Psilocybin, MDMA, and Ketamine: What’s the Difference?

Psychedelic-assisted therapies are getting a lot of attention lately. From news headlines to podcasts, people are curious: could these medicines change the way we treat depression, PTSD, and anxiety?

Below, I’ll answer some of the most common questions people ask about the three substances you’re most likely to hear about right now: psilocybin, MDMA, and ketamine.

What is psilocybin, and what is it being studied for?

Psilocybin is the active compound in “magic mushrooms.” Researchers are studying it most intensely for treatment-resistant depression but also for end-of-life distress and even addictions like alcohol or nicotine.

Psilocybin works by stimulating a serotonin receptor in the brain called 5-HT2A. This temporarily increases communication between different brain networks. People often describe the experience as deeply introspective, sometimes even mystical.

It’s not FDA-approved yet, but psilocybin has been granted “breakthrough therapy” status, which means the FDA sees its potential for major depressive disorder and is allowing trials to move quickly.

Takeaway: Psilocybin offers the possibility of long-lasting relief after just a few sessions. But it’s not for everyone, and careful preparation and integration matter as much as the medicine itself.

How does MDMA work in therapy?

MDMA (sometimes known as “Ecstasy” or “Molly” outside of medical settings) is very different from psilocybin. It’s classified as an empathogen, meaning it increases serotonin and oxytocin (a hormone linked to feelings of bonding, trust, and safety).

This combination often makes people feel emotionally open, connected, and less fearful when revisiting painful memories. Because of this, research has focused heavily on PTSD, but MDMA is also being studied for social anxiety and even in couples therapy.

It’s not yet FDA-approved, but like psilocybin, MDMA has been granted “breakthrough therapy” status. Approval was expected soon, though the FDA recently delayed the process due to concerns about trial design.

Takeaway: MDMA can create a therapeutic “window” where trauma can be processed more safely, but it’s not a standalone treatment; it works best when combined with skilled psychotherapy.

How does ketamine fit in?

Unlike psilocybin and MDMA, ketamine comes from a completely different class of medicine. Originally developed as an anesthetic, it is now being used in psychiatry for treatment-resistant depression, acute suicidality, and some anxiety conditions.

Ketamine works on the glutamate system of the brain (not serotonin) by blocking NMDA receptors. This jump-starts neuroplasticity, the brain’s ability to form new connections, and often provides rapid relief. Many people describe the experience as dissociative or “out of body,” rather than classically psychedelic.

One form, esketamine (Spravato), is FDA-approved for depression. Other forms, such as IV, IM, or S.L ketamine, are used off-label in many clinics.

Takeaway: Ketamine is the only one of these three medicines currently available in clinical settings. Its fast-acting effects make it especially valuable for people in crisis, though the benefits may fade without integration and ongoing care.

Are these medicines replacing antidepressants?

Not at all. Traditional antidepressants (like SSRIs) are still first-line treatments and help millions of people. Psilocybin, MDMA, and ketamine are being explored as options for people who haven’t found enough relief with standard care or who are interested in a different kind of therapeutic experience.

The Bottom Line

• Psilocybin: Mystical, introspective experiences with potential long-term benefits

• MDMA: Emotional openness that can help process trauma in therapy

• Ketamine: Rapid relief and a “reset” effect, already in clinical use

None of these are quick fixes. They work best when combined with careful screening, safe medical oversight, and therapeutic support.

As research moves forward, these treatments may soon become more accessible. For now, the key is to approach them with both curiosity and caution.

What about underground or non-clinical use?

It’s important to recognize that some people seek out psilocybin, MDMA, or other psychedelic experiences in underground settings as retreats, ceremonies, or with facilitators who may not be licensed therapists. While some of these guides are experienced and deeply caring, they are not always trained clinicians, and safety standards can vary widely.

In the clinical world, many of us, including myself, support a harm reduction approach. That means we don’t shame or judge people for their choices, but we encourage informed decision-making, careful screening, and integration support. If someone does choose to have a psychedelic experience outside of a medical setting, working with a trained therapist afterward can help them process insights safely and effectively.

This blog is for educational purposes only and is not a substitute for medical advice. If you are considering psychedelic or ketamine-assisted therapy, speak with a licensed clinician to understand what may be safe and appropriate for you.