鈥淪WITCHED OFF鈥, 鈥渟hort-circuited鈥 and 鈥渟hut down鈥. This is how three participants described their depression before they took part in a clinical trial for psychedelic-assisted psychotherapy at Imperial College London in 2016.
Their outlook changed dramatically after taking a high dose of psilocybin, the active ingredient in magic mushrooms. 鈥淚 was a ball of energy bouncing around the planet,鈥 one recounted in an interview with , a clinical psychologist who led the trial. Another described the experience as akin to defragging a computer hard drive: 鈥淚 visualised as it was all put into order, a beautiful experience with these gold blocks going into black drawers that would illuminate.鈥
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Such transformations are no longer surprising. Similar trials have established psychedelics as a game changer when it comes to tackling the global mental health crisis. 鈥淭here鈥檚 a huge unmet need, and psychedelics do have radical potential,鈥 says Watts.
Now, some scientists are creating new drugs that remove the psychedelic experience, or 鈥渢rip鈥, while still offering therapeutic benefits. But Watts and others are warning that this approach misunderstands how psychedelic therapy works 鈥 and that if we try to squeeze it into a pill-popping industrial healthcare model, its vast promise may never be realised.
They aren鈥檛 just dishing out warnings, though. Some of the pioneers of the field are moving beyond the simple story that psychedelics 鈥渞eset the brain鈥 by carefully investigating the role of the psychedelic experience, and the therapy that accompanies it. The aim is to establish exactly what we can鈥檛 lose if we are to make good on the hopes raised by psychedelic medicine鈥檚 recent successes.
In psychedelic therapy, people are given a high dose of psychedelics under the careful guidance of therapists, bookended by therapy. There is no doubt that it can be an effective treatment. Over the past decade, researchers have demonstrated that it can relieve various mental illnesses in people who don鈥檛 respond to existing treatments. Small-scale clinical trials have found that one or two doses of psilocybin, for instance, can , , and . In November 2021, the found that a single dose of psilocybin relieved treatment-resistant depression for three months in a quarter of patients. These people had tried at least two other treatments without success.
The results speak for themselves. But clinical trials are far from the real world of public healthcare systems. Billions of people struggle with depression, anxiety and various other mental health conditions. The big question is: if psychedelics were to become legal treatments, could you replicate this experience for everyone who wants it?
Trip-free psychedelics
For , a chemist at the University of California, Davis, the answer is to create new drugs that offer the transformative powers of psychedelics without the experience. These trip-free psychedelics would, he says, remove the risk of bad trips, known as 鈥渂ottom-margin cases鈥, which happen most often in people with pre-existing psychiatric conditions, such as schizophrenia and bipolar disorder, and can significantly worsen mental health. And they would also remove the requirement for lengthy and expensive therapy, making it accessible for as many people as possible, he says. 鈥淚 worry that this is going to become a treatment only for the people who can afford to pay out of pocket,鈥 says Olson.
To create these 鈥渘on-hallucinogenic psychoplastogens鈥, Olson鈥檚 team systematically masks different parts of the chemical structure of psychedelics to understand which bits give rise to which effects. 鈥淵ou can just keep the features that are beneficial and remove the features that are not,鈥 he says. One hallmark of depression, post-traumatic stress disorder and substance addiction is the wasting away of brain cells in the prefrontal cortex, the region associated with complex behaviours and higher-level thinking. Evidence suggests that , so Olson hung on to these functions while removing the parts that give the visceral experience.
Psychoplastogens have produced promising results in mice, , while also reducing behaviours associated with addiction or depression. 鈥淚t鈥檚 very comparable to what you see with hallucinogenic compounds, and that gave us a hint that it might be possible to do this,鈥 says Olson, who is planning human trials later this year with Delix Therapeutics, a company he co-founded. In theory, psychoplastogens could be picked up at the pharmacy like any other prescribed pill.
But some are sceptical that trip-free psychedelics will work in humans. , an experimental psychologist at Johns Hopkins University in Maryland, agrees that low-level brain cell changes play an important role in how psychedelics work, but stresses that psychoplastogens are still hypothetical. 鈥淚t鈥檚 hard to infer on the basis of rodent research what will happen in human clinical trials,鈥 he says. 鈥淢y strong suspicion is that the acute subjective effects will be necessary for full and enduring therapeutic impacts.鈥
Yaden is referring to the intense personal experiences people have when they take psychedelics and the meaning that comes with them. The extent of that intensity became clear to Roland Griffiths, also at Johns Hopkins, who collaborates with Yaden, about two months after he ran his first psilocybin clinical trial, when volunteers returned to report on their progress. 鈥淚t wasn鈥檛 uncommon for them to say: 鈥楾hat鈥檚 the most meaningful experience of my life, on a par with the birth of my firstborn child鈥,鈥 he says. Indeed, a third of participants in said it was the single most spiritually significant experience of their life.
This led Griffiths to design the Mystical Experience Questionnaire (MEQ), which tries to quantify the importance of spiritual experiences during psychedelic therapy, although he is at pains to point out that the MEQ measures a 鈥渟ecular spirituality鈥. Different research groups describe these kinds of experience with different metrics, but whether it is 鈥渆go dissolution鈥 or an 鈥渆xperience of unity鈥, they are broadly equivalent. 鈥淭hese are all what I鈥檇 consider self-transcendent experiences,鈥 says Yaden. And the upshot is that weeks or months later.
Griffiths suspects the experiences provide a new template for how people view themselves within the world, and so alter how they make decisions going forward. Still, he says that while subjective experiences are probably necessary for positive outcomes, the question isn鈥檛 settled. The only bulletproof test, he says, is to give psychedelics to people who are under anaesthetic and so are unconscious. 鈥淭hose studies are really difficult, but people are making a stab at them,鈥 he says.
In the meantime, others are working on more holistic, theoretical models of how psychedelic substances work 鈥 something that goes beyond the existing mechanistic idea of chemicals modifying brain cells. Working with Karl Friston at University College London, , a neuroscientist at the University of California, San Francisco, has developed a model that pieces together the many levels on which psychedelics act: from molecular interactions to large networks of brain regions to what they call the 鈥渞elaxation of beliefs under psychedelics鈥.
The idea, known as the , is rooted in the predictive processing theory of consciousness. This posits that we make sense of the world by predicting what will happen based on past experiences and comparing it with what we actually sense. If there is a mismatch, it creates a prediction error that is used to update our prior beliefs. Together, they form our perception of the world and ourselves.
Friston and Carhart-Harris suggest that, in all this back and forth, certain prior beliefs can become entrenched in an unhealthy way, sometimes as a result of traumatic experiences. 鈥淵ou become an expert in whatever your pathology is: negative ruminative thinking and being stuck in your head in depression, for instance,鈥 says Carhart-Harris. 鈥淚t is planted, and very resistant to treatment.鈥 What psychedelics do, according to the idea, is make the brain more sensitive to prediction errors, creating a temporary anarchy that allows you to remould your prior beliefs.
Difficult conversations
Anarchy, though, comes with risks. After all, we may dig these mental ruts for self-protection and stability. 鈥淭he outcome isn鈥檛 inevitably and unconditionally always one of healing,鈥 says Carhart-Harris. 鈥淲hen you鈥檙e opened up, you鈥檙e vulnerable to the conditions that you find yourself in.鈥 Which is why Carhart-Harris and others attribute so much importance to the experience you get when you take psychedelic drugs 鈥 and the therapy too.
The reality is that the psychedelic experience is just one part of a demanding process. Participants in clinical trials spend many hours with at least one therapist before, during and after the actual psychedelic experience. 鈥淚t鈥檚 really tender and caring, and tuned to somebody鈥檚 need. But that story doesn鈥檛 get told. It just doesn鈥檛 get translated into scientific journals as it鈥檚 not part of their language,鈥 says Watts. 鈥淧eople see it as fluffy and soft, but that is the mechanism.鈥
Olson acknowledges that psychoplastogens don鈥檛 act as holistically as psychedelics, but argues that it is 鈥渘ot an either/or thing鈥. Different drugs will be needed for different people, he says, balancing the effectiveness, safety and cost in each case. 鈥淔or some patients, psychedelic-assisted therapy will be very important. The question is, do all patients need it?鈥
It is hard to see how psychedelic therapy can fit with the industrial medical narrative, where patients are passive recipients of a treatment and contact time is limited. To find a home for psychedelic therapy in our cash-strapped public healthcare systems, some say the levels of support that were offered in clinical trials will have to be cut back. 鈥淭he cost is really substantial and it just becomes untenable,鈥 says Griffiths. 鈥淪o how far can you back that down? I don鈥檛 know, but I am concerned what will happen as this rolls out.鈥
Carhart-Harris fears that this cost-cutting approach will go too far. 鈥淲hat you鈥檙e left with is something which is no longer safe and effective enough,鈥 he says, which would not only harm those being treated, but also create a backlash for the practice as a whole. As part of his efforts to make sure that doesn鈥檛 happen, Carhart-Harris opened a lab called Neuroscape last year where he and his colleagues are testing how to best guide a patient鈥檚 psychedelic experience (see 鈥The perfect trip鈥). There, he also hopes to identify which subjective components of psychedelic therapy are most beneficial or essential for safety, and so cannot be stripped away.
Meanwhile, Watts says we should rethink the relationship between our healthcare systems and society. Last month, she launched a therapy programme called ACER Integration, which is rooted in communities rather than the traditional patient-doctor dynamic alone. While therapists would still be essential for the actual psychedelic sessions, the guidance people need afterwards could be provided by grassroots networks. In this model, those receiving treatment become guides through their own experiences, and healing is as much about making connections with other people as it is about a self-transcendent trip.
Watts hopes to realise what some see as idealistic levels of patient support 鈥 and without the price tag. 鈥淲orking together in a collaborative way to provide a safety net and support network probably sounds very dreamy, but it could work in terms of the real-world translation for the future of psychedelic medicine,鈥 says Carhart-Harris.
Relationships are important in any kind of therapy, adds Watts. Indeed, it is telling that one of the best predictors of outcomes in psychedelic therapy is . 鈥淧sychedelics are really good at helping us feel a sense of community with other people,鈥 she says. 鈥淎nd it鈥檚 something that we鈥檙e really missing in our daily lives.鈥
The perfect trip
Counterculture icon Timothy Leary coined the term 鈥渟et and setting鈥 in the 1960s to emphasise how someone鈥檚 initial mental state, together with their physical and social environment, deeply informs their psychedelic experience. Now, while some seek to make 鈥渢rip-free psychedelics鈥 (see main story), is painstakingly searching for the perfect therapeutic trip.
A neuroscientist at the University of California, San Francisco, Carhart-Harris last year opened a lab called Neuroscape to untangle which circumstances lead to the best outcomes for people undergoing psychedelic-assisted psychotherapy, and how brain-imaging technology can guide that process. There, Carhart-Harris and his colleagues can tailor the therapeutic environment during the trip itself. For example, they are testing guided meditations to prepare participants, as well as more active and engaged therapy during sessions. They are also working with musicians and film directors to create immersive audiovisuals of wild landscapes, complimented with natural scents. 鈥淭he psychedelic experience is, in a sense, a return to a simpler state,鈥 says Carhart-Harris. 鈥淛ust to be reminded of our essence seems to harmonise very nicely with the psychedelic experience.鈥
Intriguingly, Carhart-Harris and his colleagues are even developing technology that could inform therapists about their patient鈥檚 state of mind during a trip without having to ask. 鈥淲hen you鈥檙e a guide in psychedelic therapy sessions, most of the time you鈥檙e just guessing where someone is,鈥 he says. 鈥淎re they in a pretty good place? Or are they in a struggle state?鈥 The therapist could intervene accordingly to create a safer, more nurturing environment for psychedelic therapy.
No one knows what the brain looks like in those struggle states, so Carhart-Harris is combining deep-learning algorithms with functional magnetic resonance imaging (fMRI) of the brain to build a picture of how subjective experiences map onto physical brainwaves. Scanning a small number of volunteers many times will allow him to create a portrait of psychedelic substates and so map which kinds of brain pattern correspond to different experiences. Similar technology has already been used to create algorithms that can accurately predict what people are dreaming about from an fMRI read-out.
Carhart-Harris hopes that figuring out the 鈥渨inning formula鈥 could also offer solutions for people with existing psychiatric conditions like schizophrenia and bipolar disorder. They are more likely to have bad trips, and are therefore generally seen as too high risk for psychedelic-assisted therapy. 鈥淲e lack enough treatments for the really hard cases, so it鈥檚 kind of a protective motivation,鈥 he says.
