A small number of readers of this blog have followed Professor Catterall’s ideas and trialed low dose clonazepam for autism.
This post summarizes my findings from using it long-term; it would be a good place to collect the findings of other people.
The science part of this blog is courtesy of a reader who highlighted the full-text version of a paper I mentioned. Perhaps it was the author?
Before getting to that, I do get asked how I know, for sure, these therapies really do work for Monty, aged 12, with classic autism. As I told Ben-Ari, the Bumetanide researcher, the best way to convince the doubting public will be to measure IQ, not autism. If you can add 30 to 50 points to your IQ result, even the sceptics would pay attention.
I am not measuring IQ directly, but I do note things like spelling tests, math tests and handwriting. The first pleasant surprise was actually reaching the point of sitting the same tests as the NT kids. Piano playing is another interesting proxy.
Monty’s one to one Assistant (and pal) from age 3 to 9 came to visit the other day and could not believe what his handwriting now looks like. She had spent hundreds of hours with him practicing fine motor skills, like pencil control. The end result was handwriting, but even then not like that of his peers.
Cursive handwriting is now great. Spelling tests and “quick-fire” math tests are also great.
As we now know, 20% of people diagnosed very young with quite severe autism seem to make wonderful progress. This has happened by 5 or 6 years old, while the brain is still highly plastic. Spontaneous accelerated development thereafter rarely seems to happen. Monty started his Polypill therapy at the age of 9 years, in December 2012.
This is a spelling test from school, given to NT (neurotypical) ten year olds and 12 year old Monty (on paper without lines). It is not rocket science and big brother could probably have got 20/20 in this test when he was eight years old. But when Monty was eight years old, he was trying to break the windows of my car with his head and his handwriting did not look like this.
I have all the proof I need that modulating the excitatory/inhibitory imbalance in Monty’s autism is well worth the effort. The effects are reversible if you stop the therapy, as should be the case.
Clonazepam
Here I am repurposing an existing drug for a different use, at a dosage so low it is highly unlikely to cause side effects. This is mirroring the use of the same drug, at similar low doses, in mouse models of autism by Professor Catterall.
Clonazepam at “high” doses is widely used already in people with autism, to treat seizures and extreme anxiety.
Catterall showed that the drug has a totally different effect at very low doses (less than 10% of normal), via a specific mechanism which he has identified, the positive modulation of the α 2,3 subunits of GABAA receptors.
GABAA receptors are made up of five sub-units, the strict composition does indeed vary over time, just to make things even more complicated. The most common GABAA receptors have two αs, two βs, and one γ (α2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). It is these subtypes of the subunits that Catterall showed to be key. Clonazepam was one of the substances that he showed to be effective (in mice).
At “high” doses Clonazepam does have side effects, people build up tolerance to it and so take ever higher doses, and then they get hooked on it.
At very low doses the reverse seems to occur. Over time you become more sensitive to it and need lower and lower doses. This was a surprise to me.
The other surprise was that slightly above the effective “low dose” you get some anxiety and irritability. When I first wrote about this I did wonder if this was just a coincidence, but it is not.
My chart from back then:-
Another interesting point was that some other readers found the effective dose was even less than mine.
When you read about the use of Clonazepam at regular, much higher doses, it is clear that there are wide variations in people’s sensitivity to this drug. So much so that there is standard lab test to measure blood concentration of this drug, so that the clinician can vary the dose to achieve the desired level in blood.
It is not an expensive test and I did wonder if this could be used by clinicians to find the effective low dose in their patients with autism.
It did sound a clever idea, but then I read that even the same blood concentration of clonazepam (at high doses) can have markedly different effects in different people. Still it is better than doing nothing and would reduce some of the guesswork with dosage.
The effective dose
In my n=1 example, the effective dose started out at 40mcg a day. The half-life is very long and so you need three days to reach a stable level.
Other people contacted me to say that in their case 25mcg a day was effective and in one case, dosage once every two days was optimal.
In my case 40mcg, now gives the negative effects I has originally discovered at higher doses.
Currently the effective dose is 20 to 25 mcg.
This is a tiny dose, technically sub-clinical, but it really is better than giving none. I have discontinued on several occasions. There is cognitive loss, which is then regained when re-starting.
The incremental cognitive effect is not as great in magnitude as I found with Bumetanide, but in people not using Bumetanide, the effect seems to be much greater. Put more simply, Clonazepam plus Bumetanide is more beneficial than Bumetanide alone, at least in my case.
At this dose the annual cost of the therapy is one dollar/euro/pound. So it will not break the bank.
Tablets are available as 0.5mg (giving 20 days of use) and 2mg (giving 80 days of use). A bottle of 2mg tablets will last someone a few years.
I wish they made 0.025 mg (25 mcg) tablets.
I see no reason why, in ten to twenty years’ time, low dose clonazepam will not be a mainstream therapy for some autism; the only problem is the variability of the effective dosage.
Science
For those diehards who have made it this far, now I move from the Peter-reviewed science to the Peer-reviewed science, but from yet another Peter, Peter Penzes from Northwestern University, close by the Windy City.
Abstract: Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism.
Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.
This study really shows how the common genetic dysfunctions in both schizophrenia and autism come together to produce the Excitatory/Inhibitory (E/I) imbalance. Numerous different dysfunctions result in the same imbalance, some relate to GABA and some to NMDAR, but the end result is the same.
It is a really good paper, mentioning many of the genes we have encountered in this blog, plus many of the pathways like mTOR and even PAK inhibitors.
The study does not cover any therapeutic methods to correct the E/I imbalance, but this blog has those in spades. They relate to modulating GABAA, GABAB and NMDA receptors.
Low dose clonazepam is modulating GABAA , as does Bumetanide and as should Acetazolamide (Diamox). More of that in 2016.
