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Friday, 21 July 2017

Electro Convulsive Therapy (ECT) and Cannabidiol (CBD) in Autism


Today’s post is another one to fill in some of the gaps in this blog.
Psychiatrists have long been using electric shocks, of one kind or the other, to treat their patients. There is even a special school in the US (the Judge Rotenberg Center) where they used electric shocks as aversive therapy, until very recently.  


Cannabis, in the form of Cannabidiol (CBD), is currently the subject of an autism trial in Israel, home to some very innovative people.


Electroconvulsive therapy (ECT)

Electroconvulsive therapy (ECT), formerly known as electroshock therapy, and often referred to as shock treatment, is a psychiatric treatment in which seizures are electrically induced in patients to provide relief from mental disorders. The ECT procedure was first conducted in 1938 is often used as a last line of intervention for major depressive disorder, mania, and catatonia.
As of 2001, it was estimated that about one million people received ECT annually.
Several hundred people with autism have been treated with ECT in the US. 

Transcranial Magnetic Stimulation (TMS)
Do not confuse ECT with Transcranial Magnetic Stimulation (TMS).
Transcranial magnetic stimulation (TMS) is a magnetic method used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator is placed near the head of the person receiving the treatment. The coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. This is rather similar to the way the base station of a rechargeable electric toothbrush works.
A big fan of TMS is Manuel Casanova, a neurologist and Autism blogger. 

A while back I watched a BBC documentary following an autistic girl adopted from a Serbian orphanage by a US family. All was going well until she later developed a serious problem with aggression and self-injury that was being treated by monthly visits to the hospital for electroconvulsive therapy.  The shocks did indeed seem to do the trick and suppress her aggressive tendencies. She is an example of what I call double tap autism, where an autistic person later suffers a profound setback for some reason. 

Video:- 

My Child, ECT (electric shock) and Me (click the picture below)



Long article from Spectrum News:- 


What I found interesting was that you could see that when you took away the SIB, the girl was pretty high functioning. She could read, write and do math.

This made me recall a previous idea of mine that you might grade people’s autism in terms of both their good days and their bad days.  So on a scale of 100, this girl might have been 30/100.  On a bad day she was a major danger to herself and those around her and so she scored 100, but on a good day she was able to be part of the family and be educated.  She clearly had autism but not such a severe kind, so she might score a 30.
The point missed by the BBC was that in this example, electric shock therapy was not an autism therapy, it was an SIB therapy and it appears to have been a pretty effective one.
Many people with autism do not have flare-ups, they do not have SIB; they are pretty constant in their behavior, so they might be a constant 30/30.  

Cannabis 

Much is written on the internet about the use of cannabis for all kinds of conditions, the ones relevant to this blog are autism and epilepsy.  There is a study currently underway in Israel where they are using CBD oil, the non psychoactive part of cannabis, as an autism therapy.
As you might expect they had no difficulty recruiting people to participate in the study, which is still ongoing. 




Dr. Aran is the Director of the Neuro-pediatric unit in Shaare Zedek Medical Center and his latest research involves treating the symptoms of autism using medical marijuana. “So far,” Aran tells NoCamels, “our impression is that it’s working.”

The clinical study began in January 2017 in Jerusalem at the Shaare Zedek Medical Center. There are 120 participants, including children and young adults, diagnosed with various degrees of ASD ranging from mild to severe. Dr. Aran hopes to have final results by December 2017.

According to Dr. Aran, “there are theories” for why medical cannabis can alleviate symptoms of autism, “but we don’t know exactly how. There are theories and models but we don’t know. It can’t be explained.”

This is worrisome given that cannabis is being given to children with little knowledge of why or how it may help. Of course, “We are worried with children because of the long-term impact. But it is considered mostly safe and we have already tested it with epilepsy.” Other studies, like the one published in Seizure: European Journal of Epilepsy 2016, conducted in Israel, successfully demonstrated that cannabis reduced the number of seizures of children with epilepsy. Nonetheless, Aran admits that “There are always worries that something will happen that we don’t know about.”

It is key to note that the participants are receiving cannabidiol (CBD), a non-psychoactive compound, as opposed to the more commonly known tetrahyrdrocannabinol (THC), which creates the “high” feeling. Therefore, the benefits they seem gain from the treatment “help the children cooperate more,” reduce behavioral problems, and “improve their functioning.”

While the study offers much hope for the children and families affected by ASD, Aran warns that “It won’t cure the symptoms, that’s for sure. It will never cure autism. But it certainly can help the quality of life of the families.” 

The lead researcher recently made some revealing comments, he suggested that the results so far are very positive and that it seems that the quality of life has been improved but it does not cure the symptoms. That made be draw the connection to the adopted child in the US; the therapy does indeed seem to be helpful because it is treating the “100” in the 30/100. So it may not improve cognition or reduce stereotypy, but it makes life better, just like the girl receiving the electric shocks.  Hopefully when they publish the results Dr Aran will be much more precise as to the effect of his therapy, since perhaps I am inferring too much from his comments. 

Why does any of this matter?

Well if you want to solve a problem, you have to define it and the more precisely you can define it, the more likely you are to find a solution.
If you have a girl who is a stable 30/30 with no SIB and no epilepsy, it might well be shown that neither electric shocks nor CBD oil will help here.
If you have a girl who is 30/100 with SIB and epilepsy it might well be the case that both electric shocks and CBD oil might help here; but it appears that neither will improve her core autism (which is the 30).


Mode of Action

Neither the doctors using electric shocks nor CBD oil claim to fully understand the mode of action. There are of course various plausible theories.
In the case of CBD it is an antagonist of GPR55, a G protein-coupled receptor and putative cannabinoid receptor that is expressed in the caudate nucleus and putamen in the brain. It has also been shown to act as a 5-HT1A receptor partial agonist, and this action may be involved in the antidepressant, anxiolytic, and neuroprotective effects of cannabidiol. It is an allosteric modulator of the μ- and δ-opioid receptors as well.  Cannabidiol's pharmacological effects have additionally been attributed to PPARγ agonism and intracellular calcium release.

  

Do the therapies “work”?

What we have seen in this blog to date is that there are very many things that do seem to help specific people.  It is sometimes hard to figure out for sure the mode of action; but if high doses of biotin, or vitamin B6, or anything else consistently improve someone’s condition over years of use you have to take note.
The electric shocks did indeed seem to successfully control SIB for 3-4 weeks.  Maybe someone clever might figure out the biological cause triggering her SIB and so provide an alternative  drug therapy, but for now it seems she will go once a month for more shocks.
There are people who think long term use of CBD oil will have negative effects and I guess monthly electric shocks may also have some unforeseen consequences.
The Israeli researchers seem pretty keen on pursuing CBD oil and so they may well end up with a large enough clinical trial to make people take notice.
I do not see hundreds of parents signing up to a clinical trial of electric shock therapy, so it looks likely to be a niche therapy used by one or two clinicians.
CBD oil is the sort of therapy that will appeal to many parents and it is being trialed on so many different people we will soon know if there are harmful long term effects.
  

My Take

It looks to me that electroconvulsive therapy is rather crude and while it does evidently help some people, it might not be without serious risk. If the person has uncontrollable SIB, it looks a risk worth taking.
Short term use of CBD oil looks a safer bet, but if the effect required is just calming/sedating there may be other ways to achieve this.  Many parents are already using CBD oil as a home autism therapy.
There are hundreds of clinical trials completed, or in progress, using CBD to treat everything from ulcerative colitis to anxiety. It is being trialed in schizophrenia and even Dravet Syndrome and other kinds of epilepsy.  There is even a trial of a CBD chewing gum to treat Irritable Bowel Syndrome. CBD actually now has designated orphan drug status with the FDA for Dravet Syndrome.
I have no plans to use either therapy; I seem to have addressed the variable nature of my case of autism.  I am more interested in treating the core autism symptoms, the “30” in the 30/100; it is clear that much more remains possible.  

Tackling the “30”

An interesting recent finding came from a study on Oxytocin at Stanford. This time researchers had the good sense to actually measure the level of the oxytocin hormone in the blood of the trial participants before and after they started having oxytocin squirted up their noses. 

Not surprisingly it was people with low natural levels of oxytocin who were the favorable responders and interestingly those in the placebo group who also responded actually increased their natural level of oxytocin production.
As we know there are other ways to increase you level of oxytocin, one of which is via certain L. reuteri probiotic bacteria.
Oxytocin would fit in the tackling the “30” category, for those with naturally lower levels of this hormone.
The Stanford researcher is again Dr Hardan, from that interesting phase 2 trial of the antioxidant NAC.  He is now planning a larger oxytocin trial. Has he forgotten about making a phase 3 trial of NAC?   

Self Injurious Behavior (SIB)

You do wonder why some clinician does not compile a list of all the known causes and therapies for self-injurious behavior (SIB) in autism.  There is even a study planned at Emory University to test the efficacy of NAC to treat SIB, but with only 14 participants, I do not really see the point.
We do know that a small number of people with SIB respond well to NAC. If just 10% are responders, you would need a really large trial prove anything at all. With 14 participants you should have just one, but as luck might have it, it could be none.
With a more scientific/engineering approach you might identify five sometimes effective SIB therapies, and then go systematically through testing each therapy on each person with SIB. Then you would have some useful data.    
As I mentioned in a recent comment, the late Bernie Rimland from ARI, was a big believer in high dose vitamin B6 to treat SIB.  For some people it is a nicotine patch, for my son in summer it is an L-type calcium channel blocker.
The reality is that numerous complex dysfunctions can lead to SIB, but so do some simple things like untreated pain and inflammation, which could be from IBS/IBD or even tooth eruption/shedding or just tooth decay.






45 comments:

  1. Regarding cbd's partial 5ht1a agonism, wouldnt this actually shut down serotonin in the brain through 5ht1a autoreceptor activation.
    Regular 5ht1a agonism would seem like a very bad plan to me, it is well known that many autism cases there is too much serotonin floating around, resulting in social numbing and social aversive behavior.

    ReplyDelete
  2. I have a question about CBD oil,and seizures/epilepsy.I want to get approved for CBD oil for seizures.I If one does not get seizures every day,but has no idea when seizures would come on,would you still take the oil everyday?I usually go three to four weeks without a seizure,but then go through periods where I have one to two seizures a day,for anywhere from a few days to two weeks.

    SIB is often caused by seizures,it was for me for years,but the expression of my seizures has changed in the last few years.Seizures have many causes.Inborn errors of B6 metabolism are now recognized as one such cause. https://www.futuremedicine.com/doi/abs/10.2217/14796708.1.5.615

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    Replies
    1. Roger, many people who take anti-epileptic drugs every day no longer have any seizures, but they still take their drugs every day. I imagine CBD is exactly the same, people take it every day to avoid what might only be the occasional seizure.

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  3. Hi everyone,

    Here is an article from my favourite (Canadian spelling) magazine, MIT Technology Review, which has nothing to do with ASD, that I wanted to share.

    https://www.technologyreview.com/s/603737/startup-aims-to-treat-muscular-dystrophy-with-crispr/?goal=0_997ed6f472-b2b1c53080-153971985&mc_cid=b2b1c53080&mc_eid=8e0ce0f96a

    The 2 reasons I wanted to share it are:

    1. It's about CRISPR, one of the most interesting technologies in biology, and
    2. The power of patient-driven charities in getting things moving when parents / patients don't feel that enough is being done for their condition.

    It's a very interesting read, even though not directly related to ASD, as CRISPR may theoretically be applicable to ASD one day (depending on the cause of one's ASD, i.e. that its genetic) and the ability of groups of everyday people working together to improve treatment for a condition that isn't seeing improvements at an acceptable pace to those affected.

    AJ


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    Replies
    1. CRISPR has a great future as a technology for gene editing. However, so far it has been applied to diseases with a single mutation. Autism is not such a disease. Researchers still can't figure out which mutations lead to autism. Often, multiple mutations are involved. Some of them have opposite effect. For instance, one can have an MTHFR mutation that limits the rate of neurotransmitter production and a MAO-A/B mutation that increases neurotransmitters through faulty breakdown. If you are to correct one but not the other, you may end up making things worse. There could be dozens mutations that affect production and breakdown of neurotransmitters and receptor sensitivities to these neurotransmitters. With Fragile X it is easier. Only one mutation causes the disease.

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  4. A while ago I posted about IDO inhibitors in helping prevent excess quinolinic acid buildup in the brain in addition to BCAA's in lowering the amount of tryptophan converted into kynurenine as kynurenine is synthesized from tryptophan via the IDO enzyme during inflammation.

    Well a new cancer study on IDO1:

    Press Release:

    https://www.sciencedaily.com/releases/2017/07/170721084701.htm

    Paper:

    http://cancerimmunolres.aacrjournals.org/content/early/2017/07/19/2326-6066.CIR-16-0400

    Shows that COX-2 inhibition indirectly causes IDO1 inhibition as well. If there is excessive and chronic inflammation, less tryptophan will be available to the brain for conversion into serotonin and increased levels of kynurenine will cause increased production of kynurenic acid (implicated in schizophrenia) or quinolinic acid (implicated in many neurodegenerative disorders as an excitotoxin and shown to be elevated in some autism studies).

    Another study released today showed how a high-fat maternal diet (independent of comorbid obesity in the mother) strikingly damages the central serotonin system in offspring. Unfortunately, just feeding the offspring a "healthy diet" after birth does not seem to reverse the changes:

    Press Release:

    https://www.sciencedaily.com/releases/2017/07/170721164037.htm

    Paper:

    http://journal.frontiersin.org/article/10.3389/fendo.2017.00164/full

    So in this case, one could posit that one way of increasing serotonin levels in a child's brain compromised by a high-fat diet of the mother could be via COX-2 inhibitors. Aspirin of course is both a COX-1 and COX-2 inhibitors.

    My son gets Apigenin daily as in my research it seemed to be the most potent natural IDO inhibitor. Perhaps, COX-2 inhibition could improve symptoms in some with autism, especially those with high levels of inflammation that may be causing excitotoxity in the amygdala and hippocampus (regions of the brain highly susceptible to increases in blood-brain barrier permeability), while also increasing serotonin levels in the brain as well.

    Now, I am no cancer expert but I assume these findings translate generally to normal cells in the body. I think looking into answering this question may be worth the time of people who are already trying to inhibit potentially high levels of quinolinate in the brain of their children.

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  5. Hi Peter,

    I might be mistaken, but I don't recall a reference to MAOIs in any of your posts. Going along with the psychiatric bent of this post, I would like to get your opinion on the neuroprotective benefits of MAOIs in general but especially 'Tranylcypromine'.

    Please take the time to visit this site: http://www.psychotropical.info/tcp-new-review

    Dr K. Gillman has published extensively and is a Clinical Neuro-pharmacologist and retired clinical psychiatrist.

    I am looking into what benefit a drug with untapped potential could do for Autism. Notwithstanding the drug interactions and dietary precautions, I would like to know if this (once again) very old drug could have therapeutic benefit in Autism.

    Would really appreciate your thoughts Peter.

    Regards,
    D&G

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    Replies
    1. I could be wrong but I think Peter talked about L-Deprenyl a while back.

      Delete
    2. Hi D&G, given that monoamine neurotransmitters clearly are disturbed in some autism, increasing their level may very well help some people. MAOI drugs vary in their reversibility and selectivity, so their effect differs.

      There are well known dangers associated with these drugs.

      Tranylcypromine is a non-selective MAO-A/MAO-B inhibitor, so it will have the most effects. In a person that does benefit you might then investigate is it MAO-A or MAO-B that needs inhibiting.

      Under experienced supervision, some people with autism likely would benefit.

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    3. Hi Peter, what if the disturbance resulted in a down-regulation of MAO-A via genetics or otherwise?

      This is the basis for "Respen-A" treatment.This website gives an account of the theory:

      http://www.naturalnews.com/031525_Respen-A_autism.html

      Can increasing MAO-A via Reserpine (or indian snakeroot) really improve the core symptoms of Autism as extolled by this website?

      Have you or anyone tried this treatment?
      How would you establish this enzyme is down-regulated?

      Thanks Peter.

      Regards,
      D&G

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    4. D&G, Reserpine is an old drug that was discontinued in some countries because of side effects. The product you mention says it is homeopathic, but it is transdermal Reserpine. It looks like it has been around for several years and some DAN type doctors use it.

      It does not seem to be widely used.

      Delete
    5. That does not seem like a good idea at this point in time because of the Calcium balance. We are facing tremendous issues with functional health and cannot afford to create more problems for our children.

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  6. Peter
    I have a friend who's son is high functioning and 8 his issues are avoiding other kids, rigidity, the rigidity also tends towards bossiness which is the same for my son , the need to control. This boy & my son has been in Day camp together for 3 years. This daycamp is 90% neurotypical kids so they make quiet space for my son and the other boy. The day camp has video monitoring on my computer so I feel comfortable letting my son go there. The two boys have similar autism symptoms. And are both good learners. Anxiety with noise, and need for control plus repetitive with computers being their similarity, They also share telling other people please stop singing, please stop having fun!
    His mom and I have become friends due to their very strong similarities.

    THIS HAS ALL CHANGED, he now no longer hangs out in the quiet room he is in the roudy room with my NT son & now for the past 20 days is excited to tell me what happen in day camp when I pick up my boys. He also told me he never remembers seeing me before ( I have known him for 3 years!)
    I asked his mom what has happened how is your son having all this great progress?
    She said LOW DOSE Prozac just 5mg once a day before bed
    I looked it up and found new info on Prozac they thing it reopens brain plasticity at a low dose.

    http://hamodia.com/2017/06/25/prozac-treatment-children-autism/

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    1. My son is 8yo and started Lexapro (another SSRI similar to Prozac) about 2 months ago. He is now at 5mg single dose before bed. Social skills have improved. He also plays more with toys like a normal boy. Speech has improved too. You should read how SSRI's (Prozac, Zoloft, Lexapro, Celexa, etc) increase BDNF, which helps brain to form new connections. BDNF is reduced in those feeling anxiety, stress, depression. But it is needed for proper brain development. SSRI's are a key component of Dr' Goldberg's method of treating autistic children as described in his book "The Myth of Autism", in which he shows SPECT scans of the brain before and after SSRI's. If before SSRI's the brain had regions of low or no activity, after SSRI's the brain "lights up".

      Delete
    2. Pierrette, I think there are different things going on with SSRIs. Many children and adults in the US are prescribed low doses of Prozac, even Temple Grandin apparently. This is usually for anxiety and even OCD.

      Japanese researchers now suggest that very young children may have a low level of serotonin at a critical times in brain development. Giving them a short term serotonin boost (via an SSRI) appears to change the adult brain.

      In most people with a autism the research shows they have too much BDNF.

      Long term use of SSRIs, particularly at higher doses can cause problems.

      Delete
    3. >>In most people with a autism the research shows they have too much BDNF.

      How's that possible? Social anxiety is one of traits of autism. Anxiety reduces BDNF. Social interactions increase BDNF. I would like to see the research claiming that BDNF is reduced in autistic brains.

      By the way, my autistic son also tells people to stop singing. He closes his ears when he hears someone crying and wants to leave. It became a problem because we couldn't take him to places. Now, after being on 5mg of Lexapro, when he sees someone crying, he is actually curious and asks us why they are crying. In some cases he approaches a crying baby and wants to comfort it.

      Delete
    4. Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis.

      https://www.ncbi.nlm.nih.gov/pubmed/28138831

      A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p = 0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

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    5. Hi Peter,

      I've been following your blog more intensely in the last few months, though I've always been a fan and intermittent reader.

      Question about the study you reference above: do we know the relationship between BDNF levels in the blood versus brain in ASD?

      With appreciation,
      Jacalyn

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    6. Jacalyn, BDNF is not only produced in the brain, but scientists do presume that the level measured in blood is a good indicator of what is going on in the brain.

      "It is reported that the concentration of BDNF in serum and the CNS are closely correlated in rats. However, evidence of such a correlation in humans is still lacking. Therefore, whether altered BDNF values in the periphery reflect altered BDNF levels in the human CNS requires further investigation. Scientists assume that peripheral BDNF levels mirror and indirectly reflect BDNF levels in the brain."

      source: http://www.nature.com/articles/srep31241

      Delete
  7. Hi Pierrette,

    Thanks so much for sharing the story and this information! I'm going to start doing my research on this option.

    Pierrette, if you're open to sharing - are you considering doing the same protocol? If so, would you kindly share your results?

    Thanks so much for your post!

    AJ

    ReplyDelete
  8. Everyone ,,,, if I hadn't seen this change in my friends child BEFORE for 3 years then after I would NEVER have believed this. Or if I had only met him after I would not believe it if she told me how he was. I leterally would deal with his rigidity, nonsensical actions, his screaming at people to not talk or have fun & then crying in the quiet room.... my son does all these same things but to a lighter degree but enough that at our house we can not watch tv or have music on. & when his brother sings he tells him to stop. I have talked to my son's doctor about this and he said yes he just started using low dose prozac a year ago & every kid on it so far is doing good. Right now my son is getting his tonsils & adenoids out next week due to reocurring strep. & now just on the heavy duty antibiotics his behavior is better (yes he has PANS) I think they are one in the same. Anyway when he is Recovered from that I have been given an rx to give 5mg at night and after 2 or 3 weeks go to 10mg then stay at the 10 or lower if needed.
    I will keep you posted.
    My friends son is still progressing on the Prozac (fluoxetine) and yesterday he wanted to know why my son is so bossy & prefers to be alone ,,,,, how very ironic right!!!
    Also yes Peter, AJ & Anonymous, I am reading every study on autism & SSRIs that I find & autism & Prozac . & yes there are multiple mechanisms involved. I will keep you all posted
    Anonymous, my other friend has her son on low dose lexapro for 2 years she said he was EXACTLY as rigid as my son and I did not believe her,,,, but now I do!!! Yes she takes her son to Dr Goldberg!

    ReplyDelete
    Replies
    1. Pierrette, it looks SSRIs are another thing that helps some people with autism, but not enough people to make a big impact in clinical trials. This should not be a surprise, given completely different dysfunctions appear as autism.

      Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD).
      https://www.ncbi.nlm.nih.gov/pubmed/23959778

      MAIN RESULTS:

      Nine RCTs with a total of 320 participants were included. Four SSRIs were evaluated: fluoxetine (three studies), fluvoxamine (two studies), fenfluramine (two studies) and citalopram (two studies). Five studies included only children and four studies included only adults. Varying inclusion criteria were used with regard to diagnostic criteria and intelligence quotient of participants. Eighteen different outcome measures were reported. Although more than one study reported data for Clinical Global Impression (CGI) and obsessive-compulsive behaviour (OCB), different tool types or components of these outcomes were used in each study. As such, data were unsuitable for meta-analysis, except for one outcome (proportion improvement). One large, high-quality study in children showed no evidence of positive effect of citalopram. Three small studies in adults showed positive outcomes for CGI and OCB; one study showed improvements in aggression, and another in anxiety.

      AUTHORS' CONCLUSIONS:
      There is no evidence of effect of SSRIs in children and emerging evidence of harm. There is limited evidence of the effectiveness of SSRIs in adults from small studies in which risk of bias is unclear

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    2. Peter,

      the other question with those clinical trials is what dosages that were used - it appears that far more kids do better on very low doses of SSRI's, as per Dr Goldberg's protocols, than they do on standard depression doses.

      I could be wrong but I doubt any of the trials used very low dosing protocols, or god forbid tried to tweak the dose to best fit each individual.

      From personal experience with 5htp the normal weight-adjusted dose was not tolerated, whereas going low (up to 25mg once or sometimes twice a day) was one of the best things we've every done.

      I've also read reports of kids doing badly on a very low dose of SSRI protocols, but improving immensely when the dose was raised slightly (whilst still saying well below the 'normal' depression dose).


      The devil is in the detail, and in SSRI/serotonin treatments it is true probably more than anywhere else in autism.

      Delete
  9. I think we should look at meta-analyses of SSRI's with a grain of salt. Most of the studies were conducted at way too high SSRI doses, 10mg and above. My son's psychiatrist said that he participated in most of these studies (he has been practicing since 70's), and he said that the starting dose of 10mg of SSRI such as Celexa, Lexapro or Prozac would be too high for some autistic kids. He said the important thing in autistic kids is not to try and find an optimum dose of an SSRI, which is what most of those studies did, but to give a minimum therapeutic dose to "get serotonin going" as he put it. This dose is 5mg for most SSRI's. I would be concerned raising it above 5mg because schizophrenia is sometimes diagnosed as ASD in children, and SSRI is not advisable in these cases. The important thing for us, parents, is to see what each medication is doing to our children and not the whole world. If a child shows clear signs of anxiety, which interferes with social activities and communication, then SSRI might be a good med to try.

    By the way, the evidence of harm exists also with Bumetanide. In the most recent study published this year:

    The trial included 88 children with autism ranging from 2 to 18 years of age. One group took a placebo syrup, and the others received either 0.5, 1 or 2 milligrams of bumetanide twice daily for three months.

    Of the initial enrollees, 15 dropped out, most of them because of side effects such as severe dehydration. Two of the children were so dehydrated that their parents had to take them to the emergency room.

    Of the 66 children who took bumetanide, 23 showed an improvement of more than 6 points on the Childhood Autism Rating Scale (CARS); only 1 of the 22 children on the placebo showed similar gains.
    Children taking the drug also improved more on the Social Responsiveness Scale, a parent questionnaire that measures social ability, than did the placebo group.

    The children taking the highest dose of bumetanide, 2 milligrams, showed the most improvement — an average of 5.35 points on CARS. This dose also led to the most severe side effects: Of the 22 children in this group, 9 dropped out of the study.

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    Replies
    1. Most prescription drugs can do harm and that does include bumetanide. Once it is approved for autism, I think parents should have to attend a course on how to safely use it. If you do not control potassium and fluid loss you can get into serious trouble. But if you are responsible, you can entirely manage these issues. The best bumetanide dose is 2mg, but it is the one where unprepared/unsupported parents are most likely to come to grief.

      It is like a diabetic on insulin, some people manage just fine for decades and others do not control blood sugar and end up having amputations in middle age.

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    2. Serotonin is I believe the most well studied neurotransmitter to date, but in my opinion one of the least understood. And by that I mean even the best minds in the world could not give you an honest answer as to how every serotonin receptor works, especially since many of them seem to work against each other.

      I myself probably put in well over 100 hours over the last half 6 or so years reading papers on serotonin and tryptophan alone and the more I learn the more questions I have.

      That being said, ssri's should never be given to children except in experimental contexts because everything scientists thought about how serotonin works in the brain several decades ago, especially with regards to depression is understood differently now.

      Also, a psychiatrist should never be able to prescribe such powerful medicine to children, but here in the United States health care system, glorified tarot card readers are allowed to prescribe hard drugs to children, but if parents want basic well understood medicine for their children, they need to bankrupt themselves continuously with 300 dollar 15 minute doctor visits first.

      If you want to get am idea of how ssri's might actually work therapeutically you will want to look at lsd which has a stronger affinity for the 5ht2a receptor than just about anything else. Nonetheless, I would never give lsd to my child even in low doses unless strong evidence suggested doing so had long term positive impacts. Unfortunately, ssri's are routinely prescribed by people who have not even the faintest clue how they work aside from what they learneed in college decades ago which is now very out of date knowledge now. If you think I am wrong ask your favorite head shrinker to explain all the serotonin receptors to you and how they work and in what parts of the brain they are most localized and after they stutter a whole bunch ask yourself if they have any more business prescribing this medication than you or I.

      Also, on social anxiety an enlarged or hyperactive amygdala pops up more than any other brain structure in these sorts of studies and antioxidants like NAC or else activating stress response pathways like NRF2 via sulphuraphane should be a first resort in taming down oxidative stress in subcortical brain structures before resorting to ssri's whose long-term use is similar to what happens with Gabaergics or opioids in that increasing doses are required and acute withdrawal can cause serious side effects (in the case of ssri's this can mean suicidal ideation in some people).

      Last but not least, placebo response aside, many people have an acute postive response to elevated serotonin levels, but our biology is generally stubborn with neurotransmitters and will generally downregulate the number of associated receptors in return. This means for long-term stability it is usually better to restrict the neurotransmitter levles so as to upregulate the associated receptors. This is unintuitive but nevertheless leads to positive results. On the other hand if you are encouraged by an acute use of ssri's in a child, then you might as well give them ecstasy (MDMA) as it causes a massive rise in both serotonin, dopamine, and likely oxytocin as well. Of course we now know chronic ecstasy use damages serotonergic expressing axons so that is another reason to avoid ssri's, especially in children.

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    3. Very well written opinion about SSRI's, Tyler. I can add to it that a psychiatrist should never prescribe ADHD drugs either. Why mess with dopamine receptors? You will get hallucinations, psychosis, and schizophrenia. These ADHD drugs (Ritalin, Focalin, etc) have the same action as crystal meth and Cocaine. So, why parents give their children these narcotics?
      Such opinions about SSRI's and ADHD drugs would be well understood if we were talking about healthy kids who don't need extra serotonin or dopamine. But, if a child such as my son is autistic, socially withdrawn, and has an MTHFR mutation, which happens in less than 1% population and which limits the brain production of serotonin and dopamine (through limited supply of BH4), then perhaps something should be done about it. We parents are faced with a choice either letting it go as US pediatricians recommend and let a child grow into a nonfunctional member of society, requiring institutionalization or group home, or take a risk and do something early enough. I choose to do something about it. But I am conscious about it, I try to understand potential dangers of the treatments I chose and weigh them against the risk of my child becoming a non-functional member of society.

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    4. On top of that, much of the MTHFR discussion you see on the internet is not based on real science. It is kind of like people who have no evidence of Celiac disease discussing about how much their health improved once they removed grains from their diet. With the exception of a small number of genes that are fatal from a de novo mutation, for things to really go wrong in an organism, you need to have a cascade of mutations leading to major failures. If MTHFR inherited mutations were so damaging, those people would either never have been born or make it to an age of procreation.

      In addition, I think everyone who reads and posts to Peter's blog wants their children to grow up into as functional a member of society as possible and we are all frustrated by the many factors getting in the way of that goal. My oldest son has severe enough autism that if something is not done to help him cognitively, then his autism will result in him having to live with us (my wife and I) for the rest of his life and as institutions are rife with abuse as severely autistic people cannot advocate for themselves, that situation is not an option if we can help it. Institutionalization is a nightmare scenario many of us worry about and any criticism of SSRI's or someone giving them to their child is only in the spirit of discouraging parents from making the kind of desperate wrong turns that could actually hurt their child in the long-run.

      All of that being said, one commenter here has said that a moderate amount of 5-HTP (50 mg or less) seemed to help out a bunch with their child, but of course SSRI's are another story, even though it is very possible that very low-dose usage might be beneficial without the long-term problems (the conventional wisdom among those that prescribe SSRI's is that unless you do a high enough dose, you are wasting your time). And again, I would never give a standard dose of benzodiazepines to my child, but Peter says that low-dose Clonazepam has been one of his best interventions and his reasoning is based upon science not funded by the company selling the drug, so it is always good to be a contrarian on these matters because the science can always change.

      Last but not least, you should not think about "boosting serotonin" or any neurotransmitter but rather normalizing receptor signaling. This is very hard as if there is a receptor problem at the synapse (which many autism linked genes seem to point to), you are not going to improve signaling very much unless you brute force the problem which unfortunately causes the receptor count to dwindle as autoreceptors will sample the increased levels of neurotransmitter as well. SSRI's are very sloppy because they simply keep serotonin locked into receptors longer which is wholly unnatural and at the moment very unpredictable in terms of what happens intracellularly as sometimes the pattern of receptor activation (such as LTP with NMDA receptors) is very important and locking up a receptor for an extended duration is going to cause different neural signaling. If you can prove that there is an excess of reuptake happening, then maybe certain SSRI's make sense because they are correcting a defect at its source. Unfortunately, that is not the case when it comes to prescribing SSRI's as witch doctors and bloodletting would do less harm than your typical psychiatrist will do these days with these very old and powerful drugs.

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    5. Anonymous, I only spotted your comment here after posting mine, DUH. I'll repost bits here just in case it gets missed :)

      ... the other question with those clinical trials is what dosages that were used - it appears that far more kids do better on very low doses of SSRI's, as per Dr Goldberg's protocols, than they do on standard depression doses.

      ... From personal experience with 5htp the normal weight-adjusted dose was not tolerated, whereas going low (up to 25mg once or sometimes twice a day) was one of the best things we've every done.

      I've also read reports of kids doing badly on a very low dose of SSRI protocols, but improving immensely when the dose was raised slightly (whilst still saying well below the 'normal' depression dose).


      The devil is in the detail, and in SSRI/serotonin treatments it is true probably more than anywhere else in autism.

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    6. PS

      just to add also that we had 5htp on the shelf for a long time before giving it a go, due to being scared off by 'SSRIs are scary', and 'messing with serotonin is scary' type posts.

      My biggest regret of 12 years of biomed is not trying it out sooner than we did.

      Yes fiddling with serotonin and/or dopamine levels is scary, but as Anon said we are not starting from a position where the levels are anywhere near normal, and those abnormal processes have major negative effects on the present and future lives of our kids. At least this was the case here. Just observing and doing nothing is/was not a good or safe option either.

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    7. There is a big difference between how SSRI's work and how 5-HTP works with respect to serotonin signaling in the brain. Also, sometimes serotonin treatments can mask the real problem as many of the types of neurons with the densest concentration of serotonin receptors also happen to be the most morphologically aberrant parts of the brain such as the amygdala and the striatum (i.e. a coincidence), which suggests alternative interventions to serotonin modulation in those brain areas may yield better results and have less side effects than serotonin which innervates most of the brain to one degree or another.

      At this time, I would always suggest trying to influence opioid signaling (i.e. probably decrease mu-receptor signaling) first before considering any serotonergic approaches because the brain areas with neurons dense in opioid receptors are similar/same to those dense in serotonin receptors. Last but not least as serotonin tends to be somewhat antagonistic to dopamine, the root of the problem could sometimes be an excess of dopamine which can lead to low-brain serotonin as well and just increasing brain serotonin while not dealing with the excess dopamine can cause additional long-term problems.

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    8. There was an earlier post on serotonin and 5-HTP:-

      Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

      https://epiphanyasd.blogspot.com/2017/02/secondary-monoamine-neurotransmitter.html

      In that post we saw that Dr Ramaekers, a serious clinician and published researcher, uses 5-HIAA measured in the CSF to identify a serotonin deficiency. The then treats the patient with 5-HTP. He does not use SSRIs like Prozac.

      When it comes to dopamine deficiency, measured by HVA in the CSF he does use a drug.

      What would be interesting to know is whether people using 5-HTP or Prozac actually do have low serotonin, measured the way Ramaekers uses. Also what happens to the people using low doses of SSRIs when then switch to 5-HTP?

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  10. Hi Peter, tried to search if you had any posts on the use if stem cell therapy in autism in light of the recent Duke University trail. There are many other centres providing stem cells and I wondered what your thoughts/research point to in this area.

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    1. I think it is too early to draw any conclusions. Some very clever science is now being used to grow stem cells from your skin cells and then reprogram them to grow specific brain cells. This is very clever and ends up with something like a biopsy of a particular person's brain, which you could then run diagnostic tests on, that you could not on a real person's brain.

      The less sophisticated approach is just to give kids an infusion of their previously stored stem cells (umbilical cord blood) and hope for the best. This looks rather crude to me, but it apparently does no harm. Research will have to show if it has a long term benefit.

      If infusing people with their own stem cells does do some good, then you could use the clever skin-based technology to grow more stem cells from skin cells, without any need for previously stored cord blood.

      It sounds very futuristic, but you wonder why much simpler therapies are not developed. Why does NAC for autism not move forward to phase 3 and FDA/EMA approval?

      In the long run I am sure stem cell therapy will have numerous medical applications.

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  11. Since the comments have sorta Veered towards prescription drugs I've just heard of a lady that is having good success with an anti-viral Prescription drug inosine pranobex (brand Groprinosin) and is also looking at Cycloferon. I tried to research the drug a bit and while its main target is herpes and cold sores it "stimulates the immune system" is what I kept seeing. I'm trying to learn more about the science of why some of these things that have been found work to educate myself but I'm not as knowledgeable as some of the people I see on this blog but was curious to know if anyone's had any experience with this or would know why this drug may have helped her child so much. Here is a quote from her exact words about her experience with it.

    "I have to put this out there for whoever is interested ...
    Tried this stuff (brand Groprinosin) and it's ridiculous, my boy looks recovered! He even had playdate yesterday!

    This is medication so ideally you need doctor supervision and unfortunately prescription for those in US/UK but basically it kills viruses indirectly by modulating the immune and raising NK cells! Funny enough we got the proper Virus rash as well. We had absolutely no regression just major progress."

    Maybe its working by doing something else and NOT how she Thinks it is? If anyone has any insight, please share. Also i could not find and trials done with autism and this drug.
    Thanks, Daniel

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    1. Daniel, the Californian doctor (Dr Goldberg) who gives people the SSRIs, reportedly first gives them Valtrex, which is another anti-viral drug. He thinks that mild autism is caused by a virus in the brain.

      Here is his website:-

      http://www.nids.net/_page_id=2/

      It is suggested that herpes virus in the mother increases the chance of autism in the child.

      http://www.sciencemag.org/news/2017/02/herpes-virus-may-be-trigger-autism

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    2. So it's possible some forms of autism on the spectrum are caused by a virus that can be helped with anti-viral meds? Or is this a case of where it was not autism at all and something else?

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    3. Daniel, Goldberg has his ideas and followers. I expect other people think he is nuts. You have to decide.

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    4. Daniel, every single case of autism is 'something else', once you figure out the causes and mechanisms.

      In other words whenever we figure out a specific cause and pathological mechanisms in a specific individual we stop viewing it as 'autism'. Suddenly autism symptoms start making 'sense' and it stops being 'autism'. Many people have been preconditioned to think this way.

      Just because we don't have the means and the knowledge to figure out the specific causes and mechanism in most cases we call that mysterious idiopathic majority 'true autism', while the minority of cases (where we were clever enough to figure out the root cause) are just 'something else'. But if we didn't know the cause those would also still belong in 'true' autism basket. Funny.

      Don't forget that autism is a diagnosis of surface symptoms. Whether we know what causes those symptoms or not should have no bearing on the diagnosis itself.

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  12. Hi Peter, Tyler, and community,

    I'm struggling with a question, to which there may be no easy answer, but would really appreciate some input on this.

    So as Peter kindly noted recently, most ASD kids have too much Wnt / too little GSK3 Beta (my daughter is quite tall, and has a normal sized head, so she would likely have too much Wnt / too little GSK3 Beta)

    So this means these ASD kids have to many dendritic spines.

    As a result, a good treatment would be a GSK3 Beta activator or Wnt inhibitor (as GSK3 Beta inhibits Wnt).

    OK, so in theory then, for most ASD kids, a GSK3 Beta inhibitor would prevent GSK 3 Beta from inhibiting Wnt, which leads to too many dendritic spines.

    Now, this link https://selfhacked.com/blog/gsk3b-inhibition-potent-pathway-improve-brain-function-mood/ shows the following to be GSK3 Beta inhibitors:

    Minerals:
    Lithium (R)
    Zinc (R)
    Copper (potent) (R)
    Hormones:
    Melatonin (R)
    Supplements:
    Curcumin (R)
    Quercetin (R)
    Luteolin (potent) (R)
    Apigenin (potent) (R)
    Cinnamon (R)
    Angelica Sinensis (R)

    Now, I use Luteolin for reducing activation of Microglia and I know Tyler uses Apigenin as an IDO inhibitor, and many here will use Quercetin or maybe even Melatonin (for sleep issues).

    My question (and I know there isn't an easy answer) is are we better off using Luteolin for microglial inactivation or Apigenin for IDO inhibition, or are we better off not using them since they reduce GSK3 Beta which increases Wnt (resulting in too many dendritic spines)?

    In struggling with this question, I looked for a Wnt inhibitor which would help obviate the issue as we could use a Wnt inhibitor AND Lutolin / Apigenin for our other purposes, and benefit from both.

    I know Peter had identified Mebendazole, and in my research, I also found a similar drug called Pyrvinium.

    Does anyone know offhand, how long in theory one can be on these types of meds? Can you be on these forever, or do you have to cycle on and off?

    My concern is that by using Luteolin / Apigenin / Quercetin / Melatonin, we are helping in some ways and hurting in others, so the net benefit may be close to 0, and looking to find a way to get a benefit from both a Wnt Inhibitor as well as a Microglia inactivator / IDO inhibitor.

    Any thoughts would be MUCH appreciated.

    Thanks everyone!

    AJ

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    1. AJ, remember that more synapses means better memory. If your child has an exceptional memory like The Rain Man, perhaps you don't need to create more synapses. However, most autistic kids are not savants and have trouble remembering things. That is why they created summer school (or extended school year = ESY) for them. It is interesting that most of of the GSK3-beta inhibitors that you mention, including Lithium, are also activators of BDNF, which Peter suggests needs to be reduced (erroneously in my opinion). I failed to see the difference between Quercetin, Luteolin and Apigenin. All 3 will activate neurotrophic ERK/CREB/BDNF pathways. Quercetin is the best among them in my opinion because it also reduces corticotrophin releasing factor, which causes anxiety and stresses adrenal glands.

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    2. Point of clarification == I thought quercetin was a wnt inhibitor, but here it is saying it is a gsk beta inhibitor. Is that your point -- they are conflicting? Thanks, Maria

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    3. Hello both - my daughter actually has an incredible memory, which would be indicative of high number of synapses. She's obviously very bright, but then may not understand more abstract concepts. Also, socially she doesn't want to necessarily interact with other kids, but can be playful with us.

      In terms of my point around Quercetin, is that it does inhibit GSK3 Beta (which increases Wnt) but then we use it for other purposes, so the net benefit may be 0. Quercetin is an unusual example because it does also seem to block Wnt, so it may be a good option if it does truly block Wnt also, as the GSK3 Beta inactivation may be moot if it also blocks Wnt.

      AJ

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    4. AJ, I think it gets more complicated, because not all synapses may be equal. We are told that in autism the synaptic pruning process does not function correctly and so you prune the "wrong" branches, so to speak.

      Wnt signaling is affecting the shape as well as the number of spines. The shape may also change the function.

      To the extent that you can modify dendritic spines at this age, the only way to know what might "work" is to experiment a little. We are talking about repurposing substances already known to be safe in kids, rather using some unknown experimental substance.

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  13. On the subject of SSRIs and serotonin in autism, there have been some super interesting discoveries of late on serotonin signalling in the brain and possible treatment implications.

    This article summarises it all, well worth a read:

    "Rethinking serotonin could lead to a shift in psychiatric care"

    http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/newssummary/news_4-9-2017-15-50-53

    "...researchers from Imperial College London suggest that serotonin pathways are more nuanced than previously thought. They argue that the existing view should be updated to incorporate a ‘two-pronged’ model of how serotonin acts."

    Food for thought...

    (PS a posted a while ago a collection of studies on MDMA and LSD, also comments by HF adults with autism describing their experiences with 'recreational drugs', which often led to massive and long-term improvements in their ability to 'read' their environment, including other humans, and to communicate and socialise)

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