Wednesday, 23 April 2014

When Less is More - Tuning the Autistic Brain with Clonazepam

I cannot say whether there will ever be a “cure” for autism, but this blog has shown that certain types of autism can be treated today.  Actually, it is becoming much more like tuning.

Tucked away in the scientific literature, you can find that some receptors in the brain respond very differently to small stimuli than to large ones, I found this intriguing but thought little more of it.  Then, in the recent post on Glutamate receptors, I saw a chart from the MIT researcher that showed how using drugs you could increase/decrease protein synthesis in the brain, to optimize neural performance.  Rather like tuning the ignition timing on your car, some people were a little ahead of where they should be (Fragile X) and others were a little behind (Rett’s).  By using the right dose of either a positive or a negative modulator (of the mGluR5 receptor) you could tune the brain for optimal performance.

Source: Contributions of metabotropic glutamate receptors to the Pathophysiology of Autism

In the case of a recently investigated GABA dysfunction in autism, the drug is Clonazepam.  Tiny doses of this drug improve the performance of the neurotransmitter GABA, apparently by affecting the Nav1.1 ion channel.
In the research (on mice) it was shown that, within a tight dosage range, there was a measurable improvement in cognitive behaviour.  Too much, or too little of the drug and this benefit was lost.  So you would have to tune the dosing very carefully to get any effect.

It appears in humans things are more complicated than in mice, the small band of dosage where positive effects are seen does exist also in humans, but at slightly higher doses the effect turns negative before disappearing.

Source: Peter research

 This means that you have to get the dosage and timing just right to get the good effect.  Unlike tuning your car, where the effect is immediate, Clonazepam has a half-life of 30 hours.  This means that the concentration in the blood is made up of several doses from the last few days.

This made me realize what a challenge this would be to get right in other people.

I should point out that the same issue applies with TRH.  At the effective (also tiny) dosage you get a nice positive effect, but go too far and you get instant anger.  An Italian-Swiss researcher is using another analogue of TRH to treat some of the effects of aging.  He clearly had the same problem;  too much ended up having a bad effect.  Now he cycles one month on the drug and the next month with none.  TRH has numerous effects in different parts of the body, it has now been suggested that falling levels in middle age triggers hair to start to go grey.

With Clonazepam, along with some cognitive improvement, you also get very good mood, but at slightly higher concentrations happiness is replaced by anxiety. 

The effective Clonazepam dosage seems to fall over time; this is a very good thing, but further complicates getting things just right.  In high standard doses, the effect of Clonazepam normally reduces over time and patients need more of it.  The drug is normally used in doses 20 to 150 times higher to treat anxiety and seizures.

A further complication is that the optimal dose is 8% of the smallest available tablet.  The tablets do not dissolve nicely in water, you get a lumpy suspension.  As a result the dosage is always going to be a bit “hit or miss”


It looks to me that future autism treatment will include “tuning” specific dysfunctions with tiny amounts of drugs.

The good news is that tiny doses are far safer and less likely to have any secondary effects, than large doses.

The bad news is who is going to do the tuning?

People with Asperger’s, some of whom read this blog, will able to tune themselves; for others it will not be so easy.

In the case of Glutamate (mGluR5), the drugs required are still experimental.  In the case of GABA, they already exist.


  1. Hi,
    Could you please share the source of your graph and other data?
    Best regards,
    João Santos

  2. Hi João
    I am the source of the Clonazepam graph above, based on the effect it has in my 10 year old son. This is all based on the research in mice carried out by Prof Catterall and discussed recently on this blog, just google "Clonazepam autism"

  3. Thank you. Could you please tell me you son's weight?
    Best regards,
    João Santos

  4. He is 32kg. I am giving dissolving 0.5mg clonazepam in 100 ml of water. Using this solution (well shaken) I give 5 ml at 7am and 4ml at 7pm. You might want to start slightly higher and then reduce the dose.. I am also using 1mg Bumetanide as a GABA therapy, I thought it might be a case of one or the other, but they work fine together. That is also in this blog.

  5. Once again thank you.
    One last question: when you gave the dose slightly higher, did the negative effects turned in to positive effects after a few hours?
    Best regards,
    João Santos

  6. Yes that is correct. In fact the timing of the doses is key, you are trying to maintain a steady amount within the body. Each dose stays there for a few days, it drops to half in about 30 hours. The level during sleep would not matter, but you would not want an excess just before bedtime, since then the child will be anxious. The amounts are all tiny, but the effect they have is genuine.


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