Psychedelics are often administered as part of rituals and ceremonies. The so-called ‘mystical experience’ evokes reverence from both the guide and the guided. Trust matters a great deal for anyone voluntarily relinquishing their grip on reality for 4 to 6 hours, so psychedelic guides tend to advertise their deep experience with altered states. So how does a psychedelic scientist give a dose of psilocybin for the first time? 

My research partner and I were experienced in clinical trial oversight, but we were definitely not psychedelic gurus. Even after all the regulatory hurdles had been cleared and the psilocybin had been shipped and randomized, we found ourselves trying to answer questions that had never occurred to us in past clinical trials: what décor should we hang on the walls of the treatment room? How should we serve the drug to participants? What’s the easiest way to get someone on a high dose of a psychedelic across the road to the building with an MRI? 

We were fortunate to have a first participant who was stoic and easy going. P1 was neither superstitious nor needy. He was okay with the sterile ambience, the minimalist decoration and the lack of rituals.

P1’s first drug visit was on a Sunday morning (to avoid the crowds). He met us bright and early at 7 a.m. I had gotten in even earlier, to set everything up. I was so nervous the night before that I couldn’t fall asleep until 2 a.m. But I did my best to look cool, calm and collected as we brought him inside to check labs and vitals.

“From your blood pressure, I can see that you’re already relaxed”, I joked, self-consciously. Good thing I checked his blood pressure and not the other way around.

After he had passed screening, I handed P1 a prescription bottle with no profound words beyond: “here, take this. Maybe with a sip of water.” He nonchalantly downed two unmarked pills and settled in to wait. Around 9 a.m., we helped P1 into a wheelchair and rolled him across the street to the scanner.

Inside the scanner bay, he strapped on all the monitoring gear and slid into the very snug magnet bore, which, after 8 baseline visits, had become a familiar and comfortable process. So far, so good. Then BAM – the scanner wouldn't start! I scrambled to troubleshoot, rebooted the Siemens computer and tried to find an MR physicist kind enough to pick up their phone early on a Saturday morning. My nightmare was coming true. At some point, sensing our anxiety, P1 announced “It’s okay, guys, I’m pretty sure I got the placebo anyways.” I breathed a little sigh of relief. Eventually, we got the scanner working. After that, the day went smoothly.

Two weeks later, the real psilocybin dosing day arrived – July 25, 2021. I was still pretty nervous. Would the scanner work? Would he puke? Have a bad trip? Have no trip at all?

This time, everything went smoothly. Though we were functionally unblinded by then, P1 kept us in suspense. Just like last time, he stayed cool and calm as he went through a gauntlet of intensive scanning and monitoring. He had little to say as we rolled him back across the street from the MRI to the laboratory – doing our best to make casual conversation. The day mostly passed like that - nervous (at least for me) silence.

Then came the debrief.

I started out with the mystical experience questionnaire - “Looking back on your psychedelic session, please rate each of these on a scale from zero to five. Zero is none at all. Five is extremely, more than any other time in your life. Four is a strong experience. Three…” I read through the instructions, speaking slowly.

“Would you say you had a loss of your usual sense of time?” I began.

“Five” he answered, a bit too quickly.

“felt a sense of amazement?”

“Five” came another quick response. And another.

“Would you say that you gained insightful knowledge, experienced at an intuitive level?”

“Ummm,” he paused, signed heavily. “Could you say that again?”

I slowly repeated “Did you gain insightful knowledge experienced at an intuitive level?”

“Oh, yes, yeah, five.”

“Do you want to say more about that?” I asked.

“Well, the most profound part of the experience was the light I saw. I was in a room, a great and terrific space.” He started off slowly, as if searching his mind for a distant memory. “It was kind of like St. Peter's Basilica. And there was a rotation occurring. I was a part of this rotation. And as I came around, I felt a bright light radiating downward.”

To my astonishment, he described a powerful and vivid religious experience that he had inside the MRI scanner. He recalled feeling that he was no longer inside the scanner but inside a large sanctuary. The bright light radiating from above, he felt to be the presence of God.

“Feeling that you experienced something profoundly sacred and holy?” I asked.

“Five” he answered, without hesitation.

“It was just like, well, awesome is a term that’s overused, but … that was just awesome. It was a sense of awe, a sense of brilliance.” And afterward, a sense of well-being, connectedness, and euphoria.

He continued to give very high ratings on the mystical experience questionnaire – indicating a sense of transcendence of time and space, and spiritual significance greater than any other time in his life. “Look, I just want to say,” he cut in at one point,  “I try to be thoughtful when I take surveys. I don’t just do zero’s and five’s…”

We would later learn that his brain activity and functional connectivity were dramatically desynchronized during those resting fMRI scans.

 Perhaps a “five” - more than any other waking experience in his life.

We had successfully given the first legal dose of psilocybin in the state of Missouri and facilitated, for our wise and worldly study participant, one of the most meaningful experiences of his life. We were euphoric - I later learned the term ‘psychedelic narcissism’, for the mistaken conclusion that your own special talent, as the facilitator, has much to do with the powerful effects of the psychedelic. Our ego’s were riding high. But a bit more humility would come later…

Almost a year later, we asked P1 to come back to complete an open-label replication dose. By then, our team was more experienced as psychedelic researchers and facilitators. At the very least, we had gotten confident and comfortable with the role of guiding participants through from start to finish.

And yet, on the second psilocybin (replication) dose, P1’s experience was totally different. He described an unpleasant experience. He told us that he felt hot and uncomfortable in the scanner. He kept wondering if he had peed his pants or not. “Between staying still, staying focused on the crosshair, and trying not to pee, I was just completely focused on those three things.”

“So because you were focused on those things, did you have much internal reflection?” asked my co-facilitator, Subha.

“No” he answered. “The mystical divine experience of last time… no trace of that this time.” In fact, this time, he rated ‘feeling that you experience something profoundly sacred and holy’ a zero.

At the time, it was hard to hide my disappointment. As we went through the various scales and questionnaires, I did my best to play the part of objective rater, so as not to bias him. But inside I wondered, what had we done wrong this second time? A few months later, as we entered the intensive phase of data analysis, that disappointment would turn back to awe and excitement. 

Our study in Nature describes a scientific insight made possible by the existence of these two different experiences: desynchronization and disruption of brain activity strongly tracked with the intensity of the psychedelic experience (Fig. 1f-h, reproduced below). The difference in brain desynchronization when he experienced ‘the presence of God’ (Fig. 1f left, PSIL1) versus when he took psilocybin with the more veteran research team and experienced nothing special (Fig. 1f right, PSIL2) was night and day!

We also found that by intentionally turning participants’ focus away from the internal psychedelic experience and towards the physical world, we could damp down psilocybin’s desynchronizing effects. We called this ‘grounding,’ a term used by psychedelics practitioners, but also more broadly by psychologists who use this technique to curb overly intense emotions.

It so happens that the very brain areas that are responsible for internal rumination and reflection are the same brain areas that are most rich in 5HT2A receptors – the target of psychedelics. Those parts of the brain, many of which are hubs of the default mode network, are the areas that are most disrupted by psilocybin. When the mind is allowed to drive freely, those brain areas are sitting behind the steering wheel. After a high dose of psilocybin, those 5HT2A rich areas are operating in unusual ways. Populations of neurons that normally fire in harmony become dissonant. But when attention is brought back to the physical world, brain areas involved in perception and action take control of the wheel. With the more sober driver behind the wheel, the flow of information across the brain becomes more normal.

It is interesting to consider that this principle may explain why P1 showed a much smaller disruption to brain connectivity and synchronization during his second dose.  Of his second psilocybin dose, he had told us “Between staying still, staying focused on the crosshair, and trying not to pee, I was just completely focused on those three things.” It seems this was a sort of internally driven ‘grounding’, not much different from the grounding imposed experimentally by the matching task. He had been holding on to reality for dear life.

A thoughtful reviewer asked us, “why did participant 1 and participant 3 have such different experiences to the same dose of oral psilocybin between session 1 and session 2?”

This was not an easy question to answer. But I do believe that our final work provides a deeper understanding of the causes and underpinnings of variability in the psychedelic experiences. We observed that context-dependence (or ‘set and setting’ as it is more commonly known) has a crucial influence on the neurobiological effect of psychedelics. And it may well be that more dramatic desynchronization of default mode network activity translates into a more therapeutic treatment. The solemn implication for future providers of psychedelic therapy is this: you are responsible for nurturing the conditions that optimize the drug’s healing potential.

It has given our team great satisfaction to discover how the intense and fascinating experience of our participants corresponded to dramatic changes in brain activity. And it gives our team great satisfaction and pride to be able to share the results of this work with the scientific community: 

https://www.nature.com/articles/s41586-024-07624-5