Biological factors operate through permissive causality in determining an individual’s phenotype

Drawing on the definition of complexity grounded in emergence, all elements of a complex system operate through permissive causality with respect to the system’s global outcome, such as the individual’s emergent mental and behavioral phenotypes. This is because, by definition, in an emergent phenomenon, neither any individual element nor any subset of elements specifies the system’s emergent property in a one-to-one manner. When this idea is strictly applied, a bicycle – a system whose capacity for cycling is an emergent property – provides a compelling illustration of the permissive relationship between a system’s elements and its emergent properties: its components – gears, chain, and wheels – constrain and enable the capacity for cycling, yet none of them is linearly responsible for generating that capacity in isolation. At the level of the system’s constituent elements, causality operates by shaping a space of possibilities rather than by instructing a specific outcome. In complex adaptive systems (Figure 2), this inside/outside distinction becomes operationally clear because the system continuously adjusts its internal organization in response to external stimuli and contextual constraints. The same logic also applies to complex non-adaptive systems, provided that the global pattern under investigation is emergent. Even when endogenous self-organization processes converge on stable patterns and give rise to highly constrained global outcomes, the self-organized pattern still arises from interactions among multiple elements, none of which, alone or as a subset, specifies the global outcome in a one-to-one manner. Accordingly, internal manifestations that might appear instructive because of the significant role of self-organization processes, such as hallucinations in psychosis, can be understood as emergent internal states generated by multiple elements operating through permissive causality. Furthermore, hallucinations affect mental states permissively rather than by instructing a specific outcome. This is supported by clinical findings showing that hallucinations are often not directly reduced in frequency or occurrence by treatments like cognitive behavioral therapy, yet their impact is mitigated, demonstrating that such internal states act as moderators rather than deterministic instructions for specific mental states and behavioral phenotypes (Bach & Hayes, Reference Bach and Hayes2002; Chadwick & Birchwood, Reference Chadwick and Birchwood1994; Garety et al., Reference Garety, Kuipers, Fowler, Freeman and Bebbington2001; Mason, Peters, Williams, & Kumari, Reference Mason, Peters, Williams and Kumari2017).

Crucially, two boundary conditions clarify why internal elements are exclusively permissive regarding complex outcomes. First, regarding the complexity threshold, this framework pertains specifically to complex emergent phenotypes – such as mental states – contrasting with non-complex systems where linear relationships naturally occur. Second, regarding the distinction between local and global causality, we acknowledge that even within a complex adaptive system, specific mechanisms (e.g. a ‘switch’ activating a neural circuit) may operate linearly. However, as these local instructions propagate through the complex network, their linearity is lost through nonlinear interactions, feedback, and context-dependent modulation. By the time they contribute to the global emergent property, their role has transformed from determining a specific effect to modulating the dynamical landscape, and thus effectively becoming permissive. Notably, there are exceptions in which a single biological factor is linearly related to phenotype – such as in Mendelian genetic disorders – but these are not problems grounded in emergence and can be successfully addressed with a reductionist, linear approach.

Evolutionary processes embed instructive influences within the system as endogenous constraints

The evolutionary process is critical in embedding instructive influences from past environments within the individual, stabilizing the underlying architectures that support behavioral and mental dispositions through endogenous patterns of self-organization. When specific features prove effective over generations, these architectures can become genetically embedded, yielding species-specific, partially innate propensities (Tinbergen, Reference Tinbergen1951). However, these responses remain fundamentally dependent on external factors primarily for three reasons: first, they are typically triggered by external stimuli. Second, they yield reliable outcomes only in a stable environment where the conditions for their execution remain consistent with the outcomes they evolved to produce. Third, should the environment prove unstable, the embedded patterns of activation cease to specify a fixed response and instead become effectively permissive, engaging with other factors in the production of a response that adapts to the changing environment. When this shift fails to occur, a misalignment between endogenously instructed behavioral responses or mental states and the environment arises, resulting in dysfunctional outcomes that may predispose to mental disorders (Nesse, Reference Nesse2023).

It is noteworthy that the distinction between instructive and permissive causality – and their respective domains of action outside and within the individual – can be interpreted as resonating with Darwin’s theory of natural selection (Darwin, Reference Darwin1859). In the Darwinian theory, the evolutionary process relies on three core phases: variation, selection, and retention. Environmental conditions present challenges that favor some responses over others, representing the phase of selection and corresponding to the concept of instructive causality operating from outside the individual. Conversely, the repertoire of possible responses is determined by the individual’s internal capacities, representing the phase of variation and paralleling permissive causality operating from inside. Finally, the cycle is completed by retention, the mechanism by which selected variants are stabilized and preserved as endogenous patterns of self-organization.

Epigenetic embedding of instructive influences within the lifespan

While evolution operates over generations, the interplay between instructive and permissive causality is mirrored within the lifespan by epigenetic processes, which can be understood as the biological embedding of environmental experiences (Aristizabal et al., Reference Aristizabal, Anreiter, Halldorsdottir, Odgers, McDade, Goldenberg and O’Donnell2020). In this framework, environmental exposures can operate in an instructive manner by providing specific signals – such as early-life stress or nurturing – that shape chromatin-based modifications (e.g. DNA methylation and histone modifications) and thereby influence gene regulation (Meaney & Szyf, Reference Meaney and Szyf2005) and gene × environment interplay (Klengel & Binder, Reference Klengel and Binder2015), with downstream consequences for mental and behavioral outcomes. Importantly, once established, these epigenetic modifications can persist over time and become part of the individual’s internal biological substrate. At this stage, their causal role is best described as permissive with respect to emergent clinical phenotypes: epigenetic marks typically do not linearly determine a specific psychopathological outcome (Nestler, Reference Nestler2014), but rather bias gene-expression programs and constrain the range of possible regulatory states (Klengel & Binder, Reference Klengel and Binder2015). This can alter an individual’s susceptibility, changing the likelihood that future environmental challenges will increase the probability of a psychopathological outcome without uniquely specifying its form. Thus, epigenetics provides a concrete example of how contextual information can be biologically transduced and stabilized, bridging context and biology by transforming externally driven signals into internally instantiated constraints that subsequently operate permissively with respect to emergent clinical phenotypes, in parallel with the way evolutionary processes transform past environmental selection pressures into internal constraints across generations.

Targeting biological substrates

Biological substrates, including genes, molecules, and neural elements, are structurally and functionally essential because they serve as building blocks for producing mental states and behavior. However, they do not dictate which outcomes occur (Branchi, Reference Branchi2022b), but rather, through permissive causality, they determine which outcomes can be afforded. Indeed, since the brain is a complex adaptive system, deleting or adding any element of the brain does not typically have a specific and linear consequence on mental states, but it will modify the range of possible mental outcomes. If any biological substrate is missing or impaired, due to genetic mutations, lesions, or other events, a specific mental or behavioral outcome may no longer be affordable because the necessary elements to produce it are no longer available. Nevertheless, an alternative response still must be produced because of the need to cope with the contextual challenges. Such an alternative response will be selected on the basis of the biological substrates still available and may not be directly related to the missing substrate. Thus, biological elements should be considered not as drivers of a specific phenotype but as constraining factors in brain functioning and, consequently, in the production of mental and behavioral outcomes (Branchi, Reference Branchi2024).

When translating this view to clinical settings, it follows that treatments targeting biological substrates, such as pharmacological approaches, are unlikely to produce a specific outcome, although they do modify the likelihood of its occurrence, via permissive causality (Branchi, Reference Branchi2022b; Edelman & Gally, Reference Edelman and Gally2001; Prinz, Bucher, & Marder, Reference Prinz, Bucher and Marder2004). Accordingly, a growing body of research demonstrates that genetic risk factors and liabilities (Bassett, Scherer, & Brzustowicz, Reference Bassett, Scherer and Brzustowicz2010; Kendler, Prescott, Myers, & Neale, Reference Kendler, Prescott, Myers and Neale2003; Zhu, Need, Petrovski, & Goldstein, Reference Zhu, Need, Petrovski and Goldstein2014) and drugs targeting specific substrates (Ford & Young, Reference Ford and Young2022; Schneider et al., Reference Schneider, Hernandez, Brock, Eckstein, Bodenmann, Heinrichs and Ditzen2025; Viglione et al., Reference Viglione, Chiarotti, Poggini, Giuliani and Branchi2019) do not produce univocal effects but instead create a range of potential outcomes. It is noteworthy that this view does not apply to disorders that can be considered non-complex systems, which exhibit instructive relationships between specific substrates and outcomes. Examples of non-complex disorders are Mendelian genetic diseases. Moreover, while most psychiatric disorders are complex, some psychiatric syndromes are secondary to relatively circumscribed biological determinants, such as Pellagra (driven by niacin deficiency) or Phenylketonuria (driven by a single gene mutation), where a primary cause is predictably linked to the pathological outcome.

Targeting context

In complex problems, such as psychiatric disorders, instructive causality is expected to arise only in the interaction with context (Branchi, Reference Branchi2024). Therefore, contextual factors should be considered not as passive players affecting the outcome of a ‘diseased’ brain but as active determinants capable of controlling and orchestrating brain functioning. Thus, therapeutic strategies based on the modification of the objective features of the environment, or targeting the individual’s subjective appraisal, represent powerful tools to reorganize the central nervous system, promoting mental well-being (Branchi, Reference Branchi2022b). Environmental interventions, such as green care or social farming (Borgi et al., Reference Borgi, Marcolin, Tomasin, Correale, Venerosi, Grizzo and Cirulli2019; Vera, Reference Vera2020), and psychotherapy, which modifies how the individual copes with context (Cuijpers et al., Reference Cuijpers, Noma, Karyotaki, Vinkers, Cipriani and Furukawa2020; Grunder et al., Reference Grunder, Brand, Mertens, Jungaberle, Kartner, Scharf and Wolff2024), are increasingly proven effective in the treatment of psychiatric disorders. Accordingly, differences in subjective appraisal have been demonstrated to determine the outcome of psychiatric treatments, including drug administration and neuromodulation (Dutcher & Krystal, Reference Dutcher and Krystal2024; Fassi et al., Reference Fassi, Hochman, Daskalakis, Blumberger and Cohen Kadosh2024; Godlewska et al., Reference Godlewska, Browning, Norbury, Cowen and Harmer2016; Shiroma, Thuras, Johns, & Lim, Reference Shiroma, Thuras, Johns and Lim2014; Wardenaar, Conradi, Bos, & de Jonge, Reference Wardenaar, Conradi, Bos and de Jonge2014). Furthermore, psychotherapy has been demonstrated to impact biological substrates not only in brain disorders (Dichter, Felder, & Smoski, Reference Dichter, Felder and Smoski2010; Fu et al., Reference Fu, Williams, Cleare, Scott, Mitterschiffthaler, Walsh and Murray2008; Mason et al., Reference Mason, Peters, Williams and Kumari2017) but also in diseases affecting the entire body, such as cancer (Antoni et al., Reference Antoni, Lutgendorf, Cole, Dhabhar, Sephton, McDonald and Sood2006; Borgi, Collacchi, Ortona, & Cirulli, Reference Borgi, Collacchi, Ortona and Cirulli2020; Chida, Hamer, Wardle, & Steptoe, Reference Chida, Hamer, Wardle and Steptoe2008; Spiegel, Reference Spiegel2002). One of the most compelling examples of the critical role played by contextual factors in driving the organization of biological processes is the placebo effect (Benedetti, Reference Benedetti2008), where the patient’s expectation of clinical benefit is essential (Andrews, Reference Andrews2001; Bargmann, Reference Bargmann2012; Colloca & Benedetti, Reference Colloca and Benedetti2005). As such, the placebo effect is a biological phenomenon that emerges from the individual’s psychosocial and emotional context (Benedetti, Reference Benedetti2008). Pain perception is one of the key examples of the placebo response (Price et al., Reference Price, Milling, Kirsch, Duff, Montgomery and Nicholls1999; Swerts, Benedetti, & Peres, Reference Swerts, Benedetti and Peres2022). Additionally, in psychiatry, studies have shown that the response to antidepressant treatments is significantly influenced by the placebo response (Cipriani et al., Reference Cipriani, Furukawa, Salanti, Geddes, Higgins, Churchill and Barbui2009; Kirsch et al., Reference Kirsch, Deacon, Huedo-Medina, Scoboria, Moore and Johnson2008; Stone et al., Reference Stone, Yaseen, Miller, Richardville, Kalaria and Kirsch2022; Walsh, Seidman, Sysko, & Gould, Reference Walsh, Seidman, Sysko and Gould2002).

Despite its importance, the individual’s context – that is, the subjective experience of the environment according to personal history and features – is often overlooked in clinical research and mental health practice. This oversight may significantly undermine the reliability, explanatory power, and impact of studies aimed at understanding psychopathology and developing new treatments. Though there are notable exceptions (Trivedi et al., Reference Trivedi, Rush, Wisniewski, Nierenberg, Warden, Ritz and Fava2006), clinical trials in psychiatry rarely consider detailed contextual information, potentially failing to identify events and processes of clinical significance that could benefit patients (Schumann et al., Reference Schumann, Binder, Holte, de Kloet, Oedegaard, Robbins and Wittchen2014).

Plasticity-enhancing treatments: context is essential for therapeutic efficacy

The theoretical framework proposed here holds critical implications in clinical practice, particularly for novel potential treatments for depression such as psychedelics, 3,4-methylenedioxymethamphetamine, and ketamine. Since their therapeutic action relies, at least in part, on the ability to enhance plasticity, their efficacy emerges from the combination with contextual factors promoting well-being. Indeed, they have been shown to produce effects that are affected by the psychological context, and thus by the placebo effect (Bottemanne et al., Reference Bottemanne, Morlaas, Claret, Sharot, Fossati and Schmidt2022; Dutcher & Krystal, Reference Dutcher and Krystal2024; Mitchell et al., Reference Mitchell, Ot’alora, van der Kolk, Shannon, Bogenschutz, Gelfand and Group2023; R. B. Price et al., Reference Price, Spotts, Panny, Griffo, Degutis, Cruz and Howland2022; Seybert et al., Reference Seybert, Schimmers, Silva, Breeksema, Veraart, Bessa and Oliveira-Maia2025). Therefore, these treatments may be understood as adjuncts to psychotherapy or environmental interventions. Attempts to isolate the pharmacological effect from the contextual one could fail to capture the potential of these treatments in real-world settings, and prescribing them without controlling for the context in which they are administered may undermine their therapeutic efficacy. Despite valid concerns from regulatory agencies, which view psychotherapy-assisted drug treatments as overly complex and challenging to regulate (Kupferschmidt, Reference Kupferschmidt2024; Reardon, Reference Reardon2024), the theoretical framework proposed here highlights that the beneficial outcomes of plasticity-enhancing treatments can be achieved only by integrating contextual factors into the therapeutic approach. This is because exploiting both instructive and permissive causality is essential for achieving well-being, as relying on only one type of causality may not be sufficient. In other words, as plasticity is not inherently beneficial by definition, treatments aimed at enhancing it do not, per se , have a predictable therapeutic effect.