As psychedelics near approval, there’s no consensus on how they work

DENVER — The founder of Field Trip, a chain of shuttered ketamine clinics currently facing insolvency, put forward an unexpected theory of how psychedelics work to treat depression last month. “The truth is, almost all of the effect of psychedelic-assisted therapy could be placebo,” said Ronan Levy, speaking at a five-day conference on the emerging field of psychedelic medicine. “Personally I don’t have a problem with that. The outcomes are the outcomes, and that’s really what matters in my view.”

While there’s evidence to support the idea (which, if correct, would make Field Trip’s $5,250 price for six ketamine sessions an unusually expensive placebo effect), attendees at Psychedelic Science 2023 heard an array of explanations for the potential benefits of psychedelic drugs for people with various mental illnesses.

Some researchers attribute a therapeutic effect to a combination of physical changes in the brain — though where, exactly, is still uncertain — plus personal experiences while high and in the days following psychedelic treatment. Or maybe the strength of the mystical experience while on psychedelics determines the psychological response. Or, it could be entirely biochemical.

“How do you make sense of it?” said Boris Heifets, anesthesiology professor who studies ketamine at Stanford University. “Some of it just has to be wrong.”

The confusion and combination of evidence presented at the conference reflects a field still in the early stages of trying to disentangle a potential medical treatment. Many types of psychedelics — both traditional drugs, such as MDMA and psilocybin (the psychoactive compound in magic mushrooms), and newer, modified versions — are under investigation as treatment for a range of mental health conditions, including depression and post-traumatic stress disorder. Though there are plans to submit trials on MDMA for PTSD to the Food and Drug Administration for approval later this year, none of the medications has yet been definitively proven to work. And the question of how they work is very much up for debate.

“There’s an awful lot of uncertainty,” said Fred Barrett, cognitive neuroscientist and director of Johns Hopkins Center for Psychedelic and Consciousness Research. “Part of that uncertainty comes from the very small amount of data that exists.” The research to tease out the mechanisms of psychedelics is based on animals or studies of humans with small sample sizes, meaning there’s no definitive evidence yet.

The divergence of theories and lack of clarity receives little attention in journal press releases and media coverage of psychedelics, which often portray these drugs as transformative agents that work by enhancing “neuroplasticity,” rewiring the brain and creating a child-like state of learning. The concept of “neuroplasticity,” though, is too general to be meaningful. “Anything you do, any change in behavior is nominally plasticity,” said Heifets. “It’s a very broad statement.”

Some of the earlier work on how psychedelics affect the brain was led by psychologist and neuroscientist Robin Carhart-Harris, who started his investigations at Imperial College London and is now a professor of neurology and psychiatry at the University of California, San Francisco.

According to Carhart-Harris’s research, which uses fMRI imaging to track brain activity, psilocybin disrupts the typically organized activity in the default mode network, an area of the brain associated with introspection, making existing thought patterns less dominant and creating the opportunity to develop new perspectives.

“It starts with breaking down habits of mind and brain and behavior,” he told STAT. “In psychopathology of mental illness, it would be excessive order: Getting stuck in a rut in depression, getting stuck on a feeling of relief and addiction.”

In an interview at the conference, Carhart-Harris said he is 80% confident in his theories, which have the intuitive appeal of combining neuroscience and psychology. Even if they are right, though, he acknowledges there’s still more to uncover. “If you were to say to me, ‘Do you know it all about how psychedelics work in the brain,’ I would say very quickly, ‘Absolutely not.’”

Others do not share Carhart-Harris’s certainty, arguing the limited data and specificity make it difficult to test. “It’s not quite well enough specified to be a model that you can interrogate reliable brain circuits with in a well-disclosed fashion,” said Barrett.

Barrett has published work showing that psychedelics reduce activity in the claustrum, a brain area called “the seat of consciousness,” which helps people switch between mental states (for example, from calm to urgent action), and was also a researcher on separate studies showing they could be disrupting the thalamus loop, a brain region that provides a filter for sensory information going to higher levels of the brain for decision-making.

Meanwhile, research from Gul Dölen, a neuroscience professor at Johns Hopkins University, highlights psychedelics’ impact on an area of the nucleus accumbens that is associated with social reward learning. Dölen finds mice are more sociable after being given MDMA, suggesting the drug creates a state where there’s an increased sense of reward from social experiences.

“I don’t think these are blatantly contradictory theories, but they do make different predictions,” said Barrett.

The question of where and how psychedelics create changes is crucial, Thomas Insel, former head of National Institute of Mental Health, told STAT after his talk. “Neuroplasticity is a very vague concept. It means a lot of different things, and when we’re talking about neuroscience and behavior, it matters where things are happening,” said Insel.

Dölen’s recent work on social reward is a “pretty frigging cool” paper, said Insel, though he cautioned it was only in mice. “When I was at NIMH, I used to say that if you’re going to get Alzheimer’s disease, first become a mouse because we can cure you.”

These theories all share a sense that both the subjective experience of tripping while taking psychedelics and biochemical changes in the brain work together to create a therapeutic effect. Patients can have hallucinations and intense emotional experiences, such as confronting past trauma, that can be psychologically beneficial, and any subjective experience will be reflected in physical changes in the brain.

There’s no certainty, though, of what comes first or how the two interact. Plus, psychedelics are being studied as treatment alongside psychotherapy, meaning two treatments are being evaluated in conjunction, and there’s debate over which is the most effective.

“I think from immediate effect, that’s almost 100% from the drug,” said Srinivas Rao, chief scientific officer at atai Life Sciences, a for-profit psychedelic drug company. Patients haven’t had much therapy at that point, so 24 hours after treatment, any reduction in symptoms likely comes from the psychedelic. But for patients who do well longer term, Rao attributes that to therapy. “If you’ve been through therapy and, a year out [from the psychedelic experience], you’re still doing well, it’s unlikely it was the drug to me,” he said.

Then again, all these ideas could end up being dismissed. There are researchers studying psychedelics without the high, effectively trying to determine whether any therapeutic effects are entirely down to changes in brain chemistry. And Heifets recently posted a preprint (still in the process of peer review) describing a study that gave participants ketamine while they were under general anesthesia. They saw a drop in their depression regardless of whether they were given ketamine or placebo, suggesting it’s the experience of going through the trial that addresses symptoms rather than the drug itself.

Many of these questions mirror those around other mental health treatments. Prozac was released 35 years ago and there’s still no consensus on how such SSRI antidepressants work or if their effects can be disentangled from placebo. A number of scientists compare the idea that psychedelics work by “increasing neuroplasticity” to the now-disproven theory that antidepressants work by changing chemical imbalances: Both suggest a straightforward mechanism for a pill to change well-being, but don’t come close to capturing the complexities and uncertainty.

Currently, explanations about how psychedelics work should be taken with more than a pinch of salt, said Insel. “I think it’s a whole shaker of salt.”