The evidence to date suggests that serotonin 2A agonist classic psychedelics such as psilocybin have a good safety profile and may be effective in the treatment of certain psychiatric disorders when combined with therapy (Luoma et al., 2020; Nutt et al., 2010; Rucker et al., 2022). For example, results from three randomized controlled trialssuggest that psilocybin administration, in conjunction with psychological support, can reduce depressive symptoms in patients with major depressive disorder (Carhart-Harris et al., 2021; Davis et al., 2021; von Rotz et al., 2023). Such findings contribute to a growing body of evidence in support of potential mental health benefits (Reiff et al., 2020), but relatively little remains known about potential risks associated with classic psychedelic use, including use outside of the carefully selected samples and highly controlled settings in which clinical trials are occurring (Anderson et al., 2020).

The leading guidelines on classic psychedelic research suggest a number of precautions to minimize risks. For example, it is recommended that individuals who take certain medications (e.g., lithium) that may alter the effects of classic psychedelics are screened out. The guidelines also suggest that risks can be further reduced by ensuring an appropriate set (i.e., psychological state) and setting (i.e., physical setting), including a positive mindset, an aesthetically appealing physical environment, and psychological support (Johnson et al., 2008). The acute classic psychedelic experience may still, however, elicit acute anxiety or panic and paranoia among other psychologically difficult states, even when overseen in a controlled and supportive setting (Barrett et al., 2016; Cohen, 1960; Strassman, 1984; Gashi et al., 2021). The long-term effects of such experiences are not well-understood (Barrett et al., 2016; Carbonaro et al., 2016), but previous research suggests that it may be associated with a higher risk of harm to oneself or others (Carbonaro et al., 2016), which makes it an important area for harm reduction research.

The prevalence of challenging, difficult, or distressing experiences using classic psychedelics has not yet been examined in nationally representative samples free of significant self-selection bias, but the frequency and intensity of such experiences appear to be higher in naturalistic surveys than in laboratory studies (Carbonaro et al., 2016), which may be related to extra-pharmacological factors (e.g., psychological support, structured setting). The research to date suggests that a number of psychological traits and states may predict challenging, difficult, or distressing experiences using classic psychedelics (Barrett et al., 2017; Haijen et al., 2018). Yet relatively little remains known about the associations between certain medication co-use, set and setting, and challenging, difficult, or distressing classic psychedelic experiences. Here, using a subsample (n = 613) of lifetime classic psychedelic users from a representative sample of the US adult population with regard to sex, age, and ethnicity (N = 2822), we aimed to conduct exploratory research on the prevalence and associations of challenging, difficult, or distressing experiences using classic psychedelics.

1. Materials and methods

1.1. Participants and procedure

Using linear multiple regression (fixed model, R2 increase) in GPower, we calculated that a sample size of 395 classic psychedelic users would achieve 80 % power to detect a small effect size with an alpha of 0.05. Based on recent data on the prevalence of lifetime classic psychedelic use in the US adult population (Simonsson et al., 2021), we estimated that around 2800 participants would be necessary to get approximately 395 lifetime classic psychedelic users in the sample. We therefore aimed to recruit 2800 participants in total.

The participants were 18 years or older and current residents of the United States (US). The sample (N = 2822) was recruited on Prolific Academic (https://app.prolific.co ) in October (1st–9th) 2021 and was stratified across three demographic characteristics — sex (male, female), age (18–27, 28–37, 38–47, 48–57, and 58+), and ethnicity (White, Mixed, Asian, Black, Other) – to reflect the demographic distribution of the US adult population. The recruitment materials did not mention classic psychedelics to avoid potential self-selection bias (see Supplemental Materials for recruitment materials). Respondents who reported having used a classic psychedelic at least once in their lifetime (n = 613; see Supplemental Table 1 for key demographics) were asked to complete a number of items related to challenging, difficult, or distressing experiences using classic psychedelics. Study completion resulted in $2.20 payment and study procedures were approved by the Institutional Review Board at the University of Wisconsin – Madison. The data and Stata syntax are available at figshare: https://doi.org/10.6084/m9.figshare.21972953 [Data] and https://doi.org/10.6084/m9.figshare.21972956.v1 [Syntax].

1.2. Measures

1.2.1. Lifetime classic psychedelic use

All respondents were asked to report which, if any, of the following classic psychedelics they had ever used: ayahuasca, N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), mescaline, peyote, San Pedro, and psilocybin (“magic mushrooms”). Respondents who reported that they had used any of these substances were coded as positive for lifetime classic psychedelic use, whereas those indicating that they had never used any of these substances were coded as negative.

1.2.2. Challenging, difficult, or distressing experiences

Respondents who reported lifetime classic psychedelic use were asked three items related to challenging, difficult, or distressing experiences using classic psychedelics (adapted from items used in Goldberg et al., 2021): “I personally have had challenging, difficult, or distressing experiences as a result of using classic psychedelics” (Never, Rarely, Occasionally, Regularly, Frequently); “My challenging, difficult, or distressing experiences using classic psychedelics impaired my ability to function” (Not applicable; I have not had difficulties, Not at all, Somewhat, Moderately, Severely); and “How long did your impairment last?” (I did not experience impairment, 1 day or less, For a few days to 1 week, >1 week to 1 month, >1 month to 1 year, >1 year). Respondents were also asked whether the challenging, difficult or distressing experiences were associated with a specific classic psychedelic (multiple-choice). Using a modified version of the 11-item Meditation-Related Adverse Effects Scale – Mindfulness-Based Program (MRAES-MBP (Britton et al., 2018)),¹ respondents were also asked whether they had experienced any of the listed enduring adverse effects as a result of classic psychedelics (e.g., “I felt distant or cut off from other people”, “I experienced repeated, disturbing memories, thoughts, or images of a stressful experience from the past”). The responses were rated on a 5-point Likert scale: (1) Never, (2) For a few days to 1 week, (3) >1 week to 1 month, (4) >1 month to 1 year, (5) >1 year. Prior research using the MRAES-MBP has shown that endorsement of challenging, difficult, or distressing experiences is higher when specific experiences are queried versus when a single, more general item is used (Goldberg et al., 2021). Therefore, respondents who reported never having had challenging, difficult, or distressing experiences using classic psychedelics on the single item were still asked to complete the MRAES-MBP. Finally, a single item assessed whether participants felt glad to have used classic psychedelics (adapted from item used in Goldberg et al., 2021):

Consider the various experiences you have had using classic psychedelics, including any challenging, difficult, or distressing experiences. How much do you agree with the following statement: “I am glad I have used classic psychedelics.”

The responses were rated on a 1- (Strongly disagree) to 6-point (Strongly agree) Likert scale.

Most challenging, difficult, or distressing experience.

Respondents who reported lifetime classic psychedelic use were asked to look back on their most challenging, difficult, or distressing experience using a classic psychedelic and complete the 26-item Challenging Experiences Questionnaire (CEQ (Barrett et al., 2016)), which asks respondents to rate the extent to which they experienced any of the listed phenomena (e.g., “isolation and loneliness”, “I had the profound experience of my own death”, “I experienced a decreased sense of sanity”). The responses were rated on a 0- (None; not at all) to 5-point (Extreme) Likert scale. The internal consistency was excellent (alpha = 0.97).

After completing the CEQ, respondents were asked whether the challenging, difficult, or distressing experience was associated with variables related to the set and setting (list modified from (Carbonaro et al., 2016); see response items in Supplemental Materials), whether there was anything that was helpful in responding to or managing the experience (list derived from Carbonaro et al., 2016), and whether there were thoughts or attempts to hurt themselves or others in the days or weeks following the experience. Respondents were also asked whether they sought medical, psychiatric, or psychological assistance in the days or weeks following the challenging, difficult, or distressing experience and whether they were using any specific medications (i.e., tricyclic antidepressants, SSRIs, SNRIs, MAOIs, St John's Wort, or any other medications or supplements with serotonin activity; haloperidol or any other antipsychoticmedications; lithium or any other mood stabilizers; or methadone or buprenorphine/suboxone) at the time of the challenging, difficult, or distressing experience. These medications were assessed because research on their drug-drug interactions with classic psychedelics is ongoing (e.g., ClinicalTrials.gov Identifier: NCT04161066 ) or because individuals who use them are typically excluded from participation in clinical trials using classic psychedelics (e.g., ClinicalTrials.gov Identifier: NCT02037126 ), which corresponds with contemporary guidelines (Johnson et al., 2008).

1.3. Statistical analyses

We used multiple linear (for continuous dependent variables) and logistic (for dichotomous) regression models to evaluate associations related to respondents' most challenging, difficult, or distressing classic psychedelic experience. All analyses were conducted using Stata version 17.

2. Results

2.1. Challenging, difficult, or distressing experiences

Table 1 shows descriptive statistics of challenging, difficult, or distressing experiences using classic psychedelics. As indicated in the table, a little more than half of the respondents (59.1 %) reported never having had a challenging, difficult, or distressing classic psychedelic experience. Approximately one in twenty (4.6 %) reported severely impaired ability to function and roughly one in ten (8.9 %) reported impairment that lasted longer than one day. A majority (57.1 %) reported at least one of the listed enduring symptoms (feeling anxious being the most common) and most agreed (from slightly agree to strongly agree) with the gratitude statement (“I am glad I have used classic psychedelics”). Lastly, LSD was most commonly associated with challenging, difficult, or distressing classic psychedelic experiences (24.0 %; 31.5 % of lifetime LSD users), followed by tryptamines (15.3 %; 19.7 % of lifetime tryptamine users) and phenethylamines (4.1 %; 14.7 % of lifetime phenethylamine users).

2.2. Most challenging, difficult, or distressing experience

Table 2 displays variables related to the most challenging, difficult, or distressing experience using a classic psychedelic. As seen in the table, approximately one in nine (11.3 %) reported co-use of at least one type of medication at the time of their most challenging, difficult, or distressing experience using a classic psychedelic. The five most commonly reported set and setting variables associated with respondents' most challenging, difficult, or distressing classic psychedelic experience were: no preparation, negative mindset, no psychological support, disagreeable social environment, and disagreeable physical environment. The five most commonly reported helpful interventions during respondents' most challenging, difficult, or distressing classic psychedelic experience were: trying to calm the mind, changing location, asking for help from friend, changing social environment, and smoking cannabis. In the days or weeks following their most challenging, difficult, or distressing experience using a classic psychedelic, roughly one in fifteen (6.7 %) reported thoughts or attempts of hurting themselves or others (4.6 %, thoughts of hurting oneself; 2.6 % thoughts of hurting others; 1.5 %, attempts to harm oneself; 0.7 %, attempts to harm others) while nearly one in forty (2.6 %) reported seeking medical, psychiatric, or psychological assistance.

Table 3 presents results from the multiple linear regression models examining the associations between medication co-use, set and setting, and CEQ scores (see Supplemental Table 2 for unadjusted analyses). As shown in the table, both co-use of lithium and co-use of other mood stabilizers during respondents' most challenging, difficult, or distressing experience using a classic psychedelic were associated with higher CEQ scores. No associations were observed with other types of medication co-use. No preparation, disagreeable physical environment, negative mindset, no psychological support, dose was too large, and major life event prior to experience were associated with higher CEQ scores. No associations were observed with other set and setting variables.

Table 4 displays results from the multiple logistic regression models examining the associations between medication co-use, set and setting, and overall risk of harm (i.e., thoughts or attempts to hurt themselves or others; see Supplemental Table 3 for unadjusted analyses). As demonstrated in the table, both co-use of lithium and co-use of other mood stabilizers during respondents' most challenging, difficult, or distressing classic psychedelic experience were associated with higher odds of overall risk of harm. No associations were observed with other types of medication co-use. Negative mindset, no psychological support, and major life event prior to experience were associated with higher odds of overall risk of harm. No associations were observed with other set and setting variables.

3. Discussion

The present study investigated the prevalence and associations of challenging, difficult, or distressing experiences using classic psychedelics, in a representative sample of the US adult population with regard to sex, age, and ethnicity. Of the 613 respondents who reported lifetime classic psychedelic use, the majority of them (59.1 %) had never had a challenging, difficult, or distressing experience using a classic psychedelic, but 8.9 % reported functional impairment that lasted longer than one day as a result of such experiences. Notably, 2.6 % reported seeking medical, psychiatric, or psychological assistance in the days or weeks following their most challenging, difficult, or distressing experience, which broadly corresponds with findings from previous research (Carbonaro et al., 2016).

When respondents were asked about their most challenging, difficult, or distressing experience using a classic psychedelic, trying to calm the mind was the most commonly reported helpful intervention, which broadly corresponds with findings from previous research (Carbonaro et al., 2016). As part of the preparation for a classic psychedelic experience, it may therefore be useful to introduce exercises that users can utilize to calm the mind such as mindfulness-based practices (for reviews on the potential synergies between classic psychedelics and mindfulness meditation, see Eleftheriou and Thomas, 2021; Payne et al., 2021).

In covariate-adjusted regression models, co-use of lithium, co-use of other mood stabilizers, and six set and setting variables (no preparation, disagreeable physical environment, negative mindset, no psychological support, dose was too large, major life event prior to experience) were associated with the degree of difficulty during respondents' most challenging classic psychedelic experience. These findings strengthen the support for the main guidelines on safety in classic psychedelic research (Johnson et al., 2008), especially as co-use of lithium, co-use of other mood stabilizers, and three set and setting variables (negative mindset, no psychological support, major life event prior to experience) were also associated with higher odds of overall risk of harm. Notably, the associations related to the set and setting are consistent with findings from previous research (Carbonaro et al., 2016) while the associations related to lithium co-use correspond with previous findings on links between lithium co-use and classic psychedelic-related seizures (Simonsson et al., 2022; Nayak et al., 2021). It therefore appears prudent for both clinical trials and legalization initiatives to strictly follow contemporary guidelines (Johnson et al., 2008), at least until future research has provided a greater understanding of potential risks.

There are several limitations in the present study that need to be considered when interpreting the findings. First, the associations reported in this study cannot be used to infer causality due to the cross-sectional design. Second, the sampling platform (Prolific Academic) used in this study only allowed the sample to be stratified across three demographics – sex, age and ethnicity – to reflect the demographic distribution of the US adult population. It may not necessarily have been representative on other variables (e.g., indicators of socioeconomic status). Third, the respondents were asked to complete self-report measures, which are susceptible to a range of biases. Future research should use longitudinal research designs and objective measures to investigate potential causal links between classic psychedelic use and psychological risks among naturalistic users.

4. Conclusion

In summary, this study provides insight into the prevalence and associations of challenging, difficult, or distressing experiences using classic psychedelics. The findings broadly correspond with findings from previous studies and can be used to inform both ongoing harm reduction efforts and future experimental research designs.

Summary

This study examined the prevalence and correlates of negative experiences with classic psychedelics in a nationally representative sample of US adults. A substantial portion of lifetime users reported no challenging experiences, yet a notable minority experienced significant impairment. Specific factors, including medication interactions and environmental conditions, were identified as significantly associated with negative outcomes.

Materials and Methods

A sample of 2822 US adults, stratified by demographics, was recruited to obtain a subsample of 395 lifetime classic psychedelic users (achieved with n=613). Participants completed questionnaires assessing classic psychedelic use history, challenging experiences, medication use, and details of the most challenging experience. Multiple regression analyses examined associations between various factors and the severity and risk of negative outcomes.

Results

Over half of respondents (59.1%) reported no challenging psychedelic experiences. However, a minority reported severe functional impairment (4.6%) and long-lasting effects (8.9%). LSD was most frequently associated with negative experiences. In analyses of the most challenging experience, lithium and other mood stabilizers, along with inadequate preparation, negative mindset, lack of support, and unfavorable environment, predicted increased negative experience severity and heightened risk of self-harm.

Discussion

The findings corroborate existing research highlighting the importance of careful preparation, supportive environments, and screening for medication interactions to mitigate risks associated with classic psychedelic use. The study's cross-sectional design limits causal inferences. Future longitudinal research with objective measures is needed to solidify these findings.

Conclusion

This study provides valuable data on the prevalence and risk factors associated with adverse classic psychedelic experiences. The results reinforce current safety guidelines and underscore the need for further research to fully understand and minimize potential harms.

Summary

Research suggests classic psychedelics, while showing promise in treating psychiatric disorders when used therapeutically, also carry potential risks. This study explores the prevalence and associated factors of difficult or distressing experiences with classic psychedelics in a nationally representative sample of US adults.

Materials and Methods

Researchers recruited 2822 US adults aged 18+ through Prolific Academic, stratifying by sex, age, and ethnicity to mirror the US population. The sample included 613 lifetime classic psychedelic users. Participants completed questionnaires assessing challenging experiences, medication use, and set/setting factors surrounding their most difficult psychedelic experience. Multiple linear and logistic regression models analyzed associations between these variables and the severity of negative experiences and the risk of self-harm.

Results

A significant minority (40.9%) of lifetime classic psychedelic users reported at least one challenging experience. LSD was most frequently associated with negative experiences. Co-use of lithium or other mood stabilizers, alongside several set/setting factors (lack of preparation, negative mindset, lack of support, unsuitable environment, high dose, preceding life event), significantly predicted greater negative experience severity and increased odds of self-harm. Seeking professional help after a difficult experience was relatively uncommon (2.6%).

Discussion

This study confirms that negative experiences with classic psychedelics are relatively common and highlights several risk factors, aligning with existing guidelines emphasizing careful preparation and support. The study's cross-sectional design limits causal inference. Further longitudinal research with objective measures is needed to establish causal relationships and refine harm reduction strategies.

Conclusion

This research provides valuable prevalence data and identifies key risk factors for difficult psychedelic experiences, informing harm reduction and future research directions. The findings support the importance of adherence to safety guidelines in both clinical and recreational settings.

Summary

Research suggests classic psychedelics, like psilocybin, are relatively safe and might help treat mental health issues when used with therapy. Studies show psilocybin can lessen depression symptoms. However, we still don't fully understand the risks of using these drugs outside of controlled settings.

Minimizing Risks

Guidelines for psychedelic research emphasize precautions. People on certain medications, like lithium, should be screened. A positive mindset and supportive environment are crucial. Even with these precautions, difficult experiences like anxiety, panic, or paranoia can occur. The long-term effects aren't well understood, but past research suggests a possible link to self-harm.

Prevalence and Associations

The frequency of difficult psychedelic experiences hasn't been studied in a truly representative sample of the US population. Naturalistic surveys show higher rates than lab studies, likely due to differences in support and setting. Certain personality traits and states may predict negative experiences, but the roles of medication use, environment, and mindset aren't fully clear. A study examined these factors in a large US sample.

Study Methods

Researchers aimed to find 395 classic psychedelic users for a study, estimating needing around 2800 participants overall to achieve this. They recruited 2822 participants online, ensuring representation across sex, age, and ethnicity. Participants who reported past psychedelic use (613 people) answered questions about difficult experiences.

Study Results

About 60% of participants reported no difficult psychedelic experiences. A small percentage (less than 10%) reported impairment lasting over a day. LSD was the most frequently linked to negative experiences. In the most challenging experiences, lack of preparation, a negative mindset, and lack of support were common. Calming the mind was the most common helpful intervention.

Study Conclusions

This study offers insight into the prevalence and factors associated with negative psychedelic experiences. Findings largely agree with previous research. The results can inform harm reduction efforts and future research. Co-use of lithium or mood stabilizers increased the risk of difficult experiences and harm. Lack of preparation, negative mindset, and absence of support also increased the risk.

Summary

Some types of psychedelic drugs, like psilocybin ("magic mushrooms"), might help treat mental health problems when used with therapy. Studies show they can ease depression, but we don't know much about the risks of using these drugs outside of carefully controlled studies.

Safety Tips

Experts suggest ways to make psychedelic use safer. People on certain medicines shouldn't use them. A good mental state ("set") and a safe, comfortable place ("setting") are also important. Even with these precautions, some people still have bad experiences like anxiety or paranoia. The long-term effects aren't fully understood.

Study on Difficult Experiences

A large study looked at how often people have bad trips on psychedelics. It found that many people never have a bad experience, but some do. Things like a person's personality and whether they're taking other medicines might make a bad trip more likely.

How the Study Worked

Researchers surveyed almost 3,000 adults in the US. They asked about their experiences with psychedelics. Over 600 people said they had used psychedelics. The study asked detailed questions about their worst experience with these drugs.

What the Study Found

Most people (almost 60%) who used psychedelics never had a bad trip. A smaller number had problems that lasted a long time. Taking certain medicines, like lithium, along with psychedelics increased the chances of a bad experience. Being unprepared, having a bad mood, or not having support during the experience also increased the risk of a challenging experience.

Important Things to Remember

This study shows us more about the risks and benefits of using psychedelics. The study couldn't prove that specific things cause bad trips, but it shows which factors are linked to negative experiences. More studies are needed to understand these drugs better.