Expert: Psychedelics, Other Psychoplastogens Heal the Physical Damage Associated With Many Brain Disorders, Mental Health Disorders

Pharmacy Times interviewed David Olson, PhD, the chief innovation officer, head of scientific advisory board, and co-founder of delix therapeutics and an associate professor in the department of biochemistry and molecular medicine at University of California, Davis, on a recent paper he co-wrote on psychedelics and other psychoplastogens for treating mental disorders.

Alana Hippensteele: What is a psychoplastogen, and why is understanding this class of compounds important for psychedelic research?

David Olson: A psychoplastogen is a small molecule that is really good at promoting neural plasticity and allowing the brain to actually heal the physical damage that is associated with a lot of brain disorders. The reason that understanding this class of compounds is really important for psychedelic research is because psychedelics are among the most potent psychoplastogen that we know of.

Alana Hippensteele: How do psychoplastogens work differently than other compounds used for treating brain disorders?

David Olson: So, many compounds that are traditionally used to treat brain disorders simply mitigate disease symptoms, but they don't really address the underlying issue with the disease. In the case of psychoplastogens, they physically rewire the brain to get at the root cause of these illnesses.

An analogy I like to make is if your light goes out in your living room, you can use a flashlight to get around, and that would be like a traditional treatment, but what a psychoplastogen is more akin to is like an electrician that would come in and fix the broken wiring so that you can actually turn that light on again.

Alana Hippensteele: Are the origins of all psychoplastogens naturally occurring?

David Olson: Not necessarily. One of the best known psychoplastogens is a molecule called ketamine which is a completely synthetic compound and not produced in nature.

Alana Hippensteele: Just to follow up on that point, I understand ketamine isn't always placed in the same category as some other psychedelic medicines. Would you say that under the psychoplastogen category, it would align with the others even if it doesn't have the same psychedelic effects—is that the case?

David Olson: Yeah, that's right, and that's one of the reasons that we defined this new term psychoplastogen, really describing the ability of these molecules to change neural structure and function.

If you get 10 neuropharmacologist in the room and ask them to define different classes of molecules, you get 10 different answers. So, defining compounds has always been a challenge for neuropharmacology.

Some people will lump ketamine into the psychedelic class, some will not, but ketamine and traditional classic serotonergic psychedelics, like LSD and psylocibin, they are all psychoplastogens.

Alana Hippensteele: What are some other examples of psychoplastogenic compounds that would not belong to the psychedelic space or the ketamine space?

David Olson: Sure. So, one of the first ones that come to mind is a molecule called scopolamine. It's a deliriant, so it does have some these psychoactive effects, but it is not traditionally lumped into the same class as something like LSD or ketamine.

A few other examples would be something like this molecule called GLYX-13, it's also known as rapastinel. There's a lot of preclinical work demonstrating that it seemed to produce long lasting changes in neural structure and function after a single administration.

Then probably one of the fastest growing classes are the molecules that delix works on, and these are so-called non-hallucinogenic psychoplastogens. They don't have the same types of hallucinogenic effects as compounds like LSD, but they still produce really long lasting behavioral effects after a single administration.

Alana Hippensteele: How does eliminating the hallucinogenic effect impact the therapeutic benefit. Does it increase it, does it allow for it to be more sustained—how does that work exactly?

David Olson: So, at the moment there's no human data on these non-hallucinogenic psychoplastogens. So, time will tell—we'll have to really look at the human data to know for sure.

But on the preclinical side, what I can say is that the non-hallucinogenic psychoplastogens produce efficacy that is comparable to the hallucinogenic counterparts. So, what we can do is we can use benchmark compounds that have been used in the clinic, things like SSRIs, as traditional antidepressants, which are pretty slow acting, and they don't work after a single administration. And then we can use things like ketamine and psilocybin as examples of these next generation psychoplastogen medicines, and the non-hallucinogenic psychoplastogen seem to be a lot more like ketamine and psilocybin and less like traditional antidepressants.

Alana Hippensteele: How might introducing psychedelics to the treatment paradigm, or specifically psychoplastogens to the treatment paradigm, change how we think about brain disorders and mental illness and their root cause?

David Olson: Yeah, this is a really important question that really gets at the heart of modern neuroscience in our understanding of the brain.

So, for many years we thought that brain disorders were simply a result of chemical imbalances in the brain. Now, we consider them to be disorders of neural circuits. So, there's faulty neural circuitry that needs to be fixed. The paradigm shift with psychoplastogens is in their ability to physically rewire neural circuits to heal damaged circuitry.

Alana Hippensteele: What are some of the challenges with psychedelic medicine in relation to clinical scalability?

David Olson: So, currently the way psychedelic-assisted psychotherapy works is you go into the clinic to prepare you for the session, and then you come in for the administration of the drug, which can take a fair amount of time. In the case of psilocybin, we're talking about 6 to 8 hours or so.

Suring that time, you're typically in the room with a couple of medical professionals that can guide you through that experience to make sure everything is safe, and then you come back for an integration session as well.

So, in total there's a lot that goes into it, and that can be incredibly costly, and it really kind of hampers the throughput, or the number of patients that can actually benefit from this type of treatment paradigm. So, if you want a scalable medicine, really what you want is something that is safe enough that you can take it home with you, put it in your medicine cabinet, and you don't have to go into the clinic to receive it all the time, and that's really what I think these non-hallucinogenic cycle pathogens really allow for—they greatly expand the patient population that can receive psychoplastogenic medicines.

Alana Hippensteele: What are some of the key takeaways from your recently published paper—maybe just a little bit more detail into the study?

David Olson: So, this paper really has 3 key points to take away from it. The first is the idea of using structural neuroplasticity to our benefit so that we can actually physically rewire the brain and to heal damaged neural circuits. I think this is a completely new approach in neuropsychiatry.

The second really has to do with the idea of psychoplastogens working across disease indications. So, now something that I think is really important to remember is that cortical atrophy, or the physical withering of neurons in a key brain region is really at the heart of a wide variety of brain diseases, such as depression, PTSD, substance use disorder, and many others. So, the reason that psychoplastogens seem to work for multiple indications is because they address the root cause of all of these disorders.

Then the third key point to take away is the idea of using non-hallucinogenic psychoplastogens as more scalable approaches compared to first generation hallucinogenic molecules like psilocybin. In using these take-home medicines, we hope to be able to treat a large number of patients, and it's really important to remember that about 1 out of every 5 people will suffer from a brain disorder in their lifetime, so if we really want to address the scale of this problem, we need to have safe and effective medicines that you can take in your home.

Alana Hippensteele: What are some next steps you see on the horizon following this research?

David Olson: I think that some of the obvious next steps is to continue to evaluate what indications psychoplastogens can be used for, and as I mentioned before, cortical atrophy is at the heart of many brain diseases, so determining if psychoplastogens can be used in areas beyond neuropsychiatry, getting into neurodegenerative diseases, getting into neurological conditions like stroke and traumatic brain injury—these are really interesting questions that we haven't completely addressed at this time.

Alana Hippensteele: Any closing thoughts?

David Olson: While I definitely think that first generation hallucinogenic psychoplastogens like psilocybin are going to help some patients, they're just not as scalable as some of the other options. Even if we have enough therapists to administer these treatments, we build a psychedelic-assisted psychotherapy center next to every Starbucks, insurance companies decide that they will fully reimburse for this, what we have to remember is that there's still a large percentage of populations who will never be able to take these medicines because of their comorbidities, family history of psychotic illnesses like schizophrenia and bipolar disorder—these are contraindicated for psychedelic-assisted psychotherapy, and so these non-hallucinogenic psychoplastogens offer another option for those types of patients.