The three pillars of the psychedelic drug experience—set, setting, and dose—are the topics for this and the next blog post. They are inextricably intertwined. Channeling the set and setting toward well-defined goals acceptable by the mainstream requires staying within “manageable” doses of drug.

By carefully regulating dose, set, and setting, we are now witnessing the publication of a remarkable series of beneficial and heuristically useful outcomes to psychedelic drug projects. In addition, such studies report a very low incidence of serious adverse effects. Posttraumatic stress disorder, obsessive-compulsive disorder, eating disorders, anxiety, depression, creativity, spirituality, end-of-life palliation—the list seems to grow by the month. British psychiatrist Ben Sessa has even wondered if the psychedelics are the equivalent of “psychiatric penicillin.” However, the placebo effect is a more operationalized construct, and one more amenable to study. It may help us understand how one drug can benefit so many indications by means of carefully structuring drug, set, and setting issues.

I wish to propose that much of what we are seeing in this new wave of research is due to the placebo response, a phenomenon known and utilized throughout all fields of medicine and psychology. By using psychedelic drug doses that optimize placebo response, and channeling the placebo effect through standardization of set and setting, their effects are similarly optimized. A corollary of this hypothesis is that we may be misattributing the effects of psychedelics by focusing primarily on their pharmacology, rather than on the placebo effect which their pharmacology enhances. Perhaps it’s not the psychedelic drugs themselves that provide benefit, but the placebo effect amplified, accelerated, and more precisely directed in set-setting-dose optimized conditions.

“Set and setting” was the answer to the following question raised by the first wave of clinical research with these drugs: How can one drug, such as LSD, have such wide-ranging effects in the same type of patient or subject when administered at the same dose? For example, early studies using LSD to treat alcoholism demonstrated marked differences in outcome depending on the particular research group.

Imagine, if you will, the “LSD chemotherapy” approach to alcoholism in the 1960s championed by Hollister and others. Researchers administered a high dose of LSD to a patient who was not told what the effects of the LSD might be, and who could have overheard the staff talking and laughing about “hallucinogenic,” “psychotoxic,” or “psychotomimetic” drugs. S/he was locked in a brightly lit, featureless seclusion room, tied down with restraints on an uncomfortable gurney, and observed through a window every several hours by curious and various staff. They were given a large dose of Thorazine at the end of eight hours to halt the experience. As might be expected, outcomes, both acute and longer-term, were unfavorable.

Contrast this with the “psychedelic” or “peak experience” approach to alcoholism treatment pioneered by the Spring Grove group in Maryland. The patient was educated regarding potential effects, and given hope and encouragement that the effects of the drug would be beneficial. They received several hours of pre-treatment orientation and psychotherapy with an emphasis on the healing effects of particular types of experiences possible through LSD. They were instructed how to manage reactions to the drug in order to increase the likelihood of attaining such effects. On treatment day, they took the same dose of LSD used in the nightmare chemotherapy model but in a comfortable living room-like environment. They were constantly attended to by one or two members of a highly trained, motivated research team infused with the belief in the “psychedelic” or “peak” effects of LSD, effects that they encouraged through their empathic therapeutic responses. As might also be expected, effects and longer-term outcomes were impressive.

Here we see how early research discovered that LSD and related drugs produced an extraordinary degree of sensitivity to one’s physical and psychological environment, and their own pre-existing state of mind. No other drugs’ effects were so sensitive to non-drug factors. These findings led to the development of the notion of “set and setting.” Set being the state of the subject at the time of drug administration—cognitive, physical, emotional. It also includes the expectation of and intention for the drug sessions. Setting involves the external environment, both physical as well as the “sets” of those around whom one is under the influence.

The notion of “suggestibility” affecting the subjective responses to drugs was in its infancy at that time. Research in the 1950s demonstrated that if one is told to expect stimulation from a sedative drug, stimulatory effects occur more often than if they were told to expect sedation. And if one were told that a stimulant would be sedating, reports of sedation increase. In the case of psychedelics, however, these effects of suggestibility needed to include the entire newly discovered constellation of subjective responses to psychedelics. This required a considerable refinement of the relatively simple notion of “suggestibility.”

I find it useful to nest the concept of set and setting, and its relationship to placebo response, within the larger category of suggestibility. In this, I am indebted to Ido Hartogsohn’s work which has greatly clarified my thoughts on these issues. Here is the link to his seminal article:

It has been known for millennia that an “inactive” substance—a “placebo,” from the Latin “I please”—may exert profound biological and psychological responses in some individuals. We now know that these effects are not simply “imaginary.” Rather, they are biological response to conscious and unconscious psychological processes. Top-down effects, as it were. The effects of placebo on objective biological variables are being increasingly demonstrated; e.g., within the field of immunology and functional brain imaging. These are the biological effects of the placebo response; not necessarily the effects of the placebo itself as an active pharmacological agent, but the biology of the effects that they elicit. Employing rigorous research methodologies, placebo research is now determining how to optimize placebo effects: the most conducive characteristics of subjects/patients and caregivers; optimal cognitive, interpersonal, and behavioral strategies; etc. One might frame this work as an attempt to increase suggestibility, or to increase the efficacy of suggestibility.

Research in the 1960s, mostly by Levine, demonstrated that combining hypnosis and “psychotherapy” with LSD produced a more highly “altered state” than any single or paired treatment condition. And any model of hypnosis requires discussion of suggestibility; increased suggestibility increases hypnotizability, and vice versa. More recent data from Imperial College have confirmed and quantified these enhancing effects of LSD on suggestibility. Hartogsohn has summarized the disparate literature on psychedelics, placebo response, suggestibility, and set and setting. His analysis allows us to begin conceptualizing set and setting effects in psychedelic drug responses as a particular case of the placebo response. By doing so, we can examine more objectively the intuitively-appealing older notions of psychedelics as “the world’s most powerful placebos” (Andrew Weil) and “non-specific mental amplifiers” (Stanislav Grof).

By conceptualizing psychedelics as super-placebos, we can finally lay to rest labeling these drugs as anything other than “psychedelic.” Not “entheogen” or “hallucinogen.” Rather, they are “mind-manifesting/disclosing,” where we define mind in its broadest sense, as “psyche,” the aggregate of all mental functions constituting a human individual.

Consider a 1971 study by the Spring Grove group where patients with alcoholism received either 450 mcg of LSD (a large dose), or 50 mcg (a small dose) as “active-placebo.” Utilizing the same set and setting which emphasized the attainment of a “peak experience,” there were no differences in outcomes. Both groups demonstrated equal benefit, and there were no differences in the percent of patients attaining a peak experience. Does this mean that set and setting were more important than (dose of) drug? Or, that a dose simply adequate to enhance suggestibility is all that one needs, rather than a dose that produces more typical psychedelic visions, voices, out of body sensations, and other effects?

Or, take an example from the New Mexico DMT research, approaching the placebo response from the opposite direction. Administration of saline placebo was clearly distinguishable by volunteers at doses of 0.1 mg/kg and higher. However, in response to our lowest dose, 0.05 mg/kg, a substantial number of volunteers believed that they had received saline. Conversely, many identified the effects of saline as those of the very low dose. Their global assessment of the difference between the very low dose and placebo was no greater than chance. However, our rating scale, neuroendocrine, and other autonomic measures detected differences between saline and the very low dose. This suggests that much of what takes place in the “mind” is occurring behind the scenes. One’s conscious appraisal of what the “drug” is doing relates poorly to what is taking place in the preconscious or unconscious, or in the body.

These factors now influence much of today’s research with psychedelics. Researchers employ doses that enhance suggestibility without producing significant adverse effects. These doses, as I will describe in the next blog, fall short of a high dose effect. And they are standardizing set and setting to optimize the placebo effect. Placebo has a broad, theoretically unlimited, applicability. This broad applicability may be responsible for why we are seeing such positive results across such a wide spectrum of conditions, and such a low incidence of serious adverse effects.

I also wish to raise the issue of how current studies choose placebo, a critical factor in establishing that “it’s the drug, not placebo effects” determining the results. Here we see that the choice of placebo—“active” or “inactive”—may occur by attending to its minimal effects on suggestibility. Drugs like antihistamines and mild stimulants are now the active-placebos of choice, drugs that have definitely discernible psychological and physiological effects, but will probably turn out to be less effective at increasing suggestibility than psychedelics. Utilizing active-placebo drugs that have little effect on suggestibility would explain the consistent and striking differences between psychedelics and “placebo” in subjective responses and clinical outcomes we now see.

The avoidance of low doses of psychedelics as active-placebos suggests that researchers are aware of the conundrum they would face if low doses and “full” doses showed no demonstrable differences in outcome. Without dose-response data, it is more difficult to establish that the effects that you are seeing are due to the drug itself. However, such data would establish that something in addition to the drug is at work. It may be that equally beneficial outcomes result from different doses when the effects on suggestibility are equivalent.

In order to address this issue, I suggest generating dose-response data for psychedelics’ effects on suggestibility. If enhanced suggestibility is the proximate mediating cause in effecting the desired outcomes, one can tailor doses to modify that variable directly. One would then be able to choose a dose that optimizes suggestibility, not “typical” psychedelic effects.

Another series of experiments might involve suggesting a totally different set of expected outcomes to individuals receiving the same dose of drug for the same clinical situation. This would not be done in a cavalier and insincere manner; i.e., the “alternative” team wouldn’t be pretending. They would be as convinced of the validity and efficacy of their model as much as the prevailing-model team. We already have an indication, from the Maryland studies, that the same suggestions given with different doses may have similar effects. Will it also be the case that in the context of identical doses, different set and settings lead to different outcomes with identical efficacy?

One area ripe for establishing the equivalent efficacy of an alternative model using identical drug doses is clinical spiritualty research. The emphasis now is on attaining the experience of “oneness,” a mystical-unitive state, a notion borrowed from Eastern and mystical Western religious streams. Attaining “oneness” is associated with brain function changes, which are associated with beneficial effects ranging from amelioration of depression to accelerating spiritual practice. The “alternative” team might instead be steeped in the interactive-relational stream of religious experience. They would similarly educate, orient, coach, and respond to subjects using this model. Would the same dose of the same drug cause interactive-relational spiritual experiences? And would these be as beneficial as those demonstrated in subjects attaining “oneness”?

This notion of psychedelics as “super-placebos” opens some intriguing new perspectives for understanding and applying additional factors related to the psychedelic experience. One example is its biology. Brain serotonin 2A (5HT2A) receptors are believed to mediate the subjective responses to these drugs. Perhaps what we are seeing is that the 5HT2A site mediates the placebo response, both as a result of psychedelic drug administration, or endogenously by naturally-occurring 5HT2A-active substances whose activity increases in non-psychedelic placebo responses. Correlating psychedelics’ efficacy with their objective effects on, for example, brain activity, may reflect the workings of the placebo response, rather than specific effects of psychedelics. Psychedelics thus may be a potent tool with which to investigate this universal human phenomenon of the placebo effect. They would provide a potent, reliable, and safe method to enhance the placebo effect experimentally. Using such a model would provide valuable insights regarding the mechanisms and optimal utility of the placebo response.

I am not implying that there are no effects of the psychedelics independent of their placebo-enhancing ones; e.g., the visions. Psychedelic visions are compelling and their association with functional brain changes convincing. But, if I may be indulged for defaulting to the Hebrew Bible’s model of spirituality, prophetic experience, I will point out something that may be relevant. In prophecy, the visions simply indicate that one is experiencing something extraordinary, more real than real, an encounter unlike any other. The visions get the prophet’s (or research subject’s) attention for what follows—the message, the information, the healing or transformation. One may interact with the visions in order to understand the message or become accessible to aspects of the experience; but practically, the visions are unnecessary. They only provide a form by means of which the non-sensory effects appear to occur.

As one’s expectations, intention, and beliefs (set), as well as those of one’s “outside world” (setting) affect outcome of psychedelic drug administration, we may consider some of the implications of recent data indicating psychedelics’ neuro-regenerative effects. Set and setting determine placebo response, a response with biological correlates and effects. Thus set and setting may determine the biologically objective results of this psychedelic- enhanced neuronal growth. In other words, neuro-regeneration might be a nonspecific biological effect of placebo-enhancing pharmacological agents.

Of course, isolated brain tissue does not experience the placebo effect. But, it may reflect how the biology of psychedelics enhances the placebo response in the human brain-mind complex. Neuro-regeneration may be how the placebo response is more permanently established. But what is the quality of the placebo response? We’ve already seen that it is dependent on set and setting. These influence the direction of the placebo effect. If this were the case, we want to optimize how these new synapses are being laid down. Will they enhance our kindness or aggression, tolerance or intolerance, attraction to virtue or to vice? Thus, what we think about, study, where we live, who we associate with—all these will influence the mental and behavioral outcome of psychedelics’ neuro-regenerative effects.

The importance of set and setting is also apparent in meditative religious traditions. It is generally acknowledged that the optimization of these highly altered states, which may be as profound as those occurring with psychedelic use, requires a setting, a context, where education, moral training, self- and peer-evaluation play critical roles. Without these safeguards and rudders, the powerful effects of meditation can be as destructive as those seen in similarly unmoored psychedelic experiences.

Finally, the notion of psychedelics as super-placebos lends support to their restrictive legal scheduling. While advocates of freer access to psychedelics point to their current track-record of safety and efficacy, opponents point to their unpredictability and potentially crippling adverse effects. Both are right. These drugs are extraordinarily powerful and thus require a relatively short regulatory leash. While there will always be underground use, it seems to me irresponsible for advocates to equate psychedelics with any other drugs in current medical use. They belong in a category by themselves and should be regulated in a likewise unique manner. While their potential benefits are great when their super-placebo effect is directed toward beneficial goals, the opposite may be true when set and setting variables are directed or conducive to equally adverse, maladaptive, negative outcomes. Schedule I placement has served a useful purpose, but in the future, a Schedule midway between I and II may be more practical. This will provide a safety net assuring only qualified individuals administer these drugs, but increase access to those wishing to take them for any number of relatively well-supported reasons.

How then do we determine what are not placebo effects of the psychedelics? This is where high-dose studies play a role. Stay tuned for my next blog post where I will address the pros and cons of high-dose studies. What they might be good for and what they might not be good for.