Understanding psychedelics as amplifiers of the placebo response helps explain their ever-widening scope of applications—from accelerating one’s spiritual growth to reducing tobacco use. Manageable doses of these drugs may thus be conceptualized as optimizing placebo’s contribution to their observed benefits. The biological correlates of successful outcomes may therefore relate as much to indirect psychedelic-effected changes in the placebo response as to direct effects of the drugs.

A “mystical/peak experience” is now believed to be the common denominator underlying the benefits reported in current research across a wide variety of conditions. However, I believe that an enhanced placebo response is a more fundamental explanation, and may allow for even greater application of the psychedelic drug state. More on this later when I post on explanatory models and future directions.

To the extent that psychedelics enhance placebo effects within a highly structured set and setting, there necessarily exists an optimal dose range. These are the “manageable doses” discussed last week, where positive effects are maximized and adverse ones minimized. Theoretically, then, there are doses that are both higher and lower than those which most reliably and safely stimulate placebo’s contribution to clinical outcomes. Perhaps these higher doses would demonstrate more clearly the “pure” drug effects, less influenced by set, setting, and suggestion.

In our UNM project, for example, we determined that 0.2 mg/kg DMT was the “psychedelic threshold” dose of the drug, where effects were clearly “psychedelic.” The full spectrum of subjective responses characteristic of the psychedelic state nearly always occurred: emotional, cognitive, perceptual, somaesthetic, and volitional. At lower doses, not all elements of the mind were affected in concert: 0.1 mg/kg effects were primarily somatic, and those of 0.05 mg/kg were more affective, if they were felt at all.

If we had gone no higher than 0.2 mg/kg, we would have missed some of the most novel, unexpected, and intriguing effects reported by the volunteers, especially those occurring in response to 0.4 mg/kg. Here, effects were not what either the volunteers nor I expected nor intended.

With respect to psilocybin, the most commonly used psychedelic in the renewal of human research, high doses in published reports are in the range of 0.2-0.45 mg/kg. Compare this to our UNM psilocybin dose-finding work, where our high dose was to be 0.9 mg/kg. This is two to four times what is now considered a high dose.

What does this mean for how we refer to doses in current use? Perhaps it is misleading for the literature to equate moderate doses with high ones. And therefore it would be more accurate to call them “moderate.” Or, if investigators continued wishing to call modest doses “high,” then an allowance must be made for incorporating in our terminology “very high doses.”

Very high doses may be one way to tease apart what is placebo and what is drug effect. This is not to say that placebo enhancement is not a drug effect, but that placebo enhancement is not all that results from a particular psychedelic drug taken at its maximally tolerable dose. At these maximally tolerated doses, one would see the maximum effects of any particular drug. Put another way, the effects of manageable doses—those which maximize benefit and minimize harm—are not the only effects of psychedelic drugs.

There are several issues to consider when designing and performing very high dose research: the dose, the volunteer, the setting, and the effects themselves.

Regarding dose, one must guard against delirium. In our DMT work, a dose of 0.6 mg/kg impaired consciousness and recall, and confusion reigned. Similarly, we saw that 1.1 mg/kg of oral psilocybin induced a confusional state. It will require keen clinical sensitivity to administer very high doses of psychedelics safely.

Regarding volunteers, they should be more rigorously screened and followed up. One might even consider studying psychedelic-naïve volunteers, in order to minimize the influence of their previous drug experiences on acute effects occurring in the unique clinical research environment. As a corollary, staff also will need to be more rigorously screened, trained, and supervised.

Regarding setting, both the volunteers and the research team will have agreed on the primary purpose of the research: characterizing the phenomenology of very high doses in conditions of very low suggestibility. While all manner of material will come up in very high dose sessions—spiritual, psychotherapeutic, or creative—volunteers will be participating more in the spirit of explorers than of clients or patients.

Consistent with current protocols, the physical setting should be as comfortable as possible, and the sitters trained in non-judgmental responses to highly altered states. A stripped-down set of directions for a session might be as simple as “Please describe what is happening” every so often. Otherwise, the volunteer is allowed to “free range.” Headphones and eyeshades might be encouraged but their use would be optional.

In this free-range setting, there would be no video nor audio recording, and no one-way mirrors. Nothing would intrude on the natural progression of the experience. Just a sitter or two taking notes and holding down the fort. The qualitative data generated—volunteers’ reports and sitters’ observations—would then provide the bases for subsequent quantitative studies. These quantitative studies would approach the phenomena using the same rigorous methodologies as those currently being applied to more mainstream projects. For example, understanding the nature and function of the “beings” could proceed using the same biological and psychological models and tools now used with psychotherapy and spirituality protocols.

This leads to the final issue, which is the experiences themselves. Very high dose effects, for example of DMT, are not mainstream. Because they lie outside of the mainstream mindset as well as mainstream research models, it is less obvious how to understand their nature and applicability. However, one can study outside-of-the-mainstream effects with mainstream tools of science. Nevertheless, the intellectual and emotional reactions those effects arouse make studying them with mainstream tools—the scientific method, peer-review, incremental approaches—uniquely challenging.

A side note: This relates to a previous post regarding the media. Because these effects may often lie outside of mainstream acceptability, staff and volunteer availability to the media should be severely restricted.

I’d like to close with the other extreme of psychedelic drug dosing: micro-dosing. Here, sub-psychedelic, barely noticeable, doses of classical drugs like LSD or psilocybin are not taken for their psychedelic effects. Rather, they are taken for their effects on mood, anxiety, or creativity in a manner similar to antidepressants, stimulants, or nootropics.

Relevant to this discussion is the 1952 study by Savage demonstrating the antidepressant effects of low dose LSD given daily to a group of severely depressed inpatients. These doses caused minimal acute subjective effects (https://doi.org/10.1176/ajp.108.12.896). Similarly, recall that using LSD as a probe of serotonin receptor subtypes and function, scientists developed the SSRI antidepressants. Perhaps daily low dose psychedelics exert their salutary effects in a manner similar to, but not identical with, the effects of SSRIs.

Micro-dosing is an extreme form of mainstreaming psychedelics, what might be called their “prozacification.” Less tongue-in-cheek, we may be seeing the minimal doses at which placebo responses to psychedelics emerge. At the same time, the lack of psychedelic effects should not be an argument for promulgating the notion that micro-doses are legal.

Micro-doses’ lack of obvious psychedelic effects does not mean that placebo effects are not occurring. Are doses that cause visions and voices necessary for placebo enhancement? My sense is that, within certain limits, they are; especially if one wishes to maximize placebo responses. This is why it is important to determine dose-response data for psychedelics’ effects on placebo-related phenomena. Other questions arise: Is placebo response mediated by serotonin 2A receptor activation? What are the roles played by psychological factors such as suggestibility, personality, and hypnotizability? Where else might putative placebo-enhancing effects of psychedelics be directed? “Psycho-biological” treatments such as acupuncture and cognitive behavioral therapy come to mind. Such studies may reveal that the psychedelics are unsurpassed tools for understanding and optimally applying the placebo response.

One field of psychedelic research exquisitely sensitive to set, setting, and suggestion (i.e., placebo) is clinical spirituality. Next week’s blog, God-willing, will address the salient issues in this extremely interesting and important work.

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