How Do You Measure A Wall That Breathes And Placebo Research

Psychedelic consciousness: that strange, artistic state of affairs in which it seems the structure of reality around us can melt and recrystallize into different universes. This state of consciousness has been the bedrock of many epistemologies and societies throughout history (Carod-Artal, 2015), but it is now becoming the novel focus of psychiatry and western science, a tradition I find myself – sometimes begrudgingly – couched in.

Some elements of our western scientific tradition could not synergize more perfectly with psychedelia. Chemistry, for example, allows us to change, mass produce, and distribute psychedelic experiences. You would not be reading this article today if Albert Hoffman had not created LSD or if Dave Nichols had not synthesized Psilocybin for Johns Hopkins (Morris, 2021). By scientific analyses of the smallest things, we can bring about the greatest changes. 

However, our objective, reductionist, graph-and-ruler way of doing things has its pitfalls. Take the ongoing tension around schizophrenia treatment as an example. There is evidence suggesting that long-term (maintenance) antipsychotic use is damaging to schizophrenics. In one study, maintenance patients that took 50% or less of their recommended antipsychotic dose were significantly more likely to be socially functional than their fully medicated counterparts (Wunderink et al., 2013). Both the low-medication and high-medication groups outperformed the placebo group, however. The lower social function in the higher antipsychotic group is a key finding though. Antipsychotics have been linked to cortical atrophy, which is linked to decreased social function (Gual et al., 2015). From a pharmacological & historical standpoint, calling antipsychotics tranquilizers or cognitive blunting agents is accurate. Many researchers argue that these drawbacks are worth decreasing the likelihood of further psychotic episodes or hospitalizations, and most schizophrenic patients are maintained on chronic antipsychotics at the election of their families under official guidelines (Davidson, 2018).

Despite our enormous pharmacological research and efforts, we still lack a true biochemical understanding of the etiology of schizophrenia. Schizophrenics suffer worse in western countries than their counterparts in 3rd world and developing countries (Leff et al., 1992; Jablensky et a.l, 1992). There is an unsortable milieu of cultural factors that play into this. It’s no doubt that lifestyle differences, diets, and so forth are significant in their role in schizophrenia, but I think our western philosophy has a specific blind spot.

In my opinion, a massive contributor to the suffering of schizophrenics is our society’s consistent failure to deal with their anomalous experiences. It’s not surprising that the reality-breaking experiences of schizophrenics are unsettling, but our philosophy is couched in the world of atoms or divine commandment, of black-and-white objective truth and false subjective experiences.  We are too scared to walk hand in hand with the schizophrenic through the terrifying other world because it is so unfamiliar to us, and so we would rather blunt their existence with dopamine and serotonin antagonists so that it’s more in line with consensus reality. 

Luckily, the cultural paradigm of avoiding strange-mindedness is not permanent. As psychedelics become mainstream, there is an emerging curiosity, and need, to explore the other. Psychonauts are these explorers, and they’re beginning to return with early treasures of their journeys. To be explicit, I am not saying drug experiences are the same as schizophrenic experiences, but rather that both reflect an under-studied departure from consensus reality.

The other world of Subjective Effects:

Early on, there was a recognized need in the psychonaut community to be able to communicate about altered states of consciousness. Even within similar classes of drugs, the experience produced could be wildly different with even a single atom of the molecule altered. To discriminate between these effects, written trip reports became the essential medium. Measures such as the Shulgin Scale existed to broadly assess novel drugs in a low-resolution manner, essentially to rate if they were psychoactive or not.

Since the mainstreaming of the internet and the first steps of the psychedelic renaissance, subjective effects work was beginning to bloom. The early web of the 2000s became host to forums such as DMT Nexus, Erowid, and the first global gathering grounds of psychonauts, but the medium of communication was still reading trip reports.

Josie Kins co-founded Psychonautwiki in 2011, a website that provides wiki pages on most drugs you can imagine, and standardized lists of their subjective effect profile. Josie is no longer an active contributor to Psychonautwiki, but her mission remains to “create a language for the previously ineffable aspects of drug experiences.”

Currently, the mainstays of her public-facing work can be found at effectsindex.com (which builds considerably upon the effects index of PsychonautWiki), and on r/replications, a subreddit that uses AI & digital art to simulate the visual effects of psychedelics. As a day job, she works with Mindstate Design Labs, creating datasets for AI-analysis techniques of written trip reports. So far, the AI can discriminate between some drugs based on qualitative reports, but a lot of strenuous AI training (and even worse, data gathering) is still required before the AI is operational. Josie and Mindstate hope that their subjective-effects technology will eventually become integral to drug discovery and research. 

Another brilliant mind in the realm of subjective effects is Andrés Gómez Emilsson, the president of the Qualia Research Institute (QRI). Generally, QRI research plunges into the intersection of mathematics and psychology. Andres’s most viral moment is a 1-hour, detailed lecture at Harvard on the exact mathematical properties of DMT-trip geometry. QRI’s ideas are complex, more verbose than necessary, and utterly compelling. The body of QRI’s work focuses on how mathematical descriptions of subjective experiences can inform cognitive & affective science. 

Work like Josie’s and Andrés’ is a glimpse over the horizon, to a richer, computational psychology. However, until the work with AI and trip reports is further developed, we scientists must make do with clipboards and questionnaires.

Currently, the psychedelic scientific establishment has two such flagship questionnaires: The 5-Dimensional Altered States of Consciousness Scale (5D-ASC) and the Ego Dissolution Inventory (EDI). The first has 11 measures that broadly encompass most cognitive and psychological effects of psychedelics through a 97-item questionnaire. The Ego Dissolution Index allows subjects to mark on a line how much they agree with a given statement and generally measures a person’s self-reported ability to differentiate themselves from the environment. 

Both scales have been used in clinical psychedelic research, but that is typically under double-blind conditions, or at least conditions that aren’t designed to maximize the effect of placebos. This leaves an interesting open question in the space; how strong can placebo psychedelics be?

The McGill Students Take a Novel Placebo:

Let us focus on a room in McGill, where 16 students wander around for 4 hours; looking at paintings, doing art, and answering to lab coats with clipboards. These young adults of the psychedelic Renaissance are all more-or-less under the impression that the sugar they ate before entering the room was actually a novel short acting psychedelic compound. Olson and his team report that “If there were no placebo effects, we would expect [the 5D-ASC] scores to be 0.” Some may consider this to be too forgiving of a null hypothesis, but a closer look at the data tells a different story. 

The modal score of the subjects on the 5D-ASC was 0, with occasional outliers. This indicates that in this mostly-naive cohort, placebos can generate positive scores for some 5D-ASC measures, but the modal zero is strong evidence that placebos of this nature are not the same as the drug. In the qualitative data many participants verbalized experiencing some kind of psychedelic effect. This probably isn’t a reliable indicator of strong subjective effects as the 5D-ASC, but rather it’s mainly an incredibly strong expectation bias in the sample required for such a study.

Due to some word-of-mouth and lying problems, Olson’s team re-ran the experiment, in a different part of the country and no longer attempting to exclude previous psychedelic users. Three of the six (3/6) previous psychedelic users reported that they believed they had taken a psychedelic during the experiment, while seven of the ten (7/10) naïve users believed they were on the drug. These results are within error, and both groups scored similarly in the Altered State of Consciousness scale.

The European Shamans took either a Placebo or an Active Ayahuasca pellet:

So, college students aren’t good at detecting psychedelics, but their scores on the 5D-ASC may be. However, this was a population that was initially intended by the experimenters to be psychedelic naïve. What about a population steeped in psychedelic culture?

M. V. Uthaug et al (2021) asks exactly this question, in a naturalistic setting of psychedelic use across several ayahuasca retreat centers in Europe. In several sessions, tripsitters-in-training (N = 30) were double-blindly and randomly administered either a placebo or threshold dose of ayahuasca. Tripsitters-in-training were all experienced psychedelic users and had attended ceremonies both tripping and sober (as their eventual facilitator role is a sober one). Both researchers and the ceremony hosts double-blindly observed the test subjects, and all but the researchers attempted to guess whether ayahuasca or a placebo was administered to the subject. Eight out of fourtheen (8/14) subjects receiving ayahuasca guessed their treatment correctly, while eleven of the sixteen (11/16) placebo subjects correctly guessed their treatment. More interesting, fourteen of the sixteen (14/16) placebo subjects were identified by the facilitator. A small sample restricts any ‘significant’ conclusion.

Finally, it’s worth noting that there was no significant difference in scores on the Ego Dissolution Inventory between the two groups, and that even the scores for the active group were very low. It’s likely because Ego Dissolution (loss of ability to distinguish between self/environment/thoughts) is typically only induced at high psychedelic doses, and the active dose in this experiment was a “threshold” dose. The threshold dose is also a likely reason the subjects had difficulty guessing their treatment, as subjective effects were minimal.

Summary of findings:

This body of research is currently limited, though this isn’t surprising given the novel and underfunded state of our field. So, letting the obvious caveats go unsaid, what can we learn from this data? Well, there are a few things that stand out. The first is that some people can experience some acute psychedelic or psychedelic-like effects under the right conditions, with high individual variance in placebo sensitivity, and a narrow range of effects. However, at a threshold ayahuasca dose, it is difficult for experienced psychonauts to differentiate between an active and placebo. Interestingly, experienced third-person observers of psychedelic use (the ceremony hosts in Europe) are potentially the BEST at detecting if someone is on a psychedelic at threshold doses, which is an unexpected result in need of further research

Let’s turn to the 5D-ASC, and what it may tell us about some of the cognitive differences between a placebo and a threshold psychedelic dose. 

In the ayahuasca group: audiovisual synesthesia was a significant predictor (p = 0.02) of psychedelic vs placebo presence. Anxiety (p = 0.06), and elementary imagery (p = 0.11) were also strong predictors of an actual ayahuasca dose.

In the McGill group: low scores on Anxiety, Elementary imagery, and disembodiment were the highest predictors of the placebo dose. This cohort had a high variance in every category. However, these were the lowest-variance-lowest-score categories for this placebo.

So, it seems to me that alterations of sensory processing (including delineation of self) are the easiest way to distinguish a psychedelic from a placebo. Audiovisual synesthesia, disembodiment, etc., are all signs of a pharmacological alteration to our conscious-making machines at a level below what we can seemingly do with a placebo. Additionally, Anxiety being the most reliable predictor of an active dose vs placebo is an important result. I think it emphasizes that a psychedelic experience has a little more gravity to it than psychedelic-naïve participants may understand.

The field of qualitative effects research is young, and there are still so many open questions. I look forward to seeing how this beautiful intersection of art, drugs, science, and computing flourishes in the future. 

Acknowledgments:

I’d like to give a heartfelt thanks to Jay Olson of McGill for presenting his research to IPN and piquing my interest in the topic of placebo trips. I’d also like to extend a big thanks to Josie Kins for her excellent work and enthusiasm in engaging community members.

Finally, a display of gratitude to the amazing IPN members that helped review and edit this article; Luke Johnson (IPN Blog Coordinator), Cameron Smith (IPN Labs Team) & Zachary Daily (IPN General Member). 

References

Carod-Artal, F. J. (2015). Hallucinogenic drugs in pre-Columbian Mesoamerican cultures. Neurología (English Edition), 30(1), 42–49. https://doi.org/10.1016/j.nrleng.2011.07.01 

Morris, Hamilton (2021) Podcast 34: Four Hour Interview with Dr. David E Nichols, The Hamilton Morris Podcast, https://www.patreon.com/HamiltonMorris

Wunderink, L., Nieboer, R. M., Wiersma, D., Sytema, S., & Nienhuis, F. J. (2013). Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy. JAMA Psychiatry, 70(9), 913. https://doi.org/10.1001/jamapsychiatry.2013.19

Guo, J. Y., Huhtaniska, S., Miettunen, J., Jääskeläinen, E., Kiviniemi, V., Nikkinen, J., Moilanen, J., Haapea, M., Mäki, P., Jones, P. B., Veijola, J., Isohanni, M., & Murray, G. K. (2015). Longitudinal Regional Brain Volume loss in schizophrenia: Relationship to antipsychotic medication and change in social function. Schizophrenia Research, 168(1-2), 297–304. https://doi.org/10.1016/j.schres.2015.06.016

Davidson M. (2018). The debate regarding maintenance treatment with antipsychotic drugs in schizophrenia. Dialogues in clinical neuroscience, 20(3), 215–221. https://doi.org/10.31887/DCNS.2018.20.3/mdavidson

Leff, J., Sartorius, N., Jablensky, A., Korten, A., & Ernberg, G. (1992). The International Pilot Study of Schizophrenia: Five-year follow-up findings. Psychological Medicine, 22(1), 131–145. https://doi.org/10.1017/s0033291700032797

Jablensky, A., Sartorius, N., Ernberg, G., Anker, M., Korten, A., Cooper, J. E., Day, R., & Bertelsen, A. (1992). Schizophrenia: Manifestations, incidence and course in different cultures a World Health Organization ten-country study. Psychological Medicine. Monograph Supplement, 20, 1–97. https://doi.org/10.1017/s0264180100000904 

Placebo Sources:

Olson, J. A., Suissa-Rocheleau, L., Lifshitz, M., Raz, A., & Veissière, S. P. (2020). Tripping on nothing: Placebo psychedelics and contextual factors. Psychopharmacology, 237(5), 1371–1382. https://doi.org/10.1007/s00213-020-05464-5

Uthaug, M.V., Mason, N.L., Toennes, S.W. et al. (2021) A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology 238, 1899–1910   https://doi.org/10.1007/s00213-021-05817-8

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