Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential ?, Rita Kocárová, Jirí Horácek and Robin Carhart-Harris, 2021

Does Psychedelic Therapy Have a Transdiagnostic Action and Prophylactic Potential ?

Rita Kocárová, Jirí Horácek and Robin Carhart-Harris

Frontiers in Psychiatry, July 2021, Volume 12, Article 661233, 1-18.

doi : 10.3389/fpsyt.2021.661233


Addressing global mental health is a major 21st-century challenge. Current treatments have recognized 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, which are 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.

Keywords : psychedelics, hallucinogens, psilocybin, psychological flexibility, plasticity, prevention, transdiagnostic, well-being



To provide the background for our central thesis—that psychedelic therapy possesses a transdiagnostic and prophylactic potential—we first discuss current mental healthcare challenges before introducing a potential solution: the identification of a transdiagnostic treatment target that can aid prophylaxis or the long-term protection of mental health. We argue that psychedelic therapy has the potential to meet these two criteria. Key to our synthesis is evidence that psychedelics promote brain and mind “plasticity,” where plasticity can be defined in its purest sense as the quality of being easily shaped or molded (1). In the present paper, we use plasticity in this fundamental sense in relation to both the brain and mind (i.e., psychological phenomena), where enhanced plasticity of either phenomenon implies an enhanced capacity for change. In its purest, as well as in its classic biological sense, plasticity is closely related to “adaptability,” as the property of being easily shaped or molded naturally interfaces with conditional forces or factors that could shape or mold the plastic phenomenon in a particular way.

In this paper, we aim to integrate the property of enhanced brain and mind plasticity via psychedelics with a predictive processing framework that is intended to apply equally well on psychological and neurobiological levels. This model constitutes an interdisciplinary approach to the mechanism of action of psychedelic therapy. Importantly, we explain how the model implies the prophylactic potential of psychedelic therapy—with implications for efforts to aid the development of psychedelic therapy into a regulated intervention for the recovery, promotion, and protection of psychological wellness.

Consistent with recent evidence supportive of these bold claims, we elect not to treat psychological health as a mechanistically discrete entity separate from pathology (2). In our view, reinforced “problematic” habits of brain and mind are universally relevant maladaptive processes (3). Put very simply, we argue that increased mental and neuronal plasticity, in combination with ideally supportive environmental contexts, can serve to promote psychological well-being on state and trait levels.

Mental health disorders are currently among the leading causes of disability worldwide. At least 300 million people suffer from depression, and close to 800,000 suicides are committed every year, with most linked to a mental health condition (4). There are thus, enormous human, social, and economic costs linked to mental illness (5), warranting that it be regarded as a major priority area.

Considering the magnitude of the burden of mental illness, its increasing global prevalence, and growing costs of healthcare (5), purely reactive interventions are unlikely to have sufficient impact (6). Moreover, there is a dearth of truly novel and effective new psychiatric drugs (7). Most current drugs have a lag in their therapeutic onset, possess a range of side effects (8), and show a modest efficacy relative to placebo (9–11); ∼20% of patients are resistant to any of the presently licensed treatment options (10, 12). Moreover, pure pharmacotherapy, while convenient for “industrial” healthcare, may not have the correct action to target etiological causes in a manner that can serve long-term well-being (3).

While patients generally prefer talking therapies (13), questions remain over access, cost, speed of therapeutic action, and efficacy—particularly for severe cases (14). Thus, it is widely recognized that current treatments have limitations and that therapeutic breakthroughs are needed (5).

The World Health Organization (WHO) recognizes the potential value of proactive or preventative strategies for tackling the global burden of mental illness (5). Compared with preventative strategies in other domains of healthcare, progress in the prevention of mental illness has been poor (15). This may be due in part to industrial forces, including an excessive reliance on “myopic” (e.g., drug alone) interventions that may fail to target key underlying generative sources of illness (15). Consistent with this, a shift in focus in mental healthcare and research to strategies that promote wellness, and the capacity to address and cope adaptively with adversities seem justified and timely (15). The promotion of health and prevention of illness are interrelated in many respects (15)—a position backed by recent evidence of the continuous relationship between mental health and illness (2).

As the rapid discovery of effective vaccines for COVID- 19 has demonstrated, an understanding of the etiology of a disease dramatically affects our ability to find effective treatments for it. In the context of mental illness, our incomplete understanding of the etiology of psychological suffering may be a major reason why our current treatments are not sufficiently effective. Regarding etiology, there is substantial evidence for an association between acute and chronic adversity and the development of many of the most prevalent and disabling psychiatric disorders (5, 16). Traumatic experiences during childhood are a well-known risk factor for various psychiatric disorders in adulthood (17). Decades of evidence has tended to suggest that the most prevalent psychiatric disorders (such as depression and anxiety disorders) feature a substantial environmental component in their etiology (3), albeit with a non-negligible but largely transdiagnostically shared genetic component (18) that seems to confer “vulnerability” or possibly even just “sensitivity to environment” — with direct and indirect links to plasticity (18, 19).

Thus, a large body of evidence implies the existence of individual differences in vulnerability to mental illness after adverse experiences (20). This differential sensitivity may depend on polygenic (18, 21), neurobiological (22, 23), environmental (24), psychological (25), and social factors (20). A composite vulnerability factor referred to as “resilience” has been the focus of research on preventative strategies in mental healthcare research (6), but is there a related and perhaps even more fundamental and tangible treatment target?

Two main strategies have been identified for the prevention of the development of mental health disorders and promotion of mental health: (1) the identification and potential mitigation of psychological, biological, community, economic, and environmental risk factors and (2) the strengthening of protective factors (26). We argue that psychedelic therapy can serve the latter factor in particular, by promoting a generalized mental and neural plasticity in combination with an ideally nurturing or supportive therapeutic context. Again, we adopt a standard dictionary definition of plasticity as the ability to change or be shaped by surrounding conditions (1).

Borrowing from genetic science (27), we also argue that a broad range of psychopathology can be conceived of as a maladaptive “canalization” of thought and behavior. Canalization can be defined as the maintenance of a trajectory (e.g., a style of thinking, feeling, relating, and/or behavior) that is resistant to change. Thus, in a sense, canalization is the inverse of plasticity. It is tempting to infer that canalized thought and behavior are an adaptive, defensive response to adversity that may thus, perhaps, paradoxically confer some (context dependent) evolutionary advantages (28). However, where such canalization creates maladaptive phenotypes—i.e., maladaptive in the context of a demanding modern western society—the logical way to treat it is to intervene to increase plasticity. Psychedelic therapy combines a plasticity-enhancing drug action with nurturing conditions—for the purpose of fostering a reset or recalibration of “maladaptive” habits of mind or behavior (29). Put most simply, we propose that the core therapeutic value of psychedelic therapy lies in its ability to open a window for healthy change.

There is a growing view that markers of mental health and treatment targets may be transdiagnostically relevant (30, 31). The transdiagnostic approach is characterized by identifying and targeting modifiable factors that traverse standard diagnostic categories (30, 31). This view is well-supported by the strong comorbidity of mental health disorders (32, 33) and the shared polygenic overlap between them (18).

A related perspective has inspired the Research Domain Criteria (RDoc) initiative in the USA, which places greater emphasis on pathologically relevant mechanisms rather than diagnostic categories, and has attracted major funding, if (as yet) limited breakthroughs (34). A similar direction is being taken by process-based psychotherapies, where mediators and moderators of mental illness and wellness are being explored (35, 36). If sufficient supportive evidence is gathered for either approach, it could have a far-reaching impact on treatment decisions as well as interdisciplinary bridging between different treatment models, orientations, and settings (35).

It would be fair to recognize psychoanalytic psychology here, as it has long recognized the existence of transdiagnostic overlap or commonalities between difference symptom-level expressions of psychological suffering, e.g., through the recognition of defense mechanisms (37). A greater alliance between psychoanalytic theory and practice and psychedelic therapy and science could be particularly fruitful going forward.