Psychedelic Realism and Sisyphean Empiricism: A Case for Ontological Pluralism

Science has failed our world

Science has failed our mother earth

Science fails to recognize the single most

Potent element of human existence

Spirit moves through all things

– Tankian & Malakian (2001, Track 5)

Despite two decades of renewed interest and clinical investigation since the spark of the so-called psychedelic renaissance, research into these substances cannot seem to overcome the same repeated hurdles. Functional unblinding compromises randomized controlled trials (RCTs), and placebo response is predictably influenced by expectancy which inflates effect sizes. Instruments designed to understand notions such as “the mystical” become inoperable when presupposing what “mystical” means, and efforts to evaluate events only capable of being described as ineffable produce their own paradox (Jylkkä, 2021; Mosurinjohn et al., 2023; Muthukumaraswamy et al., 2021). The consistent response is to attempt to improve the same methodology with better controls, active placebos, and expectancy measures, then try again (Petrovitch et al., 2025).

Why does this keep happening? The methodologies of empirical measurement of RCTs are fundamentally incompatible with the unique phenomena of these substances. The modern Western axioms of materialism and positivism declaring that there is one reality and one observable path to understanding it cannot contend with the “hard problem” of consciousness, nor with variables that alter it (Chalmers, 1995). Subjectivity, by definition, cannot be measured objectively, and the omission of that measurement while studying substances that produce inherently subjective phenomena creates a contradiction that makes data gathered empirically uninterpretable. But the research is stuck in a state of systemic entrenchment incentivizing this monistic pattern, and it seems that the only solution is to keep refining the techniques of measurement, yearning for an eventual breakthrough that is satisfactory for regulatory approval. The boulder rolls back up the hill.

Is there no alternative? This paper argues that the field needs to rethink the scientific paradigm for psychedelic research altogether and expand its classifications of acceptable evidence in order to progress. It must be recognized that the impossible task of empirically measuring phenomena generated by psychedelics demonstrates that the ontological baseline for understanding them is plural. The monistic framework cannot support its own results because the data does not support the monistic framework in the first place.

Psychedelic Realism

Mark Fisher states in Capitalist Realism that “it is easier to imagine the end of the world than the end of capitalism (Fisher, 2009).” A tool for neoliberal proliferation is to insidiously create a sense that there simply is no alternative. This backdrop translates directly to empirical psychedelic research in the form of “psychedelic realism”: it is easier to imagine psychedelic science failing forever than to imagine abandoning the RCT as the gold standard of observable evidence. The industry sees the RCT as the only pipeline of psychedelics to FDA approval, then legality and restricted access through the medical industrial complex, subsequently percolating through global regulatory adoption. The current expectation of how the scientific world defines rigor persists because it is impossible to think outside of it, regardless of whether it works. And the expectation of how institutional approval works feels permanent and unchangeable, despite the FDA’s regulatory power only existing for less than a century for the purpose of keeping poison out of food (U.S. Food and Drug Administration, 2019).

Fisher’s (2009, pp. 21-22) description of a state he calls “depressive hedonia” also fits in the psychedelic realism framing. People in the industry are paralyzed knowing things are broken but continue anyway because they have just enough from the system to prevent them - and the system - from breaking down. Researchers understand RCTs are inadequate or misapplied to psychedelic research (Butler et al., 2022; Villiger, 2025; Williams et al., 2026). Those who are compelled to make changes to the methodological shortcomings of the paradigm simply suggest more, slightly updated versions of the same paradigm (Petrovitch et al., 2025).

However, others are actively incentivized to ignore and suppress these problems with the intent of achieving institutional approval through deception or the hope that the regulators won’t notice the methodological problems. This was famously illustrated by the Lykos MDMA trials which systematically omitted subjectively positive drug effects from adverse event reporting, despite the FDA specifically telling them that effects like euphoria, mood changes, and altered perception fall into this categorization (U.S. Food and Drug Administration, 2024).

We cannot simply blame the researchers, though. This apparent powerlessness to abandon the current pipeline of RCT to FDA approval as the only legitimate path to psychedelic access is institutionally entrenched far beyond just a philosophical preference for ontological monism manifested in scientific empiricism. This is apparent in the billions of dollars in venture capital reliant on the RCT paradigm being the only tool relevant for the clinical trial infrastructure and FDA approval pathway, therapist credential programs, and publication incentive structures.

Funding valuations of psychedelic research and pharmaceutical companies like Compass, ATAI, and MindMed assume that the current paradigm will somehow eventually work (Aday et al., 2023; Hager, 2025). A departure from that paradigm would collapse the thesis backing financial investment, and thus potentially the research altogether. The roots of this entrenchment stem from ontological commitments embedded in the scientific method itself.

Sisyphean Empiricism

Ontological monism in the form of materialism has been the modus operandi for Western science for centuries. The idea that everything that is real has an ultimately physical origin, that reality, the universe, and all phenomena within are reducible and explicable by physical processes, is a fundamental presupposition underpinning a vast amount of the knowledge and technology that society calls valid. This axiomatic approach in itself is paradoxical - nobody ran experiments proving that reality is of a singular and material nature. The scientific method built on this philosophical conjecture was established during the scientific revolution of the 16^th and 17^th centuries by figures like Descartes, Galileo, and Newton, then so thoroughly popularized during the industrial revolution’s extremely rapid technological progress, that no other ontological option looked possible (Shapin, 1996).

The origins of this ontological pathway can be traced back to Descartes’ famous rationalist certainty of “Cogito ergo sum (I think, therefore I am).” This phrase expresses that the one thing he cannot doubt is his own subjective experience of thought. Everything else - the physical world, his own body, and other people - exists upon the bedrock of his undeniable experience of consciousness. He then goes on to divide reality into “res cogitans” (mind or thought and the immaterial) and “res extensa” (matter and the physical), giving science both its limits and jurisdiction over the physical world, while thought and the immaterial are left up to philosophy and theology. The deeper irony here with intractable implications for psychedelic research is that Descartes built the foundational scientific framework explicitly excluding investigation into the singular thing he knows to be true - consciousness.

Galileo adopted this distinction and added mathematics, claiming that quantifiability is the defining feature of reality, while any quality of experience is a secondary product of the observer’s mind. This was an ontological shift cementing measurement as the essential authority on what is real. Newton came along with a proof of concept through Principia, demonstrating that the laws of mathematics alongside empirical verification can be a powerful predictive force. Finally, Comte formalizes these cumulative ontological commitments with his introduction of positivism, declaring that only observable and measurable phenomena count as knowledge, while everything else is dismissible as improperly framed questions that are relics of pre-scientific thinking (Crotty, 1998).

While much of humanity’s technological and medical progress is rightly attributable to this framework, the RCT paradigm governing psychedelic research today is a direct descendant of this lineage, carrying over ontological commitments that are structurally incompatible with the phenomena under investigation. Each of the assumptions of the framework logically follows from materialist monism: the intervention is a molecule (res extensa), the output is a symptom score (quantifiable), the experience is a confounding variable to be controlled for (secondary quality), and what is left to count as evidence is the result that survives double-blind observation (positivism).

The collision is that functional unblinding happens because the experience itself is the intervention - the molecule cannot be separated from the consciousness it alters. Set and setting confound outcomes because the entanglement of environmental and relational contexts are core parts of the experience amplified by the molecule (Ruban & van Elk, 2025). The Mystical Experience Questionnaire predefines an ontology of mystical experience in an attempt to quantify the ineffable. These methodological failures are the result of applying a framework built to exclude subjectivity to phenomena that are constituted by subjectivity. The cycle continues in a Sisyphean repetition since each refinement is on the methodology, but the failure is ontological. The boulder rolls back down the hill because the researchers have yet to try another hill.

Ontological Pluralism

History shows that every major advance in science has involved shifting ontological commitments. Kuhn (1962) demonstrated that science progresses through paradigm shifts, not linear accumulation. These revolutionary splits from ontological presuppositions fundamentally changed what is real - Copernicus moved Earth from the center of the universe to its periphery rather than recalculating planetary orbits, Darwin replaced the reality of fixed essences of species with evolutionary theory rather than collecting more specimens, Einstein dissolved the axiomatic distinction between space and time rather than refining Newtonian mathematics. Quantum mechanics didn’t just make more precise measurements; it showed that measurement itself is a constituent of phenomena and that the observer cannot be separated from the observed.

All these advancements now serve as the basis for scientific progress. But they all required abandonment of realities previously thought to be self-evident. Mainstream psychedelic research is yet to question whether the framework of reality within which it operates could itself be the problem. The field must recognize that the anomalies and failures of progress plaguing it are signals that the ontological ground needs to shift - toward ontological pluralism.

The psychologist and empiricist William James argues in A Pluralistic Universe (1909) that monism fails on empirical grounds because it cannot account for the full range of experience. His radical empiricism expands what counts as data: relations, feelings, and the qualitative nature of experience are directly observed and therefore must be included in any sufficient ontology. He addresses the same phenomena directly relevant to psychedelic research by considering mystical states as data with their own structure, epistemic value, and claims on reality, not pathology or confounding variables (James, 1902/2003). James (1904/1912) rejects Cartesian dualism, arguing that consciousness is not a separate substance (res cogitans), but a set of relations within experience itself:

Consciousness connotes a kind of external relation, and does not denote a special stuff or way of being. The peculiarity of our experiences, that they not only are, but are known, which their ‘conscious’ quality is invoked to explain, is better explained by their relations - these relations themselves being experiences - to one another. (p.25)

For psychedelic research, this is a problem for the current framework. If consciousness is relational rather than inherently substantial, the “drug effect” and molecular component of the intervention cannot be isolated from the relational context because consciousness is those relations. Functional unblinding is a relational aspect of the consciousness being measured and cannot be disregarded as a confound. These efforts are methodologically challenging because they’re ontologically incoherent.

The philosophical proposal by James is operationalized in Stengers’s ecology of practices. She argues in Cosmopolitics II that scientific practices each have their own applications, epistemologies, and criteria for evidence that cannot be reduced to a universal standard without disrupting what makes each practice work. She warns against the “curse of tolerance” - a simple acknowledgment by a dominant practice that other practices exist is not sufficient. Without explicit coexistence of all practices refusing to claim universal authority, the hierarchy is maintained and the dominant practice structurally prevents the others from serious consideration (Stengers, 2005; 2011). This is what we see in psychedelic realism and the RCT paradigm - institutional inertia propped up by the curse of tolerance.

Western multiculturalism carries the assumption that there is one natural reality and many cultures that have their own interpretations of the single truth. It acknowledges that different cultures and scientific practices exist, and thus different ways of understanding reality. Amerindian perspectivism directly inverts this idea - we are one culture and there are many natures to interpret. All beings see the world the same way, as persons through culture, but they see different worlds altogether because they are perceiving them through different bodies. Viveiros de Castro (1998) calls this “multinaturalism.”

The explicit claim that there are multiple realities to be interpreted, not just different ways of knowing reality, is the most radical form of ontological pluralism. Applying multinaturalism to psychedelic research reframes the problem completely. The materialist assumption that psychedelic experience is just a distorted perception of reality is challenged by the possibility that it may be accessing a truly different one. Shamans in Amerindian cosmologies operate on this premise and navigating between these separate natures is a core function of their practice. With this view, the psychedelic experience becomes a technology of ontological traversal.

These perspectives are not proposals, but existing knowledge systems currently in practice that have been reliably producing information about psychedelics for millennia. Fotiou (2020) argues that the Cartesian separation of mind and body is mostly absent in Indigenous epistemologies which use empirical, experiential, and relational methodologies that Western paradigms systematically exclude in their colonial legacy of superiority. This exclusion renders the Western RCT model incapable of studying what happens with psychedelic substances in Indigenous settings. These rituals tend to be rich sensorial experiences - the very elements that may be producing therapeutic effects - that RCT methodology would try to strip out and isolate. She also notes what could be seen as another cultural symptom of psychedelic realism - that the neoliberal paradigm takes over all areas of life, discouraging risk-taking in knowledge production and limiting effort towards ontological paradigm shift.

Dev (2018) ethnographically documents this tension between the experience of researchers and what their paradigms permit. She illustrates these conflicts with the example of ayahuasca, which resists the ontological categorization required by research frameworks due to its function as what she calls a “boundary being” that facilitates dialogue across species and worlds. Researchers at the World Ayahuasca Conference openly acknowledged plant intelligence and relational knowledge while expressing frustration that their work couldn’t accommodate that recognition. She argues that this needs to be taken seriously by treating plant intelligence as a given rather than a hypothesis to be proven. This reorients the research question from what can be measured about this substance to how it wishes to be known.

Dev explains how the ontological commitments of the scientific revolution established ontological hegemony through colonial power structures. This “scientism” culminated in an epistemic supremacy that defines nature as the exclusive object of inquiry and discards anything out of the boundaries of scientific questioning as supernatural or illegitimate. She proposes a straightforward decolonial approach: research must stop reducing Indigenous knowledge to an object of study and start treating it as a legitimate, additive co-participant in knowledge production. If the field accomplishes this ethical imperative of decolonization and the move toward ontological pluralism, what are the implications for how psychedelic research is done on the other side?

Beyond the Boulder

Adopting ontological pluralism does not mean abandoning rigor or empirical methods. The RCT model is simply misapplied to psychedelic research, not inherently wrong. For contexts where its ontological assumptions hold, as in much of medicine, ontological pluralism keeps it. For phenomena where these assumptions are inadequate, alternative frameworks must be developed. These alternatives could look like phenomenological methods that treat first-person experience reports as data rather than confounds, community-based participatory research designs that include Indigenous practitioners as co-investigators, or approaches that combine quantitative, qualitative, relational, and experiential measurement data.

This class of alternative methodologies produces different kinds of knowledge that the current structure cannot. Set and setting become primary objects of investigation. Instead of controlling for them as confounding variables, they’re studied for their relational and environmental configurations and the outcomes they produce. Therapeutic and social relationships become legitimate objects of study rather than something to be standardized for consistency. First-person experience data becomes a source of insight into therapeutic mechanisms, shifting analysis from whether a symptom score changed to identifying what experiential phenomena produced the change. Indigenous knowledge about preparation, plant combinations, dietas, ceremonies, social relationships and ecological balance as assessments of healing becomes evidence rather than subjects of ethnographic interest.

Ontological pluralism is not a novel Western philosophical invention suddenly arriving to rescue psychedelic research. These ways of seeing reality, and realities, are available, as are their methodological alternatives. Indigenous knowledge systems have been operating on pluralist ontological foundations all along. The Western materialist framework’s claim to universal truth is a product of the scientific revolution and the hegemony produced by colonial power relations. The extraction of psychedelic substances from their entangled, relational, and cosmological contexts and into the RCT pipeline is the ontological act that enforces monism, producing the failures the field can’t resolve.

Acknowledgement of these facts is an important part of the adoption of ontological pluralism to break the cycle of Sisyphean empiricism. But the more daunting effort is catalyzing change at the level of institutional infrastructure. Expansion of ontological legitimacy requires radical transformation of the systems that claim jurisdiction over that legitimacy. The current institutional pathways of FDA approval, publication incentive structures, investment mechanisms, and clinical credentialing apparatus only recognize evidence generated by RCTs.

But current efforts at institutional reform show psychedelic realism in action, framed as transformative interventions while ignoring the fundamental ontological problem. The April 2026 executive order in the United States directed the FDA to give three pharmaceutical research institutions “priority review vouchers” to psychedelic drugs with breakthrough therapy designations, established “right to try” pathways for investigational psychedelics, and allocated \$50 million USD in federal-state matching funds (Exec. Order, 2026). But these directives operate within the existing paradigm - faster FDA review of evidence produced by the same methodology, faster access through the same regulatory framework, and more money for the same clinical trial infrastructure. The ontological hill doesn’t change; the boulder is just being pushed faster.

There is an existing legal avenue that is underexplored in conversations about psychedelic research, which implicitly recognizes ontological pluralism. Religious protections under the Religious Freedom Restoration Act (RFRA), and the Canadian functional equivalent in the Charter of Rights and Freedoms, treat psychedelic substance use as a legitimate spiritual practice not reducible to pharmacology (Gonzales v. O Centro Espírita Beneficente União do Vegetal, 2006; Government of Canada, 1999). The fact that these pathways exist but are underutilized for access and research, obstructed by bureaucracy, and overlooked by reform efforts are yet another sign of psychedelic realism. The alternatives are right there, but the system can’t see them because it can’t think outside the medicalization framework. Could researchers advance knowledge of psychedelics through employment of methodologies unlocked by ontological pluralism in these communities where it is already legally legitimized?

The search for other hills

The continued failures in the field of psychedelic research are ontological, not methodological. The gold-standard RCT paradigm is constructed on an inherited materialist monism from the scientific revolution, and psychedelic realism keeps the field confined to that paradigm through institutional, financial, political, and epistemological entrenchment. Every refinement of the methodology repeats the Sisyphean cycle by operating on the same ontological framework that produces the failures.

Ontological pluralism has scientific philosophical foundation in the works of James and Stengers, is the working ontology of existing Amerindian cosmologies as demonstrated by Viveiros de Castro’s multinaturalism, and already has implicit legal recognition in the West through religious protections. The anomalous factors plaguing psychedelic research cannot simply be improved away and are evidence against the paradigm it operates within. Set and setting, relational context, first-person experience, and Indigenous knowledge are not simply curiosities or confounds to be controlled for, but real features of the psychedelic phenomena that must be accommodated by an adequate empirical system to advance understanding.

The inability of the modern Western scientific framework to recognize the single most potent element of human (and more-than-human) existence - that spirit moves through all things - does not have to be a permanent condition. It has contingent historical roots, and history shows that revisiting ontological commitments can produce revolutions that redefine the foundations knowledge is built upon. The boulder rolls back down the hill because the hill was decided on by a framework that predetermined what it could look for - and this hill is too steep for this boulder. Other hills exist and are already inhabited. They may have their own boulders, but the question now is whether the field can overcome psychedelic realism long enough to find out if it can push them to the other side.

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