Alterations of consciousness and mystical-type experiences after acute LSD in humans

Liechti and colleagues situate their work within a renewed interest in clinical and experimental research on classic serotonergic hallucinogens, noting that psilocybin has produced acute mystical-type experiences that have been linked to positive long-term mood and therapeutic outcomes in some studies. They highlight that although LSD is widely used recreationally and has been tested intermittently in therapeutic contexts, systematic data on LSD-induced mystical experiences assessed with standard instruments such as the Mystical Experience Questionnaire (MEQ) are lacking. Additionally, dose- and plasma concentration–response relationships for LSD with respect to alterations of consciousness have not been fully characterised, and prior fMRI studies frequently did not measure plasma LSD levels. The present study therefore aimed to (1) characterise mystical-type experiences after a therapeutically relevant oral dose of 200 μg LSD using the MEQ, (2) describe peak alterations of consciousness after oral doses of 100 and 200 μg using the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale, and (3) assess associations between plasma LSD concentrations (Cmax and AUC) and subjective effects. The investigators intended the work to inform comparisons with psilocybin research, the interpretation of imaging studies that use lower doses, and potential implications for LSD-assisted psychotherapy.

Two similar double-blind, placebo-controlled, cross-over studies were conducted. Study 1 enrolled 24 healthy participants who received oral LSD 100 μg and placebo in two balanced test sessions; study 2 enrolled 16 healthy participants who received oral LSD 200 μg and placebo in a matched cross-over design. Washout periods between sessions were at least 7 days. All procedures were approved by local ethics authorities and participants provided written consent. Forty healthy volunteers (32 men/women split evenly within each study) were recruited from a university setting; mean ages were 33 ± 11 years (range 25–60) in study 1 and 29 ± 6 years (range 25–51) in study 2. Inclusion/exclusion criteria were identical across studies and excluded people younger than 25 years, older than 65 years, pregnant participants, those with personal or first-degree family histories of major psychiatric disorders, current medications likely to interfere, significant physical illness, heavier tobacco smoking (>10 cigarettes/day), frequent lifetime illicit drug use (>10 times, except THC), recent illicit drug use, and illicit drug use during the study. Urine drug screens were performed at screening and before each session. Experimental sessions were 25 h in duration and took place in a quiet hospital room with a single participant per session; investigators remained present during the first 12 h and nearby for up to 24 h. LSD (d-LSD hydrate, >99% purity) was administered as single oral gelatin capsules of 100 or 200 μg (noting equivalence to 123 and 246 μg LSD tartrate, respectively); matching placebo capsules were used. The MEQ (43-item German version embedded in the 100-item States of Consciousness Questionnaire) was administered 24 h after dosing to obtain retrospective ratings of peak effects; a complete mystical experience on the MEQ30 was defined as ≥60% on all MEQ30 factors. The 5D-ASC scale (94 items) was used to assess peak alterations of consciousness and was also administered 24 h after dosing; in study 1 the 5D-ASC was additionally completed at 3 and 10 h. Plasma samples were collected before dosing and at multiple post-dose timepoints up to 24 h; some early timepoints were not collected in study 1. Plasma LSD concentrations were measured by liquid-chromatography-tandem mass spectrometry. Pharmacokinetic parameters (Cmax and area under the curve, AUC) were estimated using a one-compartment model with first-order input and elimination. Statistical analyses used dependent t tests for LSD versus placebo and independent t tests for dose comparisons, with Pearson correlations to assess associations; significance was defined as p < 0.05.

Mystical-type experiences after 200 μg LSD were increased relative to placebo. On the MEQ30 the mean total score after 200 μg LSD was reported as 61% (range 40–98%), and the authors report a complete mystical experience in two participants (the extracted text gives this as 12.5%, which corresponds to 2/16). MEQ scores after placebo were very low (<5% on MEQ30 in the present settings). For comparison, small MEQ increases after MDMA and methylphenidate in a similar setting and MEQ data from patients who received 200 μg LSD in a therapeutic study were presented; the patient data showed similar MEQ increases to the healthy-subject laboratory findings, and only two of 11 patients exhibited complete mystical experiences in that therapeutic sample. On the 5D-ASC scale, LSD produced pronounced peak alterations of waking consciousness with significant increases across all dimensions and subscales compared with placebo. The 200 μg dose generated significantly greater scores than 100 μg on the overall ASC total score and specifically on the Visionary Restructuralization dimension and the lower-order subscales blissful state, insightfulness, and changed meaning of percepts. Mean ego dissolution ratings (item 71: ‘‘the boundaries between myself and my surroundings seemed to blur’’) were 49 ± 6 and 53 ± 10 (mean ± SEM) after the 100 and 200 μg doses, respectively. Ratings at 3, 10, and 24 h showed only minimal differences in study 1. Plasma pharmacokinetics showed interindividual variability, especially at 100 μg. Median (range) Cmax values were 1.4 ng/ml (0.32–3.7) for 100 μg and 3.2 ng/ml (1.9–7.1) for 200 μg. The corresponding AUC values were reported as 8.5 ng·h/ml (range 1–19) for 100 μg and 20.7 ng·h/ml for 200 μg (no range provided for the latter in the extracted text). Strong positive associations were observed between LSD-induced alterations of consciousness and mystical-type reports: the ASC total score correlated with MEQ30 total score (Rp = 0.87, p < 0.001, n = 16). MEQ positive mood scores were strongly associated with ASC experience of unity and blissful state (Rp = 0.85 and 0.80, respectively; both p < 0.001, n = 16). Across subjects and within dose groups, Cmax and AUC were generally not positively correlated with peak subjective effects on the 5D-ASC or MEQ, with several exceptions. Ego dissolution (item 71) at the lower 100 μg dose showed a significant positive correlation with LSD AUC (Rp = 0.51, p < 0.05, n = 16). Within the 200 μg group, negative correlations were noted between Cmax and some subjective effects (visionary restructuralization, elementary imagery, and changed meaning of percepts). The authors report that some effects (for example, audio–visual synesthesia at 200 μg) were induced consistently across subjects, limiting variance and thus correlations with plasma exposure.

Liechti and colleagues interpret their findings to indicate that a 200 μg oral dose of LSD can produce measurable mystical-type experiences as assessed by the MEQ, but full mystical experiences were relatively infrequent in this sample and setting. They note that MEQ30 mean scores after 200 μg LSD (61%) were lower in terms of the proportion of complete mystical experiences than has been reported for high-dose psilocybin in some studies; in contrast, placebo responses on the MEQ were much lower in the present LSD studies than reported placebo or active-placebo responses in some psilocybin trials. The investigators suggest that differences in set and setting, participant characteristics (for example spiritual inclination or preparatory work), and expectancy/placebo effects likely account for some of the between-study differences in mystical outcomes. Beyond mystical-type reports, the 200 μg dose produced greater overall alterations of consciousness than 100 μg, particularly increasing visionary restructuralization and positive-emotional subscales such as blissful state and insightfulness. The authors highlight that these more positive, MDMA-like emotional effects at 200 μg may be relevant to LSD-assisted psychotherapy, given that the higher dose is used therapeutically in some contexts while lower doses (100 μg or less) are commonly used in imaging research. Regarding pharmacokinetic–pharmacodynamic relationships, the discussion emphasises that plasma LSD levels were generally not positively correlated with robust subjective effects across subjects, which the authors attribute to ceiling effects when plasma levels are sufficiently above the concentration producing half-maximal effect (EC50) and when responses are induced consistently in most participants. They interpret the observed positive correlation between AUC and ego dissolution at 100 μg as consistent with findings from an imaging study that linked ego dissolution to plasma LSD during lower-dose administration, and they caution that associations between subjective states and brain imaging should consider possible relationships to plasma levels. The negative correlations observed within the 200 μg group for some perceptual measures are noted as counterintuitive but interpreted as further evidence that above a threshold dose higher plasma levels do not necessarily produce greater subjective changes. The investigators acknowledge limitations that bear on interpretation: the relatively small sample sizes, potential influence of set and setting and participant selection on mystical outcomes, and imperfect comparability with psilocybin studies that differed in preparation and expectancy. They call for within-subject comparisons of LSD and psilocybin and for further research to determine whether mystical-type experiences are critical mediators of therapeutic benefit. Finally, the authors suggest their findings have implications for dose selection in therapeutic and imaging studies and for interpreting neuroimaging correlates of LSD-induced subjective states.