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