- [Jeff] Welcome to "Healthy Minds".

I'm Dr.

Jeff Borenstein.

Everyone is touched by psychiatric conditions, either themselves or a loved one.

Do not suffer in silence, with help, there is hope.

(light calming music) Today on "Healthy Minds".

- We've learned a lot about the brain in the past decades, and we've moved beyond the idea that neuropsychiatric diseases are caused by chemical imbalances in the brain.

We now know that they're really diseases of neuro circuits.

And SSRI can promote the growth of those neurons, but it takes daily administration for weeks to months to get that kind of growth, whereas a psychoplastogen can do it in a matter of hours to days.

- That's today on "Healthy Minds".

This program is brought to you in part by The American Psychiatric Association Foundation, The John and Polly Sparks Foundation, and The WoodNext Foundation.

(light calming music) Welcome to "Healthy Minds", I'm Dr.

Jeff Borenstein.

We've seen a lot in the press about the potential use of psychedelic drugs to treat psychiatric conditions.

Today I speak with leading researcher Dr.

David Olson, who's exploring the use of new versions of those drugs that have been changed, so as to not produce the hallucinogenic and other effects, but still have the potential therapeutic effects.

(light calming music) David, thank you for joining us today.

- Great to be here.

- I wanna jump right in and ask you about a term that probably nobody watching the show is heard before, which is psychoplastogens.

What is it?

- Psychoplastogens are chemical catalysts that repair damaged neural circuitry.

Now, many people are surprised to learn that neuropsychiatric diseases like depression, schizophrenia, and others, they're really characterized by changes in the structure of the brain.

And one particular change is the atrophy of a brain region called the prefrontal cortex.

Now, the prefrontal cortex is incredibly important, because it communicates with other brain regions that regulate mood, motivation, fear, and reward.

And so if you have dysfunction of this brain region, you can have a range of neuropsychiatric symptoms.

Now, what psychoplastogens do is they catalyze the repair and regrowth of those neurons to reestablish synaptic connectivity in that brain region to produce not only rapid therapeutic effects, but long lasting therapeutic effects.

And that's really the key with a psychoplastogens is that the therapeutic efficacy lasts well after the drug has been cleared from the body.

- So unlike other medicines that may ameliorate symptoms, this is sort of going to the core of what is bringing the symptoms about, which are those actual changes in the brain?

- Yeah, we've learned a lot about the brain in the past decades, and we've moved beyond the idea that neuropsychiatric diseases are caused by chemical imbalances in the brain.

We now know that there are really diseases of neuro circuits.

And so our goal has been to identify medicines that can repair those circuits to produce lasting therapeutic effects.

The advantage of that is now you don't necessarily need to take a medicine every single day for the rest of your life.

You might take it once, a few times intermittently.

And the hope is that by taking the drug less often you might be able to improve the safety profile of the drug.

If you take any drug daily at high doses for a long period of time, you're bound to get side effects.

But if you're just taking a drug intermittently to repair damage, the hope is that you won't have a lot of the side effects that are associated with common medications for neuropsychiatric diseases right now.

- So when I went to medical school, we thought, science thought, that old brains don't grow new cells, and that old was after the age of two, and we now know that's not true.

And this is taking advantage of that fact that new cells can grow in the brain.

Tell us about that science.

Tell us about how that works.

- Well, we have to be careful, because there's really only a couple of places in the brain where new cells are produced, so-called neurogenesis.

And while some psychoplastogens might induce neurogenesis, that is not really their primary mechanism of action.

Their primary mechanism of action is the growth of cells.

So the cells don't actually die in many of these conditions, they physically wither.

Think of a neuron like a tree.

It would be like the branches were retracting, and if the leaves are the synapses of the neuron, the leaves would fall off.

And what psychoplastogens do is they promote the growth of that arbor so that two trees can link up and communicate with each other.

But they don't necessarily promote the formation of new brain cells in the prefrontal cortex.

- And the action can be very rapid.

Tell us about that.

- It seems that with most of these psychoplastogens, the growth inducing effects occur over the course of about 24 hours, which is much, much more rapid than some of the growth inducing effects of other treatments.

Now, something that's really interesting is that the vast majority of antidepressant therapies that we have available to us now, be they pharmacologic like traditional antidepressants like SSRIs, be they things like electroconvulsive therapy or TMS or acute sleep deprivation or exercise, they all seem to do the same thing.

They promote the growth of these key neurons in the prefrontal cortex.

The difference is the timescale.

An SSRI can promote the growth of those neurons, but it takes daily administration for weeks to months to get that kind of growth, whereas the psychoplastogens can do it in a matter of hours to days.

- I wanna ask you a little bit more about these medicines.

Some of them are the psychedelic medicines that cause other effects, but you are working on medicines that don't have that psychedelic effect.

Tell us about the difference between the two.

- I guess maybe I should start with where I got interested in this field in the first place, and that was with a drug called ketamine.

Ketamine is now approved for treatment resistant depression, at least the S-Enantiomer of ketamine.

But for many years, Racemic ketamine, which is an equal combination of the right and the left hand of ketamine.

People have found that that is very effective for treatment resistant depression.

And a lot of really beautiful mechanistic work suggested that it's long lasting antidepressant effects were probably coming from its ability to promote the growth of those key cortical neurons.

And so when we started our work in this area, we wondered, is ketamine unique, or are there other molecules that might do what ketamine does and promote the growth of these neurons?

And so we started looking very broadly for all different chemical classes of compounds.

And we were really drawn to molecules that had, you know, three important characteristics.

They worked rapidly within 24 hours, they had sustained effects that lasted long after the drug was cleared from the body, and they tended to work across disease indications.

Now remember I mentioned that the prefrontal cortex is a critical hub in the brain.

It's like the conductor of the orchestra.

And so by fixing damage in the prefrontal cortex, you might imagine that you could have effects in depression or in anxiety disorders, et cetera.

Taking those considerations into account that really led us to start studying classic serotonergic psychedelics, like psilocybin, LSD, 5-methoxy-dimethyltryptamine.

Now ketamine is not a psychedelic compound, it's a dissociative anesthetic.

But we were really wondering if psychedelics could do what ketamine is capable of.

And we found many years ago that this seems to be the case.

That psychedelics are particularly good at promoting the growth of those key neurons.

Now, we thought that psychedelics might have advantages to ketamine for a number of reasons.

One of the reasons is the localization of their key receptor.

The receptor that mediates psychedelic induced neuroplasticity is a particular serotonin receptor called the serotonin 2A receptor.

And that receptor is highly expressed exactly where we want it to be.

It's on those neurons that tend to atrophy in response to chronic stress or in many neuropsychiatric diseases.

So we thought that psychedelics might have some circuit level selectivity kind of embedded within them already.

And so we started studying them broadly.

Now, after we made the discovery that psychedelics could promote this cortical neuron growth, and perhaps that could explain their enduring effects, effects that can last months after a single dose, we wondered could we separate the hallucinogenic effects of psychedelics from their beneficial effects on this neuroplasticity, this cortical neuron growth.

And we did this a variety of different ways.

The first way is with dose.

We started just giving sub hallucinogenic doses of psychedelics.

And we found that we could achieve beneficial behavioral effects in the absence of the characteristic hallucinogenic behavioral effects.

The second is with using some clever molecular tools for manipulating circuits.

And we were able to genetically tag psychedelic responsive neurons in the prefrontal cortex, and then activate them with light in the absence of drug.

And when we do that, we can drive a therapeutic response, but no hallucinogenic response.

And that told us that the circuits were different.

And if the circuits are different, we hoped that we might be able to engineer a small molecule that can take advantage of that difference, and turn on the plasticity without the hallucinations.

And that led to the evolution of what are now called non hallucinogenic psychoplastogens, or some people call them neuroplastogens.

Because I think it's a mouthful to say non hallucinogenic psychoplastogens.

But the advantage of neuroplastogens is really in the their scalability.

So right now, in order to be administered safely and effectively, you need to give psychedelics in the clinic, usually under the supervision of multiple healthcare professionals.

And that drastically increases the cost, and the complexity of the treatment, and limits the number of patients who can really benefit.

You know, when you consider the fact that one in five people will suffer from a neuropsychiatric disease at some point in their lifetime, we're talking about a billion people worldwide, that is an enormous number.

And so the ideal situation is if we have a medicine that is safe enough that you can just go to your local pharmacy, pick it up, bring it home, put it in your medicine cabinet, and take it as directed by your doctor.

And that was really the impetus for trying to develop these neuroplastogens.

- So the person can take the medicine, not have what may be referred to as the side effects of the hallucinogenic effects, and get the therapeutic effect right away.

And even one dose can bring about that therapeutic effect that lasts over an extended period of time.

- That's the idea.

Now, these drugs are still very early stages.

We've demonstrated in preclinical models that the effects of neuropathogens are just as rapid, and just as robust as psychedelics, because we can compare them head to head.

In humans, there are only a couple that are even at the clinical level.

And one compound in particular, it's called zalsupindole.

Has completed phase one B clinical trials.

And in that study they found that the antidepressant effects were rapid within one week, and that they persisted for at least a month after the drug had been cleared from the body.

And the effect size was rather large.

It was about the exact same effect size as its parent psychedelic compounds, the psychedelic that inspired its structure.

But of course, these need to be replicated in larger phase two and phase three studies.

- You referred earlier to ketamine, which is now a form of ketamine is now available approved by the FDA for refractory depression and it's rapid acting.

But one of the negatives is that the effect doesn't last, that after not that long of a period of time, it wears off.

What's the difference of the mechanism between ketamine and these others that potentially would be longer acting?

- So first I'll say we still don't completely understand how ketamine turns on this growth pathway.

We understand more about how psychedelics turn on the pathway.

We know the target, the target is the serotonin 2A receptor.

It seems that both psychedelics and ketamine turn on the same downstream pathway.

Downstream of their initial receptor activation.

They turn on a particular pathway that involves a couple of kinases.

One is called track B. It is the high affinity receptor for brain derived neurotrophic factor.

And then another kinase called mTOR that is responsible for producing all of the proteins necessary for plasticity.

All of the structural proteins that you need for neuronal growth, all of the ion channels that you need to change synaptic weight.

And so both ketamine and psychedelics turn on that pathway.

It seems that the psychedelics do it more robustly.

And even with psychedelics, their effects may not last forever.

They may last a little than ketamine, but it seems that with re-dosing, you get an even enhanced effect.

And the hypothesis is that in many of these disease states, you have cortical atrophy, some level of atrophy.

And if you give one dose of a psychoplastogen, you can get some rescue of that effect, but you might not rescue all of it.

With subsequent doses, you get more rescue until you finally come back up to baseline, and then hopefully you're in remission for a long period of time.

- You mentioned depression and anxiety.

What other conditions do you see as potentially benefiting from this type of treatment?

- Well, I'm particularly excited about schizophrenia.

One of the hallmarks of schizophrenia is the atrophy of neurons in the cortex.

And for a long time it's been hypothesized that if we could just find medicines that could promote the growth of those neurons, you might have a drug that could not only impact the positive symptoms of the disease, the hallucinations, but also the the negative symptoms, you know, the depression, and the cognitive symptoms of the disease.

Now, psychedelics are an obvious choice to promote the growth of these neurons, but very few people want to give a psychedelic to a patient with schizophrenia for the fear of either exacerbating the condition, or even precipitating it in people who might be prone to schizophrenia.

So in many psychedelic trials, people with a family history of psychosis are excluded.

So this is where I think the neuroplastogens, the non hallucinogenic variants might be very, very useful.

So that is definitely one potential application.

Another is in neurodegenerative conditions.

You'll notice that the early stages of neurodegeneration, the cells don't die.

They atrophy.

And along with that atrophy comes a lot of the biological and psychological symptoms of dementia, which includes changes in mood.

And so a lot of the depression that you see in early on in patients with dementia might be ameliorated by these types of cortical neuron growth promoting medicines.

- For the development of the the newer medicines, what's the timeframe?

How long does it take to get from an idea to actually in somebody's medicine cabinet?

- It takes a long time.

It takes a really long time.

A lot of people will quote the number 20 to 30 years to develop a drug.

We've been trying to move as rapidly as we can with the neuroplastogens.

I can say that, you know, we've been moving at lightning speed so far.

So zalsupindole was a compound that we just, it was an idea in our head back in 20, you know, 20 ish, somewhere around there.

We tested it very quickly pre-clinically.

We then did all the safety testing that we needed.

We moved it into the clinic.

It went through a hundred healthy volunteers to demonstrate that it was indeed non hallucinogenic.

And it was relatively safe, and that it impacted the brain in a way that made us believe that it was likely to impact neuroplasticity.

It was a particular biomarker that might be relevant to neuroplasticity.

And then it moved into the early stages of safety in patients.

But now it still has phase two and phase three trials to continue.

So we're still looking at probably another 10 years before a true neuroplastogen in will be on the market.

- In the meantime, if somebody has severe depression, it's not responding to the typical medicines, or post-traumatic stress, for which some of the psychedelics have been used.

Is that a reasonable approach for people to take under certain circumstances?

- Well, there are a lot of interventions that can promote the growth of these neurons with ketamine being one option.

So if somebody's doctor deems that a viable option, then that's one.

Another is electroconvulsive therapy, which is well known to have very good efficacy in treatment resistant depression.

The problem is that it's not very scalable and it's usually, you know, reserved as kind of a last resort.

There are other options like TMS, and hopefully soon, there will be psychedelic medicines approved as well.

So again, ketamine is not a psychedelic, it is a psychoplastogen.

But there are compounds like psilocybin, 5-methoxy-DMT, LSD, who have really nice phase two and phase three clinical data that if things keep progressing and the FDA deems that they are safe and efficacious, they could be on the market in the near future.

The problem with those drugs is that they're gonna be, you know, a fourth line treatment given the scalability issues, and the cost associated with them.

And so people are gonna have to try a lot of other treatments first before an insurance company is going to be willing to pay for that in-clinic administration.

But hopefully that will provide relief to some patients who haven't responded to other currently available medicines.

- Also, the rapid onset makes a big difference.

So if somebody is depressed and suicidal and at risk of harming themselves, instead of having to spend a significant amount of time for safety reasons in the hospital, they can continue their treatment on an outpatient basis safely.

- That's exactly right.

Another thing to bring up is that some people have propose using neuroplastogens to extend the usefulness of psychoplastogens.

So people either get ketamine or a psychedelic therapy in the clinic to have their initial rapid response, but they use a neuroplastogen on an intermittent basis to greatly extend the efficacy of the initial psychoplastogen treatment.

This is exactly the problem you were mentioning with ketamine, is that it needs to be dosed, you know, six times or so to be truly effective.

And that's challenging if you gotta go into the clinic six times.

But if you have to go into the clinic once, and then you can use a neuroplastogen at home.

After that, you might have substantial value.

- David, we have the psychedelics as you've mentioned.

Why do we need to go further and develop a different type of medicine that doesn't have that psychedelic effect?

- Well, it's important to remember that while psychedelics might have therapeutic properties, they were never engineered to be CNS medicines.

And as a result, every single psychedelic has an issue with it.

The hallucinogenic effects of some psychedelics, they definitely limit the clinical scalability, but that's not the only issue.

Some compounds turn on particular receptors in the heart that can lead to cardiac valvulopathy.

A compound like MDMA has psychostimulant like properties, which can lead to abuse potential.

And a compound like ibogaine binds to an ion channel in the heart that can cause cardiac arrhythmia, and in some cases even death.

And so each of these compounds is unique.

But we can use medicinal chemistry to systematically change their structures, in order to engineer safer versions of them.

Versions that retained the therapeutic benefit, but eliminate not only the hallucinogenic effects, but some of these other adverse side effects.

In addition to the adverse side effects, there are other things about these drugs that are not optimal.

For example, the root of administration, psychedelics like dimethyltryptamine, and 5-MeO-DMT, they're not orally bioavailable.

So you need to take them as an intravenous infusion or as a nasal spray.

And I think most patients would prefer to just simply take a pill.

And so again, if you just tweak their structure, you can make them orally bioavailable.

- So in many ways, the work that you are doing is very different from how drugs were developed in the past, often by serendipity, but you're really looking at the effects.

And then how do you modify the drugs to get exactly the effects that you want, where you want it.

- That's a really good point, is we are not taking a bottom up approach where we start with a completely novel idea, and then work through all of the preclinical and clinical studies to test the hypothesis in the clinic.

No, we're taking a top down approach.

We're starting with drugs like ketamine, psilocybin, 5-Methoxy-DMT, that have known clinical efficacy, and we're just reverse engineering them.

We're simply tweaking their structures to make them better versions of themselves.

- What do you say to somebody watching this show right now who's living with depression, who is hearing this hopeful message?

What should their thoughts about this be?

- That there's hope, there's hope.

We, you know, I've heard people say that we are, today where cancer biology was 20 years ago.

In neuropsychiatry, we've learned so much about the brain that we are finally getting to the point where we might be able to rationally engineer new medicines.

A lot of the medicines that we have from the past were kind of discovered by accident, you know, serendipity.

But now with a better understanding of brain science, we are getting closer to be able to rationally design these compounds.

But that requires a lot of effort and a lot of basic science.

We still have so much to learn about the brain, and we're gonna have to continue that type of basic scientific discovery if we're ever gonna truly have the chance to rationally design these types of medicines.

- Well, David, this is a very hopeful picture.

And I think a realistic picture.

And I appreciate you joining us today, and more importantly, the work that you've done in this area, which can really ultimately be a game changer for psychiatric care for so many people.

- Thank you, Jeff.

(light calming music) - Today we heard about the potential development of new medications that can help even more people who are living with psychiatric conditions.

Basically, the next generation of treatments.

Remember with help, there is hope.

(light calming music) Do not suffer in silence.

With help, there is hope.

This program is brought to you in part by, The American Psychiatric Association Foundation, The John and Polly Sparks Foundation, and The WoodNext Foundation.

(light calming music) (light calming music continues) (light calming music continues) (light calming music continues)