrol to prevent neuronal cell death caused by inflammation.²⁰⁷

Resveratrol's anti-inflammatory action was further explored by Chinese researchers who at first administered a Parkinson's disease-inducing chemical to rats, then gave them oral daily doses of resveratrol for 10 weeks. They found that after only two weeks of supplementation, the rats demonstrated significant improvement in their movement. Also, examination of their brains showed marked reduction in mitochondrial damage and loss of dopaminergic cells. Remarkably, they also found a reduction in the levels of COX-2 and TNF-alpha (inflammatory markers). They concluded with justifiable excitement that "resveratrol exerts a neuroprotective effect on [a chemically-] induced Parkinson's disease rat model, and this protection is related to the reduced inflammatory reaction."²⁰⁸

As with green tea extracts, it appears that resveratrol's potential for preventing Parkinson's disease may reside in its multi-modal mechanism of action targeting oxidant stress, and inflammation, for example.²⁰⁴ 

Mucuna pruriensis a vine whose seeds contain a high concentration of naturally occurring L-DOPA and a variety of other psychoactive compounds.²⁰⁹ Compounds in Mucuna seeds act as AADC inhibitors, mimicking the action of carbidopa, and complementing the action L-DOPA in the central nervous system. In an animal experiment, Mucuna seed extract was shown to alleviate symptoms of chemically-induced Parkinson's with similar efficacy to traditional L-DOPA treatment, but without inducing dyskinesia.²¹⁰ These results were repeated in another, similar trial.²⁰⁹

In a double-blind, randomized, placebo-controlled trial, Mucuna extract proved superior over standard L-DOPA/carbidopa therapy. Compared to traditional therapy, Mucuna led to a faster onset of symptom relief, longer duration of relief, and significantly fewer dyskinesias. The scientists conducting this study concluded that "The rapid onset of action and longer on time without concomitant increase in dyskinesias on mucuna seed powder formulation suggest that this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of [Parkinson's disease]."²¹¹

Wild Green Oat Extract

Oats (Avena sativa L.) have been a foodstuff for many centuries and are an important cereal crop in North America, Europe, and Russia.^212,213 Oats are the only known natural source of avenanthramides, which are bioavailable compounds with anti-inflammatory, anti-atherogenic, and antioxidant properties.^214-216

Monoamine oxidase B (MAO-B) is responsible for the breakdown of dopamine in neurons²¹⁷; however, excess MAO-B activity increases with age and depletes dopamine levels through excessive dopamine metabolism.^218,219 Indeed, the loss of dopaminergic neurons is considered the hallmark of Parkinson’s disease, and restoration of dopaminergic signaling is the focus of most treatments.^220-222 Drugs that inhibit MAO-B, such as deprenyl (Selegeline) and rasagiline (Azilect), are used in the treatment of early Parkinson’s disease.^223-225 Blocking MAO-B with medications such as deprenyl not only raises dopamine levels in brain tissue, but also appears to be neuroprotective. MAO-B inhibitors block free radical formation that occurs during dopamine metabolism and blocks apoptosis (programmed cell death) of neurons.²²⁶

Wild green oat extract has shown the ability to inhibit MAO-B activity^227,228 and demonstrated in numerous clinical trials to be a neuroprotective agent capable of improving cognitive function with as little as a single dose, while also increasing blood flow both systemically and to the brain by as much as 40%.^229-232 Research demonstrates wild green oat extract is a neuroactive compound that shares a critical mechanism of action, MAO-B inhibition, with important Parkinson’s disease medications. This body of evidence suggests wild green oat extract is a promising natural therapy for those concerned with Parkinson’s disease.

Pyrroloquinoline Quinone (PQQ)

Pyrroloquinoline quinone, or PQQ, is a highly bioactive compound present in a vast range of cell types, and research suggests boosting PQQ levels may improve mitochondrial function, inhibit oxidative stress, and support neurological health.^233-238 Since oxidative stress and mitochondrial dysfunction are believed to be key factors in Parkinson’s disease,²³⁹ PQQ is being actively studied as an agent to prevent and treat this condition.²⁴⁰

One mechanism by which PQQ may benefit those with Parkinson’s disease is by stimulating cerebral blood flow and oxygen use. Two studies using near-infrared spectrometry in healthy older adults have found supplementing with 20 mg PQQ daily for 12 weeks resulted in increased brain blood flow as well as increased oxygen utilization.^237,241 In one of the studies, cognitive testing revealed PQQ was also associated with better preservation of cognitive function than placebo.²³⁷ These studies confirm earlier studies where PQQ prevented neurodegeneration and maintained memory function in a rodent experiment.²⁴²

A number of laboratory and animal studies have indicated PQQ can protect nerve cells from toxic and inflammatory damage by reducing oxidative stress and protecting mitochondria.^240,243-245 Several preclinical studies have shown PQQ may prevent the accumulation of damaging amyloid proteins such as beta-amyloid,^246-249 and might in this way protect against conditions such as Parkinson’s disease and Alzheimer’s disease.

Other Promising Nutrients

Curcumin. Curcumin, a derivative of the spice turmeric, through its potent modulation of the NF-kappa B system is a natural inhibitor of inflammation. It prevents chemically-induced changes in lab models of Parkinson's disease and exerts significant neuroprotection.^250-257

Melatonin. The antioxidant hormone melatonin (synthesized and secreted by the pineal gland) may help to reduce the accumulation of alpha-synuclein proteins while preserving the cell's ability to make dopamine. It is also an invaluable sleep aid for Parkinson's patients, who often suffer from distressing problems with sleep.^258-267

N-acetyl cysteine (NAC). NAC is a precursor to the potent cellular antioxidant glutathione. In animal models, NAC prevented dopamine induced neurotoxicity and protected against some of the damaging effects of alpha-synuclein proteins.^268,269

Lipoic acid. Lipoic acid, a potent reducing agent, is considered a universal antioxidant due to its amphipathic nature (both fat- and water-soluble). Lipoic acid is produced naturally within the body and contributes to xenobiotic detoxification and antioxidant protection. It also contributes to cellular energy production.²⁷⁰ In addition to its ability to directly neutralize toxins and free radicals, lipoic acid bolsters levels of other cellular protectants such as glutathione and vitamin E.²⁷¹

The low molecular weight of lipoic acid allows it to easily cross the blood-brain barrier, delivering neuroprotection within the central nervous system. Lipoic acid also combats inflammatory reactions.²⁷¹ Large scale clinical trials have yet to be conducted in Parkinson's patients. However, given its potential for efficacy and excellent safety profile, lipoic acid should be considered as a therapeutic agent for Parkinson's disease.

Probiotics. Because dopaminergic signaling exerts considerable influence over intestinal function, constipation is a common problem in Parkinson's disease.

In a recent clinical trial, 40 Parkinson's patients complaining of constipation were treated with probiotics for five weeks. Probiotic therapy significantly increased the number of normal stools as well as reduced the incidence of bloating and abdominal pain.²⁷²

Phellodendron. The bark of the phellodendron tree (Phellodendron amurense), also known as the Amur cork tree, has been used for centuries in traditional Chinese medicine to treat various inflammatory conditions. An extract of phellodendron bark was found to reduce production of inflammatory cytokines and neurotoxic nitric oxide by microglia (specialized immune cells of the brain), indicating its potential usefulness in reducing the neuroinflammation and neurodegeneration underlying Parkinson’s disease.²⁷³ Phellodendron bark extract has also been shown to be a strong inhibitor of MAO-B, an enzyme that breaks down monoamine neurotransmitters, including dopamine.^274,275

Adenosylcobalamin. Adenosylcobalamin is one of two biologically active forms of vitamin B12, the other being methylcobalamin. While methylcobalamin is a cofactor for enzymes that regulate methylation reactions, including homocysteine breakdown, adenosylcobalamin is needed for specialized enzyme pathways in the mitochondria.^276,277 Abnormal patterns of genetic control of protein synthesis linked to neurological disorders such as Parkinson’s disease have been shown to be normalized when exposed to a high-vitamin B12 environment.²⁷⁸ In particular, adenosylcobalamin was found to regulate expression of the LRRK2 gene, prevent neurotoxicity, and restore function in dopamine-producing neurons in preclinical models of LRRK2 mutations.²⁷⁹ Because LRRK2 mutations are a common cause of familial Parkinson’s disease and increase the risk of sporadic Parkinson’s disease,^280,281 LRRK2 inhibitors with actions such as those seen with adenosylcobalamin are being investigated as possible therapeutic agents for Parkinson’s disease.²⁸²