Why don’t some people respond to psychedelics? 5 Questions for psychologist Rachel Ham

For anyone who joins a clinical trial for a mental health condition, the hope is that after the trial is over, they’ll feel better. And, that their improvement will linger past the end of the research, leading to long-lasting change.

The unfortunate truth, however, is that not all treatments will be successful for everyone, nor last forever—and psychedelic-assisted therapy is no exception to that rule. Despite showing promising outcomes in clinical trials so far, some people don’t respond to psychedelic interventions.

Rachel Ham, a doctoral candidate at Monash University in Australia, has been interviewing people in a large clinical trial on psilocybin and general anxiety disorder for her PhD project. She’s been learning about what the lived experience of being in a psychedelic trial is really like; she and her colleagues have been evaluating how people respond to therapeutic touch, and how they feel about having two therapists in the room.

In a forthcoming paper, she and her colleagues dedicated their attention to a group of low or non-responders: those who didn’t meet the threshold of a 50% reduction of their symptoms. It’s a small sample size, just seven people, but Ham thinks there’s important information to be gained from talking with them. “A motivation for us was feeling that we can learn just as much from the people who don’t have dramatic recoveries, as we can from those who do,” Ham said.

The Microdose talked to Ham about her research, and how studying limited responses can help future patients.

How do you define a psychedelic non-responder?

Psychedelic therapy has obviously shown a lot of promise, but we know that it doesn’t work for everyone. Non-response is normally defined as less than a 50% reduction in standard clinical symptom measures. We know that maybe around one-half to one-third of people meet that criteria.

For our study, we took a slightly different approach. We looked at people who did not meet that 50% symptom reduction, but we were also looking for people who had a more sustained, limited response across the whole course of their treatment.

The caveat here is when we’re dealing with real participant stories, we know that in psychedelic therapy, symptom reduction doesn’t necessarily capture everything that’s going on in this treatment. Sometimes there can be a whole host of other quality of life measures that actually improve substantially, so symptom reduction isn’t necessarily the whole picture.

And even though we often talk about “non-responders”, because this is a qualitative paper and it’s real participant stories, we’ve moved to calling them “limited responders” because it’s a little bit less pathologizing.

These limited responders go through the same therapy process as everybody else: preparation, dosing sessions, and integration. Do they just trip less? Or have less meaningful psychedelic trips? Or does their limited-response emerge later?

It’s seven participants, so we were not able to do statistical analysis, but we did look at a few acute experience measures. We looked at the challenging experiences questionnaire, the mystical experiences questionnaire, and the emotional breakthrough inventory. We compared, non-statistically, the averages between these limited responders and the broader sample. Broadly speaking, the scores are quite similar.

That’s an interesting finding out of this paper. It’s complex to make sense of, because a lot of these measures have been shown to correlate with improved therapeutic outcomes in the past. All that we can really take from that is perhaps these experiential factors don’t fully account for differences in outcomes.

Maybe there are some other pre- or post-session factors, like psychotherapeutic or relational support, that influence people meaningfully. A lot of mechanistic studies are working at a group level, so there are going to be trends. That’s very meaningful work and research. Our results caution against assuming that necessarily translates at the individual level.

How did people feel about being limited responders? Were they aware, and how did they respond?

Even within this sample, it is pretty heterogeneous. There can be quite a few different trajectories. We have three participants who show symptom scores that are increasing, which is to say that their anxiety is getting worse; we measured anxiety at three different times. And then we have four participants who actually do show reductions over time, but that did not meet the criteria for that 50% reduction.

Those are two possible trajectories of non-response. You also have another possible trajectory where someone, for example, shows a big improvement, but then has remission over time. Even within this study, we’re not necessarily capturing all of the different trajectories of limited response.

Something that we did as part of our qualitative analysis was utilize a framework that’s based around illness narratives, which explores different features of people’s storytelling in relation to their psychedelic experience and their treatment trajectory overall. A feature that we found within that was that there were some participants who tended to describe their trajectories in more sort of hopeful or future-oriented styles of narratives that kind of resembled a quest. There was something really hopeful and progress-oriented around those stories.

There were others, though, whose narratives were more marked by ambivalence and fragmentation and unresolved distress. That has been described as a chaos narrative.

These kinds of narratives might represent different stages of an ongoing therapeutic process, rather than stable endpoints.

Do you consider a limited response to be a kind of challenging psychedelic experience?

I would come back to the message that a limited response is quite heterogeneous. It’s not really a story about responders and non-responders. For a lot of people, healing is non-linear; it’s ongoing and it takes work, and that’s all deeply individual.

We did see some really challenging experiences. We had one participant that had a somatic re-experiencing of sexual assault. Another who had an emergence of a memory about childhood sexual abuse, alongside a sexuality related insight. Another witnessed violent imagery. We know that these challenging experiences have quite a lot of nuance, including what they mean in the context of psychedelic therapy and outcomes.

There’s some research by Max Wolff that looks at the acceptance process during psychedelics, and how that influences outcomes. We can start to imagine some of these mechanisms might contribute to whether a challenging experience translates into benefit or or harm. Our findings raise questions around how particular forms of challenge might indicate potential vulnerability. By trying to understand these more complex trajectories, we can build models of care that are safer, more reflexive, and therefore more ethical and more effective.

Something that I think was quite interesting is that all participants felt that they had benefited from their psychedelic experiences. I don’t want to say that too flippantly, because for a lot of people, that feeling of benefit was also accompanied by quite considerable distress. You might suggest that this treatment is not suitable for everybody coming to the end of this paper. But it is interesting that some people were still able to derive some kind of therapeutic benefit, even if they would have preferred to go about it in a slightly easier or smoother way.

Do you think that psychedelic treatment has had too high of expectations for the response rate?

It’s true that we can’t expect any given model of treatment to work perfectly for everyone.

In terms of what this is going to look like going forward, it’s difficult to know. Sometimes we think of psychedelic therapy as this like very homogenous treatment, but actually we’re still really experimenting with how much preparation is needed, and how much integration is needed, and how many doses, and so on.

I think that clinical non-response will always be with us, and how that looks when psychedelic therapy moves out of the lab and into clinical practice is yet to be seen. On the one hand, sometimes treatments that move out of clinical trials see a reduction in clinical response rates. On the other hand, psychedelic therapy in clinical trials is often constrained by clinical trial protocols that don’t give a lot of flexibility for things, like extended integration when someone really needs it.

Part of the big takeaway of this paper is that the field needs models of care that anticipate diversity. There needs to be realistic expectations, flexible integration, and ongoing support for people who have these more complex trajectories. This interview has been edited and condensed for clarity and length.