“The treatment didn’t fail, the trial did.” Here we go again with Memantine

They are all pizza, but each slice (sub-group) is very different. Only one has pepperoni 😋 and that’s the one memantine helps!

Older regular readers will be familiar with the large, well-funded trial that started a decade ago of Memantine/Nameda for autism. It had been a widely used off-label therapy for autism in the US. The regulator asked the producer to fund a large clinical trial.

The trial failed because Memantine was shown to be no more beneficial than the placebo. That trial had 400 participants and really should have been able to identify any large sub-groups that did respond. But, it did not.

I saw that a new Memantine trial has just been published, and guess what, they found that Memantine was beneficial and they used a special kind of MRI to try and identify that sub-population.

What struck me was the type of autism population they used to make the trial. You can look at IQ, comorbid diagnosis and even what other drugs the trial subjects are already on.

Here are some stand outs:

·        The average IQ in the placebo group was 110. That is top 25% by IQ.

·        Three quarters have ADHD and multiple anxiety disorders.

·        More than half have major depression.

·        In the treatment group 20% have psychosis.

That has very little in common with my son’s presentation of “autism.”

I think it would have been better to summarise this as a trial of Aspies with ADHD, who are also likely to be very unhappy.  That is a very valid treatment group, but the word autism does not fully capture it. These could be described as “lost souls.” 

The 2025 JAMA trial shows that memantine is not a failure for autism — it’s effective for a biologically distinct, high-glutamate subgroup, often corresponding to high-IQ, emotionally dysregulated “Lost Souls” autism.

My blog was always targeted at severe types of autism, but many of the messages I receive are from people with normal to high IQ, fully verbal but deeply troubled.

You can slice the autism pizza however you like. Here are some possible slices:

·        Classic autism / Profound autism / Kanner’s autism

·        Lost souls

·        Quirky autism, Aspies, some super-brainy, but most not

·        Sub-threshold autism, self-diagnosed autism, attention-seeking diagnosis

Back to the recent trial

·        All Memantine responders had high glutamate levels, and 80% of participants with  high glutamate levels were memantine responders. 

·        Notably, the abnormally high levels of glutamate were not universal but were limited to 54.0% (n = 20 of 37) of participants with ASD 

So applying some common sense:

·        Half of “Lost souls” autism (high IQ) are likely to have high glutamate when measured in the special MRI

·        80% with this biomarker are likely to find their social impairments are reduced by Memantine. 

Hurrah !!!!  

(particularly if that Lost souls definition applies to you, or your child)

The researchers themselves summarise the results as

“In this study, treatment with memantine was superior to placebo in improving social behaviors. Youths who received memantine had 4.8 times the odds (95% CI, 1.1-21.2) of responding to treatment compared with placebo. The NNT statistic was robust (NNT = 3), indicating that 1 in 3 memantine-treated youths with ASD would respond to treatment.” 

I think the autism sample in the trial is a little odd, so I will stick to my interpretation.

If about 40% of this lost souls autism really do respond to well to 20mg a day of Memantine, why did this not show up in the 2018 trial that costs many millions of dollars? That trial excluded kids with IQ ≤70 and also required at least moderate severity of social impairment.

The IQ cut off at 70 would exclude all profound autism and about 70% of Classic/Kanner’s autism.  There really should have been plenty of responders in the 2018 trial. Was the dose too low? Somebody may have wasted $20 million in trial costs.

Memantine to Treat Social Impairment in Youths With Autism Spectrum Disorder

A Randomized Clinical Trial

Several glutamate-modulating agents, including lamotrigine, amantadine, and N-acetylcysteine, have been evaluated as potential treatments for the core symptoms of ASD, demonstrating only modest efficacy.^26-30 In contrast, preliminary data from retrospective and prospective uncontrolled trials of memantine hydrochloride, with its unique mechanism of action as a moderate-affinity noncompetitive NMDA receptor antagonist, have been promising, reporting an acceptable safety and tolerability profile and substantial improvements in SCI and RRBs in youths and adults with ASD.^31-33 However, the only controlled trial of memantine in children to date, while showing improvements in ASD behaviors, failed to demonstrate superiority over an equally robust placebo response; this is likely due to the low dosing and inclusion of participants with intellectual disability, which did not adequately assess memantine’s efficacy in individuals with ASD without intellectual disability.³⁴ Addressing these limitations, preliminary findings from an uncontrolled trial of memantine at dosages of up to 20 mg/d in adults with ASD without intellectual disability demonstrated substantial improvements in social behaviors.³⁵

Spectroscopic glutamate levels in the pgACC were significantly elevated by a large magnitude in youths with ASD compared with healthy control participants, replicating previous findings by Joshi et al²⁵ of glutamate dysregulation in individuals with ASD. Notably, the abnormally high levels of glutamate were not universal but were limited to 54.0% (n = 20 of 37) of participants with ASD, with the remainder of participants without any glutamate abnormality.

Treatment response differed based on pgACC glutamate levels in participants with ASD. A significantly greater response rate to memantine compared with placebo was observed in the high-glutamate subsample, whereas no such difference was observed in the medium-glutamate subsample. All memantine responders had high glutamate levels, and the majority of participants with ASD with high glutamate levels were memantine responders (8 of 10 [80.0%]).

 

Why is Memantine used for Alzheimer’s?

In a healthy brain, glutamate is the main excitatory neurotransmitter and is crucial for learning and memory and normal neuronal activation.

In Alzheimer’s, damaged and dying neurons start to leak glutamate into the extracellular space.
This causes chronic, low-level overactivation of NMDA receptors.

That chronic stimulation:

• lets in too much calcium (Ca²⁺)
• triggers oxidative stress and mitochondrial dysfunction
• leads to progressive neuron death — a process called excitotoxicity

Memantine’s mechanism is a partial NMDA block without shutting down normal signaling.

• It binds inside the NMDA receptor channel, only when it’s open (i.e., during overactivation).
• It blocks excessive Ca²⁺ entry, protecting neurons from excitotoxic damage.
• Because its binding is voltage-dependent and rapidly reversible, it does not block normal glutamate transmission needed for learning and memory.

Unlike strong NMDA blockers (e.g. ketamine), memantine is neuroprotective without being sedating or hallucinogenic.

Why are Alzheimer’s drugs so ineffective to treat Alzheimer’s

People start treatment for Alzheimer’s disease 25 years too late.

The biological processes start two decades before the severe symptoms appear and at that point the damage is already done.

For Memantine to be truly effective you would need to start it in your 50s.

Target people very likely to develop Alzheimer’s 25 years early

We already know who is very likely to develop Alzheimer’s. There are the 3% of the general population carrying a double copy of the risk gene, so APOE ε4/ε4.

Then we have everyone with Down syndrome. Amyloid plaques have developed by their 30s and Alzheimer’s is nowadays the leading cause of death in DS.

Why not give the option of preventative treatment? Since it is very cheap and safe.

Elevated extracellular glutamate in autism?

Many studies suggest that extracellular glutamate levels are elevated in autism, at least in certain brain regions and in subgroups of individuals.

Magnetic Resonance Spectroscopy (MRS) — often called MR Spectroscopy — is a non-invasive imaging technique that is closely related to MRI, but instead of showing brain structure, it measures brain chemistry.

MRS studies show elevated glutamate or glutamine + glutamate levels have been found in regions such as:

• Anterior cingulate cortex (ACC / pgACC)
• Basal ganglia
• Hippocampus
• Thalamus

In today’s study the biomarker for responders was elevated glutamate in the Anterior cingulate cortex (ACC / pgACC)

Excluding people from autism trials based on IQ

It is increasingly common to exclude children from autism trials based on low IQ.

The right approach is probably to have separate trials for those with IQ less than 80. Then you can adapt the assessment process to suit people with limited communication and cognitive skills.

As more and more people want to get diagnosed with level 1 autism, the relevance of those at level 3 tends to get minimized. This does upset many parents.

I actually believe that raising IQ should be an endpoint in some autism trials. It is meaningful and measurable. I was very surprised to discover that you can raise IQ. Raising IQ by just 10 points is a big deal in classic/profound autism, it then makes all that expensive 1:1 therapy in childhood much more effective.

Conclusion

Memantine is a really cheap Alzheimer’s drug that can help some autistic people with high glutamate in their brain. It has been shown to be very safe.

There are much more expensive drugs like Riluzole.

Riluzole acts on multiple glutamate-related pathways:

·        ↓ Glutamate release from presynaptic neurons

·        ↑ Glutamate reuptake by astrocytes (enhancing EAAT2 transporter activity)

·        Blocks voltage-dependent sodium channels, reducing neuronal overactivation

·        Modulates NMDA and AMPA receptors, dampening excessive excitatory signaling

This results in lower extracellular glutamate, less calcium influx, and protection from oxidative stress and excitotoxicity — a key mechanism in ALS, Alzheimer’s, and possibly some autism.

I did try both Memantine and Riluzole a long time ago. Riluzole caused lethargy, which makes sense.

In Memantine clinical trials, social responsiveness is the measure the researchers always like to focus on.

Some people think the big expensive 2015-2018 trial had the wrong primary endpoint — Memantine might have modestly improve cognitive flexibility or irritability, but those were secondary measures.

The cost of the special MRI scan to diagnose high glutamate in the PgCC (Pre-genual Anterior Cingulate Cortex) is $1000 to $2000. This is way too expensive to be used at a wide scale as a biomarker.

20mg a day of Memantine costs $20 a month in the US and even less everywhere else.

Peter’s approach would be: “don’t overthink it, just try it!”

Do not expect it to be a silver bullet. If it helps, add it to your polytherapy. If there is no positive response, stop the therapy. A good investment of $20, either way.