«Triple» drugs may open up more possibilities for psychiatry. Just don't call them psychedelics.
Today's psychedelic renaissance thrives on a list of drugs that can be counted on the fingers of one hand. MDMA, psilocybin, LSD and DMT are revolutionizing psychiatry and addiction medicine, opening new horizons in the exploration of consciousness. If you add ketamine and ibogaine to the aforementioned drugs, there are enough mysteries in this small group of substances to keep researchers busy for decades.
But what if there are hundreds or thousands more? Drugs are like tiny LEGO constructors that can be rearranged in many different ways. Chemists have barely begun to discover all the infinite molecular forms contained in the psychedelic arena. In the 1960s, biochemist Alexander Shulgin, who introduced MDMA to the world, invented about 200 psychedelics (mostly in his backyard lab, where he used sheet metal to keep protein out). When President Richard Nixon outlawed psychedelics in 1970, drug discovery came to a standstill.
Nearly two decades after the resurgence of psychedelic research, the doors of drug discovery are wide open again, and recent developments have stirred up psychedelics, exposing the fault lines that have split the field in two.
Question: can we mess around with the molecular structure of psychedelic compounds enough to retain their therapeutic benefits, but give up the ride? And should we do it? For many, the trip is the point. Many researchers believe that in addition to the flow of unusual and profound experiences, the knowledge people gain from their trips is necessary to provide long-term benefits that can range from personally meaningful experiences to treating conditions such as depression or addiction.
Nearly two decades after the resurgence of psychedelic research, the doors of drug discovery are wide open again, and recent developments have stirred up psychedelics, exposing the fault lines that have split the field in two.
Question: can we mess around with the molecular structure of psychedelic compounds enough to retain their therapeutic benefits, but give up the ride? And should we do it? For many, the trip is the point. Many researchers believe that in addition to the flow of unusual and profound experiences, the knowledge people gain from their trips is necessary to provide long-term benefits that can range from personally meaningful experiences to treating conditions such as depression or addiction.
In 2020, a group of researchers led by Delix co-founder and chemist David Olson published a paper suggesting that triple psychedelics are possible. In this case, a modernized form of ibogaine — a psychoactive substance with dissociative properties found in a West African shrub, traditionally used by the Bwiti religion in Gabon, and now being studied for its anti-addiction potential — still showed therapeutic effects without accounting for the distortion of consciousness, at least in mice.
Over the years, more articles have appeared demonstrating that modernized psychedelics such as LSD can retain therapeutic effects while losing the trip — but again, all in mice.
Now these triple-action psychedelic drugs are being tested in humans for the first time. In June, Delix Therapeutics announced the successful first dosing phase I clinical trial of DLX-001, a «non-hallucinogenic» version of MDMA. If the results are repeated in humans, the consequences could be significant.
Were it not for the trip, these drugs could prove safe and therapeutically effective to take at home, bypassing the need (and expense) of multiple in-person sessions and recruitment. But even if such drugs prove effective in alleviating conditions such as depression, anxiety, or addiction, according to others in the field, you're missing the very thing that makes psychedelics so reliably life-changing.
Why do you need psychedelics devoid of trip effects?
Despite all the talk about the psychedelic renaissance, it's easy to get the wrong idea. According to a recent YouGov poll, 68% of Americans have never tried psychedelics. A survey of mental health service users found that 20% still consider psychedelics unsafe even under medical supervision, citing concerns about side effects (among other fears such as lack of knowledge and illegality). Leading researchers are already preparing for the «bursting of the psychedelic hype bubble».
However, the vast majority of clinical psychedelic trips are positive in nature. Users consistently cite them as some of the most significant events in their lives, on par with the birth of their firstborn child. And the list of promising therapeutic applications is growing. Although rare, bad-trips and negative side effects do occur, and the effects can linger for weeks or even years.
After taking mescaline (an LSD-like psychedelic found in several species of cactus), French existentialist philosopher Jean-Paul Sartre saw a hallucinatory set of crustaceans that haunted him for weeks. «After I took mescaline, I began to see crabs around me all the time. I mean, they followed me outside, into the classroom» — he recalls. Today we would call this episode a persistent hallucinogenic perception disorder, an extremely rare side effect and one of the reasons why clinical trials test participants with a predisposition to psychotic disorders.
Despite all the talk about the psychedelic renaissance, it's easy to get the wrong idea. According to a recent YouGov poll, 68% of Americans have never tried psychedelics. A survey of mental health service users found that 20% still consider psychedelics unsafe even under medical supervision, citing concerns about side effects (among other fears such as lack of knowledge and illegality). Leading researchers are already preparing for the «bursting of the psychedelic hype bubble».
However, the vast majority of clinical psychedelic trips are positive in nature. Users consistently cite them as some of the most significant events in their lives, on par with the birth of their firstborn child. And the list of promising therapeutic applications is growing. Although rare, bad-trips and negative side effects do occur, and the effects can linger for weeks or even years.
After taking mescaline (an LSD-like psychedelic found in several species of cactus), French existentialist philosopher Jean-Paul Sartre saw a hallucinatory set of crustaceans that haunted him for weeks. «After I took mescaline, I began to see crabs around me all the time. I mean, they followed me outside, into the classroom» — he recalls. Today we would call this episode a persistent hallucinogenic perception disorder, an extremely rare side effect and one of the reasons why clinical trials test participants with a predisposition to psychotic disorders.
Regardless of what new mental health paradigm psychedelics may catalyze, between those with conditions that increase the risk of travel and those who simply prefer to avoid it, there will be many people who could benefit from a variety of treatment options.
If scientists can eliminate psychedelics while retaining some therapeutic benefits, patients will be able to take these drugs at home at a fraction of the cost and time required for psychedelic therapy, expanding the range of treatment options to serve the more than 50 million Americans who report some sort of mental illness in 2020.
Don't call it psychedelics
Olson coined the term «psychoplastogen», defining a class of drugs that can rapidly increase neuroplasticity after a single dose. This distinguishes them from the depression treatments of SSRIs such as Prozac, which only increase neuroplasticity with long-term administration. But both the classic psychedelics and their newer triple relatives fit the definition of psychoplastogens. To label the triple variety, you'll encounter the unpleasant term «non-hallucinogenic psychoplastogen», which poses no threat of spreading beyond scientific circles. Instead, some have come to call them second-generation psychedelics or «non-hallucinogenic psychedelics»: which contradicts the very meaning of the word «psychedelic».
Etymologically, the word «psychedelic» comes from the ancient Greek word for «manifestation of the mind», which directly refers to what scientists today call «acute subjective experiences». Psychiatrist Humphrey Osmond coined the name in a conversation with philosopher and writer Aldous Huxley in the 1950s, writing, «To comprehend hell or soar angelically / Just take a pinch of psychedelics». A non-hallucinogenic psychedelic, subjectively showing nothing unusual, is an oxymoron.
If scientists can eliminate psychedelics while retaining some therapeutic benefits, patients will be able to take these drugs at home at a fraction of the cost and time required for psychedelic therapy, expanding the range of treatment options to serve the more than 50 million Americans who report some sort of mental illness in 2020.
Don't call it psychedelics
Olson coined the term «psychoplastogen», defining a class of drugs that can rapidly increase neuroplasticity after a single dose. This distinguishes them from the depression treatments of SSRIs such as Prozac, which only increase neuroplasticity with long-term administration. But both the classic psychedelics and their newer triple relatives fit the definition of psychoplastogens. To label the triple variety, you'll encounter the unpleasant term «non-hallucinogenic psychoplastogen», which poses no threat of spreading beyond scientific circles. Instead, some have come to call them second-generation psychedelics or «non-hallucinogenic psychedelics»: which contradicts the very meaning of the word «psychedelic».
Etymologically, the word «psychedelic» comes from the ancient Greek word for «manifestation of the mind», which directly refers to what scientists today call «acute subjective experiences». Psychiatrist Humphrey Osmond coined the name in a conversation with philosopher and writer Aldous Huxley in the 1950s, writing, «To comprehend hell or soar angelically / Just take a pinch of psychedelics». A non-hallucinogenic psychedelic, subjectively showing nothing unusual, is an oxymoron.
It's okay for Russ and Olson. They are in the business of psychoplastogens, not psychedelics. What matters is the untapped therapeutic potential of rapid bursts of neuroplasticity, not how their new drugs compare and contrast with traditional psychedelics.
As for the name, «neuroplastogen» is starting to catch on as a term to describe the triple category of psychoplastogens. We could still use a literary intervention in the spirit of Huxley and Osmand to come up with something smoother, but until then it's an improvement.
What did the researchers do?
Although the brain is still shrouded in many mysteries, it is known that the classic psychedelics — psilocybin mushrooms, DMT, LSD and mescaline — bind to the same serotonin 2A receptor, which is thought to be one of the main mechanisms underlying changes in the activity of key brain circuits associated with conscious experience.
One approach to separating trip from therapy, published last year by a team of biochemists from the Shanghai Institute of Biochemistry and Cell Biology, was to zoom in on a deeper layer. Instead of stopping at observing which receptor the drugs bind to, they looked at how the molecules actually fit into the curvature of the receptor. The fit isn't exactly tight, so using a technique known as X-ray crystallography, they were able to see where the points of contact are.
By passing X-rays through a crystallized copy of a compound, and based on how the rays twist and pass through the crystal, you can determine how all the atoms in it are arranged, creating a sort of atomic map. Co-author Sheng Wang first applied this method in a 2017 study, to see how LSD fits into the related serotonin 2B receptor, and found that it inserts into a cavity known as the orthosteric binding pocket (OBP).
In the 2022 publication, Wang and colleagues created six new crystal copies of drugs, this time bound to the 2A receptor. They found that in addition to the OBP, some, but not all, of the compounds also reside in a neighboring second cavity, the extended binding pocket (EBP).
They then injected the mice with each of the drugs. In mice, head jerking is taken as a sign of traveling, whereas increasing the amount of time they try to stay afloat in a cylinder of water before just letting themselves drown is a sign of an antidepressant effect (this is known as forced swimming test) and we should stop doing it. Wang et al. learned that drugs that fit into EBP have hallucinatory effects, while drugs that fit only into OBP, such as serotonin, show only antidepressant effects.
Armed with this insight, they created new variants of LSD designed to move away from EBP and focus on OBP. As a result, at least in mice, the two LSD relatives achieved the expected result: no head twitching, but more time spent afloat in the depression tank; in other words, as a variant of Delix MDMA, a new potential neuroplastogen.
How much of the therapy will people lose without the trip?
Despite recent advances, going from head twitching and walking on water in mice to having psychedelic experiences while treating depression in humans is a major leap. «It just seems incredible to me that you would see the full and lasting benefits of psychedelics without the acute subjective effects (of tripping)» — David Yaden, an assistant professor at Johns Hopkins University who works at the Center for Psychedelic and Consciousness Studies.
They then injected the mice with each of the drugs. In mice, head jerking is taken as a sign of traveling, whereas increasing the amount of time they try to stay afloat in a cylinder of water before just letting themselves drown is a sign of an antidepressant effect (this is known as forced swimming test) and we should stop doing it. Wang et al. learned that drugs that fit into EBP have hallucinatory effects, while drugs that fit only into OBP, such as serotonin, show only antidepressant effects.
Armed with this insight, they created new variants of LSD designed to move away from EBP and focus on OBP. As a result, at least in mice, the two LSD relatives achieved the expected result: no head twitching, but more time spent afloat in the depression tank; in other words, as a variant of Delix MDMA, a new potential neuroplastogen.
How much of the therapy will people lose without the trip?
Despite recent advances, going from head twitching and walking on water in mice to having psychedelic experiences while treating depression in humans is a major leap. «It just seems incredible to me that you would see the full and lasting benefits of psychedelics without the acute subjective effects (of tripping)» — David Yaden, an assistant professor at Johns Hopkins University who works at the Center for Psychedelic and Consciousness Studies.
In a 2021 article, Yaden and his colleague Roland Griffiths argue that travel is necessary to get the full beneficial effects of psychedelics. Even Olson, co-founder of Delix, who published a counterpoint on the same day, agrees. The trip may be «crucial to maximizing therapeutic efficacy» — he writes. Nevertheless, Olson argues that any benefits left over from not traveling can still be valuable, especially because they can reach broader patient populations.
How much benefit remains depends on an unresolved question in the world of psychedelic therapy: Is a rapid increase in neuroplasticity itself a good treatment? Olson thinks so, and there are some preclinical studies of drugs such as ketamine, MDMA and ibogaine that support this. However, a very recent preprint study showed that ketamine was given to subjects under anesthesia (excluding any associated trips) and found no difference from placebo, suggesting that something about the experience matters.
At the University of Wisconsin-Madison, anesthesiology professor Matthew Banks ponders something between giving up a trip alone and anesthesia: what if you let people have the full psychedelic experience, but then completely erase their memory of the trip? Do you need to remember the trip for the benefits to persist?
In an eight-person pilot study at the university's Transdisciplinary Center for Psychoactive Substance Research, participants were given psilocybin and midazolam, an amnesia-inducing drug that leaves conscious experience intact but erases memories (it's often used to help patients). «It's like you're one of those philosophical zombies. You're conscious and talking, but the next day you don't remember anything» — Banks said.
How much benefit remains depends on an unresolved question in the world of psychedelic therapy: Is a rapid increase in neuroplasticity itself a good treatment? Olson thinks so, and there are some preclinical studies of drugs such as ketamine, MDMA and ibogaine that support this. However, a very recent preprint study showed that ketamine was given to subjects under anesthesia (excluding any associated trips) and found no difference from placebo, suggesting that something about the experience matters.
At the University of Wisconsin-Madison, anesthesiology professor Matthew Banks ponders something between giving up a trip alone and anesthesia: what if you let people have the full psychedelic experience, but then completely erase their memory of the trip? Do you need to remember the trip for the benefits to persist?
In an eight-person pilot study at the university's Transdisciplinary Center for Psychoactive Substance Research, participants were given psilocybin and midazolam, an amnesia-inducing drug that leaves conscious experience intact but erases memories (it's often used to help patients). «It's like you're one of those philosophical zombies. You're conscious and talking, but the next day you don't remember anything» — Banks said.
He explained that finding the right dosage is difficult because psilocybin appears to form lasting memories, which Banks believes is due to increased neuroplasticity. Once the researchers increased the dose enough to erase most of the trip from memory, the benefit seemed to disappear as well. «There seems to be something going on when we eliminate some of the long-term behavioral effects of the drug» — Banks said.
In part, this was probably because the participants were healthy volunteers rather than patients suffering from conditions such as treatment-resistant depression. Because neuroplastogens are considered therapeutic agents, amnesia research tells us little about their role in treating mental illness.
Although Banks acknowledged that successful preclinical studies in mice «open up the possibility that all hallucinogens are largely irrelevant» to therapeutic outcomes, he believes that «what really matters is what you actually do with all that plasticity».
If neuroplastogens become pills that can be taken at home, they will do away with both parts of psychedelic therapy: the psychedelic experience and the therapy itself. Robin Carhart-Harris, professor of neuroscience at the University of California, San Francisco, noted in an interview with the New York Times last year that plasticity is simply a greater ability to change shape. For better or worse may depend on what happens after you take the drug.
Combining travel with therapy helps steer plasticity toward favorable outcomes. Without the trip, Carhart-Harris told the Times, the result could have been overwhelming: a drug that creates «a little plasticity but doesn't actually transform».
In part, this was probably because the participants were healthy volunteers rather than patients suffering from conditions such as treatment-resistant depression. Because neuroplastogens are considered therapeutic agents, amnesia research tells us little about their role in treating mental illness.
Although Banks acknowledged that successful preclinical studies in mice «open up the possibility that all hallucinogens are largely irrelevant» to therapeutic outcomes, he believes that «what really matters is what you actually do with all that plasticity».
If neuroplastogens become pills that can be taken at home, they will do away with both parts of psychedelic therapy: the psychedelic experience and the therapy itself. Robin Carhart-Harris, professor of neuroscience at the University of California, San Francisco, noted in an interview with the New York Times last year that plasticity is simply a greater ability to change shape. For better or worse may depend on what happens after you take the drug.
Combining travel with therapy helps steer plasticity toward favorable outcomes. Without the trip, Carhart-Harris told the Times, the result could have been overwhelming: a drug that creates «a little plasticity but doesn't actually transform».
However, the fact that neuroplastogens are completely different from psychedelic therapy doesn't mean they can't offer their own benefits. Rather than using plasticity to reprogram a particular habit, let alone change a metaphysical view of the universe, Roos described how they can help repair the wear and tear on neurons associated with everything from chronic stress to neurodegenerative diseases like Alzheimer's.
Sustained stress can destroy neurons and affect brain connectivity, especially in key areas such as the prefrontal cortex. Simply increasing neuroplasticity can help repair worn out neurons and put weakened communication networks back to work.
«These new psychoplastogens are really good at rapidly regrowing spikes [that connect neurons] and restoring circuit-level connections. The degree to which the restored connectivity leads to the behavioral changes or feelings a person is looking for will ultimately be shown by time and data» — Roos said.
No one believes that the current generation of antidepressants — SSRIs such as Prozac and Lexapro — are the pinnacle of depression treatment. In between Prozac and psychedelic therapy, there's plenty of room for mediocre treatments that improve what we have now but fall short of the transformative journeys that could be made while taking psychedelics.
Human trials will show whether neuroplastogens can find a place in the cultural medicine cabinet. But this is just one category among hundreds of thousands of potential new psychedelic drugs awaiting discovery now that research has begun again. Our single-digit list of psychoactive compounds is already changing minds and industries. As this list expands, we may find that the psychedelics we are familiar with were only a modest beginning of what's to come.
Sustained stress can destroy neurons and affect brain connectivity, especially in key areas such as the prefrontal cortex. Simply increasing neuroplasticity can help repair worn out neurons and put weakened communication networks back to work.
«These new psychoplastogens are really good at rapidly regrowing spikes [that connect neurons] and restoring circuit-level connections. The degree to which the restored connectivity leads to the behavioral changes or feelings a person is looking for will ultimately be shown by time and data» — Roos said.
No one believes that the current generation of antidepressants — SSRIs such as Prozac and Lexapro — are the pinnacle of depression treatment. In between Prozac and psychedelic therapy, there's plenty of room for mediocre treatments that improve what we have now but fall short of the transformative journeys that could be made while taking psychedelics.
Human trials will show whether neuroplastogens can find a place in the cultural medicine cabinet. But this is just one category among hundreds of thousands of potential new psychedelic drugs awaiting discovery now that research has begun again. Our single-digit list of psychoactive compounds is already changing minds and industries. As this list expands, we may find that the psychedelics we are familiar with were only a modest beginning of what's to come.