Research Briefing: Overestimating outcomes of psychedelic RCTs

This research briefing is co-published with the excellent Report on Psychedelics, you can find their weekly news briefings here.

In The Research Briefing:

  • Breaking blinds in randomized controlled trials is leading to overestimation of the outcomes
  • The positive outcomes of an ayahuasca retreat, for those who took a placebo
  • The mixed relationship between suicidality and psychedelics use


The difficulty of working with psychedelics

Randomized Controlled Trials (RCTs) are the gold standard for doing research. One group receives the intervention, the other a placebo. The participants are assigned randomly to one or the other and in the end, the outcome is measured.

This works wonders when investigating something like the nutritional effects of vitamin C. But with psychedelics, many of the participants are acutely aware of which group they are in. That is what a pre-print by Suresh Muthukamaraswamy and colleagues that reviewed the literature is hammering home.

In the review (pre-print), they argue that current RCTs have failed to properly account for participants guessing if they’ve received an actual drug or the placebo (de-blinding). With that knowledge, they caution against blindly (pun intended) taking the results of current studies at face value. And that future studies should optimize their protocols to both prevent de-blinding (e.g. with active placebos) and managing expectancy effects.

What does it mean for psychedelic RCTs?

  • Future trials should do more to measure expectancy effects, which likely also explain part of the effect size, as was seen last week in the largest placebo-controlled microdosing study
  • They can also do more to incorporate active placebos such as is already being done in some trials that give midazolam as the active placebo to ketamine
  • And when publishing results to a wider public, researchers should be more aware to not overstate the amazing results found, or at least mention what other factors than the drug have also contributed to its effect

Science is a process of iterative cycles of learning. Where studies in the 1960s were open-label and without much standardization of set and setting, the modern studies with psychedelics are a leap forward. Constructive critiques like this paper should help improve our knowledge even more.


The benefits of set and setting

A double-blind, placebo-controlled study (n=30) by Malin Uthaug and colleagues adds even more evidence to the power of set and setting. The expectation of participants, and the ceremonial environment of ayahuasca retreats (in Spain, The Netherlands, and Germany) led to lower scores on scales of depression, anxiety, and stress.

And you may have guessed it already, this reduction in scores was the same for the group that received ayahuasca or placebos. Both groups received pills, and those for the placebo group contained cacao and other substances to still taste the same when someone burbs. A clever study that once again shows the power of the environment when studying psychedelics.

What was found in this study?

  • Ayahausca, versus placebo, did have a significant effect on implicit arousal to negative stimuli, a measure that indicates increased empathy. Still, this effect was relatively small (not going higher than the baseline for the placebo group).
  • The placebo group came into this study with much higher depression and stress scores, and improved more than the ayahuasca group.
  • Of the participants, 57% and 69% guessed correctly that they were in the ayahuasca or placebo group (with 50% being chance). But, the dosage of ayahuasca was relatively low, coming in at 2 to 4 times lower than a (very) high dose.

Doing this type of analysis can provide information on what factors contribute to the beneficial effects of psychedelics. They don’t only show the power of psychedelics, but also highlight the need for a set and setting that is beneficial for participants.


Preliminary evidence for acute and sustained decreases in suicidality

A review of 64 studies investigated the relationship between suicidality and the use of psychedelics. The first part of the review looked at the relationship in natural use (not in the clinic) and found non-significant and significant relationships in both directions. Of the studies where suicidality was linked to psychedelics, often there was a lack of clear relationship between both (i.e. there were psychedelics in someone’s system but that may not be the cause of the suicide).

Modern clinical studies with classical psychedelics (e.g. psilocybin) showed decreases in suicidality after treatment. The participants in these studies also were suffering from other mental health disorders (e.g. depression) and mechanisms like regression to the mean may partly also explain the positive results.

More on psychedelics and suicidality

  • Studied now need to be done that incorporate more controls as recommended in the first article, one other suggestion from this article is the use of waitlist controlled studies (to account for the regression to the mean)
  • Several studies on ketamine and suicidality also look promising and show rapid and immediate reductions in suicidality. The effects, however, do seem to fade within a week to a month
  • On a population level, lifetime use of classical psychedelics is associated with lower psychological distress and suicidality. Correlation doesn’t equal causation though

Psychedelics are being studied for everything from depression to weight loss. Suicidality is a growing problem and future studies might find a place for psychedelics in the acute or long-term treatment for those suffering from suicidal ideation.

Research Report Readout

Lithium and serotonergic psychedelics don’t go well together. An analysis of online reports found that nearly half experienced seizures and more than one-third sought emergency medical treatment. A note of caution for those on bipolar medications.

Low doses of psilocybin and ketamine enhances motivation and attention in rats. The effect was only found in the rats that were rated as the low performers, so regression to the mean could also help explain the effects. Still, it’s a data point that speaks to the effects of microdosing.

More neurological factors found that predict someone’s level of mystical experience. This pre-print showed that the higher the theta oscillations (associated with mind-wandering) the lower the mystical experience for those who smoked DMT.

Those who use psychedelics are less likely to be obese. This study found a correlation between the lifetime use of psychedelics and various health markers. But as always, correlation doesn’t equal causation. Another study found the same relationship with hypertension.

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