Sunshine Acid, Shrooms and Sugar Pills—Placebo and Psychedelics Part One
Understanding the placebo effect is key to understanding how drugs work—but is it uniquely hard in the context of psychedelics?
This article forms part one of a deep dive into some of the issues around the placebo effect, and how it intersects with scientific studies of psychedelics, legal challenges to studying illicit compounds, and how we move forwards in our understanding of them.
The placebo effect is an often-misunderstood phenomena in medicine. You might be most familiar with the term as it is often levelled as a criticism of New Age or “alternative medicines”, like homeopathy or crystal healing. Usually when someone points out that a treatment’s effect may be a placebo, it’s mistakenly perceived that the effect is somehow not real, or that the person experiencing the effect is uniquely gullible. However, neither of these are true; placebo effects are very real and very fascinating, and we’re all prone to experiencing them.
So why is the placebo effect so fascinating? Placebos are usually delivered in the form of pills or treatments that should have no effect on a condition, yet can have both physical (e.g. reduced blood pressure) and psychological effects (e.g. reduced perception of pain). Placebos, though they should do nothing, are often experienced in a similar manner to treatments with proven effects. For example, larger doses of sugar pills have been show to have greater effects than smaller doses, saline injections have been shown to be more effective than sugar pills, and a review of placebo surgery (following the process of pre- and post-operative care, anaesthesia and sometimes even incision, but without actually doing the step thought to be therapeutically necessary) found that 74% of trials also showed an improvement in the placebo surgery, and 51% were found to show no difference between the placebo and “real” surgery conditions. Placebo effects also occur in animals, though it’s thought that it’s a second hand human placebo where their owners perceive them to have gotten better—placebo via pet, if you will.
So what is it about these fake pills, injection and surgeries that makes them effective? The main thing is expectancy—what our brain expects a treatment to do. If we go to see the doctor about a pain in our chest, we generally expect whatever treatment they recommend to work effectively. With the placebo effect, sometimes this expectation alone is enough to alleviate our symptoms on their own—merely by participating in the theatre of treatment, in the absence of active compounds or inventions, it seems our bodies can go a very long way towards healing ourselves.
The placebo effect therefore has important public health implications—if a proposed active drug or conceived treatment doesn’t actually perform better than the theatre of administering it, then it can’t really be argued to be worth the financial cost it would take to synthesise the drug or go to the trouble of, for example, implanting a pacemaker. It’s certainly not a cost healthcare systems or patients themselves should have to bear—even when studies have suggested that more expensive placebos work better than cheap ones (sorry, we’ll stop with all the fascinating examples now!).
This is why the so-called gold standard of medical studies is the “randomised double-blind placebo-controlled trial”, sometimes called randomised control trials (RCTs) for short. Randomised means that each participant is randomly assigned to either an active- or placebo-dose category. Double-blind refers to the fact that neither the participants nor the researchers know who’s receiving which treatment, to avoid expectancy effects from both parties. Placebo-controlled means that it’s tested against an inactive, but indistinguishable, dose or treatment category. In some cases, such as later-stage clinical trials when efficacy against placebo has been proven, the placebo control is replaced with a comparison to the standard approved treatment—such as the psilocybin vs escitalopram trial for depression in 2021.
At this point it’s probably worth mentioning therapy, which is neither a chemical intervention (i.e. a drug) or a physical intervention (like surgery), but is often a key component of many psychedelic studies. Some in the psychotherapy space have added nuance by considering how placebos represent a psychological or “meaning” intervention, that when administered honestly (i.e. the patient is aware they’re receiving inactive treatment) can be considered analogous to some parts of psychotherapy itself. This may also be why it’s difficult to administer RCT psychotherapy, when honesty and trust between patient and therapist are core tenets of the practice. As therapy is such a big topic, we’ll be focussing on placebo psychedelic drugs for the rest of this article.
Why are placebos so tricky to include in psychedelic studies? If we set aside psychotherapy and focus on the drugs themselves, there’s two groups of issues with placebo in psychedelic science, which can usefully be understood through macrodosing and microdosing.
Macrodosing studies
These are studies such as the recent MDMA trial for PTSD, or those for psilocybin and depression, where a full-blown psychedelic experience is a key aspect of the treatment, along with therapeutic support before, during and after the experience. As we mentioned earlier, for a drug to be approved it has to have a few RCTs supporting it; a healthcare authority such as the FDA or EMA will want to see these before approving it for broad-scale use in treating a given condition.
Here’s where we get to the problem. Most of us who’ve had an old tab of acid or some iffy vintage shrooms will know that despite all the expectation in the world, it’s pretty hard to convince yourself you’re tripping if you’ve taken something inactive. Flip this on its head, and it’s equally hard to fail to notice a psychedelic experience once you’ve taken a dose from a good batch. Despite the obvious perceptual effects of psychedelics, some studies have managed to elicit some degree of placebo response by carefully controlling set and setting, for both placebo shrooms and placebo ayahuasca. This is why some authors have compared the similarities between the placebo effect and set and setting, and how the two could be used to complement each other.
Generally speaking, however, many studies of psychedelics that include a placebo group tend to have a large proportion of participants "breaking blind”—correctly guessing which dose category of the trial they’re in, which can potentially bias experimental results. From a healthcare authority point of view, the higher the rate of blind-breaking there is in a study, the lower the quality of evidence for effect beyond that of a placebo.
Blind-breaking was one of the factors cited in the recent FDA advisory committee’s rejection of the MAPS/Lykos Therapeutics MDMA for PTSD trial. Though the MAPS trials did report their rate of blind-breaking, the success of blinding procedures is not always well reported either across psychedelic or other clinical trials more generally—leading some to ask if it was fair for the FDA to focus on blinding in their decision (though there were other factors that influenced their rejection of the data).
Tackling the issue of breaking blind in psychedelic studies is nothing new. One way to do this is with an “active placebo” which attempts to use a placebo that has some perceptible effect, but one that is not psychedelic (though sub-trippy doses of the same psychedelic are sometimes used as well). One of the first studies to do this, while testing the effects of psychedelics on spiritual experiences, was the 1962 Good Friday Experiment. Walter Pahnke and his team (under the supervision of Timothy Leary) administered either an active placebo (niacin, which causes skin flushing) or active does of psilocybin to 20 graduate students, who then sat through a two and a half hour sermon in the basement of Marsh Chapel, Boston. Though initially both participants and researchers found it hard to tell which group was which, by the later stages all participants had broken blind—likely due to the difference in effect duration for psilocybin (4-6 hours) vs niacin (1-2.5 hours), and the fact that all twenty participants were in the same room together.
Though active placebos go some of the way to addressing this problem when studying psychedelics, there are broader ways to help mitigate the effects of expectancy and blind breaking. Some researchers have recommended that studies of all drugs (not just psychedelics) should include measuring participants’ before-trial expectancy and during-trial blind-breaking as standard, to make more informed comparisons between treatments.
Others have called for regulatory bodies such as the FDA to allow greater inclusion of non-RCT evidence, to be considered when drugs like psychedelics face a placebo problem. Further still, the way we talk about psychedelics in the media may prime people’s expectancy for certain outcomes in clinical trials. Media which either overhypes the benefits of psychedelics before clinical trails have even finished, or those which hark back to D.A.R.E. era “drugs are the devil” hysteria, can both push potential trial participants expectations in one direction or the other. Calmer, more balanced science communication may be crucial here.
It seems that implementing the placebo effect in macrodose studies might be done effectively at all levels of society, from those designing the trials, to those reviewing the evidence, and from those (like us!) who communicate the science to those who read about it and talk about it with their friends and family. It may also be worth acknowledging that for desperate people suffering from mental health challenges, who might be incredibly fatigued from have trying a number of different treatments, it’s hard to untangle expectancy from the drug itself.
If a drug is safe and not prohibitively expensive (a big ask in today’s capitalist medical/wellness hellscape, we know)—is it important to know exactly how it works, or just that it works?
In the next article in this series, we’ll look at how the placebo effect has been studied (or omitted) in the science of microdosing, and whether such regimes are worth the money. In the mean time, let us give you some further reading.
These pieces in particular shaped some of our broader ideas for this article, but weren’t cited directly:
Bad Science: This book by Dr Ben Goldacre was our first experience reading about the dodgy practices in both the pharmaceutical and alternative medicine fields. Though it was written in 2008, it’s a great antidote to growing pandemic of big pharma and wellness grifters that have exploded in recent decades .
Medlife Crisis: Cardiologist Dr Rohin Francis does great, entertaining science communication around medical science. His video below on the placebo effect was particularly useful for a deeper dive as well as a nuanced, thoughtful take. He also writes on here as
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