“More GABA” for Autism and Epilepsy? Not so Simple

Today’s post was prompted by Tyler highlighting a very recent paper from MIT and Harvard, with some interesting research on GABA in autism.  It also provides the occasion to include an interesting epilepsy therapy, which I encountered a while back.  This fits with my suggestion that the onset of much epilepsy in autism could be prevented.

In the MIT/Harvard study, they were looking into the excitatory/ inhibitory (E/I) imbalance found in ASD and schizophrenia. They used a non-invasive optical method to measure E/I imbalance and this did get some media coverage.  However, I am not sure this could be a diagnostic tool in very young children with classic autism, as was suggested; most such children would not cooperate.  It is not just a problem of being non-verbal, as was suggested in the media.

Indeed, due to the nature of the experiment, the researchers involved older subjects, with milder autism and none had MR/ID (IQ<70).  Being a trial done in the US, of the 20 autistic subjects, 11  were being treated with psychiatric medications: antidepressants (n = 8), antipsychotics (n = 2), antiepileptics (n = 4), and anxiolytics (n = 2).

The easy to read version is from the MIT website:-

Study finds altered brain chemistry in people with autism

The full version is here:-

Reduced GABAergic action in the Autistic Brain

They used something called Binocular Rivalry  as a proxy for  E/I imbalance.

During binocular rivalry, two images, one presented to each eye, vie for perceptual dominance as neuronal populations that are selective for each eye’s input suppress each other in alternation [16, 17]. The strength of perceptual suppression during rivalry is thought to depend on the balance of inhibitory and excitatory cortical dynamics [12–15] and may serve as a non-invasive perceptual marker of the putative perturbation in inhibitory signaling thought to characterize the autistic brain.

We therefore measured the dynamics of binocular rivalry in individuals with and without a diagnosis of autism (41 individuals, 20 with autism). As predicted, individuals with autism demonstrated a slower rate of binocular rivalry (switches per trial: controls = 8.68, autism = 4.19; F(1,37) = 16.52, hp 2 = 0.311, p = 0.001; Figure 1A), which was marked by reduced periods of perceptual suppression (proportion of each trial spent viewing a dominant percept, (dominant percept durations)/(dominant + mixed percept durations): controls = 0.69; autism = 0.55; F(1,36) = 7.27, hp 2 = 0.172, p = 0.011; Figure 1B). The strength of perceptual suppression inversely predicted clinical measures of autistic symptomatology (Autism Diagnostic Observation Schedule [ADOS]: Rs = 0.39, p = 0.027; Figure 1) and showed high test-retest reliability in a control experiment (R = 0.94, p < 0.001; see Supplemental Experimental Procedures and also [18]). These results replicate our previous findings in an independent sample of autistic individuals [11] and confirm rivalry disruptions as a robust behavioral marker of autism.

To test whether altered binocular rivalry dynamics in autism are linked to the reduced action of inhibitory (g-aminobutyric acid [GABA]) or excitatory (glutamate [Glx]) neurotransmitters in the brain, we measured the concentration of these neurotransmitters in visual cortex using magnetic resonance spectroscopy (MRS).

GABA and glutamate are predicted to contribute to different aspects of binocular rivalry dynamics: mutual inhibition between (GABA) and recurrent excitation within (glutamate) populations of neurons coding for the two oscillating percepts [14].

. Critically, reducing either mutual inhibition or recurrent excitation is predicted to reduce the strength of perceptual suppression during rivalry in one implementation of this model [14], mirroring the dynamics we observed in autism. We therefore considered each neurotransmitter separately to test whether inhibitory or excitatory signaling was selectively disrupted in the autistic brain.

As predicted by models of binocular rivalry, GABA concentrations in visual cortex strongly predicted rivalry dynamics in controls, where more GABA corresponded to longer periods of perceptual suppression (Rs = 0.62, p = 0.002; Figure 2B). However, this relationship was strikingly absent in individuals with autism (Rs = 0.02, p = 0.473; Figure 2B). The difference between the two correlations was significant (hp 2 = 0.167, p = 0.013; Figure 2C), indicating a reduced impact of GABA on perceptual suppression in the autistic brain.

GABA was working backwards

Importantly, this finding was specific to GABA: glutamate strongly predicted the dynamics of binocular rivalry in autism (Rs = 0.60, p = 0.004; Figure 2B), to the same degree as that found in controls.

Glumate is working just fine.

These findings suggest that alterations in the GABAergic signaling pathway may characterize autistic neurobiology. Consistent with prior evidence from animal and post-mortem studies, such dysfunction may arise from perturbations in key components of the GABAergic pathway beyond GABA levels, such as receptors [3–9] and inhibitory neuronal density

Together with the pivotal roles of GABA in canonical cortical computations [39] and neurodevelopment [40], these findings point to the GABAergic signaling pathway as a prime suspect in the neurobiology of this pervasive developmental disorder [41]

This study reconfirms what regular readers of this blog already knew.

Epilepsy

I thought it was positive that the MIT researchers suggested that the high level of epilepsy in autism and this E/I imbalance really must be connected.

I have been suggesting for some time that by correcting this E/I imbalance in children with autism, it is likely that the onset of epilepsy could be avoided (in some cases).

I did suggest this to one well known researcher who thought the idea of preventing the onset of epilepsy was not something that the medical community would accept as a concept.

I also raised the novel epilepsy therapy, below, to the same researcher who thought it also would never be considered.

The therapy was to use both bumetanide and potassium bromide to switch GABA back to inhibitory and then give a little boost using a GABA agonist.   

There are many types of epilepsy and some do not respond well to current treatments.  It would seem plausible that the autism-associated type of epilepsy might constitute a specific sub-type.

Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures

Potassium Bromide was the original epilepsy therapy over a hundred years ago.  It is still used in Germany as a therapy.  Reports from a century ago suggest it has the same effect in autism as Bumetanide. (we saw this in my post on autism history). 

As you can see on Wikipedia there is a wide range of GABA agonists, but the only ones that would help in epilepsy and autism would be the ones that can cross the blood brain barrier.

GABA_A receptor Agonists

·         Bamaluzole

·         GABA

·         Gabamide

·         GABOB

·         Gaboxadol

·         Ibotenic acid

·         Isoguvacine

·         Isonipecotic acid

·         Muscimol

·         Phenibut

·         Picamilon

·         Progabide

·         Quisqualamine

·         SL 75102

·         Thiomuscimol

In an earlier post, we looked at the possible use of small doses of AEDs (anti-epileptic drugs).  One reader found that tiny dose of Valproate (known to raise GABA) had a positive effect when combines with Bumetanide.

In a recent comment one reader showed the same result by combing picamilon with bumetanide.

Both Picamilon and Valproate are having the effect proposed by the epilepsy researchers.

Potassium Bromide does have known side effects, but the idea of further boosting the effect of Bumetanide is interesting.  I have suggested before that this should also be possible using Diamox (Acetazolamide).  Diamox does not affect NKCC1 or E_GABA,  it affects the  Cl-/HCO3-exchanger AE3  to further affect Cl- levels.  

I did suggest this a long time ago in my posts on the GABAa receptor.  I am not the only one to realize this.

NKCC1 and AE3 Appear to Accumulate Chloride in Embryonic Motoneurons

   

Picamilon is well researched Russian drug, sold in other countries as a supplement.  It is a modified version of GABA that includes niacin; together it can cross the blood brain barrier (BBB).

So I think a better version of what the epilepsy researchers suggest might be:-

                           Bumetanide  +  Diamox  +  a touch of Picamilon

What would be the effect in autism?

Long Term use of Low Dose Clonazepam and More Science on the Excitatory/Inhibitory Imbalance in Schizophrenia and ASD

   

A small number of readers of this blog have followed Professor Catterall’s ideas and trialed low dose clonazepam for autism.  

This post summarizes my findings from using it long-term; it would be a good place to collect the findings of other people.

The science part of this blog is courtesy of a reader who highlighted the full-text version of a paper I mentioned.  Perhaps it was the author?

For information on Catterall’s clonazepam research, go to the “Index by Subject” tab and click on Clonazepam.

Before getting to that, I do get asked how I know, for sure, these therapies really do work for Monty, aged 12, with classic autism.  As I told Ben-Ari, the Bumetanide researcher, the best way to convince the doubting public will be to measure IQ, not autism.  If you can add 30 to 50 points to your IQ result, even the sceptics would pay attention.

I am not measuring IQ directly, but I do note things like spelling tests, math tests and handwriting.  The first pleasant surprise was actually reaching the point of sitting the same tests as the NT kids. Piano playing is another interesting proxy.

Monty’s one to one Assistant (and pal) from age 3 to 9 came to visit the other day and could not believe what his handwriting now looks like.  She had spent hundreds of hours with him practicing fine motor skills, like pencil control.  The end result was handwriting, but even then not like that of his peers. 

Cursive handwriting is now great.  Spelling tests and “quick-fire” math tests are also great.

As we now know, 20% of people diagnosed very young with quite severe autism seem to make wonderful progress.  This has happened by 5 or 6 years old, while the brain is still highly plastic.  Spontaneous accelerated development thereafter rarely seems to happen.  Monty started his Polypill therapy at the age of 9 years, in December 2012.

This is a spelling test from school, given to NT (neurotypical) ten year olds and 12 year old Monty (on paper without lines).  It is not rocket science and big brother could probably have got 20/20 in this test when he was eight years old.  But when Monty was eight years old, he was trying to break the windows of my car with his head and his handwriting did not look like this.

I have all the proof I need that modulating the excitatory/inhibitory imbalance in Monty’s autism is well worth the effort.  The effects are reversible if you stop the therapy, as should be the case.

Clonazepam

Here I am repurposing an existing drug for a different use, at a dosage so low it is highly unlikely to cause side effects.  This is mirroring the use of the same drug, at similar low doses, in mouse models of autism by Professor Catterall.

Clonazepam at “high” doses is widely used already in people with autism, to treat seizures and extreme anxiety.  

Catterall showed that the drug has a totally different effect at very low doses (less than 10% of normal), via a specific mechanism which he has identified, the positive modulation of the α _2,3  subunits of GABA_A receptors. 

GABA_A receptors are made up of five sub-units, the strict composition does indeed vary over time, just to make things even more complicated.  The most common GABA_A receptors have two αs, two βs, and one γ (α₂β₂γ). For each subunit, many subtypes exist (α_1–6, β_1–3, and γ_1–3). It is these subtypes of the subunits that Catterall showed to be key.  Clonazepam was one of the substances that he showed to be effective (in mice).

At “high” doses Clonazepam does have side effects, people build up tolerance to it and so take ever higher doses, and then they get hooked on it.

At very low doses the reverse seems to occur.  Over time you become more sensitive to it and need lower and lower doses.  This was a surprise to me.

The other surprise was that slightly above the effective “low dose” you get some anxiety and irritability.  When I first wrote about this I did wonder if this was just a coincidence, but it is not.

My chart from back then:-

Another interesting point was that some other readers found the effective dose was even less than mine.

When you read about the use of Clonazepam at regular, much higher doses, it is clear that there are wide variations in people’s sensitivity to this drug.  So much so that there is standard lab test to measure blood concentration of this drug, so that the clinician can vary the dose to achieve the desired level in blood.

Clonazepam Level (Blood) Test

It is not an expensive test and I did wonder if this could be used by clinicians to find the effective low dose in their patients with autism.

It did sound a clever idea, but then I read that even the same blood concentration of clonazepam (at high doses) can have markedly different effects in different people.  Still it is better than doing nothing and would reduce some of the guesswork with dosage.

The effective dose

In my n=1 example, the effective dose started out at 40mcg a day.  The half-life is very long and so you need three days to reach a stable level.

Other people contacted me to say that in their case 25mcg a day was effective and in one case, dosage once every two days was optimal.

In my case 40mcg, now gives the negative effects I has originally discovered at higher doses.

Currently the effective dose is 20 to 25 mcg.

This is a tiny dose, technically sub-clinical, but it really is better than giving none.  I have discontinued on several occasions.  There is cognitive loss, which is then regained when re-starting. 

The incremental cognitive effect is not as great in magnitude as I found with Bumetanide, but in people not using Bumetanide, the effect seems to be much greater.  Put more simply, Clonazepam plus Bumetanide is more beneficial than Bumetanide alone, at least in my case.

At this dose the annual cost of the therapy is one dollar/euro/pound. So it will not break the bank.

Tablets are available as 0.5mg  (giving 20 days of use) and 2mg (giving 80 days of use).  A bottle of 2mg tablets will last someone a few years.

I wish they made 0.025 mg (25 mcg) tablets.

I see no reason why, in ten to twenty years’ time, low dose clonazepam will not be a mainstream therapy for some autism; the only problem is the variability of the effective dosage.

Science

For those diehards who have made it this far, now I move from the Peter-reviewed science to the Peer-reviewed science, but from yet another Peter, Peter Penzes from Northwestern University, close by the Windy City.

Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders

Abstract: Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism.

Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

This study really shows how the common genetic dysfunctions in both schizophrenia and autism come together to produce the Excitatory/Inhibitory (E/I) imbalance.  Numerous different dysfunctions result in the same imbalance, some relate to GABA and some to NMDAR, but the end result is the same.

It is a really good paper, mentioning many of the genes we have encountered in this blog, plus many of the pathways like mTOR and even PAK inhibitors.

The study does not cover any therapeutic methods to correct the E/I imbalance, but this blog has those in spades.  They relate to modulating GABA_A, GABA_B and NMDA receptors.

Low dose clonazepam is modulating GABA_{A ,} as does Bumetanide and as should Acetazolamide (Diamox).  More of that in 2016.

OPN-300 Oxytocin and Autism

This post is about nasal spray drugs and Oxytocin.

Monty, aged 12 with ASD, uses a conventional anti-histamine nasal spray and I do sometimes wonder just how much of the drug reaches its target.  

With inhalers for asthma this is a well known problem and often even adults do not use them correctly; they are proven to work much better when they are fitted with a spacer chamber, that way the drug ends up in your lungs and not stuck to the inside of your mouth.

Many adults with asthma and COPD nowadays use spacers.

So my interest was drawn to a company called Optinose that is developing drugs for nasal delivery using a novel dispenser.  I was particularly surprised that in its small drug pipeline is an oxytocin spray for autism.

If you look on the US National Institute of Health website listing clinical trials of oxytocin and autism, you will find that thirty, yes three zero, studies are listed.

According to their website, Optinose intend to be the first to bring a product to the market approved for autism.

On the clinical trials website you may notice that other trials use an existing drug called Syntocinon that is a synthetic form of Oxytocin already approved for other purposes.

I did mention in an earlier post that the US rights to Syntocinon were sold to a company hoping to develop a therapy for Schizophrenia and Autism.

Retrophin Signs U.S. License Agreement for Syntocinon™ Nasal Spray (Oxytocin)

In Europe Syntocinon is available in most countries as a prescription drug.


The Optinose idea is that their dispenser can much more reliably dispense the correct amount of drug and have it reach the membrane deep inside the nose.  None gets in the mouth and less should get stuck at the entrance to the nose.

Previous trials of Oxytocin have yielded very mixed results.  Perhaps part of this is due to the nature of the spray pump being used?  It is certainly plausible.

The Optinose Spray

The Optinose spray is inserted in one nostril and your mouth.  You blow out through mouth, sealing the nasal cavity in the process, and the spray is forced out into your nose.  This should ensure it goes deep inside to the nasal membrane, where the oxytocin can cross directly into the blood stream.

Click on the link below and then click to play the short video.

http://www.optinose.com/optinose-platform/technical-overview

As the video points out, this kind of drug delivery can “enable new and improved brain treatments”

They are talking about direct nose-to-brain drug delivery, bypassing the blood brain barrier (BBB).  This is not fantasy and is already quite well studied.

Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting.

Coming back to Oxytocin ...

Not only is Oxytocin a well-known hormone affecting social behavior, but it also plays a role in switching the neurotransmitter GABA between excitatory and inhibitory.

Oxytocin and GABA_A

Oxytocin has a role at birth in the GABA “switch”, but it also has an ongoing role via binding to a particular subunit of GABA_A receptors.

Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring

We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Further evidence as to the precise effect of Oxytocin on GABA receptors was found by chance.  It was found that having dosed rats with Oxytocin, they did not get drunk when fed alcohol.

Oxytocin prevents ethanol actions at δsubunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats

Specifically, oxytocin (1 µg i.c.v.) given before ethanol (1.5 g/kg i.p.) attenuated the sedation and ataxia induced by ethanol in the open-field locomotor test, wire-hanging test, and righting-reflex test in male rats.

Vasopressin, which is a nonapeptide with substantial structural similarity to oxytocin, did not alter ethanol effects at δ-GABA_ARs. This pattern of results confirms the specificity of the interaction between oxytocin and ethanol at δ-GABA_ARs

The profound and direct interaction observed between oxytocin and ethanol at the behavioral and cellular level may have relevance for the development of novel therapeutics for alcohol intoxication and dependence.

Is Oxytocin a useful Autism Therapy?

Given the large number of trials and the number of people already taking Oxytocin, some people clearly believe in the therapeutic potential of Oxytocin.

What is clear is that there a numerous modes of action for Oxytocin, some of which relate to GABA_A receptors.

So why is it taking so very long for these trials to come to any usable conclusion? Well just looking at the long list of researchers, it includes some of those who have spent twenty years "researching" autism and producing absolutely nothing tangible, just papers concluding more research is needed or even producing, supposedly therapeutic, cartoons (Cambridge University).

We have the usual problem that numerous different dysfunctions lie at the root of “autism” and so only a moderate proportion, at best, would be expected to benefit from any therapy.

In the case of nasal sprays we have the question of how much actually gets delivered to the right place deep inside the nose where there is a very thin membrane that allows the Oxytocin to cross over into the blood.

OPN-300 Clinical Trials

The Phase 1 trial for OPN-300 was actually on healthy adults, and looked at things like dosing.  Low doses were more effective than high doses.  Next follows the trial on people with autism.  

Low-dose oxytocin delivered intranasally with Breath Powered device affects social-cognitive behavior: a randomized four-way crossover trial with nasal cavity dimension assessment

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

Importantly, the current findings are the first to suggest that a low dose of OT is more effective than a higher dose in modulating social cognition

Converging biological and behavioral evidence suggests that lower OT doses may be more efficacious than higher doses. For instance, compared with higher doses, lower doses increased peripheral levels of OT in saliva,⁶⁵ attenuated cortisol stress responses⁶⁶ and increased eye gaze in patients with Fragile X syndrome.⁶⁷ In animals, a low dose of OT administered shortly after birth increased partner preference later in life, whereas higher doses did not.⁶⁸ Similarly, lower doses have been associated with stronger increases in social recognition compared with higher doses.^{69, 70} The dose–response data reported here provide useful preliminary evidence concerning the optimal dose for social cognition modulation; however, extrapolation from healthy individuals to patients must be with caution. Patients with social-cognitive deficits may respond differently than healthy volunteers, so future studies should explore effects in patient populations to determine the generalizability of these findings to target illnesses. Future work should also further investigate the role of different delivery devices, administration routes, dosages and social cognition tasks on the efficacy of intranasal OT, ideally using larger sample sizes given the limitation of a relatively small sample size in the present study.

In addition, this study provides preliminary evidence that a lower dose (8 IU) may offer greater efficacy than a higher dose (24 IU) when administered with the Breath Powered device.

There are a number of interpretations regarding why no effect was observed at the 24 IU OPN-OT dose, in contrast to the 8 IU dose. For example, a higher OT dose is more likely to influence the balance of AVP/OT, as evidenced by the decrease in AVP concentration after 24 IU OPN-OT (but not 8 IU OPN-OT) observed in the present study, which can modulate social behavior.

OptiNose reports positive results from Phase 1 trial of intranasal oxytocin for autism

Jul 15 2015

OptiNose has announced that a study comparing OPN-300 intranasal oxytocin to intravenous oxytocin for the treatment of autism showed the achievement of similar blood levels but significantly greater social-cognitive effects after intranasal administration. The results were published online July 14, 2015 in Translational Psychiatry.

The randomized, placebo-controlled, double-blind, double-dummy, 4-arm cross-over study involved 16 healthy volunteers who received either intravenous oxytocin or two doses of OPN-300 delivered using OptiNose’s bi-directional breath powered intranasal delivery device. Social-cognitive effects were measured by emotional rating of facial images.

Researcher Ole A. Andreassen of the University of Oslo said, “The OptiNose technology significantly changes the way drug is delivered high up in the nose, and may be the drug delivery solution we’ve been looking for. If we can improve social cognition in healthy people with OPN-300 low-dose oxytocin, then we may be able to address a core symptom suffered by millions of patients worldwide with autism.”

OptiNose Chief Scientific Officer Per Djupesland commented, “Although animal data has been encouraging, many would argue that medication transport from the nasal cavity directly to the brain has not been previously proven in humans. Today’s results are quite promising and bolster our belief that we can enable and enhance the treatment of common brain disorders with OptiNose delivery technology.”

The company says that it is initiating a Phase 2 trial of OPN-300 in autism patients in Norway. OptiNose is also developing intranasal fluticasone for chronic sinusitis and recently reported positive results from a Phase 3 trial of that product.

Read the OptiNose press release.

Read the Translational Psychiatry article.

Conclusion

Some parents already use the Syntocinon version of oxytocin for autism; some tried it in one of the earlier clinical trials and found it did not help.  There is nothing surprising in that. 

The people at OptiNose seem to be a bit more motivated than some of the other oxytocin researchers, in relaxed leafy universities, to actually get to the finishing line.  They are initiating Phase 2 trials of OPN-300 in autism patients in Norway.  Some of the other studies have been going on for several years and are still not finished.

Hopefully we will soon have some data on what percentage of people with “autism” respond to OPN-300 and then we could compare that to the response to Syntocinon.

As we have seen several times before, it seems that smaller doses of oxytocin are more effective than larger doses.  Larger doses seem to change (reduce) vasopressin levels, which will also affect social behavior.

One you start changing the level of one hormone, like oxytocin, you are very likely to affect others.  There are many interrelations and feedback loops.  

Oxytocin may well be part of the solution for some people with autism, but I expect in others it may make them worse.  Hopefully in the later trial(s) they will try and indentify biomarkers for the responder group.

Why Low Doses can work differently, or “Biphasic, U-shaped actions at the GABAa receptor”

This post does get a little complicated, so here is a summary.

Key points

·        High doses of oral Pregnenolone are shown to help Schizophrenia, particularly in females.  (these are all adults)

·        High dose oral Pregnenolone has also been shown to help adults with autism.

·        Low doses of transdermal progesterone (and likely Pregnenolone), anecdotally, reduce anxiety in Asperger’s and ADHD

·        Unusual levels of various hormones are a hallmark of autism, this can directly affect neurotransmitters like GABA

·        Hormones are produced in the brain as well as elsewhere in the body and so supplementing them may have unintended side effects.  Some hormones do not cross the blood brain barrier.

·        Side effects should be less likely after puberty, so research is done on adults

·        Some people regularly give very young children hormones, like melatonin

·        It may be possible to get the benefit of the hormones affecting GABA_A at low doses

·        Changes in certain hormone levels actually change the structure (and hence the effect) of the GABA_A receptor

·        Modulating the GABA_A receptor via the neurosteroid site then changes how the Benzo site of the same receptor responds to modulation (hence changes the effect, and side effects of Benzodiazepines)

Today’s post has a very odd tittle.

It will explain some of the odd things that we have been seeing in seizure drugs having potent effects at tiny doses.  It really is a case where “less is more”.

We will see that modulating the GABA_A receptor using the neurosteroid binding site (not the usual Benzo site) has potential for many neurological conditions.  There are some interesting interventions possible today and some are OTC.  We will also see that the structure of the GABA_A receptor is itself dynamic and some drugs affecting it are actually changing it.

This is all very relevant because it appears that GABA_A dysfunction is at the very core of the common autism variants and a key factor in schizophrenia.

   

I did say in a recent post that  GABA_A receptor is rather complicated and best left to Professors Sigel and Catterall and their mice, but then I came across the explanation myself.  As usual, the answer is there in the science, you just have to know where to look for it; or just stumble upon it.

It also appears that the recent autism trial at Stanford of pregnenolone, may have left untold part of the story.  They gave increasing high doses of pregnenolone, which is converted in the body into allopregnanolone, a positive allosteric modulator of GABA_A receptors. 

At tiny doses, allopregnanolone stimulates GABA_A, at higher doses it inhibits it and then at very high doses again it stimulates it.  So the precise dosage of Pregnenolone, or indeed progesterone, which also produces allopregnanolone, would be critical in achieving the desired modulation of GABA.  The Stanford researcher is a psychiatrist, by the way, not a biochemist; he did not investigate the effect of small doses.

Brief report: an open-label study of the neurosteroid pregnenolone in adults with autism spectrum disorder.

There are a whole raft of similar studies in the works, trialing Pregnenolone in Schizophrenia, Bipolar, TBI and even Gulf War Illnesses.

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

   

Allopregnanolone

As usual the most up-to-date source is Wikipedia:-

Function

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding, prosocial, antiaggressive, prosexual, sedative, pro-sleep, cognitive and memory-impairing, analgesic, anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.

Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor – moderate level increases (in the range of 1.5–2 nM/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it. This seems to be a common effect of many GABA_A receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels), have been found to have negative effects on mood, while higher doses have a neutral effect.

Neurosteroids and GABA-A receptor function

Possible Explanations for the Paradoxical Effect of GABA-Steroids

In this section, possible mechanisms of the biphasic response curve of allopregnanolone on behavioral parameters are discussed. The basic idea of so called paradoxical effect where neurosteroids show one type of effect at low concentrations and another type at high concentrations is that an enhanced GABA_A-receptor activity may give an excitatory net effect in certain situations, instead of the usual inhibitory effect. The following hypotheses suggest several possible mechanisms how this can be achieved. In addition, there are no contradictions between the different hypothesis and they may very well act in parallel.

The Effect of Neurosteroids on the GABA_A-Receptor

The GABA_A-receptor can be modulated by a number of therapeutic agents, including benzodiazepines , barbiturates , anesthetics, ethanol , zinc , and neurosteroids . The effect of neurosteroids on the GABA_A-receptor depends on the type of steroids (agonist or antagonist), the type of receptors (synaptic of extrasynaptic), the subunit compositions, and the intrinsic structure of the steroid. Recent studies indicate that the existence of at least two neurosteroid actions on the GABA_A-receptor, namely an agonistic action and an antagonistic action by the sulfated and 3β-OH steroids. The agonistic action can further be divided into an allosteric enhancement of GABA-evoked Cl⁻ current and a direct activation of the GABA_A-receptor.

It is puzzling why an increase in allopregnanolone during the menstrual cycle is related to development of negative mood as allopregnanolone should be anxiolytic agent like benzodiazepines. The answer depends on the fact that all GABA_A-receptor agonists such as benzodiazepines, barbiturates, alcohol, and allopregnanolone have paradoxical anxiogenic effects in certain individuals. At low concentrations or doses they give severe adverse emotional reactions in a subset of individuals (3–6%) and moderate reactions in up to 20–30% of individuals. This paradoxical effect is induced by allopregnanolone  benzodiazepines , barbiturates , and ethanol . Symptoms induced by these GABA_A-receptor active drugs are depressive mood, irritability, aggression, and other symptoms known to occur during the luteal phase in women with PMS/PMDD. A biphasic effect was also observed for medroxyprogesterone (MPA) and natural progesterone in postmenopausal women taking hormone therapy. These women felt worse on a lower dosage of MPA or progesterone than on a higher dosage or placebo.

Thus allopregnanolone seems to have a biphasic effect on mood with an inverted U-shaped relationship between concentration and effect. In postmenopausal women receiving progesterone, a biphasic relation between the negative mood symptoms and the plasma concentrations of allopregnanolone was observed. The negative mood increased with the elevating serum concentration of allopregnanolone up to the maximum concentration seen at the luteal phase. With further increase in allopregnanolone concentration there was a decrease in symptom severity  An inverted U-shaped relation between allopregnanolone dosage and irritability/aggression has also been noted in rats 

Antagonist Neurosteroids on the GABA_A-Receptor

Neurosteroids may both enhance and inhibit GABAergic neurotransmission

Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons.

Abstract

Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the paradoxical effect of GABA steroids on behavior: (1) under certain conditions, such as puberty, the relative fraction of certain GABA-A receptor subtypes may be altered, and at those subtypes the GABA steroids may act as negative modulators in contrast to their usual role as positive modulators; (2) in certain brain areas of vulnerable women the transmembrane Cl(-) gradient may be altered by factors such as estrogens that favor excitability; (3) inhibition of inhibitory neurons may promote disinhibition, and hence excitability.

Allopregnanolone and mood disorders.

Abstract

Certain women experience negative mood symptoms during the menstrual cycle and progesterone addition in estrogen treatments. In women with PMDD increased negative mood symptoms related to allopregnanolone increase during the luteal phase of ovulatory menstrual cycles. In anovulatory cycles no symptom or sex steroid increase occurs. This is unexpected as positive modulators of the GABA-A receptor are generally increasing mood. This paradoxical effect has brought forward a hypothesis that the symptoms are provoked by allopregnanolone the GABA-A receptor system. GABA-A is the major inhibitory system in the brain. Positive modulators of the GABA-A receptor include the progesterone metabolites allopregnanolone and pregnanolone, benzodiazepines, barbiturates, and alcohol. GABA-A receptor modulators are known, in low concentrations to induce adverse, anxiogenic effects whereas in higher concentrations show beneficial, calming properties. Positive GABA-A receptor modulators induce strong paradoxical effects e.g. negative mood in 3-8% of those exposed, while up to 25% have moderate symptoms thus similar as the prevalence of PMDD, 3-8% among women in fertile ages, and up to 25% have moderate symptoms of premenstrual syndrome (PMS). The mechanism behind paradoxical reaction might be similar among them who react on positive GABA-A receptor modulators and in women with PMDD. In women the severity of these mood symptoms are related to the allopregnanolone serum concentrations in an inverted U-shaped curve. Negative mood symptoms occur when the serum concentration of allopregnanolone is similar to endogenous luteal phase levels, while low and high concentrations have less effect on mood. Low to moderate progesterone/allopregnanolone concentrations in women increases the activity in the amygdala (measured with fMRI) similar to the changes seen during anxiety reactions. Higher concentrations give decreased amygdala activity similar as seen during benzodiazepine treatment with calming anxiolytic effects. Patients with PMDD show decreased sensitivity in GABA-A receptor sensitivity to diazepam and pregnanolone while increased sensitivity to allopregnanolone. This agrees with findings in animals showing a relation between changes in alpha4 and delta subunits of the GABA-A receptor and anxiogenic effects of allopregnanolone.

CONCLUSION:

These findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor.

Neurosteroids, GABAA receptors, and escalated aggressive behavior.

Abstract

Aggressive behavior can serve important adaptive functions in social species. However, if it exceeds the species-typical pattern, it may become maladaptive. Very high or escalated levels of aggressive behavior can be induced in laboratory rodents by pharmacological (alcohol-heightened aggression), environmental (social instigation), or behavioral (frustration-induced aggression) means. These various forms of escalated aggressive behavior may be useful in further elucidating the neurochemical control over aggression and violence. One neurochemical system most consistently linked with escalated aggression is the GABAergic system, in conjunction with other amines and peptides. Although direct stimulation of GABA receptors generally suppresses aggression, a number of studies have found that positive allosteric modulators of GABAA receptors can cause increases in aggressive behavior. For example, alcohol, benzodiazepines, and many neurosteroids are all positive modulators of the GABAA receptor and all can cause increased levels of aggressive behavior. These effects are dose-dependent and higher doses of these compounds generally shift from heightening aggressive behavior to being sedative and anti-aggressive. In addition, these modulators interact with each other and can have additive effects on the GABAA receptor and on behavior, including aggression. The GABAA receptor is a heteropentameric protein that can be constituted from various subunits. It has been shown that subunit composition can affect sensitivity of the receptor to some modulators and that subunit composition differentially affects the sedative vs anxiolytic actions of benzodiazepines. Initial studies targeting alpha subunits of the GABAA receptor point to their significant role in the aggression-heightening effects of alcohol, benzodiazepines, and neurosteroids.

The Do No Harm Principle (Primum non nocere)

A guiding principle in this blog is not to do any harm, while trying to do some good.

When I read that Hardan was trialing Pregnenolone at Stanford, I thought it was very interesting, but I thought his doses were very high and did not pass the above “first, no harm” principle.  Our pediatric endocrinologist thought the dose rising to 500mg was very unwise.

When I looked into this hormone precursor a year ago I remember thinking it odd that some people were saying 5mg was a big dose, while others were using 50mg and Hardan was going up to 500mg.

Now that I have understood about the mode of action is likely GABA_A, and that allopregnanolone possesses “biphasic, U-shaped actions at the GABA_A receptor”, I understand what may be going on.  The tiny dose might be as effective as the huge dose, but without the side effects caused by all the other accompanying hormonal changes.

The endocrinologist would likely not worry about 5mg of Pregnenolone.  Unlike most other known PAMs of GABA_A, pregnenolone does not need a prescription.

I did look for reports of people trying it themselves for schizophrenia/autism, but did not find anything useful.

Depression and  anxiety, and are frequently-seen side effects of 5α-reductase inhibitors such as finasteride, and are thought to be caused, in part, by interfering with the normal production of allopregnanolone.

Experiments in Humans

The doctors/scientist amongst you will have realized the potential therapeutic value of these paradoxical behaviors at GABA_A receptors.

Instead of using the usual right hand side of the curve, where high doses are effective but may risk tolerance and side effects, we may in some cases be able to use the left hand side.  This means low doses and far less chance of any side effects.

You do of course need some data on the U curve itself and the existing levels, if any, of the chosen GABAA modulator.

In the case of pregnenolone/ allopregnanolone/progesterone this seems to exist at a constant low level in males, but in cyclical low to high levels in females.

You would need to locate where you are on the curve, or perhaps to the left of the entire curve.  By adding a positive allosteric modulator (PAM) can only move to the right.  We know that 500mg of  pregnenolone in adults move to a “better” position on the allopregnanolone curve.

Circulating Levels of Allopregnanolone in Humans:

Gender, Age, and Endocrine Influences

In males 19-39 years old the level of Allopregnanolone is 0.8 nmol/l.

In Women  it varies from from 0.6 to 4.5 nmol/l during the month.

  

Allopregnanolone Elevations Following Pregnenolone Administration are Associated with Enhanced Activation of Emotion Regulation Neurocircuits

These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacological intervention in the treatment of anxiety disorders, and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

Pregnenolone is lipophilic and readily crosses the blood brain barrier. We have previously found that pregnenolone is preferentially metabolized to allopregnanolone, rather than other compounds such as cortisol or DHEA (43, 44); however these metabolites were also assayed. Allopregnanolone serum levels have been reported to triple two hours after oral administration of 400 mg pregnenolone (45). Thus, drug administration occurred two hours before neuroimaging to ensure elevated levels during the scan.

Pregnenolone administration reduced activity in neural circuits associated with the generation of negative emotions. Across all conditions and all face types, pregnenolone administration decreased right amygdala and right insula activity, and serum levels of pregnenolone and allopregnanolone were negatively correlated with amygdala and insula activation levels. The amygdala is a key region in threat detection (52), fear conditioning (53), and emotional salience (54). The insula is responsible for interoception (55), disgust (56), emotion processing (57), emotional recall (36), and anticipation of aversive stimuli (58). Both regions are associated with negative emotional response (57), and greater amygdala activation in response to the presentation of facial expressions is associated with greater magnitude of emotional response (59–63). Additionally, activation reductions in amygdala and insula are associated with down-regulation of negative emotions (64). Thus, allopregnanolone’s reduction of activity in amygdala and insula suggests that allopregnanolone may reduce emotional reactivity to aversive stimuli.

Allopregnanolone likely impacts emotion regulation neurocircuitry through GABAergic mechanisms, though it may also impact this circuitry through its enhancement of neurogenesis (78) myelination (79) or neuroprotection (80–83). Amygdala and mPFC are rich in GABA(A) receptors (28) and endogenous allopregnanolone (48), suggesting that allopregnanolone could feasibly have a direct impact on activity in these regions. Indeed, in our sample, allopregnanolone serum level was more strongly correlated to amygdala activity than activity in any other brain region. Preclinical research suggests that the amygdala may be a particular target of allopregnanolone’s anxiolytic effects (30). In rats, microinfusions of allopregnanolone directly into the amygdala produce anxiolytic (30) antidepressant (31) and anti-aggressive (32) effects. In previous neuroimaging studies, greater endogenous allopregnanolone has been reported to be associated with lower amygdala reactivity (33, 41) and greater coupling between amygdala and dmPFC (34). Though we did not directly test the GABAergic effect of our intervention, our findings illuminate potential neural pathways through which pregnenolone administration and resulting increases in allopregnanolone levels could feasibly impact GABAergic transmission in a manner that is relevant to pathological anxiety.

In conclusion, we demonstrate that pregnenolone administration (leading to increased downstream allopregnanolone levels) reduces activity in regions associated with the generation of negative emotion and enhances activity in regions linked to regulatory control over emotion, as well as increasing connectivity between two of these regions (dmPFC and amygdala). Considering the wealth of evidence that neurocircuits involving these regions are altered in anxiety disorders, our results invite further investigation into the brain basis for allopregnanolone’s use as an anxiolytic pharmacological intervention.

  

There is plenty of research into mood changes in females linked to the GABAA receptor.  So you could figure out what happens at what concentration of Allopregnanolone, in females.

The “problem” here is that plot thickens even further, in females it has been shown that the structure of the GABAA receptor actually changes.  When estrogen levels are higher than progesterone levels, the number of delta receptors decrease, increasing nerve cell activity, in turn increasing anxiety.

http://www.ncbi.nlm.nih.gov/pubmed/15895085

Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus

Since it appears the other GABAA receptors also exhibit the same U-shaped responses, there will be a choice.

I think a little experiment with very low doses of pregnenolone is worthwhile.

You may recall earlier mention in this blog of people with Asperger’s using a topical progesterone cream.  That would likely have exactly the same effect.  

There are other theories as to why progesterone cream might reduce anxiety, but it does seem to help some people.   Here is a comment on an Amazon forum:-

“My 9-year-old son is slightly autistic, suffers from severe anxiety as well as ADD, and although the medicine he takes works wonders for him, he still has residual anxiety. I rubbed 50 mg of natural progesterone cream into his chest every night for about three weeks and noticed unbelievable results. He just blossomed emotionally. We went in for his regular neuro checkup and even the neurologist immediately noticed a difference in my son, commenting on how happy and relaxed he seemed.”

There is also a pregnenolone cream.

It should be cautioned that these are all hormones and they do other things than modulate GABA_A receptors.  The effect/dosage will vary between males/females and with age.

  

Effects of modulating multiple binding sites of GABA_A

We did learn in an earlier post that the GABAA receptors have numerous different binding sites.  Since modulating some of these sites produces paradoxical results, you might wonder what happens if you really mix things up.  For example what happens if you modulate the benzo site and the neurosteroid site at the same time.

Neurosteroid coadministration prevents development of tolerance and augments recovery from benzodiazepine withdrawal anxiety and hyperactivity in mice

or

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective Receptor GABA_A Modulators?

4.4.3. Mechanism 6: Neurosteroids

There is ample and convincing evidence that neurosteroids are endogenous allosteric regulators that interact with GABA_A receptors to modulate both tonic (extrasynaptic) and phasic (synaptic) inhibition (for reviews, see [150, 151]). Also, acute or chronic neurosteroid treatment may change GABA_A receptor subunit expression, especially extrasynaptic α₄ and δ subunits [151]. In light of the plasticity-inducing actions of neurosteroids on inhibitory signaling, long-term enhancement of the GABA system with benzodiazepines may in turn evoke changes in the neurosteroids system such as changes in neurosteroid synthesis and metabolism, although classical benzodiazepines may differ in their potency to cause such changes [152]. In support, ovariectomy attenuated the development of tolerance to the anticonvulsant actions of diazepam [153]. Moreover, co-administration of the neurosteroids allopregnanolone or pregnenolone (but not dehydroepiandrosterone) prevented the development of tolerance after chronic treatment with either triazolam and diazepam [154]. Adding to the complexity of the putative involvement of neurosteroids in benzodiazepine tolerance, factors such as GABA_A receptor subunit composition, phosphorylation mechanisms, and ((extra)synaptic) localization—which are all factors that were already found to be involved in tolerance development—influence the specific dynamics of neurosteroid activity.

Ganaxolone – an altogether better Neurosteroid ?

Ganaxolone has the same chemical structure as allopregnanolone, with the addition of a methyl group designed to prevent conversion back to an active steroid, thereby eliminating the opportunity for unwanted hormonal effects while preserving its desired CNS activity.

We came across Ganaxolone in an earlier post, which looked at drugs being trialed in Fragile X.

I thought it was interesting that it is also being trialed in epilepsy and indeed PTSD (post-traumatic stress disorder)

I think that PTSD and TBI (Traumatic Brain Injury) can provide insights for understanding autism.

It is odd that nobody has trialed Ganaxolone for schizophrenia, to see if it shares the positive effects of Pregnenolone.  Then you might expect someone to think of trialing it in autism.

Conclusion

It would seem that, depending on your own natural level of allopregnanolone, supplementing it with pregnenolone or progesterone could have very different effects, depending on the dosage.

In addition, we have the fact that in autism the GABA_A receptor is dysfunctional and some aspects may work in reverse.

Having established that very large doses of Pregnenolone (which produces allopregnanolone) seems to be helpful in autism and schizophrenia, it would be well worth measuring the level of allopregnanolone, produced by different doses and of course investigating the effect of tiny doses of Pregnenolone.

Anecdotally, in typical people, tiny doses of Pregnenolone do have an effect.

It might turn out that because of where you are actually on the curve, you might actually need a low dose Negative Allosteric Modulator (NAM), to make you move to the left.  Interestingly there is such a NAM, Pregnenolone Sulfate.

Pregnenolone sulfate  is an endogenous excitatory neurosteroid that is synthesized from pregnenolone. It is known to have cognitive and memory-enhancing, antidepressant, anxiogenic, and proconvulsant effects.^[2]

Mechanism

Pregnenolone sulfate is a neurosteroid with excitatory effects in the brain, acting as a potent negative allosteric modulator of the GABA_A receptor and a weak positive allosteric modulator of the NMDA receptor.^] To a lesser extent, it also acts as a negative allosteric modulator of the AMPA, kainate, and glycine receptors, and may interact with the nACh receptors as well. In addition to its effects on ligand-gated ion channels, pregnenolone sulfate is an agonist of the sigma receptor, as well as an activator of the TRPM1 and TRPM3 channels. It may also interact with potassium channels and voltage-gated sodium channels.

Pregnenolone and its sulfate, like DHEA and its sulfate and progesterone, belong to the group of neurosteroids that are found in high concentrations in certain areas of the brain, and are synthesized there. Neurosteroids affect synaptic functioning, are neuroprotective, and enhance myelinization. Pregnenolone and its sulfate ester are under investigation for their potential to improve cognitive and memory functioning.^[3] Pregnenolone is also being considered as a potential treatment for schizophrenia.^[1]

Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging

“Studies in animals demonstrated that the neurosteroids pregnenolone (PREG) and dehydroepiandrosterone (DHEA), as sulfate derivatives (PREGS and DHEAS, respectively), display memory-enhancing properties in aged rodents. Moreover, it was recently shown that memory performance was correlated with PREGS levels in the hippocampus of 24-month-old rats. Human studies, however, have reported contradictory results. First, improvement of learning and memory dysfunction was found after DHEA administration to individuals with low DHEAS levels, but other studies failed to detect significant cognitive effects after DHEA administration. Second, cognitive dysfunctions have been associated with low DHEAS levels, high DHEAS levels, or high DHEA levels; while in other studies, no relationship was found.”

Another NAM at the GABAA receptor is DHEA, a steroid hormone produced in the body.  Regular exercise stimulates the production of DHEA.

Lowered DHEA-S plasma levels in adult individuals with autistic disorder

Faulty serotonin--DHEA interactions in autism: results of the 5-hydroxytryptophan challenge test.

We also learnt that structure of the GABA_A receptor can be modified.  It happens continuously in females.  So as well as clever ways to use allosteric modulators, you could also copy nature and change the structure of the GABA_A receptors themselves.  In fact the genetic research does suggest this structure has been disturbed in autism; you would just be correcting a defect.

It does look like high dose Pregnenolone really is effective in reducing the symptoms in schizophrenia.  Here is yet another study showing this:-

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia