The phenomenon known as the placebo effect may be more complex than it first seems. Many often view placebo as a kind of mind-over-matter sort of effect, that you can become intoxicated without any drugs. While it is true that sober intoxication-like states certainly exist and may arise from the expectation of such effects, there may be more nuance than is at first apparent when it comes to placebo effects. This article will explore placebo in its’ possible complexities, the way that the effects of drugs may be secondary to their biological effects, and also how psychedelics relate to the placebo effect.
How much of a psychoactive drug’s effects are actually placebo?
In research that uses placebos, there is often times what is known as an ‘active’ placebo given to subjects in which a psychoactive drug that differs significantly from the main drug being studied is given in order to induce the illusion that they received the primary drug being studied. One might expect that an active placebo will have more pronounced effects than a non-active placebo. Considering this, a drug that induces the actual effects that one is expecting to occur could also theoretically produce an even more pronounced placebo effect than even the active placebo. Although this is not often explored when talking about placebos, this is inherently true in the concept of placebo. We use placebos to discern if the effect brought on by a drug is actually due to the biological effects of the drug or due to a secondary more psychological effect in response to taking the drug. Meaning, even an active drug may produce results that are placebo and the use of placebos in research is for the very purpose of detecting that.
One might wonder, how much stronger does a drug become if it produces results that further elicit placebo effects?
This is especially relevant for the case of depression. For many users of antidepressants, it is reported that the patient’s treatment loses its’ efficacy after some period of time, usually a few months or a few years. This may lead the depressed person to seek out new treatments that they have not yet tested. In antidepressant trials, a drug may show benefits simply by giving a user hope that an untested drug might provide the solution that they are looking for. This change of mindset from feeling hopeless to a newfound feeling of hope may have lasting consequences due to the way it changes behavior in daily life, assuming the individual suffers from learned helplessness that normally prevents them from even attempting to solve the issues that have left them depressed. Active drugs may even further provide hope because there is at least subjective evidence of mental change. Once the effects of the drug become imperceptible there could even be a nocebo effect in which the user assumes that their depression must come back as well.
There is also the possibility of a permanent loss in efficacy from an antidepressant once the effect appears to be diminished, but it is uncertain whether this represents purely biological changes to the user. Consider the case of heroin. Users of heroin may often be driven to use the drug during a episodes of hopelessness, seeking out a considerably drastic solution in their desperation. An individual who uses heroin may alleviate some of their hopelessness or learned helplessness, allowing them to tackle problems in which they already felt defeated by. The effects of heroin on a new user may give a profound sense of hopefulness, that they may finally be able to resolve their social issues, or tolerate their abusive spouse in order to maintain a stable mood in their workplace, or even to perform fearlessly in job interviews, and so on. As time goes on, the user gets a chance to test their abilities to tackle life problems on the drug. If the user’s problems are not resolved, they should naturally develop a diminished sense of hope through trial and error, through hypothesis testing. Repeated errors and failures would theoretically be how the individual reached the state of hopelessness in the first place, thus is the nature of learned helplessness. Expending energy and time engaging in error-producing trials is eventually deemed as too costly and not worth the person’s trouble. So when the user’s life doesn’t fully improve, learned helplessness can sink back in, with another layer of drug intoxication on top. The shame and regret of using the drug along with the withdrawals may then produce opposing effects, drastically reducing one’s coping abilities.
It seems that when users chase the initial strong effects of heroin or any other euphoriant drug they may actually be seeking to attain that elusive hopeful mindset once again. Unfortunately, that hopefulness may not purely be the biological effects of the drug but rather the implications of the drug intoxication and a state of curiosity and anticipation that the individual’s problems may be finally solvable. The experienced heroin user will already have seen the results of using the drug in their life. This user has already learned whether or not the drug will solve their problems. The reason the initial effects of heroin are so hard to restore might be due to the fact that the novelty of the effects and the imagined influence they could have in various problematic life situations may have faded with experience and hypothesis testing. Experienced users have already formed conclusions about how the drug impacts their social life, work life, home life, and there is no longer a magical sense of hope.
We’ve explored how some amount of a drug’s effect may in fact be placebo effects stacked upon biologically-induced psychoactive effects, but there may be more ways that a drug produces stacks of effects that are unrelated to the primary biological psychoactivity of the drug.
Some amount of effect of a drug may also be due to associative learning, rather than purely the biological effects of the drug itself. Pavlov’s dogs represent this quite well. The dogs were presented food along with the sound of a bell and they would salivate in response to the food. Eventually the dogs associated the food with the bell and began to salivate whenever they heard the sound of the bell, even when food was not present. Drugs can act as the bell or even the food. You could imagine that a drug that induces salivating could replace the food in Pavlov’s experiments and still associate this salivation to the sound of the bell. Mood states and intoxication effects of a drug may be hugely influenced by the prior experiences that associate to the drug as well as the subjective state of mind the drug induces. In a reddit post, a user noticed that being around an individual smoking cannabis triggered negative states of mind that they used to get while intoxicated on recreational drugs. It could be that the smell of the cannabis triggered associative memories of when the user was last high and induced conditioned psychoactive responses. Not only might these sensory cues induce states of mind based on prior intoxications, but the negative experiences during intoxication may not necessarily even be caused by the drug intoxication itself. The intoxicated state may have been associated to trauma in which re-exposure to the state of mind also leads one right back into the same anxious and traumatic states of mind. With this in mind, we might begin to wonder which effects are really caused by the biological effects of drugs and which effects are related to our own subjective reaction to the psychoactive effects of drugs.
In my own experience with cannabis, I’ve found that experiencing traumatic anxiety while on the drug inside of a grocery store caused lasting stains on my experience of grocery shopping at that exact store. Every time I entered the same store after these events I experienced a mental shift that seemed cannabis-like, at least that is what I initially thought. Now it seems that this is not necessarily the effect of cannabis by itself, but it is the way that cannabis enhanced the traumatic anxiety which left long-lasting imprints on my mind that associate with both the grocery store and the ingestion of cannabis. In each of those contexts, both cannabis consumption and shopping at that store, I would experience a similar shift in mindset, hypervigilance, anxiety, and dissociation. If this is true, then after cannabis has associated to traumatic anxiety, you could paint your environment with associations to this trauma each time you dose the drug in various environments. This may even tie into the reports of permanent changes to the effects of cannabis after consuming psychedelic drugs (in this article, this refers to serotonergic psychedelics only). I suspect it is possible that the effects of cannabis are highly programmable, but it doesn’t seem that psychedelics are programmable, but instead may loosen our mental programs and allow reprogramming.
Unpredictable drugs such as psychedelics and cannabis may produce many of their effects indirectly by disinhibiting what normally locks mental state changes, rather than inducing mental state changes directly like a drug such as heroin might. As an example, psychedelics may mostly produce effects by altering attention processes. Rather than directly altering emotion or mood, both of these may be deeply impacted by the changes in attention. It could be that one immerses so fully into experiences that are usually neglected or even forgotten that they did not realize what it was like to immerse into these experiences. These drugs appear to induce a kind of mindfulness, something along the lines of a direct flow state with all of subjective reality itself, which opens a vast array of almost mystical states that we are normally too distracted by our habitual ways of thinking to experience. In the case of experiencing an emotional event, one may find a complete inability to distract themselves or hide away from those emotions and thus feel trapped, almost eternally, in the immersive high definition experience of those emotions. This may explain the efficacy that psychedelics have in treating PTSD, perhaps by inducing mindfulness, and thus resulting in a kind of exposure therapy.
Mindfulness can greatly enhance one’s propensity to have insights about the experiences they have, but we must also always consider that subjective experience is not necessarily the best medium for scientific discovery, which is why anecdotes are not considered to be the best scientific resource. This rule about subjective experience reports might be far too deontological though. It seems that subjective experience reports would be the most superior scientific tool when attempting to understand the nature of subjective experience itself. This is likely to be one of the only exceptions to the rule. Mindfulness becomes an incredible tool for understanding various aspects of our own psychology. In this way, psychedelics could greatly enhance one’s ability to make discoveries about their subjective experience, consciousness, qualia, and maybe even more broadly applicable psychology but not be so great for making discoveries about physics, biology, or external reality. That’s not to say we should assume that these drugs have no value in understanding external reality, but that is a direction we won’t explore in this article. Being mindful about the external world can also produce insights by allowing us to look deeply into what we often overlook, dismiss, or ignore outright. If you’d like to see how psychedelics could manifest insights about external reality, check out Thought Scripts.
On the psychedelic drug one can find themselves immersing into the moment to one’s full capacity, into every facet of every experience in all of its’ complexity, feeling a state of awe and wonder over experiences that were once labeled boring and were previously being serially dismissed in daily life. We observe that there is some amount of disinterest to the familiar world whereas the novel world provides this sensation of mystery, and a lack of predictability. This lack of predictability and sudden openness to experience that occurs on psychedelics means that awareness of the present moment in detail is necessary as one needs the information in order to form predictions for the next time around. Once predictions are formed, there is less need to be aware of details. This is the nature of learning, to bring us insights that help us navigate life with ease and to reduce unnecessary awareness so we can relocate energy expenditure on more complex problems.
This increased awareness and mindfulness induced by psychedelics often brings users novel insights that are overlooked in sober life. Many of us live in a state of vast over-generalizations, a perspective of life that is lacking in nuance. This is the illusion that we know too much, that we’ve run out of interesting experiences to have. This leads a person to have lower openness to experience. Most often this predictability of experiences arises from over-fitting. As an example, to say life exists, may be true and grand but actually says very little about the true nature of reality. Broad hyper-generalized statements such as this can be true but very nonspecific and borderline meaningless. The psychedelic high may enhance the awareness and thus learning of more elaborate nuance and complexity in one’s experience of familiar life, ultimately enhancing mindfulness.
Might some placebo effects be an induced state of mindfulness that results from the expectation of a novel drug experience?
The expectation of some mysterious new intoxication by an experimental drug may lead one to becoming more attentive of their subjective experience and qualia, noticing different sensations that they were previously dismissing before the placebo was introduced. The expected effects one has will narrow the mindfulness towards observing changes that confirm their predictions. If one expects an increased heart rate or fears panic reactions from the placebo drug, this may occur via self-induced effects that result from suddenly mindfully observing of one’s own body. Imagine that you observe your heart pumping, something that you usually ignore. The noticing of one’s heart may begin to confirm the fears one has about entering a panic episode. The mere thought that one will face a panic reaction could in fact lead up to an actual episode of panic. Panic attacks themselves are frightening and because fear is the basis for panic reactions, one’s fear of impending panic can bring it on.
This ties into the fear of the unknown. The unknown presents us with the possibility of unpredictable good or bad experiences. Not knowing whether one may experience an extreme reaction to the drug is truly terrifying. On the other hand, the possibility that all of your problems may be solved by a magic drug can be incredibly enticing and lead one into a state of thrill and hopefulness. There are many experiential doors that are opened when we relinquish the sense of knowingness that typically guides our subjective experience. If we can refrain from paying attention to our expectations and simply observe the present moment we could find ourselves in a very different place than if we focus on imagined outcomes of our present experience. Meditation in the attempt of immersing totally in the present moment could help us see the world in new ways, much like psychedelics show us.
As mentioned, psychedelics may induce a disruption of the cognitive processes underlying our prior assumptions, forcing us to process reality as if we do not already have predictions about what will happen next. Our predictions may be limiting the breadth of possible experiences we can have in sober life and psychedelics may open up more possible subjective experiences by removing our fixed narratives that guide us through the passing of time. We might be stuck continuously wondering what will happen next and how this will impact our state of mind. Novel experiences in general may induce both placebo-like and psychedelic-like effects, by inducing mindfulness.
At this point you may be wondering what the placebo effect even is. Every experience is tainted by placebo-like expectations. Those who are trapped in states of depression are experiencing expectations of continued suffering or anhedonia. Those who have been traumatized are experiencing fears of intense suffering that may come when one returns to situations associated to those past traumatic experiences. Our lives are built upon placebo scripts that have immense power in how our daily lives play out. Placebo effects could be synonymous with the effects of priors, they could be thought scripts designed by our expectations of each passing moment, guiding our behavior as to fit into the most predictable experience of life, reinforced through confirmation bias. The placebo effect is to know the unfamiliar experience and thus create the impending experience so that it fits our expectations. Perhaps we may one day free ourselves from the limited scripts that dictate our lives. Perhaps we could maximize our ability to achieve sober psychoactivity when we wish it so. Practicing mindfulness meditation may be the key to attaining this kind of power.
There may be a at least three major distinct kinds of placebo-like effects.
- Placebo that models novel and untried drugs, which may induce mindfulness and an awareness that is geared towards figuring out what is going to happen on the drug.
- Placebo that models familiar and tried drugs, which may induce associative effects and mental stains left from prior intoxications that are fueled by one’s expectations of such effects. This kind of placebo is Pavlovian conditioning.
- Placebo that is the imagined predictions of a drug’s effects, in which mindfulness combined with selective attention and confirmation bias may produce the expected effects. This may be similar to meditating in order to achieve pain relief or various other psychoactive effects.
Note: All of these can occur in tandem.
There are also likely many forms of placebo that I am simply unaware of.
Moving back to the antidepressant trials, many users may have tried enough drugs and reached the learned helplessness state again and again to the point that their mind has learned to generalize new treatments as being unlikely to help in relieving their depression. A sort of meta-learned-helplessness in which even trying novel solutions does not bring hope that the individual’s situation will improve. This state in which prior experiences of new treatments are generalized to hopelessness could be what we call treatment resistant depression. There may be an element of nocebo that diminishes the positive effects of new drugs, reinforcing hopelessness instead of bringing back hopefulness. Fascinatingly, psilocybin mushrooms may both reduce priors and show strong efficacy for the treatment of these resistant types of depression. It could be that the erasure of priors allows one to restore hope and diminish this sense of generalizing new treatments. This may be especially effective when the formation of one’s depression has been built upon repeating confirmation and validation of their life’s tendency towards tragedy and suffering, which may be somewhat fueled by the mindset itself, a self-fulfilling prophecy. As an example, one may become unmotivated in a class due to an expectation of failure and then actually fail the class due to their low motivation. There would likely be a variety of patterns like this that begin to dominate the identity of the person and their life may be truly upsetting, but this could also be repairable especially if one can start fresh and with restored openness to experience.
In the case of trauma, part of the issue is that it is such a painful experience that avoidance of the trauma-associated stimuli occurs, a complete shutdown of one’s willingness to mindfully immerse into any of the stimuli associated to the pain. This unwillingness to explore the stimuli means that there can be no new development of nuance, no clarification or observation as to which aspects of one’s qualia was causing the pain more specifically. In the experience of trauma, one can learn to over-generalize the stimuli that one fears. In it’s most extreme form, one could conclude that since a human has hurt them, all humans are dangerous and must be avoided. In a more specific form, one may conclude that all males are dangerous, or even more specifically that tall males with short hair are dangerous, and so on. The psychedelics may help through the induction of mindfulness where one can develop an increasingly elaborate and clarified judgment of reality.
Our predictions of the near-future may lead us to experiencing reality through a compressed state of mind. Things can be experienced as consistent, dry, and empty. It is that we are simply not looking at reality and that we are not allowing our minds to shift naturally in response to unnoticed information. Our responses to the familiar world have been decided and so we create filters to eliminate unnecessary information processing. This is what we know as the subconsciousness. What is initially a conscious experience may eventually become sorted out, filed away, and eventually forgotten. Even some of the strange sensory experiences or perceived extrasensory phenomenon that users report on psychedelics may be the rebirth of entire sensory processing methods that were deemed unnecessary and far too costly in adult-life. These earlier child-like modes of processing sensory and cognitive information may eventually reduce and simplify into our adult mode of reality processing. This seems to be the case for eidetic memory, in which children use very much but adults do not. Psychedelics drive one to explore their reality instead of merely assuming it. For the depressed it could mean seeing without their predictions of endless boredom or suffering. For the traumatized it can mean entering an experience without anticipating pain.
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