In Alexander Shulgin’s 1990 book, PiHKAL: A Chemical Love Story, the chemist described hundreds of new chemical compounds he invented and tested on himself, his wife Ann, and his friends.
Inspired by psychedelic drugs like LSD, psilocybin mushrooms, and mescaline, Shulgin was dedicated to uncovering molecules with previously unknown effects on the human body and mind. (He is also well-known for coming up with an easier synthesis of MDMA in 1976.)
After consuming a compound he called 39 2C-T, Shulgin wrote, “Poetry was an easy and natural thing. Both the reading of it and the writing of it. This is a potential MDMA substitute since it opens things up but it doesn’t do anything to get in the way.”
Another, dubbed 41 2C-T-4, led to “persistent cold feet, and an uncertain stomach when moving around.” 43 2C-T-7 was “much like mescaline but less sparkly.” A couple of hours after taking 58 DMMDA, Shulgin ate an apple. “Maybe my mouth didn’t work quite right. The apple was incredibly noisy,” he wrote.
In 1994, four years after PiHKAL was published, the Drug Enforcement Administration (DEA) raided Shulgin’s lab, fined him $25,000, and revoked his DEA registration number. Now, almost 30 years later, the interest in tinkering with psychoactive compounds is undergoing a resurgence—and has a whole new legitimacy.
One byproduct of the so-called “psychedelic renaissance”—the boom in research on psychedelic compounds as a potential treatment option for mental health conditions—is that companies and researchers have begun anew with drug discovery for molecules that are similar to psychedelic compounds, interact with similar receptors in the brain, or create similar brain changes. Of the many companies springing up in the psychedelic sector, a large number are no longer focusing on the drugs that enthusiasts are familiar with.
They are instead intent on creating analogue and novel molecules that aim to improve upon the classic psychedelics. (An “analogue” is a molecule that has a similar structure to a pre-existing one, but is different from it in some small way; a “novel” compound is a molecule that is completely structurally different.)
Imagine a psilocybin-like drug, but with no stomach aches, no risk to the heart, and with a trip that lasts only two hours. Or an MDMA-like drug with less stimulant properties, and no tolerance build-up. Or, how about a drug that doesn’t have a hallucinogenic effect at all, but can still induce the neuroplasticity that psychedelics seem to bring about?
These are lofty promises. Drug discovery is difficult work, and just because a molecular structure is hypothesized to perform one way in the body doesn’t mean it will do so. Many aren’t sold on the premise: Last June, Rick Doblin, the founder of the Multidisciplinary Association for Psychedelic Studies (MAPS) told Forbes that non-psychedelic psychedelic compounds were a “bogus” pipedream. And a cynic might wonder if the ambition to create new molecules, which are much easier to protect as intellectual property, is a consequence of the psychedelic field being dominated by known natural products, which are harder to patent.
But the researchers coming up with these molecules say that their work is necessary—that these molecules will increase the access and scalability of psychedelic-like drugs and treatment. What is certain is that the future of psychedelic medicine will eventually include both the drugs that we know about already and a whole fleet of second- (and third- and fourth-) generation ones.
“Hundreds, if not thousands of experiments are happening in companies and in research institutions,” said Suran Goonatilake, a co-founder of April 19 Discovery Inc. and a visiting professor at University College London’s Center for Artificial Intelligence. “It’s almost like we now have this permission to innovate around whole classes of receptors that we ignored.”
There are some common targets when it comes to modifying psychedelic drugs: Trying to get rid of unwanted side effects like gastrointestinal upset or cardiovascular risks; making the trips shorter; and even removing the hallucinogenic properties altogether.
Many such compounds are already in development. Mindset Pharma, a company based in Canada, is working on psilocybin analogues that could lead to a much shorter trip while also being five to 10 times more potent than psilocybin. Another group of its potential compounds would do the opposite: They have preliminarily shown lower potency and longer duration. Joseph Araujo, chief scientific officer at Mindset Pharma, said he envisions the latter drug being for people who don’t want a strong hallucinogenic effect—the “trip” part of the experience that can include visual or auditory effects.
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The company Tactogen is trying to develop new “gentler” versions of MDMA that aren’t associated with increased heart rate and blood pressure, which could make it a better option for people who don’t have healthy cardiovascular systems.
Ron Aung-Din, the clinical medical advisor of Pyscheceutical, told Pharmacy Times about a psychedelic-like drug delivery approach that avoided the bloodstream all together, through application from “a cream or a patch at the back of the neck of the hairline where there are free nerve endings in the skin under the surface, which go right to the brain.”
The basic idea is that the compounds that we are familiar with are not the best they can be, said Joseph Tucker, chief executive officer of Enveric Biosciences. Tucker helped to create a “Psybriary” at the company MagicMed Industries, which was a large portfolio of novel molecules inspired by nature, but modified. It was then acquired by Enveric.
Many of our current drugs were once inspired by plants, so this process isn’t unprecedented. When we experience minor pains and aches, we take over-the-counter analgesics; we don’t grind up willow bark—the natural product that a drug like aspirin is derived from.
But in the case of psychedelics, it’s a drug pipeline that had been largely ignored by mainstream pharma until now. “It's a renaissance in pharmacology that for the last 10 to 15 years has not been that active,” said James Lanthier, the chief executive officer at Mindset Pharma.
Some potential drugs will seek to remove the hallucinogen part of psychedelics completely. David Olson, a chemical neuroscientist at the University of California Davis, and his colleagues have published numerous papers on non-hallucinogenic compounds he called “psychoplastogens.” Olson thinks psychedelics promote neuroplasticity in a part of the brain called the prefrontal cortex, which then contributes to positive outcomes. Based on that theory, they’re developing compounds that retain that plasticity, but remove the trip.
Delix Therapeutics, where Olson is the chief innovation officer, has raised millions to develop Olson’s academic research. So far, it has a library of nearly 1,000 compounds, some of which will begin to be tested next year.
In an opposite approach, the company Mindstate Design Labs is deliberately honing in on the experiential side of psychedelics. One of their projects involves attempting to reliably produce the state of “oceanic boundlessness” or ego loss. But they want to go beyond that to explore compounds that bring about unknown states.
“[Current psychedelic] compounds are just what happened to be available,” said Dillan DiNardo, Mindstate’s CEO. “And the experiences associated with those compounds are just what happened to be available. By no means is it the full scope of the altered states of consciousness that are possible.”
New compounds, theoretically, could produce experiences that people have never had before. That’s a challenge in terms of describing them, and even determining if you’ve discovered something new. “We will have to develop the validated rating scales to be able to capture the nature of the experience, and the intensity,” DiNardo said.
There’s so much unexplored space, Goonatilake said, that he is turning to artificial intelligence to probe the limits of what’s possible. His company, April 19 Discovery, is using AI inspired by “nature's most creative and best problem-solving machine”—evolution.
Evolution combines genetic information from parents to create variability and mutations. If the result is something that’s better fit to survive in its environment, then it will survive more and pass on certain traits to the next generation. What Goonatilake does happens entirely in a computer: An algorithm represents molecular structures, then takes parts of them and swaps them out to create something new.
As a proof of principle, he applied this evolutionary method to four compounds: LSD, DMT, psilocin, and mescaline, the very same four compounds that Alexander Shulgin had as a foundation to work with over 30 years.
Over the period of a week, the algorithm discovered 197 of the 230 compounds that Shulgin published. “Drug discovery is by and large a game of avoiding dead ends,” Goonatilake said. “It compressed, in this case, something like 30 years of work into one week.”
Why do we need new compounds? Even if the psychedelics we already know are very effective, they might only be delivered to a small portion of people. There's already been healthy debate about whether the experiential component to a psychedelic drug is necessary or critical for a mental health treatment.
Chuck Raison, a professor at the School of Human Ecology at University of Wisconsin-Madison and director of clinical and translational research for Usona Institute, told VICE in 2019, “Unless psychedelic effects are the mechanism by which these drugs work, sooner or later, these drugs will not have psychedelic effects.”
That’s because of the significant amount of therapeutic support needed before, during, and after a psychedelic treatment. Even a less effective drug available to many more people could have a bigger impact, Olson said.
“When I think about the average patient, I try to think of my mom,” said Jason Wallach, a medicinal chemist at the University of the Sciences in Philadelphia and the head of mental health company Compass Pathways’ Discovery Center. “If she had to have this medication, what would I want for her as an ideal compound and ideal experience?”
There are potential indications for psychedelic-like compounds where patients may not be interested in hallucinogenic effects, like those with cluster headaches or chronic pain. People with psychotic disorders are currently excluded from psychedelic treatments, but a future compound could pose less risk to that population, perhaps by eliminating the hallucinogenic component.
Olson doesn’t think it will be either new compounds or the already existing psychedelics, but both. It could be that a person’s individual case determines whether they try a non-hallucinogenic compound first. Then, if it doesn’t work, a person could move to other compounds that retain the experiential component.
“We start with compounds that we have, and those will move into the clinic and help patients as fast as possible,” Olson said. “But they will be replaced by things that are better than that.”
Even companies well-known for their work in classic psychedelics are investing in novel compounds. In September last year, Compass Pathways announced that they bought an “IP portfolio of novel psychedelic compounds & prodrugs.”
Compass Pathways started the Discovery Center in 2020 and former VICE journalist Hamilton Morris recently joined Compass as a full-time consultant, working primarily with Wallach on new molecules. The Discovery Center is focused on both novel and analogue compounds that could one day be Central Nervous System (CNS) drugs.
Awakn Life Sciences, which is doing research with MDMA and opening ketamine-assisted therapy clinics, is developing novel MDMA-like compounds that would last a shorter amount of time than MDMA, allowing for shorter therapy sessions. According to its website, it has patents filed for multiple compounds and plans to start human trials in 2024.
Field Trip Health recently announced that early studies of its family of novel compounds show it has a duration time of two to four hours, shorter than both psilocybin and MDMA. Florian Brand, the CEO and cofounder of Atai Life Sciences, told Forbes last year that “We believe that you don't need a 12-hour psychedelic experience, like with LSD, and the 15-minute experience of 5-MeO-DMT, is potentially too short. We believe the sweet spot of the treatment window is somewhere in between.” At the end of 2021, Atai announced the launch of “TryptageniX,” a new platform company that will “take a bioprospecting approach to develop patent-protected new chemical entities inaccessible through conventional chemical means.”
But there is another benefit to creating a new compound besides scalability and access: You can get a patent on it. Atai’s press release said this explicitly, that TryptageniX “will focus on the generation of intellectual property.” Patents are granted for inventions that are new and non-obvious, and while there’s been much debate on whether configurations and uses of already known psychedelics can be owned, coming up with something brand new side steps that concern.
This leads to important questions: Will the focus on and marketing of these new compounds be overstated because of their ability to become IP? Drugs take a substantial amount of money to develop, and patents can help secure the funds to do so. But if a new compound doesn’t have significantly meaningful improvements, but is brought to market because it can be owned and make money, was it really worth it to invent it?
One psychedelic venture capitalist tweeted recently, in response to Atai’s announcement of a new version of ketamine: “The year is 2050. There are 300 different isomers of ketamine approved for clinical use. The populace is fully sedated. The robot uprising begins.”
“Me-too” drugs are drugs that are very similar to others on the market. Right now, if someone is prescribed an antidepressant in the US, there are seven to choose from. Something similar could happen with psychedelic-like drugs, where patients will have to determine which of many drugs work best for them.
Me-too drugs can get criticism for emulating what pre-existing drugs already do, Wallach said. But he thinks there can be value in them. Once a me-too drug is used in the clinic, it’s possible that it’s a better fit for a certain patient population, or begins to be used off-label for another indication. “To some extent, if somebody can demonstrate safety and efficacy, I think the more the better,” Wallach said. “Obviously, there's a limit to that, but I think we learn a lot in that process and we'll be better off.”
Matt Baggott, a neuroscientist and the co-founder and CEO of Tactogen, said he doesn’t believe there's an infinite limit to the number of new molecules that will be made—both scientifically speaking, and economically.
“I do think that we're going to hit a point where it's not going to make financial sense for companies to continue to develop products,” he said. “A lot of the patent applications you hear about or read about, I think, are really designed to secure the company's kind of ability to operate.”
Those involved in this work have insisted it’s not about a patent land grab. “We don’t believe philosophically in trying to patent an old molecule if you've done nothing to it and you haven't even identified a new use for it,” Tucker said.
It is yet to be determined what these kinds of drugs will cost, and if they’ll be covered by insurance, along with any therapy that may need to accompany them. Another unknown is how each of these new compounds might be scheduled by the DEA, and what laws they’ll be beholden to. The DEA is continually evaluating whether new molecules should be a controlled substance or not, and it will be determined on a case by case basis.
Last week, the DEA announced new scheduling of five tryptamine hallucinogens. Field Trip’s novel drug is a pro-drug of one of those compounds, meaning that “this will add some paperwork and delays to their efforts in the US,” as Baggott tweeted.
DEA scheduling aside, the safety of all of these molecules will have to be tested—and there’s a risk that the development (and publication) of new compounds will lead to them trickling out into the recreational space.
In 2011, the chemist David Nichols wrote in Nature about when he learned that people had died taking compounds he had invented in the lab, which had not been tested for safety in humans.
Nichols had been working with MDMA, and molecules with similar structures. One was 4-methylthioamphetamine, or MTA, which inhibited an enzyme that breaks down serotonin. Between 1992 and 1997, Nichols and his colleagues published three papers on MTA in rats—one of which suggested that MTA could have potential as a depression treatment
“Without my knowledge, MTA was synthesized by others and made into tablets called, appropriately enough, 'flatliners,’” Nichols wrote. “Some people who took them died.” By 2002 there had been six deaths associated with the drug.
Wallach said that the illegal status of drugs contributes to such safety concerns. When people don’t have safe access to recreational drugs, they might be more at risk to accidentally purchasing or taking a novel compound.
“What if a substance that seems innocuous is marketed and becomes wildly popular on the dance scene, but then millions of users develop an unusual type of kidney damage that proves irreversible and difficult to treat, or even life-threatening or fatal?” Nichols wrote. “That would be a disaster of immense proportions. This question, which was never part of my research focus, now haunts me.”
It’s not a guarantee that all of these new compounds will work; nine out of 10 drugs fail to make it through the drug discovery pipeline.
But the proposed molecules do raise interesting questions we don’t have answers to. How important is the experience of the drug? How critical is the time period? Is more neuroplasticity always a good thing?
“I have mixed views on that, to be honest with you,” said Nick Cozzi, a pharmacologist and the founder of the Alexander Shulgin Research Institute. “I know there's an interest in high throughput” (by which he meant delivering treatment to many people as quickly as possible). “To the extent that making a short experience favors high throughput, I'm not sure if that's a good thing or not.”
There are ways to shorten a psychedelic experience to test that, without coming up with something new, pointed out Manoj Doss, a cognitive neuropsychopharmacologist at Johns Hopkins University; a person could be given a drug that disrupts a psychedelics’ interaction with certain brain receptors.
And just because a molecule is similar to another doesn’t guarantee it will produce the same effects in the body. A drug to treat symptoms like nausea, called ondansetron, interacts with serotonin receptors called 5-HT3, but is not a hallucinogenic drug. Rizatriptan is used to treat migraines, but 90% of its molecular structure is the same as DMT. “It’s a DMT molecule with some shrubbery,” Cozzi said.
Will a psychedelic experience be like a Starbucks order one day? Where you can say, “I want an oceanic boundlessness experience, with some LSD-like visuals, MDMA pro-sociality, and I only have 55 minutes before I go back to work”? Are “precision psychedelics” in our future?
Doss said that while he supports all this basic research, a singular focus on the drugs distracts from an area he’s more interested in: what clinicians actually do with people while they’re on the drugs. This involves the interactions and therapeutic protocols themselves. And even with a whole host of potential new compounds coming, we still don’t have head-to-head comparisons of the classic psychedelics, like LSD versus psilocybin.
There are components of the current psychedelic compounds that are very important, Olson said, and shouldn’t be ignored. “But psychedelic science will never realize its true promise if that's where we stop, if we don't innovate beyond that,” he said.
The immediate future will still center on the psychedelics we know about already, but the next generation is quickly approaching. How many psychedelic-like drugs will exist? It’s unclear, and depends on what will be discovered that actually works, and what consumer demand will be like.
“As a medicinal chemist, I would want to say, ‘I'm not trying to take [psilocybin] away from you,” Wallach said. “I'm just trying to innovate, modify and find out what else is possible.”
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