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.

Metformin to raise Cognition in Fragile X and some other Autisms?

I started to write this post a long time ago, when Agnieszka first highlighted an interview with Dr Hagerman from UC Davis.  Hagerman is experimenting in using Metformin to treat Fragile-X.

Having again be reminded about Metformin, I realized that I never finished my post on this subject. With some extras about autophagy and a nice graphic courtesy of Ling’s excellent paper, here it is. 

Metformin has already been covered in 5 previous posts.

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

One interesting point is that the researchers at UC Davis are using the measurement of IQ as one of the outcome measures in their trial of Metformin.  I have been suggesting the French Bumetanide researchers do this for a long time.

It is my opinion that simple medical interventions can have a profound impact on the IQ of some people with severe autism. I mean raising IQ not by 5-10 points as at UC Davis, but by 20-50 points.  IQ can be measured using standardized tools and is far less subjective than any autism rating scale.

The big-time potential IQ enhancers we have seen in this blog include: -

·        Bumetanide/Azosemide

·        Statins (Atorvastatin, Lovastatin, Simvastatin, but they are not equivalent and the effect has nothing to do with lowering cholesterol)

·        Micro-dose Clonazepam

·        Clemastine

·        It seems DMF, in n=2 trial

The good news is that these drugs are all off-patent cheap generics (except DMF), as is metformin.  No need for drugs costing $50,000 a year.

For those that do not know, metformin is the first line medication for type-2 diabetes. It was introduced as a medication in France in 1957 and the United States in 1995.  In many countries Metformin is extremely cheap, with 30 x 500 mg tablets costing about $2 or Eur 2. In the US it costs about $10 for generic, so not expensive. 

There are sound reasons why Metformin could increase IQ in someone with autism or Fragile-X. In the case of idiopathic autism is there a likely biomarker to identify a likely responder? One has not yet been identified.

Clearly Metformin will not work for all people with autism and MR/ID, but even if it only works for 10% that would be great.

Are all parents going to notice an increase in IQ of 5-10 points?  You might think so, but I doubt it.  I would hope therapists, teachers and assistants would notice.

I think basic mental maths is the best way to notice improved cognitive function in people with IQ less than 70.  You can easily establish a baseline and then you can notice/measure improvements.

Improved cognitive function does not just help with maths, it helps with learning basic skills like tying shoe laces, brushing teeth and later shaving.  This does also involve many other types of skill.

Diabetes Medicine MetforminMay Improve Cognition, Behavior Symptoms in Fragile X Syndrome Patients, Case Study Reports

In the study, researchers from the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute in California tested the long-term effects of metformin, delivered at 1,000 milligrams (mg) twice a day, for one year in two male patients, 25 and 30 years old. Genetic analysis confirmed that both patients had mutations in the FMR1 gene, confirming their fragile X syndrome diagnoses.

The younger patient had autism and was also diagnosed with generalized anxiety disorder. First prescribed metformin at 22, he is currently taking 500 mg of metformin twice a day and 10 mg per day of simvastatin — used to lower the level of cholesterol in the blood.

The second patient was also diagnosed with anxiety and exhibited socially nervous behaviors, including panic attacks. He had severe limitations in language use, and communicated in short sentences and by mumbling. He had been on an extended-release formulation of metformin, taking 1,000 mg once a day for one year.

Both patients showed significant cognitive and behavioral improvements. After one year of treatment with metformin, test results revealed an increase in the patients’ IQ scores, from 53 to 57 in the younger patient and from 50 to 58 in the second patient.

Verbal and nonverbal IQ — the ability to analyze information and solve problems using visual or hands-on reasoning — were also improved in both patients. Non-verbal IQ increased from 50 to 52 in the younger patient and from 47 to 51 in the other. Verbal IQ went from 61 to 66 in the first patient, and from 58 to 68 in the second.

                                                              

Diabetes drug delivers multiple benefits forpeople with fragile X syndrome

Researcher Randi Hagerman is a big proponent of metformin — a diabetes drug that helps people manage their weight. In fact, Hagerman takes the drug herself as a preventive measure against cancer.

Metformin has also unexpectedly shown promise for improving cognition in people with fragile X syndrome, a leading genetic cause of autism characterized by severe intellectual disability.

A study published in 2017 linked impaired insulin signalling in the brain to cognitive and social deficits in a fruit fly model of fragile X, and the flies improved on metformin. A second paper that year showed that metformin reverses abnormalities in a mouse model of the syndrome, including the number of branches the mice’s neurons form. It also improved seizures and hyperactivity in the mice — issues we also see in people with fragile X.

I began prescribing metformin to people with fragile X syndrome to help curb overeating. Many of the people I treat are overweight because of this habit — it’s one of the symptoms of a subtype of fragile X called the Prader-Willi phenotype, not to be confused with Prader-Willi syndrome.

I was surprised when the families of these individuals told me they could talk better and carry out conversations, where they couldn’t before. That really gave us impetus to conduct a controlled clinical trial.

It’s not a cure-all, but we do see some positive changes. It doesn’t resolve intellectual disability, but we have seen IQ improvements of up to 10 points in two boys who have been treated with metformin. We are very excited about that.

Individuals on metformin tend to start eating less, and often lose weight as a result. I could kick myself, because metformin has been approved to treat obesity for many years, but I never thought to use it in fragile X syndrome. Oftentimes children with fragile X syndrome have so many problems that you aren’t thinking about obesity as the top priority.

We’ve also seen a gradual effect on language, which we can detect after two to three months. Sometimes there are improvements in other behaviors too; I’ve seen mood-stabilizing effects. Many people with fragile X syndrome have issues with aggression, and it’s possible these could be moderated with metformin too. 

Metformin as targeted treatment in fragile X syndrome 

Individuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader‐Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS.

Materials and Methods

We present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c.

Results

We found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side‐effects were noted and most patients with obesity lost weight.

Conclusion

We recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

Recruiting: Clinical Trial of Metformin for Fragile X Syndrome

While a growing number of families are trying metformin and reporting mixed results, metformin has not yet been systematically studied in patients with Fragile X syndrome. This open-label trial is designed to better understand the safety and efficacy of this medicine on behavior and cognition, and to find the best dosages for children and adults.

20 children and adults with Fragile X syndrome will take metformin 250mg twice a day for the first week, followed by metformin 500mg twice a day for the next 8 weeks.

The study will measure changes in the total score on the Aberrant Behavior Checklist-Community (ABC-C) after 9 weeks of metformin treatment. The ABC-C is a 58-item behavior scale which is filled out by a caregiver. In addition, Transcranial Magnetic Stimulation (TMS) will be used to look for changes in cortical excitability and Electroencephalography (EEG) will assess levels of synaptic plasticity.

Participants in this study must be Canadian residents and be able to travel to the University of Sherbrooke in Quebec, Canada, for several visits. If you are interested in metformin but this trial is not convenient, there are two alternatives. FRAXA is funding a new trial of metformin in New Jersey, and Dr. Randi Hagerman is currently recruiting for a metformin trial at the University of California at Davis MIND Institute.

A Trial of Metformin in Individuals with Fragile X Syndrome (Met)

Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signalling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signalling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. The researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior.

mTOR and P13K

Hagerman highlights Metformin’s effects on mTOR and P13K pathways.

This is a highly complex subject and the graphic below from an early post shows how interconnected everything is.  If mTOR is not working correctly you can expect many things not to work as nature intended.

Numerous things can cause an imbalance in mTOR and so there are numerous ways to re-balance it.

Not surprisingly much of this pathway plays a role in many types of cancer.

Hagerman herself is taking Metformin to reduce her chances of developing cancer. I think that is a good choice, particularly if you are overweight.  My anticancer choice, not being overweight, is Atorvastatin which targets inhibition of PI3K signalling through Akt and increases PTEN.

Hagerman is 70 years old and I think many cancers actual initiate years before they are large enough to get noticed and to be effective any preventative therapy needs to be started before that initiation has occurred. Hopefully she started her Metformin long ago. 

Given that 50% of people are likely to develop one cancer or another, I am with Dr Hagerman on the value of prevention, rather than treatment/cure.

The Wrong Statin for Fragile-X?

In the first article highlighted in this post, there is a case history of a man with FX being treated by a Statin, it looks to me that he has the wrong prescription (Simvastatin). Perhaps Dr Hagerman should read this old post from this blog:-

Choose your Statin with Care in FXS, NF1 and idiopathic Autism

   Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.

So  ? = Does NOT inhibit

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.

                                                                                                     

For anyone really interested, the following graphic from a previous post shows the fragile X mental retardation protein, FMRP.  Lack of FMRP goes on increase neuroligins (NLFNS) this then creates an excitatory/inhibitory imbalance which cause mental retardation and features of autism.

This all suggests that the 25 year-old young man with Fragile X treated at UC Davis (case study above) should switch from Simvastatin to Lovastatin.

Metformin and Autophagy

I also think Dr Hagerman is less likely to get dementia now that she is talking metformin.  If she takes vigorous exercise at least once a week, I think that is also going to keep her grey cells ticking over nicely. Like Dr Ben Ari, Hr Hagerman is working way past normal retirement.  If you love your job, then why not?  As with many things, in the case of neurons, “use them or lose them”.

Autophagy in Dementias

Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND).

The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

Below is an excellent graphic from a paper highlighted by Ling. Note metformin, above AMPK.

Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity

I would highlight the presence of IP3R, the calcium channel proposed by Gargus as being a nexus in autism, for where multiple types of autism meet up, to do damage.

Verapamil, in Monty’s Polypill, increases autophagy independently of mTOR in a complicated mechanism  involving IP3R and likley calpain.  It is proposed as a therapy for Huntington’s Disease via this mechanism. At the lower right of the chart below we see calpain, a group of calcium dependent enzymes, not well understood.  ROS can activate calpains via L-type calcium channels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635566/

I would not worry about the details.  The take home point is that if you have autism, dementia or many other neurological conditions, you might well benefit from increasing autophagy.  There are very many ways to do this.      
                                                           

Conclusion

Fortunately, I am not a doctor.  I do recall when my doctor father was out visiting his sick patients at their homes, he did have not only his medical bag, but also some useful gadgets always kept in his car, that might come in handy.

The autism equivalent is the personalized Polypill therapy for daily use and the autism toolbox to delve into to treat flare-ups in autism as and when they arise.

I do think some people should have metformin in their daily Polypill therapy.

I think we can safely call Fragile-X a type of autism, so we already know it works for at least some autism.  Metformin is a very safe old drug, with minimal side effects and it is cheap.  It ticks all the boxes for a potential autism therapy.  Will it work for your case?  I can tell you with certainty that it does not work for everyone.

Metformin has been trialled to treat people with obesity and autism, since it can reduce appetite.

Metformin forTreatment of Overweight Induced by Atypical Antipsychotic Medication in YoungPeople With Autism Spectrum Disorder: A Randomized Clinical Trial.

INTERVENTIONS:

Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.

MAIN OUTCOMES AND MEASURES:

The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.

RESULTS:

Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).

CONCLUSIONS AND RELEVANCE:

Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.

My guess is that a minority will be responders, the benefit will manifest itself in different ways and so it will be a useful part of polytherapy for some people, but it will not be a silver bullet.  Other than via an IQ test, I think the benefit will be hard to measure, even when it is very evident. 

In the end there will be a clever way to predict who will respond to which therapy.  Today’s post actually replaces one that will look into genetic testing and DEGs (differentially expressed genes). Most likely testing for DEGs will be the best predictor of what drugs work for whom.

Intelligent, cautious trial and error using safe drugs is an alternative strategy.  It is available today; it is cheap and it does work.

I have not tried Metformin yet, in recent years I have had most success with my own ideas. I have some of Dr Frye's calcium folinate sitting at home waiting for a trial.  Both Metformin and calcium folinate should be trialled.  The other obvious thing to trial is that Japanese PDE4 inhibitor Ibudilast (Ketas).  Thanks to Rene we now know you can acquire this is via any international pharmacy in Germany, with a prescription. It also reappeared on the website of a Japanese online pharmacy. The Western PDE4 inhibitors, like Daxas/Roflumilast are not selective enough and so are emetic (they make you want to vomit). Low dose Roflumilast has been patented as a cognitive enhancer, but you may need to have a bucket with you at all times.