Showing posts with label H3. Show all posts
Showing posts with label H3. Show all posts

Friday, 18 September 2020

Betahistine is in the Pipeline for ADHD, but will it help Autism? Maybe for some, but not for others

 Will Betahistine provide a benefit?

Today’s post is the logical follow on from the post showing that the new drug compound E-100 gives a benefit in two models of autism.

Another Potential Autism Therapy - novel compound E100 from Krakow, a combined histamine H3 receptor blocker (H3R antagonist) and an acetylcholine esterase inhibitor (AChEI)

We saw that E-100 has two modes of action, thought to be complementary:-

·        Acetylcholinesterase inhibitor (AChEI)
·        Histamine H3 antagonists (H3R antagonist)

I think our reader Rene is thinking along the lines I suggested that you might achieve the same effects with existing generic drugs.  One combination would be Donepezil plus Betahistine.

Donepezil has long been studied in autism, a recent example is here:

The safety and efficacy of a novel combination treatment of AChE inhibitors and choline supplement was initiated and evaluated in children and adolescents with autism spectrum disorder (ASD). Safety and efficacy were evaluated on 60 children and adolescents with ASD during a 9-month randomized, double-blind, placebo-controlled trial comprising 12 weeks of treatment preceded by baseline evaluation, and followed by 6 months of washout, with subsequent follow-up evaluations. The primary exploratory measure was language, and secondary measures included core autism symptoms, sleep and behavior. Significant improvement was found in receptive language skills 6 months after the end of treatment as compared to placebo. The percentage of gastrointestinal disturbance reported as a side effect during treatment was higher in the treatment group as compared to placebo. The treatment effect was enhanced in the younger subgroup (younger than 10 years), occurred already at the end of the treatment phase, and was sustained at 6 months post treatment. No significant side effects were found in the younger subgroup. In the adolescent subgroup, no significant improvement was found, and irritability was reported statistically more often in the adolescent subgroup as compared to placebo. Combined treatment of donepezil hydrochloride with choline supplement demonstrates a sustainable effect on receptive language skills in children with ASD for 6 months after treatment, with a more significant effect in those under the age of 10 years.

I was not aware that a lot of money is being spent preparing to bring Betahistine to the US as a treatment for ADHD (Attention Deficit Hyperactivity Disorder).

Outside the US, Betahistine is cheap generic drug that is widely available.  It is used in adults for vertigo and tinnitus etc.  It is not approved for use in children, but that just means its use was never studied in children.  It was envisaged as a drug for older people.

In the US, Betahistine is not an approved drug, so if the promoter gets it approved for ADHD they will not have any cheap competition.  They might even make it in the form of nasal spray, which they say makes Betahistine much more bioavailable.  It would also make it look like a modern drug, rather than just an old drug sold for a high price.

48 mg Oral dose vs varying intranasal doses

The promoter’s idea is to use a lower dose of Betahistine intranasally and yet be more potent/effective than the oral tablet now used to treat vertigo.  They also want to use it to treat antipsychotic-induced weight gain, which seems to be a huge problem and a $600 million a year market they suggest.  It appears after this they want to use Betahistine to treat ADHD and depression.

Life on an anti-psychotic, without Betahistine

Betahistine might start as a drug for young adults with ADHD, but ADHD is normally seen as a childhood disorder (something like 7% of US school children have taken ADHD drugs) the promoter will have to carry out studies to show it is safe for pediatric use.  They are actually trialing quite high doses orally for ADHD.

Betahistine in autism, without ADHD

I am not sure that Betahistine, or E-100, is going to have a good overall effect in autism in humans.  E-100 does look good in two mouse models of autism.

Acting via the histamine H3 receptor, Betahistine will increase the levels of neurotransmitters histamineacetylcholinenorepinephrineserotonin, and GABA.  In any specific case of idiopathic autism, some of these effects may be beneficial, but quite possibly not all.

If you have GABA still working in reverse, as in some Bumetanide-responsive autism, increasing the level of GABA will cause agitation and aggression, just like taking Valium does.

The active metabolite of Betahistine is something called 2-PAA and the level peaks in your blood about an hour after taking the pill. There certainly is potential for a negative reaction, but it would fade gradually over the next few hours.  The half-life is 3.5 hours.

In the ADHD trials of Betahistine agitation was listed as a possible side effect. The promoter does say that overall the drug is very well tolerated.

Auris Medical Announces Closing of Two US Patent Acquisitions Related to the Use of Betahistine for the Treatment of Depression and ADHD

 Betahistine is a small molecule structural analog of histamine, which acts as an agonist at the H1 and as an antagonist at the H3 histamine receptors. Unlike histamine, it crosses the blood-brain-barrier. It is known to enhance inner ear and cerebral blood flow, increase histamine turnover and enhance histamine release in the brain, increase release of acetylcholine, dopamine and norepinephrine in the brain and to result in general brain arousal. Betahistine for oral administration is approved in about 115 countries, with the US being a notable exception, for the treatment of vertigo and Meniere’s disease. The compound has a very good safety profile, yet it is also known that its clinical utility is held back by poor bioavailability. Intranasal administration of betahistine has been shown to result in 4 to 26 times higher bioavailability.

Safety first

Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.

Pharmacokinetics and Dose Proportionality of Betahistine in Healthy Individuals

Betahistine dihydrochloride is widely used to reduce the severity and frequency of vertigo attacks associated with Ménière’s disease. Betahistine is an analogue of histamine, and is a weak histamine H1 receptor agonist and potent histamine H3 receptor antagonist. The recommended therapeutic dose for adults ranges from 24 to 48 mg given in doses divided throughout the day. Betahistine undergoes extensive first-pass metabolism to the major inactive metabolite 2-pyridyl acetic acid (2PAA), which can be considered a surrogate index for quantitation of the parent drug due to extremely low plasma levels of betahistine. The aim of the present investigation was to assess the pharmacokinetics and dose proportionality of betahistine in Arabic healthy adult male subjects under fasting conditions. A single dose of betahistine in the form of a 8, 16, or 24 mg tablet was administered to 36 subjects in randomized, cross-over, three-period, three-sequence design separated by a one week washout period between dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax, and Thalf were calculated for each subject from concentrations of 2-PAA in plasma, applying non-compartmental analysis. The current study demonstrated that betahistine showed linear pharmacokinetics (dose proportionality) in an Arabic population over the investigated therapeutic dose range of 8–24 mg


I think Rene is right to be curious about whether the benefit of E-100 in autism models can be replicated today with cheap generic compounds.  Our readers who are doctors outside the US will be familiar with Betahistine, a cheap drug sitting on the shelf in their local pharmacy.

In my N=1 case of autism I am not so optimistic, because I did once follow up on another idea in the published literature.  That idea was to “fix” GABAA receptors with bumetanide/bromide and then “increase GABA”, in lay-speak. It was in this post from 2015:  “More GABA” for Autism and Epilepsy? Not so Simple

GABA is not supposed to cross the blood brain barrier (BBB), but when combined with niacin the Russians discovered it does, the result was the prodrug Picamilon (until recently sold in the US as a supplement). Some people with autism do take Picamilon.

In my case of autism, a single small dose of Picamilon had a pronounced negative effect, which I interpreted as GABA still acting as excitatory (it should be inhibitory).  It is possible that the niacin part of Picamilon was the problem.

Taurine is an agonist of GABAA receptors, so it will also act like “increasing GABA”

Very many people with autism take Taurine. Some people with autism who take Leucovorin (calcium folinate) also take Taurine to reduce its side effects.

Some people take Bumetanide and Taurine, which is surprising.

The original intended use of Leucovorin is for people undergoing chemotherapy, to reduce its side effects. Taurine is also used to reduce the side effects of chemotherapy. So not a surprise to see that Leucovorin is often together prescribed with Taurine, but that is in people fighting cancer.

In autism, there is no chemotherapy and so what is the rational to prescribe Taurine with Leucoverin?

Perhaps, by chance more than anything else, Taurine does reduce the aggression that is a common side effect of Leucovorin.  I hope it does.

My conclusion is that for plenty of people with autism, and particularly those who tolerate/use Taurine or Picamilon,  Betahistine’s effect on GABA should not cause a problem. When Betahistine gets FDA approval for pediatric use in ADHD, parents in the US will likely have little difficult getting a prescription for their child with autism. ADHD is highly comorbid with autism.

If Betahistine gives a benefit and is well tolerated, all you have to do is add Donepezil or Galantamine and you have something very similar to the research drug E-100, that shines in those two mouse models of autism.

I think the effect of Betahistine  increasing the levels of neurotransmitters histamineacetylcholinenorepinephrineserotonin, and GABA released from the nerve endings is likely to be occur from the first dose. It makes sense that the effect on your inner ear takes weeks/months to develop.

I think the ADHD version of betahistine will be a much more potent dose than current generic tablets and it will be achieved intranasally.

Betahistine was withdrawn from sale in the US many years ago because it was thought not to be effective;  the chart further below shows otherwise. 

If you are an adult outside the US, with some hearing loss, it looks like you might want to ask your doctor for a trial of Betahistine.  It is safe and very cheap.  While researched for Ménière's disease, you can have sudden onset reduction in hearing caused by an inflammatory response due to a virus or bacteria, that produces something very similar in the inner ear to what gets diagnosed as Ménière's disease, as I discovered myself. 

Sudden onset hearing loss (SOHL) is a 30 dB or greater hearing loss over less than 72 hours, it is usually idiopathic (you never get to know what caused it).  It is thought that most people do not go to their doctor – big mistake. If you treat SOHL immediately with steroids, hearing loss should be temporary. For people with the inner ear disease Ménière's, it looks like they should benefit from Betahistine, and then be able to hear sounds 6 decibels quieter.  Is Betahistine going to benefit SOHL that was not treated in time?  It might be worth finding out.


Betahistine, acting via H3 receptors, reduces the pressure of the fluid that fills the labyrinth in the inner ear; it also is thought to improve blood supply.  The diuretic acetazolamide, covered in this blog because of its effects on ion channels relevant to autism, is also used to reduce fluid build-up in the inner ear in Ménière's disease.

When I had sudden onset hearing loss (SOHL), it was initially misdiagnosed and steroid therapy started very late, so I added some acetazolamide from my autism stock pile.  It all worked out well.

If someone reading this post goes on to try Betahistine off-label for:-

·        ADHD
·        Depression
·        Autism
·        Weight gain associated with antipsychotics, particularly Olanzapine
·        Previously untreated, sudden onset hearing loss (SOHL)

it would be interesting to know your results.

Take note that Betahistine is also a mild agonist of H1 receptors, which explains why it may cause mild nausea (H1 blockers are used to reduce nausea) for a short while after taking it.  This side effect seems not to appear if Betahistine is taken with or after a meal. Betahistine may also reduce the H1 histamine receptor effect of any H1 antihistamine drugs being taken.

Ultimately the new E-100 drug may well be the best solution.  Hopefully the UAE researchers will persevere to human trials, but that is something that would need a lot of time and money and probably will not happen.

Monday, 7 September 2020

Another Potential Autism Therapy - novel compound E100 from Krakow, a combined histamine H3 receptor blocker (H3R antagonist) and an acetylcholine esterase inhibitor (AChEI)


Source:  Sukiennice and Main Square as seen from St. Mary's Basilica

Krakow’s old town is well worth a visit and is notable in Poland for not having been destroyed by the Germans, Russians or the US/UK during World War 2


Brain histamine and acetylcholine are implicated in cognitive disorders such as Alzheimer’s, schizophrenia, anxiety, and narcolepsy, all of which are found to be comorbid with autism.  This led a group in the United Arab Emirates (UAE) to test a new compound developed in Krakow, Poland, to see if this new Alzheimer’s compound is effective in two different models of autism. 

The Valproic Acid induced model of autism and the BTBR models were chosen.  The BTBR model is seen as a proxy for idiopathic autism; in this model there is no corpus callosum, which joins the left are right sides of the brain (red part in the graphic below). In an earlier post we looked at agenesis of the corpus callosum, which can be full or partial and is a feature of many types of disabling autism.




The results of the mouse research were positive and it was concluded that E-100 is a potential drug candidate for future therapeutic management of autistic-like behaviours.


Simultaneous Blockade of Histamine H3 Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H3R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H3R agonist (R)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed. 

The observed results in an idiopathic ASD mice model comprehend our previously obtained palliative effects of E100 in VPA-induced ASD in mice. Also, the current observations demonstrate that simultaneous targeting of the CNS histaminergic and cholinergic neurotransmissions is crucial for palliation of several ASD-like features, namely ASD-like social deficits and repetitive/compulsive behaviors and mitigated the levels of cerebellar microglial cells and AChE activity of tested BTBR mice used as idiopathic ASD model. Whether the alleviation of autistic-like behaviors in BTBR mice is obtained after administration of H3R antagonist or co-administration of an H3R antagonist and an AChEI was beyond the scope of this project and will require dose-finding experiments for several ratios of the combination of AChEIs and H3R antagonist. Further in vivo assessments on brain levels of ACh as well as HA in BTBR mice following different systemic treatments of test compound as well as reference drugs including a standard H3R antagonist (e.g., pitolisant) are still needed to evaluate whether multiple-active compounds, e.g., E100, is superior to AChEIs or H3R antagonists when administered alone.

The design and synthesis of E100, namely 1-(7-(4-chlorophenoxy)heptyl)azepane, was carried out in the Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Krakow, Poland and as described in in previous reports.


The Dual-Active Histamine H3 Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-Like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice

The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: Ki = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC50 = 2 µM and EqBuChE: IC50 = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours.


Acetylcholinesterase inhibitor (AChEI)

An acetylcholinesterase inhibitor (AChEI) inhibits the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine, thereby increasing both its level and duration of action.

We know that a surge in acetylcholine improves learning.

Examples of acetylcholinesterase inhibitors include: -

·        Alzheimer’s drugs Donepezil and Galantamine (both used off-label in autism)

·        Caffeine

·        Rosmarinic acid


Histamine H3 antagonists

Histamine H3 antagonists bind to H3 receptors in the brain so that histamine cannot activate them, examples include: -


Betahistine/Ciproxifan produces wakefulness and attentiveness in animal studies, and produced cognitive enhancing effects without prominent stimulant effects at relatively low levels of receptor occupancy, and pronounced wakefulness at higher doses. It has therefore been proposed as a potential treatment for sleep disorders such as narcolepsy and to improve vigilance in old age, particularly in the treatment of conditions such as Alzheimer's disease 


Pitolisant/ Wakix, is a medication for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. It is a histamine 3 (H3) receptor antagonist/inverse agonist. It represents the first commercially available medication in its class. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.

The most common side effects include difficulty sleeping, nausea, and feeling worried


There is a lot in this blog about histamine, mainly in relation to mast cells and allergic responses. You do have mast cells in your brain. Science has not fully established the role of histamine in humans, particularly in the brain. 

A quick recap on histamine:- 

H1 receptor

The H1 receptor is what mediates things like pollen allergies, but it plays a role in the brain that affects sleep, appetite, body temperature and cognition.


H2 receptor

The H2 receptor in the gut is the target of acid lowering drugs. These receptors do exist in the brain, but nobody has figured out their function.


H3 receptor

The H3 receptor is mainly in the central nervous system where it regulates the release of brain histamine (HA) and acetylcholine (ACh); it also affects the release of serotonin and norepinephrine. Elsewhere in the body H3 receptors play a role in the release of gastric acids. 

H4 receptor

The H4 receptor is not well understood. It plays a role in mast cells, but its role in cognition, allergy and inflammation is not fully understood.


Histamine-gated Chloride Channels

It does not seem to have a cute name like H5, but there appears to be another target for histamine, that is a histamine gated chloride channel, which seems to be present in the brain 


Histamine is produced from the amino acid histidine.  Some food contains histamine.

Somewhat bizarrely, it seems that if you supplement the amino acid histidine you get an anti-allergy effect; it is like more histidine makes/releases less histamine.  One of nature’s feedback loops at work, I suppose.

Histamine is mainly stored in mast cells (the target of mast cell stabilizer drugs), some is stored in basophils. Within the brain histamine functions as a neurotransmitter and you have so-called histaminergic neurons.

Once released, histamine is supposed to be deactivated by the enzymes HNMT or DAO (histamine-N-methyltransferase or diamine oxidase).  If you lack HNMT or DAO you will have problems with histamine.


Is there a synergistic benefit from blocking the H3 receptors in the brain and increasing the level of acetylcholine? 

The researchers from the UAE seem to believe that the new Polish drug E-100 has the unique benefit of doing two clever things at once that together might be helpful in human autism, as well as in the original target, Alzheimer’s.




I did write in length in this blog about histamine; there are 18 posts tagged with Histamine.

This did take me to the world of mast cell stabilizers and then L-type calcium channel blockers, so it was productive; but there were clearly huge gaps in the science that still remain.

The interesting substances from my original investigation include: -

·        H1 anti-histamines that also stabilize mast cells (Azelastine, Rupatadine, Ketotifen).

·        Pure mast cell stabilizers like Cromolyn Sodium

·        L-type calcium channel blockers such as Verapamil


It seemed highly likely that H3 and H4 receptors might also be useful targets, let alone the even less understood histamine gated chloride channels.

Is the new Polish drug E-100 going to be effective in human autism? and in which people?  Are the people with mast cell problems likely to be among the responders?  



Tuesday, 2 February 2016

Central histamine (dys)function, antidepressants, appetite, autism and behavior

One day last week Monty, aged 12 with ASD, was watching an old Tom and Jerry DVD.  These DVDs, along with the other action-packed ones, once got hidden away because they drove Monty wild; now they do not.

This is what I was doing while Tom was chasing                                                                         Jerry.

I received another interesting comment from a reader who found a small dose of an antidepressant had a very positive effect on his 9 year old daughter:-

“My daughter (9, ASD) recently started on a very small dose of Remeron, in an effort to increase weight and as a bonus, hopefully improve sleep. It has done both. It also had an immediate unexpected but delightful side effect of improved social skills, more fluent speech and increased amount of conversation. The first day she tried it she made friends with random children in the park, and they had a discussion about how they would design their dream playground. (DD said she would invent and upside down slide, where you start at the bottom and slide up.) It has been amazing for her (so far.)  ”

In most families it is the parents who take the antidepressants.

I recalled that one class of antidepressant was actually developed from an old antihistamine drug, tricyclic antidepressants.

Remeron, otherwise known as Mirtazapine, is indeed a tricyclic antidepressant.

Not only is Remeron, in effect, a first generation antihistamine, i.e. one that was not designed to stay outside the blood brain barrier, but it is a rather potent one.

Within the brain Remeron/Mirtazapine:-

HR occupancy (HRO) of mirtazapine reached 80-90 % in the cerebral neocortex

Histamine H receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers.

This means that 80-90% of the type 1 histamine receptors in that part of the brain are blocked from action.

Histamine Receptors and the Blood Brain Barrier

There were several earlier posts in this blog regarding histamine.

There are four known types of histamine receptors H1, H2, H3 and H4.

In one way or the other, all four are likely relevant to autism.  Drugs are not yet available for H4.  H3 therapies are likely to improve cognitive function in some. H4 appears to play a role in the overexpression of mast cells in allergic tissues.  So those with severe mast cell issues should watch the H4 drug pipeline.

Histamine H4 Receptor Mediates Chemotaxis and Calcium Mobilization of Mast Cells

An important point to remember is that while histamine does not cross the Blood Brain Barrier (BBB), H1 antihistamines do cross, including the ones designed not to cross.

All antihistamines cross blood-brain barrier

Within the brain, histamine functions as a neurotransmitter, but it is not the same histamine as that released by mast cells in your nose, when you have hay fever.  Histamine is also produced inside the brain.

H3 receptors in the brain modulate the release of histamine.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors in the cerebral cortex. Consequently, unlike the H1 antagonist antihistamines which are sedating, H3 antagonists have stimulant and nootropic effects, and are being researched as potential drugs for the treatment of neurodegenerative conditions such as Alzheimer's disease and also for ADHD.

H1 agonists should increase appetite and H3 agonists should reduce appetite.  So one day do not be surprised to read about wonder H3 slimming pills.

Outside the brain (CNS) all four types of receptor are found and have specific functions.

H1 receptors modulate circadian rhythm (sleep) as well as all those allergy and asthma symptoms.

H2 receptors modulate sinus rhythm (in your heart), stimulate  gastric acid secretion, inhibit antibody synthesis, T-cell proliferation and cytokine production.

So histamine dysfunction would contribute to many conditions that are known to be comorbid with autism:-

·        Obesity and also low appetite (both extremes)
·        Poor sleep
·        GERD/GORD/reflux
·        Cognitive impairment
·        Allergy
·        Mood disorders

As usual things are complicated, because the histamine receptors are slightly different in each part of the brain so your histamine antagonist/blocker “sticks” better on some than on others.  So one H1 antihistamine will be more sedating, or more appetite-increasing than another one.

H1 antihistamines in Autism

Most attention in this blog has been directed to the effect of H1 antihistamines outside the brain/CNS.  To a greater or lesser extent, all H1 antihistamines are also mast cell stabilizers.  They reduce the release of histamine itself, as well as blocking H1 receptors (and so relieving allergy symptoms).

Blocking the release of histamine outside the BBB stops the release of inflammatory cytokines like IL-6, which can, directly or indirectly, cross the blood brain barrier.

However many people report that common H1 antihistamines seem to improve autistic behavior, irrespective of any allergy being present. My assumption is that this may be the case with nine year old girl, certainly worth investigating.

Either there is a mild allergy that has gone unnoticed, or this must be the effect of blocking H1 receptors within the brain/CNS.

H3 antihistamines in Autism

I think it quite likely that some people with autism and schizophrenia would experience cognitive improvement from H3 antagonists.

It is perhaps odd that nobody has investigated the cognitive effects of Betahistine.

Betahistine has a very strong affinity as an antagonist for histamine  H3 receptors and a weak affinity as an agonist for histamine H1 receptors.

The disadvantage is that betahistine increases histamine levels outside the BBB, so not good for someone with asthma.

There is data on the effect of Betahistine on weight gain in schizophrenia:-

Reducing antipsychotic-induced weight gain in schizophrenia: a double-blind placebo-controlled study of reboxetine-betahistine combination.

It was safe, well tolerated and did reduce weight gain.  I would have liked to know the effect on cognitive function.


There may be too much histamine being released, or its degradation might be impaired (DAO, SAMe, & HMT are all implicated in autism/schizophrenia), or there may be over/under expression of histamine receptors in certain places.

For example in schizophrenia,  metabolites of histamine are increased in the cerebrospinal fluid of people, while the efficiency of H1 receptor binding sites is decreased.

The role of the central histaminergic system on schizophrenia.

It would not be surprising if people with autism and histamine/mast cell related issues outside the brain, also have central (in the brain) histamine dysfunctions.

There are only 24,000 genes found in humans (there are 700+ autism genes).  As a result these genes have to be reused many times all over the body.  Any dysfunction may be reappear in surprising parts of the body.  Add to this the way the body is controlled by feedback loops and you can see a how very many things are inter-related.

This also explains why very clever ideas can work in vitro (in the lab) but completely fail when applied to humans. "Stumbled upon", which must really annoy some clever scientists, is a very valid discovery method and can still earn you top marks.

This also means that many potential therapies can have unintended side effects. Like the H3 antagonist Betahistine, which can cause gastric acid problems and itching.  Betahistine acting in the brain might be good for cognition, but might not be without drawbacks elsewhere in the body.

Coming back to Tom and Jerry and where this post started

As usual Jerry got the better of Tom.

Since continued used of Remeron might lead to obesity, it would be interesting to see if the autism benefits were maintained by using a more conventional H1 antihistamine.  The older ones should better cross the BBB, but will be more sedative.

The people currently using conventional H1 antihistamines to treat their n=1 case of autism, might want to compare the effect of the very small dose of Remeron.

The people using second generation conventional H1 antihistamines (Zyrtec, Claritin etc) to treat their n=1 case of autism might want to compare the effect of the old fashioned versions that, like Remeron, have high much higher HR occupancy in the brain.

For those still hungry (too much histamine) for more:-

Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse

The role of hypothalamic H1receptor antagonism in antipsychotic-induced weight gain.


Therapeutic potential of histamine H3 receptor agonist for thetreatment of obesity and diabetes mellitus