What Are Synthetic Psychedelics?

One of the latest major evolutions in psychedelic science research and development is the creation of new psychedelic novel chemical entities (NCEs). These psychedelic NCEs may be based on the structures of known psychedelics, but, for all intents and purposes, these NCEs are new compounds that have never been isolated in nature or synthesized.

This uniqueness makes the entities patentable, which is good news for companies looking to fund psychedelics research. But these NCEs also hold a significant amount of potential for research and drug development chemists. For example, it may be possible to create new psychedelics that have even more beneficial medicinal properties, or which have more tolerable side effect profiles.

In a panel discussion last year, Analytical Cannabis brought together five experts on psychedelics to discuss these new psychedelic NCEs, and to provide new perspectives on the future of the psychedelic drug development landscape.

What is a psychedelic NCE?

Many of the most well-known psychedelics – magic mushrooms, ayahuasca, and mescaline – are entheogens. This means that they are psychedelic substances that can be derived from plants and fungi.

While these psychedelics have arisen in nature thanks to thousands of years of evolution, psychedelic NCEs are a far more recent invention. These NCEs are developed by drug development chemists in a laboratory.

“I’m probably a bit of a skeptic on what I consider an NCE, I think there are a lot of companies working on what I consider more of a formulation play,” said Dr. Jackie von Salm, co-founder and chief scientific officer at the psychedelics-focused biotechnology research company Psilera.

“If you are swapping out for deuteration or if you are doing pro-drugs, really what you are trying to do in that process is do very small chemical modifications which you could do if you just formulated it differently. But they don’t want a different formulation, because that’s harder to patent and hold against generics.”

But as von Salm also highlights, Psilera and a handful of other companies like it are still currently engaged with a more traditional medicinal chemistry NCE design path. In this way, scientists hope to elucidate how modifications to a psychedelic drug’s structure might affect its activity against various biological receptors, and what this might mean in terms of its therapeutic applications.

For scientists, NCEs hold a significant amount of potential as “designer psychedelics”, which can be tweaked to enhance or remove certain side effects in order to maximize their accessibility and therapeutic potential. And from a more business-oriented perspective, patentable NCEs can be a bigger draw for research funding and investment than natural plant psychedelics.

“Larger pharmaceutical companies – which at the end of the day, are who is going to fund most of the late stage clinical trials for different companies – they’re going to care more when they have patent protection,” von Salm said.

Promising research areas

One interesting aspect of trying to design psychedelic NCEs that can have useful applications in medicine is that it forces scientists to look at these drugs from a slightly different perspective, says Jahan Marcu, a founding partner at Marcu & Arora.

“I think we’re starting to realize a little bit that the surface area of our questioning exceeds the surface area of our answering, and so we really have to kind of push more in that area,” said Marcu.

“So, I like the fact that a lot of these novel chemical entities are giving us new perspectives and are pushing the science and limits of what we understand, including working theories and hypotheses of things like depression and pain and anxiety.”

One particular area of promise for psychedelic NCEs is the opportunity to improve on the traditional psychedelics that are already demonstrating potential in clinical trials for severe post-traumatic stress disorder (PTSD) and treatment-resistant depression. Creating similar tailored psychedelic NCEs may be one way to remove hurdles such as unpleasant side effects, says Del Potter, a medical anthropologist and consultant at Pangea Botanica.

“My focus has most recently been on moderating the experience in such a way that it has fewer adverse side effects,” Potter told the panel attendees. “About 20% of people experience nausea when they take psilocybin, for example. How can we eliminate the feelings of nausea that people will have?”

“Largely, I’m seeing a lot of opportunities in pharmaceutical formulation and delivery, and being able to contour these legacy psychedelics in that way,” Potter continued. “I also see tremendous opportunity in the shorter-acting tryptamines. I believe that there is an opportunity to provide as much benefit in a shorter period of time, as some of these longer experience psychedelics provide. If we can accomplish that and make the experience less jarring, then we can maybe engage with more marginalized populations, like the elderly.”

This is a sentiment echoed by Chris Witowski, co-founder and CEO at Psilera. In addition to creating safe and effective drugs that are accessible to a greater number of populations worldwide, Witowski also sees these NCEs as an opportunity to investigate the relevance of the psychedelic ‘trip’ to the therapeutic effects that have already been observed.

“We have a very, I would say, limited understanding of the brain still. One mechanism of action on how these drugs actually work, it’s been theorized, is neuroplasticity. So basically, your brain's ability to retrain itself,” Witowski told the panel. “I think the psychotherapy aspect is very helpful during the psychedelic experience. But is the psychedelic experience itself necessary for neuroplasticity?”

“We’re looking at hallucinations as essentially a side effect,” he continued. “If you tune out this one hallucination [...] if you take these out, then what is left? Is it still an effective medication?”

The future for psychedelic NCEs

It is clear that these psychedelic NCEs hold a lot of promise in terms of their applied usage and also as a vehicle for furthering our knowledge of the brain and how it functions. So, just how far away are we from a situation where we might have psychedelic NCEs ready for prescription? According to Witowski, likely, still quite far away.

“MAPS [Multidisciplinary Association for Psychedelic Studies] with MDMA for PTSD, I would say probably next year they’re going to submit their application to the FDA for approval. More than likely than not, in 2024, I think this will be commercially accessible for people with PTSD,” he said.

“Psilocybin is just now beginning phase three trials, and this is likely going to be 2025, maybe 2026, before it’s approved and commercialized. And I would say these are all first-generation psychedelics, largely, a lot of optimization hasn’t been done to these compounds.”

In order to get approval, psychedelic NCEs will have to go through a similarly long process of completing pre-clinical and clinical trials designed to assess their efficacy and safety. Other factors, such as regulations set out by the US Food and Drug Administration (FDA) or the Drug Enforcement Administration (DEA), may also end up playing a large role, as Marcu explains.

“The future of I think a lot of this industry hinges on several factors, including the outcomes of FDA decisions, and ongoing clinical trials,” he said. “What would be amazing is if a psychedelic-like compound ended up in a really low scheduling category. Look what happened to Epidiolex [a purified compound from cannabis], it’s not even scheduled anymore. And it’s given to children! If you would have told me even five, six years ago that we’re going to take a part of the cannabis plant we know nothing about, concentrate it, and give it to children, I’d have been like, ‘You’re crazy!’”

“Legislative reform is going to be a big driver in this, as well as education,” he emphasized. “I think with every industry, everyone's like, ‘Oh we are 20 years away from applications.’ And, yeah, we will probably be perpetually 20 years away until there’s widespread education and more science informing these policies.”

The impact of state psychedelics programs

Another interesting aspect for the psychedelics sector to keep an eye on is the impact of the various decriminalization and legalization initiatives currently focusing on natural psychedelics. Specifically, Oregon’s recent creation of authorized psilocybin service centers, where it is legal to use psychedelics under the guidance of state-certified facilitators, is likely to have a significant impact on the public perception of psychedelics. But it will also generate a huge body of real-word data and testimony on the action of psychedelic drugs, Potter believes.

“I really see these emerging state-regulated markets as extremely disruptive to conventional pharmaceutical commercialization,” Potter said. “What we’re going to find, I think, is that Oregon with delivery through service centers is a stepping stone to showing how broadly safe these compounds are. Being able to get more access to them is going to allow their efficacy to be more highlighted.”

Of course, that’s not to say that caution should be thrown to the wind. The panel experts all agree that realistic studies on the safety of these compounds will also be needed in addition to any real-world data generated by state-run psychedelics programs.

“I, personally, don’t like when some of the state legislation gets ahead of the research, which is what we really saw in cannabis,” von Salm commented. “I don’t know that we know enough about some of these compounds to say that they’re not going to have any negative side effects.”

“I think that we have to remember what happened with opium and morphine, and opioids and opiates. I mean, opium for a long time was given to children and adults from a very early stage before we started to try to develop other drugs from it, and we’ve learned a lot hopefully from that experience,” she continued. “I personally think that I would like to see some of the safety and toxicity and research get ahead of some of the states coming up with these regulations on their own.”