Showing posts with label Speech. Show all posts
Showing posts with label Speech. Show all posts

Friday 6 March 2020

Calcium Folinate (Leucovorin) and Afobazole for Autism? Good, but …

Dr Frye is embarking on a multi-million dollar trial of Calcium Folinate (Leucovorin) to improve speech in autism.  I just completed my much humbler trial of a cheap generic Calcium Folinate.

I determined it was far cheaper and simpler to make a trial, than arrange for the blood test.  The other reason is that I note in the US they are prescribing Leucovorin, even if you test negative in the test for autoantibodies.

Dr Frye thinks many people with autism have low levels of folate inside their brain due to antibodies blocking folate crossing the blood brain barrier.  He even suggests that perhaps the source of these antibodies is your gut and they are produced as a reaction to cow’s milk.

I wondered why speech would be so directly affected by folate, but speech is something that is very noticeable and measurable.

I used 30mg of calcium folinate at breakfast and 15mg in the evening.

After a few days there was very clearly more speech. On several occasions I asked Monty a question, even without facing him eye to eye, and he gave a very much longer response than usual. The response was more like what he would produce if writing with a pencil and paper.

The problem was that three times during the trial he hit me, which is not his typical behavior. Aggression is a listed side effect of high dose calcium folinate.

Excerpt from Dr Frye’s colleague, Dr Dan Rossignol:

Dan Rossignol’s  Presentation at Synchrony 2019 | November 8, 2019

Folinic acid

• The good: Improvements in expressive speech, play skills, social skills, receptive language, attention, stereotypy

• The bad: Hyperactivity, self-stimulatory behaviors, aggression

Calcium Folinate (Leucovorin) is expensive in the US, but very much cheaper in some other countries, so it would be a viable therapy for many people.

Is there a lower dosage where you get the speech benefit without getting hit? I rather doubt it. It did actually try 15mg a day, a while back and saw no effect at all.

Since we do not really know why Calcium Folinate improves speech in particular, I doubt we can say why it produces aggression.

My old post from 2016:-

Clinical Trial of Mega-dose Folinic Acid in Autism

The new trial that is planned:-

The primary objective of this study is to evaluate the cognitive and behavioral effects of liquid leucovorin calcium on young children with autism spectrum disorder (ASD) and determine whether it improves language as well as the core and associated symptoms of ASD. The investigators will enrol 80 children across two sites, between the ages of 2.5 and 5 years, with confirmed ASD and known language delays or impairments. Participation will last approximately 26 weeks from screening to end of treatment.


Afobazole is the cheap Russian OTC treatment for anxiety that works as a sigma-1R agonist.  It has an effect on NMDA receptors.

Afobazole was covered in two recent posts.

ER Stress and Protein Misfolding in Autism (and IP3R again) and perhaps what to do about it -Activation of Sigma-1 Chaperone Activity by Afobazole?

Afobazole is primarily used to treat mild anxiety.  Indeed it appears that sigma-1 receptor activation ameliorates anxiety through NR2A-CREB-BDNF signalling.  NR2A is a sub-unit of NMDA receptors.

Hundreds of millions of dollars are being spent in the US to develop a safe sigma-1R agonist (Anavex 2-73). This drug is being trialed in various autisms (Rett, Fragile X and Angelman syndromes), Parkinson’s and Alzheimer’s.

Afobazole should reduce ER Stress and protein misfolding, making it an interesting potential therapy for many neurological conditions.

I did raise the issue as to whether Afobazole may affect the Excitatory-Inhibitory (E/I) imbalance that is present in bumetanide-responsive autism.

It turns out that in my trial, Afobazole was beneficial in reducing anxiety, it just takes the edge off - nothing drastic.  After several weeks I did notice a slight reduction in cognition, this was only really evident when working on maths. It was more noticeable on cessation.  If I did not teach Monty maths, all I would have noticed was the reduction in anxiety.  When I stopped Afobazole, Monty’s assistant commented how clever he was at school.

Since we are trying to keep up with typical children in academic work at mainstream school, cognitive function is the priority and so no more Afobazole.


I hope the millions of dollars spent on the Calcium Folinate (Leucovorin) trials produce some tangible results. Speech clearly is the area where it shows an effect, I think it has other effects that are less measurable.  It did seem to have an effect on what I would describe as “initiative”, which is completing tasks independently that otherwise you might ask for help to complete.

If you could have the benefits of Calcium Folinate (Leucovorin) without the negative effects, that would indeed be very interesting.

Perhaps giving Calcium Folinate (Leucovorin) to very young non-verbal children will give them a nudge to start speaking.  In those little children you would likely be less concerned by some aggression - they do not hit very hard.

Afobazole also has a place; anxiety is a problem in much autism and for many people a small drop in cognition, if it indeed occurs, is not such a problem.  Long term Afobazole use might produce benefits relating to reduced ER stress and less protein misfolding.

If I had a child with Rett, Fragile X or Angelman syndromes, I would definitely trial Afobazole, since the new American sigma-1R agonist (Anavex 2-73) is not yet available and I suppose will cost 100-200 times more than the Russian drug.

I think you need to find therapies free of any troubling side effects; otherwise in trying to solve one problem, you just create two new ones.

Thursday 26 July 2018

Promoting Spontaneous Speech in Autism – Behavioral Therapies and/or BHB?

One key issue for most people with more severe autism (DSM5 level 3, any DSM3, or just SDA – Strictly Defined Autism) is getting them to fully use their capacity to communicate.
Many such people do learn to talk, but often this is a very matter of fact kind of speech, that is limited to answering questions and making requests.
Often the limiting factor is not vocabulary, grammar or vocalization. Many can put ideas in words on paper, they can sing and read aloud; but something is lacking when it comes to conversation.
You can use behavioral therapy (like Verbal Behavior, VB) and some of the more relevant parts of speech therapy to encourage more extensive speech, but it is a real slog. When you spend less time on 1:1 “speech training”, in order to develop academic school work, you end up with less speech.
I was discussing this with Monty’s assistants, the need to take a step back and refocus on speech as a skill, in addition to regular school work.  It is good to be able to master algebra, but in any social situation communication remains number one.
I have long wondered if it is a behavioural problem, a structural brain problem or a treatable biological problem. I do see parallels with how typical people speak foreign languages. For example, if I was on a train in Germany and somebody wanted to talk to me in German, I would keep my answers short and simple; I would not be trying to keep the conversation going. My German is very rusty, but I can read it aloud and yes, I could sing in it. I would not make small talk in German.
I do consider people like Monty, now aged 15 with autism, not to have a first language; silence is their first language and their mother tongue is like a second language. Some readers of this blog are exceptions, but most people are pretty weak in their second language. For them it never becomes intuitive, you have to painfully learn what preposition takes what case and how to decline nouns and conjugate verbs. You can make a strong case that people who do not begin to speak until 4 years old have missed a critical window in how the brain develops and so when language does slowly begin to come, it can never become truly fluent, a bit like my German.
I do have a broader interest in how you acquire language. Monty's big brother is bilingual and also pretty fluent in Russian and German and chatty in French. This all came with minimal effort, but being exposed from birth to two languages and then learning more languages in the conventional way.  
Many readers of autism forums ask about what pill can you take to promote speech. I always thought this was rather wishful thinking, in that you cannot target such a specific aspect of someone’s autism. Just like there may be no magic pill for algebra.

Writing before talking?
One idea I had to promote more prolonged “conversation” was to first have Monty write about the subject.  I agreed with Monty’s assistants one new exercise, which is to have him write a daily diary of his day and then later on have him retell the day’s events, but without reference to the diary.
It does indeed work, having written about the subject, when later asked to talk about it, there is a much longer and more detailed conversation.
No pills required.

The Ketone BHB
The reason for all the recent posts in this blog about ketones and autism is that perhaps there actually is a “pill” you can take to promote speech.
Our reader Agnieszka in Poland has been experimenting with ketones for some time and since her son responds to most of the things in Monty’s PolyPill, I assume that there is a good chance that anything new that works for her son might also work for Monty.
One area that the ketone BHB seems to help in Agnieszka’s case is promoting speech and BHB does indeed have the very same effect in Monty.
One effect of sulforaphane/broccoli was increased verbalization. If your child is four years old, increased verbalization would be something to celebrate, but by 15 years old you want relevant speech (for some people sulforaphane does indeed produce increased relevant speech).  Very encouragingly, BHB seems to deliver an increase in intelligent, relevant, spontaneous speech. These are things that Monty could write but would not say, unprompted.
There are big gaps in the scientific data about ketone supplements in humans. These supplements are only widely available in North America, even though it looks like most commercial products are repackaged from Chinese bulk chemical producers.
It appears that the most effective therapy is a combination of a precursor to ketones (C8) and a salt of the BHB ketone (Sodium, Calcium, Magnesium or Potassium Beta-Hydroxybutyrate).
According to one Chinese bulk producer, the Calcium salt of BHB is not very effective, they recommend Sodium and/or Magnesium.
By using a salt of BHB, you are going to consume significant amounts of sodium, calcium, magnesium or potassium. This may be unwise for some people.
The objective is to raise the amount of BHB in your bloodstream.
You can measure BHB in urine inexpensively, but the more reliable blood testing equipment is more expensive.
The study below evaluated one widely available commercial supplement:- 

Figure 1b: mean, standard deviation of D-βHB (mmol/L) level in serum of all subjects () within a time period of 5.5 h after intake of βHB salt mixture (0.5 g/kg BW). 

The supplement used was Ketosports KetoCaNa Orange.
In fact the dose of Ca/Na Betahydroxybutyrate was very high, 0.5g per Kg. In the case of a typical adult that might be 40g per day.
That would contain:-

·      23g of BHB

·      2.6g of sodium

·      2.3g of calcium

That is quite a lot of sodium and calcium.
Some products are exclusively Potassium Betahydroxybutyrate, in those for each 23g of BHB you would get 8,700 mg of potassium, which is way too much to take at once. I am amazed it has not been banned.
When it comes to data on the use of C8 MCT oil in humans to produce BHB, we have the following study. The chart they produced is the total of BHB and another ketone, acetoacetate (AcAc), but we can extract the data on BHB itself. 

Results: C8 was the most ketogenic test oil with a day-long mean ± SEM of +295 ± 155 µmol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0–4 and 4–8 h (780 ± 426 µmol h/L and 1876 ± 772 µmol h/L, respectively); these values were 813% and 870% higher than CTL values (P < 0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses.

Conclusions: In healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-β-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at as NCT 02679222.

Plasma concentration and summed daily means (far right) during the metabolic study days for total ketones (β-HB and AcAc) obtained without an added test oil (CTL; ●) or after taking two 20-mL doses of CO alone (), C10 alone (□), medium-chain TGs (C8-C10; ), or C8 alone (). The open arrow indicates when the breakfast plus test oil was consumed; the solid arrow indicates when the test oil alone was consumed without an accompanying meal at midday. Data for metabolic study days on which CO+C8-C10 and CO+C8 were tested are not shown here for clarity, but their AUC data are shown in Figure 2. Values are means ± SEMs; n = 9/point. *Different from CTL, P < 0.05. AcAc, acetoacetate; CO, coconut oil; CTL, control; C8, tricaprylin; C10, tricaprin; β-HB, β-hydroxybutyrate. 

Our 2-dose test protocol (breakfast and midday) generated 2 peaks of plasma total ketones throughout 8 h, with the second dose inducing 3.5 and 2.4 times higher ketones with C8 than with CO, respectively. The first dose taken with a meal would be a more typical pattern but resulted in less ketosis that without a meal. One limitation of this study design is that the metabolic study period was only 8 h. A longer-term study lasting several weeks to months would be useful to assess the impact of regular MCT supplementation on ketone metabolism.

In summary, C8 was the most ketogenic MCT tested in this acute 8-h study and its ketogenic effect was significantly higher in the absence of an accompanying meal. Despite a low net ketogenic effect, CO may still be of interest because of its effect on plasma acetoacetate-to-β-HB ratio. With the help of positron emission tomographic imaging and the ketone tracer 11C-acetoacetate (2, 18, 20), it is now possible to investigate the impact on tissue ketone uptake of various ketogenic interventions.

Areas Under the Curve = AUC 

Plasma concentration and summed means of 0- to 4-h and 4- to 8-h AUCs for plasma total ketones (i.e., AcAc and β-HB combined) (A) and for the mean AcAc-to-β-HB ratio (B). Bars represent no test oil consumed (CTL) or values after taking 2 doses of CO alone, C10 alone, medium-chain TGs (C8-C10), C8 alone, CO+C8-C10 (50:50), or CO+C8 (50:50). Values are means ± SEMs; n = 9. The AUC for 0–4 h was significantly different from the AUC for 4–8 h under all conditions. Labeled means without a common letter differ (a < b < c < d < e and A < B < C < D < E), P < 0.05. AcAc, acetoacetate; CO, coconut oil; CTL, control; C8, tricaprylin; C10, tricaprin; β-HB, β-hydroxybutyrate.

If we assume AcAc/BHB from C8 oil is 0.8 and that taking C8 without foode gives a total peak ketone (AcAc + BHB) of 0.5 mmol/L in blood. That implies we can approximate peak BHB as 0.28 mmol/L and peak AcAc as 0.22 mmol/L.
The jumbo dose of 23g of BHB produced peak BHB of 0.6 mmol/L in adults.
If the BHB level in blood is linearly related to the dose of BHB supplement, the we might assume that 15ml of Ketoforce produces 0.15 mmol/L (3.9*1.5/23*0.6).
If the Chinese are right that calcium BHB is not effective, then 15ml of Ketoforce likely produces a bit more than 0.15mmol/L., since it contains sodium BHB and potassium BHB.
So we might assume that my 20ml of C8 and 15ml of Ketoforce would produce  a peak BHB in the bloodstream of about 0.5 mmol in a 55kg boy and that slightly more is coming from the C8 than the BHB salt.
As you can see from the chart 0.5 is not very much and just at the lower edge of nutritional ketosis. With supplementation 0.5 is the peak level; it will rapidly fall back to the starting level.

So via supplementation we have a brief period of mild nutritional ketosis.

Anyone who has done their homework on Ketones will have come across Dominic D’Agostino.  He is a researcher with a big interest in ketones. He has published interesting research and has his own blog on the subject.

I saw his advice that suggested starting with 10ml of C8 and 10ml of KetoForce.
The producer suggests 30ml a day of Ketoforce in adults.
10 ml of Ketoforce contains
·      3.9 g of BHB

·      533 mg of Potassium

·      533 mg of Sodium

Even 500mg of potassium is going increase potassium levels in your blood.
If you happen to be taking bumetanide for autism, you will be losing potassium and likely taking a potassium supplement. Depending on your bumetanide dosage and potassium supplement, you may well be able to make some adjustments and cope with 10 ml of Ketoforce. 

Speech and C8/Ketoforce Dosage
Our reader Agnieszka was very scientific and tried different BHB supplements and measured  BHB in urine. She found Ketoforce the most effective at producing BHB in urine; speech was one big area of improvement, but not the only one.
I took the advice of Dr D’Agostino, the ketone guru, and combined Ketoforce with C8 in my experiment.
Starting with 10ml of C8 and 10ml Ketoforce, it did produce a marginal change in Monty, but increasing to 20ml of C8 and 15ml of Ketoforce produced a clear increase in spontaneous speech.

Work in progress
Clearly this is a work in progress. Ideally I would want to get all the BHB from C8, since then I do not need to worry about sodium and potassium.
Ketoforce is pretty expensive in the US and very expensive in Europe. C8 is not cheap, but much more reasonable.
Other MCT oils and coconut oil may be cheaper, but are very much less potent, so C8 is the most cost effective MCT oil to produce the ketone BHB.
A naturopathic physician in the US, called Dr Bruce Fife, has written extensively about “reversing autism” with coconut oil; that kind of language will make many people wary. He does suggest the mode of action is calming microglia, which is something BHB should be doing. Regular coconut oil will produce BHB, but you would have to eat a great deal of it.  Coconut oil it is not cheap and so it is more cost effective to use C8 oil. The effect of coconut oil (CO) was shown earlier on in this post, in the above line graph, where the triangle represents coconut oil.
Coconut oil, counter intuitively, actually lowers your blood cholesterol, so it actually is a healthy oil, but if it is the ketone BHB you are after, it does not look the best choice.
It is possible that coconut oil does something clever that is unrelated to BHB.

Underlying Mode of Action
By investigating all the modes of action of BHB, this may lead to a more effective therapy. BHB is a signalling molecule and if you know which of its many effects is the key one, you may find an alternative signalling molecule that gives a more potent result.
I have a good effect from C8/Ketoforce, but I would like more of the same; but without the full ketogenic diet and not causing a problem with excess sodium, potassium, calcium or magnesium.

In the coming posts we will look into BHB's other modes of action. It will get quite interesting and we will see how one might even treat psoriasis and Multiple Sclerosis with BHB, because it is an activator of the niacin receptor HCA2. There is a potent HCA2 agonist drug, dimethyl fumarate.