Showing posts with label Desmopressin. Show all posts
Showing posts with label Desmopressin. Show all posts

Wednesday 20 March 2024

Monty in Montevideo and Recent Advances in Autism Research

It is nice to have a city named after you and Monty finally visited “his” city, Montevideo in Uruguay.

I suppose my city would be St Petersburg, which I have visited several times.

A really impressive city in Latin America is Buenos Aires; it has a very large central area with beautiful architecture. It enjoyed several decades of great wealth, the “golden age,” when the city was laid out. In 1930 there was a military coup and the party was over. It has been boom and bust ever since.

We visited what they call the Southern Cone of Latin America, which is made up of Argentina, Chile and Uruguay. We went from Buenos Aires all the way down to Tierra del Fuego.

Santiago, the capital of Chile, looks to be booming. It has a small historic centre and everything else is new.

Montevideo was more what I expected, except for the graffiti everywhere which makes it look less safe than it likely is. Uruguay has many beautiful beaches, but until you get away from the vast River Plate estuary (Río de la Plata = river of silt) and to the Atlantic ocean the water is a dirty brown colour.  Monty would not go in the water.

Southern Chile and Argentina have some stunning scenery with volcanoes, mountains and glaciers.  It looks great, but it is no longer the cheap backpacker destination it once was.



Back to the Autism Research

The highlight from the recent research comes from The RIKEN institute in Japan. It does go some way to explaining why so many people with autism appear to have nothing in their genetic results to explain their condition.

Normally, when you have your state of the art whole genome screening (WGS) the geneticist who interprets the results is looking for mutations in one of the many hundreds of known “autism genes” and nowadays, hopefully, in the non-coding areas next to them. Whole exome screening (WES) just looks at the 2% of the genome that has the instructions for how to make each of your 22,000 genes. The other 98% includes things like promoters that increase activity of a specific gene.

Many people with autism appear to show no mutations that are relevant.

The Japanese have figured out one of the reasons why this is the case. There are other reasons.

Our genetic material is not stored on something like a long role of paper, which is like a two-dimensional object.  It is a three-dimensional twisted object all folded up. As a result, the DNA physically closest to each autism gene may not be the part expected. The Japanese use the term “topologically associating domain” (TAD) to define which zones of DNA are actually interacting with each other.

They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes.

This means that geneticists now need to go back to school and learn about the TAD of each autism gene. Or else just replace the geneticist with an AI generated report.


Mutation butterfly effect: Study reveals how single change triggers autism gene network

Researchers in the RIKEN Center for Brain Science (CBS) examined the genetics of autism spectrum disorder (ASD) by analyzing mutations in the genomes of individuals and their families. They discovered that a special kind of genetic mutation works differently from typical mutations in how it contributes to the condition. In essence, because of the three-dimensional structure of the genome, mutations are able to affect neighboring genes that are linked to ASD, thus explaining why ASD can occur even without direct mutations to ASD-related genes. This study appeared in the scientific journal Cell Genomics on January 26.

The researchers analyzed an extensive dataset of over 5,000 families, making this one of the world's largest genome-wide studies of ASD to date. They focused on TADs-;three-dimensional structures in the genome that allow interactions between different nearby genes and their regulatory elements. They found that de novo mutations in promoters heightened the risk of ASD only when the promoters were located in TADs that contained ASD-related genes. Because they are nearby and in the same TAD, these de novo mutations can affect the expression of ASD-related genes. In this way, the new study explains why mutations can increase the risk of ASD even when they aren't located in protein-coding regions or in the promotors that directly control the expression of ASD-related genes.


"Our most important discovery was that de novo mutations in promoter regions of TADs containing known ASD genes are associated with ASD risk, and this is likely mediated through interactions in the three-dimensional structure of the genome."  

Atsushi Takata at RIKEN CBS



Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk

Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.




I did come across a Chinese study with an eye-catching title:-


Can bumetanide be a miraculous medicine for autism spectrum disorder: Meta-analysis evidence from randomized controlled trials



    • Bumetanide showed significant and large effects on the overall core symptoms of ASD.
    • Bumetanide’s efficacy on ASD is influenced by subjects’ age, dosage form, duration.
    • Results of RCTs on bumetanide in ASD are moderated by study designs, measurement tools

A systematic search was conducted on PubMed, EMBASE, MEDLINE, PsyclNFO, Web of Science, Clinical, and references in reviews from the earliest available date to September 2023. Randomized controlled trials (RCTs) were identified that evaluated the efficacy of bumetanide in improving overall core symptoms (OCS) of ASD. Therefore, nine studies with 1036 participants were included in the study.


Bumetanide showed significant effects on OCS of ASD (WMD = 1.91, p = 0.006), particularly in sub-domains including relation to inanimate objects, adaption to environment changes, auditory response, near sensory responses, anxiety and hyperactivity. Moderating analysis indicated that a significant effect size of bumetanide on OCS of ASD was observed in specific subgroup, including 3–6 years old (WMD = 1.08, p = 0.008), the tablet (WMD = 2.80, p = 0.003), 3-month intervention (WMD = 2.54, p = 0.003), and the single-center studies (WMD = 2.80, p = 0.003).


Bumetanide has a large and significant impact on the OCS of ASD. Given the limited number and quality of included RCTs, future research should prioritize conducting large-scale trials focusing on sub-parameters or specific clinical features to comprehensively evaluate the efficacy of bumetanide in subpopulations of children with ASD.

Meanwhile, Professor Ben Ari has written another paper on why the phase 3 trial failed and has also published a book.


Bumetanide to treat autism spectrum disorders: are complex administrative regulations fit to treat heterogeneous disorders?


Extensive experimental observations suggest that the regulation of ion fluxes and, notably, chloride are impacted in autism spectrum disorders (ASD) and other neurodevelopmental disorders. The specific NKCC1 cotransporter inhibitor Bumetanide has been shown to attenuate electrophysiological and behavioral features of ASD in experimental models. Both pilot and phase 2 double-blind randomized independent trials have validated these effects with thousands of children treated successfully. Both brain imaging and eye tracking observations also validate these observations. However, final large phase 3 trials failed, with no significant differences between placebo and treated children.


Here, I discuss the possible reasons for these failures and discuss the exclusive reliance on complex patent cooperation Treaty (PCT) regulations. Indeed, available data suggest that bumetanide responders could be identified by relying notably on EEG measures, suggesting that biological sub-populations of patients might benefit from the treatment.


These observations raise important debates on whether treating only a % of children with ASD is acceptable.


It is likely that in many disorders, the heterogeneity of the pathological event precludes a single general treatment for all, suggesting that trials centered on selective populations of responders might be essential for large clinical trials to succeed.

  Here is the new book:-

Treating Autism with Bumetanide

In spite of its high incidence, extensive media coverage and major clinical burden to families, there is not a single approved European or American drug treatment of Autism Spectrum Disorders (ASDs). The dominant genetic and psychiatric approaches to treat ASDs have various limitations, suggesting that a novel global approach to understand and treat ASDs is warranted. Based on the authors’ converged expertise on brain development, ASD treatment and brain imaging, this book provides a fresh view of the disorder which is validated by experimental imaging and large clinical trials, culminating in the first large phase 3 final pediatric trial (on 400 children in EU countries and the US) using a repositioning of a drug used for decades to treat hypertension and edema. The convergence of experimental and clinical data on this disorder is unprecedented, confirming the potential of the drug to be the first pediatric treatment of ASDs.

After explaining the mechanisms underlying ASDs, we describe specific cases of children who, after treatment, considerably improved their sociability and reduced their agitation. The book also discusses the skepticism that the authors met from the tenants of pure genetics and psychiatry, and why the abyssal poverty of information on developmental disorders has hampered progress in understanding and treating ASD.


Bumetanide dosage is key – “wonderful effects from increasing from 0.5mg to 1mg” 

One recuring feature I have noticed from bumetanide use in the United States is the low dosage often used, as if these doctors want to show the drug is ineffective.

A reader recently contacted me about his young son who responded to the low dose of 0.5mg, but his autism doctor would not increase the dose.  The parent took matters into his own hands and increased the dose and then wrote to tell me about the “wonderful effects.”


Diuresis has stopped, but restarts at a lower dose

In a minority of cases bumetanide causes no diuresis. The question is whether it can have any effect in the brain if it causes no diuresis. Has the drug been absorbed at all?

One reader contacted me to tell me that her son, who has responded well to bumetanide for several years, stopped experiencing any diuresis. Then she told me that when she reduces the dose the diuresis returns.

There are many possible explanations, but perhaps those people who find bumetanide causes no diuresis should try a lower dose and see what happens.



Much of the research into the hormone vasopressin comes from Stanford. They have published a string of papers over the years. I think they are definitely on to something, but they are taking their time and may never commercialize the result.  

The very recent one is:

Vasopressin deficiency: a hypothesized driver of both social impairment and fluid imbalance in autism spectrum disorder


For some reason there is no abstract. 

Thanks to our reader Seth, I have now added the link below that takes you directly to  Stanford's website, which holds the full text version of the paper.

The same group previously published a paper showing that people with ASD have a reduced level of vasopressin in their spinal fluid. As you can see in the chart below the level of oxytocin was normal.

There have also been successful trials using intranasal vasopressin in humans.

Cerebrospinal fluid vasopressin and symptom severity in children with autism


Vasopressin and oxytocin are closely related hormones and possibly some interactions are not yet fully understood.

Both these hormones can be given via a nasal spray.


The Bumetanide-Vasopressin interaction

Under normal circumstances you would never combine vasopressin with a diuretic.

Vasopressin stops you peeing and that it is why it is given to some children who wet their bed at night.

Bumetanide is a fast-acting diuretic that causes you to pee a lot.

So if you gave a diuretic to an elderly overweight person to reduce their blood pressure, it would be mad to also prescribe vasopressin.  The drugs are therefore contraindicated.

In autism we do not actually want the diuretic effects of bumetanide. We just want its effects on the brain.

The social and emotional beneficial effects of vasopressin have already been established by the existing Stanford research.

The combined effects of bumetanide + intranasal vasopressin might then be a win-win. Less autism and without the diuresis.

I was contacted long ago by a father whose daughter was prescribed Desmopressin, a synthetic analog of vasopressin that is an approved drug, and her autism markedly improved.

The Stanford research in humans uses a nasal spray that they have compounded specially rather than the commercially available Desmopressin.



Wednesday 13 April 2022

Personalized/Precision Medicine for Sound Sensitivity in Autism, Bipolar and Schizophrenia?


Stop the Noise!


Conventional wisdom, even among enlightened neurologists like Manuel Casanova, is that you cannot medically treat the sensory issues that occur in neurological conditions like autism, bipolar and schizophrenia.

This blog is very much driven by the peer-reviewed literature, but very often seems to comes up with alternative interpretations to what the doctors will say.  Today is another of those days.

I do tell people that you can very easily get things 100% back to front when developing personalized/precision medicine.  The general idea was correct, but the effect was the exact opposite to what was hoped for.  This is not a failure; this is a learning experience.  Today we see that what works in schizophrenia is the exact opposite of what works in bipolar.  I do like to include schizophrenia and bipolar in my autism posts, because there is a big overlap between them and the broad umbrella of dysfunctions found in autism.

Sensory problems are very common in autism, bipolar and schizophrenia.

This post is mainly about issues with sound.  Vision is closely related. Smell, taste and texture may be less closely related. 

Sound/Hearing issues in autism 

Very often young children with autism do not respond to their name, or some other sounds; the natural first step is to check their hearing.  The majority of the time, their hearing turns out to be perfect.

As the child gets older and struggles with sounds like a baby crying, or a dog barking, parents may begin to feel their child’s hearing is too good!


The medical terms


Hyperacusis is a disorder in loudness perception and should mean you hear sounds too loudly.  The opposite term is hypoacusis and in the medical jargon it means you are going deaf, rather than having a volume perception problem

Tinnitus is hearing sounds that do not exist, but there are many possible causes.

Misophonia means hatred of sound, but those hated sounds are often very specific repeated human sounds like noisy eating, chewing, sniffing, coughing or machine-made sounds like a noisy clock ticking, or even a leaf blower.

There does appear to be a visual equivalent of sound Misophonia.

For some people, visual triggers can cause a similar reaction. This might happen if you see someone:

  • wagging their legs or feet (foot flapping)
  • rubbing their nose or picking at their finger nails
  • twirling their hair or pen
  •  chewing gum 

Some people suffer from a combination of sound disorders.  Many people with tinnitus also suffer from Misophonia. 

I think many people with autism are affected by a combination of Hyperacusis and Misophonia.

It seems that many people with Asperger’s suffer from hyperacusis, a substantial minority experience tinnitus. Almost all who suffer tinnitus also experience hyperacusis.

I think it might be hard to know if a person with severe autism and ID had tinnitus.


Tinnitus and hyperacusis in autism spectrum disorders with emphasis on high functioning individuals diagnosed with Asperger's Syndrome

Objectives: To evaluate the prevalence of tinnitus and hyperacusis in individuals with Asperger's Syndrome (AS).

Methods: A home-developed case-history survey and three item-weighted questionnaires: Tinnitus Reaction Questionnaire (TRQ), Tinnitus Handicap Inventory (THI), and the Hyperacusis Questionnaire (HQ) were employed. These tools categorize the subjective response to tinnitus and hyperacusis. The research tools were mailed to a mailing list of individuals with Asperger's Syndrome.

Results: A total of 55 subjects diagnosed with AS were included in the analysis (15.5% response rate). Sixty-nine percent of all respondents (38/55) reported hyperacusis with an average HQ score of 20.7. Furthermore, 35% (19/55) reported perceiving tinnitus with average scores of 27 for the TRQ and 23 for the THI. Thirty-one percent (17/55) reported both hyperacusis and tinnitus. The prevalence of hyperacusis in the AS respondents remained relatively constant across age groups.

Conclusions: Hyperacusis and tinnitus are more prevalent in the ASD population subgroup diagnosed with AS under DSM-IV criteria than in the general public. Hyperacusis also appears to be more prevalent in the AS population than in the ASD population at large. Future research is warranted to provide insight into the possible correlation between tinnitus and hyperacusis symptoms and the abnormal social interactions observed in this group.


All three terms are just observation diagnoses, they do not tell you what is the underlying biological cause.  In this blog we are interested in the underlying biology, because the goal is to find an effective treatment.

Hearing issues are common comorbities of well-known medical conditions; for example, people with type 1 diabetes may well suffer from tinnitus and hypoacusis.



Schematic block diagram of mechanisms that produce misophonia, hyperacusis, tinnitus, polycusis, and other false auditory percepts. Afferents from the cochlea, saccule, somesthetic pathways, and visceral sensory pathways contribute to processing in auditory lemniscal pathways. Modular thalamocortical processing is hypothesized to contribute (1) a common component to comorbid features of hyperacusis and tinnitus, (2) a component that produces unique features of tinnitus, and (3) component(s) for other false auditory perceptions. A parallel, interoceptive, and affective network produces the aversion, annoyance, fear, and pain-like features that may be associated with hyperacusis and misophonia



 The research terms

The medical world is often rather short of enough descriptive words, just think about all those people with totally different biological conditions all being diagnosed with “autism”.

A really useful term you will find in the research is sensory gating.


Sensory gating is a process by which irrelevant stimuli are separated from meaningful ones.  Imagine the boy with Asperger’s sitting in a private room taking his important exams.  He is alone with the invigilator and maybe a clock on the wall.  The clock might be making a ticking sound or the invigilator might be chewing gum.  All this clever boy has to do is to concentrate on the exam and show how smart he is.  The noisy clock, or the chewing sound, should be irrelevant, but instead the boy cannot filter out these sounds and ignore them.

I had exactly this case put to me at an autism conference by a concerned Grandfather, whose clever grandson failed his important exams.

You can actually measure sensory gating using headphones to provide the annoying repetitive sound and an EEG to measure how the person’s brain responds.  The first sound should trigger the brain’s response, but when the sound keeps repeating the response should fade away.  The person has learned to filter out the annoying but irrelevant sound.

Imagine you are in a storm and the rain is beating down on a glass roof or windows.  The first sound alerts you to the storm.  Did you leave the upstairs window open? Perhaps you were drying something outside?  You might have to take some urgent action, so you want an alarm bell to go off in your head.  Panic over, you can then just ignore the sound of the rain and before you know it the storm is over.

There are different types of sensory gating, the most well studied is called P50.

People with schizophrenia often have deficits in gating the neuronal response of the P50 wave, which is why P50 is the most widespread method of diagnosis. The test is conducted through having the patients hear two uniform sounds with an interval of 500 milliseconds. While the patients are hearing the sound, an EEG cap is used to measure the brain activity in response to those sounds. A normal subject shows a decrease in brain activity while hearing a second sound, while a subject showing equal brain activity to the first sound has impaired sensory gating.

Impaired P50 sensory gating is very common in schizophrenia, also occurs in autism bipolar and even dementia.

There can also be Impaired gating of N100 and P200.  The actual definition of these terms gets complicated and you do not have to go into this level of detail unless you are really interested


What is N100 event-related potential? 

The N100 is a negative waveform that peaks at approximately 100 milliseconds after stimulus presentation. Its amplitude is measured using electroencephalography (EEG) and may be dysfunctional in people with schizophrenia who show an inability to “gate” or inhibit irrelevant sensory information, ultimately leading to conscious information overload. To test this, paired auditory clicks are presented, separated by a short interval, usually of 0.5 seconds. The first click initiates or conditions the inhibition, while the second (test) click indexes the strength of the inhibition. An absence of a reduced response to the second stimulus is interpreted as a failure of inhibitory mechanisms, postulated to represent a defect in sensory gating.


What is the evidence for N100 event-related potential? 

Moderate to high quality evidence finds a medium-sized reduction in N100 amplitude to the first stimulus, but not to the second stimulus. Review authors suggests this reflects a deficit in processing of auditory salience rather than in inhibition.





P50-N100-P200 sensory gating deficits in adolescents and young adults with autism spectrum disorders



·        In the paired-click paradigm, ASD individuals displayed a significant N100 gating deficit.

·        N100 gating deficit was associated with symptom severity of sensory sensitivity.

·        P50 and P200 in ASD did not deviate from the typically developing controls.

·        P50 and P200 were associated with social deficits and attention switching difficulty in ASD.

 We found that compared to TDC, ASD participants had significant N100 suppression deficits reflected by a larger N100 S2 amplitude, smaller N100 ratio of S2 over S1, and the difference between the two amplitudes. N100 S2 amplitude was significantly associated with sensory sensitivity independent of the diagnosis. Although there was no group difference in P50 suppression, S1 amplitude was negatively associated with social deficits in ASD. P200 gating parameters were correlated with attention switching difficulty. Our findings suggest N100 gating deficit in adolescents and young adults with ASD. The relationships between P50 S1 and social deficits and between N100 S2 and sensory sensitivity warrant further investigation.


Expanding our understanding of sensory gating in children with autism spectrum disorders



·        Children with autism showed significantly reduced gating at P50, N1, and P2 event-related potential components.

·        Children with autism show reduced orientation to auditory stimuli compared to typically-developing children.

·        Time-frequency analysis show reduced neural synchronization of stimuli in children with autism.



This study examined sensory gating in children with autism spectrum disorders (ASD). Gating is usually examined at the P50 component and rarely at mid- and late-latency components.


Electroencephalography data were recorded during a paired-click paradigm, from 18 children with ASD (5–12 years), and 18 typically-developing (TD) children. Gating was assessed at the P50, N1, P2, and N2 event-related potential components. Parents of all participants completed the Short Sensory Profile (SSP).


TD children showed gating at all components while children with ASD showed gating only at P2 and N2. Compared to TD children, the ASD group showed significantly reduced gating at P50, N1, and P2. No group differences were found at N2, suggesting typical N2 gating in the ASD group. Time-frequency analyses showed reduced orientation and neural synchronization of auditory stimuli. P50 and N1 gating significantly correlated with the SSP.


Although children with ASD have impaired early orientation and filtering of auditory stimuli, they exhibited gating at P2 and N2 components suggesting use of different gating mechanisms compared to TD children. Sensory deficits in ASD may relate to gating.


The data provide novel evidence for impaired neural orientation, filtering, and synchronization in children with ASD.


Normal P50 Gating in Children with Autism, Yet Attenuated P50 Amplitude in the Asperger Subcategory 

Autism spectrum disorders (ASD) and schizophrenia are separate disorders, but there is evidence of conversion or comorbid overlap. The objective of this paper was to explore whether deficits in sensory gating, as seen in some schizophrenia patients, can also be found in a group of ASD children compared to neurotypically developed children. An additional aim was to investigate the possibility of subdividing our ASD sample based on these gating deficits. In a case–control design, we assessed gating of the P50 and N100 amplitude in 31 ASD children and 39 healthy matched controls (8–12 years) and screened for differences between groups and within the ASD group. We did not find disturbances in auditory P50 and N100 filtering in the group of ASD children as a whole, nor did we find abnormal P50 and N100 amplitudes. However, the P50 amplitude to the conditioning stimulus was significantly reduced in the Asperger subgroup compared to healthy controls. In contrast to what is usually reported for patients with schizophrenia, we found no evidence for sensory gating deficits in our group of ASD children taken as a whole. However, reduced P50 amplitude to conditioning stimuli was found in the Asperger group, which is similar to what has been described in some studies in schizophrenia patients. There was a positive correlation between the P50 amplitude of the conditioning stimuli and anxiety score in the pervasive developmental disorder not otherwise specified group, which indicates a relation between anxiety and sensory registration in this group


Treatments for sensory gating

We know that in schizophrenia impaired P50 gating is associated with alpha 7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction and shown to be improved with nicotine and other α7 nAChR agonists.

Other α7 nAChR agonists include:-

·        Acetylcholine

·        Choline

·        Nicotine

·        Tropisetron


Galantamine is a positive allosteric modulator (PAM) of nAChRs


Why do people with schizophrenia love to smoke?


A truly remarkable observation is that smoking improves sensory gating in schizophrenia, but it has the opposite effect on people with bipolar.


Smoking as a Common Modulator of Sensory Gating and Reward Learning in Individuals with Psychotic Disorders


Motivational and perceptual disturbances co-occur in psychosis and have been linked to aberrations in reward learning and sensory gating, respectively. Although traditionally studied independently, when viewed through a predictive coding framework, these processes can both be linked to dysfunction in striatal dopaminergic prediction error signaling. This study examined whether reward learning and sensory gating are correlated in individuals with psychotic disorders, and whether nicotine—a psychostimulant that amplifies phasic striatal dopamine firing—is a common modulator of these two processes. We recruited 183 patients with psychotic disorders (79 schizophrenia, 104 psychotic bipolar disorder) and 129 controls and assessed reward learning (behavioral probabilistic reward task), sensory gating (P50 event-related potential), and smoking history. Reward learning and sensory gating were correlated across the sample. Smoking influenced reward learning and sensory gating in both patient groups; however, the effects were in opposite directions. Specifically, smoking was associated with improved performance in individuals with schizophrenia but impaired performance in individuals with psychotic bipolar disorder. These findings suggest that reward learning and sensory gating are linked and modulated by smoking. However, disorder-specific associations with smoking suggest that nicotine may expose pathophysiological differences in the architecture and function of prediction error circuitry in these overlapping yet distinct psychotic disorders.


When you look up P50 gating and also Misophonia in the clinical trials database, you get some Mickey Mouse behavioral treatments for misophonia.

For p50 gating you a decent list of drugs trialed in schizophrenia. 




My earlier posts on this subject:-


Sensory Gating in Autism, Particularly Asperger's


Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist



"I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way."


Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 




Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.


The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).


Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.


The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.


Be wary of antipsychotics!!

 Now we see again that α2A Receptor agonists like guanfacine and clonidine will improve sensory gating. We should not be surprised that drugs with the opposite effect (antagonists) will make sensory gating worse.


α2A Receptor Antagonists

·         Idazoxan

·         1-PP (active metabolite of buspirone and gepirone, anti-anxiety drugs)

·         Asenapine

·         BRL-44408

·         Clozapine , an anti-psychotic drugs used in schizophrenia

·         Lurasidone an anti-psychotic drugs used in schizophrenia and in bipolar

·         Mianserin, an anti-depressant

·         Mirtazapine, an anti-depressant

·         Paliperidone an anti-psychotic drugs used in schizophrenia

·         Risperidone, an anti-psychotic drugs used in schizophrenia and autism

·         Yohimbine


Treatment for Hyperacusis

If you look up treatments and trials for hyperacusis (sound sensitivity) you see a list of cognitive behavioral therapies.

These are not nonsense. We used something similar to deal with Monty’s extreme aversion to crying babies when he was young.  Now when he hears a baby crying, he laughs.

But really, science has much more to offer than behavioral therapy.

I did write many years ago about hypokalemic sensory overload and its big brother hypokalemic periodic paralysis (HypoPP).  In both conditions it seems that low levels of potassium cause some pretty severe reactions.  Both conditions respond rapidly to an oral potassium supplement.

Though rare, we know that HypoPP is caused by a dysfunction in the ion channels Nav1.4 and/or Cav1.1.

For decades one of the treatments for HypoPP has been a diuretic called Diamox/Acetazolamide.  Other treatments include raising potassium levels using supplements, or potassium sparing diuretics.


Way back in 2013, I defined a new term, in the post below:-

 Hypokalemic Autistic Sensory Overload


I showed an oral potassium supplement reduced sound sensitivity within 20 minutes, with a simple experiment anyone can do at home. 

Some people do find long term sensory relief just from the use of an oral potassium supplement once a day.  In my son’s case the affect does not last very long.


Therapies for hypokalemic sensory overload might be:-


·        A potassium supplement

·        A potassium sparing diuretic

·        Possibly Diamox/ Acetazolamide

·        Very likely, intra-nasal Desmopressin, this lower sodium levels and so will have the opposite impact on potassium levels

·        Ponstan, the NSAID that affects numerous potassium ion channels


In some people it appears that Humira, a long-acting TNF-alpha inhibitor, resolves visual and sound sensitivity.  I think this resolves a mixture of hyperacusis and Misophonia and the visual sensory equivalents.




Tinnitus is an extremely common, but is generally regarded as something you just have to get used to; there are no approved drug therapies.

All kinds of things can lead to tinnitus. A head injury can lead to tinnitus, exposure to a loud sound is a common cause, but there is even drug-induced tinnitus. Tinnitus is a common comorbidity of diabetes.

There is gradual onset tinnitus and acute onset tinnitus.

Tinnitus is more likely to occur the older you get and often gets worse over time.

Clearly there are many sub-types of tinnitus and inevitably there will need to be multiple different therapies



Full graphic is available at fnins-13-00802-g004.jpg (4660×2924) (


The paper below is very comprehensive: 

Why Is There No Cure for Tinnitus? 

Tinnitus is unusual for such a common symptom in that there are few treatment options and those that are available are aimed at reducing the impact rather than specifically addressing the tinnitus percept. In particular, there is no drug recommended specifically for the management of tinnitus. Whilst some of the currently available interventions are effective at improving quality of life and reducing tinnitus-associated psychological distress, most show little if any effect on the primary symptom of subjective tinnitus loudness. Studies of the delivery of tinnitus services have demonstrated considerable end-user dissatisfaction and a marked disconnect between the aims of healthcare providers and those of tinnitus patients: patients want their tinnitus loudness reduced and would prefer a pharmacological solution over other modalities. Several studies have shown that tinnitus confers a significant financial burden on healthcare systems and an even greater economic impact on society as a whole. Market research has demonstrated a strong commercial opportunity for an effective pharmacological treatment for tinnitus, but the amount of tinnitus research and financial investment is small compared to other chronic health conditions. There is no single reason for this situation, but rather a series of impediments: tinnitus prevalence is unclear with published figures varying from 5.1 to 42.7%; there is a lack of a clear tinnitus definition and there are multiple subtypes of tinnitus, potentially requiring different treatments; there is a dearth of biomarkers and objective measures for tinnitus; treatment research is associated with a very large placebo effect; the pathophysiology of tinnitus is unclear; animal models are available but research in animals frequently fails to correlate with human studies; there is no clear definition of what constitutes meaningful change or “cure”; the pharmaceutical industry cannot see a clear pathway to distribute their products as many tinnitus clinicians are non-prescribing audiologists. To try and clarify this situation, highlight important areas for research and prevent wasteful duplication of effort, the British Tinnitus Association (BTA) has developed a Map of Tinnitus. This is a repository of evidence-based tinnitus knowledge, designed to be free to access, intuitive, easy to use, adaptable and expandable.


The next paper makes the key point that to treat tinnitus you need precision (personalized) medicine and apply the neuroscience.


Towards a Mechanistic-Driven Precision Medicine Approach for Tinnitus 

In this position review, we propose to establish a path for replacing the empirical classification of tinnitus with a taxonomy from precision medicine. The goal of a classification system is to understand the inherent heterogeneity of individuals experiencing and suffering from tinnitus and to identify what differentiates potential subgroups. Identification of different patient subgroups with distinct audiological, psychophysical, and neurophysiological characteristics will facilitate the management of patients with tinnitus as well as the design and execution of drug development and clinical trials, which, for the most part, have not yielded conclusive results. An alternative outcome of a precision medicine approach in tinnitus would be that additional mechanistic phenotyping might not lead to the identification of distinct drivers in each individual, but instead, it might reveal that each individual may display a quantitative blend of causal factors. Therefore, a precision medicine approach towards identifying these causal factors might not lead to subtyping these patients but may instead highlight causal pathways that can be manipulated for therapeutic gain. These two outcomes are not mutually exclusive, and no matter what the final outcome is, a mechanistic-driven precision medicine approach is a win-win approach for advancing tinnitus research and treatment. Although there are several controversies and inconsistencies in the tinnitus field, which will not be discussed here, we will give a few examples, as to how the field can move forward by exploring the major neurophysiological tinnitus models, mostly by taking advantage of the common features supported by all of the models. Our position stems from the central concept that, as a field, we can and must do more to bring studies of mechanisms into the realm of neuroscience.


I did have a quick look the clinical trials website to see if there have been any interesting trials that did show some benefit. 

I noted the following drugs: 


Lidocaine, the anesthetic that targets sodium ion channels.  Careful titration allows for a high degree of selectivity in the blockage of sensory neurons.  This looks like a good idea. Originally, they played with intravenous delivery, but then moved no to transdermal.


Transdermal lidocaine as treatment for chronic subjective tinnitus: A Pilot Study

In this preliminary study, 5% transdermal lidocaine appears to be a potential treatment for chronic subjective tinnitus. The majority of subjects who completed 1 month of treatment had clinically significantly improved tinnitus. These findings are confounded however by the small sample size and significant drop out rate.



Clonazepam is a benzodiazepine drug that activates GABAa receptors.  The trials are a bit mixed and one showed it only worked when given together with Deanxit. Deanxit is a combination of Flupentixol, an antipsychotic, and melitracen an tricyclic antidepressant.

These look like bad options which will end up causing new problems over time. 

Clonazepam Quiets tinnitus: a randomised crossover study with Ginkgo Biloba

Conclusion Clonazepam is effective in treating tinnitus; G biloba is ineffective.


Administration of the combination clonazepam-Deanxit as treatment for tinnitus

Results: Significant tinnitus reduction was seen after intake of the combination clonazepam-Deanxit, whereas no differences in tinnitus could be demonstrated after the administration of clonazepam-placebo. This was true for all patients according to the following parameters: time patients are annoyed by the tinnitus (p = 0.026) and the visual analogue scale for tinnitus annoyance (p = 0.024).

 Conclusion: Although tinnitus reduction was recorded as modest, this article provides valuable data demonstrating a placebo-controlled tinnitus reduction after clonazepam and Deanxit intake.



There already is a lot in the blog about oxytocin and I was surprised anyone had trialed it for tinnitus, but they did and it seems to provide a benefit.  As regular readers of this blog know, there looks to be a better way to deliver oxytocin to the brain than intra-nasal. We saw how a specific gut bacteria has the same effect (Biogaia Protectis). 

TinnitusTreatment with Oxytocin: A Pilot Study


These preliminary studies demonstrated that oxytocin may represent a helpful tool for treating tinnitus and further larger controlled studies are warranted.



Acamprosate is used to treat alcoholics.

 “An inhibition of the GABA-B system is believed to cause indirect enhancement of GABAA receptors.[17] The effects on the NMDA complex are dose-dependent; the product appears to enhance receptor activation at low concentrations, while inhibiting it when consumed in higher amounts, which counters the excessive activation of NMDA receptors in the context of alcohol withdrawal”  

Impact of Acamprosate on Chronic Tinnitus: A Randomized-Controlled Trial 

Objectives: Tinnitus is a common and distressing otologic symptom, with various probable pathophysiologic mechanisms, such as an imbalance between excitatory and inhibitory mechanisms. Acamprosate, generally used to treat alcoholism, is a glutaminergic antagonist and GABA agonist suggested for treating tinnitus. Thus, we aimed to evaluate the efficacy and safety of acamprosate in the treatment of tinnitus.

Conclusions: The study results indicated a subjective relief of tinnitus as well as some degree of the electrophysiological improvement at the level of the cochlear and the distal portion of the auditory nerve among the subjects who received the acamprosate.



Magnesium supplementation, being cheap and OTC, is a common therapy for tinnitus.  It does seem to provide a benefit for some. 

Phase 2 study examining magnesium-dependent tinnitus

Conclusion: The results suggest that magnesium may have a beneficial effect on perception of tinnitus-related handicap when scored with the THI.



Neramexane is interesting because it is closely related to Memantine/Namenda, which was widely used in autism, but failed in its large clinical trial.  Memantine is seen as an NMDA receptor antagonist/blocker, but it also blocks  nicotinic acetylcholine receptors (nAChRs) which play a role in Alzheimer’s and sensory gating (Misophonia). Memantine also affects serotonin and dopamine receptors.

 Neramexane is a new drug being developed for Alzheimer’s and as a pain killer. 

A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus

Neramexane is a new substance that exhibits antagonistic properties at α9α10 cholinergic nicotinic receptors and N-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus.



This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies.



Mirtazapine is yet another drug that has been covered in this blog.  It is a very cheap anti-histamine / anti-depressant.

We saw in this blog that the effect is highly dose dependent.  It affects very many receptors and the overall effect depends on dosage. The antidepressant effect is at the dose of 15+mg.  In this person with tinnitus, they used 7.5mg. For some conditions the dose goes up to 60mg a day.

At very low dosages mirtazapine is a potent H1 anti-histamine and makes you very drowsy

One parent noted that low dose Mirtazapine had a highly beneficial effect in their child with autism.


Tinnitus Treatment With Mirtazapine

Auditory pathways are modulated by various neurotransmitters such as serotonin responsible for sound detection, location, and interpretation. The neurotransmitter gamma amino butyric acid (GABA) is inhibitory in the auditory system. Given that there is preferential innervation of the GABAergic neurons in the inferior colliculus by serotonergic neurons, it may be plausible then that antidepressant drugs, by increasing the availability of serotonin and thereby increasing GABAergic activity, provide relief from the symptoms of tinnitus.5 This report shows that mirtazapine may have a beneficial effect in the subgroup of patients suffering from tinnitus but exact mechanism is difficult to put forward.



I think we are absolutely spoilt for choice.

So many possible therapies, each one effective in some cases.

The key is precision medicine, personalized to the individual case in question.  This approach was also proposed in the recent paper on Tinnitus, only without telling us what to actually do!

In my son, now 18 with what we can call treated severe autism, the clear winner so far is Ponstan (Mefenamic Acid).  Diclofen, a very common Fenamate class drug, does share the same effect, but to a lesser extent. 

Fenamates (Diclofenac, Ponstan etc): certainly for Alzheimer’s, maybe some Epilepsy, but Autism? I’m Impressed!

Low dose Roflumilast, the P50 sensory gating therapy (that is more for Aspies) has no sensory effect at all. It is the same dose as that proposed in the research to raise IQ.

The intranasal Desmopressin mentioned by one reader is another good choice to consider, but you may need to supplement sodium.  I think if you get a short term benefit from a 500mg potassium supplement, this is worth a try.

For Aspies low dose Roflumilast everyday looks worth a try, while Humira every 2 months look interesting, but it will be hard to get and is pricey.

For people with Schizophrenia, they could look at tobacco alternatives, which would include low-dose Roflumilast.

People with Bipolar might want to look at Mirtazapine – the opposite of nicotine and which also helps some cases of tinnitus.

For tinnitus I thought oxytocin looked a very safe option.  You have intranasal, or my preference the gut bacteria probiotic that stimulates oxytocin release in the brain.

Magnesium is a safe bet for tinnitus.  Transdermal lidocaine makes sense, but is a bit more daring.  Memantine might be worth a shot, if nothing else helps.

You can also increase sound and visual sensitivity. Low dose DMF (dimethyl fumarate) increases sound sensitivity and the TRH super-agonist Ceredist increases visual sensitivity.  For most people with autism, you likely do not need either effect.