Telmisartan as a useful biological “nudge-therapy,” particularly in bumetanide-responsive autism

 

A nudge is usually better than the sledgehammer !

 

Today’s post is another one most appropriate for people living in autism treatment-friendly counties (Russia, Ukraine, India, USA, Italy, Poland etc). Others will likely see this as from an alternative reality! The post is a bit long, just skip through it. 

My trial dose continues to be 20mg in a 65kg person. Doses trialed in schizophrenia have been much higher. Low doses are always the safest.

The post started life not as a review of any peer-reviewed clinical trials, but rather as an observational report, showing that revisiting the basic science can pay off. I made my initial review several years ago for my own purposes, but shared it in my blog.

I see that in fact the research has partially caught up:

Feinstein Institutes’ scientists find common blood pressure drug could be beneficial in some cases of autism

Scientists at Northwell Health’s Feinstein Institutes for Medical Research have made a significant discovery in autism spectrum disorder (ASD): a widely used blood pressure medication, captopril, can restore healthy function to the brain’s immune cells and reverse ASD-like behaviors in a preclinical animal model. This invaluable research focuses on a specific type of ASD believed to be triggered by a mother’s immune system during pregnancy, and could better understand autism and autism-like symptoms.

 

The full paper is here: 

Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG

 

What this now means - research from 2025 supports Peter’s 2017 idea to use telmisartan for autism

In 2025, researchers at the Feinstein Institutes for Medical Research published a preclinical study showing that modulation of the brain’s renin–angiotensin system (RAS) can reverse autism-like features in a specific immune-primed mouse model. In this model, prenatal immune exposure led to persistent microglial activation, synaptic abnormalities, and altered social behavior — changes that were significantly improved by treatment with captopril, an ACE inhibitor capable of crossing the blood–brain barrier.

Importantly, the study demonstrated that central (brain) RAS signaling is biologically relevant to neurodevelopmental plasticity, and that immune-driven alterations are not necessarily fixed. The benefit was not seen with ACE inhibitors lacking brain penetration, highlighting the importance of central rather than purely peripheral effects.

While captopril was used as a proof-of-concept tool, the underlying mechanism strongly supports the rationale for angiotensin receptor blockers (ARBs) — particularly telmisartan — which offer several advantages. Telmisartan directly blocks AT1 receptors, preserves potentially beneficial AT2 signaling, has a long half-life, and exerts additional anti-inflammatory, metabolic, and mitochondrial effects that are highly relevant to common autism subtypes involving neuroinflammation, behavioral rigidity, fatigue, and impaired stress resilience.

Thus, although the 2025 study does not establish a clinical treatment for autism, it independently validates the systems-level reasoning behind using telmisartan as a chronic “nudge” therapy in carefully selected autism phenotypes. The research supports the mechanism Peter proposed years earlier: that gently modulating regulatory systems such as the brain RAS can restore function in plastic but dysregulated neurodevelopmental circuits.

 

The keep it simple approach

I set out a very simple of framework of classic (Level 3) autism many years ago in this blog. It is also in my book and some presentations.

 

Today’s post falls in to the “central hormonal dysfunction” category.

Renin and angiotensin are both hormones

For the brain, angiotensin (especially angiotensin II) is the one that really matters. Renin is mostly just the upstream trigger.

The brain has its own local renin–angiotensin system, partly independent of the circulating one.

 

A recap for the science lovers - Angiotensin II in the brain

Angiotensin II is the active signalling molecule that actually does things in neural tissue:

• Acts as a neuromodulator
• Shapes excitatory–inhibitory balance
• Influences dopamine, GABA, glutamate
• Regulates stress, threat detection, motivation
• Affects neuroinflammation, oxidative stress
• Alters plasticity and myelination

All of that happens via angiotensin receptors, mainly AT1 and AT2.

 

In the brain, which receptor is activated matters more than how much angiotensin is around:

AT1 receptor (problematic when dominant)

• Increases stress signalling
• Promotes neuroinflammation
• Increases sympathetic tone
• Worsens cognitive rigidity

AT2 receptor (generally protective)

• Promotes neurite growth
• Supports learning and repair
• Anti-inflammatory
• Pro-plasticity

This is why ARBs (especially telmisartan) are interesting neurologically:

• They block AT1
• They shunt signalling toward AT2
• They act inside the brain, not just on blood pressure

 

Back to the more readable stuff

When treating broader autism you can consider the 150-200 possible therapies as ranging from small nudges in the right direction, to a precise hit with a mallet that corrects a precise dysfunction (a specific ion channel dysfunction, a lack of folate in the brain) to a sledge hammer that affects the entire brain (potassium bromide, as an example).

If you have epilepsy and severe aggression then a sledgehammer may well be what you need.

When I first trialed Telmisartan many years ago, I saw that it had an immediate effect, but back then I did not see it as being big enough. It certainly was a nudge, but I was still looking for that mallet, or indeed a sledgehammer. So I moved on.

Last year I revisited Telmisartan and now it is a core therapy. I am happy to include nudge therapies.  

If you have mild autism then a nudge or two maybe all that you need to overcome troubling issues.

If you follow my polytherapy approach for severe autism, then you might select a few nudge therapies and some stronger ones to create a personalized optimization.

 

Telmisartan

Telmisartan is an ARB (angiotensin II type-1 receptor blocker) commonly used to lower blood pressure. But, Telmisartan is thought of best understood not as a single-target drug, but as a system-level regulator.

Telmisartan is highly fat soluble (lipophilic) so it can penetrate the brain and even your bones. Bones matter for old people and all people with level 3 autism.  

Bones are a weak point in severe autism due to the side effects of drugs commonly used, poor diet, lack of exercise and specific genetic issues (in some monogenic autisms).

Bone is not inert. It has active RAAS signalling, telmisartan reaches bone tissue and blocks local AT₁ signalling, reduces inflammatory and oxidative tone in bone microenvironments. Via PPAR-γ, can influence osteoblast/osteoclast balance improving bone density

So an unexpected nudge towards stronger bones. 

The core actions

• AT₁ receptor blockade (RAAS modulation)
  Reduces chronic angiotensin II signalling, lowering background stress, sympathetic drive, and neurovascular strain.
• PPAR-γ partial agonism
  Improves metabolic efficiency, mitochondrial function, and lipid–glucose handling; contributes to anti-inflammatory effects.
• Autonomic calming
  Lowers sympathetic tone and stress reactivity without sedation. This a nudge effect towards better sleep, in some people
• Anti-inflammatory and antioxidant effects
  Indirectly reduces microglial activation and oxidative stress signalling. Microglia are the brain’s immune cells and can be in state of constant activation, which blocks them doing their basic housekeeping duties.
• Neurovascular effects
  Improves cerebral blood flow regulation and oxygen–nutrient delivery. In many types of severe autism, and also in dementia, the brain is unable to produce enough fuel (ATP). While there are many possible factors involved a key one is delivery of glucose and oxygen from your blood.

 

Indirect downstream effects (relevant to neurodevelopment)

• Improved cellular energy status
  Supports ion-pump function and transporter regulation. This is a nudge by improving the environment, Telmisartan does not force the ion-pumps directly
• Stabilisation of chloride homeostasis (indirect)
  Biases the NKCC1–KCC2 balance toward better chloride extrusion in vulnerable circuits, without forcing a gradient shift.

This is the big plus for bumetanide responders

Neuronal chloride levels are set by the balance between NKCC1 (chloride import) and KCC2 (chloride extrusion).

In some with autism the GABA development switch failed to activate after birth and so NKCC1 is overexpressed and KCC2 is under expressed

Stress, inflammation, and high activity increase NKCC1 influence and chloride loading.

KCC2 function is energy- and redox-dependent, and degrades under metabolic strain.

Telmisartan does not directly block NKCC1 or activate KCC2.

By reducing RAAS-driven stress signalling, it lowers pressure toward chloride accumulation.

Improved metabolic and redox conditions stabilise KCC2 membrane function.

Reduced autonomic overdrive lowers activity-dependent chloride loading.

The net effect is a bias toward more reliable chloride extrusion in vulnerable circuits.

This stabilises inhibition without forcing a chloride gradient shift, which KBr the sledgehammer would do. 

• Reduced excitability pressure
  Lowers the likelihood that inhibitory signalling becomes destabilised under stress.

 

Theoretical functional consequences (when it works)

• Lower baseline arousal and irritability
• Improved mood stability
• Increased behavioural flexibility
• Greater tolerance of sensory and cognitive load
• Enhanced availability for learning and interaction

 

My experience

When I conducted my review of “all autism” several years ago I did look at angiotensin. It looked to me that Telmisartan ticked many of the boxes for a cheap generic drug that could be repurposed for autism.

I did trial it and noted an immediate mood improvement with the strange effect of making Monty want to sing.

Several years later trialing it again. Again mood improved, there was no singing, but there was a desire to dance.

It also makes him less rigid. The best example is that when he empties the dishwasher he very clearly now puts things back in different places. You could argue this is negative, or you could see that as expressing his will rather than robotically following a pattern. More on that in the basal ganglia section.

The Basal Ganglia

The basal ganglia is the part of the brain that drives conditions like Tourette syndrome and PANS-PANDAS.

In PANS-PANDAS the immune system temporarily hijacks basal ganglia signalling. This is reversable, with prompt treatment.

The basal ganglia do not generate behaviour.

They gate behaviour.

When basal ganglia inhibition is stable:

• unwanted actions are quietly suppressed  (no tics)
• chosen actions feel voluntary
• habits can be overridden (no autistic rigidity)
• novelty is possible (try new foods, or watch a different cartoon) 

When basal ganglia function is disrupted (by genetics, inflammation, chloride instability, dopamine imbalance, Purkinje cell loss):

• the repertoire of behaviours is still there
• the motor programs still exist
• the thoughts still arise

What is lost is control over which ones fire. This manifest in autism as

Rigidity and stereotypies

• Repetitive behaviours are not “added”
• They become locked in
• Alternative actions cannot pass the gate

The system defaults to what feels safe and known.

This links to 2 further subjects of interest:

·        Purkinje cell loss in severe autism
·        ARFID (Avoidant/Restrictive Food Intake Disorder)

 

Purkinje cell loss as one possible driver of basal ganglia dysfunction

Purkinje cells are the very large, energy-intensive output neurons of the cerebellar cortex, providing continuous inhibitory timing signals to the deep cerebellar nuclei.

During the first two years of life, rapid brain growth creates extreme ATP demand, and transient mitochondrial or metabolic shortfalls can cause brief “power outages.” Because Purkinje cells are among the largest and most metabolically demanding neurons, they are selectively vulnerable and may be lost early, in a patchy and permanent manner. This a classic finding in port-mortem brain studies of people who had severe autism.

Purkinje cell loss leads to clumsiness and dyspraxia, because the cerebellum’s output signal loses timing precision, causing movements to be poorly planned, sequenced, and adjusted despite normal muscle strength. It does not lead to paralysis.

The resulting noisy cerebellar output propagates via thalamocortical loops to the basal ganglia, where it destabilizes action-selection and gating, particularly in the context of immature chloride regulation and weakened GABAergic inhibition.

Although the original cerebellar injury cannot be reversed, downstream circuits remain plastic, allowing pharmacological “nudges” such as bumetanide, atorvastatin, and telmisartan to partially restore inhibitory precision, improve basal ganglia gating, and reopen a window of motor-cognitive flexibility.

 

ARFID (Avoidant/Restrictive Food Intake Disorder)

ARFID can be the feeding expression of the same underlying circuit problem.

The framework explains ARFID extremely well, especially the autism-associated form of ARFID. In fact, it explains it better than sensory-only models. 

ARFID through the basal ganglia “gate” lens

Repetitive behaviours are not added — they become locked in.
Alternative actions cannot pass the gate.
The system defaults to what feels safe and known.

That description fits ARFID almost perfectly. 

In autism and related neuroimmune states, ARFID often acts as a behavioural marker of basal ganglia gating dysfunction, reflecting loss of choice rather than loss of appetite.

ARFID is not always basal ganglia–driven.

There are other ARFID subtypes:

• trauma-based (choking/vomiting)
• primary sensory aversion
• gastrointestinal pain–avoidance
• appetite dysregulation from meds or illness

But in autism-associated ARFID, especially when it:

• fluctuates with stress or illness
• coexists with rigidity, tics, OCD traits
• improves alongside mood and flexibility

the basal ganglia model fits extremely well. 

Blunt pharmaceutical treatment (sledgehammer) of ARFID does not work. Nudges seem a better choice. Nudges can be behavioral, or biological. 

Beyond telmisartan, the most promising pharmaceutical nudges for ARFID are likely those that reduce immune and autonomic stress on basal ganglia circuits while preserving motivation and behavioural flexibility, rather than suppressing output.

Many autism interventions provide a nudge to better functioning of the basal ganglia (NAC, ALA, low dose clonidine, atorvastatin etc).

Indeed one notable immediate effect of atorvastatin on Monty 14 years ago, was that he starting to come downstairs from his bedroom by himself, and not get “stuck” at the top of the stairs awaiting instructions.

I used to call this cognitive inhibition, but perhaps the gating model explains it better.

 

What the behaviour actually shows

“Stuck at the top of the stairs awaiting instructions”
is not a strength or balance problem.

It reflects:

• failure of self-initiated action
• dependence on external cueing (prompt dependence, in ABA terminology)
• intact ability, but blocked execution

That already points away from motor cortex and toward action-selection systems.

 

Basal ganglia explanation

Basal ganglia = action gating, not movement generation

The basal ganglia decide:

• when an action is allowed to start
• whether it is safe to proceed without prompting

In autism (and related neuroimmune states), this gate can become over-conservative:

• “wait”
• “don’t move”
• “need instruction”

So the child:

• knows how to go downstairs
• but cannot release the action independently

 

Why stairs are a perfect stress test

Descending stairs requires:

• motor sequencing
• balance prediction
• suppression of fear/uncertainty
• confidence in outcome

Basal ganglia dysfunction often shows up first in:

• transitions
• initiation
• descending movements
• unprompted actions

So “stuck at the top of the stairs” is a classic gating failure.

 

Why atorvastatin could change this quickly

Atorvastatin did not:

• teach a new skill
• strengthen muscles
• improve coordination

What it plausibly did was reduce a state constraint.

Immune / inflammatory relief

If there was:

• low-grade neuroinflammation
• immune-driven basal ganglia noise

Then dampening that can:

• lower threat signalling
• stabilise dopamine–GABA balance
• relax excessive inhibitory gating

When that happens:

actions that were already available suddenly “go.”

That can be rapid.

 

Reduced “protective inhibition”

In stressed systems, the brain sometimes actively prevents independence:

• to avoid risk
• to avoid uncertainty

Once the stress signal drops, the system stops applying the brake.

This feels like:

• confidence
• initiative
• independence

 

Why instruction dependence disappears

Needing instruction is a workaround:

• the external cue substitutes for internal gating
• the basal ganglia borrow cortical direction

When gating improves:

• the workaround is no longer needed
• behaviour becomes self-initiated

This is not just basal ganglia

Other systems likely contributed:

Cerebellum

• prediction of movement outcome
• timing and sequencing
• fear of misstep

Cerebellar function improves when:

• inflammation drops
• prediction error decreases

Autonomic system

• high sympathetic tone increases “freeze”
• calming allows movement initiation

Confidence loop

• once one successful descent occurs
• future attempts are easier
• habit loop updates

But the gatekeeper is still basal ganglia.

 

Conclusion

The basal ganglia are not “movement centres” in the simple sense.
They are action–selection and state–selection systems.

They decide:

• which action to initiate
• when to initiate it
• whether to repeat the same pattern or explore a new one
• how much reward, pleasure, and motivation is attached to action

They sit at the junction of:

• movement
• mood
• motivation
• habit
• flexibility

That is why basal ganglia changes show up as movement + emotion + novelty, all together.

 

Basal ganglia are especially sensitive in autism

Basal ganglia circuits:

• are GABA-heavy
• are chloride-sensitive
• rely on finely balanced inhibition
• are vulnerable to stress, inflammation, and metabolic strain

When inhibition in these circuits is unstable:

• action initiation becomes effortful
• behaviour becomes repetitive and rigid
• novelty feels unsafe
• mood flattens or becomes anxious

What changed biologically (without forcing anything)

When inhibition becomes more reliable (not stronger, just more predictable):

• neurons fire when they should, not erratically
• “gating” improves and actions can pass through more smoothly
• reward signals are no longer drowned out by noise

 

Why did Monty become happier

Mood is not just cortical thought, it is basal ganglia tone.

With better inhibitory stability:

• dopamine signalling becomes cleaner
• reward prediction improves
• the background “threat” signal drops

The result is:

• spontaneous positive affect
• relaxed facial expression
• joy without obvious cause

This is state change, not learned happiness.

 

Why the urge to dance appears

Dancing is a near-perfect basal ganglia readout.

It requires:

• effortless movement initiation
• rhythmic pattern generation
• reward linked directly to motion

When basal ganglia output is constrained:

• movement feels heavy
• initiation is delayed
• spontaneous rhythm disappears

When the constraint lifts:

• movement becomes intrinsically rewarding
• the body “wants” to move
• rhythm emerges without instruction

That is why dancing appears before language or cognition improves.

 

Why he emptied the dishwasher differently

Changing how a familiar task is done means:

• the brain is no longer locked into a single motor–habit template
• alternative action sequences are now selectable
• exploration feels safe

This is classic basal ganglia flexibility.

Nothing taught him that new method.

The system simply allowed another option to pass through the gate.

 

 

 

ARBs and ACE inhibitors for Autism, an old Peter idea finally explored in a research model

 

 A home run? Certainly worth further consideration. 

When I was doing my review of unexplored potential autism therapies several years ago, I did look at two closely related classes of drugs. ARBs and ACE inhibitors.

I wrote about it in blog posts and set out why I thought the ARB telmisartan was the best one to trial first.

 

           Targeting Angiotensin in Schizophrenia and Some Autism          

Just when you thought we had run out hormones to connect to autism and schizophrenia, today we have Angiotensin.

Angiotensin is a hormone that causes vasoconstriction and a subsequent increase in blood pressure. It is part of the renin-angiotensin system, which is a major target for drugs (ACE inhibitors) that lower blood pressure. Angiotensin also stimulates the release of aldosterone, a hormone that promotes sodium retention which also drives blood pressure up.

Angiotensin I has no biological activity and exists solely as a precursor to angiotensin II.

Angiotensin I is converted to angiotensin II  by the enzyme angiotensin-converting enzyme (ACE).  ACE is a target for inactivation by ACE inhibitor drugs, which decrease the rate of Angiotensin II production.  

It turns out that Angiotensin has some other properties very relevant to schizophrenia, some autism and quite likely many other inflammatory conditions. 

Blocking angiotensin-converting enzyme (ACE) induces those potent regulatory T cells that are lacking in autism and modulates Th1 and Th17 mediated autoimmunity.  See my last post on Th1,Th2 and Th17. 

In addition, Angiotensin II affects the function of the NKCC1/2 chloride cotransporters that are dysfunctional in much autism and at least some schizophrenia.

Then I wrote another post and made a trial of Telmisartan.

Angiotensin II in the Brain & Therapeutic Considerations

I was pleased to see that some researchers have recently published a paper on this subject. They chose an ACE inhibitor called Captopril.

 

Captopril restores microglial homeostasis and reverses ASD-like phenotype in a model of ASD induced by exposure in utero to anti-caspr2 IgG

Microglia play a crucial role in brain development, including synaptic pruning and neuronal circuit formation. Prenatal disruptions, such as exposure to maternal autoantibodies, can dysregulate microglial function and contribute to neurodevelopmental disorders like autism spectrum disorder (ASD). Maternal antibodies targeting the brain protein Caspr2, encoded by ASD risk gene Cntnap2, are found in a subset of mothers of children with ASD. In utero exposure to these antibodies in mice leads to an ASD-like phenotype in male but not in female mice, characterized by altered hippocampal microglial reactivity, reduced dendritic spine density, and impaired social behavior. Here, we studied the role of microglia in mediating the effect of in utero exposure to maternal anti-Caspr2 antibodies and whether we can ameliorate this phenotype. In this study we demonstrate that microglial reactivity emerges early in postnatal development and persists into adulthood following exposure in utero to maternal anti-Caspr2 IgG. Captopril, a blood-brain barrier permeable angiotensin-converting enzyme (ACE) inhibitor, but not enalapril (a non-BBB permeable ACE inhibitor) ameliorates these deficits. Captopril treatment reversed microglial activation, restored spine density and dendritic arborization in CA1 hippocampal pyramidal neurons, and improved social interaction. Single-cell RNA sequencing of hippocampal microglia identified a captopril-responsive subcluster exhibiting downregulated translation (eIF2 signaling) and metabolic pathways (mTOR and oxidative phosphorylation) in mice exposed in utero to anti-Caspr2 antibodies treated with saline compared to saline-treated controls. Captopril reversed these transcriptional alterations, restoring microglial homeostasis. Our findings suggest that exposure in utero to maternal anti-Caspr2 antibodies induces sustained neuronal alterations, microglial reactivity, and metabolic dysfunction, contributing to the social deficits in male offspring. BBB-permeable ACE inhibitors, such as captopril, warrant further investigation as a potential therapeutic strategy in a subset of ASD cases associated with microglial reactivity.

 

So here is an update that incorporates all these ideas and the new study.

 ___ 

Targeting the Brain Renin-Angiotensin System: From Schizophrenia to Autism (2025 Update)

By Peter Lloyd-Thomas, Epiphany ASD Blog

In 2017, I wrote about the idea that drugs targeting the renin–angiotensin system (RAS)—ACE inhibitors and ARBs—might have therapeutic effects beyond blood pressure, including in schizophrenia and autism. At that time, the discussion was mostly mechanistic. Today, new evidence strengthens the rationale and provides translational plausibility.

 

Why the Brain RAS Matters

While angiotensin II is best known for regulating blood pressure, the brain has its own RAS, which regulates:

·         AT₁ receptors → oxidative stress, neuroinflammation, microglial activation

·         AT₂ and Mas receptors → neuroprotection, mitochondrial function, anti-inflammatory signaling

·         ACE → converts Angiotensin I → II and degrades bradykinin, affecting cerebral blood flow

Shifting the balance from AT₁-dominated to AT₂/Mas signaling can normalize microglial function, improve neuronal energy metabolism, and support synaptic plasticity.

 

New Autism-Relevant Evidence (2025)

A recent study (Spielman et al., Molecular Psychiatry, 2025) used a mouse model of maternal anti-Caspr2 antibodies, a risk factor for some forms of autism. Male offspring showed:

·         Hyperactive microglia

·         Reduced hippocampal dendritic spines

·         Impaired social behavior

Captopril, a BBB-penetrant ACE inhibitor, reversed these deficits. In contrast, enalapril, which poorly crosses the BBB, was ineffective. Single-cell RNA sequencing revealed captopril restored microglial metabolic homeostasis (mTOR, oxidative phosphorylation, eIF2 signaling), linking microglial function directly to behavioral outcomes.

 

ACE Inhibitors vs ARBs: CNS and Immune Effects

Feature	ACE inhibitors (e.g., captopril)	ARBs (BBB-permeable, e.g., telmisartan)
↓ Ang II	Yes	No (blocks AT₁ receptor)
↑ Bradykinin / NO	Yes	No
BBB penetration	Variable — captopril high, enalapril low	Most low; telmisartan high
Microglial activation	↓ via less Ang II & more NO	↓ via AT₁ blockade
NKCC1/2 chloride cotransporters	Normalized via ↓ Ang II	Normalized via AT₁ blockade
Regulatory T cells (Tregs)	Strong ↑	Moderate ↑ (telmisartan strongest among ARBs)
Th1/Th17 autoimmunity	Modulated ↓	Modulated ↓
PPAR‑γ activation	No	Yes (telmisartan)
Evidence in ASD model	Captopril reversed phenotype (2025)	Mechanistically promising; anecdotal human benefit

Both classes modulate neuroinflammation, chloride signaling, and immune function, but ACE inhibitors and ARBs differ in mechanisms and potency.

 

Clinical Evidence in Schizophrenia

Telmisartan has been trialed in adults with schizophrenia (NCT00981526), primarily for metabolic side effects of antipsychotics (clozapine, olanzapine). Secondary observations included:

·         Improvement in negative symptoms

·         Modest cognitive benefits

·         Good tolerability over 12 weeks

This demonstrates CNS activity in humans, beyond metabolic effects, supporting translational plausibility for neuropsychiatric conditions.

 

Personal Observation in Autism

Years ago, I trialed telmisartan in my son. The effect was striking: he began singing spontaneously—something no other therapy had achieved. Singing engages emotion, motivation, and executive coordination, all dependent on healthy microglial and neuronal metabolism. While anecdotal, this observation aligns with mechanistic insights from both the mouse autism model and schizophrenia trials.

 

Safety and Accessibility

ACE inhibitors and ARBs are:

·         Widely prescribed globally for hypertension and heart protection

·         Generic, inexpensive, and safe in adults

·         Typically well-tolerated (ACE-i cough, hypotension, mild electrolyte changes)

This makes them practical candidates for drug repurposing in neurodevelopmental and neuropsychiatric disorders.

 

Mechanistic Summary

1.     Microglial hyperactivation contributes to synaptic and behavioral deficits in some autism subtypes.

2.     Brain RAS modulation (ACE-i or ARB) restores microglial homeostasis, improves energy metabolism, and supports synaptic plasticity.

3.     NKCC1/2 chloride cotransporter regulation: By reducing Ang II (ACE-i) or blocking AT₁ (ARB), these drugs normalize intracellular chloride, restoring proper GABAergic inhibition.

4.     Immune regulation: ACE inhibition induces regulatory T cells (Tregs) and modulates Th1/Th17 autoimmunity. BBB-penetrant ARBs like telmisartan also modulate these pathways, enhanced by PPAR‑γ activation.

5.     Behavioral outcomes: In mice, captopril reverses ASD-like phenotypes; anecdotal human reports suggest telmisartan may improve engagement, motivation, and communication.

 

Next Steps for Research

·         Carefully designed biomarker-driven pilot trials in humans, selecting individuals with evidence of neuroinflammation or maternal autoantibody exposure.

·         CNS-focused outcome measures (microglial imaging, inflammatory markers, synaptic function).

·         Behavioral endpoints relevant to autism (social interaction, expressive communication).

Or skip that and maybe make an n=1 trial?

 

Take-Home Message

Drugs long used for cardiovascular health may have untapped potential in neurodevelopmental and neuropsychiatric disorders. BBB-penetrant ACE inhibitors and ARBs, particularly telmisartan, can modulate:

·         Microglial activity

·         Neuronal chloride gradients

·         Immune regulation

Recent mouse data (Spielman et al., 2025) and human observations in schizophrenia support mechanistic plausibility and safety, making these drugs promising candidates for further study in selected autism subgroups.

 

References and Further Reading:

Spielman et al., Molecular Psychiatry, 2025: Captopril restores microglial homeostasis in anti-Caspr2 ASD model

NCT00981526, Telmisartan in schizophrenia (Fan X, 2018)

Lloyd-Thomas, 2017: Angiotensin II in the Brain

Lloyd-Thomas, 2017: Targeting Angiotensin in Schizophrenia and Some Autism