Rethinking the role of serotonin receptor signaling in improving autism symptoms: Prucalopride for a sub-group?

For many years, serotonin has been discussed in autism as though the important question were simply whether serotonin is too high or too low. I wonder whether that is asking the wrong question.

Perhaps the more useful question is: What are the individual serotonin receptors doing? And, more importantly: Is a particular receptor signalling too much or too little in a particular person?

This distinction could be important because different serotonin receptors have very different functions and signalling pathways. Some can be stimulated by agonist drugs, while others can be blocked by antagonists. Even more interestingly, the same receptor might conceivably require opposite treatment directions in different people.

A recent email from a long-time reader prompted me to look at this question much more closely.

 

A remarkable observation from a reader

One of our long-time readers wrote to me about her adult autistic son. He has suffered from severe rages for years. BCAA and Niagen had helped to some extent, and Pantogam helped significantly for a few months, but nothing had provided a lasting solution.

More recently, his gastrointestinal motility deteriorated. The mother wondered whether this physical problem might itself be contributing to his increasingly dark mood. Then something unexpected happened. The doctor gave him a few tablets of prucalopride as a trial.

The result was remarkable. His motility improved almost immediately and, at the same time, his mood became dramatically better. His mother noticed his smile returning and described him as sometimes almost giddy.

When the prucalopride ran out, they switched to Cape Aloe, a herbal laxative. That was not successful. His doctor subsequently prescribed prucalopride again, and again there was a dramatic improvement—not only in GI but also in his mood.

There are obvious limitations to a single observation. But the pattern here is a real off-drug/on-drug rechallenge, not a one-off anecdote: prucalopride on, improvement; prucalopride replaced by Cape Aloe, no improvement; prucalopride restarted, improvement again. That is a meaningfully stronger than a single before-and-after report, even though we still do not know whether the mood improvement was caused directly by prucalopride, by the relief of gastrointestinal dysfunction, or by both.

But there is something about this report that makes it particularly interesting: Prucalopride is a selective 5-HT4 receptor agonist. That means our reader may have provided us with an observation involving a very specific serotonin receptor rather than simply “serotonin.”

 

Not the first mention on this blog

Looking back through years of reader comments, this is not actually the first time prucalopride has come up here. Several readers have independently mentioned it as a helpful prokinetic going back to 2018, when a reader recommended it alongside low-dose erythromycin for a son's motility issues. In 2020, another commenter shared a paper on prucalopride's neuroprotective effects on human enteric neurons. And a reader named Leen described, across two separate updates in 2021 and 2023, resolving years of chronic fatigue, concentration problems, autonomic symptoms and mood swings using a regimen that included prucalopride—explicitly describing it as "a serotonin agonist that works in the gut."

None of these comments were prompted by a question about prucalopride specifically, and none reported the same dramatic rage improvement our most recent correspondent described. But taken together, they mean this is not really an n of 1. It is at least four independent readers, over five years, converging on the same drug and the same broad mechanism—GI motility plus a serotonin-mediated effect on mood or energy—without any of them prompting each other. That kind of unprompted convergence is exactly the sort of signal this blog exists to notice.

 

Prucalopride is now available as a much cheaper generic drug

One practical point is worth mentioning. Prucalopride was originally marketed as a very expensive branded drug, and it was the high cost that prompted the approach to me. However, generic prucalopride is now available in the United States and is dramatically cheaper than the original brand-name product.

This is particularly important because the older generation of 5-HT4 agonists had significant safety problems. They are not good alternatives to Prucalopride for its potential effects inside the brain. Prucalopride was developed as a much more selective 5-HT4 agonist, with a substantially improved safety profile compared with some of the older drugs in this class.

It means that if 5-HT4 turns out to be an interesting biological target, there is already an existing, affordable and relatively selective drug capable of activating it.

 

5-HT4: a receptor connecting the gut and brain

5-HT4 receptors are found extensively in the GI tract, where their activation promotes intestinal motility. But they are also found in the brain. 5-HT4 signalling is involved in neurotransmitter release and has been studied in relation to learning, memory, depression and other CNS functions.

Importantly, 5-HT4 is coupled to Gs (stimulatory G protein), which stimulates adenylyl cyclase and increases intracellular cAMP. The pathway can be represented simply as:

5-HT4 → Gs → adenylyl cyclase → ↑ cAMP

This immediately caught my attention because cAMP is already a recurring theme in the EpiphanyASD research. There may therefore be a connection between three things that might initially appear unrelated: 5-HT4 signalling → cAMP signalling → GI function and brain function.

Human studies have shown that prucalopride can affect brain function and cognition. While prucalopride was designed primarily for peripheral gastrointestinal motility, functional neuroimaging and cognitive studies confirm that it crosses the blood-brain barrier to exert central effects even at standard clinical doses. Existing human studies do not establish prucalopride as an antidepressant or as a treatment for autism, but they do support the idea that 5-HT4 stimulation is capable of producing functional effects in the human brain. That makes our reader’s observation biologically interesting.

 

What about the gut?

5-HT4 is a major regulator of intestinal motility. This means that the improvement could potentially be explained in several different ways:

• Hypothesis 1: The gut improved the brain. Motility had deteriorated. Chronic constipation, discomfort and visceral distress can clearly affect quality of life, sleep and mood. Prucalopride restored motility; his mood improved because he felt physically better.
• Hypothesis 2: Direct CNS effects. Prucalopride activated 5-HT4 receptors in the brain, altering cAMP signalling, neurotransmitter release, neuronal activity or other aspects of brain function. The mood improvement therefore occurred partly independently of the GI improvement.
• Hypothesis 3: Both. This may be the most likely possibility. A single receptor system could affect both sides of the gut-brain axis simultaneously (5-HT4 → intestinal motility and 5-HT4 → CNS signalling). Improving the gut could improve mood and behaviour, while direct CNS effects could potentially contribute further.

There is also an important practical point: Prucalopride is designed to stimulate intestinal motility; it is not simply a passive normalizer of bowel function. Therefore, someone with normal baseline GI function might experience excessive stimulation or loose stools, whereas a person with severe slow transit may experience restoration toward normal function. That makes the baseline phenotype critical.

 

There is already a human autism connection to HTR4

A human genomic study found lower methylation of the HTR4 promoter in children with ASD compared with controls, with the inverse relationship between methylation and age reaching significance specifically in the male ASD cases.

Association of human serotonin receptor 4 promoter methylation with autism spectrum disorder

This is not proof that autistic people have abnormal brain 5-HT4 signalling—the study used peripheral blood rather than brain tissue, was relatively small and requires replication—but it provides a direct human autism association involving the gene encoding the receptor. One caveat worth stating plainly: lower promoter methylation generally predicts higher, not lower, gene expression. Taken at face value, this study points toward more 5-HT4 signalling in ASD, not less—which does not obviously predict that an agonist like prucalopride should help. I don't think that undermines the observation; it is a good illustration of the point made later in this post, that the same receptor could plausibly need opposite treatment directions in different people, and a peripheral blood methylation signal cannot by itself tell us which direction a given individual needs.

So we now have three separate observations:

1.     autism → HTR4 epigenetic association

2.     prucalopride → selective 5-HT4 activation

3.     one autistic adult → striking improvement in motility and mood

 

A remarkable connection: Dup15q syndrome

The story becomes even more interesting when we look at specific genetic neurodevelopmental syndromes. Dup15q syndrome is strongly associated with developmental disability, autism and epilepsy. Recent experimental work in a Dup15q mouse model found gastrointestinal dysmotility and a constipation-like phenotype. The researchers tested prucalopride and found not only improvement in GI transit, but also lower fecal corticosterone (a stress marker) and longer social contact duration in the treated mice. In other words, in this model, restoring 5-HT4-driven gut motility was associated with less stress and more social behaviour—the animal-model version of exactly the gut-to-mood connection our reader described.

This does not show that prucalopride improves autism symptoms or mood in people with Dup15q, but it raises an intriguing hypothesis: Could some autistic people with significant GI dysmotility represent a particularly interesting 5-HT4-responsive phenotype? That is certainly worth investigating.

 

5-HT4 is only one serotonin receptor

This is where the story broadens. There are multiple serotonin receptors, and they do not all do the same thing. A simplified map looks like this: 

5-HT1A → Gi/o → ↓cAMP

5-HT2A → Gq → PLC/Ca²⁺/PKC signalling

5-HT4 → Gs → ↑cAMP

5-HT7 → Gs → ↑cAMP

This immediately suggests that “serotonin” is far too crude a description of the system. Two people could theoretically have completely different problems with serotonin signalling even if their overall serotonin concentrations were identical: one person might have excessive signalling through one receptor, while another might have inadequate signalling through another. This raises a possibility particularly relevant to personalized medicine: Perhaps one person needs a receptor agonist while another needs an antagonist.

 

5-HT2A keeps appearing

5-HT2A is probably the serotonin receptor that has appeared most often in discussions of autism and altered perception. There is a substantial literature concerning 5-HT2A in autism, including genetic and receptor-function studies, alongside a remarkable amount of anecdotal material from autistic adults concerning psychedelic drugs such as psilocybin, which strongly activate 5-HT2A.

The EpiphanyASD material includes readers describing unusual responses to psychedelics, including one person with Asperger's who reported an unusually weak psychedelic response and wondered whether altered receptor biology might explain it. While such observations cannot be taken as proof of altered receptor function, they help generate hypotheses.

It is also important that drugs can move receptor signalling in opposite directions. For example, atypical antipsychotics like aripiprazole and risperidone feature potent 5-HT2A antagonist/inverse agonist activity as part of their complex pharmacology. Because these drugs act on multiple systems—particularly dopamine—we cannot attribute benefits solely to 5-HT2A blockade. However, it highlights how heavily clinical practice has tilted toward blocking this receptor, rarely considering whether baseline signaling might be deficient in certain individuals.

 

5-HT7 may be even more interesting

My investigation of 5-HT7 has produced an unexpected pattern. Like 5-HT4, 5-HT7 is a Gs-coupled receptor (5-HT7 → Gs → adenylyl cyclase → ↑cAMP). There is an increasingly interesting neurodevelopmental literature surrounding this receptor. Experimental activation of 5-HT7 has produced effects on synaptic plasticity, dendritic spines, synaptic protein synthesis, long-term potentiation, and learning and memory.

This is particularly interesting because these processes are disturbed in several genetic neurodevelopmental syndromes associated with autism:

• BTBR autism model: A recent study in BTBR mice found reduced 5-HT7 expression in cortical synaptic material. Selective activation of 5-HT7 with the agonist LP-211 restored synaptic protein synthesis and normalized dendritic spine abnormalities.
• Fragile X syndrome: In Fmr1 knockout mice, 5-HT7 activation reversed abnormalities in hippocampal synaptic plasticity via adenylyl-cyclase-dependent mechanisms, improving learning and behavioural outcomes.
• Rett syndrome: Experimental work in MECP2 models suggests 5-HT7 signaling can modify downstream neuronal plasticity despite the presence of the primary genetic abnormality.
• Angelman syndrome: 5-HT7 stimulation improved synaptic protein synthesis, dendritic spine density, long-term potentiation, and cognitive deficits in an Angelman mouse model.
• Pitt-Hopkins syndrome: TCF4 deficiency alters neuronal development and synaptic function. While 5-HT7 has not yet been directly studied in Pitt-Hopkins models, it represents an ideal system to test whether TCF4 disruption alters HTR7 expression, cAMP production, or downstream PKA/CREB signaling.

These distinct genetic disorders converge on synaptic plasticity and intracellular signaling pathways where serotonin receptors act as modifiable downstream regulators.

Note: 5-HT2A and 5-HT7 each appear twice above because the same receptor can plausibly be pushed in either direction depending on the person—that duality is the whole point of this table, not a typo. The 5-HT7 antagonist row is left without a named drug because selective 5-HT7 antagonists (e.g., SB-269970) remain research compounds only, with no clinically approved option yet.

 

Beyond "High" vs. "Low" Serotonin: A Precision Framework

Measuring overall serotonin levels is far too crude. Two individuals can share identical serotonin concentrations yet have entirely different receptor expression levels, binding sensitivities, or downstream intracellular responses.

This distinction explains why conventional clinical trials often yield inconclusive results. Imagine ten autistic people given a drug that blocks a specific serotonin receptor: if five improve because they have excessive baseline signaling and five deteriorate because they have deficient signaling, the net result in the trial is zero. The intervention is labeled ineffective, missing the critical underlying signal: different biological subgroups require opposite treatment directions.

Moving toward precision pharmacology requires mapping five specific parameters rather than searching for a single "autism neurotransmitter":

• Phenotype: (e.g., severe slow-transit GI dysmotility combined with mood dysregulation)
• Candidate Target Receptor: (e.g., 5-HT4 or 5-HT7)
• Pathway Mechanism: (e.g., Gs coupling → adenylyl cyclase → ↑cAMP)
• Directional Need: (Excessive vs. deficient baseline signaling)
• Targeted Intervention: (Selective agonist vs. selective antagonist)

 

Mapping Natural Experiments

Our reader’s report is not a proven treatment for autism, but it is a powerful hypothesis-generating observation. It connects severe GI dysmotility and severe mood disturbance directly to selective 5-HT4 activation via prucalopride—a mechanism supported by human HTR4 promoter methylation studies and preclinical Dup15q models.

Many readers have shared intriguing observations involving targeted pharmaceuticals, supplements, and 5-HT2A agonists like psilocybin. When examined systematically—preserving the individual context, baseline phenotype, specific agent, dose, duration, and direction of outcome—these natural experiments can help identify potential biomarkers or clinical features that predict whether a person needs signaling at a specific receptor pushed up or pulled down.

The future of serotonin-based interventions in autism will not be about simply raising or lowering global serotonin, but about matching the right receptor signaling direction to the right person.

Note: This post was enriched using the AI copilot to apply the EpiphanyASD knowledgebase and identify relevant reader observations (some of which I had forgotten about).

https://www.epiphanyasd.com/p/ai-copilot.html

The Kynurenine Pathway in Autism and its modification using Sulforaphane or the probiotic Lactobacillus Plantarum 299v

 

 A pathway to somewhere, hopefully

Today’s post was prompted by our reader George’s observation that the probiotic Lactobacillus Plantarum 299v increased speech in his adult son.  This widely available probiotic is commonly used to treat IBS (Irritable Bowel Syndrome) and I did mention it in a recent post about Eubiotics.

Eubiotics for GI Dysfunction and some Autism

Increased speech is a target for many people treating autism and this probiotic is known to be safely used long term - so it is interesting.

Since I already had this probiotic at home, I made a trial and I observed a very similar effect to what happened several years ago when Monty started to use Sulforaphane / broccoli sprout powder. 

The effect of broccoli powder was a brief period of euphoria about 20 minutes later and a then a marked increase in verbalization.  The effect on mood was seen by some other readers, but not the majority. I recall back then a very happy parent who was feeding broccoli powder to his child via a G-tube. A gastrostomy tube, often called a G-tube, is a surgically placed device used to give direct access to your child's stomach for supplemental feeding, hydration or medication.  Some children with autism will not eat and so are fed via a G-tube.

Broccoli powder tastes pretty bad, but this is one problem you will not experience when taking it via a G tube.

I was surprised that even some people with mild autism found broccoli powder beneficial. In diabetics it improves insulin sensitivity and so reduces the amount of insulin they need to inject.

This post is about the science, but before reading all the science, I made my trial of Lactobacillus Plantarum 299v.  One capsule a day works very nicely. The science is optional.

I wondered what might be the shared effect of these two very different therapies - broccoli and L.P. 299v.  There is indeed a plausible explanation, the Kynurenine pathway.

 

Click on the graphic, to enlarge

This may all look rather complicated, but there are some terms we are already very familiar with. We know that Serotonin is the happy hormone and we know that Melatonin is the sleep hormone.

It all starts with Tryptophan, one of those amino acids. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Good sources include milk, turkey and bananas. If you take bumetanide, you likely already eat a lot of bananas due to their potassium content.

95% of tryptophan is metabolized to Kynurenine, a very odd sounding word. So it must be that less than 5% becomes Serotonin and Melatonin. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan.

The so-called kynurenine pathway of tryptophan is altered in several diseases, including psychiatric disorders such as autism, schizophrenia, major depressive disorder and bipolar disorder.

The supplements Tryptophan and 5-hydroxytryptophan (5-HTP) are widely used for many conditions ranging from depression to autism.

 

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD⁺).

 

NAD⁺ is very important.

 

Increasing the level of NAD is itself an autism therapy in the research. 

New Preclinical Study Finds Niagen® Corrects Social Deficits in Mouse Model of Autism

First-of-its-kind preclinical study shows that Niagen® (nicotinamide riboside) resolves social deficits and anxiety-like behaviors in male mice

The amount of Tryptophan that ends up as the cute-sounding Picolinic acid is determined by how much of the enzyme ACMSD is present.

Quinolinic acid (QUIN) and Kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the NMDA receptor. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function. Emphasis has been placed upon the importance of maintaining a balanced ratio between these two metabolites.

Picolinic acid (PIC) also shows antagonistic properties towards the toxic effects of QUIN via an unknown mechanism.  There are a number of biological factors that can potentially affect PIC levels and synthesis in the CNS including age, circadian rhythms and hormonal and nutritional factors.

 

 Source: The Physiological Action of Picolinic Acid in the Human Brain

Anthranilic acid (AA), once thought to be vitamin L, is very elevated in schizophrenia, and also in type-1 diabetes and arthritis.  AA is seen as a treatment target in these conditions. 

Now for the interesting part, the effect of the probiotic Lactobacillus Plantarum 299v on the Kynurenine pathway:

 

Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study

Highlights

· There was an improvement in cognitive functions in group of depressed patients receiving probiotic Lactobacillus Plantarum 299v (LP299v) compared to the placebo group.

 · There was a significant decrease in kynurenine concentration in the LP299v group compared to the placebo group.

 · There was a significant increase in 3-hydroxykynurenine : kynurenine ratio in the LP299v group compared with the placebo group.

· Decreased kynurenine concentration due to probiotic could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group.

  

And, the effect of Sulforaphane on the Kynurenine pathway: 

 

Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, Quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased Quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD.

 

QA = Quinolinic Acid

KP = Kynurenine Pathway

 

The increased concentration of QA in ASD is also likely to be associated with increased oxidative stress. We previously showed that QA can significantly potentiate oxidative stress in human primary neuron cultures and that oxidative stress markers are increased in children with ASD.  Recently, a clinical study effectively used sulforaphane derived from the broccoli sprout to treat ASD resulting in improved behaviour.  Interestingly, sulforaphane was shown to attenuate the effect of QA-induced toxicity in rat brain by enhancing the antioxidant, glutathione. This study is coherent with our current finding of increased QA in children with ASD and our previous work showing decreased glutathione in the children with ASD.  Hence, the possibility that sulforaphane may act by attenuating QA-induce oxidative stress in ASD warrants further investigation.

 

Conclusion

Too much Quinolinic Acid (QA) does appear to be a damaging feature of autism and is produced by a malfunctioning Kynurenine pathway (KP).

The exact relevance of each part of the KP in diseases of the brain is still a work in progress, but it is clearly disturbed in a specific way in each particular CNS disorder, autism being just one.

Modifying the KP does look like a useful therapeutic avenue to follow, but it is not so simple to understand all of it.

It appears that Lactobacillus Plantarum 299v may improve some people’s autism via a mechanism that includes modification of the Kynurenine pathway (KP). It may also be the case that sulforaphane / broccoli powder has an effect that counters the disturbed KP. For whatever biological reason, the visible/audible effects of the two therapies appear to be remarkably similar.

As usual, you do not have to fully understand biological pathways, like the KP, to benefit from them.  In effect, it is all a question of where all the Tryptophan from your diet ends up – and for some people it does seem to matter.

Lactobacillus Plantarum 299v and sulforaphane / broccoli are not wonder autism therapies for most responders, but if there is an incremental benefit available, you may want to take it.

Another low hanging fruit? 

 

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.