The rise and rise of CM-AT for autism

Today's post surrounds a poster presentation delivered at INSAR 2019, the (still) premier international autism conference, albeit not without its battles. The poster was delivered by Heil and colleagues [1] and talks about a compound / preparation that has been discussed a few years back on this blog: CM-AT (see here).

CM-AT is described as a "pancreatic enzyme preparation" with chymotrypsin - a digestive enzyme - seemingly placed quite prominently in its list of ingredients. CM-AT is, from what I understand, something that is still going through the research processes with regards to its use in the context of autism. Heil and colleagues presented data on part of that research agenda, specifically pertinent to ascertaining "whether or not behavior (e.g., symptoms of irritability, hyperactivity) in preschoolers with autism could be improved with CM-AT."

Bearing in mind a conference poster presentation is not necessarily the same as a published peer-reviewed research article, the Heil data was based on the use of a "randomized, placebo-controlled, 12-week clinical trial" methodology where 92 children, aged between 3-5 years, diagnosed with an autism spectrum disorder (ASD) received CM-AT "as granules sprinkled on food" and almost a hundred boys with ASD received a placebo "which consisted of visually identical inert sprinkles." The 'Irritability' scale of the Aberrant Behavior Checklist (ABC) was the primary outcome measure.

Results: "children receiving CM-AT (relative to those receiving placebo) demonstrated significant reductions in Irritability... Hyperactivity... Inappropriate Speech... over the 12 weeks of the trial." Researchers further reported that those children with higher levels of irritability at baseline tended to show a greater positive response than when the participant sample as a whole was analysed.

I think you can perhaps see why these results - preliminary as they are - are worthy blogging material. Irritability, perhaps listed as a 'challenging behaviour' in the context of autism is something that many, many people would love to be able to effectively tackle; if not just because of the impact it can have on those with autism and those around them who have to 'cope' with such behaviours. Indeed, given the other options for managing such behaviour such as the antipsychotic risperidone (see here) and the issues which that drug and its similars can bring (see here), the idea that there may be other, less side-effect heavy options (see here) is definitely something to consider.

I'm hopeful that soon, very soon, I can talk more about CM-AT in the context of irritability and beyond in relation to autism...

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[1] Heil MF. et al. Pancreatic Replacement Therapy with CM-at Is Associated with Reduction in Maladaptive Behaviors in Preschoolers with Autism. INSAR 2019.

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Baclofen is back: "Baclofen as an adjuvant therapy for autism"

"Our data support [the] safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD [autism spectrum disorder]."

So said the findings reported by Seyedeh-Mahsa Mahdavinasab and colleagues [1] talking about the use of baclofen as an add-on medicine in the context of risperidone use in relation to autism. Baclofen by the way, is typically known as "a gamma-aminobutyric acid (GABA) agonist" (binds to the GABA receptors and activates them) which accounts for its use as "a skeletal muscle relaxant" given the inhibitory function of GABA and GABA receptors.

Why the 'baclofen is back' sentiment expressed in the title of this post? Well, a few years back there was some excitement about a compound called STX209 otherwise known as arbaclofen in the context of a genetic condition manifesting autistic signs and symptoms (see here) and autism itself. Arbaclofen is an enantiomer (mirror image in a chemical sense) of baclofen, but unfortunately fell by the wayside after some less than impressive results emerged from clinical trials (see here). Arbaclofen might have been kicked into the long grass for now but baclofen it seems, is still on the autism research agenda...

Researchers report results based on a "10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD." Risperidone is an antipsychotic which is indicated for selective use with children with autism (see here) specifically to treat/manage aggressive and challenging behaviours. They reported that several outcome measures saw a change - a positive change - specifically in relation to hyperactivity behaviours which can often accompany aggression. Importantly, they also noted that during and after 10 weeks of add-on baclofen use, adverse events were reported to be at a minimum.

There is more to do in this area before any sweeping generalisations are made. I personally would like to see more data on potential best- and non-responders in the context that GABA is still a topic of interest to autism research (see here). I know also that some people might be a little put-out by the idea that more medication is added to the lives of young children with autism and worries about how this might impact them in later years. We need a lot more data.

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[1] Mahdavinasab SM. et al. Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry. 2019 Apr 12.

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Probiotics for autism systematically reviewed

"Our review includes two randomized controlled trials, which showed improvement of ASD [autism spectrum disorder] behaviors, and three open trials, all which exhibited a trend of improvement."

So said the findings reported by Jun Liu and colleagues [1] and the results of their "updated systematic review" on the topic of probiotic 'therapy' in the context of behaviour and gastrointestinal (GI) functioning in autism.

The current scientific outlook for probiotic use in the context of autism looked to be pretty good on the basis of the Liu findings. They corroborate quite a few individual study results that have been fodder for this blog (see here and see here) and fit in well with an emerging pattern of research suggesting that the trillions of wee beasties that inhabit the gastrointestinal (GI) tract might be doing a lot more than just helping us digest food (see here and see here).

What else is required? Well Liu et al talk about more "rigorous trials" to answer questions like who on the autism spectrum might be a best responder to this type of intervention and what bacterial species might be most important. I'd also like to see a little more research on the hows-and-whys of such intervention (see here for example) and whether probiotics are as harmless as many have made them out to be.

Still...

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[1] Liu J. et al. Probiotic Therapy for Treating Behavioral and Gastrointestinal Symptoms in Autism Spectrum Disorder: A Systematic Review of Clinical Trials. Curr Med Sci. 2019 Apr;39(2):173-184.

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A gluten-free diet for "schizophrenia positive for antigliadin antibodies (AGA IgG)"

Short post alert...

"This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder."

So said the findings reported by Deanna Kelly and colleagues [1] as the conference abstract [2] of their study finally hits the peer-reviewed science literature (see here).

As per my previous musings on this study, this was the "first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA [anti-gliadin antibodies] IgG." Results were interesting insofar as "participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale... and in negative symptoms." Net result: encouraging findings with the need for more study; also with a nice focus on effect sizes too...

'Nuff said.

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[1] Kelly DL. et al. Randomized controlled trial of a gluten-free diet in patients with schizophrenia positive for antigliadin antibodies (AGA IgG): a pilot feasibility study. J Psychiatry Neurosci. 2019 Mar 27;44(3):1-9.

[2] Kelly D. et al. Randomized double-blind feasibility study of a gluten-free diet in people with schizophrenia and elevated antigliadin antibodies (AGA IgG). Schizophrenia Bulletin. 2018; 44: S190.

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The positive effects of 12 weeks of probiotics and vitamin D in chronic schizophrenia?

The findings reported by Amir Ghaderi and colleagues [1] (open-access) provide the blogging fodder today, and the results of a study looking at a "novel combination of vitamin D and probiotic on metabolic and clinical symptoms in chronic schizophrenia." Said probiotic formulation contained "Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum (each 2 × 109)" and was delivered over a period of 12 weeks alongside a vitamin D supplement - "50,000 IU vitamin D3 every 2 weeks" - utilising a "randomized, double-blind, placebo-controlled trial" design. We are also told that the trial protocol was "retrospectively registered."

The Ghaderi study wasn't solely focused on what their combined intervention might do for the 'clinical symptoms' of schizophrenia despite this being a prominent part of the results obtained. They also wanted to examine things like "biomarkers of oxidative stress and cardiometabolic risk in chronic schizophrenia." This was done via the measurement of marker compounds pertinent to establishing total antioxidant capacity, total glutathione levels and high-sensitivity C-reactive protein (hs-CRP) among other things.

Results: first things first, vitamin D supplementation raised vitamin D levels in those who received the vitamin D + probiotic supplement. Not exactly an unexpected result I grant you, but important from the point of view that any subsequent findings *could* be linked to those increasing vitamin D levels. Further: "Vitamin D and probiotic co-supplementation was associated with a significant improvement in the general... and total PANSS scores." PANSS stands for the Positive and Negative Syndrome Scale and has some important uses in the context of schizophrenia, and the presentation of positive and negative symptoms. That all being said, the authors also mention how their supplementation combination did not seemingly affect scores on another measure included in the study - the Brief Psychiatric Rating Scale (BPRS) - which kinda demonstrates that vitamin D + probiotics is not a panacea for every aspect of schizophrenia.

Researchers also report on how their combined supplement also *correlated* with a some changes in those oxidative stress and cardiometabolic risk measures included for study in line with other study results (see here). There's quite a bit of data so I won't provide details. Suffice to say that some of them might be 'positively' important to those health inequalities that seem to follow a diagnosis of schizophrenia (see here).

What else? Well, I can't seem to find too much in the way of side-effects details in the Ghaderi paper so I'm assuming that it wasn't a significant issue. The fact that participants in the study were "being hospitalized during the intervention" means that they were, I assume, being monitored with greater assiduity than for example if they were in the community, including looking for potential side-effects.

And with that, and the requirement for further study (see here and see here), I say no more...

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[1] Ghaderi A. et al. Clinical and metabolic response to vitamin D plus probiotic in schizophrenia patients. BMC Psychiatry. 2019; 19:77.

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Lactobacillus plantarum PS128 "ameliorated opposition/defiance behaviors" in boys with autism?

There was something potentially rather special about the results published by Yen-Wenn Liu and colleagues [1] suggesting that use of a probiotic - Lactobacillus plantarum PS128 - might, under "randomized, double-blind, placebo-controlled" conditions, have some important effects with some young people diagnosed with an autism spectrum disorder. Special because, if such results are eventually replicated and borne out, some of the more 'disruptive' behaviours that can sometimes be observed alongside a diagnosis of autism - "opposition/defiance behaviors" - might be amenable to quite a simple intervention. That could be important for many, many different reasons.

The basics: PS128 containing "3 × 1010 CFU/capsule of PS128 with microcrystalline cellulose as the carrier" was the compound under investigation, pitted against a placebo that "only contained microcrystalline cellulose." Eighty participants, all boys diagnosed with an autism spectrum disorder (ASD) were recruited for study; 39 were assigned to receive PS128 and 41 receiving the placebo for a period of 4 weeks. Various different schedules and questionnaires were used to measure behaviour at baseline and week 4 between the groups. With a fairly small attrition rate - data for 36 participants in the PS128 and 35 in the placebo group were analysed - the results were pretty interesting.

Results: first and foremost we are told that no adverse events were reported during the study. That's important. Next, for the vast majority of measures used when straight comparing of PS128 and placebo, no significant difference was noted. The authors even mention how a clinician rated scale, the CGI-I, basically said that "both groups were equivalent to "minimally improved""  between baseline and study end. It was only when results were stratified for age that things started to 'happen' as various behaviours around anxiety, rule-breaking, inattention and opposition/defiance showed something like a 'nominal' reduction in the PS128 group compared with placebo, particularly for those aged between 7-12 years. As per the use of the word 'nominal' to denote a small 'change' the results were not spectacular.

Caveats? Well, this was a 4-week study of boys on the autism spectrum. Not a long time in anyone's book but longer than other studies on other interventions that did show a statistically significant effect (see here for example). The Liu study was also a study that exclusively relied on behavioural observation measures, so we can't say anything about how something like PS128 might have impacted on gut bacteria for example. Other, less methodologically sound studies have been more comprehensive (see here).

But there are strengths to the Liu study; strengths around the design and use of a placebo condition. And if there is a chance that something like Lactobacillus plantarum PS128 or other preparations (see here and see here) or related techniques (see here) *might* help improve quality of life for young and old people on the autism spectrum minus any significant side-effects, they should be explored an awful lot more...

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[1] Liu Y-W. et al. Effects of Lactobacillus plantarum PS128 on Children with Autism Spectrum Disorder in Taiwan: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2019; 11: 820.

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Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a fail

"B-cell depletion using several infusions of rituximab over 12 months was not associated with clinical improvement in patients with ME/CFS [Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]."

That was the conclusion reached in the paper by Øystein Fluge and colleagues [1]. Their findings based on the use of rituximab, "a drug that is often used to treat inflammatory diseases (for example, rheumatoid arthritis) and lymphoma" were not entirely unexpected (see here) as a familiar theme of small scale results [2] being 'positive' but not translating into gains during more methodologically-sound study was rehashed.

The Fluge paper also has an accompanying easy-read summary of the results [3] which really aids my job. The long-and-short of it was that over 150 patients diagnosed with ME/CFS were enrolled into the study. Most had been ill with ME/CFS for several years. They were randomly assigned to receive either rituximab or saline (control) over the course of 1 year. Said timing and dosage of rituximab started with "2 infusions of rituximab, 500 mg/m2 of body surface area, 2 weeks apart, followed by 4 maintenance infusions with a fixed dose of 500 mg at 3, 6, 9, and 12 months." Participants completed various 'self-reported' questionnaires about their fatigue and functioning over a 2-year period alongside some more objective measurement of physical activity. Results were collated, and well, there was very little difference between rituximab and saline use noted when comparisons were made. What was notable in the published findings were the quite high rates of side-effects observed: "Twenty patients (26.0%) in the rituximab group and 14 (18.9%) in the placebo group had serious adverse events" and over a third of those adverse events were considered 'possibly or probably related to' rituximab use.

What's more to say? Well, the discrepancy between these latest findings and other previous results suggests a couple of potentially important processes *might* be at work. First, the placebo response seems to be quite prominent in this patient group. I say that on the basis that the calculated placebo response among those receiving saline ranged between 25-50% across the various centres that recruited participants for this study. Other commentators (see here) have similarly mentioned how the placebo response seems to be typically quite high in ME/CFS, and how that might have also been on show in other studies too (see here). This could have lots and lots of implications for various intervention trials relevant to ME/CFS. Second, one has to consider that similar to various other labels that include some significant heterogeneity 'under them', there may be responders and non-responders [4] to consider in relation to the use of something like rituximab [5]. Third, and also quite important is to mention that although negative, these results don't invalidate the idea that immune function seems to have something of an important relationship with quite a few cases of ME/CFS (see here for example).

Having said all that, it is difficult to talk about further research on rituximab with ME/CFS in mind on the basis of the Fluge negative results. Not least because, like all medicines, there is a risk-benefit balance to be struck with such a preparation and failures using gold-standard experimental methodologies cannot be easily brushed under the scientific carpet...

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[1] Fluge Ø. et al. B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine. 2019. April 2.

[2] Fluge Ø. & Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series. BMC Neurol. 2009 Jul 1;9:28.

[3] Patient Summary: Rituximab for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Annals of Internal Medicine. 2019. April 2.

[4] Rekeland IG. et al. Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2018 Nov 28. pii: S0149-2918(18)30514-9.

[5] Morris MC. et al. Leveraging Prior Knowledge of Endocrine Immune Regulation in the Therapeutically Relevant Phenotyping of Women With Chronic Fatigue Syndrome. Clin Ther. 2019 Mar 28. pii: S0149-2918(19)30112-2.

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Saffron for ADHD?

I'm very partial to a bit of 'left field' research on this blog. By 'left field' I mean research that is slightly unusual or atypical. I'd place the study findings by Sara Baziar and colleagues [1] in that 'left field' category because they reported results - randomised double-blind study results - suggesting that: "Short-term therapy with saffron capsule showed the same efficacy compared with methylphenidate" when it came to managing some of the symptoms of attention-deficit hyperactivity disorder (ADHD).

Saffron a.k.a Crocus sativus L is a herb commonly cultivated in places like India and Greece. As with many herbs/spices, cooking represents but one potential use of saffron. It contains a myriad of different chemical compounds, some of which seem to have a variety of potential medicinal uses. Real pharmacognosy in action.

The starting point for the Baziar study was that although methlyphenidate (ritalin) is indicated for treating / managing many cases of ADHD, not everyone is suited to such a medicine or the side-effects that it can sometimes produce. So "alternative medication, like herbal medicine, should be considered." Enter then saffron, and some evidence that it might be a useful herb for various psychiatric complaints [2], to be pitted against methylphenidate in a sort of scientific head-to-head contest with ADHD symptoms in mind.

For 6 weeks, fifty or so children and young adults with "a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD" were randomly allocated to receive methylphenidate (MPH) "20-30 mg/d (20 mg/d for <30 kg and 30 mg/d for >30 kg)" or saffron capsules "20-30 mg/d saffron capsules depending on weight (20 mg/d for <30 kg and 30 mg/d for >30 kg)." At baseline, 3 weeks and 6 weeks researchers measured ADHD-related symptoms.

The results were unsurprisingly surprising. By that, I mean that there were no statistically significant differences between the two groups, bearing in mind the clinical effectiveness profile that methylphenidate use for ADHD has already established (see here). So: "General linear model repeated measures showed no significant difference between the two groups on Parent and Teacher Rating Scale scores." Importantly too we are told that: "The frequency of adverse effects was similar between saffron and MPH groups."

The Baziar results don't immediately open the floodgates to saffron being used to 'manage ADHD' instead of a clinically-proven molecule like methylphenidate. It doesn't work like that. As far as I can see this seems to be the first time that saffron has been put under the scientific spotlight with ADHD mind (taking into account other 'herbal medicines' have been explored with ADHD in mind). We therefore need more data and some all-important replication. We need more data comparing saffron against methylphenidate and other intervention options for ADHD. And we also need more data on why? Why might saffron be a useful therapeutic option for some ADHD? What are the pertinent biological mechanisms at work?

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[1] Baziar S. et al. Crocus sativus L. Versus Methylphenidate in Treatment of Children with Attention-Deficit/Hyperactivity Disorder: A Randomized, Double-Blind Pilot Study. J Child Adolesc Psychopharmacol. 2019 Feb 11.

[2] Shafiee M. et al. Saffron in the treatment of depression, anxiety and other mental disorders: Current evidence and potential mechanisms of action. J Affect Disord. 2018 Feb;227:330-337.

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A poo(p) transplant for [some] autism? 2 years on with caveats...

The results published by Dae-Wook Kang and colleagues [1] provide some important follow-up work to a study already discussed on this blog (see here) which suggested that: "MTT is safe and well-tolerated in children with ASD ages 7–16 years" and also "led to significant improvements in both GI- and ASD [autism spectrum disorder] -related symptoms" [2]. MTT by the way, refers to Microbiota Transfer Therapy, or in other words a poo(p) transplant. A press release accompanying the recent Kang paper is also available (see here).

The original Kang study included quite a bit more than just a poo(p) transplant as per their use of a 4-stage protocol: "(1) oral vancomycin, (2) MoviPrep, (3) SHGM [Standardized Human Gut Microbiota], and (4) Prilosec" with 18 participants diagnosed with an autism spectrum disorder (ASD). The results on that last occasion were promising insofar as (a) adverse effects being small and fairly limited and (b) some improvements noted in relation to behaviour and gastrointestinal (GI) symptoms. That all being said, one needs to remember that the previous study was an open trial and results were therefore preliminary.

On this latest research occasion, Kang et al followed up their 18 participants "two years after treatment was completed." The follow-up involved "the same GI and behavior tests that we employed previously" which involved the use of various parent- and professional-report questionnaires on behaviour, questionnaire analysis of GI issues and analysis of poo(p) samples: "16 out of 18 original ASD participants provided an additional fecal sample two years after the open-label trial."

Researchers reported that "most improvements in GI symptoms were maintained, and autism-related symptoms improved even more after the end of treatment." They observed something of a possible *relationship* between bowel and behavioural signs and symptoms whereby "GI relief provided by MTT may ameliorate behavioral severity in children with ASD, or vice versa, or that both may be similarly impacted by another factor" which is interesting (see here). They also noted that the bacterial composition of stools analysed at follow-up showed evidence of sustained change "including significant increases in bacterial diversity and relative abundances of Bifidobacteria and Prevotella." In short, things were still looking pretty good after 2 years.

"Despite steady and continuous improvement in behaviors over two years, we must underscore that the original clinical trial and current follow-up study are open-label trials without a control for placebo effect." The authors are frank about the limitations of their studies, and how behavioural and GI symptoms in particular can potentially be influenced by all-manner of different variables. Indeed, they noted that "12 of 18 participants made some changes to their medication, diet, or nutritional supplements" which allied to the waxing and waning of symptoms typically associated with autism (see here), means that one has to be careful about making too many sweeping statements about cause-and-effect.

But in the context that for these 18 participants, a poo(p) transplant was seemingly not associated with too many adverse side-effects and that their behavioural and GI data typically followed a course of improvement, one cannot easily discount the Kang results. The call for further research "with a placebo-control arm" made by the authors should echo throughout the autism research landscape. And with it, further focus on how gut bacterial make-up and the all-important metabolites that specific bacterial species produce seem to be something quite important to at least some autism (see here)...

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[1] Kang D-W. et al. Long-term benefit of Microbiota Transfer Therapy on autism symptoms and gut microbiota. Scientific Reports. 2019; 9: 5821.

[2] Kang D-W. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome. 2017; 5: 10.

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"a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP)" for autism?

The study findings reported by Megan Sanctuary and colleagues [1] caught my eye recently, and their aim to "assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI [gastrointestinal], microbiome and immune factors in children with ASD [autism spectrum disorder] and GI co-morbidities."

I appreciate that such a study is probably not going to be everyone's cup of tea given, for example, the rather *interesting* history of colostrum and autism (including the words 'transfer factor' [2]). The Sanctuary study however, should be taken on its own merit regarding "concurrent supplementation with both the probiotic B. infantis and bovine colostrum product (BCP) as a source of immune factors and prebiotic glycans could alter the microbiota to a more beneficial composition in order to improve gut health in children with ASD and GI symptoms." The rationale behind such work is that (a) what goes on the in the deepest, darkest recesses of the GI tract in a microbial sense could impact on the functional gut symptoms, and (b) said functional gut symptoms seem to be 'over-represented' in relation to autism (see here) and *could* in some cases, be linked to behavioural presentation (see here). Ergo, try and impact on functional gut symptoms and one *might* be able to impact on behaviour...

Sanctuary et al report preliminary findings designed to "assess tolerability" and "to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities." This work represented a first step towards a bigger research trial to ascertain whether such a supplemental combination *might* be useful for some people on the autism spectrum in a 'clinically relevant' sense. Despite being a pilot study, researchers did conduct what is considered a gold-standard study insofar as it being a "double-blind, crossover, randomized clinical trial (RCT)." The study protocol was also research registered (see here), so quite a few methodological boxes were ticked.

Given that this study was carried out at the MIND Institute, an institution that has quite a lot of experience in all-manner of different autism research areas (see here and see here), researchers were pretty precise when it came to diagnosing autism/ASD and ascertaining the presence or not of GI symptoms in their small cohort (N=11). The authors also provide quite a bit of information about the supplements used including "the bovine colostrum product (Imucon)" and details of its safety: "The product was tested and found to be negative for Escherichia coli, Salmonella, Listeria, coagulase positive Staphylococcus and antibiotic residue." Insofar as dosages, we are told that: "The colostrum powder dose administered in this study was 0.15 g/lb body weight per day" and "The probiotic dose administered in this study was 20 billion CFU [colony forming units] per day." A couple of supplemental combinations were examined during the study including BCP on its own and BCP+probiotic.

Results: there were quite a few different types of results reported on for 8 of the original 11 participants. Importantly: "Bovine colostrum product appears to be well-tolerated in these children [diagnosed with autism] as its own treatment as well as when combined with the probiotic B. infantis." 'Well-tolerated' means that there were "no participants needing to withdraw due to adverse events" despite a small number of reports of things like gassiness. A couple of kids were also reported to find the taste of the products not too great.

Also: "Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors." Being really careful here because of the small participant number included for study for example, researchers reported that "87.5% (7/8) of participants exhibited some improvement in GI symptoms while on the BCP only arm and 100% (8/8) of participants exhibited some improvement in GI symptoms while on the combination treatment arm." The sorts of GI effects mentioned included reductions in "pain with stooling, frequency of diarrhea, and consistency." Researchers also reported that appetite seemed to be improved for some kids too, particularly the consumption of fruit and meat.

A few other changes were noted in the study, but on the basis of the small participant size and the aims of the study I'm gonna leave them for now. As the authors mention: "the lack of a clear control group receiving a placebo" means that this was a "cross-over study where each participant was his own control" and therefore one needs to be cautious for now. What is needed next is a larger trial and more focus on the behavioural presentation side of autism...

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[1] Sanctuary MR. et al. (2019) Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS ONE 14(1): e0210064.

[2] Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-3):143-7.

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Pioglitazone for autism?

Enjoyed Christmas? Welcome back. Onward...

"Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors."

So said the findings reported by Lucia Capano and colleagues [1] (open-access) describing preliminary efforts to "elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5–12 years old" taking the hypoglycemic medicine called pioglitazone. The results obtained from this phase II pilot study - "a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone" - suggest that further research on this medicine in the context of autism is warranted.

Capano et al provide quite a lot of information about the whys-and-wherefores of pioglitazone use in the context of autism. They talk about immune system 'issues' and inflammation being no strangers to autism research. They talk about various findings in relation to immune signalling and autism, drawing on data from several investigations that have looked at compounds like the cytokines and chemokines. Pioglitazone fits into this story by way of it being "an agonist of peroxisome proliferator activated receptor (PPAR)-ϒ." Activation of PPAR-ϒ leads to "insulin sensitization and enhances glucose metabolism." It also seemingly has an anti-inflammatory role to play too. Through the use of  pioglitazone ramping up the action of PPAR-ϒ, so researchers opined that this could be useful for some people diagnosed with autism where immune system and behaviour might meet...

Unlike other trials of pioglitazone in the context of autism [2], the Capano study was more exploratory than 'gold-standard' in it's design. It did however include both behavioural and biological components, where various behavioural outcome measures were included alongside the describing of various "research bloodwork" that included various cytokines ("IL1-β, IL-10, and TNF-α in plasma; IL-6 in serum") that have been discussed in other studies with autism in mind (see here for example).

Alongside those initial results mentioned in the opening sentence of this post, there are a few other important points to make. So: "Overall, pioglitazone was well tolerated." Welcome news indeed. Researchers also noted that: "There were no serious adverse events (SAEs) in any of the doses within the range tested (0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg)." This is important in the context that all medicines have the propensity for 'adverse effects' for some people, and pioglitazone is no different. Given also the focus on medication and weight gain in the context of autism (see here for example), it's a bit of relief to see that, for the study period at least, authors reported that: "BMI [body mass index] did not change significantly during the study."

I'm not going to go to heavily into the behavioural changes noted over the study period on this occasion, because these are preliminary and one has to be careful with any interpretation. I do however want to mention some of the biological results; namely: "Significant changes with treatment occurred with both IL-6 and IL-10" and "IL-1β and TNF-α did not change significantly with treatment." The authors note that the IL-6 and IL-10 findings - "decreasing IL-6 and increasing IL-10" - were "consistent with the known effect of PPAR-gamma agonists like pioglitazone." This is an interesting finding.

Cumulatively, such results suggest that quite a bit more research focus is needed on pioglitazone in the context of [some] autism. But for now, it looks quite promising (again [3])...

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[1] Capano L. et al. A pilot dose finding study of pioglitazone in autistic children. Molecular Autism. 2018; 9: 59.

[2] Ghaleiha A. et al. A pilot double-blind placebo-controlled trial of pioglitazone as adjunctive treatment to risperidone: Effects on aberrant behavior in children with autism. Psychiatry Res. 2015 Sep 30;229(1-2):181-7.

[3] Boris M. et al. Effect of pioglitazone treatment on behavioral symptoms in autistic children. J Neuroinflammation. 2007;4:3.

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"Vitamin D and omega-3 reduced irritability symptoms in children with ASD"

The title heading this post - "Vitamin D and omega-3 reduced irritability symptoms in children with ASD [autism spectrum disorder]" - comes from the findings reported by Hajar Mazahery and colleagues [1] discussing the results of their clinical trial. I have already mentioned the Mazahery trial before on this blog (see here) as a 'study to watch' based on the publication of their study protocol [2]. It looks like the wait is finally over...

So, as researchers previously reported, there were four arms to this clinical trial: supplementation with vitamin D alone ("2000 IU/day, VID"), supplementation with an omega-3 fatty acid ("722 mg/day DHA, OM"), vitamin D plus fatty acid supplementation together ("2000 IU/day vitamin D + 722 mg/day DHA, VIDOM") and a placebo group (olive oil). Results are reported for over 70 children diagnosed with an autism spectrum disorder (ASD) - "VID = 19, OM = 23, VIDOM = 15, placebo = 16" - over a 12-month period, with the primary outcome being "the Aberrant Behaviour Checklist (ABC) domains of irritability and hyperactivity."

Aside from the main finding - "vitamin D and omega-3 LCPUFA [long chain polyunsaturated fatty acid] reduced irritability symptoms in children with ASD" (compared against placebo) - a few other observations are noteworthy: "Compared to placebo, children on VID [vitamin D] also had greater reduction in hyperactivity." All this bearing in mind that the biological testing to examine for vitamin D and fatty levels reported "a good compliance rate" indicating that supplements were routinely being taken as required by the study.

Implications? Well, strike up more peer-reviewed evidence that nutrition is important not just for physiological health but also for psychological/behavioural health and wellbeing too (see here). Add this research also to other peer-reviewed science that suggests that at least 'some autism' might be particularly 'sensitive' to elements of such nutritional medicine (see here).

I could go on about how vitamin D in particular seems to be something important to autism (see here and see here for examples). I could also go on about how fatty acids have some important evidence-based history with autism in mind (see here). But do I really need to? Minus any medical or clinical advice given or intended, the Mazahery results really speak for themselves.

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[1] Mazahery H. et al. A randomised controlled trial of vitamin D and omega-3 long chain polyunsaturated fatty acids in the treatment of irritability and hyperactivity among children with Autism Spectrum Disorder. The Journal of Steroid Biochemistry and Molecular Biology. 2018. Oct 26.

[2] Mazahery H. et al. Vitamin D and omega-3 fatty acid supplements in children with autism spectrum disorder: a study protocol for a factorial randomised, double-blind, placebo-controlled trial. Trials 2016; 17:295.

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Vitamin D supplementation and autism: more work needed on the biochemistry of vitamin D metabolism

The findings reported by Conor Kerley and colleagues [1] provide the brief blogging fodder today. Researchers, who are no stranger to the research area that is vitamin D and autism (see here), decided to conduct a 'post-hoc analysis' of data from two controlled trials where vitamin D supplementation was experimentally tested for children with autism and children with asthma. They were specifically looking at the "serum response to vitamin D supplementation" rather that the amount of vitamin D supplemented as potentially being important to the clinical results obtained. They concluded that "children with ASD [autism spectrum disorder] had a lower increase in 25(OH)D levels with supplementation." Further: "Potential mechanisms include altered absorption/metabolism as well as well genetic factors."

Bearing in mind the relatively small participant group numbers used and comparisons between kids with autism and kids with asthma without any other 'asymptomatic' group involvement, I was really rather interested in the Kerley findings. This was a research group who previously concluded that vitamin D supplementation did little for their cohort of autistic children under experimental conditions [2]. Now they're perhaps suggesting that there may have been valid biological reasons behind such results with respect to the biochemistry/metabolism behind vitamin D with such issues potentially affecting how much vitamin D supplementation is required to suitably raise vitamin D levels.

Of course this is not necessarily a new finding. Science has already started to look at the genetics/biology of vitamin D metabolism in relation to autism (see here and see here) and continues to do so [3]. It also converges with the idea that a deficiency/insufficiency of vitamin D is an important clinical finding but does not necessarily mean that a universal dose of vitamin D supplementation will 'fix anything' (see here for another example in another label).

"Clinical and research work relating to vitamin D is ASD should measure 25(OHO)D response to supplementation to assess therapeutic doses." I can't argue with such sentiments on the basis of the results observed. Working back from sayings such as 'the dose makes the poison', it appears that for some on the autism spectrum, that dose may not be the same as everyone else...

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[1] Kerley CP. et al. Blunted serum 25(OH)D response to vitamin D3 supplementation in children with autism. Nutr Neurosci. 2018 Oct 10:1-6.

[2] Kerley CP. et al. Lack of effect of vitamin D3 supplementation in autism: a 20-week, placebo-controlled RCT. Arch Dis Child. 2017 Nov;102(11):1030-1036.

[3] Biswas S. et al. Fok-I, Bsm-I, and Taq-I Variants of Vitamin D Receptor Polymorphism in the Development of Autism Spectrum Disorder: A Literature Review. Cureus. 2018 Aug 29;10(8):e3228.

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"no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes"

The quote titling this post - "no evidence of any beneficial effect of monthly vitamin D3 supplementation on mood-related outcomes" - comes from the paper published by Maria Choukri and colleagues [1] (open-access available here). Their study represents an important continuation of research looking at whether supplementing with vitamin D (the sunshine vitamin/hormone) may affect depression or depressive symptoms (see here). The authors in this case observed that their study "did not provide evidence for the benefit of single monthly dose of vitamin D3 supplementation over autumn and winter on depression and other mood outcomes in healthy pre-menopausal women."

Just before heading further into the Choukri findings, it's worthwhile mentioning some of the history in this area. So, vitamin D is an essential part of maintaining good bone integrity as per the connection between deficiency of the stuff and conditions like rickets (see here). More recently, scientific and clinical eyes have turned to other possible roles for vitamin D in light, for example, of 'deficiency' connections to various developmental and/or behaviourally-defined labels such as autism, schizophrenia and depression (see here and see here and see here respectively). When deficiency (or insufficiency) is detected, people supplement with vitamin D to correct the deficiency, following Government guidance (see here). Speculation then turned to whether supplementation might also 'impact' on the presentation of some of those developmental/clinical labels as well as just correcting any biological deficiency. The results have tended to be mixed so far (see here and see here) with some important biological caveats (see here)...

"This study was a double-blind, placebo-controlled, randomised clinical trial conducted from February 2013 to October 2013 in Dunedin, New Zealand (45° 52′0 S, similar to the latitude of Montreal, Canada; or Lyon, France in the northern hemisphere)." The latitude information is important to various studies mentioning vitamin D because geography influences sun exposure which then influences vitamin D production (see here). Importantly too, the Choukri study was focused on 'healthy' women who were not currently diagnosed with a variety of exclusionary conditions/labels. "A total of 152 healthy women (18–40 years) in Dunedin, New Zealand were randomly assigned to receive 50 000 IU [international units] (1·25 mg) of oral vitamin D3 or placebo once per month for 6 months" we are told, and measures covering anxiety, depression, 'flourishing' and positive and negative mood were utilised before and after.

Results: first and foremost measured vitamin D levels did what they were expected to do as a function of vitamin D or placebo receipt. There was for example, no significant baseline difference in vitamin D levels between the groups (vitamin D vs placebo). At the end of the study, those in the placebo group showed "the expected seasonal pattern in terms of a decline in absolute level and change over the seasonal periods" in vitamin D levels, whilst the supplemented group did not.

But alongside... "There were no statistically significant differences between the vitamin D and placebo groups in any of the outcome measures – depression, anxiety, flourishing, or positive and negative mood, controlling for the baseline measures and the covariates." Indeed, across the various measures, there wasn't even anything close to a statistically significant difference reported between the groups. Ergo, in healthy women "over the winter period", vitamin D supplementation did not seemingly impact on mood-related outcomes despite altering biological vitamin D levels.

I could mention about some possible caveats attached to this study such as the fact that this was a study carried out on an already healthy population "with no vitamin D deficiency or high depressive symptoms." But this is not the first time that vitamin supplementation has 'failed' to show a demonstrable connection to improving mood and probably won't be the last either...

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[1] Choukri MA. et al. Effect of vitamin D supplementation on depressive symptoms and psychological wellbeing in healthy adult women: a double-blind randomised controlled clinical trial. J Nutr Sci. 2018 Aug 23;7:e23.

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Helminthic Trichuris Suis Ova vs. placebo for repetitive behaviours in adult autism

The trial results published by Eric Hollander and colleagues [1] were not entirely unexpected. I had previously mentioned their study on the "use of the immunomodulator Trichuris Suis Ova (TSO)" with autism in mind in another post (see here) but, at that time, still awaited the peer-reviewed publication version to appear. I wait no longer.

OK, Trichuris suis (T. suis) is a parasite. It makes its home in the deepest, darkest recesses of other creatures, apparently also having the rather important evolutionary advantage of being able to stay in egg form for quite a long time 'awaiting ingestion'. But just before you turn away John Hurt style (no, I'm not going to link to the 'chest-buster' scene), this particular parasite might not be 'all bad'. I'm specifically talking about some preliminary data suggesting that T. suis *might* have some important immunological effects [2] when ingested in a controlled manner under certain clinical circumstances.

Hollander et al took things one stage further by their insinuation of a link between use of an "immunomodulator" such as T. suis and their study to determine "the effect sizes for TSO vs. placebo on repetitive behaviors, irritability and global functioning in adults with ASD [autism spectrum disorder]." And just before you question the idea that immune function might be something important to some overt behaviour(s), there is other research out there discussing the possibility of such an effect (see here and see here) specifically with autism in mind.

"A 28-week double-blind, randomized two-period crossover study of TSO vs. placebo in 10 ASD adults, ages 17 to 35, was completed, with a 4-week washout between each 12-week period." This was a 'gold-standard' trial design albeit with a very, very small participant group who represented only a specific 'part' of the autism spectrum [3]. The trial was also registered for all to see the proposed hows-and-whys (see here) including the detail: "Have a personal or family history of allergies" as part of the inclusion criteria.

Results: "Differences between treatment groups did not reach statistical significance." This is an important point highlighting how use of T. suis ("the eggs of intestinal helminthes (trichuris suis ova) administered as 2500 ova doses every two weeks") did not translate into statistically significant group differences across measures looking at the social communication aspects of autism for example. I say this bearing in mind that the Hollander study was a cross-over trial too.

But... "Large effect sizes for improvement in repetitive behaviors (d = 1.0), restricted interests (d = 0.82), rigidity (d = 0.79), and irritability (d = 0.78) were observed after 12 weeks of treatment." What this means is that when comparing participants using T. suis vs. their baseline measurements, they seemed to do better on the T. suis portion of the trial across various different types of behaviour. Importantly too we are told that "TSO had only minimal, non-serious side effects" bearing in mind this included various gastrointestinal (GI) side-effects (and knowing that GI issues are already 'a thing' when it comes to autism).

So, there we have it. The results of the first (small scale) clinical trial using Trichuris Suis Ova (TSO) helminthic style with autism in mind. Obviously a lot more research is required before this type of intervention goes anything like 'mainstream'. Alongside there is also the 'acceptability' factor to consider: how many people would actually want to ingest a parasite such as T. suis? Indeed, one of the next courses of study is perhaps to see 'why' such helminthic therapy has the effect that it has on behaviour, and whether such an effect can be replicated in a medicine or other formulation rather than ingesting a parasite?

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[1] Hollander E. et al. Randomized Crossover Feasibility Trial of Helminthic Trichuris Suis Ova vs. Placebo for Repetitive Behaviors in Adult Autism Spectrum Disorder. World J Biol Psychiatry. 2018 Sep 19:1-25.

[2] Jouvin MH. & Kinet JP. Trichuris suis ova: testing a helminth-based therapy as an extension of the hygiene hypothesis. J Allergy Clin Immunol. 2012 Jul;130(1):3-10.

[3] Hollander E. et al. Trichuris Suis Ova (TSO) as an immune-inflammatory treatment for repetitive behaviors in ASD. European Neuropsychopharmacology. 2016; 26: 891.

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MDMA-assisted psychotherapy for the "reduction of social fear and avoidance that are common in the autistic population"

I approach the findings reported by Alicia Danforth and colleagues [1] (open-access available here) very, very carefully. Their preliminary observations on the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in the context of adult autism, specifically "to reduce social anxiety" require a lot more follow-up work before anyone gets too carried away. Not least because MDMA or "chemical entities represented as containing MDMA" is categorised as a drug of abuse.

OK, first things first: what is "MDMA-assisted psychotherapy for reduction of social fear and avoidance"? Well, MDMA is  more commonly known as Ecstasy or Molly/Mandy in drug circles. Its effects include "producing feelings of increased energy, pleasure, emotional warmth, and distorted sensory and time perception" thought to be due to its chemical activity on various neurotransmitters (and related biology) such as dopamine and serotonin. Here in Blighty it's currently listed as a Class A drug of abuse alongside things like cocaine and heroin.

MDMA-assisted psychotherapy aims to utilise some of those, and other, behavioural effects associated with recreational MDMA drug use to help further the aims of psychotherapy (talking therapy). Danforth et al have previously published on some of the background behind such a notion [2] specifically in the context of 'treating' social anxiety comorbid to autism. And just before you say/think anything, anxiety and autism is most definitively a 'happening topic' at the moment (see here and see here for examples).

Their most recent publication discusses the results of a small clinical trial of MDMA-assisted psychotherapy with 12 adults with autism. The study details were held on ClinicalTrials.gov (see here) albeit with the published paper listing the wrong trial entry. Authors used a "randomized, placebo-controlled, double-blind methodology for this exploratory phase 2 single-site study conducted from February 2014 through April 2017." MDMA was 'synthesised' and compounded into capsules alongside placebo (dummy) capsules containing lactose (I'm assuming that none of the participants were lactose intolerant given the emerging data on lactose issues and autism [3]). Then: "After three 60- to 90-min non-drug preparatory psychotherapy sessions, participants received two blinded experimental sessions with MDMA or placebo, spaced approximately 1 month apart." Said psychotherapy sessions were described as "standardized mindfulness-based therapy adapted from dialectical behavioral therapy (DBT)." Various assessments of behaviour and physiology were used during the study to ascertain any effect. Importantly too, authors describe their use of various instruments to pick up any adverse side-effects including that related to suicidality.

Results: this was a small study. Although 12 participants were enrolled and entered the study, only data for 11 were available as the authors remarked that a participant "enrolled with hypertension and pre-study substance use disorder within exclusion window for enrollment." Researchers reported however that scores on their primary outcome measure - The Liebowitz Social Anxiety Scale (LSAS) - showed evidence of "rapid and durable improvement in social anxiety symptoms in autistic adults following MDMA-assisted psychotherapy." They also commented that: "Reductions were retained for the MDMA group at 6-month follow-up compared to primary endpoint, supporting durability of improvements." And participants themselves in their subjective reporting also communicated similar sentiments regarding the use of MDMA-assisted psychotherapy as per accounts of "reduced barriers to successful social interactions and increased confidence in school, at work, in friendships, and in romantic relationships."

Then: "No SAEs [serious adverse events] were reported on this study." That's good but doesn't mean that no adverse events were reported following the use of MDMA-assisted psychotherapy, as anxiety and 'depressed mood' were listed as "treatment-emergent psychiatric adverse events" and not specifically seen in the placebo group. Also: "Suicidal ideation was the most commonly reported AE; however, prevalence was similar across groups (25.0% both groups) and was pre-existing in medical history." In other words, one needs to be a little cautious about using MDMA in this context as in other contexts.

Caveats? I've already mentioned the small participant group included for study, which kinda 'down-grades' the levels of positive effects noted by Danforth and colleagues. I was also drawn to another sentence in their paper - "Both groups in this study received the same type of psychotherapy with encouragement toward self-directed healing and meaning-making" - and a niggling question I have about how one is able to ensure that both experimental and control groups received the same type/magnitude/experience of psychotherapy. I say this in the context that DBT seems to have a lot of different 'elements' to it (see here) which are perhaps not easily tested/compared under controlled conditions. Perhaps next time authors could think about including a cross-over portion to their trial too?

That all being said, I'm still [cautiously] interested in the findings presented by Danforth and what research is yet to come on this topic. I've said it a few times on this blog about how anxiety is a real quality-of-life-drainer in many contexts but specifically with autism in mind, the evidence is pretty strong for an important effect. Anything that could safely and reliably help those who are confronted with such issues (and perhaps other issues too?) should be explored objectively and dispassionately.

And on the topic of MDMA, whoever thought it would be a good idea to give to an octopus in the name of science?

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[1] Danforth A. et al. "Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study". Psychopharmacology. 2018. Sept 8.

[2] Danforth AL. et al. MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2016; 64: 237-249.

[3] Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

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Exclusion diet plus prebiotics for [some] autism?

"To our knowledge, this is the first study where the effect of exclusion diets and prebiotics has been evaluated in autism, showing potential beneficial effects."

So said the results reported by Roberta Grimaldi and colleagues [1] and the findings of their study attempting to "understand the impact of diet on GM [gut microbiota] composition and metabolism in ASD [autism spectrum disorder] children and to investigate the modulating potential of B-GOS® intervention on these parameters."

The study by Grimaldi et al was research registered (see here) and included the 'gold-standard' research design: "A randomised, double-blind, placebo-controlled" study. Researchers divided 30 children diagnosed with an ASD into two groups (A and B), which were subsequently further divided into two groups depending on whether they followed an exclusion diet - "mainly gluten and casein free" - or an unrestricted diet based on the analysis of 4-day food diaries. Within those subdivided A and B groups, half received a placebo supplement of maltodextrin whilst the other half received a "prebiotic B-GOS® mixture" over a 6-week period. As well as including 'run-in', 'beginning of treatment' and 'end of treatment' periods, researchers also included a follow-up period of 2 weeks at the end of the study where various behavioural and physiological measures complemented their use during the experimental period.

Results: there were quite a few results reported as a function of baseline variables such as whether or not participants were following an exclusion diet or not, and as a function of the intervention(s). Behaviourally (probably most importantly), researchers reported that: "Results showed consistent reduction over time in anti-sociability score in children on the combination of the exclusion diet and B-GOS intervention, with the most apparent difference occurring at follow-up." This was measured using the autism 'rising' instrument called the A-TEC (see here) and also complemented other results based on the use of the autism spectrum quotient (AQ). As far as I can make out, all other behavioural and psychometric measures used - the "empathy and systemising quotient (EQ-SQ)... and the Spence’s Children Anxiety Scale-Parent version (SCAS-P)" - did not show any significant changes over the study duration.

Gastrointestinal (GI) symptoms were also examined during the Grimaldi study as per the use of "daily questionnaires for GI function and symptoms" and the utilisation of that fabulous graphical resource, the Bristol stool chart. Authors reported no significant changes/differences as a consequence of intervention, although: "Significantly lower scores of abdominal pain (P < 0.05) and bowel movement (P < 0.001) were reported in children following exclusion diets" at baseline. Interesting, in light of other independent results (see here).

Grimaldi and colleagues also provide quite a lot of data following their examination of fecal and urine samples taken over the course of their investigation. This is perhaps not unexpected given their previous research interests in this area and the proud reputation earned at one of the affiliated institutions. The results? Lots of them. Perhaps the most important intervention-wise was the finding of a "significant increase of Lachnospiraceae family" following B-GOS® intervention. The authors talk about this in terms of the production of butyrate (as per their previous research) and the (positive) reputation this stuff is starting to garner.

Other details? Well, going back to the baseline assessment of samples as a function of the use of an exclusion diet or not, there are some interesting findings. So: "Before prebiotic B-GOS® intervention, we evaluated the nutritional impact of exclusion diets (GFCF) and our results showed deficiency in vitamin D intake, which was significant in children on unrestricted diets." This kinda ties into other research which observed that the 'horror' that is a gluten-free, casein-free (GFCF) diet in relation to autism might actually not be that horrible in nutritional terms (see here). I'm also minded to bring in other recent research which suggested that a GF diet might be a bit of a 'fixer' when it comes to vitamin D deficiency issues under certain clinical circumstances [2]. I say this minus any sweeping generalisations or universal application to the label of autism.

Overall the Grimaldi findings are interesting and suggest further investigations are required on the use of prebiotics and diet in autism; perhaps complementing the still-growing interest in the gut microbiota and autism (see here for one example). Mindful also that diet can itself be seemingly affect gut bacterial composition too [3]. As they stand however, the current results aren't yet a glowing endorsement of B-GOS® intervention 'for' autism, mindful of the small participant group eventually included for study and the relatively short-term nature of the Grimaldi trial. We'll see where this goes... although next time, I'd also like to see a more prominent statement about any harms or side-effects encountered or not during the study period. I assume 'not' in the current study but...

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[1] Grimaldi R. et al. A prebiotic intervention study in children with autism spectrum disorders (ASDs). Microbiome. 2018 Aug 2;6(1):133.

[2] Zingone F. & Ciacci C. The value and significance of 25(OH) and 1,25(OH) vitamin D serum levels in adult coeliac patients: A review of the literature. Dig Liver Dis. 2018 Aug;50(8):757-760.

[3] Berding K. & Donovan SM. Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder. Front Neurosci. 2018 Jul 31;12:515.

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KPAX002 for Chronic Fatigue Syndrome part 2: controlled study says no

KPAX002 mentioned in the title of this post refers to "a mitochondrial modulator technology platform" according to the manufacturer that includes a low dose of methylphenidate combined with various nutrients designed to impact on mitochondrial function. Within the context of chronic fatigue syndrome (CFS) also known as myalgic encephalomyelitis (ME) (but not necessarily accurately so!), there is some preliminary research history suggesting that KPAX002 might be something to look at for intervening in some of the disabling characteristics of CFS/ME (see here). This, on the basis that mitochondria in particular, might be something quite important to at least some cases (see here and see here).

The fly in the scientific ointment?

Well the results of the "phase 2 randomized, double-blinded, placebo-controlled trial" on KPAX002 published by Jose Montoya and colleagues [1] that, from an intention-to-treat point of view, reported no significant statistical difference in self-reported group scores of fatigue and other measures between active treatment and a placebo. In keeping with the phase 2 label attached to the trial - looking at both initial clinical results and also any side- or adverse effects - authors reported no statistically significant difference in the frequency of reported adverse effects between KPAX002 and a placebo over the 12 weeks of study. First, do no harm and all that.

The Montoya paper is open-access so readers can see for themselves how things were done and the details of the results. I however, want to highlight a few points that I thought were important:

First, the authors acknowledge the "unexpectedly positive results" observed the last time around [2] that led to this more rigorous trial. Personally, I don't think there was anything too unexpected about those pilot study results, given the methodological issues typically associated with a pilot study. Y'know, a small un-blinded participant group taking part in a trial using a preparation that they probably will have been told *might* affect various symptoms they experience or themselves possibly 'exposed' to other anecdotal reports of good effects. That and no control group, no placebo included and importantly, no objective measure of fatigue (a real issue when it comes to quite a bit ME/CFS research) and well, I'd be surprised if something significant didn't come up during the initial findings. And just in case you think I'm being all 'high-and-mighty' about this, I've published using the same type of pilot study methodology before, including some of the same inherent issues (see here).

Second, I'm a little bit disappointed that the authors weren't more forthright in how the results weren't statistically significant on any and all measures included for study. I say this on the basis of both the commercial take on the results (see here) and also sentences like: "The two groups demonstrating the most robust response to KPAX002 were subjects with more severe ME/CFS symptoms at baseline (P=0.086) and subjects suffering from both fatigue and pain (P=0.057)." Both those p-values (p being a measure of statistical significance) are above the [currently] recognised threshold for p equal to or less than 0.05, yet are listed as a 'robust response'. Even more, throughout the paper I note the words 'trend in favor of' being used, which some people might translate as being 'well, they were nearly statistically significant results'. I say this also bearing in mind that the final participant numbers - KPAX002 use = 48 and placebo = 57 - are not exactly facets of what one would call an under-powered study. I'm probably being a nit-picker here but like it or not, the [current] rules of science are the [current] rules of science.

Finally, once again, I note that under the heading 'Disclosure of conflict of interest', the word 'none' appears as per the last research occasion [2]. Personally, and with no malice intended, I would have listed the detail that at least one of the authors is an employee of the manufacturer of KPXA002 given the affiliation details and email address for further correspondence provided on the paper. Again, it's a small detail but one that should nevertheless be acknowledged. I would have also like to have seen a little more on who funded the trial too and especially who funded the provision of the KPAX002 supplement for trial purposes. I reiterate that there is no malice is intended in saying that, but readers require such details.

I don't want to come down too hard on these results because it's obvious that quite a bit of work has gone into their production. I'm also not closing the door on the idea that future research with a more targeted group with ME/CFS might not produce something a little more statistically significant with regards to KPAX002. But for now, the answer must be that controlled study of the formulation did not meet clinical endpoints in a statistical sense, and hence KPAX002 cannot be said to be superior to placebo for CFS/ME. With all the setbacks that the label(s) ME/CFS has had to endure down the years with regards to the 'psychobabble' explanations (see here) and other 'eureka' moments (see here), the Montoya findings are bad news for patients yet again. But, they also should represent a further call to re-double research efforts; particularly when it comes to the biology of the condition(s) and onward the acceleration of research for interventions for this quality of life draining condition (see here).

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[1] Montoya JG. et al. KPAX002 as a treatment for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a prospective, randomized trial. Int J Clin Exp Med 2018;11(3):2890-2900

[2] Kaiser JD. A prospective, proof-of-concept investigation of KPAX002 in chronic fatigue syndrome. Int J Clin Exp Med. 2015 Jul 15;8(7):11064-74.

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