Parkinson's Disease Guide

Mechanisms of Spread

Once aggregated, mutant 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

Strategies to address α-synuclein include preventing its mutation, inhibiting aggregation, enhancing clearance from the brain, 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.

Brain Waste Management System (BWMS)

The brain waste management system (BWMS) defined herein describes the coordinated system that protects the brain from harmful substances, clears waste products, and maintains homeostasis. It consists of the blood-brain barrier (BBB), cchoroid plexus, CSF, glymphatic system, perivascular spaces, extracellular matrix (ECM), basement membrane, and brain phagocytes. BWMS dysfunction leads to α-synuclein aggregation, inflammation, and mitochondrial damage. Various interventions can improve the integrity and function of these components, with measurable effects. Solár

Impact of Dysfunction

Increased BBB permeability allows contaminants and inflammatory substances from the bloodstream to enter the brain, where they first cause harm before accumulating in the CSF as the clearance system struggles to remove them. This additional waste burden impairs the clearance of metabolic byproducts like α-synuclein, contributing to their accumulation and exacerbating neurological conditions.

The Blood–Brain Barrier (BBB)

The 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, located within the ventricles, is responsible for secreting CSF and forming a blood-CSF barrier. 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 can impair CSF production, disrupt waste clearance, and reduce the transport of essential substances, potentially contributing to cognitive decline.

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

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 brain-specific waste clearance pathway, made up of glial cells that remove metabolic waste and toxins, including misfolded proteins like α-synuclein. This system uses 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.

Brain Phagocytes

As mentioned earlier, the lysosomal system involved in autophagy helps neurons degrade internal misfolded proteins like α-synuclein and other waste. This system also supports extracellular cleanup through phagocytosis. While neurons depend on autophagy to remove their own waste, brain phagocytes, including microglia and astrocytes, rely on 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 can assist by flushing extracellular remnants out of the brain via CSF.

In PD, α-synuclein misfolding and accumulation initiates a cascade that leads to neuroinflammation. This neuroinflammation impairs phagocytosis, which in turn exacerbates α-synuclein aggregation. The resulting cycle of α-synuclein accumulation and impaired clearance promotes further aggregation, oligomerization, and fibrillization, ultimately forming Lewy bodies and driving progressive neurodegeneration. Additionally, collagen cross-linking caused by advanced glycation endproducts (AGEs) from high blood sugar, oxidative stress, or chronic inflammation further impairs phagocytosis.

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.

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 enhance 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.

References

1. 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.

2. 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.

3. The contribution of Parkin, PINK1, and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease, Marc van der Vlag, et al.
4. 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. Why is this 10-year-old paper not the standard of care!?

5. 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

6. 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.

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. 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.

10. 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.

11. Prion-like mechanisms in Parkinson Disease, Laura Volpicelli-Daley and Patrik Brundin.

Testing and Diagnosis

Upon clinical diagnosis of PD (via UPDRS score), serious damage has already been done to nerve cells of the substantia nigra. This underscores the importance of early testing and genetic testing. F. Nouri Emamzadeh

Alpha-synuclein oligomers are higher in PD patients than in healthy subjects. This can be tested with AlphaSyn-SAA salivary test or Syn-One skin biopsy.

Early Testing and Diagnosis with AlphaSyn-SAA

The AlphaSyn-SAA salivary test measures the levels of salivary alpha-amylase (SAA). The results are used to assess autonomic nervous system activity, particularly sympathetic nervous system activation. This test can, with some margin of error, identify people at risk of developing Parkinson’s disease up to ten years before symptoms appear.

Syn-One

The Syn-One skin biopsy detects the presence of phosphorylated alpha-synuclein in the skin. This is a much more accurate test than the AlphaSyn-SAA and is usually used as confirmation, rather than a preventive diagnostic.

Q & A

Below are example questions from the perspective of an active participant. These questions should be critically examined and may be used as the basis for better questions.

In your initial assessment of a patient suspected to have Parkinson's Disease, what tests and evaluations do you conduct?

✅ Good answers must include:

• Diagnostic imaging with DaTscan (Dopamine Transporter Scan) and fMRI to map dopamine distribution in the brain and assess broader brain function, respectively.
• Syn-One skin biopsy

— and that is beyond the very basic fundamentals of:—

• Detailed medical history and symptom review.
• Thorough examination of motor symptoms.
• Evaluation of non-motor symptoms such as sleep disturbances, autonomic dysfunction, and mood disorders.

❌ Bad Answers:

• Not mentioning genetic testing without providing context or justification.
• Preferring simpler imaging over more detailed fMRI and DaTscan imaging.

  DaTscan is a specialized form of SPECT optimized to detect changes in dopamine transporter density and is useful in the broader assessment of the condition.

  fMRI scans map out broader brain networks affected by PD, beyond just dopamine pathways. This information might help inform broader strategies, including supplementation.

• Generalization without specifying the detailed steps of the neurological examination and symptom review.

Why do you include or exclude genetic testing in your initial assessment for Parkinson's Disease?

✅ Good answers:

Acknowledgment of the importance of genetic factors in (1) creating custom-tailored solutions and (2) testing one's offspring for inherited traits.

How do you address non-motor symptoms in the management of Parkinson's Disease?

Treatments that the patient understands well and fall outside conventional medicine, along with their mechanisms of action, should be asked about.

❌ Bad answers:

• Dismissive generalizations about 'alternative' treatments that show bias or knowledge gaps.
• If the doctor can't explain the mechanisms of action (e.g., of turmeric, photobiomodulation) in simple terms, he likely doesn't understand them well himself.

Can you provide an example of how you adapted a treatment plan based on new research findings in Parkinson's Disease?

✅ A good response should include a recent example of implementing new research-based treatment, with evidence, rationale, and measured results.

References

1. Academic Medical Center Leadership on Pharmaceutical Company Boards of Directors, Timothy S. Anderson, et al.
2. The cognitive impact of anticholinergics: A clinical review, Noll Campbell, et al.
3. Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model, Yasumasa Yoshiyama, et al.
4. Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion, Matthew Rosebraugh, et al.
5. Molecular Effects of L-dopa Therapy in Parkinson’s Disease, Jolanta Dorszewska, et al.

6. Parkinson's Disease and Neurodegeneration: GABA-Collapse Hypothesis, Janusz W. Błaszczyk.
7. Role of GABA pathway in motor and non-motor symptoms in Parkinson's disease: a bidirectional circuit, Bandar Alharbi, et al.
8. The usual suspects, dopamine and alpha synuclein, conspire to cause neurodegeneration, Danielle E. Mor, et al.

9. Alpha Synuclein Oligomers: Dopamine Stabilization and Neurodegeneration, Patricia Thompson.

10. Dopamine induces soluble α-synuclein oligomers and nigrostriatal degeneration, Danielle E Mor, et al.
11. Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers , He-Jin Lee, et al.
12. Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons, Markus Riessland, et al.

    Highlights: Moreover, we found that SATB1 directly represses the expression of the pro-senescence factor p21 in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor in the pathology of Parkinson's disease.

COMT Inhibitors

Extend the action of levodopa by inhibiting the enzyme catechol-O-methyltransferase (COMT), which breaks down catecholamines, including dopamine, norepinephrine, and epinephrine. This results in sustained levels of these catecholamines.

Tolcapone, a COMT inhibitor, has been associated with a higher risk of liver damage, which can be severe in some cases.

Entacapone, another COMT inhibitor, has been linked to an increased risk of dyskinesias and other dopaminergic side effects.

MAO-B Inhibitors

Increase dopamine levels by blocking the enzyme monoamine oxidase B. Problems with MAO-B Inhibitors, such as side effects, dietary restrictions, and potential interactions with other medications, have contributed to a decline in their use.

Amantadine

Amantadine may help reduce dyskinesias and offer modest symptomatic relief with anticholinergic and serotonergic effects Rascol. However, Amantadine reduces GABA levels in the brain, which is implicated in the pathogenesis of PD Walia.

1. Amantadine in the treatment of Parkinson's disease and other movement disorders, Olivier Rascol, et al.
2. Amantadine exerts anxiolytic like effect in mice: Evidences for the involvement of nitrergic and GABAergic signaling pathways, Vaibhav Walia, et al.

SynuClean-D and Minzasolmin 🧪

SynuClean-D and Minzasolmin are in the research phase. There are outlets for research chemicals, and there are ongoing clinical trials.

https://sciencebeta.com/synuclean-d-parkinsons/

1. SynuClean-D Can Revert Neurodegeneration Caused By Parkinson's

   SynuClean-D inhibits α-synuclein aggregation, disrupts amyloid fibrillization, prevents degeneration of dopaminergic neurons (reference), and inhibits α-synuclein aggregation.

   SynuClean-D is available as a research chemical. It is being studied in a Phase 2 clinical trial of 450 early-stage PD patients with an expected completion date in mid-2024.

2. Minzasolmin

   Minzasolmin is a misfolding inhibitor, whereas SynuClean-D is an aggregation inhibitor. While Minzasolmin is in clinical development for Parkinson’s disease, SynuClean-D is primarily mentioned as a research compound.

   Patients with Parkinson’s disease can apply to participate in clinical trials for Minzasolmin. The clinical trial information is available on ClinicalTrials.gov (ID: NCT04658186; EudraCT Number 2020-003265).

Summary

Minzasolmin and SynuClean-D both seem promising in inhibiting the misfolding and aggregation of α-synuclein aggregation respectively. Ask your team about clinical trials or apply to participate directly with those trials' clinicians.

Hormone Replacement Therapy (HRT) for Women

HRT for women may include estrogens (17 beta-estradiol, estrone, and estriol), progesterone, pregnenolone, and DHEA.

Early Menopause: PD and HRT — Estrogen and Progesterone

Early menopause is statistically more common in women with PD. Several studies have associated postmenopausal HRT with a reduced risk of PD. Research indicates that women with PD are less likely to have used HRT compared to those without PD. The neuroprotective effects of estrogen replacement have shown positive results in animal models of PD and in early menopausal women with PD. L. Currie, D. Brann

Women's HRT is primarily aimed at alleviating vasomotor (VMS) and vaginal symptoms, but can also address osteopenia. VMS, related to thermoregulation, involves neuroendocrine, autonomic, and somatosensory systems, and is influenced by serotonergic and noradrenergic neurotransmitter pathways —systems often associated with depression. Dysfunction in these interconnected neurotransmitter systems may contribute to PD development.

A 2020 meta-analysis titled The Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Postmenopausal Women: A Meta-Analysis, presented evidence supporting ERT for the treatment of AD and PD, regardless of age, sample size, hormone therapy ascertainment, duration of the treatment, or route of administration.

Researchers determined that the beneficial effects of estrogen on dopamine receptors can delay the progression of PD. Yu-jia Song

A 2023 study published in Alzheimer's Research & Therapy found that hormone replacement therapy (HRT) is linked to better memory and increased size of brain areas involved in memory and emotions, but only in people with the APOE4 gene. Since APOE4 is also associated with more α-synuclein buildup in PD, these findings could open new research paths for HRT’s effects on memory and brain structure in PD patients with the APOE4 gene. R. Saleh

A retrospective chart review of a computerized patient database was performed at Columbia-Presbyterian. The review included only women who had symptoms of presumed PD for less than 5 years and who had not yet been on L-dopa. This research found a positive association between estrogen use and lower symptom severity in women with early PD who were not yet taking L-dopa. This indicates that estrogen therapy may be beneficial for women with early PD who also entered menopause early and have not yet started DRT. R Saunders-Pullman

In a rodent model of PD, estrogen replacement reduced dopaminergic neuron loss, promoted maturation of autophagy, improved motor function and other symptoms, and slowed disease progression. X.Z. Li

Estrogen and progesterone replacement for early menopausal women with PD may offer neuroprotective benefits, given the observed positive effects and known beneficial effects of estrogen on dopamine receptors in delaying the progression of PD.

Osteocalcin — Estrogen's Effects on Osteoblasts

Estrogen stimulates osteoblasts, which produce osteocalcin (OCN). OCN is partially modified by vitamin K into carboxylated OCN, while the rest remains undercarboxylated (ucOCN). Carboxylated OCN improves bone strength.

Undercarboxylated OCN acts as a hormone in the body and brain. OCN crosses the blood-brain barrier and has been shown to reach the midbrain and brainstem and influence brain functions such as memory and cognition. A. Obri

Decreased production of osteocalcin, including its undercarboxylated form, during menopause can reduce neuroprotection and cognitive function.

Risks of HRT in Women

Estrogen replacement carries risks such as vascular disease and certain cancers, requiring careful medical supervision. Alternatives to increasing osteocalcin levels include high-impact and weight-bearing exercise, and supplementation of vitamin K, magnesium, strontium, collagen, sleep, and vitamin D.

Progesterone: A Neuroprotective Steroid of the Intestine

A 2023 study explored how progesterone might protect nerve cells in the enteric nervous system (ENS) ("the gut"), which can be affected early in Parkinson’s Disease (PD). Researchers tested nerve cells from rats to see if they had the receptors needed to respond to progesterone. Then, they damaged these cells using MPTP, a toxin that mimics the damage seen in PD. Progesterone treatment reduced cell death by 45%, indicating a significant protective effect linked to a specific progesterone receptor. The impressive results require further human trials to confirm progesterone's effectiveness in reducing ENS dysfunction in PD. Stegemann

Combining DHEA with HRT (ERT + progesterone) may offer overall hormone balance, including testosterone and the estrogen to progesterone ratio. This combination may improve bone health and brain function by increasing estradiol and IGF-I, stimulating osteoblasts to release neuroprotective osteocalcin.

Adding pregnenolone as a DHEA precursor might help optimize hormonal balance, as progesterone is a precursor to many other hormones, including DHEA, progesterone, estrogen, and cortisol, providing more raw material to convert into these hormones as needed.

Managing HRT requires collaboration with an endocrinologist to balance PD symptom relief with potential risks.

HRT for Men

Testosterone

Testosterone has neuroprotective effects, partly due to a 5-10% conversion to estradiol via aromatase, which may enhance neuroprotection. Thus, TRT can raise testosterone to optimal levels (~800 ng/dL), resulting in a greater amount of aromatization to estradiol for some neuroprotection. V.E. Banchi

References

1. Parkinson’s Disease in Women and Men: What’s the Difference, Silvia Cerri, et al.
2. Postmenopausal estrogen use affects risk for Parkinson disease, Lillian J Currie, et al.
3. Neurotrophic and Neuroprotective Actions of Estrogen: Basic Mechanisms and Clinical Implications, Darrell W. Brann, et al.
4. Male/female differences in neuroprotection and neuromodulation of brain dopamine, Mélanie Bourque, et al.

   This review paper concluded that exogenous 17β-estradiol and/or progesterone treatments show neuroprotective properties against nigrostriatal dopaminergic toxins while androgens fail to induce any beneficial effect.

5. Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort, Rasha N. M. Saleh, et al.
6. The effect of estrogen replacement on early Parkinson's disease, R Saunders-Pullman, et al.
7. The effects and mechanism of estrogen on rats with Parkinson’s disease in different age groups, Xue-Zhong Li, et al.

8. Osteocalcin in the brain: from embryonic development to age-related decline in cognition, Arnaud Obri, et al.
9. The Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Postmenopausal Women: A Meta-Analysis, Yu-jia Song, et al.
10. Progesterone: A Neuroprotective Steroid of the Intestine, Lennart Norman Stegemann, et al.
11. Androgen Therapy in Neurodegenerative Diseases, Vittorio Emanuele Bianchi, et al.

    This thorough review cites 266 references to support a wealth of information regarding the role of testosterone in neuroprotection, neuroinflammation, and neurodegeneration.

    T improves the survival of human neurons and astrocytes, acting directly on the mitochondrial membrane, inhibiting the generation of reactive oxygen and nitrogen species, as well as sirtuin-1 expression. Conversely, its absence may contribute to neurodegenerative processes, as observed in animal models of PD and AD, and may decrease the density of spinal synapses in the hippocampus. These pathological effects were reversed following treatment with T or DHT; 17β-estradiol, likely, partially mediates these effects.

Dehydroepiandrosterone (DHEA)

DHEA, produced by the adrenal glands, ovaries, and brain, converts into hormones such as estrogen, testosterone, and cortisol, which influence various physiological processes like sleep, memory, and stress response.

DHEA's conversion to cholesterol regulation may help manage PD symptoms.

Blood-Brain Barrier (BBB)

DHEA is fat-soluble, allowing it to cross the BBB easily, and is available as a dietary supplement.

Hormonal Effects in Women

IGF-I Levels

A 2020 review concluded that estrogen, particularly in women, may help PD by increasing IGF-I levels and activating its signaling pathways, possibly inhibiting aggregation and fibrillization of α‐synuclein. Another 2020 review found that DHEA supplementation may raise IGF-I levels in women and older adults, which could benefit women in early menopause. Castilla-Cortázar, Xie

Testosterone and Estradiol Levels

A 2021 meta-analysis found that DHEA administration significantly increased testosterone levels and decreased BMI in elderly women, suggesting its hormonal effects. Y. Hu

Another 2021 meta-analysis found that postmenopausal women 60 years and above on 50 mg/day DHEA for at least 26 weeks had a more pronounced elevation of the circulating estradiol levels. Y. Zhu

A 2016 review found a positive correlation between DHEA-S levels and global cognition in both sexes. DHEA-S correlated with working memory, attention, and verbal fluency in women, possibly due to its effects on menopausal cognitive decline. DHEA supplementation increases DHEA-S levels, so it can be expected to have these effects. K. Menezes, S. Vale

Contradicting Symptomatic Evidence

A 2006 Cochrane study found no improvement in memory or cognitive function in non-demented older adults from DHEA supplements. Subsequent studies, including those mentioned above, however, have shown more promising results. J. Evans

Osteoblast Stimulation

A second mechanistic action of DHEA involves its effects on the bone-brain axis. As discussed in the section on IGF-I levels, DHEA's metabolism into estradiol (E2) and other hormones may influence osteoblasts and chondrocytes, contributing to its overall effects.

A 2020 study found that DHEA improved UPDRS scores in MPTP monkeys, a model of PD, indicating potential benefits for PD management. Bélanger

These results may be partly explained by DHEA signaling osteoblasts and chondrocytes directly and through its metabolites, including E2 and dihydrotestosterone (DHT). Osteoblast stimulation increases osteocalcin levels, which may affect the bone-brain axis and enhance cognitive function. D. Kirby

Osteocalcin promotes spatial learning and memory and prevents anxiety-like behavior. This complex interplay between the bones and the central nervous system, influencing each other's function and behavior, is elaborated on under the section on K2 supplementation and elsewhere in the document.

Supplementation

Supplementing with 50-100 mg DHEA may alleviate age-related hormonal declines, improving bone density (especially in older women), skin aging, and mild to moderate depression. It may also help manage menopausal symptoms by raising estradiol levels. Though DHEA was once thought to increase breast cancer risk, recent evidence suggests it may actually inhibit breast cancer cell proliferation and migration. Consult a knowledgeable provider to discuss DHEA supplementation. Colín-Val

Safer HRT Alternative

DHEA and pregnenolone can also be used independently of HRT, which may present a lower risk of cancer compared to steroid hormone therapies.

References

1. Impact of dehydroepianrosterone (DHEA) supplementation on serum levels of insulin-like growth factor 1 (IGF-1): A dose-response meta-analysis of randomized controlled trials, Min Xie, et al.

   Despite the misspelling in the title, dehydroepianrosterone (WRONG), this study shows DHEA supplementation may increase serum IGF-I levels especially in women and older subjects.

2. Is insulin-like growth factor-1 involved in Parkinson’s disease development?, Inma Castilla-Cortázar, et al.
3. DHEA improves symptomatic treatment of moderately and severely impaired MPTP monkeys, Nancy Bélanger, et al.
4. Dehydroepiandrosterone (DHEA) supplementation for cognitive function in healthy elderly people, John Grimley Evans, et al.
5. Impact of dehydroepiandrosterone (DHEA) supplementation on testosterone concentrations and BMI in elderly women: A meta-analysis of randomized controlled trials, Ying Hu, et al.
6. The effect of dehydroepiandrosterone (DHEA) supplementation on estradiol levels in women: A dose-response and meta-analysis of randomized clinical trials, Yan Zhu, et al.
7. Dehydroepiandrosterone, Its Sulfate and Cognitive Functions, Karina Junqueira de Menezes, et al.
8. The Relationship between Dehydroepiandrosterone (DHEA), Working Memory and Distraction – A Behavioral and Electrophysiological Approach, Sónia do Vale, et al.
9. DHEA in bone: the role in osteoporosis and fracture healing, David J Kirby, et al.
10. DHEA inhibits proliferation, migration and alters mesenchymal-epithelial transition proteins through the PI3K/Akt pathway in MDA-MB-231 cells, Zaira Colín-Val, et al.

Pregnenolone

Pregnenolone is a neurosteroid and precursor to various hormones, including cortisol, DHEA, and progesterone. It has been explored as a potential candidate for hormone replacement therapy (HRT) in female reproductive disorders targeting estrogen receptor beta (ERβ) and may improve cognitive function where it has been impaired by elevated blood glucose (in diabetics). Shin

A 2022 study on a rodent model of insulin resistance concluded that a short-term diet high in processed foods, refined sugars, and unhealthy fats impairs memory, but this is reversible by pregnenolone, which mediates memory function via the hippocampus. Ramírez

Cholesterol is converted into pregnenolone. Pregnenolone can then be converted into progesterone or DHEA, and DHEA can further be converted into androgens and estrogens.

Pregnenolone and DRT

Pregnenolone reduces levodopa-induced dyskinesias (LIDs) without compromising L-DOPA's motor benefits. The mechanism could be DHEA-S or PREG-S agonism on NMDA receptors to exert an antagonistic activity on GABA-A receptors. Corsi

Pregnenolone Dosage

Pregnenolone is available as a dietary supplement and is typically safe in doses ranging from 10 to 50 mg per day.

Pregnenolone is fat-soluble and crosses the BBB. Once in the brain, pregnenolone can be converted into other neurosteroids, such as allopregnanolone, which have various effects on neuronal function and behavior.

Several clinical studies have investigated pregnenolone as a treatment for Parkinson’s disease. One study found that pregnenolone dose-dependently countered LIDs without affecting L-DOPA-induced motor improvements.

References

1. Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders, Sara Ramírez, et al.
2. Pregnenolone as a potential candidate for hormone therapy for female reproductive disorders targeting ERβ, Ye Young Shin, et al.

3. A study found that DHEA administration alone improved the mean parkinsonian score in moderately and severely impaired MPTP monkeys, a model of Parkinson’s disease. Pregnenolone for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease, Sara Corsi, et al.

Growth Hormone and Secretagogues

Human growth hormone (GH) stimulates growth, cell repair, and metabolism, and reduces inflammation. Masternak

GH, IGF-1, and MGF

GH increases levels of Insulin-like Growth Factor 1 (IGF-1), which can then be further metabolized into Mechano Growth Factor (MGF) in response to mechanical stimuli, such as intense exercise. Mechano-growth factor is neuroprotective. (GH stimulates the liver to produce IGF-1. IGF-1 is further metabolized into MGF through alternative splicing of IGF-1 mRNA by lactate and other stress signals.)

Brain Waste Management System (BWMS), Collagen, and IGF-I

IGF-1 promotes collagen synthesis by fibroblasts, which strengthens connective tissues, including those in the BBB and choroid plexus. Increased collagen production enhances the function and structural integrity of the brain waste management system (BWMS), reducing permeability and improving waste clearance through several coordinated mechanisms of the BWMS.

IGF-1 increases the synthesis of ECM proteins beyond collagen, such as proteoglycans and glycosaminoglycans, which contribute to the structural framework of tissues.

Growth and repair of the choroid plexus, where CSF is produced, improve its functioning. Increased CSF production enhances waste clearance by increasing the volume of fluid available to remove metabolic byproducts and harmful substances from the brain.

Lower inflammation may improve the function of the choroid plexus and its ability to produce CSF.

Gh Secretagogues CJC-1295 and Tesamorelin

Growth hormone secretagogues, such as tesamorelin and CJC-1295, are peptides that stimulate the secretion of GH. The increase in GH levels from these secretagogues is generally less pronounced compared to direct GH injections.

Side Effects

Blood glucose control and hyperglycemia are known side effects of growth hormone. Potential side effects at higher doses may include joint pain, insulin resistance, and swelling. It is important to monitor for these effects and consult a healthcare provider. Sigalos

1. Growth hormone, inflammation and aging, Michal M. Masternak and Andrzej Bartke.
2. Minireview: Mechano-Growth Factor: A Putative Product of IGF-I Gene Expression Involved in Tissue Repair and Regeneration, Ronald W. Matheny, et al.
3. The Safety and Efficacy of Growth Hormone Secretagogues, John T. Sigalos and Alexander W. Pastuszak.

Peptides

GlyNAC (Glycine-N-Acetyl Cysteine)

GlyNAC (Glycine-N-Acetyl Cysteine) is a combination of two separate amino acids, glycine and N-acetylcysteine (NAC), administered together in a 1:1 ratio to promote glutathione synthesis.

GlyNAC supplementation improves glutathione levels and mitochondrial function, reduces inflammation, supports neurotrophic factor expression, and improves cognitive function. g-lizzo], P. Kumar 2, p-kumar_r-sekhar

Supplementation

GlyNAC supplementation up to 7.2g per day is safe and well tolerated in older adults. GlyNAC is best taken at night.

GlyNAC improves sleep quality. 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. 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 OxS, mitochondrial dysfunction, abnormal mitophagy and autophagy, inflammation, impaired glucose transport/uptake, elevated genomic damage, and reversing the decline in brain neurotrophic growth factors.

4. 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 increases 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.

Raw Cacao

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

Health Benefits

Cacao's flavonoids improve blood flow, lower blood pressure, and reduce heart disease risk. Increased brain blood flow and theobromine noticeably improve cognitive function. Anandamide in cacao helps regulate mood and alleviate depression. Flavonoids reduce chronic inflammation and overall disease risk. Additionally, cacao provides magnesium, manganese, and phosphorus for bone health, and about 20% fiber to support digestion and satiety.

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. 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.
2. 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

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 the 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

1. Role of Dietary Supplements in the Management of Parkinson’s Disease

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

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 of 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.

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

Matcha is a finely ground Japanese green tea powder rich in bioactives, including lutein, vitamin K, and polyphenols, particularly catechins like epigallocatechin gallate (EGCG). 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.

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. Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases, Qian Yi Eng, et al.
5. 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.
6. remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity, Jan Bieschke, et al.
7. 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 in PD

Ginseng exhibits improved motor function and increased dopamine levels in PD models. These neuroprotective effects are explained by reduced oxidative stress, inflammation, and neuronal apoptosis, with no significant toxicity observed in most studies. He, 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 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. Effect of ginsenoside-Rg1 on experimental Parkinson's disease: A systematic review and meta-analysis of animal studies, Yi-Bo He, et al.
3. A Preclinical Systematic Review of Ginsenoside-Rg1 in Experimental Parkinson's Disease, Liang Song, et al.
4. 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.
5. Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson's disease, Jackalina Van Kampen, et al.
6. 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.
7. 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.
8. Ginsenoside Rb1 inhibits fibrillation and toxicity of α-synuclein and disaggregates preformed fibrils., Mustafa T. Ardah, et al.
9. The bioavailability of red ginseng extract fermented by Phellinus linteus, Jae Sik Ryu, et al.
10. Functional compounds of ginseng and ginseng-containing medicine for treating cardiovascular diseases, Lanchun Liu, 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 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 crucial 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	Neuroprotective, 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.

Melatonin directly scavenges free radicals, reducing the oxidative burden on cells and allowing antioxidant enzymes to function more efficiently.

Melatonin receptors MT1 and MT2 in the substantia nigra are reduced in PD patients. Supplementing melatonin helps amend this deficit.

Melatonin's neuroprotective effects, bolstered by its anti-inflammatory effects, may contribute to the preservation of MT1 and MT2 receptors and contribute to neuroprotection.

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 has 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.

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

Melatonin References

1. Melatonin as a pharmacological agent against neuronal loss in experimental models of Huntington's disease, Alzheimer's disease and parkinsonism

   Melatonin easily crosses the BBB and stimulates a variety of antioxidative enzymes including superoxide dismutase, glutathione peroxidase and glutathione reductase.

2. Role of Melatonin in Neurodegenerative Diseases

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

3. Superoxide Dismutase Activity in Early and Advanced Parkinson's Disease

   A defect in SOD activity develops over time in PD.

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

   “Superoxide dismutase (SOD) is one of the most important antioxidant enzymes both inside and outside cell membranes, and it catalyzes the dismutation of superoxide radicals (O2−) to hydrogen peroxide (H2O2), which is converted to water and oxygen by catalase and glutathione peroxidase.”

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.

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 essential 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 inhibits neuroinflammation by inhibiting ROS and raising glutathione levels. H.J. Lee

DHA in Parkinson's Disease

Daily DHA has been shown to protect against core symptoms of PD in rodents, including deficits in postural stability, gait integrity, and dopamine neurochemistry in motor areas of the striatum. N.M. Chitre

DHA exhibits a neuroprotective dose-dependent response. Y.P. Zhang

DHA crosses the BBB in passive diffusion. This means that relatively high plasma levels of DHA are needed to raise brain DHA levels. When plasma DHA levels increased by 200%, CSF DHA increased by only 28%. I.C. Arellanes

Side Effects

Gastric tolerance between individuals varies. Start at 2 grams and work upwards from there. Spread consumption over time.

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

Cholinergic supplementation has been shown to improves 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, enhancing neurotransmitter synthesis, and promoting neuroprotection. This helps sustain cognitive function and neuronal survival, particularly relevant for managing neurodegenerative conditions like PD.

Given the interdependence between the cholinergic and dopaminergic systems, this section focuses on cholinergic supplements uridine monophosphate (UMP), CDP-Choline, alpha-GPC, and phosphatidylserine (PS).

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 the symptoms of PD.

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

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.

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.

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. 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)

Vitamin B6, also known as pyridoxine, is neuroprotective, and is used in neurotransmitters synthesis, glutamatergic system regulation, and nervous system balance and maintenance.

Vitamin B6 is necessary for dopamine biosynthesis and antioxidant properties. However, high doses of vitamin B6 can cause peripheral neuropathy, and it is essential to consume it as part of a balanced diet and consult with a healthcare professional before taking supplements.

Vitamin B6 helps in reducing the side effects of dopaminergic treatments,

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 involved in energy metabolism, DNA repair, and cell signaling.

NAD+ reduces oxidative stress (including in the brain). This promotes recovery on a cellular level and leads to better energy metabolism, neuroprotection, mitochondrial function, and DNA repair.

NAD+ affects macrophages to reduce the production of pro-inflammatory cytokines and increase the production of anti-inflammatory cytokines.

NAD+ promotes mitophagy, leading to mitogenesis. This promotes neuronal survival and function and decreases ROS. Lower ROS levels reduce oxidative stress, which can prevent the misfolding and aggregation of α-synuclein.

Declining NAD+ Levels

Declining NAD+ levels contribute to reduced mitochondrial function and impaired cellular energy metabolism in neurons, making them more susceptible to oxidative damage and degeneration, particularly in PD, necessitating intervention.

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 improved motor symptoms.

NAD+ is essential for mitochondrial function which is significant in the pathogenesis of Parkinson's disease.

NAD Precursors

Supplementation with NAD precursors NMN, NR, and niacin, increases cellular levels of NAD+ (nicotinamide adenine dinucleotide). Among these, NMN appears to be the safest, best-tolerated, and most effective in increasing NAD+ production. This is because NMN converts to NAD+ more directly than the other precursors.

Niacin increases NAD+ levels but through a different metabolic pathway than 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. Nicotinamide adenine dinucleotide (NADH)—a new therapeutic approach to Parkinson's disease.
2. 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.

3. 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.

4. 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.

5. A Case Report

   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.

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

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

Resveratrol has displayed potent neuroprotective efficacy in several PD animal models.

How it works:

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.

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. Brain. On. Fire | The Science of Parkinson’s. (this article covers other published research on compounds with inhibitory activities on components of the NLRP3 inflammasome pathway, including EGCG, Curcumin, Sulforaphane, and Quercetin)
2. Resveratrol in Rodent Models of Parkinson's Disease: A Systematic Review of Experimental Studies