Predictive Coding, AI: Modeling Placebos in RCTs for Psychedelics and Antidepressants

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The observation that the brain makes [something described as] predictions is a gateway to exploring how placebos work. It also includes what follows after, to have therapeutic effects—in the conditions they do.

Placebos involve the expectation to feel better and the experience of it. Placebos are used in studies. They, however, have presented a different challenge in testing the efficacies of psychedelics and antidepressants.

There is a feature in The Atlantic, Psychedelics Are Challenging the Scientific Gold Standard, stating that "In clinical trials, participants (and the researchers studying them) generally aren’t supposed to know whether they’re getting the actual drug or a placebo, to avoid allowing people’s expectations about a treatment to shape their response to it. Blinding, as this practice is called, is a key component of a randomized controlled clinical trial, or RCT—medicine’s gold standard for demonstrating that a drug actually works. But virtually no one can take a psychedelic drug and not know it. Such failure, if it exists, might extend beyond psychedelics to several kinds of psychoactive drugs. For instance, a 2022 analysis found that many antidepressant trials fail to effectively blind participants, in part because of side effects."

This contributed, in part, to a recent report by Reuters, US FDA panel votes against first MDMA-based PTSD treatment, stating that "Advisers to the U.S. Food and Drug Administration on Tuesday voted against a therapy based on the mind-altering drug MDMA for patients with post-traumatic stress disorder, marking a setback to the nascent field of psychedelic treatments. The panel voted 10-to-1 against the first MDMA-based PTSD treatment, saying the benefits did not outweigh its risks, while nine members said the available data did not show its effectiveness in PTSD patients."

There might be a few conceptual approaches around this, starting with some questions. How does the human mind do what is described as prediction or anticipation? How do relays occur in the mind—afterwards—to result in relief? How can this be explained to participants and researchers in a way that neutralizes the expected side effects of psychoactive drugs against dampening the placebo effect or group identification?

Brain science has established that electrical signals leap from node to node in myelinated axons, going faster in what is called saltatory conduction. This is different from continuous conduction in unmyelinated axons, where they travel directly along the length of the axon without leaping.

It is postulated that in a set of electrical signals [in clusters of neurons], some electrical signals split or go ahead of others to interact with chemical signals before others follow. This means that whatever initial perception an individual has, either of sight, smell, touch, taste, or sound, could be a result of this split. If the input matches with the split, then relays continue—with the incoming signals going in the same direction. However, if the input is different, the incoming electrical signals go in the right direction. This explains what is described as predictive coding, processing, and prediction error.

Simply, when two letters in a word are first seen, there could be a perception of what the word is, which may be confirmed if the rest of the letters are seen. In this case, the first and second sets of the electrical signals would go in the same direction. If the rest of the word is seen and it is different from what was perceived, then the incoming electrical signals would go in another direction.

This is a mechanistic way to explain how the brain appears to predict using electrical signals. It is proposed that electrical signals are always splitting, making it feel like predictions are common in the mind.

Splits are postulated to be a division of distributions—a feature in the human mind. Distributions are defined as the way some sets of signals get the outputs of other sets of signals. Distribution happens in attention [a feature] and in awareness [another feature, but less than attention]. For example, a word may result in the memory of an event, the sight of something may result in an emotion of fear, or the sound of something may result in an appetitive feeling. Also, experiences with side effects—or not, can also be described as distributions since electrical and chemical signals are involved in modulations of internal senses.

Some other features of mind, including intentionality, may be responsible for distributions as well. When intent does not [a non-intent feature], arrays do. However, destinations of distributions are not always constant—they may vary, sometimes widely.

There is a new paper in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Dynamic Functional Hyperconnectivity After Psilocybin Intake Is Primarily Associated With Oceanic Boundlessness, where the authors "investigated the relationship between neurobiological and experiential patterns after psilocybin by focusing on the link between dynamic cerebral connectivity and retrospective questionnaire assessment."

How does the human mind work for distributions that correlate with hyperconnectivity? How do psychedelics have an effect? What is the relationship between predictions in placebos and how psychedelics work? How can hallucinations in psychedelics be explained in comparison to those in large language models? Can AI shape future clinical trials for psychedelics?

Exploring the postulate of the human mind in the action potentials neurotransmitters theory of consciousness​, ​with examples and detailed animations, could work in explaining to participants and researchers that while there are expectations of side effects, features of the human mind ultimately decide experiences. So, it may not proportionately apply that the absence of side effects indicates that the participant is under placebo, open-label, or otherwise.