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

Chamomile, a good source of Apigenin

 

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

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

 

Why the interest in Apigenin?

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

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

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

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

 

Pleiotropic effects

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

 

Other Flavonoids used in Autism

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

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

 

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

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

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

 

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

 

Sytrinol

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

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

 

Sources of Apigenin

Apigenin is sold as a supplement.

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

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

 

The biological effects of Apigenin

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

 

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

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

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

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

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

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

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

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

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

When you push Bard a little bit you get more:

Apigenin and ion channels, Bard?

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

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

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

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

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

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

 

Which potassium channels, Bard? 

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

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

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

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

 

The effect of mefenamic acid on potassium channels, Bard? 

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

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

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

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

 

Apigenin in Down syndrome

 

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

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

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

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

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

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

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

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

 

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

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

 

Conclusion 

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

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

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

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

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

A common link between what seems to improve sound sensitivity:

•                    Oral potassium

•                    Ponstan (Mefenamic acid)

•                    Apigenin

is potassium ion channels. 

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

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

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

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

Different L-type Calcium Channel Blockers Repurposed for Different Types of Autism

 

 A Purkinje Neuron, home of P-type calcium channels

Today’s post was prompted by a reader who saw a very positive response from the L-type calcium channel blocker, Amlodipine.

So we return to the subject of calcium channels.

The good news about calcium channel defects is that many are easy to treat.

In most single gene autisms (Rett, Fragile-X, Pitt Hopkins etc) the underlying problem is that a faulty gene does not do its job of producing the expected protein.  This is a problem of too little.

In many ion channel dysfunctions the problem is not too little, it is too much expression. For example, in Timothy Syndrome the mutation in the gene produces too much of the protein, in this case the L-type calcium channel Cav1.2.

Ion channel dysfunctions can be the result of a faulty gene, or just that the on/off switch for that gene is faulty.  Fortunately, the problem is usually that it is stuck “on”.

In people who develop Type-1 diabetes we have seen how the disease process can be halted by blocking Cav1.2 in the pancreas.  This halts the decline in the beta cells that produce insulin.

Once all the beta cells are dead, the person cannot produce insulin and has type-1 diabetes. Treating the person after this point with a Cav1.2 blocker will provide no benefit; the damage has already been done

Something similar happens in Parkinson’s disease, but this time you need to block Cav1.3.  In the early stages of the disease Cav1.3 is over-expressed in a key part of the brain, which triggers a slow process of degeneration. Treating a person with all the visible symptoms of Parkinson’s with a Cav1.3 blocker will provide no benefit; the damage has already been done.

 

Calcium channel blockers are not very specific

The current drugs used to block calcium channels were mainly developed to treat heart conditions.

When treating neurological disorders like autism we are primarily focused on the brain, what goes on elsewhere can also be very relevant, but in an indirect way.

In the brain the important calcium channels are: -

L type

N type

P type

R type

T type

Plus, Inositol trisphosphate receptor (IP3R) and Ryanodine receptors. IP3R has been covered in previous posts.

Verapamil (a Phenylalkylamine class drug)

Verapamil blocks L type channels and T type channels, plus some potassium ion channels.

When it comes to specific L type channels there are 4, Cav1.1, Cav1.2, Cav1.3, and Cav1.4.

In the brain we have just Cav1.2 and Cav1.3. Verapamil mainly affects Cav1.2.

 

Amlodipine (a Dihydropyridine class drug)

Amlodipine blocks L type channels and N type channels.

Amlodipine mainly affects Cav1.3.

 

Nicardipine (a Dihydropyridine class drug)

Nicardipine blocks L type channels and N type channels.

As a Dihydropyridine, it should mainly affect Cav1.3.

In addition, it blocks the sodium ion channel Nav1.8.

The effect on Nav1.8 is why it has been proposed as a therapy for Pitt Hopkins. In this syndrome Nav1.8 is over expressed as a downstream consequence of a mutation in the TCF4 gene.

 

Effect on P channels

To some extent Verapamil, Amlodipine and Nicardipine all block P channels.

P channels are called P after the Purkinje neurons, where they are located. These Purkinje cells likely define some aspects of autism, because of their absence. Purkinje neurons are among the largest in the brain, with elaborate dendritic arbor.  I imagine this makes them vulnerable.

In the people with severe autism most of the Purkinje cells appear to have died.

Blocking P channels might have protected Purkinje cells from death.

 

The effect of too much L-type calcium channel signaling on behavior 

You can both turn on self-injury via activating L type calcium channels and extinguish it by blocking the same channels.  It is proven in mice and seems to apply to at least some humans.

Calcium channel activation and self-biting in mice

The L type calcium channel agonist (±)Bay K 8644 has been reported to cause characteristic motor abnormalities in adult mice. The current study shows that administration of this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.

The self-biting provoked by (±)Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine L type calcium channel antagonists such as nifedipine, nimodipine, or nitrendipine. However, self-biting is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine, or verapamil.

(±)Bay K 8644 functions as an L type calcium channel activator that increases calcium fluxes in response to depolarizing stimuli (19–21). In rodents, this drug has been reported to produce characteristic motor abnormalities including impaired ambulation, twisting and stretching movements, transient limb extension, back arching, spasticity, ataxia, or catatonia (22–28). Some studies have anecdotally noted the occurrence of SIB with this drug (23–25, 27), though this phenomenon has received little attention. The current study shows that (±)Bay K 8644 will reliably provoke SB and SIB under certain conditions in mice, providing a tool to study the neurobiology of this unusual behavior.

 

When I first encountered the above study, I did wonder why Verapamil did not extinguish the self-injury.

It turns out that Bay K 8644 is a modified version of the common drug nifedipine, which is a Cav1.3 blocker.  Verapamil is mainly a Cav1.2 blocker.  Bay K 8644 is like the opposite of nifedipine.

In the trial they have activated Cav1.3 causing excess calcium inside neurons. The only way to block this process is to block Cav1.3. Blocking Cav1.2 with Verapamil could not solve the problem. 

Note that activation of Cav1.3 can cause motor abnormities in mice and this might be seen as ataxia in a human. One particular reader of this blog will see the relevance of this. 

I did write extensively in earlier posts about the large amount of research that links L type calcium channels to neuropsychiatric disorders.

I did mainly focus on Cav1.2 using Verapamil, but the evidence for the role of Cav1.3 is clear as day. 

L-type calcium channels as drug targets in CNS disorders

 L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value.

 

From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms.

The L-type calcium channels (LTCCs) Ca_v1.2 and Ca_v1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder.

Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Ca_v1.2- and Ca_v1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

 

Was I surprised that Amlodipine, that targets Cav1.3 rather than Cav1.2, was very beneficial in someone with severe autism?  Not at all.

I was interested that the effect was more pro-cognitive than anti-anxiety.  Is that the effect on Cav1.3 or is it via that N channel Cav2.2?

N-type calcium channels are important in neurotransmitter release because they are localized at the synaptic terminals. Piracetam, the original cognitive enhancing drug, is also a N type channel blocker.

  

Statins and L type calcium channels blockers – it matters which one you choose

We previously saw how the statin class of drugs can be beneficial in autism, but it depends which one you chose. For example, in SLOS (Smith-Lemli-Opitz syndrome), where both copies of the gene DHCR7 are mutated, you need to push the gene to work. To increase expression of this gene you need Simvastatin. This is hard for people to understand because SLOS features very low cholesterol and statins are thought of as cholesterol lowering drugs. The body needs the enzyme DHCR7 to make cholesterol and Simvastatin increases DHCR7 expression.

In the case of L type channel blockers, the selection is very important.  The effect will not be the same.

If you have a mutation in Cav1.2, you would expect Verapamil to be a good choice.  If the mutation is in Cav1.3, you would expect Amlodipine to be better.

If you have over expression of T channels (Cav3.1, Cav3.2 or Cav3.3) then you would expect a benefit from Verapamil and none from Amlodipine.

If you have over expression of the N channel (Cav2.2) then you would want Amlodipine

If you have over expression of the sodium channel Nav1.8 then you would want Nicardipine

  

Conclusion

It is likely that many people with autism, bipolar, ADHD or schizophrenia might benefit from treating their ion channel dysfunctions.  The required drugs are cheap generics that have been in your local pharmacy for a few decades.

Back in 2019 I wrote the post below:

Cheap common drugs may help mental illness

I highlighted a new study, using historic data from Sweden, that looked at the secondary effects of statins, calcium channel blockers and metformin on psychiatric hospitalization.

 

Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness

 

Question  Are drugs in common use for physical health problems (hydroxylmethyl glutaryl coenzyme A reductase inhibitors, L-type calcium channel antagonists, and biguanides) associated with reduced rates of psychiatric hospitalization and self-harm in individuals with serious mental illness?

Findings  In this series of within-individual cohort studies of 142 691 patients with bipolar disorder, schizophrenia, or nonaffective psychosis, exposure to any of the study drugs was associated with reduced rates of psychiatric hospitalization compared with unexposed periods. Self-harm was reduced in patients with bipolar disorder and schizophrenia during exposure to all study drugs and in patients with nonaffective psychosis taking L-type calcium channel antagonists. 

We found that periods of HMG-CoA RI (statin) exposure were associated with reduced psychiatric hospitalization in all subgroups of SMI (Serious Mental Illness) and with reduced self-harm in BPD and schizophrenia.

Exposure to LTCC (L type calcium channel) antagonists was associated with reduced rates of psychiatric hospitalization and self-harm.

Periods of metformin (a type 2 diabetes drug) exposure were associated with reduced psychiatric and nonpsychiatric hospitalization across all SMI subgroups.

 

Use of L type calcium channel blockers reduces self-harm.

How much more evidence is needed?

I took an educated guess several years ago that Verapamil would tame summertime raging in my son.  It was the only calcium channel blocker I tried and it worked. This year we had the emergence of extreme sound sensitivity. My educated guess was that blocking potassium channels with Ponstan (Mefenamic acid) would resolve the problem, and it did.  

Treating ion channel dysfunctions (channelopathies) in autism clearly is not rocket science; it is just waiting to be attempted.

Medicinal Psychedelics for Neuroinflammatory conditions - Depression, Severe Headaches, OCD, Addiction and Autism

 

62 clinical trials with Psilocybin are registered

Today’s post is about treating a wide range of conditions that share neuroinflammation in common, by targeting the serotonin receptor 5-HT_2A.

Severely disabling cluster headaches, that were seen as untreatable, have been resolved by monthly micro dosing with psilocybin.

Psilocybin is a naturally occurring prodrug compound produced by more than 200 species of fungus, including magic mushrooms. Psilocybin is quickly converted by the body into Psilocin.

 

Psilocin Binding Profile
Target	Affinity	Species
	Ki (nM)
SERT	3,801.0	Human
5-HT1A	567.4	Human
5-HT1B	219.6	Human
5-HT1D	36.4	Human
5-HT1E	52.2	Human
5-HT2A	107.2	Human
5-HT2B	4.6	Human
5-HT2C	97.3	Rat
5-HT3	> 10,000	Human
5-HT5	83.7	Human
5-HT6	57.0	Human
5-HT7	3.5	Human

 

 

“The neurotransmitter serotonin is structurally similar to psilocybin.

Psilocybin is rapidly dephosphorylated in the body to psilocin, which is an agonist for several serotonin receptors, which are also known as 5-hydroxytryptamine (5-HT) receptors. Psilocin binds with high affinity to 5-HT_2A receptors and low affinity to 5-HT₁ receptors, including 5-HT_1A and 5-HT_1D; effects are also mediated via 5-HT_2C receptors.

Various lines of evidence have shown that interactions with non-5-HT₂ receptors also contribute to the subjective and behavioral effects of the drug. For example, psilocin indirectly increases the concentration of the neurotransmitter dopamine in the basal ganglia, and some psychotomimetic symptoms of psilocin are reduced by haloperidol, a non-selective dopamine receptor antagonist.

Taken together, these suggest that there may be an indirect dopaminergic contribution to psilocin's psychotomimetic effects. Psilocybin and psilocin have no affinity for dopamine receptor D2, unlike another common 5-HT receptor agonist, LSD. Psilocin antagonizes H1 receptors with moderate affinity, compared to LSD which has a lower affinity.”

  

A Canadian company, Pilz Bioscience, is trialing its version of psilocybin to treat autism.

We already know that micro dosing of Lysergic acid diethylamide (LSD) promotes social behavior via 5-HT_2A/AMPA receptors and mTOR signaling.

  

The FDA is already onside

For those worrying about the law, the FDA is well aware of the therapeutic potential of low dose psychedelics like Psilocybin, and indeed LSD. 

FDA Grants Psilocybin Second Breakthrough Therapy Designation for Resistant Depression

The US Food and Drug Administration (FDA) has granted the Usona Institute breakthrough therapy designation for psilocybin for the treatment of major depressive disorder (MDD).

 

For really motivated readers, click on the link below to read the details of Psilocybin

https://www.usonainstitute.org/wp-content/uploads/2020/08/Usona_Psilocybin_IB_V3.0_08.31.2020_cc.pdf

   

Nova (Pilz Bioscience) Launches Preclinical Autism Spectrum Disorder Therapeutic Study

 

A treatment phase with its proprietary psilocybin compound is scheduled to begin in February 2021.    

https://pilzbioscience.com/

 

PILZ BIOSCIENCE

INNOVATION IN ASD

Though ASD symptoms are diverse, underlying causes converge on common biological mechanisms, priming development of a new approach to diagnostics and treatment. Scientific studies suggest a strong association between ASD and inflammation, as well as ASD and microbiota in the gut. Likewise, parallels exist between social cognition in autism and some of the key behavioral elements already being treated with psychedelic therapy.

 

 

 

 

Micro dose LSD for Autism? via activation of 5-HT_2A/AMPA/mTORC1

  

LSD may offer viable treatment for certain mental disorders

Researchers from McGill University have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, are published in the journal PNAS.

Psychedelic drugs, including LSD, were popular in the 1970s and have been gaining popularity over the past decade, with reports of young professionals claiming to regularly take small non-hallucinogenic micro-doses of LSD to boost their productivity and creativity and to increase their empathy. The mechanism of action of LSD on the brain, however, has remained a mystery.

The researchers note that the main outcome of their study is the ability to describe, at least in rodents, the underlying mechanism for the behavioural effect that results in LSD increasing feelings of empathy, including a greater connection to the world and sense of being part of a large community. "The fact that LSD binds the 5-HT_2A receptor was previously known. The novelty of this research is to have identified that the prosocial effects of LSD activate the 5-HT₂ receptors, which in-turn activate the excitatory synapses of the AMPA receptor as well as the protein complex mTORC1, which has been demonstrated to be dysregulated in diseases with social deficits such as autism spectrum disorder,” as specified by Prof. Nahum Sonenberg, Professor at the Department of Biochemistry of McGill University, world renowned expert in the molecular biology of diseases and co-lead author of the study.

  

Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

Significance

Social behavior (SB) is a fundamental hallmark of human interaction. Repeated administration of low doses of the 5-HT_2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT_2A and AMPA receptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1, a protein involved in the modulation of SB. Moreover, the inactivation of mPFC glutamate neurotransmission impairs SB and nullifies the prosocial effects of LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic, but not in inhibitory neurons, to produce prosocial effects. This study unveils a mechanism contributing to the role of 5-HT_2A agonism in the modulation of SB.

Abstract

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT_2A, but not N-methyl-D-aspartate (NMDA) and 5-HT_1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor^f/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT_2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor^f/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT_2A/AMPA receptors and mTOR signaling. The activation of 5-HT_2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

   

D-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

Figure 1. D-Lysergic Acid Diethylamide (LSD) acts at different brain regions with a pleiotropic mechanism of action involving serotonin 5-HT1A, 5-HT2A, 5-HT2C, and dopamine D2 receptors in the Dorsal Raphe (DR); dopamine D2 receptor and Trace Amine Associate (TAAR1) receptors in the Ventral Tegmental area (VTA); and 5-HT2A in the Locus Coerules (LC). These three nuclei project to the prefrontal cortex (PFC), enhancing or inhibiting the release of neurotransmitters and ultimately medicating the psychotic-like effects and cognitive changes. mPFC: medial prefrontal cortex (mPFC); NMDA(NR2B): N-methyl-D-aspartate (NMDA) receptor subunit NR2B.

  

LSD vs Psilocybin

LSD and psilocybin have effects that overlap, but they are not identical.  Both are used by sufferers to treat cluster headaches. 

Why does low dose psilocybin provide long lasting protection from cluster headaches?  These headaches are often thought to be driven by ion channel dysfunctions (channelopathic).  Does psilocybin, or indeed LSD, directly or indirectly affect ion channels?  Nobody knows.

Regular readers will know that certain calcium/sodium channels are implicated in autism, epilepsy and MR/ID.  Some of these same ion channels are also associated with headaches.  So no surprise that some people with a mutation in one of these genes have additional problems to autism. 

 

Are all types of migraine channelopathies?

Familial hemiplegic migraine (FHM) is characterized by migraine attacks, which is with transient, unilateral motor weakness as its episodic aura. FHM is an autosomal dominant migraine, three encoding protein genes have been identified: CACNA1A encodes α1 subunit of calcium channel Cav2.1, ATP1A2 encodes α2 subunit of Na+/ K+-ATPase pump, and SCN1A encodes α subunit of sodium channel Nav1.1. All these proteins are specially expressed on nervous system, and all the mutations mainly cause brain dysfunction. Series studies on FHM indicated that mutations on Cav2.1 and ATP1A2 increased the concentration of glutamate in synapses and disturbed the excitatory and inhibitory balance, which induced the brain dysfunction. Although the same result has not yet been concluded firmly enough from the functional studies on sodium channels (Nav1.1) owe to the more perplexed expression and structure of Nav1.1 and its encoding gene SCN1A, it firmly concluded that all the mutations of the three genes cause brain dysfunction. All above indicate that FHM is a definitely channelopathy. Are other types of migraine channelopathies?

  

Conclusion

Tiny doses of psilocybin (magic mushrooms) have been used for years by a small number of people with severe headaches.  These headaches are not your typical migraine, they are totally disabling. Note that large doses of Psilocybin frequently cause headaches.

It appears that the same therapy has an effect on other neurological conditions ranging from depression to autism.  Take a look at all the trials to date:

https://clinicaltrials.gov/ct2/results?recrs=&cond=&term=psilocybin&cntry=&state=&city=&dist=

We know from anecdotes that many Aspies feel better when they activate the serotonin receptor 5-HT_2A, but I suspect that may “overshoot” with dosing. It is a non-hallucinogenic effect that we are looking for.  The dose can be as little as a micro dose once a month.

Genuinely effective micro dosing is very attractive, because it is likely to be very safe and indeed very cheap.  Intermittent micro dosing, if therapeutic, would be even better.  

Clearly, a standardized drug like PLZ-1013 from Pilz Bioscience is what many people will want.  It is very encouraging that these researchers and those at McGill University and the Usona Institute have engaged themselves.  But, prepare to wait a decade or two.

It is a pity we have to wait so long; LSD was first used as an autism therapy before I was born. LSD was then made a banned substance.  Clearly back in the days that Professor Lovaas was giving LSD to people with autism at UCLA in the 1960s, he was using the “wrong” dose, but he might have eventually stumbled upon the micro dose.  Here we are almost 60 years later, still with anecdotes.  Roll on the clinical trial of PLZ-1013.