In last week’s post, I promised to discuss high-dose psychedelic work. However, as I began writing this week’s post, I saw that it would be beneficial to first discuss not-high-doses. These are what I refer to as manageable doses.

Modern clinical research with psychedelics is generating uniformly and markedly beneficial results, both practical and heuristic. Researchers are deliberately administering modest doses of drugs, in combination with rigorously structured set and setting. In this context, modest doses maximize sessions’ effects toward desired outcomes and away from negative ones. These results enable psychedelic research to progress within the mainstream, albeit at its further edges.  However, modest doses are not the only doses available for study.

In last week’s post, I introduced the idea that psychedelics enhance the placebo response, and that this is the basis of their astonishing efficacy for so many different conditions. If so, activation of the serotonin (5HT)-2A site may mediate this placebo response. Thus, the objective brain changes we see that correlate with benefit may reflect the biology of placebo in that condition more than the more apparent psychological effects of the drug; e.g., rating scale scores, visions, feelings, insights, and so on. I suggest that the placebo response enhancement by psychedelics requires modest doses. As placebo issues overlap with those of suggestibility, what are the recent developments regarding psychedelics’ effect on suggestibility?

Important recent work out of Imperial College reported enhanced suggestibility in response to 40-80 µg intravenous LSD in normal volunteers (doi: 10.1007/s00213-014-3714-z). This increase in suggestibility occurred only when suggestions were of sufficiently long and detailed. This is a key component of the preparation sessions in the current psychedelic paradigm. Note the dose of LSD. LSD administered IV is only slightly more potent than when administered by the oral route. So, this might be equivalent to an oral dose of 100-125 µg. This is half of what was routinely considered a moderate 250 µg dose during the first generation of studies. It would be about a quarter of the 450 µg high doses used to induce a peak psychedelic experience by the Spring Grove group in the 1960s.

The most popular drug in the renewal of clinical psychedelic research is psilocybin, the active ingredient in magic mushrooms. Like other classical psychedelics, it works via activation of the 5HT-2A site. The highest oral doses used currently in the U.S. are 0.4-0.45 mg/kg, and are referred to as “high” doses. For a 160 pound individual, this is an oral dose of 29-32 mg. Swiss studies refer to 0.215 mg/kg as a high dose.

Based on dose-finding work with oral psilocybin that we performed at the University of New Mexico, the US “high” dose in current use is barely at the psychedelic threshold—the point at which effects become incontrovertibly psychedelic rather than, say, stimulatory or euphoric.

Referring to a 1965 chapter written by Gary Fisher for “The Psychedelic Reader” describing oral doses of 120 mg, we requested and obtained permission to give up to 1.1 mg/kg of psilocybin, or about 80 mg for a 160 pound person.

In about a half dozen volunteers, we administered a wide range of doses: 0.056, 0.15, 0.3, 0.45, 0.7, and 1.1 mg/kg. It was not until the dose reached 0.45 mg/kg that volunteers clearly felt “psychedelic” effects. Those who received 0.7 mg/kg stated that they could have taken more, which led us to raise the dose to 1.1 mg/kg. This last dose induced a delirium and was clearly unsuitable. We therefore chose 0.9 mg/kg as our high dose, if we had begun the double-blind placebo-controlled phase of the project. Note that 0.9 mg/kg is twice what is now referred to as a high dose in the U.S. and more than four times a Swiss high dose.

What are the implications of these disparate “high dose” ranges? One is that 0.45 mg/kg of psilocybin is not a high dose. It is a threshold psychedelic dose. Psychedelic effects are clearly present, and at the same time allow for the optimization of set and setting influences to direct the experience toward the desired goals.

Another is that 0.45 mg/kg is not a low dose because psychedelic effects do predominate. Perhaps a more accurate label would be “moderate.” And while not being suitable for clinical research purposes, the term “manageable” is that which most accurately describes these types of doses.

How then do we explain subjects reporting the full gamut of the psychedelic experience at these modest doses? Besides subjective descriptions, their rating scale scores also point to a fully psychedelic experience. For example, Hallucinogen Rating Scale scores indicate effects comparable to our very high dose of DMT. Perhaps what we’re seeing is that people can only gauge their psychedelic drug experiences based on their own lives and range of experiences with altered states. A modest dose may indeed elicit “the most meaningful experience of one’s life” because it did. But these effects are not due to a truly high dose. Here is where acute effects may be less susceptible to set, setting, and placebo issues, and the emphasis shifts more toward the drug’s pharmacology. However, this is a delicate balance, as I hope to discuss in next week’s post: “Mega and Micro.”

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