Parkinson's Disease Guide

Causes and Risk Factors

PD involves abnormal clumping of α-synuclein, a protein that regulates neurotransmitter release to help neurons communicate. In PD, α-synuclein misfolds, disrupting brain function.

Alpha-synuclein is abundant in the brain, but also exists in small amounts in the heart and muscles. It moves between the brain and body via the blood-brain and cerebrospinal fluid barriers, both affected in PD. Sui

In PD, α-synuclein misfolds, forming clumps called oligomers. Oligomers can grow into fibrils, larger, more harmful aggregates, eventually forming Lewy bodies, driving senescence. Similar α-synuclein misfolding occurs in related disorders, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), whose research on α-synuclein misfolding is relevant.

Aging, environmental hazards, and genetics interact pathologically, leading to neuronal death and neurotransmitter imbalances, α-synuclein aggregation, and mitochondrial dysfunction—another major factor in disease progression, causing oxidative damage, apoptosis, and neuroinflammation, driving disease progression. K. Burton

Alpha-Synuclein Pathology

Mutations in α-synuclein increase its tendency to clump, particularly in familial PD cases V. Ruf, J. Li. Misfolded or mutant forms resist breakdown, leading to toxic buildup, cellular stress, inflammation, waste accumulation, and Lewy body formation. Over time, these damaged cells become senescent, releasing toxic compounds that fuel neurodegeneration.

Alpha-Synuclein Aggregation

α-synuclein aggregation leads to formation of oligomers, which can then form fibrils (see figure below). As oligomers and fibrils accumulate, they create Lewy bodies—dense, toxic protein clusters in nerve cells.

Alpha-Synuclein Clearance Mechanisms

Healthy cells clear small misfolded proteins with the ubiquitin-proteasome system (UPS) and larger aggregates with the autophagy-lysosome pathway (ALP).

In PD, the structure of misfolded α-synuclein and its sheer volume hinder its degradation and clearance. Misfolded α-synuclein aggregates are not efficiently broken down by the proteasome, leading to their buildup and overwhelming the UPS. When the proteasome fails to degrade these aggregates, they are directed to the ALP, where α-synuclein fibrils further resist lysosomal breakdown. This resistance disrupts both clearance pathways, contributing to extracellular waste and increasing neuronal stress. While these processes are explored further in this guide, they remain outside conventional treatment approaches.

Intracellular α-Synuclein Accumulation Diagram

α-synuclein Misfolds

α-synuclein misfolds, forming toxic oligomers.

UPS Overload

UPS overwhelmed by excess misfolded α-synuclein. Larger oligomers block the proteasome or inhibit its activity, preventing efficient degradation.

Cellular Stress

Cellular stress from protein buildup triggers autophagy.

Autophagy Overload

Autophagy overwhelmed as misfolded α-synuclein aggregates block autophagosomes formation and impair fusion with lysosomes.

Cellular Damage

Mitochondrial stress, oxidative damage, and inflammation from misfolded α-synuclein aggregates further impair UPS and ALP function, creating a vicious cycle.

α-synuclein Misfolds

A toxic cellular environment perpetuates α-synuclein misfolding, ER stress, and glial activation, causing formation of toxic α-synuclein oligomers.

Alpha-Synuclein Clearance Mechanisms

As shown in the diagram above, small misfolded proteins like α-synuclein are cleared by the ubiquitin-proteasome system (UPS), which tags unwanted proteins for degradation. Larger aggregates are managed by the autophagy-lysosome pathway (ALP), which transports them to lysosomes for breakdown.

In PD, autophagosomes (structures that deliver cellular waste to lysosomes) try to clear away α-synuclein aggregates but become overwhelmed, leading to buildup of these aggregates that worsens cellular dysfunction.

In PD, misfolded α-synuclein overwhelms both systems, resisting degradation and leading to toxic buildup. These and other waste clearance mechanisms of the brain are explored in greater detail in the section Brain Waste Management Systems (BWMS).

What Causes Alpha-Synuclein Misfolding?

This raises a natural question: What causes α-synuclein misfolding in the first place?

Aside from genetic mutations, multiple things can contribute to alpha-synuclein misfolding, including a toxic cellular environment caused by problems resulting from the misfolding α-synuclein itself — a recursive chicken-and-egg quandary.

Propagation from Gut to Brain: The Braak Hypothesis

Misfolded α-synuclein propagating from the enteric nervous system (ENS), aka "the gut", to the brain, known as the Braak hypothesis, explained later, is one such causal pathway. This dysfunction is exacerbated by excess calcium in dopaminergic neurons, which rely on precise calcium signaling to maintain normal firing patterns. The hypothesis holds that the misfolding begins in the gut. However, PD is more complex, and as mentioned throughout, it is induced in rodents through rotenone and paraquat administration, which indicates that this phenomenological condition may come about in different ways.

Mechanisms of Spread

Once aggregated, misfolded α-synuclein spreads between neurons and neural networks, leading to abnormalities in synaptic structure and function before neuronal loss occurs. This process contributes to the progressive spread of the disease from initially affected brain regions to others. Daley, Pérez-Acuña

Senescent Spread

As senescent cells accumulate, their inflammatory response accelerate the spread of alpha-synuclein aggregates, enhancing cellular dysfunction across interconnected brain regions, in a senescence-associated secretory phenotype (SASP). Verma

Strategies to address α-synuclein include preventing its mutation, inhibiting aggregation, improving its clearance from the brain, promoting proper refolding with chaperones, and using senolytics to remove senescent cells. A comprehensive approach to address each etiological problem is more likely to improve outcomes, steering away from PN.

Gut-Brain Axis and Alpha-Synuclein Propagation

Alpha-synuclein aggregation in the GI tract may precede motor symptoms. Misfolded α-synuclein can propagate from the enteric nervous system (ENS) in the gut to the brain via the vagus nerve, creating a direct link between the gut and the central nervous system (CNS). This pathway, part of the Braak hypothesis, suggests that α-synuclein pathology may start in the gut before reaching the brain. Braak, Chao

Braak's seminal discovery led to imaging studies showing that α-synuclein pathology affects large parts of the peripheral nervous system which may further implicate the gut-brain pathway in PD progression, and sonographic studies have confirmed vagal nerve atrophy, supporting gut-brain pathway in PD progression. schaeffer

Neurotransmitters, including dopamine, serotonin, and GABA, are also produced in the gut, affecting mood, sleep, and GI health. Impaired gut health reduces neurotransmitter production, worsening PD symptoms. Rstoring gut health may improve upon these symptoms. A preliminary 2020 study out of Nanjing Medical University found that colonic fecal (FMT) improved sleep, anxiety, and depression, showing that improving gut health can lead to improved health and symptoms in PD. Xue

Alpha-synuclein pathology can propagate bidirectionally between the gut and brain, via the vagus nerve or the bloodstream, depending on individual factors. GI symptoms, such as constipation, often precede motor symptoms by years, indicating that the gut may be an early site of PD pathology. Klann, Arotcarena

Gut dysbiosis can exacerbate α-synuclein misfolding and accelerate PD progression. Conversely, DRT may worsen gut dysbiosis, further compounding the issue. This insight into gut dysbiosis and the mutually destructive interdependent effects of poor gut health and DRT usage provides yet another reason to minimize and avoid DRT overreliance in favor of a more comprehensive program to improve gut health. Klann, Breen, Mulak

Solutions

Strategies to support gut health include reducing sugar intake, increasing fiber, and consuming probiotic foods (e.g., yogurt, kimchi, natto). Such changes may help balance the microbiome and reduce GI-related symptoms in PD. Additionally, FMT has shown promise in preliminary studies, potentially reducing inflammation and oxidative stress to improve both motor and non-motor symptoms.

Strategies to support gut health include reducing sugar intake, increasing fiber, and consuming probiotic foods (e.g., yogurt, kimchi, natto). Such changes may help balance the microbiome and reduce GI-related symptoms, improve gut health, and may help mitigate the progression of PD and improve patient outcomes. Additionally, FMT has shown promise in preliminary studies, potentially reducing inflammation and oxidative stress to improve both motor and non-motor symptoms.

The gut lining can be strengthened by first eliminating things that weaken it, including NSAIDs, gluten, alcohol, and fluoride. Consuming collagen peptides and hyaluronic acid can help strengthen the gut lining.

The vagus nerve is involved in digestion and cardiovascular function. Transcutaneous vagus nerve stimulation (VNS) is a non-invasive procedure that has shown improvement in movement in PD patients. A 2022 double‐blind randomized crossover on transcutaneous cervical vagus nerve stimulation (VNS) showed improvements in stride length, swing amplitude, gait speed, and gait time showed significant changes following treatment. Marano

References

1. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen, H. Braak, et al.
2. Gut–Brain Axis: Potential Factors Involved in the Pathogenesis of Parkinson's Disease, Yin-Xia Chao, et al.
3. The Gut–Brain Axis and Its Relation to Parkinson’s Disease: A Review, Emily M Klann, et al.
4. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates, Marie-Laure Arotcarena, et al.
5. Gut-brain axis and the spread of α-synuclein pathology: Vagal highway or dead end?, David P Breen, et al.
6. Brain-gut-microbiota axis in Parkinson's disease, Agata Mulak and Bruno Bonaz.
7. Alpha Synuclein Connects the Gut-Brain Axis in Parkinson’s Disease Patients – A View on Clinical Aspects, Cellular Pathology and Analytical Methodology, Eva Schaeffer, et al.
8. Fecal microbiota transplantation therapy for Parkinson's disease, Liu-Jun Xue, et al.
9. Transcutaneous Auricular Vagus Stimulation Improves Gait and Reaction Time in Parkinson's Disease, Massimo Marano, et al.

Brain Waste Management Systems (BWMS)

The brain's waste management systems (BWMS) defined herein describes the coordinated systems of interdependent intracellular and extracellular components that protect the brain from harmful substances, clear waste, and maintain homeostasis.

Intracellular Clearance: UPS and ALP

Intracellular clearance mechanisms include the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP) introduced previously.

Extracellular Clearance

Extracellular clearance mechanisms include brain phagocytes, the blood-brain barrier (BBB), choroid plexus, CSF, glymphatic system, perivascular spaces, extracellular matrix (ECM), basement membrane. Dysfunction in any of these subsystems leads to α-synuclein aggregation, inflammation, and mitochondrial damage, which impacts other interdependent subsystems, leading to the accumulation of junk proteins and Lewy bodies. Various interventions can improve the integrity and function of these components, with measurable effects. Solár

Impact of Dysfunction

When these systems are overwhelmed, their impairment leads to neuronal damage and overburdens interconnected systems, resulting in further dysfunction. For example, α-synuclein fibrils resist breakdown, overloading the UPS and ALP. This results in extracellular waste accumulation, which strains brain phagocytes and other clearance mechanisms.

Normally, smaller misfolded proteins (like α-synuclein) are cleared by the UPS. However, the proteasomes in the UPS can't digest larger, insoluble aggregates that α-synuclein forms over time. In PD, mutant or aggregated α-synuclein resists lysosomal degradation, disrupting autophagy and causing the toxic accumulation of cellular waste. As autophagy fails, oxidative stress and inflammation increase, leading to mitochondrial damage and cell death.

Microglia and astrocytes clear extracellular α-synuclein aggregates through phagocytosis. In PD, chronic neuroinflammation impairs this process, worsening protein clearance deficits. Increased BBB permeability compounds the problem, allowing contaminants and inflammatory substances to enter and harm the brain. These substances can accumulate in the CSF, further damaging the choroid plexus and disrupting CSF homeostasis, amplifying the strain on all of these interdependent clearance systems.

The Blood–Brain Barrier (BBB)

The Blood–Brain Barrier (BBB) is a protective layer of specialized cells that line the blood vessels of the central nervous system (CNS) in the brain, controlling what enters and exits the CNS to maintain homeostasis, allowing necessary nutrients and oxygen to pass through while blocking toxins, pathogens, and other harmful substances.

Choroid Plexus and CSF

The choroid plexus is a specialized structure within the brain's ventricles that produces cerebrospinal fluid (CSF) and forms a blood-CSF barrier. It consists of epithelial cells surrounding capillaries and connective tissue. As CSF circulates through the brain, it transports essential substances such as nutrients, growth factors, hormones, proteins, electrolytes, and neurotransmitters, while also collecting waste products, including misfolded proteins like α-synuclein. The waste-laden CSF is then drained through specialized pathways, including the ventricles and the glymphatic system, before being filtered out by the liver and kidneys.

Damage to the choroid plexus impairs CSF production and disrupts waste clearance, allowing α-synuclein to accumulate, clog, and damage its epithelial cells. This accumulation hinders the brain's ability to clear waste and deliver essential nutrients and growth factors, exacerbating neuroinflammation. Al-Bachari, Saunders, Tadayon

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Ventricles

The ventricles are interconnected cavities within the brain filled with CSF. This fluid eventually moves into small structures called arachnoid granulations, tiny, finger-like extensions of the brain’s protective membrane. These granulations help reabsorb CSF into the bloodstream through the dural venous sinuses surrounding the brain, from where it is carried away by the internal jugular veins.

The ventricles circulate and hold CSF and passively drain waste-laden CSF. However, the glymphatic system actively extends through brain tissue to clear waste directly from within the brain and distribute nutrients and neurotransmitters throughout the brain.

The Glymphatic System

The glymphatic system is a dual-purpose pathway that transports nutrients and growth factors and also performs brain-specific waste clearance.

These glial cells remove metabolic waste and toxins, including misfolded proteins like α-synuclein, using CSF to flush out waste from the brain along perivascular spaces (areas surrounding arteries and veins), similar to the body's lymphatic system, hence the term "glymphatic" (glial + lymphatic). Its essential function is compromised in neurodegenerative diseases, including PD.

How it Works

The glymphatic system moves CSF from the space around the brain into brain tissue, where it mixes with interstitial fluid (fluid between brain cells) to clear waste like misfolded proteins. This waste is then carried along the spaces surrounding blood vessels and drained into the deep cervical lymph nodes in the neck for filtration and removal by the body's lymphatic system.

Protein Clearance Pathway Dysfunction

Ubiquitin-Proteasome System (UPS) Dysfunction

The UPS degrades smaller, soluble misfolded or damaged proteins by tagging them with ubiquitin and directing them to proteasomes for breakdown. In PD, UPS dysfunction leads to α-synuclein accumulation, which overwhelms other waste clearance pathways and triggers oxidative stress, mitochondrial dysfunction, and neurodegeneration.

Autophagy-Lysosomal Pathway

When α-synuclein aggregates are too large for the UPS, they are targeted for autophagic degradation. As noted earlier in the Alpha-Synuclein Clearance Mechanisms section, autophagosomes form around these aggregates, isolating them from the rest of the cellular environment. The autophagosome then fuses with a lysosome, forming an autolysosome that degrades the aggregated proteins within the autophagosome.

autophagosome — (auto — "self" + phago — "eat; consume" + some — "body") — temporary intracellular structure that engulfs damaged components and delivers them to lysosomes, which act as the cell's recycling centers.

However, in PD, lysosomal degradation becomes impacted, disrupting autophagy and causing the toxic accumulation of cellular waste. As autophagy fails, oxidative stress and inflammation increase, leading to mitochondrial damage and cell death. This accumulation contributes to extracellular waste, overburdening phagocytes and the glymphatic system, worsening neurodegeneration.

Brain Phagocytes

As mentioned earlier, the lysosomal system in autophagy helps neurons degrade internal misfolded proteins like α-synuclein. Lysosomes also assist phagocytes in clearing extracellular waste. While neurons use autophagy to clear intracellular waste, brain phagocytes, such as microglia and astrocytes, use lysosomal phagocytosis to clear external waste.

Brain phagocytes, including microglia, astrocytes, and macrophages, clear cellular debris and toxic proteins. Microglia, the primary phagocytes, engulf damaged neurons, dead cells, and toxic proteins. Astrocytes help clear apoptotic cells (cells dying in a controlled manner) and excess neurotransmitters, supporting microglia in debris removal. Macrophages, present in the perivascular space, also perform phagocytosis, though they are less involved than microglia.

Phagocytes perform the initial cleanup, breaking down harmful proteins like α-synuclein within themselves, with the remainder either recycled or expelled for further clearance. The glymphatic system helps by flushing extracellular waste from the brain via CSF.

In PD, misfolded α-synuclein accumulation triggers neuroinflammation, impairing phagocytosis and worsening α-synuclein aggregation. This neuroinflammation impairs phagocytosis, which in turn exacerbates α-synuclein aggregation. This buildup of α-synuclein leads to further aggregation, oligomerization, and fibrillization, forming Lewy bodies and advancing neurodegeneration and senescent cells. Additionally, collagen cross-linking caused by advanced glycation endproducts (AGEs) from high blood sugar, oxidative stress, or chronic inflammation further impairs phagocytosis.

Cells, impacted by this toxicity, become senescent, not functioning but failing to die and impairing phagocytic function and blocking extracellular waste clearance pathways. This leads to a feedback loop where more toxic proteins accumulate, increasing neuroinflammation and mitochondrial damage.

α-synuclein Misfolds in Neurons

Misfolded α-synuclein forms toxic oligomers and fibrils.

Impaired UPS and ALP

UPS and ALP are overwhelmed, leading to toxic buildup of α-synuclein within neurons.

Neuroinflammation & Mitochondrial Stress ⟳

Accumulated α-synuclein fibrils cause neuroinflammation and mitochondrial dysfunction, exacerbating the UPS and ALP.

↑ BBB Permeability

Chronic neuroinflammation weakens the BBB, allowing harmful substances into the brain from the bloodstream.

Choroid Plexus Damage

Choroid plexus damage reduces CSF production and waste clearance, allowing α-synuclein to accumulate and damage epithelial cells.

Impaired Glymphatic & CSF Clearance

Waste clearance systems, like the glymphatic system and CSF, struggle to remove extracellular protein aggregates.

Protein Buildup & Feedback Loop

As extracellular waste builds up, it further impairs phagocytosis and clearance mechanisms, worsening neuroinflammation and α-synuclein aggregation.

Cycle Continues

Neuroinflammation, mitochondrial stress, protein accumulation, and waste clearance create a vicious cycle, exacerbating waste buildup and neuronal damage.

Solutions

A multifaceted approach can be used to try to stop the feedback loop, including measures to prevent α-synuclein aggregation, restore choroid plexus and BBB integrity, improve UPS and ALP function, reduce neuroinflammation, and improve mitochondrial health.

Assessing BBB and Choroid Plexus Integrity

Elevated BBB permeability affects waste clearance, including the movement of α-synuclein. Contrast agents are used in DCE-MRI) to visualize changes in BBB permeability.

Strengthening the BWMS

Health strategies that promote collagen formation and support the ECM may help counteract the effects and degradation of the BBB. Promoting ECM stability and collagen synthesis contributes to maintaining the structural integrity of the BBB and reduces its permeability to harmful substances, thereby mitigating a major etiological pathway of PD.

These include HRT, DHEA, pregnenolone, Growth hormone (GH) and secretagogues (tesamorelin, CJC-1295), collagen peptides (especially collagen type IV), hyaluronic acid, vitamin C, tocotrienols, vitamin K2, vitamin D3, PQQ, beta-glucan (from mushrooms), MSCs, photobiomodulation, and last but not least, intense exercise.

Improving the Ubiquitin Proteasome System (UPS) and Autophagy-Lysosome Pathway (ALP)

Exercise, fasting, caloric restriction, and compounds like trehalose promote autophagy by enhancing cellular stress responses. mTOR inhibitors (such as rapamycin) reduce inhibitory signals on autophagy, increasing the clearance of misfolded proteins. Lithium helps stimulate autophagy and protects against neurodegeneration. Senolytics eliminate senescent cells that impair waste clearance. Mitochondrial enhancers, including Urolithin A and NAD+ boosters, support cellular energy production, further improving UPS and ALP efficiency.

Strengthening Brain Phagocytes

Addressing the root cause—α-synuclein aggregation—addresses the primary disruption in phagocytosis, which in turn reduces neuroinflammation and limits neuronal damage. Reducing α-synuclein aggregation should be considered a first line of prevention to improve brain phagocytosis.

Other health strategies to improve brain phagocytosis include reducing neuroinflammation, increasing blood flow, and increasing neurotrophins. These include supplementing DHA, beta-glucan (from mushrooms), lion's mane, cordyceps, turmeric, ginseng, creatine, EGCG (matcha), ALCAR, phosphatidylserine, tocotrienols, and senolytics. Pyridoxamine (vitamin B6) and aminoguanidine can reduce collagen cross-linking. Growth hormone (GH) and secretagogues (tesamorelin, CJC-1295) photobiomodulation and physical exercise increase neurotrophins. Mesenchymal signaling cells reduce neuroinflammation.

Increasing CSF Production

Cholinergics and related supplements can support brain function and potentially influence cerebrospinal fluid (CSF) production. Higher choline levels can improve membrane integrity and fluidity, improve BBB integrity and cellular function, and might indirectly support glymphatic system performance.

Do interventions targeting collagen/ECM strengthen the glymphatic system?

Yes, interventions that improve the health of the ECM and strengthen collagen may have a beneficial effect on the structural support around blood vessels and thus support glymphatic function. The perivascular spaces which direct CSF flow in the glymphatic system, rely on the surrounding ECM for waste clearance. In PD, these spaces enlarge, reducing waste clearance efficiency. Restoring collagen and ECM health should reduce the size of the perivascular spaces, improving glymphatic function and waste clearance of α-synuclein.

References

1. α-Synuclein propagation leads to synaptic abnormalities in the cortex through microglial synapse phagocytosis, Dayana Pérez-Acuña, et al.
2. Choroid plexus and the blood–cerebrospinal fluid barrier in disease, Peter Solár, et al.
3. Blood–Brain Barrier Leakage Is Increased in Parkinson’s Disease, Sarah Al-Bachari, et al.
4. The choroid plexus: a missing link in our understanding of brain development and function, Norman R. Saunders, et al.
5. Choroid plexus volume is associated with levels of CSF proteins: relevance for Alzheimer’s and Parkinson’s disease, Ehsan Tadayon, et al.

Mitochondrial Dysfunction

Mitochondrial dysfunction is a primary problem in PD. Disrupted energy production, increased oxidative stress, and calcium imbalances all worsen neurodegeneration. This section explores how these mitochondrial dysfunctions accelerate disease progression along with targeted strategies to support mitochondrial resilience, reduce oxidative damage, and improve cellular stability in PD.

Damage to mitochondria can cause α-synuclein aggregation by disrupting cellular processes and increasing oxidative stress. Mitochondria, the powerhouse of the cell, produce ATP, the energy currency of the cell. When mitochondria are impaired, energy production drops and oxidative stress rises, damaging neurons. This creates a cycle where disrupted cellular processes cause protein misfolding and aggregation, which worsens oxidative stress, recursively accelerating mitochondrial dysfunction and neurodegeneration. Daley

Mitochondrial Dysfunction and Waste Clearance

Mitochondrial dysfunction, coupled with impaired mitophagy, the process of mitochondrial degradation and recycling, allows dysfunctional mitochondria to accumulate, leading to cellular senescence. Senescent cells release reactive oxygen species (ROS) and inflammatory cytokines, which damage neighboring cells and promote neurodegeneration. This cycle accelerates the buildup of misfolded proteins like α-synuclein and impairs essential processes like autophagy and mitophagy, exacerbating neurodegeneration.

Mitochondrial dysfunction impairs the brain's waste management systems (BWMS), including the UPS and ALP, leading to an accumulation of misfolded proteins. Improving mitochondrial health reduces oxidative stress and supports waste clearance, helping to break the cycle of neurodegeneration.

Improving mitochondrial health decreases the amount of this waste burden and reduces the damage to the systems that remove it, thereby improving the clearance of waste from the brain.

Mitochondrial DNA Damage

Mitochondrial DNA damage further impairs function. Ineffective autophagy and mitophagy fail to remove damaged mitochondria and proteins, leading to the formation of senescent cells. These senescent cells resist lysosomal degradation due to protein aggregation, worsening cellular damage. Korolchuk

Brain Inflammation

Chronic brain inflammation, also known as neuroinflammaging, is a state of neuroinflammation and immunosenescence, a chronic, low-grade inflammatory state. This chronic, low-grade inflammatory state is both a consequence and a driver of mitochondrial dysfunction. Mitochondrial damage contributes to neuroinflammaging, while the resulting inflammation can further impair mitochondrial function, creating a vicious cycle that accelerates neurodegenerative processes.

Mitochondrial Calcium Dysregulation

Besides producing energy, mitochondria help regulate calcium levels in nerve cells by acting as a “buffer", absorbing excess calcium to maintain proper neuron function. Calcium is essential for neuron signaling; however, neurons are particularly sensitive to calcium levels, and its excess can be toxic. Learning about excess calcium can help inform options for testing and managing it, as described further in this section.

Mitochondria regulate cellular calcium to prevent mitochondrial permeability transition pore (mPTP) opening, which leads to cell death, particularly in neurodegenerative diseases like PD. Calcium dysregulation in mitochondria exacerbates oxidative stress, disrupting ATP production and causing neuronal damage.

Excess intracellular calcium occurs through three main pathways. First, channels at the cell surface (VGCCs) allow calcium inside. Second, the mitochondrial calcium uniporter (MCU) regulates calcium entry directly into mitochondria for safe storage. Third, the inositol triphosphate receptor (IP3R) moves calcium from the cell’s internal stores into mitochondria. In Parkinson’s Disease, damaged mitochondria lose their ability to manage this calcium effectively, which leads to overload, energy issues, and cell death. In PD and similar conditions, mitochondrial damage (due to oxidative stress and other issues) and excess calcium disrupts the MCU’s function, leading to uncontrolled, excess calcium uptake and an opening of the mPTP, leading to neuronal death.

High calcium levels outside cells—often due to supplementation—can trigger the IP3R pathway, which further transports calcium from the ER to the mitochondria. This further overloads mitochondria, reducing ATP production and eventually triggering cell death.

Hormonal Loss and Calcium Supplementation (Warning)

Hormonal loss, often occurring with age, disrupts calcium handling in both men and women. However, postmenopausal women face an increased risk of calcium imbalance, exacerbated by the common healthcare recommendation to supplement calcium. Rather than relying on calcium supplementation, focusing on bone strength through targeted exercise and supportive nutrients that promote calcium uptake into bones may offer a safer and more effective approach.

Blood Calcium Tests and Intracellular Calcium Levels

While standard blood calcium tests measure calcium in the bloodstream, they do not indicate levels within neurons or mitochondria. Discussing options like calcium imaging with a healthcare provider can offer insight into calcium levels specific to cellular and mitochondrial health.

Solutions to Calcium Dyregulation

The understated problem of calcium dyregulation is only worsened by the dearth of solutions. Pharmaceutical VGCC blockers (L-type) have been proposed Ntetsika, however, those come with side effects, and worse, clinical trials (STEADY III) results have been poor. A more comprehensive solution to addressing calcium management is in order.

Excess intracellular calcium can be managed with natural (non-pharmaceutical) VGCC (L-type) blockers, IP3R modulators, and osmolytes, as well as by reducing excess extracellular calcium, which contributes to excess intracellular calcium (via the IP3R pathway). Excess extracellular calcium can be reduced by stimulating bone uptake of calcium. See the Calcium Dysregulation solutions in the problems list for more.

Calcium AKG vs Strontium — Which to Supplement?

Calcium supplementation puts one at risk of calcium excess. Calcium alpha-ketoglutarate (Ca-AKG) assists with calcium regulation and improves mitochondrial function (it also reduces inflammation) Zimmermann, Gyanwali. In PD, where mitochondrial health is compromised, Ca-AKG at ~500 mg per day along with 250 mg strontium citrate and other aforementioned bone-supportive supplements, offers a more comprehensive and safer option. Strontium, while structurally similar to calcium, does not overload mitochondria in the same way, offering superior support without increased mitochondrial stress. Individual needs may vary, and patients should discuss this approach with their healthcare provider to determine the most appropriate dose and evaluate personal calcium needs beyond blood tests alone.

Osmolytes

Osmolytes help maintain a stable environment within cells by balancing water and ion concentrations, preventing mitochondrial overloads of calcium and other ions that can stress the cell. Common osmolytes include glycine, taurine, and betaine, as well as the electrolyte chloride, which together help stabilize cellular and mitochondrial environments by managing calcium and other ion concentrations.

Mitochondrial dysfunction, in the greater context of PD, also disrupts GABA-producing neurons, impairing GABAergic signaling. As GABA function declines, calcium influx increases, causing abnormal neuronal firing and excitotoxicity, accelerating neurodegeneration, contributing to disease progression. Matuz-Mares

Reactive Oxygen and Nitrogen Species (RONS)

Mitochondrial dysfunction and Reactive Oxygen and Nitrogen Species (RONS) can cause α-synuclein to misfold and aggregate, forming toxic mutant species. Combined with calcium dysregulation and inflammation, this toxic α-synuclein contributes to neuronal death and the pathology of PD. Hu

Solutions

Several strategies discussed in this document can improve mitochondrial function. These include growth hormone (GH) and secretagogues, vitamin C, tocotrienols, creatine, vitamin K2, vitamin D3, PQQ, beta-glucan, NAD+ and precursors, NAC, and many others detailed in this document.

Photobiomodulation, intermittent fasting, sauna, and cold plunges all improve mitochondrial function. Toro, Hunt, Chung

An exercise routine focused on HIIT can fight neurodegeneration and increase cerebral blood flow, improving oxygen delivery, increasing neurotrophins and growth factors, and aiding the penetration of exogenous compounds into deeper brain regions where they can exert therapeutic effects. Many substances that improve health also hasten exercise recovery, further optimizing health.

Once a comprehensive health optimization protocol is established, MSCs can halt neuroinflammation and induce healing.

References

1. Mitochondria in Cell Senescence: Is Mitophagy the Weakest Link?, Viktor I. Korolchuk, et al.
2. Novel targeted therapies for Parkinson’s disease, Theodora Ntetsika, et al.
3. Long-term treatment with calcium-alpha-ketoglutarate corrects secondary hyperparathyroidism, E Zimmermann, et al.
4. Alpha-Ketoglutarate dietary supplementation to improve health in humans, Bibek Gyanwali, et al.
5. Effects of Twelve Sessions of High-Temperature Sauna Baths on Body Composition in Healthy Young Men, Víctor Toro, et al.
6. Could Heat Therapy Be an Effective Treatment for Alzheimer’s and Parkinson’s Diseases? A Narrative Review, Andrew P. Hunt, et al.
7. The effects of exercise and cold exposure on mitochondrial biogenesis in skeletal muscle and white adipose tissue, Nana Chung, et al.

Endoplasmic Reticulum (ER) Dysfunction

The endoplasmic reticulum (ER) is a cellular organelle primarily responsible for protein folding, lipid synthesis, and calcium storage. The ER and mitochondria communicate closely through structures called mitochondrial-associated ER membranes (MAMs), which manage the flow of calcium between them. Normally, this interplay between the ER and mitochondria helps balance cellular energy needs and signaling.

In PD, accumulation of misfolded α-synuclein and other proteins disrupts ER function, leading to ER stress. These disruptions in normal ER function compromise protein homeostasis and destabilize MAMs, weakening the ER-mitochondria interface and promoting mitochondrial calcium overload. This overload disrupts cellular signaling and contributes to mitochondrial permeability, inflammation, and cell death. Matuz-Mares

Proteostasis and Chaperone Proteins

Proteostasis is the protein quality control mechanism of the cell, facilitated by chaperone proteins. Lautenschläger

Chaperone proteins, like heat shock protein 70 (Hsp70), assist in the proper folding and refolding of proteins, reducing misfolding which leads to aggregation. In PD, ER stress is exacerbated when these chaperone mechanisms become overwhelmed. Hu

Solutions

Chaperone function can be stimulated and upregulated by heat exposure from sauna therapy and photobiomodulation, both of which stimulate the production of Hsp70 and other protective proteins. Curcumin, resveratrol, and glycyrrhizin (from licorice root), also increase the expression of chaperones like HSP70. These interventions can improve protein homeostasis, reduce oxidative stress, and aid in the clearance of misfolded proteins.

1. Intra-mitochondrial proteostasis is directly coupled to alpha-synuclein and Amyloid β 1-42 pathology, Janin Lautenschläger, et al.

References

1. Alpha-Synuclein Preformed Fibrils Induce Cellular Senescence in Parkinson’s Disease Models, Dinesh Kumar Verma, et al.
2. Brain neurotransmitters and neuropeptides in Parkinson's disease, U K Rinne, et al.
3. Alpha synuclein is transported into and out of the brain by the blood-brain barrier, Yu-Ting Sui, et al.

   This rodent model study showed α-synuclein is transported across the BBB bidirectionally, in both the brain-to-blood and blood-to-brain directions.

4. Why Genetic Testing May Be Our Best Shot at Progress in PD, Kelli Whitlock Burton

   Previous studies have shown that some genetic variants increase the risk for PD after exposure to environmental factors such as pesticides. Research has also shown that patient genotype can indicate survival time and treatment approaches.

5. Different Effects of α-Synuclein Mutants on Lipid Binding and Aggregation Detected by Single Molecule Fluorescence Spectroscopy and ThT Fluorescence-Based Measurements, Viktoria C Ruf, et al.

   This study showed the differential mechanisms of metals, such as iron, in α-synuclein pathology at the molecular level.

6. Effect of Familial Parkinson's Disease Point Mutations A30P and A53T on the Structural Properties, Aggregation, and Fibrillation of Human α-Synuclein, Jie Li, et al.

   This rodent study showed that the A53T and A30P genetic mutations in α-synuclein have an increased propensity to aggregate compared with the wild-type protein, and this shows how mutant α-synuclein contributes to PD.

   They note α-synuclein in PD arose from gene-linkage experiments in familial early-onset Parkinson’s disease, which revealed the A53T mutation.

7. Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway, Jae-Hyeon Park, et al.

   This rodent model showed that pesticides can initiate the progression of PD pathology and that this progression is based on the transneuronal and "retrograde axonal transport" (that α-synuclein goes back into the cell) of alpha-synuclein. If confirmed in patients, this study would have crucial implications for strategies used to prevent and treat PD.

8. Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice, F. Pan-Montojo, et al.

   This rodent model showed that pharmacologically increasing SIRT3, as recommended in this article, can counteract α-synuclein-induced mitochondrial dysfunction by reducing α-synuclein oligomers and normalizing mitochondrial bioenergetics.

9. Intersecting pathways to neurodegeneration in Parkinson's disease: effects of the pesticide rotenone on DJ-1, alpha-synuclein, and the ubiquitin-proteasome system, Ranjita Betarbet, et al.
10. The contribution of Parkin, PINK1, and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease, Marc van der Vlag, et al.
11. Genetics of Parkinson’s Disease, Christine Klein and Ana Westenberger.

    This 2014 paper provides compelling arguments that the identification of PD gene mutations, especially in patients with early-onset PD, can provide information on prognosis and will affect treatment choices in cases of PD that were initially suspected to be psychogenic. This 10-year-old paper provides compelling arguments that testing should always be offered in the framework of genetic counseling and based on an informed decision made by the patient. A stark contrast from the current standard of care.

12. ALPHA-SYNUCLEIN: MUTATIONS

    Individuals who developed a triplication of the SNCA gene, as opposed to a duplication, displayed more severe symptoms including early-onset parkinsonism with dementia. This indicates a dose-dependent correlation between the progression of PD and SNCA gene dosage. alpha-synuclein-net

13. Vitamin B12 modulates Parkinson's disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection, Schaffner, et al.

    This in vitro study found that adenosylcobalamin (a form of B-12) protects dopaminergic neurons from LRRK2-G2019S-induced neurotoxicity in C. elegans.

14. Prion-like mechanisms in Parkinson Disease, Laura Volpicelli-Daley and Patrik Brundin.
15. Mitochondrial Calcium: Effects of Its Imbalance in Disease, Deyamira Matuz-Mares, et al.
16. Molecular chaperones and Parkinson's disease, Shenglan Hu, et al.

Overview

Treatment strategies can be grouped into symptomatic, disease progression, etiological, and holistic categories, with some overlap.

Symptomatic Approach

addresses symptoms rather than slowing or stopping their progression

Disease-Progression Approach

manages progression of the disease once it has already developed

Etiological Approach

targets the underlying causes of disease with thorough investigation and research

Holistic Approach

patient-centered care that targets underlying causes and addresses them more comprehensively

Symptomatic Approach

Gold Standard: Dopamine Agonism

The gold standard for managing PD is symptomatic management via dopamine agonism (LD/DDC inhibitors, MAO-B inhibitors, and COMT inhibitors). Unfortunately, that leads to other neurological imbalances, causes other nutrient deficiencies, and leads to PN.

Maintaining dopamine levels in the brain helps alleviate motor problems and can reduce fibrillization. However, unilateral dopamine replacement therapy creates some problems. This is because DRT does not address the root cause and in fact contributes to dyskinesias, as discussed further herein.

Some doctors may attempt to enhance dopamine function by suppressing the cholinergic system using anticholinergics, but this approach leads to adverse effects.

Disease-Progression Approach

Doctors tend to discount the idea of slowing the progression of the disease. Some off-handedly discount supplements and nutrition as "complementary" care without examination. Many of these same doctors once prescribed anticholinergics. (If the doctor falls into that category, finding a new doctor may be advisable.)

Etiological Approach

Etiological treatments target the underlying causes of disease. These providers address the root causes with scientific rigor however, some may rely on conventional medicine and focus on the disease itself, rather than individual factors and health optimization.

Holistic Approach

The holistic approach is patient-centered care that aims to address the underlying causes of disease and promote overall health. However, some holistic providers use implausible or disproven strategies (e.g. homeopathy, reiki, "mind, body, spirit", etc).

Medications

Standard of Care Medications

Conventional medicine treats PD with symptomatic management. This includes dopamine replacement therapy (DRT) using Levodopa/Carbidopa (dopamine precursors), COMT inhibitors and MAO-B inhibitors that prevent dopamine breakdown, and anticholinergics.

Criticism of Standard of Care

Standard pharmacological treatments offer short-term relief of motor symptoms but exacerbate neurotransmitter imbalances, leading to permanent damage. We’ll explore why these limitations persist in healthcare and how to address the underlying problems more comprehensively.

Shortcomings of Standard Pharmacological Treatments

DRT, the gold standard, offers short-term relief of motor symptoms but overlooks multiple problems and underlying etiological pathways.

Non-motor symptoms, including cognitive decline, sleep disturbances, and autonomic dysfunction, indicate deeper systemic dysfunction that requires careful attention. Ignoring these symptoms accelerates disease progression, making neurodegeneration a self-fulfilling outcome of DRT-focused treatment.

Mitochondrial dysfunction—a major pathology of disease progression—along with neuroinflammation, cellular senescence, α-synuclein pathology, and failure of the brain's waste management systems are all ignored by standard treatments.

Aside from temporarily addressing decreased dopamine levels, standard treatments largely overlook these mechanistic issues. Worse, DRT's interaction with α-synuclein contributes to cellular damage and the development of LIDs, further complicating the patient's condition.

Educational and Industry Bias

Medical school bias towards conventional treatments persists with pharmaceutical influence over leadership, faculty, curricula, and culture Anderson. Students, unaware of this bias, adopt industry-supported ideologies while rejecting other approaches, forming the basis for provider bias.

According to BioPharma Dive, twelve of the 19 largest pharmaceutical and biotech companies in the world had at least one director simultaneously serving in a leadership position at a nonprofit healthcare organization. Researchers who point out such conflicts of interest on corporate boards risk job security and alienation by colleagues.

Peer Pressure and Not Invented Here (NIH) Syndrome

Peer pressure in the healthcare community influences medical decision-making. Cultural and professional norms, pharmaceutical influence, and perceived lack of evidence lead to conformity over critical evaluation. Healthcare providers are embedded in a culture that emphasizes adherence to established protocols and guidelines influenced by institutional norms and the broader medical community. This creates a reluctance to deviate from conventional practices, even when proven ineffective or harmful, or when alternative approaches are supported by emerging evidence.

Government policies and regulations shape medical practice, creating conflicts of interest that favor pharmaceutical interests over patient needs. For example, the FDA’s accelerated approval of Aduhelm in 2021, despite mixed trial results, was influenced by Biogen's lobbying.

For example, NICE guidelines discourage the use of all over-the-counter supplements, specifically mentioning CoQ10, Creatine, and Vitamin E—which have neuroprotective effects. Simultaneously, they recommend anticholinergics, despite their well-documented negative impact on cognitive function and neuronal integrity Campbell, Yasumasa. This shows institutional preference for pharmaceutical solutions over patient-centered care, pushing symptom management through reliance on drugs and missing opportunities for neuroprotection through non-pharmaceutical means.

Although DRT is the standard of care used to manage motor symptoms, its over-reliance leads to permanent damage and complications such as motor fluctuations and dyskinesias, which will be discussed further below. These examples show the limitations of standard treatment approaches and the need for strategies that address underlying pathologies, minimize harmful effects, and optimize health.

Genetic Testing

Moreover, identifying PD gene mutations, especially in early-onset cases, can provide valuable information for prognosis and can influence treatment decisions, particularly in cases initially suspected to be psychogenic. Despite this, genetic testing is not part of the standard of care.

There is Hope!

There is hope! Understanding the problems is necessary for informed action to address the underlying etiological pathways. The right knowledge and strategy is the key to regaining control over personal health. This guide addresses the etiological pathways overlooked by healthcare with scientific evidence, providing specific approaches to address them.

First, we'll cover DRT and its limits. Next, we'll dive deeper into the multisystem dysfunction of PD, including GABA, serotonin, and cholinergic imbalance. Finally, we'll discuss broader therapeutic approaches (holistic strategies that address neurotransmitter imbalance, mitochondrial health, neuroprotection, etc.)

Hormonal Interventions

Hormone replacement therapy (HRT) may offer neuroprotection to improve mobility and mood, cognitive function, and quality of life in both men and women. Risk of developing PD is twice as high in men but is also elevated in women with early menopause. Estrogen and testosterone are both neuroprotective. Cerri

Collagen Degradation, BBB Permeability, and α-synuclein

Estrogen directly affects collagen synthesis and integrity, including connective tissues, including the extracellular matrix (ECM). Loss of estrogen accelerates collagen degradation, weakening the ECM of the BBB and choroid plexus, making the junctions of these barriers more permeable, and allowing harmful substances, including α-synuclein, to aggregate, form fibrils, and enter the brain.

Disease progression might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients, and HRT for men and women may offer benefits. Alternatively, DHEA can also be used in conjunction with or independently of HRT, which, at least for women, may present a lower risk of cancer compared to steroid hormone therapies.

Protocols that promote collagen formation and support the ECM may help counteract the effects of estrogen loss on the brain waste management system, which includes the BBB, choroid plexus, CSF, glymphatic system, and perivascular spaces.

Gene Therapy

Gene therapy is designed to repair the dopamine system. The procedure involves injecting a gene into the brain.

Cell Therapies

Cell replacement is the injection of dopamine cells into the brain to replace those that are lost or dying.

References

1. Exploring the Potential of Gene and Cell-Based Therapies in Parkinson’s, (Anonymous)

Stem Cells (MSC, iPSC)

Mesenchymal Stem Cells (MSCs)

Systemic injection of mesenchymal stem cells helps restore dopaminergic neurons. Park

The concomitant use of cell therapy and photobiomodulation therapy can improve the symptoms of PD. Ahrabi

Induced Pluripotent Stem Cells (iPSCs)

Induced pluripotent stem cells (iPSCs) are generated by reprogramming adult somatic cells, such as skin or blood cells, to express the same genes as embryonic stem cells in a process called induced pluripotency. iPSCs can differentiate into any cell type in the body, similar to embryonic stem cells, but they are generated from adult cells, which makes them a promising source for regenerative medicine and tissue engineering.

When injected into the striatum and substantia nigra, iPSCs may promote the regeneration of lost dopaminergic neurons. However, this practice is not well-established and carries potential risks, including tumor formation. Shastry, Bin Song

Few clinics use iPSCs. Stemaid is one of them. Stemaid is located in San José del Cabo, Mexico. Cynata in Victoria, Australia is another. Please note that no endorsement or evaluation of these clinics is being provided.

References

1. Progress in Dopaminergic Cell Replacement and Regenerative Strategies for Parkinson's Disease

   Stable cell sources, such as Embryonic stem cells (ESCs) and induced pluripotent stem cell (iPSCs), are far more suitable for clinical application than hfVM- and embryonic or fetal brain-derived NSCs.

2. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease., Hyun Jung Park, et al.
3. Photobiomodulation Therapy and Cell Therapy Improved Parkinson’s Diseases by Neuro-regeneration and Tremor Inhibition, Behnaz Ahrabi, et al.

   This review study showed the concomitant use of cell therapy and photobiomodulation therapy can improve the symptoms of PD.

4. Cell Therapy for Parkinson’s Disease, Surabhi Shastry, et al.
5. Human autologous iPSC–derived dopaminergic progenitors restore motor function in Parkinson’s disease models, Bin Song, et al.

Exercise

Maintaining a high degree of athleticism will have a positive impact on neurodegeneration by increasing blood flow to the brain, promoting neuroplasticity, and improving mood, sleep, and cognitive function.

Becoming an athlete requires maintaining a strong mindset to apply consistency with nutrition, lifestyle, exercise, supplementation. Focus on relative progress over current state. You can get better.

Physiological Response in the Brain

HIIT, more than any other type of exercise, has been shown to fight neurodegeneration. It simultaneously stimulates multiple pathways and increases cerebral blood flow. Moderate and lower intensity cardiovascular exercise. "Zone 3" and "Zone 2" respectively, and active recovery provide supplementary benefits. Lenhart, S.E. Lucas

HIIT, high-intensity cardiovascular training, resistance training, and endurance training are respectively the most effective at increasing neurotrophins such as BDNF, NGF, GDNF, FGF2, and NT-3. These neurotrophins help protect neurons and glial cells.

Such higher-intensity exercise increases the production of neuropeptides (NPY, Substance P, Enkephalins) and signaling hormones (IGF-I, VEGF, Cortisol).

IGF-I Benefits

IGF-I supports dopaminergic neuron survival by activating its receptors and inhibiting apoptosis. It also improves insulin sensitivity and glucose uptake, a problem that often accompanies disease progression.

By upregulating creatine transporters, IGF-I optimizes cellular energy metabolism, supporting neuronal health and cognitive function. Its anti-inflammatory and antioxidant properties reduce oxidative stress and inflammation, preserving cerebrovascular integrity and protecting the blood-brain barrier and choroid plexus.

These combined effects promote autophagy, which removes dysfunctional proteins and organelles, improve mitochondrial function through ATP synthesis, and reduce neural apoptosis. This can improve ischemic conditions and sleep.

Lower-intensity Exercise (Zone 2)

Lower-intensity exercise, such as "Zone 2", is moderately low-intensity aerobic exercise, such as fast walking or hiking, that occurs just below the lactate threshold and can be sustained for a long period without strain or heavy breathing. Although low-intensity exercise may not boost neurotrophic factors as acutely as high-intensity workouts, it supports overall brain health and helps maintain a baseline level of these factors for improved endurance, enhanced recovery, increased mitochondrial production, and reduced overtraining, making it an excellent addition to any fitness routine.

Proprioceptive Activities

Complex motor activities that require significant proprioception, such as dancing, have been shown to be beneficial and may increase blood flow to the midbrain. Further research is needed to clarify their precise effects on GDNF. Baudet, Aman

Peak Performance

Increasing exercise intensity, VO₂ max, duration, and frequency leads to greater benefits. Contrary to the "minimum effective dose" approach in medicine, with exercise, more is better. Improving the limits of exercise tolerance through supplementation and recovery strategies can improve physiological performance and decrease recovery times, allowing for more exercise to be performed, conferring more neurological and physical benefits.

Limits to Exercise

Intense exercise, while beneficial, is physically and mentally taxing, increasing Reactive Oxygen and Nitrogen Species (RONS) and creating metabolic waste. To maximize the benefits of exercise, incorporate active recovery strategies such as mobility work, supplementation, and red light therapy to enhance exercise tolerance.

Supplementation and Recovery

Timing supplementation around exercise is beneficial as it enhances nutrient delivery to the brain due to increased cerebral blood flow. Pre- and intra-workout supplementation can boost performance, while post-workout supplementation aids in recovery and improves subsequent performance. Protein intake immediately after exercise can increase satiety and reduce energy intake, which helps regulate blood glucose levels. Querido, D. Clayton, A. Monteyne

For example, creatine monohydrate supplementation increases brain creatine levels. During stress or trauma, such as intense exercise, creatine helps reduce oxidative DNA damage and restores normal brain and body creatine levels.

Types of Exercise

The categories of exercise that elicit a physiological effect on the brain include:

HIIT — High-Intensity Interval Training

short periods of high-intensity effort, followed by brief periods of rest or low-intensity activity. This alternating pattern is repeated until exhaustion to maintain heart rate throughout the workout.

HIT — High-Intensity Training

strength training with high intensity and brief workouts. This improves cognitive function and brain health by increasing cerebral blood flow, BDNF, IGF-1, and osteocalcin. Browne

Zone 4 cardio

High-intensity exercise zone, 80-90% of maximum heart rate (HRmax), Typically 2-10 minutes with a maximum sustained duration of around 15 minutes. Also known as "lactate threshold" or redline training.

Zone 3 — Moderate-intensity cardiovascular training (70-80% of HRmax)

Enhances cerebral blood flow, metabolic, and cardiovascular health with a reduced risk of injury.

Zone 2 — Low-intensity cardiovascular training

Boosts aerobic endurance and promotes recovery with minimal injury risk.

Active Recovery

Active recovery elevates heart rate, enhancing blood flow to deliver nutrients, remove waste from tissues, and hasten recovery. It can address mobility issues such as tight hips and a weak core or glutes, reducing injury risk.

Exercise increases brain blood flow, delivering oxygen and nutrients to brain cells. This triggers processes like neurogenesis, increased neurotransmitter production, and improved stress tolerance. Additionally, it boosts BDNF, promotes autophagy, reduces proinflammatory cytokines, and lowers blood sugar. These effects enhance memory, cognition, and mood, helping to counter neurodegeneration.

This results in better memory and cognition and improved mood, countering or staving off neurodegeneration.

Mitochondrial Benefits

Regular exercise enhances NAD+ biosynthesis, activates AMP-activated protein kinase (AMPK) and sirtuins, and stimulates mitochondrial biogenesis. It also promotes mitochondrial turnover and mitophagy, supporting healthy mitochondrial function.

Sample Exercise Plan

• Day 1: HIT + Zone 2 Cardio
• Day 2: Zone 3 Cardio (40 min ergometer)
• Day 3: HIIT + Active Recovery
• Day 4: Zone 3 Cardio
• Day 5: HIT + Zone 2 Cardio
• Day 6: Zone 3 Cardio
• Day 7: HIIT + Active Recovery

Summary

Intense exercise counteracts neurodegeneration and enhances neurological health by increasing cerebral blood flow, promoting neurogenesis, boosting neurotransmitter production, and reducing inflammation. Different exercise types, including HIIT, HIT, Zone 3, and Zone 2, offer distinct benefits. Balancing intense exercise with active recovery helps reduce injury and hasten recovery to improve exercise tolerance and maximize the results.

References

1. High-intensity interval exercise and cerebrovascular health: curiosity, cause, and consequence, Samuel J E Lucas, et al.
2. The Impact of Varying Exercise Protocols on Neurogenesis and Angiogenesis in the Dentate Gyrus, Lenhart, Darrin.
3. Positive and negative interactions of GDNF, NTN and ART in developing sensory neuron subpopulations, and their collaboration with neurotrophins, C Baudet, et al.
4. The effectiveness of proprioceptive training for improving motor function: a systematic review, Joshua E. Aman, et al.
5. Regulation of cerebral blood flow during exercise, Jordan S Querido, A William Sheel.
6. The effect of post-exercise drink macronutrient content on appetite and energy intake, David J Clayton, et al.
7. Whey protein consumption after resistance exercise reduces energy intake at a post-exercise meal, Alistair Monteyne, et al.
8. Chapter 9 - Effects of acute high-intensity exercise on cognitive performance in trained individuals: A systematic review, Sarah E. Browne, et al.

Photobiomodulation (PBM)

Photobiomodulation (PBM) is a non-invasive, low-risk treatment that improves cellular function using specific wavelengths of light. It can be done in clinics using high intensity lasers and at home using consumer devices, offering flexibility for patients seeking ongoing treatment.

Despite the large body of experimental and early clinical evidence, there is still much resistance to the use of photobiomodulation by patients and health professionals.

• Enhances mitochondrial function and ATP production. Michael Hamblin¹
• Protects cells from misfolded protein accumulation via ROS production and ATP generation. W. Fu
• Increases expression BDNF. Chengbo Meng
• Reduces oxidative stress and inflammation. Michael Hamblin
• Promotes neuroprotection and neuroregeneration. Michael Hamblin
• Improves cognitive function in PD patients. Damir Nizamutdinov¹, Damir Nizamutdinov
• Improves sleep. Jiexiu Zhao

PBM and Neurological Health

Oxidative Stress and Brain Inflammation

PBM inhibits oxidative stress-related damage in the hippocampus and elevates BDNF levels, effectively treating nerve damage and neuroinflammation. J.C. Heo

Ischemia and Blood Flow

Ischemia can affect the delivery of therapeutic agents to the desired target in the midbrain. During ischemic events, blood flow to affected brain regions can be significantly compromised, limiting the delivery of oxygen, nutrients, and therapeutic compounds like mesenchymal cells (as mentioned elsewhere), melatonin, or any substance entering the brain.

Effects on Parkinson’s Disease

Red Light's Impact on Motor Cortex and Stem Cells

Red light reaches the motor cortex, influences stem cell function, offers neuroprotection, restores functional activity, improves motor behaviors and reduces clinical signs, reduces gliosis, and induces expression of trophic growth factors. C. Hamilton

Impact on Kidney Function

Parkinson’s disease impairs renal function due to α-synuclein aggregation, inflammation, autonomic nervous system (ANS) dysfunction, and dopamine depletion (dopamine influences renal blood flow, blood pressure, and kidney function). Although the effects are less pronounced until the later stages of the disease, the damage begins earlier. Bozic

Red light improves renal function by improving renal blood flow for healing and waste clearance. Bian

Near-Infrared (NIR) vs Red Light Therapy

Although numerous positive results have been observed in humans, depth penetration of the light waves is a concern. NIR light penetrates deeper than NIR, and coherent NIR (laser) even deeper. Cellular effects observed in rodents with NIR light can't be extrapolated to the much larger head thickness (and midbrain depth) of humans. Y. Lampl

Near-infrared (NIR) light has a deeper penetration depth than red light, allowing it to reach deeper tissues and organs, including the brain, without overstimulating the skin. T.A. Henderson

Red light can also be effective but the longer duration and stronger intensity required for efficacy may overstimulate the skin. Consumer LED devices that allow blending NIR and red frequencies should use lower intensity for the red frequencies to avoid burning or overstimulating the skin. This strategy can take advantage of their dermal benefits without damaging the skin while getting more intense NIR for the deep regions of the brain.

Practical Applications of PBM

Timing and Frequency

The timing of PBM, in conjunction with the administration of substances like melatonin, may help improve delivery by mitigating the effects of ischemic inhibition on nutrient delivery to the midbrain. Whole body irradiation with red light improves sleep quality. Using it before sleep may offer better sleep effects. Jiexiu Zhao

Frequency

Alzheimer’s and Parkinson’s disease models require daily treatments to show benefits. In-home devices offer convenience, comfort, and affordability. Hamblin

References

1. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation, Michael R Hamblin.

   Cytochrome c Oxidase (CCO) absorbs NIR light, leading to increased ETC activity and greater production of ATP.

2. 625 nm Light Irradiation Prevented MC3T3-E1 Cells from Accumulation of Misfolded Proteins via ROS and ATP Production, Wenqi Fu, et al.
3. Transcranial near-infrared light in treatment of neurodegenerative diseases, Damir Nizamutdinov, et al.

4. Low-Level Laser Therapy Rescues Dendrite Atrophy via Upregulating BDNF Expression: Implications for Alzheimer's Disease, Chengbo Meng, et al.

   Synaptogenesis was found.

5. Red light and the sleep quality and endurance performance of Chinese female basketball players, Jiexiu Zhao, et al.

   Our study confirmed the effectiveness of body irradiation with red light in improving the quality of sleep of elite female basketball players and offered a nonpharmacologic and noninvasive therapy to prevent sleep disorders after training.

6. Transcranial photobiomodulation for the brain: a wide range of clinical applications, Michael R. Hamblin.

   This review discussed the highly effective use of PBMT in treating Alzheimer’s and Parkinson’s disease models using repeated daily exposures and the mechanisms that affect the mitochondria.

7. Transcranial Near Infrared Light Stimulations Improve Cognition in Patients with Dementia, Damir Nizamutdinov, et al.

   This placebo-controlled, randomized, double-blinded human study examined 6 min, twice daily eight weeks transcranial near-infrared (tNIR) light NIR light with wavelength of 1060-1080nm and 15,000mW, irradiance or power density= 23.1mW/cm2, ~650cm2 per treatment area compared with a sham placebo.

   The study group showed significant improvements in cognitive functions in several tests and showed less anxiety, improved mood, energy, and positive daily routine after ~14-21 days of treatment.

   Patients with sham treatment did not demonstrate significant changes

8. Near-infrared photonic energy penetration: can infrared phototherapy effectively reach the human brain?, Theodore A Henderson, Larry D Morries.

   Higher-wattage NIR lasers can deliver therapeutic effects to greater depths of the brain without tissue heating or damage.

9. Improvements in clinical signs of Parkinson's disease using photobiomodulation: a prospective proof-of-concept study, Ann Liebert, et al.

   This small study showed PBM was safe and effective for symptoms of PD including mobility, cognition, dynamic balance, and fine motor skills. Improvements were maintained for as long as treatment continued, for up to one year.

10. Photobiomodulation (660 nm) therapy reduces oxidative stress and induces BDNF expression in the hippocampus, Jin-Chul Heo, et al.

    These data demonstrate that PBMT inhibits hippocampal damage induced by oxidative stress and increases the expression of BDNF in the hippocampus, a part of the brain used for learning and memory, located deep in the temporal lobe.

    To examine the cellular process in the hippocampus, mice were used. Although the data are impressive, the problem with extrapolating data to humans is the size of the human head is much larger, thereby damping the intensity of the NIR waves as they aim toward the deep brain regions. A possible workaround is to direct the light towards the back, to target the CSF.

11. Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis, Milica Bozic, et al.
12. Therapeutic Potential of Photobiomodulation for Chronic Kidney Disease, Ji Bian, et al.
13. Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1), Yair Lampl, et al.

    The NeuroThera Laser System therapeutic approach involves infrared laser technology and has shown significant and sustained beneficial effects in animal models of ischemic stroke.

14. Exploring the use of transcranial photobiomodulation in Parkinson's disease patients, Catherine Hamilton, et al.

    This study found photobiomodulation penetrates the motor cortex, modulating stem cell activity, offers neuroprotection, restores functional activity, improves motor behaviors, reduces clinical signs of PD, reduces gliosis, and induces expression of trophic growth factors.

Sauna

Sauna use increases heart rate and vasodilation, strongly promoting systemic and cerebral blood flow, reducing the impact of neurodegenerative diseases. In PD, it may aid waste clearance via enhanced glymphatic activity.

Heat Shock Proteins (HSPs)

Heat exposure during sauna use stimulates the production of heat shock proteins (HSPs), also called chaperones. Among these, Hsp70 is integral to proteostasis, the cell's protein quality control mechanism (see Proteostasis and Chaperone Proteins), which is impacted in PD.

Hsp70 helps to restore and improve the correct folding and refolding of proteins, reducing aggregation of misfolded α-synuclein, which fundamentally contributes to PD pathology and progression. Repeated heat exposure upregulates HSPs and AMPK, which strengthens mitochondrial function via mitochondrial biogenesis regulator PGC-1α. Hunt, Henderson

References

1. Could Heat Therapy Be an Effective Treatment for Alzheimer’s and Parkinson’s Diseases? A Narrative Review, Andrew P Hunt, et al.
2. The Cardiometabolic Health Benefits of Sauna Exposure in Individuals with High-Stress Occupations. A Mechanistic Review, Kaemmer N Henderson

Introduction

Optimizing health is complex, and a PD diagnosis increases that. Conventional medicine fails to adequately address peripheral and autonomic nervous system (ANS) dysfunction, which typically manifests as GI issues, loss of bladder and bowel control, sleep problems, and ultimately, heart failure and death.

Seeking 'alternative' approaches without critical analysis is equally flawed. The only true alternative to effective treatment is ineffective treatment, and that raises the problem of determining efficacy.

Many medical professionals, whether conventional or alternative, fall short. Trusting them may lead you to take medications that do not improve health and may hasten disease progression. In PD, this may include beta-3 agonists, anticholinergics, or fludrocortisones. Worse, they may also offer "mind-body-spirit" treatments lacking scientific support or clear mechanisms of action.

It is the patient's responsibility to audit his medical team. Begin by consulting independent specialists and exploring reputable integrative medicine practices. Seek out patient communities for recommendations on doctors who prioritize a comprehensive approach.

The onus of responsibility to learn, assess claims, and take actions for your health is on you. This involves understanding the science behind treatments and engaging in self-advocacy to actively participate in the decision-making process. Skepticism isn’t just healthy; it’s essential for survival and well-being.

Hypothetical Care Team

This is a structured, customizable framework designed for self-directed health optimization in Parkinson's Disease.

1. Neurologist for planning, diagnosis, and oversight.
2. Functional and Integrative Medicine Specialist for personalized, holistic approach.
3. Movement Specialist.
4. Physical Therapist.
5. Research involvement for cutting-edge options.
6. Biomarker Testing Laboratory for personalized testing to monitor disease progression, treatment response, and optimization.

How to Interview Neurologists

Doctors may be limited by institutional protocols.

Assessing provider competence requires a more thorough approach than just checking credentials, affiliations, and years of experience.

Approach the interview from a position of informed knowledge without revealing too much. When given the opportunity to speak freely, how do they err?

The effectiveness of that strategy depends on one's knowledge and comprehension — specifically the depth and breadth of understanding and the ability to evaluate and scrutinize the accuracy of the interlocutor's information.

Better results are achieved by preparing detailed questions that delve into the neurologist's expertise in the specific area of concern.

Summary

These questions and expected answers help ensure doctors follow a comprehensive, current approach to PD but also demonstrate critical thinking and a nuanced understanding of the disease. Doctors are not immune to common mental errors.

Tips for Selecting Providers

Referrals typically come from a PCP or neurologist, but some patients also seek input from functional medicine specialists. The goal is to assemble a comprehensive care team, regardless of the initial referral source.

Institutional protocols often influence treatment approach. It's important to have a neurologist who is willing to consider evidence-based treatments beyond the conventional standard of care.

Patient-centered care addressing root causes and individualized needs predicts the best results. Starting with a Functional and Integrative Medicine Specialist can be great. However, to avoid unqualified practitioners, it's essential to be well-informed.

During your initial consultation with a neurologist, discuss the side-effects of DRT. Ask about specific treatments such as HRT, PBM, and 5-HTP, and how they might interact with DRT. If the doctor cannot explain their benefits or potential interactions, it may be worth seeking another opinion.

“It is better to know some of the questions than all of the answers.”

— James Thurber

Creating a health optimization plan is difficult, especially for PD, which requires specialized expertise. Those who approach this with seriousness and understanding can expect to achieve a better quality of life and longevity.

GlyNAC (Glycine-N-Acetyl Cysteine)

GlyNAC (Glycine-N-Acetyl Cysteine) is a combination of two separate amino acids, glycine, and N-acetylcysteine (NAC), both non-essential amino acids, administered together in a 1:1 ratio to promote the body's synthesis of glutathione, the master antioxidant. In addition to enhancing glutathione synthesis, GlyNAC offers several other physiological benefits.

Beyond improving glutathione production, GlyNAC supplementation improves mitochondrial function, reduces inflammation, supports neurotrophic factor expression, and improves cognitive function. g-lizzo, Premranjan Kumar, P. Kumar 2, Premranjan Kumar (2)

Cognitive Effects

A 2021 clinical trial showed GlyNAC improves glutathione levels, mitochondrial function, and insulin sensitivity while reducing oxidative stress and inflammation.f NMDARs showed pro-cognitive and antidepressant effects. Premranjan Kumar

Glycine, Collagen, and NAC

While the effects of the 1:1 ratio of glycine to NAC is proven, glycine and NAC can be taken independently for a fraction of the cost, with the same benefits.

Collagen is about 20% glycine, making its supplementation a substantial contributor to glycine intake, shattering the patented "GlyNAC" 1:1 ratio formula. Nighttime collagen supplementation was shown to improve sleep in physically active males with sleep complaints, possibly due to its glycine content Thomas. Collagen's high glycine content, however, does not necessarily obviate its benefits on bone and connective tissue, including CSF production and barrier support in the brain, choroid plexus, basement membrane, dura mater, and structural support in neurons.

Sleep-Promoting Effects

Glycine supplementation has been shown in multiple studies to improve sleep quality both subjectively and objectively. The mechanism seems to be via peripheral vasodilatation through the activation of NMDA receptors in the hypothalamus, which has the effect of increasing peripheral blood flow and lowering core temperature. These effects can also explain how it improves ischemic conditions. Kawai, Quintanilla-Villanueva

Supplementation

GlyNAC supplementation up to 7.2g per day is safe and well tolerated in older adults. GlyNAC is best taken at night. A cost-effective alternative approach would be to take 10g collagen peptides, 1g glycine powder, and 3g NAC.

The half-life of NAC in the body is about 6 hours, and the half-life of glycine is anywhere from 25-250 minutes, so taking it at night allows for optimal utilization of the amino acids. P. Kumar 2

Side Effects

N-acetyl cysteine (NAC) can cause next-day lethargy. If experiencing this, the dose should be reduced, taken earlier in the evening, and bedtime adjusted accordingly.

References

1. A Randomized Controlled Clinical Trial in Healthy Older Adults to Determine Efficacy of Glycine and N-Acetylcysteine Supplementation on Glutathione Redox Status and Oxidative Damage, Giulia Lizzo, et al.

   This double-blind RCT investigated supplementation with glycine and n-acetylcysteine (GlyNAC) at three different daily doses for 2 weeks (low dose: 2.4 g, medium dose: 4.8 g, or high dose: 7.2 g/day, 1:1 ratio) in a randomized, controlled clinical trial in 114 healthy volunteers.

2. Glycine and N-Acetylcysteine in Older Adults, Premranjan Kumar, et al.

   This clinical trial showed GlyNAC improves glutathione levels, mitochondrial function, and insulin sensitivity while reducing oxidative stress and inflammation.

3. The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus, Nobuhiro Kawai, et al.
4. The Role of Amino Acid Glycine on Cardiovascular Health and Its Beneficial Effects: A Narrative Review, Gabriela Elizabeth Quintanilla-Villanueva, et al.
5. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage, Premranjan Kumar, Ob W. Osahon, and Rajagopal V. Sekhar.

   This placebo-controlled rodent study showed that GlyNAC supplementation improves age-associated cognitive decline and supports brain health in aging by improving/correcting brain GSH deficiency, elevated oxidative stress, mitochondrial dysfunction, abnormal mitophagy and autophagy, inflammation, impaired glucose transport/uptake, elevated genomic damage, and reversing the decline in brain neurotrophic growth factors.

6. GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Old Mice Improves Brain Glutathione Deficiency, Oxidative Stress, Glucose Uptake, Mitochondrial Dysfunction, Genomic Damage, Inflammation and Neurotrophic Factors to Reverse Age-Associated Cognitive Decline: Implications for Improving Brain Health in Aging, Premranjan Kumar, et al.

   This rodent study demonstrated improved age-associated cognitive decline (ACD) with GlyNAC.

Collagen Peptides

Collagen makes up 30% of the body's protein and supports the extracellular matrix (ECM), the physical scaffolding that surrounds and supports cells throughout various tissues in the body. In the brain, the ECM also maintains neuronal structure and synapse function. This can be compromised in PD.

Collagen peptide (CP) supplementation increases glycosaminoglycan (GAG) production, which maintains tissue flexibility and moisture. It also influences gene expression related to collagen and elastin, promoting ECM stability and tissue repair. When combined with exercise, CP may improve joint health and mobility, addressing some of the physical challenges faced by PD patients.

CP is comprised of amino acids, with glycine making up roughly 20-22% of their total weight. Glycine is one of the three amino acids necessary for glutathione (GSH) synthesis, an important antioxidant in the body.

Sleep Benefits

A 2024 RCT showed collagen peptides reduced sleep interruptions and improved cognitive function in athletic males. Thomas

Relevance to PD

CP supplementation was correlated with increased gray matter, improved memory, standard verbal paired associate learning (S-PA) tests, and changes in the physical, mental, and role/social component summary scores, reflecting improved brain health. Koizumi

In PD, tissue repair and resilience are weakened. Collagen peptides supplementation strengthens the ECM and related structures such as the BBB and choroid plexus. This could help protect against neurodegenerative damage.

Research shows that ECM pathways are dysregulated in dopaminergic neurons from PD patients, impacting synaptic activity and neuronal function Rosh. Collagen peptides can improve ECM health and might help mitigate some of the neurodegenerative effects seen in PD.

Research indicates that glycine supplementation can increase glycine levels in cerebrospinal fluid (CSF), potentially offering neuroprotective effects. Bannai

A 2019 study gave collagen hydrolysates (CH) to 30 healthy people, aged 49 to 63 years, once a day for 4 weeks. This resulted in a positive effect on gray matter volume, brain structure, and cognitive language ability. Koizumi

Collagen Peptides, The Choroid Plexus, and CSF Production

CP strengthens the choroid plexus and BBB and supports CSF production. CSF.

The choroid plexus produces most of the CSF and serves as a barrier between the blood and CSF, regulating the exchange of substances between the two. 50-60% of the choroid plexus is loose connective tissue, which supports the production and regulation of CSF. CP improves connective tissue health, so probably improves the choroid plexus.

When the choroid plexus is weakened, the damage to the barrier it creates leads to neuroinflammation and impaired clearance of toxic metabolites. In PD, mutant α-synuclein spreads into the CSF, and this is proportionally facilitated by choroid plexus dysfunction. Mutant α-synuclein may also accumulate in the epithelial cells of the choroid plexus and be transported into the CSF, potentially disrupting its clearance between the brain and CSF. CP supplementation improves neurological health and strengthens the ECM, and strengthening the choroid process is likely part of the mechanism of action. This could aid in mitigating neuroinflammation and facilitating protein clearance in conditions like PD. Rosh, Koizumi

Collagen, especially types IV and XVII, is a major structural protein in the BBB that supports the basal lamina, a layer anchoring and separating epithelial cells from the underlying connective tissues such as blood vessels and nerves. Supplementing collagen types I and IV can increase type XVII (COL17) production, and IGF-I may further enhance this.

Hyaluronic Acid — Collagen Peptides' BBB Synergist

Hyaluronic acid (HA) retains moisture in the ECM and helps maintain tight junctions between endothelial cells. These tight junctions are essential for the BBB’s selective barrier, preventing harmful substances from entering the brain. Together, collagen peptides and HA support the BBB’s strength and flexibility.

Supplementation

Taking 7-10 grams of collagen peptides at night may promote relaxation, lower core temperature, reduce awakenings, and improve cognitive function. Bannai, Thomas

Collagen with NAC

Taking collagen peptides with N-acetylcysteine (NAC) helps increase glutathione (GSH) levels, reduces inflammation, and supports mitochondrial function. This combination can be an effective alternative to GlyNAC. 1.5g of NAC combined with 7.5g of CP should provide benefits similar to 3g of GlyNAC. CP is approximately 20-22% glycine, so 7.5g of CP contains roughly 1.5g of glycine.

Measuring Efficacy

Measure GAG levels before and after the intervention to directly assess changes in ECM health. Non-invasive techniques, such as ultrasound, can evaluate soft tissue or joint health. Additionally, motor tests assessing joint flexibility and movement may provide useful insights.

Procollagen Type I and III tests assess new collagen production, indicating connective tissue and ECM health. This provides a useful indicator of ECM health.

References

1. Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients, Idan Rosh, et al.
2. New Therapeutic Strategy for Amino Acid Medicine: Glycine Improves the Quality of Sleep, Makoto Bannai and Nobuhiro Kawai.
3. Collagen peptide supplementation before bedtime reduces sleep fragmentation and improves cognitive function in physically active males with sleep complaints, Craig Thomas, et al.
4. Effects of Collagen Hydrolysates on Human Brain Structure and Cognitive Function: A Pilot Clinical Study, Seiko Koizumi, et al.

Creatine Monohydrate

Creatine and Energy Production

Creatine is a naturally occurring amino acid that the body produces and obtains from diet. It stores and supplies energy to muscle, brain, and cardiac cells. Creatine helps regenerate ATP, the primary energy source for cells, in what is called the phosphagen or ATP-PC (Adenosine Triphosphate-Phosphocreatine) system, for rapid energy production during high demand.

Creatine reduces oxidative stress by lowering mitochondrial workload and scavenging free radicals, thereby minimizing mitochondrial damage, protecting cells, and reducing their death. C. Rae, A.C. Passaquin, H. Arazi

Creatine and Exercise

Creatine improves muscular strength and exercise recovery, supporting health optimization when combined with physical activity. H. Chang

Cellular Mechanism of Action

Understanding the ATP-PC system—how its energy production helps cognitive and neural health—can inform supplementation. However, this knowledge isn't required to benefit from creatine use.

Mitochondria generate energy primarily through the citric acid cycle and oxidative phosphorylation (OXPHOS). The citric acid cycle converts acetyl-CoA into energy intermediates like NADH, which fuel OXPHOS to produce ATP, the main energy source for cells. During this process, CO₂ is released, and RONS are produced. In the cell, creatine (CM) is converted by creatine kinase (CK) to creatine phosphate (CP), which quickly replenishes ATP during high-energy demands, alleviating stress on OXPHOS and reducing RONS production. This supports cellular function and mitochondrial health.

Creatine as Cellular Energy for Synapses

The brain is highly glucose-dependent, accounting for roughly 20% of the body’s total energy expenditure despite its small size. Neuronal synapses require a lot of energy to release neurotransmitters, which need ATP. Inside neurons, creatine is bound to phosphate as CP, just as it does in skeletal muscle cells. Creatine donates a phosphate to ADP to form ATP, which then supplies the energy needed for synaptic function.

Creatine supplementation increases brain creatine levels. During stress or trauma, such as intense exercise, creatine supplementation improves oxidative DNA injury and normalizes brain and body creatine levels. S. Forbes

A 2023 review study published in Sports Medicine found long-term high-dosage creatine supplementation increases brain creatine stores, improves cognition and memory, especially in older adults or during times of metabolic stress (e.g. sleep deprivation), improves aspects of recovery from traumatic brain injury in children, and has the potential to reduce symptoms of depression and anxiety. D. Candow

Creatine and PD

Creatine has shown neuroprotection in PD patients with cognitive decline via creatine transporter uptake. In a rodent model, high-dosage creatine was shown to exert anti-inflammatory, antioxidative, and anti-aggregant effects on α-synucleinopathy. Y. Leem, H. Chang

A long-term, multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial for 10g of creatine in PD patients showed benefit to the UPDRS both at 1 year and at 18 months but eventually terminated early with no determined harm or benefit. K. Kieburtz

These results are not entirely disappointing. The study's lack of focus on pairing creatine with intensive exercise may have limited its ability to detect potential benefits.

HIIT significantly mitigates and may partially reverse progressive neurodegeneration. However, high-intensity exercise also depletes brain creatine, which impacts neurological function.

Had the patients in this study been assigned to a HIIT regimen, they would have benefitted from the exercise. HIIT depletes creatine levels and may deplete brain creatine levels. Creatine supplementation might result in less exercise-induced depletion of creatine, less oxidative damage caused by the exercise, and better exercise recovery (allowing for more frequent training). Such a design might have revealed a more significant benefit to the 10g ED creatine supplementation. However, despite the study's design, beneficial effects were observed at 1 year and at 18 months. B. Laat

Supplementation

Taking creatine with food improves absorption. Eating stimulates insulin-like growth factor-1 (IGF-1) production, which helps increase creatine uptake. Because dosages recommended for neurological function tend to be much higher, in excess of 20g per day, those with impaired kidney function might consider a more moderate dose as a compromise.

Safety and Efficacy

Creatine is commonly used with minimal adverse effects reported in clinical studies.

Creatine supplementation alone may not significantly slow the progression of Parkinson's disease, especially not in the later stages. But its neuroprotective and antioxidant effects contribute to overall disease management when used as part of a comprehensive treatment approach, particularly in combination with exercise, to stave off disease progression in the early stages of the disease. Because creatine helps with exercise recovery, its use allows for more frequent training to enjoy the benefits of exercise.

References

1. Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial, Caroline Rae, et al

   Creatine supplementation had a significant positive effect on both working memory (backward digit span) and intelligence (Raven's Advanced Progressive Matrices), both tasks that require speed of processing.

2. The potential role of creatine supplementation in neurodegenerative diseases, Hyukki Chang, et al.

   This review study concluded creatine supplementation had neuroprotective effects in animal models and in vitro studies of certain neurodegenerative diseases, but that clinical trials failed to reproduce favorable outcomes.

3. Creatine supplementation reduces skeletal muscle degeneration and enhances mitochondrial function in mdx mice, Anne-Catherine Passaquin , et al.

   This study found creatine supplementation in mice improves muscle health and may provide a scientific basis for its use as adjuvant therapy in Duchenne muscular dystrophy.

4. Creatine Supplementation, Physical Exercise and Oxidative Stress Markers, Hamid Arazi, et al.

   This review study concluded creatine's antioxidant mechanisms include reduced ROS and RNS, and that creatine can maintain mitochondrial integrity, increase creatine phosphate (CP) resources, act as a cellular energy buffer, and protect two important cellular targets, mtDNA and RNA, from oxidative damage.

5. Creatine supplementation with exercise reduces α-synuclein oligomerization and necroptosis in Parkinson's disease mouse model, Yea-Hyun Leem, et al.

   These authors found that creatine supplementation with exercise has anti-inflammatory, antioxidative, and anti-α-synucleinopathy effects, thereby reducing necroptotic cell death in a PD mouse model.

6. Effects of Creatine Supplementation on Brain Function and Health, Scott C. Forbes, et al.

7. “Heads Up” for Creatine Supplementation and its Potential Applications for Brain Health and Function”, Darren G. Candow, et al.

8. Effect of Creatine Monohydrate on Clinical Progression in Patients With Parkinson Disease, Karl Kieburtz, et al.

   This researchers of this RCT found 10g creatine daily was not harmful, and showed benefits at 12 months and 18 months, but then concluded that this did not support the use of creatine monohydrate in patients with Parkinson disease.

9. Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson’s disease, Bart de Laat, et al.

Taurine

Taurine is a naturally occurring non-essential amino acid found in meat, fish, and eggs, with benefits for cardiovascular and neurological health, mitochondrial function, antioxidant protection, bone and cartilage formation, and calcium regulation. Taurine acts as an antioxidant and osmolyte, helping to regulate intracellular osmotic pressure and maintaining cellular homeostasis, helping to protect against DNA damage and prevent cell death.

Taurine and Aging

A 2023 study on taurine in various animals found that circulating taurine levels decreased with age. Supplementation with taurine slowed markers of aging, including DNA damage, telomerase deficiency, impaired mitochondrial function, and cellular senescence. Loss of taurine in humans was associated with aging-related diseases, and concentrations of taurine and its metabolites increased in response to exercise. Taurine supplementation improved lifespan in mice and healthspan in monkeys.

For one of their experiments, the researchers gave 14-month-old mice—middle-aged mice—500 or 1000mg taurine per day for 10-12 months. This supplementation increased median lifespan by 10 to 12%. When they investigated the health of taurine-fed middle-aged mice, they found an improved functioning of bone, muscle, pancreas, brain, fat, gut, and immune system, indicating an overall increase in health span. Singh

Calcium-Regulating Effects

Taurine helps the body use and regulate calcium, both intracellularly, by preventing its excessive entry into neurons and systemically, by helping shuttle extracellular calcium into bones.

Taurine's functioning as an osmolyte helps to prevent calcium overload, counteracting the adverse effects of glutamate toxicity, reducing endoplasmic reticulum stress, and sparing mitochondrial function. Under excitotoxic conditions (e.g., excess glutamate), intracellular calcium can increase due to NMDA receptor hyperactivity. Taurine’s osmoregulatory effect helps buffer against these sudden ionic shifts and subsequent calcium influx that would otherwise contribute to ER stress and mitochondrial overload. Baliou, Schaffer

Taurine influences calcium, including voltage-gated calcium channels and the NMDA receptor channel, by stabilizing membrane potential, or difference in the concentration of electrolytes between the intracellular and extracellular environments, and reducing excitability. This moderates excessive calcium entry into the cell without directly acting as a strong agonist of GABA receptors. Schaffer

Taurine also uses calcium to help promote differentiation of neural progenitor cells (NPCs), leading to neurite outgrowth (neurogenesis), part of a regulated process in progenitors that allows for beneficial calcium entry without overstimulation, beneficial to the brain and cognitive health. Gutiérrez-Castañeda

Effects on Bone and Cartilage

Taurine stimulates osteogenesis (bone formation) and chondrogenesis (cartilage formation), improving bone density, development, and remodeling. It stimulates osteoblasts and inhibits osteoclasts, favoring osteocalcin production, signaling calcium uptake into bone. Taurine helps cartilage maintenance by increasing the synthesis of ECM components, such as glycosaminoglycans and collagen, in chondrocytes. Pérez-Hernández

Taurine's osteogenic effects draw calcium from the blood, reducing excess extracellular calcium from damaging neurons or calcifying arteries. Because excess extracellular calcium can contribute to neuronal intracellular calcium overload, taurine's effects on intracellular and extracellular calcium strongly support mitochondrial protection and neuronal health in PD. W Q Chen

Ergogenic Effects

Taurine's calcium-regulating effects in both skeletal muscle and cardiac tissue significantly improve several performance metrics, including muscle force, lipid metabolism, and insulin sensitivity. A 2020 review found taurine supplementation improved anaerobic and aerobic performance metrics, including VO2 max, time to exhaustion, muscle damage, peak power, and recovery. Kurtz

Taurine's osmolytic effects stabilize cell membranes and regulate electrolyte balance, which helps restore muscle cells to their resting state after intense physical activity. This stabilizing effect reduces muscle fatigue and oxidative stress post-exercise, improving exercise recovery.

Supplementation

3 grams of taurine pre-workout safely improves performance, reduces cellular damage, and improves recovery. The high dose used on rodents in the Singh study (1000mg/kg/day for mice), translates to a higher, but still safe human dose of about 5.6g for a 70kg person (1000mg/kg×0.081 = 81mg/kg/day for humans).

1. A Key Metabolic Regulator of Bone and Cartilage Health, Elizabeth Pérez-Hernández, et al.
2. Taurine deficiency as a driver of aging, Parminder Singh, et al.
3. Effects and Mechanisms of Taurine as a Therapeutic Agent, Stephen Schaffer, Ha Won Kim.
4. Protective role of taurine against oxidative stress, Stella Baliou, et al.
5. Taurine Promotes Differentiation and Maturation of Neural Stem/Progenitor Cells from the Subventricular Zone via Activation of GABAA Receptors, Gutiérrez-Castañeda, et al.
6. Role of taurine in regulation of intracellular calcium level and neuroprotective function in cultured neurons, W Q Chen, et al.
7. Taurine in sports and exercise, Jennifer A Kurtz, et al.

Citrulline Malate

Citrulline malate is a 2:1 compound of L-citrulline, a non-essential amino acid, with malic acid to enhance absorption. It promotes vasodilation and circulation, exercise recovery, and is an intermediary in the urea cycle.

Pre-Workout Benefits

Citrulline malate works best when used as a pre-workout supplement, due to its ability to increase nitric oxide production, delay muscle fatigue, improve oxygen delivery, increase energy production, and help workout performance and recovery.

Anti-Oxidant Effects

In a 2021 RCT on diabetic patients, L-citrulline supplementation increased the activity of antioxidant enzymes SOD and catalase, which neutralize reactive oxygen species (ROS). Azizi

Cognitive Effects

A three-month study on mice with Alzheimer's found that males given citrulline showed improved memory performance in maze tests, possibly due to higher arginine levels in cerebrospinal fluid. This suggests a nitric oxide-related benefit for cognitive function. Martínez-González

Oral administration of L-citrulline was shown to prevent hippocampal neuron loss and capillary damage after brain ischemia in mice, likely due to restored expression of eNOS, nitric oxide synthase, in endothelim, the layer of cells that line blood vessels and lymphatic vessels. This finding may have implications for neuroprotection in PD. Yabuki

Supplementation

A pre-workout dose of 4-8 grams of citrulline malate effectively improves blood flow and recovery for most individuals without adverse effects. Start with a lower dose, adjusting based on body size and workout intensity. Vårvik

1. Oral l-Citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection, Y. Yabuki, et al.
2. Citrulline supplementation improves spatial memory in a murine model for Alzheimer's disease., Katia Martínez-González, et al.
3. Acute Effect of Citrulline Malate on Repetition Performance During Strength Training: A Systematic Review and Meta-Analysis., F. T. Vårvik, et al
4. Oxidative stress and nitrate/nitrite (NOx) status following citrulline supplementation in type 2 diabetes: a randomised, double-blind, placebo-controlled trial., S Azizi, et al.

Raw Cacao

Raw Cacao vs Cocoa (Processed Chocolate)

Raw cacao is made from cold-pressed, unroasted cocoa beans, preserving the nutritional content, in contrast to cocoa, which is heavily processed, roasted at high temperatures, and often has added sugar.

Health Benefits

Raw cacao contains polyphenols and stimulants that contribute to its neuroprotective, cognitive, and physical performance-enhancing effects. Cacao's flavonoids improve blood flow, reduce inflammation, and provide antioxidant neuroprotection. Catechin and epicatechin may enhance neurotransmitter function. Stimulants like theobromine, caffeine, phenylethylamine (PEA), theophylline, tyramine, and anandamide, a natural endocannabinoid, all improve neurotransmitter function, alertness, and mood. Together, these compounds synergistically protect neurons to support cognitive function and physical performance, providing multifaceted benefits for conditions like PD.

Stimulants and Neurotransmitters

While cacao contains several stimulants, its overall effects are generally milder and more sustained compared to caffeine. Theobromine, in particular, has a slower onset and longer duration of action than caffeine. Phenylethylamine, tyramine, and anandamide are all endogenously produced neurotransmitters, also present in cacao, and are all significantly lowered in PD, which may contribute to disease progression. Consuming cacao improves these levels, and catechin and epicatechin may help prolong their effects. Zhou

Phenylethylamine (PEA)

Phenylethylamine (PEA) is a naturally occurring neurotransmitter also present in cacao, but is significantly decreased in PD. PEA affects mood, attention, and motivation, and reduced levels seen in PD might contribute to the non-motor symptoms of mood, depression, and cognitive decline. miura

Anandamide

Anandamide, a known endocannabinoid also present in cacao, is decreased in PD. By reducing NMDA receptor-mediated calcium influx through cannabinoid receptor-dependent mechanisms, anandamide might reduce the excitatory pathways that lead to calcium influx and damage dopaminergic neurons, which are calcium-sensitive and thus particularly vulnerable to excitotoxic damage in PD and exacerbated by DRT (see also: Impact of DRT). hampson

GABAergic dysfunction in PD impairs inhibitory signaling, contributing to prolonged nueronal excitatory states. This leads to unregulated NMDA receptor activity and subsequent calcium overload. Anandamide helps this by modulating NMDA receptor activity and reducing calcium influx via cannabinoid receptor activation, helping to dampen glutamate-induced excitotoxicity, possibly reducing neuronal damage associated with GABAergic dysfunction and prolonged excitatory states.

Cognitive Benefits

Studies on raw cacao show cognitive improvement in healthy individuals of various ages. A 2024 single-blind study from Japan examined the cognitive effects of high versus low polyphenol cacao. The high polyphenol group showed improvements in mental and physical fatigue, stress, boredom, sleepiness, motivation, healing, enjoyment, relaxation, concentration, and willingness after two sets of cognitive performance tests. R. Lalonde, A. Sasaki

Preparation

To maximize the health benefits of cacao, it should be consumed in its raw or minimally processed form, such as raw cacao paste or powder. Heat processing degrades beneficial flavonoids and other nutrients, so should be minimized during preparation. Additionally, added sugar not only diminishes the potential health benefits but also contributes to the formation of advanced glycation end-products (AGEs), which are associated with aging and various chronic diseases. Unsweetened, high-quality cacao is best for optimal health.

Cacao powder contains fat-soluble compounds but can be dissolved in hot water as a beverage with fats like coconut oil added.

Stimulatory Effects

Cacao contains theobromine (dimethylxanthine), a stimulant similar to caffeine but less methylated. Both bind to adenosine receptors in the brain, increasing activity and alertness, and can interfere with sleep. Therefore, it is advisable to avoid consuming cacao later in the day.

References

1. Plasma beta-phenylethylamine in Parkinson's disease, Y Miura.
2. Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission, A J Hampson, et al.
3. Decreased β-phenylethylamine in CSF in Parkinson's disease, G. Zhou, et al.
4. Cacao Polyphenol-Rich Dark Chocolate Intake Contributes to Efficient Brain Activity during Cognitive Tasks: A Randomized, Single-Blinded, Crossover, and Dose-Comparison fMRI Study, Akihiro Sasaki, et al.
5. Cocoa Flavanols and the Aging Brain, Robert Lalonde, Catherine Strazielle.

Cinnamon

Cinnamon is a spice obtained from the inner bark of several species of trees. Ceylon cinnamon is preferred, as it contains no coumarin, a natural carcinogen. Cinnamon contains both water-soluble and fat-soluble compounds. Cinnamon's fat-soluble compounds include cinnamaldehyde and epicatechin and its water-soluble compounds include procyanidin type-A trimer, cinnamic acid, and various flavonoids.

Antidiabetic Effects

Cinnamon exhibits anti-hyperglycemic properties, with the most significant effects observed in Ceylon cinnamon. These effects are species-specific. N.J. Hayward

It does this by mimicking insulin receptor kinase, increasing glucose uptake, and glycogen synthase activity, and increasing GLP-1 concentrations. n-Kizilaslan, J. Hlebowicz

In a 2006 randomized, placebo-controlled, double-blind study, an aqueous solution of cinnamon found improvements on fasting blood glucose and systolic blood pressure, and improvements in body composition in men and women with metabolic syndrome. T. Ziegenfuss

Neuroprotective Effects

Glucose metabolism is impaired in PD. Improved glucose response and blood glucose levels from cinnamon's antidiabetic effects may benefit PD patients. A. Marques

Ingested cinnamon metabolizes to sodium benzoate (NaB). Both cinnamon and NaB upregulate neuroprotective molecules (Parkin and DJ-1) and protect the nigrostriatum in a mouse model. S. Khasnavis

Supplementation

Translating the mouse dosage used in the Khasnavis study to a human dosage, using the study's 100 mg/kg to a 12x k-factor results in 1.2 g/kg. For a 50 lb human, this equates to 60 grams of cinnamon daily — an impractical amount. Consuming 3g daily is only 5% of the suggested dose, offering minimal neuroprotection. This small dose can be achieved by adding cinnamon to premixed powders such as the cacao mix, post-workout protein mix, and golden milk. Consuming CinnulinPF can achieve more optimal levels. Patel

References

1. Effects of a Water-Soluble Cinnamon Extract on Body Composition and Features of the Metabolic Syndrome in Pre-Diabetic Men and Women, Tim N Ziegenfuss, et al.
2. Cinnamon Shows Antidiabetic Properties that Are Species-Specific: Effects on Enzyme Activity Inhibition and Starch Digestion, Nicholas J. Hayward, et al.
3. The Effect of Different Amounts of Cinnamon Consumption on Blood Glucose in Healthy Adult Individuals, Nildem Kizilaslan

   3–6 g of cinnamon consumption was found to affect certain blood parameters of individuals positively.

4. Cinnamon treatment upregulates neuroprotective proteins Parkin and DJ-1 and protects dopaminergic neurons in a mouse model of Parkinson's disease, Saurabh Khasnavis, et al.

5. Effects of 1 and 3 g cinnamon on gastric emptying, satiety, and postprandial blood glucose, insulin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and ghrelin concentrations in healthy subjects, Joanna Hlebowicz, et al.

   Ingestion of 3 g cinnamon reduced postprandial serum insulin and increased GLP-1 concentrations without significantly affecting blood glucose, GIP, ghrelin concentration, satiety, or GER in healthy subjects. The results indicate a relation between the amount of cinnamon consumed and the decrease in insulin concentration.

   (GIP, is a glucose-dependent insulinotropic polypeptide, an incretin hormone secreted by K cells in the upper small intestine in response to nutrient ingestion, particularly glucose.)

6. Glucose dysregulation in Parkinson's disease: Too much glucose or not enough insulin?, Ana Marques, et al.

   Glucose control is impaired in moderate to advanced non-diabetic PD patients, due to impaired adaptive insulin response which may be a novel non-motor consequence of PD-associated dysautonomia.

7. Cinnamon and its Metabolite Protect the Nigrostriatum in a Mouse Model of Parkinson’s Disease Via Astrocytic GDNF, Dhruv Patel, et al.

   In this mouse model of MPTP-induced PD, mice were treated with either cinnamon or NaB dissolved in 0.5% methylcellulose at individual doses (100 mg/kg, orally) once daily for 7 days, and following behavior analysis the mice were sacrificed for biochemical studies.

Carvacrol (TODO)

Carvacrol is a a volatile oil present in mint, basil, oregano, thyme, and other herbs, exhibiting various biological activities that may help neurodegenerative conditions with anti-inflammatory, antioxidant, and anticholinesterase effects. Azizi, Ciulla

References

1. Neuroprotective effects of carvacrol against Alzheimer’s disease and other neurodegenerative diseases: A review, Zahra Azizi, et al.

   Established that carvacrol is also able to inhibit acetylcholinesterase activity, with positive effects on memory and cognitive performance in PD.

2. Role of Dietary Supplements in the Management of Parkinson’s Disease, Michele Ciulla, et al.

Lion's Mane

Lion’s mane is a white, edible mushroom that grows on hardwood and has neuroprotective effects. It contains fat-soluble bioactive compounds, hericenones and erinacines, and water-soluble beta-glucans, which are found in the cell walls of various mushrooms, including lion's mane.

Beta-glucans

Beta-glucans, found in the cell walls of many mushrooms, including lion's mane and cordyceps, are potent immunomodulators that improve synaptic plasticity, provide neuroprotective effects, and enhance cognition and behavior. These effects are particularly relevant in PD, where cognitive decline and synaptic damage are common issues. c-cerletti

A 2022 study on mice found that mushroom-derived β-glucans significantly increased synaptic thickness in the prefrontal cortex (PFC), but β-glucans from oats and curdlan did not. BDNF and the post-synaptic protein 95 (PSD95) increased in the PFC of all groups. hu

A 2015 rodent study demonstrated a decrease in α-synuclein levels in the substantia nigra of Parkinson’s disease rat models following beta-glucan administration. Rahayu

A pilot clinical trial involving children with autism spectrum disorder (ASD) found that beta-glucan supplementation (Nichi Glucan) improved behavior and sleep patterns, along with increased melatonin levels. Raghavan

Beta-glucans improve gut microbiota and integrity, leading to a saccharolytic shift and increased short-chain fatty acids (SCFAs). This may have implications for PD, as alterations in gut microbiota have been linked to the condition. bhardwaj

Hericinones and Erinacines

Hericenones and erinacines increase BDNF and NGF levels, promote neurite outgrowth, support neuronal survival, and enhance memory and cognitive function. Mori, Docherty

However, in some studies, hericenones failed to promote NGF gene expression in human astrocytoma cells while erinacine A successfully upregulated them in rats. Li

A 2022 RCT found that lion's mane supplementation improved cognitive performance in elderly patients with mild cognitive impairment, potentially due to its positive effects on blood biomarkers and reduced brain structural deterioration in regions associated with memory. Li

Lion's Mane in PD

Lion’s mane promotes neurogenesis through increased BDNF and NGF activity, which helps regenerate neurons and improves cognitive function. Mori, Li, Docherty, Lai

Supplementation

Lion's mane is generally safe and well-tolerated at doses between 1-3 grams per day. When selecting reputable lion's mane supplements, look for brands that provide Certificates of Analysis (CoA) to ensure product quality and authenticity. Some well-regarded brands known for their quality and CoA include Nammex, Real Mushrooms, Host Defense, and Mushroom Science.

References

1. Edible Mushrooms and Beta-Glucans: Impact on Human Health, Chiara Cerletti, et al.
2. Three Different Types of β-Glucans Enhance Cognition: The Role of the Gut-Brain Axis, Minmin Hu, et al.
3. The effect of beta glucan of saccharomyces cerevisae in the parkinson’s wistar strain rats (rattus norvegicus) model induced with rotenone, M. Rahayu, et al.
4. Improvement of sleep and melatonin in children with autism spectrum disorder after β‐1,3/1,6‐glucan consumption: An open‐label prospective pilot clinical study, Kadalraja Raghavan, et al.
5. β-glucans: a potential source for maintaining gut microbiota and the immune system, Ravindra Pal Singh and Aditi Bhardwaj.
6. Improvement of Cognitive Functions by Oral Intake of Hericium erinaceus, Koichiro Mori, et al.

   This double-blind, parallel-group, placebo-controlled RCT found that elderly men and women with mild cognitive impairment who took Lion's mane mushroom extract for 16 weeks showed significant improvements in cognitive function compared to the placebo group.

7. Prevention of Early Alzheimer's Disease by Erinacine A-Enriched Hericium erinaceus Mycelia Pilot Double-Blind Placebo-Controlled Study, I Chen Li, et al.
8. Lion’s Mane Supplementation on Cognitive Function, Stress, and Mood in Young Adults, Sarah Docherty, et al.

   The findings tentatively suggest that Hericium erinaceus may improve performance speed and reduce subjective stress in healthy, young adults.

9. Neurotrophic Properties of the Lion’s Mane Medicinal Mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia, Puei-Lene Lai, et al

   The extract contained neuroactive compounds that induced the secretion of extracellular NGF in NG108-15 cells, thereby promoting neurite outgrowth activity.

Turkey Tail (TODO)

Reishi (TODO)

Chaga (TODO)

Tremella (TODO)

Tiger Milk Mushroom (TODO)

Saffron

Saffron is a spice made from the red stigmas or "threads" of the Crocus flower used in South Asian and Middle Eastern medicine as an emmenagogue, general tonic, aphrodisiac, and nerve stimulant in low doses either in tea or in meals.

Saffron has antioxidant, anti-inflammatory, and neuroprotective effects. Scientific research shows its beneficial effects on improving mood and sleep, enhancing cognitive function, and supporting cardiovascular health. The primary active components, such as crocin and picrocrocin, are water-soluble, while safranal, responsible for saffron's aroma, is fat-soluble.

Sleep

A 28-day, parallel-group, double-blind RCT recruited sixty-three healthy adults aged 18–70 with self-reported sleep problems who were randomized to receive either saffron or a placebo. Results showed that saffron was associated with greater improvements in the Insomnia Severity Index (ISI), Restorative Sleep Questionnaire (RSQ), and the Pittsburgh Sleep Diary (PSD) and was well-tolerated with no reported adverse effects. A. Lopretsi

Saffron in Neurodegenerative Disease

Saffron has been proven to alleviate the symptoms of AD and its effects on PD are of continuing research, particularly for its antidepressant and anxiolytic effects. Y. Bian

A 2024 review found that saffron's compounds inhibit neuroinflammation and excitotoxic pathways, modulate autophagy and apoptosis, attenuate oxidative damage, and activate defensive antioxidant enzymes, providing neuroprotection against neurodegenerative diseases. S. G.-Hamedani

A 2019 rodent model study found saffron had a neuroprotective effect and could be recommended as a possible therapeutic agent to prevent neurotoxicity allied to heavy metals and related neurodegenerative disorders like PD. L. Tamegart

Saffron inhibits damage and inflammation to astrocytes, a type of glial cell, through multiple pathways. Its active compounds modulate oxidative stress, reduce pro-inflammatory cytokine production, and support the maintenance of cellular integrity, thereby protecting astrocytes from injury and dysfunction. Maqbool

Glial cells, and specifically astrocytes, support the function and survival of neurons. Astrocytes can release neurotransmitters, such as glutamate and ATP, which can influence neuronal activity.

Glial scar formation is a common pathological feature in various central nervous system (CNS) diseases, including PD. In PD, the glial scars form around damaged dopaminergic neurons, blocking their repair.

Antifibrillogenic Effects

A few in vitro studies found that saffron dose-dependently inhibited α-synuclein aggregation and dissociated α-synuclein fibrils. Although the antifibrillogenic evidence is preliminary, daily consumption of saffron might help with this. Given its other more established beneficial effects and the mild to no side effects in moderate doses, there’s really no good reason not to enjoy this delicious, beautiful spice. Saffari, Inoue

Supplementation

Some of the compounds in saffron are fat-soluble, while others are water-soluble. Saffron can be drunk with turmeric and cinnamon in golden milk. Excessive amounts may cause bloating and gas and gut microbiota may positively affect the gut-brain axis, therefore, it's a good idea to consume saffron with prepared food.

Saffron References

1. Therapeutic effects of saffron and its components on neurodegenerative diseases, Sahar Golpour-Hamedani, et al.
2. Neuroprotective Potency of Saffron Against Neuropsychiatric Diseases, Neurodegenerative Diseases, and Other Brain Disorders: From Bench to Bedside, Yaqi Bian, et al.

   This review study discussed the neuroprotective effects of crocin and crocetin, and that both could provide neuroprotection by reducing Aβ aggregation.

3. Crocus sativus restores dopaminergic and noradrenergic damages induced by lead in Meriones shawi: A possible link with Parkinson's disease, Lahcen Tamegart, et al.

   This rodent study showed that movement disorder caused by Pd (lead)-induced damage to dopaminergic and noradrenergic systems in the midbrain was reversed by saffron (crocus sativus).

4. Effects of saffron on sleep quality in healthy adults with self-reported poor sleep: a randomized, double-blind, placebo-controlled trial , Adrian L Lopresti, et al.

   This 28-day, parallel-group, double-blind, randomized controlled trial included sixty-three healthy adults aged 18-70 with self-reported sleep problems. Subjects were randomized to receive either saffron extract (saffron; 14 mg twice daily) or a placebo.

   Conclusions: Saffron intake was associated with improvements in sleep quality in adults with self-reported sleep complaints.

5. Evidence of neuroprotective effects of saffron and crocin in a Drosophila model of parkinsonism, Sriranjini Venkat Rao, et al.

   This drosophila model of parkinsonism study showed the neuroprotective effects of saffron and crocin. It concluded that these effects may be largely attributable to its antioxidant action and recommended saffron be exploited as a supplementary therapeutic agent in PD and other oxidative stress-mediated neurodegenerative conditions.

6. Potential Role of Phytochemical Extract from Saffron in Development of Functional Foods and Protection of Brain-Related Disorders, Zahra Maqbool, et al.
7. Crocin Inhibits the Fibrillation of Human α-synuclein and Disassembles Mature Fibrils: Experimental Findings and Mechanistic Insights from Molecular Dynamics Simulation, Babak Saffari, Mehriar Amininasab.
8. Effects of saffron and its constituents, crocin-1, crocin-2, and crocetin on α-synuclein fibrils, Eiji Inoue, et al.

Coconut Oil

Coconut oil is extracted from the meat of mature coconuts. It is high in saturated fats and commonly used in cooking and food preparations.

Rich in lauric acid and MCTs, coconut oil supports heart health by increasing HDL and providing antimicrobial effects. Lauric acid, a 12-carbon variety, may contribute to its positive effects on HDL. MCTs boost energy and enhance metabolic health, which can improve brain function and aid conditions like AD, PD, and MS. Additionally, coconut oil supports fat loss, nutrient absorption, and gut health.

Metabolic Health Effects

A 2018 double-blind RCT investigated the effects of various vegetable oils, including coconut, safflower, chia, and soybean (placebo) oils, on obese women following a hypocaloric diet.

The coconut oil group showed significant improvements in cardiovascular risk factors, including reduced abdominal adiposity, decreased waist circumference, decreased waist-to-height ratio, lower blood glucose and glycated hemoglobin levels, reduced body fat, and increased lean mass. Oliveira de Lira

The increase in lean mass was likely due to MCTs, which provide quick energy, enhance exercise performance, and stimulate muscle growth without promoting fat storage. Maintaining or increasing lean mass supports metabolic health and cardiovascular outcomes. The quick energy boost also makes coconut oil a good pre-workout option.

Mitigating PD

A 2022 review study found that coconut oil improves PD through multiple pathways, mediating oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, and excitotoxicity in various in vitro and in vivo models. Dietary intake of coconut oil has also been associated with a reduced incidence of PD. During digestion, coconut oil is broken down into smaller molecules, such as ketone bodies (KBs). These KBs can cross the BBB and serve as an alternative energy source for the brain, making coconut oil a significant natural remedy for neurodegenerative conditions. deepika

Coconut oil has been shown to reduce obesity, improve insulin resistance, and support metabolic health. These improvements can reduce inflammation, enhance mitochondrial function, and increase cerebral blood flow. These effects may help explain how coconut oil potentially benefits neurodegenerative disorders such as AD, PD, and MS. Oliveira de Lira, Ibrahim

Mitochondrial Effects

Although progressive damage to dopaminergic neurons in the substantia nigra is a primary etiological pathway in PD, mitochondrial dysfunction and oxidative stress contribute substantially to its pathogenesis. Coconut oil's MCTs are metabolized into glycerol and medium-chain fatty acids, which support mitochondrial ATP production and may enhance mitochondrial biogenesis. Ying Wang

A 2020 rodent model study even showed that coconut oil helped neural function and mitigated the effects of L-dopa supplementation, lending its use as a potential strategy to reduce reliance on DRT. Shehata

References

1. Supplementation-Dependent Effects of Vegetable Oils with Varying Fatty Acid Compositions on Anthropometric and Biochemical Parameters in Obese Women, Luciene Oliveira de Lira, et al.
2. Neuroprotective role of coconut oil for the prevention and treatment of Parkinson's disease: potential mechanisms of action,
3. Beneficial Effects of Coconut Oil in Treatment of Parkinson’s Disease, K. S. Ibrahim and E. M. El-Sayed.
4. Medium Chain Triglycerides enhances exercise endurance through the increased mitochondrial biogenesis and metabolism, Ying Wang, et al.
5. Neurochemical, neurobehavioral and histochemical effects of therapeutic dose of l-dopa on striatal neurons in rats: Protective effect of virgin coconut oil, Ahmed M Shehata, et al.

Matcha

Bioactive Compounds

Matcha is a finely ground Japanese green tea powder rich in bioactives, including lutein, vitamin K, and polyphenols, particularly catechins like epigallocatechin gallate (EGCG), and caffeine. EGCG exhibits potent antioxidant and neuroprotective effects that help mitigate oxidative stress, neuroinflammation, and neurodegeneration.

Cognitive Effects

A 2020 randomized, double-blind, placebo-controlled trial over 12 weeks on 15 men and 39 women found that Matcha improved cognitive function (MoCA test), with the effects being more pronounced in women than in men, especially in the cognitive domain of language. Researchers speculated that this may be associated with physiological changes that accompany estrogen loss and menopause in elderly women, attributing the potential effects to matcha's EGCG, vitamin K, and lutein content. Sakurai

Metabolic Effects

A 2017 review found that EGCG exhibited a wide range of therapeutic properties including anti-atherosclerosis, anti-diabetes, anti-inflammatory, and antioxidant effects. The reduction in plasma glucose and inflammatory markers and the inhibition of ROS generation have multiple benefits to cardiopulmonary and neurological health. Eng

Low-dose EGCG and caffeine, two components of matcha, elicit substantial synergistic anti-obesity effects by improving gut microbiota and enhancing short-chain fatty acid (SCFA) production. The gut microbiota regulates obesity and metabolic disorders through various physiological pathways, including SCFAs and their receptors. These effects on the gut microbiota may help explain the metabolic and cognitive benefits associated with matcha consumption. Zhu

Anti-aggregant and Antifibrillogenic Effects

EGCG has been shown to inhibit the effects of preformed oligomers of α-synuclein and other proteins from damaging vesicle membranes and causing cytotoxicity in rat brains. Lorenzen, Zhao

A few in vitro studies have explored EGCG's antifibrillogenic potential with positive results. EGCG has been shown to prevent the formation of amyloid plaques and the misfolding of disease proteins and prions. Researchers demonstrated that EGCG inhibits α-synuclein and amyloid-β fibrillogenesis and can disaggregate amyloid fibrils of α-synuclein in a dose-dependent manner. bieschke, Xu

EGCG's anti-aggregant and antifibrillogenic effects in humans are not supported by clinical trials, primarily due to the difficulty and cost of such studies. However, positive evidence from in vitro and rodent studies suggests that regular consumption might have a dose-dependent effect, potentially slowing disease progression. Considering the minimal mild side effects, there is no strong reason not to include matcha or an EGCG supplement in a PD regimen.

Ceremonial-Grade Matcha

Ceremonial-grade matcha is made from the youngest tea leaves with higher concentrations of chlorophyll and lower fluoride content compared to culinary-grade matcha made from older leaves, which accumulate fluoride from the soil as they grow.

Fluoride and Oxalates Warning

Matcha also has moderate levels of oxalates with younger leaves having higher oxalate concentrations than older leaves. Oxalates can contribute to inflammation and kidney damage. Moderate amounts of quality ceremonial-grade matcha are safe for drinking (10 g of matcha contains approximately 60 mg of oxalate). Those seeking a much higher dose of EGCG and lutein without the fluoride and oxalate can consider supplemental EGCG.

Matcha Preparation

• Grade: Use ceremonial-grade matcha for higher polyphenols and less caffeine and fluoride.
• Timing: Consume in the morning or early afternoon to avoid nighttime caffeine effects.
• Water Temperature: Heat water to 160–175°F (70–80°C; well below boiling) to preserve polyphenols.
• Milk: Avoid milk to maintain polyphenol effectiveness.

Reducing LIDs vs Too Much Caffeine

Caffeine was shown to reduce the risk of LIDs in a large-scale clinical trail and its cohort Willis. However, higher doses can increase the production of ROS, which exacerbates oxidative stress.

Dose and Supplementation

For caffeine-sensitive individuals, lower doses of matcha (1–2 g), paired with supplemental EGCG and theanine, offer a more balanced neuroprotective strategy. This combination allows for beneficial polyphenol intake while theanine mitigates caffeine’s stimulating effects, reducing the risk of excessive caffeine-induced ROS production and the potential exacerbation of LIDs. Higher doses (up to 5 g) earlier in the day may provide increased pre-workout energy without affecting sleep.

References

1. Effects of Matcha Green Tea Powder on Cognitive Functions of Community-Dwelling Elderly Individual, Keisuke Sakurai, et al.
2. How Epigallocatechin Gallate Can Inhibit α-Synuclein Oligomer Toxicity in Vitro, Nikolai Lorenzen, et al.
3. Epigallocatechin Gallate (EGCG) Inhibits Alpha-Synuclein Aggregation: A Potential Agent for Parkinson’s Disease, Yan Xu, et al.

   This study found EGCG significantly decreased the number of cerebral SNCA aggregates and their activity in mice.

4. Caffeine Consumption and Risk of Dyskinesia in CALM-PD, Anne-Marie A. Wills, et al,
5. Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases, Qian Yi Eng, et al.
6. Combined use of epigallocatechin-3-gallate (EGCG) and caffeine in low doses exhibits marked anti-obesity synergy through regulation of gut microbiota and bile acid metabolism, Ming-zhi Zhu, et al.
7. remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity, Jan Bieschke, et al.
8. Epigallocatechin-3-gallate (EGCG) inhibits fibrillation, disaggregates amyloid fibrils of α-synuclein, and protects PC12 cells against α-synuclein-induced toxicity, Juan Zhao, et al.

Ginseng

Ginseng is a traditional herbal medicine used for energy and vitality, metabolic (BG) and cardiovascular health, stress relief, sexual dysfunction, and cancer protection. Its ginsenoside components, primarily Rb1 and Rg1, and saponins have shown neuroprotective effects, alleviating PD symptoms and slowing disease progression.

Ginseng and Physical Performance

In a placebo controlled trial, panax ginseng administered 1 hour before endurance performance increased lipolysis, eased heart rate, and reduced plasma lactate concentrations. Wong

A 2022 review assessed dose responses of ginseng at low (<300 mg/day) and high (>300 mg/day), and found that ginseng showed significant short-term effects (up to 4 weeks) at high dosage for vertical jump. Khan

Mitochondrial Mechanism of Action?

A 2020 rodent study found that red ginseng improves exercise endurance. Rats were fed ginseng and subjected to a swim test, testing time to exhaustion. Rats fed RG had significantly longer swimming endurance. Analysis showed RG treatment enhanced ATP production levels in myoblasts and RG increased mRNA expressions of mitochondrial biogenesis regulators, suggesting mitochondrial energy-generating capacity, which would also explain the improved exercise performance. Shin

Intracellular Calcium Reduction

Ginseng was shown to protect mitochondria by reducing intracellular calcium through increased phosphorylation of IP3R Kwon. This is helpful, because in PD, excess intracellular calcium damages mitochondria, exacerbating oxidative stress, disrupting ATP production, and causing neuronal damage. Ginseng helps this by reducing excess intracellular calcium, thereby protecting mitochondria and the neurons they function in.

Secondarily, ginsenoside Rb1 extract has demonstrated inhibition of L-type calcium channels (LTCCs) in rodent studies. LTCC blocking helps keep excess calcium from entering the cell, thereby preventing excess intracellular calcium. However, significant calcium channel blocking from ginseng alone would require a human dose of ginseng thirty times that of typical supplementation, which may contribute to ginseng's neuroprotective effects, and can complement other mild calcium channel blockers, like ginger. Zhi-ying Lin

Ginseng in PD

Ginseng improved motor function and increased dopamine levels in PD models. These neuroprotective effects are explained by reduced oxidative stress, neuroinflammation, α-synuclein aggregation, and neuronal apoptosis, with no significant toxicity observed in most studies. He, Ong, Song, Zaafan, van-kampen, Choi

Ginsenoside Rb1 inhibits fibrillation, oligomerization, and toxicity of α-synuclein, and disaggregates preformed fibrils. Heng, Ardah

Supplementation

Ginseng's energizing effects make it suitable for pre-workout or earlier in the day. Fermented ginseng offers significantly better absorption with higher ginsenoside concentration, compared to the low oral absorption of non-fermented ginsenosides (0.1 – 3.7%). Ryu Start with 200-400 mg of 10% ginsenoside powder daily, gradually increasing the dose as needed. Select a high-quality product with clear labeling.

Side Effects

Side effects may include a mildly elevated heart rate, increased blood pressure, and insomnia if consumed in the evening. Ginseng may enhance the activity of MAOIs, which could allow for reductions in medication dosage. Consult a healthcare professional for potential interactions and monitoring. l-liu

Products

References

1. Qualitative detection of ginsenosides in brain tissues after oral administration of high-purity ginseng total saponins by using polyclonal antibody against ginsenosides, Yu-Nan Zhao, et al.
2. Effects of Panax ginseng supplementation on physiology responses during endurance performance, Chee Ping Fadzel Wong, et al.
3. Dose-response and temporal ergogenic effects of ginseng supplementation in athletes and active participants: A systematic review and meta-analysis, Nasreen Khan, et al.
4. Red Ginseng Improves Exercise Endurance by Promoting Mitochondrial Biogenesis and Myoblast Differentiation, Eun Ju Shin, et al.
5. Protective effects of ginseng on neurological disorders, Wei-Yi Ong, et al.
6. Anti-thrombotic effects of ginsenoside Rk3 by regulating cAMP and PI3K/MAPK pathway on human platelets, Hyuk-Woo Kwon, et al.
7. Ginsenoside Rb1 selectively inhibits the activity of L-type voltage-gated calcium channels in cultured rat hippocampal neurons , Zhi-ying Lin, et al.
8. Effect of ginsenoside-Rg1 on experimental Parkinson's disease: A systematic review and meta-analysis of animal studies, Yi-Bo He, et al.
9. A Preclinical Systematic Review of Ginsenoside-Rg1 in Experimental Parkinson's Disease, Liang Song, et al.
10. The Protective Effect of Korean Red Ginseng Against Rotenone-Induced Parkinson's Disease in Rat Model: Modulation of Nuclear Factor-κβ and Caspase-3, Mai A Zaafan, et al.
11. Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson's disease, Jackalina Van Kampen, et al.
12. Multitarget effects of Korean Red Ginseng in animal model of Parkinson's disease: antiapoptosis, antioxidant, antiinflammation, and maintenance of blood–brain barrier integrity, Jong Hee Choi, et al.
13. Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting α-synuclein abnormalities in the substantia nigra, Yang Heng, et al.
14. Ginsenoside Rb1 inhibits fibrillation and toxicity of α-synuclein and disaggregates preformed fibrils., Mustafa T. Ardah, et al.
15. The bioavailability of red ginseng extract fermented by Phellinus linteus, Jae Sik Ryu, et al.
16. Functional compounds of ginseng and ginseng-containing medicine for treating cardiovascular diseases, Lanchun Liu, et al.

Rhodiola Rosea

Rhodiola rosea, an adaptogenic herb, contains over 140 active compounds, notably rosavins and salidroside. These improve mitochondrial health and strengthen cellular stress resilience, reducing anxiety, fatigue, and depression.

Cognitive and Neuroprotective Benefits

Rhodiola rosea has been shown to improve learning and memory functions in animal models through antioxidant activity, cholinergic regulation, anti-apoptosis, anti-inflammatory effects, and improved cerebral metabolism. Ma

Rhodiola rosea and its active compounds can help to alleviate the disease in the brain at the cellular level by reducing oxidative damage, improving protein folding, and promoting dopaminergic cell growth and blood flow in the substantia nigra. However, direct evidence in PD-specific models remains limited. Bernatoniene

Rhodiola rosea components have demonstrated neuroprotective effects in ischemic stroke models. These include improved neural functional scores, reduced brain edema, increased cell viability, decreased apoptotic cells and inflammatory markers, and improved BBB function via salidroside. Li, Zhilan

Mechanisms of Action

Rhodiola rosea's multiple neuroprotective benefits come from its antioxidant and anti-inflammatory effects, which help reduce oxidative stress and inflammation in the brain, enhancing mitochondrial function to boost ATP synthesis, strengthen the BBB, and improve neurotransmitter function.

Mitochondrial Function

Rhodiola rosea helps in reducing cell death by inhibiting apoptosis, which is beneficial in conditions involving neuronal damage like PD.

Effects on Mood

Rhodiola rosea modulates stress by upregulating the production and activity of neurotransmitters serotonin, dopamine, and acetylcholine, helped by increasing the permeability of the blood–brain barrier to dopamine and serotonin precursors. Amsterdam, Stojcheva, Li

Supplementation

Rhodiola improves mood, exercise recovery, and is generally very well-tolerated. Effective doses range from 3-5 mg/kg (210 - 350 mg mg for a 70 kg adult), in one or two doses. It is best used earlier in the day, due to its mildly stimulating effects.

References

1. Rhodiola rosea L. Improves Learning and Memory Function: Preclinical Evidence and Possible Mechanisms, Gou-ping Ma, et al.
2. Preclinical Evidence and Possible Mechanisms of Rhodiola rosea L. and Its Components for Ischemic Stroke: A Systematic Review and Meta-Analysis, Yan Li, et al.
3. Salidroside promotes pro-angiogenesis and repair of blood brain barrier via Notch/ITGB1 signal path in CSVD Mode, Tu Zhilan, et al.
4. Rhodiola rosea L. as a putative botanical antidepressant, Jay D Amsterdam and Alexander G Panossian.
5. Phenolic Compounds of Rhodiola rosea L. as the Potential Alternative Therapy in the Treatment of Chronic Diseases, Jurga Bernatoniene, et al.
6. The Effectiveness of Rhodiola rosea L. Preparations in Alleviating Various Aspects of Life-Stress Symptoms and Stress-Induced Conditions—Encouraging Clinical Evidence, Emilija Ivanova Stojcheva and José Carlos Quintela.
7. Salidroside Protects Dopaminergic Neurons by Preserving Complex I Activity via DJ-1/Nrf2-Mediated Antioxidant Pathway, Ruru Li, et al.

Acetyl-L-Carnitine (ALCAR)

Acetyl-L-Carnitine (ALCAR) is a modified form of L-Carnitine, an amino acid that transports fatty acids into the mitochondria for energy.

Blood-Brain Barrier

ALCAR’s acetyl group allows it to cross the blood-brain barrier more effectively than L-carnitine, enhancing brain energy metabolism and cognitive function.

How ALCAR Works

ALCAR facilitates the transport of fatty acids into mitochondria, boosting energy production decreases and reducing oxidative stress. This helps boost brain energy and neurotransmitter activity. Therapeutic benefits may include improved cognitive function, potential support for depression, reduced oxidative stress, and fat loss.

Performance and Recovery

Forms of l-carnitine, including ALCAR, improve exercise performance and recovery. A 2018 study published in the Journal of Exercise Nutrition and Biochemistry found that L-carnitine supplementation enhances exercise performance while attenuating blood lactate and oxidative stress responses to resistance training. Koozehchian

A comprehensive 2018 review in Nutrients analyzed multiple studies across various populations, concluding that l-carnitine intake improves recovery after exercise, alleviates muscle injury, and reduces markers of cellular damage and free radical formation accompanied by attenuation of muscle soreness. Studies in older adults further showed that l-Carnitine supplementation can lead to increased muscle mass accompanied by a decrease in body weight and reduced physical and mental fatigue. Fielding

Fat Loss

Two other meta-analyses of high-quality RCTs found that 2 g l-carnitine supplementation improved body weight and fat mass, especially in overweight subjects. These results can be explained by carnitine's effects on energy production. Askarpour, Talenezhad

Metabolic Health

A 2021 review study investigated the effects of L-Carnitine, ALCAR, and Propionyl-L-Carnitine (PLCAR) on body mass in type 2 diabetes mellitus (T2DM) patients. After reviewing several studies, they concluded that 2 g/day l-carnitine for at least 2 weeks affects body mass in T2DM patients, and no differentiating effects were found in acetyl-l-carnitine or propionyl-l-carnitine groups. Wang

Neurological Effects

ALCAR protects dopaminergic neurons by reducing neuroinflammation, apoptosis, astrogliosis (damage to astrocytes (glial cells)), and oxidative stress. ALCAR has shown neuroprotective effects in rodent models of PD, both in vitro and in vivo, protecting cells against the accumulation of alpha-synuclein. Majd, S Burks

A 1990 study on PD patients showed that 2g of ALCAR improved the H-reflex and enhanced sleep architecture, including spindle activity, in non-placebo subjects.

Researchers found that the 2 g of supplemental ALCAR improved the H-response, sleep stages, and spindling in test (non-placebo) subjects. The H-response, or Hoffmann reflex, is a muscle reflex response to specific nerve stimulation, measured by latency and amplitude. Spindling refers to brain wave activity occurring during NREM sleep, particularly in stages N2 (lighter sleep) and N3 (deeper sleep). Puca

A later 2018 multicenter, randomized double-blind, placebo-controlled 28-day clinical trial studied the efficacy of 1500 mg ALCAR per day in patients with cerebrovascular dementia. Although the study excluded patients with PD, researchers found that 1.5g of ALCAR significantly improved cognitive assessment. ys-yang

A 2022 randomized, observational, double-blind, placebo-controlled study on ALCAR scheduled prefrail elderly patients. 92 patients received 3 months of treatment with ALCAR at 1.5 grams or placebo, twice daily, and then 3 months of follow-up. They found that ALCAR treatment delayed the incidence and severity of onset of degenerative disorders of the elderly in prefrail subjects with improvement in memory and cognitive processes. Malaguarnera

ALCAR supports exercise performance and recovery, mitochondrial health, cognitive function, and fat loss via its energy-producing effects in the mitochondria. Cognitive function is improved in the elderly, likely due to ALCAR's ability to stimulate mitochondrial energy production.

Supplementation

Taking 1.5 - 2 g ALCAR pre-workout enhances exercise performance. Intense exercise increases cerebral blood flow, potentially enhancing ALCAR uptake in the brain. It is avoid taking ALCAR before sleeping, as its stimulating effects may interfere with sleep.

Products

References

1. Acetyl-L-carnitine permeability across the blood-brain barrier and involvement of carnitine transporter OCTN2, Akihiro Inano, et al.
2. Effects of nine weeks L-Carnitine supplementation on exercise performance, anaerobic power, and exercise-induced oxidative stress in resistance-trained males, Majid S. Koozehchian, et al.
3. Acetyl-l-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-induced model of Parkinson's disease in the rat, Siamak Afshin-Majd, et al.
4. Neuroprotective effects of acetyl-l-carnitine (ALC) in a chronic MPTP-induced Parkinson’s disease mouse model: Endothelial and microglial effects, Susan Burks, et al.
5. The Effects of L-Carnitine, Acetyl-L-Carnitine, and Propionyl-L-Carnitine on Body Mass in Type 2 Diabetes Mellitus Patients, Dong-Dong Wang, et al.
6. Beneficial effects of l-carnitine supplementation for weight management in overweight and obese adults: An updated systematic review and dose-response meta-analysis of randomized controlled trials, Moein Askarpour, et al.
7. Effects of l-carnitine supplementation on weight loss and body composition: A systematic review and meta-analysis of 37 randomized controlled clinical trials with dose-response analysis, Nasir Talenezhad, et al.
8. l-Carnitine Supplementation in Recovery after Exercise, Roger Fielding, et al.
9. Clinical pharmacodynamics of acetyl-L-carnitine in patients with Parkinson's disease, F M Puca, et al.
10. A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial for Efficacy of Acetyl-L-carnitine in Patients with Dementia Associated with Cerebrovascular Disease, YoungSoon Yang, et al.
11. Acetyl-L-carnitine Slows the Progression from Prefrailty to Frailty in Older Subjects: A Randomized Interventional Clinical Trial, Giulia Malaguarnera, et al.

Alpha-Lipoic Acid (ALA)

Alpha-Lipoic Acid (ALA) improves mitochondrial function and reduces oxidative damage. J. Liu

Supplement Forms: s- and r-Enantiomers, and Binding

Most research on ALA uses both s- and r-isoforms. The naturally-occurring r-form has higher absorption and bioavailability than the synthetically produced s-form. B. Salehi

Na-r-ALA — Increased Absorption

Despite its advantages, free-form r-ALA is still prone to polymerization. Na-r-ALA (sodium-bound r-ALA) is comparatively more stable, less prone to polymerization, and has better absorption compared to free-form r-ALA. Lysine R-lipoate may offer greater absorption compared to r-ALA. D.A. Carlson

How R-ALA Works

R-ALA activates AMPK which stimulates mitophagy. This leads to mitochondrial biogenesis and improved mitochondrial function. It increases glucose uptake and decreases glucose production in the liver, resulting in enhanced insulin sensitivity and reduced oxidative stress. Y. Wang, W. J. Lee

R-ALA in Parkinson's Disease

Insulin resistance (IR) is commonly associated with an increased risk of developing Parkinson’s disease. IR leads to elevated brain glucose, which damages brain cells and accelerates neurodegeneration. E. Hogg

Iron in Parkinson's Disease

Alpha-synuclein pathology disrupts iron homeostasis in PD. High iron levels harm dopaminergic neurons, inducing cell death and leading to more severe motor deficits with mutant α-synuclein. f-jia, p-lingor

ALA's mitochondrial and antioxidant benefits are ideal for PD. J. Liu

R-ALA decreases intracellular ROS and iron levels. S. Tai

Overexpression of α-synuclein inhibits AMPK activity, contributing to the neurodegenerative process in PD. ALA increases AMPK, which improves mitochondrial function — a problem in PD. A rodent model experiment showed that treatment with acetyl-L-carnitine or α-lipoic acid improved motor performance, reduced oxidation, and improved ATP production. W. Bobela, S. Zaitone, H. Zhang

Synergy: Na-r-ALA, Creatine, ALCAR, and Carbohydrates

R-ALA, an antioxidant, helps protect the mitochondria from damage, allowing them to function more efficiently. H. Zhang

Combining ALCAR, r-ALA, and creatine amplify each other's effects, making this combination a potent pre-workout mitochondrial activator. D.G. Burke

Side Effects

Gastrointestinal upset can occur. Some individuals experience this when taking Na-r-ALA on a full stomach, but not when taking r-ALA in the morning with water and fruit.

Products

References

1. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview, Jiankang Liu.

   This review study found ALA improves upon the age-associated decline of memory, mitochondrial structure and function, age-associated increase of oxidative damage, and antioxidation.

   The also found that co-administration of LA with other mitochondrial nutrients, such as acetyl-L-carnitine and coenzyme Q10, appears more effective in improving cognitive dysfunction and reducing oxidative mitochondrial dysfunction …

2. Insights on the Use of α-Lipoic Acid for Therapeutic Purposes, Bahare Salehi, et al.

   The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiometer.

3. The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects, David A Carlson, et al.

   Na-r-ALA is less prone to polymerization, completely soluble in water, and displays significantly higher Cmax and AUC values and decreased time to maximum concentration (Tmax) and T1/2 values than RLA or rac-LA.

4. Alpha-lipoic acid increases energy expenditure by enhancing AMPK-PGC-1α signalling in the skeletal muscle of aged mice, Yi Wang, et al.

5. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle, Woo Je Lee, et al.

   This study suggests that ALA-induced improvement of insulin sensitivity is mediated by activation of AMPK and reduced triglyceride accumulation in skeletal muscle.

6. High Prevalence of Undiagnosed Insulin Resistance in Non-Diabetic Subjects with Parkinson's Disease, Elliot Hogg, et al.

   The study revealed nearly 60% of the non-diabetic study participants may have undiagnosed insulin resistance — despite having normal blood sugar levels.

7. High Dietary Iron Supplement Induces the Nigrostriatal Dopaminergic Neurons Lesion in Transgenic Mice Expressing Mutant A53T Human Alpha-Synuclein, Fengju Jia, et al.

   These results suggested high dietary iron supplement could induce nigral dopaminergic neuron lesions in A53T mice, which might be due to the vulnerability of SN to accumulate iron.

8. Alpha-synuclein and iron: two keys unlocking Parkinson's disease, Paul Lingor, et al.

   This short review focuses on two disease mechanisms: alpha-synuclein pathology and dysfunction of iron homeostasis, as well as their intricate interaction.

9. Alpha-Lipoic Acid Mediates Clearance of Iron Accumulation in PD Model, Shengyan Tai, et al.

   This PD-induced rodent model showed that ALA could provide significant protection from 6-OHDA-induced cell damage in vitro by decreasing the levels of intracellular reactive oxygen species and iron.

10. AMPK activation mitigates α-synuclein toxicity, Wojciech Bobela, et al.

    Researchers modulated AMPK activity to overexpress AMPK. Overexpression of AMPK mitigated α-synuclein toxicity in nigral dopamine neurons.

11. Acetyl-L-carnitine and α-lipoic acid affect rotenone-induced damage in nigral dopaminergic neurons of rat brain, implication for Parkinson's disease therapy, Sawsan A Zaitone, et al.

    Treatment with acetyl-L-carnitine or α-lipoic acid improved the motor performance and reduced the level of lipid peroxides in rat brains as compared to rotenone group. Further, ATP production was enhanced along with acetyl-L-carnitine treatments (p≤0.05).

12. Combined R-alpha-lipoic acid and acetyl-L-carnitine exerts efficient preventative effects in a cellular model of Parkinson's disease, Hongyu Zhang, et al.
13. Effect of alpha-lipoic acid combined with creatine monohydrate on human skeletal muscle creatine and phosphagen concentration, Darren G Burke, et al.

    This small human trial found that co-ingestion of alpha-lipoic acid with creatine and a small amount of sucrose can enhance muscle total creatine content as compared to the ingestion of creatine and sucrose or creatine alone.

GABA, 5-HTP, and Melatonin

GABA, 5-HTP, and melatonin can help PD patients through multiple neurological pathways. They're grouped because they all promote sleep and should all be taken at night.

Dopaminergic, Serotonergic, and GABAergic Systems

PD affects the dopaminergic, serotonergic, and GABAergic systems, which are interdependent. Doctors typically focus on the dopaminergic system, leading to imbalances in other systems, nutrient deficiencies, and progressive neurodegeneration (PN).

Addressing only the dopaminergic system without considering the broader neurochemical landscape results in inadequate management of PD symptoms, exacerbates non-motor symptoms, and leads to treatment-related complications.

Comprehensive PD Management

A comprehensive approach to PD must consider not only the direct effects of medications but also their broader implications for nutritional status and metabolic function for improved outcomes and quality of life.

Medical Team Awareness

All medical team members must understand the broader implications of PD treatments to prevent nutrient depletion and exacerbation of neurodegeneration.

5-HTP (5-Hydroxytryptophan)

Mechanisms	Sleep, Dopaminergic side-effects
Dose	50 - 100 mg 💤 (at night)
Fat-soluble	❌
🩸🧠 BBB	✅
Safety	Moderately Safe
Efficacy	Moderately Effective

5-HTP (5-Hydroxytryptophan) is an amino acid that converts to serotonin (5-HT) and then to melatonin, a hormone that helps regulate sleep and relaxation.

Serotonin signaling changes occur early in Parkinson's. Addressing this system early, before gastrointestinal symptoms appear is important.

DRT Side Effect Counterbalance

DRT can cause involuntary movements called L-DOPA-induced dyskinesia (LID). 5-HTP supplementation helps restore serotonin levels and modulate dopamine release, which can reduce the severity of symptoms associated with LID.

DRT depletes vitamin B6, which is necessary for nerve health and neurotransmitter synthesis, leading to neuropathy and neurotransmitter system failure. Vitamin B12 deficiency can also contribute to neuropathy.

Mitigating Serotonergic Damage in PD

PD affects not only the dopaminergic system but also other neurotransmitter systems, including the serotonergic system, by the same mechanisms that affect the CNS (mitochondrial dysfunction, α-synuclein aggregation, etc.). This leads to the degeneration of serotonergic terminals, non-motor symptoms, and complications such as gastrointestinal dysfunction and, in some cases, visual hallucinations.

Neurotransmitter metabolic pathways are complex. These interactions, illustrated in the figure Competitive Neurotransmitter Inhibitors, function normally in healthy individuals but are disrupted in PD and further affected by DRT. a-munoz, m-hinz

A randomized, double-blind, placebo-controlled crossover study with 12 PD patients with LIDs and motor fluctuations was conducted over 4 weeks. Participants received either a placebo or 50 mg of 5-HTP daily. Significant improvements in LIDs were observed with 5-HTP, as measured by the UDysRS and UPDRS-IV scores. Meloni

A follow-up RCT crossover study compared placebo and 50 mg of 5-HTP daily over 4 weeks. Results showed significant improvements in motor function (UPDRS Part II), increased REM sleep without a rise in REM sleep behavior disorder (RBD), and enhanced global clinical impression with 5-HTP. The study demonstrated 5-HTP’s safety and efficacy in improving sleep stability and overall sleep quality in PD. Meloni 2

The discussed pathways, including dopamine, norepinephrine, epinephrine, glutathione, SAMe, methionine, cysteine, tryptophan, serotonin, and vitamin B6, interact to influence neurological function, oxidative stress regulation, mood, and overall health.

Reducing DRT while supporting other neurotransmitter systems helps manage neurotransmitter balance more effectively.

A balanced approach involving diet, exercise, supplementation, and regular monitoring is essential for slowing disease progression.

The impact of PD on the serotonergic system is significant and often overlooked by conventional medicine approaches. Several studies have shown serotonergic dysfunction in Parkinson's disease is associated with the development of motor and non-motor symptoms and complications. Politis

5-HTP has demonstrated neuroprotective effects in humans and in animal models of neurodegenerative diseases, including PD. It reduces oxidative stress, inflammation, and mitochondrial dysfunction, which are primary etiological pathways in progressive neurodegeneration (PN).

Supplementation

A 50 mg dose of 5-HTP is typically safe and well-tolerated. PD patients should consult their care team, as DRT and 5-HTP dosages may require careful adjustment. Taking it nightly is a conservative approach to improve sleep, depression, and constipation, reduce LIDs, provide neuroprotection, and balance neurotransmitter systems.

Contraindication

5-HTP elevates serotonin levels without the body's typical feedback mechanisms. Serotonergic imbalance affects other neurotransmitters like dopamine and norepinephrine that share precursor pathways (tryptophan and tyrosine, respectively). The magnitude of this risk depends on dosage, medications, and individual factors. Moderate caution should be exercised. Individuals who take SSRIs or MAOIs, or have a history of serotonin-related disorders should communicate this with their healthcare providers.

In rodent studies, high doses of 5-HTP (150 mg/kg) have compromised the blood-brain barrier (BBB). In humans, this would roughly translate to 850 mg/day for a 70 kg individual, though this is purely hypothetical and not clinically recommended. A. Sharma

References

1. Serotonergic Dysfunction in Parkinson's Disease and Its Relevance to Disability, Marios Politis and Clare Loane.

   This study confirms the lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to L-DOPA-induced dyskinesia (LID).

2. Efficacy and safety of 5-Hydroxytryptophan on levodopa-induced motor complications in Parkinson's disease: A preliminary finding, Mario Meloni, et al.
3. Preliminary finding of a randomized, double-blind, placebo-controlled, crossover study to evaluate the safety and efficacy of 5-hydroxytryptophan on REM sleep behavior disorder in Parkinson’s disease, Mario Meloni, et al.
4. Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson’s Disease and Adverse Effects of L-DOPA, Ana Muñoz, et al.

   PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances.

   The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID).

5. Parkinson’s disease managing reversible neurodegeneration (retracted), Marty Hinz, et al.

   This study explains the interactions between serotonin and dopamine along with their precursors in synthesis, transport, and metabolism.

   The study was retracted for conflict of interest, not factual inaccuracies.

6. 5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology, Aruna Sharma, et al.

Melatonin

Mechanisms	Antioxidant, Anti-inflammatory, Mitochondrial, Anti-ischemic
Dose	10 mg per day 💤 (at night)
Fat-soluble	✅
🩸🧠 BBB	✅
Safety	Very Safe
Efficacy	Very Effective

Melatonin is a hormone produced by the pineal gland, a small endocrine gland located in the midbrain between the two hemispheres.

Neuroprotective

Melatonin protects neurons against oxidative stress, a problem exacerbated by PD. It interacts with nuclear receptors and signaling pathways to regulate gene transcription. This causes an increase in the production of superoxide dismutase (SOD), glutathione peroxidase, and glutathione reductase.

Neuroinflammation leads to increased ROS production. Increased ROS production contributes to neuronal damage which perpetuates further neuroinflammation. Melatonin reduces inflammation, thereby reducing oxidative stress.

Antioxidant Effects

Melatonin easily crosses the BBB and stimulates a variety of antioxidative enzymes including superoxide dismutase (SOD), glutathione peroxidase and glutathione reductase, which scavenge free radicals, reducing the oxidative burden on cells and allowing antioxidant enzymes to function more efficiently. Reiter

SOD is one of the most important antioxidant enzymes inside and outside cell membranes. However, in PD, SOD levels decline, and melatonin's restorative effects may help counteract this deficit. Bostantjopoulou, Yang

Melatonin receptors MT1 and MT2 in the substantia nigra are reduced in PD patients, however supplementing it helps amend this deficit. Shin

Vasodilation Effects

Brain ischemia, a common problem in PD, occurs when blood flow and oxygen supply are restricted to various parts of the brain. Worse, ischemia to the substantia nigra exacerbates the problem of decreased dopamine output. This impairs mitochondrial function, leading to energy depletion and cell death. Melatonin is vasodilatory effects, relaxing blood vessels, and improving blood flow. This may help improve perfusion to ischemic brain regions, potentially reducing tissue damage and promoting recovery.

Mitoprotective

Melatonin protects mitochondrial function and integrity, mitigating cellular damage caused by ischemia.

A 2005 review concluded that melatonin preserves mitochondrial homeostasis, reduces free radical generation by enhancing mitochondrial glutathione levels, and safeguards proton potential and ATP synthesis by stimulating complex I and IV activities. Srinivasan

Supplementation

Melatonin is safe to take. Excessive doses over 10-15mg may cause next-day tiredness and headache.

Time-released formulations help maintain melatonin levels for a longer period. The reduced peak concentration helps maintain sleep throughout the night.

Product

References

1. Melatonin as a pharmacological agent against neuronal loss in experimental models of Huntington's disease, Alzheimer's disease and parkinsonism, R J Reiter, et al.
2. Role of Melatonin in Neurodegenerative Diseases, V Srinivasan, et al.
3. Superoxide Dismutase Activity in Early and Advanced Parkinson's Disease, S Bostantjopoulou, et al.
4. Contra-Directional Expression of Plasma Superoxide Dismutase with Lipoprotein Cholesterol and High-Sensitivity C-reactive Protein as Important Markers of Parkinson’s Disease Severity, Wanlin Yang, et al.
5. titNeuroprotective effects of melatonin in neurodegenerative and autoimmune central nervous system diseases le, Jung-Won Shin.

L-Theanine

L-theanine, an amino acid found in green tea, has neuroprotective, mood-improving, and sleep-promoting effects that can help PD.

Cognitive Effects

A 2021 double-blind, randomized, placebo-controlled study in Japan evaluated the effects of 100.6 mg of L-theanine taken daily for 12 weeks in participants aged 50–69 years.

The theanine group showed improved attention, reaction times, working memory, and executive function–higher-level cognitive skills for decision-making, problem-solving, and adapting to new situations. Baba

Another double-blind, crossover RCT in Japan investigated the effects of 200 mg/day of L-theanine over four weeks on stress and cognitive function in healthy adults.

In a double-blind, crossover RCT, 200 mg/day of L-theanine for four weeks improved cognitive function, verbal fluency, and executive function in healthy adults aged 36–60. Cognitive function, verbal fluency and executive function scores improved after L-theanine administration. The study's crossover design and methodologies supports their findings that L-theanine can promote mental health in the general population with stress-related cognitive impairments. Hidese

Effects on Sleep

Another crossover RCT from Japan investigated chronic L-theanine administration on stress-related symptoms and cognitive function in a non-clinical population.

Subjects were randomly assigned to L-theanine (200 mg/day) or placebo tablets for 4 weeks. After a 2 week wash-out, the crossover study was continued for 4 weeks. Results showed the L-theanine group experienced shorter sleep latency, reduced sleep disturbances, and decreased reliance on sleep medication. Kunugi

Mechanism of Action

L-theanine has been found to inhibit the NMDA receptor pathway, thereby preventing excessive glutamate-induced calcium influx and subsequent neuronal damage (Di et al., 2010). Theanine has potential competitively bind to glutamate receptors in the nervous system and may increase GABA levels. Nathan

Supplementation

L-theanine is considered very safe, with a recommended dose of 100–200 mg taken about 30 minutes before bedtime. An additional daytime dose may enhance mental clarity or counterbalance the stimulating effects of caffeine. Theanine can be taken with GABA for their combined effects on sleep.

References

1. Effects of l-Theanine on Cognitive Function in Middle-Aged and Older Subjects: A Randomized Placebo-Controlled Study, Yoshitake Baba, et al.
2. Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial, Shinsuke Hidese, et al.
3. Effects of Chronic L-theanine on Stress-related Symptoms and Cognitive Function in a Non-clinical Population: A Randomized Controlled Trial, Hiroshi Kunugi, et al.
4. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent, Pradeep J Nathan, et al.

TMG (Trimethylglycine)

TMG (trimethylglycine), also known as betaine, is a natural compound in the body and found in various foods. It helps convert homocysteine into methionine, a process that may reduce inflammation linked to PD. Sleeman, Murray, Bhattacharjee

High homocysteine levels contribute to oxidative stress and inflammation, damaging neurons and blood vessels, including those in the brain.

DRT Elevates Homocysteine

Levodopa metabolism in the liver raises homocysteine levels, potentially worsening neurological and vascular risks in PD. Lowering homocysteine may help mitigate these risks in patients on DRT. Kocer

TMG or B Vitamins?

TMG supports methylation alongside B6, B12, and folate by lessening B-vitamin demand, particularly in individuals with high methylation demands, like those on DRT. Machek

TMG Raises Glutathione

TMG indirectly supports glutathione synthesis, as methionine produced from TMG can convert to SAMe, a precursor to glutathione, an important antioxidant. Zhao

Glycine Support

When TMG donates a methyl group to homocysteine, a small amount of glycine is released, which helps promote relaxation by acting on NMDA receptors in the brain.

Osmotic Balance

TMG helps cells maintain a healthy balance of water and solutes, potentially protecting neurons from stress. As a stabilizing osmolyte, TMG supports the maintenance of native protein structures, helping to reduce cellular stress and the likelihood of protein misfolding—a process linked to neurodegenerative diseases like PD. However, these osmolytic effects are not unique to TMG. Other osmolytes, such as taurine, creatine, glycerol, and glycine, contribute to cellular stability in similar ways. By stabilizing proteins and maintaining cellular hydration, osmolytes like these may collectively support brain health by reducing the conditions that lead to protein aggregation and cellular dysfunction. Knight & Knight, Kushwah

Supplementation

A split dose of 1g post-exercise and 1g before bed may enhance antioxidant support and improve sleep.

References

1. Urate and Homocysteine: Predicting Motor and Cognitive Changes in Newly Diagnosed Parkinson’s Disease, Isobel Sleeman, et al.
2. The role of one-carbon metabolism and homocysteine in Parkinson's disease onset, pathology and mechanisms, Lauren K Murray and Nafisa M Jadavji.
3. Chronic exposure of homocysteine in mice contributes to dopamine loss by enhancing oxidative stress in nigrostriatum and produces behavioral phenotypes of Parkinson’s disease, Nivedita Bhattacharjee, et al.
4. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?, Bilge Kocer, et al.
5. Human Serum Betaine and Associated Biomarker Concentrations Following a 14 Day Supplemental Betaine Loading Protocol and during a 28 Day Washout Period: A Pilot Investigation, Steven B Machek, et al.
6. Betaine in Inflammation: Mechanistic Aspects and Applications, Guangfu Zhao, et al.
7. Making the case for prophylactic use of betaine to promote brain health in young (15–24 year old) athletes at risk for concussion, Leena S Knight and Thomas A Knight.
8. Osmolytes: A Possible Therapeutic Molecule for Ameliorating the Neurodegeneration Caused by Protein Misfolding and Aggregation, Neetu Kushwah, et al.

Mitochondrial Quinones (PQQ, CoQ10) and Vitamin K2

PQQ and CoQ10 promote mitochondrial biogenesis, improving ATP production and reducing oxidative stress. Their combined supplementation can have synergistic effects, enhancing mitochondrial efficiency, reducing fatigue, and improving overall cellular health. Vitamin K2 supports mitochondrial function to some extent via SIRT1 activation and supports other vital functions such as bone mineralization, gut health, and cardiovascular health.

Geranylgeraniol (GG)

Geranylgeraniol (GG) is naturally synthesized in the human body via the mevalonate (cholesterol) pathway and can also be extracted from annatto seeds. GG is a precursor of CoQ10, vitamin K2, cholesterol, testosterone, and protein synthesis and modification. GG production declines with age, which can reduce levels of CoQ10, vitamin K2, and testosterone. Ho

GG suppresses inflammation by improving the gut microbiome and enhancing glucose response, benefiting both gut health and systemic inflammation. Chung

Mechanism of Action

GG converts mevalonic acid (MVA), the precursor for cholesterol, into CoQ10, vitamin K2, and sex hormones, which helps protect mitochondrial function.

CoQ10 and cholesterol are synthesized endogenously in both the body and brain, but their levels decline due to aging and mitochondrial dysfunction, a major problem in PD. The brain contains around 20% of the body’s total cholesterol. GG supplementation may help counteract these deficits by providing the raw material for their synthesis, supporting mitochondrial and neuronal function.

Cholesterol Turnover

Cholesterol is essential for synaptogenesis. Studies suggest that higher cholesterol levels are associated with a lower risk of PD, while lower cholesterol may be a risk factor for PD. GG can increase cholesterol turnover in the brain, potentially supporting brain cholesterol levels and neurological function. huang

A 2006 rodent study demonstrated that GG restored hippocampal long-term potentiation (LTP) levels. The study found that GG, but not cholesterol, increased cholesterol turnover in the brain and activated the mevalonate pathway. The research indicated that continuous production of GG in specific neurons is necessary for LTP and learning. Kotti

Dopamine synthesis requires substantial cellular energy. CoQ10 is a vital energy substrate for brain mitochondria, aiding their function and dopamine production. GG is essential for CoQ10 production, thereby supporting neuronal energy metabolism. Ho, Tan

While some forms of supplemental CoQ10 may cross the BBB, this remains uncertain. However, GG supplementation supports the body's natural synthesis of CoQ10 and cholesterol, both of which decline with age and mitochondrial dysfunction. Therefore, GG supplementation may help maintain mitochondrial health, support brain energy production, and protect neurons in PD.

BBB Permeability

GG, with a molecular weight (MW) of 268.39 g/mol, is likely to cross the BBB, as molecules with an MW under 400 Da often can. This may offer an advantage over CoQ10, which has a higher MW of 731 Da and might not cross the BBB (chemspider).

Supplementation

Supplementing geranyl geraniol at 150mg per day is safe, as the body has a natural regulatory mechanism to keep levels from exceeding a healthy range.

Product

• Xtendlife GG Pure - Geranylgeraniol

References

1. Beneficial effect of dietary geranylgeraniol on glucose homeostasis and bone microstructure in obese mice is associated with suppression of proinflammation and modification of gut microbiome, Eunhee Chung, et al

   This rodent study concluded that GG improves glucose homeostasis and bone microstructure in obese mice via suppression of pro-inflammation and modification of microbiome composition.

2. Brain cholesterol metabolism and Parkinson’s disease, Xuemei Huang,et al.
3. Brain cholesterol turnover required for geranylgeraniol production and learning in mice, Tiina J. Kotti, et al.
4. Potential role of geranylgeraniol in managing statin-associated muscle symptoms: a COVID-19 related perspective, Barrie Tan, Kok-Yong Chin.

   CoQ10 supplementation has not been shown to reverse statin-associated muscle symptoms, therefore, this paper proposes GG for CoQ10 synthesis.

5. A novel function of geranylgeraniol in regulating testosterone production

Nattokinase

Nattokinase is a proteolytic and fibrinolytic enzyme Nattokinase that reduces inflammation.

Nattokinase has been shown to degrade amyloid fibrils in mice, which may help to slow down the progression of Parkinson’s disease.

Nattokinase has been shown to promote the non-amyloidogenic processing of Aβ, which may help to reduce the accumulation of amyloid plaques in the brain.

Docosahexaenoic Acid (DHA)

Docosahexaenoic acid (DHA) is an omega-3 fatty acid found in eggs, fish, krill, and algae, and produced in small amounts in humans. DHA is necessary for normal brain function, for cognition, memory, and attention.

DHA reduces neuroinflammation by mitigating oxidative stress, helping to neutralize ROS, and increasing the master antioxidant glutathione. H.J. Lee

DHA in Parkinson's Disease

Daily DHA supplementation in rodent studies has been shown to protect against core PD symptoms like problems with balance, walking, and dopamine function in brain areas responsible for movement. N.M. Chitre

A 2017 review found that higher doses of DHA were more effective than EPA in increasing the levels of nerve growth factors of NGF and BDNF in a dose-dependent response. Y.P. Zhang

A placebo-controlled trial in adults without cognitive impairments found that supplementing 2g of DHA daily for 6 months led to small increases in CSF DHA following supplementation, with APOE4 carriers having a lower increase than non-carriers.

The study explained that DHA crosses the BBB through passive diffusion, meaning that high blood levels are required to significantly raise DHA levels in the brain. A 200% increase in blood DHA resulted in only a 28% rise in CSF. I.C. Arellanes

Supplementation

Based on the discussed research, DHA can be started at 2 grams per day, and increased gradually. Liquid DHA products may be more effective for those requiring higher doses, but should be kept refrigerated to prevent oxidation. Higher doses of DHA are generally well tolerated, but individual tolerance varies, so splitting doses across meals can help with absorption and reduce the risk of stomach upset.

DHA Product

DHA References

1. Docosahexaenoic acid prevents paraquat-induced reactive oxygen species production in dopaminergic neurons via enhancement of glutathione homeostasis, Hyoung Jun Lee, et al.
2. Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson's disease via mechanisms associated with increased protein kinase activity in the striatum , Neha Milind Chitre, et al.
3. DHA, EPA, and their combination at various ratios differently modulated Aβ_25-35-induced neurotoxicity in SH-SY5Y cells, Yong-Ping Zhang, et al.
4. Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial, Isabella C. Arellanes, et al.

Cholinergics and Membrane Support

Cholinergics strengthen cell membranes, which can dampen calcium channel overactivation, thereby reducing excitatory states.

Cholinergic supplementation has been shown to improve cognitive function, increase physical power output, provide neuroprotection, and improve conditions of neurological disorders. Restoring phosphatidylcholine (PC) to healthy levels has been shown to combat neurological decline and reduce DRT dependence and its associated side effects. M. Zhou, M. Amalric, B.S. Baumel

Cholinergic supplements support neuronal health by maintaining cell membrane integrity, improving neurotransmitter synthesis, and providing neuroprotection. This helps sustain cognitive function and neuronal survival.

The cholinergic and dopaminergic systems are interdependent. Cholinergic supplements uridine monophosphate (UMP), CDP-Choline, alpha-GPC, and phosphatidylserine (PS) strengthen the cholinergic system and can help restore balance when DRT is used.

Cholinergic and Dopaminergic Interdependence

The cholinergic and dopaminergic systems interact and converge in various brain regions, including the basal ganglia and hippocampus, to regulate cognition, movement, and behavior. Disruption of these interactions contributes to various symptoms of PD, including dyskinesia.

Interactions with DRT

Supplementation with CDP-choline, UMP, and alpha-GPC reduces the need for DRT and should be considered and monitored under medical supervision. However, the benefits of these supplements extend beyond merely reducing the required dose of DRT. R. Eberhardt

Phosphatidylserine (PS) levels are often decreased in idiopathic PD and its supplementation may also alleviate dopamine replacement therapy (DRT) side effects. G. Zhai

Cholinergics Example Stack

An example cholinergic supplement stack might include UMP and CDP-choline at 250 mg each, twice daily, 500 mg alpha-GPC pre-workout, 200 mg PS after dinner, and 3000 mg DHA daily.

Phospholipids and Alpha-Synuclein

Experimental evidence suggests that phospholipids alter the structure and reduce the toxicity of α-synuclein oligomers. T. Dou

Choline References

1. Effects of different fatty acids composition of phosphatidylcholine on brain function of dementia mice induced by scopolamine, Miao-miao Zhou, et al.
2. Where Dopaminergic and Cholinergic Systems Interact: A Gateway for Tuning Neurodegenerative Disorders, Marianne Amalric, et al,
3. Potential Neuroregenerative and Neuroprotective Effects of Uridine/Choline-Enriched Multinutrient Dietary Intervention for Mild Cognitive Impairment: A Narrative Review, Barry S. Baumel, et al.
4. Phosphatidylcholine and Phosphatidylserine Uniquely Modify the Secondary Structure of α-Synuclein Oligomers Formed in Their Presence at the Early Stages of Protein Aggregation
5. Serum-Based Lipid Panels for Diagnosis of Idiopathic Parkinson’s Disease, Guangju Zhai.

Magnesium L-Threonate

Magnesium L-Threonate is a highly bioavailable form of magnesium that, unlike most magnesium supplements, crosses the blood-brain barrier to strongly support brain health and cognitive function.

In a 2019 rodent study where magnesium L-Threonate was compared to magnesium sulfate, only the L-Threonate form crossed the blood-brain barrier, where it then inhibited oxidative stress, attenuated motor deficits, and slowed the progression of neurodegeneration. Y. Shen

A 2022 study from Nanjing Medical University found that Magtein® significantly improved memory and cognition in healthy Chinese adults, with greater benefits in older participants. C. Zhang

Calcium Regulation

Magnesium acts as a calcium antagonist in cells, helping to control intracellular calcium levels and reduce excitotoxicity. Excessive mitochondrial calcium, a common problem in PD, damages mitochondria, reducing energy output and contributing to cell death, as dopaminergic neurons are highly sensitive to calcium fluctuations and vulnerable to the excitotoxic damage it causes. Maier

BBB Dysfunction

Magnesium also protects the integrity and function of the BBB, necessary for homeostasis, to protect the CNS and maintain healthy neurological function. Romeo, Daneman

Supplementation

Magnesium can promote relaxation and improve sleep quality. Therefore, it is recommended to take this supplement in the evening.

Product

References

1. The treatment with MgT is associated with an increase of Mg in the CSF. MgT, rather than MgSO4, can significantly attenuate MPTP-induced motor deficits and dopamine (DA) neuron loss, Yanling Shen, et al.
2. A Magtein®, Magnesium L-Threonate, -Based Formula Improves Brain Cognitive Functions in Healthy Chinese Adults, Chengxiang Zhang, et al.
3. Magnesium and the Brain: A Focus on Neuroinflammation and Neurodegeneration, Jeanette A. M. Maier, et al.
4. Magnesium and the blood-brain barrier in vitro: effects on permeability and magnesium transport, Valentina Romeo, et al.
5. The Blood–Brain Barrier, Richard Daneman and Alexandre Prat.

Vitamin D3

Vitamin D3 stimulates the osteoblasts to produce osteocalcin (OCN). Vitamin K2 converts some of this osteocalcin into its active form, carboxylated OCN. The remaining undercarboxylated OCN (ucOCN) enters the bloodstream and acts as a hormone in various tissues, including the brain. C. Shan

D3 and Parkinson's Disease

The Parkinson’s Disease Research, Education, and Clinical Center at the Portland and Puget Sound Veteran Affairs (VA) Clinics conducted an add-on study to a longitudinal study on neuropsychiatric function in individuals with PD. Researchers found that higher plasma vitamin D levels were associated with improved cognition and mood in PD patients without dementia. A. Peterson

Supplementation

More is not always better! Too much vitamin D3 can disturb calcium levels. Vitamin D3 levels can be optimized with regular bloodwork and refined supplementation accordingly. 4,000 IU per day is safe. D3 is stored in the body, so a missed dose can be compensated by doubling the intake the next day.

Vitamin D References

1. Memory, Mood, and Vitamin D in Persons with Parkinson’s Disease, Amie L. Peterson, et al.
2. Roles for osteocalcin in brain signalling: implications in cognition- and motor-related disorders, Chang Shan, et al.

Vitamin B-1 (Thiamine)

Vitamin B1, also known as thiamine, is an essential vitamin that helps the body turn food into energy by supporting glycolysis, a process necessary for nerve, muscle, and heart health. This is particularly important in PD, where energy production in cells is typically impaired. Deficiencies in thiamine can further disrupt glycolysis, exacerbating energy production issues.

Benfotiamine — Fat Soluble Thiamine

Benfotiamine is a fat-soluble form of thiamine that has shown advantages for neurological disorders due to its exceptional bioavailability and capacity to traverse the blood-brain barrier. It has been extensively researched demonstrated protection of dopaminergic neurons, enhanced motor function, and increased antioxidant enzymes. Wang

Thiamine and Mitochondrial Function

Thiamine, in its active form (thiamine pyrophosphate, TPP), serves as a cofactor for several enzymes involved in energy production, from glycolysis to oxidative phosphorylation within the mitochondria. These processes are necessary for meeting the cellular energy demands of neurons, the heart, and other tissues, particularly in conditions like PD, where mitochondrial dysfunction is common.

High-dose Thiamin in PD

High-dose thiamine has repeatedly been shown to reverse motor and non-motor symptoms in PD. An observational open-label pilot study beginning June 2012, published in the Journal Alternative and Complementary Medicine injected patients with 100 mg of thiamine intramuscularly twice a week, without altering patients' existing therapies. Patients were re-evaluated after 1 month and then every 3 months during treatment. This high-dose thiamine was effective in reversing PD motor and non-motor symptoms. The clinical improvement was stable over time in all patients. a-constantini

Researchers hypothesized that thiamine-dependent metabolic processes could cause selective neural damage typically affected by PD which provokes neurodegeneration, and that thiamine could counteract that process, having both restorative and neuroprotective action in PD.

DJ-1 Genetic Mutations, Thiamine

Mutations in the DJ-1 gene, also known as PARK7, are confirmed in about 1-2% of early-onset PD cases, but this figure could be higher due to limited genetic screening. The DJ-1 gene is responsible for thiamine biosynthesis. Since DJ-1 mutations contribute to oxidative stress and mitochondrial dysfunction, patients with these mutations might see greater benefits from therapies that support mitochondrial function, such as high-dose thiamine supplementation. However, this is more related to enhancing mitochondrial health and less about directly addressing DJ-1's function. Genetic testing for DJ-1 mutations may help predict thiamine's usefulness. k-luong

BBB

Thiamine has poor bioavailability but can cross the BBB through passive diffusion when its levels in the blood are high.

Supplementation

High-dose thiamine therapy for PD is not widely recommended by mainstream medical organizations, and long-term safety and efficacy data in humans is lacking. However, some forum users on HealthUnlocked have reported significant benefits from high-dose oral supplementation, with doses up to 1,000 mg per day. Patients should consult with their healthcare providers before initiating high-dose thiamine therapy.

1. Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study, A. Costantini, et al.

   Patients received 100 mg of thiamine, injected intramuscularly twice a week, without any change to personal therapy. All the patients were re-evaluated after 1 month and then every 3 months during treatment. Administration of parenteral high-dose thiamine was effective in reversing PD motor and nonmotor symptoms.

2. Benfotiamine protects MPTP-induced Parkinson’s disease mouse model via activating Nrf2 signaling pathway, Kai Wang, et al.
3. The Beneficial Role of Thiamine in Parkinson Disease, Khanh v. q. Lương and Lan T. H. Nguyễn.

   DJ-1 gene is responsible for such as thiamin biosynthesis. Mutations in the DJ-1 gene can result in a loss of function of the protein.

Vitamin B-6 (Pyridoxine) or P-5-P (Pyridoxal 5-Phosphate)

Vitamin B6, also known as pyridoxine, is used for synthesis of neurotransmitters including dopamine and serotonin, glutamatergic system regulation, and nervous system balance and maintenance.

Vitamin B6 is necessary for dopamine biosynthesis and may help reduce the side effects of dopaminergic treatments.

P-5-P (Pyridoxal 5-Phosphate)

P-5-P (Pyridoxal 5-Phosphate) is the active coenzyme form of vitamin B6, which bypasses the need for liver conversion. While most research focuses on B-6, p-5-p may offer advantages over it.

Relevance to Parkinson's Disease

Supplementation of vitamin B-6, along with vitamin B-12 and folic acid, can reduce high homocysteine levels caused by levodopa metabolism, which may help in managing metabolic and clinical complications such as peripheral neuropathy and osteoporosis. Keun

Supplementation

Balanced methylated B-complex formulations generally provide sufficient amounts, from 10 - 50 mg of B-6 or P-5-P. A few such products include Pure Encapsulations B-Complex Plus and Integrative Therapeutics Active B-Complex. Talk to your neurologist about reducing DRT and supplementing with B-6, B-12 and folic acid.

References

1. Dietary Approaches to Improve Efficacy and Control Side Effects of Levodopa Therapy in Parkinson's Disease: A Systematic Review, Jikke T Boelens Keun, et al.

Vitamin B-12 (Cobalamin)

How B-12 helps Parkinson's Disease

Vitamin B-12 reduces ROS and improves mitochondrial biogenesis regulator PGC-1α.

Vitamin B-12 has multiple mechanisms related to LRRK2 expressions that protect dopaminergic neurons. B-12 inhibits LRRK2 kinase activity. This protects dopaminergic neurons from toxicity induced by LRRK2 and its mutant form, LRRK2-G2019S.

Vitamin B-12 prevents LRRK2-G2019S-potentiated α-synuclein accumulation in dopaminergic neurons.

1. Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

   Vitamin B-12 protected dopaminergic neurons from toxicity induced by LRRK2 and its mutant form, LRRK2-G2019S. The effect was shown to improve deficits in dopamine transmission in LRRK2-PD mouse models.

2. Vitamin B12 Ameliorates the Pathological Phenotypes of Multiple Parkinson’s Disease Models by Alleviating Oxidative Stress

   This multiple-model study demonstrated that vitamin B-12 significantly ameliorated oxidative stress by reducing ROS and alleviating reductants in a cellular PD model. In vivo, B-12 rescued the movement deficit of C. Elegans in the mouse PD model. Mechanistically, B-12 reduced JNK phosphorylation and improved the mitochondrial biogenesis regulator PGC-1α.

Tocotrienols and Tocopherols

Vitamin E is a group of eight fat-soluble compounds, comprising four tocopherols and four tocotrienols that offer a spectrum of benefits.

Tocopherols

α- — most common and studied form, antioxidant, immune-enhancing, vascular, and skin effects

β- — antioxidant, anti-inflammatory

γ- — antioxidant, anti-inflammatory, neutralizes RONS

δ- — antioxidant, anti-inflammatory, neutralizes RONS

Tocotrienols

α- — strongly neuroprotective, stabilizes cellular membranes

β- — antioxidant, anti-inflammatory

γ- — anti-tumorogenic, antihyperlipidemic

δ- — anti-cancer, strong antioxidant

Full-Spectrum Vitamin E

Tocopherols

Most vitamin E supplements are only alpha-tocopherol, which has the effect of reducing the body's levels of gamma-tocopherol D. Wolf. This is bad because, compared to alpha-tocopherol, gamma-tocopherol and delta-tocopherol can scavenge a wider range of RONS Sen.

Tocotrienols

Tocotrienols are neuroprotective, anti-cancer, anti-oxidative, and cholesterol-lowering in ways tocopherols aren't. A. Abraham, M. Clarke, Sen

Consuming the full spectrum of all eight natural forms of vitamin E avoids problems with unilateral α-tocopherol supplementation and provides maximum synergy and health benefits. C. Sen

Neuroprotective Effects

Tocotrienols have been shown to improve learning impairment in elderly subjects. A 2018 double-blind study out of Japan showed that the combination of tocotrienols with astaxanthin improves the composite memory and verbal memory of Japanese adults who feel memory decline. Astaxanthin and vitamin E are anti-oxidative, but tocotrienols are more than that. T. Sekikawa

Tocotrienols cross the BBB, exerting neuroprotective effects independent of their antioxidant activity by binding to the estrogen receptor, as shown in multiple studies. T. Matsura, R. Naomi

Tocotrienols also reduce BBB permeability by modulating tight junction proteins and reducing oxidative and inflammatory damage to the BBB. This helps maintain its integrity, which is essential for protecting the brain. N. Kaneai

Tocotrienols more effectively inhibit lipid peroxidation compared to tocopherols, due to better incorporation into cell membranes. This action protects mitochondria and reduces oxidative stress. Tocotrienols have been shown to induce apoptosis of cancer cells while protecting neuronal cells from glutamate- and peroxidative-induced death. B. Aggarwal R.C. Chiste

A 2021 controlled rodent model study showed that α- and γ- tocotrienols improved motor function and neuronal uptake in hippocampal cells, with α-tocotrienol demonstrating superior neuroprotective effects and preventing further reduction of dopaminergic neurons. M. Kumari

Human Trial Underway

A large-scale human trial, Tocotrienols in Parkinson's Disease (PD): A Pilot, Randomised, Placebo-controlled Trial, was opened on April 2021. This two-year study is designed to compare the effects of 400mg/day tocotrienols vs placebo on neuropsychological conditions using cognitive tests and bloodwork, to evaluate PD biomarkers and for safety monitoring. Tocotrienols are available over the counter, so participation in the trial is not required to use them.

Supplementation and Safety

Vitamin E is best taken with dietary fat and other fat-soluble supplements.

Vitamin E can thin the blood. Individuals taking blood thinners, and those with a history of stroke or brain bleeding should be cautious when taking vitamin E supplements.

Light to moderate supplementation consisting of a naturally-sourced, balanced blend of the four tocotrienols and four tocopherols provides benefits while avoiding these risks. Do not exceed the recommended dose. High doses of vitamin E, particularly the synthetic form dl-alpha-tocopherol, are unhelpful to neurodegenerative conditions and are toxic.

References

1. Vitamin E and its anticancer effects, Annette Abraham, et al.
2. Tocotrienols: Vitamin E beyond tocopherols, Chandan K. Sen, et al.
3. Supplementation with mixed tocopherols increases serum and blood cell gamma-tocopherol but does not alter biomarkers of platelet activation in subjects with type 2 diabetes., M. Clarke, et al.

   This RCT found that supplementation with alpha-tocopherol (the common form) decreased red blood cell gamma-tocopherol, whereas mixed tocopherols increased both serum alpha-tocopherol and serum and cellular gamma-tocopherol.

4. How an Increased Intake of Alpha-Tocopherol Can Suppress the Bioavailability of Gamma-Tocopherol, George Wolf, DPhil.
5. Cognitive function improvement with astaxanthin and tocotrienol intake: a randomized, double-blind, placebo-controlled study, Takahiro Sekikawa, et al.
6. Protective Effect of Tocotrienol on In Vitro and In Vivo Models of Parkinson's Disease, Tatsuya Matsura.

   This rodent model study demonstrated that tocotrienols bind to the estrogen receptor in vitro, resulting in relieved PD-related symptoms. The result was explained by the observed cellular signalling that led to cytoprotective effects.

7. An Interactive Review on the Role of Tocotrienols in the Neurodegenerative Disorders, Ruth Naomi, et al.
8. Tocotrienol improves learning and memory deficit of aged rats, Nozomi Kaneai, et al.
9. Tocotrienols, the Vitamin E of the 21st Century: It’s Potential Against Cancer and Other Chronic Diseases, Bharat B. Aggarwal, et al.
10. In vitro scavenging capacity of annatto seed extracts against reactive oxygen and nitrogen species, Renan Campos Chisté, et al.

    Annatto seeds contain several carotenoids, terpenoids, tocotrienols and flavonoids, which reduce RONS.

11. Tocotrienols Ameliorate Neurodegeneration and Motor Deficits in the 6-OHDA-Induced Rat Model of Parkinsonism: Behavioural and Immunohistochemistry Analysis, Mangala Kumari.

    “…this study revealed that supplementation of α- and γ-T3 was able to ameliorate the motor deficits induced by 6-OHDA and improve the neuronal functions by reducing inflammation, reversing the neuronal degradation, and preventing further reduction of dopaminergic neurons in the SN and striatum (STR) fibre density.”

NAD+ and its precursors NMN, NR, and Niacin

Nicotinamide Adenine Dinucleotide (NAD+)

NAD+ is a coenzyme necessary for mitochondrial health, energy metabolism, DNA repair, and cell signaling. Mitochondrial dysfunction, including reduced NAD+ levels, is a primary pathology of PD requiring thorough attention.

NAD+ regulates sirtuins, a family of enzymatic proteins that protect cells under stress, reducing inflammatory processes throughout the body and brain, protecting neurons in neurodegenerative diseases like PD, AD, and MS. Mitochondrial sirtuins specifically protect neurons in various PD models. He

NAD+ reduces oxidative stress, promoting cellular recovery and improving energy metabolism, neuroprotection, and DNA repair by modulating mitochondrial function. It reduces inflammation through immune modulation, causing macrophages to lower pro-inflammatory cytokines and increase anti-inflammatory cytokines.

NAD+ promotes mitophagy, which leads to mitogenesis. Mitophagy, the controlled breakdown of damaged mitochondria, results in new mitochondrial formation, enhancing neuronal survival and reducing reactive oxygen species (ROS). Lower ROS levels reduce oxidative stress and may help prevent α-synuclein misfolding and aggregation.

Declining NAD+ Levels

Declining NAD+ levels contribute to reduced mitochondrial function and impaired cellular energy metabolism in neurons. This increases neurons' susceptibility to oxidative damage and degeneration.

Raising NAD levels (through injection, precursor supplementation, and upregulation via exercise) improves mitochondrial function and count in neuronal cells. This explains how it improves neurotransmission, synaptic plasticity, and motor symptoms.

How NAD+ Decline Impacts Brain Health in Aging and PD

A 2019 study in Cell Metabolism found that NAD+ decline accelerates cellular aging and predisposes cells to neurodegenerative diseases. Sufficient NAD+ levels support normal autophagy/mitophagy, mitochondrial stress responses, proteasomal degradation (see Protein Clearance Pathway Dysfunction), and mitochondrial biogenesis—all of which maintain cellular quality and function. Age-increased NAD+ utilization and depletion disrupt these regulatory processes, impairing mitochondrial homeostasis and neuronal function. Lautrup

Mitochondrial dysfunction leads to reduced ATP production and increased reactive oxygen species (ROS), which further damage mitochondria, further impacting its energy production mechanisms, including oxidative phosphorylation (OXPHOS), and the TCA cycle. This leads to excessive calcium influx which damages mitochondrial membrane potential and damages neurons. Calcium dysregulation in PD worsens mitochondrial dysfunction, further reducing ATP and damaging neurons. (see: Mitochondrial Calcium Dysregulation).

NAD+ depletion compounds these mitochondrial issues, especially by disrupting mitophagy and promoting accumulation of damaged mitochondria. A 2019 study in Cell Metabolism found that NAD+ decline accelerates cellular aging and predisposes cells to neurodegenerative diseases.

This research explains how age-associated declines in mitochondrial function accelerates susceptibility to diseases like PD, ALS, and AD, where impaired NAD+-dependent pathways, reduced mitophagy, and increased oxidative stress accelerate neurodegeneration.

NAD Precursors

Supplementation with NAD precursors NMN, NR, and niacin, increases cellular levels of NAD+ (nicotinamide adenine dinucleotide). Among these, NMN is considered the safest and most effective precursor for increasing NAD+ levels, due to its direct conversion pathway.

Niacin increases NAD+ levels but through a different metabolic pathway, separate from the more direct conversion of NMN and NR.

NAD+ Injection & IV Drip

Mechanisms	Antioxidant, Anti-inflammatory, Mitochondrial health promoter, Neuroprotective, Neurorestorative, Anti-aggregant
Dose	Varies (injections or infusions)
Fat-soluble	❌
🩸🧠 BBB	✅
Safety	Moderately Safe
Efficacy	Moderately Effective

NAD can be injected intramuscularly, subcutaneously, or intravenously via a drip. It is popular, safe, generally enjoyed, and very well-tolerated.

NAD Product

NAD+ Injection References

1. A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+

   Eleven (Test n = 8, Control n = 3) male participants aged 30–55 years received 750 mg NAD+ in normal saline over a 6 h period. This resulted in a significant and quick elevation of intracellular NAD+.

NAD+ References

1. Mitochondrial Sirtuins in Parkinson's Disease, Ling He, et al.
2. NAD+ in Brain Aging and Neurodegenerative Disorders, Sofie Lautrup, et al.
3. NAD+ repletion reverses age-related behavioral and synaptic deficits in mice

   This study demonstrates supplementation with NAD+ precursors, including NMN, improves mitochondrial function, synaptic plasticity, and cognitive function in aged mice. The findings suggest that NAD+ repletion may have potential therapeutic benefits for age-related neurological disorders.

4. NAD+ metabolism and its roles in cellular processes during ageing

   NAD+ metabolism in cellular processes associated with aging and age-related diseases, including neurodegenerative disorders like PD. It highlights the potential therapeutic implications of NAD+ precursors in mitigating age-related declines in cellular function and promoting healthy aging.

5. Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich's ataxia cardiomyopathy model

   Although this study focuses on a cardiomyopathy model in Friedrich's ataxia, it provides insights into the potential benefits of NMN supplementation in a disease characterized by mitochondrial dysfunction. The findings suggest that NMN administration improves cardiac function and bioenergetics through SIRT3-mediated mechanisms, highlighting the importance of NAD+ metabolism in mitochondrial health.

6. Intravenous Administration of Nicotinamide Adenine Dinucleotide Alleviates Tremors Associated with Parkinson’s Disease A Case Repor

   This single case study used BR+NAD ("Brain Restoration Plus" NAD) comprised of multiple IV infusions of NAD+ over six days, as well as added oral supplementation of Vitamin C, B6, Folate, Selenium, N-acetyl-L-cysteine, N-acetyl-L-tyrosine, and electrolytes. Following Day 6, he received sublingual NAD+ tablets (300mg, twice per day) for 14 days.

   The patient initially presented with bilateral hand tremors (significantly more pronounced in the right hand), shuffling gate/gait rigidity, and impairments in movements of the hands and fingers

   Over the six NAD+ the six NAD+ treatment days, the patient showed a significant decline in hand tremors, development of a steady gate, increased sociability, increased cognitive functioning, and improved sleep.

Bacopa Monnieri (TODO)

Berberine (TODO)

Ginkgo Biloba (TODO)

Lutein (TODO)

Zeaxanthin (TODO)

Blueberry

Blueberries are rich in a variety of bioactive compounds that work together to offer health benefits. These compounds, when consumed from whole blueberries or their extracts, may be more effective than consuming individual components separately.

Pterostilbene — Blueberry's Powerful Polyphenol

Pterostilbene, a compound in blueberries, protects it against viral, bacterial, and fungal attack and excessive sunlight, similar to resveratrol, another stilbene produced by blueberries and also found in grapes.

Mechanism of Action

Pterostilbene exerts its neuroprotective effects by crossing the blood brain barrier, reducing oxidative stress and inflammation, increasing BDNF and neuroplasticity, altering CNS neurotransmitter systems (GABAergic, glutamatergic, and cholinergic), and improving symptoms of anxiety and depression.

Compared to resveratrol, pterostilbene has been shown to have four times the oral bioavailability, making it much more effective at low doses. McCormack

Cognitive Effects

A double-blind RCT investigated the effects of dietary blueberry on cognition in adults aged 60-75 years, randomly assigned to receive either 24 g/day of freeze-dried blueberry powder (equivalent to 1 cup of fresh blueberries) or a placebo powder for 90 days, finding that freeze-dried blueberry powder improved verbal memory and executive function. miller

Blueberry Juice Plus Exercise

Exercise combined with polyphenol consumption may impart neuroprotective benefits greater than either treatment alone.

A 2022 placebo-controlled rodent study on rats with amphetamine-induced rotational behavior assessed the effects of blueberry juice (BBJ) and exercise (EX) on four groups of rats, with controls for both exercise and blueberry juice (placebo). BBJ alone did not improve rotation in the rats, but exercise alone did, significantly decreasing the number of amphetamine-induced rotations by 42%. However, most impressively, exercise + BBJ improved upon rotational behavior by 80%. Catro

Real Blueberry vs. Pterostilbene Intake

Blueberries contain very small amounts of pterostilbene—around 99 to 520 ng per gram, meaning vast quantities would need to be consumed approach an effective dosage. For context, a daily dose of 100-250 mg of pterostilbene would require about 300,000 to 1.25 million blueberries, totalling over 40,000 kCal per day — an impossible amount.

Whole Blueberry plus Extract Consumption Strategy

Blueberries are packed with multiple bioactive compounds (e.g., anthocyanins, resveratrol, flavonoids) that provide synergistic health benefits. However, relying on whole blueberries or concentrated forms like FruitFast to achieve therapeutic pterostilbene levels is impractical for the purposes of targeting effects like cognitive protection or reducing oxidative stress.

Blueberry extract (e.g., FruitFast) provides a range of bioactive compounds but is low in pterostilbene. A pterostilbene supplement (50-100 mg/day), taken with fats, targets specific neuroprotective and antioxidant effects. Higher pterostilbene doses (>50 mg/day) have been associated with gastrointestinal discomfort and elevated LDL cholesterol, which may require individual testing and dose adjustments.

References

1. A Review of Pterostilbene Antioxidant Activity and Disease Modification, Denise McCormack and David McFadden.
2. Dietary blueberry improves cognition among older adults in a randomized, double-blind, placebo-controlled trial, Marshall G Miller, et al.
3. Blueberry juice augments exercise-induced neuroprotection in a Parkinson’s disease model through modulation of GDNF levels, Sandra L Castro, et al.

Senolytics

Senolytics are used to selectively induce the death of senescent cells. Senolytic means "senescent cell destruction".

Senolytics in Parkinson's Disease

Senolytics inhibit and help degrade α-synuclein aggregation.

In PD, α-synuclein and especially its mutant forms damage mitochondria, causing a leak of sirtuins from the inner membrane of the mitochondria leading to mitochondrial failure and eventual cell failure.

Aggregates of α-synuclein form Lewy bodies inside the cell and block T-cells from activating the lysosome of non-functioning "zombie" cells.

Senolytics help prevent the formation of α-synuclein aggregates. This has numerous benefits, including neuroprotection, decreased neuroinflammation, improved mitochondrial function, neurogenesis, and autophagy.

Senolytics reduce the formation of Lewy bodies and facilitate T-cell activation of the lysosome in senescent cells by preventing obstruction by α-synuclein.

Urolithin-A

Mechanisms	Antioxidant, Anti-inflammatory, Mitochondrial, Neuroprotective, Neurorestorative, Anti-aggregant
Dose	1000mg ED
Fat-soluble	✅
🩸🧠 BBB	✅
Safety	Moderately Safe
Efficacy	Moderately Effective

Overview

Urolithin-A is a naturally occurring compound produced by gut bacteria through the transformation of polyphenols, such as ellagitannins and ellagic acid, found in small amounts of some foods like wild berries (pomegranates, etc), walnuts, and tea. Urolithin-A supplementation stimulates mitophagy and mitochondrial function in several tissues.

Benefits

Urolithin-A-induced mitophagy promotes mitogenesis. This promotes neuronal survival and function, making Urolithin-A strongly neuroprotective. P. Andreux

Mitophagy

Mitophagy is a cellular process that recycles and removes damaged or unhealthy mitochondria, leading to their replacement with new, healthy mitochondria.

Urolithin-A and the PINK1-Parkin Pathway

The PINK1-Parkin pathway is necessary for the removal of damaged mitochondria. In some conditions, including PD, it is impacted. When PINK1 enters healthy mitochondria, the mitochondria remove it. However, when the mitochondria are damaged, PINK1 accumulates on the outer membrane. This signals the recruitment of Parkin to the outer membrane, which marks the damaged mitochondria for recognition by autophagosomes. The autophagosomes engulf the damaged mitochondria and transport them to the cell's lysosome for degradation. This process, known as mitophagy, signals the cell to initiate mitochondrial biogenesis, restoring cellular energy and function.

Mitophagy in Parkinson's Disease

In PD, there is an abnormally higher number of damaged mitochondria. These damaged mitochondria accumulate alpha-synuclein and contribute to the formation of Lewy bodies. Inducing mitophagy helps clear these harmful mitochondria and restore cellular energy production. This process protects against dopaminergic neurodegeneration.

A 2021 study using a PD-induced rodent model found urolithin-A exerted neuroprotective effects by promoting mitochondrial biogenesis via SIRT1-PGC-1α signaling pathway and ameliorated both motor deficits and nigral-striatal dopaminergic neurotoxicity. J. Liu

A 2019 rodent study out of Guangzhou, China found Urolithin-A, in a mouse model of AD, significantly improved spatial learning and memory, protected neurons from death, reduced neuroinflammation, and triggered neurogenesis. Z. Gong

A 2023 review study found Urolithin-A was neuroprotective, protected against brain injuries, improved mitophagy and overall mitochondrial functions of the nerve cells, inhibited monoamine oxidase, and reduced cognitive decline. O. Wojciechowska

Product

Exercise Performance

A 2022 RCT found Urolithin-A improved muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. A. Singh

Mice were gavage-fed with vehicle or taurine (500 or 1000 mg per kg body weight) daily for 10–12 month and culled at the age of 24 months for terminal assays

Another RCT in 2022 found Urolithin-A conferred a significant improvement in muscle endurance and reduced CRP. S. Liu

Supplementation

1000mg per day of Urolithin-A is safe and well-tolerated in humans.

Urolithin-A is fat-soluble and can cross the BBB. Taking with food or other fat-soluble vitamins may improve absorption.

Food Sources

Pomegranates contain ellagitannins, convertible to urolithin A by gut bacteria in 30% to 50% of people. Optimistically, eating 1 pomegranate might yield a negligible 2 milligrams of Urolithin-A — not enough!

Side Effects

Potential unknown side effects might include gastric upset or potential interactions with certain medications that also undergo hepatic metabolism. Taking with food may help.

References

1. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans, Pénélope A Andreux, et al.

   This clinical trial found Urolithin-A induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

2. Urolithin-A protects dopaminergic neurons in experimental models of Parkinson's disease by promoting mitochondrial biogenesis through the SIRT1/PGC-1α signaling pathway, Jia Liu, et al.

   This rodent study demonstrated Urolithin-A's neuroprotective effects, promoting mitochondrial biogenesis via SIRT1-PGC-1α signaling.

3. Urolithin-A attenuates memory impairment and neuroinflammation, Zhuo Gong, et al.

   Urolithin-A significantly improved spatial learning and memory, protected neurons from death, reduced neuroinflammation, and triggered neurogenesis.

4. Urolithin-A in Health and Diseases: Prospects for Parkinson’s Disease Management, Olga Wojciechowska and Małgorzata Kujawska.

   This review study found Urolithin-A reduced cognitive decline, increased mitochondrial quality and content, and protected against neurodegeneration.

5. Urolithin-A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults, Anurag Singh, et al.

   This randomized, placebo-controlled trial in middle-aged adults found Urolithin-A improved muscle strength, exercise performance, inflammation, and biomarkers of mitochondrial health.

6. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults, Sophia Liu, et al.

   Ceramides and plasma CRP were significantly lower in the Urolithin A group compared to the placebo group. (Ceramides are sphingolipids used in cellular signaling, membrane integrity, and cellular stress response. Elevated ceramides indicate inflammation and metabolic disorder.)

Resveratrol

Mechanisms	Antiaggregant, Anti-inflammatory, Mitochondrial, Endoplasmic Reticulum Dysfunction
Dose	500-1000 mg per day
🩸🧠 BBB	✅ due to its lipophilic properties and molecular weight of 228 Da, which is below the 500 Da threshold for BBB penetration
Fat-soluble	✅
Safety	Moderately Safe
Efficacy	Somewhat Effective

Resveratrol, a natural polyphenol commonly found in grapes, has shown potential in improving PD as an antioxidatant and anti-inflammatory, which ameliorate mitochondrial dysfunction to help preserve neuronal function and reduce neurodegeneration.

Endoplasmic Reticulum Effects

Resveratrol reduces ER stress-mediated apoptosis by enhancing autophagic activity. This aids in clearing misfolded proteins from the ER, thereby reducing the burden on this organelle and preventing apoptosis. Gaballah, Singh

Mitochondrial Effects

Resveratrol helps maintain mitochondrial in PD. It enhances mitochondrial dynamics and promotes mitophagy, reducing the accumulation of damaged mitochondria. Su, Wang

Anti-Aggregant Effects

By scavenging reactive oxygen species (ROS), resveratrol can alleviate some of the initial triggers that lead to protein misfolding. Resveratrol inhibits α-synuclein aggregation and cytotoxicity, lowering the levels of total α-synuclein and oligomers, and reducing neuroinflammation and oxidative stress in a dose-dependent manner. gaballah, Hung

Product

Purity Labs Organic Trans-Resveratrol 1,500MG Enhanced with Quercetin

Purity Labs Trans-Resveratrol is a high dose, 2 pills per day formula. It might be better to take just one

Resveratrol References

1. Resveratrol in Rodent Models of Parkinson’s Disease: A Systematic Review of Experimental Studies, Cheng-Fu Su, et al.
2. Oxidative Stress, Mitochondrial Dysfunction, and Neuroprotection of Polyphenols with Respect to Resveratrol in Parkinson’s Disease, Heng-Chung Kung, et al.
3. Modulatory effects of resveratrol on endoplasmic reticulum stress-associated apoptosis and oxido-inflammatory markers in a rat model of rotenone-induced Parkinson's disease, Hanaa Hibishy Gaballah.
4. Mechanism for antiParkinsonian effect of resveratrol: Involvement of transporters, synaptic proteins, dendrite arborization, biochemical alterations, ER stress and apoptosis, Ashish Singh, et al.
5. Resveratrol alleviates motor and cognitive deficits and neuropathology in the A53T α-synuclein mouse model of Parkinson's disease, Li-Fan Zhang, et al.
6. MicroRNA-214 participates in the neuroprotective effect of Resveratrol via inhibiting α-synuclein expression in MPTP-induced Parkinson's disease mouse, Zhao-Hui Wang, et al.
7. Resveratrol in Rodent Models of Parkinson's Disease: A Systematic Review of Experimental Studies