MDMA, psilocybin, and ketamine therapy can dramatically improve symptoms of the hardest-to-treat conditions, including severe depression and PTSD. How do psychedelics work? Scientists are still learning.
Psychedelics are changing minds — literally and figuratively.
When administered at carefully selected dosages in clinical settings, and combined with therapy before and after treatment, psychedelics have been found to provide rapid relief from some of the most painful and difficult-to-treat mental health conditions. Ketamine is being used for depression and suicidality in clinical trials. MDMA is treating severe post-traumatic stress disorder (PTSD), and psilocybin is being used for treatment-resistant depression, alcohol use disorder, and more.
However, important questions remain about the long-term efficacy and safety of psychedelics, as well as patient suitability. Several large-scale studies are now under way to address these concerns, including the first-ever phase 3 clinical trial on psilocybin-assisted therapy — the largest randomized, controlled, double-blind study on the drug, with more than 800 participants. Initial results are expected this summer.
Research shows that psychedelics improve many neuropsychiatric disorders, but the way they work is less clear. Functional MRIs and laboratory studies offer possible explanations:
But these biochemical explanations don’t tell the full story, says Gül Dölen, M.D., Ph.D., professor of psychology and researcher at University of California Berkeley’s Center for the Science of Psychedelics. Psychedelics only reliably improve psychiatric conditions when administered with therapy. “Therapy is the context to get the cure,” Dölen explains. “You can’t take MDMA and go to a rave and expect it to cure your PTSD.”
Indeed, when taken on their own, psychedelics aren’t hugely effective, according to studies; therapy unlocks the drugs’ enduring benefits. Also, there are serious risks to taking the drugs without medical supervision.
[Read: The Truth About Lion’s Mane, Psychedelics & Caffeine]
Most psychiatric medications must be taken daily, often for a lifetime. By contrast, a single dose of certain psychedelics paired with therapy can result in full-blown remission. This claim appears too good to be true when viewed through the traditional “biochemical imbalance” model of neuropsychological disease that has dominated the field for the past 50 years. “The idea is that depression, for example, is a biochemical imbalance in serotonin,” Dölen says. “So, we’ll restore serotonin levels with a pill, and you’ll get better.”
But what if there were an approach that treated depression by restoring the fundamental ability to learn (and unlearn) behaviors and ways of thinking, and not by raising serotonin levels? It’s an entirely different framework for understanding neuropsychiatric disorders — the learning model — and Dölen says it’s the best way to comprehend how psychedelics work.
Psychedelics act like master keys unlocking what scientists call “critical periods” of learning—specific times when individuals have a heightened ability to soak in new information. During brain development, these are the critical windows in which we acquire vision, language, motor development, and more. And after these critical windows close, they remain locked.
Or so we thought.
In a study that involved giving mice MDMA, Dölen found that the drug unlocks a critical period for social reward learning, restoring adult mice to child-like levels of openness for social development.4 Dölen’s next study uncovered the potential of all psychedelics—including LSD, psilocybin, ketamine, and ibogaine—to open these critical periods.5
[Watch: “Psychedelic Therapy for Mood Disorders: Research & Potential”]
“This is a big deal,” says Dölen. “And if it’s true, it’s going to revolutionize things, but only if we understand what a critical period is. It’s not that you take a pill and you speak Japanese. It’s that you take a pill and you restore the ability to learn Japanese.”
The drugs open the mind to learning. The therapy provides the learning itself.
“Patients talk about how they had an epiphany, how the trip enabled them to see how they’d built their lives around a foundational myth that wasn’t true, whether about their relationship to other people, their personality, their deserving to be in the world,” Dölen says. The post-trip therapy, in turn, allowed them to identify how that myth led to maladaptive ways of interacting with the world, and understand how to integrate that knowledge into their daily lives.
The potential of psychedelics to re-open critical periods has far-reaching implications. Dölen’s lab is exploring the possibilities of treating conditions like stroke and blindness with psychedelics through a project called PHATHOM (Psychedelic Healing: Adjunct Therapy Harnessing Opened Malleability).
“Psychedelics are not going to be the magic bullet that fixes everything, but we’re excited about the possibilities,” Dölen says. “Being able to restore child-like learning is a major therapeutic opportunity.”
Nicole C. Kear is Consumer Health Editor at ADDitude.
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1 Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay MA, Baker GB, Dursun SM. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020 May 11;10:2045125320916657. doi: 10.1177/2045125320916657. PMID: 32440333; PMCID: PMC7225830.
2 Mitchell, J.M., Bogenschutz, M., Lilienstein, A. et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med 27, 1025–1033 (2021). https://doi.org/10.1038/s41591-021-01336-
3 Smausz R, Neill J, Gigg J. Neural mechanisms underlying psilocybin’s therapeutic potential – the need for preclinical in vivo electrophysiology. J Psychopharmacol. 2022 Jul;36(7):781-793. doi: 10.1177/02698811221092508. Epub 2022 May 30. PMID: 35638159; PMCID: PMC9247433.
4 Nardou, R., Lewis, E.M., Rothhaas, R. et al. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569, 116–120 (2019). https://doi.org/10.1038/s41586-019-1075-9
5 Nardou, R., Sawyer, E., Song, Y.J. et al. Psychedelics reopen the social reward learning critical period. Nature 618, 790–798 (2023). https://doi.org/10.1038/s41586-023-06204-3
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MDMA, Psilocybin, Ketamine Therapy: How Do Psychedelics Work? – ADDitude magazine
