Over the past decade a number of over-the-counter (OTC) supplements and prescription drugs have been reported to slow down progression of impairment in animal models of Huntington's disease (HD). Whether Huntington's people "should" take supplements for potential human benefit is unknown. This author's opinion has evolved over the years and I am now more skeptical about using mouse model results than when we initiated the HDDW trials. What follows will be a supplement update.
But -- to keep this discussion in perspective -- it is much more likely that a healthy life style will give greater benefit than any present supplement.
What is a supplement? Nutritional supplements include vitamins, minerals, herbs, products derived from plants and animals, or natural foods. They are appealing because they can be obtained over-the-counter. Those studied in HD include:
Coenzyme Q-10 is a molecule that that serves both as part of the electron transport energy chain in mitochondria and as antioxidant. Benefit has been shown in several HD mouse models, but not in all. A 13% benefit (considered non-significant) was seen in CARE-HD, the human trial using 600 mg/day. The dosage of 2400 mg/day in the ongoing 2-CARE human trial is much closer to the 2% used in successful mouse studies. The higher 6% dose was toxic in mice. CARE-HD, with enrollment almost complete is slated to last 5 years, though we may have results earlier. A large Phase 3 trial of CoQ-10 for Parkinson's disease was recently halted due to lack of efficacy.
Creatine is an organic acid necessary for respiratory energy production. Benefit has been shown in several HD mouse models, but not all. The dosage being used in the CREST-E human clinical trial is 40 mg/day. Creatine supplementation has been shown to increase creatine levels in brain and normalize CK-BB, and important brain energy enzyme in model mice [Kim J 2010]. Though there have been positive reports from Phase 2 study in humans, this information has not been published in a peer-reviewed scientific journal. A Phase 3 trial of creatine for amyotrophic lateral sclerosis (ALS) failed to show benefit.
Trehalose is a disaccharide sugar that is classified as a food product. This molecule stabilizes membranes, decreases inflammatory response, helps maintain protein structure, and increases autophogy, which is one of the cellular processes to destroy the mutant protein. Benefit has been shown in both rat and mouse models of HD, as well as mouse models of other neurodegenerative diseases. Though trehalose has FDA-approved human medical uses, and it appeared to be helpful in the small HDDW observational study, it has not been been further studied in HD people.
EGCG (epigallocatechin 3-gallate) is an antioxidant found in green tea. There has been benefit shown in cell and fly models [Ehrnhoefer DE 2006], but there are no reports of mouse model studies. A human trial of this agent for HD is in process in Germany.
Cannabinoids include several different chemical compounds. In addition to medical marijuana, two are presently approved for medical use: Marinol for control of nausea, and appetite stimulation in cancer and AIDS, and Salivex for treatment of neuropathic pain and spasticity associated with Multiple Sclerosis (approved in Canada, UK, Spain, New Zealand, but not in the U.S.). Has been studied in the toxin mouse model [Sagredo O 2011]. And is presently in human clinical trial for HD in Spain.
Nicotinomide is derived from Vitamin B3 (Niacin). This has been shown to be helpful in a mouse model [Hathorn T 2011]. Nicotinomide, unlike Niacin, does not cause flushing. In the mouse model this agent increases levels of protective BDNF and PGC-1a. The dosage used in mice translates to about 3.5 gm/day human equivalent. This agent has not had human study in HD, but has an extensive safety record at these doses when used for other medical indication.
Melatonin a peptide hormone that is involved in sleep and metabolism regulation. Benefit in mouse model of HD used doses several hundred times higher than that used for sleep [Wang X 2011]. Though it is being studied in other neurodegenerative diseases, there are no human studies for HD.
Selenium is a metal antioxidant. Levels of this metal are reported to be low in brains of HD individuals. Though these results have not been published, benefit was reported in a mouse model study reported at the 2012 CHDI meeting. Dosage used in this mouse study translates to about 100 mcg, or twice the daily RDA recommendation.
Vitamin E at high dose showed no benefit in a 1995 human trial for HD [Peyser CE 1995].
Vitamin C study in model mice suggested benefit only at doses not tolerated by people [Rebec GV 2006].
Resveratrol is a phenol molecule found in grapes. There has been only negative study in mouse models of HD [Pasinetti GM 2011].
Author's comments Confess that I am more skeptical about the importance of mouse model results than when HDDW initiated our observational trials about 8 years ago. Why? Because I better understand the limitations of mouse studies. The validity of reported supplement or drug results in HD models might be questioned as it was in ALS models [Scott S 2008]. Unlike the rigorous procedures used in human clinical trials: adequate numbers, double blinded controls, uniformity of testing procedures across different sites, etc. had not been applied in the research community's mouse model study of ALS or HD. So we probably can't rely on many of these mouse study results any more than we can rely on results from a small poor quality human clinical trial.
My present opinions regarding supplements?
- Antioxidants: Doses 2 or 3 times higher than the RDA (recommended daily dose) are safe. But stay away from very high doses unless you are in a trial. There is laboratory evidence that some high dose antioxidants decrease autophagy [Underwood BR 2010], which could worsen HD.
- CoQ-10: Because there is a positive signal and no safety issues seen in the earlier CoQ-10 trial, this agent is a good option. However, I'd stick with either the 600 mg dose used in that trial or at most double it. The downside is that this agent is expensive.
- Creatine: This one is a toss-up. Publication of Phase 2 data -- if positive -- would lead to a more favorable opinion. If used, I favor a 20 gm dose range. Continuous use of this agent is safe only with doctor supervision. It has the advantage of lower cost than CoQ-10.
- Trehalose: My bias is to use it. It is safe, non-expensive and has membrane stabilizing and anti-inflammatory effect, and if FDA approved for other medical conditions.
The use of supplements is appealing because it gives hope, and a feeling of self-control. And it is a lot easier than maintaining the components of a healthy life style. But remember they are probably less likely to be therapeutic. Until human trials tell us otherwise, the best course to follow is to seek adequate treatment for HD symptoms from an HD knowledgeable physician, and to work hard every day on healthy life style factors.
Kim J, Amante DJ, Moody JP, Edgerly CK, Bordiuk OL, Smith K, Matson SA, Matson WR, Scherzer CR, Rosas HD, Hersch SM, Ferrante RJ. Reduced creatine kinase as a central and peripheral biomarker in Huntington's disease. Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):673-81. doi: 10.1016/j.bbadis.2010.05.001. Epub 2010 May 9. PubMed abstract
Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet. 2006 Sep 15;15(18):2743-51. Epub 2006 Aug 7. PubMed abstract
Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernández-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. J Neurosci Res. 2011 Sep;89(9):1509-18. doi: 10.1002/jnr.22682. Epub 2011 Jun 14. PubMed abstract
Hathorn T, Snyder-Keller A, Messer A. Nicotinamide improves motor deficits and upregulates PGC-1α and BDNF gene expression in a mouse model of Huntington's disease. Neurobiol Dis. 2011 Jan;41(1):43-50. doi: 10.1016/j.nbd.2010.08.017. Epub 2010 Aug 22. PubMed abstract
Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, Friedlander RM. The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci. 2011 Oct 12;31(41):14496-507. doi: 10.1523/JNEUROSCI.3059-11.2011. PubMed abstract
Peyser CE, Folstein M, Chase GA, Starkstein S, Brandt J, Cockrell JR, Bylsma F, Coyle JT, McHugh PR, Folstein SE. Trial of d-alpha-tocopherol in Huntington's disease. Am J Psychiatry. 1995 Dec;152(12):1771-5. PubMed abstract
Rebec GV, Conroy SK, Barton SJ. Hyperactive striatal neurons in symptomatic Huntington R6/2 mice: variations with behavioral state and repeated ascorbate treatment. Neuroscience. 2006;137(1):327-36. Epub 2005 Oct 28. PubMed abstract
Pasinetti GM, Wang J, Marambaud P, Ferruzzi M, Gregor P, Knable LA, Ho L. Neuroprotective and metabolic effects of resveratrol: therapeutic implications for Huntington's disease and other neurodegenerative disorders. Exp Neurol. 2011 Nov;232(1):1-6. doi: 10.1016/j.expneurol.2011.08.014. Epub 2011 Aug 30. PubMed abstract
Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. 2008;9(1):4-15. doi: 10.1080/17482960701856300. PubMed abstract
Underwood BR, Imarisio S, Fleming A, Rose C, Krishna G, Heard P, Quick M, Korolchuk VI, Renna M, Sarkar S, García-Arencibia M, O'Kane CJ, Murphy MP, Rubinsztein DC. Antioxidants can inhibit basal autophagy and enhance neurodegeneration in models of polyglutamine disease. Hum Mol Genet. 2010 Sep 1;19(17):3413-29. doi: 10.1093/hmg/ddq253. Epub 2010 Jun 21. PubMed abstract