Slices being removed from a magic mushroom by robotic arms
Illustration by Hunter French

Can a Trip-Free Psychedelic Still Help People With Depression?

Psilocybin has shown promise for conditions like depression. Now, researchers are asking if the psychedelic experience is absolutely necessary to treat mental health.

A patient with depression once described their condition as "being enclosed in the most narrow confined space imaginable, it was like a sack over my head." Another said it was as if he was locked in a metal cage "from the shoulders up," or in a "mental prison."

During and after taking a high dose of psilocybin, the active ingredient in magic mushrooms, something changed. "It was like being on holiday away from the prison of my brain," one person said. "I was a ball of energy bouncing around the planet, I felt carefree, re-energized."


These testimonies came from a clinical trial for treatment-resistant depression at Imperial College London in 2016. As soon as one week after taking psilocybin—and for as long as three months after—the subjects' depressive symptoms were "markedly reduced," a paper on the results said. Since then, psilocybin and other psychedelics have been hailed as powerful and much-needed interventions for mental illness. Psychedelic research centers have been formed at Imperial College, and more recently at Johns Hopkins University in Baltimore, Maryland. In October 2018, psilocybin received Breakthrough Therapy designation from the Food and Drug Administration, recognizing it as a promising treatment for hard-to-treat depression, and potentially expediting the process for its approval as a legal medication. (Psilocybin is currently illegal at the federal level in the U.S. and the U.K.)

As scientists strive to understand exactly how these drugs lead to such dramatic outcomes, there's a growing desire to tease apart the experience of psychedelics from the drugs' other effects. Can the hallucinogenic trips that psychedelics induce be separated from other interactions the drugs might be having on the brain?

The experiences people have on psychedelics can be profound, emotional, painful, blissful, and seemingly transformative. One patient in an Imperial College study reported that they "had an encounter with a being, with a strong feeling that that was myself, telling me it’s alright, I don’t need to be sorry for all the things I’ve done. I had an experience of tenderness towards myself. During that experience, there was a feeling of true compassion I had never felt before.”


But what if this "trip" is just smoke and mirrors? A window dressing on a neurobiological process happening elsewhere that itself is reducing depression symptoms? Psychedelic drugs interact with receptors in the brain that cause the trip itself, but there are many other effects that are distinct from the hallucinogenic journeys people go through. For instance, they can create an increase in the connections among regions of the brain, and disruptions in other brain circuitry. Yet, up until this point, many experts have considered the entire psychedelic experience one single thing.

"Psychedelics produce profound experiences,” said Chuck Raison, a professor at the School of Human Ecology at University of Wisconsin-Madison. “Psychedelics have an antidepressant effect. They do both at the same time, so they get mythically linked, because the human brain works like that. It sees causation where there’s association.”

Researchers are now attempting an uncoupling: What, exactly, is responsible for the positive mental health outcomes? Which components of a psychedelic treatment are required, and could any be removed? Initiatives from academia, government, and the biotech industry are beginning to dissect psychedelics to see if they can be tweaked, optimized, or even stripped of the psychedelic experience altogether—and still be an effective treatment.

This area of study raises the question: What would a non-hallucinogenic psychedelic be like? It might be less subjectively spiritual or profound, and it very possibly would not work at all. But if it did work for depression, some experts say the arrival of a non-hallucinogenic (or somehow modified) psychedelic is inevitable. This kind of drug would be more scalable, marketable, and profitable than one that causes trips. It could also be more accessible than current frameworks for psilocybin treatment for depression—treatments that take hours at a time—providing the most large-scale benefit to those who desperately need more options for treating mental illness.


"Unless psychedelic effects are the mechanism by which these drugs work, sooner or later, these drugs will not have psychedelic effects," Raison said.

After the depression studies at Imperial College thrust psilocybin's potential medical benefits into the spotlight, clinicians have started to see that, for some patients, the effects can wear off after a few months—even in people who initially showed massive improvement.

“That suggests that it’s not just a change in your perspective of the world from an experience that benefits you,” Raison said. If an incredibly powerful experience fundamentally shifted your worldview, why would that benefit start to fade? “That there’s some kind of physiological something along with it."

He's in the process of recruiting participants for a study that will attempt to answer part of this basic science question regarding psychedelics: What is the role that conscious experience plays during a trip? To do this, he'll have people trip on psilocybin, and then prevent their brains from making memories of the experience.

If someone took psychedelics while unconscious or asleep, and it still led to an antidepressant effect, it would suggest that the "trip" isn't necessary for the clinical outcome. But Raison's study is an even subtler investigation.

He's assessing the importance of something called access consciousness. If you take shrooms, you'll have an immediate experience of your trip, or phenomenal consciousness. But later, you'll access the experience again, remembering what happened—reflecting and integrating whatever your experiences were.


"We prefer to try to peel the onion and start with that outer layer of consciousness, which is the memory of the event,” Raison said.

They plan to use a sedative drug called midazolam, which has been shown in studies to produce a kind of amnesia that can temporarily prevent people from forming new memories. At certain doses, a subject could remain awake and have a psychedelic experience—but not remember it. “This is like going on a bender,” Raison said. “You’re dancing, you’re screaming, you’re kissing people, but you don’t remember."

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They'll first test what doses of midazolam puts healthy volunteers in this state. Then, they'll repeat the process with a group of people who have depression and compare those who take psilocybin and remember it to those who don’t. If both groups have equal benefit from the psilocybin, it would suggest that you don't actually need the memory of the experience for it to be used for depression.

"You might still need the phenomenal conscious experience," or the awareness of the trip actually happening, Raison said. If psilocybin still works with a memory erase, the next step would be to do it again with unconscious participants. On the other hand, if erasing people's memories of a trip with midazolam does lead to a dulled effect on their depression symptoms, it indicates that the memory and reflection of the event is an important component.


Raison thinks that even with the results from the existing trials, we won’t really know how to treat a disease like depression unless we fully understand what the psychedelics are doing. His study could be a portal into that.

“We can begin to ask: what’s the difference in the brain between people who are getting psilocybin by itself versus psilocybin plus midazolam?” Raison said. “Then you’re beginning to identify pathways that are specifically associated with a sort of antidepressant effect.”

A non-hallucinogenic psychedelic already exists and there is another medical context where it's been shown to have benefit: headaches.

Emmanuelle Schindler, a neurologist at Yale School of Medicine, treats cluster headaches, which have acquired the sinister nickname "suicide headaches" from the frequent and excruciating pain they cause.

Schindler heard anecdotally about people using traditional psychedelics to improve their cluster headaches, and from a 2010 study that surveyed people's use of something called 2-bromo-LSD, or BOL, for their headache disorders.

BOL differs from LSD by just a single atom, and is non-hallucinogenic. When a chemical compound called bromide is attached to LSD, it removes its psychedelic effects. BOL was created by Albert Hoffman, who also invented LSD. (When Hoffman first made LSD, he was actually looking for new medications for migraine headaches.)

In interviews with a group of headache patients named Cluster Busters, Harvard Medical School psychiatrist John Halpern found that 41 percent of them had less painful or less frequent headaches when they took a variety of psychedelics, and for 52 percent of them, their cluster cycles stopped completely. A survey on BOL use found it can provide similar relief for cluster headaches.


"Those who got their hands on [BOL] or those who took part in that small study have said that when they use it in the same way that they would use psilocybin or LSD, it had similar effects on their headaches,” Schindler said.

It's still unknown how BOL—or LSD or psilocybin, for that matter—ease cluster headache symptoms. One clue is that both the psychedelics, whether hallucinogenic or not, chemically resemble a lot of other headache medications.

Psilocybin’s chemical structure is very similar to sumatriptan (brand name Imitrex), a medication used to treat one headache at a time. It’s also similar to melatonin, a hormone that helps regulate our sleep cycles but can also help treat headache disorders, too. LSD is similar to methysergide, a headache medication that isn’t available anymore, and dihydroergotamine, which is used to treat headaches and, when taken over the course of several days, can help to prevent future headaches.

But psilocybin, LSD, and BOL differ from those drugs in a big way: They can lead to long-term relief even after a few doses, similar to what researchers are seeing in the trials with treatment-resistant depression. Other headache medications don’t do that, Schindler said.

BOL is not officially being used to treat any headache disorders, but it's still an intriguing example in which the hallucinogenic piece of the puzzle isn’t necessary. BOL can have similar effects as psilocybin and LSD, Schindler said, and so patients aren't required to go on a psychedelic trip to find relief.


A more customizable psychedelic therapy like that is appealing to many—both patients who might not want the trip, as well as private companies and governmental groups tinkering with these drugs to make better versions of them, or using psychedelics' interactions with the brain as a launch point to make something entirely new.

One such effort is a new AI-enabled psychedelics lab called Entheogenix Biosciences, launched by two companies, ATAI Life Sciences and Cyclica. Srini Rao, the Chief Scientific Officer of ATAI and the CEO of Entheogenix, agreed that there are intersecting, and sometimes competing, theories of how psychedelics help people—experientially or biologically. Depending on which holds true, it will likely influence the ways psychedelic drugs are brought to market.

Entheogenix will be studying several psychedelics—ketamine and DMT as well as psilocybin—and evaluate which parts of their chemical structures are associated with mental health benefits. “Then we can start taking out those pieces associated with hallucinations, for example,” Rao said. “We can design new compounds that presumably don't hit those pieces but maybe maintain some of the other pieces of pharmacology that are critical, particularly those around neuroplasticity.”

They're not only seeking out non-hallucinogenic psychedelics (after all, the hallucination bit might be crucial) but also analyzing different chemical versions of psilocybin that could "improve" on the original model. These versions might retain the psychedelic element, but at much shorter durations. Instead of the normal six to eight hours, it could be condensed to 30 to 45 minutes. They could also potentially fix other issues with the drug, like one with another serotonin receptor that is associated with damage to the heart.


"If you’re going to design new molecules, you might as well make those as pristine as possible,” Rao said.

It's an approach that The Defense Advanced Research Projects Agency (DARPA), the U.S. military's research branch, will be attempting their own version of, too. In September, DARPA announced the launch of the Focused Pharma program which will develop new "neuropsychiatric" drugs loosely inspired by the results from various clinical trials of psychedelics. The goal of DARPA's program is to develop treatment for service members and veterans with PTSD, depression, and substance abuse.

The project is explicitly not investigating psychedelics themselves, a spokesman for DARPA said, but the existence of psychedelic research had an influence on the group's work—it showed it's possible for a drug to have such immediate effects on depression, as well as interact with the brain in complex ways, said Tristan McClure-Begley, the program director of Focused Pharma.

McClure-Begley said that even if psychedelics as they exist now were approved for such a purpose, their use would be limited given their side effects. He doesn't see how psilocybin could realistically be implemented for veterans and other populations on a wide scale given that as the treatment exists now, a person needs hours of preparation, hours for their trip (or two trips), and then hours of follow-up. There are two trained, and therefore expensive, clinicians with them during the trips, and others to facilitate the prep and integration sessions.


“This is costly, it’s hard to bring to scale,” Raison said. If the experience of tripping isn’t tied to the mechanism in psychedelics that has a positive effect on depression, then “it’s hard to see why, if you’re trying to treat a disease, you’d insist on people having them. Tons of people are going to be working to try to find a way to optimize these molecules and make their delivery as simple as possible."

It might not be so easy to draw a line in the sand between biology and experience, said Chris Timmermann, a neuroscientist at the Psychedelic Research Group at Imperial College. All drugs have an experiential component to them, even those that aren't psychedelic. If you take an antidepressant and it makes you feel better through "biological" means, you’re still going to have healing experiences from engaging with other people, again, or your work, family, and finding more pleasure in life.

“There’s a huge interplay between contextual factors and the experience people have, and there seems to be a very strong relationship with the quality of people’s experiences and the psychological outcome, from a clinical perspective," Timmermann said.

He thinks that from a scientific standpoint, it is important to dissect the psychedelic experience from its biological impact. But he hopes that the push to analyze the experience leads to more attention paid to experience overall—no matter what the research ends up finding.


Let’s suppose that Raison’s study finds the psychedelic experience is, in fact, necessary for depression relief. Timmermann doesn't think we should stop there, and continue to treat “experience” as one event, rather than a combination of many.

Timmermann has been studying DMT, the psychedelic compound found in ayahuasca, and said that in reports of what people experience, they often bring up similar themes or visions, as with psilocybin. “Like, 'I went to a different dimension' or 'I saw these entities or beings,' and so on,” he said. “We have good evidence that experience is a crucial factor for people to get better. But it's also very valid to try to make sure why this is the case.”

Many of what people say are the most meaningful pieces of the experience are ones they have a hard time describing. We could be missing out on understanding those breakthrough moments. “It’s almost like it’s uncharted territory,” Timmermann said. “Science hasn’t veered in the direction of phenomenology of experience. It’s like we have no language for it.”

Not only do the fuzzy lines between experience and biology need to be scrutinized, but the very experience itself needs to be dissected and analyzed too, he said. Perhaps experience is important, but certain types at certain times are more or less so. In a study forthcoming in Scientific Reports, Timmernmann and his co-authors broke down the experience of a DMT trip, showing what people felt at different time points after taking DMT, the associated intensity, and the associated brain activity.

This kind of discipline and rigor may seem like an unconventional way to approach a psychedelic trip, but if we're seriously going to use these drugs as medicines, that will be necessary, Raison said. Since psychedelics can produce intensely profound feelings, it can seem wrong to strip psychedelics for their parts, categorize the mystical, taxonomize the spiritual, or come up with psychedelic-inspired meds that will be produced and sold by big pharma at astonishing profit.

Raison said if he's honest with himself, his gut feeling is that the conscious experience of the trip is a factor. He thinks many clinicians who witness the profound and life-changing experiences their patients go through would agree. But the point is we don't know for sure, and he doesn't think researchers in this field should gravitate to either extreme—one assuming it's all biological, and getting rid of all the woo-woo psychedelic stuff; the other treating psychedelics like they’re so sacred that they shouldn’t be tampered with.

"I'm personally rooting for consciousness," he said. "But as a mentor once told me, ‘If you're afraid of the truth, you should get out of science.’ You never know, right?"

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