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 histamine, acetylcholine, norepinephrine, serotonin, 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
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
Conclusion
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 histamine, acetylcholine, norepinephrine, serotonin, 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.