Can We Quantify the Placebo Effect in Psychedelic Medicine?

Here, take these pills. It will make you better. Likely you’ve heard these phrases before if you’re living in a medicalized society. For whatever ails you, there is a pill or an entire arsenal of medications that your doctor may prescribe.

Some of these drugs are life-saving remedies with biological targets that interrupt disease progression or kill infectious bacteria. But some of the most effective pills for certain chronic conditions, carry formulations of inert material, commonly known as a placebo.

Repeatedly documented, the phenomenon of a ‘placebo effect’ describes symptom improvement or even full recovery after taking pills or treatments that have no known biological activity. The placebo effect also refers to a positive response that surpasses what can be explained by the intervention alone.

Psychedelics clearly have potent effects on the brain and psychological processes. Accumulating research is showing that psilocybin and MDMA can be paired with psychotherapy to alleviate treatment-resistant depression and posttraumatic stress disorder (PTSD). The results from these trials are phenomenal and how these drugs boost therapy is a question to be unraveled.

While there are presumably several mechanisms at play, the placebo effect likely plays some role in psychedelic medicine. Can we quantify how much of the outcomes are related to placebo effect? Can we gain a better understanding of how these processes work in order to amplify improvements even more? Possibly.

The power of believing: placebo and nocebo effects

So what is happening in double-blind experiments when both the patient and the doctor are not told whether the patient receives an inactive substance, like a sugar pill, or the active test drug. In adequately designed studies with sufficient blinding, the same set of instructions and procedures are followed for all patients, regardless of the group assignment (placebo or active drug).

If there is a true effect of the investigational drug a statistical difference between groups will emerge, yet in many studies there is some number of participants who present a ‘placebo response’ – positive outcomes, often times equivalent to those that received the actual drug.

The notion that this could be spurious data points of outliers or spontaneous remission of symptoms is debunked by the fact that placebo responses are consistently replicated, especially for certain conditions associated with chronic pain, stress, and anxiety.

The placebo response is a variable that can be manipulated. How and by whom a treatment is administered can impact a patient’s response. For example, a study showed that patients given a skin cream by a distant and distracted doctor faired far worse than the same cream applied by an attentive and competent doctor.

Expectation is another factor that has pronounced effects when manipulated in clinical trials. Simply telling a person that the drug they will receive has helped others with a similar condition can shift responses in the positive direction.

Research has identified a neurochemical basis for not one, but many placebo responses. The most well characterized placebo effect is activation of the endogenous opioid system by the release of endorphins that can knock down pain severity.

Placebos can also cause dopamine release that fires up the reward pathway and reduces anxiety by suppressing the amygdala. These mechanisms explain, at least in part, why placebos can be quite effective for treating certain types of pain and anxiety-related conditions.  

Psychological factors, or how a person perceives a treatment, also influence the response. The power of suggestion and the magic of believing are psychological constructs with measurable outcomes in performance and body functioning. It’s not always that responses are shifted in the positive direction. Expectations or thinking that a treatment won’t work can result in the opposite direction, known as the “nocebo effect” or worsening of symptoms.

The idea that thought patterns can mediate seemingly independent physical processes shows up in other spheres of biohacking and transcendent experiences. Take for example neurofeedback, where a person can learn to moderate heart rate, breathing, and skin conductance by practicing with audio or visual cues to tune brain firing patterns that control these physiologic functions.

How we think and what we imagine can have powerful consequences on how our bodies function.

Psychedelics persuade us

What about psychedelic substances being used for treatment of mental health conditions? By definition, these drugs possess qualities to alter conscious perceptions of self and the material world. There are felt experiences that validate what the user has read or been told. Combine this with a therapeutic environment tailored to amplify the experiences psychedelics invoke, it appears the perfect stage has been assembled for the placebo effect to come into play.

Set and setting are often referred to when talking about psychedelics. The person’s internal state and the external environment are critical variables in how the psychedelic experience unfolds.

In psychedelic clinical trials, bleak clinics are transformed into aesthetically pleasing living room like settings that bring in elements of nature and sensory-enhancing musical and visual stimuli. Two guides or therapists are always present, offering an empathetic ear and support in whatever ways are needed. In these carefully manufactured environments, deep healing can occur, and the belief that it can, surely propels the therapeutic effects.

One of the guiding principles in MAPS MDMA Therapy Treatment Manual is talking to participants about their “inner healing intelligence”. The manual says to convey this concept to study participants by describing that similar to how a doctor can set conditions for healing to occur by cleaning and bandaging a cut to the skin, the body is responsible for the actual healing to occur. Creation of new skin cells and the fabrication of tissue layers occurs largely through unconscious processes of the physical body, and not from a doctor waving of a magic wand. So too, is the case for emotional healing. The power to heal comes from within and every individual possesses it.

In the case of MDMA-assisted psychotherapy, the role of the therapists and the drug is to help the person activate this inner healer and support them in the healing process which can be painful and challenging. Same for a laceration to the arm, tenderness and discomfort are intrinsic in path to healing.

During the preparatory sessions prior to taking MDMA, the seed has been firmly planted that self-directed uprooting of internal resources can and should be pursued in the drug-assisted sessions. Is it possible that this “inner healer” has a neurochemical basis? Does it overlap with recognized mechanisms of placebo effects? MDMA releases dopamine in the reward pathway in the brain, as do placebos. Perhaps there are synergistic effects of drug- and placebo-stimulated release of neurochemicals, the sum being greater than either on its own.

Drug effects vs. placebo reponse

It appears that psychonaunt guidebooks and clinical trial protocols tap into many of the variables known to impact the ‘placebo response.’ Leading one to ask, is it possible to delineate how much of the reported outcomes for MDMA and psilocybin are due to biological drug effects or from placebo effects?

Current trials are not designed to evaluate this question. Even though the studies randomly assign participants to receive active drug or a placebo, or even an active placebo where some minimal psychoactive effects may occur, the fact that the majority of participants and therapists can easily recognize the psychoactive properties limit interpretation of results because they suspect with good certainty that they received the drug, or not.

A simple subtraction of blinded psychedelic drug group response minus placebo group response won’t give the true effect because of the confounded blind. Add to that the media reports that these substances are panaceas for all aliments of the mind-body continuum, its undeniable that implicit bias must exist.

But perhaps an even more relevant question to ask is whether or not it even matters if some degree of the positive changes we observe after psychedelic treatments are due to amplification of the classical “placebo response”? Mega dollars have been invested by large pharmaceutical companies to understand how to minimize the placebo response to more easily pass drugs with minimal efficacy into FDA approval.

Perhaps the alternative approach of maximizing the psychological processes already at work to promote greater and faster recovery is worth investigating more. Manipulating the environment and the information given to participants in clinical trials of psychedelic therapy could help us learn more about the psychological factors involved.

As more information is generated, who knows we may find that psychedelics can strengthen the effects of other drugs or therapies by a common pathway converging on our innate ability to consciously heal ourselves.