The Science and Therapeutic Potential of Psychedelics for Mental Disorders with Dr. Matthew Johnson

This episode features Dr. Matthew Johnson, a leading expert from Johns Hopkins' Center for Psychedelic and Consciousness Research, discussing the current understanding and therapeutic applications of psychedelics. The conversation delves into the complex nomenclature of psychedelics, distinguishing between classic psychedelics (like psilocybin and LSD, which are serotonin 2A receptor agonists) and other compounds like NMDA antagonists (ketamine) and entactogens (MDMA). Dr. Johnson emphasizes that despite their diverse pharmacological mechanisms, all psychedelics profoundly alter one's sense of reality and self, often by 'dissolving' the brain's predictive models of the world.

The discussion highlights the distinction between microdosing and macrodosing, with a focus on the latter's use in clinical trials for conditions like depression, trauma, and addiction. A detailed walkthrough of a typical psychedelic therapy session is provided, including rigorous screening for psychiatric and cardiovascular conditions, extensive preparation to build therapeutic rapport, the guided experience itself, and post-session integration. A critical point of comparison is made with ketamine (Spravato) therapy for treatment-resistant depression, noting that while effective, it often lacks the 'psychedelic therapy' framework of preparation and integration, potentially limiting its long-term impact compared to classic psychedelics.

Dr. Johnson explains that psychedelics, particularly classic ones, are thought to work by increasing glutamate transmission downstream of serotonin 2A receptor activation, leading to a state of enhanced neuroplasticity. This allows individuals to challenge deeply ingrained mental models and perspectives, facilitating new learning and insights that can lead to lasting therapeutic change. The episode touches on the potential for profound, reality-altering experiences, including hallucinations and altered perceptions of space-time, which are central to the therapeutic process rather than mere side effects.

Ultimately, the conversation underscores the immense promise of psychedelic-assisted therapy as a paradigm shift in mental healthcare. It emphasizes the need for careful clinical protocols, robust research, and a nuanced understanding of these compounds' diverse effects and mechanisms. The potential for long-lasting benefits, extending a year or more post-treatment, positions psychedelics as a powerful tool for addressing severe and persistent mental health challenges, provided they are administered within a supportive and therapeutically informed framework.

Dr. Johnson's laboratory is among the premier laboratories in the world understanding how these compounds work, how things like Psilocybin, and LSD, and related compounds allow neural circuitry in the brain to be shaped and changed, such that people can combat diseases, like depression, or trauma, or other disorders of the mind that cause tremendous suffering.

all of the so-called psychedelics across these distinct classes that I can talk more about, the way I put it, is they all have the ability to profoundly alter one's sense of reality, and that can mean many things. Part of that is profoundly altering the sense of self acutely, so when someone's on the psychedelic.

All of these classic psychedelics serve as agonist, or partial agonists, at the serotonin 2A receptor, so a subtype of serotonin receptor.

MDMA works on the pitcher side of just basically throwing out more of the natural, the endogenous- Dumping more serotonin. - Dumping more serotonin. - Yeah. - Flooding the synapse.

I think of these psychedelics as profoundly altering models. We're prediction machines. So much of that is top-down. And psychedelics have a good way of, loosely speaking, dissolving those models, and one of, the reality-

And it's not filtered out, you know? And this might sound extreme, but there are these cases, it was overblown, and sort of the propaganda of the late '60s, early '70s, but there are credible cases of people, it's very atypical of, it sounds like they really thought they could fly, and jump out of a window.

People claim that these NMDA antagonist psychedelics are extremely insightful in a very similar way to the experiences with the classic psychedelics.

With Spravato, the model is- Is esketamine. - Okay. - It's the, yeah, the spray form of ketamine. It's been FDA-approved for treatment resistant depression. You'll probably feel different. Ignore that. That's a side effect. [laughs] That's an adverse effect. Just ignore it. We don't think that has anything to do with the way it works. But just get this thing. It's a direct sort of chemotherapeutic effect in a sense . It's not facilitating a learning process.

We're seeing effects a year or more later with psilocybin and some of the classic psychedelics that could be a pharmacological difference, or it could be that they get a lot more mileage out of ketamine if they treated it like psychedelic therapy.

But man, we're all human, and the issues seem to come to the surface.