Which non-pharmacological factors really matter?

Psychedelic drugs produce a remarkably vast range of effects, from psychotic-like to mystical-like, even when the same substance is taken at the exact same dose. Both the acute psychedelic experience and longer-term therapeutic outcomes appear to be shaped not only by the pharmacology of the drug, but by a number of factors external to it. Commonly referred to as extra- or non-pharmacological factors, these variables can be separated into those concerned with ‘set’-the individual’s mindset, expectations, and psychological state–and ‘setting’.

Those grouped under the umbrella of ‘setting’ comprise aspects of the physical environment, exposure to sensory inputs, the therapeutic container or modality, and the ritual or cultural framings embedded within the practice. 

One element of setting that has received increasing attention is exposure to nature. Sam Gandy and colleagues detail the potential synergistic interaction between psychedelics and contact with the natural world, noting that the combination may amplify a sense of calm, beauty, and interconnectedness with all life. Indeed, many facilitators intentionally design nature-based retreat settings, and although Western clinical psychedelic models typically mandate controlled indoor settings, several major protocols attempt to evoke a sense of nature through plants, nature-based photography, and artwork in dosing rooms.

Beyond the physical environment, music similarly appears to enhance and influence the psychedelic experience. It can guide the emotional tone, imagery, and meaning attributed to unfolding experiences, and is widely regarded as integral for self-exploration during psychedelic therapy.  However, while music often promotes calm and safety, interview data also highlight its potential to evoke distress or a sense of being “misguided” when poorly matched. As Steven Gelberg observes, “In psychedelic states, music is no longer music as we ‘know’ it. As if in a dream, it shape-shifts into something vastly more significant, multi-dimensional, an opening to other worlds.” (If interested, consider watching East Forest’s documentary exploring the pairing of music with psychedelics).

Importantly, neither the emphasis on nature nor the centrality of music is novel. Indigenous ceremonial traditions have long been inherently immersed in natural landscapes and have cultivated these relationships for generations. Within these traditions, music similarly serves as a critical component, with icaros functioning as key navigational tools in Amazonian Ayahuasca practices, for example. Understood as channels of healing, communication, and catalysts for extraordinary visual experiences, icaros reflect longstanding ideas about the metaphysical and spiritual properties of music.

Despite the clear importance of these non-pharmacological factors related to setting, we still lack clarity on which of these factors—if any—matter most to the therapeutic process, or how they exert their influence. Conclusive research remains lacking, an issue perpetuated by inconsistent reporting standards across studies (as highlighted in a previous Issue).

The ReSPCT Guidelines have aimed to establish an international consensus on the most important non-pharmacological influences on psychedelic effects. Designed for reporting in psychedelic clinical research, the checklist of items resulted from four rounds of anonymous surveys, yielding 30 extra-pharmacological variables of interest. While the focus was primarily on those falling under ‘setting’, a few exceptions relate more closely to ‘set’, though the cohort of experts was notably divided on the perceived separability of the two concepts.

Music and access to nature consistently solicited high agreement across rounds, whereas items related to cultural competence and safety—defined as the ability to care for patients with diverse backgrounds and address power imbalances in patient-provider interactions—increased markedly across rounds, from 50% to 73% agreement. This pattern may hint at broader trends in Western psychedelic research and practice whereby cultural dimensions gain prominence less through widespread agreement, and more through sustained advocacy which acts to reorient the field’s sense of what matters.

While the guidelines provide a valuable foundation, the demographic composition of the “experts” warrants mention. Despite spanning 17 countries, the panel was overwhelmingly homogenous. Nearly one third of experts had just 1-5 years of experience in the psychedelic field, and more than 80% identified as white; the next largest ethnic group—those identifying as ‘Indigenous’—comprised just 6.5%, with no specification of which Indigenous communities or regions this referred to. Experts from the U.S., UK, and Canada were markedly overrepresented, accounting for 25.8%, 22.6%, and 19.4%, respectively.

The authors acknowledged these limitations, noting that the focus on clinical trials inevitably shaped the panel’s demographics given the concentration of psychedelic research in Western institutions. Even so, the skew raises important questions about what constitutes ‘expertise’, whose voices may be inadvertently excluded in these contexts, and how future complementary endeavours can incorporate non-clinical, community-based, and culturally diverse perspectives when answering these critical questions.

As the field awaits widespread adoption of the ReSPCT guidelines, Robin Carhart-Harris and colleagues at University of California, San Francisco (UCSF) began work last year on a new trial examining the interaction effects of psilocybin and the surrounding context (set and setting). Using a 2×2 factorial design, 120 participants will receive either psilocybin or placebo in one of two distinct settings to assess how pre-defined contextual variables influence wellbeing, connectedness, and the quality of the acute experience.

Together, these efforts could deliver progress toward improving the transparency, reproducibility, and validity of this evolving field’s research output, while laying the groundwork for future clinical implementation that is both safe and effective.

Bottom Line: Psychedelic outcomes appear as much determined by mindset and context as by the drug itself. Nature, music, rituals, and cultural context all meaningfully shape individual’s experiences—a reality long recognised in Indigenous traditions and now increasingly acknowledged in clinical research. The ReSPECT guidelines, along with ongoing research at UCSF, aim to systematically understand these influences in clinical settings, promising clearer guidance for delivering psychedelic treatments that are safe, effective, and culturally attuned.