The Bridge Between Set and Setting and Placebo Theory in Psychedelic Science

This article is a synthesis and interpretation of the paper “Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology” (Hartogsohn et al., 2016). Any errors in interpretation are my own.

In the emerging field of psychedelic science, it is common knowledge that the context and your mental state have a tremendous impact on the experience you have under the effects of psychedelics. Over the development of research and clinical practice, extra-pharmacological factors, which refer to the non-drug-related influences that can affect the experience and outcomes of a pharmacological agent, have been shown to indeed have more impact when taking psychedelics compared to other pharmacological agent. In 1963, the term “Set and setting” has be coined by Timothy Leary to define the mindset (set) and the environment (setting) in which a person experiences psychoactive substances, particularly psychedelics [1].

In this article, we are going to go over an article by Ido Hartogsohn [2] that proposes a perspective rooted on the placebo theory and the set and setting that explains how the two are linked together and can have profound impact in the research and in clinical applications for the psychedelic field.

Placebo Theory

The word “placebo” had different meaning over history, but can be defined as the ´Ability of inactive treatments (e.g., sugar pills) to produce clinical improvement through non-biological mechanisms, primarily driven by the patient’s expectation of recovery.’ [3]. Initially not considered seriously, the placebo effect got more popular with the publication of ‘The powerful placebo’ that claimed placebo as being responsible of 35% of a drug’s effect [4].

With the rise of clinical trials, a trend developed where the goal of these trials was to evaluate if a treatment had a greater effect than a placebo. This became the gold standard to evaluate treatments, and drove multiple research that evaluated the placebo effect and found concluding evidences that the placebo effect has a significant effect on patient’s improvement rate. Many contributing factors of the placebo effect were identified, such as the expectancy of a treatment, the social interactions with a clinician, or even the cultural setting.

According to some models, placebo should be an inherent part of the treatment efficacy, rather than a separate entity. Notably, Gordon Claridge conceptualized the effects of a drug with (1) the drug itself (i.e : it’s form, color, size, shape, etc.), (2) the status and attitude towards the prescriber, (3) the personality and suggestibility of the person receiving the drug and (4) the physical setting where the drug has been taken [5]. This model resembles the set and setting term that Leary defined, as we previously saw.

Set and setting

It became clear through the first researches in the 1940s that non-pharmacological elements had a tremendous impact on the subject’s experience of psychedelics. The first conceptualization of this was made by Robert Hyde who studied the effect of the environment over a period of three years on people taking LSD in the Boston Psychopathic Hospital studied the effects of the social milieu and study design over a period of three years, modulating the research setting year after year in an attempt to isolate the role of social and psychological factors. [5,6]. He conceptualized four dimensions that impacted the response to LSD, which are :

• Rigidity-flexibility of goals
• Familiarity-unfamiliarity of environment
• Attitude of acceptance-nonacceptance of the subject’s feelings and behaviors
• Absence of others with a common culture

Others therapist at that time also played with variables such as music, light, flowers and candlelight, to modulate the environments and enhance the psychedelic experience. However, it is in 1963 that Timothy Leary defined the term “Set and Setting” that can be divided into two components :

1. Set: The internal psychological state of the user, including personality, preparation, expectation, and intention.

2. Setting: The external environment, encompassing physical, social, and cultural surroundings.

Together, set and setting surround most of the extra-pharmacological factors explaining the psychedelic experience. The concept has expanded in research with non-psychedelic substances, like heroine, cocaine, crack-cocaine, methamphetamine. It explains notably why people react differently to a drug depending on the environment they used it, such as veterans who used heroin during the Vietnam war our of boredom who came back in the U.S lost, for 88% of them, all desire to reuse it [7]

As researchers studied psychedelics in different context, it has became more and more apparent that the extra-pharmacological have a drastic impact on the psychedelic experience. Indeed, taking psychedelics by yourself at the confort of your home with no prior experience will induce a totally different experience than when you take psychedelics in a clinical trial where everything is carefully monitored and two clinicians are with you at any time.

Relationship between Placebo Theory and Set and Setting

Similar to placebo theory, set and setting posits that extra-pharmacological variable have an impact on your experience under drugs. The difference is that set and setting comes directly from psychedelic research, and placebo theory have a longer history in studies in medicine to measure health indices like symptom improvement/reduction. Furthermore, while placebo is a term we mostly hear in the medical world, set and setting extended it’s root to drug users and the general population, by being mentioned in community organization, rituals or context where people use psychedelics and non-psychedelic drugs.

In his article, Ido Hartogsohn argues that Placebo Theory and Set and Setting are interconnected through a unifying concept : meaning response. The meaning response, proposed by Daniel Moerman, refers to the physiological or psychological effects of meaning in medical treatment [8]. It suggests that individuals may respond to the meanings associated with their medical care rather than to inert treatments like placebos. It relates essentially to how we understand illness and the methods to treat it. For instance, you could go see a shaman that would treat you with incenses, smoke, chant, sounds and more, but if you don’t attach any meaning to these methods, it won’t affect you as much. The same applies to western medecine. When you enter into the doctor’s office, you see his multiple diplomas, you probably heard about him and his research, which gives more weight and meaning to his health recommendation. This will influence the placebo effect if you are then being given a pill, because you trust that it is the right treatment, backed by decades of science. According to Moerman even argued that meaning response could even replace placebo effect in it’s entirety, because, as he mentions, humans need to attribute meaning to even experience benefits from a placebo [9]

Similarly to placebo, set and setting is highly influenced by our cultural narrative and will be defined by the meaning we attribute to the environment in which we are experiencing the world. Taking psychedelics in a doctor’s office can be perceived as being very safe and healing for someone, where the same could not be true for someone who doesn’t attribute the same meaning to western medicine.

How the field of placebo and set and setting could benefit each other

Now that we know the link between placebo theory and set and setting, the author proposes ways that both concepts help each other out.

As we saw earlier, placebo response can help us understand the mechanisms underlying psychedelic’s effect. If we understand placebo through the lens of a meaning response mechanism, where humans infers phenomenon out of things they attribute meaning to, psychedelics can be seen as tools, or “Magnifier of consciousness” (if we use Leary's term), to augment that meaning response and increase the perception of meaning we attribute to things. Under this lens, psychedelics can heighten the sense of meaning we attribute to internal states or external cues. This helps explain why, in ritualistic or personally significant contexts, some individuals have reported dramatic placebo-like improvements in conditions such as chronic pain, substance dependence, stuttering, allergies, or even severe illness.

Taken together, these ideas suggest that the profound shifts in consciousness induced by psychedelics may increase the likelihood or intensity of the types of placebo responses described in the literature. In other words, psychedelics may not create entirely new therapeutic mechanisms but may instead strengthen or reveal placebo pathways that are already present in human cognition and neurobiology. If we are able to modulate the set and setting to optimize the psychedelic experience, this can have a rippling effect on the placebo effect, by the augmentation of the meaning response of the participant.

Table 1. shows the overlap regarding the factor influencing the drug intake that have been investigated in the literature for both theories (Hartogsohn, 2016)

Clinical and research significance

Current work on placebo effects and the psychedelic concepts of set and setting shows that these two frameworks strongly complement one another. Both emphasize how expectations, mindset, and environment shape therapeutic outcomes, which can have clinical and research outcomes worth exploring by the scientific community.

The authors propose several research directions to clarify these links. For instance, we could ask ourselves how does LSD or any other psychedelic amplify the placebo response. Or perhaps, what are the brain region associated with placebo, and can psychedelics augment those same neural circuit in different set and settings? There has been evidences that show that placebo-induced pain is linked with a change of activity in the rostral anterior cingulate cortex and posterior cerebellum [10]. For clinicians, knowing that the outcome of their patient is dependent on the meaning response that their patient attribute to the therapy is a key element in the therapeutic process. It allows patient will have a more active role in their treatment and therapist to have more tools to ensure positive outcomes. Furthermore, it requires the clinician to have an intimate understanding of their patient’s history, as well as a therapeutic link strong enough to allow the therapeutic experience to be meaningful for it’s patient.

Conclusion

Overall, integrating placebo theory with set and setting provides a promising framework that may deepen our understanding of psychedelic mechanisms and improve clinical outcomes. Both approaches emphasize that context heavily shapes healing, and exploring their overlap could potentially refine the design of the treatment, as well as clearer guidelines for futur psychedelic therapists. It is impossible to dissociate the effect of placebo and set and setting, especially in the context of clinical research with psychedelic substances. It is a reality that researchers and clinicians have to deal with, in order to ensure that their research findings are valid and methodologically correct, and that their patient have a positive experience that will have a rippling effect in their daily life after the integration period.

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