Classic psychedelics (aka hallucinogens) are a class of psychoactive drugs that include LSD (lysergic acid diethylamide), psilocybin (the main compound in “magic mushrooms”), dimethyltryptamine (DMT, the psychoactive substance in ayahuasca), and mescaline (as mentioned in a review by Johansen et al., 2022; Hart, 2021). Psychedelics are known for their ability to change perception and emotions (Johansen et al., 2022).
Classic psychedelics activate a specific kind of serotonin receptors, 5-HT2A receptors (Johansen et al., 2022). Madsen et al. (2019) found that when the participants ingested higher doses of psilocybin, more 5-HT2A receptors were occupied. Receptor occupancy was related to the concentration of the drug in the blood and participants’ ratings of the intensity of the experience (Madsen et al., 2019). Binding of psychoactive compounds to these receptors causes glutamate release, for instance, when rodents repeatedly received 5-HT2A/C agonists, they had higher glutamate levels in their somatosensory cortex (Scruggs et al., 2003). This, in turn, is theorized to be one of the potential mechanisms for hallucinations (Scruggs et al., 2003).
Psychedelics, like any other drug, can cause adverse effects, colloquially known as a “bad trip.” Challenging experiences using psychedelics are extremely rare. In a nationally representative sample of US adults, 59.1 % reported never experiencing a “bad trip” (Simonsson et al., 2023). 27.2 % of the respondents said that they experienced symptoms such as anxiety, difficulty sleeping, feeling disconnected from the world, and feeling isolated. While high doses of the drug might be responsible for some of these “bad trips,” most respondents linked them to set and setting factors (Simonsson et al., 2023).
Set refers to the individual characteristics of the person taking the drug and includes the person’s intentions, expectations, and emotions (Barrett et al., 2017). An online prospective study by Haijen et al. (2018) looked at the relationship between set and trait characteristics and “bad trips.” The results revealed that being in a good mood, feeling open toward the psychedelic experience, and having low levels of anxiety predicted lower chances of a distressing experience. In another study, Barrett et al. (2017) found that the personality trait neuroticism was associated with more intense negative psychedelic experiences. Neuroticism is described as the tendency to experience negative affect and have poor stress management skills, which means that highly neurotic people are more likely to experience feelings of anxiety and stress pre-hallucinogen use and thus, they are more likely to have a “bad trip” (Barrett et al., 2017). People high in neuroticism reported feelings of fear, grief, physical distress, isolation, and paranoia during their psychedelic trips more often than their less neurotic counterparts.
Setting, on the other hand, refers to the physical and social environment in which the drug is taken (Hart, 2021). Psychedelics can be taken in a variety of settings. Traditionally, many non-Western cultures used them as a part of ritual ceremonies (Johansen et al., 2022). Nowadays, hallucinogens are most often used outside of the traditional cultural context: raves, ayahuasca retreats, and even in psychotherapy (Kettner et al., 2021). Unfortunately, most psychedelic research focuses on psychedelic use in individual settings, whereas in reality, most people take these drugs in a social context (Kettner et al., 2021). A correlational online study of psychedelic retreat participants suggests the importance of the shared sense of togetherness in having a pleasant psychedelic experience (Kettner et al., 2021). This feeling of togetherness, achieved by creating a supportive social environment and trust between drug users and facilitators (e.g., people who guide the psychedelic retreats), was associated with better psychological well-being (Kettner et al., 2021).
While using drugs is not the best idea to begin with, if one decides to embark on a “trip,” keeping in mind the importance of set and setting is helpful. When taking any illicit substances, it’s a good idea to make sure that you’re relaxed, and prepared for the experience, and to take them in a safe, comfortable environment with people you trust. Though this is not a fool-proof rule, taking care of set and setting will reduce the chances of a “bad trip.” Even if you do experience adverse psychedelic effects, they most likely won’t stick around for long. For the majority of adults who had a bad experience with psychedelics, the negative effects lasted for no more than a day (Simonsson et al., 2023). Psychedelic research is an emerging field, and more studies need to be done on how set and setting affect the experience.
References
Barrett, F. S., Johnson, M. W., & Griffiths, R. R. (2017). Neuroticism is associated with challenging experiences with psilocybin mushrooms. Personality and Individual Differences, 117, 155-160. https://doi.org/10.1016/j.paid.2017.06.004
Haijen, E. C., Kaelen, M., Roseman, L., Timmermann, C., Kettner, H., Russ, S., … & Carhart-Harris, R. L. (2018). Predicting responses to psychedelics: a prospective study. Frontiers in Pharmacology, 897. https://doi.org/10.3389/fphar.2018.00897
Hart, C. L. (2022). Drug use for grown-ups: Chasing liberty in the land of fear. Penguin.
Johansen, L., Liknaitzky, P., Nedeljkovic, M., Mastin-Purcell, L., & Murray, G. (2022). The psychological processes of classic psychedelics in the treatment of depression: a systematic review protocol. Systematic Reviews, 11(1), 85. https://doi.org/10.1186/s13643-022-01930-7
Kettner, H., Rosas, F. E., Timmermann, C., Kärtner, L., Carhart-Harris, R. L., & Roseman, L. (2021). Psychedelic communitas: intersubjective experience during psychedelic group sessions predicts enduring changes in psychological wellbeing and social connectedness. Frontiers in Pharmacology, 234. https://doi.org/10.3389/fphar.2021.623985
Madsen, M. K., Fisher, P. M., Burmester, D., Dyssegaard, A., Stenbæk, D. S., Kristiansen, S., … & Knudsen, G. M. (2019). Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology, 44(7), 1328-1334. https://doi.org/10.1038/s41386-019-0324-9
Scruggs, J. L., Schmidt, D., & Deutch, A. Y. (2003). The hallucinogen 1-[2, 5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neuroscience Letters, 346(3), 137-140. https://doi.org/10.1016/S0304-3940(03)00547-0
Simonsson, O., Hendricks, P. S., Chambers, R., Osika, W., & Goldberg, S. B. (2023). Prevalence and associations of challenging, difficult or distressing experiences using classic psychedelics. Journal of Affective Disorders, 326, 105-110. https://doi.org/10.1016/j.jad.2023.01.073
On Psychology and Neuroscience 
This is a great blog post, Dana! You wrote it in a very easy-to-read manner. It’s important to know how set and setting affect drug experiences so I’m glad you wrote about this.
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Dana, your post is excellent!! Your point about set and setting resonated with me. I know from what others have shared how crucial the right mindset and environment are when it comes to psychedelic experiences. To be honest, I was a little surprised by the finding that bad trips are relatively rare. In my experience, most people who have used psychedelics seem to have had at least one really bad trip at some point. I wonder how exactly Simonsson et al. (2023) defined a “bad trip”? Did they only count incidents involving a complete loss of contact with reality, or did they include challenging but insightful experiences too?
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