Showing posts with label SIB. Show all posts
Showing posts with label SIB. Show all posts

Tuesday, 6 November 2018

When is an SSRI not an SSRI? Low dose SSRIs as Selective Brain Steroidogenic Stimulants (SBSSs) via Allopregnanolone modifying GABAa receptors and neonatal KCC2 expression

Today’s post might seem to have a very complicated tittle, but to regular readers it is really just another take on what we have seen time and time again.
Today we see how another steroid imbalance in autism – low levels of allopregnenolone in this case – affects the neurotransmitter GABA and indeed the chloride transporter KCC2.

Putting Prozac/Zoloft to a better use?

I did report previously on a trial in adults with autism where pregnenolone was used.

Recall that disturbed hormonal homeostasis is a key feature of autism. What matters is the level of each hormone inside the brain (i.e. centrally), not in your blood. The only way to get a reliable idea of what is going on would be to take a sample of spinal fluid.

Today we look at boosting allopregnenolone not with a steroid hormone, but with a 1/10th dose of Prozac (Fluoxetine) or indeed Zoloft (Sertraline). Prozac is a selective serotonin reuptake inhibitor (SSRI) when given at the usual dose of 20-80mg, but at 2.5mg it does not function as an SSRI.
At regular doses selective serotonin reuptake inhibitors (SSRI) drugs like Prozac are well known to cause problems, as do benzodiazepines like Clonazepam.
Thanks to Professor Catterall we saw in earlier posts how tiny doses of Clonazepam have an effect on one particular sub-unit of GABAA receptors. By fine tuning the response of this receptor we saw how a cognitive improvement can be achieved, in some people. The dose is so low there appear to be no long term side effects. At least one other professor of medicine, I am in contact with, has been treating his son with autism with low dose clonazepam for years.
Many adults and children with autism are prescribed Prozac for anxiety. Even Temple Grandin has said she takes Prozac.
At low, non-serotonergic doses, some drugs like Prozac show a different mode of action, they potently, positively, and allosterically modulate GABA action at GABAA receptors. These drugs achieve this by increasing the amount of the steroid hormone allopregnanolone.
Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition are a feature of several neurological conditions, including some autism.
Stimulating allopregnenalone biosynthesis will have multiple effects including on TSPO and endocannabinoid receptors.

Brain principal glutamatergic neurons synthesize 3α-hydroxy-5α-pregnan-20-one (Allo), a neurosteroid that potently, positively, and allosterically modulates GABA action at GABAA receptors. Cerebrospinal fluid (CSF) Allo levels are decreased in patients with posttraumatic stress disorder (PTSD) and major depression. This decrease is corrected by fluoxetine in doses that improve depressive symptoms. Emotional-like behavioral dysfunctions (aggression, fear, and anxiety) associated with a decrease of cortico-limbic Allo content can be induced in mice by social isolation. In socially isolated mice, fluoxetine and analogs stereospecifically normalize the decrease of Allo biosynthesis and improve behavioral dysfunctions by a mechanism independent from 5-HT reuptake inhibition. Thus, fluoxetine and related congeners facilitate GABAA receptor neurotransmission and effectively ameliorate emotional and anxiety disorders and depression by acting as selective brain steroidogenic stimulants (SBSSs).                               
When the results of these in vitro studies are compared to those of our in vivo studies, it becomes evident that in mice the doses of fluoxetine and norfluoxetine that cause a rapid increase in brain Allo levels do not exceed brain concentrations in the low nanomolar range, whereas the fluoxetine concentrations that directly activate 3a-HSD in vitro are in the micromolar range. Moreover, the high potency and stereospecificity of fluoxetine and norfluoxetine in decreasing aggressive behavior and normalizing brain Allo content during social isolation (see Table 1, and Figure 3) support the notion that these compounds facilitate the action of 5a-R type I or 3a-HSD by an unidentified indirect mechanism, which is most probably perturbed by protracted social isolation.

Thus, these drugs, which were originally termed ‘SSRI’ antidepressants, may be beneficial in psychiatric disorders because in doses that are inactive on 5-HT reuptake mechanisms, they increase the bioavailability of neuroactive GABAergic steroids. On the basis of these considerations, we now propose that the term ‘SSRIs’ should be changed to the more appropriate term ‘selective brain steroidogenic stimulants’ (SBSSs), which more accurately defines the pharmacological mechanisms expressed by fluoxetine and its congeners.


The pharmacology of the S stereoisomers of fluoxetine and norfluoxetine appears to be prototypic for molecules that possess specific neurosteroidogenic activity. The doses of S-fluoxetine and S-norfluoxetine required to normalize brain Allo content downregulation, pentobarbital action, aggressiveness, and anxiety in socially isolated mice are between 10-fold to 50-fold lower than those required to induce SSRI activity. However, the precise mechanisms of action by which S-fluoxetine and S-norfluoxetine increase neurosteroids remain to be investigated.

Derivatives of S-fluoxetine and S-norfluoxetine, acting with high potency and specificity on brain neurosteroid expression at doses devoid of significant action on brain 5-HT reuptake mechanisms, may represent a new class of pharmacological tools important for the management of anxiety, related mood disorders, dysphoria, fear, and impulsive aggression.

On the basis of these data, new drugs devoid of SSRI activity but that are potent neurosteroidogenic agents should be developed for the treatment of psychiatric disorders that result from the downregulation of neurosteroid expression, including major depression, and in the prevention of PTSD.

France often gets very negative comments about how it treats people with autism, but in the case studies below it looks like some innovative work is going on in some of their day hospitals, where boys and girls with severe autism are sent to pass their time. 

The system in England has recently been highlighted as being pretty appalling, where over 2,000 people with autism are currently detained in Assessment and Treatment Units (ATUs), privately run secure residential "hospitals", at great cost paid for by the State. Those inside might enter with the approval of their family to stay for 3 weeks for respite care, but end up being detained for 3 years, or even longer. The State assumes their guardianship and the individual and parents are powerless. The individuals are kept in prison-like conditions and not surprisingly get worse not better, the worse they get, the harder it is ever to be released. Hard to believe this is still happening.  If you live in England, best not to hand your child over to the State. Someone has even written a book about escaping from such a unit. This is no better than the old State Hospitals in the US, that finally were closed down in the 1970s, that warehoused mentally disabled people, until their premature death.

Autism Spectrum Disorder (ASD) is defined by the copresence of two core symptoms: alteration in social communication and repetitive behaviors and/or restricted interests. In ASD children and adults, irritability, self-injurious behavior (SIB), and Attention Deficit and Hyperactivity Disorders- (ADHD-) like symptoms are regularly observed. In these situations, pharmacological treatments are sometimes used. Selective Serotonin Reuptake Inhibitors- (SSRI-) based treatments have been the subject of several publications: case reports and controlled studies, both of which demonstrate efficacy on the symptoms mentioned above, even if no consensus has been reached concerning their usage. In this article four clinical cases of children diagnosed with ASD and who also present ADHD-like symptoms and/or SIB and/or other heteroaggressive behaviors or irritability and impulsivity treated with low doses of fluoxetine are presented.
Case 1 
An 8-year-old girl (19 kg) had an ASD diagnosis according to the DSM-5 and ADI-R criteria based on information provided by parents. She also had significant mental retardation, with severe SIB (banging her head against objects and biting her hands), forcing her entourage to maintain a daily and permanent physical restraint. She spends most of her time in a day hospital. She received the following pharmacological treatment: risperidone 2 mg/d and cyamemazine 80 mg/d without modifications to her SIB and at the price of a major slowing down and a manifestation of a tendency toward blunting. The CGI severity of illness score was at five (markedly ill). We decreased and stopped risperidone and started valproic acid. After four weeks of valproic acid 400 mg/d in combination with cyamemazine (60 mg/day), SIBs did not improve. Then, we added fluoxetine 2.5 mg/d and increased it after one week to 5 mg/d and to 10 mg/d in the third week. After one week, the CGI improvement scale (CGI-I) was at two; after three weeks, it lowered to 1 (very much improved). We also observed a significant decrease in anxiety as well as the disappearance of SIB (disappearance of the behavior consisting of the banging and rubbing her head against objects). However, it should be noted that the entourage kept the bandages on her hands because she continued to bite them, even if she did it with less intensity than before. There were no side effects. After three months of fluoxetine, her clinical state remains stable.

Case 2 
A 12-year-old boy (70 kg), with DSM-5 criteria for an ASD and ADI-R confirming this diagnosis, exhibited extreme irritability, violence, and impulsiveness as well as SIB (he had thrown seven television sets out of the window). The CGI severity illness scoring was at six (severely ill). In the day hospital where he spent most of his time, it was difficult for staff to manage his impulsivity and unpredictability. His treatment included risperidone 4 mg/d as well as loxapine 80 mg/d. Despite this pharmacological treatment, episodes of aggression and SIBs continued. This treatment induced a significant weight gain (8 kg in 5 months). Treatment with fluoxetine 2.5mg/d was introduced and increased to5mg/d after one week and to 10 mg/d at the beginning of the third week. After one week, there was a CGI-I score of three, which decreased to two after two weeks of treatment and to one after three weeks. Such a positive clinical response allowed for a reduction in risperidone to 2mg/d and in loxapine to 60 mg/d. The treatment was tolerated well by the patient, and he began to lose weight (4 kg). After two months off luoxetine, his clinical state remains stable.

Case 3
 A 6-year-old male child (30 kg) with DSM-5 criteria and ADI-R for an ASD exhibited problems of SIB and repetitive behaviors (washing his hands for more than 30 minutes at least two to three times per day), severe irritability, frequent crying, social withdrawal, and inappropriate speech. Treatment with risperidone 2mg/d had improved irritability and partially the SIB, but it had also produced significant weight gain (four kg in three months). A decrease in the risperidone dosage seemed necessary. Treatment with fluoxetine2.5mg/d was begun, which quickly led to a reduction in inappropriate behavior (for example, impulsive crawling on the ground in the classroom). After one week, the CGI-I scoring was at two. The dosage was gradually increased to 5 mg/d the second week and to 7.5mg/d the third week. The repetitive behaviors gradually subsided. After three weeks the CGI-I score was at one, and it remained stable for nine weeks. The risperidone dosage could be decreased to 0,5 mg/day and the patient’s weight remained the same.
Case 4 
A 12-year-old boy (62kg) withDSM-5 and ADI-R criteria for a severe case of ASD, including severe ADHD-like symptoms, often required physical restraint and did not improve despite a long-term treatment of risperidone 3 mg/d as well as melaton in 4mg at bedtime. The CGI severity illness scoring was at 6 (severely ill). The behavioral pattern included irritability, marked agitation, crying, severe hyperactivity, and other behaviors typical of this disorder. He was also anxious, rendering the situation at his day hospital where he spent most of his time all the more difficult. A prescription of fluoxetine 2.5mg/d was initiated with an immediate and complete improvement of ADHD-like symptoms:CGI-I at one week of treatment was at a one, making this case the most remarkable of the four presented here. Treatment with fluoxetine was continued with a dosage increase up to 5 mg/d to allow for a decrease in the risperidone dose to 1 mg/d. CGI-I score remained stable at one for the duration of the nine weeks.

Our reader Mira, whose son has FXS, recently referred to Dr Hagerman’s trial of low dose Sertaline/Zoloft in Fragile X. GABAA malfunction appears to be a feature of Fragile X, but it is not necessarily the identical malfunction to those with idiopathic autism who respond to bumetanide.


Observational studies and anecdotal reports suggest sertraline, a selective serotonin reuptake inhibitor (SSRI), may improve language development in young children with fragile X syndrome (FXS). We evaluated the efficacy of six months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 52 children with FXS ages 2–6 years.


Eighty-one subjects were screened for eligibility and 57 were randomized to sertraline (27) or placebo (30). Two subjects from the sertraline arm and three from the placebo arm discontinued. Intent-to-treat analysis showed no difference from placebo on the primary outcomes: the Mullen Scales of Early Learning (MSEL) expressive language age equivalent and Clinical Global Impression-Improvement (CGI-I). However, analyses of secondary measures showed significant improvements, particularly in motor and visual perceptual abilities and social participation. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events occurred.


This randomized controlled trial of six-months of sertraline treatment showed no primary benefit with respect to early expressive language development and global clinical improvement. However, in secondary, exploratory analyses there were significant improvements seen on motor and visual perceptual subtests, the Cognitive T score sum on the MSEL, and on one measure of Social Participation on the Sensory Processing Measure–Preschool. Further, post hoc analysis found significant improvement in early expressive language development as measured by the MSEL among children with ASD on sertraline. Treatment appears safe for this 6-month period in young children with FXS, but we do not know the long-term side effects of this treatment. These results warrant further studies of sertraline in young children with FXS using refined outcome measures, as well as longer term follow-up studies to address long-term side effects of low-dose sertraline in early childhood.

Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition: a biomarker axis in stress‐induced cognitive and emotional impairment

By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction. While benzodiazepines are inefficient, selective serotonin reuptake inhibitors (SSRIs) represent the first choice treatment for depression and PTSD. Their mechanisms to improve behaviour in preclinical studies include neurosteroidogenic effects at low non-serotonergic doses. Unfortunately, half of PTSD and depressed patients are resistant to current prescribed 'high' dosage of these drugs that engage serotonergic mechanisms. Unveiling novel biomarkers to develop more efficient treatment strategies is in high demand. Stress-induced down-regulation of neurosteroid biosynthesis and changes in GABAA receptor subunit expression offer a putative biomarker axis to develop new PTSD treatments. The advantage of stimulating Allo biosynthesis relies on the variety of neurosteroidogenic receptors to be targeted, including TSPO and endocannabinoid receptors. Furthermore, stress favours a GABAA receptor subunit composition with higher sensitivity for Allo. The use of synthetic analogues of Allo is a valuable alternative. Pregnenolone or drugs that stimulate its levels increase Allo but also sulphated steroids, including pregnanolone sulphate which, by inhibiting NMDA tonic neurotransmission, provides neuroprotection and cognitive benefits. In this review, we describe current knowledge on the effects of stress on neurosteroid biosynthesis and GABAA receptor neurotransmission and summarize available pharmacological strategies that by enhancing neurosteroidogenesis are relevant for the treatment of SSRI-resistant patients. Linked Articles This article is part of a themed section on Pharmacology of Cognition: a Panacea for Neuropsychiatric Disease? To view the other articles in this section visit

Too little allopregnanalone can induce autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms of social impairments and restrictive repetitive behaviors. Recent evidence has implicated a dysfunction in the GABAergic system in the pathophysiology of ASD. We investigated the role of endogenous allopregnanolone (ALLO), a neurosteroidal positive allosteric modulator of GABAA receptors, in the regulation of ASD-like behavior in male mice using SKF105111 (SKF), an inhibitor of type I and type II 5α-reductase, a rate-limiting enzyme of ALLO biosynthesis. SKF impaired sociability-related performance, as analyzed by three different tests; i.e., the 3-chamber test and social interaction in the open field and resident-intruder tests, without affecting olfactory function elucidated by the buried food test. SKF also induced repetitive grooming behavior without affecting anxiety-like behavior. SKF had no effect on short-term spatial working memory or long-term fear memory, but enhanced latent learning ability in male mice. SKF-induced ASD-like behavior in male mice was abolished by the systemic administration of ALLO (1mg/kg, i.p.) and methylphenidate (MPH: 2.5mg/kg, i.p.), a dopamine transporter inhibitor. The effects of SKF on brain ALLO contents in male mice were reversed by ALLO, but not MPH. On the other hand, SKF failed to induce ASD-like behavior or a decline in brain ALLO contents in female mice. These results suggest that ALLO regulates episodes of ASD-like behavior by positively modulating the function of GABAA receptors linked to the dopaminergic system. Moreover, a sex-dependently induced decrease in brain ALLO contents may provide an animal model to study the main features of ASD.

Some steroids, whose levels are raised in autism (allopregnanolone, androsterone, pregnenolone, dehydroepiandrosterone and their sulfate conjugates) are neuroactive and modulate GABA, glutamate, and opioid neurotransmission, affecting brain development and functioning. These steroids may contribute to autism pathobiology and symptoms such as elevated anxiety, sleep disturbances, sensory deficits, and stereotypies among others.

Tuning the Brain
I did write a post a while back to show the effect of tuning GABAa receptors.

The effect of allopregnanolone of KCC2 expression and hence the level of chloride within neurons.

Neonatal allopregnanolone or finasteride administration modifies hippocampal K(+) Cl(-) co-transporter expression during early development in male rats.


The maintenance of levels of endogenous neurosteroids (NS) across early postnatal development of the brain, particularly to the hippocampus, is crucial for their maturation. Allopregnanolone (Allop) is a NS that exerts its effect mainly through the modulation of the GABAA receptor (GABAAR). During early development, GABA, acting through GABAAR, that predominantly produces depolarization shifts to hyperpolarization in mature neurons, around the second postnatal week in rats. Several factors contribute to this change including the progressive increase of the neuron-specific K(+)/Cl(-) co-transporter 2 (KCC2) (a chloride exporter) levels. Thus, we aimed to analyze whether a different profile of NS levels during development is critical and can alter this natural progression of KCC2 stages. We administrated sustained Allop (20mg/kg) or Finasteride (5α-reductase inhibitor, 50mg/kg) from the 5th postnatal day (PD5) to PD9 and assessed changes in the hippocampal expression of KCC2 at transcript and protein levels as well as its active phosphorylated state in male rats. Taken together data indicated that manipulation of NS levels during early development influence KCC2 levels and point out the importance of neonatal NS levels for the hippocampal development.                                                                                                                           

Add very low dose Prozac to the long list of possible SIB therapies, more practical than electroconvulsive therapy (ECT), that is for sure!

This post was long waiting in my “to-complete” pile. I thought it would be a short one, but it kept growing.  It does draw together several interesting issues and shows there is a pattern developing in all these blog posts.
The majority of psychiatric drugs have such severe drawbacks that the great majority of children are better off without them.  However, there are many existing drugs that have little known neurological effects that can be highly beneficial and are known to be safe to use long term.
Psychiatric drugs that can be repurposed at lower dosages for different purposes may indeed be free of the major drawbacks encountered at higher doses.
It looks like humans with Fragile X Syndrome (FXS) are leading the way with low dose SSRI therapy to modulate GABA.  It would seem highly plausible that other idiopathic autism might also benefit and the French case studies in this post are examples of those who did benefit.
I think this is another example of fine-tuning the brain to optimize its functioning. It probably will not produce miracles, but the science shows that allopregnenalone can be tuned to vary mood in humans.  Low levels of allopregnenalone can produce autistic-like behaviours in mouse models.
The effect of allopregnenalone on KCC2 expression may only be present in tiny babies, if it continues into childhood that would be another reason to consider it as a target for modulation.  If that were the case, then Finasteride the cheap generic drug for prostate enlargement, should be investigated.
As is always the case in autism, both extremes are likely to exist; some people will likely benefit from low dose SSRIs but it will make some others worse (anxiety, SIB etc). If you start with elevated allopregnenalone, you would want less, not more.
Repurposing existing drugs has huge unrealized potential.
The OTC antihistamine Clemastine, which I highlighted in an earlier post as being a Positive Allosteric Modulator (PAM) of P2X7, and so helps remyelination, is yet another example of repurposing a safe drug.  Reportedly, it has this effect even below the regular dosage for allergy; at the high dosage usage in MS trials it will send you to sleep and risk some other side effects. As MS is not a singular condition, it seems that some people respond much more so than others. It also seems to have a benefit is some psychiatric disorders; not bad for a cheap OTC antihistamine.

Wednesday, 13 September 2017

Verapamil still working after 3+ years, for SIB in Autism

There are numerous ideas about how to treat self injurious behavior (SIB) associated with autism. ARI (the former home of Defeat Autism Now) have just had their take on the subject published.
In this blog we have seen that Tyler has developed a BCAA (branch chained amino acid) therapy, based on the idea of Acute Tryptophan Depletion, to control his son’s type of self injury.
The silver bullet for my son’s summer time raging and self-injury continues to be the L-type calcium channel blocker Verapamil.
I think many people will be skeptical of both BCAAs and Verapamil, which is entirely understandable. Unlike other aspects of autism, which are hard to measure, self-injury is really easy to measure and so you know when you have cracked the problem; what other people think tends not to matter.  
Now that Monty, aged 14 with ASD, has moved to secondary/high school the routine has changed a little and his assistant forgets to give him his midday dose of verapamil.
On the days she forgets, between 4.00pm and 4.30pm Monty starts to punch himself. On all other days and during the entire summer there has been no sign of self injury.
So when asked is it really necessary Monty keeps taking his pills, my answer remains yes.  In the case of verapamil I now have further evidence that after more than three years of use, his pollen allergy driven self injury continues to be entirely controllable using this therapy.
I do not know what ARI have put forward in their book. If your child has SIB that does not respond to whatever therapies you have tried, it might well be a helpful read. 

Other readers have noted GI and behavioral improvement from Verapamil and our doctor reader Agnieszka did try and collect case reports, but it seems parents are more interested in reading reports than writing them.

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. 


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.  


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.

Tuesday, 26 July 2016

Autism, Allergies and Summertime Raging in 2016

This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.

Not just for Stomach Health

It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.

In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.

Tuesday, 13 January 2015

Cytokines from the Eruption of Permanent Teeth causing Flare-ups in Autism

A recent post looked again at inflammation in autism and some possible therapies to try.  Over Christmas and New Year, Monty, aged 11 with ASD, had occasional outbursts, more typical of his summertime raging, which was later solved using allergy /mast cell therapies.

At least it did let me establish whether Verapamil was a universal “cure” for SIB.  It is not.  It works great for allergy-driven aggressive behaviors, but had no effect on these ones.

Christmas is often a stressful period for many people with, or without, autism; but Monty likes presents and he loves food.

Having pulled out a wobbly tooth on Boxing Day and noticed an apparent behavior change, I thought that perhaps the loss of milk teeth and development of permanent teeth might cause an effect similar to that of his mild pollen allergy.  Monty, in common with many people with autism, has a high pain threshold.  While teething causes well known problems in babies, most children have minimal problems when their milk teeth are replaced by their permanent ones.

I just wondered if perhaps the underlying biological mechanism might provide an inflammatory insult to the highly inflammation-sensitive autistic brain.

Just as histamine provokes a release of inflammatory cytokines like IL-6, perhaps losing your milk teeth does something similar.

Ibuprofen experiment

I decided that I would buy some Ibuprofen, the least problematic NSAID.   A day or two later, Monty declared that another tooth was wobbly and needed to be pulled out.  This tooth was, and remains, well and truly attached.

So I decided that in advance of another, potentially stressful, Christmas event, I would give 10 ml of Ibuprofen.  I did not give it in response to any comment about pain.

It did indeed seem to work.


A few days later we were in the Alps for skiing.

Monty can ski, but we always give him a 1:1 instructor.  On the first day, without Ibuprofen, he got agitated during the queuing at the bottom of the beginners’ ski lift.  The instructor thought it was the loud booming music.  It was clear that by the end of the lesson, it was no fun at all.

The following days, I gave 10 ml of Ibuprofen, 20 minutes before the lesson started.  He had a great time, going up by cable car to the top of the mountain and skiing along the blue/red slopes and coming down in a neighboring resort a couple of hours later.  Even a change of instructor on one day, passed without issue.

It might not be scientific proof of the effectiveness of Ibuprofen, but it was enough for me.

The Science

Since this is a scientific blog, arriving home I did some checking on the biology of what happens when you lose your milk teeth.

There is more written about “teething” when you first get your milk teeth, but there is information about “root resorption” of milk teeth and “eruption” of the permanent teeth.  The process is indeed modulated by inflammatory cytokines and transcription factors.

These cytokines will then circulate around the body and cross the blood brain barrier.


The aim of this study was to investigate whether there are increased levels of the inflammatory cytokines IL-1beta, IL-8, and TNF alpha in the gingival crevicular fluid (GCF) of erupting primary teeth. This increase could explain such clinical manifestations as fever, diarrhea, increased crying, and sleeping and eating disturbances that occur at this time.


Sixteen healthy children aged 5 to 14 months (mean=9.8 months) were examined twice a week over 5 months. Gingival crevicular fluid samples were taken from erupting teeth. As a control, GCF was collected from the same teeth 1 month later. Cytokine production was measured by ELISA. Signs and clinical symptoms were listed. Pearson correlation coefficients were used in the comparisons described below. A paired t test was used to analyze the same variable at different times.


Fifty teeth of the 16 children were studied. GCF samples were collected from 21 of these teeth. Statistically significant differences (P<.05) were found with regard to the occurrence of fever, behavioral problems, and coughing during the teething period and the control period. During the control period, 72% of the children did not exhibit any clinical manifestations, whereas during the teething period only 22% of the children did not exhibit any clinical manifestations. The study revealed high levels of inflammatory cytokines during the teething period, with a statistically significant difference in TNF alpha levels (P<.05) between the teething period and the control period. Correlations were found between cytokine levels and some of the clinical symptoms of teething: IL-1beta and TNF alpha were correlated with fever and sleep disturbances; IL-beta and IL-8 were correlated with gastrointestinal disturbances; IL-1beta was correlated with appetite disturbances.


Cytokines appear in the GCF of erupting primary teeth. The cytokine levels are correlated to some symptoms of teething.

Mechanism of Human Tooth Eruption: Review Article Including a New Theory for Future Studies on the Eruption Process

Physiologic root resorption in primary teeth: molecular and histological events

Root resorption is a physiologic event for the primary teeth. It is still unclear whether odontoclasts, the cells which resorb the dental hard tissue, are different from the osteoclasts, the cells that resorb bone. Root resorption seems to be initiated and regulated by the stellate reticulum and the dental follicle of the underlying permanent tooth via the secretion of stimulatory molecules, i.e. cytokines and transcription factors. The primary root resorption process is regulated in a manner similar to bone remodeling, involving the same receptor ligand system known as RANK/RANKL (receptor activator of nuclear factor-kappa B/ RANK Ligand). Primary teeth without a permanent successor eventually exfoliate as well, but our current understanding on the underlying mechanism is slim. The literature is also vague on how resorption of the pulp and periodontal ligament of the primary teeth occurs. Knowledge on the mechanisms involved in the physiologic root resorption process may enable us to delay or even inhibit exfoliation of primary teeth in those cases that the permanent successor teeth are not present and thus preservation of the primary teeth is desirable. (J. Oral Sci. 49, 1-12, 2007)

Nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, work by inhibiting the enzyme COX which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins ,which are mediators of pain, inflammation, and fever.

Prostaglandin E synthase

Prostaglandin E2 (PGE2) is generated from the action of prostaglandin E synthases on prostaglandin H2 (PGH2).

PGE2 has various known effects, but one known effect is to increase the pro-inflammatory cytokine IL-6.  The same one that is increased by histamine released from mast cells during allergic reactions.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.


Injection of mineral oils such as pristane into the peritoneal cavities of BALB/c mice results in a chronic peritonitis associated with high tissue levels of interleukin 6 (IL-6). Here we show that increased prostaglandin E2 (PGE2) synthesis causes induction of IL-6 and that expression of an inducible cyclooxygenase, Cox-2, may mediate this process. Levels of both PGE2 and IL-6 are elevated in inflammatory exudates from pristane-treated mice compared with lavage samples from untreated mice. The Cox-2 gene is induced in the peritoneal macrophage fraction isolated from the mice. A cause and effect relationship between increased macrophage PGE2 and IL-6 production is shown in vitro. When peritoneal macrophages are activated with an inflammatory stimulus (polymerized albumin), the Cox-2 gene is induced and secretion of PGE2 and IL-6 increases, with elevated PGE2 appearing before IL-6. Cotreatment with 1 microM indomethacin inhibits PGE2 production by the cells and reduces the induction of IL-6 mRNA but has no effect on Cox-2 mRNA, consistent with the fact that the drug inhibits catalytic activity of the cyclooxygenase but does not affect expression of the gene. Addition of exogenous PGE2 to macrophages induces IL-6 protein and mRNA synthesis, indicating that the eicosanoid stimulates IL-6 production at the level of gene expression. PGE2-stimulated IL-6 production is unaffected by addition of indomethacin. Taken together with the earlier finding that indomethacin diminishes the elevation of IL-6 in pristane-treated mice, the results show that PGE2 can induce IL-6 production in vivo and implicate expression of the Cox-2 gene in the regulation of this cytokine

Indomethacin is another NSAID, like Ibuprofen.


If, as seems likely, many incidents of anxiety, aggression, explosive behavior, or "meltdowns" are made possible by elevated levels of the pro-inflammatory cytokine IL-6, then the occasional use of drugs known to inhibit IL-6 makes a lot of sense.

Ibuprofen is an NSAID and it is known that some people respond much better to certain NSAIDs and suffer side effects from others.   NSAID drugs work by affecting both COX-1 and COX-2.  It appears that desired effect of NSAIDs comes from their effect on COX-2, while the side effects come from changes made to COX-1.  So it is logical that some NSAIDs are better tolerated than others and for some people a different NSAID may be more appropriate.

Other common drugs also lower IL-6;  leukotriene receptor antagonists like Montelukast (Singulair)  being an example.  This drug is used in autism, but a known side-effect in typical people is to worsen behavior, sometimes severely.  There are plenty of reports of Singulair in autism, some good and some bad.  Since almost all drugs have multiple effects, this is not surprising.

Interestingly, one of the drugs in my Polypill, NAC, is also known to reduce IL-6; but it also reduces the “good” anti-inflammatory cytokines like IL-10.  Perhaps this is why NAC is not beneficial to some people with autism?

Occasional use of Ibuprofen at times anticipated to be stressful makes a lot of sense. 


While it is well known that Ibuprofen relieves pain from teething, low level pain is often completely ignored by people with ASD.  The cytokine release associated with the resorption of the milk teeth and the eruption of the permanent tooth appears to be much more problematic.

Ibuprofen, available OTC, limits the production of pain mediators, called prostaglandins, which in turn stimulate production of the inflammatory cytokine IL-6.

Ibuprofen will reduce both pain and the level of cytokines like IL-6.

In earlier extensive posts on mast cell degranulation in autism, I concluded that the resulting elevated levels of IL-6 likely produced behaviors ranging from anxiety, through aggression, all the way to self-injury.