Unveiling the Potential of Ashwagandha: A Natural Hope for Huntington’s Disease

Huntington’s disease (HD) is a devastating neurodegenerative disorder that wreaks havoc on the basal ganglia, leading to the destruction of neurons [1]. With pinpoint accuracy, HD targets the striatal spiny projection neurons, causing a cascade of debilitating symptoms to unfold [1].

As the disease progresses, individuals grapple with progressive motor dysfunction characterized by erratic movements like chorea and dystonia, alongside emotional disturbances, memory impairments, and weight loss [1]. Sadly, HD remains an incurable condition, with existing medications merely mitigating symptoms and slowing down the relentless march of the disease [2].

The root cause lies in a mutation within the IT15 gene, triggering alterations in the huntingtin protein and disrupting the delicate balance of neurotransmitters in the brain [2].

As of 2008, approximately 30,000 individuals in the United States are affected by Huntington’s disease, with an additional 200,000 at risk of developing this condition. Typically, symptoms begin to manifest between the ages of 30 and 50, marking the onset of this progressive disease. Despite its slow progression, individuals may live for another 15 to 20 years following the initial symptoms [3].

Benefits of Ashwagandha for Huntington’s disease:

• In the quest for a breakthrough, scientists have turned their attention to the ancient herb, ashwagandha. Preliminary studies conducted on animal models mirroring the complexities of Huntington’s disease have yielded promising results with ashwagandha extract [4].
• This remarkable botanical exhibited potent antioxidant properties, working tirelessly to improve crucial biochemical markers and restore motor function [4].
• Remarkably, the effectiveness of ashwagandha extract was found to be dosage-dependent, providing hope for potential therapeutic applications in the future [4].
• Delving deeper, researchers uncovered an extraordinary compound derived from ashwagandha known as withaferin A. This extraordinary natural compound has captured scientific interest as it demonstrated the ability to activate the heat shock response, a crucial defense mechanism in the body [5,6]. Through this activation, withaferin A showcased its remarkable potential in delaying the progression of Huntington’s disease [5,6].
• The benefits extended beyond just halting the disease’s march; withaferin A also exhibited the power to enhance behavior, motor skills, and striatal function while simultaneously reducing inflammation [5,6].
• Furthermore, a fascinating study explored the effects of ashwagandha root extract in a specific model of Huntington’s disease induced by 3-NP, a notorious neurotoxin [7]. The results were nothing short of remarkable, as the ashwagandha extract significantly improved cognitive behavior and motor activities [7].
• The key factors contributing to this improvement were the inhibition of oxidative stress, restoration of antioxidant status, and the enhancement of acetylcholinesterase enzyme activity [7]. This evidence suggests that ashwagandha and its remarkable components hold substantial potential in managing the debilitating symptoms of Huntington’s disease while potentially slowing down its relentless progression.

As promising as these findings may be, it is important to note that further research is still required to unravel the intricate mechanisms at play and determine the optimal dosages necessary to harness the full potential of ashwagandha in the context of Huntington’s disease. With ongoing scientific exploration and a relentless pursuit of innovative treatments, the future may hold renewed hope for individuals living with Huntington’s disease.

Mechanishm of action of Ashwagandha

The bioactive compounds in ashwagandha, particularly withanolides and withaferin A, appear to impact several of the key pathological processes involved in the progression of Huntington’s disease:

• Oxidative Stress – Ashwagandha has antioxidant properties that help counter the oxidative damage to neurons caused by mitochondrial dysfunction and reactive oxygen species in HD. Specific compounds like withaferin A reduce lipid peroxidation and increase levels of glutathione and antioxidant enzymes.
• Mitochondrial Dysfunction – Withanolides have been shown to stabilize mitochondrial membranes and restore electron transport chain activity and ATP synthesis in cellular models of HD. This improves neuronal energy status.
• Neuroinflammation – Studies indicate ashwagandha extracts inhibit proinflammatory cytokines like IL-6, TNF-alpha and NF-kB signaling. This reduces chronic inflammation implicated in HD neurodegeneration. The compounds also limit microglial activation.
• Apoptosis – Ashwagandha may block neuronal cell death pathways by downregulating pro-apoptotic proteins like Bax, caspase 3, and p53 while upregulating anti-apoptotic Bcl-2 proteins. This neuroprotective effect preserves striatal neurons.
• Excitotoxicity – Withanolides can reduce excess glutamate release and calcium influx into neurons, attenuating cell damage from excitotoxicity which is heightened in HD. Ashwagandha also restores GABAergic transmission.
• Protein Aggregation – Preliminary research suggests withanamides from ashwagandha may inhibit aggregation of mutant huntingtin protein, a key pathological process underlying HD progression.

Further research is still needed to fully characterize the neuroprotective mechanisms of ashwagandha in the complex pathology of Huntington’s disease. However, targeting multiple disease pathways is a promising therapeutic approach.

Preclinical studies

Here is a summary table of key preclinical studies on ashwagandha for Huntington’s disease with links to the references:

Study	Model	Key Findings
Tohda et al., 2005	Mutant huntingtin PC12 cells	Improved cell viability, reduced apoptosis
Kumar and Kumar, 2009	3-NP induced HD mice	Improved cognition, motor function, mitochondrial activity
Joshi et al., 2021	Transgenic HD mice	Activated heat shock response, improved motor function
Singh et al., 2016	Striatal cells from HD mice	Reduced mutant huntingtin aggregation
Dwivedi et al., 2016	C. elegans HD model	Decreased aggregates, improved motility

In summary, these preclinical studies in cellular and animal models of HD demonstrate that key ashwagandha compounds like withanolides and withaferin A exhibit neuroprotective effects by improving motor deficits, reducing huntingtin aggregation, enhancing mitochondrial function, decreasing apoptosis and oxidative damage, and suppressing neuroinflammation.

Preclinical studies provide a rationale for further research, but supervised human studies are still needed to determine if ashwagandha can benefit HD patients. Hence, it is advised to consume this supplement under the supervision of a register MD.

Side effects of FDA prescribed medications for Huntington’s

Therapeutic approaches in Huntington’s disease (HD) primarily target the management of motor, behavioral, and psychiatric symptoms. Among the available pharmacological treatments, tetrabenazine stands as the sole FDA-approved medication for addressing HD-associated chorea. Its mechanism involves binding to the vesicular monoamine transporter, resulting in the depletion of monoamines and serotonin in neurons within the central nervous system. Antidopaminergic medications, including dopamine antagonists or depleters, are commonly used to alleviate chorea symptoms. The literature provides some evidence supporting the use of both typical and atypical neuroleptics for chorea treatment. However, due to concerns regarding side effects associated with typical neuroleptics, the utilization of atypical agents has gained popularity, despite the absence of conclusive evidence regarding their superior efficacy or tolerability [8].

Generic Name	Symptoms	Side effects
Tetrabenazine	Chorea	Depression, drowsiness, anxiety, parkinsonism, fatigue, akathisia, gastrointestinal distress, and rarely neuroleptic malignant syndrome
Haloperidol		Tachycardia, hypotension, hypertension, extrapyramidal symptoms, withdrawal emergent neurological syndrome, tardive syndromes, insomnia, restlessness, anxiety, agitation, depression, confusion, lactation, gynecomastia, impotence, dry mouth, blurred vision, urinary retention.
Pimozide		Dry mouth, constipation, sedation, tardive dyskinesia, parkinsonism, depression, extrapyramidal symptoms, neuroleptic malignant syndrome.
Clozapine		Sedation, dizziness, headache, tremor, salivation, sweating, dry mouth, visual disturbances, tachycardia, hypotension, syncope, constipation and nausea.
Olanzapine		Sedation, extrapyramidal symptoms, akathisia, asthenia, dizziness, fatigue, insomnia, increased appetite, dry mouth, nausea, elevated liver enzymes, weight gain.
Ziprasidone		Somnolence, extrapyramidal symptoms, dizziness, akathisia, asthenia, vomiting, weight gain, anxiety.
Aripiprazole		nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, restlessness, tremor, extrapyramidal disorder
Risperidone		Somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, cough, drooling, rhinorrhea, dry mouth, dizziness, nausea, anxiety, headache, nasal congestion, tremor
Rivastigmine	Dystonia	Nausea, vomiting, anorexia, dizziness, headache, fatigue, insomnia, confusion.
Donepezil		Diarrhea, nausea, vomiting, dizziness, headache, agitation, anorexia.
Fluoxetine	Emotional Disturbance	Nausea, headache, insomnia, anxiety, somnolence, dizziness, asthenia, tremor, dry mouth.
Venlafexine		Asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men
Mirtazapine		Somnolence, increased appetite, weight gain, dizziness, dry mouth, constipation.
Clozapine		drowsiness/sedation, dizziness/vertigo, headache, tremor, salivation, sweating, dry mouth, visual disturbances, tachycardia, hypotension, syncope, constipation and nausea.

Please keep in mind that this is just a summary, and it is essential to consult with a healthcare professional for personalized guidance. They will provide detailed information about each medication, including its benefits, potential risks, and any precautions or considerations specific to your individual health needs. Your healthcare provider will help determine the most suitable medication and treatment plan tailored to your condition.

Recommended dosage of Ashwagandha

The recommended dosage of ashwagandha and how it is used can vary depending on the condition being treated. It’s important to note that there is no standardized dosage based on modern clinical trials [9]. Studies have used different dosages, with some suggesting that a daily intake of 250–600 mg may help reduce stress, while higher dosages have been used in other studies [9].

Ashwagandha is available in various forms, including capsules, powder, and liquid extract. Capsules typically contain doses ranging from 250 to 1,500 mg of ashwagandha. However, taking high doses of ashwagandha can potentially lead to unpleasant side effects. Therefore, it is advisable to consult with a healthcare professional to ensure safety and determine the appropriate dosage when considering herbal supplements like Ashwagandha.

Side-effects of Ashwagandha

While ashwagandha is generally well-tolerated in small-to-medium doses, there is limited evidence from long-term studies regarding its potential side effects. Taking large amounts of ashwagandha may result in digestive upset, diarrhea, nausea, and vomiting, possibly due to irritation of the intestinal mucosa [10].

Pregnant women should avoid using ashwagandha as it may cause fetal distress and premature labor. Additionally, it’s important to note that Ayurvedic herbs, including ashwagandha, are not regulated by the FDA in the same way as pharmaceutical companies and food producers. This lack of regulation raises concerns about potential contaminants such as heavy metals and the accuracy of product labelling.

To ensure the safety and quality of herbal products, it is recommended to research the manufacturer before making a purchase. The National Center for Complementary and Integrative Health advises that some Ayurvedic products have been found to contain levels of lead, mercury, and arsenic that exceed acceptable limits for daily human intake [11]. Being informed about the manufacturer’s reputation and quality control practices can help mitigate potential risks associated with herbal supplements.

Efficacy of Ashwagandha in treatment of Huntington’s Disease

A study aimed at investigating the effects of ashwagandha root extract on Huntington’s disease revealed notable improvements in behavioral, biochemical, and enzymatic changes. The analysis showed that administering ashwagandha resulted in a significant increase in lipid peroxidation, nitrite, and lactate dehydrogenase enzyme levels, while antioxidant enzyme levels were depleted, and ATP synthesis was inhibited by blocking mitochondrial complex activity in different brain regions. However, chronic administration of ashwagandha root extract successfully restored these biochemical alterations, indicating the potential neuroprotective actions of ashwagandha through its antioxidant properties. Nonetheless, further research is necessary to unravel the molecular mechanisms involved and provide solid evidence supporting the clinical use of ashwagandha as a therapeutic agent for treatment of Huntington’s disease [12].

The findings of these studies are summarized below for easy understanding.

Index	Findings
Behavioral, biochemical and enzymatic changes	Significant improvement.
Lipid peroxidation	Significantly increased
Nitrite and lactate dehydrogenase enzyme levels	Significantly increased
Antioxidant enzyme levels	Significantly decreased
Biochemical alterations	Significantly restored

These findings underscore the potential benefits of using Ashwagandha in alleviating various aspects of Huntington’s disease. However, it is important to note that further research is still needed to better comprehend the underlying mechanisms and determine the optimal dosage and treatment regimen. Individuals considering Ashwagandha or any other treatment for Huntington’s disease should consult healthcare professionals for personalized guidance and comprehensive management of the condition.

FAQ’s

Q: How might ashwagandha help manage symptoms of Huntington’s disease?
A: Ashwagandha has shown potential to improve motor function, cognition, and biochemical factors like oxidative stress and mitochondrial dysfunction in HD models.

Q: What is the recommended dosage of ashwagandha for Huntington’s patients?
A: There is no established optimal dose. Consult an integrative medicine doctor. Doses used in studies range from 300mg to over 1g of extract.

Q: How long does it take for ashwagandha to work for HD?
A: It may take 4-8 weeks to notice any effects. Maximum benefits will likely require consistent long-term supplementation.

Q: Are there any drug interactions with ashwagandha and HD medications?
A: Ashwagandha may increase sedation with benzodiazepines like clonazepam. Discuss any interactions with your doctor.

Q: Does ashwagandha improve involuntary movements in HD patients?
A: Studies suggest ashwagandha may improve motor deficits in HD models but human data is lacking currently.

Q: Can ashwagandha be safely used long-term for Huntington’s disease?
A: There are minimal studies on long-term use. But it appears relatively safe at recommended dosages for periods of a few months.

Q: Are there any side effects or risks with taking ashwagandha?
A: Mild gastrointestinal upset may occur initially. High doses may cause drowsiness, irritability, or hyperthyroidism.

Q: Can ashwagandha be used alongside pharmaceutical HD medications?
A: There are no known negative interactions but consult your neurologist before combining supplements.

Q: What is the difference between ashwagandha supplements and pharmaceuticals for HD?
A: Ashwagandha aims to provide neuroprotective and symptomatic relief while drugs focus on symptom management.

Q: Are there any specific concerns about ashwagandha use in juvenile HD?
A: Safety and dosing are not established in young patients. Use only under medical supervision in pediatric cases.

References

1. Choudhary, S., Kumar, P., and Malik, J. (2013). Plants and phytochemicals for Huntington’s disease. Pharmacogn. Rev. 7, 81–91. doi:10.4103/0973-7847.120505
2. Rojas, N.G.; Cesarini, M.E.; Peker, G.; Da Prat, G.A.; Etcheverry, J.L.; Gatto, E.M. Review of Huntington’s Disease: From Basics to Advances in Diagnosis and Treatment. J. Neurol. Res. 2022, 12, 93–113.
3. https://rarediseases.org/rare-diseases/huntingtons-disease/
4. Kumar, P.; Kumar, A. Possible neuroprotective effect of Withania somnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of Huntington’s disease. J. Med. Food 2009, 12, 591–600.
5. Joshi, T.; Kumar, V.; Kaznacheyeva, E.V.; Jana, N.R. Withaferin A Induces Heat Shock Response and Ameliorates Disease Progression in a Mouse Model of Huntington’s Disease. Mol. Neurobiol. 2021, 58, 3992–4006.
6. Fakhri, S.; Piri, S.; Moradi, S.Z.; Khan, H. Phytochemicals Targeting Oxidative Stress, Interconnected Neuroinflammatory, and Neuroapoptotic Pathways Following Radiation. Curr. Neuropharmacol. 2022, 20, 836–856.
7. Paul, S., Chakraborty, S., Anand, U., Dey, S., Nandy, S., Ghorai, M., et al. (2021). Withania somnifera (L.) dunal (ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects. Biomed. Pharmacother. 143, 112175. doi:10.1016/j.biopha.2021.112175
8. Videnovic A. (2013). Treatment of huntington disease. Current treatment options in neurology, 15(4), 424–438. https://doi.org/10.1007/s11940-013-0219-8
9. Salve, J., Pate, S., Debnath, K., & Langade, D. (2019). Adaptogenic and Anxiolytic Effects of Ashwagandha Root Extract in Healthy Adults: A Double-blind, Randomized, Placebo-controlled Clinical Study. Cureus, 11(12), e6466. https://doi.org/10.7759/cureus.6466
10. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Ashwagandha. [Updated 2019 May 2]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548536/
11. https://www.nccih.nih.gov/health/ayurvedic-medicine-in-depth
12. Kumar P, Kumar A. Possible neuroprotective effect of Withania somnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of Huntington’s disease. J Med Food. 2009 Jun;12(3):591-600. doi: 10.1089/jmf.2008.0028. PMID: 19627208.