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Showing posts with label headache. Show all posts
Showing posts with label headache. Show all posts

Monday 1 March 2021

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-HT2A.

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-HT2A receptors and low affinity to 5-HT1 receptors, including 5-HT1A and 5-HT1D; effects are also mediated via 5-HT2C 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-HT2A/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-HT2A/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-HT2A 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-HT2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT2A 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-HT2A 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-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, 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 (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/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 (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/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-HT2A, 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.












Friday 5 February 2016

Propranolol, Autism and Sodium Ion Channels Nav1.1, Nav1.2, Nav1.3 and Nav1.5









When writing this blog I frequently wonder what happened to all the very clever people; why are these full-time paid researchers often missing the obvious?







Boy with severe headache and ASD, awaiting Propranolol


The answer is, with a few notable exceptions (Catterall, Ben-Ari etc), the clever ones do not study autism, they study things that are much better defined, rare things like Angelman Syndrome and, recently, Pitt-Hopkins Syndrome.  These researchers seem much more rigorous.  For example:-


David Sweatt (Pitt Hopkins)

Pitt–Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription



Edwin Weeber (Angelman syndrome)



So autism is left to what might be termed the Baron Cohen brigade.



Propranolol

Propranolol is a medication of the beta blocker type.  It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, performance anxiety, and essential tremors. It is used to prevent migraine headaches, and to prevent further heart problems in those with angina or previous heart attacks.

It is a nonselective beta blocker which works by blocking β-adrenergic receptors.

While once a first-line treatment for hypertension, they do not perform as well as other drugs, particularly in the elderly, and evidence is increasing that the most frequently used beta blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.

Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine(noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. Some block all activation of β-adrenergic receptors and others are selective.

It is occasionally used to treat performance anxiety.   Given the effect (above) on the fight or flight response this is logical.

The sympathetic nervous system's primary process is to stimulate the body's fight-or-flight response. It is, however, constantly active at a basic level to maintain homeostasis.

Evidence to support the use in other anxiety disorders is poor.

But what the ever useful Wikipedia almost glosses over is the part I find more interesting:-



  
Now we have to hope that cardiologists prescribing Propranolol are fully aware of the role of Nav1.5 in the heart and its role in heart rate.  This has nothing to do with it being a beta blocker.

Hopefully neurologists prescribing it for certain severe headaches understand the role of Nav1.1 in the brain.

It would not surprise me if they did not.



Propranolol earlier in this Blog

Earlier in this blog there are comments regarding the use of low doses of Propranolol to treat anxiety in autism.

Some people report it works wonders, while for others it did nothing.


  


Propranolol in Autism Research


A study was published recently and a reader drew my attention to it, but there have also been a few others.

Blood pressure medicine may improve conversational skills of individuals with autism


An hour after administration, the researchers had a structured conversation with the participants, scoring their performance on six social skills necessary to maintain a conversation: staying on topic, sharing information, reciprocity or shared conversation, transitions or interruptions, nonverbal communication and maintaining eye contact. The researchers found the total communication scores were significantly greater when the individual took propranolol compared to the placebo.
"Though more research is needed to study its effects after more than one dose, these preliminary results show a potential benefit of propranolol to improve the conversational and nonverbal skills of individuals with autism," said Beversdorf

  

Effect of propranolol on verbal problem solving in autism spectrum disorder


Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study




Back to Channelopathies

There are 24,000 human genes, but a much more manageable number of ion channels.  For each ion channel or transporter, there is a gene that expresses it.

When ion channels malfunction, it is called a channelopathy.  Channelopathies are quite well researched and very common in autism.  Early on in this blog I simplified idiopathic classic autism with the following chart.

I suspect that people with channelopathies (Nav1.1, Nav1,2, Nav1.3) caused by dysfunctions in the genes SCN1A, SCN2A, SCN3A are the ones that will most benefit from Propranolol.

I suspect those people will already suffer terrible headaches and/or seizures.

These three channelopathies have been known to be associated with autism for ten years.









Nav1.1 / SCN1A


Migraine, other headaches
Epilepsy


Regular readers will know that Professor Catterall is the expert on sodium channels and here he is again below




Nav1.2 / SCN2A

http://ghr.nlm.nih.gov/gene/SCN2A

Epileptic encephalopathy, early infantile, 11 (EIEE11): An autosomal dominant seizure disorder characterized by neonatal or infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG


Nav1.3 / SCN3A


neuronal hyperexcitability and epilepsy 

         Novel SCN3A variants associated with focal epilepsy in             children.





Nav1.5 / SCN5A

http://ghr.nlm.nih.gov/gene/SCN5A

Mainly heart conditions, since this ion channel is expressed mainly in the heart.




Autism and Nav1.1, Nav1.2, Nav1.3

For many years it has been known that the hundreds of variations in the genes SCN1A, SCN2A and SCN3A are associated with autism.  So we can consider them pretty well established autism genes.

Clearly any drug affecting expression of those genes, or affecting the ion channels they express, should be a target autism drug.






Conclusion

Some people with autism and severe headaches, or epilepsy, have an underlying sodium channelopathy.  Sodium channel blockers are not as well understood/ developed as calcium channel blockers.

In some cases, but maybe not all, this should be detectable by genetic testing of the genes SCN1A, SCN2A and SCN3A.

If you live in a country that does not bother with genetic testing, you might want to fall back on trial and error and discuss Propranolol with your doctor.

Did all the people with Asperger’s, in the recent study, who became more conversational after a single dose of Propranolol, have problems with Nav1.1, Nav1.2 or Nav1.3 ?  I doubt it.  The other commonly known effects of Propranolol should also play a role.

But for a sub-set of people with Strictly Defined Autism, Propranolol might be hugely beneficial.  Perhaps Professor Catterall should investigate?