Pentoxifylline – Clearly an Effective add-on Autism Therapy for some

 

They also had Pentoxifylline for autism back in the 1970s – time for a revival?

 

Pentoxifylline and other more modern PDE inhibitors have been mentioned many times in this blog.

https://epiphanyasd.blogspot.com/search/label/PDE4

https://epiphanyasd.blogspot.com/search/label/Pentoxifylline

Pentoxifylline has been used in autism clinical trials dating back almost 50 years. A casual observer would naturally assume it cannot possibly be effective, or else surely its use would have caught on by now.

Some readers have long been using a PDE inhibitor as part of their child’s autism polytherapy. People have been asking me to let them know my thoughts on Pentoxifylline, the most accessible PDE inhibitor.

I think the key is that we are talking about an add-on, or adjunct, therapy.  We are no longer talking about pentoxifylline therapy vs no therapy, as they were in the 1970s.  Even in those decades-old studies there was a sub group of “super responders”.  Either the percentage of such responders, or the “super-response” itself was just too small to create waves leading to wider adoption.

In my autism world, I had been trying to develop more expressive language using sulforaphane and calcium folinate (leucovorin). A comment from Valentina prompted me to finally start my trial of Pentoxifylline.  It became apparent that the amount of expressive language was increasing, but the major factor was the Pentoxifylline not the calcium folinate (leucovorin).  To avoid GI side effects, I give Pentoxifylline after meals, which means it does sometimes get omitted/forgotten. It emerged that expressive language was clearly correlated to whether Pentoxifylline was taken or forgotten.

Reviewing the old studies, increased use of language does get a mention as an effect of Pentoxifylline.

 

What is the biological effect of Pentoxifylline?

Pentoxifylline is a non-selective PDE inhibitor, which you might think is a bad thing, since it looks like is it just PDE4 that we want to inhibit.

Pentoxifylline is also a non-selective antagonist of adenosine receptors A₁ and A_2A that are located in both the heart and brain.  These two adenosine receptors have important roles in the brain, regulating the release of other neurotransmitters such as dopamine and glutamate.

Pentoxifylline is normally prescribed because of its effects on your blood.  It improves red blood cell deformability, reduces blood viscosity and decreases the potential for platelet aggregation and blood clot formation.  So not a bad potential drug for the effects of severe Covid (which causes "sticky" blood), or indeed the extremely rare negative reaction to Astra Zeneca’s vaccine reported in Norway.  I had my Astra Zeneca Covid shot last week and Monty will be having his. Even young children with severe autism have been vaccinated where we live, at the parents' insistence. It looks like crossing international borders is going to to be much easier with proof of vaccination, so even if you had the virus the vaccine is useful.  Most people we know have had the virus, since where we live public policy was more towards protecting livelihoods than lives.  A lack of obesity and very old people kept the death rate quite low.  Now we seem to have more vaccines than demand for them.

Studies show that Pentoxifylline increases blood flow to the brain.  We know that blood flow to the brain in autism is impaired; the research describes it as unstable rather than just weak.

It sounds like Pentoxifylline is a polytherapy in itself, it has so many effects possibly relevant to autism.

 

Are Ibudilast and Roflumilast/Daxas an alternative to Pentoxifylline?

This question has come up already in the comments section.

We know that Ibudilast and Roflumilast are much more selective for PDE4 than Pentoxifylline.  We know that both Ibudilast and Roflumilast have interesting effects on the brain.

Pentoxifylline has some potentially beneficial effects that are not shared by Ibudilast or Roflumilast.  Pentoxifylline is cheap and proven safe in a series of trials in young children. 

I think that the typical autism dose of Pentoxifylline, 200mg twice a day, likely does not provide the effect on PDE4 provided by the small dose of Roflumilast/Daxas used in trials to improve cognition and sensory gating.

I think you would need to trial the drugs separately and, if they indeed provide a benefit, find the effective combination.  

So far I have trialed the 100 mcg dose of Roflumilast/Daxas on myself to check for GI side effects and see if it affects how thoughts and sensory inputs are processed, as the research suggests it does. I think it does indeed have the cognitive effects, but in me personally the GI effects also appear.  Some readers have told me this 100 mcg dose works for Aspies, and without side effects.

Some readers have tried Ibudilast.

Ling favours Pterostilbene, a natural PDE4 inhibitor. Pterostilbene has many other modes of action, including relating to inflammation, diabetes, aging and even cancer.

  

Conclusion 

Polytherapy is becoming fashionable these days and it is about time too.  Here it is all about MS (Multiple Sclerosis):-

 

UK to test existing drugs as treatment for MS in world-first trial

“Ultimately, MS will be treated with a combination of drugs,” said Gray. “You’ll have immunomodulatory drugs and anti-inflammatory drugs that stop the immune attacks, and they will be combined with treatments that can protect nerves from damage, and treatments that can repair the damaged myelin. That should stop MS.”

 

Each drug, given individually, will not deliver a dramatic result, but in combination the effective can be substantial.

Autism also requires polytherapy.  A few small steps can take you a large stride forwards. 

I did once consider using the analogy of fixing an old car, but I thought people might not like it and also autism develops very early in life not at the end; but Professor Ramaekers used the analogy on me, so I will follow suit.

You may need to fix many things on an old car, to get it back to its former glory.  The more problems you fix, the better the result will be.  You just have to start and keep on going.

In autism, and car restoration, the order in which you fix things does matter.  You probably need to learn this the hard way.

In a near perfect car (Asperger’s) really small issues, like faulty electric windows or squeaky suspension, can be extremely annoying, though the car remains perfectly functional; it gets you from A to B.

Pentoxifylline, by itself, is not going to “cure” anyone’s autism, but for some people it will be another step in that direction.

 

Another old idea has resurfaced - sodium phenylbutyrate (shortened to NaPB).

I think this drug was used for completely the wrong reasons, by a tiny number of people, a decade ago, but now common mouse models of autism are showing that this pan-HDAC inhibitor and ER-stress inhibitor has potent beneficial effects.  It is changing gene expression via an epigenetic mechanism.

If you look on Google, it appears as another quack therapy.

Four autism treatments that worry physicians – LA Times in 2009

Four that worry physicians. The Chicago Tribune examined four treatments in depth. Medical experts said that the therapies have not been proved to help children with autism and that each also carries risks. 

#4 Phenylbutyrate

Kennedy Krieger Institute: “No research conducted into use for autism.” -- Trine Tsouderos and Patricia Callahan

 

https://www.chicagotribune.com/lifestyles/ct-xpm-2009-11-23-chi-autism-science-nov23-story.html

Patricia Kane, who calls herself "the queen of fatty acid therapy," initially sounds like a skeptic of alternative autism treatments. She distances herself from the Defeat Autism Now! approach and says hyperbaric oxygen therapy, IVIG and chelation drugs all can be harmful.

"If you could see what happens to children when they're given some of these crazy interventions that ruin their life, and it's so painful," said Kane, whose office is in New Jersey. "Parents say, 'Patricia Kane will tell us the truth,' and I believe parents deserve the medical truth when it comes to their children."

One of her fans is Kent Heckenlively, a California science teacher who writes for ageofautism.com, self-described as the "daily web newspaper of the autism epidemic." After spending "a couple of hundred thousands" on treatments, from chelation to stem cell therapy, for his daughter with autism, Heckenlively said Kane appealed to him in part because her protocol includes lab tests run by the prestigious Kennedy Krieger Institute.

"I can trust them, I think," Heckenlively said.

Kane, who points to neuroinflammation as a feature of autism, discusses Pardo's study in a chapter she co-wrote on autism treatments for the book "Food and Nutrients in Disease Management."

Kane says many children with autism have a buildup in their brains of a substance called very-long-chain fatty acids. Her "PK Protocol" -- named after her initials -- is aimed at burning them off with a prescription drug, phenylbutyrate, that is normally used to treat extremely rare genetic disorders in which ammonia builds up in the body.

Side effects of phenylbutyrate include vomiting, rectal bleeding, peptic ulcer disease, irregular heartbeat and depression. No clinical trials have evaluated this drug as an autism therapy, and the idea that very-long-chain fatty acids have a role in autism is not proven by science.

Kane is not a medical doctor. When treating children with autism, she says, she works in concert with the child's physician, who supervises treatment.

She said she holds a doctorate in nutrition that was issued by Columbia Pacific University, an unaccredited institution that was shut down after a lengthy court battle with the state of California. An administrative law judge in 1997 found that the school awarded excessive credit for prior experiential learning, failed to employ qualified faculty and didn't meet requirements for issuing degrees.

Kane said Columbia Pacific granted her a doctorate after the school "consolidated my work," which Kane described as "clinical work" and continuing medical education courses for doctors. Her doctorate is valid, she said, because it was issued before the university ran into problems with the state.

Last year she was the subject of a television news investigation about her work with patients with ALS, also known as Lou Gehrig's disease. The disease, which affects motor neurons, is a death sentence.

but now in 2021, things have changed:-

 

Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism

We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)–induced mouse model of autism

These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

Correcting miss-expressed genes is the holy grail for the treatment of many diseases and in particular for all those parents whose child has a single gene type of autism.  In this blog I also call them DEGs (differentially expressed genes); everyone with autism has some DEGs. There is a lot in this blog about HDAC inhibitors, these can modify gene expression via the epigenome.  HDAC inhitors therefore can potentially fix DEGs.  NaPB was approved 25 years ago by the FDA to treat urea cycle disorders and is used in children over 20 kg.  It is not cheap and as usual it is much more expensive in the United States, at a high dose it is crazily expensive like cancer drugs, many of which are also HDAC inhibitors.  NaPB is another bulk chemical they put in tablets and multiply that cost by whatever they feel like. There is a reaction against this trend in some countries, for example using cheap generic Potassium Bromide for Dravet syndrome, instead of the overly expensive tablets. 

NaPB is used off-label to treat ALS/motor neuron disease.

 

Ski Weekend

 

Monty has been skiing for many years, after a shaky start when he was 5 years old.  He went to a small ski school in Austria where they only teach kids with special needs. The Porsche family own the ski lifts in Zell am See and give the school free tickets, so at least you don’t have to pay for that part.  Skiing is never cheap, but our local slopes are less than four hours drive away and those one-to-one lessons are a fading memory.

Big brother had gone for a week skiing with his friends and he stayed on so he could accompany Monty for 3 days of skiing.

Even though Monty is actual a very safe skier, people tend not to believe it and they think he must have constant supervision.  In reality, he goes up the ski lift with his brother and he can make his way down entirely by himself.  His brother takes him to all the slopes but mainly the black ones (the hardest), far out of sight of their parents.

This year Monty was on skis and his brother was learning snowboarding; Monty was the one arriving first at the bottom.

To be honest, years ago it was really difficult to ski - the boots, the helmet and all the different kinds of ski lift to get used to.  Some people thought I was mad to be encouraging it.  Now skiing is all instinctive, no need for lessons or even reminders.  The myelin is well and truly doing its job.

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.