Consequences of folate deficiency – treated by immunomodulators (Infliximab, IVIG, Propes and Inflamafertin) and the relevance of mutations in MTHFR, MTR, and MTRR genes in identifying those at risk. Plus the effect of rTMS and tDCS on milder autism

 

Today’s post returns to folate deficiency, but before that a quick mention of magnetic/electrical brain stimulation therapies for autism without impaired cognition.

I encountered a new term IC-ASD. It stands for intellectually capable autism spectrum disorder. Most people with autism these days seem to have IC-ASD. Some struggle and some do not.

 

The effects of rTMS and tDCS on repetitive/stereotypical behaviors,cognitive/executive functions in intellectually capable children and young adults with autism spectrum disorder: A systematic review and meta-analysis of randomized controlled trials

 

Objective

This study aims to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on repetitive/stereotypical behaviors and cognitive/executive functions in children and young adults with intellectually capable autism spectrum disorder (IC-ASD).

Methods

Literature searches across PubMed, Web of Science, Cochrane Library, Embase, and Scopus were performed to identify randomized controlled trials (RCTs) evaluating the efficacy of rTMS and tDCS in children and young adults with IC-ASD. The search encompassed articles published up to April 25, 2025. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated and pooled. Sensitivity and subgroup analyses were conducted to assess potential sources of heterogeneity and refine the robustness of the findings.

Results

This meta-analysis included 18 RCTs involving 813 participants. Compared with sham interventions, tDCS demonstrated significant improvements in social communication, repetitive and stereotypical behaviors, cognitive and executive functions among individuals with IC-ASD (e.g., Social Responsiveness Scale: SMD = –0.48; 95 % CI: –0.75 to –0.22; p < 0.01). Similarly, rTMS improved social communication, repetitive and abnormal behaviors (Social Responsiveness Scale: SMD = –0.21; 95 % CI: –0.42 to –0.00; p < 0.05; Repetitive Behavior Scale-Revised: SMD = –0.62; 95 % CI: –1.17 to –0.07; p = 0.04; Aberrant Behavior Checklist: SMD = –0.53; 95 % CI: –0.79 to –0.26; p < 0.01). No significant heterogeneity was observed across studies.

Conclusion

tDCS and rTMS may enhance cognitive and executive functions and reduce repetitive behaviors in children and young adults with IC-ASD. However, these findings require careful interpretation due to the limited high-quality studies and variability in treatment protocols. Future research should prioritize the development of standardized protocols to address inconsistencies in stimulation parameters (including frequency, intensity, and duration) and core outcome sets. Additionally, larger-scale, rigorously blinded multi-center RCTs are necessary to accurately evaluate the clinical efficacy and applicability of these neuromodulation techniques in these populations.

 

rTMS and tDCS look like interesting non-pharmaceutical options for those with milder types of autism. How well they work in those with lower cognitive function is not addressed.

 

Back to Folate Deficiency

Stephen recently highlighted a Chinese study that looked at the relevance of mutations in the genes MTHFR, MTR, and MTRR to try and identify those most at risk of folate deficiency.

I also highlight research into treating some of the downstream consequences that occur when folate metabolism is impaired. The lack of folate disrupts the immune system causing anomalies such as low NK cells, low NKT cells, high TNF-alpha.

Immunodeficiency (Low NK and NKT cells): The deficiency in these crucial innate immune cells means the body's ability to fight off infections (particularly opportunistic ones) and perform immune surveillance (e.g., against abnormal cells) is compromised. This immunosuppression is a direct consequence of the impaired cell proliferation due to the folate cycle defect.

Systemic Inflammation (High TNF-alpha): Despite the low numbers of certain immune cells, there can be an overproduction of pro-inflammatory cytokines like TNF-alpha. This leads to chronic systemic inflammation. This phenomenon is often referred to as hypercytokinemia.

Beyond TNF-alpha, you might expect a possible overproduction of:

• Interleukin-1 beta (IL-1β): This is a potent pro-inflammatory cytokine involved in various immune responses and neuroinflammation.
• Interleukin-6 (IL-6): Another major pro-inflammatory cytokine that plays a role in systemic inflammation and can affect brain development and function.
• Interferon-gamma (IFN-γ): This is a key cytokine in Th1 immune responses and is also pro-inflammatory.

 

The recent Chinese study concludes that high-dose folinic acid appears to be a promising intervention for children with autism. Its efficacy is notably associated with specific folate metabolism gene polymorphisms. The researchers suggest that high-dose folinic acid may help to improve neurodevelopmental outcomes by alleviating the folate metabolism abnormalities caused by single or combined mutations in these genes.

This research indicates that providing a metabolically active form of folate (folinic acid, calcium folinate, leucovorin etc) can be a direct approach to address the underlying metabolic challenges in a subset of people with autism who have specific genetic predispositions related to folate metabolism. Children with MTHFR A1298C or MTRR A66G mutations showed greater improvements in various developmental domains compared to those with the standard versions.

The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group.

No significant adverse effects were observed during the intervention period.

 

How does this fit in with US research into brain folate deficiency in autism

US researchers consider an autoimmune mechanism where the body produces antibodies that specifically target the Folate Receptor Alpha (FRα). FRα is a crucial protein responsible for transporting folate across the blood-brain barrier (and into other cells).

When these antibodies bind to FRα, they block or interfere with the normal transport of folate into the cells, particularly into the brain. This results in Cerebral Folate Deficiency (CFD), where folate levels in the cerebrospinal fluid are low, despite potentially normal folate levels in the blood.

US research indicates that FRAAs are prevalent in a significant percentage of children with ASD (up to 70% in some studies) and are associated with specific physiological and behavioral characteristics.

Treatment with folinic acid/ leucovorin has been shown to be effective in many children with autism who are positive for FRAAs, improving symptoms like communication, irritability, and stereotypical behaviors. It is believed that high doses of folinic acid can overcome the transport blockade caused by the antibodies

The US and Chinese research avenues complement each other by identifying different, but potentially converging, pathways that lead to folate dysfunction in autism, both of which demonstrate the therapeutic potential of folinic acid.

Here is the Chinese paper: 

Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms

Background/Objectives: Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms and efficacy. Methods: A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (n = 50) or a control group (n = 30). The intervention group was administered folinic acid (2 mg/kg/day, max 50 mg/day) in two divided doses. Efficacy was measured using the Psycho-Educational Profile, Third Edition (PEP-3) at baseline and 12 weeks by two trained professionals blind to the group assignments. Methylenetetrahydrofolate reductase (MTHFR C677T, MTHFR A1298C), methionine synthase (MTR A2756G), and methionine synthase reductase (MTRR A66G) were genotyped by the gold standard methods in the intervention group. Results: 49 participants in the intervention group and 27 in the control group completed this trial. Both groups showed improvements from baseline to 12 weeks across most outcome measures. The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group. Children with MTHFR A1298C or MTRR A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as MTHFR C677T and A1298C. No significant adverse effects were observed during the intervention. Conclusions: High-dose folinic acid may be a promising intervention for children with ASD, and its efficacy is associated with folate metabolism gene polymorphisms. High-dose folinic acid intervention may promote better neurodevelopmental outcomes by alleviating folate metabolism abnormalities caused by single or combined mutations in folate metabolism genes.

 

Treating the downstream consequences of low brain folate

Today’s next papers highlight Infliximab, IVIG, Propes, and Inflamafertin as immunomodulatory therapies that target the downstream consequences of folate deficiency; they do not address or improve the underlying lack of folate.

Folate Deficiency in the Brain: This means there is an inherent problem in the body's ability to process or utilize folate, even if dietary intake is sufficient. It is often due to mutations in genes encoding enzymes of the folate cycle (like MTHFR) or transporters. This leads to issues with DNA synthesis, cell proliferation, and methylation, impacting various systems, including the immune system.

 

Infliximab

Infliximab is a TNF-alpha inhibitor. It blocks the activity of TNF-alpha, a key pro-inflammatory cytokine.

It does not put more folate into the system or fix how folate is metabolized. It is like putting out a fire (inflammation) that was started because of a broken electrical wire (folate deficiency's impact on immunity).

 

IVIG (Intravenous Immunoglobulin)

IVIG is a broad-acting immunomodulatory therapy composed of pooled antibodies from thousands of healthy donors. Its mechanisms are complex and include neutralizing autoantibodies, blocking Fc receptors, modulating cytokine production, affecting T and B cell function, and influencing complement activation.

IVIG aims to rebalance a dysregulated immune system, reduce inflammation, and sometimes provide passive immunity. It is like resetting an overactive or misdirected immune alarm system. The effect may not last.

 

Propes

Propes contains alpha- and beta-defensins and has a "pronounced immunoactivating and lymphoproliferative effect." It directly stimulates the growth and activity of immune cells like NK and NKT cells. It directly addresses the numbers and activity of NK and NKT cells that are deficient due to the folate cycle problem. It makes the existing cells (or promotes the creation of new ones) work better, despite the underlying folate issue.

 

Inflamafertin

This drug, containing alarmines and adrenomedulin of placental origin, has "pronounced anti-inflammatory and immunomodulatory effects mediated by the induction of interleukin 10 synthesis." Its role is to temper the immune activation  and ensure a more balanced, anti-inflammatory environment.

 

In summary

These therapies are all symptomatic or compensatory treatments for the consequences of genetic folate deficiency on the immune system and the body. They address the resulting immunodeficiency, inflammation, and associated clinical symptoms (like behavioral issues or opportunistic infections).

 

They do not:

• Add more folate to the body (like folic acid or L-methylfolate supplementation would).
• Correct the genetic defect that causes the folate cycle deficiency.
• Improve the body's intrinsic ability to metabolize folate.

Genetic deficiency in the folate cycle disrupts fundamental cellular processes required for the normal development, proliferation, and function of NK and NKT cells, leading to their deficiency in affected children. This deficiency, in turn, contributes to the complex immune dysregulation often seen in autism.

 

Key Findings on NK Cells:

• Initial Deficiency: A significant number of children in the study group (53 patients) had an initial deficiency of NK cells.
• Response to Immunotherapy:
• During the 3-month course of Propes and Inflamafertin, the average number of NK cells in the blood almost doubled.
• NK cell counts reached the lower limit of normal in 74% (39 out of 53) of the patients with a deficiency.
• There was a strong statistical link between the immunotherapy and NK cell normalization.
• Sustainability: A notable finding was that the NK cell numbers returned to almost their initial level within 2 months after the immunotherapy was stopped. This suggests that the effect on NK cells might be temporary and dependent on continuous treatment.

 

Key Findings on NKT Cells:

• Initial Deficiency: A larger proportion of children in the study group (87 patients) had an initial deficiency of NKT cells.
• Response to Immunotherapy:
• The average number of NKT cells in the blood increased by half during the 3-month immunotherapy course.
• NKT cell counts were normalized in 89% (78 out of 87) of the patients with a deficiency.
• There was an even stronger statistical link between the immunotherapy and NKT cell normalization compared to NK cells.
• Sustainability: Importantly, the NKT cell numbers continued to grow for an additional 2 months after the discontinuation of the immunotropic drugs. This suggests a more sustained and potentially longer-lasting effect on NKT cells.

Overall Conclusions from the Study:

• Combination immunotherapy with Propes and Inflamafertin is presented as an effective treatment strategy for the immunodeficiency (specifically NK and NKT cell deficiency) found in children with ASD linked to genetic folate deficiency.
• Both biological drugs were able to normalize the reduced numbers of NK and NKT cells during the 3-month treatment period.
• The study highlights that the effect on NKT cells was more frequent, stronger, and more lasting compared to the effect on NK lymphocytes.

 

The research papers:

EFFICACY OF INFLIXIMAB IN AUTISM SPECTRUM DISORDERS IN CHILDREN ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

 The notion of systemic inflammation in autism spectrum disorders in children has been established. A recent meta-analysis of randomized controlled trials published in 2019, which included a systematic review of 25 case-control studies, suggests an association between genetic deficiency of the folate cycle and autism spectrum disorders in children [18]. This evidence is consistent with an earlier meta-analysis of randomized controlled trials from 2013, which included data from 8 studies [17]. The encephalopathy that develops in children with genetic deficiency of the folate cycle and manifests as autism spectrum disorders is associated with oxidative stress. The reason for the latter can be seen in the suppression of the immune system with the development of a special form of immunodeficiency, which is based on the deficiency of natural killers, natural killer T lymphocytes and CD8 +  cytotoxic T cells [11]. Immunodeficiency mediates all three known mechanisms of brain damage in children with genetic deficiency of the folate cycle, namely the development of opportunistic infections [2, 15], autoimmune reactions against neuronal antigens [3, 6] and manifestations of systemic inflammation, which is based on the phenomenon of hypercytokinemia [13, 20]. Children with autism spectrum disorders have been shown to have overproduction of several proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, and interleukin-6

In SG, there was a pronounced positive dynamics in the direction of hyperactivity, hyperexcitability and stereotyped behavior, but no significant effect was noted on the stability of eye contact and the development of expressive-receptive language, while in CG some positive changes were achieved specifically in terms of expressive language and the level of eye contact, which indicates different points of action of infliximab and specialized educational programs (Table 11.1). The psychotropic effect obtained with infliximab differs from that of intravenous immunoglobulin, which has also demonstrated clinical efficacy in ASD associated with GDFC [10, 12]. The changes induced by infliximab are more pronounced and develop in a shorter time frame, but they are significantly narrower in terms of the spectrum of positive psychotropic effects compared to high-dose immunoglobulin therapy, which has a total modifying effect on the psyche of such children.

Materials and methods. This prospective controlled single-center non-randomized clinical study included 225 children diagnosed with autism spectrum disorders associated with genetic deficiency of the folate cycle. The diagnosis of autism spectrum disorders was made by psychiatrists from regional hospitals or specialized departments according to DSM–IV–TR (Diagnostic and Statistical Manual of mental disorders) and ICD–10 criteria. Children were recruited into the study group (SG) in 2019–2020. These were patients from different regions of Ukraine aged 2 to 9 years, in whom elevated serum TNF-alpha concentrations were observed. As is known, the phenotype of genetic deficiency of the folate cycle includes 5 main syndromes: autism spectrum disorders, intestinal syndrome (persistent enteritis/colitis) [7], PANDAS [4, 9], epileptic syndrome [5] and signs of pyramidal tract damage.

 

Conclusions. Infliximab leads to significant improvements in hyperactivity and hyperexcitability, as well as stereotypic behavior in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Responders to immunotherapy are 76 % of patients with this pathology, which is twice as high as with standard therapy. However, there is no effect of infliximab on such manifestations of autism as the level of eye contact and language development. Psychotropic effects of infliximab immunotherapy are closely related to the normalization of previously elevated serum TNF-alpha concentrations and are probably due to the elimination of the pathological activating effect of this pro-inflammatory cytokine on CNS neurons. In parallel, there is an improvement in other clinical syndromes of genetic deficiency of the folate cycle in children with autism spectrum disorders – intestinal pathology, epileptic syndrome, and PANDAS, in the pathogenesis of which, as is known, TNF-alpha and the systemic and intracerebral inflammation induced by this cytokine are involved. However, under the influence of immunotherapy, there is no change in the dynamics of motor deficit in children with symptoms of pyramidal tract damage. Further clinical studies in this direction with a larger number of participants and randomization are necessary to obtain more convincing data.

Efficacy of combined immunotherapy with Propes and Inflamafertin in selective deficiency of NK and NKT cells in children with autism spectrum disorders associated with genetic deficiency of the folate cycle

 Objectives. The results of previous small clinical trials indicate the potential benefit of combination immunotherapy with Propes and Inflamafertin to compensate for NK and NKT cell deficiency due to genetic deficiency of the folate cycle in children with autism spectrum disorders. The purpose of the research was to study the effectiveness of combined immunotherapy with Propes and Inflamafertin in NK and NKT cell deficiency in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Material and methods. This single-center, prospective, controlled, nonrandomized clinical trial included 96 children aged 2 to 10 years with autism spectrum disorders associated with a genetic folate deficiency (study group, SG). Children of SG received Propes at a dose of 2 ml IM every other day for 3 consecutive months (45 injections), and Inflamafertin at a dose of 2 ml IM every other day for 3 months in a row, alternating with Propes (45 injections). The control group (CG) consisted of 32 children of similar age and gender distribution who suffered from autism spectrum disorders associated with genetic deficiency of the folate cycle, but who did not receive immunotherapy. Outcomes. The number of NK cells reached the lower limit of normal in 39 out of 53 patients (74% of cases), with the resulting deficiency of these lymphocytes, and the average number of NK cells in the blood in SG almost doubling during the 3-month course of immunotherapy (р ˂ 0.05; Z ˂ Z0.05). However, it returned to almost initial level in the 2 months following the discontinuation of immunotherapeutic agents (р˃0.05; Z˃Z0.05). The number of NKT cells was normalized in 78 out of 87 patients (89% of cases) with an initial deficiency of these cells, and the average number of NKT cells in the blood in the DG increased during the course of immunotherapy by half (р ˂ 0.05; Z ˂ Z0.05) and continued to grow for the next 2 months after the discontinuation of immunotropic drugs (р ˂ 0.05; Z ˂ Z0.05). There was a link between immunotherapy and normalization of NK - (χ2 = 18.016; OR = 13.929; 95%CI = 3.498-55.468) and NKT-cells (χ2 = 60.65; OR = 46.800; 95%CI = 14.415-151.937) in the blood with a strong association between these processes (criterion φ = 0.504 and 0.715 respectively; С = 0.450 and 0.581 respectively). Conclusions. Combination immunotherapy with Propes and Inflamafertin is an effective strategy for the treatment of immunodeficiency caused by genetic deficiency of the folate cycle in children with autism spectrum disorders.

 

The results obtained in this controlled non-randomized clinical trial indicate that combination immunotherapy with Propes and Inflamafertin is an effective treatment strategy for immunodeficiency caused by genetic folate deficiency in children with autism spectrum disorders. These biological immunotropic drugs are able to normalize the previously reduced number of NK and NKT cells in the blood in this category of patients during a 3-month course of immunotherapy, with a more frequent, stronger and more lasting effect on NKT cells compared to NK lymphocytes.

  

Conclusion

Folinic acid supplementation is an effective therapy for many people with autism. There are many anomalies that appear, for example those people who test positive for the folate transporter antibodies but a lumbar punction then finds normal levels of folate in the brain.  Many people report agitation or aggression when children take calcium folinate at high doses, but this does not seem to get noted in clinical trials. Nonetheless it looks like everyone with autism should at least make a trial.

Note that you should always add a vitamin B12 supplement when giving high dose calcium folinate. This is because more B12 will be required by the biological processes ongoing in the brain and deficiency will cause side effects.

Many people who respond well to calcium folinate end up needing some kind of immunotherapy on top. IVIG is extremely expensive and quite a bother if you need to take it forever. Some of the therapies from the two papers today also involve a very large number of injections, so are not really practical.  The less intrusive immunotherapies look more practical but are not cheap.

I think that rTMS and tDCS will be attractive to those seeking non-pharmaceutical options that have a scientific basis. The same applies to low level laser therapy, also known as photobiomodulation therapy.

Pioglitazone for Autism and Specifically Summertime Raging and Verapamil-responsive Autism?

 

Adult-sized people with autism can cause property damage and much worse.

I am told that summertime raging is a common problem encountered by neurologists, but it remains poorly understood and usually remains untreated.

The most common worry for parents of toddlers diagnosed with severe autism is their lack of speech.

By the time these children reach adulthood, the biggest worry for parents is often aggression and self-injury. Often it is the mother who faces the worst episodes of aggression, which is a really cruel turn of events.

Aggression is usually not present in young children with autism, in some people it never develops, but in others it later becomes established as a learned behavior and then you are stuck with how to deal with it.

One of my own therapy targets has long been to improve cognitive function; this can indeed be achieved and then you can improve important daily living skills (adaptive function). Some steps that you can take to improve cognition, and indeed speech, have a downside in that they increase anxiety, which may lead to aggression. Calcium Folinate (Leucovorin) does cause aggression in a significant minority of people.  I think that low dose Roflumilast (60mcg) is cognitive enhancing, as proposed by the researchers at 100mcg, but it does seem to increase edginess/anxiety. DMF (Dimethyl fumarate) increases alertness, which is a good thing, but too much alertness will make you anxious.

When dealing with a full sized adult, which is more important, increased cognition/speech or avoiding explosive aggression?

Clearly there is a need for a compromise.

In adults with severe autism, living at home, entirely extinguishing aggressive behavior looks like the number one treatment goal.

For children in mainstream school, following the regular curriculum, cognitive function has to be a top priority.  Fortunately, this is our case, but only after starting Bumetanide therapy in 2012.

It looks like you can potentially have the best of both worlds - increased IQ and adaptive function, but without aggressive behavior. That is my own experience, but it was not simple.

Pioglitazone has been covered quite extensively in this blog and it is again featuring in the research. Pioglitazone is an interesting old drug used to treat people with type 2 diabetes; the phase 2 trial for autism has been completed.  I doubt there will be a phase 3 trial due to the high costs. Pioglitazone is broadly anti-inflammatory; it reduces the pro-inflammatory cytokine IL-6 and increases the anti-inflammatory cytokine IL-10.

We have seen in early posts how important is IL-6 and that it plays a key role in both allergy and even how milk teeth roots “dissolve” and then permanent teeth erupt. This transition to permanent teeth is another common cause of raging in autism, in our case it was mostly wintertime raging. 

IL-6, either directly or indirectly, seems to negatively affect behavior.

 

PPAR gamma

In earlier posts there was a lot about the various PPARs. These are used in medicine as targets to treat conditions like high cholesterol and type 2 diabetes.

Resveratrol and Pterostilbene are the OTC supplements that some readers are using. Sytrinol is another such supplement, but its cognitive benefit unfortunately just lasts a few days.

Here is a relatively recent paper on the subject, for those seeking the details. 

 

Nuclear Peroxisome Proliferator-Activated Receptors (PPARs) as Therapeutic Targets of Resveratrol for Autism Spectrum Disorder

 

Or just look up the old posts in this blog:- 

https://epiphanyasd.blogspot.com/search/label/PPAR%CE%B3

PPARs are rather complicated, but do seem to be very relevant.  For example, the master regulator of mitochondrial biogenesis, something called PGC-1 alpha, is activated by PPAR gamma. If you have mitochondrial dysfunction that included a reduced number of mitochondria, you might want to make more mitochondria. A PPAR gamma agonist might be beneficial.

Dysregulation of PGC-1 alpha is associated with neurodegenerative and metabolic disorders including Parkinson's, Alzheimer's and Huntington's.

Outside this blog, there is some interest in PGC-1 alpha and autism, particularly in connection with oxidative stress and mitochondrial dysfunction.

 

“In conclusion, we demonstrated mitochondrial oxidative stress may affect a significant subgroup of ASD children and that the SIRT1/PGC-1α signaling pathway may be a promising medical treatment for ASD.”

Source: Role of SIRT1/PGC-1α in mitochondrial oxidative stress in autistic spectrum disorder

It does look like PPARs can be targeted and provide a benefit for at least some types of autism. My choice is Pioglitazone.

 

Dumber in the Summer

In parallel with summertime raging comes the phenomenon I called “Dumber in the Summer”, where cognitive function regresses.

Monty’s assistant told me recently there is no “Dumber in the Summer” this year, and I opened my medicine cupboard and explained why this is indeed the case.

At least in our case, when you resolve summertime raging, you also protect against cognitive regression. That therapy involves Verapamil, Pioglitazone and allergy therapies, Dymista spray (azelastine + fluticasone) plus Ceterizine and Clemastine. Clemastine also has the pro-myelination effect and stabilizes microglia.

 

Pioglitazone Side effects

In the stage 2 trials for autism doses of 0.25 mg/kg, 0.5 mg/kg and 0.75 mg/kg were all found to be safe and well tolerated.

As a summertime add-on therapy it appears very well tolerated.

In adults with type 2 diabetes, who will tend to be overweight and not so healthy, there are common side effects.  At one point, it was thought that there was an association between this drug and bladder cancer. Now this is thought not to be the case.

For adults with severe untreated autism, who are aggressive and self-injure, these behaviors very much limit where they can live and what they can do during the day. Life expectancy is also severely reduced. If Pioglitazone can help control these behaviors, some side effects are likely a price worth paying. 

 

Conclusion

Pioglitazone, by the standards of autism drugs, has plenty of evidence in the literature, regarding both mouse models and humans, to support an n=1 trial.  It addresses neuro-inflammation, one key feature of autism and it has beneficial effects on mitochondria.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

In a small cohort of autistic children, daily treatment with pioglitazone eased some autistic behaviors, such as irritability, lethargy, stereotypy, and hyperactivity, without significant side effects

 pioglitazone treatment inhibits the secretion of proinflammatory factors, such as nitric oxide and IL-6, and enhances the levels of the secretion of anti-inflammatory factors IL-4 and IL-10. Therefore, considering the results of Qiu and Li and our present findings, pioglitazone acted to benefit autistic-like behaviors possibly via the inhibition of IL-6 secretion in astrocytes stimulated by LPS, which inhibited the neuroinflammatory response.

 

I think for people whose child with autism has a behavioural or cognitive regression in summer, there is good reason to expect a benefit.  They very likely have allergies or other autoimmune conditions.

For people who deal with aggression and self-injury in a person who responds partially, but not 100%, to Verapamil, they may find that Pioglitazone helps to complete their anti-aggression therapy.

Our doctor reader Agnieszka did her best to collect case studies of people with autism responsive to Verapamil, but not enough parents wanted to participate.

Based on the comments section in this blog, it would look like our reader George in Romania has a son whose son’s aggression is reduced by Verapamil.  If some aggression persists in summer, I think there is a very good chance that Pioglitazone will help reduce it.  George did recently share with us the the anti-inflammatory Probiotic Lactobacillus Plantarum 299v, from the previous post and widely used for irritable bowel syndrome (IBS), improved his son's speech.  

Note that the research clearly shows that most autism has an "inflammatory" element, but the exact nature varies (for details read the work of Paul Ashwood at the MIND Institute).  There are very many different anti-inflammatory therapies that are reported to benefit specific people, but there are no unifying therapies that work for all. Some will inevitably make non-responders worse and potentially dramatically so, like L.reuteri ATCC PTA 6475, found in Biogaia Gastrus. Trial and error seems unavoidable if you want to find an effective therapy.

The research proposes Pioglitazone as a year round therapy for idiopathic autism.  In the phase 2 trial almost half of the children were deemed to be responders to the treatment; not a bad result. I think it also has potential as just a summertime add-on therapy. We used it last summer and now again this summer.

People with a diagnosis of mitochondrial disease, who also present with lethargy, might be another target group because of PGC-1 alpha.

Psychobiotics (PS128) for Autism, Stereotypy and Sometimes Effective Therapies for what might be SIBO (Rifaximin and Herbal)

By 品璉 江 - originally posted to Flickr as [1]This file has been extracted from another file: Taipei panorama.jpg, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=79310952

Taipei, home to Lactobacillus plantarum PS128, isolated from fu-tsai, which is a spontaneously fermented mustard product

Our reader Prada is a fan of the Biogaia Gastrus probiotic and did comment recently that her doctor does not believe in SIBO (Small Intestinal Bacterial Overgrowth).  We know that many doctors, particularly in English-speaking countries, believe that probiotics have no serious medical value. Many autism parents think their child has SIBO and give them probiotics, among other therapies.

Unless there is a consistently reliable diagnostic test that is affordable and widely available, you inevitably get the situation where patients are convinced that they have a condition (SIBO, PANS/PANDAS, Fibromyalgia etc) while their local doctor thinks it is all in their imagination.

When it comes to probiotic bacteria as a therapy, Italian doctors take them entirely seriously, while many English-speaking doctors regard them as little more than a placebo.  I discovered to my surprise 20 years ago that some really do work.

One reader of this blog in Italy was recommended the new Taiwanese-developed “Psychobiotic” Neuraxbio (Lactobacillus plantarum PS128) by her gastroenterologist and found it was beneficial for her child’s stereotypy. Anyway, her enthusiasm brought me back to Psychobiotics.

I did consider writing a post a while back on Psychobiotics, which are probiotic bacteria that can provide reliable modulation of something useful inside the brain and may have nothing to do with treating GI problems.  It is a nice idea, but the problem is the “reliable” part. In this blog we have already seen that in some people certain commercially available probiotics can have a benefit on behaviour. The problem is that in most people there was either no effect, or actually a negative effect.

There is a small probiotic company in Taiwan, called Bened, that is developing products specifically targeting neurological conditions, including: -

·        Depression

·        Autism

·        ADHD

·        Parkinson’s disease

In 2016 they patented their first product, Lactobacillus plantarum PS128 (isolated from fu-tsai) and started selling it in Asia, where it is widely available and now it is sold in Europe and the US.

In Hong Kong it is sold as “Smart Kids Probiotics” (智樂益生素), under the brand Boost & Guard (補健).

In France it is sold as Neurobiotique, in Italy as Neuraxbio and in the US as Solace.  The US vendor has an easy to read brochure

https://solaceprobiotic.com/pages/brochure

For readers in the Balkans, PS128 is also coming your way soon, Corona virus permitting.

http://www.benedbiomed.com/en/news/The%20world’s%20unique%20Psychobiotic%20PS128™%20will%20reach%20the%20Balkans.-103.html

In Bened’s view, the current opportunities are: -

·        Psychobiotics, that regulate both serotonin and dopamine and can treat anxiety and depression.  (Lactobacillus plantarum PS128)

“Chronic administration of Lactobacillus plantarum PS128 significantly ameliorates anxiety and depression-like behaviors, increases dopaminergic activity in the prefrontal cortex, and reduced stress-induced elevation of serum corticosterone and inflammatory cytokine levels in mice subjected to early maternal separation. Oral administration with Lactobacillus plantarum PS128 significantly decreases visceral hypersensitivity in a rat animal model. Lactobacillus plantarum PS128 shows potential for irritable bowel syndrome (IBS) treatment.”

·        Immunobiotics, that rebalance the production of Th1/Th2 cytokines (Lactococcus lactis A17)

“In vitro experiment reveals cytokines IFN-γ production by human peripheral blood mononuclear cells stimulated with Lactococcus lactis A17 is higher compared with those with other 17 Lactic acid bacteria strains, including Lactobacillus rhamnosus GG and Lactobacillus casei strain Shirota. The Ovalbumin (OVA)-sensitized BALB/c mouse model was further conducted to further examine the Immunomodulatory activities of A17. Repression of NOD-1, NOD-2, TLR-4 production”

·        Metabolicbiotics, that reduce weight, cholesterol and triglycerides in those with a high fat diet (Lactobacillus plantarum K21)

“Supplementation of Lactobacillus plantarum K21 appeared to alleviate body weight gain and epididymal fat mass accumulation, reduce plasma leptin levels, decrease cholesterol and triglyceride levels, and mitigate liver damage in diet-induced obese mice. In addition, Lactobacillus plantarum K21 supplementation strengthens intestinal permeability and modulates the amount of Lactobacillus spp., Bifidobacterium spp., and Clostridium perfringens in the cecal contents of diet-induced obese mice. Dietary intake of Lactobacillus plantarum K21 does protect against the onset of high-fat diet induced obesity through multiple mechanisms of action.”

  

What does Lactobacillus PS128 do?

The research suggests that PS128 affects serotonin and dopamine while also being anti-inflammatory by reducing the expression of the inflammatory cytokine IL-6 and increasing the expression of the anti-inflammatory cytokine IL-10.  In the jargon, it shifts the Th1/Th2 balance.

Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice. 

 Highlights

·        We found a Lactobacillus plantarum strain PS128 changed emotional behaviors.

·        PS128 reduced depression-like behavior in ELS mice.

·        PS128 reduced anxiety-like behavior in normal adult mice.

·        PS128 modulated prefrontal cortical serotonergic and dopaminergic systems.

  

Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms.

Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice.

 

Probiotics, defined as live bacteria or bacterial products, confer a significant health benefit to the host, including amelioration of anxiety-like behavior and psychiatric illnesses. Here we administered Lactobacillus plantarum PS128 (PS128) to a germ-free (GF) mouse model to investigate the impact of the gut-brain axis on emotional behaviors. First, we demonstrated that chronic administration of live PS128 showed no adverse effects on physical health. Then, we found that administration of live PS128 significantly increased the total distance travelled in the open field test and decreased the time spent in the closed arm in the elevated plus maze test, whereas the administration of PS128 had no significant effects in the depression-like behaviors of GF mice. Also, chronic live PS128 ingestion significantly increased the levels of both serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus. These results suggest that the chronic administration of PS128 is safe and could induce changes in emotional behaviors. The behavioral changes are correlated with the increase in the monoamine neurotransmitters in the striatum. These findings suggest that daily intake of the L. plantarum strain PS128 could improve anxiety-like behaviors and may be helpful in ameliorating neuropsychiatric disorders.

New perspectives of Lactobacillus plantarum as a probiotic: The gut-heart-brain axis

Lactobacillus plantarum is a non-gas-producing lactic acid bacterium that is generally regarded as safe (GRAS) with Qualified Presumption of Safety (QPS) status. Although traditionally used for dairy, meat and vegetable fermentation, L. plantarum is gaining increasing significance as a probiotic. With the newly acclaimed gut-heart-brain axis, strains of L. plantarum have proven to be a valuable species for the development of probiotics, with various beneficial effects on gut health, metabolic disorders and brain health. In this review, the classification and taxonomy, and the relation of these with safety aspects are introduced. Characteristics of L. plantarum to fulfil the criteria as a probiotic are discussed. Emphasis are also given to the beneficial functions of L. plantarum in gut disorders such as inflammatory bowel diseases, metabolic syndromes, dyslipidemia, hypercholesteromia, obesity, and diabetes, and brain health aspects involving psychological disorders.

Psychobiotics

According to the definition by WHO, mental health is an integral and essential component of health, a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. Furthermore, mental health is more than just the absence of mental disorders or disabilities (WHO, 2016). Major depressive disorder and anxiety disorders are debilitating illnesses that are rising as a global burden of disease (Whiteford et al., 2015; Logan et al., 2016). Dr. Dinan and colleagues defined a new group of bacteria, termed psychobiotics, as ‘live organisms that produce health benefits in patients suffering from psychiatric illness when ingested in adequate amounts’ and the ingestion of psychobiotics may induce psychotropic effects on behavior and additional neurochemicals in the brain (Dinan et al., 2013). This concept has shed light on microbe-based psychopharmacology. The human intestine has a large surface area, ranging from 30 to 400 cubic meters (Perez-Lopez et al., 2016), and is inhabited by 1013 to 1014 microorganisms. The number of microorganisms is 10 times greater than that of human cells, and the encapsulated genetic material exceeds the human genome content by 150-fold (de Vos and de Vos, 2012; Lozupone et al., 2012; Dinan et al., 2013). Because the large number of microorganisms live with human, it is logical to infer that associated microorganisms may play roles in human health and even in mental health. Considering that the gut-brain axis is a new concept and the applications of probiotics to enhance mental health is at its infancy, only few strains of L. plantarum have been investigated for this purpose. One of the more prominent strains of L. plantarum investigated as a psychobiotic is L. plantarum PS128 (Liu et al., 2016a, 2016b). The psychotropic effects of L. plantarum PS128 were investigated in an early life stress (ELS) mouse model. ELS negatively impacts brain development and results in behavioral changes in adulthood (Lupien et al., 2009). Maternal separation triggers ELS in rodents (O’Mahony et al., 2011). Mice that experience maternal separation exhibit lasting behavioral abnormalities, enhanced stress responses, increased anxiety-like and depression-like behaviors, elevated HPA reactivity, and altered neurochemical expression (Cryan and Holmes, 2005). Several behavior tests were employed to evaluate the effects of L. plantarum PS128 on abnormal behaviors, namely the sucrose preference test (SPT) and forced swimming test (FST). L. plantarum PS128 at a daily dose of 109 CFU/mouse reduced ELS-induced depression-like behaviors (Liu et al., 2016b). Maternal separation-triggered stress responses are evidenced by elevated levels of corticosterone before and after FST stress treatment. L. plantarum PS128 significantly reduced corticosterone levels at baseline and after FST, indicating that PS128 normalizes the HPA axis. Elevated serum levels of IL-6 are often observed in people experiencing childhood stress (Coelho et al., 2014). Modulation of IL-6 expression also potentiates the beneficial effects of L. plantarum PS128 on depression. Reduced levels of dopamine (DA) and serotonin (5-HT) and increased turnover rates of DA and 5-HT have been observed in the prefrontal cortex (PFC) of ELS mice. L. plantarum PS128 reversed these changes to a status similar to normal control mice, demonstrating the potential of PS128 as a psychobiotic to improve mental health. L. plantarum C29 was reported to protect memory deficit induced by scopolamine (Jung et al., 2012), D-galactose (Woo et al., 2014), aging (Jeong et al., 2015), and IBD (Lee et al., 2018). Increased expression of derived neurotrophic factor (BNDF) was observed in the above studies. BDNF protein is widely distributed throughout the adult brain in almost all cortical areas and was believed to be necessary for the continued survival and phenotypic maintenance of mature, fully developed neurons. In review of Zuccato and Cattaneo (2009), the levels of BDNF in brain were decreased in neurodegenerative diseases, Alzheimer disease, Parkinson disease, and Huntington disease (Zuccato and Cattaneo, 2009). The protective effects of L. plantarum C29 on memory deficit may attribute to the ability to elevate BDNF in brain

Does Lactobacillus PS128 work for “autism”?

People understandably assume a product should do what it says.  Probiotics to treat GI problems from diarrhea to IBS to IBD are pretty well researched and though some are expensive (e.g. VSL#3, Vivomixx) they do work for many people.

Some people use Biogaia Gastrus as a Pyschobiotic with success and our reader Prada has joined that group.  The only way to find out is to try it, but in the case of Biogaia Gastrus it actually makes some people much worse.

There actually is a published study investigating the effect of Lactobacillus plantarum PS128 on Children with Autism.

The study suggests that our reader in Italy and the people with the testimonials in US version of PS128 are not just exceptions.

Effects of Lactobacillus plantarum PS128 on Children with Autism Spectrum Disorder in Taiwan: A Randomized,Double-Blind, Placebo-Controlled Trial

This four-week, randomized, double-blind, placebo-controlled study investigated the effects of Lactobacillus plantarum PS128 (PS128) on boys with autism spectrum disorder (ASD) aged 7–15 in Taiwan. All subjects fulfilled the criteria for ASD diagnosis of DSM-V and the Autism Diagnostic Interview-Revised (ADI-R). Questionnaires used for the primary outcome measure include the Autism Behavior Checklist-Taiwan version (ABC-T), the Social Responsiveness Scale (SRS) and the Child Behavior Checklist (CBCL). The Swanson, Nolan, and Pelham-IV-Taiwan version (SNAP-IV) and the Clinical Global Impression-improvement (CGI-I) were used for the secondary outcome measure. The results showed that PS128 ameliorated opposition/defiance behaviors, and that the total score of SNAP-IV for younger children (aged 7−12) improved significantly compared with the placebo group. Additionally, several elements were also notably improved in the PS128 group after 28-day consumption of PS128. Further studies are needed to better clarify the effects of PS128 for younger children with ASD on broader symptoms.

I think the following study is relevant to our Italian reader, for whom NAC did not benefit stereotypy, but PS128 did.

I did mention to her the Tourette’s type autism, that was studied in Siena. In these people a dopamine disorder causes the repetitive behavior, so the behaviors are really better described as tics than stereotypy.  Note that a serotonin agonist can cause a dopamine driven tic.

  

Inflammatory Response to GAS (Group A Strep) and Dysmaturational Syndrome (Tourette’s Syndrome with Autism “Recovery” by 6 Years Old)

Lactobacillus plantarum PS128 ameliorates2,5-Dimethoxy-4-iodoamphetamine-induced tic-like behaviors via its influenceson the microbiota–gut-brain-axis

Highlights

Serotonin receptor agonist DOI causes tic-like behaviors and gut dysbiosis in rat.

DOI triggers hyperactive signaling in mesocortical and nigrostriatal pathways.

PS128 alleviates DOI-induced behavior and hyperactive signaling.

PS128 modulates enteric serotonergic system and stabilizes gut microbiota.

PS128 strengthens the microbiota–gut–brain axis function of the host.

 

Abstract

We previously reported a novel psychobiotic strain of Lactobacillus plantarum PS128 (PS128) which could ameliorate anxiety-like& depression-like behaviors and modulate cerebral dopamine (DA) and serotonin (5-HT) in mice. Here, we examine the possibility of using PS128 administration to improve tic-like behaviors by using a 5-HT_2A and 5-HT_2C receptor agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI). PS128 was orally administered to male Wistar rat for 2 weeks before two daily DOI injections. We recorded the behaviors immediately after the second DOI injection and compared the results with control and haloperidol treatment groups. PS128 significantly reduced tic-like behaviors and pre-pulse inhibition deficit in a threshold-dose of 10⁹ CFU per day. Brain tissue analysis showed that DOI induced abnormal DA efflux in the striatum and prefrontal cortex, while PS128 ingestion improved DA metabolism and increased norepinephrine (NE) levels in these two regions. In addition, PS128 ingestion increased DA transporter and β-arrestin expressions and decreased DOI-induced phosphorylation of DA and cAMP regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) at Thr34 and extracellular regulated protein kinases (ERK). PS128 ingestion also modulated peripheral 5-HT levels and shaped the cecal microbiota composition, which helps to alleviate DOI-induced dysbiosis. These results suggested that PS128 ameliorated DOI-induced tic-like hyper-active behaviors via stabilizing cerebral dopaminergic pathways through its modulation of host’s microbiota–gut–brain axis. Thus, we believe there are potentials for utilizing psychobiotics to improve syndromes caused by DA dysregulation in DA-related neurological disorders and movement disorders such as Tourette syndrome.

Lactobacillus PS128 clearly does benefit some people. It does have an effect on GI problems, but it may well benefit some people who have no GI problems.  It is specifically targeted at the brain, not the gut.

If available locally it is worth a trial.

Is it going to make some people “worse”?  It affects serotonin and dopamine and it is “anti-inflammatory” (raises IL-10 and lowers 1L-6), so some people undoubtedly will not be compatible.

It is not a cheap product, but is sold to be refrigerated and contains 30 billion colony forming units (CFU).  It looks like a serious probiotic like VSL#3, Vivomixx and Biogaia.

People are making home-made yogurt with Biogaia Protectis and Biogaia Gastrus, so if Lactobacillus PS128 is effective but looks pricey, you can make your own. Lactobacillus bacteria grow well in milk

Some yoghurts have Lactobacillus rhamnosus added.

Making fermented milk products is actually very easy, this how you can grow your own Lactobacillus PS128.

I can envisage adding Lactobacillus PS128 fermented in milk to Monty’s breakfast yoghurt.

The other possible reason that Lactobacillus PS128 helped our Italian reader’s daughter is its effect on serotonin.

Some people find that SSRI drugs like Prozac reduce stereotypy along with anxiety.  SSRI drugs can have side effects and may not be an ideal therapy for stereotypy.

Research in apes supports the fact that some people find inositol reduces stereotypy.  Inositol is a naturally occurring sugar found in the brain that acts both as a messenger and a precursor to other neurotransmitters. The inositol trisphosphate receptor (IP3R) is a Ca²⁺ channel activated by inositol trisphosphate (IP3).  IP3R appears to be a downstream nexus where many different types of autism converge.

Inositol is used to treat PCOS due to its metabolic effects.

Inositol appears to indirectly have an effect on serotonin, but it gets very complicated.

Source: Potential role and therapeuticinterests of myo-inositol in metabolic diseases

As you would expect, the serotine-type stereotypy is the result of one specific receptor.  It appears to be 5-HT₇ or 5-HT_1A.

An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models

Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT₇ receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT_1A partial agonist with relevant affinity at 5-HT₇ receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2′-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT₇ (K_i = 5.8 nM, EC₅₀ = 34 nM) and 5-HT_1A (K_i = 22 nM, EC₅₀ = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT₂ agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A  Randomized Trial 

Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy.

Results

There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups.

Conclusions

Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions.

  

Stereotypies in Captive Primates and the Use of Inositol: Lessons from Obsessive–Compulsive Disorder in Humans

Animal stereotypies have long been used in the study of obsessive–compulsive disorder (OCD) in humans. These studies have led to the understanding of some of the molecular pathways in the disorder and the use of selective serotonin reuptake inhibitors and myo-inositol in the treatment of these conditions. If animal models, especially nonhuman primate models, were used to study human disorders and if the resulting treatments were successful, then conversely one should be able to treat nonhuman primate stereotypies with similar methods. We here summarize animal models of OCD (including nonhuman primate models) and human OCD treatments, and using successful human treatment by myo-inositol as models, recommend the use of myo-inositol in good captive management practice and the treatment of nonhuman primate stereotypies. We believe that this would be particularly useful in the treatment of stereotypies in nonhuman primates because they are physiologically so similar to humans.

Inositol holds much promise in the treatment and prevention of stereotypic behavior, and although much research is required to understand the molecular mechanisms behind its mode of action and the reason for failure in 30 % of human cases, its use does mean the possibility of treatment and prevention in 60–70 % of cases that would otherwise be untreatable.

Back to SIBO

Many people think their child with autism has SIBO (Small intestinal bacterial overgrowth). Most likely some do and some do not.

To diagnose SIBO you need a breath test

Here is what Johns Hopkins have to say about SIBO: -

https://www.hopkinsmedicine.org/gastroenterology_hepatology/diseases_conditions/small_large_intestine/small-intestinal-bacterial-overgrowth.html

Our gastroenterologists (doctors who specialize in the digestive system) diagnose SIBO with a lactulose breath test. For the test, you will swallow a drink containing the sugar lactulose. Next, you will breathe into a balloon approximately every 15 minutes over the course of three hours. Each time, we remove the breath sample from the balloon and test it. SIBO may be present if your breath sample contains hydrogen or methane shortly after drinking the solution.

Treatment

·         hydrogen-predominant SIBO: The primary treatment is the antibiotic rifaximin.

·         methane-predominant SIBO This type of SIBO is harder to treat, and it may take longer to respond to treatment. We use rifaximin plus neomycin for these cases.

·         recurrent SIBO: We closely monitor you for a recurrence of SIBO. If it happens, you will benefit from our experience treating the disease. We have experience with formulations of antimicrobial herbs, which can be used to treat recurrences and as an alternative for initial treatment of hydrogen- or methane-predominant SIBO.

As part of your treatment, we recommend following a FODMAP (low fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet and consulting with a nutritionist.

The symptoms of SIBO are not unique to SIBO

SIBO is an abnormal number of bacteria in the small intestine that can lead to:

·         bloating and increased passing of gas (flatulence)

·         diarrhea or constipation

·         abdominal pain

·         nausea

·         fatigue

What are SIBO risk factors?

Structural or anatomic abnormalities may affect normal movement of the small intestine (motility). Stasis, or lack of movement, can lead to bacterial imbalance. This can occur if you:

·         Have diverticulosis — tiny bulging pouches (diverticula) in the small intestine

·         Had surgery that changed the small intestine’s structure, such as Roux-en-Y gastric bypass surgery, or surgery on the right colon with removal of the ileocecal valve, or surgery on the last part of the small bowel.

·         Have adhesions (scar tissue) that developed after radiation therapy or after multiple abdominal surgeries

·         Have amyloidosis (a buildup of amyloid protein deposits) — deposits can accumulate in the small intestine and change its structure

Use of certain medications could be linked to SIBO. These include:

·         Narcotic medications

·         Anti-spasm medications for irritable bowel syndrome (IBS), such as hyoscyamine or dicyclomine

·         Long-term use of proton pump inhibitors (PPIs) — medications that decrease acid in the stomach to control heartburn

·         Frequent use of antibiotics, which may alter the bacteria in the small bowel

Chronic systemic conditions can cause motility issues. If you have these conditions, you may be at a higher risk for SIBO:

·         Diabetes

·         Lupus

·         Scleroderma or connective tissue disorders

What is the problem with rifaximin?

Rifaximin is a generic antibiotic used to treat traveler’s diarrhea, irritable bowel syndrome and SIBO.

In much of the world Rifaximin is very cheap, it costs a few dollars/euros where I live, but in the US it costs thousands of dollars a year.

So, the land of the free is where big pharma is free to make obscene profit margins, as they do even with life-saving drugs like insulin.  In developed countries Type-1 diabetic people get their insulin free and there is universal healthcare.

There are many other drug options other than Rifaximin and in the study below they found some herbal treatments as effective as Rifaximin.

Herbal Therapy Is Equivalent to Rifaximin for the Treatment of Small Intestinal Bacterial Overgrowth

Objective:

Patients with small intestine bacterial overgrowth (SIBO) have chronic intestinal and extraintestinal symptomatology which adversely affects their quality of life. Present treatment of SIBO is limited to oral antibiotics with variable success. A growing number of patients are interested in using complementary and alternative therapies for their gastrointestinal health. The objective was to determine the remission rate of SIBO using either the antibiotic rifaximin or herbals in a tertiary care referral gastroenterology practice.

Design:

One hundred and four patients who tested positive for newly diagnosed SIBO by lactulose breath testing (LBT) were offered either rifaximin 1200 mg daily vs herbal therapy for 4 weeks with repeat LBT post-treatment.

Results:

Three hundred ninety-six patients underwent LBT for suspected SIBO, of which 251 (63.4%) were positive 165 underwent treatment and 104 had a follow-up LBT. Of the 37 patients who received herbal therapy, 17 (46%) had a negative follow-up LBT compared to 23/67 (34%) of rifaximin users (P=.24). The odds ratio of having a negative LBT after taking herbal therapy as compared to rifaximin was 1.85 (CI=0.77-4.41, P=.17) once adjusted for age, gender, SIBO risk factors and IBS status. Fourteen of the 44 (31.8%) rifaximin non-responders were offered herbal rescue therapy, with 8 of the 14 (57.1%) having a negative LBT after completing the rescue herbal therapy, while 10 non-responders were offered triple antibiotics with 6 responding (60%, P=.89). Adverse effects were reported among the rifaximin treated arm including 1 case of anaphylaxis, 2 cases of hives, 2 cases of diarrhea and 1 case of Clostridium difficile. Only one case of diarrhea was reported in the herbal therapy arm, which did not reach statistical significance (P=.22).

Conclusion:

SIBO is widely prevalent in a tertiary referral gastroenterology practice. Herbal therapies are at least as effective as rifaximin for resolution of SIBO by LBT. Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for rifaximin non-responders. Further, prospective studies are needed to validate these findings and explore additional alternative therapies in patients with refractory SIBO

Table 1

Conditions That Predispose Toward the Development of Small Intestine Bacterial Overgrowth

Achlorhydria (surgical, iatrogenic, autoimmune)

Motor abnormalities

Scleroderma

Intestinal pseudo-obstruction

Diabetic enteropathy

Vagotomy

Abnormal communication between colon and small bowel

Fistulas between colon and small bowel

Resection of ileocecal valve

Structural abnormalities

Systemic and intestinal immune deficiency states

Surgical loops (Billroth II, entero-entero anastomosis, Rou-en-Y)

Duodenal or jejunal diverticula

Partial obstruction of small bowel (stricture, adhesions, tumors)

Large small Intestine diverticulosis

Systemic diseases (celiac disease, cirrhosis, pancreatic exocrine insufficiency, non-alcoholic fatty liver disease)

Alcoholism

Table 2

Protective Factors That Protect Against the Development of Small Intestine Bacterial Overgrowth

• Gastric acid

• Pancreatic enzymes

• Bile acids

• Cholecystectomy

• Motility

• Migrating motor complex

• Biofilm

• Secretory immunoglobulin A

Table 3

Extrinsic Factors That Alter the Gut Microbiome and May Influence the Development of Small Intestine Bacterial Overgrowth

FODMAPsa (fructose, lactose, galactans, fructans, sugar alcohols)

Proton pump inhibitors

Anti-motility agents

Fiber

Prebiotics

Probiotics

Antibiotics

Table 4

Antibiotic Regimens Used for Small Intestine Bacterial Overgrowth

Agent                                        Dose                Frequency

Amoxicillin-clavulanate               500 mg             3 times/day

Cephalexin                                250 mg             4 times/day

Chloramphenicol                       250 mg             4 times/day

Ciprofloxacin                            500 mg             twice daily

Doxycycline                              100 mg             twice daily

Metronidazole                           250 mg             3 times/day

Neomycin                                 500 mg             twice daily

Norfloxacin                               400 mg             twice daily

Rifaximin                                  400 mg             3 times/day

Tetracycline                               250 mg             4 times/day

Trimethoprim-                            1 double-          twice daily

Sulfamethoxazole                      strength tablet

Conclusion

I think PS-128 is very likely to be a winner for many people diagnosed with Tourette’s syndrome.

Repetitive behaviors in autism that are caused by a dopamine anomaly may well respond to PS-128. Note that a serotonin anomaly can cause a dopamine anomaly.

Undoubtedly, some people with autism are going to develop a motor/verbal tic when they take PS-128.  They should stop taking it and the tic should fade away, just like the negative reaction to Biogaia Gastrus fades away in those so affected. 

Anxiety is a common feature in autism, but has numerous underlying mechanisms, so I think PS-128 will help some and not others.  It is certainly worth trying.

Tics and stereotypy get confused and the causes may indeed overlap.  Dopamine anomalies can lead to tics and movement disorders.  Serotonin anomalies can lead to repetitive behaviors and of course anxiety.  Oxidative stress can lead to stereotypy and even compulsive behavior like Trichotillomania (pulling out your own hair).  

Autoimmune encephalopathy can give symptoms of tics, OCD and/or stereotypy, and even schizophrenia depending on which receptors in the brain are affected - PANS/PANDAS is a subtype of autoimmune encephalopathy.

·        Low dose Buspirone. It is not an SSRI, but this anxiety medicine at very low doses (2.5 to 5 mg) looks interesting for serotonin-type stereotypy

·        Inositol (it’s cheap and OTC)

·        Prednisone for Autoimmune encephalopathy

You might think the supplement 5HTP would help with the serotin type of stereotypy; 5HTP is a precursor of serotonin that is sold widely for anxiety etc.  Long term use may cause you problems.

5-HTP efficacy and contraindications

The most significant side effects and adverse reactions may occur with long-term use (many months or longer). Administration of 5-HTP alone depletes catecholamines (dopamine, norepinephrine, and epinephrine). When dopamine depletion is great enough, 5-HTP will no longer function.  If other centrally acting monoamine-related disease processes involving catecholamines are present, administration of 5-HTP alone may deplete dopamine, norepinephrine and epinephrine thereby exacerbating these conditions

Some doctors and indeed autism self-advocates think that stereotypy is a healthy calming behavior.  These autism self-advocates tend to be the ones that had a terrible time during their school years, because they were not accepted and now feel that qualifies them to give advice to others.  I not so sure they are right, I would rather take autism advice from happy/successful Aspies, rather than bitter ones.

I think that uncontrollable stereotypy gets in the way of normal life and learning in particular; if its origin is biological, it can be treated.  Since there are multiple possible mechanisms at work, it can take time to find your effective therapy.  As usual, perseverance yields results in most cases.

Back to the SIBO part of this post

I think most people with intestinal dysbiosis do not have SIBO.  If you live in the US, it looks quite easy to get a breath test for SIBO.

Rifaximin seems to benefit many people with autism and GI problems; they may well not have SIBO.  For people outside the US, Rifaximin looks a good choice, for recurring use.  Our reader Maja is a big fan of Rifaximin for her daughter.

If you have to pay thousands of dollars a year for Rifaximin, you may want to look at both the drug and herbal alternatives.

For SIBO caused by long term use of PPIs (acid reducing drugs) you can try alternate day dosing, or the old remedy of drinking diluted apple cider vinegar.  Both methods should increase acidity in the small intestine making it hostile to unwanted bacteria, the way nature intended.  If you drink apple cider vinegar you have to rinse your mouth out afterwards or you will damage your teeth.

Probiotics have been in widespread use to treat GI problems in some countries for half a century.  That is plenty time to judge their effectiveness, if people care to look.

Probiotics have been shown to have far reaching effects beyond the gut and this causes many people to have serious doubts.  How can your gut affect your brain, your eczema or your asthma?

When it comes to the brain, the research has proved that there is bidirectional communication between the brain and the gut via the vagus nerve.  Sever the vagus nerve (which used to be a medical procedure for IBS) and the effect is lost.

Many probiotics sold lack potency either because they were not stored correctly, and the bacteria died or because the producer has included too few bacteria to start with.

The users of Biogaia Gastrus for autism are taking 5 tablets a day, because one tablet contains only 100 million CFU.