Showing posts with label Misophonia. Show all posts
Showing posts with label Misophonia. Show all posts

Monday 4 September 2023

The therapeutic effects of apigenin are pleiotropic. Is its effect on sound sensitivity mediated via potassium channels?

Chamomile, a good source of Apigenin


Today we return to flavonoids, those healthy chemicals found in fruits, vegetables, flowers etc.

In particular, the focus is on apigenin, found in things like chamomile, parsley, oregano and in medicinal herbs like Bacopa monnieri.


Why the interest in Apigenin?

I did discover a while back that sound sensitivity in some autism responds almost immediately to low dose Ponstan (Mefenamic acid), which is a widely used as a pain reliever.

I was recently informed by a reader who responds well to Ponstan (250mg once a day) that he gets exactly the same relief from sound sensitivity from taking the flavonoid Apigenin (500mg a day). 

Both Ponstan and Apigenin are OTC in many countries. In countries like Greece Ponstan is extremely cheap.  In the US Ponstan is very expensive and supplements tend to be cheap. 

For adults with sound sensitivity drinking chamomile tea might be a good source of 50 mg of Apigenin (you would need about 20g of chamomile flowers). Using the dried flowers likely gives better results than ready-made tea bags.


Pleiotropic effects

Both Ponstan and apigenin have numerous beneficial effects.  I noted in my earlier posts on Ponstan that it seems to offer protection from Alzheimer’s. Perhaps surprisingly, people who take Ponstan are much less likely to develop Alzheimer’s. Nobody has studied apigenin in human Alzheimer’s, but in animal studies, apigenin has been shown to improve cognitive function, reduce amyloid plaques, and protect neurons from damage.


Other Flavonoids used in Autism

Dr Theoharides wrote a lot about flavonoids to treat autism and mast cell disorders.  His product Neuroprotek is a combination of three flavonoids: luteolin, quercetin, and rutin, which are found in plants such as celery, onions, and citrus fruits.

Epigallocatechin gallate (EGCG) is a flavonoid found in green tea. The Spanish like doing research on EGCG and they believe it has promise as an autism therapy. One of the effects is to modify the gut microbiome. EGCG has also been shown to accumulates in mitochondria making it an interesting therapeutic candidate for neurodegenerative diseases involving neuronal apoptosis triggered by mitochondrial oxidative stress. It has been studied in Down syndrome, Rett syndrome and some other models of autism.


A very detailed overview is available in the paper below:-

The Emerging Role of Flavonoids in Autism Spectrum Disorder: A Systematic Review

Although autism spectrum disorder (ASD) is a multifaceted neurodevelopmental syndrome, accumulating evidence indicates that oxidative stress and inflammation are common features of ASD. Flavonoids, one of the largest and best-investigated classes of plant-derived compounds, are known to exert antioxidant, anti-inflammatory, and neuroprotective effects. This review used a systematic search process to assess the available evidence on the effect of flavonoids on ASD. A comprehensive literature search was carried out in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. A total of 17 preclinical studies and 4 clinical investigations met our inclusion criteria and were included in the final review. Most findings from animal studies suggest that treatment with flavonoids improves oxidative stress parameters, reduces inflammatory mediators, and promotes pro-neurogenic effects. These studies also showed that flavonoids ameliorate the core symptoms of ASD, such as social deficits, repetitive behavior, learning and memory impairments, and motor coordination. However, there are no randomized placebo-controlled trials that support the clinical efficacy of flavonoids in ASD. We only found open-label studies and case reports/series, using only two flavonoids such as luteolin and quercetin. These preliminary clinical studies indicate that flavonoid administration may improve specific behavioral symptoms of ASD. Overall, this review is the first one to systematically report evidence for the putative beneficial effects of flavonoids on features of ASD. These promising preliminary results may provide the rationale for future randomized controlled trials aimed at confirming these outcomes.


It seems that the many flavonoids have numerous beneficial effects - this is why it is important to include them in your diet.



Years ago, I wrote about Sytrinol, a dietary supplement that is made from citrus peel extract. It contains polymethoxylated flavones (PMFs), which are a type of flavonoid. It mainly contains nobiletin and tangeritin, flavones that are found in citrus fruits, such as lemons, oranges, and grapefruits. They have been shown to have a number of health benefits, including lowering cholesterol, reducing inflammation, and protecting cells from damage.

The idea was of interest because these flavones are known to activate PPAR-gamma, which seemed potentially beneficial in autism.  Readers did confirm Sytrinol provided a cognitive benefit, but it only lasts a few days and is then lost.


Sources of Apigenin

Apigenin is sold as a supplement.

Chamomile is one of the oldest, most widely used and well documented medicinal plants in the world and has been recommended for a variety of healing applications for centuries. Apigenin is thought to be one of the most potent substances found within it.

Bacopa monnieri is another rich source of flavonoids being a good source of luteolin and apigenin. An extract of Bacopa monnieri, a nootropic herb, has been used to evaluate its neuroprotective effect in a valproic acid (VPA) model of ASD. The results showed that B. monnieri extract may attenuate VPA-induced damage by restoring antioxidant enzymes and reducing inflammatory cytokines in the hippocampus and prefrontal cortex.


The biological effects of Apigenin

 What does the Google AI (artificial intelligence) program Bard have to say:-


Apigenin is a flavonoid that is found in a variety of plants, including chamomile, parsley, celery, and citrus fruits. It has several potential health benefits, including:

Antioxidant. Apigenin is an antioxidant, which means it can help protect cells from damage caused by free radicals. Free radicals are unstable molecules that can damage DNA, proteins, and other cellular structures.

Anti-inflammatory. Apigenin has anti-inflammatory properties, which can help reduce inflammation in the body. Inflammation is a contributing factor to many diseases, including heart disease, cancer, and arthritis.

Cancer prevention. Apigenin has been shown to have cancer-fighting properties in both animal and human studies. It may help prevent cancer by blocking the growth and spread of cancer cells.

Brain health. Apigenin may be beneficial for brain health. It has been shown to improve cognitive function in animal studies, and it may also help protect against Alzheimer's disease and other neurodegenerative diseases.

Heart health. Apigenin may help improve heart health. It has been shown to lower blood pressure and cholesterol levels, and it may also help protect against heart arrhythmias.

Hormone modulation. Apigenin may modulate the production of hormones, such as estrogen and testosterone. This could have benefits for women's health, such as reducing the risk of breast cancer and improving menopausal symptoms.

Immune health. Apigenin may boost the immune system. It has been shown to increase the production of white blood cells, which help fight infection.

Other benefits. Apigenin may also have other health benefits, such as relieving anxiety, promoting sleep, and strengthening bones.

When you push Bard a little bit you get more:

Apigenin and ion channels, Bard?

Apigenin is a flavonoid that has been shown to interact with a variety of ion channels in the body. These include:

Voltage-gated calcium channels. Apigenin has been shown to inhibit the activity of voltage-gated calcium channels, which are involved in the regulation of many cellular processes, including muscle contraction, cell growth, and cell death.

Transient receptor potential vanilloid 4 (TRPV4) channels. TRPV4 channels are activated by heat and inflammation, and they play a role in pain perception, thermoregulation, and inflammation. Apigenin has been shown to activate TRPV4 channels, which could have potential implications for the treatment of pain and inflammation.

Nicotinic acetylcholine receptors (nAChRs). nAChRs are ligand-gated ion channels that are activated by acetylcholine. They are involved in a variety of functions, including learning, memory, and muscle contraction. Apigenin has been shown to potentiate the activity of nAChRs, which could have potential implications for the treatment of Alzheimer's disease and other neurodegenerative diseases.

Potassium channels: Potassium channels are responsible for the efflux of potassium ions from cells. Apigenin has been shown to activate some types of potassium channels, which can have cardioprotective effects.

Gamma-aminobutyric acid (GABA)A receptors. GABAA receptors are ligand-gated ion channels that are activated by GABA. They are involved in the regulation of anxiety, sleep, and epilepsy. Apigenin has been shown to modulate the activity of GABAA receptors, which could have potential implications for the treatment of anxiety and epilepsy.


Which potassium channels, Bard? 

Apigenin has been shown to activate some types of potassium channels, including:

Small conductance calcium-activated potassium channels (SK channels): SK channels are activated by calcium ions and play a role in regulating cell excitability. Apigenin has been shown to activate SK channels in a number of cell types, including neurons, smooth muscle cells, and cardiac cells.

Large conductance calcium-activated potassium channels (BK channels): BK channels are also activated by calcium ions and play a role in regulating cell excitability and blood pressure. Apigenin has been shown to activate BK channels in some cell types, but the effects are less well-studied than the effects on SK channels.

Transient receptor potential vanilloid 4 (TRPV4) channels: TRPV4 channels are activated by a variety of stimuli, including heat, inflammation, and mechanical stress. Apigenin has been shown to activate TRPV4 channels in some cell types, but the effects are less well-studied than the effects on SK and BK channels.


The effect of mefenamic acid on potassium channels, Bard? 

Mefenamic acid has been shown to have effects on a variety of ion channels, including potassium channels.

In vitro studies have shown that mefenamic acid can activate certain types of potassium channels, such as small conductance calcium-activated potassium channels (SK channels) and large conductance calcium-activated potassium channels (BK channels). This activation of potassium channels can lead to a decrease in the excitability of cells, which can be beneficial in conditions where excessive cell excitability is a problem, such as epilepsy and arrhythmias.

 However, mefenamic acid can also inhibit certain types of potassium channels, such as ATP-sensitive potassium channels (KATP channels). This inhibition of KATP channels can lead to an increase in the excitability of cells, which can be harmful in conditions where excessive cell excitability is a problem, such as heart arrhythmias.

The effects of mefenamic acid on potassium channels are complex and depend on the type of channel, the concentration of mefenamic acid, and the cell type. More research is needed to fully understand the mechanisms by which mefenamic acid interacts with potassium channels and the implications for its potential therapeutic applications.


Apigenin in Down syndrome


Plant Compound Apigenin Reduces Cognitive Deficits in Mouse Model of Down Syndrome

Mice treated with apigenin had better memory and developmental milestone scores.

The plant compound apigenin improved the cognitive and memory deficits usually seen in a mouse model of Down syndrome, according to a study by researchers at the National Institutes of Health and other institutions.

Apigenin is found in chamomile flowers, parsley, celery, peppermint, and citrus fruits. The researchers fed the compound to pregnant mice carrying fetuses with Down syndrome characteristics and then to the animals after they were born and as they matured.

The findings raise the possibility that a treatment to lessen the cognitive deficits seen in Down syndrome could one day be offered to pregnant women whose fetuses have been diagnosed with Down syndrome through prenatal testing. The study appears in the American Journal of Human Genetics.

Down syndrome is a set of symptoms resulting from an extra copy or piece of chromosome 21. The intellectual and developmental disabilities accompanying the condition are believed to result from decreased brain growth caused by increased inflammation in the fetal brain.

Apigenin is not known to have any toxic effects, and previous studies have indicated that it is an antioxidant that reduces inflammation. Unlike many compounds, it is absorbed through the placenta and the blood brain barrier, the cellular layer that prevents potentially harmful substances from entering the brain.

Compared to mice with Down symptoms whose mothers were not fed apigenin, those exposed to the compound showed improvements in tests of developmental milestones and had improvements in spatial and olfactory memory. Tests of gene activity and protein levels showed the apigenin-treated mice had less inflammation and increased blood vessel and nervous system growth.


Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro, T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo, apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2, and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS.



I am still delighted to have found a treatment for my son’s sound sensitivity, which got much more extreme almost overnight a couple of years ago.

I had already established long ago that he got short term sound sensitivity relief from taking a potassium supplement.  Some readers found a potassium supplement provided long term relief.

I thought that Ponstan might provide a good longer term solution and indeed it worked from the first pill.  This low dose therapy also works for other people with sound sensitivity, even one adult who has no autism.  The effective adult dose is 250 mg once a day.

Unlike other fenamate class drugs, like Diclofenac, Ponstan seems to be free from GI side effects at this low dose in most people.

Apigenin is an interesting alternative for those who do not tolerate Ponstan well, or who cannot access it.

A common link between what seems to improve sound sensitivity:

                    Oral potassium

                    Ponstan (Mefenamic acid)


is potassium ion channels. 

If you ask Google’s AI program Bard, he will tell you:

“It is possible that all 3 substances could affect the same potassium ion channel in some cell types, but this has not been definitively shown. More research is needed to fully understand the effects of these substances on potassium ion channels.”

Technically Bard is genderless, but he is a reflection of the programmers behind the software. In our house he is called Bart anyway.

Bart does make mistakes, contradicts himself in the same answer and he gives you different answers if you ask the same question more than once. He is also prone to mixing things up, just like humans do.

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.