Long-lasting subjective effects of LSD in normal subjects

Classic serotonergic hallucinogens such as LSD act primarily at 5-HT2A receptors and have been reported to produce profound acute alterations of consciousness and, in some reports, enduring positive changes in attitudes, mood, values and well-being. Earlier human research, including older studies of LSD and more recent work with psilocybin, has described persisting subjective benefits and increases in lifetime mystical-type experiences after single high-dose sessions. However, contemporary experimental data on long-term effects following administratively controlled LSD in psychiatrically healthy volunteers remain scarce, particularly using instruments comparable to those applied in recent psilocybin trials. Schmid and colleagues therefore designed a study to characterise persisting subjective effects after a single oral dose of LSD (200 μg) in healthy participants. The a priori hypotheses were that participants would attribute personally meaningful and spiritually significant effects to the LSD experience up to 12 months later, that mystical-experience scales would increase at 1 and 12 months versus pre-LSD screening, that acute alterations of consciousness would correlate with longer-term changes, and that trait openness might increase as has been reported in some prior hallucinogen studies.

The study used a randomised, double-blind, balanced cross-over design with two 25-hour experimental sessions (LSD 200 μg p.o. and placebo), separated by at least a 7-day washout. Ethical and regulatory approvals were obtained in Switzerland, participants provided written consent, and the trial was registered. Although the crossover compared acute LSD and placebo effects, the present report focuses on safety and persisting effects after the single LSD session with follow-up assessments at approximately 1 month (mean 37 ± 14 days) and at least 12 months (mean 491 ± 199 days) post-LSD. Sixteen healthy adults (eight men, eight women; mean age 28.6 ± 6.2 years) were recruited; most were well educated and screened for psychiatric, medical and recent substance-use exclusions. Seven participants reported one to three prior hallucinogen uses and nine were hallucinogen-naive. During each test session participants were supervised continuously for up to 16 hours after dosing and remained in a calm hospital research ward environment overnight. LSD (200 μg; Lipomed AG) was administered in gelatin capsules. Outcome measures mirrored those used in contemporary psilocybin work: the Persisting Effects Questionnaire (PEQ), Mysticism Scale (MS; lifetime version), Death Transcendence Scale (DTS), NEO-Five-Factor Inventory (NEO-FFI) for personality traits, and the Spielberger State-Trait Anxiety Inventory (STAI) for trait anxiety. Acute measures included the Mystical Experience Questionnaire (MEQ) and the Five Dimensions of Altered States of Consciousness (5D-ASC), administered 24 hours after dosing to capture retrospective peak effects. Because some instruments were not available in validated German versions, the study team forward- and back-translated and pretested translations; the authors note these versions were not formally validated. Statistical analyses used paired t tests for acute MS comparisons between LSD and placebo, repeated-measures ANOVA (screening, 1 month, 12 months) with Tukey post hoc tests for longitudinal measures, and one-sample t tests to compare PEQ domain scores to a no-change value of zero. Sex was assessed as a between-subjects factor where relevant. Associations between acute responses and 12-month outcomes used Spearman rank correlations. The significance threshold was P < 0.05 and the authors report results without correction for multiple comparisons because many hypotheses were a priori. Some attrition occurred: one subject was lost to follow-up at 12 months and several participants did not complete all items on some questionnaires, yielding 14 complete datasets for many key outcomes and 15 for some personality measures.

Acute effects: Compared with placebo, LSD produced robust acute increases on the Mysticism Scale (MS). Mean MS total scores 24 hours after dosing were 194 ± 14 for LSD versus 45 ± 9 for placebo (t13 = 8.9, P < 0.001). All three MS factors (interpretation, introvertive mysticism and extrovertive mysticism) were significantly higher after LSD than placebo (for example, interpretation 72 ± 6 vs 17 ± 3, t13 = 7.6, P < 0.001; introvertive 55 ± 3 vs 12 ± 2, t13 = 13.2, P < 0.001). The authors also report significant acute increases in 5D-ASC total and MEQ30 scores after LSD (details summarised in a table not fully reproduced in the extracted text). Persisting subjective effects (PEQ): On the Persisting Effects Questionnaire, ratings of positive attitudes about life/self, positive mood changes, altruistic/positive social effects and positive behavioural changes were significantly greater than zero at both 1 and 12 months, indicating participant-attributed positive changes. Conversely, ratings of negative attitudes, negative mood, antisocial/negative social effects and negative behavioural changes were not different from zero at either follow-up. Ratings of personal meaningfulness and spiritual significance increased at 1 and 12 months compared with minimal reference values: at 12 months 10 of 14 participants rated the LSD experience among the top 10 most meaningful experiences of their lives (rating ≥ 6), and among these 10 participants five rated it among the top five (rating = 7). Spiritual-significance ratings at 12 months showed that eight of 14 participants rated the experience as very strongly spiritual (rating ≥ 4), five of these rated it among the five most spiritually meaningful experiences (rating ≥ 5), and one participant rated it as the single most spiritually significant experience (rating = 6). Ratings of well-being or life satisfaction increased at both follow-ups compared with no change; no participant reported decreased well-being attributed to the LSD session. Mysticism Scale (lifetime) and Death Transcendence: The MS lifetime total score and the introvertive and extrovertive factors were significantly increased at 1 and 12 months relative to pre-LSD screening. The Death Transcendence Scale (DTS) total score and its mysticism subscale were also significantly higher at 1 and 12 months; mysticism subscale ratings further increased from 1 to 12 months. No sex differences were observed for these longitudinal measures. Personality and anxiety measures: No relevant changes in personality traits (NEO-FFI) were detected at 1 or 12 months; the study did not replicate an increase in trait openness. Trait anxiety on the STAI remained unchanged across time. Correlations: Greater acute alterations of consciousness, reflected by the 5D-ASC total score, were positively associated with several 12-month outcomes attributed to LSD: PEQ positive mood (Rs = 0.56, P < 0.05), PEQ behaviour (Rs = 0.53, P < 0.05), PEQ well-being/life satisfaction (Rs = 0.53, P < 0.05), MS total score (Rs = 0.62, P < 0.05) and DTS total score (Rs = 0.76, P < 0.01). Acute mystical-type measures also predicted long-term outcomes: MEQ30 total correlated with PEQ well-being/life satisfaction at 12 months (Rs = 0.60, P < 0.05), and MS total and MEQ30 total correlated with DTS changes (Rs = 0.66, P < 0.01 and Rs = 0.65, P < 0.05, respectively). Adverse events: Transient adverse effects were minimal. At 1 month one subject reported a 10-day period of increased vivid dreams and difficulty falling asleep; no participants reported psychological problems or perceptual disorders such as flashbacks up to 1 month, and there were no spontaneous reports of adverse effects at 12 months.

Schmid and colleagues interpret their findings as evidence that a single high oral dose of LSD (200 μg) administered in a controlled hospital setting can produce an experience that participants subsequently regard as personally meaningful and associated with enduring positive changes in attitudes, mood, social behaviour and well-being up to 12 months later. The investigators note that the magnitude of acute alterations of consciousness, particularly the 5D-ASC total score, and measures of acute mystical-type experiences predicted greater long-term positive changes, consistent with prior work linking acute phenomenology to persisting outcomes. The authors position these results alongside earlier LSD reports and a larger body of contemporary psilocybin research. They observe similarities with psilocybin studies showing lasting positive subjective effects and increases in lifetime mysticism scores, but they also note differences: in this study LSD did not alter personality trait measures such as openness, whereas some prior reports have described transient openness changes after different dosing regimens. The investigators highlight that the 5D-ASC, reflecting overall mind-altering effects, was a stronger predictor of long-term subjective changes in their sample than more specific mystical-type scales, suggesting that broad alterations of consciousness may be an important mechanistic correlate of persisting benefits. Schmid and colleagues discuss the likely importance of set and setting and preparatory support in determining the frequency and intensity of mystical-type experiences and downstream effects. They compare their hospital-based protocol and participant sample (mostly students, paid, not selected for spiritual practice) with studies by other groups in which participants were spiritually active, received substantial preparatory contact and group support, and reported higher absolute MEQ scores and higher rates of complete mystical experiences. The authors caution that some high MEQ scores reported in other studies may partly reflect setting and preparatory interventions rather than drug effects alone. Several limitations are acknowledged. First, there was no parallel control group to evaluate longer-term effects, so attribution of persisting changes specifically to LSD cannot be definitively established and expectation bias cannot be excluded. Second, the sample size was small and underpowered to detect small personality effects. Third, many questionnaires were translated into German but not formally validated in translation. Fourth, the study population consisted of healthy volunteers studied under stringent safety precautions, limiting generalisability to other populations or settings where adverse acute or long-term responses could be more likely. The authors conclude that, in their sample, a single LSD session produced lasting, subjectively positive and spiritually meaningful effects without relevant long-term adverse outcomes or changes in personality trait measures.