Wednesday, 19 August 2015

Low Dose Clonazepam for Autism - SFARI Webinar with William Catterall

This post will be mainly of interest to the small number of people using low-dose clonazepam for autism and those considering doing so.

This therapy modifies the excitatory/inhibitory (im)balance between the GABA and Glutamate neurotransmitters.  The big advantage is that it should be very safe, is extremely inexpensive and, unlike Bumetanide, does not cause diuresis.   The disadvantage is that the effective dose is only in a narrow window, and you have to find it by trial and error.

Does it work?

It certainly does work in some children with autism.

It also appears to have an additional effect over Bumetanide alone, at least my son.

Questions remain:

·        Does it work with everyone who responds to bumetanide?
·        Does it only work in people with a Nav1.1 dysfunction?
·        Will bumetanide work in everyone who responds to Clonazepam?

One of my earlier, detailed, posts on this subject is this one:-

Just google “clonazepam epiphany” or use the site index, for the other posts.

Professor Catterall

I have already covered the science behind low-dose Clonazepam and Professor Catterall’s trials in two mouse models.  It is quite a complex subject and in the end most people just want to know does it work in humans with autism or not.

Catterall’s research was funded by the Simons Foundation, so no surprise really that he made a Webinar for SFARI.  It covers the ground of those two papers and indicates the next steps for his research.

It is a bit lighter going than his papers, but it is a full hour of science.

Catterall plans to trial it in humans with autism, starting with those known to have sodium channel dysfunction. So he is following the same pattern he used with his mice.

The first mouse model he used was Dravet syndrome, a rare condition leading to epilepsy and autism which is caused by a sodium ion channel (Nav1.1) dysfunction.  The second experiment used a standard mouse model of autism called the BTBR mouse model, so no connection with sodium channels.

My question to Catterall was whether this therapy would only work in people with a Nav1.1 dysfunction.  He did respond via the comments on the post, but did not really answer the question.  The fact that he plans to trial his idea on humans with autism with a known sodium ion channel dysfunction, does suggest something at least.

I think that since the actual mechanism of the drug is on a sub-unit of the GABAA receptor, sodium channels may actually be more of a coincidence, meaning that while autism Nav1.1 dysfunction may indeed indicate this therapy, it may be applicable in other autism where GABA is dysfunctional.

Bumetanide Use

The downside of bumetanide use to correct the E/I imbalance often found in autism is the diuresis and excessive loss of potassium in about 20% of people.

If you revisit the original paper suggesting an  E/I imbalance might be fundamental to many kinds of autism, you will see that this E/I imbalance is not just an ongoing issue, it is potentially an avoidable cause of disruption at key points in the brain’s development prior to maturation. In simpler terms, an E/I imbalance during development may cause the physical brain abnormalities often observed in autism.

That would suggest you should try and reverse E/I imbalance as soon as possible, well before maturation of the brain. 

One day an analog of bumetanide may be developed, that avoids the diuresis;  it is already being discussed.

Bumetanide (or low dose Clonazepam) use, even before autism has become established ?

In something like 30% of cases of classic autism there is macrocephaly (a big head), which even shows up on ultrasound scans of the pregnant mother.  A big head does not necessarily mean autism, but specific types of autism are clearly associated with big heads.

There are many other well known risk factors, like siblings with autism, siblings with other disabilities, older parents, family history (schizophrenia, bipolar, auto-immune conditions, COPD, Nobel Laureates, math prodigies) etc.

Since we also know that an indicator of this kind of E/I imbalance is that benzodiazepine drugs can show paradoxical effects (they work in reverse), it should be possible to make some kind of predictive diagnostic test.

So it would not be rocket science to identify many babies at elevated risk of autism and then treatment could be started very early and well before brain maturation.

This is rather like the Japanese researchers in the previous post suggesting that sulforaphane consumption in childhood might prevent susceptible people developing schizophrenia in adulthood.


  1. Hi Peter
    I went to a genetics clinic at a major hospital to check for chromosomal disease and mitochondrial disorder and they said to stop all supplements like NAC coq10 etc for genetic tests but I could use prescription medicines
    So I was wondering how long does clonzepam show effect in my son is 3
    My neurologist wants me to use an anti anxiety drug so he can prescribe that
    I might start with bumex and add it on
    Also I am not seeing any major difference
    After stopping NAC and l carnisone

    1. If you have found the effective dose, clonazepam should take about three days to show effect. The drug has a long half-life and it takes about three days to reach a stable level in the body.

  2. Peter, I found an interesting website during my search for evidence that baclofen might be useful in autism. I can't find an email address for you or I would email a link. The website addresses issues around the effect of GABA-B agonists, it mentions clonazepam. The thrust of the website is medications for schizophrenia, but as we know, there are features in common with autism. You can find it by googling "advancingschizophreniatherapeutics".

    1. Thanks

      You can always put the link in your comment, to share with others.

  3. Hi Peter, having just read once again a paper by Martha Herbert "Autism and Dietary Therapy...” I found her case report relevant to your new blog entry. The girl described in the paper experienced regression into autism at the age of 4 and later epilepsy with treatment finding “complicated by a past history of prolonged paradoxical screaming associated with benzodiazepine use at 2 years of age”. Do you think that it indicated E/I imbalance long before her ASD diagnosis?

    Her regression seems similar to what dr Kelley described: “Developmentally she was on target, with borderline delay in motor skills and advanced and cognitive and verbal skills. Immediately after her 4-year-old well child visit her language regressed to the 18 month level. ”Maybe children with autism risk factors or paradoxical BDZ reaction should be also screened for mitochondrial dysfunction and follow dr Kelley recommendations as another prophylactic step? Full testing is expensive, but dr Kelley also found in AMD “AST/ALT ratio between 2 and 2.5, presumably secondary to mitochondrial dysfunction in muscle.” In my life I saw medical data for only three kids with autism and all of them had AST/ALT > 2, so I looked at their younger, healthy siblings and surprisingly the results were the same. Unfortunately with my n=3+2 I don’t know if these tests are specific enough.
    Have you ever checked AST/ALT in Monty?

    Also you wrote once about a child who developed late onset, regressive autism and was diagnosed with AMD personally by dr Kelley. Do you know how old was the child then and do his parents suspect any trigger for the regression?

    1. I think you are right that the E/I imbalance was likely always there and perhaps if it had been corrected, the regression at age 4 might have been avoided.

      There appears to be mitochondrial disease distinct from the much more common mitochondrial dysfunction. Dr Kelley is diagnosing mitochondrial disease. In that case I referred to, none of the elements in my Polypill had any effect; Dr Kelley's cocktail stabilized the child and allowed for slow improvement. The cause of the regression, aged 4, is unknown, but they are looking for a genetic rather than environmental cause. It was seen as very late to have such a regression.

      I think that mitochondrial disease often results in profound autism.

      I have never checked AST/ALT in Monty. If he had mitochondrial disease the statin would make him worse, but it makes him better. Also, carnitine has a very minimal effect, if any.

      In my next post I will refer to the case of Hannah Poling, the daughter of a neurologist, who received substantial compensation for her autism that resulted from her childhood vaccines and mitochondrial disease. This is indirectly referred to by Dr Kelley.

      Dr Kelley does respond to emails from doctor parents, so you could always contact him.

    2. Peter, If you have mitochondrial dysfunction, what types of medications and supplements would make you worse. Also, separately, trying to understand the mechanism if for example cinnamon would make you worse?

    3. I attach an abstract from a paper below. As you can see even paracetamol/Tylenol is bad for your mitochondria; you should not give this to someone with autism anyway because it depletes GSH. Antioxidants should all be good, but some more than others eg melatonin.

      If cinnamon makes this worse this indicates a possible histamine intolerance. This is quite common in autism and apparently shows up on the 23andme genetic test. Cinnamon is metabolized to sodium benzoate which is a DAO inhibitor. This causes a problem for people with histamine intolerance. You can have allergies and not be histamine intolerant.

      Medication-induced mitochondrial damage and disease:- Abstract

      Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis. Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have statin medications, analgesics such as acetaminophen, and many others. While targeted nutrient therapies using antioxidants or their prescursors (e. g., N-acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge. The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects.

    4. Thanks Peter for information. Poling’s paper about his daughter ends with “Additional studies” section describing abnormalities in AST and ALT based on Kennedy Krieger Institute patients data. The conclusion is not surprising: “further prospective biochemical studies are needed to evaluate mitochondrial function in children within the autistic spectrum”. Although there are many papers now about mitochondrial issues in autism, I am afraid that this simple thing, which might be important also for siblings at risk, hasn’t been clarified.

    5. There are plenty of unanswered questions, but there are now some good review papers that collect in one place what research there is. The following is a very good example, it does cover mitochondria.

      Biomarkers in Autism

      Mitochondrial dysfunction markers

      Mitochondrial dysfunction is marked by impaired energy production. Some children with ASD are reported to have a spectrum of mitochondrial dysfunction of differing severity (44) (Table ​(Table3).3). Mitochondrial dysfunction, most likely an early event in neurodegeneration (76), is one of the more common dysfunctions found in autism (77) and is more common than in typical controls (78). There is no reliable biomarker to identify all cases of mitochondrial dysfunction (79). It is possible that up to 80% of the mitochondrial dysfunction in patients with both ASD and a mitochondrial disorder are acquired rather than inherited (44).

      Table 3

      Table 3

      Mitochondrial function biomarkers in ASD (see text for references).

      Mitochondrial dysfunction can be a downstream consequence of many proposed factors including dysreactive immunity and altered calcium (Ca2+) signaling (80), increased nitric oxide and peroxynitrite (68), propionyl CoA (81), malnutrition (82), vitamin B6 or iron deficiencies (83), toxic metals (83), elevated nitric acid (84, 85), oxidative stress (86), exposure to environmental toxicants, such as heavy metals (87–89), chemicals (90), polychlorinated biphenyls (PCBs) (91), pesticides (92, 93), persistent organic pollutants (POPs) (94), and radiofrequency radiation (95). Other sources of mitochondrial distress include medications such as valproic acid (VPA), which inhibits oxidative phosphorylation (96) and neuroleptics (97, 98).

      Markers of mitochondrial dysfunction include lactate, pyruvate and lactate-to-pyruvate ratio, carnitine (free and total), quantitative plasma amino acids, ubiquinone, ammonia, CD, AST, ALT, CO2 glucose, and creatine kinase (CK) (44). Many studies of ASD report elevations in lactate and pyruvate, others report a decrease in carnitine, while others report abnormal alanine in ASD patients (44) or elevations in aspartate aminotransferase and serum CK (99). Increases in lactate are not specific and may only occur during illness, after exercise or struggling during a blood draw (100).

      Rossignol and Frye (44) recommend a mitochondrial function screening algorithm. This includes fasting morning labs of lactate, pyruvate, carnitine (free and total), acyl carnitine panel, quantitative plasma amino acids, ubiquinone, ammonia, CK, AST/ALT, CO2, and glucose (44). The interpretation of such a panel and the indications for specific treatments has not yet been established.

  4. Hi Peter,
    I want to thank for your patience and helping us through your blog.
    I had a question related to ABA: my son - 3 years was on waiting lists for a home based therapy and a good ABA center here in town as per reviews. The center also does ABA one on one with an individual therapist.
    We were wondering if you or any of your readers have any experience with doing ABA in home vs a center, we were worried he might get too stimulated in the center vs at home (concern of the psychologist he saw), but center has good sppech therapy and we started a trial with the home based program last week and one of the three therapists seem not to be trained.

    Also, our son had an MRI recently and it showed CHiari 1, do you know if this is of any significance in autism - does it need to be treated.

    1. I think you need to find a good neurologist who reads the literature. It seems that corrective surgery can make a big difference. I would deal with this before worrying about which ABA is best. Maybe you will not need ABA.

      Chiari malformation I and autism spectrum disorder: an underrecognized coexistence.



      Patients with symptomatic Chiari malformation Type I (CM-I) frequently present with headaches, neck pain, difficulty swallowing, and balance disturbances. In children with autism spectrum disorder (ASD), diagnosing CM-I can be a challenging task. Moreover, even if symptomatic, some patients do not undergo further evaluation or management, as their presentations are attributed to autism and its myriad symptoms. Therefore, cranial MRI findings were reviewed after evaluating and treating patients with coexisting ASD and CM-I. In this paper, the authors report on 5 children with ASD and symptomatic CM-I, including their clinical presentation, imaging studies, management, and outcomes, and discuss the likely underrecognized coexistence of these conditions.


      All pediatric patients with ASD and cranial MRI conducted for any reason in the period from 1999 to 2013 were considered for analysis. All cases with concomitant symptomatic CM-I were eligible for this retrospective analysis.


      One hundred twenty-five pediatric patients diagnosed with ASD had undergone MRI, and 9 of them had evidence of cerebellar tonsillar herniation. Five patients were symptomatic and underwent suboccipital craniectomy, a C-1 or a C-1 and C-2 laminectomy, and duraplasty with bovine pericardium or Type I collagen allograft. There were no intraoperative complications. All patients showed symptom improvement and/or resolution of presenting symptoms, which included headache, dysphasia, speech, and irritability.


      There is no identified cause of autism. Children with ASD can be difficult to assess specifically in a neurological examination. Thus, cranial MRI considered when completing a comprehensive diagnostic evaluation. While cranial MRI is not a routine part of ASD evaluation, this study demonstrates that CM-I and ASD may coexist and be underrecognized. The study reinforces the importance of a comprehensive medical evaluation designed to elucidate neurological findings in children with impaired communication abilities and suggests the judicious use of neuroimaging.

  5. I have recently started giving my 8yo classic ASD son a micro dose of clonazepam. I was prepared to wait 3 days to see if there was any effect but to my delight I noticed positive effects within hours of the first dose on the first day. There has been a shift to more cheerfulness and a better disposition. He is speaking spontaneously a lot more and attempting new types of sentences. He is a lot more curious and interested in things. He is more interested in other people. He uses people's names now when he speaks to them. He answers your questions now instead of ignoring you.

    Fortunately, it's not just me who has noticed these positive changes. His teachers have also reported that he is speaking more at school and completing his desk work, and showing a lot more interest in what's going on around him.

    I started on 0.05mg and had good effects but I noticed hyperactivity and a short attention span. So I dropped it down to 0.025mg and this is the right dose for him. He also takes a low dose of propranolol daily. These two pharmaceutical interventions are the two best things I have ever done for him. We are in a much better position now than we were at the beginning of the year. I am truly grateful for all of Peter's blog posts.

    1. Thanks Nina for the feedback.

      The effective clonazepam dosage does seem to vary from person to person. I expect that any other drugs/supplements being taken may have an impact on the effective dose.

      The effects you are seeing look like the ones I saw when we started bumetanide, which is logical.

      I also found that above the effective dose things seemed to get worse, but it could have been a coincidence.

    2. Peter could I ask if LDC can lead to hair loss.We have had a lot of this recently.In saying this no speech yet but more awareness more control the best two weeks ever .My child is placed in the class with the most challenging pupils two weeks only positive remarks only positive .i also give her img of nystastin when she sleeps she seems good better on this as well.I hope to add bume again but it made behaviour aggresive after some time

    3. Hair loss, or gain is a listed as a rare side effect of clonazepam. But your dose is tiny, so it might be something else. My son has not had hair loss.


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