Non-Hallucinogenic Drug Inspired by Psychedelics Enters First-in-Human Study

Psychedelics research has provided fascinating insights into the effects of LSD, MDMA (ecstasy) psilocybin, ketamine and other compounds on neuroplasticity – the ability to form new neural connections. However, their psychoactive nature requires them to be administered in controlled clinical settings under the supervision of medical professionals.

Clinical research company Delix Therapeutics has been working on  “neuroplastogen" compounds to treat psychiatric conditions such as depression. These drugs are non-hallucinogenic alternatives to psychedelics. Delix hopes to develop these drugs as at-home treatments with the potential to provide some of the neuroplastic effects of psychedelics, without the stigma and hallucinogenic effects. This is a budding area of research, with investigators recently gathering to discuss the landscape of psychedelics at the Multidisciplinary Association for Psychedelic Studies conference – Psychedelic Science 2023 – in Denver, Colorado. Delix has announced the completion of dosing of the first cohort in a Phase 1 clinical trial of its first neuroplastogen compound, DLX-001.

To learn more about the progress and development of non-hallucinogenic psychedelic therapies for conditions such as depression, Technology Networks spoke with the head of research and development at Delix Therapeutics, Dr. Eliseo Salinas.

Ruairi Mackenzie (RM): What’s the state of play in psychedelic research in 2023?

Eliseo Salinas (ES): There are many components in the world of psychedelics. There’s all the work that comes from the actual psychedelics like LSD, psilocybin, etc. That research tries to capitalize on the known facts about psychedelics and different ways of using them effectively. But then there is a second group, starting bottom-up from the science. They're trying to say, “We want to take the good aspects of psychedelics, promoting all the things that we think psychedelics do, but without the high or the hallucination.”

There is a divide, because the people that are in the first group say, “We can't do that, it's part of the treatment. Part of the trick is that you make the patient hallucinate.” We are not convinced about that.

What we know about psychedelics is that clinically, when you give them to patients, they tend to have effects very quickly. Sometimes these don't last, but they act within hours, so a day after a dose, you see something.

With traditional antidepressants, it doesn’t happen that way. You need to wait three to four weeks for them to work. They work for a good majority of patients, but it takes weeks to work, and nobody understood why that is. In the last 10 years a research group, including our founder, looked at exactly what the difference is between new drugs like ketamine and psychedelics and the old, traditional ones. It’s known that when a patient is depressed that in some areas of the brain, the patient loses synapses – the little branches that come out of the neuron and connect them with other neurons. When the patient is depressed, in some areas of the brain the neurons don't touch each other. Those branches retract, resembling a tree in the winter without its leaves.

But when the patient – or in the current preclinical research, the rat – is doing well you see the regrowth of the synaptic connections. This is new science from the last 10 years. It was found that ketamine produces this regrowth in hours, while with traditional antidepressants they would regrow in weeks, so the field said that is why one acts more quickly than the other. Interestingly, electroshock therapy does the same thing as ketamine and psychedelics – it regrows those synapses acutely.

There are some companies – of which we are the most advanced company on this front – that are looking to reproduce that effect, to regrow synapses without producing the high or the psychedelic effects. The reason why we think it's possible is that electroshock therapy makes you regrow synapses but doesn't make you high or hallucinate. We don't criticize those experiences – maybe for psychedelics, they are needed. But we believe that they are not necessary for regrowing synapses quickly, because electroshock therapy does it and we know it doesn't produce that high. Even ketamine doesn't produce a hallucinatory experience. You have some confusion and dizziness, or what are called dissociative symptoms, but it only rarely produces hallucinations.

RM: Delix's non-hallucinatory compounds have sometimes put it at odds with other groups within the psychedelics space. Where do you feel your compounds sit within that space?

ES: We also have some drugs that produce a little bit of a hallucinatory experience – we don't consider that necessarily negative. The problem is that depression affects a lot of people, and it wouldn't be feasible for every depressed patient to have a two- or three-hour psychotherapy session with a couple of therapists in the room. What we are looking at is what we call the at-home type of treatment that, like an antibiotic, the patient could take at home and improve more rapidly. That's the concept we’re trying to accomplish.

RM: Is DLX-001 a proprietary compound? Is it a derivative of any existing psychedelic?

ES: Dr. David Olsen, our founder and professor at UC Davis, along with others, established that psychedelic drugs like LSD, psilocybin, MDMA, etc. regrew synapses in animals. He looked at the chemical structure of [these compounds]. What he and the medicinal chemists did was say, “What if we remove this hydrogen atom? Are the effects the same? Can I maintain the effects on the synapses, without producing hallucinatory effects in animals?” He found a number of changes and we created our pipeline on the basis of these modified structures. The modifications are really different from existing psychedelics because once you start chopping or adding a nitrogen atom, taking out a hydrogen atom, etc., you end up with a structure that is not very similar.

So DLX001 was inspired by the chemical structure of some of the initial psychedelics, but it was modified so much that it's a proper proprietary compound and that's why we have a patent on that. It's not the original, it's a completely changed version of the original compound.

RM: The marker of 5-HT2A activation in mice is the head twitch response – how do non-hallucinatory psychedelics activate the 5-HT2A receptor without inducing head twitches?

ES: The 5-HT2A receptor is a complex receptor on the membrane of the cell, which is targeted by serotonin and other agonists. But there is also a cytosolic 5-HT2A receptor inside the cell. Interestingly, serotonin, which is the physiological agonist of the 5-HT2A receptor, does not get inside the cell because it doesn't have that lipophilicity. So, serotonin does not affect the intracellular 5-HT2A receptor but some molecules, including ours, do. The idea would be that the head twitches and the hallucinogenic effects are produced by the membrane-regulated receptor and not the intracytosolic. This is all in a recent paper published three months ago – we don't understand everything, but the data and the science seem to be in that direction.

The head twitch response is very interesting. Some of our compounds not only do not produce head twitches, but when you give an agonist of the 5-HT2A that does produce head twitches – like LSD – and you give our compounds, they block the effect of the LSD. They behave like an antagonist, although they are agonists of the 5-HT2A receptor. It's an interesting dilemma.

Our upcoming human study will tell us if DLX001 produces hallucinations or not, because we're going to use as high [a dose] as is necessary. If our thesis is correct, some of those people are going to start vomiting, having headaches or side effects of some sort without hallucinations – or not – but we will see soon.

RM: Does it give you pause that we are at a point where classical psychedelics likely will be licensed in the next two or three years, but we don't really understand the molecular mechanisms behind these drugs?

ES: No, I am absolutely bullish. I'm a psychiatrist and psychopharmacologist by training. When you talk to cardiologists or hepatologists during drug development, they have this superiority: “You don't understand it. You don't understand.” I tell them, well, we do understand, but we're dealing with a much more complex organ – the brain. It’s not a muscle like the heart, and it's not a filter like the liver – where you can understand everything. We’re talking about the most complex biology in the world with the brain.

Beyond the humor of the metaphor I'm using, the progress in our understanding of the brain has been fantastic. What I told you about regrowing synapses in distressed animals was not known 15 or 20 years ago, but like with everything in science, when you understand one element, then you realize that there are a number of downstream effects that you don't understand. So, part of the criticism is, “These psychiatrists are like sorcerers, and they don't understand what you're doing, it's like the Middle Ages.” It's not. We’re not going to understand everything at any time point.

RM: 2023 has been a year where the industry has pulled back. Some companies have retracted or collapsed. How would you rate the health of the industry more widely? Do you think it's in a good place?

ES: Yes. We have seen this before. I'm amazed at the people who say that the roof has fallen on our heads. Where were you in the last bear market and the one before last? It always happens. Alan Greenspan put it very well – you have a bull market with irrational exuberance and people start putting money in absurd, ridiculous endeavors. Then you have the bear market, where people have what I call this irrational despondency where they say that nothing's going to work. I like what some analysts are saying that the market has become more selective. There are outfits that waste money, but it's more selective. It wasn't long ago in 2019 when it was crazy; look at gene therapy companies with an explosion of funding.

I think that the field is in a good position. I don't know if Delix is going to make it, I don't know, we might fail. I'm confident, and I think that we have a very strong rationale. I've been doing drug development in CNS for more than 30 years and the rationale for these drugs, like growing synapses, is based on the actual pathophysiology that you can see in animals.

One of the things I found fascinating in this work on growing synapses is this: in order to make an animal behave like they're depressed, which is called learned helplessness, you submit the animal to uncontrollable stress. The animal retracts, doesn't eat, doesn't sleep well and doesn't interact with females. You give them the drugs, and you get the results that I described. But then you stop bothering the animal and leave him alone, the animal is going to go back to the normal rodent life in about three or four weeks – eating more, sleeping better, interacting with females, etc. Then you look at the synapses – they regrew, suggesting strongly that this retraction of synapses is associated with depression and the regrowing of synapses when the animals are well, because of the drugs you give them or because you stop stressing the animal, is a natural phenomenon.

This explains why depression is not like schizophrenia, ADHD or autism, as you're not depressed for life. The typical depressed patient has a normal life until 20 or 25 years of age, with one episode of depression that was treated and then, with or without treatment, it goes back to normal. It's likely that what happened at some time point is that this synapse growth took place. What these drugs do through various biochemical processes is accelerate that natural healing process.

RM: Can you outline the next steps and milestones in your human clinical trial?

ES: This is a combined single-ascending dose and multiple ascending-dose study. Because it's ascending doses, you never know at which time point you're going to say, "I found my top dose,” so we don't know exactly when it's going to end. But it's reasonable to expect that in Q1 2024, we are going to have results from this study. The next study will be in patients. Exactly how big or how small is important, and we're still discussing it, but the next study would be in depressed patients.

Eliseo Salinas was speaking to Ruairi J Mackenzie, Senior Science Writer for Technology Networks