Engineering non-hallucinogenic psychedelics: 5 Questions for researcher David Olson

Olson discusses the potential of psychoplastogens and the intersection of academic research and private companies in the psychedelics space.

As a neuroscience postdoctoral researcher at the Broad Institute of MIT and Harvard, David Olson became interested in ketamine. The drug had yet to be approved by the U.S. Food and Drug Administration to treat depression, but research suggested that ketamine could promote the growth of cortical neurons within 24 hours, which could help treat a variety of neuropsychiatric diseases. Olson began looking into other drugs with the same properties, which led him towards classical psychedelics including LSD and psilocybin. When he became a professor at University of California, Davis in 2015, he started investigating psychedelics’ potential to stimulate neuronal growth.

Olson aims to engineer what he calls non-hallucinogenic psychoplastogens, which include psychedelic-like drugs minus the trip. He’s also trying to make other tweaks to these drug molecules that could increase their efficacy and safety.  Olson is the founding director of UC Davis’s new Institute for Psychedelics and Neurotherapeutics, and is also co-founder of Delix Therapeutics, a neuroscience biotech company that has thus far raised $118 million according to Crunchbase. The Microdose spoke with him about the potential of these substances, and the intersection of academic research and private companies in the psychedelics space.

Why make non-hallucinogenic psychedelic-like drugs? What are they for and how do you imagine them being taken?

When I started at UC Davis, we wanted to ask the question of whether the hallucinogenic effects of psychedelics were directly related to the neuroplasticity effects or whether those two things could be decoupled. We tried to address this by engineering non-hallucinogenic analogs of psychedelics that might produce therapeutic properties. We started making compounds from every major psychedelic scaffold family: ergolines like LSD, amphetamines like MDMA, tryptamines like DMT and psilocybin. 

It's important to remember that psychedelics, while they might have some therapeutic properties, were never engineered to be medicines or to be drugs. Lots of cultures have used them as medicines, but they're produced by plants and they haven't been optimized for treating various indications. What we've been trying to do is to take those molecules and tweak them to improve both their safety and their efficacy. 

In terms of how they might be used, we're anticipating that after consulting with a doctor and having that drug prescribed, a patient will be able to go to their local pharmacy, pick up the drug, take it home and keep it in their medicine cabinet, and use it as prescribed. We're not anticipating that these are going to be medicines like traditional antidepressants that you take every single day, because these psychoplastogens produce more lasting changes in neuronal growth. So you take a dose, you have some relief for some period of time, exactly how long that is and when you need to redose will be dependent on the patient and their condition, and that will be determined empirically in the clinic. But whether they're taken once a week, once a month, or once a year, I think that's all a possibility depending on the particular situation. 

There’s a lot of excitement right now about psychedelics’ potential to promote neural plasticity, meaning the brain’s ability to adapt and form new connections. Enhancing plasticity could help treat not only mental health issues but also neurodegenerative diseases like Alzheimers. There’s also concern in the field about how to scale up the availability of psychedelic treatments. You already mentioned the possibility that these psychoplastogens could be taken at home instead of in a clinic. In what other ways might non-hallucinogenic psychoplastogens increase access to neuroplasticity-promoting drugs? 

I expect that there will be some patient populations that respond very well to traditional psychedelic psychotherapy and others that will respond very well to these non-hallucinogenic psychoplastogens. It’s important to develop all these different kinds of medicines because we need more solutions. It’s critical to understand the scale of the problem. One in five people will suffer from a neuropsychiatric disease at some point in their lifetime. We're talking about a billion people worldwide. Psychedelic-assisted psychotherapy is definitely going to help some people, but it’s not going to make a dent in that problem because of the scalability issues. The cost is really high. We don't have enough treatment centers. We don't have enough therapists to administer this treatment to that many people. So we need alternatives. We need something that is more scalable so that a large number of patients can benefit. 

There are some patients that will never be allowed to take psychedelics because they have a family history or a co-occurring condition that precludes them from taking a psychedelic like schizophrenia. And there's a subset of patients who simply don't want to take a psychedelic for personal or religious reasons. Non-hallucinogenic psychoplastogens are a nice opportunity for those types of patients to also receive treatment. 

Another way that these compounds might be used is to extend the duration or durability of psychedelic-assisted psychotherapy. Imagine going in for a session of psychedelic-assisted psychotherapy and then using these non-hallucinogenic psychoplastogens as a chance to maintain the response over time so that you don't have to go in six or ten times for ketamine infusions — to take off work and pay the costs associated with that. 

What is the process of engineering these novel psychoplastogens?

There’s a lot about the pharmacology of psychedelics that we still don’t know. We took a traditional medicinal chemistry approach by starting with the base structure of psychedelic molecules. Structure begets function; the function of a small molecule is directly related to its chemical structure. So, what we did was take these psychedelic compounds and tweak their structures in a systematic way. If you do that systematically, you can start to construct what medicinal chemists call a structure-activity relationship study; that’s an understanding of how modifications in structure impact function. We started to chemically evolve psychedelics into something that doesn’t necessarily look like a psychedelic anymore, but has the function we care about. In our case, that is this cortical neuronal growth, as well as safety considerations, like low-hallucinogenicity and improved cardiotoxicity profiles for drugs like ibogaine, which is known to bind to channels in the heart and cause cardiac arrhythmias. 

You started your career as an academic researcher, then co-founded Delix, a biotech company synthesizing psychoplastogens. Why start a company?

Academics don’t have the infrastructure to do the massive clinical trials and other hard work you need to get the drug into patients. It costs around $1 billion to develop a drug and bring it to market. That is just not something that is done at the university level; I mean, we're in the lab holding things together with duct tape. Companies can do that work best, which is why we spun out Delix. It’s grown substantially since its founding; it’s taken some of our initial research and expanded upon it substantially, continuing to develop neuroplasticity-promoting compounds for a variety of different indications. 

You also founded the Institute for Psychedelics and Neurotherapeutics at UC Davis. How is this new institute at a public university working together with a private start-up biotech company like Delix and what role do you see this new institute playing?

The goal of the Institute for Psychedelics and Neurotherapeutics is to understand the basic mechanisms by which psychedelics impact the brain, and use that info to develop novel targeted therapeutics with improved efficacy and safety profiles. For instance, plasticity-promoting molecules might help with recovery from things like stroke or traumatic brain injuries, or for pain and migraines. We’re doing basic neurobiology to understand the molecular pathways involved with these drugs’ therapeutic and subjective effects. If you understand everything from molecules to cells to circuits, you have a better chance of developing more targeted therapeutics. Companies like Delix can help sponsor research to facilitate basic science and pharmacology; if we’re going to make phenomenal progress, it’s going to take a lot of people working together. 

In the case of this institute, we’ve gotten a $5 million investment from the dean of the College of Letters and Sciences, the dean of the School of Medicine, and the provost and the vice chancellor for research. This is, to my knowledge, the first time a major university has committed university money to a psychedelic science center. As far as I know, all the other centers have been founded based on philanthropy. I think the founding of this institute is a big step for the field – a major public institution like UC Davis is saying, “We think that this is a really important area that we want to invest in.” 

This interview has been edited and condensed for clarity and length.