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How Psychedelics Work in the Brain

By Roger Torda, New York Academy of Sciences

How Psychedelics Work in the Brain
David Nichols

David E. Nichols, PhD

Heffter Research Institute

Studies are showing psychedelics can be effective in treating depression and other psychological conditions. Results from a recent Phase 3 clinical trial, for example, show MDMA – often known as Ecstasy – can be effective in treating Post Traumatic Stress Disorder (PTSD). Researchers and clinicians are excited about the results, for psychedelics may offer a new therapeutic avenue for several psychiatric disorders that have been difficult to treat.

But how do psychedelics work? Their long-term effects remain something of a mystery. Our knowledge is growing, however, about the short-term changes they bring about in our brains.

David E. Nichols, PhD, who is president and co-founder of the Hefftner Research Institute, explained during a New York Academy of Sciences webinar that drugs known as "classical psychedelics"­­—including psilocybin, DMT, LSD, and mescaline—mimic serotonin, leading to changes in the dynamics of brain function.

Roland Griffiths

Roland Griffiths, PhD

Johns Hopkins University School of Medicine

Studies using brain imaging have shed light on how this activation of HT2 receptors impact a network of connections across the entire brain. Scientists don’t know how this leads to therapeutic efficacy, but research led by a group at Imperial College London suggests there may be something of a “reset” of key brain circuits that play a role in depression.

Roland Griffiths, PhD, of the Johns Hopkins University School of Medicine, also spoke at the symposium. He explained that the immediate effects of psilocybin in the brain subside quickly, but some changes persist, even though it remains something of a mystery how this happens.

There is evidence to suggest the classical psychedelics, while creating connections across the brain, decrease organized activity in a something scientists call the “default mode network.” These changes may lead to a temporary weakening in our sense of ego or “self”, which may explain why the drugs seem to promote a heightened sense of connection with “others.”

Additional research suggests the drugs may affect how the brain uses new information to affect prior beliefs. The brain uses these “priors” to make predictions. New sensory data are normally used to update and correct the underlying beliefs. Psychedelics may interrupt this process, leading to changes in how an individual perceives the world.

Much research lies ahead, and Dr. Griffiths says scientists are humbled by what remains unknown about these processes.

During the webinar, Dr. Griffiths and Rachel Yehuda, PhD, of the Icahn School of Medicine, took viewers behind-the-scenes of clinical trials with psychedelics. Click here for Dr. Griffiths’ description of what volunteers experience with psilocybin, and read this for Dr. Yehuda’s description of what a volunteer goes through in a clinical trial with MDMA.


The webinar, Psychedelics to Treat Depression and Psychiatric Disorders, was moderated by John Krystal, MD, of Yale School of Medicine.