We welcome the renewed interest in the therapeutic potential of psychedelic compounds. In their recent editorial, Sessa & Johnson ^{Reference Sessa and Johnson1} echo the fervent research climate of psychedelics spanning the 1950s and ’60s. They suggest that psychedelics may cause prolonged changes in participants’ personalities and attitudes following mystical-spiritual experiences. This unique and exciting potential mechanism of action certainly warrants the current renaissance in psychedelic research, and has important implications for study design and participant selection. As we move towards re-exploring the clinical applications of psychedelics, however, we must appreciate that the phenomenology of the psychedelic experience is likely to depend not only on the drug’s pharmacodynamic properties, but also on the makeup of the participant (‘set’) and the environmental context (‘setting’) in which the drug is administered.

Recent work suggests that the potential importance of set in the psychedelic experience should not be overlooked. Hallucinogenic compounds act via the serotonergic 5-HT_2A receptor to affect experience and behaviour. Genetic and neuroimaging evidence suggests that inter-individual differences in serotonergic neurotransmission relate to personality differences and vulnerability to psychiatric illness. ^{Reference Ebstein2} Relatedly, research with hallucinogenic compounds has reported sustained changes in personality traits and behaviour. ^{Reference MacLean, Johnson and Griffiths3} Moreover, reports from individuals who have taken hallucinogenic compounds suggest that the quality of the experience (whether the ‘trip’ is good or bad) has some connection to the attitude and particular psychological landscape of the individual. ⁴ Finally, a closer look at the psychological profile of participants who volunteer for these studies reveals that they may not be representative of the general population, and in particular may be more open to new experiences. ^{Reference MacLean, Johnson and Griffiths3} Together, these ideas suggest that the effect of a hallucinogenic compound on an individual’s experience has complex links with their neurobiological and psychological composition.

The quality of the psychedelic experience is also inextricably linked to the environmental and social setting. In the late 1960s, several studies strove to isolate the action of a drug from external influence, including concomitant therapy. ⁴ Their efforts generated less promising results than studies that, by design, emphasised the importance of the setting. ^{Reference Oram5} As an illustrative example, one study found sensory deprivation to be antagonistic to the ‘LSD experience’. ^{Reference Hoffer and Osmond6} Consequently, the relationship between the psychedelic experience and the setting must be considered in experimental design. Even a structured test or interview can radically alter the resulting phenomenology. ^{Reference Hoffer and Osmond6}

We propose that a fruitful future research programme investigating the therapeutic potential of psychedelic compounds must take the complex interaction between set and setting into account in its participant recruitment and study design. By acknowledging this association, future research will be in a position to understand the full breadth of the psychedelic experience and its potential clinical applications. Although practically challenging, such a comprehensive approach will allow us to re-examine the perhaps premature assertions of the mid-1970s that psychedelics had no therapeutic applications. ^{Reference Oram5}