Ajmandi M, Agah E, Nafissi S, et al. Safety and efficacy of nanocurcumin as add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a pilot randomized clinical trial. Neurotherapeutics. 2018;15(2):430-438.
To determine if the addition of nanocurcumin to riluzole is safe and/or efficacious for treatment of amyotrophic lateral sclerosis (ALS).
Double-blind, randomized, placebo-controlled, parallel-group trial
Participants were women and men aged 18 to 85 with definite or probable ALS based on the El Escorial World Federation criteria for probable or definite ALS and normal renal and liver function tests.1 The trial ran from June 2015 to March 2016.
Participants were randomized to either the nanocurcumin (NC) group (n=27) or the placebo group (n=27). In the NC group 2 patients were lost at 4 and 9 months, respectively, and in the placebo group 3 patients were lost at 6, 9, and 10 months, respectively. There were 7 events total, with 5 deaths in the placebo group and 1 mechanical ventilation dependency in each group. All of these 7 participants had bulbar ALS symptoms at baseline.
Amyotrophic lateral sclerosis is a progressive neurodegenerative condition that should be viewed as a systemic process.
Patients with familial ALS or first-degree relatives with ALS, severe respiratory dysfunction (assisted ventilation >8 h/day), severe renal, liver, or heart dysfunction, prominent cognitive impairment (eg, dementia, major psychiatric disorder), and women who were pregnant or breastfeeding were excluded from the study. All patients were tested for lung function; patients whose tests indicated the need for mechanical ventilation were excluded from the study.
Study Parameters Assessed
Complete blood count (CBC), liver enzymes, blood urea nitrogen (BUN), and creatinine were assessed before the trial started. Liver function tests were performed every 3 months and also when an adverse drug reaction was reported. The ALS Assessment Questionnaire-40, Revised ALS Functional Rating Scale (ALS-RS), manual muscle testing, and nerve conduction velocity testing were performed at baseline and end of study. All participants were contacted at least every 3 months to monitor adverse drug effects, appearance of new symptoms, and survival status.
All patients received 50 mg riluzole 2 times a day during the study. Antacid was prescribed for all patients to avoid gastrointestinal side effects of curcumin. The NC used in the study was SinaCurcumin (IRC:1228225765; marketed by Exir NanoSina, Tehran, Iran), a soft gelatin capsule containing 80 mg curcuminoids (curcumin, desmethoxycurcumin, bisdemethoxycurcumin) in nanomicelles less than 100 nm in diameter. Placebo capsules were provided by the same company and matched for size, shape, odor, and color. The treatment period was 12 months. All participants who had at least 1 dose of their assigned treatment were included in the survival analysis.
Primary Outcome Measure
The primary outcome measure was survival at the end of the study period.
Kaplan-Meier survival curves revealed a significant difference favoring NC vs placebo (P=0.036). Kaplan-Meier survival was also significantly better (P=0.031) for the NC group when there were bulbar symptoms at baseline. The lowest ALS-RS scores did not deteriorate at a significantly different rate between NC and placebo (P=0.297). The rate of progression was less in the NC group, but the difference was not significant (P=0.162). The mean manual muscle testing scores were better in the NC group, but the difference was not significant. The mean rates of decline in compound muscle action potential of the median, ulnar, tibial, and common peroneal nerves did differ significantly between NC and placebo treatments. Disease progression rate was more rapid in patients with bulbar symptoms of ALS at baseline.
Adverse events did not cause patient withdrawal from the study. Reported events included itching by 1 participant in the NC group, increased muscle fasciculation by 1 participant in the NC group, and decrease in lung function tests by 1 participant in the NC group and 1 participant in the placebo group.
Nanocurcumin significantly improved survival over the 12 months of the trial. Other outcomes including ALS-RS score, rate of progression, manual muscle testing, and muscle action potential did not differ significantly between NC and placebo. Nanocurcumin was more effective when bulbar symptoms of ALS were present. Survival was significantly higher in patients with bulbar symptoms who received NC.
ALS, the most common neurodegenerative disease of the motor system, has an incidence rate of 2/100,000 (men: women, 3.0: 2.4).2 It is an upper and lower motor neuron disease involving the cortex, brainstem, and spinal cord and is both progressive and highly lethal.2 ALS is characterized as spinal onset or bulbar onset; bulbar symptoms include dysarthria (93%), dysphagia (86%), and tongue fasciculation (64%) in about 30% of bulbar patients. Bulbar ALS has a worse prognosis than spinal onset, but almost all spinal onset patients progress to bulbar involvement at later stages. Onset of ALS is around age 60, age 50 if inherited, with average survival of 2 to 4 years. Most patients die within 30 months, and only 10% survive 10 years.2 The condition was described in 1824 by Dr Charles Bell, for whom Bell’s palsy is named, although the name ALS was first given by Dr Jean-Martin Charcot in 1874.3 Famous people with ALS include Lou Gehrig and Stephen Hawking, who died March 14, 2018, after having ALS for 55 years.
In ALS glia cells release pro-inflammatory cytokines that lead to neurodegeneration. Within the ALS brain environment (human superoxide dismutase [SOD]1-G93A gene in mice) there is a decrease in NF-kB and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 and an increase in arginase-1 and P2Y12 receptor due to histamine, as well as increases in proinflammatory interleukin (IL)-6, IL-10, CD163 and CD206.4,5 The prevention of histamine synthesis causes the microglia to undergo an increased inflammatory reaction and this facilitates elevation of glutamate.4 The histamine H3 receptor is the last to be affected in the end stages of ALS, which leads to rapid, unimpaired histaminergic deficiency at the level of the hypothalamus, neuron damage from increased excitotoxicity, and end-stage symptoms.4,5 All of this strongly suggests that ALS is a complex systemic disease rather than a disease of only the central nervous system.5
Riluzole is approved for ALS and may slow disease progression. Riluzole is thought to compensate for harmful glutamate levels by enhancing glutamate uptake. It can also reduce anxiety and depression and is dependent on CYP1A2 activity.6,7 Riluzole can extend lifespan by a few months, a modest but significant increase, and can inhibit hypoxia-induced gasping.
Antioxidant treatment with vitamin E and coenzyme Q10 (CoQ10) in animals can slow disease progression.8,9 In a case report, CoQ10 improved hand grip and hand sensation, slowing the rate of progression.10 Vitamin E and vitamin A, as beta carotene, may lower risk but do not improve disease outcome.10 Given that pesticide use, lead exposure, and participation in athletics increase the risk of ALS, antioxidant treatment seems logical but clinical trial results have not been positive.11-15
The most promising herbal formula, known as KCHO-1, consists of extracts of Curcuma longa, Salvia miltiorrhiza, Gastrodia elata, Chaenomeles sinensis, Polygala tenuifolia, Paeonia japonica, Glycyrrhiza uralensis, Atractylodes japonica, and Aconitum carmichaeli extracted in 30% ethanol at 84° to 90° C.16,17 The formula was tested in transgenic mice and reduced oxidative stress, reduced proliferation of microglia but not astrocytes, and alleviated inflammation via NF-KB in microglial cells and via the mitogen-activated protein kinase (MAPK) pathway, prompting the authors to call for human trials.16
The authors of this study reported that the shelf life of the NC nanomicelles was at least 24 months and oral absorption in mice was at least 50 times that of curcumin powder. As with other manufactured curcumin product claims, this needs to be confirmed in an independent study.
Another possible treatment for ALS is EGCG (epigallocatechin-3-gallate). A mouse study using the human SOD1-G93A gene found that more than 2.9 micrograms of EGCG per gram body weight delayed symptom onset, prolonged lifespan, and attenuated disease symptoms.18 It has also been shown to protect motor neurons from glutamate excitotoxicity due to 3-hydroxy-aspartate.19 Quercetin and quercitrin were found to be more effective than EGCG for inhibition of SOD1 associated ALS models.20 A case report of a 78-year-old Caucasian man with monoclonal gammopathy of undetermined significance (MGUS), B12 deficiency, pernicious anemia, and hyperparathyroidism concluded that the gentleman actually had ALS and that B12 would not be therapeutic.21,22
Ginkgo biloba protects mitochondria and reduces oxidative stress.23 In one study, gingko extract EGb761 given to transgenic (SOD1-G93A) mice at 0.022% or 0.045% of the diet was associated with significantly reduced loss of spinal cord anterior horn neurons and improved motor function and survival in male mice, but not in littermate female mice.23 Female mice who received EGb761 lived longer, but not significantly. There was a significant reduction in weight loss in mice of both sexes receiving the extract.23
The relationship between diet and ALS has also been explored. Using the Cancer Prevention Study II, a cohort of over 1 million women and men enrolled in 1982, analysis of data from 1989 to 2002 found that 862 of the participants died from ALS during that time period.24 The strongest inverse association of ALS with diet was chicken consumption (P=0.0006). There was increased risk of ALS with consumption of brown rice/whole wheat/barley (P=0.006) and decaffeinated coffee (P=0.01). The decreased risk associated with consumption of tea (P=0.02) and French fries (P=0.02) was negated after multiple comparisons. The authors called for the inverse association of chicken consumption and ALS to be assessed in future studies.
In a review of 5 cohort studies (Nurses’ Health Study, Health Professionals Follow-up Study, Cancer Prevention Study II, Multiethnic Cohort Study, and the National Institutes of Health AARP Diet and Health Study) involving over 1,010,000 women and men, with a mean follow-up of 18 years, there were 1,279 cases of ALS.25 In these studies, caffeine, coffee, and tea were not associated with ALS risk.25 This contradicts a study in SOD1-G93A mice that found caffeine significantly shortened survival (P=0.01) and advanced the disease process.26
ALS is a progressive neurodegenerative condition that should be viewed as a systemic process. Numerous compounds have been tested in mice (SOD1-G93A), but few have been tested in humans. Several appear worthy of human study, including EGCG, quercetin, Ginkgo biloba, KCHO-1, and perhaps caffeine. In this trial, nanocurcumin combined with riluzole improved survival but not function, and was more effective when the bulbar symptoms were present; however, the dose was small even for a more bioavailable curcumin. Using curcumin that is well-absorbed seems necessary in ALS patients, but in the end, given the eclectic nature of naturopathic medical practice and the complexity of the ALS disease process, effective combinations of herbs, extracts, nutrients, and pharmaceuticals are likely to yield better results.
- Ludolph A, Drory V, Hardiman O, et al. A revision of the El Escorial criteria – 2015. Amyotroph Lateral Scler and Frontotemporal Degener. 2015;16(5-6):291-292.
- Kuhnlein P, Gdynia HJ, Sperfeld AD, et al. Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis. Nature Clin Prac Neuro. 2008;4(7):366-374.
- Rowland LP. How amyotrophic lateral sclerosis got its name: the clinical-pathological genius of Jean-Martin Charcot. Arch Neurol. 2001;58(3):512-515.
- Apolloni S, Fabbrizio P, Amadio S, et al. Histamine regulates the inflammatory profile of SOD1-G93A microglia and the histaminergic system is dysregulated in amyotrophic lateral sclerosis. Front Immunol. 2017;8:1689.
- Kjaeldgaard AL, Pilely K, Olsen KS, et al. Amyotrophic lateral sclerosis: the complement and inflammatory hypothesis [published online ahead of print June 19, 2018]. Mol Immunol.
- Song JH, Juang CS, Nagata K, Yeh JZ, Narahashi T. Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 1997;282(2):707-714.
- Bellingham MC. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther. 2011;17(1):4-31.
- Gurney ME, Cutting FB, Zhai P, et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol. 1996;39(2):147-157.
- Matthews RT, Yang L, Browne S, Baik M, Beal MF. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effect. Proc Nat Acad Sci USA. 1998;95(15):8892-8897.
- Kawasaki T, Singh RB, Germaine C, Halberg F. Effects of coenzyme Q10 administration in amyotrophic lateral sclerosis (ALS). Open Nutraceuticals J. 2012;5:187-192.
- Freedman DM, Kuncl RW, Weinstein SJ, Malila N, Virtamo J, Albanes D. Vitamin E serum levels and controlled supplementation and risk of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(4):246-251.
- Kamel F, Umbach DM, Munsat Tl, Shefner JM, Hu H, Sandler DP. Lead exposure and amyotrophic lateral sclerosis. Epidemiology. 2002;13(3):311-319.
- Johnson FO, Atchison WD. The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. Neurotoxicology. 2009; 30(5):761-765.
- Chio A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain. 2005;128 (Pt 3): 472-476.
- Zarei S, Carr K, Reiley L, et al. A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int. 2015;6:171.
- Lee DS, Ko W, Song BK, et al. The herbal extract KCHO-1 exerts neuroprotective effect by ameliorating stress via heme oxygenase-1 upregulation. Mol Med Rep. 2016;13(6):4911-4919.
- Kook MG, Choi SW, Seo Y, et al. KCHO-1, a novel herbal anti-inflammatory compound, attenuates oxidative stress in an animal model of amyotrophic lateral sclerosis. J Vet Sci. 2017;18(4):487-497.
- Koh SH, Lee SM, Kim HY, et al. The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice. Neurosci Lett. 2006;395(2):103-107.
- Yu J, Jia Y, Guo Y, et al. Epigallocatechin-3-gallate protects motor neurons and regulates glutamate level. FEBS Lett. 2010;584(13):2921-2925.
- Ip P, Sharda PR, Cunningham A, Chakrabartty S, Pande V, Chakrabartty A. Quercitrin and quercetin 3-beta-D-glucoside as chemical chaperones for the A4V SOD1 ALS causing mutant. Protein Eng Des Sel. 2017;30(6):431-440.
- Rison RA, Beydoun SR. Amyotrophic lateral sclerosis-motor neuron disease, monoclonal gammopathy, hyperparathyroidism, and B12 deficiency: case report and review of literature. J Med Case Rep. 2010;4:298.
- Kroliunitskaia T. On the treatment of patients with lateral amyotrophic lateral sclerosis with vitamin B12 [article in Russian]. Zh Nevropatol Psikhiatr Im S S Korsakova. 1959;59:1447-1450.
- Ferrante RJ, Klein AM, Beal MF. Therapeutic efficacy of EGb761 (Ginkgo biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. J Mol Neurosci. 2001;17(1):89-96.
- Morozova N, Weisskopf MG, McCullough ML, et al. Diet and amyotrophic lateral sclerosis. Epidemiology. 2008;19(2):324-337.
- Fondell E, O’Reilly EJ, Fitzgerald KC, et al. Intakes of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis: results of five cohort studies. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):366-371.
- Potenza RL, Armida M, Ferrante A, et al. Effects of chronic caffeine intake in a mouse model of amyotrophic lateral sclerosis. J Neurosci Res. 2013;91(4):585-592.