Showing posts with label Betahistine. Show all posts
Showing posts with label Betahistine. 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.

Sunday, 26 March 2017

Sensory Gating in Autism, Particularly Asperger's

Sensory gating is an issue in autism, schizophrenia and ADHD.   It is the neurological process of filtering out redundant or unnecessary stimuli in the brain; like the child who sits in his classroom and gets bothered by the noise of the clock on the wall.  He is unable to filter out and ignore this sound. He becomes preoccupied by the sound and cannot concentrate on his work.
There are also sometimes advantages to not filtering out environmental stimuli, because you would have more situational awareness and notice things that others miss.
An example of sensory gating is the fact that young children are not waken by smoke detectors that have high pitched siren, but are waken by a recorded human voice telling them there is a fire and to wake up.
There may be times when sensory overload in autism is not a case of too much volume from each of the senses, but rather too many inputs being processed by the brain, instead of some just being ignored.  It is more a case of information overload.
Note that this blog has already covered hypokalemic sensory overload in some depth, which is treatable.
Much is known about sensory gating because it has long been known to be a problem in schizophrenia.
An EEG (Electroencephalography) test measures your brain waves / neural oscillations. Many people with autism have EEGs, but mainly those in which epilepsy is a consideration.
In the world of the EEG, the P50 is an event occurring approximately 50 millisecond after the presentation of an auditory click.  The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.
Abnormal P50 suppression is a biomarker of schizophrenia, but is present in other disorders, including Asperger’s, post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI).
In more severe autism abnormal P50 suppression was found not to be present in one study.  This might be because cognition and the senses are dimmed by the excitatory-inhibitory imbalance.
More broadly, sensory gating is seen as an issue in wider autism and ADHD.

Correcting P50 gating
It is known that α7 nicotinic acetylcholine receptor (α7 nAChR) agonists can correct the impaired P50 gating. It is also known that people with schizophrenia have less expression of this receptor in their brains than typical people.

One short term such agonist is the nicotine released from smoking.  This likely contributes to why people with schizophrenia can be heavy smokers.  The effect is thought to last for about 30 minutes.
Clinical trials using Tropisetron, a drug that is a α7 nAChR agonist and used off-label to treat fibromyalgia, have shown that it can correct defective P50 gating and improve cognitive function in schizophrenia.

An alternative α7 nAChR agonist that is widely available is varenicline, a drug approved to help people stop smoking.
So you might expect varenicline to improve P50 gating and improve cognition. You might also expect it to help people with fibromyalgia and indeed some other people with chronic inflammation, as shown by elevated inflammatory cytokines.

You may recall that the α7 nAChR is the key to stimulating the vagus nerve and this should be beneficial to many people with inflammatory conditions (from arthritis to fibromyalgia).

Abnormalities in CHRNA7, the alpha7-nicotinic receptor gene, have been reported in autism spectrum disorder. These genetic abnormalities potentially decrease the receptor’s expression and diminish its functional role. This double-blind, placebo-controlled crossover study in two adult patients investigated whether an investigational receptor-specific partial agonist drug would increase the inhibitory functions of the gene and thereby increase patients’ attention. An electrophysiological biomarker, P50 inhibition, verified the intended neurobiological effect of the agonist, and neuropsychological testing verified a primary cognitive effect. Both patients perceived increased attention in their self-ratings. Alpha7-nicotinic receptor agonists, currently the target of drug development in schizophrenia and Alzheimer Disease, may also have positive clinical effects in autism spectrum disorder.

A role for H3 and HI histamine receptors
It has also been suggested that histamine plays a role in sensory gating via the H1 and H3 receptors.

It had also been thought H3 receptors could be targeted to improve cognition in schizophrenia, but that research really did not go anywhere.

Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.

The aim of this study was to investigate an established rat model of decreased PPI induced by administration of the NMDA antagonist, dizocilpine and the reversal of this PPI impairment by the histaminergic H1-antagonist, pyrilamine. H1-antagonism is a potential mechanism of the therapeutic effects of the atypical antipsychotic, clozapine, which improves PPI following dizocilpine administration in rats as well as in patients with schizophrenia. In the present study we show that chronic pyrilamine administration prevents the PPI impairment induced by chronic dizocilpine administration, an effect that is correlated with a reduction in ligand-binding potential of H1 receptors in the anterior cingulate and an increase in nicotinic receptor α7 subunit binding in the insular cortex. In light of the functional anatomical connectivity of the anterior cingulate and insular cortex, both of which interact extensively with the core PPI network, our findings support the inclusion of both cortical areas in an expanded network capable of regulating sensorimotor gating.

The brain histamine system has been implicated in regulation of sensorimotor gating deficits and in Gilles de la Tourette syndrome. Histamine also regulates alcohol reward and consumption via H3 receptor (H3R), possibly through an interaction with the brain dopaminergic system. Here, we identified the histaminergic mechanism of sensorimotor gating and the role of histamine H3R in the regulation of dopaminergic signaling. We found that H3R knockout mice displayed impaired prepulse inhibition (PPI), indicating deficiency in sensorimotor gating. Histamine H1 receptor knockout and histidine decarboxylase knockout mice had similar PPI as their controls. Dopaminergic drugs increased PPI of H3R knockout mice to the same level as in control mice, suggesting that changes in dopamine receptors might underlie deficient PPI response when H3R is lacking. Striatal dopamine D1 receptor mRNA level was lower, and D1 and D2 receptor-mediated activation of extracellular signal-regulated kinase 1/2 was absent in the striatum of H3R knockout mice, suggesting that H3R is essential for the dopamine receptor-mediated signaling. In conclusion, these findings demonstrate that H3R is an important regulator of sensorimotor gating, and the lack of H3R significantly modifies striatal dopaminergic signaling. These data support the usefulness of H3R ligands in neuropsychiatric disorders with preattentional deficits and disturbances in dopaminergic signaling.


Other than nicotine, varenicline would seem a good potential therapy for sensory gating.  There are α7-nicotinic acetylcholine receptor agonists in development.
There are many H1 histamine antagonists.  Histamine release in the brain triggers secondary release of excitatory neurotransmitters such as glutamate and acetylcholine via stimulation of H1 receptors. Centrally acting H1 antihistamines are sedating.

H3 antagonists have stimulant and nootropic effects. Betahistine is an approved drug in this class, there are many research drugs.

The aim of this study is to investigate the role of the neurotransmitter histamine in sensory and cognitive deficits as they often occur in schizophrenia patients (e.g. hearing voices, planning and memory problems). The ideal location to conduct the study and to obtain a unique learning experience is at the Institute of Psychiatry, London, United Kingdom, where staff comprises of leading experts in the field of schizophrenia and Magnetic Resonance Imaging of pharmacological effects. Current pharmacological treatment of psychotic symptoms including sensory and cognitive deficits remains partially unsuccessful due to side effects and treatment resistance. The neurotransmitter histamine seems to be a very promising target for new treatments. It has been found that histamine neurotransmission is altered in brains of schizophrenics, which may contribute to both the hallucinatory and cognitive symptoms. However, this specific role of histamine has not been investigated before. I will assess the effects of increased histaminergic activity, by administration of betahistine to healthy volunteers, on performance (sensory gating, executive functioning or planning and memory) and associated brain activity using fMRI. Altered performance and brain activity would support the importance of histamine in schizophrenia and would provide a research model and target for new treatments.