- Placebo Problems: Boundary Works in the Psychedelic Science Renaissance - December 20, 2022
First synthesized and patented at the beginning of the twentieth century, MDMA was largely ignored until the 1970s, when it was incorporated into psychedelic therapy. In 1985, the US classified MDMA as a Schedule I substance as part of President Reagan’s War on Drugs, thus, making the therapeutic use of MDMA illegal. Then, in 2001, the Food and Drug Administration (FDA) approved a new Investigational New Drug Application (IND) for the drug.
The sponsor of the IND was the non-profit organization Multidisciplinary Association for Psychedelic Studies (MAPS), itself founded in the wake of MDMA’s scheduling in the 1980s. While MAPS’ mission is to promote education and research on the therapeutic use of psychedelics and marijuana, the development of MDMA as a prescription pharmaceutical has been its focus.
In its first MDMA-assisted therapy pilot study, lactose was used as the placebo control, and the results were positive—the majority of subjects saw improvements in their symptoms. The FDA and the private Institutional Review Board (IRB) that reviewed the study had no problem with the use of the inert placebo. In fact, lactose had a significant advantage: Using a placebo without any physiological or psychoactive effects meant that one could easily tell if MDMA caused any adverse events.
In its first MDMA-assisted therapy pilot study, lactose was used as the placebo control, and the results were positive—the majority of subjects saw improvements in their symptoms. The FDA and the private Institutional Review Board (IRB) that reviewed the study had no problem with the use of the inert placebo. In fact, lactose had a significant advantage: Using a placebo without any physiological or psychoactive effects meant that one could easily tell if MDMA caused any adverse events.
The mid-century development of psychedelic therapy corresponded with the rise of psychopharmaceutical treatments and the institutionalization of the randomized controlled trial (RCT).
These studies are notable, not only because of the unusual substance used, but also because of the negotiations around blinding and placebo controls. The mid-century development of psychedelic therapy corresponded with the rise of psychopharmaceutical treatments and the institutionalization of the randomized controlled trial (RCT). While psychedelics promised to bridge the gap between psychotherapy and pharmaceuticals, recent scholarship has shown that they conflicted with emerging norms for pharmaceutical research that required blinding both the study subjects and researchers.
This article makes two intersecting arguments about the work of the placebo. First, placebos must have effects on the investigators themselves—specifically, they must be fooled. Second, methodological negotiations around placebos in the psychedelic renaissance are a critical site for tracking credibility struggles around psychedelics, and thus key for investigating the politics of psychedelic research.
An Anthropologist in the Trial
Early social anthropologists traveled the world to live in small villages and tribes—for at least a year—in order to document the diverse social structures of human societies. Anthropologists now use those early ethnographic methods—sometimes called “deep hanging out”—to study a variety of modern social forms. The goal is to learn how modern society works by spending time participating in its production. While anthropologists are still interested in kinship, economics, and religion, they are also interested in thinking about science, biomedicine, and bureaucracy.
In this spirit, I spent over 18 months working with clinical researchers coordinating MDMA-assisted therapy trials. Clinical trials produce an incredible amount of paperwork: protocols, informed consents (ICFs), standard operating procedures (SOPs), case report forms (CRFs) and source records—to name a few. I followed the day-to-day practices of clinical research through which therapeutic efficacy and safety are established, to understand exactly how the facts about a drug emerge through clinical research. Much of my fieldwork—like much clinical research—took place around a speakerphone or hunched over a computer screen.
The social studies of science is an interdisciplinary field that examines how science works and how its knowledge claims are produced. Rather than value-free and politically neutral, science studies scholars hold that scientific practices are key sites of negotiation over values and politics; even the actual objective workings of science are never without values or political contestation.
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Psychedelics, Psychiatry, and the Institutionalization of RCTs
The MDMA studies are just one of a number of contemporary clinical trials studying the therapeutic use of psychedelics. While the substances called “psychedelic” are quite diverse, many current studies are reviving therapeutic techniques developed mid-century in North America and Europe by psychiatrists.
The intertwining of psychedelics and psychiatry dates back to the 1950s, when LSD was distributed by Sandoz pharmaceuticals to researchers throughout North America and Europe. By 1966, over 2,000 articles had been published on psychedelics in medical journals. Two approaches emerged during this period: psychedelic and psycholytic therapy. Humphry Osmond and Abram Hoffer in Saskatchewan, Canada, developed psychedelic therapy, involving a single large dose of a psychedelic in conjunction with psychotherapy. Psycholytic therapy was developed in England by Ronald Sandison, using small doses of LSD in conjunction with psychoanalysis. Psychedelic therapy was supposed to induce a new perspective on one’s life, while psycholytic therapy was supposed to induce a dreamlike experience during which material from the unconscious could surface.
At this time, psychiatry was shifting towards biologically based pharmaceutical treatments. Psychiatry, like biomedicine, was beginning to emphasize treatments that were disease-specific. In order for psychiatry to make this jump into specific treatments, the diseases themselves needed to become objects of diagnostic precision. Gradually, these institutionalized standards established set diagnostic criteria and corresponding psychometric testing.
It is significant that psychedelics are not simply once again being studied as therapeutic treatments, but are now being studied in double-blind placebo-controlled trials approved by the FDA. Research on the therapeutic use of psychedelics slowed down in the 1960s due in part to changes in federal regulation of clinical research. The movement for double-blind placebo-controlled studies had been building, but wasn’t required by the FDA until after the thalidomide crisis, when it became linked to birth defects.
Psychedelic therapy did not fit easily into the emerging institutional and methodological standards for research. The complex relationship between psychedelic drugs and their psychological aspects made them difficult to study in double-blind placebo-controlled trials. It was not merely their association with the counterculture; psychedelics stopped being developed as pharmaceuticals due psychedelic researchers’ inability to shift towards the new techniques for pharmaceutical research. While the criminalization of these drugs was in response to their widespread use in the counterculture, halting their development as pharmaceuticals is enmeshed in the institutionalization of the techniques of “regulatory science.”
The techniques of the randomized controlled trial (RCT) were themselves long in coming. Initially, the US had no bureaucratic agencies dedicated to monitoring pharmaceuticals. Therapeutic reformers during the Progressive Era were critical to establishing regulatory oversight of the pharmaceutical industry, and championing the use of scientific experiments to evaluate the therapeutic efficacy of a wave of new pharmaceuticals.
By the second half of the twentieth century, RCT became institutionalized as the gold standard of pharmaceutical research. According to historian of medicine Harry Marks, the RCT shifted authority from institutions to methods. RCTs utilize blinded controls and randomized assignment of subjects to different treatment conditions; all of which remove physicians’ judgment from the treatment regimen. Earlier researchers had understood the methodological value of controls and randomization; however, they lacked the social and organizational structures necessary to coordinate and standardize their work. It was only through the rise in the status of statisticians that these shifts could take place.
Initially, some physicians thought that the double-blind violated medical ethics because the treating physician did not know what exactly their patients were being given. They held that it was unethical for a physician to be blinded to their patient’s treatment condition. Even today, debates continue as to whether withholding treatment from subjects assigned to a placebo group is ethical or not. While some believe that withholding care is unethical, others charge that producing the best quality data on pharmaceuticals is paramount.
When MAPS confronted the issue of blinding and placebos, they were confronting two intertwined issues: what did the drug actually do, and how objective were their results?
When MAPS confronted the issue of blinding and placebos, they were confronting two intertwined issues: what did the drug actually do, and how objective were their results? The best way to combat these concerns would be to find a placebo that closely mimicked MDMA. To put it another way: the more difficult to tell the two substances apart in the treatment session, the easier to discern differences in efficacy in the data.
This is no small problem, since MDMA is intensely psychoactive. MDMA is not considered a classic psychedelic, like LSD, mescaline, or psilocybin. It has been classified by some as an “entactogen”—meaning “touching within”—to characterize the intense emotional effects of the drug. The effects of MDMA are very difficult to mask.
In MAPS’ protocols, subjects alternate between 60-to-90-minute psychotherapy sessions, and experimental sessions, which take eight-plus hours in which either a placebo or MDMA is administered. Even though a subject might have over a dozen sessions with the therapists, the “MDMA” will only be administered three times. However, it is blinding the subjects and researchers on those three occasions that is the issue for researchers. How do you blind an experience of non-ordinary consciousness? Psychedelic researchers must find novel ways to use placebos and blinds, even when working with substances for which blinding may be impossible.
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The Problem
MAPS’ clinical team wanted a placebo dose that could adequately blind the studies of MDMA-assisted therapy for PTSD. The goal was to find, as Doblin put it: “the dose that fools without working,” high enough to produce some amount of psychoactivity and confusion, but not so high as to be therapeutic.
Ideally, the placebo group receives only the form—not the content—of the treatment. The placebo group controls for both the ritual of the treatment and the ebb and flow of symptoms over time. Some subjects may get better simply because the illness resolves itself, or because symptoms are unstable, or because they think they have been treated. Whatever the reason, the placebo group is supposed to account for everything but the contents of the investigational product. The effects seen in the placebo group are removed to reveal what, if any, biochemical effects might be produced by the investigational product.
However, placebos may be inactive as therapeutic agents, but they must be effective as research techniques. Imbedded in Doblin’s statement is a careful calibration between the two mandates of the placebo: similar enough to fool, but not so similar that it works.
MAPS’ clinical team initially considered using Ritalin as a placebo, but ended up using different levels of MDMA, varying from 25 mg to 40 mg and including a “medium” dose of 75 mg. The goal was to find the dose of just enough that there was confusion, but not so much that there was a therapeutic effect.
When some peer reviewers contested the blinding of the study, they were not contesting the results as much as the source of treatment efficacy. Thus, at some level, the improvement in PTSD symptoms was real, or at least documentable, but how much of these documented effects could be attributed to the drug, and how much to the expectancy of what the drug might do?
Expectancy effect works like this: The doctor says a therapy may do these particular things. If a subject believes that they have been given that therapy, then they will expect that those effects will manifest. The authority emanating from the doctor endows the substance with efficacy.
Medical anthropologists have critically ignored the placebo as a research technique, and instead focused on the effects of placebos on patients. It is not just the study subjects who need to be fooled, but also the therapists themselves. As such, the effects of a placebo cannot be narrowly discussed through the idea of when they treat or don’t.
The Placebo Effect, Meaning Response, and Ethical Quandaries
Social scientists narrowly frame placebos as affecting only those being treated; however, they are meant to produce effects on the researchers as well. Historian Ann Harrington has traced three different arcs of epistemological and moral questions that the placebo has come to answer: medical humbug, research confound, and as medically interesting therapeutic phenomena. Initially, placebos were used to expose fraudulence. However, in the middle of the twentieth century, a second meaning emerged: the placebo effect was a universal confound in research design. This meant that all treatments were subject to it, and all studies had to control for it.
The placebo effect was thus both real and not: It was a confound that needed to be eliminated from the experiment—and thus not the real effect of a drug. In the 1970s, a third sense of the placebo effect emerged; this time, as a robust phenomena in itself that could yield new treatments. Developments in brain science lent credibility to the idea that the brain could affect the body, including credence to existing ideas about the power of positive thinking and holistic healing. What if treatments didn’t have to directly intervene in disease, but only had to unleash the power of the body to heal?
Soon, medical anthropologists used the placebo effect to make the case for equivalence between the ritual authority granted to traditional healers and those granted to Western biomedical practitioners. This wave of medical anthropology used the placebo response to critique biomedicine’s concept of the individualized body held distinct from mind.
Where and for whom placebo controls are considered ethical varies by location, disease, and population. However, when clinical trials involve vulnerable populations—due to location or type of disease—the ethics of placebo controls becomes murky.
Where and for whom placebo controls are considered ethical varies by location, disease, and population. However, when clinical trials involve vulnerable populations—due to location or type of disease—the ethics of placebo controls becomes murky.
For-profit pharmaceutical business and scientific methods in determining the safety and efficacy of new biomedical treatments also raise important questions: what are the methodological assumptions of RCTs, and their correlate, evidence-based medicine (EBM)? How and where did these methods and practices emerge? Medical anthropologists have pointed out that EBM is not without politics; EBM was not simply the transformation of medicine into science, but has been implemented in ways that reflect and create different political possibilities. Further, the claims derived from an RCT are difficult to expand to the broader population.
Despite attention to the ethical quandaries and methodological suppositions of RCTs, the research technique has largely gone unnoticed. Notably, Andrew Lakoff has argued that researchers frame the placebo response as either real or artifactual—an error in study design. Researchers have postulated that, in the case of “real” placebo response, some subjects are more responsive to hopes and expectations, and thus must be eliminated from the trial. The remaining study population is believed to more clearly demonstrate the drug’s efficacy.
For the MDMA trials, the worry was that the placebo response was not to the placebo but to the investigational product. It is in this unusual case where placebos fail—rather than work—that the negotiations around blinding reveal the political struggle for psychedelics to be included under the sign of science.
The Boundary-Bridging Work of the Placebo
Placebos must work on both researchers and subjects. While the subjects must be fooled to make sure that expectancy or placebo effect are not clouding the data, the researchers must also be fooled to prevent bias from entering the treatment situation. The placebo is effective as a technique of deception; however, the use of double-blind placebo controls is a relatively recent phenomena in pharmaceutical research, and involved in debates over ethics and validity. The maneuvers around placebos can be framed as a kind of “boundary-work” that is politically necessary to translate the work of psychedelics into pharmaceutical terms.
Boundary-work is a rhetorical move that scientists make to distinguish scientific from non-scientific work in order to consolidate authority. Sociologist of science, Thomas Gieryn calls attention to the shifting norms by which the boundary between scientific and non-scientific practices are enacted. In the case of placebo controls, it is less that scientists themselves declared that non-placebo controlled studies were unscientific, and more that new norms for research were institutionalized, which excluded other modes of knowledge production about psychedelics.
The work of placebos and blinding procedures in contemporary psychedelic research is not just about doing good research, but also about bridging the humanistic and spiritual world of psychedelic therapy and the objective world of pharmaceutical research. Rather than achieve a new neurochemical balance, psychedelic therapy leverages a radical change in consciousness. Thus, at its core, psychedelic therapy challenges the very model of psychopharmacological intervention that is commonly used today.
The Epigraph
In the end, the search for the active placebo for MDMA has been disregarded. The FDA recently approved the third and final phase of the clinical trials. MAPS has agreed to return to using lactose as the placebo because of problems using MDMA as its own active placebo; subjects receiving the low dose experienced an uptick in anxiety during the experimental sessions. Not simply less than the full-dose MDMA, the low dose produced a different experience of the drug altogether. So while it improved blinding, the anxiety it produced actually made the full dose look better by comparison.
The next phase of studies will use lactose as a placebo, but the design calls for comparing MDMA-assisted therapy to the therapy by itself. The shift in comparison is critical because it negotiates one of the central tensions around the development of MDMA-assisted therapy, which is that the drug works with the therapy. It requires a specific set of techniques to make it work. What is more, the use of lactose is still critical to sorting out the safety issues, which are incredibly significant in the assessment of MDMA and any other psychedelic medicine.
As the larger psychiatric and medical communities weigh in, will the measures taken to ensure objectivity be enough to persuade the gatekeepers of the validity of psychedelic therapy?
Perhaps most critically, in moving back to the lactose placebo, the researchers are also making changes to address the question of bias by increasing the blinding of the independent raters who administer the outcome measures. In current proposals, a randomized pool of raters, who will not know which stage of the study the subjects are in, will administer outcome measures.
Of course, the question remains: What will happen when they publish the results? The FDA is just one of the gatekeepers around pharmaceutical research. In order to attain legitimacy for psychedelic research, the studies will need to be validated by peer-reviewed journals—preferably top-tier journals. As the larger psychiatric and medical communities weigh in, will the measures taken to ensure objectivity be enough to persuade the gatekeepers of the validity of psychedelic therapy?
This article is a summary adapted from Hendy’s chapter in Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, edited by Beatriz Caiuby Labate & Clancy Cavnar.
Art by Trey Brasher.
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