Time for T? Targeting language-associated gene Cntnap2 with a T-type calcium channel blocker corrects hyperexcitability driving sensory abnormalities, repetitive behaviors, and other ASD symptoms, but will it improve language? Will it also benefit Pitt Hopkins syndrome (PTHS) and broader autism?

 

  

 

There are at least 2 Natasas I can think of who will like this post.

Today’s post revisits the subject of calcium channels in autism.  Ion channel dysfunctions are a favourite area of mine because many should be treatable by repurposing safe, existing drugs. I do take note that many readers of this blog have reported success by targeting L-type calcium channels.

Many years ago, at the start of this blog, I recall reading about Timothy syndrome and a researcher at Stanford, Ricardo Dolmetsch, who was exploring treatment using a T-type calcium channel blocker.  It turned out that he had a son with severe autism, which was driving his interest at that time. He won all kinds of awards, but I always wondered why he did not treat his own son.

It is quite strange because Timothy syndrome is caused by a gain of function of an L-type channel. This mutation causes the Cav1.2 channel to fail to inactivate properly after opening. As a result, there is prolonged calcium influx into cells.

Instead of blocking Cav1.2, the researchers blocked the T-channels Cav3.2 and 3.3.

I did my homework on idiopathic autism a dozen years ago and concluded I needed to block Cav1.2. I went ahead and did it – it works like a charm.

It was a real drama back in those days, with self-injury and aggression, so Timothy syndrome and T channels remains stuck in my mind a decade later.

 

Language Genes

Even before parents worry about self-injurious behavior (SIB), they go through the phase of worrying about if their child will ever speak. Some do and some do not.  What really matters is communication, rather than speech.

 

FOXP2 - The language Gene

FOXP2 is a transcription factor involved in the development of neural circuits related to speech and language production, particularly in areas such as the basal ganglia and cerebellum. Mutations in FOXP2 can lead to speech and language deficits.

FOXP2 influences motor control and vocalization processes that are critical for speech, and it is thought to have evolved specifically in humans to support complex language abilities.

 

CNTNAP2 - The language-associated gene

CNTNAP2 (Contactin-associated protein-like 2) is a gene that encodes a cell adhesion protein. It plays a critical role in the development of neural connectivity and the formation of synapses in areas of the brain involved in language, such as the broca’s area and temporal lobes. CNTNAP2 is also involved in the regulation of neuronal excitability and is crucial for the development of white matter tracts that connect language-related brain regions.

Mutations in CNTNAP2 have been implicated in neurodevelopmental disorders such as specific language impairment (SLI), autism, and developmental language disorders.

 

FOXP2 and CNTNAP2 Interaction

FOXP2 and CNTNAP2 work together in the development of the neural circuits that are crucial for language and speech. They are both involved in the formation and maintenance of synaptic connections in key brain regions like the cortex, basal ganglia, and cerebellum, which are critical for motor control, vocalization, and language processing.

There is evidence to suggest that FOXP2 may regulate the expression of CNTNAP2 as part of a broader gene network that governs language development. FOXP2 may influence CNTNAP2 gene expression, which in turn impacts neural connectivity and synaptic function in brain regions responsible for speech and language.

 

CNTNAP2 sounds familiar?

We have come across this gene before.

At least one reader has a child with a mutation in this gene.

We also discovered that the Pitt Hopkins gene TCF4 regulates CNTNAP2 and that

“PTHS (Pitt Hopkins syndrome) is characterised by severe intellectual disability, absent or severely impaired speech, characteristic facial features and epilepsy. Many of these features are shared with patients carrying CNTNAP2 mutations, leading researchers to test patients with PTHS-like features for CNTNAP2 mutations”

Several readers have children with PTHS (Pitt Hopkins syndrome).

It is not inconceivable that what works for CNTNAP2 will also work for at least some PTHS (Pitt Hopkins syndrome).

The question is whether what works for CNTNAP2 will work much more broadly and could it even improve language development?

Here is the recent research from Stanford:

 

Reticular Thalamic Hyperexcitability Drives Autism Spectrum Disorder Behaviors in the Cntnap2 Model of Autism

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by social communication deficits, repetitive behaviors, and comorbidities such as sensory abnormalities, sleep disturbances, and seizures. Dysregulation of thalamocortical circuits has been implicated in these comorbid features, yet their precise roles in ASD pathophysiology remain elusive. This study focuses on the reticular thalamic nucleus (RT), a key regulator of thalamocortical interactions, to elucidate its contribution to ASD-related behavioral deficits using a Cntnap2 knockout (KO) mouse model. Our behavioral and EEG analyses comparing Cntnap2^+/+ and Cntnap2^-/- mice demonstrated that Cntnap2 knockout heightened seizure susceptibility, elevated locomotor activity, and produced hallmark ASD phenotypes, including social deficits, and repetitive behaviors. Electrophysiological recordings from thalamic brain slices revealed increased spontaneous and evoked network oscillations with increased RT excitability due to enhanced T-type calcium currents and burst firing. We observed behavior related heightened RT population activity in vivo with fiber photometry. Notably, suppressing RT activity via Z944, a T-type calcium channel blocker, and via C21 and the inhibitory DREADD hM4Di, improved ASD-related behavioral deficits. These findings identify RT hyperexcitability as a mechanistic driver of ASD behaviors and underscore RT as a potential therapeutic target for modulating thalamocortical circuit dysfunction in ASD.

Teaser RT hyperexcitability drives ASD behaviors in Cntnap2-/- mice, highlighting RT as a therapeutic target for circuit dysfunction.

 

Overall, this study identifies elevated RT burst firing and aberrant thalamic oscillatory dynamics in Cntnap2^−/− mice as a key driver of ASD-related behavioral deficits. If this is a common mechanism of ASD-circuit pathology arising from a variety of genetic causes, then compounds such as Z944, or subtype specific T-type calcium channel antagonists that would target the Cav3.2 and Cav3.3 expressed in RT neurons, might be an effective therapeutic strategy. Furthermore, future research should focus on elucidating RT’s roles in sensory, emotional, and sleep regulation to optimize therapeutic strategies in the context of ASD.

 

Existing T-type calcium channel blockers for humans

Mibefradil is one of the most well-known T-type calcium channel blockers. It was initially developed for hypertension and angina because of its ability to block T-type channels. However, mibefradil was withdrawn from the market in 1998 due to serious drug interactions with other medications, particularly those that inhibit liver enzymes involved in drug metabolism, like statins.

Despite its withdrawal, mibefradil has been studied for other potential uses, including in epilepsy and chronic pain, due to its effects on neuronal excitability.

Zonisamide is an anticonvulsant medication that has some T-type calcium channel blocking properties. It is approved for epilepsy and partial seizures, but it is not typically used specifically for Timothy syndrome or conditions involving T-type channel dysfunction.

Zonisamide is also used to treat seizures in pet dogs and cats.  

Zonisamide: chemistry, mechanism of action, and pharmacokinetics

Zonisamide is a novel antiepileptic drug (AED) that was developed in search of a less toxic, more effective anticonvulsant. The drug has been used in Japan since 1989, and is effective for simple and complex partial seizures, generalized tonic-clonic seizures, myoclonic epilepsies, Lennox–Gastaut syndrome, and infantile spasms. In Japan, zonisamide is currently indicated for monotherapy and adjunctive therapy for partial onset and generalized onset seizures in adults and children. In the United States, zonisamide was approved by the Food and Drug Administration (FDA) in 2000 as an adjunctive treatment for partial seizures.

The drug’s broad spectrum of activity and favorable pharmacokinetic profile offer certain advantages in the epilepsy treatment armamentarium. Chemically distinct from other AEDs, zonisamide has been shown to be effective in patients whose seizures are resistant to other AEDs. Zonisamide’s long plasma elimination half-life has allowed it to be used in a once-daily or twice-daily treatment regimen in Japan.

It is believed that zonisamide’s effect on the propagation of seizure discharges involves blocking the repetitive firing of voltage-sensitive sodium channels, and reducing voltage-sensitive T-type calcium currents without affecting L-type calcium currents. These mechanisms stabilize neuronal membranes and suppress neuronal hypersynchronization, leading to the suppression of partial seizures and generalized tonic–clonic seizures in humans.

Zonisamide possesses mechanisms of action that are similar to those of sodium valproate, e.g., suppression of epileptogenic activity and depression of neuronal responses. These mechanisms are thought to contribute to the suppression of absence and myoclonic seizures.

  

Conclusion

It would seem that zonisamide should be trialed in:

·        CNTNAP2-related neurodevelopmental disorder

·        Pitt Hopkins syndrome (PTHS)

·        Timothy syndrome

·        Idiopathic/polygenic autism

(But, don’t hold your breath!)

Due to the nature of CNTNAP2 disorder and PTHS, I think the greatest impact will be if given from a very young age. However, we do see improvements with many autism interventions regardless of age.

It is certainly conceivable that even mild autism can benefit from damping down reticular thalamic (RT) hyperexcitability.

If shown effective, zonisamide would join the long list of anti-epileptic drugs (AEDs) “repurposable” to treat certain subtypes of autism.

Calcium channelopathies and intellectual disability

 

Changsha, another big city in China you probably have not heard of

 

Today’s post follows up on the use of calcium channel blockers to treat autism.  This is a subject that I first looked at in this blog several years ago.  One of our readers even wrote a book entirely about this subject.

There has been plenty of research going back a decade or more, but no effort to translate it into common therapy.

By coincidence, one reader recently sent me a list of about 20 suspect genes from her daughter’s tests. 7 are related to just a pair of L-type calcium channels, the suggested action was to take magnesium sulfate. I referred her back to my old posts, particularly since her main concern is self-injury. I have written a great deal about Cav1.2 and self-injury, since it is treatable using Verapamil. 

I think a better interpretation of the genetic testing results would have been to say possible channelopathies in Cav1.2 and Cav1.3.  Given that mutations usually lead to over expression of ion channels, a likely effective therapy would be to block these channels.

Magnesium does act as a calcium channel blocker, among its very many other effects.

Is magnesium sulfate the best choice of Cav1.2 and Cav1.3 blocker?  I doubt it, but at least it is OTC. 

 

Treating Intellectual Disability (ID) rather than Autism

I do often think that we should be talking more about treating ID rather than autism.

Who would object to treating ID? Hopefully nobody.

Today’s paper is about treating intellectual disability (ID) and global developmental delay (GDD).

Almost all people with level 3 autism could also be described as ID + GDD.

Level 3 autism = ID + GDD

We also have IDD which is Intellectual and Developmental Disability.

Too many names for the same thing, if you ask me.

The paper below from Changsha, China starts with the hypothesis that:-

Calcium Channels play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD.

The paper is published in the  Orphanet Journal of Rare Diseases.

2.3% of the general population have an IQ less than 70 and so have intellectual disability (ID).  ID is not really rare. More than 1 million people in the United States have intellectual disability (ID). 

There are many different processes involved in intellectual disability (ID).  On the one hand that makes it complicated, but on the other hand that means there are many options beyond just L-type calcium channels blockers.

The paper below is really only looking and at Cav1.2 and Cav1.3.  As I pointed out in my previous post, there is much more to it than just this pair.

On the bright side, at least some people in China are looking at this.

  

Calcium channelopathies and intellectual disability: a systematic review

Background

Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.

 

Main body

A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.

 

Conclusion

Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

 

Discussion

Overall, this condition seems to be progressive, however, most primary authors provided less information on the course of the disease. Many of the reported cases with electrophysiological studies had gain-of- function variants. Severe to profound ID/GDD was more predominant for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. The possible reasons as why these genes associated with more severe phenotype include (1) the neuronal location of the genes; all of them are located in the pre-synaptic membrane, (2) brain distribution; most of them are distributed in the brain cortex and/or hippocampus and/or cerebellum, (3) function of the genes; they all regulate the release of neurotransmitter, and (4) the effect of the variants; most of the reported variants in these genes had gain-of-function property. This review has also revealed some hotspots for future research.

  

Conclusion

Gain of function of Cav1.2 and Cav1.3 continues to be well documented in the literature.  That means too much calcium (Ca²⁺ ) entering neurons, from outside.

Note that inside cells/neurons you have a store of Ca²⁺ in something called the Endoplasmic Reticulum (ER). There is supposed to be a high level of Ca²⁺ inside the ER.  When things go wrong, there can be ER stress and Ca²⁺ may get pushed out, or too much Ca²⁺ may be let in. ER stress plays a role in many diseases including autism. In autism the channel implicated is called IP3R. ER stress ultimately leads to cell death. This is the mechanism behind how people with diabetes stop producing insulin. ER stress in the beta cells in their pancreas caused the beta cells to die. No beta cells means no insulin. In such people very prompt treatment by blocking Cav1.2 stops the beta cells dying.

The people seeing a benefit from blocking Cav1.2 and/or Cav1.3 in someone with autism, ID, IDD, GDD, ADHD, epilepsy, SIB, or chronic headaches etc, have science on their side.  It is not just Chinese science; it is science from everywhere.

Note that ion channel dysfunctions can be genetic (they show up on genetic tests) or they can be acquired (they do not show up on testing).

The open issue is what is the most effective therapy.  This is going to vary from person to person, but it is unlikely to be magnesium sulfate.

Magnesium is an important mineral to get from a healthy diet, but it has many effects including blocking NMDA receptors.  This effect might be good or it might be bad. High doses of magnesium supplements will cause GI problems. Most people lack magnesium so a little extra would seem fine, but using enough to block calcium channels may not be wise.

Blocking Cav1.3 will Amlodipine should be the subject of a clinical trial.

Blocking Cav1.2 with Verapamil should be the subject of a clinical trial.

Maybe in China?

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.