There has long been a debate among scientists about what happens to a person after taking psychedelic drugs. This experience may be due, at least in part, to the placebo effect, based on the belief that psilocybin or ketamine use transforms perception to some degree.
Boris D. Heifitz, associate professor of anesthesiology at Stanford University, is exploring this question as part of his laboratory research aimed at identifying the processes that occur in the mind and brain when psychedelics are consumed. It explores how much of their sometimes dramatically life-changing experiences are due to chemical changes, experiential realities, and how much is mental and subjective.
These effects, it turns out, may be due to more complex factors than just a biochemical reaction to substances affecting, for example, the brain's serotonin receptors.
Dr. Heifitz shares his years of work aimed at understanding the nature of the psychedelic experience.
Boris D. Heifitz, associate professor of anesthesiology at Stanford University, is exploring this question as part of his laboratory research aimed at identifying the processes that occur in the mind and brain when psychedelics are consumed. It explores how much of their sometimes dramatically life-changing experiences are due to chemical changes, experiential realities, and how much is mental and subjective.
These effects, it turns out, may be due to more complex factors than just a biochemical reaction to substances affecting, for example, the brain's serotonin receptors.
Dr. Heifitz shares his years of work aimed at understanding the nature of the psychedelic experience.
Are we moving toward a better understanding of the mechanisms of action of psychedelics, especially in the context of therapeutic applications? Is it becoming possible to utilize these transformative experiences for the therapy of mental disorders?
Despite his long time in the field, he still faced the intractable problem of studying psychedelics. Heifitz has found a very useful scheme dividing this question into three categories.
The first category involves the biochemical effects of the drug, which deal with the basic workings of the brain — the interaction of chemicals with cell receptors. This occurs whether or not the person is aware of the effects of the drug.
The next category is conscious experiences involving perceptual changes, vivid, hallucinatory and extraordinary feelings. These experiences are usually associated with the taking of the drug, but it is difficult to determine whether the changes in mood or outlook were the result of the drug or an experiential party in themselves.
The third category encompasses all aspects of the overall experience that are independent of the drug or trip, known as non-narcotic factors. These are what psychologist and psychedelics advocate Timothy Leary called «attitude and environment». How much do your mood and environment affect your results? This category includes expectations of improvement, such as states of depression, anticipatory experiences, stress levels, and environment. It also touches on the integration stage, after which intense experiences are conceptualized and incorporated into daily life.
Despite his long time in the field, he still faced the intractable problem of studying psychedelics. Heifitz has found a very useful scheme dividing this question into three categories.
The first category involves the biochemical effects of the drug, which deal with the basic workings of the brain — the interaction of chemicals with cell receptors. This occurs whether or not the person is aware of the effects of the drug.
The next category is conscious experiences involving perceptual changes, vivid, hallucinatory and extraordinary feelings. These experiences are usually associated with the taking of the drug, but it is difficult to determine whether the changes in mood or outlook were the result of the drug or an experiential party in themselves.
The third category encompasses all aspects of the overall experience that are independent of the drug or trip, known as non-narcotic factors. These are what psychologist and psychedelics advocate Timothy Leary called «attitude and environment». How much do your mood and environment affect your results? This category includes expectations of improvement, such as states of depression, anticipatory experiences, stress levels, and environment. It also touches on the integration stage, after which intense experiences are conceptualized and incorporated into daily life.
It is useful to consider each of these categories separately, as each exhibits a degree of independence. The aim is to make each of these categories as specific as possible in order to gain a deeper understanding of each aspect.
How did the study begin?
In our study, we conducted an experiment in which participants with depression were administered ketamine under general anesthesia. The aim was to isolate the biochemical effect of the drug, excluding conscious experience, and to find out whether it improves the condition of depressed patients.
We sought to answer an important question: what exactly contributes to the improvement of the person's condition — the substance itself or the experience of it?
One possible approach is to modify the drug to eliminate the subjective experience. However, this is a long process. As an anesthesiologist, I decided to use general anesthesia to suppress conscious perception of the psychic effects associated with ketamine, which many consider key to its antidepressant effects.
How did the study begin?
In our study, we conducted an experiment in which participants with depression were administered ketamine under general anesthesia. The aim was to isolate the biochemical effect of the drug, excluding conscious experience, and to find out whether it improves the condition of depressed patients.
We sought to answer an important question: what exactly contributes to the improvement of the person's condition — the substance itself or the experience of it?
One possible approach is to modify the drug to eliminate the subjective experience. However, this is a long process. As an anesthesiologist, I decided to use general anesthesia to suppress conscious perception of the psychic effects associated with ketamine, which many consider key to its antidepressant effects.
We worked closely with psychiatrists Laura Heck and Alan Schatzberg at Stanford Medical School and designed our study to meet the standards of prior ketamine studies over the past 15 years.
We chose a similar sample of participants — people with moderate to severe depression who had failed to improve from other treatments. We used the same questionnaires and the same dosage of ketamine.
The main difference was that the participants underwent hip, knee, or hernia surgery, and we gave them a standard dose of the antidepressant ketamine during anesthesia. Because the patients were under anesthesia and could not know if they had taken the drug, our study was the first blind test of ketamine.
Surprisingly, the placebo group who did not receive ketamine also showed improvement that was not different from those who took the drug. Nearly 60% of the patients saw their symptoms halved, and 30% experienced complete remission of their major depressive disorder. These patients had been suffering for years, and the result came as a big surprise. In a way, the study can be considered a failure because we were not able to detect differences between the groups.
We chose a similar sample of participants — people with moderate to severe depression who had failed to improve from other treatments. We used the same questionnaires and the same dosage of ketamine.
The main difference was that the participants underwent hip, knee, or hernia surgery, and we gave them a standard dose of the antidepressant ketamine during anesthesia. Because the patients were under anesthesia and could not know if they had taken the drug, our study was the first blind test of ketamine.
Surprisingly, the placebo group who did not receive ketamine also showed improvement that was not different from those who took the drug. Nearly 60% of the patients saw their symptoms halved, and 30% experienced complete remission of their major depressive disorder. These patients had been suffering for years, and the result came as a big surprise. In a way, the study can be considered a failure because we were not able to detect differences between the groups.
From this, I conclude that our results do not provide a clear understanding of the mechanisms of action of ketamine. Instead, they emphasize the importance of non-medication factors in treatment, which refers to what is often referred to as the placebo effect. This term covers a variety of phenomena, from the use of sugar pills to surgical manipulation.
In our case, it may be related to preoperative preparation and interaction with patients who are not used to having someone interested in their mental state.
What did you discuss with the study participants?
We talked to them at length, listening to their stories and getting to know them better. I believe they felt that they were really seen and heard, which many patients don't experience before surgery. This reminds me of the stages of preparation for psychedelic research. Participants in both groups were motivated to participate.
In our study, they were informed that they were participating in testing the therapeutic effect of the drug and that they had a 50% chance of receiving it. Then came the important moment, the surgery itself, which is a stressful and momentous event.
Patients closed their eyes during the operation and opened them feeling that time had not passed. They felt that something significant had happened to them, even though they had bandages and scars to confirm the facts of the experience.
It follows that non-medicinal factors such as outcome expectancy probably play an important role in most psychedelic research and can have a marked therapeutic effect. It was becoming apparent that the participants were experiencing deep emotions. Most people do not recover on their own from long-term depression; they feel worse after surgery, and this is supported by the data.
It is important to note that our positive impact achieved after a few hours of communication and shared experience emphasizes the importance of non-medication factors such as expectation and hope. To ignore these aspects in the development of therapy would be wrong. In fact, many clinicians use similar techniques every day when interacting with patients, actively engaging the placebo effect.
It follows that non-medicinal factors such as outcome expectancy probably play an important role in most psychedelic research and can have a marked therapeutic effect. It was becoming apparent that the participants were experiencing deep emotions. Most people do not recover on their own from long-term depression; they feel worse after surgery, and this is supported by the data.
It is important to note that our positive impact achieved after a few hours of communication and shared experience emphasizes the importance of non-medication factors such as expectation and hope. To ignore these aspects in the development of therapy would be wrong. In fact, many clinicians use similar techniques every day when interacting with patients, actively engaging the placebo effect.
Does this mean that the effects of psychedelics can be largely or entirely based on the placebo effect?
The question here is: what do we mean by placebo? The word usually has a negative connotation, doesn't it? If a person has a reaction to a placebo, it may indicate that everything was fine. But that's not what our study is about.
Think about everyday life events. A heart attack or near-death experience can push a person to change their lifestyle habits — to exercise and eat right. All of this can be characterized as the «placebo effect».
Another way is to have a transformational experience that then leads to life changes. The question is how to achieve this in practice. You can't just give someone a heart attack or send them on an extreme vacation, but you can offer a psychedelic experience. It's a powerful, unique experience that can be a landmark and promote positive change.
How does the use of psychedelics in clinical trials relate to the three previously mentioned categories?
Let's return to the concept that psychedelic transformation depends on biochemical effects, dreams during a trip, or non-medicinal factors. Our study of ketamine under anesthesia emphasizes the role of non-medicamental aspects such as expectations, but does not address the question «Is it the drug or the trip?».
To clarify this, some scientists are investigating «non-psychedelics» — derivatives of psychedelics without hallucinogenic properties, to see if depressed patients can get relief after taking such drugs. This is the «drug tripping cure».
But what if we could «cure the drug from the trip» by creating an experience that can be replicated and that fulfills many of the characteristics of a classic psychedelic-induced trip, but does not require the use of psychedelics? In this case, we are providing people with a deep and standardized experience that can be studied and from which we can expect powerful, vivid and revelatory experiences with lasting effects. Would we get the same results without psychedelics?
This will not be definitive proof, but it will provide compelling evidence that there may not be anything special about the activation of certain receptors responsible for the effects of psychedelics. It will highlight the importance of human experience in psychological transformation.
Thus, is it possible to achieve the desired results without a psychedelic drug by using non-psychoactive substances?
But what if we could «cure the drug from the trip» by creating an experience that can be replicated and that fulfills many of the characteristics of a classic psychedelic-induced trip, but does not require the use of psychedelics? In this case, we are providing people with a deep and standardized experience that can be studied and from which we can expect powerful, vivid and revelatory experiences with lasting effects. Would we get the same results without psychedelics?
This will not be definitive proof, but it will provide compelling evidence that there may not be anything special about the activation of certain receptors responsible for the effects of psychedelics. It will highlight the importance of human experience in psychological transformation.
Thus, is it possible to achieve the desired results without a psychedelic drug by using non-psychoactive substances?
It may be real — but we don't know right now. It's a question that requires experimentation. I worked with Harrison Shung-Wen Chou, an anesthesiologist at Stanford, on a protocol we called «dreaming during anesthesia». This state of consciousness occurs before coming out of anesthesia. Patients, when they wake up after surgery, move from a greater depth of sleep and go through different states of consciousness, some of which are interpreted as dreams. Approximately 20% of patients have memories of dreams.
We lengthen this process and use EEG to focus on biomarkers of this state. We can keep the patient in this pre-awakening state for up to 15 minutes. When participants awaken, they share vivid, significant stories. Their dreams are very realistic.
Patients with physical injuries report re-integrating their bodies, making sense of their bodies as a whole. One participant, assigned male at birth and having undergone gender confirmation surgery, talked about reimagining her life after gender confirmation, imagining herself in intense military exercises with a body that matched her gender.
These experiences are vivid, emotional, and sometimes hallucinatory. We have already published several cases where we have observed therapeutic effects comparable to those found in psychedelic medicine: intense experiences followed by an improvement in the symptoms of a mental disorder.
The observed physiology as a result of EEG in these sleep states can be compared with EEG during the action of psychedelics. We see some similarities in the phenomenology of the described processes and similar therapeutic effects.
What's planned next?
In addition to the possibility of creating a convincing therapeutic agent based on the widely used anesthetic propofol, we are actively pursuing the development of experimental tools based on our knowledge of the mechanisms of placebo action in the brain.
Our goal is to separate three key elements: drug effect, experiential effect, and non-medication factors. At least two of these significant effects, which are independent of psychedelic use, are capable of producing profound therapeutic effects sufficient to explain the results observed in psychedelic studies.
This emphasizes that perhaps the emphasis is not where it should be when we focus on rethinking the drug in order to eliminate hallucinogenic effects. We need to focus on changing the experience itself.
However, we are still working on the third aspect, the drug effect. We are collaborating with David E. Olson, a chemist at the University of California, Davis, who pioneered the use of non-hallucinogenic psychedelics. We are helping to investigate the profound neuroplastic changes induced by a drug he developed that, at least in mice, does not activate brain processes the way classical psychedelics do.
We aim to show that by applying these methods we can make progress in experimentally defining, isolating, and identifying the components of this complex therapeutic approach that we call psychedelic therapy.
We aim to show that by applying these methods we can make progress in experimentally defining, isolating, and identifying the components of this complex therapeutic approach that we call psychedelic therapy.