ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

ALSUntangled reviews alternative and off-label treatments (AOTs) for people with ALS (PALS). Here we evaluate ‘Basis’ therapy for ALS in response to 148 requests (1). As with all our previous revie...

Accilion is a topical mineral cream advertised by Advanced Mineral Compounds, LLC (AMC, 2). It is one of several products with different names and websites (Table I) that trace their origin to a botanist named John Wayne Kennedy (20) and his patent entitled ‘Bioavailable minerals for plant health’ (19). Three of these products are topical mineral creams while a fourth is a mineral supplement marketed to be sprayed on agricultural crops to promote disease resistance and improve growth. These products appear to have similar ingredients and similar proposed mechanisms, and nearly identical description by which they claim to distinguish themselves from other mineral compounds (Table I). A representative from AMC has told us that these products are different in important ways including ‘‘zinc/copper ratios’’ and ‘‘redox’’, that there is a legal dispute underway between the current owners, and that ‘‘efforts to have these compounds independently assessed and thoroughly verified are now routinely obstructed’’ (21). Interestingly, the same cancer-patient testimonials appear for three of these products and the same ALS-patient testimonial appears for two of them (Table I).

Genervon makes several claims on its website (3) regarding possible mechanisms of GM604 without any supporting data or references. Multiple members of ALSUntangled contacted Genervon by phone and emails in the hope of establishing a dialogue that would allow us to eventually better understand this and several other issues described below; unfortunately, our requests were either never answered (4) or were answered along with the following statement, which prevents us from sharing: ‘This email is sent on behalf of Genervon Biopharmaceuticals, LLC. It may be privileged and contains confidential information intended only for the use of the recipient(s) named above. Use by anyone else is strictly prohibited’ (5). PubMed searches of GM6 and GM604 identified only a single possibly relevant publication (2). In this study, GM604 or vehicle were administered to mice following an experimentally induced stroke and reperfusion. Treatment with GM604 was associated with lower markers of inflammation and apoptosis, reduced stroke size, and improved behavioral outcomes relative to treatment with vehicle. It is not clear that recovery from stroke bears any similarity to neuroprotection in ALS, so this paper cannot be relied upon to provide foundation for a relevant ALS mechanism. This study was funded by Genervon, and one of the authors of this paper is a member of the Genervon leadership team (6), which creates a potential conflict of interest. There may be other unpublished mechanistic data on GM604. The paper on GM604 (2) states ‘Studies with the synthesized GM6 also demonstrated similar trophic effects in a transected femoral nerve rat model. In a zebrafish bioassay, GM6 protected the organism from L-2-hydroxyglutaric acid (LGA), induced oxidative stress and apoptosis in the CNS, and reduced apoptosis by 85% in the midbrain’. However, the only references we can find to support this work are patent applications. Based on all this, ALSUntangled assigns a TOE ‘Mechanism’ grade of D. It should be noted here that various other neurotrophic factors have been tested in ALS, including IGF1 (7), CNTF (8) and BDNF (9)

HBOT involves treating patients with 100% oxygen at pressures several times higher than atmospheric pressure. This is accomplished by placing patients in a sealed, pressurized chamber (2). HBOT was initially used to treat decompression sickness after diving. There are currently 14 approved, evidencebased indications for HBOT including treatment of air embolism, carbon monoxide poisoning, nonhealing wounds (such as diabetic wounds), burns, gangrene, brain abscess, and radiation injury (3). Numerous websites advertise off-label HBOT for a wide variety of other conditions including multiple sclerosis, dementia, stroke and ALS (4,5). Metaanalyses conclude that there is insufficient evidence to support the use of HBOT in multiple sclerosis (6), dementia (7) and stroke (8). The FDA has warned patients against such off-label use (9).

ISSN 2167-8421 print/ISSN 2167-9223 online © 2015 Informa Healthcare DOI: 10.3109/21678421.2015.1024571 into the extremity muscles and the spinal fl uid of the person who donated the fat. No safety or effi cacy outcome measures appear to have been objectively or systematically monitored. This description is similar to what two independent groups reported in their own reviews of PSC in early 2013 (9,10). Over the remainder of 2013, Williams apparently changed his protocol (7). On 20 August 2013 he told us that he had started to use umbilical-derived cells from donors without ALS, was working with “ gene therapy ” , and was testing image guided injections into the spinal cord and nerve roots (7). Our email requests for additional details on these changes have largely gone unanswered (7). With regard to the gene therapy, the PSC website notes a partnership with a company called Neuralgene (6). The Neuralgene website states that they use a virus (AAV) to deliver various genes to various tissues for patients with different diseases (11). For ALS, the website says: ‘ The AAV9 viral vector delivers multiple genes, which include Factor H (a regulator of complement activity), neural growth factors and regulators of TDP-43, to the neural cells ’ (12). The status of Neuralgene ’ s ALS product development program is unclear; animal studies of this gene therapy were reported to begin in May 2013 (12) but the website also claims: ‘ Neuralgene has initiated initial human testing in it ’ s gene therapy for ALS ’ (11). Typically, animal studies would be completed before human testing begins. A PubMed search identifi ed no published studies on Neuralgene protocols in animals or humans and there are no Neuralgene trials listed on ClinicalTrials.gov. Williams is listed as the CEO and director of R & D for Neuralgene (13). On 24 September 2014 Williams wrote: “ We are not doing much with stem cells anymore, mostly just a little orthopedic work ... .we tried aav, vegf, gdnf, igf2, but nothing exciting ” (7). ALSUntangled has been unable to obtain any additional details. According to the PSC website (6) and an email from Williams dated 7 October 2014, some form of MSC treatment is still being offered to patients with ALS (7). ALSUntangled reviews alternative and off-label treatments for patients with ALS (PALS). Here, we examine the treatment offered at Precision Stem Cell, for which we have had more than 1100 requests (1). This is the fi rst review that incorporates our new Table of Evidence (TOE, (2)). Precision Stem Cell (PSC) is a clinic formerly in Gulf Shores, Alabama now in Bogota, Columbia. It is led by Jason Williams, a radiologist (3). He uses imaging techniques such as MRI, CT, fl uoroscopy and ultrasound (4) to insert mesenchymal (meaning loosely packed in a gelatinous ground substance such as fat, umbilical cord or bone marrow) stem cells (MSCs) into patients with various ailments. This is primarily marketed toward athletes as a way to help them recover faster from musculoskeletal injuries (5).

Over the past two decades complementary and alternative medicine treatments relying on dubious science have been embraced by medical academia. Despite low to nonexistent prior probability that testing these treatments in randomized clinical trials (RCTs) will be successful, RCTs of these modalities have proliferated, consistent with the principles of evidence-based medicine, which underemphasize prior plausibility rooted in science. We examine this phenomenon and argue that what is needed is science-based medicine rather than evidence-based medicine.

The response of Rutten et al. to our recent article [1], in which we contend that it is unscientific and unethical to test highly implausible treatments such as homeopathy and reiki in randomized clinical trials (RCTs), represents a common and misguided complaint by advocates of alternative medicine against interpreting clinical trials through the lens of prior plausibility. It is a complaint that is, from a scientific viewpoint, unjustified and relies on a misunderstanding of the history of science, a straw man characterization of arguments for science-based medicine, and an incorrect interpretation of Bayes’ theorem applied to clinical trials of homeopathy.

Pain is a big problem. If you read about pain management centers, you might think it had been solved. It has not. And when no effective treatment exists for a medical problem, it leads to a tendency to clutch at straws. Research has shown that acupuncture is little more than such a straw.Although it

Course No. 9344 © 2012 The Teaching Company. Professor Steven Novella is an Academic Neurologist at Yale School of Medicine and is a leading force in medical education for patients, the public, medical students, and medical professionals. He earned his M.D. from Georgetown University and completed his residency training at Yale School of Medicine. Dr. Novella is the founder and senior editor of Science-Based Medicine—a popular blog dedicated to promoting the highest standards of science in medical practice. Your D ecptive M nd