Psychedelic clinical trial researcher Albert Garcia-Romeu’s eyes lit up when I asked if participants’ expectations have increased in the wake of the publication of Michael Pollan’s (2018) bestselling book on the psychedelic revival.

Oh my God yeah! It's a huge problem. There's not much we can do about it though, and that's the thing. All our stuff is published, so people read our papers. And they're like, “80 percent of people quit smoking . . . sign me up!” And we have to explain to them that yep, that was an initial finding, but now we're dealing with things a little differently—we're using a single high dose [rather than two to three doses used in the pilot trial], and also, we're still learning . . . These are people who hear about these mystical experiences, and 80 percent success rate, and then they have a session where they don't feel anything, and obviously there's a huge disappointment and people feel like sometimes they're failures, in some sense. So obviously that can be really frustrating, because you want people coming into this with some openness, and typically once you have all these preconceived ideas, they think they know what they want. That doesn't always work out well.

As a postdoctoral researcher, I worked with Al between 2013 and 2015, conducting retrospective qualitative research on the fifteen-person pilot trial (a precursor to the current one) to ascertain the perceived “mechanisms of change” by which psychedelics helped participants quit smoking cigarettes. Back then, I was struck by how little the participants had known about psychedelics when they began enrolling in 2008. Seeing local adverts in Baltimore, many considered the trial to be pretty “out there” but nonetheless a last-ditch attempt to break their smoking habit. During the course of interviewing, parsing out participants’ interpretive frameworks from one another and from descriptions of experiences was an enduring worry. For instance, did psychedelics really act as a “reset button” or were participants drawing on a wider trope from our technological age? Powerful psychedelic experiences in today’s carefully constructed clinical research spaces undoubtedly compel enthusiastic, often internet-based, research.

A decade on and the Johns Hopkins Behavioral Pharmacology Research Unit has received philanthropic funding to become the world’s largest psychedelic research center. Returning in early 2019, I was reminded of the professionalism, the care and the feel of cutting-edge science that would accompany participants taking their first steps into a research trial. All of this matters: psychedelic drug effects are sensitive to the context of their use, to the point of being dubbed “non-specific amplifiers” of awareness (Grof 1975). This understanding is not without its own history (see Langlitz 2012, 118–28), conditioned by debates between perennialism and constructionism, and configuring (albeit rarely testing) claims that psychedelic drug effects boil down to what psychopharmacologists call “set and setting” (see the introduction to this series). In seeking to amass objective knowledge about the clinical effects of psychedelics, psychedelic scientists are chasing a moving target (cf. Hacking 2007), victims of their own successes as every trial produces knowledge that shapes the expectations of the participants of future trials. Al’s frustration revealed cultural looping effects breaking through.

In this vein, many psychedelic clinical researchers are concerned that the efficacy of psychedelic treatments may be compromised if they are understood to work as “magic bullets.” A few months after our interview, Al wrote to me,

For my part I definitely think this issue is a big problem, and my guess is that it will only be getting worse in the near-term. I actually just drew up a slide for a talk at APA [American Psychological Association] next month with the title in bold, PSYCHEDELICS ARE NOT A MAGIC BULLET. I'll also be talking about . . . this mythology that with psychedelics they can take this brief trip to a faraway place (like Disneyland) and come back magically transformed/cured, whereas the reality is much more complex.

Even while welcoming the impact of such hype in securing funding and recognition, researchers battle against the emerging expectations and imaginaries when preparing new participants for their psychedelic sessions. Today’s research imperative to tame the effects of psychedelics through controlled clinical settings is itself culturally specific, one approach among many. The resultant knowledge of psychedelics’ effects (contra those of set and setting) is then doubly particularized, subtracted from set and setting variables, and produced out of a particular context (cf. Sanabria, this series).

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How can we even compare across research studies, when the cultural understandings that condition the experience of psychedelics for participants vary across them? The idea of a “revival” refers to the first wave of research into psychedelics. Henry David Abraham, Andrew M. Albridge, and Prashant Gogia (1996, 287) report that psychedelic research in the 1960s swung from positively to negatively valenced studies, presumably due to shifting public opinion, revealing a “strong cohort-period effect of scientific activity.” Political and sociocultural changes were undoubtedly being reflected in researchers’ choices of what to study and how. However not just the discursive context but the experiences themselves were turning sour—with greater drug impurities stemming from a flourishing black market, greater surveillance of drug users, and “drug war” campaigning declaring drugs to be inherently dangerous. All looping effects that ought to be foregrounded in the psychopharmacological doxa of “set and setting.” All complicating objective evaluation.

Could the contemporary science turn just as quickly as it did in the 1960s? If it did it would not be for the same reasons. Currently drug war messaging is waning across Europe and the Anglophone West, while psychedelic therapy is successfully professionalizing and medicalizing, utilizing evidence of clinical efficacy generated through highly resourced research clinics. Drug regulators are on board. Yet they are insisting on green-lighting late stage clinical trials only if trial sponsors demonstrate viable means to scale up the provision of any resultant treatments. This is feeding back incentives to attenuate current research protocols in pursuit of more cost-efficient interventions. Thus, Johns Hopkins’ current psilocybin-for-smoking cessation trial has one single psychedelic session, instead of the pilot trial’s two to three sessions.

The feedback loops branding psychedelics are not marginal but integral to how psychedelics operate. Turning Al’s frustration into an opportunity requires investigating how the efficacy of the clinical interventions changes over time, including complex interactions with cultural understandings and expectations surrounding psychedelics. The clinic may not be best-placed to grasp this. As with social movements to decriminalize and legalize that appear to be outpacing the medicalization of psychedelics, new modalities and technologies of knowing and evidencing—including informal and algorithmic—could lead researchers and regulators into updating their static evidentiary imperatives for drug approval with more dynamic couplings of efficacy and cultural understanding. Being so loopy in their nature, psychedelics may end up showing the way.