Clonidine and Guanfacine for ADHD, mast cell activation, sleep disorders, tics and some self-injurious behavior (SIB)

 

Both clonidine and guanfacine were raised recently to me, they have been covered in various earlier posts and in my book. Here is a round-up of the information.

These two drugs are α2A-adrenergic receptor agonists originally used to treat high blood pressure. Subsequently many additional uses of these drugs have been discovered.

I was asked about its use to treat mast cell activation syndrome (MCAS) and the mechanism by which it achieves this effect is interesting.

Calming mast cells – the ones that release histamine during an allergic reaction

Clonidine/guanfacine, as alpha-2 adrenergic agonists, inhibit mast cells primarily by interacting with the central and peripheral nervous systems, leading to a decrease in the release of inflammatory mediators. Its mechanism involves stimulating alpha-2 adrenergic receptors, which in turn suppresses the release of norepinephrine and other neurotransmitters.

In terms of mast cell stabilization, clonidine/guanfacine is thought to reduce intracellular calcium levels and inhibit the degranulation process that releases histamine and other pro-inflammatory substances. Lower intracellular calcium prevents the activation of key signaling pathways that normally trigger mast cell activation and degranulation.

This stabilizing effect helps prevent excessive allergic and inflammatory responses, making clonidine/guanfacine beneficial in conditions where such inhibition is useful.

Clonidine/guanfacine have some calcium channel-blocking properties, though they are not classified as a traditional calcium channel blocker. By indirectly lowering intracellular calcium levels, clonidine/guanfacine inhibit the signaling pathways that lead to mast cell degranulation and the release of inflammatory mediators. The end result is a reduction in cellular excitability and a dampening of the inflammatory response, including mast cell stabilization.

Clearly, you could just go directly to a calcium channel blocker like verapamil.

Clonidine/guanfacine and indeed verapamil are not seen as first line treatments for MCAS but may well be beneficial.

Conventional First-Line Treatments for MCAS

Antihistamines

H1 blockers (e.g., cetirizine, loratadine) to manage allergic-type symptoms like itching, hives, and flushing.

H2 blockers (e.g., famotidine, ranitidine) to control gastrointestinal symptoms and histamine release in the stomach.

Mast Cell Stabilizers

Cromolyn sodium is often considered one of the most effective mast cell stabilizers for MCAS, especially for gastrointestinal symptoms.

Ketotifen, another mast cell stabilizer with antihistamine properties, can also be helpful.

Rupatadine and azelastine are also potentially beneficial as mast cell stabilizers.

Leukotriene Inhibitors

Medications like montelukast can help manage symptoms related to leukotrienes, which are other mediators released by mast cells.

Aspirin

Aspirin can play a role in managing MCAS, particularly in controlling specific symptoms like flushing, hives, and inflammation. Its primary action in MCAS involves inhibiting prostaglandin D2 (PGD2), which is one of the inflammatory mediators released by mast cells and contributes to the vascular symptoms seen in MCAS.

Sleep disorders

Some people with autism do not sleep well.

Clonidine/guanfacine can help some individuals fall asleep faster and stay asleep longer by promoting relaxation and calming overactivity in the brain.

It is sometimes used in pediatric populations, such as children with autism or ADHD, to help with sleep initiation and minimize frequent nighttime awakenings.

Clonidine/guanfacine, being alpha-2 adrenergic agonists, lower the activity of the sympathetic nervous system (the fight-or-flight response).

Clonidine/guanfacine is typically prescribed at a low dose for sleep, as higher doses can lead to daytime drowsiness. Taking clonidine at night, about 30-60 minutes before bed, is common practice.

Guanfacine has a longer half-life than clonidine, which means it provides a more sustained effect throughout the night and may lead to fewer night-time awakenings. This can be particularly useful for individuals who need consistent support for sleep through the night.

Tics

Clonidine/guanfacine have long been used off-label to treat Tourette’s syndrome, which is a tic disorder.

Clonidine/guanfacine can help manage some stereotypical behaviors (repetitive, non-functional behaviors) in individuals with autism, when these behaviors are driven by hyperactivity, impulsivity, or anxiety.

Clonidine/guanfacine helps manage tics by calming the nervous system, modulating norepinephrine release, reducing stress, and helping with impulse control.

This effect has been noted by our reader AW.

Self-injurious behavior (SIB)

Self-injurious behavior (SIB) is usually considered the worst feature of autism. It becomes a learned behavior which can be very hard to extinguish.

Clonidine/guanfacine is on the long list of sometimes effective therapies. Take a note of this!

 

Clonidine as a Treatment of Behavioural Disturbances in Autism Spectrum Disorder: A Systematic Literature Review

Clonidine has a limited evidence base for use in the management of behavioural problems in patients with ASD. Most evidence originates from case reports. Given the paucity of pharmacological options for addressing challenging behaviours in ASD patients, a clonidine trial may be an appropriate and cost-effective pharmaceutical option for this population.

Beneficial Effects of Clonidine on Severe Self-Injurious Behavior in a 9-Year-Old Girl with Pervasive Developmental Disorder

ADHD

ADHD is very commonly diagnosed these days.

The genes involved in ADHD, autism, bipolar and schizophrenia are overlapping, so it is not surprising that many people are now being diagnosed with both ADHD and autism.

What I find very odd is that people with ADHD line up for medical treatment, but most people with comorbid autism think there cannot be a medical treatment for their autism because it is just how their brain is “wired-up differently.” It is hard to reconcile these views - both conditions are clearly treatable.

Most ADHD treatments are stimulants. Medications like methylphenidate (Ritalin, Concerta) and amphetamine-based drugs (Adderall, Vyvanse) are typically considered first-line treatments for ADHD. They work by increasing levels of dopamine and norepinephrine in the brain, which help improve focus, attention, and impulse control in people with ADHD.

Not all individuals with ADHD can tolerate stimulants, and in some cases, they may experience unwanted side effects like anxiety, sleep disturbances, or increased irritability.

The most common non-stimulant options are Clonidine and Guanfacine. They does not directly increase dopamine or norepinephrine but instead reduces norepinephrine release, promoting a calming effect.

Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor (NRI), which increases norepinephrine in the brain by blocking its reuptake.

After years of off-label use in by 2010 both clonidine and guanfacine were FDA approved for use in ADHD.

 

Conclusion

As I mentioned to one reader, we should take note that both clonidine and guanfacine are approved for use in children (with ADHD) and so there is plenty of safety information and dosage guidance.

The effective dose for MCAS, sleep disorders, tics and SIB may well vary from person to person but the safe boundaries are well established from ADHD.

In general, guanfacine tends to be better tolerated than clonidine.

AW might note that guanfacine can cause sleep problems, including insomnia or vivid dreams.

Here is a useful list I found:

Common Side Effects:

Sedation/Drowsiness: Like clonidine, guanfacine can cause drowsiness, especially during the initial stages of treatment or when the dose is increased.

Fatigue: Many people report feeling fatigued or tired when starting guanfacine, which can affect daytime functioning.

Low Blood Pressure (Hypotension): Guanfacine also lowers blood pressure, potentially leading to dizziness or light-headedness, particularly when standing up quickly.

Dry Mouth: This is another common side effect, similar to clonidine, and may cause discomfort.

Headache: Some people experience headaches, especially when starting treatment.

Stomach Problems (e.g., abdominal pain, constipation): Gastrointestinal side effects can occur in some individuals, such as constipation or stomach discomfort.

Irritability and Mood Swings: In some cases, guanfacine may cause irritability or emotional instability.

Less Common but Serious Side Effects:

Bradycardia (slow heart rate): As with clonidine, guanfacine can cause a slow heart rate, which could be concerning for individuals with underlying heart issues.

Rebound Hypertension: Discontinuing guanfacine too abruptly can cause rebound hypertension (a sudden increase in blood pressure), so it should be tapered gradually under a healthcare provider’s guidance.

Sleep disturbances: In some cases, though less common than with clonidine, guanfacine can cause sleep problems, including insomnia or vivid dreams.

Walnuts for Brain Health in Aging and ADHD, but in Autism?

 

Source: Ivar Leidus - Own work, CC BY-SA 4.0,  https://commons.wikimedia.org/w/index.php?curid=98723321

 

Diet does seem to be the most popular intervention for autism and it does appear to give benefits, particularly in those with milder autism.

There are lessons to be learnt from healthy aging, when looking at how to optimise brain function in those with a neurodevelopmental disorder like autism.

As we age, multiple processes in the body start to function sub-optimally and this pretty much determines our healthy life expectancy. There are overlaps between features of this sub-optimal function (oxidative stress, mitochondrial dysfunction, neuroinflammation etc) and what is present in people with level 3 autism and/or intellectual disability.

The dietary keys to healthy aging:

A healthy varied diet rich in fruits, berries, vegetables, whole grains, legumes and nuts.

Healthy fats and lean protein.

To this we have to add all those herbs and spices.

Herbs, in large quantities, are a key element of the Mediterranean diet and are often omitted by people trying to copy this diet. I still remember meeting our reader Petra in Greece and receiving her gift of olive oil and oregano – it was a huge bag of oregano, not the size you might find in a supermarket in Northern Europe.

The healthy Okinawa diet is distinguished by low-calorie intake, fish, very little meat, fermented food (like natto), not to forget the seaweed. They also consume large amounts of a purple sweet potato. Okinawan sweet potatoes, also known as purple sweet potatoes, are a type of sweet potato that is native to Okinawa. They are characterized by their deep purple flesh, which is due to the presence of anthocyanins, a type of antioxidant.

I have to say that having visited an island in the Okinawa archipelago they also have some very unhealthy food adopted from US military bases. Spam sushi was everywhere, as are US style fast food outlets, with over-sized burgers. I found it hard going eating fish three times a day, albeit those small amounts.

 

Greece is no different, there are older Greeks with healthy traditional diets, but no shortage of giros and souvlaki joints catering to the locals and the tourists alike.

 

 

Nuts!  Not just at Christmas

Nuts are on the list of healthy foods, but I think most people neglect them.

It is difficult to incorporate sufficient nuts into your diet unless you are going to spend time eating them by the handful.

Incorporating large amounts of herbs like oregano, basil, sage, rosemary, thyme, parsley, mint etc is not so hard and you end up with much tastier food. They provide numerous health benefits. 

I was very surprised to find that there was so much evidence to support the humble walnut.

I was also surprised where some of the evidence comes from.

I did exchange emails many years ago with Abha Chauhan, a well-known researcher at the Institute for Basic Research in Developmental Disabilities in New York. She has written some very cutting edge research about oxidative stress.

She turns out to be a fan of walnuts.

She does actually list nutrition among her research interests:-

Alzheimer's disease, amyloid, free radicals, glutathione, mitochondria, nutrition, oxidative stress, protein kinases

 Her paper is here:-

Beneficial Effects of Walnuts on Cognition and Brain Health

I did previously wonder why New York has a research center into intellectual disabilities. Here is some information.

 

The Institute for Basic Research in Developmental Disabilities (IBR) is a proud part of New York State’s long history of caring for its citizens with developmental disabilities. It was in the 1940s and 1950s that the idea of creating an institute dedicated to studies in mental retardation was first discussed. In 1958, enabling legislation was passed for the creation of the Institute for Research in Mental Retardation within the New York State Department of Mental Hygiene. Ground was broken for the Institute’s research tower in 1964, and when its first laboratories opened in 1968, IBR was the first large-scale institute in the world with the mandate to conduct basic and clinical research into the causes of mental retardation. IBR became part of OPWDD, then known as the New York State Office of Mental Retardation and Developmental Disabilities (OMRDD) in 1979; a year later, it was renamed the Institute for Basic Research in Developmental Disabilities to reflect OMRDD’s broader focus on many developmental disabilities.  

Research is always good, but what really matters is translating it to therapy. How about actually getting kids with autism treated for oxidative stress? This I recall discussing with Abha and her response was that the funding is lacking for clinical trials. My response was that she could always give Mike Bloomberg a call.  How much money do you really need? 

Abha, Alzheimer’s and the walnut

As we saw Alzheimer’s was number one on Abha’s research interests. Here we have her paper suggesting walnuts for Alzheimer’s.

 

Benefits of a diet with walnuts in Alzheimer’s disease

Alzheimer’s disease is a severe neurodegenerative disorder, responsible for 60-70% of cases of dementia. The most common symptoms are memory loss, disorientation and loss of cognition. To date, there is no known cure for this disease, but Dr Abha Chauhan, based at the New York State Institute for Basic Research in Developmental Disabilities, New York, USA, has shown how supplementation with walnuts in the diet can help Alzheimer’s mice slow down the development of the disease. Her research demonstrates that walnuts can limit the oxidative stress characteristic of this condition, as well as promote the body’s natural antioxidant defence mechanisms. 

Based on these results, it’s reasonable to suggest that supplementation with walnuts may help in reducing the risk of developing Alzheimer’s disease, delaying its onset and/or slowing its progression due to the antioxidant and anti-inflammatory effects of different components of walnuts. At the very least, these results indicate that it may be worth conducting similar studies in humans.

 

It’s difficult to say at this stage what exactly in the walnut is responsible for these benefits, but in addition to antioxidants in walnuts, ALA (omega-3 fatty acid) may also be a contributing factor. While most nuts contain monounsaturated fats, only walnuts consist primarily of polyunsaturated fat, of which ALA is the main constituent. This fatty acid is the precursor of vital fatty acids, important for regulating serotonin and dopamine concentrations, as well as modulating key inflammatory and immune functions.

 

Beneficial Effects of Walnuts on Cognition and Brain Health

Oxidative stress and neuroinflammation have important roles in the aging process, mild cognitive impairment (MCI), Alzheimer’s disease (AD), and other brain disorders. Amyloid beta protein (Aβ) is the main component of amyloid plaques in the brains of people with AD. Several studies suggest that Aβ increases the generation of free radicals in neurons, which leads to oxidative damage and cell death. Aβ can also induce neuroinflammation by increasing pro-inflammatory cytokines and enzymes. Walnuts contain several components that have antioxidant and anti-inflammatory effects. Animal and human studies from our and other groups suggest that supplementation with walnuts in the diet may improve cognition and reduce the risk and/or progression of MCI and AD. In the transgenic AD mouse model (AD-tg), we have reported the beneficial effects of a diet with walnuts on memory, learning, motor coordination, anxiety, and locomotor activity. Human clinical trials have also suggested an association of walnut consumption with better cognitive performance and improvement in memory when compared to baseline in adults. Our recent study in AD-tg mice has shown that a walnut-enriched diet significantly improves antioxidant defense and decreases free radicals’ levels, lipid peroxidation, and protein oxidation when compared to a control diet without walnuts. These findings suggest that a diet with walnuts can reduce oxidative stress by decreasing the generation of free radicals and by boosting antioxidant defense, thus resulting in decreased oxidative damage to lipids and proteins. An in vitro study with synthetic Aβ showed that walnut extract can inhibit Aβ fibrillization and solubilize the preformed Aβ fibrils, suggesting an anti-amyloidogenic property of walnuts. Because it takes many years for cognitive impairment and dementia to develop, we suggest that early and long-term dietary supplementation with walnuts may help to maintain cognitive functions and may reduce the risk of developing, or delay the onset and/or slow the progression of, MCI and dementia by decreasing Aβ fibrillization, reducing oxidative damage, increasing antioxidant defense, and decreasing neuroinflammation. Furthermore, several animal and human studies have suggested that walnuts may also decrease the risk or progression of other brain disorders such as Parkinson’s disease, stroke, and depression, as well as of cardiovascular disease and type 2 diabetes. Together, these reports suggest the benefits of a walnut-enriched diet in brain disorders and in other chronic diseases, due to the additive or synergistic effects of walnut components for protection against oxidative stress and inflammation in these diseases.

  

Walnuts for teenagers? 

That’s Nuts! Eating Walnuts Regularly Improves Cognitive Development and Psychological Maturation in Teens

Summary: Teens who added walnuts to their diet for 100 days showed improvements in attention function, and for those with ADHD, frequent walnut consumption was associated with improvements in behavior. Researchers also noted an increase in fluid intelligence in those who frequently consumed walnuts as part of their daily diet.

  

Walnuts May Help Teens with Maturity, Thinking, and Attention

 

Effect of walnut consumption on neuropsychological development in healthy adolescents: a multi-school randomised controlled trial

Background

Omega-3 fatty acids are critical for neuropsychological functioning. Adolescence is increasingly believed to entail brain vulnerability to dietary intake. The potential benefit on adolescent neurodevelopment of consuming walnuts, a source of omega-3 alpha-linolenic acid (ALA), remains unclear.

Methods

We conducted a 6-month multi-school-based randomised controlled nutrition intervention trial to assess whether walnut consumption has beneficial effects on the neuropsychological and behavioural development of adolescents. The study took place between 04/01/2016 and 06/30/2017 in twelve different high schools in Barcelona, Spain (ClinicalTrials.gov Identifier: NCT02590848). A total of 771 healthy teenagers aged 11–16 years were randomised into two equal groups (intervention or control). The intervention group received 30 g/day of raw walnut kernels to be incorporated into their diet for 6 months. Multiple primary endpoints concerning neuropsychological (working memory, attention, fluid intelligence, and executive function) and behavioural (socio-emotional and attention deficit hyperactivity disorder [ADHD] symptoms) development were assessed at baseline and after intervention. Red blood cell (RBC) ALA status was determined at baseline and 6 months as a measure of compliance. Main analyses were based on intention-to-treat using a linear mixed-effects model. A per-protocol effect of the intervention was analysed using inverse-probability weighting to account for post-randomisation prognostic factors (including adherence) using generalised estimating equations.

Findings

In intention-to-treat analyses, at 6 months there were no statistically significant changes between the intervention and control groups for all primary endpoints. RBC ALA (%) significantly increased only in the intervention group, coefficient = 0.04 (95% Confidence Interval (CI) = 0.03, 0.06; p < 0.0001). The per-protocol (adherence-adjusted) effect on improvement in attention score (hit reaction time variability) was −11.26 ms (95% CI = −19.92, −2.60; p = 0.011) for the intervention group as compared to the control group, improvement in fluid intelligence score was 1.78 (95% CI = 0.90, 2.67; p < 0.0001), and reduction of ADHD symptom score was −2.18 (95% CI = −3.70, −0.67; p = 0.0050).

Interpretation

Our study suggested that being prescribed eating walnuts for 6 months did not improve the neuropsychological function of healthy adolescents. However, improved sustained attention, fluid intelligence, and ADHD symptoms were observed in participants who better complied with the walnut intervention. This study provides a foundation for further clinical and epidemiological research on the effect of walnuts and ALA on neurodevelopment in adolescents.  

Walnuts for Autism? 

I did find a case study from the Middle East putting forward reasons why walnuts and pumpkin may benefit some types of autism.  It was not a robust study, but I was surprised to find anything at all on this subject. 

Effects of Walnut and Pumpkin on Selective Neurophenotypes of Autism Spectrum Disorders: A Case Study

Special diets or nutritional supplements are regularly given to treat children with autism spectrum disorder (ASD). The increased consumption of particular foods has been demonstrated in numerous trials to lessen autism-related symptoms and comorbidities. A case study on a boy with moderate autism who significantly improved after three years of following a healthy diet consisting of pumpkin and walnuts was examined in this review in connection to a few different neurophenotypes of ASD. We are able to suggest that a diet high in pumpkin and walnuts was useful in improving the clinical presentation of the ASD case evaluated by reducing oxidative stress, neuroinflammation, glutamate excitotoxicity, mitochondrial dysfunction, and altered gut microbiota, all of which are etiological variables. Using illustrated figures, a full description of the ways by which a diet high in pumpkin and nuts could assist the included case is offered.

This case study does not support broad food treatments as a treatment for ASD, but it does imply that specialized dietary interventions over time may play a role in the management of certain ASD symptoms, functions, and clinical domains. The pumpkin/walnut healthy diet improved nutritional status, presumably increasing the brain’s ability to function and learn by reducing oxidative stress, neuroinflammation, glutamate excitotoxicity, mitochondrial dysfunction, and altered gut microbiota, all of which are etiological mechanisms behind the clinical presentation of ASD.   

Impact of Nut Consumption on Cognition across the Lifespan 

Cognitive health is a life-long concern affected by modifiable risk factors, including lifestyle choices, such as dietary intake, with serious implications for quality of life, morbidity, and mortality worldwide. In addition, nuts are a nutrient-dense food that contain a number of potentially neuroprotective components, including monounsaturated and polyunsaturated fatty acids, fiber, B-vitamins, non-sodium minerals, and highly bioactive polyphenols. However, increased nut consumption relates to a lower cardiovascular risk and a lower burden of cardiovascular risk factors that are shared with neurodegenerative disorders, which is why nuts have been hypothesized to be beneficial for brain health. The present narrative review discusses up-to-date epidemiological, clinical trial, and mechanistic evidence of the effect of exposure to nuts on cognitive performance. While limited and inconclusive, available evidence suggests a possible role for nuts in the maintenance of cognitive health and prevention of cognitive decline in individuals across the lifespan, particularly in older adults and those at higher risk. Walnuts, as a rich source of the plant-based polyunsaturated omega-3 fatty acid alpha-linolenic acid, are the nut type most promising for cognitive health. Given the limited definitive evidence available to date, especially regarding cognitive health biomarkers and hard outcomes, future studies are needed to better elucidate the impact of nuts on the maintenance of cognitive health, as well as the prevention and management of cognitive decline and dementia, including Alzheimer disease.

   

Conclusion

We are told in dietary advice from public health authorities that we should include nuts in our daily diet. The suggested daily amount is about 30 grams (1 ounce).

If you had to choose one nut, it looks like the walnut is the one most likely to help the brain.

Teenagers with ADHD are suggested to benefit in the research from Spain.

Abha Chauhan over in New York is a proponent of walnuts for potentially slowing down Alzheimer’s disease.

Whether walnuts may benefit some with autism is an open question, but there are reasons to believe that it should. Over in Abu Dhabi one autism practitioner is suggesting combining walnuts with pumpkin for optimal effect. 

Ensuring healthy aging with diet and exercise is actually very straight forward, but most people still choose not to do it.

Treating severe autism is much more hit and miss, but many of those who persevere see good results.

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:

Improvement of Language in Children with Autism with Combined Donepezil and Choline Treatment

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

Source: https://ir.aurismedical.com/static-files/093ed1ec-9744-4144-92d3-7f6faca3a18a

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

 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

Safety, tolerability and pharmacokinetics of 2-pyridylacetic acid, a major metabolite of betahistine, in a phase 1 dose escalation study in subjects with ADHD

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 C_max, AUC_0–t, AUC_0–∞, T_max, and T_half 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” GABA_A 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

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

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 GABA_A receptors, so it will also act like “increasing GABA”

Taurine and GABA neurotransmitter receptors, a relationship with therapeutic potential?

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.

 

 Hearing function after betahistine therapy inpatients with Ménière's disease

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.