The Placebo Paradox: Why Placebos Are Ineffective In Psychedelic Research
Within the first hour, almost every participant knows whether they're in the active or placebo group. 🍄 This fact makes researching psychedelics very difficult.
The psychedelic experience is undeniably profound, often resulting in dramatic changes in sensory perception, cognition, and consciousness.
Imagine the absurdity of giving two people either a drug like LSD (lysergic acid diethylamide) or an inactive placebo and believing they won’t be able to know which one was which.
This is the problem researchers are encountering as they explore the potential of these drugs. Normally, placebos play a crucial role in analyzing the power of a substance over our brain's ability to create an effect based entirely on expectation.
Placebo control is impossible to keep a secret when it comes to high doses of psychedelics — for a few reasons:
Subjective Experience — As we mentioned, the psychedelic experience does not come on quietly. It announces itself with force, and its existence or lack thereof becomes quickly apparent to participants.
Physiological Symptoms — Along with the visuals and hallucinations come changes in body temperature, nausea, heart rate, and more.
Expectations — Both the participants and the researchers can easily discover who's in the control group, but they have to go through the motions of pretending they don't anyway. Participants who expect a better outcome from the psychedelics will elicit more positive effects after realizing they're in the active group, and the opposite will be true for those discovering they took a placebo.
What is the Placebo Effect: How the Mind Treats Itself
The placebo effect is a well-known phenomenon whereby someone’s condition improves after receiving a treatment devoid of any therapeutic properties. This healing capacity is driven solely by their belief in the drugs effectiveness.
The opposite can also be true. Sometimes called a “nocebo,” — an inactive drug a user believes is going to cause harm can result in measurable detrimental effects on the body despite no pharmacological explanation for the effect.
The placebo effect suggests the mind has a powerful, unconscious capacity to heal (or cause harm) based on expectations alone.
This concept gives wind to the old adage “mind over matter.”
Placebos are inactive substances designed to look like active medicine. They're used in medical trials to rule out changes in health produced solely by the mind — which is expecting healing to occur. Researchers want to know that the drug itself is the cause of healing, not the expectations behind taking it.
Placebos are used to block the bias of the researchers too.
If the researcher knows her patient is getting an active medicine instead of the placebo, she may give off unconscious signals to clue in the participants. This is why such careful planning goes into an effective clinical trial. Only researchers who don’t interact directly with the patient can know what substance goes to which patient — but the researchers administering the medicines are just as clueless as the patients themselves.
As one survey put it, "placebo effects are not just about dummy pills: the effects of symbols and clinician interaction can dramatically enhance the effectiveness of pharmaceuticals."
To illustrate this, Drs. Ted Kaptchuk and Franklin Miller point to a study with patients suffering from migraines.
The 2014 study took patients with episodic migraines and gave them envelopes labeled either "placebo" or "Maxalt" — Maxalt being a verified treatment for migraine headaches. Researchers mixed the pills inside and alternated between labeling them correctly and mislabeling them.
The purpose of this was to keep track of how the labels may alter the effectiveness of both the medication and a placebo. If people expect a placebo to be the correct medication or, conversely, believe their medication to be a placebo, how significant is the effect?
The findings were astounding: "Although Maxalt was superior to placebo under each type of information, we were surprised the efficacy of Maxalt mislabeled as placebo was not significantly better than the efficacy of placebo mislabeled as Maxalt."
Negative consequences of labeling an active drug as an inactive one were seemingly equal to the positive results of doing the opposite. While active drugs will consistently outperform placebo, this points to the importance of knowledge and understanding.
If someone knows what they're getting into with treatment and they have a firm belief in how it will help, it's likely to be far more effective.
Why Placebos Don't Work In Psychedelic Trials
Placebos — either "active" or "inactive" substances without effect on the topic of study—have been a major element of scientific research for years. Distinguishing the effects a drug can have on a person against any preconceived expectations they have about it has been the gold standard of proof for efficacy.
This measure of randomly allocating participants to either placebo or active groups — or randomized control trials (RCTs) — has been the only method of operation for decades. RCTs using placebos are the only way to prove a drug is capable of outperforming our own ability to heal.
Blinding the participants and researchers from their assigned groups is critical. If mindset and expectations start to shift, the placebo effect becomes stronger or weaker alongside it.
With psychedelics, blinding becomes nearly impossible for both parties for three main reasons:
1. Subjective Experience of Psychedelics Negates Placebos
One recent report on the effects of ketamine on visual senses found 88% of participants correctly guessed which drug they took. This number would likely have been higher if not for researchers utilizing an active placebo — a light dissociative with far less potency — to aid in tricking participants into thinking they were in the active group.
Even with this measure, almost everyone broke blinding protocol because of the undeniable experience of ketamine. Subjective experiences of psychedelics — the "trip" of it all — make them easy to tell apart from a placebo, even an “active” one.
2. Physiological Effects Give Away Placebos
Putting aside the experience of psychedelics, they also create physiological changes that are hard to miss.
Some of the physiological effects of psychedelics include:
Elevated blood pressure
Increase heart rate
Nausea or vomiting
Loss of Appetite
Dry Mouth
Restlessness
Fluctuations in body temperature, excessive sweating, and cold sweats
While some active placebos — like niacin — can mimic some of these effects (facial flushing, tingling sensations), it's hard to maintain a veil of secrecy for long. Eventually, whether these symptoms build or add up to anything becomes apparent to everyone present.
3. Expectations Influence Psychedelic Trial Results
Psychedelics are seeing a similar renaissance to the one we experienced with cannabis, including some of the downsides. Namely, there are voices pushing psychedelics as a panacea capable of treating, curing, and maintaining just about every medical condition we can think of.
Some researchers are even calling for a reevaluation of our current data, stating the elevation of expectations could result in overly positive results. While initial results are positive, the collective anticipation of what these drugs can accomplish bolsters the placebo effect.
This problem also contributes to the "nocebo" effect — whereby patients experience negative outcomes from a placebo after their expectations have been shattered after expectations have been shattered.
Imagine how negative your experience would turn if you went into a trial for clinical depression, knowing this could be the cure you've been looking for, only to realize you're in the inactive placebo group.
The disappointment lowers the baseline placebo score researchers measure psychedelics against. At the same time, the excitement and anticipation of participants add further distance between the two.
As Dr. Muthukumaraswamy et al. put it in their study published in Expert Review of Clinical Pharmacology:
“While psychedelic RCTs have generally shown promising results, with large effect sizes reported, we argue that treatment effect sizes in psychedelic RCTs are likely over-estimated due to de-blinding of participants and high levels of response expectancy.”
Is There A Solution? What Alternative Options Exist?
Knowing placebos are ineffective, researchers have tried out a few alternatives with mixed levels of success.
Here are a few options for replacing a standard placebo in psychedelic research and some shortcomings these other solutions may present.
1. Create a Full Placebo "Experience"
One report found there's potential to create a placebo psychedelic experience. In the study, 33 participants took an inactive placebo in an environment conducive to a psychedelic experience with music, lighting, art, and even other researchers masquerading as participants pretending to heavily feel the effects.
Astoundingly enough, 61% of participants claimed a psychedelic experience or some subjective effects. Even more surprising was that many of these people had previous experience with psychedelics, which could point to even higher effectiveness in populations that have not.
This could mean a placebo isn't out of the question for psychedelic research — it may simply require more work on behalf of the researchers.
2. Crossover Trials for Psychedelic Research
Crossover trials involve participants taking both a placebo and an active dose at different times to compare the two.
Many psychedelic studies have already applied this method, but it's not without its limitations. If a group takes both an active and inactive drug, they'll be even more likely to know which they took. Even if participants maintain blinding through the control group, they'll break it after comparing the two.
Effects from one session may also bleed over to the next, contaminating the data.
3. Using An Active Group
Instead of comparing the effectiveness of psychedelics to the effect of a placebo, researchers can compare it to known intervention methods.
For example, one study by Robin Carhart-Harris et al. found psilocybin to be as effective for depression as the established SSRI treatment of Escatilprom.
While this doesn't provide a baseline to work from, researchers can compare the effectiveness of the two treatments.
The obvious downsides of this includes:
Differences in Dosage Methods — A single dose of psilocybin has inherent differences from the daily use of SSRIs that researchers may not be able to account for.
No Baseline Experience — Evaluating effectiveness without a baseline is like trying to measure a building and not starting at the foundation. It's hard to know how effective something is if you can't start from 0.
No Masking — Without a masking effect, participants are likely to experience some level of the placebo effect for both medications.
Final Thoughts: Placebos in Psychedelic Research
Despite the inherent difficulties of running placebo controls in clinical trials involving psychedelics, these controls are a necessary component of scientific rigor.
The subjective nature of psychedelic experiences, coupled with physiological symptoms and participant expectations, renders traditional placebo methods ineffective — but there are alternative methods that, when cleverly applied, can provide validity and reliability to the study results.
Researchers are exploring alternatives to traditional placebos in psychedelic trials, such as creating placebo psychedelic experiences or comparing psychedelics directly to established treatments. These approaches aim to address the limitations of blinding while still providing valuable insights into psychedelic therapy.
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