Showing posts with label anxiety. Show all posts
Showing posts with label anxiety. Show all posts

Monday 16 May 2022

Mopping up harmful gut metabolites with Carbon (AB 2004) or Silicone (Enterosgel) to improve GI and behavioral problems in Autism


We have seen in previous posts that certain metabolites produced in the gut can worsen existing autism and even create autism in mouse models.

Much has been written about propionic acid, which when produced in the gut, rather than the beneficial butyric acid, causes behavioral problems.  This is what underlies the Nemechek Protocol, developed by Patrick Nemecheck, DO.  In his therapy you try to increase butyric acid production using inulin as a dietary fiber.  It does work for some people, but they are in the minority; in a small group it makes matters worse.

We also saw that P-cresol, another chemical produced by fermentation in the gut, can trigger autistic behaviors.

P-Cresol, like Propionic acid – a cause of Transitory Autism for some and a further burden for others

A few years ago in the research we did come across a “wonder” bacteria called B. fragilis (Bacteroides fragilis).  This bacterium was able to reverse autism in the mouse model of maternal immune activation (MIA).  The actual mechanism was by reducing a gut metabolite called 4EPS.  It turns out that 4EPS is closely related to P-cresol. The B. fragilis bacteria is essential to healthy gastrointestinal function, but it must not enter the bloodstream because it can cause a fatal blood infection. 

Antibiotics and Autism(s) – Pass the Bacteroides Fragilis?


How to defeat 4EPS

You would think that the easiest way to get rid of that harmful 4EPS would be simply to take B. fragilis, as a probiotic.

An Australian company called Axial decided instead to use a special form of carbon taken orally to “mop up” the 4EPS. The research drug is called AB-2004.

This carbon cannot be selective for 4EPS, so it will also “mop up” other things as well.

It does look like elevated 4EPS in autism is also associated with GI problems and that anxiety is the key feature of autism that is made worse.

I think you could describe AB-2004 as a therapy to restore GI integrity in autism that will also reduce anxiety is a sub-group.

If you have autism with anxiety, but perfect GI function, it does not look like you are going to benefit from AB-2004.


What about Silicone rather than Carbon? 

I was recently introduced to a product normally used to treat IBS-D (irritable bowel syndrome with Diarrhea).  The other type is called IBS-C, with C being for constipation.

It seems that some people with autism and GI problems respond very well to the OTC product Enterosgel, which claims to mop up harmful substances using a silicon gel (polymethylsiloxane polyhydrate) in combination with purified water

As with the experimental AB-2004, the silicone gel cannot be selective for any particular metabolite.

There are clinical trials looking at the benefit of Enterosgel in IBS-D.


Here is a current trial in the United Kingdom:



You can actually measure 4EPS in urine, (as you can P-cresol).  It would not be hard to see if Enterosgel lowers the elevated 4EPS found in people with autism + GI dysfunction. 

Of note is that for our reader Dragos in Romania, Enterosgel worked wonders in his adult son with IBS-C plus challenging behaviors, rather than IBS-D. 



The microbiota modulates gut physiology and behavioral abnormalities associated with autism 

A Serum Metabolite Induces ASD-Related Behavior

MIA-dependent increases of specific metabolites, and their restoration by B. fragilis, suggest that small molecules may play a role in ASD-related behaviors. To test this hypothesis, we examined whether increasing serum 4EPS is sufficient to cause any ASD-related behavioral abnormalities in naïve mice. Mice were treated with 4EPS potassium salt (Figures S7A–C) or vehicle, daily from 3 weeks of age (when MIA offspring display gut permeability) to 6 weeks of age (when behavior testing begins). Remarkably, systemic administration of the single metabolite, 4EPS, to naïve wild-type mice is sufficient to induce anxiety-like behavior similar to that observed in MIA offspring (Figure 6C). Relative to vehicle-treated controls, mice exposed to 4EPS travel comparable distances in the open field but spend less time in the center arena (Figure 6C). Also, in the PPI test, 4EPS-treated mice exhibit increased intensity of startle in response to the unconditioned primary stimulus, but no significant alterations in PPI (Figure 6D), representing anxiety-associated potentiation of the startle reflex (Bourin et al., 2007). Conversely, there are no significant differences between 4EPS-treated versus saline-treated mice in marble burying or USV behavior (Figures S7D and S7E), suggesting that elevating serum 4EPS levels specifically promotes anxiety-like behavior. While not a core diagnostic criterion, anxiety is a common co-morbidity that may contribute to cardinal ASD symptoms. Furthermore, it is possible that complex behaviors may be modulated by combinations of metabolites. In summary, these data reveal that elevated systemic levels of a metabolite regulated by gut microbes causes an ASD-related behavior, suggesting that molecular connections between the gut and the brain maybe associated with autism.

In a proof-of-concept test of the this hypothesis, we reveal that the microbially-modulated metabolite 4EPS, which is elevated in the circulation by MIA and restored by B. fragilis treatment, is sufficient to induce anxiety-like behavior in naïve mice. These data indicate that metabolomic changes contribute to the onset and/or persistence of autism-related behavioral abnormalities. Notably, we show that commensal microbes are required for the production of serum 4EPS in mice. Several species of Clostridium are believed to be producers of the precursor 4-ethylphenol (Nicholson et al., 2012), consistent with our findings that levels of the Lachnospiraceae family of Clostridia and serum 4EPS are elevated in MIA offspring, and both are corrected by B. fragilis treatment. Moreover, the structural similarity of 4EPS to p-cresol, which also derives from Clostridium species (Persico and Napolioni, 2013), suggests they may be produced through similar biosynthetic pathways (see Figure S6A). Although not all autism-like behaviors are affected by 4EPS alone, our results warrant the examination of several other serum metabolites, perhaps in combination, for their potential to impact the spectrum of autism-related behaviors. 


The Gut Microbiota and Autism Spectrum Disorders

AB-2004, its orally administered, drug candidate that has demonstrated the ability to repair leaky gut and improve repetitive behavior, anxiety, and ASD-related sensorimotor gating deficits by removing key microbial metabolites in animal models with Autism Spectrum Disorder (ASD).


The main highlights from the poster presentation titled, “Characterization of GI barrier integrity and gut microbiome-derived metabolites in BTBR, Shank3 and Cntnap2 mouse models of ASD and demonstration of AB-2004 as a potential mitigating therapeutic” include:


·     The Cntnap2-/- mouse model accurately recapitulated the leaky gut phenotype and elevated levels of the gut microbiome-derived metabolite 4-EPS that have been reported in ASD patients

·     Treatment with AB-2004 effectively restored GI integrity and reduced elevated 4-EPS levels in Cntnap2-/- mice

·     The Cntnap2-/- model has been identified as a promising and translationally relevant animal model for the development of microbiome-inspired therapies for the effective treatment of GI and behavioral dysfunctions in ASD

·     These data support the development of AB-2004 as a treatment for GI dysfunction in ASD and potentially behavioral symptoms through reduction of pathologically active microbiome-derived metabolites Axial is currently screening ASD adolescents for its Phase 1b/2a clinical trial of AB-2004.

Scientific evidence has shown there may be a link between bacteria commonly found in the digestive tract, and the brain which could contribute to certain characteristics, such as irritability, in children with ASD. AB-2004 is designed to adsorb certain substances produced by gut bacteria to reduce their ability to enter the bloodstream and reach the brain.   


The active ingredient in AB-2004 is a highly engineered form of spherical carbon designed with human safety and biological selectivity in mind, making it very different from activated charcoal. Each sphere of AB-2004 consists of a network of pores that allows it to selectively adsorb metabolites that may contribute to characteristics associated with ASD like irritability and anxiety.


Axial reports findings of elevated 4-EPS in children with ASD 

The findings showed that concentrations of the bacterial metabolite, 4-ethylphenylsulfate (4-EPS) were elevated as much as six-fold in serum samples from children with ASD compared to healthy controls in replicate analyses.

This research builds on previous work published by Axial's Co-founder and Caltech Professor, Sarkis Mazmanian, Ph.D., that demonstrated causality between 4-EPS and anxiety-like behaviors in the "maternal immune activation" (MIA) mouse model of ASD. The MIA model recapitulates key features of the autism phenotype, including increased anxiety, stereotypic behaviors, and decreased vocalizations and social behaviors. Dr. Mazmanian found changes in the gut microbiome (dysbiosis), increased intestinal permeability (IP), and elevated levels of the putative bacterial metabolite 4-EPS in MIA mice, compared to controls. Oral treatment with B. fragilis, a human commensal gut bacterial species, resulted in restoration of gut microbial profiles, decreased IP, and markedly reduced serum concentrations of 4-EPS.

The current study aimed to evaluate 4-EPS levels in children with ASD compared to samples from control children. Two analyses were performed, a 4-EPS targeted analysis in 103 pediatric subjects and a non-targeted serum metabolomics study involving 230 children (cohorts from the "Childhood Autism Risks from Genetics and the Environment" study ongoing at the Univ. of California Davis). 4-EPS concentrations were found to be significantly elevated in children with ASD vs. healthy controls in both analyses. In addition, elevated levels were associated with worse social performance on two separate measurements. The impact of this elevation on behavior, and the impact of treatment with B. fragilis and with Axial's small molecule therapeutic, AB-2004, will be the subject of subsequent human clinical studies.


Anxiety Linked to Gut Microbial Metabolite in Mouse and Human

In a small, single-cohort pilot study reported simultaneously in a Nature Medicine article titled, “Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial“(trial registration no. ACTRN12618001956291), Mazmanian’s team tested an oral drug (AB-2004) that adsorbs 4EPS in the gut in 30 adolescents with autism. In addition to reducing 4EPS levels in blood and urine, and improving gut health, a subset of the tested participants showed reduced irritability and anxiety.



What is Enerosgel?  (click the link)




I imagine both AB-2004 and Enterosgel are removing numerous metabolites from the digestive tract.

We know that at least 3 metabolites (Propionic acid, P-cresol and 4EPS) can induce autism in a previously not autistic mammal.  There are undoubted other metabolites that will be added to this list.  In the case of Propionic acid the autism was reversable using NAC (N-acetylcysteine).

Since you will have to wait years for AB-2004 to become an approved drug, if indeed it ever happens, you might just have to hope that Enterosgel is equally effective at mopping up that 4EPS with silicone.

It is pretty clear that the Australians are targeting anxious Aspies with GI problems, with AB-2004.

Is Enterosgel going to benefit those with autism and without GI dysfunction?  I think it is less likely, but it could happen.  The effect might not relate just to 4EPS. 



Enterosgel for food allergy? 

I do wonder about the use of Enterosgel following an acute food allergy.

Many people take the mast cell stabilizer cromolyn sodium (Nalcrom) to deal with food allergy.  Indeed, for some people, instead of eliminating the food they are allergic to, they take Nalcrom.

Apparently, some people with food allergies are taking Enterosgel regularly.

What happens if you consume a food substance by mistake that you are allergic too?

This is what happened recently to Monty while on holiday in Greece.  Two small red patches appeared on either side of his face and his mood and behavior changed dramatically.  It was like his pollen allergy triggered summertime raging, but it was not due to pollen allergy.

The effect of an allergic reactions continues even after you remove the allergen.  If you are allergic to bee stings you might end up needing a steroid injection to settle your immune system down.  In the immediate term you can take an oral H1 antihistamine.

Monty had his H1 antihistamine and a single oral dose of Prednisone; after 3 days he was back to his usual self.

People who get severe allergic reactions carry an Epipen (an epinephrine autoinjector).

In Monty’s case there is never a severe allergic reaction, but there is a severe behavioral reaction to a modest allergic reaction.  I think this is likely to be quite common in people with autism and challenging behaviors.  It often goes untreated, or is poorly treated using anti-psychotic drugs, which then cause serious side-effects including tardive dyskinesia (motor tics), obesity, males growing breasts (drug-induced gynecomastia) etc.

Even though Monty has no GI problems, perhaps I should acquire some Enterosgel to use in case of a future acute food allergy attack?

Friday 26 April 2019

The Autonomic Nervous System (ANS), Heart Rate Variability (HRV), Performance Anxiety, Propranolol, Vagus Nerve Stimulation and Autism

Performance anxiety symptoms may include:
·       Racing pulse and rapid breathing.

·       Dry mouth and tight throat.

·       Trembling hands, lips, and voice.

·       Sweaty and cold hands.

·       Nausea 

·       Vision changes.

Today’s post started out to be all about Propranolol, a very old and widely prescribed drug that lowers your blood pressure, but does other interesting things as well. It is used to treat several psychiatric disorders and has been widely trialled in autism. As I started researching I decided to broaden the post to bring in Heart Rate Variability (HRV), which one reader of this blog suggested as a useful measure of the effect of supplements.   HRV is actually a good indicator of a dysfunction in the Autonomic Nervous System (ANS). 

The Autonomic Nervous System (ANS) is a control system that acts largely unconsciously and regulates bodily functions such as the heart rate, digestion, respiratory rate, pupillary response and urination.
Within the brain, the autonomic nervous system is regulated by the hypothalamus. Autonomic functions include control of respiration, cardiac regulation, vasomotor activity (actions upon a blood vessel which alter its diameter) and certain reflex actions such as coughing, sneezing, swallowing and vomiting.
Dysfunctions in the Autonomic Nervous System (ANS) are known to be a common feature of autism.  Propranolol is known to affect the Autonomic Nervous System (ANS) and has been shown in numerous trials and case studies to improve some cases of autism.
Performance anxiety is a well-known off-label use of Propranolol.
Vagus Nerve Stimulation (VNS) is known to affect the Autonomic Nervous System (ANS) and is sometimes used to treat performance anxiety.

Vagus nerve stimulation (VNS) using an implanted device can have profound benefits in severe epilepsy. Less invasive VNS can be achieved transcutaneously and in particular via a branch of the vagus nerve that extends to your ear.
The vagus nerve has many roles including sending inflammatory signalling from the gut to the brain. We saw how this was proved, at least in mice, by severing the vagus nerve. Stimulating the vagus nerve can have significant anti-inflammatory effects, which is why it is being developed to treat a wide range of conditions ranging from arthritis to COPD (severe asthma).

We also saw in a post last year that drinking sodium/potassium bicarbonate has an effect that is very similar to VNS, in that it tamps down your immune system in a very similar way.

The Propranalol Autism Research
Fortunately, in 2018 a review of all Propranolol-related autism research was published. I found this out after having started to trawl through the old research.  The issue of Heart Rate Variability (HRV) as potential marker for propranolol responders that I focused in on, was also picked up in the review paper.

We can start with review paper, which happens to be from England, which still has not fully recovered from the Wakefield saga.  There is a real stigma about treating autism, better call it encephalopathy and treat that!

To date, there is no single medication prescribed to alleviate all the core symptoms of Autism Spectrum Disorder (ASD; National Institute of Health and Care Excellence, 2016). Both serotonin reuptake inhibitors and drugs for psychosis possess therapeutic drawbacks when managing anxiety and aggression in ASD. This review sought to appraise the use of propranolol as a pharmacological alternative when managing emotional, behavioural and autonomic dysregulation (EBAD) and other symptoms.
This review indicates that propranolol holds promise for EBAD and cognitive performance in ASD. Given the lack of good quality clinical trials, randomised controlled trials are warranted to explore the efficacy of propranolol in managing EBAD in ASD.

From the 16 articles identified, propranolol dosages ranged from 7.5 mg to 360 mg per day across a range of patients. All studies had a range of outcome measures for those diagnosed with ASD, including a focus on cognitive enhancement, management of social behaviours, EBAD, SIBs, and aggression.

Summary of evidence

Across multiple domains, propranolol had significant benefits in the treatment of adults and children diagnosed with ASD. Propranolol improved cognitive performance, with individuals with ASD demonstrating an improvement in verbal problem solving (Beversdorf et al., 2008; Zamzow et al., 2017), semantic processing (Beversdorf et al., 2011) and working memory (Bodner et al., 2012). No changes in cognitive performance for individuals without ASD were reported (Beversdorf et al., 2008, 2011). Additionally, propranolol exhibited greater functional connectivity in individuals with ASD (Hegarty et al., 2017; Narayanan et al., 2010). Not only does this provide evidence for the ability of propranolol to improve functional connectivity in those with ASD, but also that central and peripheral blockade is more effective than just peripheral blockade as seen by nadolol (Hegarty et al., 2017). It is important to note that a non-significant difference for functional connectivity between placebo and propranolol conditions can be attributed to other hemodynamic factors, such as differences in blood pressure, confounding the effects on blood-oxygen-level-dependent responses during fMRI sessions (Narayanan et al., 2010). Moreover, propranolol decreased functional connectivity in various subnetworks where high baseline functional connectivity was observed. Conversely, for those with low baseline functional connectivity, functional connectivity in these subnetworks increased after the introduction of propranolol, irrespective of diagnostic group (Hegarty et al., 2017). These differences suggest that propranolol, and other beta-adrenergic antagonists may have a greater role in maintaining appropriate patterns of functional connectivity, allowing for more efficient integration of functional networks (Hegarty et al., 2017). These findings also highlight the potential for propranolol to support cognitive processing. Indeed, by modulating noradrenaline, greater associative processing and integration of subnetworks may be achieved. Subsequently, potential improvements in attention-shifting, sensory processing, language communication, and the processing of social information could be observed in those with ASD (Hegarty et al., 2017). Furthermore, propranolol reduced mouth fixation, improving facial scanning at a global level (Zamzow et al., 2014). Although, non-significant findings were reported when investigating the efficacy of single-dose propranolol treatment for eye contact, this may be attributable to the sample used. The majority of subjects fulfilling diagnostic criteria for ASD were high functioning, suggesting that scores for eye contact may have already been at a ceiling prior to the administration of propranolol. Therefore, none or only marginal improvements would be attained from post administration of propranolol leading to non-significant results when compared with controls. Moreover, non-verbal communication improvements (Zamzow et al., 2016) and reductions in hypersexual behaviours (Agrawal, 2014) were also observed. These improvements were reported in studies using a 40 mg dose of propranolol, with just one study utilising a low dose of 20 mg (Agrawal, 2014). However, it may be noteworthy to consider that for this case, the hypersexual behaviours did not decrease while the patient was alone, but the patient was able to manage behaviours more appropriately in the presence of others. This may indicate an improved ability to understand and interpret social contexts, rather than a reduction in hypersexual behaviours. Indeed, social cues and social situations are a challenge for those with ASD, and these findings highlight potential clinical implications for propranolol. In light of this, both studies by Sagar-Ouriaghli et al. (2017) and Santosh et al. (2017) highlight again that on average, a 40 mg dose is suitable for children and adolescents in managing symptoms associated with ASD and EBAD. Furthermore, Santosh et al. (2017) and Zamzow et al. (2017) provide supporting evidence for the use of wearable technologies in measuring biomarkers such as HRV and skin conductance in order to identify treatment responders and monitoring the impact of propranolol on therapeutic outcomes. Alongside these benefits, propranolol significantly helped manage SIBs and aggressive outbursts in those with ASD (Knabe and Bovier, 1992; Lyskowski et al., 2009; Ratey et al., 1987). Two cases reported no significant improvement when using propranolol (Connor, 1994; Luiselli et al., 2000). One case was required to change propranolol due to hypotension and bradycardia despite a decreasing trend in aggressive behaviours (Luiselli et al., 2000). Across these cases, dosing ranged from 7.5 mg–360 mg, indicating a higher dose may be required for SIBs and aggression, in comparison with cognitive performance (20 mg–40 mg). In summary, these results and a subsequent overview by Fleminger et al. (2006) conclude that β-blockers have the best evidence for the management of such symptoms and that propranolol improves impulse control and subsequent violence associated with brain dysfunction of diverse aetiologies.

You can read the original 16 studies referred to if you are seriously interested in Propranolol. I have just highlighted some I found interesting.  It is interesting that beneficial effects are reported across the spectrum from severe autism to Asperger’s. 

People with intellectual disability often exhibit various behavioral problems, which are referred to as “challenging behaviors.” Aggression is among the commonest of these, affecting about 7% of this population. The management of aggression in these patients involves both behavior therapy and medications. Various medications, such as lithium, anticonvulsants, and antipsychotics, have been used, but their evidence base is limited and recent research suggests that antipsychotics, in particular, should not be routinely used
Propranolol is a centrally acting β-adrenergic antagonist used in a variety of medical conditions. It has also been used to manage aggression in various neuropsychiatric conditions, including organic brain syndromes, schizophrenia, dementia, and intellectual disability. Doses used in these studies have been as high as 520 mg/d, but some authors have reported benefits at much lower doses. The following is the case of a young man with intellectual disability, epilepsy, and severe aggression who responded remarkably to low-dose propranolol.
Case report. Mr A, a 20-year-old man diagnosed as having moderate intellectual disability and generalized epilepsy, presented to our clinic with severe aggression, both verbal and physical, occurring with little or no provocation over the past 3 years. These episodes would last up to several hours and often led to food refusal. Before this, he could attend to his personal needs, helped his mother in household tasks, and could communicate in short sentences despite an articulation defect. However, after the onset of his aggression, it was difficult to engage him in any activities, including basic self-care. There was no evidence of a mood disorder or psychosis or of seizures either preceding or following the episodes of aggression. He was seizure-free for the past 4 years on carbamazepine 1,000 mg/d and diazepam 10 mg/d, and he had never exhibited postictal aggression in the past. He had already received trials of olanzapine (up to 15 mg/d for 6 weeks) and chlorpromazine (up to 400 mg/d for 3 months) without significant improvement and was currently on olanzapine 10 mg/d and chlorpromazine 300 mg/d in addition to his medications for epilepsy.

As his mother reported features of autonomic arousal—such as increased perspiration, motor agitation, and rapid breathing—during each episode, he was given a trial of propranolol, starting at 20 mg/d and increased by 20 mg every week. At 40 mg/d, there was a significant reduction in his aggression, and his food intake was better. On further increasing the dose to 60 mg/d, his mother reported that he was essentially “normal,” with no significant episodes of aggression. Over the next year, olanzapine and chlorpromazine were tapered and stopped, and he remained stable. He has been well on carbamazepine 1,000 mg/d, propranolol 60 mg/d, and diazepam 10 mg/d for the past 3 months with no recurrence of either seizures or aggression, and it is now possible to engage him in household tasks and speech therapy.
The management of aggression in the intellectually disabled is a clinical challenge. The best evidence suggests that antipsychotics are of limited use, and the evidence for other medications is even more limited. Behavioral management is valuable, but may not be feasible in a very violent or uncooperative patient, and pharmacotherapy may be required initially in such cases.
Propranolol is effective in reducing aggression in a variety of neurologic and psychiatric conditions. Its exact mechanism of action is unknown, but may involve central β-adrenergic blockade, peripheral effects on the sympathetic nervous system, or serotonergic blockade. It may be effective not only in aggression, but also in the self-injurious behavior commonly seen in the intellectually disabled. Recent evidence suggests that it may improve some aspects of learning in patients with autism. Given these properties, and the uncertainties surrounding other treatment options, low-dose propranolol may be a valuable treatment option in the management of aggression in intellectually disabled adults, even if they do not respond to other drugs.

Amelioration of Aggression and Echolalia With Propranolol in Autism Spectrum Disorder


Although the autonomic hyperactivity hypothesis of aggression in ASD partially explains the behavior of our patient, aggression likely stems from multiple sources beyond just peripheral autonomic arousal. The rapid improvement with propranolol at a fairly low dose suggests that a subpopulation of patients may benefit from non-selective beta blockers. As beta blockers have hemodynamic side effects that include hypotension and bradycardia, clinicians should record baseline vitals and monitor for orthostasis, dizziness, and syncope. Overall, beta blockers may serve as an important therapy for aggression but should not replace a multimodal interventional plan that encompasses pharmacology, psychotherapy, and social support. It will be beneficial to validate the utility of propranolol and other beta blockers for ASD in future randomized controlled trials.
·       Though autism spectrum disorder (ASD) is primarily a disorder of language and social functioning, there may also be significant autonomic dysfunction that could contribute to aggression and impulsivity often seen in the disorder.
·       Beta-adrenergic blocking agents have been shown to reduce aggression in patients with traumatic brain injury and adult-onset neuropsychiatric disorders, but evidence is still limited in patients with ASD.
·       The non-selective beta-blockers propranolol and nadolol may significantly alleviate aggression, echolalia, and vital sign derangements in autistic patients; it is unknown whether β1-selective antagonists would have similar effects.

Here we have the effect on high functioning autism:-


Autism is characterized by repetitive behaviors and impaired socialization and communication. Preliminary evidence showed possible language benefits in autism from the β-adrenergic antagonist propranolol. Earlier studies in other populations suggested propranolol might benefit performance on tasks involving a search of semantic and associative networks under certain conditions. Therefore, we wished to determine whether this benefit of propranolol includes an effect on semantic fluency in autism.


A sample of 14 high-functioning adolescent and adult participants with autism and 14 matched controls were given letter and category word fluency tasks on 2 separate testing sessions; 1 test was given 60 minutes after the administration of 40 mg propranolol orally, and 1 test was given after placebo, administered in a double-blinded, counterbalanced manner.


Participants with autism were significantly impaired compared with controls on both fluency tasks. Propranolol significantly improved performance on category fluency, but not letter fluency among autism participants. No drug effect was observed among controls. Expected drug effects on heart rate and blood pressure were observed in both the groups.


Results are consistent with a selective beneficial effect of propranolol on flexibility of access to semantic and associative networks in autism, with no observed effect on phonological networks. Further study will be necessary to understand potential clinical implications of this finding.

This paper is interesting because it looks at how you can identify people who are likely to respond to Propranolol:-

Autism spectrum disorders are a group of developmental disorders, which display significant heterogeneity of symptoms. Besides the core symptoms, various comorbidities are common for individuals with autism. A growing body of evidence suggests dysfunction of autonomic nervous system within the ASD population. The detection of autonomic abnormalities could help in more personalized approach, which takes into account individual etiologic differences. It has also been suggested that interventions focused on autonomic function could possibly be beneficial for treatment of aggression, anxiety, as well as the core symptoms of autism.
Detection of autonomic alterations in autism spectrum disorders

Invasive methods 
The measurement of circulating catecholamines belongs to most common methods of assessment of sympathetic nervous system function (SNS) (Zygmunt & Stanczyk 2010). Activity of the SNS can be assessed using the measurement of the plasma or urine concentration of norepinephrine, or its metabolites. Measurement of catecholamines provides useful information about the activity of SNS, however, they are determined by location of vessel used for blood collection and therefore do not reflect the whole amount of neurotransmitter secreted from axon terminal (Sinski et al 2006). Acetylcholine, neurotransmitter released by postganglionic fibers of the parasympathetic system, is very quickly inactivated by acetylcholinesterase, so its plasma levels cannot be used as a marker of parasympathetic nervous system activity (McCorry 2007). Interestingly, plasma norepinephrine concentrations have been reported to be elevated in autism (Launay et al 1987). However, blood and urine samples acquisition represent extremely stressful stimuli for children with autism spectrum disorders and thus pose a challenge for researchers in obtaining such samples from both ethical and methodological reasons. Therefore, various non-invasive methods of ANS activity detection have been developed. 
Non-invasive methods 
To assess autonomic nervous system activity, various non-invasive methods are used. For example, measurement of sympathetic skin response is used frequently (Claus & Schondorf 1999, Kucera et al 2004). This method is based on determination of the alterations in skin electrical resistance in response to activation of sweat glands which are stimulated by impulses conducted by cholinergic postganglionic sympathetic fibers. However, it is important to note, that in general, skin conductance level are not stable and therefore it is difficult to define baseline values and there are large intra- and inter-individual differences (Boucsein et al 2012). Another widely used method has become pupillometry, biomarker of LC-NE system. Several studies found both dysregulated tonic pupil responses to various stimuli (e.g. Anderson et al 2006, Martineau et al 2011) and greater skin conductance level (Prince et al 2016) in children with ASD. One of the most reliable methods for measurement of ANS activity, namely cardiac autonomic responses, has become heart rate variability (HRV). HRV refers to beat-to-beat variations of the heart rate that is determined by autonomic nervous system. In resting conditions, the variability of beat-to-beat intervals remains large and becomes more regular when influenced by stressful environmental factors (Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology 1996). Because of the fast degradation of acetylcholine by acetylcholinesterase, the influence of parasympathetic activation is quick and thus accounts for fast changes in heart rate. Sympathetic influence changes more slowly, its effect is observable as a change in heart rate after longer period, and thus is responsible for slower oscillations. HRV has been found to be decreased in autism spectrum disorders in number of studies (Daluwatte et al 2013, Ming et al 2005). These data

Interventions affecting vagal activity for adjuvant treatment of children with ASD 

In the light of above mentioned findings, several new treatment options are now being explored. Vagus nerve stimulation, which involves surgical implantation of electrodes around cervical portion of the vagus nerve, was found to increase HRV. Study of Hull et al (2015) showed decreased severity and duration of seizures in children with refractory epilepsy and autism after stimulation of vagus nerve. Moreover, they found the improvement in ASD symptoms not related to epilepsy, such as communication skills, or stereotyped behavior. Furthermore, considerable improvement in regulation of aggressive behavior and receptive communication skills were noted and maintained over 1 year. The biggest drawback of vagus nerve stimulation method is cost and requirement of invasive neurosurgery. However, recent studies confirmed the possibility of noninvasive transcutaneous stimulation of the vagus nerve with electrodes located in the auricular concha area that is densely innervated by branches of the vagus nerve (Fang et al 2016). Electrical stimulation of the cervical vagus nerve with handheld device represent another non-invasive method (Schoenen et al 2016). In preterm infants or high-risk infants, kangaroo care or massage therapy may increase vagal tone and promote optimal neurodevelopment (Feldman & Eidelman 2003). Similar preliminary data were obtained on children with ASD, as well (Escalona et al 2001).

This new clinical trial looks very interesting because it includes looking at predictors for responders:-

The specific aim of this study is to examine the effects of serial doses of propranolol on social interaction, and secondarily on language tasks, anxiety, adaptive behaviors, and global function in high functioning adults and adolescents with autism in a double-blinded, placebo-controlled trial. The investigators will also examine whether response to treatment can be predicted based upon markers of autonomic functioning, such as skin conductance, heart rate variability (HRV), and the pupillary light reflex (PLR), and whether anxiety can predict treatment response. The hypothesis is that social functioning and language abilities will benefit from serial doses of propranolol, and that those with the greatest degree of autonomic dysregulation, or the lowest functional connectivity, will demonstrate the greatest benefit from the drug.

Propanolol will be given on a titration schedule in which participants will begin with small doses (single capsules) of the drug and increase to a larger dosage (divided over 3 capsules) over the course of three weeks. Participants aged 15-24 years will undergo an MRI.

 Autonomic Dysfunction in Autism


Objective: To report a case series of clinically significant autonomic dysunction in ASD. 
Background:Autonomic nervous system (ANS) impairment has been increasingly recognized in autism spectrum disorders (ASD). Abnormalities in pupillary light reflex, resting heart rate, heart rate response to social cognitive tasks, respiratory rhythm, and skin conductance suggest that autonomic dysfunction is common in ASD and may play a role in the social, behavioral, and communication problems that are the hallmark of this neurodevelopmental disorder. This case series confirms the presence of clinically significant multisystem ANS dysfunction in ASD. 
Methods: Patients with a history of ASD who underwent an evaluation for ANS dysfunction at our institution were identified. Clinical features, findings on autonomic testing, and laboratory results were reviewed.
Results: Six patients with ASD underwent clinical and autonomic evaluation, ranging in age from 12 to 28, and autonomic symptom duration ranging from 10 months to 6 years. All reported postural lightheadedness, near-syncope, and rapid heart rate. Five reported significant gastrointestinal (GI) symptoms including constipation, diarrhea, and early satiety. Autonomic testing revealed an excessive postural tachycardia with head-up tilt (HUT) in all patients, with a mean heart rate (HR) increment of 50 bpm, mean maximum HR on HUT of 118 bpm, absence of orthostatic hypotension on HUT. Abnormal blood pressure profile with the Valsalva maneuver was identified in three patients. All five patients were diagnosed with orthostatic intolerance. Supine norepinephrine (NE) was low in three of the four patients tested and an inadequate rise in standing NE was noted in two of these patients. GI motility testing was performed in two patients, and suggested gastroparesis in one patient.
Conclusions: Clinically significant ANS dysfunction may occur in ASD, with symptoms suggestive of orthostatic intolerance and gastrointestinal dysmotility, and findings on autonomic testing demonstrating an excessive postural tachycardia.

Functional autonomic nervous system profile in children with autism spectrum disorder


Autonomic dysregulation has been recently reported as a feature of autism spectrum disorder (ASD). However, the nature of autonomic atypicalities in ASD remain largely unknown. The goal of this study was to characterize the cardiac autonomic profile of children with ASD across four domains affected in ASD (anxiety, attention, response inhibition, and social cognition), and suggested to be affected by autonomic dysregulation.


We compared measures of autonomic cardiac regulation in typically developing children (n = 34) and those with ASD (n = 40) as the children performed tasks eliciting anxiety, attention, response inhibition, and social cognition. Heart rate was used to quantify overall autonomic arousal, and respiratory sinus arrhythmia (RSA) was used as an index of vagal influences. Associations between atypical autonomic findings and intellectual functioning (Weschler scale), ASD symptomatology (Social Communication Questionnaire score), and co-morbid anxiety (Revised Children’s Anxiety and Depression Scale) were also investigated.


The ASD group had marginally elevated basal heart rate, and showed decreased heart rate reactivity to social anxiety and increased RSA reactivity to the social cognition task. In this group, heart rate reactivity to the social anxiety task was positively correlated with IQ and task performance, and negatively correlated with generalized anxiety. RSA reactivity in the social cognition task was positively correlated with IQ.


Our data suggest overall autonomic hyperarousal in ASD and selective atypical reactivity to social tasks.

The Vagus nerve as a means to affect the ANS 

Vagal Nerve Stimulation in Autonomic Dysfunction – A Case Study

Background: Autonomic nervous system function is influenced by the balance of the parasympathetic and sympathetic systems. Management for imbalance of these components causing dysfunction is largely focused on medications primarily improving cardiovascular tone. However, there appears to be an opportunity for therapy by modulating neurotransmission. Methods: Our patient is a nine year old female with history of intractable epilepsy and developmental delay related to confirmed genetic abnormalities and also complaints of episodic pallor, fatigue, light-headedness and headaches concerning for dysautonomia. Results: Our patient underwent vagal nerve stimulator (VNS) implantation for treatment of epilepsy and showed improvement of these symptoms at typical settings. Headup tilt test (HUTT) was subsequently performed and revealed normal findings and no subjective symptoms of autonomic dysfunction. A repeat HUTT was performed five months later with VNS output currents set to zero and revealed cardiovascular changes and clinical symptoms consistent with dysautonomia. With resumption of previous VNS settings, clinical symptoms resolved.

Conclusions: Neurotransmission from vagal afferents to brainstem nuclei is increased during VNS affecting multiple brainstem areas and the cerebral cortex, including regions controlling autonomic function. Studies have suggested a role for VNS in patients with clinical signs of autonomic dysfunction showing improvement in sympathovagal balance after VNS implantation. In our patient, we observed subjective and objective improvement in autonomic function. This initial case demonstrates a phenomenon that requires further study, may lead to improved understanding of autonomic function and the response to vagal nerve stimulation, and possibly a new indication for VNS therapy.

The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to the maintenance of cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant, and this change in dominance is negatively correlated with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that the extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be attributable to activation of the afferent branch of the vagus and, potentially, other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

The Vagus Nerve as a target to reduce inflammation
Regardless of its effects on the autonomic nervous system (ANS), we know from the research in earlier blog posts that vagus nerve stimulation can significantly reduce inflammation.  Here is an easy to read article as a reminder.

Vagus Nerve Stimulation Dramatically Reduces Inflammation

Stimulating the vagus nerve reduces inflammation and the symptoms of arthritis.

Healthy vagal tone is indicated by a slight increase of heart rate when you inhale, and a decrease of heart rate when you exhale. Deep diaphragmatic breathing—with a long, slow exhale—is key to stimulating the vagus nerve and slowing heart rate and blood pressure, especially in times of performance anxiety.
A higher vagal tone index is linked to physical and psychological well-being. Conversely, a low vagal tone index is associated with inflammation, depression, negative moods, loneliness, heart attacks, and stroke.

There are many ways put forward to  stimulate the vagus nerve simply without electrical devices. Here is one list I came across:-

1.     Slow deep breathing. An example would be to breathe in slowly for a count of 4 and out for a count 6 to 8. The average normal breathing rate is between 12 and 14 per minute. This slow breathing reduces it to 6 to 7 per minute.
2.     Any exposure to cold. eg rinse your hands and face in cold water.
3.     Singing, chanting, gargling and humming
4.     Laughter
5.     Restorative yoga postures such as the cat cow posture and downward dog
6.     Meditation.
7.     Evoking the emotions of love, compassion and empathy.
8.     Exercise
9.     Massage/acupuncture, acupressure
10. Intermittent fasting

I found re-reading this old post interesting

Drinking Baking Soda for Vagal Nerve Stimulation?

It prompted me to order some potassium bicarbonate.


I think when you read about what the Autonomic Nervous System (ANS) does in your body you are likely to be able to judge whether or not it may be dysfunction. Hopefully the research will identify reliable markers, whether it is heart rate variability (HRV) or pupillary light reflex (PLR).
I do not think Autonomic Nervous System (ANS) dysfunction is a cause of autism, but it may be a consequence of it. Correcting any such dysfunction may have an impact ranging from trivial to profound.
I know that some readers of this blog have been using Propranolol for some time already. It has been very well researched, by the standards of autism. Being a cheap generic drug, there is little interest to spend $8 million in Europe to have it approved for autism, or the $20 million needed in the US. 
It should be noted that while Propranolol is a very widely used drug it does have side effects and interactions. Some other autism drugs used off-label do reduce blood pressure.
Propranolol is a competitive antagonist of beta-1-adrenergic receptors in the heart. It competes with sympathomimetic neurotransmitters for binding to receptors, which inhibits sympathetic stimulation of the heart. Blockage of neurotransmitter binding to beta 1 receptors on cardiac myocytes inhibits activation of adenylate cyclase, which in turn inhibits cAMP synthesis leading to reduced PKA production. This results in less calcium influx to cardiac myocytes through voltage gated L-type calcium channels meaning there is a decreased sympathetic effect on cardiac cells, resulting in antihypertensive effects including reduced heart rate and lower arterial blood pressure.

One side effect of Propranolol is low heart rate (bradycardia), but some people do have too high a heart rate.
Propranolol is a so-called negative inotropic agent, meaning it reduces the strength of contractions of heart muscle. This is why it reduces blood pressure.
Negative inotropic effects can be additive, which means not surprisingly if you take another negative inotropic agent, like an L-type calcium channel blocker, you have to be careful.
There are medical conditions for which the combined use of Propranolol and Verapamil has been suggested, but at the high doses often used this looks rather unwise.
There are interactions between Propranolol and many drugs; note that Verapamil will raise the serum level of propranolol.
The good news is that the dosage often effective in autism is quite low.

The adult dose for Migraine Prophylaxis is up to 240mg a day.  Some of the regular pediatric doses are also huge, compared to the “autism dosage” which can be 40mg of even less.
The initial paper we looked at in this post, from ultra-sceptical that autism can be treated England, concluded:

 “… randomised controlled trials are warranted to explore the efficacy of propranolol in managing EBAD (emotional, behavioural and autonomic dysregulation) in ASD”
Are severe headaches that occur in some autism another possible predictor of Propranolol responders?

Is stuttering another symptom to look out for?