Does psychedelic therapy have a transdiagnostic action and prophylactic potential?

This hypothesis paper (2021) proposes that the transdiagnostic (psychedelics being effective for many mental health disorders) quality of psychedelics lies in its ability to increase neuronal and mental plasticity. The combination with therapy can aid adaptation and resilience to lead to long-term well-being.


Addressing global mental health is a major twenty-first century challenge. Current treatments have recognised limitations; in this context, new ones that are prophylactic and effective across diagnostic boundaries would represent a major advance. The view that there exists a core of transdiagnostic overlap between psychiatric disorders has re-emerged in recent years, and evidence that psychedelic therapy holds promise for a range of psychiatric disorders supports the position that it may be transdiagnostically effective. Here we propose that psychedelic therapy’s core, transdiagnostically relevant action, lies in its ability to increase neuronal and mental plasticity, thus enhancing the potential for change, which we consider to be a key to its therapeutic benefits. Moreover, we suggest that enhanced plasticity via psychedelics, combined with a psychotherapeutic approach, can aid healthy adaptability and resilience, protective factors for long-term well-being. We present candidate neurological , and psychological markers of this plasticity and link them with a predictive processing model of the action of psychedelics. We propose that a model of psychedelic induced plasticity combined with an adequate therapeutic context has prophylactic and transdiagnostic potential, implying that it could have a broad, positive impact on public health.

Authors: Rita Kočárová, Jiri Horacek & Robin L. Carhart-Harris


Addressing global mental health is a major 21st-century challenge. We propose that psychedelic therapy’s core, transdiagnostically relevant action lies in its ability to increase neuronal and mental plasticity, thus enhancing the potential for change, and aiding healthy adaptability and resilience.


To provide the background for our central thesis, we discuss current mental healthcare challenges before introducing a potential solution: psychedelic therapy. We argue that psychedelic therapy has the potential to meet these two criteria, as it promotes brain and mind “plasticity”.

This paper aims to integrate the property of enhanced brain and mind plasticity via psychedelics with a predictive processing framework, and to explain how the model implies the prophylactic potential of psychedelic therapy.

We argue that reinforced “problematic” habits of brain and mind are universally relevant maladaptive processes, and that increased mental and neuronal plasticity can promote psychological well-being.

Mental health disorders are among the leading causes of disability worldwide, and are costing the global healthcare system enormous amounts of money. There are no truly novel and effective new psychiatric drugs, and 20% of patients are resistant to any of the presently licensed treatment options.

The World Health Organization recognizes the potential value of proactive or preventative strategies for tackling the global burden of mental illness. These strategies include promoting wellness and the capacity to address and cope adaptively with adversities.

There is substantial evidence for an association between acute and chronic adversity and the development of many psychiatric disorders, and that there are individual differences in vulnerability to mental illness after adverse experiences, which may depend on polygenic, neurobiological, environmental, psychological, and social factors.

Two main strategies have been identified for the prevention of mental health disorders: the identification and mitigation of risk factors and the strengthening of protective factors. Psychedelic therapy can serve the latter factor.

Borrowing from genetic science, we argue that a broad range of psychopathology can be conceived of as a maladaptive canalization of thought and behavior. Psychedelic therapy combines a plasticity-enhancing drug action with nurturing conditions to foster a reset or recalibration of “maladaptive” habits of mind or behavior.

There is a growing view that markers of mental health and treatment targets may be transdiagnostically relevant, and that this approach could have a far-reaching impact on treatment decisions and interdisciplinary bridging between different treatment models, orientations, and settings.

Psychoanalytic psychology has long recognized the existence of transdiagnostic overlap, and a greater alliance with psychedelic therapy may be fruitful.


Psychedelic substances such as psilocybin, DMT, and LSD have shown promise in the treatment of several mental health disorders, and there is naturalistic and historical evidence supporting their use for functional neurological disorders, eating disorders, psychosomatic disorders, post-traumatic stress disorder, and personality disorders.

Psychedelic therapy can improve mental health in broader populations. Psychedelic use is associated with a lower rate of inpatient psychiatric treatment, prescription of psychotropic medication, and serious psychological distress, as well as suicidal thinking, planning, and attempts.

Peyote and ayahuasca “users” had better mental health profiles than matched controls, and psychedelic use was associated with prosocial attitudes and behavior, increased nature-relatedness, and the personality traits “self-transcendence” and “openness to experience”.

The above-listed findings support the central hypothesis of this paper that psychedelic therapy can have transdiagnostically relevant, mental health-promoting effects. However, there is a dearth of evidence to support the potential of psychedelic therapy to treat psychiatric disorders with a clear organic etiology.


There is growing evidence that psychedelic therapy promotes a variety of psychological traits, including psychological flexibility, cognitive flexibility, mindfulness, and resilience to adversity. This increase may be related to the quality of the acute subjective psychedelic experience.

We hypothesize that the pharmacological action of psychedelics depends in large part on the triggering of plasticity, which is a psychological counterpart to brain plasticity. Mental plasticity is a simple and useful term that is in-keeping with dictionary definitions.

Psychological Flexibility

Psychological flexibility is the ability to feel and think with openness, to attend voluntarily to one’s experience of the present moment, and to move one’s life in directions that are important to him/her. The inverse of psychological flexibility, i.e., psychological inflexibility, is a pathological phenomenon associated with psychological distress.

Psychological flexibility refers to an individual’s capacity for staying in contact with experiences eliciting negative emotions, and a commitment to living congruently with his/her own values. It has been proposed that psychological flexibility is a common component underlying several effective psychotherapeutic interventions.

The acceptance component of the Hexaflex process was identified as a key mediating factor in psilocybin therapy for treatment-resistant depression, as well as in ayahuasca therapy for addictions and end-of-life distress.

Psychological flexibility was found to be a transdiagnostically relevant therapeutic phenomenon, and was associated with increased therapeutic change after psychedelic experiences. It was also found to integrate well with a developing approach to psychedelic psychotherapy.

Cognitive Flexibility

Cognitive flexibility is a construct separate from psychological flexibility, and is more closely linked to perseveration (its inverse). It is deficient in patients with eating disorders, general anxiety disorder, depression, autism, addiction, and obsessive-compulsive disorder, but may be enhanced by mindfulness-based treatments.

Increased cognitive flexibility has been observed 24 h after ayahuasca experience (82) and during the acute phase of LSD experience (143), with mixed findings on reversal learning (a construct closely associated with cognitive flexibility) in humans.

LSD and other psychedelic drugs have been found to enhance reversal learning in rodents, and antagonism of the 5-HT2AR promotes perseveration, reflective of cognitive inflexibility, in rats and rabbits. In humans, individuals with anorexia exhibit lower 5-HT2AR expression and lower cognitive flexibility than healthy controls.

Future work is needed to determine whether cognitive flexibility is dose and context dependent. High doses might impair cognitive flexibility, while low doses could conceivably enhance it.

The creative process is characterized by divergent thinking and cognitive persistence. Psychedelics may promote aspects of the creative process, but the relationship between psychedelics and creativity is difficult to define.

Openness to experience is a personality trait that has been shown to be positively correlated with divergent thinking and creativity, cognitive flexibility, and psychological flexibility. It has been observed that openness increases during clinical trials with LSD, psilocybin therapy, and MDMA-assisted therapy for PTSD.


Mindfulness is the process of regulating attention with the aim of bringing its focus onto one’s current experience, observing lived experience with curiosity, openness and acceptance, and also processing gained insights.

Mindfulness has been widely studied and applied in diverse areas, and has been shown to be useful in the treatment of mental illness and the promotion of psychological well-being.

Ayahuasca, LSD, and 5-MeO-DMT have been shown to increase mindfulness capacities. Mindfulness capacities are measured by the Five-Facet Mindfulness Questionnaire (FFMQ) and are related to non-judgmental and nonreactive processing and observing as well as acting with awareness.

The Acute Psychedelic Experience

Evidence suggests that the quality of an individual’s acute experience under a psychedelic reliably predicts and mediates longer-term psychological outcomes. Certain traits, such as absorption and contextual framing, can shape the intensity and nature of this experience.

A progressive step toward framework agnosticism might be to focus on the mechanisms underlying unitive experiences, such as non-dual awareness and ego-dissolution.

Psychedelics induce unitive states of consciousness, marked by “ego-dissolution” and a sense of oneness or interconnectedness, which are consistent with a flattened energy or attractor landscape and a system that is both globally interconnected and desegregated.


Neuroplasticity is the ability of the nervous system to reorganize its structure, function, and connections in response to a changing environment or a shifting set of demands. Some psychiatric treatments, such as antidepressant drugs, ketamine, and psychedelics, may promote neuroplasticity.

Based on their ability to promote cortical neuroplasticity, psychedelics have been dubbed “psychoplastogens”. Ketamine’s psychotomimetic effects are thought to be mediated by its rapid induction of neuroplastic effects.

Recent studies have found increased neuroplasticity post-psychedelics, including increased synaptogenesis, BDNF doubling, and increased gene expression in the cortex and hippocampus. Ayahuasca has been shown to promote neurogenesis, and psilocybin has been shown to accelerate association learning rates.

Neuroplasticity may be outcome-agnostic, in the sense that it could just as easily mediate pathogenesis as salutogenesis or wellness – consistent with the so-called “plastic paradox”.

Entropic Brain

The network level changes described above may relate to the dysregulation of ongoing brain activity and an increase in entropy or complexity of spontaneous population level neural activity. This may be why psychedelics have an “after-glow” effect.

Psychedelics may activate key neuronal adaptability mechanisms by directly activating the 5-HT2AR. This is just one level of a multilevel, generic brain and mind plasticity.


We reviewed relevant phenomena and observations of mind and brain plasticity linked to psychedelic use and therapy, and propose a multilevel “process-of-change” model that takes inspiration from the Bayesian brain or predictive-coding mechanisms.

We speculate that psychedelics may increase neuroplasticity by increasing 5-HT2ARs, which are densely expressed in the cortex. This may lead to an accelerated learning rate, which could help with the relaxation and revision of canalized thoughts and behaviors linked to psychiatric disorders.

Setting some context for these ideas, destabilization or dysregulation is not entirely anomalous in medicine or cognitive and computer science, and can sometimes be welcomed as an opportunity for therapeutic growth or learning.

Psychedelic therapy is proposed to relax over-weighted mental and neuronal habits, which are canalized thought and behavior in mental illness. This process is called cognitive de-fusion, and is achieved through an acute brain and mind plasticity aiding a healthy learning process.

Psychedelic experiences are often associated with personal or transpersonal insights, and are recognized components of effective psychotherapy more generally. The occurrence of insight strongly predicts positive long-term clinical outcomes.

Cognitive fusion, canalization, and the over-weighting of priors may occur as an adaptive response to psychological distress linked to actual or perceived adversity. Greater scores of psychological flexibility are associated with lower scores of post-traumatic stress and higher scores of post-traumatic growth.

The densest expression of 5-HT2AR is found in regions of the brain that process longer temporal sequences of information and more abstract semantic material, and that are most spatially removed regions from unimodal cortex. These regions also show the greatest expansion throughout ontogenetic development.


This paper has reviewed literature supporting the claim that psychedelic therapy may have prophylactic or preventative potential in mental healthcare, and a related transdiagnostic therapeutic action, focused on increased brain and mind plasticity. We have proposed a process of change model to explain how psychedelic therapy possesses these valuable properties.

The present paper has not sought to critically appraise the central hypothesis that psychedelic therapy can aid prophylaxis or possess a transdiagnostic action, and has cherry-picked findings supportive of its central narrative.

One relevant recent debate concerns whether acute subjective effects are necessary for longer-term therapeutic outcomes, and whether positive expectancy drives therapeutic outcomes. It seems reasonable to consider positive expectancy as a harnessable component of the model itself. There are a number of cautionary factors to consider if psychedelic therapy is to be legitimately explored as a preventative measure, including the risk of iatrogenesis and hallucinogen-persisting perceptual disorder.

Psychedelics may facilitate adaptive processes, but they may also augment maladaptive processes, e.g., retriggering trauma and/or associated defense mechanisms. Psychological preparation, support, and integration are likely to be essential components of any future therapeutic and prophylactic application of psychedelics.

The maladaptive canalization and associated “too strong priors” model fits well with a broad range of psychiatric disorders, but not all. However, those with weak high-level priors may be more amenable to effective treatment via psychedelic therapy.

Psychedelics flatten the mind’s energy landscape, which may reflect a therapeutic window for the subsequent longer-term de-weighting/flattening of relevant pathological attractors, but the acute state itself may mirror certain states that could be construed as pathological.

Although many studies have been done to support the central hypothesis of this paper, some have been observational in nature, some have small sample sizes, and some may have failed to maintain the study blind.

The present paper does not cite direct evidence for the hypothesized prophylaxis via psychedelic use or therapy, but the best evidence comes from prospective observational studies and population studies.

We have not properly discussed optimal delivery of psychedelic therapy, nor have we addressed the question of how best to maximize its hypothesized prophylactic potential.

Recent proposals that psychedelics could be effectively twinned with third wave psychotherapies are also consistent with the proposal that psychedelic therapy can promote psychological flexibility. More research is needed on transdiagnostic targets and processes of change.

Psychedelic therapy is a promising new therapeutic strategy for treating, enhancing, and maintaining mental health that transcends diagnostic boundaries. It is based on a synthesis of theories and observations from psychology and neuroscience, and emphasizes the importance of regulated use and therapeutic support.

We hope that a careful roll-out of psychedelic medicine, closely aligned with psychedelic science, will advance our understanding of mental illness and help bridge the pharmacology vs. psychology divide in mental healthcare and research.


RK and RC-H contributed to the conception and writing of the manuscript.


This study was supported by Charles University, the Technological Agency of the Czech Republic, REDOX s.r.o., the Alex Mosley Charitable Trust, the Centre for Psychedelic Research, and the MEYS under the NPU I program.


Authors associated with this publication with profiles on Blossom

Robin Carhart-Harris
Dr. Robin Carhart-Harris is the Founding Director of the Neuroscape Psychedelics Division at UCSF. Previously he led the Psychedelic group at Imperial College London.