Memantine – yet another failed Autism Trial

Memantine (Namenda/ Ebixa) is an Alzheimer’s drug that has been used off-label in autism for many years; but does it actually work?

More than a thousand people with autism have completed clinical trials and yet more trials are in progress. 

A few years ago, at the FDA’s request, the producer of the drug, Forest Laboratories, funded two clinical trials enrolling 903 children with autism.  The results were never fully published because the trials were deemed to have failed to find any positive effect and a note to reflect this is included in each pack of Namenda.

A quick look at ClinicalTrials.gov website shows yet more autism trials in the pipeline.

What is going on?

When Dr Chez made a trial in 2007 he found Memantine to be effective; he has since moved on to stem cell therapy which he also finds to be effective.

The latest study to be published includes Dr Hardan from Stanford, who published that study showing NAC to be effective in autism.  This time his study shows no positive effect.

If you look on the clinical trials site you can see some data for the primary endpoint used in the very big trial funded by Forest Laboratories.  It seems to show 517 responders.

By the time the results were reviewed in detail the conclusion drawn by Forest was “there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo”. 

In other words it does not work.

The drug itself now carries this note:-

8.4 Pediatric Use

The safety and effectiveness of memantine in pediatric patients have not been established.

Memantine failed to demonstrate efficacy in two 12-week controlled clinical studies of 578 pediatric patients aged 6-12 years with autism spectrum disorders (ASD), including autism, Asperger’s disorder, and Pervasive Development Disorder — Not Otherwise Specified (PDD-NOS). Memantine has not been studied in pediatric patients under 6 years of age or over 12 years of age. Memantine treatment was initiated at 3 mg/day and the dose was escalated to the target dose (weight-based) by week 6. Oral doses of memantine 3, 6, 9, or 15 mg extended-release capsules were administered once daily to patients with weights < 20 kg, 20-39 kg, 40-59 kg and ≥ 60 kg, respectively.

In a randomized, 12-week double-blind, placebo-controlled parallel study (Study A) in patients with autism, there was no statistically significant difference in the Social Responsiveness Scale (SRS) total raw score between patients randomized to memantine (n=54) and those randomized to placebo (n=53). In a 12-week responder-enriched randomized withdrawal study (Study B) in 471 patients with ASD, there was no statistically significant difference in the loss of therapeutic response rates between patients randomized to remain on full-dose memantine (n=153) and those randomized to switch to placebo (n=158).

So if it does not work, why do researchers continue to carry out further trials, like the recent one below, including Hardan?

Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension

OBJECTIVE:

Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension.

METHODS:

A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day.

RESULTS:

There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks.

CONCLUSIONS:

This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

  

Dr Chez? 

So how reliable then are Dr Chez’s other findings?  He is a "big name" in autism research.

Back in 2007 Dr Chez published a very positive study on the use of Memantine in autism. 

Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: an observationof initial clinical response and maintenance tolerability.

 

Abstract

Autism and Pervasive Developmental Disorder Not Otherwise Specified are common developmental problems often seen by child neurologists. There are currently no cures for these lifelong and socially impairing conditions that affect core domains of human behavior such as language, social interaction, and social awareness. The etiology may be multifactorial and may include autoimmune, genetic, neuroanatomic, and possibly excessive glutaminergic mechanisms. Because memantine is a moderate affinity antagonist of the N-methylD-aspartic acid (NMDA) glutamate receptor, this drug was hypothesized to potentially modulate learning, block excessive glutamate effects that can include neuroinflammatory activity, and influence neuroglial activity in autism and Pervasive Developmental Disorder Not Otherwise Specified. Open-label add-on therapy was offered to 151 patients with prior diagnoses of autism or Pervasive Developmental Disorder Not Otherwise Specified over a 21-month period. To generate a clinician-derived Clinical Global Impression Improvement score for language, behavior, and self-stimulatory behaviors, the primary author observed the subjects and questioned their caretakers within 4 to 8 weeks of the initiation of therapy. Chronic maintenance therapy with the drug was continued if there were no negative side effects. Results showed significant improvements in open-label use for language function, social behavior, and self-stimulatory behaviors, although self-stimulatory behaviors comparatively improved to a lesser degree. Chronic use so far appears to have no serious side effects.

Making sense of Memantine

Personally, I think it likely that Memantine may indeed have a positive effect in some people with autism.  For most people it probably does no good, but no harm, so it is a harmless placebo that may make the parents feel better and gives the doctor something to prescribe.

Memantine and the very similar Galantamine probably do deserve a place in the long list of drugs and supplements that may be effective in some people.  But how great is that “effect”?  I suspect this is the problem; it is big enough for Dr Chez but not big enough for the others.

I suspect this will be a recurring problem in almost all future autism drug trials.  What is a responder?  How big an effect is a worthwhile effect?

I think a better approach would be to focus on the so-called responders identified by Dr Chez and others.  Document the claimed positive effects and then see if these effects continue when the responders are given a dummy placebo.

This is the approach I use in my trials; when I stop a therapy, I look to see if there is a change.  When you suspend an effective therapy things should get worse.

The hundreds or thousands of kids currently on Memantine should do the same; take a break and see if there is any change, be it positive or negative. 

Many people believe no valid treatments for autism exist and that those thinking otherwise are all deluded.

I think that many people are giving their kids drugs and supplements of no therapeutic value and in some cases are making the situation worse.

However, effective therapies do exist for many people with autism and they stand up to scrutiny.  The effect is apparent to third parties, like teachers and therapists, and when you stop the therapy the positive effect is lost and people notice, only to return when it is restarted.  Then you know it is not wishful thinking and at that point what the FDA says does not really matter and you do not need bother with what subsequent trials say.

So when a reader asked me what I thought about the recent “failed” trial of NAC, to treat social impairment in autism, I took a very relaxed view.  If they had identified 50 kids with classic autism and stereotypy and looked at whether NAC reduced this, I would take note.  They choose the wrong primary endpoint, social impairment, and wasted a lot of money.

A randomized placebo-controlled pilot study of N-acetylcysteine in youth with autism spectrum disorder

Conclusions
The results of this trial indicate that NAC treatment was well tolerated, had the expected effect of boosting GSH production, but had no significant impact on social impairment in youth with ASD.

      

I only wait to see what happens when Ben Ari publishes the results of his large trial on Bumetanide.  Whatever data they choose to collect, is it going to convince the European Medicines Agency that it is an effective therapy?  I hope so, but nothing would surprise me.

I would love to know how Dr Chez rationalizes the fact that so many others cannot replicate his positive research findings.  But he keeps on going.

Rather off-topic, a recent comment on my post on Clonidine, informed us that this drug, often prescribed off-label in autism and ADHD, really is acting as a sedative to calm the person down. So no effect on core autism.  Sedation does have a role to play in some people’s disorders.  Very low doses of Mirtazapine (Remeron) are also sedating via its effect of central H1 receptors; it occurred to me that this might be a safe long term therapy for some "out of control" people with severe autism; likely safer than the usual antipsychotics. 

Autism, Allergies and Summertime Raging in 2016

  

This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.

Not just for Stomach Health

It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.

A single species of gut bacteria can reverse autism-related social behavior in mice

In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.

Ongoing Clinical Trial of Vivomixx Probiotic in Children with Autism

Since there is now interest in the potential benefit of probiotic bacteria to treat some autism, I wanted to point out that there actually is a clinical trial underway in Italy.  It is funded the Italian Ministry of Health and by the Tuscany Region.  They use Vivomixx, an OTC probiotic from the Italian speaking region of Switzerland.   

Vivomixx contains:

Streptococcus thermophilus DSM 24731, bifidobacteria (B. breve DSM 24732, B. longum DSM 24736, B. infantis DSM 24737) 
lactobacilli (L. acidophilus DSM 24735, L. plantarum DSM 24730, L. paracaseiDSM 24733, L. delbrueckii subsp. bulgaricus DSM 24734).

Before you start wondering, it is not cheap; the Swiss do not do cheap.

There is a detailed explanation of the trial in the full version of the paper below.  It is due to be completed at the end of 2017.

  
Vivomixx is virtually identical to a well known expensive probiotic called VCL#3, which has been used in research.  Due to some dispute the originator of VCL#3 started a new company which now sells Vivomixx.  In some countries one is available and in other countries it is the other one.  VCL#3 is even more expensive. 

Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters

Background

A high prevalence of a variety of gastrointestinal (GI) symptoms is frequently reported in patients with Autism Spectrum Disorders (ASD). The GI disturbances in ASD might be linked to gut dysbiosis representing the observable phenotype of a “gut-brain axis” disruption. The exploitation of strategies which can restore normal gut microbiota and reduce the gut production and absorption of toxins, such as probiotics addition/supplementation in a diet, may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this randomized controlled trial is to determine the effects of supplementation with a probiotic mixture (Vivomixx®) in ASD children not only on specific GI symptoms, but also on the core deficits of the disorder, on cognitive and language development, and on brain function and connectivity. An ancillary aim is to evaluate possible effects of probiotic supplementation on urinary concentrations of phthalates (chemical pollutants) which have been previously linked to ASD.

Methods

A group of 100 preschoolers with ASD will be classified as belonging to a GI group or to a Non-GI (NGI) group on the basis of a symptom severity index specific to GI disorders. In order to obtain four arms, subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotics or with placebo for 6 months. All participants will be assessed at baseline, after three months and after six months from baseline in order to evaluate the possible changes in: (1) GI symptoms; (2) autism symptoms severity; (3) affective and behavioral comorbid symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal function; (5) neurophysiological patterns.

Discussion

The effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trials. Examining the impact of probiotics not only on clinical but also on neurophysiological patterns, the current trial sets out to provide new insights into the gut-brain connection in ASD patients. Moreover, results could add information to the relationship between phthalates levels, clinical features and neurophysiological patterns in ASD.

Trial registration

ClinicalTrials.gov Identifier: NCT02708901. Retrospectively registered: March 4, 2016.

So in the coming years it looks like there will be some actual data with which you can decide whether or not to trial specific probiotic bacteria. 

Hopefully, the Biogaia people in Sweden will provide their products for some independent researchers to trial on humans with autism, probably Swedish ones.

Biogaia Trial for Inflammatory Autism Subtypes

UPDATE: A significant minority of parents report negative reaction to Bio Gaia, this seems to relate to histamine; but more than 50% report very positive effects without any side effects; so best to try a very small dose initially to see if it is not well tolerated. 

Histamine Reaction to Bio Gaia gastrus

Alli, our reader from Switzerland, has established that a large daily dose (5 tablets a day, cycled 3 weeks on and 3 weeks off) of the Biogaia Gastrus probiotic has a positive effect on the inflammatory sub-type of her son’s autism and also in other people she has shared her therapy with.  There is plenty of science to support its use.

In earlier posts I looked at a different probiotic bacteria (Clostridium butyricum Miyairi 588) that is widely used in animals to improve auto-immune health.  That bacteria is used in humans, but as is the case with BioGaia Gastrus, the focus is on stomach health not auto immunity.  Nobody has proposed an effective dose of Miyairi 588 in human autism; I have only used it in small doses.

It turns out that there is vast wealth of research into the effects of specific probiotic bacteria.  The research is really very interesting for anyone with any kind of allergy.  I expect that, as Alli found, the potential therapeutic benefit goes far wider, to many kinds of inflammatory disease outside the gut, particularly the very hard to treat ones, perhaps even MS (multiple sclerosis).

Biogaia and Lactobacillus Reuteri 

Lactobacillus reuteri is a species of bacteria that belongs to one of the major lactic-acid producing genera of bacteria. It can be found in the human intestinal tract, though not always and often in relatively low numbers. Lactobacillus reuteri is also found in the gut of other mammals and birds.

Initially, Lactobacillus reuteri was used to treat necrotizing colitis, a gastrointestinal disease characterized by infection and inflammation that is particularly dangerous for infants, particularly those born prematurely. Lactobacillus reuteri was used due to its anti-inflammatory effects.

The research on Lactobacillus reuteri and necrotizing colitis used the Lactobacillus reuteri strains ATCC 55730 and its daughter strain DSM 17938, both of which can survive oral supplementation.

Interest in Lactobacillus reuteri grew after research confirmed that changing aspects of the digestive system can influence the immune system. A strain of Lactobacillus reuteri called ATCC PTA 6475 has been found to improve levels of testosterone and oxytocin, as well as skin quality in animal studies. Research on animals has also found potential benefits for hair quality, bone mass and preventing weight gain from obesity-causing diets.

One of the ways Lactobacillus reuteri may work involves a kind of T cell called a Treg cell (a T cell that down-regulates the immune system in part by producing a cytokine called IL-10). Lactobacillus reuteri increases the amount of Treg cells in the body, which suppresses the actions of another kind of T cell called a Th17 cell (which secretes IL-17). Preserving or reversing this process (either by increasing IL-10 or by blocking IL-17) appears to provide therapeutic benefits.

Lactobacillus reuteri increases the number of Treg cells in the intestines, which can then be absorbed back into the blood to benefit the rest of the body.

BioGaia Gastrus is a combination of the well-researched probiotic strain Lactobacillus reuteri17938 (Lactobacillus reuteri Protectis) and the anti-inflammatory strain Lactobacillus reuteri ATCC PTA 6475. It contains 200 million CFU of live bacteria.

The original Biogaia product is called BioGaia Protectis; it only contains Lactobacillus reuteri 17938 (Lactobacillus reuteri Protectis).  It contains 100 million CFU of live bacteria.

Since some readers are already trialing Alli’s therapy, I thought it would be useful to have a single place on this blog where people could leave feedback.  Here is her explanation:-

Dear all,

Lactobacillus Reuteri ATCC 55730 was initially discovered and sourced from women from Peru who carried this strain in their breast milk. 

"The first strain of Lactobacillus reuteri for human use was isolated in 1990 from the breast milk of a Peruvian mother living in the Andes. This strain was deposited at the American Type Culture Collection (ATCC) as Lactobacillus reuteri SD 2112 (SD = safety deposit), and was later given the number ATCC 55730.

In 2007 Lactobacillus reuteri ATCC 55730 was replaced by the “daughter strain” Lactobacillus reuteri DSM 17938. The only difference between the strains is the loss of two plasmids of ATCC 55730 that carried resistance to tetracycline and lincomycin, respectively."http://www.biogaia.com/history-lactobacillus-reuteri

Through my personal review of immunology literature and ASD/immunity related literature and documenting crossroads between immune pathways and Mtor pathways, I came to the conclusion more than one year ago that this was a very interesting strain to try on my son with ASD and a TH1 profile. Biogaia Gastrus was only available in Korea and Italy at the time so I ordered it from an Italian pharmacy online.
It has helped my son significantly in combination with other interventions.

The mechanism at stake is probably the following:

- downregulation of TH1 through upregulation of IL-10 and downregulation of IL-17
This prevents autoimmune phenomena and cytokine flares which affect cognition in certain subtypes of ASD. However, the downside is that long term intake also impairs one's immune system's capacity to fight off infections... 

We use Biogaia on and off for 3 week periods- at a dosage of 5 tablets a day (less is useless in terms of potency).

Use must be stopped if a child shoes any sign of infection.

I have shared this over the past year with several parents around me who have children with similar subtypes and they report similar results.

Effect of Lactobacillus reuteri 17938 on Monty

My son Monty, aged 12 with autism, pollen allergy and occasional asthma, was again my willing test subject.  This is the worst time of the year when his allergy triggers asthma and autism flare-ups.

Where we live, only the older version of Biogaia is sold.  So he has been taking Lactobacillus reuteri 17938, 400 million CFU a day.

In Alli’s dosage there is 500 million CFU of reuteri 17938 and 500 million of reuteri ATCC PTA 6475.

There was an effect almost immediately on his allergy; his nose changed colour.  His pollen allergy gets gradually worse in the summer and the sides of his nose becomes bright red.  Short term use of topical steroids reverses this, but the pollen season is four months long.

Along with his red nose, his behavior gets worse leading to aggression,SIB and cognitive decline.  This lasts from mid June to October.  The aggression and SIB responds very well to treatment with Verapamil, but this does not reverse the cognitive decline.  

My behavioural observations might be wishful thinking, but I cannot be imagining bright red fading to a mild pink.

Clearly even at my reduced dosage and lack of the second anti-inflammatory bacteria (L. reuteri ATCC PTA 6475) something very helpful is happening.

As is my habit, I did a quick review of the literature and found plenty of supporting evidence for the potential benefit of specific bacteria on allergy.

As Alli has found, the potential benefit goes far beyond allergy.

  

Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice

RESULTS:

Oral treatment with live Lactobacillus reuteri but not Lactobacillus salivarius significantly attenuated the influx of eosinophils to the airway lumen and parenchyma and reduced the levels of tumor necrosis factor, monocyte chemoattractant protein-1, IL-5, and IL-13 in bronchoalveolar lavage fluid of antigen-challenged animals, but there was no change in eotaxin or IL-10. L. reuteri but not L. salivarius also decreased allergen-induced airway hyperresponsiveness. These responses were dependent on Toll-like receptor 9 and were associated with increased activity of indoleamine 2,3-dioxygenase. Killed organisms did not mimic the ability of the live L. reuteri to attenuate inflammation or airway hyperresponsiveness.

CONCLUSION:

Oral treatment with live L. reuteri can attenuate major characteristics of an asthmatic response in a mouse model of allergic airway inflammation. These results suggest that oral treatment with specific live probiotic strains may have therapeutic potential in the treatment of allergic airway disease.

Probiotic Therapy as a Novel Approach for Allergic Disease

Various effects of different probiotic strains in allergic disorders: an update from laboratory and clinical data

The various effects of different probiotic strains in allergic diseases are shown from laboratory and clinical studies referred to in the text.

↑: Increase in symptoms or negative effect; ↓: decrease in symptoms or positive effect; ↔: no change in symptoms or no effect

References	Probiotic strain	Type of allergic disease	Outcome
		Atopic dermatitis (eczema)
Sistek et al.[31]	Lctbs rhamnosus + Bfdbm lactis	Food-sensitized atopic children	↓
Kalliomäki et al.[45]	Lactobacillus GG	Atopic dermatitis	↓
Kopp et al.[46]	Lactobacillus GG	Atopic dermatitis	↔, ↑
Wickens et al.[47]	Lctbs rhamnosus	IgE-associated eczema	↓
Viljanen et al.[41,48]	LGG	Atopic eczema/dermatitis syndrome	↓
Rosenfeldt et al.[49]	Lctbs rhamnosus + Lctbs reuteri	Atopic dermatitis	↓
Kuitunen et al.[50]	Lctbs + Bfdbm + propionibacteria	IgE-associated allergy	↓
Boyle et al.[54]	Various	Eczema	↔
Lee et al.[55]	Various	Atopic dermatitis	↔
Soh et al.[63]	Bfdbm longum + Lctbcs rhamnosus	Eczema and atopic sensitization	↔
		Food allergy and anaphylaxis
Kim et al.[27]	Lctbs acidophilus + Bfdbm lactis	OVA-induced allergic symptoms	↓
Isolauri et al.[56]	Bfdbm or Lctbs	Food allergy	↓
Majamaa et al.[57]	LGG	Food-sensitized eczema	↓
Shida et al.[60]	VSL#3 + Lctbs casei strain Shirota	Anaphylaxis with food allergy	↓
Hol et al.[61]	Lctbs casei + Bfdbm Bb-12	Cow's milk allergy	↔
Taylor et al.[62]	LGG or Lctbs acidophilus	Cow's milk allergy	↔, ↑
		Allergic rhinitis
Di Felice et al.[59]	VSL#3	Allergic rhinitis	↓
Giovannini et al.[67]	Lctbs casei	Allergic rhinitis	↓
Morita et al.[69]	LGG + Lctbs gasseri	Allergic rhinitis	↓
Xiao et al.[71]	Bfdbm longum	Allergic rhinitis; JCP	↓
Tamura et al.[72]	Lctbs casei strain Shirota	Allergic rhinitis; JCP	↔
		Asthma
Kruisselbrink et al.[33]	Lctbs plantarum	Dermatophagoides (Der p1) sensitization	↓
Feleszko et al.[43]	Bfdbm-12	Airway reactivity	↓
Blümer et al.[73]	LGG	Allergic asthma	↓
Repa et al.[74]	Lactococcus lactis + Lctbs plantarum	Birch pollen allergen (Bet v1) sensitization	↓
Karimi et al.[75]	Lctbs reuteri	Allergic airway inflammation	↓
Helin et al.[78]	LGG	Pollen allergy	↔

Reader Trials

It would be helpful if readers would share feedback on their use of high dose Biogaia probiotics.

There are many other types of probiotic, but it would be helpful to first focus on the one that has been shown by Alli to be effective.

It seems to me that within a week you are going to know if you have a responder.  As usual you need to see how the effect varies over time.  Numerous interventions seem to be effective and then fade away and some even go from positive to negative.  I will certainly be continuing to see the longer term effect and hopefully finally adding something new to my PolyPill.