Als untangled no. 20: the deanna protocol

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2013; Early Online: 1–5 REVIEW ARTICLE
ALS Untangled No. 20: The Deanna Protocol
The Christian Broadcasting Network (CBN) aired a procedures (5), and L-arginine supplementation is story in November 2012 giving anecdotal informa- thought to potentially increase blood fl ow to mus- tion about the ‘ Deanna Protocol ’ , a regimen of nutri- cle during exercise through nitric oxide production tional supplementation that has been proposed as a treatment for amyotrophic lateral sclerosis (ALS) Additional supplements in the Deanna Protocol (1). Vincent Tedone, a retired orthopedic surgeon, include nicotinamide adenine dinucleotide (NADH), created the protocol for his daughter, Deanna, when coenzyme Q10 (CoQ10), and ubiquinol (a CoQ10 she was diagnosed with ALS. Tedone states that the formulation), which are substances that also play a protocol was designed after surveying the literature role in the citric acid cycle. Ibedenone is a synthetic to prevent nerve cells from dying, and he has observed compound that is structurally related to CoQ10 and slowing of disease progression in his daughter. Although he is not the treating physician for any Gamma-aminobutyric acid (GABA) is a natu- patients with ALS, he has disseminated his protocol rally occurring inhibitory neurotransmitter that pos- and reports that other ALS patients have noted slow- sibly is reduced in the motor cortex of patients with ing of disease progression or improvement in symp- ALS compared to normal controls (8). Glutathione toms after initiating this regimen. Here, on behalf of is a tripeptide that can be synthesized in the body patients with ALS who require more information, from amino acids and plays a role as an antioxidant ALSUntangled reviews the evidence for the Deanna Why might the Deanna Protocol work in ALS?
What is the Deanna Protocol?
Some of the supplements in the Deanna Protocol The Deanna Protocol is a collection of commercially are given in hope that they will provide a more available nutritional supplements listed below in effi cient energy source for mitochondria. Previous Table I. The protocol also recommends daily mas- research shows that mitochondrial dysfunction plays sage of extra virgin coconut oil into the muscles an important role in ALS pathophysiology (10). along with oral coconut oil supplementation if toler- Cells extracted from patients with ALS show dec- ated. In addition, Tedone recommends resistance, reased complex 1 activity (11), which contributes to aerobic, stretching, and range of motion exercises. impaired energy production. In cultured neurons According to Tedone and advocates of the pro- treated with drugs that impair complex 1 function, tocol, the crucial supplement in this regimen is the addition of ketone bodies restored complex 1 arginine alpha ketogluturate (AAKG). Alpha keto- function (12). It is possible that supplementation of glutarate (AKG) is produced in the citric acid cycle, ketone bodies or increasing mitochondrial effi ciency Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Downloaded from informahealthcare.com by 72.184.55.20 on 05/07/13 a series of chemical reactions that takes place in by other means could be benefi cial to counteract mitochondria to generate energy by oxidizing fuel the impaired cellular energy production in patients molecules such as amino acids, fatty acids, and car- bohydrates (2). L-arginine is an amino acid that Other supplements in the Deanna Protocol aim plays a role in protein synthesis and serves as a to prevent glutamate excitotoxicity. Excess gluta- precursor for nitric oxide (3). AKG has been used mate causes damage to nerve cells due to calcium as a nutritional supplement based on the belief that dysregulation and repetitive cell fi ring (13). The it can boost protein metabolism and prevent mus- transporter that clears glutamate from motor nerve cle breakdown during exercise (4) or after surgical terminals is depleted in patients with ALS (14). ISSN 2167-8421 print/ISSN 2167-9223 online 2013 Informa Healthcare DOI: 10.3109/21678421.2013.788405 Table I. The original Deanna Protocol, as provided by Tedone. The purpose of each supplement described in the table is according to Tedone and is not based on the evidence provided in this paper. The protocol below has recently been revised to now include additional AKG supplementation hourly while awake. Protects against glutamate excitotoxicity 1 pill daily, one dose contains:1500 mcg of Vitamin B12;300 mcg of Folate;250 mg of Benfotiamine;150 mg of CoQ10;120 mg of R-Lipoic acid;150 mg of Glutathione;300 mg of Acetyl-L-Carnitine;150 mg of PhosphatidylserineNerve metabolism Increases bioavailability of zinc, stabilized Protects against glutamine overstimulation * These supplements are indicated by Tedone as the most important supplements in the protocol. Riluzole, currently the only FDA approved medica- a SOD1-G93A ALS mouse model. The mice are tion to slow the progression of ALS, inhibits gluta- being given AAKG, idebenone, GABA, and R-alpha mate neurotransmission as part of its mechanism of lipoic acid as supplementation to the standard rodent feed, and survival data will be collected. His Additionally, some supplements are recom- group is also studying a ketogenic diet high in mended in the Deanna Protocol to exert antioxidant caprylic acid, capric acid, and omega-3 in the ALS effects. Markers of oxidative damage are elevated in mouse model and is monitoring motor perfor- the brain and spinal cord in patients and animal mance. According to D ’ Agostino, the preliminary models of ALS (16). In some familial cases of ALS, data are encouraging, but experiments are still Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Downloaded from informahealthcare.com by 72.184.55.20 on 05/07/13 impaired copper/zinc superoxide dismutase (SOD1) ongoing and cannot yet be interpreted (18). leads to toxic accumulation of reactive oxygen spe- Additional preclinical data are available regar- cies and free radicals with subsequent death of motor ding ketogenesis and ALS, which may be relevant given the proposed mechanisms of AKG and coco-nut oil in ALS. A small study in the SOD1 mouse model found that mice that were fed a ketogenic What relevant animal data exist for the
diet had improved motor performance and decreased Deanna Protocol?
motor neuron death compared to mice that were Currently, no published studies could be found fed a standard diet (19). However, there was no regarding AKG supplementation and ALS. As difference in survival between the two groups. The mentioned in the CBN story, Dominic D ’ Agostino authors proposed that increasing the availability of and his group at the University of South Florida ketone bodies could allow for more ATP produc- are currently studying the Deanna Protocol in tion, which would counteract the mitochondrial dysfunction seen in SOD1 mice and perhaps in taking the Deanna Protocol, and eight ALS and one PLS patients gave accounts of perceived treatment CoQ10 and creatine showed promise in preclin- effects. One ALS and one PLS patient endorse major ical studies due to their neuroprotective properties effectiveness, one ALS patient reported moderate (20,21); however, clinical trials in patients with ALS effectiveness, two reported slight effectiveness, two showed no benefi t of either supplement compared to reported no effect, and two were unsure. Side-effects placebo (22,23). No signifi cant safety concerns were of diarrhea or upset stomach were described by four identifi ed in patients taking CoQ10 or creatine. patients. All 15 patients have been on the protocol While many preclinical studies implicate glutamate for three months or less, with fi ve patients on the excitotoxicity as a contributing mechanism to ALS protocol for less than one month. Cost is reported and have found benefi ts when anti-glutamaterigic as greater than $ 200 per month by 71% of patients. therapies are used in an animal model (24 – 27), these Patients seen at the Emory ALS center who have fi ndings have not translated into successful therapies elected to try the protocol report that taking only the when studied in human clinical trials. Lithium (28), ceftriaxone (29), memantine (30), lamotrigine (31), $ 150 – 200 per month, while the entire protocol costs and gabapentin (32) all block glutamate excitotoxicity and showed promise in animal studies yet showed no benefi t in ALS human trials. Based on this precedent, Dosing issues
it is necessary to interpret results of ALS animal stud-ies cautiously rather than assume successful transla- From review of patient reports and emails, there appears to be signifi cant variability in the number and brand of supplements being used by those attempting to follow the Deanna Protocol. Supple- What are the effi cacy, safety and cost of the
ment content is known to vary widely across brands Deanna Protocol in human ALS?
(33). Even further variability is introduced by the No data are available regarding the clinical progres- lack of specifi c instructions related to the dosing of sion of Deanna Tedone to either support or refute certain supplements; for example, B-complex and the claims in the CBN story. According to her father Co-Q10 are to be taken at ‘ standard dosage from she was diagnosed by a neurologist but has not been bottle ’ and both exist in a variety of formulations seen in follow-up. The CBN story also mentions an ALS patient who noted improvement in his swal- Where specifi c supplement dosages are provided, lowing and breathing abilities after initiating the it is not clear how these were determined. Dosages Deanna Protocol. Review of his records by the pri- of creatine and CoQ10 in the Deanna Protocol are mary author (CF) indicates that he did have an far lower than the dosages that have failed to pro- objective improvement in vital capacity measure- duce benefi t in human ALS trials (22,23). On the ments after initiating the protocol. However, vari- other hand, dosages of magnesium, zinc, and vita- ability due to technical issues is not unusual and is min D are in excess of daily doses recommended by possible in this scenario. By other objective mea- the Food and Nutrition Board, Institute of Medi- sures, this patient has demonstrated slow progres- sion of disease both before and after treatment with Finally it has not yet been shown that the supple- ments in the Deanna Protocol, used at the recom- At the Duke University ALS Clinic, fi ve patients mended dosages and routes, can produce biologically with ALS have reported trying the Deanna Protocol. meaningful changes in motor neurons or surround- All of these have continued to progress by objective ing cells in the central nervous system. measurements. Only one has had enough measure-ments to calculate slopes of decline in ALSFRS-R Conclusions
and FVC before and during the Deanna Protocol. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Downloaded from informahealthcare.com by 72.184.55.20 on 05/07/13 Before starting, ALSFRS-R decline was 2.0 points Mitochondrial dysfunction, glutamate excitotoxicity, per month; during three months on the Deanna Pro- and oxidative stress have all been implicated in ALS tocol it was 2.3 points per month. Before starting, pathogenesis, and targeting these mechanisms indi- FVC decline was 0.2 liters per month; during three vidually or by a cocktail such as the Deanna Proto- months on the Deanna Protocol it was 0.3 liters per col could play a role in future ALS therapies. However, many of the preclinical and animal studies Several patients have emailed Tedone, describing related to these pathways have not translated into a wide variety of subjective improvements on the successful treatments in patients with ALS. While Deanna Protocol. Records have been requested by there are anecdotal reports of improvements in ALSUntangled in hope of verifying some of these, patients with ALS on the Deanna Protocol, there is but have not yet been received. On the Patients- no convincing objective evidence of benefi t yet. LikeMe website, 14 patients with ALS and one Thus, at this time, ALSUntangled does not recom- patient with primary lateral sclerosis (PLS) reported mend the Deanna Protocol to patients with ALS. Before it can be recommended, a reproducible ver- double-blind, placebo-controlled trial . J Int Soc Sports Nutr. sion of the Deanna Protocol should be shown to infl uence plausible physiologic mechanisms such Vinnars E. Alpha-ketoglutarate preserves protein synthesis as central nervous system ketone bodies, as well as and free glutamine in skeletal muscle after surgery . Surgery. clinically meaningful outcome measures such as Glutamine and arginine: immunonutrients and The ALSUntangled Group currently consists of the following members: Christina Fournier, Richard 7. Carbone C , Pignatello R , Musumeci T , Puglisi G . Chemical Bedlack, Orla Hardiman, Terry Heiman-Patterson, and technological delivery systems for idebenone: a review Laurie Gutmann, Mark Bromberg, Lyle Ostrow, Gregory Carter, Edor Kabashi, Tulio Bertorini, Tahseen Mozaffar, Peter Andersen, Jeff Dietz, Josep Gamez, Mazen Dimachkie, Yunxia Wang, Paul Wicks, gamma-aminobutyric acid in amyotrophic lateral sclerosis . James Heywood, Steven Novella, L. P. Rowland, Erik Pioro, Lisa Kinsley, Kathy Mitchell, Jonathan Glass, Sith Sathornsumetee, Hubert Kwiecinski, Jon Baker, Nazem Atassi, Dallas Forshew, John Ravits, play in a motor neuronal model of amyotrophic lateral scle-rosis reveals altered energy metabolism Robin Conwit, Carlayne Jackson, Alex Sherman, Kate Dalton, Katherine Tindall, Ginna Gonzalez, 10. Martin LJ . Mitochondrial pathobiology in ALS . J Bioenerg Janice Robertson, Larry Phillips, Michael Benatar, Eric Sorenson, Christen Shoesmith, Steven Nash, 11. Swerdlow RH , Parks J , Cassarino D , Trimmer P , Miller S , Nicholas Maragakis, Dan Moore, James Caress, lateral sclerosis . Exp Neurol. 1998 ; 153 : 135 – 42 . Kevin Boylan, Carmel Armon, Megan Grosso, Bonnie Gerecke, Jim Wymer, Bjorn Oskarsson, Robert Bowser, Vivian Drory, Jeremy Shefner, Noah Lechtzin, drial respiration and mitigates features of Parkinson’s dis- Melanie Leitner, Robert Miller, Hiroshi Mitsumoto, ease . J Clin Invest. 2003 ; 112 : 892 – 901 . Todd Levine, James Russell, Khema Sharma, David 13. Redler RL , Dokholyan NV . The complex molecular biology of amyotrophic lateral sclerosis (ALS) . Prog Mol Biol Transl Saperstein, Leo McClusky, Daniel MacGowan, Jonathan Licht, Ashok Verma, Michael Strong, 14. Cleveland DW , Rothstein J . From Charcot to Lou Gehrig: Catherine Lomen-Hoerth, Rup Tandan, Michael deciphering selective motor neuron death in ALS . Nat Rev Rivner, Steve Kolb, Meraida Polak, Stacy Rudnicki, Pamela Kittrell, Muddasir Quereshi, George Sachs, Durrleman S , et al. A confi rmatory dose-ranging study of Gary Pattee, Michael Weiss, John Kissel, Jonathan riluzole in ALS. ALS/Riluzole Study Group-II . Goldstein, Jeffrey Rothstein, Dan Pastula, Gleb Levitsky, Mieko Ogino, Jeffrey Rosenfeld, Efrat 16. Petri S , Korner S , Kiaei M . Nrf2/ARE Signaling Pathway: Carmi, Craig Oster, Paul Barkhaus, Eric Valor. Key Mediator in Oxidative Stress and Potential Therapeutic Note: this paper represents a consensus of those Target in ALS . Neurol Res Int. 2012 ; 2012 : 878030 . 17. Borg J , London J. Copper/zinc superoxide dismutase over- weighing in. The opinions expressed in this paper are expression promotes survival of cortical neurons exposed to not necessarily shared by every investigator in this neurotoxins in vitro . J Neurosci Res. 2002 ; 70 : 180 – 9 . 18. Personal communication with Dominic D’Agostino, Depart- ment of Molecular Pharmacology and Physiology at the University of Southern Florida . Acknowledgement
Suh J , et al. A ketogenic diet as a potential novel therapeutic ALSUntangled is sponsored by the Packard Center intervention in amyotrophic lateral sclerosis . BMC Neurosci. and the Motor Neurone Disease Association. Coenzyme Q10 administration increases brain mitochon- Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Downloaded from informahealthcare.com by 72.184.55.20 on 05/07/13 Declaration of interest: The authors report no
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