Companies invest in non-hallucinogenic, psychedelic-like drugs to treat depression, addiction

Today’s psychedelic renaissance is thriving thanks to a list of drugs that you could count on just one hand. MDMA, psilocybin, LSD, and DMT are driving a revolution in psychiatry while opening new frontiers in the exploration of consciousness. If you expand to your other hand with drugs like ketamine and ibogaine, there’s enough mystery in that small gang of substances to keep researchers busy for decades.

But what if there were hundreds, or thousands, more? Drugs are like tiny Legos that can be rearranged in a staggering variety of ways. Chemists have hardly begun to discover all the endless molecular forms contained within the psychedelic arena. In the 1960s, the biochemist Alexander Shulgin, who introduced MDMA to the world, invented nearly 200 psychedelics (largely in his backyard laboratory, where he used sheet metal to keep the squirrels out). When President Richard Nixon outlawed psychedelics in 1970, drug discovery went dark.

Nearly two decades into a revival of psychedelic research, the doors of drug discovery have swung wide open once again, and the latest development is roiling psychedelia, revealing fault lines that split the field into two.

The question: Can we tinker just enough with the molecular structure of psychedelic compounds so as to retain their therapeutic benefits, but ditch the trip? And should we? For many, the trip is the point. Cutting it out would be, to use 1960s terminology, a major bummer. Beyond a stream of unusual and profound experiences, many researchers believe that the insights people have on their trips are necessary for securing the long-term benefits, which can range from personally meaningful experiences to treating conditions such as depression or addiction.

For others, the trip is a barrier to treatment. Not everyone wants to have their entire consciousness rearranged in unfamiliar and sometimes unsettling ways for a little while. And integrating trips into existing models of therapy is both time-consuming and expensive. In Australia, the first country to legalize medically prescribed psychedelic therapy (which spans multiple days), one psychiatrist’s estimate put the combined cost of medication and the therapists’ time around $10,000 at the estimate’s lower end. In the US, Oregon is the first state to offer licensed access for adults over 21, where a single session costs $2,800. “Take your pick: Comorbidities, cost, convenience, or other challenges will get in the way for some people who may not be able to access those [psychedelic] treatments,” Mark Rus, the CEO of Delix Therapeutics, a company working on developing variations on tripless psychedelics, told me.

In 2020, a group of researchers led by Delix co-founder and chemist David Olson published work suggesting tripless psychedelics are possible. In this case, a reengineered form of ibogaine — a psychoactive substance with dissociative properties found in a West African shrub, traditionally used by the Bwiti religion in Gabon and being studied today for its anti-addictive potential — still displayed therapeutic effects while leaving out the distortions of consciousness, at least in mice. In the years since, more papers have come out demonstrating that reengineered psychedelics like LSD can retain therapeutic effects while losing the trip — but again, all in mice.

Now, these psychedelic-inspired, tripless drugs are heading into human trials for the first time. In June, Delix Therapeutics announced a successful first round of dosing as part of their Phase I clinical trials of DLX-001, a ”non-hallucinogenic” version of MDMA. If the results replicate in humans, the implications could be significant. Rid of the trip, these drugs could prove safe and therapeutically effective to take at home, bypassing the need (and expense) for multiple in-person sessions and staffing. But even if such drugs prove effective in mitigating conditions like depression, anxiety, or addiction, according to others in the field, you’d be missing out on the very thing that makes psychedelics so reliably life-changing.

Why would you want a psychedelic without the trip?

With all the talk of a psychedelic renaissance, it’s easy to get the wrong idea. Sixty-eight percent of Americans have never tried psychedelics, according to a recent YouGov poll. A survey of mental health service users found that 20 percent still viewed psychedelics as unsafe, even under medical supervision, citing concerns about adverse effects (among other concerns like lack of knowledge and illegality). Leading researchers are already preparing for the “bursting of the psychedelic hype bubble.”

Yet the vast majority of clinical psychedelic trips lean positive. Users consistently report them as among the most meaningful experiences of their lives, on par with the birth of one’s first-born child. And the list of promising therapeutic applications is growing. While uncommon, bad trips and negative side effects still happen, and the effects can persist for weeks or even years.

After a shot of mescaline (an LSD-like psychedelic found in several species of cacti), the French existential philosopher Jean-Paul Sartre saw a hallucinatory assortment of crustaceans that followed him around for weeks. “After I took mescaline, I started seeing crabs around me all the time. I mean they followed me into the street, into class,” he recalled. Today, we would call this episode hallucinogenic persisting perception disorder, an extremely rare side effect, and part of the reason clinical studies screen for participants with a predisposition for psychotic disorders.

No matter what sort of new mental health paradigm psychedelics may catalyze, between those with conditions that raise the risks of a trip, and those who may simply prefer to avoid experiencing one, there will be plenty of people who can benefit from different treatment options. If scientists can cut the trip out of psychedelics while leaving some of the therapeutic benefits intact, patients could take these drugs at home for a fraction of both the expense and time commitment of psychedelic therapy, widening the umbrella of treatment options to serve the over 50 million Americans who reported some kind of mental illness in 2020.

Just don’t call them psychedelics

One wrinkle in the development of these new drugs is semantic: If you successfully carve out the trip, what you are left with is not a psychedelic. And frankly, finding a name for these new compounds offers no simple options, and lots of room for confusion.

Olson coined the term “psychoplastogen,” drawing a boundary around the class of drugs that can rapidly boost neuroplasticity after a single dose. That distinguishes them from SSRI depression treatments like Prozac, which only boost neuroplasticity when taken over time. But both classical psychedelics and their new tripless relatives fit within the definition of psychoplastogens. To specify the tripless variety, you’ll find the offputting term “non-hallucinogenic psychoplastogen,” which poses no threat of catching on outside of academia. Instead, some have turned to calling them second-generation psychedelics, or “non-hallucinogenic psychedelics,” which grate against the very meaning of the word psychedelic.

Etymologically, psychedelic draws on the Ancient Greek for “mind manifesting,” referring directly to what scientists today call the “acute subjective experiences.” The psychiatrist Humphry Osmond came up with the name in conversation with the philosopher and novelist Aldous Huxley in the 1950s, writing: “To fathom Hell or soar angelic / Just take a pinch of psychedelic.” A non-hallucinogenic psychedelic that subjectively manifests nothing out of the ordinary is an oxymoron.

To Rus and Olson, that’s fine. They’re in the business of psychoplastogens, not psychedelics. What matters is the untapped healing potential in rapid spikes of neuroplasticity, not how their new drugs compare and contrast to traditional psychedelics.

As far as naming goes, “neuroplastogen” is beginning to stick as a term describing the tripless category of psychoplastogens. We could still do with a Huxley-and-Osmand-like literary intervention to come up with something smoother, but until then, it’s an improvement.

How scientists carved the trip out of psychedelics (in mice)

While plenty of mystery still blankets the tripping brain, the classical psychedelics — psilocybin mushrooms, DMT, LSD, and mescaline — are at least known to all bind to the same serotonin 2A receptor, which is believed to be one of the main mechanisms underlying changes in activity across key brain circuits related to conscious experience.

One approach to untangling the trip from the therapy, published by a group of biochemists from the Shanghai Institute of Biochemistry and Cell Biology last year, involved zooming in a layer deeper. Instead of stopping at the observation of which receptor the drugs bind to, they looked at how the molecules actually fit into the curvature of the receptor. The fit is not perfectly snug, so using a method known as X-ray crystallography, they were able to see where the contact points are.

By shooting X-rays through a crystallized replica of a compound, and based on how the rays twist and turn through the crystal, you can determine how all the atoms therein are arranged, creating a sort of atomic map. A co-author on the publication, Sheng Wang, first used the method in a 2017 study to see how LSD fits into the related serotonin 2B receptor, and found that it slots into a cavity known as the orthosteric binding pocket (OBP).

In the 2022 publication, Wang and colleagues produced six new crystalline drug replicas, this time bound to the 2A receptor. They found that in addition to the OBP, some, but not all, compounds also nestle into a nearby second cavity, the extended binding pocket (EBP).

Next, they dosed mice with each of the drugs. In mice, head twitching is taken as the sign of a trip, while increasing the amount of time they struggle to stay afloat in a cylinder of water before simply allowing themselves to drown is the sign of antidepressant effects (this is known as the forced swimming test, and we should stop doing it). Wang and colleagues learned that drugs slotting into the EBP show hallucinatory effects, while drugs that only fit into the OBP — like serotonin — display only antidepressant effects.

Armed with that insight, they created new variations of LSD designed to lean away from the EBP, focusing on the OBP. The result, at least in mice, was two relatives of LSD that achieved the hoped-for result: no head twitching, but more time spent keeping afloat in the depression tank; in other words, like Delix’s MDMA variant, a new potential neuroplastogen.

How much of the therapy will humans lose without the trip?

Despite recent advances, jumping from head-twitching and water-treading in mice to carving out psychedelic experiences while still treating depression in humans is a serious leap. “I just find it very implausible that you’ll see full and enduring benefits from psychedelics without the acute subjective effects [or: the trip],” David Yaden, an assistant professor at Johns Hopkins who works in the Center for Psychedelic and Consciousness Research, told me earlier this year.

In a 2021 paper, Yaden and his colleague Roland Griffiths contend that to get the full beneficial effects of psychedelics, the trip is necessary. That’s not exactly controversial: Even Olson, the Delix co-founder, who published a counterpoint on the same day, agrees. The trip may be “critical for achieving maximal efficacy,” he writes. However, Olson argues that whatever benefits are left over after cutting out the trip can still have value, especially since they may be able to reach wider patient populations.

How much benefit remains depends on an unsettled question in the world of psychedelic therapy: Is rapidly boosting neuroplasticity, on its own, good treatment? Olson believes so, and there’s some preclinical research in drugs like ketamine, MDMA, and ibogaine to back it up. More recently, however, a preprint study reported ketamine was given to subjects under anesthesia (eliminating any associated trip), and found no difference from placebo, suggesting that something about having the experience makes a difference.

At the University of Wisconsin-Madison, anesthesiology professor Matthew Banks is tinkering with something in between leaving the trip alone and anesthesia: What if you let people have their full-on psychedelic experience, but then erase their memory of the trip altogether? Do you need to remember a trip for the benefits to stick?

As part of an eight-person pilot study at the university’s Transdisciplinary Center for Research in Psychoactive Substances, participants received both psilocybin and midazolam, an amnesia-inducing drug used to leave conscious experience intact, but wipe away memories (it’s often used to help patients forget about colonoscopies). “It’s like you’re one of those philosophical zombies. You’re conscious and having conversations, but you have no recollection the next day,” Banks said.

He explained that getting the dosing right is tricky because psilocybin seems to lay down durable memories, which Banks speculates is due to the elevated neuroplasticity. Once researchers boosted the dose enough to wipe most of the trip from memory, the benefits seemed to have departed, too. “There appears to be something happening where we’re wiping out some of those long-term behavioral effects of the drug,” Banks said.

In part, this was likely because participants were healthy volunteers, not patients suffering from conditions like treatment-resistant depression. Since neuroplastogens are imagined as therapies, the amnesia study doesn’t tell us much about their fate in treating mental illness. While Banks admitted that successful preclinical studies in mice “open the possibility that all the hallucinogenic stuff is largely irrelevant” for therapeutic outcomes, he believes that “it really does matter what you actually do with all that plasticity.”

If neuroplastogens become take-at-home pills, then they do away with both parts of psychedelic therapy: the psychedelic experience, and the therapy itself. Robin Carhart-Harris, a professor of neurology at the University of California, San Francisco, pointed out to the New York Times last year that plasticity is just a greater capacity to be reshaped. Whether for better or worse may depend on what happens after you take the drug. Pairing trips with therapy helps guide the plasticity towards beneficial outcomes. Without the trip, Carhart-Harris said in the Times, the result could be underwhelming: a drug that creates “a little bit of plasticity but it’s not really transformative.”

However, just because neuroplastogens are entirely unlike psychedelic therapy doesn’t mean they can’t still offer their own benefits. Instead of using plasticity to reprogram a particular habit, let alone altering one’s metaphysical view of the universe, Rus described how they may help repair the neuronal wear and tear associated with everything from chronic stress to neurodegenerative diseases such as Alzheimer’s. Sustained stress can grind away at neurons and affect brain connectivity, especially in key regions such as the prefrontal cortex. Simply spiking neuroplasticity may help repair the worn neurons, and bring those dampened networks of connectivity back online.

“What these new psychoplastogens are really good at doing is rapidly regrowing those spines [which connect neurons] and restoring circuit-level connectivity. The degree to which that repaired connectivity results in the behavioral changes or feelings that one seeks, time and data will ultimately tell,” Rus said.

No one believes current-generation antidepressants — SSRIs such as Prozac and Lexapro — are the pinnacle of depression treatments. In the space between Prozac and psychedelic therapy, there’s plenty of room for middling treatments that improve upon what we have now, but fall short of the transformative trips one might have on psychedelics.

Human trials will tell whether neuroplastogens may find a place in the cultural medicine cabinet. But these are just one category among hundreds of thousands of potential new psychedelic-inspired drugs that await discovery now that research is back online. Our single-digit list of psychoactive compounds is already transforming minds and industries alike. As that inventory expands, we may discover that the psychedelics we’re familiar with were only the modest beginnings of what will come next.