Psychedelics are psychoactive substances that temporarily alter perception, emotions, cognition, and the sense of self (Griffiths et al., 2016; Carhart-Harris et al., 2016a,b; Muttoni et al., 2019).

After decades of dormancy, the number of publications on psychedelics has rapidly increased in recent years (Petranker et al., 2020; Hadar et al., 2022). A fast-growing body of clinical studies shows increasing evidence of promising therapeutic effects of psychedelics for various conditions (Goldberg et al., 2020; Romeo et al., 2020; Andersen et al., 2021; Lawrence et al., 2021; Hadar et al., 2022), including major depression (Carhart-Harris et al., 2016a, 2021; Davis et al., 2021), anxiety and depression in patients diagnosed with a life-threatening disease (Griffiths et al., 2016; Ross et al., 2016), and substance use disorders (Johnson et al., 2014, 2017; Bogenschutz et al., 2015, 2022). These results demonstrate the psychedelics’ potential for assisting psychotherapeutic processes (Garcia-Romeu and Richards, 2018; Reiff et al., 2020; Nayak and Johnson, 2021; Scheidegger, 2021b), rendering psychedelics a priority in psychiatric research and beyond, including pharmacological, neuroscientific, and phenomenological research.

Since these clinical results are promising, it is important to understand the specific conditions under which psychedelics’ therapeutic effects unfold. Pharmacological research is targeted toward the primary therapeutic mechanism of psychedelics on a pharmacological or biochemical level. Neuroscientific research is targeted toward the neurobiological mechanisms underlying psychedelic therapeutic experiences (Vollenweider and Preller, 2020; Vollenweider and Smallridge, 2022). In contrast, psychological and phenomenological research is targeted toward the subjective features of psychedelic experiences that predict therapeutic success (Roseman et al., 2018; Yaden and Griffiths, 2021). It is evident that pharmacological, neurobiological, and psychological research on psychedelics have gained renewed interest.

These empirical findings on the biochemical, the neural, and the experiential level suggest that processes on each level may exhibit a causal role on the effects of psychedelics. This warrants the question how to relate these different levels of analysis to each other. van Elk and Yaden (2022) have recently distinguished two ways to relate these levels using two most common views in the current psychedelic literature: an integration view and a pluralistic view on causation.

The integration view on psychedelics targets a common pathway underlying the therapeutic effects of psychedelics for a variety of disorders. It aims to integrate various levels of description by converging them into a unified causal mechanism (van Elk and Yaden, 2022). One most influential integrative approach to psychedelic effects is the aforementioned REBUS model. The REBUS model describes a cascade of events, starting at the molecular level, then causing anatomical and functional changes in the brain that eventually culminate in the subjective experience of relaxed prior beliefs. In the words of Carhart-Harris (2019, p. 16), “it is proposed that psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high-level beliefs”.

Thereby, the REBUS model focuses on one specific aspect of the effects of psychedelics: the ability to acutely relax beliefs and assumptions. As a main cause of psychedelic effects, it suggests a single mechanism and reduces their complexity to a single cognitive process. While the REBUS model acknowledges the significance of how other factors should be considered for a comprehensive understanding of psychedelic effects, it proposes a specific neural mechanism as a key factor in shaping the therapeutic effects of psychedelics (see Figure 1). This single-pathway focus can be considered reductionist. When reduced to its proposition of a key neural mechanism leading to the relaxation of prior assumptions and expectations, the REBUS model implies a unidirectional linear molecule-to-brain and brain-to-experience relationship. The psychedelic molecule creates changes in brain activity and the brain creates the psychedelic experience.

The REBUS model, as one integrative view, has provided an influential and important contribution to the field of psychedelic research, incorporating significant insights from the entropic brain hypothesis, the free-energy principle, and predictive processing. Simultaneously, this integrative view has also received criticism. While the REBUS model illuminates a single neural mechanism, it may neglect other important aspects, other possible mechanisms, and the multi-faceted subjective nature of psychedelic experiences.

The pluralistic or holistic view on psychedelics shares this critique by emphasizing that psychedelic experiences cannot be reduced to a single cause-and-effect pathway: It needs an account of the interplay of multiple causal pathways to comprehensively understand a given phenomenon (Johnson et al., 2019). Accordingly, the pluralistic view, such as the biopsychosocial model to psychiatry, emphasizes the complex, multidimensional nature of causation involving multiple factors at different levels including biological, psychological, and social influences (Engel, 1977). Applied to psychedelic research, pluralistic theories of causation emphasize that social, cultural, and historical factors need to be considered in the study of psychedelic experiences (van Elk and Yaden, 2022). Likewise, it is argued that psychopharmacology needs to embrace interactions at various levels through multiple top-down and bottom-up causal pathways in order to account for therapeutic effects (Aftab and Stein, 2022).

While the integration view and the pluralistic view are distinct perspectives, they are not mutually exclusive. The causal mechanism described by the REBUS model to account for therapeutic effects of psychedelics can be seen as one of the multiple factors identified by the pluralistic view. The pluralistic view can incorporate the integration view but the integration view, if postulating a mono-causal cascade, cannot accommodate the pluralistic view.

Moreover, it has been argued that, in order to fully account for the multi-faceted nature of psychedelic experiences, a pluralistic theory of experience may be needed (van Elk and Yaden, 2022). In support of the pluralistic inclination toward the complexity and multidimensionality of causation, we wish to address this need through contributing a third and distinct but complementary and promising perspective on causality in psychedelic experiences: an enactive view. We argue that the enactive view on psychedelics complements the integration view by adding multiple pathways from the psychological and contextual level, while enriching the pluralistic view by explaining how biopsychosocial levels interact.

The enactive approach is a cognitive science framework that has its origin in The Embodied Mind from 1991 by Varela, Thompson, and Rosch. Since then, it has gained substantial influence in the field of cognitive science. In this article, when referencing “the enactive approach,” we will refer to the work by Varela et al. (2017) and to its consistent advancement by Thompson (2007) and Di Paolo et al. (2010) among others. The enactive approach has its roots in various fields, including the autopoiesis theory by Maturana and Varela, phenomenological philosophy such as Merleau-Ponty’s Phenomenology of Perception and Hans Jonas’ philosophy of life. Moreover, it is inspired by dynamical systems theory and complex system science (Thompson, 2007) and Buddhist Abhidharma and Mādhyamaka philosophies (Varela et al., 2017). In recent years, the enactive approach has been applied to psychiatry (de Haan, 2020), placebo effects (Arandia and Di Paolo, 2021), pain (Stilwell and Harman, 2019; Coninx and Stilwell, 2021), consciousness research (Høffding and Martiny, 2016; Høffding et al., 2022; Valenzuela-Moguillansky and Demšar, 2022), artistic practices including dance and music improvisation (Schiavio and Høffding, 2015; Ravn and Høffding, 2022), meditation experiences (Meling, 2021, 2022), and ethics (Di Paolo and De Jaegher, 2022) among other fields.

The enactive approach provides a network of interrelated ideas including its central concepts of autonomy, dynamic co-emergence, sense-making, groundlessness, and experience (Thompson, 2007; Di Paolo et al., 2010; Varela et al., 2017). We propose that these are highly relevant for conceptualizing psychedelic drugs and their relation to psychedelic experiences. Some of them we will elaborate on in the main section of this article. The enactive approach’s differentiating factor is that it requires us to confront the lack of ultimate foundations through consistently following the thread of interdependence in various seemingly dualistic relationships, including those between parts and whole, self and world, and subject and object (Varela et al., 2017).

While the enactive approach has been widely ignored in the field of psychedelic research, the free-energy principle (FEP) and predictive processing (PP), two other recent and interrelated developments in cognitive science, have been very influential on neuroscientific research on psychedelics as they inspired the aforementioned REBUS model (Carhart-Harris et al., 2014; Carhart-Harris and Friston, 2019). Despite frequent claims from several authors about the compatibility between the FEP (or PP) and theories of autopoiesis and enaction (Clark, 2015; Allen and Friston, 2018; Constant et al., 2021; Korbak, 2021; Ramstead et al., 2021; Wiese and Friston, 2021), this has been recently criticized as misrepresenting enactive concepts (Di Paolo et al., 2022). While the details of this comparison go beyond the scope of this article, it underscores that applying FEP to psychedelics does not already entail applying the enactive approach to psychedelics. Therefore, a thorough application of enactive ideas to psychedelics is yet to be accomplished.

The main aim of this article is to explore psychedelics from an enactive perspective and more specifically to provide an enactive view on the causal relationship between psychedelic drugs, neural events, and experience. This aim is approached via the following two interconnected research questions:

What is the causal relationship between the psychedelic drug and brain activity?

In this subsection we address the first main research question. Guided by an enactive perspective, we re-evaluate the relationship between the psychedelic molecule and neural events through inquiring whether (1) the psychedelic molecule determines brain activity and (2) whether the psychedelic molecule transmits information.

In this subsection, we address the second main research question. From an enactive perspective, we re-evaluate the relationship between neural events and experience through inquiring whether the psychedelic-influenced brain determines the psychedelic experience. This can be addressed through the enactive concepts of autonomy and dynamic co-emergence.

In exploring the first research question, we applied the concept of autonomy to the psychedelic molecule-brain relationship (research question 1): The consequences of the human nervous system integrating a psychedelic molecule into its autonomous activity is not mono-causally determined by the specific features of the psychedelic substance but by the particular interaction between the temporary structure of the nervous system’s autonomous activity and the psychedelic molecule. The consequences neither belong to the psychedelic molecule nor to the nervous system’s activity. They depend on the specific molecule-organism interaction.

In exploring the second research question, we applied the concept of dynamic co-emergence to the psychedelic brain-experience relationship (research question 2): The psychedelic experience is not epiphenomenal or linearly determined by the neural activity in reaction to a psychedelic drug. Rather, they are co-dependently emerging. Neural events give rise to the psychedelic experience and the psychedelic experience limits the range of potential neural events. Rather than being a mere epiphenomenon of neural activity, the psychedelic experience is causally efficacious on neural activity: Neural activity and experience are co-emergent. As with the psychedelic molecule-brain relationship, from an enactive perspective the psychedelic brain-experience relationship is not unidirectional but bidirectional and circular (see Figure 1).

The inquiry into both research questions from an enactive view resulted in a perspective that emphasizes interdependence. Therefore, the main contribution of this article is a framework of ideas that accounts for the interdependence of psychedelic experiences including their nonlinear causality and non-reducibility. This results in a complex account of causality in psychedelic experiences.

While the REBUS model, as one exemplary integration view, proposes that the biochemical, neural, and experiential aspects of psychedelics converge on a single causal cascade, there is also contradicting evidence. First, while there are studies corroborating the REBUS model through showing LSD-induced reductions in electrophysiological responses to surprising stimuli (Timmermann et al., 2018), other studies have not observed such reductions in surprise responses (Umbricht et al., 2003; Vollenweider and Preller, 2020). Second, while the REBUS model proposes that effects on the default-mode network (DMN) are central in psychedelics, even stronger effects have been reported in changing activity in other networks (Lebedev et al., 2016; Mason et al., 2020). Third, psychedelics may elicit a broad variety of experiences rather than only the relaxation of high-level beliefs. It has been argued that psychedelics, depending on dosage, may also lead to a strengthening of beliefs (Safron, 2020). Fourth, there is evidence suggesting a potential causal role of subjective experiences on therapeutic outcomes (Roseman et al., 2018; Yaden and Griffiths, 2021). The REBUS model, however, with its focus on a key neural mechanism does not account for a causal role of the quality of subjective experience. Fifth, the role of set and setting, i.e., extrapharmacological or non-biological factors that shape the response to psychedelics, are increasingly recognized in psychedelic research: The expectation, preparation, and intention (set) and the physical and social environment (setting) affect to some degree the consequences of the psychedelic substance-human interaction (Hartogsohn, 2016, 2017). This relevance of set and setting is not captured in an integration account that focuses on a single causal neural pathway.

These findings suggest other causal pathways, creating tension with the integrative proposal that the different levels converge on a single causal pathway. From an enactive perspective, however, these empirical findings confirm the causal complexity that mediates psychedelic effects: As an example, the aforementioned measured surprise response depends not only on the substance but also on the instruction of the task, on the participants’ expectations and intentions, on their felt relationship to the researchers, their individual bodily constitution, their history of interactions with their environment, and many more factors. Keeping this complexity of causal influences in mind, it is not surprising that some studies showed psychedelic-induced reductions in electrophysiological responses to surprising stimuli (Timmermann et al., 2018), while other studies have not observed such reductions in surprise responses (Umbricht et al., 2003; Vollenweider and Preller, 2020). The same applies to the mentioned finding of a variety of brain networks that show changed activity and to the finding that psychedelics may not only lead to a relaxation of beliefs but also to their strengthening. Depending on other causal influences, as from the body, the environment, the experience, the measured effects naturally vary. And the enactive approach can accommodate this variety of causal influences as its emphasis on the dynamic co-emergence between different levels suggests bidirectional causality on multiple levels. First, neural activity is not dependent only on the substance but on the entire body’s constitution, other perturbations from the environment, the subject’s lived experience, and many further factors that cannot be entirely controlled within an empirical study. Neural activity under the effects of a psychedelic substance is contextual and situated: Therefore, it strongly varies across studies. Second, from an enactive perspective subjective experiences co-emerge with neural processes so that neural processes have causal efficacy on subjective experience while subjective experience has causal efficacy on neural processes. Third, the enactive account emphasizes the organism-environment interaction that shapes cognition. This includes a causal role of extrapharmacological factors, such as psychological, social, and historical factors that shape the psychedelic experience.

From an enactive view, the integrative view that “psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high-level beliefs” (Carhart-Harris, 2019, p. 16) is not negated.¹ Rather, it is expanded through adding multiple causal pathways in order to capture the causal complexity that contributes to a psychedelic experience. This focus on the complexity and multidimensionality of causation is shared between the pluralistic view and the enactive approach.

The pluralistic view and the enactive approach have several commonalities regarding the notion of causality. Both approaches emphasize causal complexity and that multiple factors contribute to psychedelic effects, including the environmental setting, the socio-cultural context, and the individual’s expectations. In other words, both approaches consider the context-dependency and observer-relativity of a psychedelic experience and acknowledge the importance of the subjective experience.

However, as argued by de Haan (2021) in the context of psychiatry, the biopsychosocial model as one pluralistic view of causation faces an integration problem, as it does not tell how processes of largely differentiating natures can causally affect each other. The enactive approach, however, can explain such biopsychosocial interaction (de Haan, 2020). Likewise, the enactive approach substantially enriches the pluralistic view of causation regarding psychedelics as it provides a principled account of how biochemical, neural, and experiential processes affect each other through local-to-global and global-to-local determination. They are mutually dependent autonomous processes that co-emerge and therefore exert circular causality. These interactions on multiple levels shape the psychedelic experience.

In acknowledging the plurality of causes on therapeutic effects, the enactive view provides a theoretical basis for a holistic approach to psychiatry (de Haan, 2020). Rather than advocating a specific form of treatment, the enactive view of therapy targets a better understanding of how various influences interact. Accordingly, it embraces a plurality of treatment forms in a personalized approach that targets the dynamic and complex person-world system as the unit of analysis (de Haan, 2020).

Likewise, the presented enactive approach to causality in the psychedelic molecule-brain-experience relationship suggests similar implications for psychedelic therapy. In acknowledging the multiple and circular causal pathways between the psychedelic substance, neural activity, the subjective experience, the social and physical environment, and many other factors, the enactive approach embraces a plurality of ways of how therapeutic effects can emerge in psychedelic-assisted psychotherapy. In principle, it can be derived that therapeutic effects can co-emerge with a variety of causal factors and their mutual interactions, including a particular molecular substance effect (e.g., binding on 5-HT_2A receptors), a particular pattern of neural activity (e.g., activity in the claustro-cortical circuit), particular experiences (e.g., a mystical-type experience), a particular bodily state (e.g., a comfortable and relaxed body posture or a release of muscular tension), a particular physical environment (e.g., a calm and warm space with soothing music), a particular social context (e.g., a friendly, accepting, and nonjudgmental atmosphere), and a particular intention or expectation (e.g., the intention to turn one’s attention to unpleasant aspects of one’s life in an accepting and nonjudgmental way). Therefore, the enactive view supports a holistic approach to psychedelic-assisted psychotherapy that acknowledges the potentially therapeutic effects of psychedelic substances and simultaneously goes beyond the focus on the psychedelic substance through emphasizing the importance of the ecology of causes that surrounds the organism’s interaction with the psychedelic substance.

Finally, suggestions for a psychedelic research agenda can be derived from the enactive view on the psychedelic molecule-brain-experience relationship. As we have seen, the enactive view admits that there is definitely an impact on experience from the molecule via neural activity. Simultaneously, it prompts us to acknowledge the vast complexity of causes and conditions that enable a trial participant to report a certain psychedelic experience or therapeutic improvements. The enactivist insistence on the complexity of causes that shape a psychedelic experience prompts questions that go beyond the reduction to the drug or to the brain: How did the neural system take up this molecule, what was the structure of the nervous system integrating that psychedelic substance? What impacted that structure of the nervous system, e.g., other bodily processes or environmental factors? Under which conditions were these experiences reported? What were the expectations of the participants, what was their environmental context?

Further research is needed to operationalize these questions and other implicit hypotheses from this article in order to empirically test them; employing a compatible scientific methodology that connects different views and disciplinary methodologies in a way that acknowledges the enactive view of circular causality.

Accordingly, psychedelic research inspired by the enactive approach may require an interdisciplinary endeavor that integrates different perspectives, such as neuroscientific, phenomenological, cultural, anthropological, and historical, among others, in order to provide a more comprehensive understanding of the complex interactions across different levels involved in the psychedelic experience.