The main findings of the present study were that the administration of a single dose of LSD (200 μg p.o.) in healthy volunteers induced a subjectively meaningful experience with lasting positive effects that were attributed to the LSD experience by the participants. Greater ratings of acute LSD-induced alterations of mind on the 5D-ASC and/or mystical-type experiences on the MEQ30 scales were associated with greater ratings of well-being 12 months after the experience and changes in lifetime mystical experiences. LSD did not increase trait openness or produce relevant changes in personality measures. In the present study, LSD was not associated with lasting negative effects, as no lasting increases of negative attitudes, negative mood, and negative behavior could be observed after one and 12 months.

The present findings confirmed most of our hypotheses and complemented similar recent reports of lasting effects of psilocybin in healthy subjects using the same outcome measures (Griffiths et al. 2006, 2008, 2011, 2017; MacLean et al. 2011). The lasting effects of LSD were also reported in psychiatrically healthy subjects in older studies (McGlothlin et al. 1967). Short-term effects on personality measures were reported in one recent study (Carhart-Harris et al. 2016a). Specifically, in the older study by McGlothlin et al. (1967), psychological tests were administered before and 2 weeks and 6 months after three single dose sessions (200 μg LSD p.o. in each session) in 24 healthy subjects to explore potential changes in attitudes and values (McGlothlin et al. 1967). The participants were graduate students, were paid for participation, were LSD-naive, and received the drug in a secure setting but without suggestions of possible lasting effects (McGlothlin et al. 1967). In contrast to our study, the drug sessions were held in a “tastefully decorated room specifically designed to enhance the drug experience” without distractions by experiments (McGlothlin et al. 1967). A higher proportion of participants reported lasting effects on personality and greater appreciation of music and art 6 months after LSD administration compared with controls who received either amphetamine (20 mg p.o.) or a very low dose of LSD (25 μg p.o.; McGlothlin et al. 1967). The majority of the participants also rated the acute LSD response as a very dramatic and interesting experience. However, the pre-LSD vs. post-LSD comparison of a series of personality and creativity test ratings did not document relevant changes (McGlothlin et al. 1967). These previous findings of LSD-attributed subjective changes in attitudes, values, and esthetic interests in the absence of alterations in more objective test measures (McGlothlin et al. 1967) were largely confirmed by the present results.

More recently, Griffiths and colleagues administered a single dose of psilocybin in a supportive setting in 30 hallucinogen-naive and spiritually active healthy subjects to evaluate the long-term effects of psilocybin (Griffiths et al. 2006, 2008). A cross-over study design was used, including a control condition (methylphenidate, 40 mg/70 kg p.o.), to assess the acute effects of psilocybin (30 mg/70 kg p.o.). The MS and MEQ were used to assess acute mystical-type experiences (Barrett et al. 2015; Griffiths et al. 2006), similar to the present study (Liechti et al. 2017). Lasting effects of psilocybin were assessed at 2 and 14 months using the PEQ and MS (Griffiths et al. 2008). In contrast to the present study with LSD, the volunteers did not receive monetary compensation for participation. The investigators met with the participants on four occasions (for a total of 8 h) before the psilocybin session to prepare them for the experience. In contrast to the present study, this presession preparation explicitly included the monitor’s expectation that the psilocybin session could increase personal awareness and insight (Griffiths et al. 2006) and thus could have lasting positive effects. Additionally, all of the subjects participated at least intermittently in religious or spiritual activities, in which 56% of the volunteers reporting daily engagement, and 39% indicated at least monthly activities (Griffiths et al. 2006, 2008). Griffiths and colleagues also conducted a dose-effect study that included the administration of four different single doses of psilocybin and placebo in 18 participants and assessed lasting effects at 1 and 14 months using the PEQ, MS, DTS, and NEO Personality Inventory (NEO-PI) (Griffiths et al. 2011), similar to the present study. Similar to LSD in the present study, a single dose of psilocybin (30 mg/70 kg) significantly increased ratings of acute mystical-type experiences on the MS and MEQ (Barrett et al. 2015; Griffiths et al. 2006, 2011). However, 17 of the overall 54 participants also reported strong or extreme fear sometimes during the session after administration of psilocybin at this dose (Griffiths et al. 2006, 2011). Consistent with the present findings, psilocybin also produced significant positive effects but no negative effects on the PE compared with the control condition, which lasted up to 1, 2, and 14 months after the sessions (Griffiths et al. 2006, 2008, 2011). Total scores on the MS lifetime version increased 2 months after a single dose of psilocybin (Griffiths et al. 2006, 2008) and at the 14-month follow-up (Griffiths et al. 2008, 2011), similar to the present findings, in which MS scores increased 1 and 12 months after LSD administration. In the present study, we also observed a lasting increase in scores on the DTS Mysticism subscale, indicating an increase in mystical experiences, which is consistent with increases in lifetime mystical experiences on the MS, but no effects on the other subscale. In contrast, psilocybin only slightly changed scores on the DTS, with a slight increase on the religious subscale but not mysticism subscale at 14 months compared with pre-psilocybin screening (Griffiths et al. 2011).

Overall, the present study found no lasting effects of LSD on various personality trait measures 1 or 12 months after LSD administration. We did not confirm our study hypothesis that LSD would increase trait openness on the NEO-FFI. In contrast to the lack of long-term effects of LSD on personality in the present study, NEO-PI Openness scores increased 2 weeks after administration of a lower dose of LSD (75 μg i.v.) in healthy subjects with mostly significant prior LSD use (Carhart-Harris et al. 2016a). These mid-term personality changes were likely transient. Consistent with the present LSD follow-up results, psilocybin did not alter personality trait ratings 2 or 14 months after a single dose of psilocybin compared with pre-psilocybin screening (Griffiths et al. 2006, 2008). Although increases in openness were noted 14 months after psilocybin administration in a pooled analysis of both studies (MacLean et al. 2011), another more recent study by the same group again found no effects of psilocybin on NEO-PI personality measures 6 months after psilocybin administration (Griffiths et al. 2017). Trait anxiety ratings on the STAI were unchanged after LSD administration compared with pre-LSD screening in the present study. In contrast, LSD reduced trait anxiety ratings in patients with anxiety that was associated with life-threatening diseases (Gasser et al. 2014, 2015).

Altogether, the findings of controlled clinical studies, including the present study (Griffiths et al. 2006, 2008, 2011, 2017; MacLean et al. 2011; McGlothlin et al. 1967), are consistent with the view that serotonergic hallucinogens mainly produce lasting increases in lifetime mystical experiences and enduring positive effects on attitudes, mood, and behavior that are subjectively attributed to the hallucinogen experience. In contrast, the subjectively perceived changes did not result in relevant long-lasting changes in personality trait measures in healthy subjects.

The use of LSD and psilocybin has been associated with mystical experiences (Barrett and Griffiths 2017; Lyvers and Meester 2012). Mystical experiences that are induced by the hallucinogen psilocybin have been shown to be associated with long-term positive effects in healthy subjects (Griffiths et al. 2017; MacLean et al. 2011) and therapeutic outcomes in patients (Garcia-Romeu et al. 2015; Griffiths et al. 2016; Ross et al. 2016). An interesting line of investigation is to explore the factors that contribute to these mystical experiences and whether they specifically predict the long-term effects of hallucinogens. Mystical-type experiences predicted positive therapeutic outcomes in patients even after controlling for subjective intensity of the drug effect (Griffiths et al. 2016; Ross et al. 2016). Similar to previous studies with psilocybin in healthy subjects (Griffiths et al. 2008, 2017), the present study found that the long-term effects of LSD were associated with the extent of the acute response to LSD. However, the overall alterations of mind, reflected by 5D-ASC scores, better predicted the long-term effects of LSD compared with assessments of the more specific acute mystical-type experience, such as MS acute total scores or MEQ30 scores. Thus, the present findings indicate that the overall alterations in consciousness that are acutely induced by LSD may contribute to LSD’s lasting positive effects in normal subjects and in patients (Gasser et al. 2015; Liechti et al. 2017).

The extent of acute hallucinogen-induced mystical-type experiences has been shown to be mainly dose-dependent (Griffiths et al. 2011). Higher rates of meditation/spiritual practice or greater support for spiritual practice also increased ratings of acute mystical-type effects and contributed to the positive long-term effects compared with a group that received psilocybin but less spiritual support (Griffiths et al. 2017). In this study, spiritual practice suggestions to all participants included 10–30 min of daily meditation, awareness practice, journaling, and other activities personally judged to facilitate spiritual growth (Griffiths et al. 2017). However, high support for spiritual practice included dialog group sessions to discuss implementing and sustaining spiritual practices of meditation and spiritual awareness and a total of 35 h of guide-participant contact from study start to the 6-month follow-up compared with no group sessions and only 7 h of contact in the group with less spiritual support (Griffiths et al. 2017). Absolute ratings of the acute mystical-type effects of the hallucinogen on the MS and MEQ were generally higher in the studies by Griffiths and colleagues (Barrett et al. 2015; Griffiths et al. 2006, 2008, 2011, 2017) compared with the present study (Liechti et al. 2017). Importantly, this was the case in both the hallucinogen and control conditions, whereas the acute hallucinogen-induced increases in MS and MEQ scores relative to the control condition were greater after LSD than psilocybin administration (Barrett et al. 2015; Griffiths et al. 2006, 2011; Liechti et al. 2017). In the present study, LSD produced mean MEQ30 ratings of 61% and a complete mystical experience in only two subjects (12.5%; Liechti et al. 2017). In contrast, psilocybin produced mean MEQ30 score ratings of 77% and a complete mystical experience in 67% of the subjects (Barrett et al. 2015). However, placebo or active placebo (i.e., methylphenidate) also produced MEQ30 mean ratings of 23 and 33%, respectively, in these studies (Barrett et al. 2015), indicating relevant differences between the studies, including research subjects characteristics (set) and setting (Barrett and Griffiths 2017). In contrast to the studies by Griffiths and colleagues (Griffiths et al. 2006, 2011), the participants in the present study were mostly university students. They received monetary compensation for participation and were not required to be spiritually active (Liechti et al. 2017; Schmid et al. 2015). The participants in the present study had a personal or scientific interest in experiencing the mind-altering effects of the hallucinogen in a safe hospital environment, but no explicit expectations or suggestions of mystical or lasting effects were conveyed by the research team. Thus, these differences in the study populations (spiritually active vs. not explicitly active), preparation (suggestion of mystical/lasting effects vs. no suggestions), and setting (esthetic living room-like environment designed specifically for the study vs. hospital ward) likely accounted for the overall lower ratings of mystical-type effects in the present study compared with the studies by Griffiths and colleagues (Griffiths et al. 2006, 2011). We also observed no cases of relevant mystical-type effects after placebo administration (Liechti et al. 2017), whereas approximately 5% of the subjects in the studies by Griffiths and colleagues experienced a marked or total mystical experience after placebo (Barrett et al. 2015; Griffiths et al. 2011). Thus, the settings of the studies by Griffiths and colleagues appeared to be highly optimized to foster the emergence of mystical experiences (Barrett and Griffiths 2017), whereas fewer mystical-type experiences were reported in studies that were conducted by other groups (Carhart-Harris et al. 2016a; Gasser et al. 2015; Liechti et al. 2017; Studerus et al. 2011, 2012). Notably, the effects of LSD (200 μg) in the present study and psilocybin (30 mg/70 kg) on 5D-ASC scores were comparable (Griffiths et al. 2017; Liechti et al. 2017), indicating similar alterations in consciousness despite the different settings and acute mystical experiences. Remaining to be tested are what the high acute mystical experiences and associated long-term effects truly reflect. High MEQ scores (also after placebo) were observed in settings that involved more spiritual practice/support, and these scores and associated long-term changes may partly reflect such settings (Griffiths et al. 2017) and not the effects of psilocybin per se. Finally, the 5D-ASC and MEQ acute effect ratings were intercorrelated in the present study (Liechti et al. 2017). In fact, the acute effect ratings on both the 5D-ASC and MEQ significantly predicted long-term changes in subjective well-being and life satisfaction on the PEQ at 12 months in the present study. In contrast, MEQ ratings and thus specifically the mystical-type experiences appeared to mainly predict various long-term effects of psilocybin in more spiritually active subjects (Griffiths et al. 2008, 2017).

The present study has several limitations. First, the study did not include a true control condition for the long-term effects of LSD (i.e., a parallel control group for the long-term effects and not only for the acute effects of LSD). The lasting effects were subjectively attributed to the LSD experience and/or compared with measures prior to the LSD session over time and within-subjects. Thus, we cannot exclude the possibility that all of these subjective effects were attributable to expectations of positive long-term effects of LSD. Second, the study sample was small and not sufficiently powered to detect small effects on personality. Third, the questionnaires were previously used in English but were mostly not validated and the translations not validated in German. Forth, the study was conducted in healthy subjects and used many safety precautions (Johnson et al. 2008). Therefore, the results cannot necessarily be generalized to other settings or patients. Negative acute responses or negative long-term effects could occur in different populations or environments (Carbonaro et al. 2016; Halpern et al. 2016).

In conclusion, after 1 year, a single LSD experience produced personal meaning and enhanced well-being, which were subjectively attributed to the LSD experience, but no relevant changes in measures of personality traits.